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Gaydarski L, Petrova K, Stanchev S, Pelinkov D, Iliev A, Dimitrova IN, Kirkov V, Landzhov B, Stamenov N. Morphometric and Molecular Interplay in Hypertension-Induced Cardiac Remodeling with an Emphasis on the Potential Therapeutic Implications. Int J Mol Sci 2025; 26:4022. [PMID: 40362262 PMCID: PMC12071960 DOI: 10.3390/ijms26094022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/16/2025] [Accepted: 04/19/2025] [Indexed: 05/15/2025] Open
Abstract
Hypertension-induced cardiac remodeling is a complex process driven by interconnected molecular and cellular mechanisms that culminate in hypertensive myocardium, characterized by ventricular hypertrophy, fibrosis, impaired angiogenesis, and myocardial dysfunction. This review discusses the histomorphometric changes in capillary density, fibrosis, and mast cells in the hypertensive myocardium and delves into the roles of key regulatory systems, including the apelinergic system, vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathways, and nitric oxide (NO)/nitric oxide synthase (NOS) signaling in the pathogenesis of hypertensive heart disease (HHD). Capillary rarefaction, a hallmark of HHD, contributes to myocardial ischemia and fibrosis, underscoring the importance of maintaining vascular integrity. Targeting capillary density (CD) through antihypertensive therapy or angiogenic interventions could significantly improve cardiac outcomes. Myocardial fibrosis, mediated by excessive collagen deposition and influenced by fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta (TGF-β), plays a pivotal role in the structural remodeling of hypertensive myocardium. While renin-angiotensin-aldosterone system (RAAS) inhibitors show anti-fibrotic effects, more targeted therapies are needed to address fibrosis directly. Mast cells, though less studied in humans, emerge as critical regulators of cardiac remodeling through their release of pro-fibrotic mediators such as histamine, tryptase, and FGF-2. The apelinergic system emerges as a promising therapeutic target due to its vasodilatory, anti-fibrotic, and cardioprotective properties. The system counteracts the deleterious effects of the RAAS and has demonstrated efficacy in preclinical models of hypertension-induced cardiac damage. Despite its potential, human studies on apelin analogs remain limited, warranting further exploration to evaluate their clinical utility. VEGF signaling plays a dual role, facilitating angiogenesis and compensatory remodeling during the early stages of arterial hypertension (AH) but contributing to maladaptive changes when dysregulated. Modulating VEGF signaling through exercise or pharmacological interventions has shown promise in improving CD and mitigating hypertensive cardiac damage. However, VEGF inhibitors, commonly used in oncology, can exacerbate AH and endothelial dysfunction, highlighting the need for therapeutic caution. The NO/NOS pathway is essential for vascular homeostasis and the prevention of oxidative stress. Dysregulation of this pathway, particularly endothelial NOS (eNOS) uncoupling and inducible NOS (iNOS) overexpression, leads to endothelial dysfunction and nitrosative stress in hypertensive myocardium. Strategies to restore NO bioavailability, such as tetrahydrobiopterin (BH4) supplementation and antioxidants, hold potential for therapeutic application but require further validation. Future studies should adopt a multidisciplinary approach to integrate molecular insights with clinical applications, paving the way for more personalized and effective treatments for HHD. Addressing these challenges will not only enhance the understanding of hypertensive myocardium but also improve patient outcomes and quality of life.
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Affiliation(s)
- Lyubomir Gaydarski
- Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria; (K.P.); (S.S.); (D.P.); (A.I.); (B.L.); (N.S.)
| | - Kristina Petrova
- Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria; (K.P.); (S.S.); (D.P.); (A.I.); (B.L.); (N.S.)
| | - Stancho Stanchev
- Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria; (K.P.); (S.S.); (D.P.); (A.I.); (B.L.); (N.S.)
| | - Dimitar Pelinkov
- Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria; (K.P.); (S.S.); (D.P.); (A.I.); (B.L.); (N.S.)
| | - Alexandar Iliev
- Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria; (K.P.); (S.S.); (D.P.); (A.I.); (B.L.); (N.S.)
| | - Iva N. Dimitrova
- Department of Cardiology, University Hospital “St. Ekaterina”, Medical University of Sofia, 1431 Sofia, Bulgaria;
| | - Vidin Kirkov
- Department of Health Policy and Management, Faculty of Public Health ‘Prof. Dr. Tzekomir Vodenicharov’, Medical University of Sofia, 1527 Sofia, Bulgaria;
| | - Boycho Landzhov
- Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria; (K.P.); (S.S.); (D.P.); (A.I.); (B.L.); (N.S.)
| | - Nikola Stamenov
- Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria; (K.P.); (S.S.); (D.P.); (A.I.); (B.L.); (N.S.)
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Roy R, Wilcox J, Webb AJ, O’Gallagher K. Dysfunctional and Dysregulated Nitric Oxide Synthases in Cardiovascular Disease: Mechanisms and Therapeutic Potential. Int J Mol Sci 2023; 24:15200. [PMID: 37894881 PMCID: PMC10607291 DOI: 10.3390/ijms242015200] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, as well as the nitrate-nitrite-NO pathway. The three isoforms of NOS, namely neuronal (NOS1), inducible (NOS2), and endothelial (NOS3), have different localisation and functions in the human body, and are consequently thought to have differing pathophysiological roles. Furthermore, as we continue to develop a deepened understanding of the different roles of NOS isoforms in disease, the possibility of therapeutically modulating NOS activity has emerged. Indeed, impaired (or dysfunctional), as well as overactive (or dysregulated) NOS activity are attractive therapeutic targets in cardiovascular disease. This review aims to describe recent advances in elucidating the physiological role of NOS isoforms within the cardiovascular system, as well as mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease. We then discuss the modulation of NO and NOS activity as a target in the development of novel cardiovascular therapeutics.
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Affiliation(s)
- Roman Roy
- Cardiovascular Department, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK;
| | - Joshua Wilcox
- Cardiovascular Department, Guy’s and St. Thomas’ NHS Foundation Trust, London SE1 7EH, UK;
| | - Andrew J. Webb
- Department of Clinical Pharmacology, British Heart Foundation Centre, School of Cardiovascular and Metabolic Medicine and Sciences, King’s College London, London SE1 7EH, UK;
| | - Kevin O’Gallagher
- Cardiovascular Department, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK;
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NU, UK
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Jasińska-Stroschein M. Searching for Effective Treatments in HFpEF: Implications for Modeling the Disease in Rodents. Pharmaceuticals (Basel) 2023; 16:1449. [PMID: 37895920 PMCID: PMC10610318 DOI: 10.3390/ph16101449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/04/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND While the prevalence of heart failure with preserved ejection fraction (HFpEF) has increased over the last two decades, there still remains a lack of effective treatment. A key therapeutic challenge is posed by the absence of animal models that accurately replicate the complexities of HFpEF. The present review summarizes the effects of a wide spectrum of therapeutic agents on HF. METHODS Two online databases were searched for studies; in total, 194 experimental protocols were analyzed following the PRISMA protocol. RESULTS A diverse range of models has been proposed for studying therapeutic interventions for HFpEF, with most being based on pressure overload and systemic hypertension. They have been used to evaluate more than 150 different substances including ARNIs, ARBs, HMGR inhibitors, SGLT-2 inhibitors and incretins. Existing preclinical studies have primarily focused on LV diastolic performance, and this has been significantly improved by a wide spectrum of candidate therapeutic agents. Few experiments have investigated the normalization of pulmonary congestion, exercise capacity, animal mortality, or certain molecular hallmarks of heart disease. CONCLUSIONS The development of comprehensive preclinical HFpEF models, with multi-organ system phenotyping and physiologic stress-based functional testing, is needed for more successful translation of preclinical research to clinical trials.
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Cai Z, Wu C, Xu Y, Cai J, Zhao M, Zu L. The NO-cGMP-PKG Axis in HFpEF: From Pathological Mechanisms to Potential Therapies. Aging Dis 2023; 14:46-62. [PMID: 36818566 PMCID: PMC9937694 DOI: 10.14336/ad.2022.0523] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/23/2022] [Indexed: 11/18/2022] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) accounts for almost half of all heart failure (HF) cases worldwide. Unfortunately, its incidence is expected to continue to rise, and effective therapy to improve clinical outcomes is lacking. Numerous efforts currently directed towards the pathophysiology of human HFpEF are uncovering signal transduction pathways and novel therapeutic targets. The nitric oxide-cyclic guanosine phosphate-protein kinase G (NO-cGMP-PKG) axis has been described as an important regulator of cardiac function. Suppression of the NO-cGMP-PKG signalling pathway is involved in the progression of HFpEF. Therefore, the NO-cGMP-PKG signalling pathway is a potential therapeutic target for HFpEF. In this review, we aim to explore the mechanism of NO-cGMP-PKG in the progression of HFpEF and to summarize potential therapeutic drugs that target this signalling pathway.
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Affiliation(s)
- Zhulan Cai
- Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, China.
| | - Cencen Wu
- Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, China.
| | - Yuan Xu
- Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, China.
| | - Jiageng Cai
- Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, China.
| | - Menglin Zhao
- Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, China.
| | - Lingyun Zu
- Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, China.
- Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, China.
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China
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Shcheblykin DV, Bolgov AA, Pokrovskii MV, Stepenko JV, Tsuverkalova JM, Shcheblykina OV, Golubinskaya PA, Korokina LV. Endothelial dysfunction: developmental mechanisms and therapeutic strategies. RESEARCH RESULTS IN PHARMACOLOGY 2022. [DOI: 10.3897/rrpharmacology.8.80376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Introduction: Every year the importance of the normal functioning of the endothelial layer of the vascular wall in maintaining the health of the body becomes more and more obvious.
The physiological role of the endothelium: The endothelium is a metabolically active organ actively involved in the regulation of hemostasis, modulation of inflammation, maintenance of hemovascular homeostasis, regulation of angiogenesis, vascular tone, and permeability.
Risk factors for the development of endothelial dysfunction: Currently, insufficient bioavailability of nitric oxide is considered the most significant risk factor for endothelial dysfunction.
Mechanisms of development of endothelial dysfunction: The genesis of endothelial dysfunction is a multifactorial process. Among various complex mechanisms, this review examines oxidative stress, inflammation, hyperglycemia, vitamin D deficiency, dyslipidemia, excess visceral fat, hyperhomocysteinemia, hyperuricemia, as well as primary genetic defect of endotheliocytes, as the most common causes in the population underlying the development of endothelial dysfunction.
Markers of endothelial dysfunction in various diseases: This article discusses the main biomarkers of endothelial dysfunction currently used, as well as promising biomarkers in the future for laboratory diagnosis of this pathology.
Therapeutic strategies: Therapeutic approaches to the endothelium in order to prevent or reduce a degree of damage to the vascular wall are briefly described.
Conclusion: Endothelial dysfunction is a typical pathological process involved in the pathogenesis of many diseases. Thus, pharmacological agents with endothelioprotective properties can provide more therapeutic benefits than a drug without such an effect.
