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Gonçalves PR, Nascimento LD, Gerlach RF, Rodrigues KE, Prado AF. Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure. Pharmaceuticals (Basel) 2022; 15:ph15080920. [PMID: 35893744 PMCID: PMC9331741 DOI: 10.3390/ph15080920] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/11/2022] [Accepted: 07/11/2022] [Indexed: 12/18/2022] Open
Abstract
Heart failure (HF) is an acute or chronic clinical syndrome that results in a decrease in cardiac output and an increase in intracardiac pressure at rest or upon exertion. The pathophysiology of HF is heterogeneous and results from an initial harmful event in the heart that promotes neurohormonal changes such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, and inflammation. Cardiac remodeling occurs, which is associated with degradation and disorganized synthesis of extracellular matrix (ECM) components that are controlled by ECM metalloproteinases (MMPs). MMP-2 is part of this group of proteases, which are classified as gelatinases and are constituents of the heart. MMP-2 is considered a biomarker of patients with HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). The role of MMP-2 in the development of cardiac injury and dysfunction has clearly been demonstrated in animal models of cardiac ischemia, transgenic models that overexpress MMP-2, and knockout models for this protease. New research to minimize cardiac structural and functional alterations using non-selective and selective inhibitors for MMP-2 demonstrates that this protease could be used as a possible pharmacological target in the treatment of HF.
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Affiliation(s)
- Pricila Rodrigues Gonçalves
- Cardiovascular System Pharmacology and Toxicology Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil; (P.R.G.); (L.D.N.); (K.E.R.)
| | - Lisandra Duarte Nascimento
- Cardiovascular System Pharmacology and Toxicology Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil; (P.R.G.); (L.D.N.); (K.E.R.)
| | - Raquel Fernanda Gerlach
- Department of Basic and Oral Biology, Faculty of Dentistry of Ribeirao Preto, University of Sao Paulo (FORP/USP), Ribeirao Preto 14040-904, SP, Brazil;
| | - Keuri Eleutério Rodrigues
- Cardiovascular System Pharmacology and Toxicology Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil; (P.R.G.); (L.D.N.); (K.E.R.)
| | - Alejandro Ferraz Prado
- Cardiovascular System Pharmacology and Toxicology Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil; (P.R.G.); (L.D.N.); (K.E.R.)
- Correspondence:
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Relationships between sodium levels, haemodynamics and metalloproteinases in heart failure patients. Heart Vessels 2022; 37:986-993. [PMID: 35031882 DOI: 10.1007/s00380-021-02004-9] [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: 05/27/2021] [Accepted: 12/03/2021] [Indexed: 11/04/2022]
Abstract
To estimate the associations between dysnatraemia and inflammatory marker [including interleukin-6 (IL-6)], and tissue remodelling marker [matrix metalloproteinase (MMP)-9 and tissue inhibitor of MMP (TIMP)-1], the pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (PAP), and left ventricular end-diastolic pressure (EDP), and the prognostic relevance in patients with heart failure. The serum sodium level and circulating levels of IL-6, MMP-9, and TIMP-1 were measured in 173 heart failure patients. Dual heart catheterisation was performed to measure PCWP, mean PAP, and EDP. All-cause mortality was assessed during the follow-up period (mean 88 ± 49 months). Restricted cubic spline (RCS) regression showed a U-shaped association of serum sodium level with TIMP-1, with the lowest values in the 138-140 mmol/L range (P for effect = 0.042, P for non-linearity = 0.017). IL-6 and MMP-9 levels showed non-significant associations with serum sodium level. U-shaped associations of serum sodium level with PCWP (P for effect = 0.004, P for non-linearity = 0.001) and mean PAP (P for effect = 0.042, P for non-linearity = 0.017) were found with the RCS regression model. The random forest model revealed that TIMP-1, MMP-9, and IL-6 were important predictors for serum sodium levels. Restricted cubic spline Cox regressions demonstrated that TIMP-1 levels indicated a U-shaped, concaved, non-linear association with all-cause mortality (P for effect = 0.011, P for non-linearity = 0.022). Dysnatraemia is an index of TIMP-1 aggravation and elevated PCWP, mean PAP; hence, it is associated with worsening all-cause mortality.Clinical Trial Registration: UMIN000023840.
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Milajerdi A, Bagheri F, Mousavi SM, Hassanzadeh Keshteli A, Saneei P, Esmaillzadeh A, Adibi P. Breakfast skipping and prevalence of heartburn syndrome among Iranian adults. Eat Weight Disord 2021; 26:2173-2181. [PMID: 33184767 DOI: 10.1007/s40519-020-01065-5] [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: 03/14/2020] [Accepted: 10/23/2020] [Indexed: 11/28/2022] Open
Abstract
PURPOSE Limited data are available linking breakfast consumption to Heart Burn Syndrome (HBS). This study was done to investigate to find whether breakfast consumption is associated with HBS. This cross-sectional study was done to investigate the association between breakfast consumption and HBS among Iranian adults. METHODS This cross-sectional study was performed among 4763 general adults of Isfahan, Iran. Participants' patterns of breakfast eating were assessed by asking two questions from them. How often do you eat breakfast in a week?" Participants were able to respond as: "never or 1 day/wk", "2-4 days/wk", "5-6 days/wk", "every day". HBS was defined as the presence of HBS at sometimes, often or always using a Persian version of validated self-administered modified ROME III questionnaire. RESULTS Totally, 4763 patients with HBS completed this cross-sectional study, where about 32.4% of them intake breakfast less than one time per week. After controlling for potential confounders, participants who consumed breakfast every day had a 43% lower risk for having HBS as compared with those who had breakfast ≤ 1 times/wk (OR 0.57; 95% CI 0.41-0.80). A significant inverse relationship was found between breakfast consumption and frequent than scare HBS (OR 0.57; 95% CI 0.40-0.77) among the whole population, not in patients with HBS. No significant association was observed between breakfast intake and severity of HBS (OR 0.56; 95% CI 0.31-1.04). CONCLUSION We found an inverse association between frequency of breakfast consumption and odds of HBS as well as the frequency of HBS among the adult population. Prospective studies are required to confirm these findings. LEVEL OF EVIDENCE Level V, cross-sectional descriptive study.
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Affiliation(s)
- Alireza Milajerdi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Fariba Bagheri
- Department of Community Nutrition, School of Nutrition and Food Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyed Mohammad Mousavi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Ammar Hassanzadeh Keshteli
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.,Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parvane Saneei
- Department of Community Nutrition, School of Nutrition and Food Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.,Students' Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ahmad Esmaillzadeh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran. .,Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. .,Food Security Research Center, Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Peyman Adibi
- Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Gresele P, Falcinelli E, Momi S, Petito E, Sebastiano M. Platelets and Matrix Metalloproteinases: A Bidirectional Interaction with Multiple Pathophysiologic Implications. Hamostaseologie 2021; 41:136-145. [PMID: 33860521 DOI: 10.1055/a-1393-8339] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Platelets contain and release several matrix metalloproteinases (MMPs), a highly conserved protein family with multiple functions in organism defense and repair. Platelet-released MMPs as well as MMPs generated by other cells within the cardiovascular system modulate platelet function in health and disease. In particular, a normal hemostatic platelet response to vessel wall injury may be transformed into pathological thrombus formation by platelet-released and/or by locally generated MMPs. However, it is becoming increasingly clear that platelets play a role not only in hemostasis but also in immune response, inflammation and allergy, atherosclerosis, and cancer development, and MMPs seem to contribute importantly to this role. A deeper understanding of these mechanisms may open the way to novel therapeutic approaches to the inhibition of their pathogenic effects and lead to significant advances in the treatment of cardiovascular, inflammatory, and neoplastic disorders.
