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1
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Lu G, Zhao L, Hui K, Lu Z, Zhang X, Gao H, Ma X. Angiography-Derived Microcirculatory Resistance in Detecting Microvascular Obstruction and Predicting Heart Failure After STEMI. Circ Cardiovasc Imaging 2025:e017506. [PMID: 40177747 DOI: 10.1161/circimaging.124.017506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 03/11/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND Microvascular obstruction (MVO) is associated with heart failure (HF) following ST-segment-elevation myocardial infarction. Angiography-derived microcirculatory resistance (AMR), a wire- and adenosine-free measure, may facilitate early assessment of microvascular function post-primary percutaneous coronary intervention. This study aimed to evaluate the ability of AMR to detect MVO and its prognostic value for predicting HF in patients with ST-segment-elevation myocardial infarction post-primary percutaneous coronary intervention. METHODS Patients with consecutive ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention with a cardiac magnetic resonance examination 2 to 7 days post-procedure between April 2016 and February 2023 were retrospectively reviewed. AMR was computed from coronary angiography. MVO was identified and quantified via cardiac magnetic resonance. The end point was new-onset HF during follow-up. RESULTS Overall, 475 patients (aged 56.8±11.7 years; 399 males) were included. The area under the curve for AMR to detect MVO was 0.821 (95% CI, 0.782-0.859), with an optimal cutoff value of 2.7 mm Hg*s/cm. During a median follow-up of 37.3 months, 121 (25.5%) patients developed HF. AMR, whether as a continuous (per 0.5-mm Hg*s/cm increase; hazard ratio, 1.29 [95% CI, 1.10-1.52]; P=0.002) or categorical (AMR >2.7 mm Hg*s/cm; hazard ratio, 2.15 [95% CI, 1.43-3.22]; P<0.001) variable, was independently associated with HF after adjusting for traditional risk factors (age, symptom-to-balloon time, left anterior descending coronary artery, and ejection fraction) and late gadolinium enhancement-cardiac magnetic resonance parameters. AMR improved prognostication over traditional risk factors and late gadolinium enhancement-cardiac magnetic resonance parameters (net reclassification improvement, 0.533; P<0.001; integrative discrimination index, 0.023; P=0.005). CONCLUSIONS AMR showed good diagnostic performance in detecting MVO and was an independent and incremental predictor of HF in patients with ST-segment-elevation myocardial infarction post-primary percutaneous coronary intervention.
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Affiliation(s)
- Guanyu Lu
- Department of Interventional Diagnosis and Treatment (G.L., K.H., Z.L., X.M.), Beijing Anzhen Hospital, Capital Medical University, China
| | - Lei Zhao
- Department of Radiology (L.Z.), Beijing Anzhen Hospital, Capital Medical University, China
| | - Keyao Hui
- Department of Interventional Diagnosis and Treatment (G.L., K.H., Z.L., X.M.), Beijing Anzhen Hospital, Capital Medical University, China
| | - Zhihui Lu
- Department of Interventional Diagnosis and Treatment (G.L., K.H., Z.L., X.M.), Beijing Anzhen Hospital, Capital Medical University, China
| | - Xiaoli Zhang
- Department of Nuclear Medicine, Molecular Imaging Laboratory (X.Z.), Beijing Anzhen Hospital, Capital Medical University, China
| | - Hai Gao
- Department of Cardiology, Emergency Coronary Artery Unit (H.G.), Beijing Anzhen Hospital, Capital Medical University, China
| | - Xiaohai Ma
- Department of Interventional Diagnosis and Treatment (G.L., K.H., Z.L., X.M.), Beijing Anzhen Hospital, Capital Medical University, China
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2
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Denicolai M, Morello M, Golino M, Corna G, Del Buono MG, Agatiello CR, Van Tassell BW, Abbate A. Interleukin-1 Blockade in Patients With ST-Segment Elevation Myocardial Infarction Across the Spectrum of Coronary Artery Disease Complexity. J Cardiovasc Pharmacol 2025; 85:200-210. [PMID: 39531530 DOI: 10.1097/fjc.0000000000001652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024]
Abstract
ABSTRACT Patients with ST-segment elevation myocardial infarction (STEMI) and complex coronary artery disease (CAD) face a poor prognosis, including increased heart failure (HF) risk. Phase 2 clinical trials of anakinra have shown inhibition of the acute inflammatory response and prevention of HF after STEMI, but data on its effects based on CAD complexity are lacking. We performed a pooled secondary analysis of 139 patients with STEMI. The SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery), SYNTAX II, and Gensini scores were calculated, and patients were divided into 2 groups below and above the median. We evaluated the effect of anakinra on the area-under-the-curve of high-sensitivity C-reactive protein (hsCRP-AUC) at 14 days, and the composite endpoint of new-onset HF, HF hospitalization, or all-cause death at 1-year follow-up using Kaplan-Meier survival curves, Cox regression analysis for hazard ratios (HRs), and tested interactions between subgroups. All 3 CAD complexity scores (SYNTAX, SYNTAX II, and Gensini) were associated with an increased risk of adverse events (HR 1.02-1.06, all P-values ≤0.025). We found no statistically significant interactions between CAD extent, measured as single-vessel or multivessel CAD, SYNTAX score ≤9 or >9, SYNTAX II score ≤24 or >24, Gensini score ≤32 or >32, and treatment effect of anakinra on hsCRP-AUC or the composite clinical endpoint (all P - values for interaction >0.05). In conclusion, among patients with STEMI, IL-1 blockade with anakinra significantly attenuated the acute inflammatory response and reduced the risk of HF-related events regardless of the spectrum of CAD complexity.
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Affiliation(s)
- Martin Denicolai
- Robert M. Berne Cardiovascular Research Center and Department of Medicine, University of Virginia, Charlottesville, VA
- Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Matteo Morello
- Robert M. Berne Cardiovascular Research Center and Department of Medicine, University of Virginia, Charlottesville, VA
| | - Michele Golino
- Robert M. Berne Cardiovascular Research Center and Department of Medicine, University of Virginia, Charlottesville, VA
- Pauley Heart Center, Virginia Commonwealth University, Richmond, VA
| | - Giuliana Corna
- Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Marco G Del Buono
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy ; and
| | - Carla R Agatiello
- Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Benjamin W Van Tassell
- Department of Pharmacotherapy & Outcomes Sciences, Virginia Commonwealth University, Richmond, VA
| | - Antonio Abbate
- Robert M. Berne Cardiovascular Research Center and Department of Medicine, University of Virginia, Charlottesville, VA
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3
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Zhang J. Non-coding RNAs and angiogenesis in cardiovascular diseases: a comprehensive review. Mol Cell Biochem 2024; 479:2921-2953. [PMID: 38306012 DOI: 10.1007/s11010-023-04919-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 12/18/2023] [Indexed: 02/03/2024]
Abstract
Non-coding RNAs (ncRNAs) have key roles in the etiology of many illnesses, including heart failure, myocardial infarction, stroke, and in physiological processes like angiogenesis. In transcriptional regulatory circuits that control heart growth, signaling, and stress response, as well as remodeling in cardiac disease, ncRNAs have become important players. Studies on ncRNAs and cardiovascular disease have made great progress recently. Here, we go through the functions of non-coding RNAs (ncRNAs) like circular RNAs (circRNAs), and microRNAs (miRNAs) as well as long non-coding RNAs (lncRNAs) in modulating cardiovascular disorders.
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Affiliation(s)
- Jie Zhang
- Medical School, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
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4
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Yang S, Pei L, Huang Z, Zhong Y, Li J, Hong Y, Long H, Chen X, Zhou C, Zheng G, Zeng C, Wu H, Wang T. Inhibition of tartrate-resistant acid phosphatase 5 can prevent cardiac fibrosis after myocardial infarction. Mol Med 2024; 30:89. [PMID: 38879488 PMCID: PMC11179352 DOI: 10.1186/s10020-024-00856-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 06/08/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND Myocardial infarction (MI) leads to enhanced activity of cardiac fibroblasts (CFs) and abnormal deposition of extracellular matrix proteins, resulting in cardiac fibrosis. Tartrate-resistant acid phosphatase 5 (ACP5) has been shown to promote cell proliferation and phenotypic transition. However, it remains unclear whether ACP5 is involved in the development of cardiac fibrosis after MI. The present study aimed to investigate the role of ACP5 in post-MI fibrosis and its potential underlying mechanisms. METHODS Clinical blood samples were collected to detect ACP5 concentration. Myocardial fibrosis was induced by ligation of the left anterior descending coronary artery. The ACP5 inhibitor, AubipyOMe, was administered by intraperitoneal injection. Cardiac function and morphological changes were observed on Day 28 after injury. Cardiac CFs from neonatal mice were extracted to elucidate the underlying mechanism in vitro. The expression of ACP5 was silenced by small interfering RNA (siRNA) and overexpressed by adeno-associated viruses to evaluate its effect on CF activation. RESULTS The expression of ACP5 was increased in patients with MI, mice with MI, and mice with Ang II-induced fibrosis in vitro. AubipyOMe inhibited cardiac fibrosis and improved cardiac function in mice after MI. ACP5 inhibition reduced cell proliferation, migration, and phenotypic changes in CFs in vitro, while adenovirus-mediated ACP5 overexpression had the opposite effect. Mechanistically, the classical profibrotic pathway of glycogen synthase kinase-3β (GSK3β)/β-catenin was changed with ACP5 modulation, which indicated that ACP5 had a positive regulatory effect. Furthermore, the inhibitory effect of ACP5 deficiency on the GSK3β/β-catenin pathway was counteracted by an ERK activator, which indicated that ACP5 regulated GSK3β activity through ERK-mediated phosphorylation, thereby affecting β-catenin degradation. CONCLUSION ACP5 may influence the proliferation, migration, and phenotypic transition of CFs, leading to the development of myocardial fibrosis after MI through modulating the ERK/GSK3β/β-catenin signaling pathway.
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Affiliation(s)
- Shujun Yang
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China
| | - Liying Pei
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China
| | - Zijie Huang
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China
| | - Yinsheng Zhong
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China
| | - Jun Li
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China
| | - Yinghui Hong
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China
| | - Huibao Long
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China
| | - Xuxiang Chen
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China
| | - Changqing Zhou
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China
| | - Guanghui Zheng
- Department of Emergency, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, Guangdong, P. R. China
| | - Chaotao Zeng
- Department of Emergency, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, Guangdong, P. R. China
| | - Haidong Wu
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China
| | - Tong Wang
- Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China.
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Moroni F, Corna G, Del Buono MG, Golino M, Talasaz AH, Decotto S, Markley R, Trankle C, Biondi-Zoccai G, Carbone S, Agatiello CR, Van Tassell B, Abbate A. Impact of C-reactive protein levels and role of anakinra in patients with ST-elevation myocardial infarction. Int J Cardiol 2024; 398:131610. [PMID: 38016623 PMCID: PMC10896664 DOI: 10.1016/j.ijcard.2023.131610] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 10/30/2023] [Accepted: 11/23/2023] [Indexed: 11/30/2023]
Abstract
BACKGROUND Interleukin-1 blockade with anakinra reduces C-reactive protein (CRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). The effectiveness of anakinra according to the degree of systemic inflammation in STEMI has not been addressed. METHODS We analyzed 139 patients from three Virginia Commonwealth University Anakinra Response Trial randomized clinical trials to assess whether CRP levels predicted HF hospitalization or death in patients with STEMI, and if CRP levels influenced the effects of treatment with anakinra. RESULTS CRP cut-off levels for prediction of the composite of death or HF hospitalization for CRP at admission, 3 and 14 days were, respectively 6.45 mg/L (100% of sensitivity and 66.1% specificity), 26 mg/L (100% of sensitivity and 78% specificity) and 9.56 mg/L (100% of sensitivity and 80% specificity). More patients with elevated CRP levels died or had a HF hospitalization (5/47 [11%] vs 0/82 [0%], p = 0.004 for CRP at admission; 5/32 [15.6%] vs 0/92 [0%], p < 0.001 for day 3 and 5/26 [19%] vs 0/89 [0%], p < 0.001 for day 14). A greater number of patients treated with anakinra had low CRP levels at 3 and 14 days compared to placebo (Odds Ratio 0.11 [95% IC 0.04-0.28], p < 0.0001 and OR 0.35 [95% CI 0.14-0.86], p = 0.02, respectively). Anakinra significantly prevented death or HF hospitalization in patients with high inflammatory burden (p = 0.04 for admission, p = 0.24 for day 3, and p = 0.05 for day 14). CONCLUSION Patients with elevated CRP had higher incidence of HF hospitalization or death. Anakinra reduced the number of patients with elevated CRP levels and prevented death or HF hospitalization in patients with elevated CRP levels.
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Affiliation(s)
- Francesco Moroni
- Robert M. Berne Cardiovascular Research Center, and Division of Cardiology, University of Virginia, Charlottesville, VA, United States; Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States; Cardiovascular Division, Medicine Department, Università Milano-Bicocca, Milan, Italy
| | - Giuliana Corna
- Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States; Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Marco Giuseppe Del Buono
- Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States; Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Michele Golino
- Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States; Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Azita H Talasaz
- Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Santiago Decotto
- Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States; Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Roshanak Markley
- Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Cory Trankle
- Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Giuseppe Biondi-Zoccai
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Roma, Italy; Mediterranea Cardiocentro, Via Orazio, 2, 80122 Napoli, NA, Italy
| | - Salvatore Carbone
- Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Carla R Agatiello
- Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Benjamin Van Tassell
- Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States.
| | - Antonio Abbate
- Robert M. Berne Cardiovascular Research Center, and Division of Cardiology, University of Virginia, Charlottesville, VA, United States.
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6
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Corna G, Golino M, Talasaz AH, Moroni F, Del Buono MG, Damonte JI, Chiabrando JG, Mbualungu J, Trankle CR, Thomas GK, Markley R, Canada JM, Turlington J, Agatiello CR, VAN Tassell B, Abbate A. Response to interleukin-1 blockade with anakinra in women and men with ST-segment elevation myocardial infarction. Minerva Cardiol Angiol 2024; 72:67-75. [PMID: 37987681 DOI: 10.23736/s2724-5683.23.06439-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
BACKGROUND Interleukin-1 blockade with anakinra reduces high-sensitivity C-reactive protein (hsCRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). Sex-based differences in STEMI patients have been reported, but no data are available regarding response to anakinra. METHODS We analyzed the systemic inflammation and composite end-point of new-onset HF or death in women and men with STEMI treated with anakinra from three different Virginia Commonwealth University Anakinra Response Trial (VCUART) randomized clinical trials. RESULTS We analyzed 139 patients, 29 (21%) were women while 110 (79%) were men. Baseline hsCRP was higher in women compared to men (8.9 [5.2-13.5] vs. 4.2 [2.1-7.7] mg/L, P<0.001). Eighty-four patients were treated with anakinra (22 [75%] women and 62 [56%] men). The area under the curve of hsCRP (hsCRP-AUC) after 14 days was numerically lower in patients receiving anakinra versus placebo both in men (86 [37-130] vs. 223 [119-374] mg day/L) and in women (73 [46-313] vs. 242 [102-988] mg day/L) (P<0.001 for multiple groups, P for interaction 0.22). The incidence of the composite endpoint was also numerically lower in the anakinra group compared to placebo, both in men (4 [6.4%] vs. 14 [29.1%]) and in women (3 [13.6%] vs. 2 [28.5%]) (P=0.019 for multiple groups, P for interaction 0.44). There were no statistically significant differences between women and men in hsCRP-AUC and death or HF events when comparing separately the anakinra and placebo groups (all P>0.05). CONCLUSIONS Women were underrepresented in the VCUART trials, they appeared to have higher hsCRP levels at time of presentation, yet to benefit similar to men by treatment with anakinra in STEMI.