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Cornuault L, Rouault P, Duplàa C, Couffinhal T, Renault MA. Endothelial Dysfunction in Heart Failure With Preserved Ejection Fraction: What are the Experimental Proofs? Front Physiol 2022; 13:906272. [PMID: 35874523 PMCID: PMC9304560 DOI: 10.3389/fphys.2022.906272] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) has been recognized as the greatest single unmet need in cardiovascular medicine. Indeed, the morbi-mortality of HFpEF is high and as the population ages and the comorbidities increase, so considerably does the prevalence of HFpEF. However, HFpEF pathophysiology is still poorly understood and therapeutic targets are missing. An unifying, but untested, theory of the pathophysiology of HFpEF, proposed in 2013, suggests that cardiovascular risk factors lead to a systemic inflammation, which triggers endothelial cells (EC) and coronary microvascular dysfunction. This cardiac small vessel disease is proposed to be responsible for cardiac wall stiffening and diastolic dysfunction. This paradigm is based on the fact that microvascular dysfunction is highly prevalent in HFpEF patients. More specifically, HFpEF patients have been shown to have decreased cardiac microvascular density, systemic endothelial dysfunction and a lower mean coronary flow reserve. Importantly, impaired coronary microvascular function has been associated with the severity of HF. This review discusses evidence supporting the causal role of endothelial dysfunction in the pathophysiology of HFpEF in human and experimental models.
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Musicante M, Kim HH, Chen Y, Liao F, Bhattacharya SK, Lu L, Sun Y. Regulation of endothelial nitric oxide synthase in cardiac remodeling. Int J Cardiol 2022; 364:96-101. [PMID: 35654172 DOI: 10.1016/j.ijcard.2022.05.013] [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: 11/11/2021] [Revised: 03/25/2022] [Accepted: 05/06/2022] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Our previous study demonstrated that endothelial nitric oxide synthase (eNOS) gene serves as a candidate for modifiers of hypertrophic cardiomyopathy (HCM), which alters severity of HCM phenotypes. Herein, we sought to further elucidate the role of eNOS on cardiac myocyte hypertrophy and fibrosis, the major phenotypes of HCM. METHODS Male eNOS-deficient mice (eNOS-/-) and wild type control mice (eNOS+/+, C57B1/6 J) were used in this study. Myocyte size was analyzed in hematoxylin/eosin stained sections using an image analyzing system. Cardiac β-myosin heavy chain (β-MHC) and α-skeletal actin (α-SKA) levels, markers of myocyte hypertrophy were evaluated by Western blot. Cardiac collagen volume fraction (CVF) was examined in picrosirius red stained section using an image analyzing system. Cardiac expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and transforming growth factor beta 1 (TGF-β1), markers of fibrosis, were determined by Western blot. RESULTS Compared to eNOS+/+ mice, we found that; 1) myocyte size was significantly increased in eNOS-/- mice; 2) cardiac expression of β-MHC was markedly elevated, while α-SKA levels remained unchanged in eNOS-/- mice; 3) cardiac total and interstitial CVF levels were significantly higher in eNOS-/- mice; and 4) cardiac TIMP-1 levels were significantly greater in eNOS-/- mice, however, cardiac TGF-β1 was not differently expressed between the two groups. CONCLUSION The current study revealed that eNOS plays a beneficial role in cardiac remodeling, preventing the heart from development of myocyte hypertrophy and cardiac fibrosis. These findings support our previous report that eNOS may modify the severity of HCM phenotypes.
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Affiliation(s)
- Meryl Musicante
- University of Tennessee Health Science Center, United States of America
| | - Hannah H Kim
- University of Tennessee Health Science Center, United States of America
| | - Yuanjian Chen
- Division of Cardiovascular Diseases, Department of Medicine(,) University of Tennessee Health Science Center, Memphis, TN, United States of America
| | - Fang Liao
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, United States of America
| | - Syamal K Bhattacharya
- Division of Cardiovascular Diseases, Department of Medicine(,) University of Tennessee Health Science Center, Memphis, TN, United States of America
| | - Lu Lu
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, United States of America.
| | - Yao Sun
- Division of Cardiovascular Diseases, Department of Medicine(,) University of Tennessee Health Science Center, Memphis, TN, United States of America.
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Adekunle AO, Adzika GK, Mprah R, Ndzie Noah ML, Adu-Amankwaah J, Rizvi R, Akhter N, Sun H. Predominance of Heart Failure With Preserved Ejection Fraction in Postmenopausal Women: Intra- and Extra-Cardiomyocyte Maladaptive Alterations Scaffolded by Estrogen Deficiency. Front Cell Dev Biol 2021; 9:685996. [PMID: 34660569 PMCID: PMC8511782 DOI: 10.3389/fcell.2021.685996] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 09/09/2021] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) remains a public health concern as it is associated with high morbidity and death rates. In particular, heart failure with preserved ejection fraction (HFpEF) represents the dominant (>50%) form of HF and mostly occurring among postmenopausal women. Hence, the initiation and progression of the left ventricular diastolic dysfunctions (LVDD) (a typically clinical manifestation of HFpEF) in postmenopausal women have been attributed to estrogen deficiency and the loss of its residue cardioprotective effects. In this review, from a pathophysiological and immunological standpoint, we discuss the probable multiple pathomechanisms resulting in HFpEF, which are facilitated by estrogen deficiency. The initial discussions recap estrogen and estrogen receptors (ERs) and β-adrenergic receptors (βARs) signaling under physiological/pathological states to facilitate cardiac function/dysfunction, respectively. By reconciling these prior discussions, attempts were made to explain how the loss of estrogen facilitates the disruptions both ERs and βARs-mediated signaling responsible for; the modulation of intra-cardiomyocyte calcium homeostasis, maintenance of cardiomyocyte cytoskeletal and extracellular matrix, the adaptive regulation of coronary microvascular endothelial functions and myocardial inflammatory responses. By scaffolding the disruption of these crucial intra- and extra-cardiomyocyte physiological functions, estrogen deficiency has been demonstrated to cause LVDD and increase the incidence of HFpEF in postmenopausal women. Finally, updates on the advancements in treatment interventions for the prevention of HFpEF were highlighted.
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Affiliation(s)
| | | | - Richard Mprah
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | | | | | | | - Nazma Akhter
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Hong Sun
- Department of Physiology, Xuzhou Medical University, Xuzhou, China.,Xuzhou Medical University, Xuzhou, China
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Chi C, Liu Y, Xu Y, Xu D. Association Between Arterial Stiffness and Heart Failure With Preserved Ejection Fraction. Front Cardiovasc Med 2021; 8:707162. [PMID: 34458336 PMCID: PMC8385653 DOI: 10.3389/fcvm.2021.707162] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 07/14/2021] [Indexed: 01/23/2023] Open
Abstract
Cardiovascular diseases are the leading cause of mortality in the world. Heart failure with preserved ejection fraction (HFpEF) accounts for about half of all heart failure. Unfortunately, the mechanisms of HFpEF are still unclear, leading to little progress of effective treatment of HFpEF. Arterial stiffness is the decrement of arterial compliance. The media of large arteries degenerate in both physiological and pathological conditions. Many studies have proven that arterial stiffness is an independent risk factor for cardiovascular disorders including diastolic dysfunction. In this perspective, we discussed if arterial stiffness is related to HFpEF, and how does arterial stiffness contribute to HFpEF. Finally, we briefly summarized current treatment strategies on arterial stiffness and HFpEF. Though some new drugs were developed, the safety and effectiveness were not adequately assessed. New pharmacologic treatment for arterial stiffness and HFpEF are urgently needed.
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Affiliation(s)
- Chen Chi
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yifan Liu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yawei Xu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Dachun Xu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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Lin Y, Fu S, Yao Y, Li Y, Zhao Y, Luo L. Heart failure with preserved ejection fraction based on aging and comorbidities. J Transl Med 2021; 19:291. [PMID: 34229717 PMCID: PMC8259336 DOI: 10.1186/s12967-021-02935-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 06/10/2021] [Indexed: 12/25/2022] Open
Abstract
Heart failure (HF) with preserved ejection fraction (HFpEF) is a leading cause of hospitalizations and mortality when diagnosed at the age of ≥ 65 years. HFpEF represents multifactorial and multisystemic syndrome and has different pathophysiology and phenotypes. Its diagnosis is difficult to be established based on left ventricular ejection fraction and may benefit from individually tailored approaches, underlying age-related changes and frequent comorbidities. Compared with the rapid development in the treatment of heart failure with reduced ejection fraction, HFpEF presents a great challenge and needs to be addressed considering the failure of HF drugs to improve its outcomes. Further extensive studies on the relationships between HFpEF, aging, and comorbidities in carefully phenotyped HFpEF subgroups may help understand the biology, diagnosis, and treatment of HFpEF. The current review summarized the diagnostic and therapeutic development of HFpEF based on the complex relationships between aging, comorbidities, and HFpEF.
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Affiliation(s)
- Ying Lin
- Department of Cardiology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, 572013, China
| | - Shihui Fu
- Department of Cardiology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, 572013, China.
- Department of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China.
| | - Yao Yao
- Centre for the Study of Ageing and Human Development and Geriatrics Division, Medical School of Duke University, Durham, NC, 27708, USA
- Centre for Healthy Ageing and Development Studies, National School of Development, Peking University, Beijing, 100871, China
| | - Yulong Li
- Department of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Yali Zhao
- Central Laboratory, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, 572013, China.
| | - Leiming Luo
- Department of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China.
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Generation and identification of endothelial-specific Hrh2 knockout mice. Transgenic Res 2021; 30:251-261. [PMID: 33786748 DOI: 10.1007/s11248-021-00244-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 03/13/2021] [Indexed: 12/11/2022]
Abstract
Histamine H2 receptor (HRH2) is closely associated with the development of cardiovascular and cerebrovascular diseases. However, systematic Hrh2 knockout mice did not exactly reflect the HRH2 function in specific cell or tissue types. To better understand the physiological and pathophysiological functions of endothelial HRH2, this study constructed a targeting vector that contained loxp sites flanking the ATG start codon located in Hrh2 exon 2 upstream and a neomycin (Neo) resistance gene flanked by self-deletion anchor sites within the mouse Hrh2 allele. The targeting vector was then electroporated into C57BL/6J embryonic stem (ES) cells, and positively targeted ES cell clones were micoinjected into C57BL/6J blastocysts, which were implanted into pseudopregnant females to obtain chimeric mice. The F1 generation of Hrh2flox/+ mice was generated via crossing chimeric mice with wild-type mice to excise Neo. We also successfully generated endothelial cell-specific knockout (ECKO) mice by crossing Hrh2flox/+ mice with Cdh5-Cre mice that specifically express Cre in endothelial cells and identified that Hrh2 deletion was only observed in endothelial cells. Hrh2flox/+ and Hrh2ECKO mice were normal, healthy and fertile and did not display any obvious abnormalities. These novel animal models will create new prospects for exploring roles of HRH2 during the development and treatment of related diseases.
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Daiber A, Andreadou I, Oelze M, Davidson SM, Hausenloy DJ. Discovery of new therapeutic redox targets for cardioprotection against ischemia/reperfusion injury and heart failure. Free Radic Biol Med 2021; 163:325-343. [PMID: 33359685 DOI: 10.1016/j.freeradbiomed.2020.12.026] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/10/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023]
Abstract
Global epidemiological studies reported a shift from maternal/infectious communicable diseases to chronic non-communicable diseases and a major part is attributable to atherosclerosis and metabolic disorders. Accordingly, ischemic heart disease was identified as a leading risk factor for global mortality and morbidity with a prevalence of 128 million people. Almost 9 million premature deaths can be attributed to ischemic heart disease and subsequent acute myocardial infarction and heart failure, also representing a substantial socioeconomic burden. As evidenced by typical oxidative stress markers such as lipid peroxidation products or oxidized DNA/RNA bases, the formation of reactive oxygen species by various sources (NADPH oxidases, xanthine oxidase and mitochondrial resperatory chain) plays a central role for the severity of ischemia/reperfusion damage. The underlying mechanisms comprise direct oxidative damage but also adverse redox-regulation of kinase and calcium signaling, inflammation and cardiac remodeling among others. These processes and the role of reactive oxygen species are discussed in the present review. We also present and discuss potential targets for redox-based therapies that are either already established in the clinics (e.g. guanylyl cyclase activators and stimulators) or at least successfully tested in preclinical models of myocardial infarction and heart failure (mitochondria-targeted antioxidants). However, reactive oxygen species have not only detrimental effects but are also involved in essential cellular signaling and may even act protective as seen by ischemic pre- and post-conditioning or eustress - which makes redox therapy quite challenging.
