James D. Rossen

Maximal Coronary Flow Reserve and Metabolic Coronary Vasodilation in Patients With Diabetes Mellitus

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.

Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both

BACKGROUND In humans, the use of cocaine and cigarette smoking each increase the hearts metabolic need for oxygen but may also decrease the supply of oxygen. As cocaine abuse has proliferated, cocaine-associated chest pain, myocardial infarction, and sudden death have occurred, especially among smokers. We assessed the influence of intranasal cocaine and cigarette smoking, alone and together, on myocardial oxygen demand and coronary arterial dimensions in subjects with and subjects without coronary atherosclerosis. METHODS In 42 smokers (28 men and 14 women; age, 34 to 79 years; 36 with angiographically demonstrable coronary artery disease), we measured the product of the heart rate and systolic arterial pressure (rate-pressure product) and coronary arterial diameters before and after intranasal cocaine at a dose of 2 mg per kilogram of body weight (n = 6), one cigarette (n = 12), or intranasal cocaine at a dose of 2 mg per kilogram followed by one cigarette (n = 24). RESULTS No patient had chest pain or ischemic electrocardiographic changes after cocaine use or smoking. The mean (+/- SE) rate-pressure product increased by 11 +/- 2 percent after cocaine use (n = 30, P < 0.001), by 12 +/- 4 percent after one cigarette (n = 12, P = 0.021), and by 45 +/- 5 percent after both cocaine use and smoking (n = 24, P < 0.001). As compared with base-line measurements, the diameters of nondiseased coronary arterial segments decreased on average by 7 +/- 1 percent after cocaine use (P < 0.001), by 7 +/- 1 percent after smoking (P < 0.001), and by 6 +/- 2 percent after cocaine use and smoking (P < 0.001). The diameters of diseased segments decreased by 9 +/- 2 percent after cocaine use (n = 18, P < 0.001), by 5 +/- 5 percent after smoking (n = 12, P = 0.322), and by 19 +/- 4 percent after cocaine use and smoking (n = 12, P < 0.001). The increase in the rate-pressure product and the decrease in the diameters of diseased segments caused by cocaine use and smoking together were greater (P < 0.001 and P = 0.037, respectively) than the changes caused by either alone. CONCLUSIONS The deleterious effects of cocaine on myocardial oxygen supply and demand are exacerbated by concomitant cigarette smoking. This combination substantially increases the metabolic requirement of the heart for oxygen but simultaneously decreases the diameter of diseased coronary arterial segments.

A Randomized Controlled Trial of a Paclitaxel-Eluting Stent Versus a Similar Bare-Metal Stent in Saphenous Vein Graft Lesions: The SOS (Stenting Of Saphenous Vein Grafts) Trial

OBJECTIVES The aim of this study was to compare the frequency of angiographic restenosis and clinical events between a paclitaxel-eluting stent (PES) and a similar bare-metal stent (BMS) in saphenous vein graft (SVG) lesions. BACKGROUND There are conflicting and mostly retrospective data on outcomes after drug-eluting stent implantation in SVGs. METHODS Patients requiring SVG lesion stenting were randomized to BMS or PES. The primary study end point was binary in-segment restenosis at 12-month follow-up quantitative coronary angiography. Secondary end points included death, myocardial infarction, ischemia-driven target vessel and lesion revascularization, and target vessel failure. RESULTS Eighty patients with 112 lesions in 88 SVGs were randomized to a BMS (39 patients, 43 grafts, 55 lesions) or PES (41 patients, 45 grafts, 57 lesions). Binary angiographic restenosis occurred in 51% of the BMS-treated lesions versus 9% of the PES-treated lesions (relative risk: 0.18; 95% confidence interval [CI]: 0.07 to 0.48, p < 0.0001). During a median follow-up of 1.5 years the PES patients had less target lesion revascularization (28% vs. 5%, hazard ratio: 0.38; 95% CI: 0.15 to 0.74, p = 0.003) and target vessel failure (46% vs. 22%, hazard ratio: 0.65; 95% CI: 0.42 to 0.96, p = 0.03), a trend toward less target vessel revascularization (31% vs. 15%, hazard ratio: 0.66; 95% CI: 0.39 to 1.05, p = 0.08) and myocardial infarction (31% vs. 15%, hazard ratio: 0.67; 95% CI: 0.40 to 1.08, p = 0.10), and similar mortality (5% vs. 12%, hazard ratio: 1.56; 95% CI: 0.72 to 4.11, p = 0.27). CONCLUSIONS In SVG lesions, PES are associated with lower rates of angiographic restenosis and target vessel failure than BMS.

