C J Pepine

Asymptomatic Cardiac Ischemia Pilot (ACIP) Study Two-Year Follow-up Outcomes of Patients Randomized to Initial Strategies of Medical Therapy Versus Revascularization

BACKGROUND Patients with ischemia during stress testing and ambulatory ECG monitoring have an increased risk of cardiac events, but it is not known whether their prognosis is improved by more aggressive treatment with anti-ischemic drugs or revascularization. METHODS AND RESULTS The Asymptomatic Cardiac Ischemia Pilot study randomized 558 such patients who had coronary anatomy suitable for revascularization to three treatment strategies: angina-guided drug therapy (n=183), angina plus ischemia-guided drug therapy (n=183), or revascularization by angioplasty or bypass surgery (n=192). Two years after randomization, the total mortality was 6.6% in the angina-guided strategy, 4.4% in the ischemia-guided strategy, and 1.1% in the revascularization strategy (P<.02). The rate of death or myocardial infarction was 12.1% in the angina-guided strategy, 8.8% in the ischemia-guided strategy, and 4.7% in the revascularization strategy (P<.04). The rate of death, myocardial infarction, or recurrent cardiac hospitalization was 41.8% in the angina-guided strategy, 38.5% in the ischemia-guided strategy, and 23.1% in the revascularization strategy (P<.001). Pairwise testing revealed significant differences between the revascularization and angina-guided strategies for each comparison. CONCLUSIONS A strategy of initial revascularization appears to improve the prognosis of this population compared with angina-guided medical therapy. A larger long-term study is needed to confirm this benefit and to adequately test the potential of more aggressive drug therapy.

In vivo validation of a thermodilution method to determine regional left ventricular blood flow in patients with coronary disease.

SUMMARY Several methods have been used to measure left ventricular regional blood flow in humans. However, limitations and lack of validation in patients are major problems. A continuous thermodilution technique to measure regional left ventricular blood flow in patients with coronary disease was validated in vivo. This technique permits simultaneous assessment of venous blood flow draining predominantly from the anterior wall and of the total left ventricular effluent. Thermodilution measurements with simultaneous electromagnetic flowmeter recordings from anterior descending vein grafts were compared in patients with occluded or subtotally occluded anterior descending coronary arteries. The thermodilution method yielded values for both absolute anterior regional blood flow and changes in anterior regional flow that compared closely to anterior descending bypass graft flow measured independently. The multithermistor technique may be useful in monitoring flow effects of regional coronary disease over time, as well as in studies of agents purported to alter regional blood flow.

Acute effect of intravenous dipyridamole on regional coronary hemodynamics and metabolism.

The acute coronary hemodynamic and metabolic effects of intravenous dipyridamole were studied in 13 patients. Total left ventricular (LV), anterior (supplied by the left anterior descending coronary artery) and inferior (supplied by circumflex and right coronary arteries) regional flows and metabolic responses were assessed from the coronary sinus and great cardiac vein. Perfusion to LV regions was classified as potentially “normal” or “abnormal,” based on coronary angiographic findings. Before dipyridamole, coronary flow, LV oxygen delivery and lactate extraction in both the normal and abnormal regions were similar. Within 1 minute after injection of 20 mg of dipyridamole by i.v. bolus, total coronary flow increased 51% (p < 0.05). Fifteen minutes after injection the flow increase persisted. Flow decreased to approximately control level by 20 minutes. The major component of this increased total coronary flow resulted from increased flow in normal regions (75% at 1 minute, p < 0.05). Mean regional LV oxygen delivery and lactate extraction were not changed significantly in either normal or abnormal regions. However, lactate production occurred more often after dipyridamole in abnormal regions. These results suggest that during dipyridamole-induced hyperemia, regional coronary flow and metabolic responses depend upon the status of the arteries supplying the LV region. Regional differences in flow and metabolism occur independent of major changes in heart rate and aortic and LV pressures.

Magnitude of dilatation of large and small coronary arteries of nitroglycerin.

