C-terminal variable AGES domain of Thymosin β4: the molecule's primary contribution in support of post-ischemic cardiac function and repair

Repairing defective cardiac cells is important towards improving heart function. Due to the frequency and severity of ischemic heart disease, management of patients featuring this type of cardiac failure receives significant interest. Previously we discovered that Thymosin β4 (TB4), a 43 amino-acid secreted actin sequestering peptide, is beneficial for myocardial cell survival and coronary re-growth after infarction in adult mammals. Considering the regenerative potential of full-length TB4 in the heart, and that minimal structural variations alter TB4's influence on actin assembly and cell movement, we investigated how various TB4 domains affect cardiac cell behavior and post-ischemic mammalian heart function.We synthesized 17 domain combinations of full-length TB4 and analyzed their impact on embryonic cardiac cells in vitro, and after cardiac infarction in vivo. We discovered the domains of TB4 affect cardiac cell behavior distinctly. We revealed TB4 specific C-terminal tetrapeptide, AGES, increases embryonic cardiac cell migration and myocyte beating in culture, and improves adult mammalian heart function following ischemia. Investigating the molecular background and mechanism we discovered systemic injection of AGES enhances early myocyte survival by activating Akt-mediated signaling mechanisms, increases coronary vessel growth and inhibits inflammation in mice and pigs. Biodistribution analyses revealed cardiomyocytes uptake AGES efficiently in vitro and in vivo projecting a potential independent clinical utilization for the tetrapeptide. Our comprehensive domain investigations also suggest, preservation and/or restoration of cardiomyocyte communication is a target of TB4 and AGES, and critical to improve post-ischemic heart function in pigs.In summary, we identified the C-terminal four amino-acid variable end of TB4 as the essential and responsible domain for the molecule's full benefits in the hypoxic heart. Additionally, we introduced AGES as a novel, systemically applicable drug candidate to aid cardiac infarction in adult mammals.     

Differential regulation of EHD3 in human and mammalian heart failure

Electrical and structural remodeling during the progression of cardiovascular disease is associated with adverse outcomes subjecting affected patients to overt heart failure (HF) and/or sudden death. Dysfunction in integral membrane protein trafficking has long been linked with maladaptive electrical remodeling. However, little is known regarding the molecular identity or function of these intracellular targeting pathways in the heart. Eps15 homology domain-containing (EHD) gene products (EHD1-4) are polypeptides linked with endosomal trafficking, membrane protein recycling, and lipid homeostasis in a wide variety of cell types. EHD3 was recently established as a critical mediator of membrane protein trafficking in the heart. Here, we investigate the potential link between EHD3 function and heart disease. Using four different HF models including ischemic rat heart, pressure overloaded mouse heart, chronic pacing-induced canine heart, and non-ischemic failing human myocardium we provide the first evidence that EHD3 levels are consistently increased in HF. Notably, the expression of the Na/Ca exchanger (NCX1), targeted by EHD3 in heart is similarly elevated in HF. Finally, we identify a molecular pathway for EHD3 regulation in heart failure downstream of reactive oxygen species and angiotensin II signaling. Together, our new data identify EHD3 as a previously unrecognized component of the cardiac remodeling pathway.     

Diabetic cardiomyopathy: Where are we 40 years later?

Diabetic cardiomyopathy is a cardiac disease that arises as a result of the diabetic state, independent of vascular or valvular pathology. It manifests initially as asymptomatic diastolic dysfunction, which progresses to symptomatic heart failure. The compliance of the heart wall is decreased and contractile function is impaired. The pathophysiology is incompletely understood, but appears to be initiated both by hyperglycemia and changes in cardiac metabolism. These changes induce oxidative stress and activate a number of secondary messenger pathways, leading to cardiac hypertrophy, fibrosis and cell death. Alterations in contractile proteins and intracellular ions impair excitation-contraction coupling, while decreased autonomic responsiveness and autonomic neuropathy impair its regulation. Extensive structural abnormalities also occur, which have deleterious mechanical and functional consequences.     