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Affiliation(s)
- Andreas Daiber
- Department of Cardiology 1, Molecular Cardiology, University Medical Center, Langenbeckstr. 1, 55131, Mainz, Germany; Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr. 1, 55131, Mainz, Germany.
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
| | - Matthias Oelze
- Department of Cardiology 1, Molecular Cardiology, University Medical Center, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, 67 Chenies Mews, London, WC1E 6HX, United Kingdom
| | - Derek J Hausenloy
- The Hatter Cardiovascular Institute, 67 Chenies Mews, London, WC1E 6HX, United Kingdom; Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore; National Heart Research Institute Singapore, National Heart Centre, Singapore; Yong Loo Lin School of Medicine, National University Singapore, Singapore; Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan.
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13
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Wintrich J, Kindermann I, Ukena C, Selejan S, Werner C, Maack C, Laufs U, Tschöpe C, Anker SD, Lam CSP, Voors AA, Böhm M. Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future. Clin Res Cardiol 2020; 109:1079-1098. [PMID: 32236720 PMCID: PMC7449942 DOI: 10.1007/s00392-020-01633-w] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 03/11/2020] [Indexed: 02/07/2023]
Abstract
In contrast to the wealth of proven therapies for heart failure with reduced ejection fraction (HFrEF), therapeutic efforts in the past have failed to improve outcomes in heart failure with preserved ejection fraction (HFpEF). Moreover, to this day, diagnosis of HFpEF remains controversial. However, there is growing appreciation that HFpEF represents a heterogeneous syndrome with various phenotypes and comorbidities which are hardly to differentiate solely by LVEF and might benefit from individually tailored approaches. These hypotheses are supported by the recently presented PARAGON-HF trial. Although treatment with LCZ696 did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among HFpEF patients, subanalyses suggest beneficial effects in female patients and those with an LVEF between 45 and 57%. In the future, prospective randomized trials should focus on dedicated, well-defined subgroups based on various information such as clinical characteristics, biomarker levels, and imaging modalities. These could clarify the role of LCZ696 in selected individuals. Furthermore, sodium-glucose cotransporter-2 inhibitors have just proven efficient in HFrEF patients and are currently also studied in large prospective clinical trials enrolling HFpEF patients. In addition, several novel disease-modifying drugs that pursue different strategies such as targeting cardiac inflammation and fibrosis have delivered preliminary optimistic results and are subject of further research. Moreover, innovative device therapies may enhance management of HFpEF, but need prospective adequately powered clinical trials to confirm safety and efficacy regarding clinical outcomes. This review highlights the past, present, and future therapeutic approaches in HFpEF.
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Affiliation(s)
- Jan Wintrich
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany.
| | - Ingrid Kindermann
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany
| | - Christian Ukena
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany
| | - Simina Selejan
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany
| | - Christian Werner
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany
| | - Christoph Maack
- Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany
| | - Ulrich Laufs
- Klinik und Poliklinik für Kardiologie im Department für Innere Medizin, Neurologie und Dermatologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Carsten Tschöpe
- Department of Cardiology, Universitätsmedizin Berlin, Charite, Campus Rudolf Virchow Clinic (CVK), Augustenburger Platz 1, 13353, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site, Berlin, Germany
- Berlin-Brandenburg Institute of Health/Center for Regenerative Therapies (BIHCRT), Berlin, Germany
| | - Stefan D Anker
- Department of Cardiology, Universitätsmedizin Berlin, Charite, Campus Rudolf Virchow Clinic (CVK), Augustenburger Platz 1, 13353, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site, Berlin, Germany
- Berlin-Brandenburg Institute of Health/Center for Regenerative Therapies (BIHCRT), Berlin, Germany
| | - Carolyn S P Lam
- National Heart Centre, Singapore and Duke-National University of Singapore, Singapore, Singapore
- University Medical Centre Groningen, Groningen, The Netherlands
- The George Institute for Global Health, Sydney, Australia
| | - Adriaan A Voors
- University Medical Centre Groningen, Groningen, The Netherlands
| | - Michael Böhm
- Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany
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14
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Liu X, Wu J, Zhu C, Liu J, Chen X, Zhuang T, Kuang Y, Wang Y, Hu H, Yu P, Fan H, Zhang Y, Liu Z, Zhang L. Endothelial S1pr1 regulates pressure overload-induced cardiac remodelling through AKT-eNOS pathway. J Cell Mol Med 2019; 24:2013-2026. [PMID: 31854513 PMCID: PMC6991681 DOI: 10.1111/jcmm.14900] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 11/07/2019] [Accepted: 11/19/2019] [Indexed: 12/15/2022] Open
Abstract
Cardiac vascular microenvironment is crucial for cardiac remodelling during the process of heart failure. Sphingosine 1‐phosphate (S1P) tightly regulates vascular homeostasis via its receptor, S1pr1. We therefore hypothesize that endothelial S1pr1 might be involved in pathological cardiac remodelling. In this study, heart failure was induced by transverse aortic constriction (TAC) operation. S1pr1 expression is significantly increased in microvascular endothelial cells (ECs) of post‐TAC hearts. Endothelial‐specific deletion of S1pr1 significantly aggravated cardiac dysfunction and deteriorated cardiac hypertrophy and fibrosis in myocardium. In vitro experiments demonstrated that S1P/S1pr1 praxis activated AKT/eNOS signalling pathway, leading to more production of nitric oxide (NO), which is an essential cardiac protective factor. Inhibition of AKT/eNOS pathway reversed the inhibitory effect of EC‐S1pr1‐overexpression on angiotensin II (AngII)‐induced cardiomyocyte (CM) hypertrophy, as well as on TGF‐β‐mediated cardiac fibroblast proliferation and transformation towards myofibroblasts. Finally, pharmacological activation of S1pr1 ameliorated TAC‐induced cardiac hypertrophy and fibrosis, leading to an improvement in cardiac function. Together, our results suggest that EC‐S1pr1 might prevent the development of pressure overload‐induced heart failure via AKT/eNOS pathway, and thus pharmacological activation of S1pr1 or EC‐targeting S1pr1‐AKT‐eNOS pathway could provide a future novel therapy to improve cardiac function during heart failure development.
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Affiliation(s)
- Xiuxiang Liu
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jinjin Wu
- Cardiovascular Department, Shanghai Children's Medical Center, Shanghai Jiaotong University, Shanghai, China
| | - Chenying Zhu
- Heart Failure Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jie Liu
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoli Chen
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tao Zhuang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yashu Kuang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yanfang Wang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hao Hu
- Heart Failure Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ping Yu
- Heart Failure Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Huimin Fan
- Heart Failure Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuzhen Zhang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhongmin Liu
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lin Zhang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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15
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Gogiraju R, Bochenek ML, Schäfer K. Angiogenic Endothelial Cell Signaling in Cardiac Hypertrophy and Heart Failure. Front Cardiovasc Med 2019; 6:20. [PMID: 30895179 PMCID: PMC6415587 DOI: 10.3389/fcvm.2019.00020] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 02/14/2019] [Indexed: 12/30/2022] Open
Abstract
Endothelial cells are, by number, one of the most abundant cell types in the heart and active players in cardiac physiology and pathology. Coronary angiogenesis plays a vital role in maintaining cardiac vascularization and perfusion during physiological and pathological hypertrophy. On the other hand, a reduction in cardiac capillary density with subsequent tissue hypoxia, cell death and interstitial fibrosis contributes to the development of contractile dysfunction and heart failure, as suggested by clinical as well as experimental evidence. Although the molecular causes underlying the inadequate (with respect to the increased oxygen and energy demands of the hypertrophied cardiomyocyte) cardiac vascularization developing during pathological hypertrophy are incompletely understood. Research efforts over the past years have discovered interesting mediators and potential candidates involved in this process. In this review article, we will focus on the vascular changes occurring during cardiac hypertrophy and the transition toward heart failure both in human disease and preclinical models. We will summarize recent findings in transgenic mice and experimental models of cardiac hypertrophy on factors expressed and released from cardiomyocytes, pericytes and inflammatory cells involved in the paracrine (dys)regulation of cardiac angiogenesis. Moreover, we will discuss major signaling events of critical angiogenic ligands in endothelial cells and their possible disturbance by hypoxia or oxidative stress. In this regard, we will particularly highlight findings on negative regulators of angiogenesis, including protein tyrosine phosphatase-1B and tumor suppressor p53, and how they link signaling involved in cell growth and metabolic control to cardiac angiogenesis. Besides endothelial cell death, phenotypic conversion and acquisition of myofibroblast-like characteristics may also contribute to the development of cardiac fibrosis, the structural correlate of cardiac dysfunction. Factors secreted by (dysfunctional) endothelial cells and their effects on cardiomyocytes including hypertrophy, contractility and fibrosis, close the vicious circle of reciprocal cell-cell interactions within the heart during pathological hypertrophy remodeling.
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Affiliation(s)
- Rajinikanth Gogiraju
- Center for Cardiology, Cardiology I, Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.,Center for Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.,Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., Partner Site RheinMain (Mainz), Mainz, Germany
| | - Magdalena L Bochenek
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.,Center for Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.,Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., Partner Site RheinMain (Mainz), Mainz, Germany
| | - Katrin Schäfer
- Center for Cardiology, Cardiology I, Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.,Center for Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany.,Deutsches Zentrum für Herz-Kreislauf-Forschung e.V., Partner Site RheinMain (Mainz), Mainz, Germany
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16
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Daiber A, Xia N, Steven S, Oelze M, Hanf A, Kröller-Schön S, Münzel T, Li H. New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease. Int J Mol Sci 2019; 20:ijms20010187. [PMID: 30621010 PMCID: PMC6337296 DOI: 10.3390/ijms20010187] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 12/27/2018] [Accepted: 12/28/2018] [Indexed: 02/07/2023] Open
Abstract
The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupling” of the enzyme by adverse regulation of well-defined “redox switches” in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an important role for these processes. Accordingly, eNOS protein represents an attractive therapeutic target that, so far, was not pharmacologically exploited. With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation.
