J D Bristow

Active downregulation of myocardial energy requirements during prolonged moderate ischemia in swine.

We studied the effects of rapid atrial pacing during the final 10 minutes of a 70-minute, 31% reduction in coronary blood flow in anesthetized swine to understand the significance of apparent metabolic improvements during the initial 60 minutes of segmental ischemia. Within 5-10 minutes of ischemia, subendocardial phosphocreatine (PCr) and ATP were depleted to 47% and 63% of control, respectively; lactate accumulated within the subendocardium to 300% of control; and net arteriovenous lactate production occurred. Despite continued ischemia and no significant changes in the external determinants of myocardial oxygen consumption, by 60 minutes subendocardial PCr and lactate contents returned to near control levels and there was net arteriovenous lactate consumption. Ischemic left ventricular wall thickening and ATP levels remained depressed throughout the experiment. Atrial pacing during the final 10 minutes of ischemia again resulted in depletion of PCr and lactate production. Since the myocardium was capable of hydrolyzing PCr in response to atrial pacing at 60 minutes of ischemia, we conclude it was capable of hydrolyzing PCr during the period of constant ischemia when instead it was accumulating PCr. We propose the ischemic myocardium downregulates regional energy requirements below blood flow-limited rates of energy production during ischemia. This appears to be an active adaptation to ischemia and not a result of passive damage or cellular injury.

Chronic Aortic Insufficiency: Factors Associated with Progression to Aortic Valve Replacement

STUDY OBJECTIVE To determine whether the initial measurement of clinical variables in patients with chronic stable aortic insufficiency is helpful in identifying patients at risk for earlier progression to aortic valve replacement. DESIGN Prospective analysis of a cohort of patients for a median follow-up time of 44 months (range, 8 to 57). SETTING Referral-based cardiology clinics at two university hospitals and their affiliated Veterans Administration medical centers. PATIENTS Cohort of 50 asymptomatic or minimally symptomatic patients with chronic aortic insufficiency and left ventricular enlargement. Patients had preserved left ventricular ejection fraction at rest and no evidence of coronary artery disease or significant noncardiac illness. INTERVENTION None. MEASUREMENTS AND MAIN RESULTS Baseline evaluation included a history and physical examination, chest roentgenogram. M-mode echocardiogram, treadmill test, and radionuclide angiogram done at rest and during supine bicycle exercise. Ten patients progressed to surgery because of the onset of limiting symptoms or objective evidence of left ventricular dysfunction, or both; the overall rate was 4% +/- 3% per year. The Breslow and Mantel-Cox statistics were used to compute survival (surgery-free) dichotomized by prognostic variables. The progression to surgery was earlier in patients with left ventricular end-diastolic volume indices of 150 cc/m2 or more, end-systolic volume indices of 60 cc/m2 or more, a left ventricular ejection fraction at maximal exercise of less than 0.50, or an end-systolic wall stress of 86 dynes/cm2 or more. CONCLUSIONS Patients at higher and lower risk for early progression to aortic valve replacement can be identified through the measurement of left ventricular size and function. This information can be used to decide the frequency and intensity of follow-up evaluation in these patients.

Long-term vasodilator therapy of chronic aortic insufficiency. A randomized double-blinded, placebo-controlled clinical trial.

Although vasodilator drugs acutely reduce regurgitation and improve cardiac performance in aortic insufficiency, their long-term effects on left ventricular size and function are uncertain. Consequently, we performed a double-blinded, placebo-controlled trial using hydralazine in 80 minimally symptomatic patients who had clinically stable, moderate-to-severe aortic insufficiency. Patients randomized to hydralazine displayed a progressive reduction in left ventricular end-diastolic volume index (LVEDVI) measured by radionuclide angiography, the predetermined end point of the study. At 24 months, mean LVEDVI had been reduced by 30 +/- 38 ml/m2, an 18% reduction from baseline. In contrast, LVEDVI changed minimally in patients randomized to placebo, and the intergroup differences over time were statistically significant (p less than 0.03). The hydralazine group also experienced reductions in left ventricular end-systolic volume index and increases in ejection fraction that were significantly different (both p less than 0.01) from changes in placebo-treated patients. These findings show that long-term treatment with hydralazine reduces the volume overload in aortic insufficiency and suggest that such therapy may have a beneficial effect on the natural history of the disease.

No reflow and extent of infarction during maximal vasodilation in the porcine heart.

To explore the relation between myocardial and vascular injury in the generation of the no-reflow phenomenon, the pressure-flow relation during maximal vasodilation after coronary artery reperfusion was studied in the open-chest porcine model. During both endogenous and maximal vasodilation with intracoronary adenosine, pressure-flow (P/Q) plots were constructed before and after 20-minute (n = 9) or 40-minute (n = 17) circumflex artery occlusions. Decreases in circumflex vascular bed conductance were represented by downward shifts in P/Q plot regression lines. No significant change occurred in P/Q line slope or pressure at zero flow 30 minutes after release of the 20-minute occlusion, and no infarction was found. After release of the 40-minute occlusion, a small but insignificant decrease in P/Q line slope occurred during endogenous vasodilation. However, during maximal vasodilation, a significant (p less than 0.01) decrease in P/Q line slope was present during reperfusion compared with preocclusion corresponding to a decrease in vasodilatory reserve (P/Q line slope = 1.52 +/- 0.14 ml/min/mm Hg preocclusion vs. 1.03 +/- 0.13 at 15 minutes reperfusion). Pretreatment with aspirin did not prevent this decrease in vascular conductance during maximal vasodilation. Total circumflex, as well as subendocardial, midmyocardial, and subepicardial blood flows, was measured with radioactive microspheres. There was a good correlation between the extent of infarction measured by triphenyltetrazolium chloride staining and the decrease in vascular conductance during maximal vasodilation for all three myocardial layers as well as for the total circumflex vascular bed. Hence, the degree of no-reflow correlates closely with the extent of infarction during maximal vasodilation (but not during endogenous vasodilation) and is not altered by aspirin therapy.

