The aging population with heart failure (HF) worldwide has been increasing steadily. In elderly patients aged >= 65 years, the two main comorbidities leading to HF are hypertension (HTN) and myocardial infarction (MI). Aging results in progressive cardiovascular changes and the aging phenotype can impact negatively on disease expression and response to therapy. Aging-related changes per se contribute to adverse cardiac remodeling and HF with preserved ejection fraction (HFpEF). HTN also leads to HFpEF while MI leads to HF with reduced EF (HFrEF). Aging and concomitant HTN or MI aggravate HFpEF or HFrEF phenotypes and accelerate the march to HF. The extracellular matrix (ECM) plays a key role in maintaining cardiac shape and function and is a key factor in the exacerbation of and march to HF in HTN and MI. Dysregulation of ECM homeostasis and metabolism and disruption of the ECM network exacerbate adverse cardiac remodeling, shape deformation and dysfunction that spur the march to HF, disability and death. In older patients, aging-related cardiac remodeling with superimposed progressive left ventricular remodeling leading to HFpEF or HFrEF is a persistent problem that has important therapeutic implications. Studies suggest that in the elderly, novel pathways can be targeted for optimizing therapy in HFrEF post-MI and HFpEF post-HTN. Therapeutic strategies that include targeting of adverse cardiac ECM remodeling could prevent, limit and reverse progression of HF in aging patients.

Heart failure (HF) is a leading cause of morbidity and mortality in the Western world. Despite implementation of current recommended therapies for the treatment of the HF syndrome [1, 2], prevalence, mortality, and costs associated with HF are rising. Expansion of our aging population with high prevalence of such comorbidities as coronary artery disease, myocardial infarction, hypertension, diabetes, and obesity that predispose patients to this complex syndrome is expected to increase HF prevalence even further in the future. Current treatment options and strategies [1, 2] predominantly slow the progression of the HF syndrome. There is a need to develop novel preventative and reparative therapy options. However, development of these novel HF therapies requires testing of the putative therapeutic strategies in appropriate HF animal models [3]. The primary goal of experimental animal HF models is to simplify an indeed complex syndrome into manageable research questions in reproducible settings. The ultimate goal is to elucidate pathophysiological mechanisms and identify key pathways that can be targeted for developing therapies that can be tested in appropriate translational animal models before evaluation in clinical trials for prevention and improving outcome of HF in humans. While there are multiple causes of HF, the dominant ones are valvular heart disease, dilated cardiomyopathies, hypertensive heart disease, and restrictive cardiomyopathies. The two major clinical phenotypes are HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) [4]. Right-sided HF and pulmonary hypertension also play important roles in the HF phenotype. Various small and large animal models have been used to induce HF [3], including volume and pressure overload, rapid pacing, myocardial infarction with or without coronary reperfusion, coronary embolization, cardiotoxic drugs, or genetic variations (in small animals). The number of HF patients is increasing owing to the deficiency of therapeutic approaches to treat this population of patients. A discourse between clinicians and scientists seems to be essential to develop novel experimental animal models of HF that accurately imitate the complex clinical syndrome of HF. During the past decades, the use of experimental animal models to examine complex cardiovascular pathophysiology has been confirmed to be irreplaceable in this field [5]. As a result of basic and translational experiments in small animal models, our understanding of the pathophysiology of HF and its treatment has advanced significantly. In addition, the ability to manipulate the mouse genome has simplified a particularly important approach to detect novel therapeutic targets, offering a significant approach to explore the mechanisms underlying development and progression of the HF syndrome [5]. Moreover, the adaptation of present experimental animal models will be required to entirely translate scientific findings into new drugs and therapeutic approaches. Future animal models of HF will hopefully give mechanistic insights that could lead to novel options of therapies. Experimental animal models of HF, as opposed to isolated organ and/or cell preparations, do empower examination of the physiological effects of cardiac functioning, which are of excessive significance in the HF phenotype [3]. Moreover, manipulation of the mouse and rat genomes has allowed significant mechanistic insights into different HF phenotypes in humans. Although mice are relatively economical and suitable, substantial differences exist between mouse and human heart physiology and especially during development and/or progression of HF [5]. For instance, mouse hearts are very small and do beat very fast (400–600 beats per minute) [6] compared with human hearts (60–90 beats per minute). These dissimilarities lead to important alterations in calcium handling and ion currents between the two species. Mutations in the giant sarcomeric protein titin (Ttn) are a major cause for inherited forms of dilated cardiomyopathy (DCM). In this issue, Q. Zhou et al. investigated a pattern