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Affiliation(s)
- Andreas Daiber
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany.
| | - Ning Xia
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
| | - Sebastian Steven
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
| | - Matthias Oelze
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
| | - Alina Hanf
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
| | - Swenja Kröller-Schön
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
| | - Thomas Münzel
- Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany.
| | - Huige Li
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
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17
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Hou HT, Wang J, Zhang X, Wang ZQ, Chen TN, Zhang JL, Yang Q, He GW. Endothelial nitric oxide synthase enhancer AVE3085 reverses endothelial dysfunction induced by homocysteine in human internal mammary arteries. Nitric Oxide 2018; 81:21-27. [PMID: 30300735 DOI: 10.1016/j.niox.2018.10.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 09/07/2018] [Accepted: 10/04/2018] [Indexed: 12/23/2022]
Abstract
Homocysteine (Hcy) is an independent risk factor for endothelial dysfunction in cardiovascular diseases. We hypothesized that the eNOS transcription enhancer AVE3085 may protect the endothelial function damaged by Hcy in the human internal mammary artery (IMA). Cumulative concentration-relaxation curves to acetylcholine (-10 to -4.5 log mol/L) or sodium nitroprusside were established in IMA from patients undergoing coronary artery surgery precontracted by U46619 (-8 log mol/L) in the absence/presence of Hcy (100 μmol/L) with/without AVE3085 (30 μmol/L) in vitro in a myograph. RT-qPCR and ELISA were used to quantify the mRNA and protein levels of eNOS. Colorimetric assay method was used to detect the production of nitric oxide (NO). Maximal relaxation was significantly attenuated by Hcy in human IMA. Co-incubation with AVE3085 protected endothelium from the impairment by Hcy and increased the production of NO. Exposure to Hcy for 24 h downregulated eNOS protein expression (P < 0.05) whereas it upregulated the expression of eNOS at mRNA levels (P < 0.05). The presence of AVE3085 in addition to Hcy significantly increased the eNOS protein (P < 0.05) and slightly decreased the mRNA level. The study for the first time revealed that in the human blood vessels (IMA) the clinically-relevant high concentration of Hcy directly causes endothelial dysfunction by downregulating eNOS protein that may be reversed by AVE3085. These findings not only provide new direction for protecting endothelium during coronary artery bypass grafting and improving long-term patency of the grafts, but also provide evidence to the use of eNOS enhancer in the patients with endothelial dysfunction in various pathological conditions.
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Affiliation(s)
- Hai-Tao Hou
- Department of Cardiovascular Surgery & Center for Basic Medical Research, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, China; The Affiliated Hospital of Hangzhou Normal University& Zhejiang University, Hangzhou, China
| | - Jun Wang
- Department of Cardiovascular Surgery & Center for Basic Medical Research, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, China
| | - Xi Zhang
- Department of Cardiovascular Surgery & Center for Basic Medical Research, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, China
| | - Zheng-Qing Wang
- Department of Cardiovascular Surgery & Center for Basic Medical Research, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, China
| | - Tie-Nan Chen
- Department of Cardiovascular Surgery & Center for Basic Medical Research, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, China
| | - Jian-Liang Zhang
- Department of Cardiovascular Surgery & Center for Basic Medical Research, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, China
| | - Qin Yang
- Department of Cardiovascular Surgery & Center for Basic Medical Research, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, China
| | - Guo-Wei He
- Department of Cardiovascular Surgery & Center for Basic Medical Research, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, China; The Affiliated Hospital of Hangzhou Normal University& Zhejiang University, Hangzhou, China; Department of Surgery, Oregon Health and Science University, Portland, OR, USA.
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18
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Tschöpe C, Van Linthout S, Kherad B. Heart Failure with Preserved Ejection Fraction and Future Pharmacological Strategies: a Glance in the Crystal Ball. Curr Cardiol Rep 2017; 19:70. [PMID: 28656481 DOI: 10.1007/s11886-017-0874-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW The current definition of heart failure is mainly based on an inappropriate measure of cardiac function, i.e., left ventricular ejection fraction (LVEF). The initial sole entity, heart failure with reduced ejection fraction (HFrEF, LVEF <40%), was complemented by the addition of heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%) and most recently, heart failure with mid-range ejection fraction (HFmrEF, LVEF 40-49%). Initially, HFpEF was believed to be a purely left ventricular diastolic dysfunction. Pathophysiological concepts of HFpEF have changed considerably during the last years. In addition to intrinsic cardiac mechanisms, the heart failure pathogenesis is increasingly considered as driven by non-cardiac systemic processes including metabolic disorders, ischemic conditions, and pro-inflammatory/pro-fibrotic or immunological alterations. Presentation and pathophysiology of HFpEF is heterogeneous, and its management remains a challenge since evidence of therapeutic benefits is scarce. Up to now, there are no therapies improving survival in patients with HFpEF. RECENT FINDINGS Several results from clinical and preclinical interventions targeting non-cardiac mechanisms or non-pharmacological interventions including new anti-diabetic or anti-inflammatory drugs, mitochondrial-targeted anti-oxidants, anti-fibrotic strategies, microRNases incl. antagomirs, cell therapeutic options, and high-density lipoprotein-raising strategies are promising and under further investigation. This review addresses mechanisms and available data of current best clinical practice and novel approaches towards HFpEF.
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Affiliation(s)
- Carsten Tschöpe
- Department of Cardiology, Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany. .,Berliner Zentrum für Regenerative Therapien (BCRT), Campus Virchow Klinikum (CVK), Berlin, Germany. .,Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Berlin, Germany. .,Campus Virchow Clinic, Department of Cardiology, Charité - Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353, Berlin, Germany.
| | - Sophie Van Linthout
- Berliner Zentrum für Regenerative Therapien (BCRT), Campus Virchow Klinikum (CVK), Berlin, Germany.,Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Berlin, Germany.,Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Föhrerstrasse 15, 13353, Berlin, Germany
| | - Behrouz Kherad
- Department of Cardiology, Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany.,Campus Virchow Clinic, Department of Cardiology, Charité - Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353, Berlin, Germany.,Privatpraxis Dr. Kherad, Große Hamburger Strasse 5-11, 10115, Berlin, Germany
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19
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Tschöpe C, Birner C, Böhm M, Bruder O, Frantz S, Luchner A, Maier L, Störk S, Kherad B, Laufs U. Heart failure with preserved ejection fraction: current management and future strategies : Expert opinion on the behalf of the Nucleus of the "Heart Failure Working Group" of the German Society of Cardiology (DKG). Clin Res Cardiol 2017; 107:1-19. [PMID: 29018938 DOI: 10.1007/s00392-017-1170-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 10/02/2017] [Indexed: 12/21/2022]
Abstract
About 50% of all patients suffering from heart failure (HF) exhibit a reduced ejection fraction (EF ≤ 40%), termed HFrEF. The others may be classified into HF with midrange EF (HFmrEF 40-50%) or preserved ejection fraction (HFpEF, EF ≥ 50%). Presentation and pathophysiology of HFpEF is heterogeneous and its management remains a challenge since evidence of therapeutic benefits on outcome is scarce. Up to now, there are no therapies improving survival in patients with HFpEF. Thus, the treatment targets symptom relief, quality of life and reduction of cardiac decompensations by controlling fluid retention and managing risk factors and comorbidities. As such, renin-angiotensin-aldosterone inhibitors, diuretics, calcium channel blockers (CBB) and beta-blockers, diet and exercise recommendations are still important in HFpEF, although these interventions are not proven to reduce mortality in large randomized controlled trials. Recently, numerous new treatment targets have been identified, which are further investigated in studies using, e.g. soluble guanylate cyclase stimulators, inorganic nitrates, the angiotensin receptor neprilysin inhibitor LCZ 696, and SGLT2 inhibitors. In addition, several devices such as the CardioMEMS, interatrial septal devices (IASD), cardiac contractility modulation (CCM), renal denervation, and baroreflex activation therapy (BAT) were investigated in different forms of HFpEF populations and some of them have the potency to offer new hopes for patients suffering from HFpEF. On the basic research field side, lot of new disease-modifying strategies are under development including anti-inflammatory drugs, mitochondrial-targeted antioxidants, new anti-fibrotic and microRNA-guided interventions are under investigation and showed already promising results. This review addresses available data of current best clinical practice and management approaches based on expert experiences and summarizes novel approaches towards HFpEF.
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Affiliation(s)
- Carsten Tschöpe
- Department of Cardiology, Universitätsmedizin Berlin, Charite, Campus Rudolf Virchow Clinic (CVK), Augustenburger Platz 1, 13353, Berlin, Germany. .,Berliner Zentrum für Regenerative Therapien (BCRT), Charite, Campus Virchow Clinic (CVK), Berlin, Germany. .,Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Standort Berlin/Charité, Berlin, Germany.
| | - Christoph Birner
- Germany Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Michael Böhm
- Innere Medizin III-Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Homburg, Germany
| | - Oliver Bruder
- Department of Cardiology and Angiology, Elisabeth Hospital, Essen, Germany
| | - Stefan Frantz
- Department of Internal Medicine III, University Halle, Halle, Germany
| | - Andreas Luchner
- Department of Internal Medicine I, Clinic St. Marien, Amberg, Germany
| | - Lars Maier
- Germany Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Stefan Störk
- Deutsches Zentrum für Herzinsuffizienz, Universitätsklinikum und Universität Würzburg, Würzburg, Germany
| | - Behrouz Kherad
- Department of Cardiology, Universitätsmedizin Berlin, Charite, Campus Rudolf Virchow Clinic (CVK), Augustenburger Platz 1, 13353, Berlin, Germany.,Privatpraxis Dr. Kherad, Berlin, Germany
| | - Ulrich Laufs
- Klinik und Poliklinik für Kardiologie im Department für Innere Medizin, Neurologie und Dermatologie, Universitätsklinikum Leipzig, Leipzig, Germany
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20
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Management of Heart Failure with Preserved Ejection Fraction: Current Challenges and Future Directions. Am J Cardiovasc Drugs 2017; 17:283-298. [PMID: 28316006 DOI: 10.1007/s40256-017-0219-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in patients older than 65 years. Among elderly women living in the community, HFpEF comprises nearly 90% of incident HF cases. The health and economic impact of HFpEF is at least as great as that of HF with reduced ejection fraction (HFrEF), with similar severity of acute hospitalization rates and substantial mortality. Despite the importance of HFpEF, our understanding of its pathophysiology is incomplete, and optimal treatment remains largely undefined. Unlike the management of HFrEF, there is a paucity of large evidence-based trials demonstrating morbidity and mortality benefit for the treatment of HFpEF. The agents tested in trials to date, which were based upon an incomplete understanding of the pathophysiology of HFpEF, have not been positive. There is an urgent need to understand HFpEF pathophysiology and to focus on developing novel therapeutic targets.
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21
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Abstract
Most elderly patients, particularly women, who have heart failure, have a preserved ejection fraction. Patients with this syndrome have severe symptoms of exercise intolerance, frequent hospitalizations, and increased mortality. Despite the importance of heart failure with preserved ejection fraction (HFpEF), the understanding of its pathophysiology is incomplete, and optimal treatment remains largely undefined. Unlike the management of HFrEF, there is a paucity of large evidence-based trials demonstrating morbidity and mortality benefit for the treatment of HFpEF. An update is presented on information regarding pathophysiology, diagnosis, management, and future directions in this important and growing disorder.
