Currie Wd

Depressed high-energy phosphate content in hypertrophied ventricles of animal and man: the biologic basis for increased sensitivity to ischemic injury.

It is frequently stated that hypertrophied ventricles tolerate ischemia less well than nonhypertrophied ventricles. The authors earlier studies in a rat supravalvular aortic stenosis model and canine valvular aortic stenosis model, both with concentric left ventricular hypertrophy, disclosed accelerated rates of ischemic contracture and diminished basal myocardial high energy phosphate stores. These studies have been extended to ten patients with severe left ventricular hypertrophy caused by valvular aortic stenosis and normal coronary arteries. ATP (endocardial and epicardial) from transmural left ventricular biopsies taken at operation before aorta cross-clamping, and frozen immediately in liquid nitrogen, were compared with similar biopsies from patients with nonhypertrophied myocardium supplied by normal coronary arteries. The subendocardial high energy phosphate levels in the nonhypertrophied myocardium was greater than high energy phosphate levels in the subepicardium of nonhypertrophied ventricles (ATP-micromoles/gram-protein, epi = 36.8 +/- 3.3, endo = 37.7 +/- 3.3) (p = NS). However, in the hypertrophied myocardium the subendocardium consistently showed significantly depressed high-energy phosphate levels when compared with subepicardial levels (ATP-hypertrophied myocardium, epi = 31.5 +/- 1.6, endo = 25.9 +/- 1.7) (p less than 0.05). This uniform depression of ATP stores, greatest in the subendocardium, in left ventricular hypertrophy suggests a common biologic mechanism for the enhanced sensitivity to ischemia. Of importance for patients may be the prior observation in rats that repletion of ATP( stores before ischemia eliminates the accelerated rate to ischemic contracture. Diminished subendocardial ATP stores appear to be an intrinsic property of severely hypertrophied myocardium and probably contribute to its enhanced sensitivity to ischemia.

Protection of mitochondrial function during ischemia by potassium cardioplegia: correlation with ischemic contracture.

The effect of potassium cardioplegia on mitochondrial function was evaluated in the ischemic isolated rat heart. Mitochondrial function as well as adenosine triphosphate (ATP) levels were determined at the initiation of ischemic contracture, at the completion of ischemic contracture, and 20 minutes following contracture completion. Group I received no cardioplegia prior to ischemia, while Group II received potassium cardioplegia prior to the onset of ischemia. The respiratory control index (RCI), which is the primary measure of the intactness of mitochondrial function, was calculated with both a NAD (nicotinamide adenine dinucleotide)-linked substrate and a FAD (flavin adenine dinucleotide)-linked substrate. Potassium cardioplegia significantly delayed ischemic contracture initiation and completion. Although the RCI and ATP levels decreased significantly at successive levels of contracture, there was no difference in the RCI or ATP content between Group I and Group II at contracture initiation or completion. Unlike previous investigations that have used a time-base to examine mitochondrial function and acute cardiac ischemic injury, we correlated mitochondrial function with the measurable physiologic event ischemic contracture. The data indicated that potassium cardioplegia preserved ATP content and mitochondrial function, and that contracture initiation and completion correlate well with specific ATP levels and mitochondrial respiratory control. The relationship between mitochondrial function and ATP content indicates that the beneficial effect of potassium cardioplegia on mitochondrial function may be secondary to the preservation of high-energy phosphate levels which provide energy for mitochondrial maintenance.

Relationship of ischemic contracture to high energy phosphate content and mitochondrial function in hypertrophied myocardium

