The development of familial hypertrophic cardiomyopathy: from mutation to bedside

Abstract

Hypertrophic cardiomyopathy (HCM) is a familial disorder characterized by left ventricular hypertrophy in the absence of other cardiac or systemic disease likely to cause this hypertrophy. HCM is considered a disease of the sarcomere as most causal mutations are identified in genes encoding sarcomeric proteins, although several other disorders have also been linked to the HCM phenotype. The clinical course of HCM is characterized by a large inter-and intrafamilial variability, ranging from severe symptomatic HCM to asymptomatic individuals. The general picture emerges that the underlying pathophysiology of HCM is complex and still scarcely clarified. Recent findings indicated that both functional and morphological (macroscopic and microscopic) changes of the HCM muscle are present before the occurrence of HCM phenotype. This review aims to provide an overview of the myocardial alterations that occur during the gradual process of wall thickening in HCM on a myofilament level, as well as the structural and functional abnormalities that can be observed in genetically affected individuals prior to the development of HCM with state of the art imaging techniques, such as tissue Doppler echocardiography and cardiovascular magnetic resonance imaging. Additionally, present and future therapeutic options will be briefly discussed.

The influence of cell dimensions on the vulnerability of ventricular myocytes to lethal injury by high-intensity electrical fields

“…Although in the whole heart cells are electrically connected and thus the myocardium should behave as a functional syncytium, a remarkable similarity of the electrical interaction with external field has been observed in isolated myocytes and whole hearts of neonatal rats (Gomes et al, 2001(Gomes et al, , 2002. Increase in cell length is known to occur in some physiological (pregnancy; Virgen-Ortiz et al, 2009) and pathophysiological conditions, such as mitral insufficiency (Dillon et al, 2012), spontaneous arterial hypertension (R.A. Bassani, unpublished results), dilated cardiomyopathy (Kaistura et al, 1995), and familial hypertrophic cardiomyopathy (Brouwer et al, 2011). Cardiac hypertrophy has been considered an independent factor associated with increased risk of arrhythmia and sudden death (Bender et al, 2012;Reinier et al, 2011), particularly in the case of hypertrophic cardiomyopathy (Brouwer et al, 2011).…”

“…Increase in cell length is known to occur in some physiological (pregnancy; Virgen-Ortiz et al, 2009) and pathophysiological conditions, such as mitral insufficiency (Dillon et al, 2012), spontaneous arterial hypertension (R.A. Bassani, unpublished results), dilated cardiomyopathy (Kaistura et al, 1995), and familial hypertrophic cardiomyopathy (Brouwer et al, 2011). Cardiac hypertrophy has been considered an independent factor associated with increased risk of arrhythmia and sudden death (Bender et al, 2012;Reinier et al, 2011), particularly in the case of hypertrophic cardiomyopathy (Brouwer et al, 2011). Although during defibrillation/cardioversion only a fraction of the cardiac myocytes are expected to be in parallel orientation with the field, our results are suggestive that these cells might be at risk of severe injury, which might compromise the success of defibrillation (due to possible conduction block) and recovery of adequate cardiac pumping function.…”

“…In addition to providing a test of the usefulness of the K-P model for field intensities close to the range of those attained during defibrillation, this study also addresses a point of potential clinical importance, as cardiomyocyte hypertrophy is commonly associated with conditions that increases the probability of cardiac fibrillation and sudden death occurrence (e.g., Bender et al, 2012;Brouwer et al, 2011;Reinier et al, 2011).…”

The Use of Contrast-Enhancement Cardiovascular Magnetic Resonance Imaging in Cardiomyopathies

“…The gene mutations predominantly encode for contractile proteins, such as cardiac myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7) (thick filament of the sarcomere), and troponin T and troponin I (encoding for thin filament of the sarcomere; accounting for ≈ 6% of the hypertrophic cardiomyopathy-causing mutations). Next to sarcomeric mutations, several metabolic disorders are linked to the hypertrophic cardiomyopathy phenotype, such as Fabry disease (as mentioned above), an X chromosome-linked lysosomal storage disease (Brouwer et al, 2011). Thus, there is currently no consensus of a definitive screening test based on genetic studies for hypertrophic cardiomyopathy.…”

Utility of cadiovascular magnetic resonance imaging with contrast enhancement : beyond the scope of viability

“…These gene mutations predominantly encode for contractile proteins, such as cardiac myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7) (thick filament of the sarcomere), and troponin T and troponin I. 64 Besides sarcomeric mutations, several metabolic disorders have been linked to the phenotype of hypertrophic cardiomyopathy. An example may be the X chromosomelinked lysosomal storage disorder called Fabry disease.…”