of DCM that can be induced by TAC-mediated pressure overload in a Ttn-truncated mouse model. This model expands the resource of cardiac disease models, adding a valuable tool to understand cardiac pathophysiological remodeling processes and to develop therapeutic approaches to combat HF. J. Talavera et al. examined an improved protocol in the rabbit model of anthracycline-induced cardiomyopathy. Current protocols of anthracycline-induced cardiomyopathy in rabbits had disadvantages for long-term studies such as high premature mortality and toxicities (e.g., nephrotoxicity). With the aim of obtaining a more appropriate protocol for this kind of research, the researchers developed a shortened protocol of anthracycline-induced cardiomyopathy using daunorubicin of 4 mg/kg/week over a period of six weeks resulting in high incidence of overt dilated cardiomyopathy with more stable signs of congestive HF, associated with reduced systemic compromise and very low premature mortality. This refined model in rabbits can be very useful for long-term studies aimed at evaluation of the functional effects of novel therapies for HF in anthracycline-induced cardiomyopathy. E. Roussel et al. performed a gene expression profile of the model of chronic volume overload in rats with severe aortic valve regurgitation (AR) over a period of 9 months. The investigators focused on the study of genes associated with myocardial energetics in that model. Their results displayed that the myocardium with chronic volume overload sustained significant metabolic stress and developed important energetics adaptations. Clinicians currently follow those patients without any intervention for a good number of years, simply waiting for the left ventricle to become too dilated, for the occurrence of symptoms, or until systolic function begins to fall. The findings of E. Roussel et al. in this issue suggest that those hearts develop severe metabolic abnormalities even when systolic function appears to be preserved and that intervention then can limit the dilation and metabolic abnormalities. Focusing on myocardial metabolism by various interventions such as targeted drugs, specific diets, or exercise may help this metabolically stressed myocardium to improve its energy production and may prolong the pre-HF state significantly. However, E. Roussel et al. have observed that treatment with fenofibrate, a PPARα-agonist, normalized both fatty acid and glucose uptakes while reducing left ventricular dilation caused by AR. Right ventricular (RV) dysfunction due to chronic pressure overload is a common feature of congenital heart diseases. Here, M. Hirata et al. propose an improved pulmonary artery (PA) banding procedure using a half-closed clip (PAC) instead of partial ligation in the rat model of RV dysfunction secondary to chronic pressure overload. T.-H. Chen et al. used the conditional HSP60 transgenic mouse model to demonstrate neonatal death and HF with transgenic HSP60 expression, likely due to atrial septal defects, increased apoptosis, and myocyte degeneration and other cardiac developmental defects. Since this mitochondrial heat shock protein is essential for maintaining life, they suggest that the model can be useful for addressing other important biological questions about HSP60. There exists a solid body of evidence that the carotid body (CB) chemoreflex is relevant during the progression of chronic HF. Here, D. C. Andrade et al. reviewed the relevance of CB chemoreflex during the progression of HF. The authors emphasize that several HF experimental models also display a heightened CB chemoreflex drive which correlates positively with the severity of the disease. Moreover, recent exciting studies indicate that ablation of the CB chemoreceptors not only improves autonomic function and reduces disordered breathing patterns in experimental CHF, but also improves survival. These findings raise the question of whether the CB chemoreflex should be tested in all types of HF (i.e., HFrEF and HFpEF). To sum up, future studies should discuss the role of the CB in the progression of autonomic imbalance and disordered breathing patterns in nonsystolic chronic HF (HFpEF). We hope that this special issue will help readers become familiarized with recent progress regarding experimental heart failure models and their pathophysiological mechanisms.

The search for hidden truths behind established concepts and dogma is often a never-ending, uphill climb and the history of Science and Medicine is full of examples of this. " To raise new questions, new possibilities, to regard old questions from a new angle, requires creative imagination and marks real advances in science " (Albert Einstein). The story of the renin-angiotensin system (RAS), hypertension and kidney disease began nearly two centuries ago,1 with report of a clinico-pathophysiologic study of albuminuria in patients followed by Goldblatt's induction of hypertension in experimental dogs in the 1930's.2 It took seven more decades of basic, translational and clinical research to discover the pressor effect of renal extracts (ascribed to renin) in 1898 and another ten decades of imaginative work by many to culminate in the discovery of angiotensin-II (Ang-II), the primary effector peptide of the RAS, and its receptors (AT1R and AT2R) in 2000.3 Since then, expansion of the RAS to the renin-angiotensin-aldosterone (RAAS) system and discovery of several bioactive peptides produced through Ang-II degradation has contributed to the increasing complexity of the RAS (Figures 1A and1B) and the search continues.

