Arrhythmogenic cardiomyopathy: diagnosis,genetic background,and risk management

Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a hereditary disease characterised by ventricular arrhythmias, right ventricular and/or left ventricular dysfunction, and fibrofatty replacement of cardiomyocytes. Patients with AC typically present between the second and the fourth decade of life with ventricular tachycardias. However, sudden cardiac death (SCD) may be the first manifestation, often at young age in the concealed stage of disease. AC is diagnosed by a set of clinically applicable criteria defined by an international Task Force. The current Task Force Criteria are the essential standard for a correct diagnosis in individuals suspected of AC. The genetic substrate for AC is predominantly identified in genes encoding desmosomal proteins. In a minority of patients a non-desmosomal mutation predisposes to the phenotype. Risk stratification in AC is imperfect at present. Genotype-phenotype correlation analysis may provide more insight into risk profiles of index patients and family members. In addition to symptomatic treatment, prevention of SCD is the most important therapeutic goal in AC. Therapeutic options in symptomatic patients include antiarrhythmic drugs, catheter ablation, and ICD implantation. Furthermore, patients with AC and also all pathogenic mutation carriers should be advised against practising competitive and endurance sports.     

Effect of simvastatin on left ventricular mass in hypercholesterolemic rabbits

Epidemiological studies showed that hypercholesterolemia is associated with higher left ventricular mass. Endothelin signaling is activated in hyperlipidemic animals and may contribute to progressive ventricular hypertrophy. Simvastatin has been shown to inhibit endothelin-1. However, the behavior of simvastatin on ventricular hypertrophy in hyperlipidemic animals is not well understood. In this study, we evaluated the hemodynamic, biochemical, and morphological responses to simvastatin in cholesterol-fed (1%) rabbits. The left ventricular weight increased 8 wk after cholesterol feeding compared with that in normocholesterolemic rabbits. Simvastatin at a clinical therapeutic dose (1.2 mg x kg(-1) x day(-1)) significantly decreased left ventricular weight by 14% and left ventricular myocyte sizes by 14% as isolated by enzymatic dissociation. Hypercholesterolemia upregulated ventricular preproendothelin-1 mRNA as assessed by real-time quantitative RT-PCR and elevated production of cardiac endothelin-1 concentration. The increased endothelin-1 responses can be inhibited after simvastatin administration. Left ventricular mass indexed by body weight positively correlated with tissue endothelin-1 levels (P = 0.0003). In Langendorff-perfused rabbit hearts, hyperlipidemia led to significant QT prolongation compared with normocholesterolemia, which can be reversed by administering simvastatin. In contrast, simvastatin-induced beneficial effects were reversed by the addition of mevalonate. The addition of bosentan, a nonspecific endothelin receptor blocker, improved the response in hypercholesterolemic rabbits and did not have additional beneficial effects in simvastatin-treated rabbits. The results of the present study suggest that the antihypertropic and electrocardiographic effects of simvastatin at a clinical therapeutic dose are mediated through inhibition of tissue endothelin-1 expression, which is linked to mevalonate metabolism, and result in an amelioration of cardiomyocyte hypertrophy development by an atherogenic diet.     