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Affiliation(s)
- Giuliana Corna
- Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
- Department of Interventional Cardiology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Michele Golino
- Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Azita H Talasaz
- Department of Pharmacotherapy and Outcomes Sciences, Virginia Commonwealth University, Richmond, VA, USA
| | - Francesco Moroni
- Department of Internal Medicine, University of Virginia, Charlottesville, VA, USA
- Department of Medicine, University of Milano-Bicocca, Milan, Italy
| | - Marco G Del Buono
- Department of Cardiovascular Medicine, IRCCS A. Gemelli University Polyclinic Foundation, Rome, Italy
| | - Juan I Damonte
- Department of Interventional Cardiology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Juan G Chiabrando
- Department of Interventional Cardiology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - James Mbualungu
- Division of Cardiology, Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
| | - Cory R Trankle
- Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Georgia K Thomas
- Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Roshanak Markley
- Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Justin M Canada
- Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Jeremy Turlington
- Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Carla R Agatiello
- Department of Interventional Cardiology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Benjamin VAN Tassell
- Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
- Department of Pharmacotherapy and Outcomes Sciences, Virginia Commonwealth University, Richmond, VA, USA
| | - Antonio Abbate
- Division of Cardiology, Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA -
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Lin XY, Chu Y, Zhang GS, Zhang HL, Kang K, Wu MX, Zhu J, Xu CS, Lin JX, Huang CK, Chai DJ. Retinoid X receptor agonists alleviate fibroblast activation and post-infarction cardiac remodeling via inhibition of TGF-β1/Smad pathway. Life Sci 2023; 329:121936. [PMID: 37453576 DOI: 10.1016/j.lfs.2023.121936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/10/2023] [Accepted: 07/10/2023] [Indexed: 07/18/2023]
Abstract
Retinoid X receptor (RXR), particularly RXRα, has been implicated in cardiovascular diseases. However, the functional role of RXR activation in myocardial infarction (MI) remains unclear. This study aimed to determine the effects of RXR agonists on MI and to dissect the underlying mechanisms. Sprague-Dawley (SD) rats were subjected to MI and then treated (once daily for 4 weeks) with either RXR agonist bexarotene (10 or 30 mg/kg body weight) or vehicle. Heart function was determined using echocardiography and cardiac hemodynamic measurements. Four weeks post MI, myocardial tissues were collected to evaluate cardiac remodeling. Primary cardiac fibroblasts (CFs) were treated with or without RXR ligand 9-cis-RA followed by stimulation with TGF-β1. Immunoblot, immunofluorescence, and co-immunoprecipitation were performed to elucidate the regulatory role of RXR agonists in TGF-β1/Smad signaling. In vivo treatment with Bexarotene moderately affects systemic inflammation and apoptosis and ameliorated left ventricular dysfunction after MI in rat model. In contrast, bexarotene significantly inhibited post-MI myocardial fibrosis. Immunoblot analysis of heart tissue homogenates from MI rats revealed that bexarotene regulated the activation of the TGF-β1/Smad signaling pathway. In vitro, 9-cis-RA inhibited the TGF-β1-induced proliferation and collagen production of CFs. Importantly, upon activation by 9-cis-RA, RXRα interacted with p-Smad2 in cytoplasm, inhibiting the TGF-β1-induced nuclear translocation of p-Smad2, thereby negatively regulating TGF-β1/Smad signaling and attenuating the fibrotic response of CFs. These findings suggest that RXR agonists ameliorate post-infarction myocardial fibrosis, maladaptive remodeling, and heart dysfunction via attenuation of fibrotic response in CFs through inhibition of the TGF-β1/Smad pathway activation.
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Affiliation(s)
- Xiao-Yan Lin
- Ultrasonography Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Yong Chu
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Guo-Shan Zhang
- Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, China
| | - Hai-Lin Zhang
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Kai Kang
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Min-Xia Wu
- Electron Microscopy Laboratory of Public Technology Service Center, Fujian Medical University, Fuzhou 350004, China
| | - Jiang Zhu
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Chang-Sheng Xu
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Jin-Xiu Lin
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Chun-Kai Huang
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China
| | - Da-Jun Chai
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, Fuzhou 350005, China; Cardiovascular Department, National Regional Medical Center, Binhai Branch of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
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8
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Del Buono MG, Garmendia CM, Seropian IM, Gonzalez G, Berrocal DH, Biondi-Zoccai G, Trankle CR, Bucciarelli-Ducci C, Thiele H, Lavie CJ, Crea F, Abbate A. Heart Failure After ST-Elevation Myocardial Infarction: Beyond Left Ventricular Adverse Remodeling. Curr Probl Cardiol 2023; 48:101215. [PMID: 35460680 DOI: 10.1016/j.cpcardiol.2022.101215] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 04/13/2022] [Indexed: 12/11/2022]
Abstract
ST-segment elevation myocardial infarction (STEMI) remains a significant source of morbidity and mortality worldwide. Despite advances in treatment leading to a significant reduction in the early complications and in-hospital mortality, a significant proportion of STEMI survivors develop heart failure (HF) at follow-up. The classic paradigm of HF after STEMI is one characterized by left ventricular adverse remodeling (LVAR) and encompasses the process of regional and global structural and functional changes that occur in the heart as a consequence of loss of viable myocardium, increased wall stress and neurohormonal activation, and results in HF with reduced ejection fraction (HFrEF). More recently, however, with further improvements in the treatment of STEMI the incidence and entity of LVAR appear to be largely reduced, yet the risk for HF following STEMI is not abolished and remains substantial, identifying a new paradigm by which patients with STEMI present with HF and preserved EF (HFpEF) characterized by reduction of diastolic or systolic reserve independent of LVAR.
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Affiliation(s)
- Marco Giuseppe Del Buono
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA; Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Cristian M Garmendia
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA; Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Ignacio M Seropian
- Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Germán Gonzalez
- Pontificia Universidad Católica Argentina (UCA), Instituto de Investigaciones Biomédicas (UCA-CONICET), Buenos Aires, Argentina
| | - Daniel H Berrocal
- Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Giuseppe Biondi-Zoccai
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; Mediterranea Cardiocentro, Napoli, Italy
| | - Cory R Trankle
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA
| | - Chiara Bucciarelli-Ducci
- Royal Brompton and Harefield Clinical Partership, Guys and St Thomas NHS Trust anD King's College London, London, UK
| | - Holger Thiele
- Heart Center Leipzig at University of Leipzig and Leipzig Heart Institute, Leipzig, Germany
| | - Carl J Lavie
- Department of Cardiovascular Diseases, Ochsner Clinical School, New Orleans, LA
| | - Filippo Crea
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Antonio Abbate
- Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
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Del Buono MG, Damonte JI, Moroni F, Chiabrando JG, Markley R, Turlington J, Trankle CR, Kang L, Biondi-Zoccai G, Kontos MC, Roberts CS, Van Tassell BW, Abbate A. Clinical and Pharmacological Implications of Time to Treatment with Interleukin-1 Blockade in ST-Segment Elevation Myocardial Infarction. J Pharmacol Exp Ther 2023; 386:156-163. [PMID: 37037651 PMCID: PMC10353076 DOI: 10.1124/jpet.123.001601] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/24/2023] [Accepted: 03/31/2023] [Indexed: 04/12/2023] Open
Abstract
Interleukin-1 (IL-1) blockade with anakinra given within 12 hours from reperfusion has been shown to reduce the inflammatory response as well as prevent heart failure (HF) events in patients with STEMI. We sought to determine whether time-to-treatment influences the efficacy of anakinra on systemic inflammation and incidence of HF events in patients with STEMI. We divided the cohort in two groups base6d on the median time from percutaneous coronary intervention (PCI) to investigational drug, and analyzed the effects of anakinra on the area-under-the-curve for C reactive protein (AUC-CRP) and on incidence of the composite endpoint of death or new onset HF. We analyzed data from 139 patients: 84 (60%) treated with anakinra and 55 (40%) with placebo. The median time from PCI to investigational treatment was 271 (182-391) minutes. The AUC-CRP was significantly higher in patients receiving placebo versus anakinra both in those with time from PCI to treatment <271 minutes (222.6 [103.9-325.2] vs. 78.4 [44.3-131.2], P < 0.001) and those with time from PCI to treatment ≥271 minute (235.2 [131.4-603.4] vs. 75.5 [38.9-171.9], P < 0.001) (P > 0.05 for interaction). Anakinra significantly reduced the combined endpoint of death or new onset HF in patients with time from PCI to treatment <271 minutes (5 [11%] vs. 9n[36%], log-rank χ 2 5.985, P = 0.014) as well as in patients with time from PCI to drug ≥271 minutes (2n[5%] vs. 7 [23%], log-rank χ 2 3.995, P = 0.046) (P > 0.05 for interaction). IL-1 blockade with anakinra blunts the acute systemic inflammatory response and prevents HF events independent of time-to-treatment. SIGNIFICANCE STATEMENT: In patients with ST segment elevation presenting within 12 hours of pain onset and treated within 12 hours of reperfusion, interleukin-1 blockade with anakinra blunts the acute systemic inflammatory response, a surrogate of interleukin-1 activity, and prevents heart failure events independent of time-to-treatment.
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Affiliation(s)
- Marco Giuseppe Del Buono
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Juan Ignacio Damonte
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Francesco Moroni
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Juan Guido Chiabrando
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Roshanak Markley
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Jeremy Turlington
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Cory R Trankle
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Le Kang
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Giuseppe Biondi-Zoccai
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Michael C Kontos
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Charlotte S Roberts
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Benjamin W Van Tassell
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
| | - Antonio Abbate
- VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, West Hospital, Richmond, Virginia (M.G.D.B., J.I.D., F.M., J.G.C., R.M., J.T., C.R.T., M.C.K., C.S.R., B.W.V.T., A.A.); Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (M.G.D.B.); Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy (M.G.D.B.); Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (J.I.D., J.G.C.); Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia (A.A.); Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia (L.K.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.B.-Z.); Mediterranea Cardiocentro, Napoli, Italy (G.B.-Z.); and Department of Pharmacotherapy and Outcomes Science, MedStar Washington Hospital Center, Washington, DC (B.W.V.T.)
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Wei X, Lv Y, Yang C, Gao R, Zou S, Xu Y. Bufalin reduces myocardial infarction-induced myocardial fibrosis and improves cardiac function by inhibiting the NLRP3/IL-1β signalling pathway. Clin Exp Pharmacol Physiol 2023. [PMID: 37243403 DOI: 10.1111/1440-1681.13783] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 03/23/2023] [Accepted: 05/01/2023] [Indexed: 05/28/2023]
Abstract
Early inflammatory responses post myocardial infarction (MI) is associated with increased myocardial fibrosis and cardiac remodelling. The NLRP3 inflammasome, a key factor in this response, regulates the expression of interleukins (IL)-1β and IL-18. Inhibiting the inflammatory process may be beneficial for post-MI recovery. Bufalin effectively inhibits inflammation and fibrosis. The aim of this study was to evaluate the effects of bufalin and MCC950, an NLRP3 inflammasome inhibitor, as potential treatment agents for MI using an experimental mouse model. Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and subsequently treated with bufalin (0.5 mg/kg), MCC950 (10 mg/kg) or saline thrice a week for 2 weeks. After 4 weeks, cardiac function and myocardial fibrosis were evaluated. Myocardial levels of fibrotic markers and inflammatory factors were analysed using western blotting, enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction and immunofluorescence. In mice with MI, cardiac ultrasonography showed decreased cardiac function and myocardial fibrosis. Bufalin treatment restored left ventricular ejection fraction and fractional shortening and decreased the myocardial infarct size. Moreover, both bufalin and MCC950 preserved cardiac function and relieved myocardial fibrosis, with no significant difference. Hence, the present study findings suggest that bufalin can alleviate fibrosis and improve cardiac function in a mouse model by suppressing NLRP3/IL-1β signalling post-MI.
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Affiliation(s)
- Xiang Wei
- Fifth People's Hospital of Shanghai Fudan University, Shanghai, China
| | - Yang Lv
- Fifth People's Hospital of Shanghai Fudan University, Shanghai, China
| | - Chenxi Yang
- Fifth People's Hospital of Shanghai Fudan University, Shanghai, China
| | - Rifeng Gao
- Fifth People's Hospital of Shanghai Fudan University, Shanghai, China
| | - Su Zou
- Fifth People's Hospital of Shanghai Fudan University, Shanghai, China
| | - Yingjia Xu
- Fifth People's Hospital of Shanghai Fudan University, Shanghai, China
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11
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Liu Z, Wang L, Xing Q, Liu X, Hu Y, Li W, Yan Q, Liu R, Huang N. Identification of GLS as a cuproptosis-related diagnosis gene in acute myocardial infarction. Front Cardiovasc Med 2022; 9:1016081. [PMID: 36440046 PMCID: PMC9691691 DOI: 10.3389/fcvm.2022.1016081] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/24/2022] [Indexed: 11/12/2022] Open
Abstract
Acute myocardial infarction (AMI) has the characteristics of sudden onset, rapid progression, poor prognosis, and so on. Therefore, it is urgent to identify diagnostic and prognostic biomarkers for it. Cuproptosis is a new form of mitochondrial respiratory-dependent cell death. However, studies are limited on the clinical significance of cuproptosis-related genes (CRGs) in AMI. In this study, we systematically assessed the genetic alterations of CRGs in AMI by bioinformatics approach. The results showed that six CRGs (LIAS, LIPT1, DLAT, PDHB, MTF1, and GLS) were markedly differentially expressed between stable coronary heart disease (stable_CAD) and AMI. Correlation analysis indicated that CRGs were closely correlated with N6-methyladenosine (m6A)-related genes through R language "corrplot" package, especially GLS was positively correlated with FMR1 and MTF1 was negatively correlated with HNRNPA2B1. Immune landscape analysis results revealed that CRGs were closely related to various immune cells, especially GLS was positively correlated with T cells CD4 memory resting and negatively correlated with monocytes. Kaplan-Meier analysis demonstrated that the group with high DLAT expression had a better prognosis. The area under curve (AUC) certified that GLS had good diagnostic value, in the training set (AUC = 0.87) and verification set (ACU = 0.99). Gene set enrichment analysis (GSEA) suggested that GLS was associated with immune- and hypoxia-related pathways. In addition, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, competing endogenous RNA (ceRNA) analysis, transcription factor (TF), and compound prediction were performed to reveal the regulatory mechanism of CRGs in AMI. Overall, our study can provide additional information for understanding the role of CRGs in AMI, which may provide new insights into the identification of therapeutic targets for AMI.
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Affiliation(s)
- Zheng Liu
- Clinical Pharmacy, Xiangtan Center Hospital, Xiangtan, China
- Zhou Honghao Research Institute Xiangtan, Xiangtan, China
| | - Lei Wang
- Department of Cardiovascular Medicine, Xiangtan Center Hospital, Xiangtan, China
| | - Qichang Xing
- Clinical Pharmacy, Xiangtan Center Hospital, Xiangtan, China
- Zhou Honghao Research Institute Xiangtan, Xiangtan, China
| | - Xiang Liu
- Clinical Pharmacy, Xiangtan Center Hospital, Xiangtan, China
- Zhou Honghao Research Institute Xiangtan, Xiangtan, China
| | - Yixiang Hu
- Clinical Pharmacy, Xiangtan Center Hospital, Xiangtan, China
- Zhou Honghao Research Institute Xiangtan, Xiangtan, China
| | - Wencan Li
- Clinical Pharmacy, Xiangtan Center Hospital, Xiangtan, China
- Zhou Honghao Research Institute Xiangtan, Xiangtan, China
| | - Qingzi Yan
- Clinical Pharmacy, Xiangtan Center Hospital, Xiangtan, China
- Zhou Honghao Research Institute Xiangtan, Xiangtan, China
| | - Renzhu Liu
- Clinical Pharmacy, Xiangtan Center Hospital, Xiangtan, China
- Zhou Honghao Research Institute Xiangtan, Xiangtan, China
| | - Nan Huang
- Clinical Pharmacy, Xiangtan Center Hospital, Xiangtan, China
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Núñez J, Lorenzo M, Miñana G, Palau P, Monmeneu JV, López‐Lereu MP, Gavara J, Marcos‐Garcés V, Rios‐Navarro C, Pérez N, de Dios E, Núñez E, Sanchis J, Chorro FJ, Bayés‐Genís A, Bodí V. Risk of death associated with incident heart failure in patients with known or suspected chronic coronary syndrome. ESC Heart Fail 2022; 10:264-273. [PMID: 36196583 PMCID: PMC9871680 DOI: 10.1002/ehf2.14179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/21/2022] [Accepted: 09/15/2022] [Indexed: 01/27/2023] Open
Abstract
AIMS Traditional adverse events in chronic coronary syndrome (CCS) include atherothrombotic events but usually exclude heart failure (HF). Data are scarce about how new-onset HF modifies mortality risk. We aimed to determine the incidence of HF and compare its long-term mortality risk with myocardial infarction (MI) and stroke in patients with known or suspected CCS. METHODS We prospectively evaluated 5811 consecutive HF-free patients submitted to vasodilator stress cardiac magnetic resonance (CMR) for known or suspected CCS. Ischaemic burden and left ventricular ejection fraction were assessed by CMR. HF included outpatient diagnosis or acute HF hospitalization. The mortality risk for the incident events and their cross-comparisons were evaluated using a Markov illness-death model with transition-specific survival models. RESULTS The mean age was 55 ± 11 years, and 38.9% were female. At a median follow-up of 5.44 (IQR = 2.53-8.55) years, 591 deaths were registered (1.79 per 100 P-Y). The rates of new-onset HF were higher compared with MI and stroke [1.02, 0.62, and 0.51, respectively (P < 0.05)]. The adjusted association between new-onset HF, MI, and stroke, and subsequent mortality was time dependent. The risk increased almost linearly for HF and became significant by the third year. By Year 10, the mortality risk attributable to new-onset HF was more than 2.5-fold (HR: 2.68, 95% CI = 1.74-4.12). For MI, there was a significant increase in mortality risk up to the second year, followed by a monotonic decrease. For stroke, the mortality risk increased for the entire follow-up but became significant by the third year. A cross-comparison among incident endpoints HF outnumbers risk for those with MI by the sixth year (HRyear6.3 : 1.88, 95% CI = 1.03-3.43). There was no difference in mortality risk between incident HF and stroke. CONCLUSIONS In patients with CCS, long-term rates of incident HF were higher than MI and stroke. Patients with new-onset HF showed a higher risk of long-term mortality.