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Affiliation(s)
- Bharathi Upadhya
- Cardiovascular Medicine Section, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA
| | - Dalane W Kitzman
- Cardiovascular Medicine Section, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
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Chi L, Belardinelli L, Zeng A, Hirakawa R, Rajamani S, Ling H, Dhalla AK. Inhibition of late Na+ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats. Am J Physiol Heart Circ Physiol 2016; 310:H1313-20. [PMID: 26993228 DOI: 10.1152/ajpheart.00863.2015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 03/11/2016] [Indexed: 12/19/2022]
Abstract
Late Na(+) current (INaL) is enhanced in myocytes of animals with chronic heart failure and patients with hypertrophic cardiomyopathy. To define the role of INaL in diastolic heart failure, the effects of GS-458967 (GS-967), a potent INaL inhibitor on mechanical and electrical abnormalities, were determined in an animal model of diastolic dysfunction. Dahl salt-sensitive (DSS) rats fed a high-salt (HS) diet for 8 wk, compared with a normal salt (NS) diet, had increased left ventricular (LV) mass (1,257 ± 96 vs. 891 ± 34 mg) and diastolic dysfunction [isovolumic relaxation time (IVRT): 26.8 ± 0.5 vs. 18.9 ± 0.2 ms; early transmitral flow velocity/early mitral annulus velocity (E/E') ratio: 25.5 ± 1.9 vs. 14.9 ± 0.9]. INaL in LV myocytes from HS rats was significantly increased to 0.41 ± 0.02 from 0.14 ± 0.02 pA/pF in NS rats. The action potential duration (APD) was prolonged to 136 ± 12 from 68 ± 9 ms in NS rats. QTc intervals were longer in HS vs. NS rats (267 ± 8 vs. 212 ± 2 ms). Acute and chronic treatment with GS-967 decreased the enhanced INaL to 0.24 ± 0.01 and 0.17 ± 0.02 pA/pF, respectively, vs. 0.41 ± 0.02 pA/pF in the HS group. Chronic treatment with GS-967 dose-dependently reduced LV mass, the increases in E/E' ratio, and the prolongation of IVRT by 27, 27, and 20%, respectively, at the 1.0 mg·kg(-1)·day(-1) dose without affecting blood pressure or LV systolic function. The prolonged APDs in myocytes and QTc of HS rats were significantly reduced with GS-967 treatment. These results indicate that INaL is a significant contributor to the LV diastolic dysfunction, hypertrophy, and repolarization abnormalities and thus, inhibition of this current is a promising therapeutic target for diastolic heart failure.
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Affiliation(s)
- Liguo Chi
- Department of Cardiovascular Biology, Gilead Sciences, Fremont, California
| | - Luiz Belardinelli
- Department of Cardiovascular Biology, Gilead Sciences, Fremont, California
| | - Aliya Zeng
- Department of Cardiovascular Biology, Gilead Sciences, Fremont, California
| | - Ryoko Hirakawa
- Department of Cardiovascular Biology, Gilead Sciences, Fremont, California
| | - Sridharan Rajamani
- Department of Cardiovascular Biology, Gilead Sciences, Fremont, California
| | - Haiyun Ling
- Department of Cardiovascular Biology, Gilead Sciences, Fremont, California
| | - Arvinder K Dhalla
- Department of Cardiovascular Biology, Gilead Sciences, Fremont, California
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Ihori H, Nozawa T, Sobajima M, Shida T, Fukui Y, Fujii N, Inoue H. Waon therapy attenuates cardiac hypertrophy and promotes myocardial capillary growth in hypertensive rats: a comparative study with fluvastatin. Heart Vessels 2015; 31:1361-9. [PMID: 26686369 DOI: 10.1007/s00380-015-0779-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 12/02/2015] [Indexed: 12/26/2022]
Abstract
Cardiac hypertrophy and fibrosis in heart failure with preserved ejection fraction are associated with a pro-inflammatory state and reduced NO bioavailability. Effects on myocardial structural and molecular alterations were compared between Waon therapy (WT; repeated dry sauna therapy) and statin in hypertensive rats. Seven-week-old Dahl salt-sensitive rats were assigned to 4 groups: low-salt (LS) diet, high-salt (HS) diet, HS diet with oral fluvastatin (FL; 10 mg/kg/day for 4 weeks) starting from the age of 9 weeks, and HS diet with WT treatment in a far-infrared dry sauna (39 °C for 15 min followed by 34 °C for 20 min once daily for 4 weeks). HS rats developed left ventricular (LV) hypertrophy with preserved LV systolic function. WT reduced LV wall thickness and myocyte cross-sectional area along with decreased levels of myocardial ANP and BNP mRNA expression compared with HS rats. Reduction in LV fibrosis and increase in capillary density in WT animals were accompanied by reductions in myocardial levels of TGF-β1, MMP2, p22(phox) and gp91(phox) mRNA expression, and increases in myocardial levels of VEGF and HSP90 mRNA and phosphorylated eNOS protein. These effects were comparable between WT and FL animals. WT improves structural and molecular alterations in salt-induced hypertensive rats similarly to fluvastatin.
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Affiliation(s)
- Hiroyuki Ihori
- Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Takashi Nozawa
- Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Mitsuo Sobajima
- Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Takuya Shida
- Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yasutaka Fukui
- Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Nozomu Fujii
- Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Hiroshi Inoue
- Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
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24
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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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25
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Glezeva N, Gilmer JF, Watson CJ, Ledwidge M. A Central Role for Monocyte-Platelet Interactions in Heart Failure. J Cardiovasc Pharmacol Ther 2015; 21:245-61. [PMID: 26519384 DOI: 10.1177/1074248415609436] [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: 05/06/2015] [Accepted: 08/04/2015] [Indexed: 01/08/2023]
Abstract
Heart failure (HF) is an increasingly prevalent and costly multifactorial syndrome with high morbidity and mortality rates. The exact pathophysiological mechanisms leading to the development of HF are not completely understood. Several emerging paradigms implicate cardiometabolic risk factors, inflammation, endothelial dysfunction, myocardial fibrosis, and myocyte dysfunction as key factors in the gradual progression from a healthy state to HF. Inflammation is now a recognized factor in disease progression in HF and a therapeutic target. Furthermore, the monocyte-platelet interaction has been highlighted as an important pathophysiological link between inflammation, thrombosis, endothelial activation, and myocardial malfunction. The contribution of monocytes and platelets to acute cardiovascular injury and acute HF is well established. However, their role and interaction in the pathogenesis of chronic HF are not well understood. In particular, the cross talk between monocytes and platelets in the peripheral circulation and in the vicinity of the vascular wall in the form of monocyte-platelet complexes (MPCs) may be a crucial element, which influences the pathophysiology and progression of chronic heart disease and HF. In this review, we discuss the role of monocytes and platelets as key mediators of cardiovascular inflammation in HF, the mechanisms of cell activation, and the importance of monocyte-platelet interaction and complexes in HF pathogenesis. Finally, we summarize recent information on pharmacological inhibition of inflammation and studies of antithrombotic strategies in the setting of HF that can inform opportunities for future work. We discuss recent data on monocyte-platelet interactions and the potential benefits of therapy directed at MPCs, particularly in the setting of HF with preserved ejection fraction.
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Affiliation(s)
- Nadezhda Glezeva
- School of Medicine & Medical Science, UCD Conway Institute, University College Dublin, Dublin, Belfield, Dublin, Ireland
| | - John F Gilmer
- School of Pharmacy & Pharmaceutical Sciences, TCD Centre for Health Sciences, Trinity College Dublin, College Green, Dublin, Ireland
| | - Chris J Watson
- School of Medicine & Medical Science, UCD Conway Institute, University College Dublin, Dublin, Belfield, Dublin, Ireland
| | - Mark Ledwidge
- Chronic Cardiovascular Disease Management Unit and Heart Failure Unit, St Vincent's Healthcare Group/St Michael's Hospital, County Dublin, Ireland
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26
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Hoendermis ES, Liu LCY, Hummel YM, van der Meer P, de Boer RA, Berger RMF, van Veldhuisen DJ, Voors AA. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J 2015; 36:2565-73. [PMID: 26188003 DOI: 10.1093/eurheartj/ehv336] [Citation(s) in RCA: 249] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 06/30/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Heart failure with preserved ejection fraction (HFpEF), with associated pulmonary hypertension is an increasingly large medical problem. Phosphodiesterase (PDE)-5 inhibition may be of value in this population, but data are scarce and inconclusive. METHODS AND RESULTS In this single centre, randomized double-blind, placebo-controlled trial, we included 52 patients with pulmonary hypertension [mean pulmonary artery pressure (PAP) >25 mmHg; pulmonary artery wedge pressure (PAWP) >15 mmHg] due to HFpEF [left ventricular ejection fraction (LVEF) ≥45%]. Patients were randomized to the PDE-5 inhibitor sildenafil, titrated to 60 mg three times a day, or placebo for 12 weeks. The primary endpoint was change in mean PAP after 12 weeks. Secondary endpoints were change in mean PAWP, cardiac output, and peak oxygen consumption (peak VO2). Mean age was 74 ± 10 years, 71% was female, LVEF was 58%, median NT-proBNP level was 1087 (535-1945) ng/L. After 12 weeks, change in mean PAP was -2.4 (95% CI -4.5 to -0.3) mmHg in patients who received sildenafil, vs. -4.7 (95% CI -7.1 to -2.3) mmHg in placebo patients (P = 0.14). Sildenafil did not have a favourable effect on PAWP, cardiac output, and peak VO2. Adverse events were overall comparable between groups. CONCLUSION Treatment with sildenafil did not reduce pulmonary artery pressures and did not improve other invasive haemodynamic or clinical parameters in our study population, characterized by HFpEF patients with predominantly isolated post-capillary pulmonary hypertension. (ClinicalTrials.gov, number NCT01726049).
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Affiliation(s)
- Elke S Hoendermis
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Licette C Y Liu
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Yoran M Hummel
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Peter van der Meer
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rudolf A de Boer
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rolf M F Berger
- Center for Congenital Heart Diseases, Department of Pediatric Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Dirk J van Veldhuisen
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Adriaan A Voors
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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27
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[New therapy concepts for heart failure with preserved ejection fraction]. Herz 2015; 40:194-205. [PMID: 25737289 DOI: 10.1007/s00059-015-4210-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The management of patients with heart failure and preserved ejection fraction (HFpEF) remains challenging and requires an accurate diagnosis. Although currently no convincing therapy that can prolong survival in patients with HFpEF has been established, treatment of fluid retention, heart rate and control of comorbidities are important cornerstones to improve the quality of life and symptoms. In recent years many new therapy targets have been tested for development of successful interventional strategies for HFpEF. Insights into new mechanisms of HFpEF have shown that heart failure is associated with dysregulation of the nitric oxide-cyclic guanosine monophosphate-protein kinase (NO-cGMP-PK) pathway. Two new drugs are currently under investigation to test whether this pathway can be significantly improved by either the neprilysin inhibitor LCZ 696 due to an increase in natriuretic peptides or by the soluble guanylate cyclase stimulator vericiguat, which is also able to increase cGMP. In addition, several preclinical or early phase studies which are currently investigating new mechanisms for matrix, intracellular calcium and energy regulation including the role of microRNAs and new devices are presented and discussed.
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28
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Chen Y, Chen C, Feng C, Tang A, Ma Y, He X, Li Y, He J, Dong Y. AVE 3085, a novel endothelial nitric oxide synthase enhancer, attenuates cardiac remodeling in mice through the Smad signaling pathway. Arch Biochem Biophys 2015; 570:8-13. [PMID: 25712222 DOI: 10.1016/j.abb.2015.02.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Revised: 02/09/2015] [Accepted: 02/13/2015] [Indexed: 10/23/2022]
Abstract
AVE 3085 is a novel endothelial nitric oxide synthase enhancer. Although AVE 3085 treatment has been shown to be effective in spontaneously restoring endothelial function in hypertensive rats, little is known about the effects and mechanisms of AVE 3085 with respect to cardiac remodeling. The present study was designed to examine the effects of AVE 3085 on cardiac remodeling and the mechanisms underlying the effects of this compound. Mice were subjected to aortic banding to induce cardiac remodeling and were then administered AVE 3085 (10 mg kg day(-1), orally) for 4 weeks. At the end of the treatment, the aortic banding-treated mice exhibited significant elevations in cardiac remodeling, characterized by an increase in left ventricular weight relative to body weight, an increase in the area of collagen deposition, an increase in the mean myocyte diameter, and increases in the gene expressions of the hypertrophic markers atrial natriuretic peptide (ANP) and β-MHC. These indexes were significantly decreased in the AVE 3085-treated mice. Furthermore, AVE 3085 treatment reduced the expression and activation of the Smad signaling pathway in the aortic banding-treated mice. Our data showed that AVE 3085 attenuated cardiac remodeling, and this effect was possibly mediated through the inhibition of Smad signaling.