The use of muscle flaps to treat left ventricular assist device infections

Left ventricular assist devices have become an important adjunct in the therapeutic armamentarium for patients with end-stage heart failure. Although they may provide a bridge to transplantation, they are prone to certain problems, expecially infection. Because these are life-sustaining devices, changing the device or simple explantation may be a risky, if not impossible, option. Therefore, we evaluated the effectiveness of a surgical alternative, namely, coverage of infected devices with muscle or myocutaneous flaps. Eighty-two consecutive patients who underwent the insertion of 88 left ventricular assist devices at our institution over a 6.5-year period were evaluated. Follow-up was provided for all patients and ranged from 1 to 7.5 years. The duration of ventricular support ranged from 0 to 434 days. All patients who demonstrated clinical evidence of infection were identified. Overall, 54 patients (66 percent) had infections locally at the device site, at distant sites, or systemically during support. Cultured organisms included gram-positive and -negative bacteria, fungi, and viruses. Of the 56 infections in these 54 patients, 21 (38 percent) were device-related, i.e., in the pocket created by the device, in the device itself, or from the driveline. Thus, 24 percent (21 of 88) of all ventricular support devices inserted demonstrated device infection during use. Therapeutic modalities used to combat device-related infection included both nonsurgical management with antibiotics alone and surgical procedures such as device change or relocation, device explant, and flap coverage. Eight of the 20 patients in whom the 21 device-related infections occurred underwent surgical intervention. Four of these eight patients undenwent local flap coverage of their infected left ventricular assist devices. All four patients also had evidence of systemic infection, or "device endocarditis." Coverage was successfully achieved in all cases with pedicled rectus abdominis flaps. There were no perioperative complications. Two patients later underwent successful transplantation; the other two died from causes unrelated to the flap. In conclusion, the treatment of infected left ventricular assist devices currently includes both nonsurgical and surgical alternatives. Of the latter, muscle flaps should be considered a first-line intervention to assist in eradicating infection by providing well-vascularized tissue. Although there were no perioperative complications, the 50 percent mortality rate is consistent with that reported for patients with "device endocarditis." It may be that flap coverage of infected ventricular assist devices, if instituted at an earlier stage in the therapeutic process, could help prevent systemic infection in these patients and, therefore, improve their overall outcome.     

Left ventricular false tendons

Left ventricular false tendons (LVFTs) are fibromuscular structures, connecting the left ventricular free wall or papillary muscle and the ventricular septum.There is some discussion about safety issues during intense exercise in athletes with LVFTs, as these bands have been associated with ventricular arrhythmias and abnormal cardiac remodelling. However, presence of LVFTs appears to be much more common than previously noted as imaging techniques have improved and the association between LVFTs and abnormal remodelling could very well be explained by better visibility in a dilated left ventricular lumen.Although LVFTs may result in electrocardiographic abnormalities and could form a substrate for ventricular arrhythmias, it should be considered as a normal anatomic variant. Persons with LVFTs do not appear to have increased risk for ventricular arrhythmias or sudden cardiac death.     

USE OF AN EXTRACARDIAC CONDUIT IN THE REPAIR OF l-TRANSPOSITION WITH l-LOOPING ASSOCIATED WITH SEVERE SUBVALVULAR PULMONIC STENOSIS AND A VENTRICULAR SEPTAL DEFECT

Total correction was performed in a child with l-transposition of the great arteries, severe subpulmonic stenosis, and a ventricular septal defect. The subpulmonic obstruction was bypassed with an extra-cardiac valved conduit. This alternate method of relieving ventricular outflow obstruction should be considered when conventional techniques cannot be employed because of complex intracardiac anatomy. Proper placement of the pulmonary ventriculotomy is important in order to avoid injury to coronary arteries on the upper and lower ventricular wall and to papillary muscles in the mid-portion of the ventricle.     

Ventricular arrhythmias.

Sudden cardiac death claims thousands of Canadians annually. Ventricular tachycardia and fibrillation account for up to 85% of these deaths. Identifying the patients at risk remains a major challenge. Those who have recurrent ventricular tachycardia or have been resuscitated from ventricular fibrillation are generally considered to be at highest risk. Although ventricular premature beats in the absence of previous ventricular tachycardia or fibrillation are not helpful in identifying such patients in most cases, they can indicate increased risk for sudden cardiac death in the presence of a structural cardiac abnormality, particularly recent myocardial infarction; however, the need for treatment in such cases is speculative and is being investigated. Treatment is mandatory for survivors of an episode of ventricular fibrillation and those with recurrent sustained ventricular tachycardia or torsade de pointes ventricular tachycardia. The approach to management is either invasive or noninvasive. Selection of an antiarrhythmic agent is facilitated by knowledge of some basic electrophysiologic features of the heart and of the classification of antiarrhythmic drugs. However, drug therapy has to be individualized on the basis of efficacy, left ventricular function and adverse effects or potential adverse effects of the drug. Amiodarone therapy or nonpharmacologic therapy should be considered if a suitable antiarrhythmic agent cannot be found.     