Acute effect of cigarette smoking on the coronary circulation: Constriction of epicardial and resistance vessels☆

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.

Comparison of coronary vasodilation with intravenous dipyridamole and adenosine

Although both intravenous dipyridamole and adenosine have been used to produce coronary vasodilation during cardiac imaging, the relative potency of the commonly administered doses of these agents has not been evaluated. Accordingly, the coronary and systemic hemodynamic effects of intravenous adenosine (140 micrograms/kg per min) and intravenous dipyridamole (0.56 mg/kg over 4 min) were compared with a maximally dilating dose of intracoronary papaverine in 15 patients. Coronary blood flow responses were assessed using a Doppler catheter in a nonstenotic coronary artery. The protocol was discontinued in two patients because of transient asymptomatic atrioventricular (AV) block during adenosine infusion. The mean heart rate increased more with adenosine (11 +/- 9 beats/min) and dipyridamole (11 +/- 7 beats/min) than with papaverine (4 +/- 3 beats/min, p less than 0.05 vs. adenosine and papaverine). The mean arterial pressure decreased less with dipyridamole (-10 +/- 3 mm Hg) and papaverine (-9 +/- 4 mm Hg) than with adenosine (-16 +/- 5 mm Hg, p less than 0.01 vs. dipyridamole and papaverine). The peak/rest coronary blood flow velocity ratio was greater with papaverine (3.9 +/- 1.1) than with adenosine (3.4 +/- 1.2, p less than or equal to 0.05 vs. papaverine) or dipyridamole (3.1 +/- 1.2, p less than 0.01 vs. papaverine). A larger decrease in coronary resistance as measured by the coronary vascular resistance index occurred with papaverine (0.25 +/- 0.06) and adenosine (0.26 +/- 0.09) than with dipyridamole (0.31 +/- 0.10, p less than 0.01 vs. papaverine, p less than 0.05 vs. adenosine).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of increases in heart rate and arterial pressure on coronary flow reserve in humans

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.

Evidence That Macrophages in Atherosclerotic Lesions Contain Angiotensin II

BACKGROUND We have reported that human mononuclear leukocytes contain large amounts of angiotensin II (Ang II). The goal of the present study was to test the hypothesis that Ang II is present in monocyte/macrophages in atherosclerotic lesions. METHODS AND RESULTS Segments of thoracic aorta and left circumflex coronary artery were obtained from 3 groups of cynomolgus monkeys: normal, atherosclerotic, and regression. Samples of human coronary arterial atherosclerotic lesions were obtained from directional atherectomy. Sections were stained for Ang II with 3 different polyclonal rabbit anti-human Ang II antisera. In aorta and coronary arteries from normal monkeys, there was no or minimal anti-Ang II staining in endothelial cells. All sections from atherosclerotic monkeys displayed discrete, localized regions of staining for Ang II in intima-media. Macrophages were present throughout the atherosclerotic intima-media, and anti-Ang II staining appeared to colocalize with macrophages. All human coronary atherectomy samples stained positive for Ang II and macrophages. Staining for both Ang II and macrophages was observed in vascular lesions from all 5 monkeys after regression of atherosclerosis, but staining was less extensive than in atherosclerotic blood vessels from monkeys. CONCLUSIONS These findings suggest that Ang II is present in atherosclerotic lesions in monkeys and humans, colocalizes with macrophages in intima-media of atherosclerotic vessels from monkeys, and decreases in lesions in monkeys with regression of atherosclerosis.