HomeCirculationVol. 131, No. 16Expanding Saga of the Renin-Angiotensin System Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBExpanding Saga of the Renin-Angiotensin SystemThe Angiotensin II Counter-Regulatory AT2 Receptor Pathway Bodh I. Jugdutt, MD, DM, FRCPC Bodh I. JugduttBodh I. Jugdutt From Cardiology Division, Department of Medicine, Faculty of Medicine, University of Alberta, Edmonton, Canada. Search for more papers by this author Originally published25 Mar 2015https://doi.org/10.1161/CIRCULATIONAHA.115.016328Circulation. 2015;131:1380–1383Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 21, 2015: Previous Version 1 The search for hidden truths behind established concepts and dogma is often a never-ending, uphill climb, and the history of science and medicine is full of examples of this. “To raise new questions, new possibilities, to regard old questions from a new angle, requires creative imagination and marks real advances in science” (Albert Einstein). The story of the renin-angiotensin system (RAS), hypertension, and kidney disease began nearly 2 centuries ago,1 with report of a clinico-pathophysiologic study of albuminuria in patients followed by Goldblatt’s induction of hypertension in experimental dogs in the 1930s.2 It took 7 more decades of basic, translational, and clinical research to discover the pressor effect of renal extracts (ascribed to renin) in 1898 and another 10 decades of imaginative work by many to culminate in the discovery of angiotensin II (Ang-II), the primary effector peptide of the RAS, and its receptors (AT1R and AT2R) in 2000.3 Since then, expansion of the RAS to the renin-angiotensin-aldosterone (RAAS) system and discovery of several bioactive peptides produced through Ang-II degradation has contributed to the increasing complexity of the RAS (Figure), and the search continues.Download figureDownload PowerPointFigure. A, Major pathways in the RAS and RAAS cascades. B, Enzymatic cascades and key receptor activation pathways in the RAS. Angiotensinogen, angiotensin II, angiotensin III, angiotensin IV, and angiotensin-(1–7) are the main biologically active peptides of RAS. VIF is a non-RAS peptide that acts via AT2R.14 ACE indicates angiotensin-converting enzyme; ACE-I, ACE inhibitor; ACE2, angiotensin-converting enzyme 2; Ang, angiotensin; ARB, angiotensin receptor blocker; AT1R and AT2R, Ang-II type 1 and type 2 receptor respectively; cGMP, cyclic guanosine 3′ 5′ monophosphate; EDHF, endothelin-derived hyperpolarizing factor; eNOS, endothelial nitric oxide synthase; Mas R, Ang 1 to 7 receptor; MRA, mineralocorticoid receptor antagonist; PAI-1, plasminogen activator inhibitor-1; PGI2, prostacyclin; PKCε, protein kinase Cε; RAS, renin-angiotensin system; RAAS, renin-angiotensin-aldosterone system; t-PA, tissue plasminogen activator; and VIF, vasoconstriction inhibiting factor.Article see p 1426Since the 1990s, therapy based on inhibition of the effects of Ang-II with angiotensin-converting enzyme (ACE) inhibitors and AT1R blockers has dominated the experimental and clinical research arenas. Cumulative evidence has indicated that the RAS, through Ang-II generated primarily by the ACE, plays a critical role in the regulation of blood pressure, fluid and electrolyte balance, cardiovascular and renal homeostasis, and pathophysiology of hypertension and cardiovascular and renal disease.4,5 Ang-II was implicated in increased blood pressure and vascular remodeling with vascular inflammation, endothelial dysfunction, atherosclerosis, and smooth muscle hypertrophy, as well as cardiac remodeling with myocardial fibrosis and hypertrophy leading to diastolic and systolic heart failure.4,5 Ang-II was shown to stimulate release of aldosterone, which in turn stimulates inflammation, fibrosis, and cardiovascular remodeling (Figure, A). Evidence that most of the effects of Ang-II are mediated via AT1 receptors provided the rationale for use of ACE inhibition and AT1 receptor blockade (Figure). With evidence that ACE inhibitors do not block Ang-II generated via non-ACE pathways in cardiovascular and other tissues,6 the ability of AT1R blockers to selectively block Ang-II at the AT1R, thereby producing more complete inhibition was considered advantageous (Figure, A). Although ACE inhibitors increase bradykinin by suppressing its degradation thereby enhancing vasodilation, this benefit may be offset by a nearly 20% risk of troublesome cough and angioneurotic edema.5 However, AT1R blockers may also result in enhanced vasodilation via unopposed AT2R activation