Role of echocardiography in diagnosis and risk stratification in heart failure with left ventricular systolic dysfunction

Congestive heart failure with preserved left ventricular systolic function has emerged as a growing epidemic medical syndrome in developed countries, which is characterized by high morbidity and mortality rates. Rapid and accurate diagnosis of this condition is essential for optimizing the therapeutic management. The diagnosis of congestive heart failure is challenging in patients presenting without obvious left ventricular systolic dysfunction and additional diagnostic information is most commonly required in this setting. Comprehensive Doppler echocardiography is the single most useful diagnostic test recommended by the ESC and ACC/AHA guidelines for assessing left ventricular ejection fraction and cardiac abnormalities in patients with suspected congestive heart failure, and non-invasively determined basal or exercise-induced pulmonary capillary hypertension is likely to become a hallmark of congestive heart failure in symptomatic patients with preserved left ventricular systolic function. The present review will focus on the current clinical applications of spectral tissue Doppler echocardiography used as a reliable noninvasive surrogate for left ventricular diastolic pressures at rest as well as during exercise in the diagnosis of heart failure with preserved left ventricular systolic function. Chronic congestive heart failure, a disease of exercise, and acute heart failure syndromes are characterized by specific pathophysiologic and diagnostic issues, and these two clinical presentations will be discussed separately.     

Inhibition of Angiotensin II-Induced Cardiac Hypertrophy and Associated Ventricular Arrhythmias by a p21 Activated Kinase 1 Bioactive Peptide

Cardiac hypertrophy increases the risk of morbidity and mortality of cardiovascular disease and thus inhibiting such hypertrophy is beneficial. In the present study, we explored the effect of a bioactive peptide (PAP) on angiotensin II (Ang II)-induced hypertrophy and associated ventricular arrhythmias in in vitro and in vivo models. PAP enhances p21 activated kinase 1 (Pak1) activity by increasing the level of phosphorylated Pak1 in cultured neonatal rat ventricular myocytes (NRVMs). Such PAP-induced Pak1 activation is associated with a significant reduction of Ang II-induced hypertrophy in NRVMs and C57BL/6 mice, in vitro and in vivo, respectively. Furthermore, PAP antagonizes ventricular arrhythmias associated with Ang II-induced hypertrophy in mice. Its antiarrhythmic effect is likely to be involved in multiple mechanisms to affect both substrate and trigger of ventricular arrhythmogenesis. Thus our results suggest that Pak1 activation achieved by specific bioactive peptide represents a potential novel therapeutic strategy for cardiac hypertrophy and associated ventricular arrhythmias.     

Nonviral vector gene modification of stem cells for myocardial repair

Therapeutic angiogenesis and myogenesis restore perfusion of ischemic myocardium and improve left ventricular contractility. These therapeutic modalities must be considered as complementary rather than competing to exploit their advantages for optimal beneficial effects. The resistant nature of cardiomyocytes to gene transfection can be overcome by ex vivo delivery of therapeutic genes to the heart using genetically modified stem cells. This review article gives an overview of different vectors and delivery systems in general used for therapeutic gene delivery to the heart and provides a critical appreciation of the ex vivo gene delivery approach using genetically modified stem cells to achieve angiomyogenesis for the treatment of infarcted heart.     

An Unusual Hazard of Fixed-Rate Cardiac Pacemakers

Rapid stimulation of the heart is an unusual and serious complication of implanted fixedrate cardiac pacemakers. This complication was observed in two patients. In one, stimuli occurred at 336 per minute with a ventricular rate of 168, and at 750 per minute with ventricular arrest. In the other patient, stimuli occurred at 150 per minute with a 1:1 ventricular response. This complication should be recognized and treated promptly by exposing and cutting the electrode lead wires.     

