HypothesisPathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy
Section snippets
Hypothesis
I propose that, despite the preserved LVEF and in contrast to the general belief, the primary abnormality in human hypertrophic cardiomyopathy is decreased contractility of the cardiac myocytes. Cell stress is therefore increased and as a result, expression of the stress-responsive trophic and mitotic factors such as insulin-like growth factor 1 (IGF-1), transforming growth factor β1 (TGF-β), and angiotensin II are upregulated (figure 1). I suggest that increased expression of the trophic and
Evidence for the hypothesis
Expression of mutant sarcomeric proteins in adult cardiac myocytes impairs their mechanical performance.7, 8 In addition, decreased left-ventricular end-systolic stress-volume ratio, a measure of myocardial contractility, has been shown in patients with hypertrophic cardiomyopathy.9 The molecular markers of compensatory hypertrophy due to pressure overload, such as TGF-β,10 IGF-1,10 and endothelin 111 are also upregulated in the myocardium in these patients. Thus, the hypertrophic pathways in
Testing the hypothesis
To prove this hypothesis, several sets of experiments are required. First, the contractile performance of isolated cardiac myocytes from the hearts of patients with hypertrophic cardiomyopathy must be measured in an in-vitro system. Myocardial sections can be obtained from the hearts of patients with hypertrophic cardiomyopathy who are undergoing myomectomy, and cardiac myocytes can be isolated from the myomectomy samples. Then indices of contractility (and relaxation), such as maximum velocity
References (15)
- et al.
Hypertrophic nonobstructive cardiomyopathy; a precise assessment of hemodynamic characteristics and clinical implications
Am J Cardiol
(1982) - et al.
The influence of the angiotensin I converting enzyme genotype in familial hypertrophic cardiomyopathy varies with the disease gene mutation
J Mol Cell Cardiol
(1997) - et al.
The cardiomyopathies and myocarditides: toxic, chemical, and physical damage to the heart
- et al.
Sudden death in young competitive athletes: clinical, demographic, and pathological profiles
JAMA
(1996) - et al.
Hypertrophic cardiomyopathy—pathology and pathogenesis
Histopathology
(1995) - et al.
Molecular genetics of hypertrophic cardiomyopathy
J Cardiac Electrophysiol
(1998) - et al.
Prognostic significance of β-myosin heavy chain mutations is reflective of their hypertrophic expressivity in patients with hypertrophic cardiomyopathy
J Invest Med
(1997)
Cited by (195)
Spotlight on Myocardial Deformation in Hypertrophic Cardiomyopathy: Putting the Puzzle Together?
2023, JACC: Cardiovascular ImagingIsogenic models of hypertrophic cardiomyopathy unveil differential phenotypes and mechanism-driven therapeutics
2020, Journal of Molecular and Cellular CardiologyNew perspectives in the pharmacological treatment of hypertrophic cardiomyopathy
2020, Revista Portuguesa de CardiologiaiPSCs for modeling of sarcomeric cardiomyopathies
2020, Recent Advances in iPSC Disease ModelingModeling Hypertrophic Cardiomyopathy: Mechanistic Insights and Pharmacological Intervention
2019, Trends in Molecular MedicineCitation Excerpt :A hypocontractile phenotype in HCM can be clinically explained by the concentric nature of the hypertrophy: thickening of the ventricular walls without increase in heart size leads to a smaller LV end-diastolic volume. This causes an apparent hypercontraction [resulting in similar or higher LV ejection fraction, (LVEF)] but not when normalized to cardiomyocyte or myofibril density [87,88]. Interestingly, echo-based strain imaging has consistently reported hypocontractile function in HCM patients [89].
Role of the Extracellular Matrix in the Pathogenesis of Hypertrophic Cardiomyopathy
2019, JACC: Basic to Translational Science