Association between the exercise ejection fraction response and systolic wall stress in patients with chronic aortic insufficiency.

We studied the exercise ejection fraction response in 56 patients with chronic aortic insufficiency. All had left ventricular dilatation but preserved resting ejection fraction and minimal or no symptoms. The exercise ejection fraction increased by 0.05 units or greater in 18 (32%) patients (group I), remained within 0.05 units of the resting value in 18 (32%) patients (group II), and fell by 0.05 units or greater in 20 (36%) patients (group III). There were no significant differences among the groups in left ventricular end-diastolic dimension, end-systolic dimension, or fractional shortening by echocardiography or in resting left ventricular volumes and ejection fraction by radionuclide angiography. Left ventricular end-systolic wall stress was significantly higher in group III than in either group I or group II (89 +/- 20 vs 70 +/- 18 and 69 +/- 17 X 10(3) dyne/cm2; p less than .005). At peak exercise there were no differences among groups in systolic blood pressure. However, end-systolic volume increased from 65 +/- 28 to 77 +/- 36 ml/m2 in group III and fell from 50 +/- 21 to 28 +/- 18 ml/m2 in group I during exercise. Thus, at peak exercise end-systolic volume was nearly three times greater in group III than in group I. Although stress could not be determined directly during exercise, the directional changes in its determinants suggest that it also would have been higher in group III patients. A highly significant inverse correlation was present between the ejection fraction response and the change in end-systolic volume (r = -.87, p less than .0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Low zero-flow pressure and minimal capacitance effect on diastolic coronary arterial pressure-flow relationships during maximum vasodilation in swine

During maximum dilation with adenosine in dogs, the diastolic coronary pressure at which flow ceases (Pzf) has been observed to be up to 27 mm Hg above coronary sinus and right atrial pressures. We studied swine to measure the Pzf and to determine the effects of interventions that change collateral flow and coronary capacitance. In 44 swine, the left anterior descending coronary artery (LAD) was instrumented with two catheters, a hydraulic occluder, and a flowmeter. Late diastolic and mean pressure-flow relationships were constructed at a series of pressures produced by partial LAD occlusions during maximum vasodilation. The late diastolic Pzf was 7.0 +/- 2.2 mm Hg (mean +/- SD), less than 4 mm Hg above right atrial pressure; the mean Pzf was 12.1 +/- 3.1 mm Hg, less than 9 mm Hg above right atrial pressure. The Pzf in the LAD did not change significantly (1) during transient simultaneous occlusion of the right coronary artery (RCA) in seven swine (late diastolic Pzf with the RCA open was 6.6 +/- 1.5 mm Hg and with the RCA closed it was 6.0 +/- 1.5 mm Hg), (2) during increased left ventricular systolic pressure (LVSP) in seven swine (late diastolic Pzf with LVSP of 123 mm Hg was 5.5 +/- 2.2 mm Hg and with LVSP of 184 mm Hg it was 7.3 +/- 2.8 mm Hg), or (3) during increased heart rate in eight swine (late diastolic Pzf at heart rate of 107 per minute was 10.8 +/- 2.9 mm Hg and at 180 per minute it was 12.7 +/- 2.1 mm Hg). Similar results were obtained from analysis of the mean pressure and flow data. The Pzf in the LAD of swine is very close to right atrial pressure, and it did not change significantly during interventions that would modify collateral flow (reduced by RCA occlusion and enhanced by increased LVSP) and coronary capacitance (increased LVSP and increased heart rate). This low Pzf is beneficial in maintaining flow at lower coronary arterial perfusion pressures.

Energy metabolism and contractile function after 15 beats of moderate myocardial ischemia.

Difficulties in studying myocardial metabolism with adequate time resolution have led to contradictory conclusions regarding the mechanisms causing contractile abnormalities during the early stages of ischemia. In acutely instrumented swine, we investigated whether abnormalities in subendocardial ATP, phosphocreatine, or lactate content develop rapidly enough during the first few heart beats after onset of partial myocardial ischemia to contribute to contractile failure. Within the first 15 beats of a 40-50% reduction in left anterior descending coronary artery blood flow, regional myocardial function was significantly reduced but continuing to deteriorate. Rapidly frozen transmural left ventricular biopsies obtained on the 15th heart beat (+/- 1.5 beats) after the onset of ischemia revealed significant decrements in subendocardial phosphocreatine and ATP levels to 77% (p less than 0.05) and 84% (p less than 0.005) of control values, respectively, but minimal change in lactate content. Metabolic effects as assessed by transmural averages took longer to become detectable; thus, there was a tendency to underestimate the importance of subendocardial metabolic effects on myocardial function. When left ventricular preload was assessed during this early time period, left ventricular end-diastolic wall thickness only decreased by 3%, and left ventricular end-diastolic pressure did not change significantly despite a large fall in coronary perfusion pressure. Thus, in an in vivo pig model with techniques optimized to detect subendocardial metabolic changes within the period of very early moderate myocardial ischemia, abnormalities in high energy phosphate compounds occurred rapidly enough to contribute to developing myocardial dysfunction, whereas preload-mediated mechanisms related to vascular distending pressure could not explain the functional deterioration under these conditions.