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Affiliation(s)
- Julio Núñez
- Cardiology DepartmentHospital Clínico Universitario de ValenciaValenciaSpain,Instituto de Investigación Sanitaria INCLIVAValenciaSpain,Centro de Investigación Biomédica en Red ‐ Cardiovascular (CIBER‐CV)MadridSpain,Department of Medicine, School of Medicine and OdontologyUniversity of ValenciaValenciaSpain
| | - Miguel Lorenzo
- Cardiology DepartmentHospital Clínico Universitario de ValenciaValenciaSpain
| | - Gema Miñana
- Cardiology DepartmentHospital Clínico Universitario de ValenciaValenciaSpain,Instituto de Investigación Sanitaria INCLIVAValenciaSpain,Centro de Investigación Biomédica en Red ‐ Cardiovascular (CIBER‐CV)MadridSpain,Department of Medicine, School of Medicine and OdontologyUniversity of ValenciaValenciaSpain
| | - Patricia Palau
- Cardiology DepartmentHospital Clínico Universitario de ValenciaValenciaSpain,Instituto de Investigación Sanitaria INCLIVAValenciaSpain,Department of Medicine, School of Medicine and OdontologyUniversity of ValenciaValenciaSpain
| | - Jose V. Monmeneu
- Cardiovascular Magnetic Resonance UnitExploraciones Radiológicas Especiales (ERESA)ValenciaSpain
| | - Maria P. López‐Lereu
- Cardiovascular Magnetic Resonance UnitExploraciones Radiológicas Especiales (ERESA)ValenciaSpain
| | - Jose Gavara
- Instituto de Investigación Sanitaria INCLIVAValenciaSpain,Center for Biomaterials and Tissue EngineeringUniversitat Politècnica de ValènciaValenciaSpain
| | - Víctor Marcos‐Garcés
- Cardiology DepartmentHospital Clínico Universitario de ValenciaValenciaSpain,Instituto de Investigación Sanitaria INCLIVAValenciaSpain
| | | | - Nerea Pérez
- Instituto de Investigación Sanitaria INCLIVAValenciaSpain
| | - Elena de Dios
- Instituto de Investigación Sanitaria INCLIVAValenciaSpain
| | - Eduardo Núñez
- Cardiology DepartmentHospital Clínico Universitario de ValenciaValenciaSpain
| | - Juan Sanchis
- Cardiology DepartmentHospital Clínico Universitario de ValenciaValenciaSpain,Instituto de Investigación Sanitaria INCLIVAValenciaSpain,Centro de Investigación Biomédica en Red ‐ Cardiovascular (CIBER‐CV)MadridSpain,Department of Medicine, School of Medicine and OdontologyUniversity of ValenciaValenciaSpain
| | - Francisco J. Chorro
- Cardiology DepartmentHospital Clínico Universitario de ValenciaValenciaSpain,Instituto de Investigación Sanitaria INCLIVAValenciaSpain,Centro de Investigación Biomédica en Red ‐ Cardiovascular (CIBER‐CV)MadridSpain,Department of Medicine, School of Medicine and OdontologyUniversity of ValenciaValenciaSpain
| | - Antoni Bayés‐Genís
- Centro de Investigación Biomédica en Red ‐ Cardiovascular (CIBER‐CV)MadridSpain,Cardiology DepartmentHospital Universitari Germans Trias i PujolBadalonaSpain
| | - Vicent Bodí
- Cardiology DepartmentHospital Clínico Universitario de ValenciaValenciaSpain,Instituto de Investigación Sanitaria INCLIVAValenciaSpain,Centro de Investigación Biomédica en Red ‐ Cardiovascular (CIBER‐CV)MadridSpain,Department of Medicine, School of Medicine and OdontologyUniversity of ValenciaValenciaSpain
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Yan T, Zhu X, Zhang X, Jia X, Liu J, Wang X, Xiao Y, Xiao Z, Liu T, Dong Y. The application of proteomics and metabolomics to reveal the molecular mechanism of Nutmeg-5 in ameliorating cardiac fibrosis following myocardial infarction. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 105:154382. [PMID: 35963196 DOI: 10.1016/j.phymed.2022.154382] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 07/28/2022] [Accepted: 08/02/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Nutmeg-5, an ancient and classic formula in traditional Mongolian medicine comprising five kinds of traditional Chinese medicine, is widely used in the treatment of myocardial infarction (MI, called heart "Heyi" disease in Mongolian medicine). Cardiac fibrosis plays a critical role in the development and progression of heart failure after MI. However, the material basis and pharmacological mechanisms of the effect of Nutmeg-5 on cardiac fibrosis after MI remain unclear. OBJECTIVE The aim of this study was to first explore the potential material basis and molecular mechanism of action of Nutmeg-5 in improving cardiac fibrosis after MI via a multiomics approach. METHODS The constituents in Nutmeg-5 were identified by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). High-performance liquid chromatography (HPLC) and gas chromatography (GC)-based fingerprints of Nutmeg-5 were analysed, and characteristic peaks were identified by comparison to standard samples. A rat MI model was created by permanent ligation of the left anterior descending artery. The protective effect of Nutmeg-5 on cardiac fibrosis after MI was evaluated by tissue histology and measurement of the serum biomarkers of myocardial injury. Cardiac fibrosis levels were evaluated by Sirius red staining. Differentially expressed proteins in the myocardium and metabolites in the serum were explored by proteomic and untargeted metabolome analyses, respectively. Pearson correlation analysis was performed to explore the association between serum metabolites and myocardial proteins. RESULTS A total of 67 constituents were identified in Nutmeg-5 by UPLC-MS/MS. Sixteen components were identified in the fingerprint of Nutmeg-5 by comparison with a standard sample. Six lactones were isolated from Nutmeg-5 and quantified by HPLC and GC. MI was significantly alleviated in Nutmeg-5-treated rats compared to MI rats, as demonstrated by their decreased mortality, improved cardiac function, and attenuated cardiac fibrosis and myocardial injury. A total of 252 significant differential metabolites were identified in plasma between model and Nutmeg-5-treated rats by untargeted metabolome analysis. Among these, 36 critical metabolites were associated with Nutmeg-5 activity. Proteomic analysis identified 338 differentially expressed proteins in the rat myocardium between MI and Nutmeg-5-treated rats, including 204 upregulated and 134 downregulated proteins. Protein set enrichment analysis revealed that Nutmeg-5 treatment significantly inhibited the extracellular matrix (ECM)-receptor interaction pathway, which was activated in the myocardium of MI rats. A significant decrease in collagen and alpha smooth muscle actin expression levels was found in the myocardium of Nutmeg-5-treated rats compared to MI rats. These results illustrated that Nutmeg-5 had a significant protective effect on cardiac fibrosis after MI. A significant correlation was found between the ECM-receptor interaction pathway in the myocardium and critical metabolites in the serum. In addition, there were positive correlations between the levels of critical metabolites and the expression levels of transforming growth factor (TGF)-β1 and Smad2 in the rat myocardium. CONCLUSIONS Nutmeg-5 alleviated cardiac fibrosis after MI in rats by inhibiting the myocardial ECM-receptor interaction pathway and TGF-β1/Smad2 signalling, which was achieved by regulating plasma metabolites.
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Affiliation(s)
- Tingting Yan
- Department of Natural Medicinal Chemistry, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development Zone, Hohhot 010110, PR China; Engineering Technology Research Center of Pharmacodynamic Substance and Quality Control of Mongolian Medicine in Inner Mongolia, Hohhot 010110, PR China
| | - Xiaoling Zhu
- Inner Mongolian International Mongolian Hospital, University East Street, Hohhot 010065, PR China
| | - Xueni Zhang
- Department of Natural Medicinal Chemistry, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development Zone, Hohhot 010110, PR China; Engineering Technology Research Center of Pharmacodynamic Substance and Quality Control of Mongolian Medicine in Inner Mongolia, Hohhot 010110, PR China
| | - Xin Jia
- Department of Natural Medicinal Chemistry, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development Zone, Hohhot 010110, PR China; Engineering Technology Research Center of Pharmacodynamic Substance and Quality Control of Mongolian Medicine in Inner Mongolia, Hohhot 010110, PR China; Department of Pharmacy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010059, PR China
| | - Jing Liu
- Department of Pharmacy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010059, PR China
| | - Xianjue Wang
- Clinical Medical Research Center, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010059, PR China
| | - Yunfeng Xiao
- Center for New Drug Safety Evaluation and Research, Inner Mongolia Medical University, Hohhot, PR China
| | - Zhibin Xiao
- Department of Clinical Pharmacy, College of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Tianlong Liu
- Department of Pharmacy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010059, PR China.
| | - Yu Dong
- Department of Natural Medicinal Chemistry, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development Zone, Hohhot 010110, PR China; Engineering Technology Research Center of Pharmacodynamic Substance and Quality Control of Mongolian Medicine in Inner Mongolia, Hohhot 010110, PR China.
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Abbate A, Wohlford GF, Del Buono MG, Chiabrando JG, Markley R, Turlington J, Kadariya D, Trankle CR, Biondi-Zoccai G, Lipinski MJ, Van Tassell BW. Interleukin-1 blockade with anakinra and heart failure following ST-segment elevation myocardial infarction: results from a pooled analysis of the VCUART clinical trials. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2022; 8:503-510. [PMID: 34617567 PMCID: PMC9366639 DOI: 10.1093/ehjcvp/pvab075] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/17/2021] [Accepted: 10/05/2021] [Indexed: 12/15/2022]
Abstract
AIMS ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). In this study, we sought to evaluate the effect of anakinra, a recombinant interleukin-1 receptor antagonist, on the incidence of HF. METHODS AND RESULTS We performed a pooled analysis of three early phase randomized clinical trials. The endpoints included the composite of all-cause death and new-onset HF, and the composite of all-cause death and hospitalization for HF at 1-year follow-up. Safety events, including injection site reaction and serious infections, were also recorded. We analysed 139 patients with STEMI from three separate trials: VCUART (N = 10), VCUART2 (N = 30), and VCUART3 (N = 99). Of these, 84 (60%) patients were randomized to anakinra and 55 (40%) to placebo. Treatment with anakinra significantly reduced the incidence of all-cause death or new-onset HF (7 [8.2%] vs. 16 [29.1%], log-rank P = 0.002) and of all-cause death or HF hospitalization (0 [0] vs. 5 [9.1%], log-rank P = 0.007). Patients treated with anakinra had significantly higher injection site reactions (19 [22.6%] vs. 3 [5.5%], P = 0.016) without a significant difference in the incidence of serious infections (11 [13.1%] vs. 7 [12.7%], P = 0.435). Treatment with anakinra significantly reduced the area under the curve for high-sensitivity C-reactive protein between baseline and 14 days (75.48 [41.7-147.47] vs. 222.82 [117.22-399.28] mg day/L, P < 0.001). CONCLUSION IL-1 blockade with anakinra for 14 days in patients with STEMI reduces the incidence of new-onset HF or hospitalization for HF at 1 year following STEMI.
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Affiliation(s)
- Antonio Abbate
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - George F Wohlford
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | | | | | - Roshanak Markley
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Jeremy Turlington
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Dinesh Kadariya
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Cory R Trankle
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Giuseppe Biondi-Zoccai
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Napoli, Italy
| | - Michael J Lipinski
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
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Del Buono MG, Damonte JI, Chiabrando JG, Markley R, Turlington J, Trankle CR, Kang L, Biondi-Zoccai G, Van Tassell BW, Abbate A. Effect of IL-1 Blockade With Anakinra on Heart Failure Outcomes in Patients With Anterior Versus Nonanterior ST Elevation Myocardial Infarction. J Cardiovasc Pharmacol 2022; 79:774-780. [PMID: 35170493 PMCID: PMC9177574 DOI: 10.1097/fjc.0000000000001240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/22/2022] [Indexed: 11/26/2022]
Abstract
Patients with ST elevation myocardial infarction (STEMI) are at risk of future heart failure (HF), particularly those with anterior STEMI. Interleukin-1 (IL-1) is a key mediator of the inflammatory response, and its blockade has emerged as a potential therapeutic strategy to prevent HF events. The aim of this analysis was to explore the effects of anakinra, an IL-1 receptor antagonist, on HF outcomes based on anterior versus nonanterior location STEMI and to explore whether this effect is mediated through the amelioration of left ventricular systolic function and cardiac remodeling. We pooled data from 3 early phase randomized clinical trials. The primary end point was a composite of all-cause death and new-onset HF at 1-year follow-up. The left anterior descending coronary artery as culprit vessel was used to identify anterior STEMI. We included 139 patients, 47 (34%) with anterior STEMI and 92 (66%) with nonanterior STEMI. Anakinra significantly reduced the combined end point of death or new-onset HF in patients with anterior STEMI [4 (13%) vs. 7 (42%), log-rank P value = 0.049] and in patients with nonanterior STEMI [3 (6%) vs. 9 (24%), log-rank P value = 0.014]. We found no significant differences comparing anakinra versus placebo in interval changes in left ventricular ejection fraction and volumes in anterior and nonanterior STEMI. In conclusion, anakinra is associated with a reduction of HF events in patients with STEMI, irrespective of anterior or nonanterior location, or of changes in left ventricular ejection fraction or cardiac remodeling.
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Affiliation(s)
- Marco Giuseppe Del Buono
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
- Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Juan Ignacio Damonte
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
- Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Argentina
| | - Juan Guido Chiabrando
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
- Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Argentina
| | - Roshanak Markley
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Jeremy Turlington
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Cory R. Trankle
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Le Kang
- Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, USA
| | - Giuseppe Biondi-Zoccai
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Napoli, Italy
| | - Benjamin W. Van Tassell
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
- Department of Pharmacotherapy and Outcomes Sciences, Virginia Commonwealth University, Richmond, VA, USA
| | - Antonio Abbate
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
- Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, USA
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Del Buono MG, Trankle CR, Buckley L, Kadariya D, Canada JM, Carbone S, Turlington J, Markley R, Bressi E, VAN Tassell BW, Abbate A. Early changes in N-terminal pro-brain natriuretic peptide levels predict new-onset heart failure in patients with STEMI. Minerva Cardiol Angiol 2022; 70:25-31. [PMID: 32657561 DOI: 10.23736/s2724-5683.20.05303-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Previous studies suggested that N-terminal pro-brain natriuretic peptide (NT-proBNP) level is a powerful independent predictor of death or heart failure (HF) when measured at admission in patients with chest pain or acute coronary syndrome. Little is known about the role of NT-proBNP level measured during a hospitalization for ST segment elevation myocardial infarction (STEMI) in predicting clinical outcomes. We evaluated the optimal NT-proBNP timing (admission, 72 hours, or delta [Δ] NT-proBNP [72 hours minus admission]) to predict 1-year new-onset HF in STEMI patients. METHODS We measured NT-proBNP levels at admission and 72 hours in 72 patients with STEMI. HF events were adjudicated and defined as hospitalization for HF or need for new initiation of a loop diuretic at 1-year follow-up. Values are presented as medians and interquartile range or frequencies (%) as appropriate. Cox regression analysis was used to determine predictors of adverse events. A receiver-operative-curve was constructed to identify the discriminative value and optimal cut-off points for NT-proBNP. RESULTS Patients (age 56 [49-64] years, males 59 [82%]) were followed for a median duration of 365 [180-365] days. HF events were recorded in 9 (12.5%) patients. NT-proBNP values at admission, 72 hours, and ΔNT-proBNP were 89 (26-268) pg/mL, 452 (223-1064) pg/mL, and 283 (68-686) pg/mL, respectively. NT-proBNP at 72 hours and ΔNT-proBNP, but not admission NT-proBNP predicted new-onset HF events at follow-up (P=0.03, P=0.002 and P=0.89, respectively). The optimal area under the curve of 0.771 (95%, CI [0.630-0.912], P= 0.009) and cut-off value of 830 pg/mL (sensitivity 79%; specificity 76%) were found for NT-proBNP at 72 hours. The Kaplan-Meier survival curves for NT-proBNP at 72 hours dichotomized above and below this cut-off value, confirmed NT-proBNP at 72 hours >830 pg/mL as predictive of HF events (log-rank statistic = 8.688, P=0.003). CONCLUSIONS NT-proBNP level at 72 hours and ΔNT-proBNP (72 hours minus admission), but not at time of admission, predicted HF events in patients following STEMI.
