Diagnostic, Prognostic, and Therapeutic Implications of Genetic Testing for Hypertrophic Cardiomyopathy

Over the last 2 decades, the pathogenic basis for the most common heritable cardiovascular disease, hypertrophic cardiomyopathy (HCM), has been investigated extensively. Affecting approximately 1 in 500 individuals, HCM is the most common cause of sudden death in young athletes. In recent years, genomic medicine has been moving from the bench to the bedside throughout all medical disciplines including cardiology. Now, genomic medicine has entered clinical practice as it pertains to the evaluation and management of patients with HCM. The continuous research and discoveries of new HCM susceptibility genes, the growing amount of data from genotype-phenotype correlation studies, and the introduction of commercially available genetic tests for HCM make it essential that the modern-day cardiologist understand the diagnostic, prognostic, and therapeutic implications of HCM genetic testing

The Z-Disk Final Common Pathway in Cardiomyopathies

The sarcomeres represent the essential contractile units of the cardiac myocyte and are bordered by two Z-lines (disks) that are made by various proteins. The cardiac Z-disk is recognized as one of the nodal points in cardiomyocyte structural organization, mechano-sensation and signal transduction. Rapid progress in molecular and cellular biology has significantly improved the knowledge about pathogenic mechanisms and signaling pathways involved in the development of inherited cardiomyopathies. Genetic insult resulting in expression of mutated proteins that maintain the structure of the heart can perturb cardiac function. The primary mutation in the cardiac contractile apparatus or other subcellular complexes can lead to cardiac pathology on a tissue level, resulting in organ and organism level pathophysiology. The “final common pathway” hypothesis interpreting the genetic basis and molecular mechanisms involved in the development of cardiomyopathies suggests that mutations in cardiac genes encoding proteins with similar structure, function, or location and operating in the same pathway, are responsible for a particular phenotype of cardiomyopathy with unique morpho-histological remodeling of the heart. This chapter will describe genetic abnormalities of cardiac Z-disk and related “final common pathways” that are triggered by a Z-disk genetic insult leading to heart muscle diseases. In addition, animal models carrying mutations in Z-disk proteins will be described

Adenovirus infection in the lung results in graft failure after lung transplantation

AbstractObjectives: Our goal was to examine the relationship between viral pneumonia and outcome in pediatric patients undergoing lung or heart-lung transplantation. Methods: Prospective surveillance for common respiratory viruses of childhood was performed in all patients undergoing lung or heart-lung transplantation. Specimens were examined for the presence of replicating virus (by culture), viral genome (by polymerase chain reaction), and viral antigen (by immunofluorescence and immunohistochemical staining). The relationship between viral infection and outcome was examined. Results: Sixteen patients underwent 19 transplants during the study period, with follow-up of 1 to 26 months. Virus was identified in the transplanted lung in 29 instances; adenovirus was identified most commonly (8/16 patients) and had the greatest impact on outcome. In 2 patients with early, fulminant infection, adenovirus was also identified in the donor. Adenovirus was significantly associated with respiratory failure leading to death or graft loss and with the histologic diagnosis of obliterative bronchiolitis (P ≤ .002 in each case). Conclusions: Adenovirus infection in the transplanted lung is significantly associated with graft failure, histologic obliterative bronchiolitis, and death. Health care personnel and families must be vigilant in preventing exposure of transplant recipients to this virus. Availability of a rapid and reliable test for adenovirus in donors and recipients would have an impact on management and could improve outcome for pediatric lung recipients. (J Thorac Cardiovasc Surg 1998;116:617-23

Myocardial Remodeling with Ventricular Assist Devices

Most prominent functional abnormalities seen in the failing human heart are impaired contraction and slowed rates of relaxation of cardiac cells in the face of increased neurohormonal activation, sustained inflammation, mechanical and volume overload, and progressive maladaptive remodeling of the myocardium. Mechanical circulatory support devices (MCS) improve cardiac function and outcomes of patients with end-stage heart failure, allowing to bridge to heart transplantation and permitting the removal of MCS device as a bridge to recovery, in some patients with the sufficient recovery of heart function. Numerous reports have demonstrated favorable myocardial recovery and reverse remodeling after prolonged ventricular unloading by MCS. Ventricular unloading by MCS leads to a decreased concentration of peripheral natriuretic peptides in plasma, reduction in cardiac cytokines, kinases, collagens, and proteins involved in hypertrophy, fibrosis, programmed cell death, and necrosis in the heart. This chapter will summarize and review the effects and underlying mechanisms of myocardial remodeling during prolonged MCS in patients with end-stage heart failure. The mechanisms of myocardial recovery are multifactorial and remain to be further explored on cellular, organ, and systems levels

Pediatric and adult dilated cardiomyopathy represent distinct pathological entities

Pediatric dilated cardiomyopathy (DCM) is the most common indication for heart transplantation in children. Despite similar genetic etiologies, medications routinely used in adult heart failure patients do not improve outcomes in the pediatric population. The mechanistic basis for these observations is unknown. We hypothesized that pediatric and adult DCM comprise distinct pathological entities, in that children do not undergo adverse remodeling, the target of adult heart failure therapies. To test this hypothesis, we examined LV specimens obtained from pediatric and adult donor controls and DCM patients. Consistent with the established pathophysiology of adult heart failure, adults with DCM displayed marked cardiomyocyte hypertrophy and myocardial fibrosis compared with donor controls. In contrast, pediatric DCM specimens demonstrated minimal cardiomyocyte hypertrophy and myocardial fibrosis compared with both age-matched controls and adults with DCM. Strikingly, RNA sequencing uncovered divergent gene expression profiles in pediatric and adult patients, including enrichment of transcripts associated with adverse remodeling and innate immune activation in adult DCM specimens. Collectively, these findings reveal that pediatric and adult DCM represent distinct pathological entities, provide a mechanistic basis to explain why children fail to respond to adult heart failure therapies, and suggest the need to develop new approaches for pediatric DCM

