Grey zones in cardiomyopathies: defining boundaries between genetic and iatrogenic disease

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Key Points

  • Early description of cardiomyopathies originated from severe, paradigmatic case series that described worst-case scenarios

  • The entire range of cardiomyopathies has subsequently emerged, including mild phenotypes that might overlap with normal variation

  • Current screening policies have the potential to identify affected individuals at very early stages, leading to effective prevention of cardiomyopathy-related complications, including sudden cardiac death, but also increase the risk of overdiagnosing healthy individuals

  • A systematic approach is necessary in patients with mild phenotypes suggestive of, but not definitely diagnostic for, cardiomyopathies

  • We propose that at least one of five major criteria should be fulfilled before a diagnosis of cardiomyopathy is made

Abstract

Genetic cardiomyopathies are complex diseases with heterogeneous clinical presentation and phenotypes. Early descriptions of cardiomyopathies originated from case studies involving individuals with severe, paradigmatic presentation, which provided insight into the worst-case scenarios of these conditions. With time, improved diagnostic sensitivity and awareness of cardiomyopathies has uncovered a more heterogeneous disease spectrum, including mild phenotypes overlapping with physiological variation. This diagnostic 'grey area' poses important dilemmas, particularly in athletes. Current screening policies have the potential to identify affected individuals at very early stages, leading to effective prevention of cardiomyopathy-related complications such as sudden cardiac death. Conversely, however, some physicians actively impose diagnoses on individuals who perceive themselves to be disease-free. In addition, the high sensitivity of contemporary diagnostic techniques carries a serious risk of misinterpreting physiological variation as disease. In this Review, three of the most common and controversial areas are discussed, including left ventricular hypertrophy; left ventricular dilatation, noncompaction, and fibrosis; and arrhythmias originating from the right ventricle. A systematic and cautious approach is necessary in patients with mild phenotypes suggestive of, but not definitely diagnostic for, cardiomyopathies. Preventing the mislabelling of healthy individuals and overdiagnosis should be a priority, with the aim to combine adequate counselling and optimal protection.

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Figure 1: Athlete's heart versus hypertrophic cardiomyopathy (HCM).
Figure 2: Typical late gadolinium enhancement image in a patient with hypertrophic cardiomyopathy.
Figure 3: Mild ventricular trabeculation: enough to diagnose a cardiomyopathy?
Figure 4: Comprehensive clinical evaluation in an asymptomatic patient with suspected left ventricular noncompaction (LVNC).
Figure 5: Electrocardiographical characteristics of patients with right ventricular outflow tract tachycardia (RVOTT) and arrhythmogenic right ventricular cardiomyopathy (ARVC).
Figure 6: Electrophysiological characteristics of patients with right ventricular outflow tract tachycardia (RVOTT) and arrhythmogenic right ventricular cardiomyopathy (ARVC).

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Acknowledgements

I.O. is supported by the Italian Ministry of Health: “Left ventricular hypertrophy in aortic valve disease and hypertrophic cardiomyopathy: genetic basis, biophysical correlates and viral therapy models” (RF-2013-02356787), and “Mechanisms and treatment of coronary microvascular dysfunction in patients with genetic or secondary left ventricular hypertrophy” (NET-2011-02347173).

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G.Q. and L.O. researched data for the article. G.Q., M.P., P.D.D., N.M., A.I., and L.O. wrote the manuscript, and G.Q., M.P., A.G., M.S., and L.O. reviewed and edited the manuscript before submission. All the authors contributed to discussion of content.

Correspondence to Giovanni Quarta.

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Quarta, G., Papadakis, M., Donna, P. et al. Grey zones in cardiomyopathies: defining boundaries between genetic and iatrogenic disease. Nat Rev Cardiol 14, 102–112 (2017) doi:10.1038/nrcardio.2016.175

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