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Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis). Treatment with the lipid-lowering, antiatherosclerosis, and antioxidation drug probucol extended life to as long as 60 weeks (mean 36 weeks), and at 5–6 weeks of age, virtually completely reversed the cardiac and most RBC pathologies and corrected the unesterified to total cholesterol ratio (0.3) and associated distinctive abnormal lipoprotein morphologies. Manipulation of the timing of administration and withdrawal of probucol could control the onset of death and suggested that critical pathological changes usually occurred in untreated double knockout mice between ≈3 (weaning) and 5 weeks of age and that probucol delayed heart failure even after development of substantial CHD. The ability of probucol treatment to modulate pathophysiology in the double knockout mice enhances the potential of this murine system for analysis of the pathophysiology of CHD and preclinical testing of new approaches for the prevention and treatment of cardiovascular disease.

Study Objective: In transthoracic defibrillation, the American Heart Association (AHA) recommends wide separation of electrodes and avoidance of gel smearing between electrodes. Few data support this recommendation. Our objective was to determine the importance of electrode placement and gel-application technique on transcardiac defibrillation current and the effect of changes caused by postexercise vasodilation and sweating., Methods: Our subjects were 10 normal adults, 5 men and 5 women, who ranged in age from 22 to 48 years. We determined interelectrode impedance (Z) using a validated test-pulse method that does not require shock delivery. Electrode placement/gel-application techniques were varied among four types: (1) AHA-recommended technique (apex-to-anterior electrode placement, no smearing of gel between electrodes); (2) parasternal-to-anterior placement, electrodes within 2 cm of each other, no smearing of gel between electrodes; (3) parasternal-to-anterior placement, electrodes within 2 cm of each other with smearing of gel between electrodes (worst-case scenario); and (4) apex-to-anterior placement, smearing of gel between electrodes. To assess the effect of cutaneous vasodilation and sweating on interelectrode impedance, we repeated these measurements after the subjects performed 12 to 18 minutes of treadmill exercise. The ratio of predicted transcardiac current of the AHA technique to that of the nonstandard technique was estimated with this formula: square root of Z, non-standard technique divided by square root of Z, AHA technique., Results: Resting interelectrode impedance declined 38% from 58 +/- 10.3 omega (AHA-recommended technique) to 36 +/- 7.6 omega (electrode paddles adjacent, gel smeared between) (P < .01). Predicted transcardiac current ratio was reduced to .78 +/- .09 (P < .01), a 22% reduction. We noted no change in the results after exercise., Conclusion: Adjacent placement of electrodes and smearing of gel between electrodes creates a low-impedance pathway along the chest wall, which shunts current away from the heart. Thus improper application of electrodes and gel substantially degrades transcardiac current and may result in failed defibrillation. Sweating and vasodilation did not cause a similar problem.