and downstream AT2-mediated signaling.5 Other evidence indicates that angiotensin receptor blockers can also release kinins and increase bradykinin levels in hypertensive patients,7 which may augment benefits that are offset by the risk of cough and angioedema. Randomized clinical trials mounted to resolve well-known arguments for using AT1R blockers have shown benefits of both ACE inhibitors and AT1R blockers for controlling blood pressure in hypertension.8–10 A downside of chronic ACE-inhibitor therapy in heart failure patients is that Ang-II levels increase and symptoms worsen.5 Importantly, aging is associated with RAS dysregulation and increased Ang-II and other RAS components, which in turn may contribute to increased cardiovascular remodeling and risk in elderly patients.4,5 In diabetic nephropathy, excessive RAAS activation results in progressive renal damage.11Up until a decade ago, the collective evidence favored the concept of a regulatory arm of the RAS with an ACE/Ang-II/AT1R axis that mediates vasoconstriction, whereas under AT1R blockade the AT2R mediates vasodilation (Figure, A). Evidence over the last decade unraveled existence of a counter-regulatory arm of the RAS via an Ang-(1–7)/ACE-2/mas receptor axis that opposes vasoconstrictor, proliferative, profibrotic, and prothrombotic actions of Ang-II (Figure).12,13 The Ang-(1–7)/Mas axis regulates several signaling pathways, such as phospho-inositide 3-kinase/AKT and extracellular signal–regulated kinase pathways and involves downstream effectors such as nitric oxide, forkhead box O1, and cyclo-oxygenase 2. In the counter-regulatory and vasodepressor arm, both ACE-inhibitors and AT1 receptor blockers can increase angiotensin-(1–7).5,10 This axis is a potential therapeutic target in cardio-renal disease.In summary, RAAS blockade with ACE inhibitors or AT1R blockers is standard recommended therapy for hypertension, heart failure, and nondiabetic/diabetic chronic renal disease, and aldosterone blockade is used in selected patients.5,9–11 Clinicians recognize that optimal therapy is critical for survival with a favorable outcome, and combination therapies are often needed. Over the last 2 decades, several laboratories have been searching for specific molecular targets that may lead to the development of therapies and strategies to optimize therapy of hypertension, heart failure, and chronic renal disease, prevent adverse remodeling, and improve outcome. Many studies have been conducted in experimental animal models and humans. However, therapy to limit adverse remodeling in patients with these diseases, especially the elderly, remains suboptimal, and hearts continue to enlarge after hypertension and heart failure.In this issue of Circulation, Salem and colleagues14 tested the provocative and bold hypothesis that a novel peptide acts as an endogenous cofactor in Ang-II–mediated vasoregulatory effects. The observation that plasma Ang-II concentrations were not increased in patients with heart failure and chronic kidney disease triggered the idea that unknown endogenous cofactors may be involved in the action of Ang-II.14,15 They present a large volume of compelling data suggesting that this peptide, a fragment of chromogranin-A that they named vasoconstriction inhibiting factor (VIF), modulates vasoconstrictive effects of Ang-II and exerts vasodilator effects mediated by AT2R, and may provide a potential counter-regulatory mechanism against hypertension.14 This interesting non-RAS peptide acting through AT2R further underscores the complexity of the RAS/RAAS (Figure, B) and need for more research to establish its importance as a potential target for the prevention and therapy of cardiovascular disease. Marie Curie, winner of separate Nobel Prizes for Physics and Chemistry, is credited with saying “be more curious about ideas.”It is known that chromogranin-A is produced by chromaffin cells of the adrenal medulla and other tissues and is elevated in pheochromocytomas. It serves as precursor to several functional peptides, including vasostatin I, vasostatin II, pancreastatin, catestatin, and parastatin, which negatively modulate autocrine and paracrine functions.16–18 Some of these peptides, such as vasostatin I and vasostatin II, inhibit vasoconstriction while concentrations of catestatin are reduced and those of chromogranin-A are increased in hypertensive patients. Here Salem et al14 report at least 7 important findings. First, they nicely demonstrated that VIF released from the adrenal glands and derived from chromogranin-A