Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways

We investigated 18 AIDS hearts (5 with and 13 without cardiomyopathy) by using immunocytochemistry and computerized image analysis regarding the roles of HIV-1 proteins and tumor necrosis factor ligands in HIV cardiomyopathy (HIVCM). HIVCM and cardiomyocyte apoptosis were significantly related to each other and to the expression by inflammatory cells of gp120 and tumor necrosis factor-alpha. In HIVCM heart, active caspase 9, a component of the mitochondrion-controlled apoptotic pathway, and the elements of the death receptor-mediated pathway, tumor necrosis factor-alpha and Fas ligand, were expressed strongly on macrophages and weakly on cardiomyocytes. HIVCM showed significantly greater macrophage infiltration and cardiomyocyte apoptosis rate compared with non-HIVCM. HIV-1 entered cultured neonatal rat ventricular myocytes by macropinocytosis but did not replicate. HIV-1- or gp120-induced apoptosis of rat myocytes through a mitochondrion-controlled pathway, which was inhibited by heparin, AOP-RANTES, or pertussis toxin, suggesting that cardiomyocyte apoptosis is induced by signaling through chemokine receptors. In conclusion, in patients with HIVCM, cardiomyocytes die through both mitochondrion- and death receptor-controlled apoptotic pathways.     

Sudden death in nondilated cardiomyopathies: Pathophysiology and prevention

Sudden cardiac death is a frequent cause of death and has been well studied in the setting of both ischemic and dilated cardiomyopathies. The primary and secondary prevention of sudden cardiac death has not been the focus of randomized clinical trials in the large cohort of patients with nondilated, nonischemic cardiomyopathies, however. Those disorders include hypertrophic cardiomyopathy and its apical variant, arrhythmogenic right ventricular cardiomyopathy, takotsubo cardiomyopathy, left ventricular noncompaction, cardiac amyloidosis, and cardiac sarcoidosis. In these conditions, risk stratification for sudden death is based on observational data.     

Plasma levels of tumor necrosis factor-alpha correlate with the six-minute walk test results in patients with mild to moderate heart failure.

BACKGROUND: The plasma levels of brain natriuretic peptide, tumor necrosis factor-alpha, big endothelin-1 and cardiac troponins have been reported to correlate with the severity of heart failure. METHODS: In a single population of 80 outpatients with mild to moderate chronic heart failure the correlation between the patient's functional capacity, as evaluated at a 6-min walk test, the clinical parameters and plasma levels of brain natriuretic peptide, tumor necrosis factor-alpha, big endothelin-1 and cardiac troponins was evaluated. RESULTS: A significant inverse correlation was found with the patient's age (p < 0.0001), NYHA functional class (p < 0.0001), left ventricular dysfunction etiology (ischemic vs dilated cardiomyopathy, p < 0.0005), heart rate (p < 0.05), plasma levels of brain natriuretic peptide (p < 0.05) and of tumor necrosis factor-alpha (p < 0.0005). At multiple regression analysis a correlation was found between the 6-min walk test results and the patient's age (p < 0.05), NYHA functional class (p < 0.01), left ventricular dysfunction etiology (ischemic vs dilated cardiomyopathy, p < 0.05) and tumor necrosis factor-alpha plasma levels (p < 0.05). CONCLUSIONS: In our patients with mild to moderate heart failure, a significant correlation was found between the results of the 6-min walk test and only the plasma concentrations of tumor necrosis factor-alpha among the laboratory parameters analyzed in this study.     

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.     

Sudden cardiac death and the role of device therapy in dilated cardiomyopathy

Both nonischemic and ischemic dilated cardiomyopathy are associated with an increased risk of sudden cardiac death, most commonly as a result of ventricular tachyarrhythmias. The pathophysiology of sudden death is complex and results from the interplay of scarred myocardium with physiologic and environmental triggers. Clinical trials completed within the past decade have clarified the role of implantable defibrillators in prolonging survival and have expanded the indications for the use of these devices in patients with heart failure. This article examines the pathophysiology of sudden cardiac death and reviews the clinical trials that have defined the role of device therapy in current practice.     

