Mechanisms of Cardiac Dysfunction in Heart Failure due to Myocardial Infarction

Acute myocardial infarction (MI) is associated with marked elevation of plasma vasoactive hormones, ventricular arrhythmias, scar formation in the ischemic portion of left ventricle (LV) and hypertrophy of the viable LV as well as the right ventricle (RV). Particularly, elevated levels of plasma catecholamines and angiotensin II activate their membrane receptors and stimulate different signal transduction systems for producing cardiac hypertrophy, augmenting the activities of subcellular organelles and increasing cardiac function. While marked arrhythmias due to acute MI produce 30 to 40% mortality, hypertrophic alterations in the viable LV as well as RV are compensatory for maintaining hemodynamic homeostasis due to loss of cardiomyocytes. On the other hand, prolonged elevation of plasma vasoactive hormones in chronic MI produce deleterious effects on the hypertrophied heart by promoting the formation of oxyradicals, inducing Ca2+ - handling abnormalities in subcellular organelles, depressing cardiac gene expression, activating different proteases and resulting in the development of cardiac dysfunction. Thus, in view of the complexities of mechanisms for both acute and chronic effects of MI, there is a real challenge of developing new interventions for preventing the transition of cardiac hypertrophy to heart failure as well as progression of the MI-induced cardiovascular abnormalities.

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Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽

10.3390/antiox10060931 ◽

2021 ◽

Vol 10 (6) ◽

pp. 931

Author(s):

Anureet K. Shah ◽

Sukhwinder K. Bhullar ◽

Vijayan Elimban ◽

Naranjan S. Dhalla

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Cardiac Dysfunction ◽

Critical Role ◽

Pressure Overload ◽

Hypertrophied Heart ◽

Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

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JDP2, a Novel Molecular Key in Heart Failure and Atrial Fibrillation?

International Journal of Molecular Sciences ◽

10.3390/ijms22084110 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4110

Author(s):

Gerhild Euler ◽

Jens Kockskämper ◽

Rainer Schulz ◽

Mariana S. Parahuleva

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Atrial Fibrillation ◽

Cardiac Dysfunction ◽

Therapeutic Target ◽

Close Correlation ◽

Disease Development ◽

Major Life ◽

Life Threatening ◽

Current Therapies

Heart failure (HF) and atrial fibrillation (AF) are two major life-threatening diseases worldwide. Causes and mechanisms are incompletely understood, yet current therapies are unable to stop disease progression. In this review, we focus on the contribution of the transcriptional modulator, Jun dimerization protein 2 (JDP2), and on HF and AF development. In recent years, JDP2 has been identified as a potential prognostic marker for HF development after myocardial infarction. This close correlation to the disease development suggests that JDP2 may be involved in initiation and progression of HF as well as in cardiac dysfunction. Although no studies have been done in humans yet, studies on genetically modified mice impressively show involvement of JDP2 in HF and AF, making it an interesting therapeutic target.

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GW26-e2455 Vagal Nerve Stimulation Reverses Cardiac Dysfunction and Subcellular Calcium Handling in Heart Failure Rats After Myocardial Infarction

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2015.06.1162 ◽

2015 ◽

Vol 66 (16) ◽

pp. C35 ◽

Cited By ~ 2

Author(s):

Yunhe Zhang ◽

Ao Chen ◽

Lei Song ◽

Min Li ◽

Ben He ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Nerve Stimulation ◽

Cardiac Dysfunction ◽

Vagal Nerve ◽

Vagal Nerve Stimulation ◽

Calcium Handling

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UCP3 Ablation Exacerbates High-Salt Induced Cardiac Hypertrophy and Cardiac Dysfunction

Cellular Physiology and Biochemistry ◽

10.1159/000489244 ◽

2018 ◽

Vol 46 (4) ◽

pp. 1683-1692 ◽

Cited By ~ 5

Author(s):