modulates Ang-II–induced vasoconstriction by testing different VIF concentrations on Ang-II–induced vasoconstriction and calculating the EC50. Second, they probed mechanisms and showed that VIF impairs Ang-II–induced phosphorylation of p38MAPK but not extracellular signal–regulated kinase 1/2. Third, they present evidence suggesting that elevated plasma VIF may modulate the harmful effects of Ang-II in chronic renal disease and heart failure patients, especially since chromogranin-A is also elevated in these patients. Fourth, they showed that VIF reduced Ang-II–induced increase in blood pressure in vivo. Fifth, they confirmed absence of homology in amino acid sequences between VIF and the other main Ang peptides. Sixth, they confirmed that VIF but neither scrambled nor truncated peptides caused a significant effect on Ang-II–induced vasoconstriction. Seventh, they addressed the affinity of VIF for AT2R by showing that VIF inhibits Ang-II–induced vasoconstriction in a large physiologically relevant range, and maintains its effect in the presence of L-NG-Nitro arginine methyl ester (hence independent of nitric oxide), but its effect is abolished by the AT2R blocker PD 123 319. These findings unmasking the nitric oxide–independent effect of VIF on the AT2 receptors further underscore the importance of AT2R in the regulation of blood pressure.The overall findings of Salem et al14 underscore the complexity of vasoregulation as pointed out by the authors. Importantly, the findings suggest a potentially novel strategy for promoting counterregulatory vasodilation thereby limiting hypertension, adverse remodeling, and heart failure. Whether targeting the VIF/AT2R pathway might be a potential approach for preventing adverse remodeling and improving outcome in hypertension warrants study. Whether VIF levels are decreased with aging and explain the poorer outcome in older patients also deserves study. The authors deserve to be applauded for the idea that non-RAS–derived peptides may interact with ≥1 of the 3 major RAS receptors (AT1R, AT2R, and Mas) and produce significant physiological and pathophysiological effects. This possibility opens up a new area of research into other biologically active peptides. The authors have suggested testing for interactions of VIF with other angiotensin peptides (such as angiotensinogen, Ang-II, Ang-III, Ang-IV, and Ang-[1–7]), angioprotectin, and alamandine.14 However, the possibility that peptide interactions may not always be beneficial but rather might be harmful and contribute to disease progression should also be considered.Sources of FundingThis work was supported in part by grant IAP99003 (2010-2012) from the Canadian Institutes of Health Research.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Bodh I. Jugdutt, MD, DM, FRCPC, FACC, FAHA, 2C2 Walter MacKenzie Health Sciences Centre, Division of Cardiology, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada. E-mail [email protected]References1. Basso N, Terragno NA.History about the discovery of the renin-angiotensin system.Hypertension. 2001; 38:1246–1249.LinkGoogle Scholar2. 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Wang Y, Fan Z, Xu C, Yan X, Zhou Y, Qiu Z, Yuan Q, Zheng J, Liao Y and Chen X (2021) Anti-ATR001 monoclonal antibody ameliorates atherosclerosis through beta-arrestin2 pathway, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2021.01.054, 544, (1-7), Online publication date: 1-Mar-2021. Czick M, Shapter C and Shapter R (2020) COVID’s Razor: RAS Imbalance, the Common Denominator Across Disparate, Unexpected Aspects of COVID-19, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 10.2147/DMSO.S265518, Volume 13, (3169-3192) Kim H, Lee M, Jo S, Seo W, Kim S, Kim K, Choi J, Ahn H, Choi D and Ryu K (2019) Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers in Heart Failure With Chronic Kidney Disease ― Propensity Score Matching Analysis ―, Circulation Journal, 10.1253/circj.CJ-19-0782, 84:1, (83-90), Online publication date: 25-Dec-2019. Saavedra J and Armando I (2017) Angiotensin II AT2 Receptors Contribute to Regulate the Sympathoadrenal and Hormonal Reaction to Stress Stimuli, Cellular and Molecular Neurobiology, 10.1007/s10571-017-0533-x, 38:1, (85-108), Online publication date: 1-Jan-2018. Nemecz M, Alexandru N, Tanko G and Georgescu A (2016) Role of MicroRNA in Endothelial Dysfunction and Hypertension, Current Hypertension Reports, 10.1007/s11906-016-0696-8, 18:12, Online publication date: 1-Dec-2016. Yang M, Wang B, Miao L, Xu X and He X (2016)(2016) Autophagy is