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Background: Structural and functional abnormalities of the coronary microcirculation have been reported in experimental diabetes mellitus. The purpose of this study was to evaluate coronary microvascular function in human diabetes., Methods and Results: Twenty-four diabetic and 31 nondiabetic patients were studied during cardiac catheterization. A Doppler catheter or guidewire was used to measure changes in coronary blood flow velocity in a nonstenotic artery. Maximal coronary blood flow reserve was determined by using intracoronary adenosine or papaverine. Coronary dilation in response to an increase in myocardial metabolic demand was assessed by using rapid atrial pacing. Maximal vasodilator responses to papaverine and adenosine were compared in 12 diabetic patients. Maximal pharmacologic coronary flow reserve was depressed in diabetic (2.8 +/- 0.2, n = 19) compared with nondiabetic (3.7 +/- 0.2, n = 21, P < .001) patients. During atrial pacing, the decrease in coronary vascular resistance was attenuated in the diabetic (-14 +/- 3%) compared with the nondiabetic (-24 +/- 2%, P < .05) patients. Differences in coronary microvascular function between diabetic and nondiabetic patients were not attributable to differences in drug therapy, resting hemodynamics, or incidence of hypertension. In 12 diabetic patients the maximal coronary vasodilator responses to papaverine and adenosine were similar., Conclusions: This study demonstrates both reduced maximal coronary vasodilation and impairment in the regulation of coronary flow in response to submaximal increases in myocardial demand in patients with diabetes mellitus. These microvascular abnormalities may lead to myocardial ischemia in the absence of epicardial coronary atherosclerosis in some circumstances, and thus contribute to adverse cardiovascular events in diabetic patients.

Objectives: This study was performed to determine the acute effect of cigarette smoking on proximal and distal epicardial conduit and coronary resistance vessels., Background: Cigarette smoking causes constriction of epicardial arteries and a decrease in coronary blood flow in patients with coronary artery disease, despite an increase in myocardial oxygen demand. The role of changes in resistance vessel tone in the acute coronary hemodynamic effect of smoking has not been examined., Methods: Twenty-four long-term smokers were studied during cardiac catheterization after vasoactive medications had been discontinued. The effect of smoking one cigarette 10 to 15 mm long on proximal and distal conduit vessel segments was assessed before and immediately after smoking and at 5, 15 and 30 min after smoking (n = 8). To determine the effect of smoking on resistance vessels, coronary flow velocity was measured in a nonobstructed artery with a 3F intracoronary Doppler catheter before and for 5 min after smoking (n = 8). Eight patients were studied without smoking to control for spontaneous changes in conduit arterial diameter (n = 5) and resistance vessel tone (n = 3)., Results: The average diameter of proximal coronary artery segments decreased from 2.56 +/- 0.12 mm (mean +/- SEM) before smoking to 2.41 +/- 0.09 mm 5 min after smoking (-5 +/- 2%, p < 0.05). Distal coronary diameter decreased from 1.51 +/- 0.07 to 1.39 +/- 0.06 mm (-8 +/- 2%, p < 0.01). Marked focal vasoconstriction after smoking was observed in two patients. Coronary diameter returned to baseline by 30 min after smoking. There was no change in vessel diameter in control patients. Despite a significant increase in the heart rate-mean arterial pressure product, coronary flow velocity decreased by 7 +/- 4% (p < 0.05) and coronary vascular resistance increased by 21 +/- 4% (p < 0.01) 5 min after smoking. There was no change in these variables in the control subjects., Conclusions: Smoking causes immediate constriction of proximal and distal epicardial coronary arteries and an increase in coronary resistance vessel tone, despite an increase in myocardial oxygen demand. These acute coronary hemodynamic effects may contribute to the adverse cardiovascular consequences of cigarette smoking.