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Affiliation(s)
- Marco G Del Buono
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA, USA
- Department of Cardiovascular and Thoracic Sciences, Sacred Heart Catholic University, Rome, Italy
| | - Cory R Trankle
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA, USA
| | - Leo Buckley
- Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA
| | - Dinesh Kadariya
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA, USA
| | - Justin M Canada
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA, USA
| | - Salvatore Carbone
- Department of Kinesiology and Health Sciences, College of Humanities and Sciences, Virginia Commonwealth University, Richmond, VA, USA
| | - Jeremy Turlington
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA, USA
| | - Roshanak Markley
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA, USA
| | - Edoardo Bressi
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA, USA
| | - Benjamin W VAN Tassell
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA, USA
- Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA
| | - Antonio Abbate
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA, USA -
- Department of Cardiovascular and Thoracic Sciences, Sacred Heart Catholic University, Rome, Italy
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Huang D, Zheng S, Liu Z, Zhu K, Zhi H, Ma G. Machine Learning Revealed Ferroptosis Features and a Novel Ferroptosis-Based Classification for Diagnosis in Acute Myocardial Infarction. Front Genet 2022; 13:813438. [PMID: 35145551 PMCID: PMC8821875 DOI: 10.3389/fgene.2022.813438] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/05/2022] [Indexed: 12/30/2022] Open
Abstract
Acute myocardial infarction (AMI) is a leading cause of death and disability worldwide. Early diagnosis of AMI and interventional treatment can significantly reduce myocardial damage. However, owing to limitations in sensitivity and specificity, existing myocardial markers are not efficient for early identification of AMI. Transcriptome-wide association studies (TWASs) have shown excellent performance in identifying significant gene–trait associations and several cardiovascular diseases (CVDs). Furthermore, ferroptosis is a major driver of ischaemic injury in the heart. However, its specific regulatory mechanisms remain unclear. In this study, we screened three Gene Expression Omnibus (GEO) datasets of peripheral blood samples to assess the efficiency of ferroptosis-related genes (FRGs) for early diagnosis of AMI. To the best of our knowledge, for the first time, TWAS and mRNA expression data were integrated in this study to identify 11 FRGs specifically expressed in the peripheral blood of patients with AMI. Subsequently, using multiple machine learning algorithms, an optimal prediction model for AMI was constructed, which demonstrated satisfactory diagnostic efficiency in the training cohort (area under the curve (AUC) = 0.794) and two external validation cohorts (AUC = 0.745 and 0.711). Our study suggests that FRGs are involved in the progression of AMI, thus providing a new direction for early diagnosis, and offers potential molecular targets for optimal treatment of AMI.
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Affiliation(s)
- Dan Huang
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Shiya Zheng
- Department of Oncology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Zhuyuan Liu
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Kongbo Zhu
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Hong Zhi
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Genshan Ma
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
- *Correspondence: Genshan Ma,
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Cavender MA, O'Donoghue ML, Abbate A, Aylward P, Fox KAA, Glaser RX, Park JG, Lopez-Sendon J, Steg PG, Sabatine MS, Morrow DA. Inhibition of p38 MAP kinase in patients with ST-elevation myocardial infarction - findings from the LATITUDE-TIMI 60 trial. Am Heart J 2022; 243:147-157. [PMID: 34508693 DOI: 10.1016/j.ahj.2021.08.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 08/24/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND p38 mitogen activated kinase (MAPK) mediates the response to pro-inflammatory cytokines following myocardial infarction (MI) and is inhibited by losmapimod. METHODS LATITUDE-TIMI 60 (ClinicalTrials.gov NCT02145468) randomized patients with MI to losmapimod or placebo for 12 weeks (24 weeks total follow-up). In this pre-specified analysis, we examined outcomes based on MI type [ST-segment elevation MI (STEMI) (865, 25%) and non-STEMI (2624, 75%)]. RESULTS In patients with STEMI, inflammation, measured by hs-CRP, was significantly attenuated with losmapimod at 48 hours (P <0.001) and week 12 (P = 0.01). Losmapimod lowered NT-proBNP in patients with STEMI at 48 hours (P = 0.04) and week 12 (P = 0.02). The effects of losmapimod on CV death (CVD), MI, or severe recurrent ischemia requiring urgent coronary artery revascularization at 24 weeks [MACE] differed in patients with STEMI (7.0% vs 10.8%; HR 0.65, 95%CI 0.41 - 1.03; P= 0.06) and NSTEMI (11.4% vs 8.5%; HR 1.30, 95%CI 1.02 - 1.66; P = 0.04; p[int] = 0.009). CVD or HHF among patients with STEMI were 5.6% (losmapimod) and 8.3% (placebo) (HR 0.66; 95%CI 0.40 - 1.11; P = 0.12) and in NSTEMI were 4.8% (losmapimod) and 4.4% (placebo) (HR 1.09; 95%CI 0.76 - 1.56) in patients with NSTEMI. CONCLUSIONS Patients with STEMI treated with losmapimod had an attenuated inflammatory response. Our collective findings raise the hypothesis that mitigating the inflammatory response may result in different outcomes in patients with STEMI and NSTEMI. While the difference in outcomes is exploratory, these findings do support separate examination of patients with STEMI and NSTEMI and increased emphasis on heart failure in future investigation of modulators of inflammation in MI.
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Li MF, Wei ZT, Li S, Feng QM, Li JB. Association of Mild Thyroid Dysfunction and Adverse Prognosis Among Chinese Patients With Acute ST Segment Elevation Myocardial Infarction. Front Endocrinol (Lausanne) 2022; 13:879443. [PMID: 35574034 PMCID: PMC9097552 DOI: 10.3389/fendo.2022.879443] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
AIMS Thyroid hormones widely affect the cardiovascular system, but the effects of mild thyroid dysfunction on the clinical prognosis of patients with acute ST segment elevation myocardial infarction (STEMI) remains unclear. Our aims were to analyze the relations between mild thyroid dysfunction at admission and clinical outcomes in Chinese patients with STEMI. METHODS A total of 1,176 STEMI patients with the available data of thyroid function and follow-up were analyzed, including 348 patients with mild thyroid dysfunction [subclinical hypothyroidism (n=81), hyperthyroidism (SHyper) (n=51), and low triiodothyronine syndrome (LT3S) (n=216)] and 828 patients with euthyroid function. During a median 4.4-year follow-up, in-hospital mortality, cardiac and all-cause mortalities were subsequently compared among the four groups. RESULTS Compared with the euthyroid group, STEMI patients in the SHyper and LT3S groups faced obviously increased risks of in-hospital death [odds ratio (OR): 5.007, 95% confidence interval (CI): 1.246-20.124, p = 0.023 and OR: 2.491, 95% CI: 1.054-5.887, p = 0.037, respectively) even after adjustment for various confounding factors. During a median 4.4-year follow-up, STEMI patients with LT3S at baseline had higher cardiovascular mortality [hazard ratio (HR): 1.880, 95% CI: 1.178-2.998, p = 0.008] and all-cause mortality HR: 1.647, 95% CI: 1.072-2.531, p = 0.023] than those with euthyroid at baseline, whereas no significantly increased mortality was found for STEMI patients with SCH and SHyper at baseline. CONCLUSIONS STEMI patients with SHyper at admission had increased risk of in-hospital mortality, and STEMI patients with LT3S at baseline had worse prognosis and higher incidences of in-hospital mortality and cardiovascular and all-cause deaths compared with euthyroid patients.
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Affiliation(s)
- Mei-Fang Li
- Department of Emergency, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Ze-Tao Wei
- Department of Emergency, Dan Zhou People’s Hospital, Dan Zhou, China
| | - Shuai Li
- Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Qi-Ming Feng
- Department of Emergency, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- *Correspondence: Qi-Ming Feng, ; Jing-Bo Li,
| | - Jing-Bo Li
- Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- *Correspondence: Qi-Ming Feng, ; Jing-Bo Li,
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Mangali S, Bhat A, Dasari D, Sriram D, Dhar A. Inhibition of double stranded RNA dependent protein kinase (PKR) abrogates isoproterenol induced myocardial ischemia in vitro in cultured cardiomyocytes and in vivo in wistar rats. Eur J Pharmacol 2021; 906:174223. [PMID: 34081906 DOI: 10.1016/j.ejphar.2021.174223] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 05/22/2021] [Accepted: 05/28/2021] [Indexed: 12/29/2022]
Abstract
Protein kinase R (PKR) plays a main role in inflammation, insulin resistance, and glucose balance. It is activated by various stress signals and is key mediators of diabetes and associated complications. In the present study, we investigated the effect of PKR inhibition on myocardial dysfunction, inflammatory, cell death and interrelated signalling pathways in isoproterenol induced myocardial ischemia in vivo in wistar rats and in vitro in cultured cardiomyocytes. H9C2 rat cardiomyocytes were treated with 10 μM Isoproterenol (ISO). For in vivo studies, rats were divided into 4 groups: control, ischemic group (ISO), preventive group, curative group and each group consist of 8 rats. Myocardial Ischemia (MI) was induced with two subsequent doses of ISO (100 mg/kg, s.c.). The rats were treated with PKR inhibitor, C16 (166.5 μg/kg, i.p.) for 14 days. Heart rate, systolic, diastolic and mean arterial pressures were measured by non-invasive BP apparatus. Cardiac biomarkers were measured by commercial kits. Ischemic Zone, Morphological abnormalities and fibrosis of heart was detected by TTC, haematoxylin & eosin staining, Masson's and Sirius red staining respectively. Protein expression was done by western blotting and immune histochemistry. mRNA expression was done by RT-PCR. MI was characterized by declined myocardial performance along with elevation of cardiac biomarkers and associated with increased expression of PKR, oxidative-nitrosative stress, activated various inflammatory pathways (nuclear factor kappa light chain enhancer of activated B cells -NF-κB); Mitogen-activated protein kinases-MAPK; c-Jun N-terminal kinase-JNK), increased expression of inflammatory markers (Tumour necrosis factor alpha-TNF-α), markers of fibrosis (Alpha smooth muscle actin -α-SMA; Transforming growth factor beta-TGF-β), enhanced cell death (Ischemic zone) and increased expression of extracellular regulated-kinases (ERK-1/2) and advanced glycation end products (AGE's). Interestingly, inhibition of PKR attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrosative stress, inflammation, cell death, and inter-related signalling pathways. Our findings report that inhibition of PKR improves the ischemic mediated inflammation, apoptosis, cardiac hypertrophy and fibrosis in MI induced rats. Hence, inhibition of PKR might be one of intervention therapy for the treatment of myocardial ischemia.
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Affiliation(s)
- Sureshbabu Mangali
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana, 500078, India
| | - Audesh Bhat
- Department of Molecular Biology, Central University of Jammu, India
| | - Deepika Dasari
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana, 500078, India
| | - Dharmarajan Sriram
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana, 500078, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana, 500078, India.
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Song J, Frieler RA, Whitesall SE, Chung Y, Vigil TM, Muir LA, Ma J, Brombacher F, Goonewardena SN, Lumeng CN, Goldstein DR, Mortensen RM. Myeloid interleukin-4 receptor α is essential in postmyocardial infarction healing by regulating inflammation and fibrotic remodeling. Am J Physiol Heart Circ Physiol 2021; 320:H323-H337. [PMID: 33164548 PMCID: PMC7847075 DOI: 10.1152/ajpheart.00251.2020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 10/23/2020] [Accepted: 10/29/2020] [Indexed: 02/06/2023]
Abstract
Interleukin-4 receptor α (IL4Rα) signaling plays an important role in cardiac remodeling during myocardial infarction (MI). However, the target cell type(s) of IL4Rα signaling during this remodeling remains unclear. Here, we investigated the contribution of endogenous myeloid-specific IL4Rα signaling in cardiac remodeling post-MI. We established a murine myeloid-specific IL4Rα knockout (MyIL4RαKO) model with LysM promoter-driven Cre recombination. Macrophages from MyIL4RαKO mice showed significant downregulation of alternatively activated macrophage markers but an upregulation of classical activated macrophage markers both in vitro and in vivo, indicating the successful inactivation of IL4Rα signaling in macrophages. To examine the role of myeloid IL4Rα during MI, we subjected MyIL4RαKO and littermate floxed control (FC) mice to MI. We found that cardiac function was significantly impaired as a result of myeloid-specific IL4Rα deficiency. This deficiency resulted in a dysregulated inflammatory response consisting of decreased production of anti-inflammatory cytokines. Myeloid IL4Rα deficiency also led to reduced collagen 1 deposition and an imbalance of matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs), with upregulated MMPs and downregulated TIMPs, which resulted in insufficient fibrotic remodeling. In conclusion, this study identifies that myeloid-specific IL4Rα signaling regulates inflammation and fibrotic remodeling during MI. Therefore, myeloid-specific activation of IL4Rα signaling could offer protective benefits after MI.NEW & NOTEWORTHY This study showed, for the first time, the role of endogenous IL4Rα signaling in myeloid cells during cardiac remodeling and the underlying mechanisms. We identified myeloid cells are the critical target cell types of IL4Rα signaling during cardiac remodeling post-MI. Deficiency of myeloid IL4Rα signaling causes deteriorated cardiac function post-MI, due to dysregulated inflammation and insufficient fibrotic remodeling. This study sheds light on the potential of activating myeloid-specific IL4Rα signaling to modify remodeling post-MI. This brings hope to patients with MI and diminishes side effects by cell type-specific instead of whole body treatment.
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Affiliation(s)
- Jianrui Song
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Ryan A Frieler
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Steven E Whitesall
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Yutein Chung
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Thomas M Vigil
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Lindsey A Muir
- Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan
| | - Jun Ma
- Department of Thoracic Surgery, Shanxi Province People's Hospital, Taiyuan, People's Republic of China
| | - Frank Brombacher
- International Center for Genetic Engineering and Biotechnology, University of Cape Town, Cape Town, South Africa
| | - Sascha N Goonewardena
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Carey N Lumeng
- Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan
| | - Daniel R Goldstein
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- Institute of Gerontology, University of Michigan, Ann Arbor, Michigan
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan
| | - Richard M Mortensen
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
- Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan
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22
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Kim MC, Ahn Y, Cho KH, Sim DS, Hong YJ, Kim JH, Jeong MH, Cho JG, Kim D, Lee K, Jeong I, Cho YS, Jung YH, Jeung KW. Benefit of Extracorporeal Membrane Oxygenation before Revascularization in Patients with Acute Myocardial Infarction Complicated by Profound Cardiogenic Shock after Resuscitated Cardiac Arrest. Korean Circ J 2021; 51:533-544. [PMID: 34085425 PMCID: PMC8176069 DOI: 10.4070/kcj.2020.0499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/12/2021] [Accepted: 03/10/2021] [Indexed: 11/28/2022] Open
Abstract
Few studies have focused on acute myocardial infarction (AMI) with cardiogenic shock after resuscitated out-of-hospital cardiac arrest (OHCA). Only a small number of studies have reported the timing of extracorporeal membrane oxygenation (ECMO) in patients with AMI with cardiogenic shock. The current study, which used the large nationwide OHCA registry, shows that ECMO treatment before revascularization can decrease 30-day mortality, compared to ECMO after revascularization, in patients with AMI complicated by profound cardiogenic shock after resuscitated cardiac arrest. The current study emphasized the importance of early ECMO therapy before revascularization in circumstance which is difficult to determine optimal revascularization timing. Background and Objectives The study sought to investigate the impact of early extracorporeal membrane oxygenation (ECMO) support before revascularization in patients with acute myocardial infarction (AMI) complicated by profound cardiogenic shock after resuscitated cardiac arrest. It is difficult to determine optimal timing of ECMO in patients with AMI complicated by profound cardiogenic shock after resuscitated cardiac arrest. Methods Among 116,374 patients experiencing out-of-hospital cardiac arrest in South Korea, a total of 184 resuscitated patients with AMI complicated by profound cardiogenic shock, and who were treated successfully with percutaneous coronary intervention (PCI) and ECMO, were enrolled. Patients were divided into 2 groups according to the timing of ECMO: pre-PCI ECMO (n=117) and post-PCI ECMO (n=67). We compared 30-day mortality between the 2 groups. Results In-hospital mortality was 78.8% in the entire study population and significantly lower in the pre-PCI ECMO group (73.5% vs. 88.1%, p=0.020). Thirty-day mortality was also lower in the pre-PCI ECMO group compared to the post-PCI ECMO group (74.4% vs. 91.0%; adjusted hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.47–0.93; p=0.017). Shockable rhythm at the emergency room (HR, 0.57; 95% CI, 0.36–0.91; p=0.019) and successful therapeutic hypothermia (HR, 0.40; 95% CI, 0.23–0.69; p=0.001) were also associated with improved 30-day survival. Conclusions ECMO support before revascularization was associated with an improved short-term survival rate compared to ECMO after revascularization in patients with AMI complicated by profound cardiogenic shock after resuscitated cardiac arrest.