Taurine depletion caused by knocking out the taurine transporter gene leads to cardiomyopathy with cardiac atrophy

The sulfur-containing β-amino acid, taurine, is the most abundant free amino acid in cardiac and skeletal muscle. Although its physiological function has not been established, it is thought to play an important role in ion movement, calcium handling, osmoregulation and cytoprotection. To begin examining the physiological function of taurine, we generated taurine transporter− (TauT−) knockout mice (TauTKO), which exhibited a deficiency in myocardial and skeletal muscle taurine content compared with their wild-type littermates. The TauTKO heart underwent ventricular remodeling, characterized by reductions in ventricular wall thickness and cardiac atrophy accompanied with the smaller cardiomyocytes. Associated with the structural changes in the heart was a reduction in cardiac output and increased expression of heart cardiac failure (fetal) marker genes, such as ANP, BNP and β-MHC. Moreover, ultrastructural damage to the myofilaments and mitochondria was observed. Further, the skeletal muscle of the TauTKO mice also exhibited decreased cell volume, structural defects and a reduction of exercise endurance capacity. Importantly, the expression of Hsp70, ATA2 and S100A4, which are upregulated by osmotic stress, was elevated in both heart and skeletal muscle of the TauTKO mice. Taurine depletion causes cardiomyocyte atrophy, mitochondrial and myofiber damage and cardiac dysfunction, effects likely related to the actions of taurine. Our data suggest that multiple actions of taurine, including osmoregulation, regulation of mitochondrial protein expression and inhibition of apoptosis, collectively ensure proper maintenance of cardiac and skeletal muscular structure and function.     

Regenerative Therapy for Cardiomyopathies

Despite substantial advances in the development of medical and interventional strategies in ischemic and non-ischemic heart diseases, cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity worldwide. Stem cell therapy for heart disease has gained traction over the past two decades and is an emerging option for the treatment of myocardial dysfunction. In this review, we summarize the current literature on different types of stem cells and their potential usage in ischemic and non-ischemic heart diseases. We emphasize the clinical utility of stem cells to improve myocardial structural and function, promote microvascular angiogenesis, and diminish scar size and major adverse cardiovascular events. We also discuss the therapeutic potential of microvesicles, such as exosomes, in the treatment of CVDs, which may open novel avenues for further clinical studies.     

器质性心脏病合并室上性心动过速的射频消融治疗

目的 探讨器质性心脏病合并阵发性室上性心动过速射频消融的疗效和安全性.方法 对11例器质性心脏病合并房室折返性或房室结折返性心动过速患者进行了射频消融治疗,并与80例无器质性心脏病患者进行对照.结果 射频消融治疗的首次成功率为90.9%,无严重并发症.与对照组比较,手术时间和X线爆光时间长.结论 器质性心脏病合并阵发性室上性心动过速射频消融治疗仍安全有效,术前明确其解剖学改变和心功能状态,对于选择射频消融途径、增加成功率、减少操作时间及减低并发症具有重要意义.     

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.     

Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy

Vascular endothelial growth factor (VEGF)-B is poorly angiogenic but prominently expressed in metabolically highly active tissues, including the heart. We produced mice expressing a cardiac-specific VEGF-B transgene via the alpha-myosin heavy chain promoter. Surprisingly, the hearts of the VEGF-B transgenic mice showed concentric cardiac hypertrophy without significant changes in heart function. The cardiac hypertrophy was attributable to an increased size of the cardiomyocytes. Blood capillary size was increased, whereas the number of blood vessels per cell nucleus remained unchanged. Despite the cardiac hypertrophy, the transgenic mice had lower heart rate and blood pressure than their littermates, and they responded similarly to angiotensin II-induced hypertension, confirming that the hypertrophy does not compromise heart function. Interestingly, the isolated transgenic hearts had less cardiomyocyte damage after ischemia. Significantly increased ceramide and decreased triglyceride levels were found in the transgenic hearts. This was associated with structural changes and eventual lysis of mitochondria, resulting in accumulation of intracellular vacuoles in cardiomyocytes and increased death of the transgenic mice, apparently because of mitochondrial lipotoxicity in the heart. These results suggest that VEGF-B regulates lipid metabolism, an unexpected function for an angiogenic growth factor.     

Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure

The structural integrity of the heart is maintained by the end-to-end connection between the myocytes called the intercalated disc. The intercalated disc contains different junctional complexes that enable the myocardium to function as a syncytium. One of the junctional complexes, the zonula adherens or adherens junction, consists of the cell adhesion molecule, N-cadherin, which mediates strong homophilic cell-cell adhesion via linkage to the actin cytoskeleton. To determine the function of N-cadherin in the working myocardium, we generated a conditional knockout containing loxP sites flanking exon 1 of the N-cadherin (Cdh2) gene. Using a cardiac-specific tamoxifen-inducible Cre transgene, N-cadherin was deleted in the adult myocardium. Loss of N-cadherin resulted in disassembly of the intercalated disc structure, including adherens junctions and desmosomes. The mutant mice exhibited modest dilated cardiomyopathy and impaired cardiac function, with most animals dying within two months after tamoxifen administration. Decreased sarcomere length and increased Z-line thickness were observed in the mutant hearts consistent with loss of muscle tension because N-cadherin was no longer available to anchor myofibrils at the plasma membrane. Ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous ventricular tachycardia, confirming that the deaths were arrhythmic in nature. A significant decrease in the gap junction protein, connexin 43, was observed in the N-cadherin-depleted hearts. This animal model provides the first demonstration of the hierarchical relationship of the structural components of the intercalated disc in the working myocardium, thus establishing N-cadherin's paramount importance in maintaining the structural integrity of the heart.     

Pathophysiologic and diagnostic aspects of heart failure

Ventricular dysfunction due to an abnormality of the heart which is associated with typical hemodynamic, renal and hormonal reactions, characterizes the clinical syndrome heart failure. The traditional definition of heart failure as the inability to pump an amount of blood sufficient to cover the metabolic needs of the body in the presence of adequate venous return, emphasizes mainly the reduction in cardiac output but not the increase in intracardiac pressures. Pressure or volume overload, decreased contractility, loss of muscle mass or restricted filling represent the most important pathological processes leading to heart failure. The disturbance of systolic ventricular function due to pressure or volume overload or diminished contractility is characterized by a decrease in the ejection fraction, the disturbance in diastolic ventricular function associated with restricted filling is characterized by elevated chamber stiffness. Decreased contractility is most commonly responsible for the development of heart failure. Impairment of diastolic ventricular function can only be regarded as the dominant mechanism leading to heart failure in the presence of a small noncompliant ventricle. Impairment of diastolic ventricular function in an enlarged heart is always associated with an impairment of systolic ventricular function and is, then, relegated to a subordinate role. Common causes of heart failure are coronary artery disease, hypertension, cardiomyopathies, valvular heart diseases and congenital heart diseases, for the incidence of which coronary artery disease is most frequently responsible. Most of these diseases lead to heart failure not via a single, but rather several of the specified pathophysiological processes. Possible mechanisms for loss of contractility include structural changes as well as alterations in excitation-contraction coupling. Possible mechanisms responsible for impaired diastolic ventricular function encompass, in addition to altered calcium flux, structural changes such as fibrosis and hypertrophy and factors such as asynchrony and abnormal loading conditions. With increasing derangement of cardiac function, there is recruitment of the compensatory mechanisms: hypertrophy of the cardiac muscle, Frank-Starling mechanism, activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system and the arginine-vasopressin system. The goal is maintenance of adequate blood pressure and cardiac output whereby blood flow is redistributed in favor of the heart and brain and away from the skin, musculature and visceral organs. Activation of the neurohumoral system can lead to excessive vasoconstriction as well as sodium and water retention resulting in an undesired elevation of preload and afterload which, in turn, leads to further worsening of the heart failure.(ABSTRACT TRUNCATED AT 400 WORDS)     

