SUBENDOCARDIAL O2 SUPPLY AND DEMAND IN AORTIC STENOSIS

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The increased susceptibility to ischemic injury of the deeper, subendocardial layers of hypertrophied hearts continues to challenge the surgeon in patients undergoing valve replacement for aortic stenosis. We wish to study the mechanism of this increased susceptibilty in a chronic dog model of aortic stenosis. Indirect evidence suggests that hypertrophy affects 02 balance in the subendocardium more adversely than in the subepicardium. Regional blood flow limitations in the subendocardium have been documented for many disease processes, including cardiac hypertrophy, but the limits of regional 02 extraction and 02 consumption are unknown. The specific aims of this proposal are to determine regional 02 supply/consumption balance and myocardial "efficiency" of hypertrophied hearts subjected to different forms of acute increases in workload to dissect out the factors leading to the increased vulnerability of the subendocardium. All studies will be conducted on anesthetized open chest dogs 6 months after creation of aortic valve stenosis as puppies. We will determine regional 02 supply/consumption relationships by combining direct measurements of hemoglobin 02 saturation in small arteries and veins using microspectrophotometry with regional blood flow measurements using radioactive microspheres. We will perform these measurements in subendo- and subepicardium of dog hearts with and without hypertrophy. Combining regional "work" (area of pressure-regional dimension loops) with regional 02 consumption we will be able for the first time to assess local myocardial "efficiency". We plan to test reserve limits of regional blood flow by maximal pharmacological vasodilatation, of 02 extraction by using partial coronary artery occlusion and by normovolumic hemodilution and limits of 02 consumption by stressing the dogs with rapid pacing, with acute increases in afterload and workload using various inotropic drugs acting through different mechanisms. By adding maximal pharmacological vasodilatation to these acute stresses, we will differentiate between 02 supply and intrinsic metabolic limitations of 02 consumption. For the first time, we will be able to fully dissect out the physiological or pathophysiological responses to imbalances in regional 02 supply and consumption and local "efficiency" in cardiac hypertrophy leading to a better understanding of the cause for the increased vulnerability of the subendocardium to ischemic injury. Long- term, we wish to study ways to improve imbalances in regional 02 supply/consumption and inefficiencies using beta blockade.