Electrocardiographic markers of sudden death

The 12-lead ECG has limited utility to predict the risk for sudden cardiac death in common cardiac diseases such as coronary artery disease and idiopathic dilated cardiomyopathy. However, it is quite useful in diagnosing less common cardiac conditions that are associated with an increased risk for sudden death.     

Programmed ventricular stimulation in coronary artery disease and dilated cardiomyopathy: influence of the underlying heart disease on the results of electrophysiologic testing

In order to evaluate the clinical and prognostic significance of programmed ventricular stimulation (PVS), 100 patients were investigated. Twenty-four of 51 patients with coronary artery disease and 22 out of 49 with dilated cardiomyopathy had clinical ventricular tachycardia (VT). The study protocol included 24-h Holter ECG, cardiac catheterization and angiography, and PVS employing 1 and 2 premature extrastimuli and incremental pacing. In patients with coronary artery disease, VT was induced in 67% with prior VT and in 18% without such episodes (p less than 0.01). In dilated cardiomyopathy, however, patients with and without clinical VT did not differ with regard to VT inducibility (18% vs. 15%, NS). The inducibility of monomorphic sustained VT--most frequently induced in VT patients--was significantly higher in patients with coronary artery disease (p less than 0.05). Polymorphic nonsustained VT (in both coronary artery disease and dilated cardiomyopathy) was only initiated in patients without clinical VT. In patients with coronary artery disease, left ventricular ejection fraction could be correlated to clinical arrhythmia (p less than 0.001), while induced VT could only be correlated to depressed left ventricular function in patients with left ventricular aneurysm. Neither clinical nor induced VT could be correlated to left ventricular ejection fraction in patients with dilated cardiomyopathy. During a mean follow-up of 21 months, 7 patients died from sudden cardiac death. Six of them had clinical VT, but in only 1 patient with coronary artery disease was VT initiated. There was no apparent difference in the antiarrhythmic therapy of the patients with sudden death with respect to the surviving population. In conclusion, the response to PVS with the stimulation protocol applied is different in patients with coronary artery disease and dilated cardiomyopathy. The prognostic significance of the results obtained from PVS remains uncertain.     

Idiopathic dilated cardiomyopathy: prognostic significance of electrocardiographic and electrophysiologic findings in the nineties.

BACKGROUND: With the exception of a few cases such as aborted sudden cardiac death, sustained ventricular tachycardia, and syncope of unexplained origin, there is no consensus on the clinical findings identifying patients with idiopathic dilated cardiomyopathy with an increased risk of sudden cardiac death or malignant ventricular arrhythmias. METHODS: To verify whether electrocardiographic and arrhythmologic features could be useful for prognostic stratification, 78 consecutive patients with an invasive diagnosis of idiopathic dilated cardiomyopathy, but without symptomatic ventricular arrhythmias, were enrolled in a prospective study. Signal-averaged ECG, 24 to 48 hour ECG monitoring and electrophysiologic study were performed at the time of diagnosis to identify arrhythmogenic predictors of outcome. Transplant-free and arrhythmic event-free survival was evaluated on the basis of initial parameters. RESULTS: During a mean follow-up of 85 months, 9 patients died (6 of sudden cardiac death and 3 of congestive heart failure), 10 patients underwent cardiac transplantation for refractory heart failure, and 3 presented with sustained ventricular tachycardia. The independent predictors for death and cardiac transplantation were an HV interval > 55 ms and the combination of frequent repetitive ventricular ectopics with a poor left ventricular function. A strong index of arrhythmic events proved to be the association of a prolonged HV interval with a wide (> 110 ms) QRS complex (odds ratio 4.53, 95% confidence interval 1.57-13.04, p < 0.005). CONCLUSIONS: An accurate measurement of the HV interval and QRS duration at baseline evaluation may add prognostic information in patients with idiopathic dilated cardiomyopathy. In our experience, abnormal values of both parameters identified a group of patients with a very high risk of late occurring arrhythmic events.     

Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs

Prolonged cardiac hypertrophy of pathologic etiology is associated with arrhythmia, sudden death, decompensation, and dilated cardiomyopathy. In an attempt to understand the mechanisms that underlie the hypertrophic response, extensive investigation has centered on a characterization of the molecular pathways that initiate or maintain the pathologic growth of individual cardiac myocytes. While a large number of signal transduction cascades have been identified as critical regulators of cardiac hypertrophy, here the scientific evidence implicating the protein phosphatase calcineurin (PP2B) and the mitogen-activated protein kinases (MAPK) as co-regulators of reactive hypertrophy will be discussed. Gain- and loss-of-function studies in genetically altered mice and in cultured cardiomyocytes have demonstrated the necessity and sufficiency of calcineurin to regulate pathologic cardiac hypertrophy. However, using similar approaches, the hypertrophic regulatory role attributed to various branches of the MAPK signaling pathway has been less conclusive, although a loose consensus suggests that the c-Jun N-terminal kinases (JNK) and p38 kinases function as mediators of dilated cardiomyopathy, while extracellular signal-regulated kinases (ERKs) function as regulators of hypertrophy. More recently, the actions of calcineurin and MAPK signaling pathways have been shown to be co-dependent such that unitary activation of calcineurin in myocytes leads to up-regulation in ERK and JNK signaling, but down-regulation in p38 signaling. Conversely, unitary activation of JNK or p38 in cardiac myocytes leads to down-regulation of calcineurin effectiveness by directly antagonizing nuclear factor of activated T cells (NFAT) nuclear occupancy. Thus, an emerging paradigm suggests that calcineurin-NFAT and MAPK signaling pathways are inter-dependent and together orchestrate the cardiac hypertrophic response.     

心源性晕厥或猝死的原因分析

分析 32例在入院时或入院后至少发生 1次或 1次以上心源性晕厥或猝死患者的原因及其发作时与发作前、后的常规 12导联心电图或持续心电监视心电图。结果 :引起心源性晕厥或猝死的基本原因可分为以下几种类型 :①冠心病急性或陈旧性心肌梗死 ;②长QT(U)综合征 ;③Brugada综合征 ;④扩张型和肥厚型心肌病 ;⑤特发性巨大异常J波 ;⑥其他原因。上述各种心源性晕厥或猝死患者有各自不同的心电学特征。结论 :心源性晕厥或猝死是由不同原因、不同心电学特征所致的非单一独立的临床实体     

心源性猝死危险因素分析

目的探讨和分析心源性猝的危险因素。方法收集和整理在我院2012年04月-2013年10月诊治时发生心源性猝死的心肌患者64例为研究对象,对上述收集对象的临床资料进行整理和分析。结果本组单因素分析显示自发性持续室速、心室颤动(心脏骤停)、晕阙、左室流出道梗阻、非持续性室速等因素为心肌疾病患者发生心源性猝死的危险因素;多因素Logistic分析发现自发性持续性室速、心室颤动、晕阙以及猝死家族史是发生心源性猝死的重要危险因素。结论心肌疾病患者发生心源性猝死的为危险因素呈现综合化、多样化,临床治疗中应给予针对性的预防或治疗,这对降低心肌疾病患者心源性猝死率有着积极的意义。     

Myocarditis: basic and clinical aspects

Myocarditis represents a heterogeneous final common pathway for myocardial inflammation of diverse etiologies and accounts for up to one-third of cases of dilated cardiomyopathy. The pathophysiology of viral myocarditis can be disaggregated into the effects of direct viral mediated injury, triggered acute and chronic autoimmune responses, and subsequent adverse remodeling. Recent research highlights the pathogenic role of persistent viral genome expression, Fas-ligand, tumor necrosis factor-alpha receptor 1, and antimyosin autoantibodies in the evolution of chronic systolic and diastolic heart failure. Recent refinements in endomyocardial biopsy evaluation, cardiac magnetic resonance imaging, and cytokine assays augment existing diagnostic modalities. Novel specific immunosuppressive targets aimed at interrupting myocyte injury and apoptosis, including interferon-beta seem promising to date in small clinical studies performed on selected patients.     