Tissue inhibitor of metalloproteinases (TIMPs) in heart failure

Remodeling of the myocardium and the extracellular matrix (ECM) occurs in heart failure irrespective of its initial cause. The ECM serves as a scaffold to provide structural support as well as housing a number of cytokines and growth factors. Hence, disruption of the ECM will result in structural instability as well as activation of a number of signaling pathways that could lead to fibrosis, hypertrophy, and apoptosis. The ECM is a dynamic entity that undergoes constant turnover, and the integrity of its network structure is maintained by a balance in the function of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs). In heart disease, levels of MMPs and TIMPs are altered resulting in an imbalance between these two families of proteins. In this review, we will discuss the structure, function, and regulation of TIMPs, their MMP-independent functions, and their role in heart failure. We will review the knowledge that we have gained from clinical studies and animal models on the contribution of TIMPs in the development and progression of heart disease. We will further discuss how ECM molecules and regulatory genes can be used as biomarkers of disease in heart failure patients.     

Is there a cardiomyopathy of obesity?

Obesity is associated with structural and functional changes in the heart. These changes may be precursors to more overt forms of cardiac dysfunction and heart failure. However, it is not known 1) whether cardiac hypertrophy in obese individuals results directly from increased adioposity or from the effects of comorbid conditions such as hypertension, diabetes, and sleep-disordered breathing and 2) whether functional changes (eg, mild reductions in systolic and diastolic function) in obese patients progress over time to the point where they cause heart failure, unless ischemic heart disease develops. Establishing a clear link between obesity and heart failure is complicated by the fact that obesity must be present for many decades before the risk of heart failure increases substantially. At present, there are no longitudinal studies of changes in cardiac size and function in humans with obesity. This article reviews data showing structural and functional changes in the heart in obesity and the evidence that these are or are not progressive over time. At present, we believe it is uncertain whether there is a true “cardiomyopathy of obesity.”     

Intercellular communication lessons in heart failure

Cell–cell or inter‐organ communication allows the exchange of information and messages, which is essential for the coordination of cell/organ functions and the maintenance of homeostasis. It has become evident that dynamic interactions of different cell types play a major role in the heart, in particular during the progression of heart failure, a leading cause of mortality worldwide. Heart failure is associated with compensatory structural and functional changes mostly in cardiomyocytes and cardiac fibroblasts, which finally lead to cardiomyocyte hypertrophy and fibrosis. Intercellular communication within the heart is mediated mostly via direct cell–cell interaction or the release of paracrine signalling mediators such as cytokines and chemokines. However, recent studies have focused on the exchange of genetic information via the packaging into vesicles as well as the crosstalk of lipids and other paracrine molecules within the heart and distant organs, such as kidney and adipose tissue, which might all contribute to the pathogenesis of heart failure. In this review, we discuss emerging communication networks and respective underlying mechanisms which could be involved in cardiovascular disease conditions and further emphasize promising therapeutic targets for drug development.     

Matricellular proteins in the heart: possible role during stress and remodeling

Matricellular proteins are extracellular matrix proteins that modulate cell-matrix interactions and cell function, and do not seem to have a direct structural role. The family includes tenascin-C (TN-C), tenascin-X (TN-X), osteonectin, osteopontin, thrombospondin-1 (TSP1) and thrombospondin-2 (TSP2). Expression of matricellular proteins is high during embryogenesis, but almost absent during normal postnatal life. Interestingly, it re-appears in response to injury. Left ventricular remodeling is a complicated process that occurs in the stressed heart, and is still not completely understood. Several members of the matricellular protein family, like tenascin-C, osteopontin, and osteonectin are up-regulated after cardiac injury. Therefore, this group of proteins may have crucial functions in the heart coping with stress. This review will focus on the expression, regulation and function of these matricellular proteins, and will discuss the crucial functions that these proteins might exert during remodeling of the stressed heart.     