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Affiliation(s)
- P Gresele
- Department of Medicine and Surgery, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
| | - E Falcinelli
- Department of Medicine and Surgery, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
| | - S Momi
- Department of Medicine and Surgery, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
| | - E Petito
- Department of Medicine and Surgery, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
| | - M Sebastiano
- Department of Medicine and Surgery, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy
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Morishita T, Uzui H, Sato Y, Mitsuke Y, Tada H. Associations between cachexia and metalloproteinases, haemodynamics and mortality in heart failure. Eur J Clin Invest 2021; 51:e13426. [PMID: 33111322 DOI: 10.1111/eci.13426] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/28/2020] [Accepted: 09/29/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Addressing cachexia in chronic heart failure (CHF) patients is an urgent issue in Japan, the most aged country in the world. We investigated the possible relationships between cachexia and, metalloproteinases and haemodynamics assessed by the cardiac catheterization. We also clarified the prognostic value of cardiac cachexia in the Japanese CHF population. METHODS AND RESULTS A total of 370 participants (median age, 69 years; 35% women) were included. The haemodynamic effects of cachexia were analysed by right heart catheterization. The serum levels of matrix metalloproteinase (MMP) and tissue inhibitors of MMP (TIMP), as myocardial collagen turnover markers, were also assessed. Cachexia was present in 88 patients (31%). Overall, 59 patients (16%) had all-cause death. Serum MMP-2 and TIMP-2 levels were higher in cachectic patients than in noncachectic patients (797.5 [649.0-1066.8] vs 610.0 [461.8-756.8] ng/mL; P = .004 and 39.0 [28.0-49.0] vs 24.0 [19.0-37.0] ng/mL; P = .008, respectively). Cachectic patients had greater values of pulmonary vascular resistance (PVR) (161.9 [119.4-225.4] vs 127.8 [90.7-164.8] dynes/sec/cm-5 , P = .020). Kaplan-Meier survival analysis demonstrated higher probabilities of all-cause death in the cachexia group (log-rank P = .010). Cox proportional hazards modelling showed cachexia was an independent predictor of mortality (hazard ratio, 1.89; 95% confidence interval, 1.06-3.37; P = .029). The random forest model showed that C-reactive protein, age, haemoglobin, PVR and MMP-2 were predictors of cardiac cachexia. CONCLUSIONS Cachexia, applying the globally accepted definition, was associated with adverse outcomes in the Japanese CHF population and accompanied by increased activity of MMP species and PVR.
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Affiliation(s)
- Tetsuji Morishita
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Japan.,Department Cardiovascular Medicine, National Hospital Organization Awara Hospital, Awara City, Japan
| | - Hiroyasu Uzui
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Japan
| | - Yusuke Sato
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Japan
| | - Yasuhiko Mitsuke
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Japan.,Department Cardiovascular Medicine, National Hospital Organization Awara Hospital, Awara City, Japan
| | - Hiroshi Tada
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Japan
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Li Y, Qin L, Bai Q, Zhang J, Chen R, Song K. CD100 modulates cytotoxicity of CD8 + T cells in patients with acute myocardial infarction. BMC Immunol 2021; 22:13. [PMID: 33593275 PMCID: PMC7888114 DOI: 10.1186/s12865-021-00406-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/03/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND CD100 is an immune semaphorin family member that highly expressed on T cells, which take part in the development of acute myocardial infarction (AMI). Matrix metalloproteinases (MMPs) are important mediators for membrane-bound CD100 (mCD100) shedding from T cells to generate soluble CD100 (sCD100), which has immunoregulatory effect on T cells. The aim of this study was to investigate modulatory role of CD100 on CD8+ T cell activity in AMI patients. METHODS Peripheral sCD100 and MMP-2 level, as well as mCD100 level on T cells was assessed in patients with stable angina pectoris (SAP), unstable angina pectoris (UAP), and AMI. The regulatory function of MMP-2 on mCD100 shedding, sCD100 formation, and cytotoxicity of CD8+ T cells was analyzed in direct and indirect contact co-culture system. RESULTS AMI patients had higher peripheral sCD100 and lower mCD100 expression on CD8+ T cells in comparison with SAP, UAP, and controls. CD8+ T cells in AMI patients showed elevated direct cytotoxicity, enhanced cytokine production, and increased perforin/granzyme B secretion. Recombinant sCD100 stimulation promoted cytolytic function of CD8+ T cells in controls and AMI patients. Furthermore, AMI patients also had elevated circulating MMP-2 level. Recombinant MMP-2 stimulation induced mCD100 shedding from CD8+ T cells and sCD100 generation, resulting in enhancement of CD8+ T cell cytotoxicity in AMI patients. CONCLUSION Up-regulation of MMP-2 might contribute to elevation of mCD100 shedding and sCD100 formation, leading to increased cytotoxicity CD8+ T cells in AMI patients.
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Affiliation(s)
- Yan Li
- Department of Cardiovascular Medicine Ward II, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 16 North Tongbai Road, Zhongyuan District, Zhengzhou, 450000, Henan Province, China
| | - Li Qin
- Department of Cardiovascular Medicine Ward II, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 16 North Tongbai Road, Zhongyuan District, Zhengzhou, 450000, Henan Province, China
| | - Qijun Bai
- Department of Cardiovascular Medicine Ward II, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 16 North Tongbai Road, Zhongyuan District, Zhengzhou, 450000, Henan Province, China
| | - Jingjing Zhang
- Department of Cardiovascular Medicine Ward II, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 16 North Tongbai Road, Zhongyuan District, Zhengzhou, 450000, Henan Province, China
| | - Ruixue Chen
- Department of Cardiovascular Medicine Ward II, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 16 North Tongbai Road, Zhongyuan District, Zhengzhou, 450000, Henan Province, China
| | - Kunpeng Song
- Department of Cardiovascular Medicine Ward II, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 16 North Tongbai Road, Zhongyuan District, Zhengzhou, 450000, Henan Province, China.
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Shirakawa T, Fujisue K, Nakamura S, Yamamoto N, Oshima S, Matsumura T, Tsunoda R, Hirai N, Koide S, Tayama S, Kikuta K, Hirose T, Maruyama H, Fujimoto K, Kajiwara I, Sakamoto T, Nakao K, Sakaino N, Nagayoshi Y, Hokamaki J, Shimomura H, Sakamoto K, Yamamoto E, Izumiya Y, Kaikita K, Hokimoto S, Ogawa H, Tsujita K. Dose-Dependent Inhibitory Effect of Rosuvastatin in Japanese Patients with Acute Myocardial Infarction on Serum Concentration of Matrix Metalloproteinases-INVITATION Trial. J Atheroscler Thromb 2021; 29:229-241. [PMID: 33408315 PMCID: PMC8803556 DOI: 10.5551/jat.59477] [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] [Indexed: 12/02/2022] Open
Abstract
Aim:
Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI.
Methods:
This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment.
Results:
Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [−52.8–60.1]% vs. 70.1 [−14.5–214.2]%,
P
=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period.
Conclusions:
This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.
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Affiliation(s)
- Takuhiro Shirakawa
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University.,Department of Cardiovascular Medicine, Fukuoka Tokushukai Medical Center
| | - Koichiro Fujisue
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University
| | - Shinichi Nakamura
- Division of Cardiology, Japan Community Health care Organization Hitoyoshi Medical Center
| | | | | | - Toshiyuki Matsumura
- Division of Cardiology, Japan Labor Health and Welfare Organization Kumamoto Rosai Hospital
| | - Ryusuke Tsunoda
- Division of Cardiology, Japanese Red Cross Kumamoto Hospital
| | - Nobutaka Hirai
- Division of Cardiology, Kumamoto Regional Medical Center
| | - Shunichi Koide
- Division of Cardiology, Health Insurance Kumamoto General Hospital
| | - Shinji Tayama
- Division of Cardiology, Health Insurance Kumamoto General Hospital
| | | | - Toyoki Hirose
- Division of Cardiology, Minamata City General Hospital & Medical Center
| | - Hideki Maruyama
- Division of Cardiology, Minamata City General Hospital & Medical Center
| | - Kazuteru Fujimoto
- Department of Cardiology, National Hospital Organization Kumamoto Medical Center
| | | | - Tomohiro Sakamoto
- Division of Cardiology, Saiseikai Kumamoto Hospital Cardiovascular Center
| | - Koichi Nakao
- Division of Cardiology, Saiseikai Kumamoto Hospital Cardiovascular Center
| | | | | | | | - Hideki Shimomura
- Department of Cardiovascular Medicine, Fukuoka Tokushukai Medical Center
| | - Kenji Sakamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University
| | - Eiichiro Yamamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University
| | - Yasuhiro Izumiya
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University.,Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine
| | - Koichi Kaikita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University
| | - Seiji Hokimoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University
| | | | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University
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Munhoz DB, Carvalho LSF, Venancio FNC, Rangel de Almeida OL, Quinaglia E Silva JC, Coelho-Filho OR, Nadruz W, Sposito AC. Statin Use in the Early Phase of ST-Segment Elevation Myocardial Infarction Is Associated With Decreased QTc Dispersion. J Cardiovasc Pharmacol Ther 2020; 25:226-231. [PMID: 32008366 DOI: 10.1177/1074248420902302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Although there is strong evidence supporting the use of statin therapy after myocardial infarction (MI), some mechanistic gaps exist regarding the benefits of this therapy at the very onset of MI. Among the potential beneficial mechanisms, statins may improve myocardial electrical stability and reduce life-threatening ventricular arrhythmia, as reported in stable clinical conditions. This study was designed to evaluate whether this mechanism could also occur during the acute phase of MI. METHODS Consecutive patients with ST-segment elevation MI were treated without statin (n = 57) or with a simvastatin dose of 20 to 80 mg (n = 87) within the first 24 hours after MI symptom onset. Patients underwent digital electrocardiography within the first 24 hours and at the third and fifth days after MI. The QTC dispersion (QTcD) was measured both with and without the U waves. RESULTS Although QTcD values were equivalent between the groups at the first day (80.6 ± 36.0 vs 80.0 ± 32.1; P = 0.36), they were shorter among individuals using simvastatin than in those receiving no statins on the third (90.4 ± 38.6 vs 86.5 ± 36.9; P = .036) and fifth days (73.1 ± 31 vs 69.2 ± 32.6; P = .049). We obtained similar results when analyzing the QTcD duration including the U wave. All values were adjusted by an ANCOVA model after propensity-score matching. CONCLUSIONS Statins administered within 24 hours of ST-segment elevation MI reduced QTc dispersion, which may potentially attenuate the substrate for life-threatening ventricular arrhythmias.