Nitric oxide and cardiac failure

Cardiac myocytes express two types of nitric oxide (NO) synthase, eNOS and iNOS. eNOS activity is regulated by the contractile state of the heart, while iNOS expression is induced by cytokines. Nitric oxide induced by cytokines causes negative inotropic and lethal effects on cardiac myocytes. Expression of iNOS in the myocardium is increased in patients with dilated cardiomyopathy with clinical evidence of heart failure. Several neurohumoral factors activated in chronic heart failure augment cardiac iNOS expression and could cause cardiac dysfunction and cell damage.     

Cardiac features of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutations.

AIMS: Retrospective studies have identified a mutation in the lamin A/C (LMNA) gene in patients selected on the basis of a phenotype characterized by dilated cardiomyopathy, atrioventricular conduction disturbances and sudden death. However, the features of cardiac abnormalities in patients with an initial diagnosis of Emery-Dreifuss muscular dystrophy (EDMD) are poorly known. Aim of the present study was to investigate the spectrum of cardiac disease in patients with an initial diagnosis of EDMD caused by a mutation in the LMNA gene. METHODS AND RESULTS: Ten consecutive patients with EDMD and a LMNA gene mutation were evaluated with structured medical interview, physical examination, ECG, echocardiogram and 24-h Holter monitoring. Electrophysiological testing and cardiac catheterization were performed if a class 1 or 2 American Heart Association guidelines indication was present. Cardiac disease was found in eight of 10 patients and consisted in the variable combination of supraventricular arrhythmias, disorders of atrioventricular conduction, ventricular arrhythmias, dilated cardiomyopathy, non-dilated cardiomyopathy, restrictive cardiomyopathy and sudden death despite pacemaker implant. CONCLUSIONS: Cardiac disease is common in patients with an initial diagnosis of EDMD caused by a mutation in the LMNA gene and consists of arrhythmias, disorders of atrioventricular conduction, cardiomyopathies and sudden death despite pacemaker implant.     

Midwall myocardial fibrosis in Becker-Kiener muscular dystrophy

We report on a 38- year-old man with Becker-Kiener muscular dystrophy (BMD) and dilated cardiomyopathy without clinical symptoms of congestive heart failure who was referred for risk evaluation of sudden cardiac death. The degree of cardiac involvement in BMD varies greatly from no or hardly any cardiac abnormality to severe arrhythmias, dilatative cardiomyopathy and heart failure to heart transplantation or sudden cardiac death. These cardiac abnormalities have been related to replacement of the cardiomyocytes by connecting tissue or fat. In the clinical setting, cardiovascular magnetic resonance (CMR) has been proved to be a valid non-invasive method for obtaining anatomical and structural information of the heart. Furthermore, gadolinium-enhanced CMR can also characterize areas of myocardial fibrosis. Demonstration of extensive areas of fibrosis in an early stage of the disease might be a surrogate marker for an impaired clinical outcome. Therefore, serial CMR examinations starting upon diagnosis of the disease should be considered, as this may lead to an earlier recognition of cardiac involvement and may affect further management of the patient.     

The properties of the pacemaker current I(F)in human ventricular myocytes are modulated by cardiac disease

The pacemaker current I(f)is present in ventricular myocytes from the human failing heart where it may contribute to arrhythmogenesis. The role of cardiac disease in the modulation of I(f)expression is still uncertain. We studied the functional expression and properties of I(f)in human ventricular myocytes isolated from control donor hearts or from explanted failing hearts of patients with ischemic and dilated cardiomyopathy. In patch-clamped cells, I(f)was elicited by hyperpolarization. Membrane capacitance (C(m)) was significantly higher in dilated cardiomyopathy than in control or ischemic cardiomyopathy. I(f)was present in all ischemic and dilated cardiomyopathy tested cells and in 76% of control cells. In ischemic and dilated cardiomyopathy, I(f)amplitude measured at -120 mV was significantly greater than in control. However, I(f)density (i.e. current normalized to C(m)) was significantly higher in ischemic cardiomyopathy (2.0+/-0.2 pA/pF) than in dilated cardiomyopathy (1.2+/-0.1 pA/pF) or control (1.0+/-0.1 pA/pF). In diseased hearts, the activation curve was significantly shifted to more positive values compared to control. The slope of the fully-activated I-V relations was greater in ischemic cardiomyopathy than in dilated cardiomyopathy or control (P<0.05) while the intercept with the x -axis (V(rev)) was similar. In conclusion, I(f)is overexpressed in human ventricular myocytes from failing hearts; its functional expression seems related to the etiology of the disease, being higher in ischemic than in dilated cardiomyopathy, and not to the degree of cell hypertrophy.     