Ventricular noncompaction and long QT syndrome – A deadly double hit for the foetus

Congenital long QT syndrome [LQTS] is a channelopathy characterized by QT prolongation and polymorphic VT. LQTS however need not be a purely electrical disease. Defects in ion channels may cause myocardial architectural disruption leading to ventricular non compaction [VNC]. It is defined as the presence of prominent ventricular trabeculations and deep intertrabecular recesses within the endomyocardium. We describe the in-utero management of a foetus who was later found to have LQTS with VNC. The detection of ventricular tachycardia and complete heart block in utero should arouse the suspicion of LQTS. It would be wise to avoid QT prolonging antiarrhythmics in this subset of patients.     

Life-long tailoring of diagnosis and management of patients with idiopathic ventricular fibrillation—future perspectives in research

The diagnosis and management of idiopathic ventricular fibrillation is challenging, as it requires extensive diagnostic testing and offers few curative options due to unknown underlying disease. The resulting population is a heterogeneous group of patients with a largely unknown natural history. Structural patient characterisation, follow-up and innovations in diagnostic testing can improve our understanding of the disease mechanisms of idiopathic ventricular fibrillation, detect underlying disease during follow-up and aid in therapeutic management. Recently, initiatives have been launched in the Netherlands to investigate the role of high-resolution non-invasive electrocardiographic imaging and genetic and familial screening in idiopathic ventricular fibrillation.     

Role of catheter ablation in arrhythmogenic right ventricular dysplasia

Arrhythmogenic right ventricular dysplasia/cardiomyopathy is a disorder characterized by frequent ventricular tachycardia originating from the right ventricle and fibro-fatty replacement of right ventricular myocardium. Though the disorder was originally described during surgical ablation of refractory ventricular tachycardia, catheter ablation of tachycardia is one of the options for patients not responding to anti arrhythmic agents. Direct current fulguration was used in the initial phase followed by radiofrequency catheter ablation. In the present day scenario, all patients with risk for sudden cardiac death should receive an implantable cardioverter defibrillator. Radiofrequency catheter ablation remarkably reduces the frequency of defibrillator therapies. Direct current fulguration can still be considered in cases when radiofrequency ablation fails, though it requires higher expertise, general anesthesia and carries a higher morbidity. Newer mapping techniques have helped in identification of the site of ablation. In general, the success rate of ablation in arrhythmogenic right ventricular dysplasia is less than in other forms of right ventricular tachycardias like right ventricular outflow tract tachycardia.     

Early left ventricular remodelling following acute coronary accident

Ventricular remodelling following acute coronary syndromes is both complex and multiform. It is due to the response of the myocardium to the different agressions associated with these syndromes, in particular the ischemia and necrosis downstream of the occluded artery. We must not however neglect the role of the remodelling of the lesions resulting from spontaneous reperfusion or provoked by the cells and tissues associated with coronary microcirculation embolisms and the no-reflow phenomenon. Acute post-infarct remodelling is dominated by early ventricular dilatation which largely affects late prognosis, necrosis elimination and its replacement by a fibrotic scar in parallel with a compensatory hypertrophy of the non-infarcted myocardium. The diverse cellular and molecular components of this remodelling are increasingly well-known, allowing us to better explain the beneficial effects of the currently available medications and providing us with new potential therapeutic targets. A grading of this knowledge associated with the identification of new risk factors and early therapeutic interventions should help us to further limit the deleterious aspects of this remodelling in the goal of preventing, or at least delaying, the devolution towards heart failure.     

Dyssynchronous Ventricular Activation in Asymptomatic Wolff-Parkinson-White Syndrome: A Risk Factor for Development of Dilated Cardiomyopathy

A subset of children and adults with Wolff-Parkinson-White (WPW) syndrome develop dilated cardiomyopathy (DCM). Although DCM may occur in symptomatic WPW patients with sustained tachyarrhythmias, emerging evidence suggests that significant left ventricular dysfunction may arise in WPW in the absence of incessant tachyarrhythmias. An invariable electrophysiological feature in this non-tachyarrhythmia type of DCM is the presence of a right-sided septal or paraseptal accessory pathway. It is thought that premature ventricular activation over these accessory pathways induces septal wall motion abnormalities and ventricular dyssynchrony. LV dyssynchrony induces cellular and structural ventricular remodelling, which may have detrimental effects on cardiac performance. This review summarizes recent evidence for development of DCM in asymptomatic patients with WPW, discusses its pathogenesis, clinical presentation, management and treatment. The prognosis of accessory pathway-induced DCM is excellent. LV dysfunction reverses following catheter ablation of the accessory pathway, suggesting an association between DCM and ventricular preexcitation. Accessory pathway-induced DCM should be suspected in all patients presenting with heart failure and overt ventricular preexcitation, in whom no cause for their DCM can be found.     