Hongmei Lang ◽

Yang Xiang ◽

Zhihua Ai ◽

Zhiqing You ◽

Xiaolan Jin ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Dysfunction ◽

Salt Intake ◽

Uncoupling Protein ◽

Left Ventricular ◽

High Salt ◽

Whole Body ◽

Endurance Capacity ◽

Respiratory Dysfunction

Background/Aims: Excessive salt intake and left ventricular hypertrophy (LVH) are both critical for the development of hypertension and heart failure. The uncoupling protein 3 (UCP3) plays a cardio-protective role in early heart failure development. However, the potential role for UCP3 in salt intake and LVH is unclear. Methods: UCP3-/- and C57BL/6 mice were placed on either a normal-salt (NS, 0.5%) or a high-salt (HS, 8%) diet for 24 weeks. The cardiac function, endurance capacity, energy expenditure, and mitochondrial functional capacity were measured in each group. Results: Elevated blood pressure was only observed in HS-fed UCP3-/- mice. High salt induced cardiac hypertrophy and dysfunction were observed in both C57BL/6 and UCP3-/- mice. However, the cardiac lesions were more profound in HS-fed UCP3-/- mice. Furthermore, HS-fed UCP3-/-mice experienced more severe mitochondrial respiratory dysfunction compared with HS-fed C57BL/6 mice, represented by the decreased volume of oxygen consumption and heat production at the whole-body level. Conclusion: UCP3 protein was involved in the incidence of high-salt induced hypertension and the progression of cardiac dysfunction in the early stages of heart failure. UCP3 ablation exacerbated high-salt-induced cardiac hypertrophy and cardiac dysfunction.

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NRSF-GNAO1 Pathway Contributes to the Regulation of Cardiac Ca 2+ Homeostasis

Circulation Research ◽

10.1161/circresaha.121.318898 ◽

2021 ◽

Author(s):

Hideaki Inazumi ◽

Koichiro Kuwahara ◽

Yasuaki Nakagawa ◽

Yoshihiro Kuwabara ◽

Takuro Numaga-Tomita ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Dysfunction ◽

Molecular Mechanisms ◽

Systolic Function ◽

Expression Profiles ◽

Survival Rates ◽

Gene Expression Profiles ◽

Dominant Negative ◽

Mouse Heart ◽

Cardiac Gene

Background: During the development of heart failure, a fetal cardiac gene program is reactivated and accelerates pathological cardiac remodeling. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF), suppresses the fetal cardiac gene program, thereby maintaining cardiac integrity. The underlying molecular mechanisms remains to be determined, however. Methods: We aim to elucidate molecular mechanisms by which NRSF maintains normal cardiac function. We generated cardiac-specific NRSF knockout mice and analyzed cardiac gene expression profiles in those mice and mice cardiac-specifically expressing a dominant-negative NRSF mutant. Results: We found that cardiac expression of Gαo, an inhibitory G protein encoded in humans by GNAO1, is transcriptionally regulated by NRSF and is increased in the ventricles of several mouse models of heart failure. Genetic knockdown of Gnao1 ameliorated the cardiac dysfunction and prolonged survival rates in these mouse heart failure models. Conversely, cardiac-specific overexpression of GNAO1 in mice was sufficient to induce cardiac dysfunction. Mechanistically, we observed that increasing Gαo expression increased surface sarcolemmal L-type Ca 2+ channel activity, activated Calcium/calmodulin-dependent kinase-II (CaMKII) signaling and impaired Ca 2+ handling in ventricular myocytes, which led to cardiac dysfunction. Conclusions: These findings shed light on a novel function of Gαo in the regulation of cardiac Ca 2+ homeostasis and systolic function and suggest Gαo may be an effective therapeutic target for the treatment of heart failure.

