Defective glycosylation of calsequestrin in heart failure

OBJECTIVE: Levels of Ca2+ regulatory proteins have been extensively analyzed in cardiomyopathies as possible indices of change in sarcoplasmic reticulum (SR) structure and function. Measures of calsequestrin (CSQ), however, a critical protein component of the Ca2+ release complex in junctional sarcoplasmic reticulum, have provided little or no evidence of underlying dysfunction. We previously reported that calsequestrin isolated from heart tissue exists in a variety of glycoforms and phosphoforms reflecting mannose trimming of N-linked glycans and phosphorylation and dephosphorylation on protein kinase CK2-sensitive sites. METHODS: Here, we tested whether the distribution of molecular forms changes in heart failure (HF) reflecting possible remodeling of diseased tissue. Canine hearts were paced (220 beats/min) for 6-8 weeks to induce heart failure. Calsequestrin was purified from heart failure and sham-operated (control) treated canine ventricles and analyzed by electrospray mass spectrometry. RESULTS: The results showed striking changes in the mass distribution of calsequestrin molecules present in tissue from heart failure (five animals) compared with control (five animals). In heart failure, calsequestrin contained glycan structures that were uncharacteristic of normal junctional sarcoplasmic reticulum, consistent with altered metabolism or altered trafficking through secretory compartments. Glycoforms containing Man8,9, expected for a phenotype less muscle-like, were more than doubled in heart failure hearts, and molecules were also phosphorylated to a higher level. CONCLUSIONS: These data reveal in tachycardia-induced heart failure a new and potentially important change in the mannose content of calsequestrin glycans, perhaps indicative of defective junctional SR trafficking and Ca2+ release complex assembly.     

Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling

Cardiac remodeling is generally accepted as a determinant of the clinical course of heart failure (HF). Defined as genome expression resulting in molecular, cellular and interstitial changes and manifested clinically as changes in size, shape and function of the heart resulting from cardiac load or injury, cardiac remodeling is influenced by hemodynamic load, neurohormonal activation and other factors still under investigation. Although patients with major remodeling demonstrate progressive worsening of cardiac function, slowing or reversing remodeling has only recently become a goal of HF therapy. Mechanisms other than remodeling can also influence the course of heart disease, and disease progression may occur in other ways in the absence of cardiac remodeling. Left ventricular end-diastolic and end-systolic volume and ejection fraction data provide support for the beneficial effects of therapeutic agents such as angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking agents on the remodeling process. These agents also provide benefits in terms of morbidity and mortality. Although measurement of ejection fraction can reliably guide initiation of treatment in HF, opinions differ regarding the value of ejection fraction data in guiding ongoing therapy. The role of echocardiography or radionuclide imaging in the management and monitoring of HF is as yet unclear. To fully appreciate the potential benefits of HF therapies, clinicians should understand the relationship between remodeling and HF progression. Their patients may then, in turn, acquire an improved understanding of their disease and the treatments they are given.     

细胞外信号调节激酶的变化在心力衰竭患者心肌重构中的意义

目的了解慢性心力衰竭（CHF）患者心肌组织细胞外信号调节激酶（ERK）的变化与心肌重构和心功能的关系。方法采用Westernblot技术测定31例瓣膜病所致CHF患者不同心功能组心肌细胞ERK蛋白基础表达和激活情况。结果瓣膜病所致CHF患者心肌组织呈心肌重构的病理改变,轻度CHF患者ERK基础表达受抑,激活的磷酸化ERK显著增高。重度CHF患者ERK蛋白大多以无活性的形式存在,激活降低。结论ERK表达与CHF患者心肌重构和心功能关联密切,重度CHF患者较轻度患者心肌组织的磷酸化ERK活性显著降低。     

Clinical modifiers for heart failure following myocardial infarction

Heart failure (HF) is a clinical syndrome that occurs when the ability of the heart to meet the requirements of the body fails. Myocardial infarction (MI) is a common antecedent event that predisposes a patient to HF. Loss of cardiac function following MI occurs in the context of myocyte death and ventricular remodeling. The clinical significance of HF following MI is underscored by the fact that among MI survivors, the risk of death is markedly elevated in those who develop HF compared with those who do not. Various modifying factors associated with the development of HF following MI have been identified. Use of multimodality therapy with improved clinical outcomes for HF has increased the need to specifically identify the failing heart at an earlier stage. The ability to identify heart failure early in its pathogenesis will enable finer risk stratification following MI. This article reviews various risk predictors for the development of HF following MI.     