involved in aldosterone-induced mesangial cell proliferation, Molecular Medicine Reports, 10.3892/mmr.2016.5807, 14:5, (4638-4642), Online publication date: 1-Nov-2016. Wang B, Lin L, Wang H, Guo H, Gu Y and Ding W (2016) Overexpressed cyclophilin B suppresses aldosterone-induced proximal tubular cell injury both in vitro and in vivo , Oncotarget, 10.18632/oncotarget.12503, 7:43, (69309-69320), Online publication date: 25-Oct-2016. Jugdutt B (2015) Suppression of Ventricular Arrhythmias After Myocardial Infarction by AT1 Receptor Blockade: Role of the AT2 Receptor and Casein Kinase 2/Kir2.1 Pathway, Cardiovascular Drugs and Therapy, 10.1007/s10557-015-6608-3, 29:3, (201-206), Online publication date: 1-Jun-2015. April 21, 2015Vol 131, Issue 16 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.115.016328PMID: 25810337 Originally publishedMarch 25, 2015 Keywordsreceptorspeptidesrenin-angiotensin systemangiotensinhypertensionEditorialsPDF download Advertisement SubjectsRemodeling

The aging population with heart failure (HF) is increasing worldwide. Hypertension (HTN) and myocardial infarction (MI) are the two main comorbidities leading to HF in the elderly (age ≥ 65 years). Aging is progressive and results in cardiovascular changes that lead to an aging phenotype and negatively impact disease expression and response to therapy. Aging-related changes contribute to adverse cardiac remodeling and HF with preserved ejection fraction (HFpEF). HTN also leads to HFpEF whereas MI leads to HF with reduced EF (HFrEF). Aging and concomitant HTN or MI accelerates the march to HF. The cardiac extracellular matrix (ECM) is critical for maintaining cardiac shape/function. A key mechanism in the development and progression of HF due MI and HTN involves adverse cardiac ECM remodeling. Disruption of the ECM network and dysregulation of ECM homeostasis and metabolism result in adverse cardiac remodeling with shape deformation and dysfunction that lead to HF, disability and death. Agingrelated cardiac remodeling with superimposed progressive left ventricular remodeling leading to HFpEF or HFrEF in older patients is a persistent problem that has important therapeutic implications. Studies suggest that in the elderly, novel pathways can be targeted for optimizing therapy in HFrEF post-MI and HFpEF post-HTN. Therapeutic strategies that include targeting of adverse cardiac ECM remodeling could prevent/limit/reverse progression to HF in aging patients.

Abbreviations AAD Antiarrhythmic drug AngII Angiotensin II AT1R AngII type 1 receptor AT2R AngII type 2 receptor ARB AT1R blocker CK2 Casein kinase 2 ICD Implantable cardioverter-defibrillator IK1 Inward rectifier K+ current LV Left ventricular MI Myocardial infarction PES Programmed electrical stimulation PVC Premature ventricular complex RAAS Renin-angiotensin-aldosterone system SCD Sudden cardiac death VAs Ventricular arrhythmias VT Ventricular tachycardia VF Ventricular fibrillation

The cardiac extracellular matrix (ECM) is critical for maintaining cardiac shape and function. Disruption of the ECM network and dysregulation of matrix homeostasis and metabolism result in adverse cardiac remodeling with shape deformation and dysfunction that leads to heart failure (HF), disability and death. A key mechanism in the development and progression of HF due to injury caused by myocardial infarction and hypertension, the two leading causes of HF, involves adverse cardiac ECM remodeling, which participates in the march to end-stage HF. Improved therapeutic strategies that include targeting of adverse cardiac ECM remodeling could prevent, limit or reverse progression to HF.

The elderly population (age ≥65) is increasing and with it morbidity, hospitalizations, costs and mortality due to heart failure (HF). HF is a progressive disorder that is superimposed on an on-going aging process. The two broad categories of HF, HF with left ventricular (LV) systolic dysfunction or low ejection fraction (HF/low-EF) and HF with preserved ejection fraction (HF/PEF) are equally prevalent in the elderly. Trials of therapy for HF/low-EF in primarily non-elderly patients showed mortality benefit in elderly patients. In contrast, trials for HF/PEF have not shown mortality benefit in elderly or non-elderly patients. HF pharmacotherapy in the elderly is challenging and needs to be individualized and consider several aging-related changes. More research into the biology of aging and more clinical trials in elderly patients are needed to improve morbidity and mortality in elderly HF patients.