Heterozygous disruption of SERCA2a is not associated with impairment of cardiac performance in humans: implications for SERCA2a as a therapeutic target in heart failure.
OBJECTIVE
To verify whether a deficiency in the cardiac sarcoplasmic reticulum pump SERCA2a causes cardiac dysfunction in humans.


METHODS
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.


CONCLUSIONS
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.
Mayosi
B M
BM
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Kardos
A
A
Davies
C H
CH
Gumedze
F
F
Hovnanian
A
A
Burge
S
S
Watkins
H
H
D000252:Calcium-Transporting ATPases / Q000172:deficiency / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D016022:Case-Control Studies; D007644:Darier Disease / Q000235:genetics*; D017079:Exercise Tolerance; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006333:Heart Failure / Q000235:genetics* / Q000628:therapy; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D000252:Calcium-Transporting ATPases