Mechanisms of disease: ion channel remodeling in the failing ventricle

In an attempt to compensate for compromised hemodynamics in heart failure, neurohumoral mechanisms are activated that trigger fundamental changes in gene expression and in protein processing, trafficking and post-translational regulation, resulting in myocyte hypertrophy. Unfortunately, over time these changes become maladaptive, predisposing to myocyte loss, chamber dilatation, interstitial hyperplasia and intercellular uncoupling. Intrinsic and peripheral responses to mechanical dysfunction alter the expression and function of key ion channels and calcium-handling proteins, thereby remodeling the cellular action potential and the intracellular calcium transient. This electrophysiological remodeling renders the heart more vulnerable to ventricular arrhythmias that underlie sudden cardiac death. In this Review, we consider key ventricular ionic changes that are associated with heart failure, with the intention of identifying molecular targets for antiarrhythmic therapy.     

Abnormalities of calcium metabolism and myocardial contractility depression in the failing heart

Heart failure (HF) is characterized by molecular and cellular defects which jointly contribute to decreased cardiac pump function. During the development of the initial cardiac damage which leads to HF, adaptive responses activate physiological countermeasures to overcome depressed cardiac function and to maintain blood supply to vital organs in demand of nutrients. However, during the chronic course of most HF syndromes, these compensatory mechanisms are sustained beyond months and contribute to progressive maladaptive remodeling of the heart which is associated with a worse outcome. Of pathophysiological significance are mechanisms which directly control cardiac contractile function including ion- and receptor-mediated intracellular signaling pathways. Importantly, signaling cascades of stress adaptation such as intracellular calcium (Ca²⁺) and 3′-5′-cyclic adenosine monophosphate (cAMP) become dysregulated in HF directly contributing to adverse cardiac remodeling and depression of systolic and diastolic function. Here, we provide an update about Ca²⁺ and cAMP dependent signaling changes in HF, how these changes affect cardiac function, and novel therapeutic strategies which directly address the signaling defects.     

甲状腺功能减退对心力衰竭的影响及分子机制

心脏是甲状腺激素重要的靶器官之一,甲状腺激素通过基因和非基因途径影响心肌收缩力、舒张功能、心率、血管外周阻力和心排出量。随着研究的不断深人,甲状腺功能减退对心力衰竭的影响逐渐得到关注。心衰患者常出现甲状腺功能减退,即使这种异常状态的存在被认为是一种适应性的保护反应,但低甲状腺功能状态仍具有潜在的负性作用,其可引起心功能逐步恶化、心肌重塑、是一个强有力的死亡预测因子。结合最新及早期研究证据,我们的研究总结了甲状腺功能减退对心力衰竭的影响及分子机制。在临床实践中,关注心衰患者的甲状腺功能变化,并给与适当干预至关重要。     

Stimulated emission depletion live-cell super-resolution imaging shows proliferative remodeling of T-tubule membrane structures after myocardial infarction

Rationale: Transverse tubules (TTs) couple electric surface signals to remote intracellular Ca(2+) release units (CRUs). Diffraction-limited imaging studies have proposed loss of TT components as disease mechanism in heart failure (HF). Objectives: Objectives were to develop quantitative super-resolution strategies for live-cell imaging of TT membranes in intact cardiomyocytes and to show that TT structures are progressively remodeled during HF development, causing early CRU dysfunction. Methods and Results: Using stimulated emission depletion (STED) microscopy, we characterized individual TTs with nanometric resolution as direct readout of local membrane morphology 4 and 8 weeks after myocardial infarction (4pMI and 8pMI). Both individual and network TT properties were investigated by quantitative image analysis. The mean area of TT cross sections increased progressively from 4pMI to 8pMI. Unexpectedly, intact TT networks showed differential changes. Longitudinal and oblique TTs were significantly increased at 4pMI, whereas transversal components appeared decreased. Expression of TT-associated proteins junctophilin-2 and caveolin-3 was significantly changed, correlating with network component remodeling. Computational modeling of spatial changes in HF through heterogeneous TT reorganization and RyR2 orphaning (5000 of 20 000 CRUs) uncovered a local mechanism of delayed subcellular Ca(2+) release and action potential prolongation. Conclusions: This study introduces STED nanoscopy for live mapping of TT membrane structures. During early HF development, the local TT morphology and associated proteins were significantly altered, leading to differential network remodeling and Ca(2+) release dyssynchrony. Our data suggest that TT remodeling during HF development involves proliferative membrane changes, early excitation-contraction uncoupling, and network fracturing.     

