Elsevier

The Lancet

Volume 355, Issue 9197, 1 January 2000, Pages 58-60
The Lancet

Hypothesis
Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy

https://doi.org/10.1016/S0140-6736(99)06187-5Get rights and content

Summary

Myocardial contractility is generally believed to be increased in hypertrophic cardiomyopathy. I propose the opposite—that cardiac myocyte contractility is decreased in this disorder. Accordingly, the contractile deficit provides the primary stimulus for increased expression of trophic factors in the heart, which leads to hypertrophy, interstitial fibrosis, and other phenotypes. Variation among individuals in expression of trophic factors would account for the variability of phenotypes. Gene transfer studies in cardiac myocytes showing impaired contractility and increased expression of trophic factors in the myocardium of patients with hypertrophic cardiomyopathy support this hypothesis. Testing of the hypothesis would require measurement of contractility of cardiac myocytes isolated from patients with hypertrophic cardiomyopathy, identification of the main trophic factors in the hearts of these patients, and investigation of whether their inhibition can prevent or lead to regression of the cardiac phenotypes.

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

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    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].

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