Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion

doi:10.1016/S0168-9525(03)00081-7

Trends in Genetics

Volume 19, Issue 5, May 2003, Pages 263-268

https://doi.org/10.1016/S0168-9525(03)00081-7 Get rights and content

Abstract

Genetic analysis of hypertrophic cardiomyopathy (HCM), a mendelian form of cardiac hypertrophy, indicates that the primary defect is in sarcomeric function. However, the initial proposal that depressed myocardial contraction leads to a ‘compensatory’ hypertrophy has proven inconsistent with laboratory and clinical evidence. Drawing on observations of mutant contractile protein function, together with mouse models and clinical studies, we propose that sarcomeric HCM mutations lead to inefficient ATP utilization. The suggestion that energy depletion underlies HCM is supported by the HCM-like phenotype found with mutations in a variety of metabolic genes. A central role for compromised energetics would also help explain the unresolved clinical observations of delayed onset and asymmetrical hypertrophy in HCM, and would have implications for therapy in HCM and, potentially, in more-common forms of cardiac hypertrophy and failure.

Section snippets

HCM that is not attributable to contractile protein mutations

Mutations in the known HCM disease genes are only found in ∼60% of families. As contemporary mutation detection techniques are highly sensitive, and most mutations are dominant negatives confined to coding sequences, it is unlikely that very many mutations are missed. Furthermore, as the vast majority of contractile protein isoforms have been screened, it appears likely that undiscovered disease genes might encode quite different proteins. Identification of the remaining HCM disease genes will

The pathogenesis of hypertrophy

Early attempts to explain the pathogenesis of HCM suggested that incorporation of mutant sarcomeric proteins depresses contractile function 10, 11, and that subsequent activation of neuroendocrine and mechanical responses leads to compensatory hypertrophy (Fig. 2) [12]. Although appealing, this hypothesis fails to explain three cardinal features of HCM.

First, whereas initial biochemical studies on βMHC mutants showed that actin filament translocation and force generation were reduced 10, 13,

The energy depletion hypothesis

To reconcile the lack of consistent contractile abnormalities in HCM, we propose that the unifying dysfunction in HCM is increased energy demand owing to inefficient sarcomeric ATP utilization. The increased demand compromises the capacity of the cardiomyocyte to maintain energy levels in subcellular compartments responsible for contraction and critical homeostatic functions, such as Ca²⁺ re-uptake. The ensuing myocyte dysfunction results in hypertrophy.

How would different classes of sarcomeric HCM mutation cause inefficient energy utilization?

Biochemical studies have shown that HCM mutations in βMHC alter the cycling rate of myosin heads [14] and, as patients are heterozygous for these mutations, their thick filaments will be composed of wild-type myosin heads interspersed with mutant heads. Although the kinetics of attachment and detachment of individual myosin heads are stochastic, the detachment of crossbridges is increased by the strain produced by active crossbridges on the same filament [20]. Therefore, a greater proportion of

Energy depletion would explain the unresolved clinical features of HCM

Numerous distinct stimuli can induce cardiac hypertrophy, yet the majority of the downstream signalling cascades converge upon intracellular Ca²⁺ and its downstream Ca²⁺-sensor proteins. It is becoming clear that, in addition to the role of the Ca²⁺ transient in excitation–contraction coupling (Box 2), cytosolic Ca²⁺ levels (probably including characteristics of the transients and their pathological variants) appear to co-ordinate transcriptional processes that result in hypertrophy 37, 38.

Acknowledgements

We thank Stefan Neubauer for helpful advice on the manuscript. The British Heart Foundation and Wellcome Trust support the authors' research.

Glossary

Cardiomyocytes: : heart muscle cells.
Coronary sinus: : the principle venous drainage from the myocardium.
Sarcomere: : a structural unit of the contractile apparatus of striated muscle.
Septum: : the muscle wall that divides the two ventricular chambers of the heart.

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Trends in Genetics

Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion

Abstract

Section snippets

HCM that is not attributable to contractile protein mutations

The pathogenesis of hypertrophy

The energy depletion hypothesis

How would different classes of sarcomeric HCM mutation cause inefficient energy utilization?

Energy depletion would explain the unresolved clinical features of HCM

Acknowledgements

Glossary

Glossary

Cell

Cell

J. Am. Coll. Cardiol.

Lancet

Trends Cardiovasc. Med.

J. Biol. Chem.

J. Mol. Cell. Cardiol.

Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy

New Engl. J. Med.

Prognostic implications of novel β cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy

J. Clin. Invest.

Mutations in the genes for cardiac troponin T and α-tropomyosin in hypertrophic cardiomyopathy

New Engl. J. Med.

Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy

New Engl. J. Med.

Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene

Circulation

Heart Disease; a Textbook of Cardiovascular Medicine

Abnormal contractile properties of muscle fibers expressing β-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy

J. Clin. Invest.

Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. Evidence for a dominant negative action

J. Clin. Invest.

Functional analysis of the mutations in the human cardiac β-myosin that are responsible for familial hypertrophic cardiomyopathy. Implication for the clinical outcome

J. Clin. Invest.

Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function

Proc. Natl. Acad. Sci. U. S. A.

Regulation of force and unloaded sliding speed in single thin filaments: effects of regulatory proteins and calcium

J. Physiol.

Direct, convergent hypersensitivity of calcium-activated force generation produced by hypertrophic cardiomyopathy mutant α-tropomyosins in adult cardiac myocytes

Nat. Med.

Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy

Circulation

Molecular model of muscle contraction

Proc. Natl. Acad. Sci. U. S. A.