Vasodilatory responses of segments of large epicardial left coronary artery (CA), small intramyocardial CAs (0.3-1.0 mm), coronary stenoses and CAs filled by collaterals were determined in 34 patients. Measurements were made before and after nitroglycerin (0.4 mg, sublingual) by means of quantitative magnification coronary angiography using photospot film and a calibrated 6-power viewing device. The left main CA, proximal, middle and distal anterior descending and circumflex segments, and small CAs showed dilatation that varied in magnitude. When magnitude of dilatation was compared with control diameter of the vessel and its location, control diameter proved to be the significant independent variable. CAs with the smallest control diameter showed the greatest magnitude of vasodilatation. CA branches filled by collaterals had vasodilatation similar in magnitude to that of CAs of comparable control diameter. Although coronary stenoses dilated, the magnitude of dilatation was less than that observed in nonstenosed arterial segments of similar control diameter. When areas of stenosis were excluded, however, results were similar regardless of whether the patient had CA disease. These data indicate that a principal determinant of the CA vasodilatory response to nitroglycerin is the size of the artery before nitroglycerin.

Analysis of coronary responses to various doses of intracoronary nitroglycerin.

We studied the degree of coronary artery dilation resulting from increasing doses of intracoronary nitroglycerin (NTG). Heart rate, aortic pressure and coronary artery angiograms were recorded before and after 5‐, 50‐, 150‐ and 250‐μg doses of NTG infused into the left main coronary artery. Coronary artery diameters were measured by a magnification angiographic technique. After intracoronary NTG, heart rate was unchanged 2 minutes after each dose. Mean aortic pressure was unchanged after 5 μg (NS), but declined 5 mm Hg (mean) after 50 μg, 9 mm Hg after 150 μg and 18 mm Hg after 250 μg (all p < 0.05) compared with before NTG. The maximal increase in diameter occurred after 150 μg, and no additional increase was seen after 250 μg. After 5‐ and 50‐μg doses, 67% and 75% maximal dilation responses, respectively, were observed. Compared with coronary artery diameter before NTG, the 150‐μg dose increased the diameter of left main coronary artery by 5%, proximal coronary artery segments by 9%, middle segments by 19%, distal segments by 34%, collateral‐filled coronary arteries by 38%, coronary artery stenoses by 5%, and small coronary arteries (0.4–1.0 mm) by 54%. These data indicate that relatively small doses of intracoronary NTG produce potentially important coronary artery dilation without important changes in heart rate and aortic pressure. These observations should prove helpful in choosing dosage schedules for intracoronary NTG.

Ventricular/vascular interaction in patients with mild systemic hypertension and normal peripheral resistance.

Total left ventricular external power and aortic input impedance spectra were calculated from recordings of pulsatile pressure and flow in the ascending aorta of 22 human subjects undergoing cardiac catheterization. Eleven subjects had increased aortic pressure (systolic 153 +/- 3.8[SEM] mm Hg, p less than .001; diastolic 91 +/- 2.4 mm Hg, p less than .03; mean 118 +/- 2.4 mm Hg, p less than .001) and constituted the group with mild hypertension (average age 50 +/- 1.9 years). The other 11 (age-matched) subjects had normal arterial pressures and constituted the control group. Cardiac output in the hypertensive group was abnormally high (6.9 +/- 0.3 liters/min, p less than .04) compared with that in control subjects (6.1 +/- 0.2 liters/min), so that peripheral resistance was similar. Characteristic aortic impedance (index of aortic elastance) was increased in the hypertensive group (142 +/- 19 vs 72 +/- 4.5 dyne-sec-cm-5, p less than .002), as was the fluctuation of impedance moduli and phase. These elevated pulsatile components of arterial load were associated with a significant (p less than .002) increase in pulsatile left ventricular external power (89%), and the increased cardiac output was associated with a significant (p less than .001) increase in steady flow power (31%). The ratio of pulsatile to total power was also increased (38%) in the hypertensive group (p less than .001). Increased characteristic aortic impedance in the hypertensive group suggests that the human aorta is stiffer, and fluctuations in the impedance spectra suggest increased or less dispersed wave reflections.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional coronary hemodynamic effects of ergonovine in patients with and without variant angina.

