What is the clinical evidence from this study?

Study design: Other. Population: Aortic stenosis and early heart failure. Intervention: Transgenic expression of SERCA2a vs. Wild-type. Primary outcome: Mortality at 7 weeks of aortic stenosis.

What does this research mean for the field?

Transgenic expression of SERCA2a in mice subjected to chronic pressure overload results in significantly lower mortality and preserves contractile reserve during the transition to early heart failure. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

August 31, 2001

Transgenic Expression of Sarcoplasmic Reticulum Ca 2+ ATPase Modifies the Transition From Hypertrophy to Early Heart Failure

Key Result

Transgenic expression of SERCA2a in mice subjected to 7 weeks of aortic stenosis resulted in lower mortality (6.7% vs 29%) and preserved contractile reserve compared to wild-type mice.

Structured PICO

Does transgenic expression of SERCA2a modify the transition from hypertrophy to early heart failure in mice subjected to aortic stenosis?

Population

Transgenic (TG) mice expressing SERCA2a gene and wild-type (WT) mice subjected to aortic stenosis (AS)

Intervention

Transgenic expression of SERCA2a gene

Comparator

Wild-type (WT) mice

Outcome

Mortality and in vivo hemodynamic/echocardiographic indices at 7 weeks of aortic stenosissurrogate

Transgenic expression of SERCA2a preserves contractile reserve and reduces mortality in a mouse model of pressure overload-induced heart failure, suggesting defective SR Ca2+ loading contributes to contractile failure.

Main Result

Absolute Event Rate: 6.7% vs 29%

Abstract

To examine the contribution of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) to early heart failure, we subjected transgenic (TG) mice expressing SERCA2a gene and wild-type (WT) mice to aortic stenosis (AS) for 7 weeks. At an early stage of hypertrophy (4-week AS), in vivo hemodynamic and echocardiographic indices were similar in TG and WT mice. By 7 weeks of AS, which is the stage of early failure in this model, TG mice with AS had lower mortality than WT mice with AS (6.7% versus 29%). The magnitude of left ventricular (LV) hypertrophy was similar in WT and TG 7-week AS mice. In vivo LV systolic function was higher in TG than in WT 7-week AS mice. In LV myocytes loaded with fluo-3, fractional cell shortening and the amplitude of the Ca(2+)(i) transients were higher in TG than in WT 7-week AS mice under baseline conditions (0.5 Hz, 1.5 mmol/L Ca(2+)(o), 25 degrees C). The rates of relengthening and decay in Ca(2+)(i) were faster in TG than in WT 7-week AS myocytes. In myocytes from WT 7-week AS compared with sham-operated WT mice, contractile reserve in response to rapid pacing was depressed with impaired augmentation of both peak-systolic Ca(2+)(i) and the SR Ca(2+) load. In contrast, contractile reserve and the capacity to augment SR Ca(2+) load were maintained in TG 7-week AS mice. SERCA2a protein levels were depressed in WT 7-week AS mice, but were preserved in TG 7-week AS mice. These data suggest that defective SR Ca(2+) loading contributes to the onset of contractile failure in animals with chronic pressure overload.