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Affiliation(s)
- Yili Chen
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, PR China
| | - Cong Chen
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, PR China
| | - Cong Feng
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, PR China
| | - Anli Tang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, PR China
| | - Yuedong Ma
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, PR China
| | - Xin He
- Class 3 of Year 2011, Faculty of Clinical Medicine (Eight-year Programme), Zhongshan School of Medicine, Sun Yat-sen University, PR China
| | - Yanhui Li
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, PR China
| | - Jiangui He
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, PR China.
| | - Yugang Dong
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, PR China.
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29
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Bahnson ESM, Koo N, Cantu-Medellin N, Tsui AY, Havelka GE, Vercammen JM, Jiang Q, Kelley EE, Kibbe MR. Nitric oxide inhibits neointimal hyperplasia following vascular injury via differential, cell-specific modulation of SOD-1 in the arterial wall. Nitric Oxide 2014; 44:8-17. [PMID: 25460325 DOI: 10.1016/j.niox.2014.10.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/20/2014] [Accepted: 10/27/2014] [Indexed: 12/29/2022]
Abstract
Superoxide (O2(•-)) promotes neointimal hyperplasia following arterial injury. Conversely, nitric oxide ((•)NO) inhibits neointimal hyperplasia through various cell-specific mechanisms, including redox regulation. What remains unclear is whether (•)NO exerts cell-specific regulation of the vascular redox environment following arterial injury to inhibit neointimal hyperplasia. Therefore, the aim of the present study was to assess whether (•)NO exerts cell-specific, differential modulation of O2(•-) levels throughout the arterial wall, establish the mechanism of such modulation, and determine if it regulates (•)NO-dependent inhibition of neointimal hyperplasia. In vivo, (•)NO increased superoxide dismutase-1 (SOD-1) levels following carotid artery balloon injury in a rat model. In vitro, (•)NO increased SOD-1 levels in vascular smooth muscle cells (VSMC), but had no effect on SOD-1 in endothelial cells or adventitial fibroblasts. This SOD-1 increase was associated with an increase in sod1 gene expression, increase in SOD-1 activity, and decrease in O2(•-) levels. Lastly, to determine the role of SOD-1 in (•)NO-mediated inhibition of neointimal hyperplasia, we performed the femoral artery wire injury model in wild type and SOD-1 knockout (KO) mice, with and without (•)NO. Interestingly, (•)NO inhibited neointimal hyperplasia only in wild type mice, with no effect in SOD-1 KO mice. In conclusion, these data show the cell-specific modulation of O2(•-) by (•)NO through regulation of SOD-1 in the vasculature, highlighting its importance on the inhibition of neointimal hyperplasia. These results also shed light into the mechanism of (•)NO-dependent redox balance, and suggest a novel VSMC redox target to prevent neointimal hyperplasia.
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Affiliation(s)
- Edward S M Bahnson
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | - Nathaniel Koo
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | | | - Aaron Y Tsui
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | - George E Havelka
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | - Janet M Vercammen
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | - Qun Jiang
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | - Eric E Kelley
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Melina R Kibbe
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.
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30
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Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis. Clin Sci (Lond) 2014; 127:435-48. [PMID: 24655024 DOI: 10.1042/cs20130716] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Histamine H2 receptor (H2R) blockade has been reported to be beneficial for patients with chronic heart failure (CHF), but the mechanisms involved are not entirely clear. In the present study, we assessed the influences of H2R disruption on left ventricular (LV) dysfunction and the mechanisms involved in mitochondrial dysfunction and calcineurin-mediated myocardial fibrosis. H2R-knockout mice and their wild-type littermates were subjected to transverse aortic constriction (TAC) or sham surgery. The influences of H2R activation or inactivation on mitochondrial function, apoptosis and fibrosis were evaluated in cultured neonatal rat cardiomyocytes and fibroblasts as well as in murine hearts. After 4 weeks, H2R-knockout mice had higher echocardiographic LV fractional shortening, a larger contractility index, a significantly lower LV end-diastolic pressure, and more importantly, markedly lower pulmonary congestion compared with the wild-type mice. Similar results were obtained in wild-type TAC mice treated with H2R blocker famotidine. Histological examinations showed a lower degree of cardiac fibrosis and apoptosis in H2R-knockout mice. H2R activation increased mitochondrial permeability and induced cell apoptosis in cultured cardiomyocytes, and also enhanced the protein expression of calcineurin, nuclear factor of activated T-cell and fibronectin in fibroblasts rather than in cardiomyocytes. These findings indicate that a lack of H2R generates resistance towards heart failure and the process is associated with the inhibition of cardiac fibrosis and apoptosis, adding to the rationale for using H2R blockers to treat patients with CHF.
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31
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TRPV1 Activation Attenuates High-Salt Diet-Induced Cardiac Hypertrophy and Fibrosis through PPAR-δ Upregulation. PPAR Res 2014; 2014:491963. [PMID: 25152753 PMCID: PMC4131514 DOI: 10.1155/2014/491963] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 06/20/2014] [Indexed: 12/30/2022] Open
Abstract
High-salt diet-induced cardiac hypertrophy and fibrosis are associated with increased reactive oxygen species production. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, exerts a protective role in cardiac remodeling that resulted from myocardial infarction, and peroxisome proliferation-activated receptors δ (PPAR-δ) play an important role in metabolic myocardium remodeling. However, it remains unknown whether activation of TRPV1 could alleviate cardiac hypertrophy and fibrosis and the effect of cross-talk between TRPV1 and PPAR-δ on suppressing high-salt diet-generated oxidative stress. In this study, high-salt diet-induced cardiac hypertrophy and fibrosis are characterized by significant enhancement of HW/BW%, LVEDD, and LVESD, decreased FS and EF, and increased collagen deposition. These alterations were associated with downregulation of PPAR-δ, UCP2 expression, upregulation of iNOS production, and increased oxidative/nitrotyrosine stress. These adverse effects of long-term high-salt diet were attenuated by chronic treatment with capsaicin. However, this effect of capsaicin was absent in TRPV1−/− mice on a high-salt diet. Our finding suggests that chronic dietary capsaicin consumption attenuates long-term high-salt diet-induced cardiac hypertrophy and fibrosis. This benefit effect is likely to be caused by TRPV1 mediated upregulation of PPAR-δ expression.
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32
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Tashiro Y, Yogo K, Serizawa K, Endo K. Nicorandil suppresses urinary protein excretion and activates eNOS in Dahl salt-sensitive hypertensive rats. Clin Exp Nephrol 2014; 19:343-9. [DOI: 10.1007/s10157-014-0998-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Accepted: 06/06/2014] [Indexed: 10/25/2022]
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33
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Besnier M, Galaup A, Nicol L, Henry JP, Coquerel D, Gueret A, Mulder P, Brakenhielm E, Thuillez C, Germain S, Richard V, Ouvrard-Pascaud A. Enhanced angiogenesis and increased cardiac perfusion after myocardial infarction in protein tyrosine phosphatase 1B-deficient mice. FASEB J 2014; 28:3351-61. [PMID: 24760754 DOI: 10.1096/fj.13-245753] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The protein tyrosine phosphatase 1B (PTP1B) modulates tyrosine kinase receptors, among which is the vascular endothelial growth factor receptor type 2 (VEGFR2), a key component of angiogenesis. Because PTP1B deficiency in mice improves left ventricular (LV) function 2 mo after myocardial infarction (MI), we hypothesized that enhanced angiogenesis early after MI via activated VEGFR2 contributes to this improvement. At 3 d after MI, capillary density was increased at the infarct border of PTP1B(-/-) mice [+7±2% vs. wild-type (WT), P = 0.05]. This was associated with increased extracellular signal-regulated kinase 2 phosphorylation and VEGFR2 activation (i.e., phosphorylated-Src/Src/VEGFR2 and dissociation of endothelial VEGFR2/VE-cadherin), together with higher infiltration of proangiogenic M2 macrophages within unchanged overall infiltration. In vitro, we showed that PTP1B inhibition or silencing using RNA interference increased VEGF-induced migration and proliferation of mouse heart microvascular endothelial cells as well as fibroblast growth factor (FGF)-induced proliferation of rat aortic smooth muscle cells. At 8 d after MI in PTP1B(-/-) mice, increased LV capillary density (+21±3% vs. WT; P<0.05) and an increased number of small diameter arteries (15-50 μm) were likely to participate in increased LV perfusion assessed by magnetic resonance imaging and improved LV compliance, indicating reduced diastolic dysfunction. In conclusion, PTP1B deficiency reduces MI-induced heart failure promptly after ischemia by enhancing angiogenesis, myocardial perfusion, and diastolic function.
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Affiliation(s)
- Marie Besnier
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and
| | - Ariane Galaup
- INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris, France
| | - Lionel Nicol
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and
| | - Jean-Paul Henry
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and
| | - David Coquerel
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and
| | - Alexandre Gueret
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and
| | - Paul Mulder
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and
| | - Ebba Brakenhielm
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and
| | - Christian Thuillez
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and
| | - Stéphane Germain
- INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris, France
| | - Vincent Richard
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and
| | - Antoine Ouvrard-Pascaud
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and
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Abstract
Approximately half of heart failure patients have a normal ejection fraction, a condition designated as heart failure with preserved ejection fraction (HFpEF). This heart failure subtype disproportionately affects women and the elderly and is commonly associated with other cardiovascular comorbidities, such as hypertension and diabetes. HFpEF is increasing at a steady rate and is predicted to become the leading cause of heart failure within a decade. HFpEF is characterized by impaired diastolic function, thought to be due to concentric remodeling of the heart along with increased stiffness of both the extracellular matrix and myofilaments. In addition, oxidative stress and inflammation are thought to have a role in HFpEF progression, along with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling. Surprisingly a number of clinical studies have failed to demonstrate any benefit of drugs effective in heart failure with systolic dysfunction in HFpEF patients. Thus, HFpEF is one of the largest unmet needs in cardiovascular medicine, and there is a substantial need for new therapeutic approaches and strategies that target mechanisms specific for HFpEF. This conclusion is underscored by the recently reported disappointing results of the RELAX trial, which assessed the use of phosphodiesterase-5 inhibitor sildenafil for treating HFpEF. In animal models, endothelial nitric oxide synthase activators and If current inhibitors have shown benefit in improving diastolic function, and there is a rationale for assessing matrix metalloproteinase 9 inhibitors and nitroxyl donors. LCZ696, a combination drug of angiotensin II receptor blocker and neprilysin inhibitor, and the aldosterone receptor antagonist spironolactone are currently in clinical trial for treating HFpEF. Here we present an overview of the etiology and diagnosis of HFpEF that segues into a discussion of new therapeutic approaches emerging from basic research and drugs currently in clinical trial that primarily target diastolic dysfunction or imbalanced ventricular-arterial coupling.