缬沙坦联合培哚普利对慢性心力衰竭患者心功能及血浆BNP、CRP、IL-6

目的：观察缬沙坦联合培哚普利对慢性-22力衰竭（CHF）的治疗效果,以及对患者心功能、血浆脑利钠肽（BNP）、c反应蛋白（CRP）和IL-6的影响。方法：95例CHF患者随机分为缬沙坦治疗组（30例）、培哚普利治疗组（30例）和联合治疗组（35例）,患者均予以常规西医治疗,缬沙坦治疗组或培哚普利治疗组在常规治疗基础上加用缬沙坦或培哚普利,联合治疗组则同时加用缬沙坦和培哚普利。观察治疗效果及患者心功能变化,检测治疗前后血浆BNP、CRP、IL-6的浓度。结果：联合治疗组总有效率达到91．43％,高于缬沙坦治疗组73．33％和培哚普利53．33％的总有效率（P〈0．05）;与缬沙坦治疗组和培哚普利治疗组相比,缬沙坦联合培哚普利可有效改善患者心功能指标,降低血浆BNP、CRP、IL-6含量。结论：缬沙坦联合培哚普利能有效改善心功能,调节细胞因子表达,优于单用缬沙坦或培哚普利治疗。     

Electrophysiological changes in heart failure and their implications for arrhythmogenesis

Heart failure is the final common pathway of various cardiac pathologies and is associated with sudden cardiac death, mostly caused by ventricular arrhythmias. In this paper we briefly review the electrophysiological remodeling and the alterations in intracellular calcium handling, and the resulting arrhythmogenic mechanisms associated with heart failure. Intercellular uncoupling and fibrosis are identified as a major arrhythmogenic factors. Diet and ventricular wall stretch are discussed as modulating factors. Finally, emphasis is placed on the hitherto poorly studied aspects of right ventricular failure. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.     

Augmentation of autophagy by mTOR-inhibition in myocardial infarction: When size matters

The extent of adverse myocardial remodeling contributes essentially to the prognosis after myocardial infarction (MI). Currently, therapeutic strategies that inhibit remodeling are limited to inhibition of neurohumoral activation. mTOR-dependent signaling mechanisms are centrally involved in the myocardial remodeling process. There exists a controversy as to whether autophagy is beneficial in the setting of myocardial infarction. We now provide evidence that induction of autophagy by inhibition of mTOR with everolimus (RAD) prevents adverse left ventricular remodeling and limits infarct size following myocardial infarction. mTOR inhibition increases autophagy and concomitantly decreases proteasome activity especially in the border zone of the infarcted myocardium. The induction of autophagy via mTOR inhibition is a novel potential therapeutic approach to limit infarct size and to attenuate adverse left ventricular remodeling following MI.     

Natural history and management of chronic aortic valve disease.

Chronic aortic valve disease involving stenosis, regurgitation or both is insidious and progressive. Severe valvular dysfunction may be present for years without symptoms, but functional deterioration is often rapid once congestive heart failure, angina or syncope with effort is present. As the severity of aortic stenosis may not be easy to assess clinically, the relative usefulness of various tests is considered in this paper. The difficulty with chronic aortic regurgitation lies not in diagnosing the problem but in detecting early left ventricular dysfunction in time to perform the surgery that can prevent further functional deterioration. Patients with significant aortic valve disease should undergo surgery when the important symptoms of dyspnea, angina or syncope with effort first appear. Surgery should also be considered in selected patients with aortic regurgitation in whom left ventricular function has diminished even without symptoms.