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Heterozygous disruption of SERCA2a is not associated with impairment of cardiac performance in humans: implications for SERCA2a as a therapeutic target in heart failure
  1. B M Mayosi1,*,
  2. A Kardos1,
  3. C H Davies1,,
  4. F Gumedze2,
  5. A Hovnanian3,
  6. S Burge4,
  7. H Watkins1
  1. 1Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
  2. 2Department of Statistical Sciences, University of Cape Town, Cape Town, South Africa
  3. 3INSERM U563, Purpan Hospital, Toulouse, France
  4. 4Department of Dermatology, The Churchill Hospital, Old Road, Headington, Oxford, UK
  1. Correspondence to:
    Professor Hugh Watkins
    Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK; hugh.watkins{at}


Objective: To verify whether a deficiency in the cardiac sarcoplasmic reticulum pump SERCA2a causes cardiac dysfunction in humans.

Design: Cardiac performance was measured in a serendipitous human model of primary SERCA2a deficiency, Darier’s disease, an autosomal dominant skin disorder caused by mutations inactivating one copy of the ATP2A2 gene, which encodes SERCA2a.

Methods: Systolic and diastolic function and contractility were assessed by echocardiography at rest and during exercise in patients with Darier’s disease with known mutations. Fourteen patients with Darier’s disease were compared with 14 normal controls and six patients with dilated cardiomyopathy with stable heart failure.

Results: Resting systolic and diastolic function was normal in patients with Darier’s disease and in controls. The increase in systolic function during exercise was not different between patients with Darier’s disease and normal controls; neither was there a difference in contractility. As expected, patients with dilated cardiomyopathy had impaired diastolic and systolic function with depressed contractility at rest and during exercise.

Conclusion: Contrary to expectations, heterozygous disruption of SERCA2a is not associated with the impairment of cardiac performance in humans. Attempts to increase SERCA2a levels in heart failure, although showing promise in rodent studies, may not be addressing a critical causal pathway in humans.

  • DT, deceleration time of the E wave
  • FS, fractional shortening
  • Vo2, oxygen consumption
  • heart failure
  • sarco(endo)plasmic reticulum Ca2+ ATPase 2 (ATP2A2) gene
  • ATP2A2 gene
  • Darier’s disease

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  • * Also the Cardiac Clinic, Department of Medicine, University of Cape Town, Cape Town, South Africa

  • Also the Department of Cardiology, Oregon Health Science University, Portland, Oregon, USA

  • Published Online First 21 April 2005