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Affiliation(s)
- Daniel B Munhoz
- Cardiology Division, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, Sao Paulo, Brazil
| | - Luiz Sergio F Carvalho
- Cardiology Division, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, Sao Paulo, Brazil
| | - Frank N C Venancio
- Hospital de Base do Distrito Federal, Brasilia, Brazil.,University of Brasilia, Brasilia, Brazil
| | | | | | - Otavio R Coelho-Filho
- Cardiology Division, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, Sao Paulo, Brazil
| | - Wilson Nadruz
- Cardiology Division, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, Sao Paulo, Brazil
| | - Andrei C Sposito
- Cardiology Division, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, Sao Paulo, Brazil
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Belmadani S, Matrougui K. Broken heart: A matter of the endoplasmic reticulum stress bad management? World J Cardiol 2019; 11:159-170. [PMID: 31367278 PMCID: PMC6658386 DOI: 10.4330/wjc.v11.i6.159] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/29/2019] [Accepted: 06/12/2019] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases are the number one cause of morbidity and mortality in the United States and worldwide. The induction of the endoplasmic reticulum (ER) stress, a result of a disruption in the ER homeostasis, was found to be highly associated with cardiovascular diseases such as hypertension, diabetes, ischemic heart diseases and heart failure. This review will discuss the latest literature on the different aspects of the involvement of the ER stress in cardiovascular complications and the potential of targeting the ER stress pathways as a new therapeutic approach for cardiovascular complications.
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Affiliation(s)
- Souad Belmadani
- Department of Physiological Science, Eastern Virginia Medical School, Norfolk, VA 23501, United States
| | - Khalid Matrougui
- Department of Physiological Science, Eastern Virginia Medical School, Norfolk, VA 23501, United States
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11
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Dose-dependent INhibitory effect of rosuVastatin In Japanese patienTs with Acute myocardial infarcTION on serum concentration of matrix metalloproteinases - INVITATION trial. J Cardiol 2018; 72:350-355. [PMID: 29735336 DOI: 10.1016/j.jjcc.2018.03.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 02/24/2018] [Accepted: 03/22/2018] [Indexed: 11/23/2022]
Abstract
BACKGROUND Acute myocardial infarction (AMI) is mainly characterized by the rupture of lipid-rich vulnerable atherosclerotic plaque. The matrix metalloproteinases (MMPs) have been shown to play a critical role in inflammatory processes underlying plaque rupture. Some reports suggested statins inhibit the increased MMP levels after AMI. However, there are a few comparison studies between the different dosages of the same statin and circulating levels of MMPs. PURPOSE This study will preliminarily investigate the potential effects of appropriate or low dose of rosuvastatin on circulating MMPs levels in AMI patients. Moreover, we will also obtain plasma from patients while undergoing diagnostic angiography to determine differences in various cardiac sites and peripheral vessels. METHODS This study is a multicenter, open-label, randomized, parallel-group study to be conducted to compare the appropriate or low dose of rosuvastatin in the effect on serum levels of inflammatory markers in AMI patients. The eligible patients undergoing percutaneous coronary intervention (PCI) will be randomly assigned to receive either appropriate or low-dose rosuvastatin daily using a web-based randomization software within 24h after PCI. The low-dose group will be treated with rosuvastatin 2.5mg once daily with a follow-up. The appropriate-dose group will begin treatment with rosuvastatin 5mg once daily, and the dose of rosuvastatin will be titrated to 10mg within 4 weeks. During administration of the study treatment, subjects will undergo laboratory testing including MMPs and be monitored for the occurrence of adverse events up to 24 weeks. The primary endpoint will be the change rate of MMPs at 24 weeks after administration. CONCLUSIONS INVITATION will compare the appropriate or low dose of rosuvastatin in the effects on serum levels of inflammatory markers including MMPs in AMI patients. This study will provide significant information on rosuvastatin as an anti-inflammatory agent for AMI.
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12
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Matrix Metalloproteinases in Myocardial Infarction and Heart Failure. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 147:75-100. [PMID: 28413032 DOI: 10.1016/bs.pmbts.2017.02.001] [Citation(s) in RCA: 181] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cardiovascular disease is the leading cause of death, accounting for 600,000 deaths each year in the United States. In addition, heart failure accounts for 37% of health care spending. Matrix metalloproteinases (MMPs) increase after myocardial infarction (MI) and correlate with left ventricular dysfunction in heart failure patients. MMPs regulate the remodeling process by facilitating extracellular matrix turnover and inflammatory signaling. Due to the critical role MMPs play during cardiac remodeling, there is a need to better understand the pathophysiological mechanism of MMPs, including the biological function of the downstream products of MMP proteolysis. Future studies developing new therapeutic targets that inhibit specific MMP actions to limit the development of heart failure post-MI are warranted. This chapter focuses on the role of MMPs post-MI, the efficiency of MMPs as biomarkers for MI or heart failure, and the future of MMPs and their cleavage products as targets for prevention of post-MI heart failure.
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Morishita T, Uzui H, Mitsuke Y, Amaya N, Kaseno K, Ishida K, Fukuoka Y, Ikeda H, Tama N, Yamazaki T, Lee JD, Tada H. Association between matrix metalloproteinase-9 and worsening heart failure events in patients with chronic heart failure. ESC Heart Fail 2017; 4:321-330. [PMID: 28772055 PMCID: PMC5542740 DOI: 10.1002/ehf2.12137] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 11/30/2016] [Accepted: 12/28/2016] [Indexed: 12/14/2022] Open
Abstract
AIMS Matrix metalloproteinase (MMP) is up-regulated during heart failure (HF) and influences ventricular remodeling. We hypothesized that disparity between MMP-9 and tissue inhibitors of MMP-1 (TIMP-1) results in clinical manifestations and is related to prognostic risk in patients with chronic HF. METHODS AND RESULTS Plasma levels of MMP-9, TIMP-1, and brain natriuretic peptide (BNP) were measured in 173 patients with chronic HF. Combined endpoints of worsening HF events were assessed during follow-up (median 109 months). MMP-9 and TIMP-1 levels and the MMP-9/TIMP-1 ratio increased with increasing severity of the New York Heart Association class (P for trend = 0.003, 0.011, and 0.005, respectively). Patients with HF events (n = 35) had significantly higher MMP-9 than those without HF events (P = 0.004). Kaplan-Meier analysis demonstrated a higher probability of HF events with high MMP-9 values (>23.2 ng/mL; P = 0.005). A multivariate Cox proportional hazard model showed that high MMP-9 values were an independent predictor of HF events (hazard ratio, 3.73; 95% confidence interval (CI), 1.03-13.46; P = 0.043). In patients with lower BNP levels (≤210 pg/mL), the adjusted hazard ratio for HF events was 3.63 (95% CI, 1.20-11.02; P = 0.023) among patients with high MMP-9 values compared with patients with low BNP and low MMP-9 values. CONCLUSIONS MMP-9 and TIMP-1 levels correlate with the severity of chronic HF. MMP-9 is a strong predictor of HF events, suggesting that a disparity between MMP-9 and TIMP-1 levels and increased MMP-9 levels may help predict HF events.