MONDAY, MARCH 10, 1980 AM MYOCARDIAL PROTECTION 10:3012:oo RELATIONSHIP OF ISCHEMIC CONTRACTURE TO HIGH ENERGY PHOSPHATE CONTENT AND MITOCHONDRIAL FUNCTION IN HYPERTROPHIED MYOCARDIUM James D. Sink, MD, William D. Currie, Ph.D., Ronald C. Hill. MD. Craig 0. Olsen. MD. Robert N. Jones. MD. Andrew S; Wechsler, MD, Duke-and VA Medical C:nte;s, Durham, North Carolina Hypertrophied (H) myocardium appears more susceptible to ischemic injury, however, the biochemical response of H hearts to ischemia has not been fully elucidated. ATP, and CP (umoles/gm dry weight) and mitochondrial function (respiratory control index, RCI). were determined in 75 normal (N) and 63 H isolated rat hearts following 15 minutes of Langendorf perfusion (control), at initiation of ischemic contracture, and at completion of contracture. Duration of ischemia prior to occurrence of these events was noted. H, produced by banding the ascending aorta was confirmed by left ventricular (mg)/body weight (pm) ratio (N 1.92 wet, 0.43 dry; H 2.69 wet, 0.59 dry). Results are below (*p<O.O5 for N vs H): RCI ATP CP Ischemia -p-p control<f: 6.6*0.4 29.2Cl.l 33.9k2.4 (min) a.1+0.5* 20.3+1.3* 28.3*2.4* Initia-<N 5.320.3 14.3+1;0 6;120.4 10.1*0.7 tion H 7.1*0.8* 12.0+0.5* 2.4+0.1* 6.7+0.5* Comple-<N 3.4AO.2 4.620.7 5.2fO.5 19.950.7 tion H 5.7*0.3* 2.0+0.2* 2.4+0.1* 23.1!zl.O* H hearts had accelerated initiation of contracture. Our study suggests that the increased susceptibility of H myocardium to contracture may result from the lower ATP stores present at onset of ischemia. The imbalance in ATP anerobic uroduction and utilization Dresent durinn the first mom;?nts of ischemia due to coniinued contractile activity may also be greater in the H heart resulting in a more precipitous decline fn already decreased energy stores and a more rapid onset of contracture. THE NO-REFLOW PHENOMENON: NOT A TIME-LIMITING FACTOR FOR REPERFUSION FOLLOWING CORONARY OCCLUSION John R. Darsee, MD, Robert A. Kloner, MD, PhD. Peter B Brigham Hasp/Harvard Med Sch. Boston. MA Foliowing release of a coronary occlusion (occ) some tissue may not reperfuse (no-reflow phenomenon). To ascertain whether this is a critical factor determining the time beyond which revascularization can no longer salvage ischemic myocardium and to determine whether reperfusion damages tissue otherwise not destined to necrosis, 13 open-chest anesthetized dogs had either 2 hrs left anterior descending (LAD) occ and 4 hrs reflow (n=7) or 6 hrs of occ with reflow only to allow dye injection (<2min;n= 6). Prior to sacrifice, left atria1 injectionsofthioflavin-S (1 cc/kg) were made with the LAD unclamped followed by methylene blue (3 cc/kg) with the LAD reclamped. Hearts were sliced into 5 mm transverse sections andareas not perfused by thioflavin-S (area of no reflow=rp=NS). However, An/A, was significantly smaller in dogs with 2 hrs of occ plus reflow (.39t.03) than in dogs with 6 hrs of occ &/Ar=.96+.07, pc.001). The A /A in 2 hr dogs was significnatly smaller than An/A, (:fl+f02 vs .39?.03, p<.Ol);Anr/Ar was also smaller than A,,/Ar in 6 hr dogs (.46+.05 vs .96+.07, pc.01). In all dogs the An, was contained geographically within the A, and was subendocardial. We conclude: 1) the Anr does not determine critical time for salvageability by revascularization since An, always occurs within dead myocardium; and 2) reperfusion does not increase the quantity of ischemic tissue which becomes necrotic and in fact salvages substantial quantities of subepicardial tissue. EFFECTS OF PULSATILE AND NONPULSATILE REPERFUSION ON THE POST-ISCHEMIC MYOCARDIUM Frederick H. Levine MD. Geir J. Grotte, MBBS; John T. --u Fallon, MD, PhD; W. Gerald Austen, MD, FACC; Mortimer J. Buckley, MD, FACC, Massachusetts General Hospital, Boston, Ma 02114 Pulsatile perfusion has been reported to improve myocardial function, metabolism and blood flow distribution, and therefore to be of clinical value in myocardial protection. No studies have evaluated the clinically relevant effect of pulsatile reperfusion after a period of aortic cross-clamping. Twenty-two dogs were therefore studied during cardiopulmonary bypass with either a period of normothermic ischemia (N-lOdogs-60min) or hypothermic potassium cardioplegia (KCP-12 dogs-90min) and divided equally into pulsatile (P) and non-pulsatile (NP) groups. After cross-clamp removal either P or NP reperfusion was carried out for 45 minutes with a beating vented heart. Left ventricular (LV) function was analyzed prior to ischemia and again after the reperfusion period by analysis of computer drawn Sarnoff curves. Microspheres were used to study regional myocardial blood flow and coronary venous samples were taken for lactate and oxygen utilization. LV biopsies were obtained for electron microscopy. Percent recovery of LV function in the N groups was P-57% and NP-62%, and in the KCP groups was P-92% and NP-89%. Total coronary blood flow and subendocardial perfusion were similar in both pulsatile and non-pulsatile groups. Lactate utilization and oxygen consumption were also unchanged with pulsatile perfusion. Electron microscopy demonstrated significant myocytic and capillary endothelial damage in the N groups but there was no alteration with pulsation. Pulsatile reperfusion offers no advantage over non-pulsatile reperfusion in the post-ischemic vented beating heart. COMPARATIVE HEMODYNAMIC EFFECTS OF NITROGLYCERIN AND NITROPRUSSIDE DURING RECOVERY Michael Todd, M.D., Phillip Morris, M.D., Daniel Philbin, M.D., FACC. Massachusetts General Hospital, Boston, Mass 02114 Both nitroglycerin (NG) and nitroprusside (NP) have been used extensively intraoperatively to control or reduce blood pressure with similar hemodynamic changes reported. This study was undertaken to determine the changes following discontinuation of these drugs. Ten dogs anesthetized with halothane were studied. Five each received either NG or NP to reduce @ to 70% of control for 30 min. During recovery measurements were made at 5,15,30 and 60 min of E,CVP,x,PCW,heart rate and CO. There was no significant change in HR in either group. Neither group had returned to control s at 60 min but the NP group was higher (842 4 vs 7224 mmHg1. In the NG group E (12.6f0.3 to 12.120.6 mmHg) PCW(5.5f0.7 to 4.56fO.S mmHg) and CVP(2.8f0.4 to 2.7+0.6mmHg) were close to control at 5 min. In contrast, in the NP group the PA rebounded above control values (13.E1.6 to 14.7kl.S(5min) to 15.9f1.9 mmHg (15min) and remained elevated at 60 min (16.9k1.5 pcO.05). The CVP followed a similar pattern (2.29+1 to 3.15fO.l mmHg at 5 min pcO.05). These data demonstrate that while the hypotension produced by NG and NP have similar hemodynamic effects, NG action is more prolonged. Discontinuation of NP is associated with a more rapid rise in BP and an apparent rebound effect on the PA rising above control. This suggests reflex pulmonary vasoconstriction following abrupt cessation of NP which may be clinically significant in patients with pre-existing pulmonary hypertension or pre-existing right ventricular dysfunction. 394 February 1980 The American Journal of CARDIOLOGY Volume 45