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Hamdani N, Franssen C, Lourenço A, Falcão-Pires I, Fontoura D, Leite S, Plettig L, López B, Ottenheijm CA, Becher PM, González A, Tschöpe C, Díez J, Linke WA, Leite-Moreira AF, Paulus WJ. Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model. Circ Heart Fail 2013; 6:1239-49. [PMID: 24014826 DOI: 10.1161/circheartfailure.113.000539] [Citation(s) in RCA: 239] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Obesity and diabetes mellitus are important metabolic risk factors and frequent comorbidities in heart failure with preserved ejection fraction. They contribute to myocardial diastolic dysfunction (DD) through collagen deposition or titin modification. The relative importance for myocardial DD of collagen deposition and titin modification was investigated in obese, diabetic ZSF1 rats after heart failure with preserved ejection fraction development at 20 weeks. METHODS AND RESULTS Four groups of rats (Wistar-Kyoto, n=11; lean ZSF1, n=11; obese ZSF1, n=11, and obese ZSF1 with high-fat diet, n=11) were followed up for 20 weeks with repeat metabolic, renal, and echocardiographic evaluations and hemodynamically assessed at euthanization. Myocardial collagen, collagen cross-linking, titin isoforms, and phosphorylation were also determined. Resting tension (Fpassive)-sarcomere length relations were obtained in small muscle strips before and after KCl-KI treatment, which unanchors titin and allows contributions of titin and extracellular matrix to Fpassive to be discerned. At 20 weeks, the lean ZSF1 group was hypertensive, whereas both obese ZSF1 groups were hypertensive and diabetic. Only the obese ZSF1 groups had developed heart failure with preserved ejection fraction, which was evident from increased lung weight, preserved left ventricular ejection fraction, and left ventricular DD. The underlying myocardial DD was obvious from high muscle strip stiffness, which was largely (±80%) attributable to titin hypophosphorylation. The latter occurred specifically at the S3991 site of the elastic N2Bus segment and at the S12884 site of the PEVK segment. CONCLUSIONS Obese ZSF1 rats developed heart failure with preserved ejection fraction during a 20-week time span. Titin hypophosphorylation importantly contributed to the underlying myocardial DD.
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Affiliation(s)
- Nazha Hamdani
- Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
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Kanwar M, Agarwal R, Barnes M, Coons J, Raina A, Sokos G, Murali S, Benza RL. Role of phosphodiesterase-5 inhibitors in heart failure: emerging data and concepts. Curr Heart Fail Rep 2013; 10:26-35. [PMID: 23114592 DOI: 10.1007/s11897-012-0121-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Novel treatment of congestive heart failure (HF) involves utilizing unique pathways to improve upon contemporary therapies. Increasing the availability of cyclic guanosine monophosphate (cGMP) by inhibition of phosphodiesterase-5 (PDE5) is a relatively new, but promising therapeutic strategy. Preclinical studies suggest a favorable myocardial effect of PDE5 inhibitors by blocking adrenergic, hypertrophic and pro-apoptotic signaling, thereby supporting their use in HF. The clinical benefits of acute and chronic PDE5 inhibition on lung diffusion capacity, exercise performance and ejection fraction in humans are emerging and appear promising. Larger, controlled trials are now on-going to assess the safety, efficacy and tolerability of PDE5 inhibitors on morbidity and mortality in patients with both systolic and diastolic heart failure. If the results of these trials are positive, a new avenue for the treatment of HF will open, which will help curtail the societal effects of this costly and morbid disease.
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Affiliation(s)
- Manreet Kanwar
- Department of Medicine, Division of Cardiovascular Diseases, The Cardiovascular Institute at Allegheny General Hospital, 320 East North Ave, Pittsburgh, PA 15212, USA
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Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013; 62:263-71. [PMID: 23684677 DOI: 10.1016/j.jacc.2013.02.092] [Citation(s) in RCA: 2508] [Impact Index Per Article: 209.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Revised: 01/07/2013] [Accepted: 02/05/2013] [Indexed: 12/17/2022]
Abstract
Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity.
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Affiliation(s)
- Walter J Paulus
- Department of Physiology, Institute for Cardiovascular Research VU, VU University Medical Center Amsterdam, Amsterdam, the Netherlands.
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van Heerebeek L, Franssen CPM, Hamdani N, Verheugt FWA, Somsen GA, Paulus WJ. Molecular and cellular basis for diastolic dysfunction. Curr Heart Fail Rep 2013; 9:293-302. [PMID: 22926993 DOI: 10.1007/s11897-012-0109-5] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is frequently associated with metabolic risk factors. Patients with HFpEF have only a slightly lower mortality than patients with HF and reduced EF. The pathophysiology of HFpEF is currently incompletely understood, which precludes specific therapy. Both HF phenotypes demonstrate distinct cardiac remodeling processes at the macroscopic, microscopic, and ultrastructural levels. Increased diastolic left-ventricular (LV) stiffness and impaired LV relaxation are important features of HFpEF, which can be explained by changes in the extracellular matrix and the cardiomyocytes. In HFpEF, elevated intrinsic cardiomyocyte stiffness contributes to high diastolic LV stiffness. Posttranslational changes in the sarcomeric protein titin, affecting titin isoform expression and phosphorylation, contribute to elevated cardiomyocyte stiffness. Increased nitrosative/oxidative stress, impaired nitric oxide bioavailability, and down-regulation of myocardial cyclic guanosine monophosphate and protein kinase G signaling could trigger posttranslational modifications of titin, thereby augmenting cardiomyocyte and LV diastolic stiffness.
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Affiliation(s)
- Loek van Heerebeek
- Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
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39
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Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr Opin Pharmacol 2013; 13:161-7. [PMID: 23395155 DOI: 10.1016/j.coph.2013.01.006] [Citation(s) in RCA: 205] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 01/11/2013] [Accepted: 01/13/2013] [Indexed: 01/01/2023]
Abstract
Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is an antihypertensive, antithrombotic and anti-atherosclerotic molecule. Hypercholesterolemia leads to a reduction in vascular NO bioavailability. This is attributed to a dysfunction of the eNOS enzyme and a reduced eNOS activity. NADPH oxidase-mediated oxidative stress leads to oxidation of tetrahydrobiopterin (BH4), the essential cofactor of eNOS. In BH4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting eNOS to a superoxide-producing enzyme. As a consequence of eNOS uncoupling, NO production is reduced and the pre-existing oxidative stress is enhanced, which contribute significantly to atherogenesis. Therefore, pharmacological approaches that prevent eNOS uncoupling and enhance eNOS activity are of therapeutic interest. Angiotensin-converting enzyme inhibitors, AT1 receptor blockers, statins, nebivolol and resveratrol have been shown to reverse eNOS uncoupling and to stimulate eNOS activity concurrently. Molecular mechanisms of the aforementioned drugs/compounds on eNOS functionality is summarized and discussed in this review.
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Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II-induced heart failure in vivo. Basic Res Cardiol 2012; 107:308. [DOI: 10.1007/s00395-012-0308-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 08/03/2012] [Accepted: 10/17/2012] [Indexed: 12/20/2022]
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41
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Xuan C, Chang FJ, Liu XC, Bai XY, Liao XL, He GW, Ou JS. Endothelial nitric oxide synthase enhancer for protection of endothelial function from asymmetric dimethylarginine-induced injury in human internal thoracic artery. J Thorac Cardiovasc Surg 2012; 144:697-703. [PMID: 22336756 DOI: 10.1016/j.jtcvs.2012.01.020] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Revised: 12/01/2011] [Accepted: 01/04/2012] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine is a cardiovascular risk factor that is elevated in patients with coronary artery disease. We hypothesized that novel endothelial nitric oxide synthase enhancer AVE3085 might improve the endothelial function altered by asymmetric dimethylarginine in the human internal thoracic artery. METHODS Cumulative concentration-relaxation curves to acetylcholine (-11 to -5 log mol/L) were established in left internal thoracic artery rings (n = 65) from 27 patients undergoing coronary artery bypass grafting in precontraction induced by U46619 (-8 log mol/L) in the absence or presence of asymmetric dimethylarginine (100 μmol/L) or AVE3085 (30 μmol/L). Protein expressions of endothelial nitric oxide synthase and levels of superoxide anion production were detected. RESULTS Maximal relaxation induced by acetylcholine was significantly attenuated by asymmetric dimethylarginine (12.7% ± 2.3% vs 35.3% ± 5.0% in control; P < .05) and significantly restored by AVE3085 (23.4% ± 2.8%; P < .05). AVE3085 also markedly restored endothelial nitric oxide synthase expression (0.29 ± 0.008; P = .012) reduced by asymmetric dimethylarginine (0.05 ± 0.04 vs 0.36 ± 0.03 in control; P = .014). Increased superoxide anion production by asymmetric dimethylarginine (2.97 ± 0.25 vs 0.51 ± 0.10 relative light units/[s/mg] in control; P < .05) was inhibited by AVE3805 (0.62 ± 0.104 relative light units/[s/mg]; P < .05). CONCLUSIONS AVE3085 may restore endothelium-dependent relaxation reduced by asymmetric dimethylarginine through upregulation of endothelial nitric oxide synthase expression and inhibition of production of superoxide anion in human internal thoracic artery. These findings provide new insights into endothelial protection of coronary bypass grafting vessels to improve long-term patency of grafts.
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Affiliation(s)
- Chao Xuan
- TEDA International Cardiovascular Hospital, Medical College, Nankai University, Tianjin, China
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Diastolic tolerance to systolic pressures closely reflects systolic performance in patients with coronary heart disease. Basic Res Cardiol 2012; 107:251. [PMID: 22311733 DOI: 10.1007/s00395-012-0251-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2011] [Revised: 01/05/2012] [Accepted: 01/26/2012] [Indexed: 12/18/2022]
Abstract
In animal experiments, elevating systolic pressures induces diastolic dysfunction and may contribute to congestion, a finding not yet translated to humans. Coronary surgery patients (63 ± 8 years) were studied with left ventricular (LV) pressure (n = 17) or pressure-volume (n = 3) catheters, immediately before cardiopulmonary bypass. Single-beat graded pressure elevations were induced by clamping the ascending aorta. Protocol was repeated after volume loading (n = 7). Consecutive patients with a wide range of systolic function were included. Peak isovolumetric LV pressure (LVP(iso)) ranged from 113 to 261 mmHg. With preserved systolic function, LVP elevations neither delayed relaxation nor increased filling pressures. With decreasing systolic function, diastolic tolerance to afterload progressively disappeared: relaxation slowed and filling pressures increased (diastolic dysfunction). In severely depressed systolic function, filling pressures increased even with minor LVP elevations, suggesting baseline load-dependent elevation of diastolic pressures. The magnitude of filling pressure elevation induced in isovolumetric heartbeats was closely and inversely related to systolic performance, evaluated by LVP(iso) (r = -0.96), and directly related to changes in the time constant of relaxation τ (r = 0.95). The maximum tolerated systolic LVP (without diastolic dysfunction) was similarly correlated with LVP(iso) (r = 0.99). Volume loading itself accelerated relaxation, but augmented afterload-induced upward shift of filling pressures (7.9 ± 3.7 vs. 3.0 ± 1.5; P < 0.01). The normal human response to even markedly increased systolic pressures is no slowing of relaxation and preservation of normal filling pressures. When cardiac function deteriorates, the LV becomes less tolerant, responding with slowed relaxation and increased filling pressures. This increase is exacerbated by volume loading.