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Affiliation(s)
- Tetsuji Morishita
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Hiroyasu Uzui
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yasuhiko Mitsuke
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Naoki Amaya
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Kenichi Kaseno
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Kentaro Ishida
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yoshitomo Fukuoka
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Hiroyuki Ikeda
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Naoki Tama
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Taketoshi Yamazaki
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Jong-Dae Lee
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Hiroshi Tada
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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Abstract
Myocardial infarction is defined as sudden ischemic death of myocardial tissue. In the clinical context, myocardial infarction is usually due to thrombotic occlusion of a coronary vessel caused by rupture of a vulnerable plaque. Ischemia induces profound metabolic and ionic perturbations in the affected myocardium and causes rapid depression of systolic function. Prolonged myocardial ischemia activates a "wavefront" of cardiomyocyte death that extends from the subendocardium to the subepicardium. Mitochondrial alterations are prominently involved in apoptosis and necrosis of cardiomyocytes in the infarcted heart. The adult mammalian heart has negligible regenerative capacity, thus the infarcted myocardium heals through formation of a scar. Infarct healing is dependent on an inflammatory cascade, triggered by alarmins released by dying cells. Clearance of dead cells and matrix debris by infiltrating phagocytes activates anti-inflammatory pathways leading to suppression of cytokine and chemokine signaling. Activation of the renin-angiotensin-aldosterone system and release of transforming growth factor-β induce conversion of fibroblasts into myofibroblasts, promoting deposition of extracellular matrix proteins. Infarct healing is intertwined with geometric remodeling of the chamber, characterized by dilation, hypertrophy of viable segments, and progressive dysfunction. This review manuscript describes the molecular signals and cellular effectors implicated in injury, repair, and remodeling of the infarcted heart, the mechanistic basis of the most common complications associated with myocardial infarction, and the pathophysiologic effects of established treatment strategies. Moreover, we discuss the implications of pathophysiological insights in design and implementation of new promising therapeutic approaches for patients with myocardial infarction.
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Affiliation(s)
- Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
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Bencsik P, Sasi V, Kiss K, Kupai K, Kolossváry M, Maurovich-Horvat P, Csont T, Ungi I, Merkely B, Ferdinandy P. Serum lipids and cardiac function correlate with nitrotyrosine and MMP activity in coronary artery disease patients. Eur J Clin Invest 2015; 45:692-701. [PMID: 25944577 DOI: 10.1111/eci.12458] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 05/01/2015] [Indexed: 12/13/2022]
Abstract
AIMS Peroxynitrite-matrix metalloproteinase (MMP) signalling has been shown to contribute to myocardial ischaemia/reperfusion injury and heart failure and to be influenced by hyperlipidaemia in preclinical models. Therefore, here we investigated the correlation between the markers of peroxynitrite-MMP signalling and hyperlipidaemia in patients with significant coronary stenosis. METHODS Five minutes before percutaneous coronary intervention (PCI), arterial blood samples were collected from 36 consecutive patients with coronary artery disease (CAD) selected for elective PCI. RESULTS Serum nitrotyrosine positively correlated with MMP-9 activity (r = 0·54, P = 0·01), but not with MMP-2 activity. Nitrotyrosine positively correlated with total (r = 0·58; P < 0·01) and LDL cholesterol (r = 0·55; P < 0·01), serum triglyceride (r = 0·47; P < 0·05), and creatinine (r = 0·42; P < 0·05) and negatively correlated with HDL cholesterol (r = -0·46; P < 0·05) and with left ventricular ejection fraction (LVEF; r = -0·55; P < 0·05), respectively. MMP-2 activity correlated positively with total (r = 0·55; P < 0·05) and LDL cholesterol (r = 0·45; P < 0·05). In statin-treated patients, a significantly reduced serum nitrotyrosine was found as compared to statin naives; however, MMP activities and serum cholesterol levels were not different. MMP-9 activity correlated with urea nitrogen (r = 0·42; P < 0·05) and LVEF (r = -0·73; P < 0·01). Serum creatinine correlated negatively with LVEF (r = -0·50, P < 0·01). CONCLUSIONS This is the first demonstration that (i) serum nitrotyrosine correlates with MMP-9 activity, (ii) lipid parameters correlate with nitrotyrosine and MMP-2 activity, (iii) myocardial function correlates with creatinine, nitrotyrosine and MMP-9 activity, and (iv) creatinine correlates with nitrotyrosine and urea nitrogen with MMP-9 activity in patients with CAD. Studying the biomarkers of peroxynitrite-MMP pathway in large prospective trials may reveal their diagnostic avails.
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Affiliation(s)
- Péter Bencsik
- Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Viktor Sasi
- Division of Invasive Cardiology, Second Department of Internal Medicine and Center of Cardiology, University of Szeged, Szeged, Hungary
| | - Krisztina Kiss
- Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary
| | - Krisztina Kupai
- Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary
| | - Márton Kolossváry
- MTA-SE Cardiovascular Imaging Research Group, Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Pál Maurovich-Horvat
- MTA-SE Cardiovascular Imaging Research Group, Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Tamás Csont
- Metabolic Diseases and Cell Signaling Research Group, Department of Biochemistry, University of Szeged, Budapest, Hungary
| | - Imre Ungi
- Division of Invasive Cardiology, Second Department of Internal Medicine and Center of Cardiology, University of Szeged, Szeged, Hungary
| | - Béla Merkely
- MTA-SE Cardiovascular Imaging Research Group, Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Péter Ferdinandy
- Pharmahungary Group, Szeged, Hungary.,Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
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Morishita T, Uzui H, Mitsuke Y, Arakawa K, Amaya N, Kaseno K, Ishida K, Nakaya R, Lee JD, Tada H. Predictive utility of the changes in matrix metalloproteinase-2 in the early phase for left ventricular reverse remodeling after an acute myocardial infarction. J Am Heart Assoc 2015; 4:e001359. [PMID: 25616975 PMCID: PMC4330062 DOI: 10.1161/jaha.114.001359] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND The relationship between the serum levels of matrix metalloproteinase (MMP) and tissue inhibitors of MMP (TIMP) and left ventricular (LV) reverse remodeling (LV-RR) after an acute myocardial infarction (AMI) has not been sufficiently examined. METHODS AND RESULTS In 25 patients with successful reperfusion after an AMI and 15 normal control subjects, the serum MMP-2 and TIMP-2 levels were measured on days 1, 2, 3, and 7 and at 1 and 6 months after the AMI onset. LV-RR was defined as a >15% decrease in the LV end-systolic volume index at 6 months after the AMI. The MMP-2 level on day 1 and TIMP-2 levels throughout the study period were comparable between the patients with and without LV-RR. The MMP-2 on day 7 (P<0.05) and the changes in the MMP-2 from day 1 to day 7 (∆MMP-2; P<0.01) were lower in patients with than in those without LV-RR. The ∆MMP-2 was strongly correlated with the changes in the LV volume and ejection fraction from 1 month to 6 months after the AMI. The ∆MMP-2 value of <-158.5 ng/mL predicted LV-RR with a high accuracy (91.7% sensitivity and 76.9% specificity; area under the curve=0.82). CONCLUSIONS Changes in MMP-2 are associated with LV-RR after an AMI. The ΔMMP-2 might be a useful predictor of subsequent LV-RR.