Objectives: The objective of this study was to determine the effect of increases in heart rate and arterial pressure on maximal pharmacologic coronary blood flow reserve., Background: Coronary flow reserve measurements are useful in assessment of the physiologic significance of coronary lesions. However, animal studies suggest that alterations in hemodynamic status may influence coronary flow reserve independent of coronary stenosis., Methods: Coronary flow reserve was measured during cardiac catheterization with the use of a 3F coronary Doppler catheter and intracoronary papaverine. Flow reserve was measured under control conditions and during increases in heart rate produced by atrial pacing (18 patients) or during elevation of arterial pressure by intravenous phenylephrine infusion (9 patients) with intracoronary alpha-adrenergic blockade by phentolamine., Results: Coronary flow reserve progressively decreased from 3.7 +/- 0.9 (mean +/- SD) at the rate of 71 +/- 8 beats/min at rest to 3.0 +/- 0.6 during pacing at 100 beats/min and to 2.6 +/- 0.5 during pacing at 120 beats/min. Flow reserve decreased because of a progressive increase in rest coronary flow velocity during pacing (122 +/- 16% of control value at 100 beats/min, 139 +/- 16% of control value at 120 beats/min), whereas papaverine hyperemia peak velocity remained unchanged. Flow reserve decreased with pacing tachycardia whether the initial flow reserve was normal or depressed. Mean arterial pressure increased from 95 +/- 12 mm Hg to 130 +/- 8 mm Hg during intravenous phenylephrine infusion and to 123 +/- 10 mm Hg during combined intravenous phenylephrine and intracoronary phentolamine infusions. Coronary flow reserve was not affected by the blood pressure increases (control value 4.3 +/- 1.0, phenylephrine 4.4 +/- 1.5, phenylephrine and phentolamine 4.4 +/- 2.0)., Conclusions: Sudden increases in heart rate but not mean arterial pressure lead to a substantial reduction in maximal coronary blood flow reserve. These data suggest that the diagnostic utility of all flow reserve measurement techniques might be improved by standardization of heart rate during measurement or extrapolation of the measured flow reserve to that expected at a reference heart rate.

Objectives: The objective of this study was to compare left anterior descending coronary artery Doppler blood flow velocity and great cardiac vein thermodilution blood flow measurements of coronary flow reserve and submaximal coronary vasodilation in humans., Background: Reported maximal coronary flow reserve values obtained with the coronary venous thermodilution method are lower than those obtained with other measurement methods., Methods: Thermodilution measurements of great cardiac vein flow in 11 subjects were compared with simultaneous Doppler measurements of changes in left anterior descending coronary flow velocity after intracoronary administration of papaverine, nitroglycerin, iohexol and intravenous administration of dipyridamole., Results: Coronary flow reserve (papaverine peak/rest flow ratio) was 3.7 +/- 1.7 (mean +/- SD) by the Doppler method and 2.0 +/- 0.7 by the thermodilution technique (p less than 0.001). Thermodilution flow changes were also smaller than Doppler-measured changes during submaximal vasodilation and during prolonged coronary dilation after dipyridamole administration., Conclusions: Coronary flow reserve and submaximal flow increases measured with the thermodilution method were consistently and substantially smaller than Doppler-derived measurements. This discrepancy has important implications for the comparison of coronary flow reserve measurements performed with the use of different techniques.

