What is the clinical evidence from this study?

Study design: Other. Population: Myocardial ischemia-reperfusion injury. Intervention: Heart-targeted overexpression of Caspase3 vs. Wild-type littermates. Primary outcome: Left ventricular percent fractional shortening (%FS) at 9 weeks (p=<0.03).

August 7, 2001Open Access

Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function

Q: What are the key findings of this study?

Cardiac-specific overexpression of Caspase3 in mice significantly depressed left ventricular fractional shortening at 9 weeks (29.9% vs 36.9%) and increased infarct size and mortality following ischemia-reperfusion injury.

Key Result

Cardiac-specific overexpression of Caspase3 in mice significantly depressed left ventricular fractional shortening at 9 weeks (29.9% vs 36.9%) and increased infarct size and mortality following ischemia-reperfusion injury.

Structured PICO

Does cardiac-specific overexpression of Caspase3 increase infarct size and depress cardiac function in mice?

Population

Transgenic mice with cardiac tissue-specific overexpression of Caspase3 induced by the rat alpha-myosin heavy chain promoter, and wild-type littermates.

Intervention

Cardiac-specific overexpression of Caspase3

Comparator

Wild-type littermates

Outcome

Cardiac function (fractional shortening, velocity of circumferential LV shortening), ultrastructural damage, infarct size, and survival after ischemia-reperfusion injurysurrogate

Cardiac-specific overexpression of Caspase3 in mice transiently depresses cardiac function and exacerbates myocardial damage and mortality following ischemia-reperfusion injury.

Main Result

Absolute Event Rate: 29.9% vs 36.9%

p-value: p=<0.03

Limitations

Mosaic type of expression generated by using the alpha-MHC promoter
Whether increased infarct size was due to increased cardiomyocyte apoptosis or necrosis was not determined

Abstract

Up-regulation of proapoptotic genes has been reported in heart failure and myocardial infarction. To determine whether caspase genes can affect cardiac function, a transgenic mouse was generated. Cardiac tissue-specific overexpression of the proapoptotic gene Caspase3 was induced by using the rat promoter of alpha-myosin heavy chain, a model that may represent a unique tool for investigating new molecules and antiapoptotic therapeutic strategies. Cardiac-specific Caspase3 expression induced transient depression of cardiac function and abnormal nuclear and myofibrillar ultrastructural damage. When subjected to myocardial ischemia-reperfusion injury, Caspase3 transgenic mice showed increased infarct size and a pronounced susceptibility to die. In this report, we document an unexpected property of the proapoptotic gene caspase3 on cardiac contractility. Despite inducing ultrastructural damage, Caspase3 does not trigger a full apoptotic response in the cardiomyocyte. We also implicate Caspase3 in determining myocardial infarct size after ischemia-reperfusion injury, because its cardiomyocyte-specific overexpression increases infarct size.

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