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Affiliation(s)
- Tetsuji Morishita
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Matsuokashimoaizuki, Japan (T.M., H.U., Y.M., K.A., N.A., K.K., K.I., R.N., J.D.L., H.T.)
| | - Hiroyasu Uzui
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Matsuokashimoaizuki, Japan (T.M., H.U., Y.M., K.A., N.A., K.K., K.I., R.N., J.D.L., H.T.)
| | - Yasuhiko Mitsuke
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Matsuokashimoaizuki, Japan (T.M., H.U., Y.M., K.A., N.A., K.K., K.I., R.N., J.D.L., H.T.)
| | - Kenichi Arakawa
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Matsuokashimoaizuki, Japan (T.M., H.U., Y.M., K.A., N.A., K.K., K.I., R.N., J.D.L., H.T.)
| | - Naoki Amaya
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Matsuokashimoaizuki, Japan (T.M., H.U., Y.M., K.A., N.A., K.K., K.I., R.N., J.D.L., H.T.)
| | - Kenichi Kaseno
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Matsuokashimoaizuki, Japan (T.M., H.U., Y.M., K.A., N.A., K.K., K.I., R.N., J.D.L., H.T.)
| | - Kentaro Ishida
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Matsuokashimoaizuki, Japan (T.M., H.U., Y.M., K.A., N.A., K.K., K.I., R.N., J.D.L., H.T.)
| | - Reiko Nakaya
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Matsuokashimoaizuki, Japan (T.M., H.U., Y.M., K.A., N.A., K.K., K.I., R.N., J.D.L., H.T.)
| | - Jong-Dae Lee
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Matsuokashimoaizuki, Japan (T.M., H.U., Y.M., K.A., N.A., K.K., K.I., R.N., J.D.L., H.T.)
| | - Hiroshi Tada
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Matsuokashimoaizuki, Japan (T.M., H.U., Y.M., K.A., N.A., K.K., K.I., R.N., J.D.L., H.T.)
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Vale N, Nordmann AJ, Schwartz GG, de Lemos J, Colivicchi F, den Hartog F, Ostadal P, Macin SM, Liem AH, Mills EJ, Bhatnagar N, Bucher HC, Briel M, Cochrane Heart Group. Statins for acute coronary syndrome. Cochrane Database Syst Rev 2014; 2014:CD006870. [PMID: 25178118 PMCID: PMC11126893 DOI: 10.1002/14651858.cd006870.pub3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND The early period following the onset of acute coronary syndrome (ACS) represents a critical stage of coronary heart disease, with a high risk of recurrent events and deaths. The short-term effects of early treatment with statins on patient-relevant outcomes in patients suffering from ACS are unclear. This is an update of a review previously published in 2011. OBJECTIVES To assess the effects, both harms and benefits, of early administered statins in patients with ACS, in terms of mortality and cardiovascular events. SEARCH METHODS We updated the searches of CENTRAL (2013, Issue 3), MEDLINE (Ovid) (1946 to April Week 1 2013), EMBASE (Ovid) (1947 to 2013 Week 14), and CINAHL (EBSCO) (1938 to 2013) on 12 April 2013. We applied no language restrictions. We supplemented the search by contacting experts in the field, by reviewing the reference lists of reviews and editorials on the topic, and by searching trial registries. SELECTION CRITERIA Randomized controlled trials (RCTs) comparing statins with placebo or usual care, with initiation of statin therapy within 14 days following the onset of ACS, follow-up of at least 30 days, and reporting at least one clinical outcome. DATA COLLECTION AND ANALYSIS Two authors independently assessed risk of bias and extracted data. We calculated risk ratios (RRs) for all outcomes in the treatment and control groups and pooled data using random-effects models. MAIN RESULTS Eighteen studies (14,303 patients) compared early statin treatment versus placebo or no treatment in patients with ACS. The new search did not identify any new studies for inclusion. There were some concerns about risk of bias and imprecision of summary estimates. Based on moderate quality evidence, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction, and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) or four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up when compared to placebo or no treatment. There were no statistically significant risk reductions from statins for total death, total myocardial infarction, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month or at four months, although there were favorable trends related to statin use for each of these endpoints. Moderate quality evidence suggests that the incidence of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine individuals with myopathy (elevated creatinine kinase levels more than 10 times the upper limit of normal) in statin-treated patients (0.13%) versus one (0.015%) in the control groups. Serious muscle toxicity was mostly limited to patients treated with simvastatin 80 mg. AUTHORS' CONCLUSIONS Based on moderate quality evidence, due to concerns about risk of bias and imprecision, initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction, or stroke up to four months, but reduces the occurrence of unstable angina at four months following ACS. Serious side effects were rare.
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Affiliation(s)
- Noah Vale
- St Mary's Hospital, McGill UniversityFamily Medicine377 Rue Jean BrilliantMontrealQCCanadaH3T 1M5
| | - Alain J Nordmann
- University Hospital BaselInstitute for Clinical Epidemiology and BiostatisticsHebelstrasse 10BaselSwitzerland4031
| | - Gregory G Schwartz
- VA Medical Center and University of Colorado1055 Clermont StDenverColoradoUSA
| | - James de Lemos
- University of Texas Southwestern Medical SchoolCardiology/Internal Medicine5909 Harry Hines BlvdDallasTexasUSA
| | - Furio Colivicchi
- S. Filippo Neri HospitalCardiovascular Department330 Viale Gorgia da LeontiniRomeItaly00124
| | - Frank den Hartog
- Gelderse Vallei HospitalCardiology Departmentpostbus 9025EdeNetherlands6710 HN
| | - Petr Ostadal
- Na Homolce HospitalDepartment of CardiologyPragueCzech Republic
| | - Stella M Macin
- Instituto de CardiologiaCoronary Intensive Care UnitJuana F CabrelCorrientesArgentina
| | - Anho H Liem
- Franciscus Gasthuis RotterdamDepartment of CardiologyRotterdamNetherlands
| | - Edward J Mills
- University of OttawaFaculty of Health Sciences451 Smyth RoadOttawaONCanadaK1H 8M5
| | - Neera Bhatnagar
- McMaster UniversityDepartment of Clinical Epidemiology and Biostatistics1200 Main Street WestHamiltonONCanadaL8N 3Z5
| | - Heiner C Bucher
- University Hospital Basel (USB)Basel Institute for Clinical Epidemiology and BiostatisticsBaselSwitzerland
| | - Matthias Briel
- University Hospital Basel (USB)Basel Institute for Clinical Epidemiology and BiostatisticsBaselSwitzerland
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Abstract
Statins lower serum cholesterol and are employed for primary and secondary prevention of cardiovascular events. Clinical evidence from observational studies, retrospective data, and post hoc analyses of data from large statin trials in various cardiovascular conditions, as well as small scale randomized trials, suggest survival and other outcome benefits for heart failure. Two recent large randomized controlled trials, however, appear to suggest statins do not have beneficial effects in heart failure. In addition to lowering cholesterol, statins are believed to have many pleotropic effects which could possibly influence the pathophysiology of heart failure. Following the two large trials, evidence from recent studies appears to support the use of statins in heart failure. This review discusses the role of statins in the pathophysiology of heart failure, current evidence for statin use in heart failure, and suggests directions for future research.
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Affiliation(s)
- Kwadwo Osei Bonsu
- School of Medicine and Health Sciences, Monash University Sunway Campus, Bandar Sunway, Malaysia
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Ogita M, Miyauchi K, Morimoto T, Daida H, Kimura T, Hiro T, Nakagawa Y, Yamagishi M, Ozaki Y, Matsuzaki M. Association between circulating matrix metalloproteinase levels and coronary plaque regression after acute coronary syndrome--subanalysis of the JAPAN-ACS study. Atherosclerosis 2012; 226:275-80. [PMID: 23159100 DOI: 10.1016/j.atherosclerosis.2012.10.063] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Revised: 10/10/2012] [Accepted: 10/24/2012] [Indexed: 11/25/2022]
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) have been implicated in development of atherosclerosis. MMPs are activated in patients with acute coronary syndrome (ACS). However, little data exist regarding the correlation between circulating levels of MMPs and plaque volume (PV) in patients with ACS. We therefore evaluated the impact of MMPs on coronary PV as a post hoc analysis from the JAPAN-ACS study. METHODS The multicenter JAPAN-ACS trial revealed that aggressive statin therapy for patients with ACS significantly reduces coronary PV determined by intravascular ultrasound (IVUS). We studied 248 ACS patients who had serial IVUS examinations over 8-12 months in the trial. For each patient, MMP-1, 2, and 3 were measured both at baseline and at study end to evaluate the correlation between the percent change of PV and MMP levels. RESULTS MMP-3 levels were significantly decreased during the follow-up period (100 ng/mL to 73 ng/mL, p < 0.001), in contrast, MMP-1, -2 levels were significantly increased. MMP-3 levels at follow-up correlated with coronary plaque regression (p for trend = 0.016). A multivariable linear regression model showed both MMP-2 and MMP-3 levels at follow-up were independent variables for change of coronary PV (p = 0.038 and p = 0.016, respectively). CONCLUSION Circulating MMPs levels are associated with changes in coronary plaque volume determined by serial IVUS in patients with ACS.