Intracoronary nitroglycerin (NTG) increases coronary blood flow and NTG inhibits thromboxane (Tx) A2 production and release. However, whether an alteration in TxA2 is the mechanism by which NTG increases coronary blood flow is not known. Coronary sinus (CS) blood flow (BF) (by thermodilution) and the concentration of TxB2 (the stable metabolite of TxA2) in CS blood were measured in 23 patients (16 men and 7 women, aged 26 to 65 years) with coronary artery disease before, during and after injection of normal saline solution (n = 5, control subjects) or NTG, 100 micrograms (n = 18), into the left coronary artery. In the 5 control subjects, saline solution caused no change in CSBF or the concentration of TxB2 in CS blood. Ten of the 18 patients to whom NTG was given had received no cyclooxygenase inhibitors for 10 days. In these patients, NTG caused a marked increase in CSBF (from 112 +/- 64 to 152 +/- 70 ml/min, p less than 0.01) but no consistent change in the concentration of TxB2 in CS blood (141 +/- 132 to 160 +/- 155 pg/ml, difference not significant [NS]). The remaining 8 patients to whom NTG was given received aspirin before the study. In these patients, NTG caused a marked increase in CSBF (from 111 +/- 39 to 180 +/- 63 ml/min, p less than 0.01), even though the concentration of TxB2 in CS blood (8 +/- 10 to 6 +/- 6 pg/ml, NS) was lower (p less than 0.05) than that in control subjects and patients not receiving aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium channel antagonists have been shown to blunt maximal coronary flow after brief coronary occlusion and during pharmacologic coronary dilation in animals. This property, if present in humans, would result in a reduction in coronary flow reserve in the absence of intrinsic abnormalities of the coronary circulation. A reduction of maximal vasodilator capacity by calcium channel antagonists could also constitute an important anti-ischemic mechanism of action of these agents. To evaluate the effect of calcium channel antagonists on coronary flow reserve in awake humans, we measured coronary flow reserve using the coronary Doppler catheter and intracoronary papaverine at baseline and after diltiazem administered by intravenous (125 or 250 micrograms/kg bolus, 5 micrograms/kg/min infusion, n = 8) or intracoronary (150-600 micrograms bolus, n = 10) routes. Intravenous diltiazem reduced heart rate from 77 +/- 18 to 72 +/- 17 beats/min (mean +/- SD, p less than 0.005) and reduced mean arterial pressure from 96 +/- 11 to 86 +/- 15 mm Hg (p less than 0.005). Intravenous diltiazem resulted in a small decrease in coronary flow reserve (peak-to-resting flow velocity ratio) from 3.9 +/- 1.2 to 3.6 +/- 1.1 (p less than 0.01). After intracoronary diltiazem, mean arterial pressure was unchanged (control 99 +/- 12 mm Hg, diltiazem 97 +/- 13 mm Hg), and heart rate was maintained constant by atrial pacing. Coronary flow reserve was unchanged at 3.8 +/- 0.9 at baseline and after intracoronary diltiazem. Thus, treatment with diltiazem does not invalidate the measurement of coronary flow reserve for diagnostic purposes. Furthermore, these results suggest that attenuation of maximal coronary dilation by diltiazem is not a mechanism responsible for its antianginal effects.

Coronary blood flow responses to nitroglycerin (NTG) in patients have been reported to be extremely variable. In dogs, NTG has a striking biphasic effect on coronary hemodynamics, consisting of a brisk increase followed by a decrease in coronary flow. To determine the effect of the drug on the coronary circulation in normal humans, NTG was injected I.C. (50 and 300 mcg) in 11 normals, and its effects on coronary flow velocity were compared to those of I. C. papaverine (6, 8, 10, and 12 mg) and saline (0.5 and 3.0 ml). Coronary flow velocity was measured using a 3F coronary Doppler catheter. The effect of each drug on coronary blood flow was analyzed in terms of both magnitude and duration (s) of the transient vasodilatory response following administration. Changes in coronary flow velocity (expressed as peak/resting velocity ratio) after 6, 8, 10, and 12 mg papaverine were (mean +/- SEM) 2.7 +/- 0.1, 3.4 +/- 0.3, 3.7 +/- 0.2, and 3.9 +/- 0.2, respectively. Very mild changes were observed with saline (1.3 +/- 0.1 and 1.7 +/- 0.1 after 0.5 and 3.0 ml, respectively), while ratios of 2.4 +/- 0.2 and 3.1 +/- 0.3 were obtained after NTG 50 and 300 mcg, respectively. The effect of 300 mcg NTG was significantly greater (p less than 0.01) than that of saline, 6 mg papaverine and 50 mcg NTG, lower than that of 12 mg papaverine and not significantly different from that of 8 and 10 mg papaverine. In terms of duration, the effect of 300 mcg NTG on coronary flow velocity was more prolonged than that of saline and 50 mcg NTG, and shorter than that of 6 to 12 mg papaverine.(ABSTRACT TRUNCATED AT 250 WORDS)