Genes, Geography and Geometry

Abstract

As recently stated by Elliott and Spirito, "the prevention of premature death from ventricular tachyarrhythmia, heart failure and stroke remains a major aim of clinical management in what is now called hypertrophic cardiomyopathy."1 Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, the first myocardial affliction for which a genetic basis was identified and, in essence, a disease of the contractile sarcomeric proteins. The stigmata of the disease are myocardial hypertrophy, often asymmetric and with any possible diffuse or segmental pattern of left ventricle (LV) thickening, and impaired LV contractile and diastolic function. HCM can be classified as obstructive or non obstructive. In the 25% of HCM patients with LV outflow tract obstruction, there is the presence of a dynamic ventricular gradient. A pronounced LV outflow tract obstruction directly correlates with the severity of the clinical manifestations while adversely impacting the prognosis. 2HCM results from excessive cardiac growth, increased number of fibroblasts with secretion of collagen (fibrosis), and disruption of the characteristic cell-to-cell alignment of the sarcomere and myocyte. Electrical instability (ie, atrial and ventricular arrhythmias) is another prominent feature of HCM and a leading cause of death, particularly in young athletes.3 Although HCM is a relatively benign syndrome in adult populations, with an annual frequency of sudden cardiac death (SCD) of 0.5% to 1%, HCM still remains the most common cause of death among children and adolescents (1% to 2%). 4 Early age of onset, family history of SCD, malignant arrhythmias and exercise-induced hypotension, in addition to specific genetic mutations, all contribute to a higher risk for SCD.5,6 As a matter of fact, "the major clinical challenge is the identification of the small number of individuals who are prone to serious complications and rapid disease progression." 2 Typical clinical manifestations of HCM include chest pain, exertion-related dyspnea (exercise intolerance), palpitations and, less frequently, syncope. However, HCM is clinically variable, with some patients remaining asymptomatic throughout their lifetime, while others experience the most serious complications. This heterogeneity is likely one of the major reasons for the complexity of HCM management. Unfortunately, SCD is quite often the presenting manifestation in young individuals. Current treatments focus on relieving the symptoms of HCM, treating arrhythmias (ie, atrial fibrillation and nonsustained ventricular tachycardia) that occur commonly in HCM, and, foremost, preventing SCD. These interventions include changes in lifestyle (ie, diet and exercise) and pharmacological tools such as ␤-blockers, Ca 2ϩ channel blockers and diuretics. The implantation of cardiac defibrillators is also a valid option, particularly for those patients that are at the highest risk for sudden death.HCM is caused by mutations in one of a number of genes. Approximately 450 different mutations have been discovered in gene...

Survival and Clinical Behavior of Hypertrophic Cardiomyopathy in a Latin American Cohort in Contrast to Cohorts from the Developed World

“…Actin mutation Glu101Lys was found to be consistently associated with apical HCM. However, as highlighted earlier by the findings of Kaludercic et al, 2) actin mutations are generally associated to better prognosis than those in the MHC-β.…”

“…The aggressiveness of a particular variant of HCM could depend more on the genotype than on the morphological characteristics (i.e., phenotype). 18) Kaludercic et al 2) alludes to the fact that specific mutations in certain genes have a clinical and prognostic relevance in HCM.…”

“…Despite its identification as an autosomal dominant feature, many genetic mutations are involved in the expression of the disease and the primary etiology is still elusive. 1) 2) …”