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Affiliation(s)
- Min Chul Kim
- Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Youngkeun Ahn
- Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea.
| | - Kyung Hoo Cho
- Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Doo Sun Sim
- Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Young Joon Hong
- Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Ju Han Kim
- Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Myung Ho Jeong
- Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Jeong Gwan Cho
- Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Dowan Kim
- Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Kyoseon Lee
- Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Inseok Jeong
- Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Yong Soo Cho
- Department of Emergency Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Yong Hun Jung
- Department of Emergency Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Kyung Woon Jeung
- Department of Emergency Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
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23
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Gao RF, Li X, Xiang HY, Yang H, Lv CY, Sun XL, Chen HZ, Gao Y, Yang JS, Luo W, Yang YQ, Tang YH. The covalent NLRP3-inflammasome inhibitor Oridonin relieves myocardial infarction induced myocardial fibrosis and cardiac remodeling in mice. Int Immunopharmacol 2021; 90:107133. [PMID: 33168408 DOI: 10.1016/j.intimp.2020.107133] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 10/18/2020] [Accepted: 10/26/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Myocardial infarction (MI) triggers a strong inflammatory response that is associated with myocardial fibrosis and cardiac remodeling. Interleukin (IL)-1β and IL-18 are key players in this response and are controlled by NLRP3-inflammatory bodies. Oridonin is a newly reported NLRP3 inhibitor with strong anti-inflammatory activity. We hypothesized that the covalent NLRP3 inhibitor Oridonin could reduce IL-1β and IL-18 expression and ameliorate myocardial fibrosis after myocardial infarction in mice, improve poor heart remodeling, and preserve heart function. METHODS Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and then treated with Oridonin (1, 3, or 6 mg/kg), MCC950 (10 mg/kg), CY-09 (5 mg/kg) or saline three times a week for two weeks. Four weeks after MI, cardiac function and myocardial fibrosis were assessed. In addition, myocardial expressions of inflammatory factors and fibrotic markers were analyzed by western blot, immunofluorescence, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction. RESULTS Oridonin treatment preserved left ventricular ejection fraction and fractional shortening, and markedly limited the myocardial infarct size in treated mice. The myocardial fibrosis was lower in the 1 mg/kg group (15.98 ± 1.64)%, 3 mg/kg group (17.39 ± 2.45)%, and 6 mg/kg group (16.76 ± 3.06)% compared to the control group (23.38 ± 1.65)%. Moreover, similar with the results of Oridonin, MCC950 and CY-09 also preserved cardiac function and reduced myocardial fibrosis. The expression levels of NLRP3, IL-1β and IL-18 were decreased in the Oridonin treatment group compared to non-treated group. In addition, myocardial macrophage and neutrophil influxes were attenuated in the Oridonin treated group. CONCLUSIONS The covalent NLRP3-inflammasome inhibitor Oridonin reduces myocardial fibrosis and preserves cardiac function in a mouse MI model, which indicates potential therapeutic effect of Oridonin on acute MI patients.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Cells, Cultured
- Disease Models, Animal
- Diterpenes, Kaurane/pharmacology
- Fibrosis
- Furans
- Heterocyclic Compounds, 4 or More Rings/pharmacology
- Indenes
- Inflammasomes/antagonists & inhibitors
- Inflammasomes/metabolism
- Interleukin-1beta/metabolism
- Macrophages/drug effects
- Macrophages/metabolism
- Male
- Mice, Inbred C57BL
- Myocardial Infarction/drug therapy
- Myocardial Infarction/metabolism
- Myocardial Infarction/pathology
- Myocardial Infarction/physiopathology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors
- NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
- Neutrophil Infiltration/drug effects
- Neutrophils/drug effects
- Neutrophils/metabolism
- Receptors, Interleukin-18/metabolism
- Signal Transduction
- Stroke Volume/drug effects
- Sulfonamides
- Sulfones/pharmacology
- Thiazolidines/pharmacology
- Thiones/pharmacology
- Ventricular Function, Left/drug effects
- Ventricular Remodeling/drug effects
- Mice
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Affiliation(s)
- Ri-Feng Gao
- Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Xiao Li
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 20032, China
| | - Hai-Yan Xiang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Heng Yang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Chun-Yu Lv
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiao-Lei Sun
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 20032, China
| | - Hong-Zhang Chen
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yang Gao
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 20032, China
| | - Jue-Sheng Yang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Wei Luo
- Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Yi-Qing Yang
- Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
| | - Yan-Hua Tang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang 330006, Jiangxi Province, China.
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24
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Expression Profiles and Ontology Analysis of Circular RNAs in a Mouse Model of Myocardial Ischemia/Reperfusion Injury. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2346369. [PMID: 32596283 PMCID: PMC7273412 DOI: 10.1155/2020/2346369] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 04/09/2020] [Accepted: 04/27/2020] [Indexed: 12/17/2022]
Abstract
Circular RNAs (circRNAs) play important roles in cellular physiology. The association between circRNAs and myocardial ischemia/reperfusion (I/R) injury remains largely unknown. The aim of this study was to test the effects of myocardial I/R circRNA expression and explore the potential roles of these circRNAs. CircRNAs were screened by high-throughput sequencing, and the expression of dysregulated circRNAs was further validated using quantitative real-time polymerase chain reaction. Nineteen upregulated and 20 downregulated circRNAs were identified. Gene Ontology analysis indicated that the dysregulated transcripts were associated with fundamental pathophysiologic processes. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed significant changes in adherens junction, the HIF-1 signaling pathway, the cell cycle, and the FoxO signaling pathway which have a close relationship with myocardial I/R injury. The circRNA-miRNA analysis demonstrated the broad potential of the differentially expressed circRNAs to regulate target genes by acting on the miRNAs. This study provides a foundation for understanding the roles and mechanisms of circRNAs in myocardial I/R injury.
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25
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Abbate A, Trankle CR, Buckley LF, Lipinski MJ, Appleton D, Kadariya D, Canada JM, Carbone S, Roberts CS, Abouzaki N, Melchior R, Christopher S, Turlington J, Mueller G, Garnett J, Thomas C, Markley R, Wohlford GF, Puckett L, Medina de Chazal H, Chiabrando JG, Bressi E, Del Buono MG, Schatz A, Vo C, Dixon DL, Biondi‐Zoccai GG, Kontos MC, Van Tassell BW. Interleukin-1 Blockade Inhibits the Acute Inflammatory Response in Patients With ST-Segment-Elevation Myocardial Infarction. J Am Heart Assoc 2020; 9:e014941. [PMID: 32122219 PMCID: PMC7335541 DOI: 10.1161/jaha.119.014941] [Citation(s) in RCA: 188] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 12/05/2019] [Indexed: 02/06/2023]
Abstract
Background ST-segment-elevation myocardial infarction is associated with an intense acute inflammatory response and risk of heart failure. We tested whether interleukin-1 blockade with anakinra significantly reduced the area under the curve for hsCRP (high sensitivity C-reactive protein) levels during the first 14 days in patients with ST-segment-elevation myocardial infarction (VCUART3 [Virginia Commonwealth University Anakinra Remodeling Trial 3]). Methods and Results We conducted a randomized, placebo-controlled, double-blind, clinical trial in 99 patients with ST-segment-elevation myocardial infarction in which patients were assigned to 2 weeks treatment with anakinra once daily (N=33), anakinra twice daily (N=31), or placebo (N=35). hsCRP area under the curve was significantly lower in patients receiving anakinra versus placebo (median, 67 [interquartile range, 39-120] versus 214 [interquartile range, 131-394] mg·day/L; P<0.001), without significant differences between the anakinra arms. No significant differences were found between anakinra and placebo groups in the interval changes in left ventricular end-systolic volume (median, 1.4 [interquartile range, -9.8 to 9.8] versus -3.9 [interquartile range, -15.4 to 1.4] mL; P=0.21) or left ventricular ejection fraction (median, 3.9% [interquartile range, -1.6% to 10.2%] versus 2.7% [interquartile range, -1.8% to 9.3%]; P=0.61) at 12 months. The incidence of death or new-onset heart failure or of death and hospitalization for heart failure was significantly lower with anakinra versus placebo (9.4% versus 25.7% [P=0.046] and 0% versus 11.4% [P=0.011], respectively), without difference between the anakinra arms. The incidence of serious infection was not different between anakinra and placebo groups (14% versus 14%; P=0.98). Injection site reactions occurred more frequently in patients receiving anakinra (22%) versus placebo (3%; P=0.016). Conclusions In patients presenting with ST-segment-elevation myocardial infarction, interleukin-1 blockade with anakinra significantly reduces the systemic inflammatory response compared with placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01950299.
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Affiliation(s)
- Antonio Abbate
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
- Kenneth and Dianne Wright” Center for Clinical and Translational ResearchMedStar Washington Hospital CenterWashingtonDC
| | - Cory R. Trankle
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Leo F. Buckley
- Department of Pharmacotherapy and Outcomes ScienceMedStar Washington Hospital CenterWashingtonDC
| | - Michael J. Lipinski
- Medstar Heart and Vascular InstituteMedStar Washington Hospital CenterWashingtonDC
| | | | - Dinesh Kadariya
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Justin M. Canada
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Salvatore Carbone
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Charlotte S. Roberts
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Nayef Abouzaki
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Ryan Melchior
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
- Virginia Cardiovascular SpecialistsRichmondVA
| | - Sanah Christopher
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Jeremy Turlington
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - George Mueller
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
- Virginia Cardiovascular SpecialistsRichmondVA
| | | | - Christopher Thomas
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
- Virginia Cardiovascular SpecialistsRichmondVA
| | - Roshanak Markley
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - George F. Wohlford
- Department of Pharmacotherapy and Outcomes ScienceMedStar Washington Hospital CenterWashingtonDC
| | - Laura Puckett
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
- Virginia Cardiovascular SpecialistsRichmondVA
| | - Horacio Medina de Chazal
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Juan G. Chiabrando
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Edoardo Bressi
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Marco Giuseppe Del Buono
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Aaron Schatz
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Chau Vo
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Dave L. Dixon
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
- Department of Pharmacotherapy and Outcomes ScienceMedStar Washington Hospital CenterWashingtonDC
| | - Giuseppe G. Biondi‐Zoccai
- Department of Medico‐Surgical Sciences and BiotechnologiesSapienza’ University of RomeLatinaItaly
- Mediterranea CardiocentroNapoliItaly
| | - Michael C. Kontos
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
| | - Benjamin W. Van Tassell
- Virginia Commonwealth University Pauley Heart CenterMedStar Washington Hospital CenterWashingtonDC
- Department of Pharmacotherapy and Outcomes ScienceMedStar Washington Hospital CenterWashingtonDC
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26
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Kulek AR, Anzell A, Wider JM, Sanderson TH, Przyklenk K. Mitochondrial Quality Control: Role in Cardiac Models of Lethal Ischemia-Reperfusion Injury. Cells 2020; 9:cells9010214. [PMID: 31952189 PMCID: PMC7016592 DOI: 10.3390/cells9010214] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/10/2020] [Accepted: 01/12/2020] [Indexed: 02/07/2023] Open
Abstract
The current standard of care for acute myocardial infarction or 'heart attack' is timely restoration of blood flow to the ischemic region of the heart. While reperfusion is essential for the salvage of ischemic myocardium, re-introduction of blood flow paradoxically kills (rather than rescues) a population of previously ischemic cardiomyocytes-a phenomenon referred to as 'lethal myocardial ischemia-reperfusion (IR) injury'. There is long-standing and exhaustive evidence that mitochondria are at the nexus of lethal IR injury. However, during the past decade, the paradigm of mitochondria as mediators of IR-induced cardiomyocyte death has been expanded to include the highly orchestrated process of mitochondrial quality control. Our aims in this review are to: (1) briefly summarize the current understanding of the pathogenesis of IR injury, and (2) incorporating landmark data from a broad spectrum of models (including immortalized cells, primary cardiomyocytes and intact hearts), provide a critical discussion of the emerging concept that mitochondrial dynamics and mitophagy (the components of mitochondrial quality control) may contribute to the pathogenesis of cardiomyocyte death in the setting of ischemia-reperfusion.
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Affiliation(s)
- Andrew R. Kulek
- Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.R.K.); (A.A.); (T.H.S.)
- Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Anthony Anzell
- Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.R.K.); (A.A.); (T.H.S.)
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Departments of Emergency Medicine and Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
| | - Joseph M. Wider
- Departments of Emergency Medicine and Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
| | - Thomas H. Sanderson
- Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.R.K.); (A.A.); (T.H.S.)
- Departments of Emergency Medicine and Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
| | - Karin Przyklenk
- Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.R.K.); (A.A.); (T.H.S.)
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Correspondence: ; Tel.: +1-313-577-9047
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27
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Gao R, Shi H, Chang S, Gao Y, Li X, Lv C, Yang H, Xiang H, Yang J, Xu L, Tang Y. The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction. Int Immunopharmacol 2019; 74:105575. [PMID: 31299609 DOI: 10.1016/j.intimp.2019.04.022] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 04/08/2019] [Accepted: 04/09/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND/AIMS Early inflammatory responses after myocardial infarction (MI) are likely to increase myocardial fibrosis and subsequent cardiac remodeling. MCC950, a specific NLRP3 inhibitor, was previously found to effectively inhibit the release of inflammatory factors IL-18 and IL-1β. In this study, we evaluated the effect of MCC950, as a potential new treatment strategy for MI, on myocardial fibrosis and cardiac remodeling using an experimental mouse model. METHODS Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and then treated with MCC950 (10 mg/kg) or PBS for 14 days. After 30 days, echocardiography was performed to assess cardiac function and myocardial fibrosis was evaluated using H&E- and Masson's Trichrome-stained sections. Myocardial expression of inflammatory factors and fibrosis markers was analyzed by western blotting, immunofluorescence, ELISA, and real-time quantitative PCR. RESULTS The ejection fraction in the 10 mg/kg group (40.7 ± 4.2%; N = 6, p = 0.0029) was statistically preserved compared to that in the control group (14.0 ± 4.4%). Myocardial fibrosis was also reduced in MCC950-treated animals (MCC950, 23.2 ± 3.0 vs PBS, 36.2 ± 3.7; p < 0.05). Moreover, myocardial NLRP3, cleaved IL-1β, and IL-18 levels were reduced in MCC950-treated animals. H&E and molecular examination revealed decreases in inflammatory cell infiltration and inflammatory factor expression in the heart. In vitro, MCC950 inhibited NLRP3, reduced caspase-1 activity, and further downregulated IL-1β and IL-18. CONCLUSION MCC950, as a specific NLRP3 inhibitor, can alleviate fibrosis and improve cardiac function in a mouse model by suppressing early inflammatory responses post-MI.
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Affiliation(s)
- Rifeng Gao
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi Province, China
| | - Huairui Shi
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Suchi Chang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yang Gao
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao Li
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chunyu Lv
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi Province, China
| | - Heng Yang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi Province, China
| | - Haiyan Xiang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi Province, China
| | - Juesheng Yang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi Province, China
| | - Lei Xu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Yanhua Tang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi Province, China.