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Increased cardiovascular risk in rats with primary renal dysfunction; mediating role for vascular endothelial function. Basic Res Cardiol 2012; 107:242. [PMID: 22258067 PMCID: PMC3329880 DOI: 10.1007/s00395-011-0242-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Revised: 12/01/2011] [Accepted: 12/23/2011] [Indexed: 11/04/2022]
Abstract
Primary chronic kidney disease is associated with high cardiovascular risk. However, the exact mechanisms behind this cardiorenal interaction remain unclear. We investigated the interaction between heart and kidneys in novel animal model for cardiorenal interaction. Normal Wistar rats and Munich Wistar Fromter rats, spontaneously developing renal dysfunction, were subjected to experimental myocardial infarction to induce cardiac dysfunction (CD) and combined cardiorenal dysfunction (CRD), respectively (N = 5–10). Twelve weeks later, cardiac- and renal parameters were evaluated. Cardiac, but not renal dysfunction was exaggerated in CRD. Accelerated cardiac dysfunction in CRD was indicated by decreased cardiac output (CD 109 ± 10 vs. CRD 79 ± 8 ml/min), diastolic dysfunction (E/e′) (CD 26 ± 2 vs. CRD 50 ± 5) and left ventricular overload (LVEDP CD 10.8 ± 2.8 vs. CRD 21.6 ± 1.7 mmHg). Congestion in CRD was confirmed by increased lung and atrial weights, as well as exaggerated right ventricular hypertrophy. Absence of accelerated renal dysfunction, measured by increased proteinuria, was supported by absence of additional focal glomerulosclerosis or further decline of renal blood flow in CRD. Only advanced peripheral endothelial dysfunction, as found in CRD, appeared to correlate with both renal and cardiac dysfunction parameters. Thus, proteinuric rats with myocardial infarction showed accelerated cardiac but not renal dysfunction. As parameters mimic the cardiorenal syndrome, these rats may provide a clinically relevant model to study increased cardiovascular risk due to renal dysfunction. Peripheral endothelial dysfunction was the only parameter that correlated with both renal and cardiac dysfunction, which may indicate a mediating role in cardiorenal interaction.
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Kayrak M, Acar K, Gul EE, Bağlıcaklıoğlu M, Kaya Z, Sonmez O, Aydogdu I. Assessment of left ventricular myocardial performance by tissue Doppler echocardiography in patients with polycythemia vera. Echocardiography 2011; 28:948-54. [PMID: 21929589 DOI: 10.1111/j.1540-8175.2011.01503.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
AIMS The aim of this study was to evaluate myocardial performance index (MPI) which reflects the combined systolic and diastolic performance of the ventricles by tissue Doppler imaging (TDI) in patients with polycythemia vera (PV). METHOD AND MATERIALS Twenty-eight patients with PV (17 men; mean age 60±9 years) and 30 age-matched healthy subjects were prospectively evaluated. The diagnosis of PV was performed according to the World Health Organization (WHO) criteria. Left ventricular (LV) systolic and diastolic functions were assessed by conventional echocardiography and TDI. MPI of both the LV and right ventricles (RV) were measured by TDI method. RESULTS The LV MPI was significantly higher in PV group than in the controls (0.61±0.16 vs. 0.49±0.05; P=0.001). Also, the RV MPI was impaired in patients with PV compared to the control subjects (0.51±0.11 vs. 0.43±0.09; P=0.005). RV late A filling velocity (Am) and RV isovolumetric relaxation time were significantly higher in the PV group compared to healthy subjects (P=0.03 and 0.05, respectively). In logistic regression models, PV was determined as an independent predictor of impaired MPI (odds ratio: 3.7; CI 95%, 1.2-7.5). In addition, pulmonary arterial pressure was significantly elevated in patients with PV compared to the controls (P=0.02). CONCLUSION This study demonstrated that biventricular MPI is impaired in patients with PV.
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Affiliation(s)
- Mehmet Kayrak
- Department of Cardiology, Meram School of Medicine, Selcuk University, Konya, Turkey
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46
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Zhang Y, Janssens SP, Wingler K, Schmidt HHHW, Moens AL. Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy. Am J Physiol Heart Circ Physiol 2011; 301:H634-46. [PMID: 21622818 DOI: 10.1152/ajpheart.01315.2010] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The pathogenesis of many cardiovascular diseases is associated with reduced nitric oxide (NO) bioavailability and/or increased endothelial NO synthase (eNOS)-dependent superoxide formation. These findings support that restoring and conserving adequate NO signaling in the heart and blood vessels is a promising therapeutic intervention. In particular, modulating eNOS, e.g., through increasing the bioavailability of its substrate and cofactors, enhancing its transcription, and interfering with other modulators of eNOS pathway, such as netrin-1, has a high potential for effective treatments of cardiovascular diseases. This review provides an overview of the possibilities for modulating eNOS and how this may be translated to the clinic in addition to describing the genetic models used to study eNOS modulation.
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Affiliation(s)
- Yixuan Zhang
- Department of Cardiology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
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47
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Fang Y, Nicol L, Harouki N, Monteil C, Wecker D, Debunne M, Bauer F, Lallemand F, Richard V, Thuillez C, Mulder P. Improvement of left ventricular diastolic function induced by β-blockade: a comparison between nebivolol and metoprolol. J Mol Cell Cardiol 2011; 51:168-76. [PMID: 21640121 DOI: 10.1016/j.yjmcc.2011.05.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Revised: 05/05/2011] [Accepted: 05/16/2011] [Indexed: 10/18/2022]
Abstract
OBJECTIVES Enhanced adrenergic drive is involved in the development of left ventricular (LV) diastolic dysfunction observed in metabolic syndrome (MS). Thus, β-blockers might improve LV dysfunction observed in MS, but whether this occurs is unknown. METHODS We assessed in Zucker fa/fa rats the effects of short- (5 days) and long-term (90 days) metoprolol ('pure' β-blockade; 80 mg/kg/day) or nebivolol (β-blocker with vasodilating properties; 5mg/kg/day) treatment on LV hemodynamics and remodeling, as well as the long-term effects on coronary and peripheral endothelial dysfunction. RESULTS At identical degree of β(1)-receptor blockade, metoprolol and nebivolol decreased heart rate to the same extent and preserved cardiac output via increased stroke volume. None of the β-blockers, either after long- or short-term administration, modified LV end-systolic pressure-volume relation. Both β-blockers reduced, after long-term administration, LV end-diastolic pressure, Tau and end-diastolic pressure-volume relation, and this was associated with reduced LV collagen density, but not heart weight. Similar hemodynamic effects were also observed after short-term nebivolol, but not short-term metoprolol. These short-term effects of nebivolol were abolished by NO synthase inhibition. At the vascular level, nebivolol, and to a lesser extend metoprolol, improved NO dependent coronary vasorelaxation, which was abolished by NO synthase inhibition. CONCLUSIONS In a model of MS, the β-blockers metoprolol and nebivolol improve to the same extent LV hemodynamics, remodeling and diastolic function, but nebivolol prevent more markedly endothelium dependent vasorelaxation involving a more marked enhancement of NO bio-availability.
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Affiliation(s)
- Yuehua Fang
- INSERM U644, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides n°23 Institut de Recherche et d'Innovation Biomédicale de Haute Normandie, UFR de Médecine et de Pharmacie, Rouen, France
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Sirker A, Zhang M, Shah AM. NADPH oxidases in cardiovascular disease: insights from in vivo models and clinical studies. Basic Res Cardiol 2011; 106:735-47. [PMID: 21598086 PMCID: PMC3149671 DOI: 10.1007/s00395-011-0190-z] [Citation(s) in RCA: 150] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 04/11/2011] [Accepted: 04/28/2011] [Indexed: 02/07/2023]
Abstract
NADPH oxidase family enzymes (or NOXs) are the major sources of reactive oxygen species (ROS) that are implicated in the pathophysiology of many cardiovascular diseases. These enzymes appear to be especially important in the modulation of redox-sensitive signalling pathways that underlie key cellular functions such as growth, differentiation, migration and proliferation. Seven distinct members of the family have been identified of which four (namely NOX1, 2, 4 and 5) may have cardiovascular functions. In this article, we review our current understanding of the roles of NOX enzymes in several common cardiovascular disease states, with a focus on data from genetic studies and clinical data where available.
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Affiliation(s)
- Alexander Sirker
- Cardiovascular Division, King's College London British Heart Foundation Centre, London SE5 9PJ, UK
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49
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Baliga RS, MacAllister RJ, Hobbs AJ. New perspectives for the treatment of pulmonary hypertension. Br J Pharmacol 2011; 163:125-40. [PMID: 21175577 PMCID: PMC3085874 DOI: 10.1111/j.1476-5381.2010.01164.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Revised: 11/12/2010] [Accepted: 11/16/2010] [Indexed: 11/30/2022] Open
Abstract
Pulmonary hypertension (PH) is a debilitating disease with a poor prognosis. Therapeutic options remain limited despite the introduction of prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors within the last 15 years; these interventions address predominantly the endothelial and vascular dysfunctionS associated with the condition, but simply delay progression of the disease rather than offer a cure. In an attempt to improve efficacy, emerging approaches have focused on targeting the pro-proliferative phenotype that underpins the pulmonary vascular remodelling in the lung and contributes to the impaired circulation and right heart failure. Many novel targets have been investigated and validated in animal models of PH, including modulation of guanylate cyclases, phosphodiesterases, tyrosine kinases, Rho kinase, bone morphogenetic proteins signalling, 5-HT, peroxisome proliferator activator receptors and ion channels. In addition, there is hope that combinations of such treatments, harnessing and optimizing vasodilator and anti-proliferative properties, will provide a further, possibly synergistic, increase in efficacy; therapies directed at the right heart may also offer an additional benefit. This overview highlights current therapeutic options, promising new therapies, and provides the rationale for a combination approach to treat the disease.
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Angelone T, Pasqua T, Di Majo D, Quintieri AM, Filice E, Amodio N, Tota B, Giammanco M, Cerra MC. Distinct signalling mechanisms are involved in the dissimilar myocardial and coronary effects elicited by quercetin and myricetin, two red wine flavonols. Nutr Metab Cardiovasc Dis 2011; 21:362-371. [PMID: 20096547 DOI: 10.1016/j.numecd.2009.10.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Revised: 09/29/2009] [Accepted: 10/19/2009] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND AIMS Moderate red wine consumption associates with lower incidence of cardiovascular diseases. Attention to the source of this cardioprotection was focused on flavonoids, the non-alcoholic component of the red wine, whose intake inversely correlates with adverse cardiovascular events. We analysed whether two red wine flavonoids, quercetin and myricetin, affect mammalian basal myocardial and coronary function. METHODS AND RESULTS Quercetin and myricetin effects were evaluated on isolated and Langendorff perfused rat hearts under both basal conditions and α- and β-adrenergic stimulation. The intracellular signalling involved in the effects of these flavonoids was analysed on perfused hearts and by western blotting on cardiac and HUVEC extracts. Quercetin induced biphasic inotropic and lusitropic effects, positive at lower concentrations and negative at higher concentrations. Contrarily, Myricetin elicits coronary dilation, without affecting contractility and relaxation. Simultaneous administration of the two flavonoids only induced vasodilation. Quercetin-elicited positive inotropism and lusitropism depend on β1/β2-adrenergic receptors and associate with increased intracellular cAMP, while the negative inotropism and lusitropism observed at higher concentrations were α-adrenergic-dependent. NOS inhibition abolished Myricetin-elicited vasodilation, also inducing Akt, ERK1/2 and eNOS phosphorylation in both ventricles and HUVEC. Myricetin-dependent vasodilation increases intracellular cGMP and is abolished by triton X-100. CONCLUSIONS The cardiomodulation elicited on basal mechanical performance by quercetin and the selective vasodilation induced by myricetin point to these flavonoids as potent cardioactive principles, able to protect the heart in the presence of cardiovascular diseases.
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Affiliation(s)
- T Angelone
- Lab of Cardiovascular Pathophysiology, Dept of Cell Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Italy.
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