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Affiliation(s)
- Manabu Ogita
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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Immediate administration of atorvastatin decreased the serum MMP-2 level and improved the prognosis for acute heart failure. J Cardiol 2012; 59:374-82. [PMID: 22402418 DOI: 10.1016/j.jjcc.2012.01.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 01/17/2012] [Accepted: 01/20/2012] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND PURPOSE We have reported that matrix metalloproteinase-2 (MMP-2) increased in acute heart failure (AHF) and better prognosis was found in patients with greater reduction in MMP-2. We assessed whether a statin decreased MMP-2 in AHF. METHODS AND RESULTS The serum MMP-2 levels were measured on admission (Day 1), Day 3, Day 7, and Day 14 in 50 AHF patients. The patients were randomized to either atorvastatin (n=25) or control group (n=25). Atorvastatin (10-20mg/day) was started within 12h after their admission and then was continued for two weeks. There were no differences in the serum levels of MMP-2 on Day 1 between atorvastatin group (1400.4±318.6ng/ml) and control group (1292.7±384.7ng/ml). MMP-2 significantly decreased in both groups on Day 3, 7, and 14. However, the MMP-2 value on Day 3 compared to Day 1 was observed to have decreased significantly in atorvastatin group (561.8±235.1ng/ml) compared to control group (272.6±270.6ng/ml; p=0.001). HF events which were defined as death from HF, readmission to hospital for HF, or prolonged hospital stay because of uncontrollable HF, occurred more in control group than in atorvastatin group. Kaplan-Meier curves showed that the prognosis of HF was significantly better in atorvastatin group as compared with control group (log-rank test, p=0.037). CONCLUSION In addition to conventional HF therapy, an early start of atorvastatin caused a great decrease in MMP-2 and also improved HF events in AHF.
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Vale N, Nordmann AJ, Schwartz GG, de Lemos J, Colivicchi F, den Hartog F, Ostadal P, Macin SM, Liem AH, Mills E, Bhatnagar N, Bucher HC, Briel M. Statins for acute coronary syndrome. Cochrane Database Syst Rev 2011:CD006870. [PMID: 21678362 DOI: 10.1002/14651858.cd006870.pub2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND The early period following the onset of acute coronary syndromes (ACS) represents a critical stage of coronary heart disease with a high risk for recurrent events and deaths. The short-term effects of early treatment with statins in patients suffering from ACS on patient-relevant outcomes are unclear. OBJECTIVES To assess the benefits and harms of early administered statins in patients with ACS from randomized controlled trials (RCTs). SEARCH STRATEGY We searched CENTRAL, MEDLINE, EMBASE, and CINAHL (to 1 February 2010). No language restrictions were applied. We supplemented the search by contacting experts in the field, by reviewing reference lists of reviews and editorials on the topic, and by searching trial registries. SELECTION CRITERIA RCTs comparing statins with placebo or usual care, initiation of statin therapy within 14 days following the onset of ACS, and follow-up of at least 30 days reporting at least one clinical outcome. DATA COLLECTION AND ANALYSIS Two authors independently assessed study quality and extracted data. We pooled treatment effects and calculated risk ratios (RRs) for all outcomes in the treatment and control groups using a random effects model. MAIN RESULTS Eighteen studies (14,303 patients) compared early statin treatment versus placebo or usual care in patients with ACS. Compared to placebo or usual care, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction (MI), and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) and four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up. There were no statistically significant risk reductions from statins for total death, total MI, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month and at four months, although there were favorable trends related to statin use for each of these endpoints. The incidence of episodes of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine individuals with myopathy (elevated creatinine kinase levels > 10 times the upper limit of normal) in statin treated patients (0.13%) versus one (0.015%) in the control groups. Serious muscle toxicity was mostly limited to patients treated with simvastatin 80 mg. AUTHORS' CONCLUSIONS Based on available evidence, initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction, or stroke up to four months, but reduces the occurrence of unstable angina at four months following ACS.
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Affiliation(s)
- Noah Vale
- Family Medicine, St Mary's Hospital, McGill University, 377 Rue Jean Brilliant, Montreal, Quebec, Canada, H3T 1M5
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OKUMURA YASUO, WATANABE ICHIRO, NAKAI TOSHIKO, OHKUBO KIMIE, KOFUNE TATSUYA, KOFUNE MASAYOSHI, NAGASHIMA KOICHI, MANO HIROAKI, SONODA KAZUMASA, KASAMAKI YUJI, HIRAYAMA ATSUSHI. Impact of Biomarkers of Inflammation and Extracellular Matrix Turnover on the Outcome of Atrial Fibrillation Ablation: Importance of Matrix Metalloproteinase-2 as a Predictor of Atrial Fibrillation Recurrence. J Cardiovasc Electrophysiol 2011; 22:987-93. [DOI: 10.1111/j.1540-8167.2011.02059.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Lewandowski KC, Banach E, Bieńkiewicz M, Lewiński A. Matrix metalloproteinases in type 2 diabetes and non-diabetic controls: effects of short-term and chronic hyperglycaemia. Arch Med Sci 2011; 7:294-303. [PMID: 22291770 PMCID: PMC3258712 DOI: 10.5114/aoms.2011.22081] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2009] [Revised: 11/25/2009] [Accepted: 12/17/2009] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION The role of matrix metalloproteinases (MMPs) in type 2 diabetes mellitus (DM) is not clear as increased activation of MMPs in the vasculature contrasts with decreased activity of MMPs in the kidneys, contributing to development of nephropathy. MATERIAL AND METHODS We measured serum MMP-2 and MMP-9 in 22 subjects with type 2 DM age (mean ± SD) 56.7 ±16.8 years, BMI 31.8 ±4.6 kg/m(2), HbA(1c) 8.45 ±1.78% and in 32 controls, age 39.2 ±16.0 years, BMI 35.2 ±8.5 kg/m(2). In 15 subjects with 2 DM we also measured MMP-2 and MMP-9 at discharge from hospital and after 3 months (n = 8). In controls, MMP-2 and -9 were also measured during 75 g oral glucose tolerance test (OGTT). RESULTS Concentrations of MMP-2 and MMP-9 were lower in subjects with type 2 DM (219 ±62 ng/ml vs. 305 ±63 ng/ml and 716 ±469 ng/ml vs. 1285 ±470 ng/ml, for MMP-2 and MMP-9, respectively, p < 0.05). MMP-9 concentrations fell at 120 min of OGTT from 1675 ±372 ng/ml to 1276 ±422 ng/ml (p < 0.05). In diabetic subjects there was a correlation between MMP-9 and HbA(1c) (r = 0.51, p< 0.05). In subjects with diabetes there was a fall of HbA(1c) from 9.77 ±1.76% to 8.36 ±1.54% (p < 0.01), at three months post-discharge. There was no difference in MMP-2, but there was a fall in MMP-9 at three months post-discharge in comparison to concentrations observed at admission (854 ±560 ng/ml vs. 500 ±235 ng/ml, p= 0.02). CONCLUSIONS Matrix metalloproteinases in type 2 and MMP-9 concentrations were lower in subjects with 2 DM than in non-diabetic controls. Regulation of MMPs appears to be complex as hyperglycaemia during OGTT results in a decrease in MMP-9, while chronic hyperglycaemia, reflected by HbA(1c), correlates with MMP-9 concentrations in subjects with 2 DM.