细胞性心肌成形术研究进展

许多基本的心血管疾病发展到晚期会演变为充血性心力衰竭 ,尽管治疗手段已有了明显进步 ,但充血性心力衰竭仍然是一个主要并且将继续为人类关注的健康问题。充血性心力衰竭可使具有完整舒缩功能的心肌细胞数量减少 ,心肌结构完整性遭到破坏。心脏移植治疗终末期心力衰竭是金标准 ,但供体的不足限制了其临床广泛应用 ,就需要其它新方法来替代以挽救丧失的心肌细胞。细胞性心肌成形术被证明是一种行之有效的替代治疗方法。细胞性心肌成形术就是将包括自体心肌细胞在内的不同类型的细胞移植到宿主心肌组织中加固其结构和改善其功能。最近研究发现胚胎干细胞和成体干细胞均可以向心肌细胞方向分化。自体骨骼肌成肌细胞、内皮祖细胞等其它类型细胞同样成功地在宿主受损心肌组织中存活并增殖分化 ,改善宿主心脏功能。这里对目前细胞性心肌成形术的移植细胞类型作一综述。     

Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure

Chronological myocardial aging is viewed as the inevitable effect of time on the functional reserve of the heart. Cardiac failure in elderly patients is commonly interpreted as an idiopathic or secondary myopathy superimposed on the old heart independently from the aging process. Thus, aged diseased hearts were studied to determine whether cell regeneration was disproportionate to the accumulation of old dying cells, leading to cardiac decompensation. Endomyocardial biopsies from 19 old patients with a dilated myopathy were compared with specimens from 7 individuals of similar age and normal ventricular function. Ten patients with idiopathic dilated cardiomyopathy were also analyzed to detect differences with aged diseased hearts. Senescent cells were identified by the expression of the cell cycle inhibitor p16INK4a and cell death by hairpin 1 and 2. Replication of primitive cells and myocytes was assessed by MCM5 labeling, myocyte mitotic index, and telomerase function. Aged diseased hearts had moderate hypertrophy and dilation, accumulation of p16INK4a positive primitive cells and myocytes, and no structural damage. Cell death markedly increased and occurred only in cells expressing p16INK4a that had significant telomeric shortening. Cell multiplication, mitotic index and telomerase increased but did not compensate for cell death or prevented telomeric shortening. Idiopathic dilated cardiomyopathy had severe hypertrophy and dilation, tissue injury, and minimal level of p16INK4a labeling. In conclusion, telomere erosion, cellular senescence, and death characterize aged diseased hearts and the development of cardiac failure in humans.     

Diastology: 2020-A practical guide

Left ventricular (LV) diastolic function can be most conveniently assessed by echocardiography which provides reliable assessments of LV structure and function. Most patients with structural heart disease have variable degrees of myocardial dysfunction. LV structural changes as pathologic hypertrophy and systolic functional abnormalities as depressed LV long-axis systolic function are associated with diastolic dysfunction. The recognition of structural abnormalities and abnormal LV long-axis function as indices of diastolic dysfunction is an important difference between 2016 and 2009 guidelines. In addition, there are other Doppler findings indicative of diastolic dysfunction and abnormally elevated LV filling pressures. In the absence of clinical, 2D echocardiographic, and specific Doppler indices of diastolic dysfunction, mitral annulus early diastolic velocity (e’), left atrium (LA) maximum volume index, peak velocity of tricuspid regurgitation jet by continuous-wave Doppler, and ratio of mitral inflow early diastolic velocity to e’ velocity can be used to draw inferences about LV diastolic function. In the presence of diastolic dysfunction, mean LA pressure and grade of diastolic dysfunction should be determined. When LA pressure at rest is normal, it is reasonable to proceed to diastolic stress testing in an attempt to identify patients with dyspnea due to heart failure. There are specific algorithms recommended in patients with atrial fibrillation, moderate or severe mitral annular calcification, and noncardiac pulmonary hypertension.