In vivo gene delivery of XIAP protects against myocardial apoptosis and infarction following ischemia/reperfusion in conscious rabbits.

AIMS: We tested the hypothesis that an in vivo gene delivery of the pro-survival protein XIAP (X-chromosome linked inhibitor of apoptosis protein) protects against myocardial apoptosis and infarction following ischemia/reperfusion. MAIN METHODS: Nineteen rabbits were chronically instrumented with a hydraulic occluder placed around the circumflex coronary artery. Adenovirus harboring XIAP (Ad.XIAP; 1×10(10)pfu/ml) or ß-galactosidase (5×10(9)pfu/ml), as a control, was constructed and transfected into the heart using a catheter placed into the left ventricle accompanied by cross-clamping. 1-2weeks after gene delivery, myocardial ischemia was induced by a 30-min occlusion followed by reperfusion for four days. Protein expression was determined by Western blot and apoptosis (% of myocytes) was quantified by TUNEL staining. KEY FINDINGS: Myocardial infarct size, expressed as a fraction of the area at risk, was reduced in Ad.XIAP (n=5) compared to control (n=7) rabbits (21±3% vs. 30±2%, p<0.05). Apoptosis was reduced in Ad.XIAP rabbits compared to control rabbits (2.96±0.68% vs. 8.98±1.84%, p<0.01). This was associated with an approximate 60% decrease in the cleaved caspase-3 level in Ad.XIAP rabbits compared to control rabbits. SIGNIFICANCE: The current findings demonstrate that overexpression of XIAP via in vivo delivery in an adenovirus can reduce both myocardial apoptosis and infarction following ischemia/reperfusion, at least in part, due to the ability of XIAP to inhibit caspase-3. These findings confirm previous work suggesting a link between myocardial apoptosis and infarction i.e., anti-apoptotic therapy was effective in reducing myocardial infarct size.

Sleep-induced hypotension precipitates severe myocardial ischemia.

STUDY OBJECTIVES: Epidemiologic studies have shown a high frequency of major cardiac events at night in patients with coronary artery disease. This has been attributed to the sympathetic surges accompanying rapid eye movement (REM) sleep; the role of non-REM sleep, which comprises 80% of total sleep duration, has been largely neglected. Accordingly, we evaluated the effect of non-REM sleep on contractile function in a region of the left ventricular wall supplied by a flow-limiting coronary stenosis. DESIGN: Eight domestic pigs were chronically instrumented to measure regional left ventricular contractile function (wall thickening), coronary blood flow, and systemic hemodynamic variables. Measurements were obtained: (1) during wakefulness, i.e., conscious condition, prior to imposition of coronary stenosis; (2) during wakefulness following imposition of coronary stenosis (30% reduction of baseline coronary blood flow from 40 +/- 4 to 27 +/- 3 mL/min); and (3) during non-REM sleep with coronary stenosis maintained. RESULTS: During wakefulness, coronary stenosis reduced wall thickening (from 23.3 +/- 3.4% to 15.7 +/- 2.0%), whereas mean arterial pressure and heart rate were unchanged. With coronary stenosis maintained, the onset of non-REM sleep caused 20% decreases in mean arterial pressure and coronary blood flow, accompanied by a cessation of regional wall thickening, i.e., akinesis (wall thickening = 0.2 +/- 2.8%), indicating severe myocardial ischemia. CONCLUSIONS: The arterial hypotension, and associated reduction in coronary blood flow, during non-REM sleep precipitated severe myocardial ischemia in a region of the left ventricular wall supplied by flow-limiting coronary stenosis. Such episodes would occur repeatedly during the sleep cycle and could potentially set the stage for a major cardiac event during the sympathetic activation accompanying REM sleep or morning activities.