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Affiliation(s)
- Krzysztof C. Lewandowski
- Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Polish Mother’s Memorial Hospital – Research Institute, Lodz, Poland
| | - Ewa Banach
- Department of Internal Medicine, St. Alexander Hospital, Kielce, Poland
| | - Małgorzata Bieńkiewicz
- Department of Quality Control and Radiation Protection, Medical University of Lodz, Poland
| | - Andrzej Lewiński
- Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Polish Mother’s Memorial Hospital – Research Institute, Lodz, Poland
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Shirakabe A, Asai K, Hata N, Yokoyama S, Shinada T, Kobayashi N, Mizuno K. Clinical significance of matrix metalloproteinase (MMP)-2 in patients with acute heart failure. Int Heart J 2011; 51:404-10. [PMID: 21173516 DOI: 10.1536/ihj.51.404] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The serum levels of matrix metalloproteinases (MMPs) increase during chronic heart failure (HF) and the MMP-2 are related to a poor prognosis. However, the roles of MMP-2 in acute HF (AHF) remain unclear. We investigated the change and clinical significance of MMP-2 in these conditions. The serum levels of MMP-2 were measured in 83 AHF patients before starting treatment (day 1), 3 (day 3) and 7 (day 7) days after admission, and before discharge (predischarge). MMP-2 decreased rapidly and significantly from day 3 to day 1 (902.9 ± 304.2 versus 1220.4 ± 330.5 ng/mL; P < 0.0001), whereas that of MMP-2 was not significantly different on day 7 and at predischarge (894.7 ± 278.9 and 920.0 ± 269.6 ng/mL, respectively) compared to day 3. We evaluated the relationships between ΔMMPs, defined as the changes in MMPs from day 1 to day 3 and HF events including cardiac death, readmission to hospital for HF, and uncontrollable HF. The MMP-2 value was significantly (P = 0.004) more decreased in the event-free group (381.4 ± 256.5 ng/mL) than in the event group (211.9 ± 225.5 ng/mL) between day 1 and day 3. The results of the multivariate logistic regression model for predicting HF events found that the specific factor for HF events was ΔMMP-2. Cutoff values of ΔMMP-2 were determined and event-free curves were constructed. Kaplan-Meier curves showed that the prognosis was significantly better among the patients with reductions in ΔMMP-2 values of more than 342 ng/mL. The serum levels of MMP-2 decreased with improvements in AHF. Rapid decreases in MMP-2 may be important for a better clinical outcome in patients with AHF.
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Affiliation(s)
- Akihiro Shirakabe
- Intensive Care Unit, Chiba Hokusoh Hospital, Nippon Medical SchoolInzai, Chiba, Japan
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25
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Abstract
The focus of this review is on translational studies utilizing large-animal models and clinical studies that provide fundamental insight into cellular and extracellular pathways contributing to post-myocardial infarction (MI) left ventricle (LV) remodeling. Specifically, both large-animal and clinical studies have examined the potential role of endogenous and exogenous stem cells to alter the course of LV remodeling. Interestingly, there have been alterations in LV remodeling with stem cell treatment despite a lack of long-term cell engraftment. The translation of the full potential of stem cell treatments to clinical studies has yet to be realized. The modulation of proteolytic pathways that contribute to the post-MI remodeling process has also been examined. On the basis of recent large-animal studies, there appears to be a relationship between stem cell treatment post-MI and the modification of proteolytic pathways, generating the hypothesis that stem cells leave an echo effect that moderates LV remodeling.
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Affiliation(s)
- Jennifer A. Dixon
- Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina 29425
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401
| | - Francis G. Spinale
- Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina 29425
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401
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26
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Effects of standard treatment on the dynamics of matrix metalloproteinases gene expression in patients with acute coronary syndromes. Pharmacol Rep 2010; 62:1108-16. [DOI: 10.1016/s1734-1140(10)70373-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2009] [Revised: 02/04/2010] [Indexed: 11/23/2022]
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27
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Politei JM. Can we use statins to prevent stroke in Fabry disease? J Inherit Metab Dis 2009; 32:481-7. [PMID: 19495571 DOI: 10.1007/s10545-009-1156-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2009] [Revised: 03/20/2009] [Accepted: 04/15/2009] [Indexed: 02/02/2023]
Abstract
UNLABELLED Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of alpha-galactosidase A, which results in the progressive accumulation of globotriaosylceramide and other neutral glycolipids in a range of cells and tissues. In association with the renal and cardiac insufficiency, cerebrovascular complications can result in the death of the patients. Several mechanisms causing vascular damage that leads to the development of deep-white matter lesions have been described. Recent clinical trials strongly suggest that statins protect against stroke by neuroprotective properties or pleiotropic effects. AIM To evaluate evidence and potential beneficial effects of statins in the vasculopathy of Fabry disease.
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Affiliation(s)
- J M Politei
- Neurology Service, Juan A Fernandez Hospital, Buenos Aires, Argentina.
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28
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Ishii H, Amano T, Matsubara T, Murohara T. Pharmacological intervention for prevention of left ventricular remodeling and improving prognosis in myocardial infarction. Circulation 2009; 118:2710-8. [PMID: 19106394 DOI: 10.1161/circulationaha.107.748772] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Hideki Ishii
- Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
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29
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Castro PF, Miranda R, Verdejo HE, Greig D, Gabrielli LA, Alcaino H, Chiong M, Bustos C, Garcia L, Mellado R, Vukasovic JL, Godoy I, Lavandero S. Pleiotropic Effects of Atorvastatin in Heart Failure: Role in Oxidative Stress, Inflammation, Endothelial Function, and Exercise Capacity. J Heart Lung Transplant 2008; 27:435-41. [DOI: 10.1016/j.healun.2008.01.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2007] [Revised: 12/12/2007] [Accepted: 01/08/2008] [Indexed: 11/16/2022] Open
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30
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Suzuki H, Kusuyama T, Sato R, Yokota Y, Tsunoda F, Sato T, Shoji M, Iso Y, Koba S, Katagiri T. Elevation of matrix metalloproteinases and interleukin-6 in the culprit coronary artery of myocardial infarction. Eur J Clin Invest 2008; 38:166-73. [PMID: 18257779 DOI: 10.1111/j.1365-2362.2007.01919.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND Interleukin-6 (IL-6) and metalloproteinases (MMPs) are involved in the instability of vulnerable plaque associated with the induction of acute myocardial infarction (AMI). We examined the regional changes of cytokines, MMPs and adhesion molecules in patients with AMI to elucidate how these factors are involved in the onset of AMI. MATERIALS AND METHODS One hundred and twenty-two patients with AMI were included. Blood was aspirated from the culprit coronary artery with a thrombectomy catheter, and was also sampled from peripheral veins during the coronary intervention. Control samples were obtained from the peripheral blood of age-matched patients. RESULTS The serum levels of IL-6 (P < 0.05), tumour necrosis factor-alpha (P < 0.005), MMP-1 (P < 0.001), MMP-13 (P < 0.001), soluble intercellular adhesion molecule-1 (P < 0.005), and soluble vascular cellular adhesion molecule-1 (P < 0.05) in peripheral blood were significantly higher in the AMI group than in the controls. Aspirated serum contained significantly higher levels of IL-6 (P < 0.001), MMP-1 (P < 0.001), and MMP-13 (P < 0.05) compared to the peripheral blood of AMI. Serum IL-6 levels were significantly higher in the aspirated than in the peripheral blood in the patients hospitalized within 6 h and 6-12 h, but were similar in the aspirated and peripheral blood of the patients hospitalized 12-24 h after the onset of AMI. There were no differences between the aspirated serum and peripheral blood in the levels of interleukin-1beta and MMP-2. CONCLUSIONS The levels of MMP-1, MMP-13 and IL-6 were higher in the culprit coronary artery than in the peripheral blood. These factors appear to be involved in the early stage of AMI.
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Affiliation(s)
- H Suzuki
- Third Department of Internal Medicine, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan.
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31
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Abstract
Cardiovascular disease is the leading cause of morbidity and mortality in industrial societies, with myocardial infarction as the primary assassin. Pharmacologic agents, including the myocardial cell membrane receptor agonists adenosine, bradykinin/angiotensin-converting enzyme inhibitors, opioids and erythropoietin or the mixed cell membrane and intracellular agonists, glucose insulin potassium, and volatile anesthetics, either clinically or experimentally reduce the extent of myocardial injury when administered just prior to reperfusion. Agents that specifically target proteins, transcription factors or ion channels, including PKC agonists/antagonists, PPAR, Phosphodiesterase-5 inhibitors, 3-Hydroxy-3-methyl glutaryl coenzyme A reductase and the ATP-dependent potassium channel are also promising. However, no agent has been specifically approved to reduce reperfusion injury clinically. In this review, we will discuss the advantages and limitations of agents to combat reperfusion injury, their market development status and findings reported in both clinical and preclinical studies. The molecular pathways activated by these agents that preserve myocardium from reperfusion injury, which appear to commonly involve glycogen synthase kinase 3beta and mitochondrial permeability transition pore inhibition, are also described.