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Zhang L, Xu C, Liu J, Bai X, Li R, Wang L, Zhou J, Wu Y, Yuan Z. Baseline plasma fibrinogen is associated with haemoglobin A1c and 2-year major adverse cardiovascular events following percutaneous coronary intervention in patients with acute coronary syndrome: a single-centre, prospective cohort study. Cardiovasc Diabetol 2019; 18:52. [PMID: 31014348 PMCID: PMC6480802 DOI: 10.1186/s12933-019-0858-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Despite revascularisation, a large proportion of acute coronary syndrome (ACS) patients continue to experience major adverse cardiovascular events (MACEs), which are worsened by diabetes mellitus (DM). Fibrinogen (FIB) is a risk factor for MACEs in coronary artery disease and often elevated in DM. However, the relationships between FIB, glucose metabolism (haemoglobin A1c [HbA1c] and fasting blood glucose [FBG]) and MACEs following percutaneous coronary intervention (PCI) in DM, non-DM or whole patients with ACS remains unknown. METHODS A total of 411 ACS patients undergoing PCI were enrolled in this study. We compared baseline FIB levels between DM (n = 103) and non-DM (n = 308) patients and divided participants into three groups according to FIB level, i.e. FIB-L, FIB-M and FIB-H, to compare baseline characteristics and MACEs. Linear regression analysis of the relationship between glucose metabolism and FIB, Cox regression, survival and landmark analyses of MACEs were also performed over a median of 27.55 months of follow-up. RESULTS Patients with DM had higher FIB levels than non-DM patients (3.56 ± 0.99 mg/dL vs. 3.34 ± 0.80 mg/dL, P < 0.05). HbA1c and FBG were significantly positively correlated with FIB in whole and DM patients but not in non-DM patients (all P < 0.05). Compared with the FIB-L group, the FIB-M (hazard ratio [HR] 1.797, 95% CI 1.117-2.892, P = 0.016) and FIB-H (HR 1.664, 95% CI 1.002-2.763, P = 0.049) groups were associated with higher MACEs in whole; the FIB-M (HR 7.783, 95% CI 1.012-59.854, P = 0.049) was associated with higher MACEs in DM patients. FIB was not associated with MACEs in non-DM patients. During landmark analysis, FIB showed better predictive value for MACEs after PCI in the first 30 months of follow up than in the subsequent period. CONCLUSION In this study from China, FIB was positively associated with glucose metabolism (HbA1c and FBG) in whole and DM populations with ACS. Moreover, elevated baseline FIB levels may be an important and independent predictor of MACEs following PCI, especially amongst those with DM. However, as the follow-up period increased, the baseline FIB levels lost their ability to predict MACEs.
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Affiliation(s)
- Lisha Zhang
- Department of Cardiovascular Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, 277 West Yanta Rd., Xi'an, 710061, Shaanxi, People's Republic of China
| | - Chenbo Xu
- Department of Cardiovascular Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, 277 West Yanta Rd., Xi'an, 710061, Shaanxi, People's Republic of China
| | - Junhui Liu
- Department of Clinical Laboratory, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Xiaofang Bai
- Department of Cardiovascular Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, 277 West Yanta Rd., Xi'an, 710061, Shaanxi, People's Republic of China
| | - Ruifeng Li
- Department of Cardiovascular Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, 277 West Yanta Rd., Xi'an, 710061, Shaanxi, People's Republic of China
| | - Lijun Wang
- Department of Cardiovascular Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, 277 West Yanta Rd., Xi'an, 710061, Shaanxi, People's Republic of China
| | - Juan Zhou
- Department of Cardiovascular Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, 277 West Yanta Rd., Xi'an, 710061, Shaanxi, People's Republic of China.,Key Laboratory of Molecular Cardiology, Shaanxi Province, Xi'an, Shaanxi, People's Republic of China
| | - Yue Wu
- Department of Cardiovascular Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, 277 West Yanta Rd., Xi'an, 710061, Shaanxi, People's Republic of China. .,Key Laboratory of Molecular Cardiology, Shaanxi Province, Xi'an, Shaanxi, People's Republic of China.
| | - Zuyi Yuan
- Department of Cardiovascular Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, 277 West Yanta Rd., Xi'an, 710061, Shaanxi, People's Republic of China. .,Key Laboratory of Molecular Cardiology, Shaanxi Province, Xi'an, Shaanxi, People's Republic of China. .,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, People's Republic of China.
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Inhibiting the Inflammatory Injury After Myocardial Ischemia Reperfusion With Plasma-Derived Alpha-1 Antitrypsin: A Post Hoc Analysis of the VCU-α1RT Study. J Cardiovasc Pharmacol 2019; 71:375-379. [PMID: 29634656 DOI: 10.1097/fjc.0000000000000583] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Despite the benefits of reperfusion in limiting myocardial injury, the infarct size continues to expand after reperfusion because of secondary inflammatory injury. Plasma-derived alpha-1 antitrypsin (AAT) inhibits the inflammatory injury in myocardial ischemia and reperfusion. To explore the effects of plasma-derived AAT on the inflammatory response to ischemia-reperfusion injury, we analyzed time-to-reperfusion and enzymatic infarct size estimates in a post hoc analysis of the VCU-α1RT clinical trial (clinicaltrials.gov NCT01936896). METHODS Ten patients with ST-segment elevation acute myocardial infarction (STEMI) were enrolled in an open-label, single-arm treatment study of Prolastin C, plasma-derived AAT, at 60 mg/kg infused intravenously within 12 hours of reperfusion. Biomarkers were measured serially over the first 72 hours, and patients were followed clinically for the occurrence of new-onset heart failure, recurrent MI, or death. Twenty patients with STEMI who had been enrolled in previous randomized trials with identical inclusion/exclusion criteria and had been assigned to placebo served as historical controls. RESULTS Time to percutaneous coronary intervention and time to drug did not significantly differ between groups. AAT-treated patients had a significantly shorter time-to-peak creatine kinase myocardial band (CK-MB) values (525 [480-735] vs. 789 [664-959] minute, P = 0.005) and CK-MB area under the curve (from 1204 [758-2728] vs. 2418 [1551-4289] U·day, P = 0.035), despite no differences in peak CK-MB (123 [30-196] vs. 123 [71-213] U/mL, P = 0.71). CONCLUSIONS A single administration of Prolastin C given hours after reperfusion in patients with STEMI led to a significant shorter time to peak and area under the curve for CK-MB, despite similar peak CK-MB values. These preliminary data support the hypothesis that Prolastin C shortens the duration of the ischemia-reperfusion injury in patients with STEMI.
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Vilahur G, Casaní L, Peña E, Crespo J, Juan-Babot O, Ben-Aicha S, Mendieta G, Béjar MT, Borrell M, Badimon L. Silybum marianum provides cardioprotection and limits adverse remodeling post-myocardial infarction by mitigating oxidative stress and reactive fibrosis. Int J Cardiol 2018; 270:28-35. [PMID: 29936043 DOI: 10.1016/j.ijcard.2018.06.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 05/15/2018] [Accepted: 06/06/2018] [Indexed: 11/25/2022]
Abstract
AIMS Milk thistle (Silybum marianum; SM) is an herb commonly used for hepatoprotection with antioxidant and antifibrotic properties. We investigated in pigs the cardiac effects of SM intake during the acute phase of myocardial infarction (MI) and remodeling period post-MI. METHODS Study-1 tested the effect of SM use on the acute phase of MI. Hence, animals were distributed to a control group or to receive SM prior infarction (1.5 h ischemia). Animals were sacrificed after 2.5 h of reperfusion. Study-2 tested the effect of SM use in the cardiac remodeling phase. Accordingly, animals received for 10 d diet ± SM prior MI and followed the same regime for 3 weeks and then sacrificed. Study-3 tested the effect of SM in a non-infarcted heart; therefore, animals received for 10 d diet ± SM and then sacrificed. RESULTS Animals taking SM before MI showed a reduction in cardiac damage (decreased oxidative damage, ROS production and xanthine oxidase levels; preserved mitochondrial function; and increased myocardial salvage; p < 0.05) versus controls. Animals that remained on chronic SM intake post-MI improved left ventricular remodeling. This was associated with the attenuation of the TGFß1/TßRs/SMAD2/3 signaling, lower myofibroblast transdifferentiation and collagen content in the border zone (p < 0.05 vs. all other groups). Cardiac contractility improved in animals taking SM (p < 0.05 vs. post-MI-control). No changes in cardiac function or fibrosis were detected in animals on SM but without MI. CONCLUSION Intake of SM protects the heart against the deleterious effects of an MI and favors cardiac healing. These benefits may be attributed to the antioxidant and antifibrotic properties of SM.
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Affiliation(s)
- Gemma Vilahur
- Cardiovascular Program - ICCC - IR Hospital Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; CIBERCV, Instituto Salud Carlos III, Spain
| | - Laura Casaní
- Cardiovascular Program - ICCC - IR Hospital Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; CIBERCV, Instituto Salud Carlos III, Spain
| | - Esther Peña
- Cardiovascular Program - ICCC - IR Hospital Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; CIBERCV, Instituto Salud Carlos III, Spain
| | - Javier Crespo
- Cardiovascular Program - ICCC - IR Hospital Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - Oriol Juan-Babot
- Cardiovascular Program - ICCC - IR Hospital Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - Soumaya Ben-Aicha
- Cardiovascular Program - ICCC - IR Hospital Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - Guiomar Mendieta
- Cardiovascular Program - ICCC - IR Hospital Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - Maria Teresa Béjar
- Cardiovascular Program - ICCC - IR Hospital Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - María Borrell
- Cardiovascular Program - ICCC - IR Hospital Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; CIBERCV, Instituto Salud Carlos III, Spain
| | - Lina Badimon
- Cardiovascular Program - ICCC - IR Hospital Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; CIBERCV, Instituto Salud Carlos III, Spain; Cardiovascular Research Chair UAB, Autonomous University of Barcelona, Spain.
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Cao Q, Jiao Y, Yu T, Sun Z. Association between mild thyroid dysfunction and clinical outcome in acute coronary syndrome undergoing percutaneous coronary intervention. Cardiol J 2018; 27:262-271. [PMID: 30234907 DOI: 10.5603/cj.a2018.0097] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 08/31/2018] [Accepted: 08/02/2018] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Thyroid hormones profoundly influence the cardiovascular system, but the effects of mild thyroid dysfunction on the clinical outcome of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) are not well defined. This study aimed to determine the effect of mild thyroid dysfunction on 12-month prognosis in ACS patients undergoing PCI. METHODS In this prospective cohort study with a 12-month follow-up, 1560 individuals were divided into four groups based on thyroid hormone levels upon admission: euthyroidism (used as a reference group), subclinical hypothyroidism, subclinical hyperthyroidism, and low triiodothyronine syndrome (low T3 syndrome). The outcomes measured were all-cause mortality, cardiac mortality, nonfatal rein-farction, and unplanned repeat revascularization. RESULTS In this study, the prevalence of mild thyroid dysfunction was 10.8%. Multivariate analysis showed that low T3 syndrome, but not subclinical hypothyroidism or subclinical hyperthyroidism, was associated with a higher rate of all-cause (HR 2.553, 95% CI 1.093-5.964, p = 0.030) and cardiac mortality (HR 2.594, 95% CI 1.026-6.559, p = 0.034), compared with the euthyroidism group. CONCLUSIONS Mild thyroid dysfunction was frequent in patients with ACS undergoing PCI. Low T3 syndrome was the predominant feature and was associated with 12-month adverse outcomes in these patients.
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Affiliation(s)
- Qian Cao
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, P.R. China, 36 Sanhao Street, Heping District, 86110004
| | - Yundi Jiao
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, P.R. China, 36 Sanhao Street, Heping District, 86110004
| | - Tongtong Yu
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, P.R. China, 36 Sanhao Street, Heping District, 86110004
| | - Zhaoqing Sun
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, P.R. China, 36 Sanhao Street, Heping District, 86110004.
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Yu T, Tian C, Song J, He D, Wu J, Wen Z, Sun Z, Sun Z. Value of the fT3/fT4 ratio and its combination with the GRACE risk score in predicting the prognosis in euthyroid patients with acute myocardial infarction undergoing percutaneous coronary intervention: a prospective cohort study. BMC Cardiovasc Disord 2018; 18:181. [PMID: 30200880 PMCID: PMC6131820 DOI: 10.1186/s12872-018-0916-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 09/03/2018] [Indexed: 12/11/2022] Open
Abstract
Background Thyroid hormones deeply influence the cardiovascular system; however, the association between the fT3/fT4 ratio and the clinical outcome in euthyroid patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) is not well defined. Therefore, the present study aimed to assess the prognostic performance of the fT3/fT4 ratio in predicting the long-term prognosis in euthyroid patients with AMI undergoing PCI. Methods In a prospective cohort study with a 1-year follow-up, according to the clinical end point, 953 euthyroid individuals (61.0 ± 11.6; female, 25.8%) were divided into two groups: (1) the survival group (n = 915) and (2) the death group (n = 38). Results According to Cox regression multivariate analysis, fT4 (HR: 1.249, 95% CI: 1.053–1.480, p = 0.010) and the fT3/fT4 ratio (HR: 3.546, 95% CI: 1.705–7.377, p = 0.001) were associated with an increased risk of 1-year all-cause mortality. The prognostic performance of the fT3/fT4 ratio was similar to the Global Registry of Acute Coronary Events (GRACE) score in predicting 1-year all-cause mortality (C-statistic: z = 0.261, p = 0.794; IDI: -0.017, p = 0.452; NRI: -0.049, p = 0.766), but better than fT4 (C-statistic: z = 2.438, p = 0.015; IDI: 0.053, p = 0.002; NRI: 0.656, p < 0.001). The fT3/fT4 ratio also significantly improved the prognostic performance of the GRACE score (GRACE score vs GRACE score + fT3/fT4 ratio: C-statistic: z = 2.116, p = 0.034; IDI: 0.0415, p = 0.007; NRI: 0.614, p < 0.001). Conclusions In euthyroid patients with AMI undergoing PCI, the fT3/fT4 ratio was an independent predictor of 1-year all-cause mortality. Its prognostic performance was similar to the GRACE score, and also improved its prognostic performance (GRACE score vs GRACE score + fT3/fT4 ratio).
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Affiliation(s)
- Tongtong Yu
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Chunyang Tian
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Jia Song
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Dongxu He
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Jiake Wu
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Zongyu Wen
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Zhijun Sun
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Zhaoqing Sun
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
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Van Tassell BW, Lipinski MJ, Appleton D, Roberts CS, Kontos MC, Abouzaki N, Melchior R, Mueller G, Garnett J, Canada J, Carbone S, Buckley LF, Wohlford G, Kadariya D, Trankle CR, Oddi Erdle C, Sculthorpe R, Puckett L, DeWilde C, Shah K, Angiolillo DJ, Vetrovec G, Biondi‐Zoccai G, Arena R, Abbate A. Rationale and design of the Virginia Commonwealth University-Anakinra Remodeling Trial-3 (VCU-ART3): A randomized, placebo-controlled, double-blinded, multicenter study. Clin Cardiol 2018; 41:1004-1008. [PMID: 30033595 PMCID: PMC6153042 DOI: 10.1002/clc.22988] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 05/25/2018] [Accepted: 05/29/2018] [Indexed: 02/05/2023] Open
Abstract
There is clear association between the intensity of the acute inflammatory response during acute myocardial infarction (AMI) and adverse prognosis after AMI. Interleukin-1 (IL-1) is a pro-inflammatory cytokine released during AMI and involved in adverse remodeling and heart failure (HF). We describe a study to evaluate the safety and efficacy of IL-1 blockade using an IL-1 receptor antagonist (anakinra) during the acute phase of ST-segment elevation myocardial infarction (STEMI). The Virginia Commonwealth University-Anakinra Remodeling Trial-3 (VCU-ART3; http://www.ClinicalTrials.gov NCT01950299) is a phase 2, multicenter, double-blinded, randomized, placebo-controlled clinical trial comparing anakinra 100 mg once or twice daily vs matching placebo (1:1:1) for 14 days in 99 patients with STEMI. Patients who present to the hospital with STEMI within 12 hours of symptom onset will be eligible for enrollment. Patients will be excluded for a history of HF (functional class III-IV), severe valvular disease, severe kidney disease (stage 4-5), active infection, recent use of immunosuppressive drugs, active malignancy, or chronic autoimmune/auto-inflammatory diseases. We will measure the difference in the area under the curve for C-reactive protein between admission and day 14, separately comparing each of the anakinra groups with the placebo group. The P value will be considered significant if <0.025 to adjust for multiple comparisons. Patients will also be followed for up to 12 months from enrollment to evaluate cardiac remodeling (echocardiography), cardiac function (echocardiography), and major adverse cardiovascular outcomes (cardiovascular death, MI, revascularization, and new onset of HF).