Left Ventricular Noncompaction Cardiomyopathy: From Clinical Features to Animal Modeling

Cardiomyopathy or disease of the heart muscle involves abnormal enlargement and a thickened, stiff, or spongy-like appearance of the myocardium. As a result, the function of the myocardium is weakened and does not sufficiently pump blood throughout the body nor maintain a normal pumping rhythm, leading to heart failure. The main types of cardiomyopathies include dilated hypertrophic, restrictive, arrhythmogenic, and noncompaction cardiomyopathy. Abnormal trabeculations of the myocardium in the left ventricle are classified as left ventricular noncompaction cardiomyopathy (LVNC). Myocardial noncompaction most frequently is observed at the apex of the left ventricle and can be associated with chamber dilation or muscle hypertrophy, systolic or diastolic dysfunction, or both, or various forms of congenital heart disease. Animal models are incredibly important for uncovering the etiology and pathogenesis involved in this disease. This chapter will describe the clinical and pathological features of LVNC in humans and present the animal models that have been used for the study of the genetic basis and pathogenesis of this disease

Arrhythmogenic Phenotype in Dilated Cardiomyopathy: Natural History and Predictors of Life-Threatening Arrhythmias

BACKGROUND-\u2014Patients with dilated cardiomyopathy (DCM) may present with ventricular arrhythmias early in the disease course, unrelated to the severity of left ventricular dysfunction. These patients may be classified as having an arrhythmogenic DCM (ARDCM). We investigated the phenotype and natural history of patients with AR-DCM. METHODS AND RESULTS-\u2014Two hundred eighty-five patients with a recent diagnosis of DCM (median duration of the disease 1 month, range 0 to 7 months) and who had Holter monitoring at baseline were comprehensively evaluated and followed for 107 months (range 29 to 170 months). AR-DCM was defined by the presence of 651 of the following: unexplained syncope, rapid nonsustained ventricular tachycardia ( 655 beats, 65150 bpm), 651000 premature ventricular contractions/24 hours, and 6550 ventricular couplets/ 24 hours, in the absence of overt heart failure. The primary end points were sudden cardiac death (SCD), sustained ventricular tachycardia (SVT), or ventricular fibrillation (VF). The secondary end points were death from congestive heart failure or heart transplantation. Of the 285 patients, 109 (38.2%) met criteria for AR-DCM phenotype. AR-DCM subjects had a higher incidence of SCD/SVT/VF compared with non\u2013AR-DCM patients (30.3% vs 17.6%, P=0.022), with no difference in the secondary end points. A family history of SCD/SVT/VF and the AR-DCM phenotype were statistically significant and cumulative predictors of SCD/SVT/VF. CONCLUSIONS-\u2014One-third of DCM patients may have an arrhythmogenic phenotype associated with increased risk of arrhythmias during follow-up. A family history of ventricular arrhythmias in DCM predicts a poor prognosis and increased risk of SCD

Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome

AbstractOBJECTIVESThe study compared the influence of sympathetic stimulation on transmural and spatial dispersion of repolarization between LQT1 and LQT2 forms of congenital long QT syndrome (LQTS).BACKGROUNDCardiac events are more associated with sympathetic stimulation in LQT1 than in LQT2 or LQT3 syndrome. Experimental studies have suggested that the interval between Tpeak and Tend (Tp-e) in the electrocardiogram (ECG) reflects transmural dispersion of repolarization across the ventricular wall.METHODSWe recorded 87-lead body-surface ECGs before and after epinephrine infusion (0.1 μg/kg/min) in 13 LQT1, 6 LQT2, and 7 control patients. The Q-Tend (QT-e), Q-Tpeak (QT-p), and Tp-e were measured automatically from 87-lead ECGs, corrected by Bazett’s method (QTc-e, QTc-p, Tcp-e), and averaged among all 87-leads and among 24-leads, which reflect the potential from the left ventricular free wall. As an index of spatial dispersion of repolarization, the dispersion of QTc-e (QTc-eD) and QTc-p (QTc-pD) were obtained among 87-leads and among 24-leads, and were defined as the interval between the maximum and the minimum of the QTc-e and the QTc-p, respectively.RESULTSEpinephrine significantly increased the mean QTc-e but not the mean QTc-p, resulting in a significant increase in the mean Tcp-e in both LQT1 and LQT2, but not in control patients. The epinephrine-induced increases in the mean QTc-e and Tcp-e were larger in LQT1 than in LQT2, and were more pronounced when the averaged data were obtained from 24-leads than from 87-leads. Epinephrine increased the maximum QTc-e but not the minimum QTc-e, producing a significant increase in the QTc-eD in both LQT1 and LQT2 patients, but not in control patients. The increase in the QTc-eD was larger in LQT1 than in LQT2 patients.CONCLUSIONSOur data suggest that sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than in LQT2 syndrome, and this may explain why LQT1 patients are more sensitive to sympathetic stimulation