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Evolution of hypertrophic cardiomyopathy in sarcomere mutation carriers
  1. Gabriella Captur1,2,
  2. James C Moon2,3,4
  1. 1UCL Biological Mass Spectrometry Laboratory, Institute of Child Health and Great Ormond Street Hospital, London, UK
  2. 2NIHR University College London Hospitals Biomedical Research Centre, London, UK
  3. 3UCL Institute of Cardiovascular Science, University College London, London, UK
  4. 4Barts Heart Center, The Cardiovascular Magnetic Resonance Imaging Unit and The Center for Rare Cardiovascular Diseases Unit, St Bartholomew's Hospital, London, UK
  1. Correspondence to Professor James C Moon, Institute of Cardiovascular Science, University College London, Gower Street, London WC1E 6BT, UK; j.moon{at}ucl.ac.uk

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Hypertrophic cardiomyopathy (HCM) is, in most cases, caused by autosomal-dominant mutations in sarcomere protein genes. How these mutations lead to the development of symptoms, heart failure and sudden death, via the familiar clinical phenotype including left ventricular hypertrophy (LVH), is beginning to be unravelled. Before overt LVH, there is an earlier, subclinical stage. The detection of this is also useful—in the USA alone, there are 600, 000 or so people who either have subclinical HCM or who have now passed into overt disease. In addition, there are a similarly important number of first-degree relatives in whom status may be uncertain. Considering a ‘whole-of-life’ approach to HCM, the ultimate goal would be to develop specific therapies that prevent disease onset (not just mitigate risk and symptoms), while at the same time robustly predicting who will and will not develop disease, and identify how to modify this. Understanding disease mechanisms and phenotype development is one likely route to these insights.

The subclinical phase of HCM occurs before overt LVH criteria are reached, and it consists of a cluster of measurable abnormalities. Recognised electrocardiographic and imaging changes form the basis of the 1997 familial criteria,1 where in spite of the relatively sparse data minor and major criteria for its identification were constructed. Sparse data result in conflicting opinions however, with the later 2011 American College of Cardiology Foundation/American Heart Association guidelines classifying an HCM sarcomere gene mutation carrier as ‘genotype-positive/phenotype-negative leaving no room for a subclinical HCM state. Later guidelines (the 2014 European Society of Cardiology guidelines) acknowledged the subclinical phenotype but did not assign a firm status beyond “The clinical significance of mild morphological and functional abnormalities is uncertain …”.

Since the familial criteria almost 20 years ago, there has been progress in understanding HCM phenotype development with additional identified changes, particularly …

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