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Affiliation(s)
- Eric R Gross
- Medical College of Wisconsin, Department of Pharmacology and Toxicology, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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32
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Tsouli SG, Liberopoulos EN, Goudevenos JA, Mikhailidis DP, Elisaf MS. Should a statin be prescribed to every patient with heart failure? Heart Fail Rev 2007; 13:211-25. [PMID: 17694432 DOI: 10.1007/s10741-007-9041-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Accepted: 06/06/2007] [Indexed: 12/22/2022]
Abstract
Chronic heart failure (HF) represents an emerging epidemic since its prevalence is continuously increasing despite advances in treatment. Many recent clinical studies have clearly demonstrated that statin therapy is associated with improved outcomes in HF irrespective of aetiology (ischaemic or not) or baseline cholesterol levels. Indeed, most of the conducted large statin trials and trials in HF have demonstrated a positive effect of statins in HF patients. Furthermore, the use of statins in HF seems to be safe as none of the recent trials has resulted in worse outcomes for HF patients treated with statins. Potential mechanisms through which statins could benefit the failing myocardium include non-sterol effects of statins, as well as effects on nitric oxide and endothelial function, inflammation and adhesion molecules, apoptosis and myocardial remodelling and neurohormonal activation. This review discusses the pathophysiological basis of statin effects on HF and focuses on clinical data for the benefit from statin use in this setting. Until today there are no official recommendations in both the American and the European guidelines regarding the use of statins in HF patients, as the available data come from small observational or larger but retrospective, non-randomised studies. Therefore, HF patients should be treated according to current lipid guidelines. Large randomised clinical trials are underway and will further delineate the role of statin therapy in HF patients. Until more data are available, we could not recommend statin use to every patient with HF irrespective of HF aetiology and baseline cholesterol levels.
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Affiliation(s)
- Sofia G Tsouli
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina 45110, Greece.
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33
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Jguirim-Souissi I, Jelassi A, Addad F, Hassine M, Najah M, Ben Hamda K, Maatouk F, Ben Farhat M, Bouslema A, Rouis M, Slimane MN. Plasma metalloproteinase-12 and tissue inhibitor of metalloproteinase-1 levels and presence, severity, and outcome of coronary artery disease. Am J Cardiol 2007; 100:23-7. [PMID: 17599435 DOI: 10.1016/j.amjcard.2007.01.069] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2006] [Revised: 01/29/2007] [Accepted: 01/29/2007] [Indexed: 10/23/2022]
Abstract
Several matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in the development and outcome of coronary artery disease (CAD). We investigated whether MMP-12 and TIMP-1 levels were associated with risk, severity, and outcome of CAD. Plasma MMP-12 and TIMP-1 levels are measured in 50 and 44 patients with CAD, respectively, by enzyme-linked immunosorbent assay. Of all patients, 16 were taking statins. Patients who were not on statins were classified into 3 groups according to number of >50% stenotic vessels. Compared with 29 volunteers without CAD, patients without statins (n = 34) had higher MMP-12 concentrations (1.71 vs 1.08 ng/ml, p = 0.021). MMP-12 levels were significantly lower in patients with than in those without statin treatment (0.99 vs 1.71 ng/ml, p = 0.008). There was no association between MMP-12 levels and number of >50% stenotic vessels. MMP-12 concentrations were not associated with outcome of CAD. However, plasma TIMP-1 levels were associated with restenosis independently of number of stenotic vessels and age (p = 0.035) but not with risk or severity of CAD. In conclusion, plasma MMP-12 concentration was associated with the presence of CAD. Statin therapy decreases plasma MMP-12 levels in patients with CAD. Increased TIMP-1 levels may prevent restenosis after angioplasty.
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Affiliation(s)
- Imen Jguirim-Souissi
- Unit of Research, Genetic and Biologic Factors of Atherosclerosis, Faculty of Medicine, CHU Fattouma, Bourguiba, Monastir, Tunisia
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34
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Turhan H, Aksoy Y, Yetkin E, Kosar F. Ventricular remodeling following acute myocardial infarction: The role of altered collagen homeostasis. Int J Cardiol 2007; 119:124-5; author reply 126. [PMID: 17049392 DOI: 10.1016/j.ijcard.2006.07.101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2006] [Accepted: 07/15/2006] [Indexed: 10/24/2022]
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Yasuda S, Miyazaki S, Kinoshita H, Nagaya N, Kanda M, Goto Y, Nonogi H. Enhanced cardiac production of matrix metalloproteinase-2 and -9 and its attenuation associated with pravastatin treatment in patients with acute myocardial infarction. Clin Sci (Lond) 2007; 112:43-9. [PMID: 16939410 DOI: 10.1042/cs20060110] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Previous experimental studies have demonstrated that MMPs (matrix metalloproteinases) contribute to LV (left ventricular) remodelling. We hypothesized that cardiac MMPs are activated in patients with AMI (acute myocardial infarction) and, if so, MMP production may be attenuated by statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) through their cardiovascular protective actions. We studied 30 patients, ten control patients with stable angina pectoris and 20 patients with AMI, in whom LV catheterization at the chronic stage was performed 22+/-12 days (value is mean+/-S.D.) after the onset of AMI. Blood samples were collected from the CS (coronary sinus) and a peripheral artery. In patients with AMI, the levels of MMP-2 and MMP-9 were significantly (P<0.05) higher in the CS than the peripheral artery (MMP-2, 853+/-199 compared with 716+/-127 ng/ml; MMP-9, 165+/-129 compared with 98+/-82 ng/ml), whereas no significant differences were observed in the patients with angina pectoris. The CS-arterial concentration gradients of MMP-2 and MMP-9 correlated positively with BNP (brain natriuretic peptide) levels (MMP-2, R=0.68, P<0.01; MMP-9, R=0.59, P<0.05) and LV end-diastolic volume index (MMP-2, R=0.70, P<0.01; MMP-9, R=0.70, P<0.01). When patients with AMI treated with 10 mg of pravastatin or without (n=10 in each group) were compared, this statin therapy significantly (P<0.05) decreased the CS-arterial concentration gradients of MMP-2 (69+/-43 compared with 213+/-185 ng/ml) and MMP-9 (14+/-27 compared with 119+/-84 ng/ml). In conclusion, the enhanced production of cardiac MMP-2 and MMP-9 is associated with LV enlargement and elevated BNP levels in patients with AMI. A pleiotropic effect of statins appears to be associated with the modulation of cardiac MMP activation, which may be potentially beneficial in the attenuation of post-infarction LV remodelling.
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Affiliation(s)
- Satoshi Yasuda
- Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
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Hawkins BT, Lundeen TF, Norwood KM, Brooks HL, Egleton RD. Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases. Diabetologia 2007; 50:202-11. [PMID: 17143608 DOI: 10.1007/s00125-006-0485-z] [Citation(s) in RCA: 259] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2006] [Accepted: 09/14/2006] [Indexed: 11/26/2022]
Abstract
AIMS/HYPOTHESIS Although diabetes mellitus is associated with peripheral microvascular complications and increased risk of neurological events, the mechanisms by which diabetes disrupts the blood-brain barrier (BBB) are not known. Matrix metalloproteinase (MMP) activity is increased in diabetic patients, is associated with degradation of tight junction proteins, and is a known mediator of BBB compromise. We hypothesise that diabetes leads to compromise of BBB tight junctions via stimulation of MMP activity. MATERIALS AND METHODS Diabetes was induced in the rat with streptozotocin. At 14 days after injection, BBB function was assessed by in situ brain perfusion. Tight junction proteins were assessed by immunoblot and immunofluorescence. Plasma MMP activity was quantified by fluorometric gelatinase assay and gel zymography. RESULTS In streptozotocin-treated animals, permeability to [(14)C]sucrose increased concurrently with decreased production of BBB tight junction proteins occludin (also known as OCLN) and zona occludens 1 (ZO-1, also known as tight junction protein 1 or TJP1). Insulin treatment, begun on day 7, normalised blood glucose levels and attenuated BBB hyperpermeability to [(14)C]sucrose. Neither acute hyperglycaemia in naive animals nor acute normalisation of blood glucose in streptozotocin-treated animals altered BBB permeability to [(14)C]sucrose. Plasma MMP activity was increased in streptozotocin-treated animals. CONCLUSIONS/INTERPRETATION These data indicate that diabetes increases BBB permeability via a loss of tight junction proteins, and that increased BBB permeability in diabetes does not result from hyperglycaemia alone. Increased plasma MMP activity is implicated in degradation of BBB tight junction proteins and increased BBB permeability in diabetes. Peripheral MMP activity may present a novel target for protection of the BBB and prevention of neurological complications in diabetes.
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Affiliation(s)
- B T Hawkins
- Department of Medical Pharmacology, The University of Arizona College of Medicine, 1501 N. Campbell Ave., P.O. Box 245050, Tucson, AZ 85724-5050, USA
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