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CXCR4 Cardiac Specific Knockout Mice Develop a Progressive Cardiomyopathy

International Journal of Molecular Sciences ◽

10.3390/ijms20092267 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2267 ◽

Cited By ~ 5

Author(s):

Thomas J. LaRocca ◽

Perry Altman ◽

Andrew A. Jarrah ◽

Ron Gordon ◽

Edward Wang ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Myocytes ◽

Knockout Mice ◽

Cardiac Dysfunction ◽

Left Ventricular ◽

Subsequent Increase ◽

Transition Electron Microscopy ◽

Cardiac Phenotype

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates β-adrenergic receptor (β-AR) signaling and ultimately limits β-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy. Cardiomyocyte specific-CXCR4 knockout (CXCR4 cKO) mice demonstrate a progressive cardiac dysfunction leading to cardiac failure by 12-months of age. Histological assessments of CXCR4 cKO at 6-months of age revealed significant tissue fibrosis in knockout mice versus wild-type. The expression of atrial naturietic factor (ANF); a marker of cardiac hypertrophy; was also increased with a subsequent increase in gross heart weights. Furthermore, there were derangements in both the number and the size of the mitochondria within CXCR4 cKO hearts. Moreover, CXCR4 cKO mice were more sensitive to catocholamines, their response to β-AR agonist challenge via acute isoproterenol (ISO) infusion demonstrated a greater increase in ejection fraction, dp/dtmax, and contractility index. Interestingly, prior to ISO infusion, there were significant differences in baseline hemodynamics between the CXCR4 cKO compared to littermate controls. However, upon administering ISO, the CXCR4 cKO responded in a robust manner overcoming the baseline hemodynamic deficits reaching WT values supporting our previous data that CXCR4 negatively regulates β-AR signaling. This further supports that, in the absence of the physiologic negative modulation, there is an overactivation of down-stream pathways, which contribute to the development and progression of contractile dysfunction. Our results demonstrated that CXCR4 plays a non-developmental role in regulating cardiac function and that CXCR4 cKO mice develop a progressive cardiomyopathy leading to clinical heart failure.

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Inhibition of Endogenous Mst1 Prevents Apoptosis and Cardiac Dysfunction Without Affecting Cardiac Hypertrophy After Myocardial Infarction

Circulation Research ◽

10.1161/01.res.0000265846.23485.7a ◽

2007 ◽

Vol 100 (9) ◽

pp. 1344-1352 ◽

Cited By ~ 101

Author(s):

Mari Odashima ◽

Soichiro Usui ◽

Hiromitsu Takagi ◽

Chull Hong ◽

Jing Liu ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Hypertrophy ◽

Cardiac Dysfunction

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Myocardial infarction remodeling that progresses to heart failure: a signaling misunderstanding

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00131.2018 ◽

2018 ◽

Vol 315 (1) ◽

pp. H71-H79 ◽

Cited By ~ 16

Author(s):

Alan J. Mouton ◽

Osvaldo J. Rivera ◽

Merry L. Lindsey

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Wound Healing ◽

Current Knowledge ◽

Healing Process ◽

Cell Types ◽

Left Ventricular ◽

Wound Healing Process ◽

The Status ◽

The Right

After myocardial infarction, remodeling of the left ventricle involves a wound-healing orchestra involving a variety of cell types. In order for wound healing to be optimal, appropriate communication must occur; these cells all need to come in at the right time, be activated at the right time in the right amount, and know when to exit at the right time. When this occurs, a new homeostasis is obtained within the infarct, such that infarct scar size and quality are sufficient to maintain left ventricular size and shape. The ideal scenario does not always occur in reality. Often, miscommunication can occur between infarct and remote spaces, across the temporal wound-healing spectrum, and across organs. When miscommunication occurs, adverse remodeling can progress to heart failure. This review discusses current knowledge gaps and recent development of the roles of inflammation and the extracellular matrix in myocardial infarction remodeling. In particular, the macrophage is one cell type that provides direct and indirect regulation of both the inflammatory and scar-forming responses. We summarize current research efforts focused on identifying biomarker indicators that reflect the status of each component of the wound-healing process to better predict outcomes.

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