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Affiliation(s)
- Benjamin W. Van Tassell
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
- Department of Pharmacotherapy and Outcomes ScienceVirginia Commonwealth UniversityRichmondVirginia
- VCU Johnson Center for Pulmonary and Critical Care ResearchVirginia Commonwealth UniversityRichmondVirginia
| | - Michael J. Lipinski
- Medstar Heart and Vascular InstituteMedStar Washington Hospital CenterWashingtonDistrict of Columbia
| | | | | | - Michael C. Kontos
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
| | - Nayef Abouzaki
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
| | - Ryan Melchior
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
- Virginia Cardiovascular SpecialistsRichmondVirginia
| | - George Mueller
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
- Virginia Cardiovascular SpecialistsRichmondVirginia
| | | | - Justin Canada
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
- Department of Kinesiology and Health SciencesVirginia Commonwealth UniversityRichmondVirginia
| | - Salvatore Carbone
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
| | - Leo F. Buckley
- Department of Pharmacotherapy and Outcomes ScienceVirginia Commonwealth UniversityRichmondVirginia
| | - George Wohlford
- Department of Pharmacotherapy and Outcomes ScienceVirginia Commonwealth UniversityRichmondVirginia
| | - Dinesh Kadariya
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
| | - Cory R. Trankle
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
| | | | - Robin Sculthorpe
- Investigational PharmacyVirginia Commonwealth UniversityRichmondVirginia
| | - Laura Puckett
- VCU Johnson Center for Pulmonary and Critical Care ResearchVirginia Commonwealth UniversityRichmondVirginia
- Virginia Cardiovascular SpecialistsRichmondVirginia
| | - Christine DeWilde
- VCU Johnson Center for Pulmonary and Critical Care ResearchVirginia Commonwealth UniversityRichmondVirginia
| | - Keyur Shah
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
| | | | - George Vetrovec
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
| | - Giuseppe Biondi‐Zoccai
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, and Department of AngioCardioNeurologyIRCCS NeuromedPozzilliItaly
| | - Ross Arena
- Department of Physical Therapy, College of Applied Health SciencesUniversity of Illinois at ChicagoChicagoIllinois
| | - Antonio Abbate
- VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondVirginia
- VCU Johnson Center for Pulmonary and Critical Care ResearchVirginia Commonwealth UniversityRichmondVirginia
- Kenneth and Dianne Wright Center for Clinical and Translational ResearchVirginia Commonwealth UniversityRichmondVirginia
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Rizk FH, Abdel Ghafar MT, Soliman NA, Shaaban AE, Atlam R, Elsaadany A, Eshra KA, Shalaby MM. Vildagliptin Recruits Regulatory T Cells in Patients Undergoing Primary Percutaneous Coronary Intervention. Immunol Invest 2018; 47:583-592. [DOI: 10.1080/08820139.2018.1467927] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Fatma H. Rizk
- Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Nema A. Soliman
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Aliaa E. Shaaban
- Department of Cardiology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ramy Atlam
- Department of Cardiology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Amiraa Elsaadany
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Kareman Ahmed Eshra
- Department of Microbiology, Faculty of Medicine, Tanta University, Tanta, Egypt
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Xu J, Tang Y, Bei Y, Ding S, Che L, Yao J, Wang H, Lv D, Xiao J. miR-19b attenuates H2O2-induced apoptosis in rat H9C2 cardiomyocytes via targeting PTEN. Oncotarget 2017; 7:10870-8. [PMID: 26918829 PMCID: PMC4905445 DOI: 10.18632/oncotarget.7678] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 02/15/2016] [Indexed: 12/21/2022] Open
Abstract
Myocardial ischemia-reperfusion (I-R) injury lacks effective treatments. The miR-17-92 cluster plays important roles in regulating proliferation, apoptosis, cell cycle and other pivotal processes. However, their roles in myocardial I-R injury are largely unknown. In this study, we found that miR-19b was the only member of the miR-17-92 cluster that was downregulated in infarct area of heart samples from a murine model of I-R injury. Meanwhile, downregulation of miR-19b was also detected in H2O2-treated H9C2 cells in vitro mimicking oxidative stress occurring during myocardial I-R injury. Using flow cytometry and Western blot analysis, we found that overexpression of miR-19b decreased H2O2-induced apoptosis and improved cell survival, while downregulation of that had inverse effects. Furthermore, PTEN was negatively regulated by miR-19b at the protein level while silencing PTEN could completely block the aggravated impact of miR-19b inhibitor on H2O2-induced apoptosis in H9C2 cardiomyocytes, indicating PTEN as a downstream target of miR-19b controlling H2O2-induced apoptosis. These data indicate that miR-19b overexpression might be a novel therapy for myocardial I-R injury.
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Affiliation(s)
- Jiahong Xu
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yu Tang
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yihua Bei
- Regeneration and Ageing Laboratory, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai, China
| | - Shengguang Ding
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of NanTong University, Nantong, China
| | - Lin Che
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jianhua Yao
- Department of Cardiology, Shanghai Yangpu District Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongbao Wang
- Department of Cardiology, Shanghai Yangpu District Hospital, Tongji University School of Medicine, Shanghai, China
| | - Dongchao Lv
- Regeneration and Ageing Laboratory, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai, China
| | - Junjie Xiao
- Regeneration and Ageing Laboratory, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai, China
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Abstract
The heart is extremely sensitive to ischaemic injury. During an acute myocardial infarction (AMI) event, the injury is initially caused by reduced blood supply to the tissues, which is then further exacerbated by an intense and highly specific inflammatory response that occurs during reperfusion. Numerous studies have highlighted the central role of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in this process. The inflammasome, an integral part of the innate immune system, is a macromolecular protein complex that finely regulates the activation of caspase 1 and the production and secretion of powerful pro-inflammatory cytokines such as IL-1β and IL-18. In this Review, we summarize evidence supporting the therapeutic value of NLRP3 inflammasome-targeted strategies in experimental models, and the data supporting the role of the NLRP3 inflammasome in AMI and its consequences on adverse cardiac remodelling, cytokine-mediated systolic dysfunction, and heart failure.
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Affiliation(s)
- Stefano Toldo
- Pauley Heart Center, Sanger Hall, 1201 East Marshall Street, Richmond, Virginia 23298, USA.,VCU Johnson Center for Critical Care and Pulmonary Research, Molecular Medicine Research Building, 1220 East Broad Street, Richmond, Virginia 23298, USA.,Division of Cardiothoracic Surgery, Sanger Hall, 1201 East Marshall Street, Richmond, Virginia 23298, USA
| | - Antonio Abbate
- Pauley Heart Center, Sanger Hall, 1201 East Marshall Street, Richmond, Virginia 23298, USA.,VCU Johnson Center for Critical Care and Pulmonary Research, Molecular Medicine Research Building, 1220 East Broad Street, Richmond, Virginia 23298, USA
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Proteomic footprint of myocardial ischemia/reperfusion injury: Longitudinal study of the at-risk and remote regions in the pig model. Sci Rep 2017; 7:12343. [PMID: 28955040 PMCID: PMC5617837 DOI: 10.1038/s41598-017-11985-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 08/25/2017] [Indexed: 12/28/2022] Open
Abstract
Reperfusion alters post-myocardial infarction (MI) healing; however, very few systematic studies report the early molecular changes following ischemia/reperfusion (I/R). Alterations in the remote myocardium have also been neglected, disregarding its contribution to post-MI heart failure (HF) development. This study characterizes protein dynamics and contractile abnormalities in the ischemic and remote myocardium during one week after MI. Closed-chest 40 min I/R was performed in 20 pigs sacrificed at 120 min, 24 hours, 4days, and 7days after reperfusion (n = 5 per group). Myocardial contractility was followed up by cardiac magnetic resonance (CMR) and tissue samples were analyzed by multiplexed quantitative proteomics. At early reperfusion (120 min), the ischemic area showed a coordinated upregulation of inflammatory processes, whereas interstitial proteins, angiogenesis and cardio-renal signaling processes increased at later reperfusion (day 4 and 7). Remote myocardium showed decreased contractility at 120 min- and 24 h-CMR accompanied by transient alterations in contractile and mitochondrial proteins. Subsequent recovery of regional contractility was associated with edema formation on CMR and increases in inflammation and wound healing proteins on post-MI day 7. Our results establish for the first time the altered protein signatures in the ischemic and remote myocardium early after I/R and might have implications for new therapeutic targets to improve early post-MI remodeling.
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Cahill TJ, Kharbanda RK. Heart failure after myocardial infarction in the era of primary percutaneous coronary intervention: Mechanisms, incidence and identification of patients at risk. World J Cardiol 2017; 9:407-415. [PMID: 28603587 PMCID: PMC5442408 DOI: 10.4330/wjc.v9.i5.407] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 01/20/2017] [Accepted: 03/13/2017] [Indexed: 02/06/2023] Open
Abstract
Myocardial infarction (MI) remains the most common cause of heart failure (HF) worldwide. For almost 50 years HF has been recognised as a determinant of adverse prognosis after MI, but efforts to promote myocardial repair have failed to translate into clinical therapies. Primary percutaneous coronary intervention (PPCI) has driven improved early survival after MI, but its impact on the incidence of downstream HF is debated. The effects of PPCI are confounded by the changing epidemiology of MI and HF, with an ageing patient demographic, an increasing proportion of non-ST-elevation myocardial infarction, and the recognition of HF with preserved ejection fraction. Herein we review the mechanisms of HF after MI and discuss contemporary data on its incidence and outcomes. We review current and emerging strategies for early detection of patients at risk of HF after MI, with a view to identification of patient cohorts for novel therapeutic agents.
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Vilahur G, Oñate B, Cubedo J, Béjar MT, Arderiu G, Peña E, Casaní L, Gutiérrez M, Capdevila A, Pons-Lladó G, Carreras F, Hidalgo A, Badimon L. Allogenic adipose-derived stem cell therapy overcomes ischemia-induced microvessel rarefaction in the myocardium: systems biology study. Stem Cell Res Ther 2017; 8:52. [PMID: 28279225 PMCID: PMC5345145 DOI: 10.1186/s13287-017-0509-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 02/10/2017] [Accepted: 02/14/2017] [Indexed: 12/19/2022] Open
Abstract
Background Myocardial microvascular loss after myocardial infarction (MI) remains a therapeutic challenge. Autologous stem cell therapy was considered as an alternative; however, it has shown modest benefits due to the impairing effects of cardiovascular risk factors on stem cells. Allogenic adipose-derived stem cells (ASCs) may overcome such limitations, and because of their low immunogenicity and paracrine potential may be good candidates for cell therapy. In the present study we investigated the effects of allogenic ASCs and their released products on cardiac rarefaction post MI. Methods Pig subcutaneous adipose tissue ASCs were isolated, expanded and GFP-labeled. ASC angiogenic function was assessed by the in-vivo chick chorioallantoic membrane (CAM) model. Pigs underwent MI induction and 7 days after were randomized to receive: allogenic ASCs (intracoronary infusion); conditioned media (CM; intravenous infusion); ASCs + CM; or PBS/placebo (control). Cardiac damage and function were monitored by 3-T cardiac magnetic resonance imaging upon infusion (baseline CMR) and 1 and 3 weeks thereafter. We assessed in the myocardium: microvessel density; angiogenic markers (CD105, CD31, TF, VEGFR2, VEGFR1, vWF, eNOS, CD62); collagen deposition; and reparative fibrosis (TGFβ/TβRII/collagen). Differential proteomics of ASCs and CM was performed to characterize the ASC protein signature. Results CAM indicated a significant ASC proangiogenic capacity. In pigs after MI, only PBS/placebo animals displayed an impaired cardiac function 3 weeks after infusion (p < 0.05 vs baseline). Administration of ASCs + CM significantly enhanced neovessel formation and favored cardiac repair post MI (p < 0.05 vs the other groups). Molecular markers of angiogenesis were significantly upregulated both at transcriptional and protein levels (p < 0.05). The in-silico bioinformatics analysis of the ASC and CM proteome (interactome) indicated activation of a coordinated protein network involved in the formation of microvessels and the resolution of rarefaction. Conclusion Coadministration of allogenic ASCs and their CM synergistically contribute to the neovascularization of the infarcted myocardium through a coordinated upregulation of the proangiogenic protein interactome. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0509-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Gemma Vilahur
- Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain.,CIBERCV, ISCIII, Madrid, Spain
| | - Blanca Oñate
- Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain
| | - Judit Cubedo
- Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain
| | - Maria Teresa Béjar
- Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain
| | - Gemma Arderiu
- Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain
| | - Esther Peña
- Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain.,CIBERCV, ISCIII, Madrid, Spain
| | - Laura Casaní
- Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain.,CIBERCV, ISCIII, Madrid, Spain
| | | | | | | | | | | | - Lina Badimon
- Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain. .,CIBERCV, ISCIII, Madrid, Spain. .,Cardiovascular Research Chair, UAB (Autonomous University of Barcelona), Barcelona, Spain.
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Gombozhapova A, Rogovskaya Y, Shurupov V, Rebenkova M, Kzhyshkowska J, Popov SV, Karpov RS, Ryabov V. Macrophage activation and polarization in post-infarction cardiac remodeling. J Biomed Sci 2017; 24:13. [PMID: 28173864 PMCID: PMC5297120 DOI: 10.1186/s12929-017-0322-3] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 01/31/2017] [Indexed: 02/07/2023] Open
Abstract
Adverse cardiac remodeling leads to impaired ventricular function and heart failure, remaining a major cause of mortality and morbidity in patients with acute myocardial infarction. It have been shown that, even if all the recommended therapies for ST-segment elevation myocardial infarction are performed, one third of patients undergoes progressive cardiac remodeling that represents morphological basis for following heart failure. The need to extend our knowledge about factors leading to different clinical scenarios of myocardial infarction and following complications has resulted in a research of immuno-inflammatory pathways and molecular activities as the basis for post-infarction remodeling. Recently, macrophages (cells of the innate immune system) have become a subject of scientific interest under both normal and pathological conditions. Macrophages, besides their role in host protection and tissue homeostasis, play an important role in pathophysiological processes induced by myocardial infarction. In this article we summarize data about the function of monocytes and macrophages plasticity in myocardial infarction and outline potential role of these cells as effective targets to control processes of inflammation, cardiac remodeling and healing following acute coronary event.
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Affiliation(s)
- Aleksandra Gombozhapova
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 111a Kievskaya Street, 634012, Tomsk, Russian Federation. .,National Research Tomsk State University, 36 Lenin Avenue, 634050, Tomsk, Russian Federation.
| | - Yuliya Rogovskaya
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 111a Kievskaya Street, 634012, Tomsk, Russian Federation.,National Research Tomsk State University, 36 Lenin Avenue, 634050, Tomsk, Russian Federation
| | - Vladimir Shurupov
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 111a Kievskaya Street, 634012, Tomsk, Russian Federation
| | - Mariya Rebenkova
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 111a Kievskaya Street, 634012, Tomsk, Russian Federation.,National Research Tomsk State University, 36 Lenin Avenue, 634050, Tomsk, Russian Federation
| | - Julia Kzhyshkowska
- National Research Tomsk State University, 36 Lenin Avenue, 634050, Tomsk, Russian Federation.,University of Heidelberg, 1-3 Theodor-Kutzer Ufer, 68167, Mannheim, Germany
| | - Sergey V Popov
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 111a Kievskaya Street, 634012, Tomsk, Russian Federation
| | - Rostislav S Karpov
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 111a Kievskaya Street, 634012, Tomsk, Russian Federation.,Siberian State Medical University, 2 Moscovsky trakt, 634055, Tomsk, Russian Federation
| | - Vyacheslav Ryabov
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 111a Kievskaya Street, 634012, Tomsk, Russian Federation.,National Research Tomsk State University, 36 Lenin Avenue, 634050, Tomsk, Russian Federation.,Siberian State Medical University, 2 Moscovsky trakt, 634055, Tomsk, Russian Federation
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41
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Chen J, Yu L, Zhang S, Chen X. Network Analysis-Based Approach for Exploring the Potential Diagnostic Biomarkers of Acute Myocardial Infarction. Front Physiol 2016; 7:615. [PMID: 28018242 PMCID: PMC5145872 DOI: 10.3389/fphys.2016.00615] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 11/24/2016] [Indexed: 02/05/2023] Open
Abstract
Acute myocardial infarction (AMI) is a severe cardiovascular disease that is a serious threat to human life. However, the specific diagnostic biomarkers have not been fully clarified and candidate regulatory targets for AMI have not been identified. In order to explore the potential diagnostic biomarkers and possible regulatory targets of AMI, we used a network analysis-based approach to analyze microarray expression profiling of peripheral blood in patients with AMI. The significant differentially-expressed genes (DEGs) were screened by Limma and constructed a gene function regulatory network (GO-Tree) to obtain the inherent affiliation of significant function terms. The pathway action network was constructed, and the signal transfer relationship between pathway terms was mined in order to investigate the impact of core pathway terms in AMI. Subsequently, constructed the transcription regulatory network of DEGs. Weighted gene co-expression network analysis (WGCNA) was employed to identify significantly altered gene modules and hub genes in two groups. Subsequently, the transcription regulation network of DEGs was constructed. We found that specific gene modules may provide a better insight into the potential diagnostic biomarkers of AMI. Our findings revealed and verified that NCF4, AQP9, NFIL3, DYSF, GZMA, TBX21, PRF1 and PTGDR genes by RT-qPCR. TBX21 and PRF1 may be potential candidates for diagnostic biomarker and possible regulatory targets in AMI.