Iron overload thalassemic cardiomyopathy: Iron status assessment and mechanisms of mechanical and electrical disturbance due to iron toxicity

Patients with thalassemia major have inevitably suffered from complications of the disease, due to iron overload. Among such complications, cardiomyopathy is the leading cause of morbidity and mortality (63.6% to 71%). The major causes of death in this group of patients are congestive heart failure and fatal cardiac tachyarrhythmias leading to sudden cardiac death. The free radical-mediated pathway is the principal mechanism of iron toxicity. The consequent series of events caused by iron overload lead to catastrophic cardiac effects. The authors review the electrophysiological and molecular mechanisms, pathophysiology and correlated clinical insight of heart failure and arrhythmias in iron overload thalassemic cardiomyopathy.     

Cardiomyocyte apoptosis in hypertensive cardiomyopathy

It is widely accepted that there are two principal forms of cell death; namely, necrosis and apoptosis. According to the classical view, necrosis is the major mechanism of cardiomyocyte death in cardiac diseases. However, in the past few years observations have been made showing that cardiomyocyte apoptosis occurs in diverse conditions and that apoptosis may be a contributing cause of the loss and functional abnormalities of cardiomyocytes with important pathophysiological consequences. In this regard, although a number of formal proofs are pending, it is conceivable that cardiomyocyte apoptosis may be an important variable in the clinical evolution of hypertensive cardiomyopathy. This review summarizes recent evidence demonstrating that cardiomyocyte apoptosis is abnormally stimulated in the heart of animals and humans with arterial hypertension. In addition, the potential mechanisms of cardiomyocyte apoptosis in hypertension and its detrimental impact on cardiac function will be addressed. Finally, the perspectives of strategies aimed to detect and modulate apoptosis of cardiomyocytes in hypertensive cardiomyopathy will be considered.     

Automatic Implantable Cardioverter Defibrillator Lead Dislodgement Resulting in Sudden Cardiac Death: A Case Report

A 39-year-old subject with nonischemic dilated cardiomyopathy experienced sudden cardiac death 13 days after automatic implantable cardioverter defibrillator (AICD) implant. A hitherto unreported cause of death secondary to AICD lead dislodgement is presented along with a brief review of the literature on this subject. This case highlights the need for intensive monitoring of subjects at high risk of AICD lead dislodgement for early detection and intervention.     

Dilated cardiomyopathy and myocarditis: natural history, etiology, clinical manifestations, and management

This monograph begins and ends with a statement of uncertainty regarding many aspects of dilated cardiomyopathy. Natural history studies identify patients with widely differing outcomes. A host of prognostic factors have emerged, yet it would appear that the major determinants of survival are as yet unrecognized. The diagnosis remains primarily one of exclusion, and management is largely nonspecific and supportive. The frequency of sudden cardiac death is well documented, but the ability to accurately identify patients at risk and the efficacy of antiarrhythmic therapy is unestablished. The emerging success of cardiac transplantation is a source of encouragement. The causes of dilated cardiomyopathy remain a source of intense investigation. Accumulating evidence (much of it circumstantial) does, however, implicate a viral etiology and perhaps altered function of the immunoregulatory system. However, the disparity between the severity of functional disturbance with the relative lack of histologic markers of cellular necrosis implies a disturbance at a cellular level. The etiology or etiologies remain elusive. Future investigation directed at fundamental aspects of cardiac cellular biology may provide the answers.