SUMMARYTo define more completely the regional coronary hemodynamic significance of ergonovineprovoked coronary angiographic responses, we measured coronary sinus flow (CSF) and great cardiac vein flow (GCVF) aortic and left ventricular pressures, and coronary artery diameters before and after ergonovine administration in 13 patients with variant angina (VA) and 19 patients without VA. After ergonovine, a major diameter reduction occurred in the left coronary artery of 10 patients with VA and also in the right coronary artery of two of these patients. In three other patients with VA a major diameter reduction occurred only in the right coronary artery. All 13 patients with VA developed angina, and 12 had ST-segment shifts. In patients with VA and a major left coronary artery diameter reduction, both CSF and GCVF decreased (31% and 30%, respectively) as total and anterior regional coronary resistance increased (47% and 46%, respectively) (all p < 0.01). In the three patients with VA who developed only right coronary artery diameter reduction, CSF decreased in one and was unchanged in two; GCVF was unchanged in all. In patients without VA, ergonovine induced only minor coronary artery diameter reduction (15%); none had ST-segment shifts, and four had chest pain. Both CSF and GCVF increased minimally (14%) as total and anterior regional coronary resistance decreased slightly (5% and 11%, respectively) (all p < 0.01). These data provide evidence that ergonovine-induced major diameter reduction of the left coronary artery reduces total and anterior regional left ventricular flow. These results support the concept that ergonovine evokes a significant decrease in myocardial oxygen delivery in certain patients with VA coincident with angina and ST-segment shifts.

Action of intracoronary nitroglycerin in refractory coronary artery spasm.

Coronary artery spasm usually responds to sublingual nitroglycerin. This report describes four patients with variant angina and one patient with rest angina who had coronary spasm that was refractory to sublingual or i.v. nitroglycerin. In four patients, spasm occurred spontaneous and in one patient after 0.05 mg of ergonovine. In each case, 25-100 micrograms of intracoronary nitroglycerin promptly (30-45 seconds) resulted in reopacification of the vessel involved in spasm and resolution of evidence for ischemia. Thus, intracoronary nitroglycerin can reverse coronary artery spasm that does not respond to systemic nitroglycerin administration.

Coronary hemodynamic findings during spontaneous angina in patients with variant angina.

To define more completely regional coronary hemodynamic changes that occur during spontaneous angina pectoris in patients with variant angina, we measured coronary sinus and great cardiac vein blood flow (CSF and GCVF) and aortic and left ventricular pressures before and during spontaneous angina in six patients with variant angina. During spontaneous angina, ECGs in four patients showed evidence for transient anterior regional ischemia (ST-T-wave changes in I, aVL, V,.,) and in two patients showed evidence for transient inferior regional ischemia (ST-T-wave changes in II, III, aVF). During spontaneous angina, CSF decreased in five of six patients (27 ± 10 ml/min, p < 0.05), compared with measurements made during a painfree interval. In all four patients with anterior ischemia, GCVF decreased 34 ± 13 ml/min (p < 0.05). In the two patients with inferior ischemia, GCVF was unchanged, but the difference between CSF and GCVF, an index of inferior regional blood flow, decreased 36 ± 20 ml/min during ischemia. Heart rate was not significantly different during angina, and mean aortic pressure decreased in three patients, increased in two and was unchanged in the other. Left ventricular end-diastolic pressure increased 10 ± 2 mm Hg during spontaneous angina (p < 0.01).These data provide direct evidence that blood flow to the ischemic region during spontaneous angina is decreased in patients with variant angina. These results support the concept that a functionally important decrease in regional myocardial oxygen delivery occurs in certain patients with variant angina coincident with angina and ST-segment and T-wave changes.

Age-Related Changes in Left Ventricular/Arterial Coupling

To understand the influence of the aging process on left ventricular/arterial coupling (or interaction), it is important first to consider the effects of age on ventricular and arterial functions separately. The function of the left ventricle is to pump blood (the cardiac output) through the systemic arterial system to the organs and tissues in an amount sufficient to meet their metabolic requirements. The arterial system has two distinct and separate functions: (1) It serves as a vascular conduit system that delivers blood at high pressure to the various peripheral beds and (2) it serves as a buffering system (Windkessel) that smooths out pulsations resulting from intermittent ventricular ejection so that the capillaries receive a steady or continuous flow of blood.