Mitochondrial involvement in myocyte death and heart failure

As the heart is an energy-demanding organ, impaired cardiac energy metabolism and mitochondrial function have been inexorably linked to cardiac dysfunction. There is a growing recognition that mitochondrial dysfunction contributes to impaired myocardial energetics and increased oxidative stress in cardiomyopathies, cardiac ischemic damage and heart failure (HF), and mitochondrial permeability transition pore opening has been reported a critical trigger of myocyte death and myocardial remodeling. It is well established that mitochondria play pivotal roles in intracellular signaling in both cell death as well as in cardioprotective pathways. Moreover, recent studies have shown that defects in mitochondrial dynamics affecting biogenesis and turnover are linked to cardiac senescence and HF. Accordingly, there has been an increasing interest in targeting mitochondria for HF therapy. This article reviews the background and recent evidence of mitochondrial involvement in several types of cell death (apoptosis, necrosis and autophagy) occurring in HF. In addition, potential strategies for targeting mitochondria are examined, and their utility in HF therapy considered.     

Do statins prevent heart failure in patients after myocardial infarction?

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, reduce morbidity and mortality in patients with coronary artery disease (CAD). Because CAD is the major cause of heart failure (HF) in developed countries, prevention of CAD may result in reduced HF. Evidence from randomized trials on lipid reduction (Cholesterol and Recurrent Events and the Scandinavian Simvastatin Survival Study) has shown statins to decrease progression to HF. Recently, many beneficial effects of statins have been demonstrated beyond cholesterol lowering. These agents improve endothelial function, exhibit anti-inflammatory properties, and prevent cardiac hypertrophy. Experimental studies have shown attenuation of left ventricular remodeling after myocardial infarction, possibly through reduced oxidative stress. However, no clinical evidence exists to support an effect on ventricular remodeling. Small, short-lasting clinical studies have also suggested that statin therapy might be associated with improved survival in ischemic and nonischemic HF.     

Induction of pulmonary connective tissue growth factor in heart failure is associated with pulmonary parenchymal and vascular remodeling

OBJECTIVES: Pulmonary remodeling is a well recognized consequence of heart failure (HF). However, the cellular and molecular mechanisms orchestrating the structural alterations of the lungs in HF are poorly understood. We have previously reported induction of the profibrotic peptide connective tissue growth factor (CTGF) in myocardial tissue of rats with HF, suggesting a role of CTGF during myocardial remodeling. The aim of the present study was to explore the potential role of CTGF in pulmonary remodeling in HF. METHODS: Pulmonary tissue samples were obtained from rats with myocardial infarction (MI) subsequent to ligation of the left coronary artery. Real-time quantitative RT-PCR was employed to investigate mRNA levels. The cellular distribution of CTGF was analysed by immunohistochemistry. RESULTS: Seven days after induction of myocardial infarction (MI) and HF in rats we found 2.3-fold and 1.9-fold increase of pulmonary transforming growth factor-beta1 and procollagen alpha1(I) mRNA levels, respectively, and typical morphological characteristics of pulmonary remodeling including interstitial fibrosis and medial thickening of pulmonary arteries. Pulmonary CTGF mRNA levels were substantially elevated in HF rats compared to sham-operated rats (4-fold; P<0.05) and corresponded with similar increase (3-fold; P<0.05) of pulmonary CTGF protein contents. Immunohistochemical analysis revealed increased pulmonary anti-CTGF immunoreactivity in HF, with immunostaining predominantly localized to alveolar macrophages and interstitial fibroblasts. Isolated alveolar macrophages from HF rats demonstrated substantial induction of CTGF mRNA expression (16-fold; p<0.05). Interestingly, platelets caused robust induction of CTGF mRNA expression in alveolar macrophages upon co-culture in vitro. CONCLUSION: Pulmonary CTGF was substantially increased in parallel with pulmonary remodeling in rats with HF. Our data indicate that alveolar macrophages are a major source of increased pulmonary CTGF in HF and that CTGF may be a player in the profibrotic mechanisms associated with HF.     