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Affiliation(s)
- Jiaqi Chen
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University Changchun, China
| | - Ling Yu
- Department of Pharmacy, The Second Hospital of Jilin University Changchun, China
| | - Siwei Zhang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University Changchun, China
| | - Xia Chen
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University Changchun, China
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42
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Li X, Liu M, Sun R, Zeng Y, Chen S, Zhang P. Protective approaches against myocardial ischemia reperfusion injury. Exp Ther Med 2016; 12:3823-3829. [PMID: 28101167 PMCID: PMC5228114 DOI: 10.3892/etm.2016.3877] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 09/16/2016] [Indexed: 01/04/2023] Open
Abstract
Myocardial ischemia-reperfusion is the leading cause for the events of cardiovascular disease, and is considered as a major contributor to the morbidity and mortality associated with coronary occlusion. The myocardial damage caused by ischemia-reperfusion injury constitutes the primary pathological manifestation of coronary artery disease. It results from the interaction between the substances that accumulate during ischemia and those that are delivered on reperfusion. The level of this damage can range from a small insult resulting in limited myocardial damage to a large injury culminating in myocyte death. Importantly, major ischemia-reperfusion injury to the heart can result in permanent disability or death. Given the worldwide prevalence of coronary artery disease, developing a strategy to provide cardioprotection against ischemia-reperfusion-induced damage is of great importance. Currently, the treatment of reperfusion injury following ischemia is primarily supportive, since no specific target-oriented therapy has been validated thus far. Nevertheless, therapeutic approaches to protect against myocardial ischemia-reperfusion injury remain an active area of investigation given the detrimental effects of this phenomenon.
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Affiliation(s)
- Xianchi Li
- Department of Cardiology, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
| | - Min Liu
- Department of Cardiology, Xuzhou Clinical School of Xuzhou Medical College, Xuzhou, Jiangsu 221009, P.R. China
| | - Rongrong Sun
- Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Yi Zeng
- Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Shuang Chen
- Department of Cardiology, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
| | - Peiying Zhang
- Department of Cardiology, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
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43
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Trankle C, Thurber CJ, Toldo S, Abbate A. Mitochondrial Membrane Permeability Inhibitors in Acute Myocardial Infarction: Still Awaiting Translation. ACTA ACUST UNITED AC 2016; 1:524-535. [PMID: 30167535 PMCID: PMC6113419 DOI: 10.1016/j.jacbts.2016.06.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 06/27/2016] [Accepted: 06/27/2016] [Indexed: 12/22/2022]
Abstract
Despite therapeutic advances, acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. One potential limitation of the current treatment paradigm is the lack of effective therapies to optimize reperfusion after ischemia and prevent reperfusion-mediated injury. Experimental studies indicate that this process accounts for up to 50% of the final infarct size, lending it importance as a potential target for cardioprotection. However, multiple therapeutic approaches have shown potential in pre-clinical and early phase trials but a paucity of clear clinical benefit when expanded to larger studies. Here we explore this history of trials and errors of the studies of cyclosporine A and other mitochondrial membrane permeability inhibitors, agents that appeared to have a promising pre-clinical record yet provided disappointing results in phase III clinical trials.
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Affiliation(s)
- Cory Trankle
- Division of Cardiology, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia
| | - Clinton J Thurber
- Division of Cardiology, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia
| | - Stefano Toldo
- Division of Cardiology, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.,Division of Cardiac Surgery, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia
| | - Antonio Abbate
- Division of Cardiology, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.,Johnson Research Center for Critical Care, Virginia Commonwealth University, Richmond, Virginia.,Department of Medical and Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Rome, Italy
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44
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Rossello X, Yellon DM. A critical review on the translational journey of cardioprotective therapies! Int J Cardiol 2016; 220:176-84. [DOI: 10.1016/j.ijcard.2016.06.131] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 06/03/2016] [Accepted: 06/23/2016] [Indexed: 01/08/2023]
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45
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Impact of Nonalcoholic Fatty Liver Disease on Myocardial Perfusion in Nondiabetic Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction. Am J Cardiol 2015; 116:1810-4. [PMID: 26506122 DOI: 10.1016/j.amjcard.2015.09.021] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 09/19/2015] [Accepted: 09/19/2015] [Indexed: 12/13/2022]
Abstract
Limited data exist on the role of nonalcoholic fatty liver disease (FLD) as a potential independent risk factor in the setting of acute coronary syndromes. The aim of this study was to evaluate the impact of FLD on myocardial perfusion and inhospital major adverse cardiac events (MACE) in the setting of ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). We examined 186 consecutive nondiabetic patients (mean age 58 ± 11 years and 76% men) who underwent primary PCI for STEMI by ultrasound within 72 hours of admission. FLD was graded according to a semiquantitative severity score as mild (score <3) or moderate to severe (score ≥3). Myocardial perfusion was determined by measuring myocardial blush grade (MBG) and ST-segment resolution (STR) analysis. Patients were divided into 2 groups according to FLD score (<3 or ≥3). There were no differences with regard to postprocedural Thrombolysis In Myocardial Infarction 3 flow grade between the 2 groups (89% vs 83%, p = 0.201). Patients with FLD score ≥3 were more likely to have absent myocardial perfusion (MBG 0/1, 37% vs 12%, p <0.0001), absent STR (27% vs 9%, p = 0.001), and higher inhospital MACE rate (31% vs 8%, p <0.0001). By multivariate analysis, FLD ≥3 score was found to be an independent predictor of absent MBG 0/1 (odds ratio [OR] 2.856, 95% confidence interval [CI] 1.214 to 6.225, p = 0.033), absent STR (OR 2.862, 95% CI 1.242 to 6.342, p = 0.031), and inhospital MACE (OR 2.454, 95% CI 1.072 to 4.872, p = 0.048). In conclusion, we found that despite similar high rates of Thrombolysis In Myocardial Infarction 3 after primary PCI, patients with FLD score ≥3 are more likely to have impaired myocardial perfusion which may contribute to adverse inhospital outcome.
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46
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Gaspar A, Pereira MÁ, Azevedo P, Lourenço A, Marques J, Leite-Moreira A. Remote ischemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI): study protocol for a randomized controlled trial. Trials 2015; 16:398. [PMID: 26350480 PMCID: PMC4563839 DOI: 10.1186/s13063-015-0937-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 09/01/2015] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND ST-elevation myocardial infarction (STEMI) accounts for nearly one third of acute coronary syndromes. Despite improved STEMI patient care, mortality remains high, contributing significantly to the ischemic heart disease burden. This may partly be related to ischemia-reperfusion injury (IRI). Remote ischemic conditioning (RIC), through short cycles of ischemia-reperfusion applied to a limb, has been shown to reduce IRI in various clinical settings. Our primary hypothesis is that RIC will reduce adverse events related to STEMI when applied as adjunctive therapy to primary percutaneous coronary intervention (PCI). METHODS/DESIGN "Remote ischemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty" (RIC-STEMI) is an ongoing prospective, single-center, open-label, randomized controlled trial to assess whether RIC as an adjunctive therapy during primary PCI in patients presenting with STEMI can improve clinical outcomes. After enrollment, participants are randomized according to a computer-generated randomization schedule, in a ratio of 1:1 to RIC or no intervention, in blocks of four individuals. RIC is begun at least 10 min before the estimated time of the first balloon inflation and its duration is 30 min. Ischemia is induced by three cycles of inflation of a blood pressure cuff placed on the left lower limb to 200 mmHg and then deflation to 0 mmHg for another 5 min. Primary endpoint is a combined endpoint of death from cardiac cause or hospitalization for heart failure (HF) on follow-up (including device implantation: implantable cardioverter defibrillator, cardiac resynchronization and left ventricular assist device). Secondary endpoints are myocardial infarction (MI) size (estimated by the 48 h area under the curve of serum troponin I levels), development of Q-wave MI, left ventricular function (assessed by echocardiography within the first 3 days after admission), contrast-induced nephropathy, in-hospital mortality, all-cause mortality and, finally, major adverse cardiovascular events. Patients will have a minimum follow-up period of 12 months. From 11 March 2013 to 31 December 2014, 324 patients have been enrolled and randomized. We expect to complete enrollment of the 494 patients deemed necessary within 3 years. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02313961; registered on 8 December 2014.
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Affiliation(s)
- António Gaspar
- Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. .,Cardiology Department, Hospital of Braga, Braga, Portugal.
| | | | - Pedro Azevedo
- Cardiology Department, Hospital of Braga, Braga, Portugal.
| | - André Lourenço
- Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. .,Department of Cardiothoracic Surgery, Hospital of S. João, Porto, Portugal.
| | - Jorge Marques
- Cardiology Department, Hospital of Braga, Braga, Portugal.
| | - Adelino Leite-Moreira
- Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. .,Department of Cardiothoracic Surgery, Hospital of S. João, Porto, Portugal.
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47
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Ibáñez B, Heusch G, Ovize M, Van de Werf F. Evolving Therapies for Myocardial Ischemia/Reperfusion Injury. J Am Coll Cardiol 2015; 65:1454-71. [DOI: 10.1016/j.jacc.2015.02.032] [Citation(s) in RCA: 527] [Impact Index Per Article: 52.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 02/22/2015] [Indexed: 12/28/2022]
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48
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Seropian IM, Sonnino C, Van Tassell BW, Biasucci LM, Abbate A. Inflammatory markers in ST-elevation acute myocardial infarction. EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE 2015; 5:382-95. [PMID: 25681486 DOI: 10.1177/2048872615568965] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 01/02/2015] [Indexed: 01/05/2023]
Abstract
After acute myocardial infarction, ventricular remodeling is characterized by changes at the molecular, structural, geometrical and functional level that determine progression to heart failure. Inflammation plays a key role in wound healing and scar formation, affecting ventricular remodeling. Several, rather different, components of the inflammatory response were studied as biomarkers in ST-elevation acute myocardial infarction. Widely available and inexpensive tests, such as leukocyte count at admission, as well as more sophisticated immunoassays provide powerful predictors of adverse outcome in patients with ST-elevation acute myocardial infarction. We review the value of inflammatory markers in ST-elevation acute myocardial infarction and their association with ventricular remodeling, heart failure and sudden death. In conclusion, the use of these biomarkers may identify subjects at greater risk of adverse events and perhaps provide an insight into the mechanisms of disease progression.
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Affiliation(s)
- Ignacio M Seropian
- Interventional Cardiology Department, Hospital Italiano de Buenos Aires, Argentina
| | - Chiara Sonnino
- VCU Pauley Heart Center, Virginia Commonwealth University, USA Victoria Johnson Research Laboratory, Virginia Commonwealth University, USA Department of Cardiovascular Medicine, Catholic University, Italy
| | - Benjamin W Van Tassell
- VCU Pauley Heart Center, Virginia Commonwealth University, USA Victoria Johnson Research Laboratory, Virginia Commonwealth University, USA School of Pharmacy, Virginia Commonwealth University, USA
| | - Luigi M Biasucci
- Department of Cardiovascular Medicine, Catholic University, Italy
| | - Antonio Abbate
- VCU Pauley Heart Center, Virginia Commonwealth University, USA Victoria Johnson Research Laboratory, Virginia Commonwealth University, USA
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49
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Abbate A, Kontos MC, Abouzaki NA, Melchior RD, Thomas C, Van Tassell BW, Oddi C, Carbone S, Trankle CR, Roberts CS, Mueller GH, Gambill ML, Christopher S, Markley R, Vetrovec GW, Dinarello CA, Biondi-Zoccai G. Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies). Am J Cardiol 2015; 115:288-292. [PMID: 25482680 DOI: 10.1016/j.amjcard.2014.11.003] [Citation(s) in RCA: 126] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Revised: 11/03/2014] [Accepted: 11/03/2014] [Indexed: 02/08/2023]
Abstract
Two pilot studies of interleukin-1 (IL-1) blockade in ST-segment elevation myocardial infarction (STEMI) showed blunted acute inflammatory response and overall favorable outcomes at 3 months follow-up. We hereby present a patient-level pooled analysis with extended follow-up of 40 patients with clinically stable STEMI randomized to anakinra, a recombinant IL-1 receptor antagonist, 100 mg/day for 14 days or placebo in a double-blinded fashion. End points included death, cardiac death, recurrent acute myocardial infarction (AMI), stroke, unstable angina, and symptomatic heart failure. Median follow-up was 28 (interquartile range 3 to 38) months. Sixteen patients (40%) had a total of 22 adverse cardiovascular events: 1 cardiac death, 4 recurrent AMI, 5 episodes of unstable angina pectoris requiring hospitalization and/or urgent revascularization, and 11 new diagnoses of heart failure. Treatment with anakinra was associated with a hazard ratio of 1.08 (95% confidence interval 0.31 to 3.74, p = 0.90) for the combined end point of death, recurrent AMI, unstable angina pectoris, or stroke and a hazard ratio of 0.16 (95% confidence interval 0.03 to 0.76, p = 0.008) for death or heart failure. In conclusion, IL-1 blockade with anakinra for 2 weeks appears, therefore, to have a neutral effect on recurrent ischemic events, whereas it may prevent new-onset heart failure long term after STEMI.
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Affiliation(s)
- Antonio Abbate
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia.
| | - Michael Christopher Kontos
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Nayef Antar Abouzaki
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Ryan David Melchior
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Christopher Thomas
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Benjamin Wallace Van Tassell
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Claudia Oddi
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Salvatore Carbone
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Cory Ross Trankle
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Charlotte Susan Roberts
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - George Herman Mueller
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Michael Lucas Gambill
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Sanah Christopher
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - Roshanak Markley
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | - George Wayne Vetrovec
- VCU Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia
| | | | - Giuseppe Biondi-Zoccai
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Latina, Italy
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Fernández-Jiménez R, Ibanez B. Health and cost benefits associated with the use of metoprolol in heart attack patients. Expert Rev Clin Pharmacol 2014; 7:687-9. [PMID: 25231274 DOI: 10.1586/17512433.2014.960847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Heart attack (myocardial infarction) is a highly prevalent entity worldwide. Widespread implementation of reperfusion strategies has dramatically reduced the mortality associated with infarction. Paradoxically, the mortality reduction has significantly increased the incidence of chronic heart failure (HF). Treatment of HF, once present, represents a huge socioeconomic burden on individuals and healthcare systems. The possibility of preventing rather than treating post-infarction HF would be of paramount importance. Given that infarct size is the main determinant of adverse post-infarction outcomes (including chronic HF), therapies able to reduce infarct size are needed. The single administration of intravenous metoprolol before reperfusion has been recently shown to reduce infarct size and reduce the cases of chronic HF in a proof-of-concept trial. If confirmed in larger trials, this low-cost therapy is expected to have a major health and socioeconomic impact.
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Affiliation(s)
- Rodrigo Fernández-Jiménez
- Department of "Atherothrombosis, Imaging and Epidemiology", Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3. 28029, Madrid, Spain
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