Molecular Imaging of Interstitial Alterations after Myocardial Infarction

To prevent progression of heart failure (HF), it is necessary to understand the cellular and molecular processes that precede more irreversible stages. Molecular imaging of HF has hitherto focused on myocytic and neuronal components. More recently, interstitial changes, particularly interstitial fibrosis, have been targeted both for diagnostic and therapeutic purposes. Molecular imaging of interstitial changes may identify patients at risk to develop HF, before adverse remodeling has occurred. In addition, it may also serve as a surrogate endpoint for the assessment of treatment efficacy.     

Molecular restoration of beta-adrenergic receptor signaling improves contractile function of failing hearts

beta-adrenergic receptor (betaAR) antagonists, or beta blockers, are now a part of the standard therapeutic arsenal in the medical management of chronic heart failure (HF). Conversely, betaAR stimulation remains the most efficient way to enhance cardiac contractile function acutely, although long-term inotropic therapy based on enhanced betaAR stimulation is likely detrimental. Although altered betaAR signaling plays a pivotal role in the genesis of HF, the choice to therapeutically agonize or antagonize this receptor pathway remains an area of ongoing investigation. Research from the authors' laboratory as well as other research conducted over the last 10 years has produced evidence to support the fact that "normalizing" the betaAR system at a molecular level and improving signaling, instead of blocking it, leads to significant enhancement of cardiac contractile function and prevents ventricular remodeling in HF. This review summarizes the extensive in vivo animal model experimentation that supports the still-controversial hypothesis that increasing the myocardial density of beta(2)-ARs or, more effectively, inhibiting the activity of the betaAR kinase (also referred to as G-protein-coupled receptor kinase 2), represent potential novel therapeutic strategies for HF.     

Evolving concepts in left ventricular systolic and diastolic remodeling: Implications for therapy

Left ventricular (LV) remodeling describes dynamic changes in ventricular size and shape that result from hemodynamic and metabolic insults to the failing heart. The remodeling hypothesis in heart failure asserts that LV remodeling is the central pathophysiologic lesion whereby alterations in cardiac structure are followed by impairment in function, with a wide range of genetic-environment interactions that determine the ultimate phenotype. Several therapeutic targets of LV remodeling have already been exploited (such as neurohormonal and cytokine activation). On the other hand, great efforts are still being made to understand the complex array of genetic and metabolic derangements. Nevertheless, we have realized that there is no single phenotypic change, protein expression, or signal-transduction pathway that is dominant in the process of cardiac remodeling. This implies that better characterization of this heterogeneous heart failure phenotype is desperately needed.     

The fibrosis-cell death axis in heart failure

Cardiac stress can induce morphological, structural and functional changes of the heart, referred to as cardiac remodeling. Myocardial infarction or sustained overload as a result of pathological causes such as hypertension or valve insufficiency may result in progressive remodeling and finally lead to heart failure (HF). Whereas pathological and physiological (exercise, pregnancy) overload both stimulate cardiomyocyte growth (hypertrophy), only pathological remodeling is characterized by increased deposition of extracellular matrix proteins, termed fibrosis, and loss of cardiomyocytes by necrosis, apoptosis and/or phagocytosis. HF is strongly associated with age, and cardiomyocyte loss and fibrosis are typical signs of the aging heart. Fibrosis results in stiffening of the heart, conductivity problems and reduced oxygen diffusion, and is associated with diminished ventricular function and arrhythmias. As a consequence, the workload of cardiomyocytes in the fibrotic heart is further augmented, whereas the physiological environment is becoming less favorable. This causes additional cardiomyocyte death and replacement of lost cardiomyocytes by fibrotic material, generating a vicious cycle of further decline of cardiac function. Breaking this fibrosis-cell death axis could halt further pathological and age-related cardiac regression and potentially reverse remodeling. In this review, we will describe the interaction between cardiac fibrosis, cardiomyocyte hypertrophy and cell death, and discuss potential strategies for tackling progressive cardiac remodeling and HF.     

Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy

Over the past 2 decades our understanding of the pathologic mechanisms that lead to heart failure (HF) has evolved from simplistic hemodynamic models to more complex models that have implicated neurohormonal activation and adverse cardiac remodeling as important mechanisms of disease progression. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have become a standard part of the armamentarium in the prevention and treatment of coronary artery disease. Apart from their lipid-lowering capabilities, statins seem to have non-lipid-lowering effects that impact neurohormonal activation and cardiac remodeling. This review will examine the potential benefits of statins in HF patients with ischemic and nonischemic cardiomyopathy as well as potential concerns regarding the use of statins in these patients.