Coronary dilation with standard dose dipyridamole and dipyridamole combined with handgrip.

Intravenous dipyridamole is widely used to produce coronary vasodilation during cardiac imaging procedures. However, the routinely used dose of dipyridamole (0.56 mg/kg IV over 4 min) does not always result in maximal coronary dilation. The addition of isometric handgrip during dipyridamole coronary dilation has been reported to substantially increase coronary blood flow over dipyridamole alone. We compared the coronary vasodilation resulting from infusion of the standard dose of dipyridamole with that resulting from a maximally dilating dose of intracoronary papaverine in 12 patients with angiographically normal coronary arteries. We also assessed the effect on coronary blood flow velocity of the addition of isometric handgrip during dipyridamole coronary dilation. Changes in coronary blood flow velocity were measured with a 3F coronary Doppler catheter. The coronary flow reserve (peak/resting coronary flow velocity ratio) after dipyridamole (3.7 +/- 1.2 [mean +/- SD] was less than that seen after papaverine (4.4 +/- 0.5, p less than 0.05), and the coronary vascular resistance index during dipyridamole coronary vasodilation (0.28 +/- 0.09) was greater than during papaverine (0.22 +/- 0.03, p less than 0.05). The dipyridamole coronary flow reserve was less than 3.0 in four subjects and was 2.0 or less in two subjects. The addition of isometric handgrip to dipyridamole coronary vasodilation produced an 8% increase in mean heart rate and a 17% increase in mean arterial pressure, but coronary flow reserve was unchanged (3.8 +/- 1.1 before handgrip vs. 4.0 +/- 1.1 with handgrip). Quantitative angiography in six patients revealed no change in coronary caliber with the addition of handgrip.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial Hemodynamic Effects of Oral Levodopa in Heart Failure: Relation to the Generation of Dopamine

Among the positive inotropic drugs available to improve myocardial contractility in congestive heart failure, only digitalis glycosides are suitable for oral administration. In this study, we administered oral levodopa (1.5 to 2.0 g), which is decarboxylated to form dopamine, to 10 patients with severe congestive heart failure. Peak hemodynamic responses occurred one hour after the ingestion of levodopa, with the mean (+/- S.E.M.) cardiac index increasing from 1.8 +/- 0.1 to 2.4 +/- 0.2 liters per minute per square meter of body-surface area (P less than 0.01) and systemic vascular resistance declining from 1905 +/- 112 to 1513 +/- 121 dyn X sec X cm-5 (P less than 0.01). These effects persisted for four to six hours. Left ventricular filling pressure, heart rate, and mean arterial pressure were unchanged. Plasma concentrations of dopamine rose to a peak level of 34 +/- 5 ng per milliliter one hour after drug ingestion and decreased toward base line over the ensuing five hours. A significant correlation was observed between plasma dopamine levels and changes in cardiac index (r = 0.8; P less than 0.02). Five patients enrolled in a trial to evaluate the effectiveness of long-term therapy with levodopa had similar hemodynamic responses to the drug after 6.8 +/- 1.7 months of treatment. Thus, oral administration of levodopa to patients with severe heart failure produced a sustained improvement in cardiac function. The hemodynamic responses observed can be attributed to the activation of beta 1-adrenergic, dopamine, and dopamine receptors by dopamine derived from levodopa.

Plaque development, vessel curvature, and wall shear stress in coronary arteries assessed by X-ray angiography and intravascular ultrasound

The relationships among vascular geometry, hemodynamics, and plaque development in the coronary arteries are complex and not yet well understood. This paper reports a methodology for the quantitative analysis of in vivo coronary morphology and hemodynamics, with particular emphasis placed on the critical issues of image segmentation and the automated classification of disease severity. We were motivated by the observation that plaque more often developed at the inner curvature of a vessel, presumably due to the relatively lower wall shear stress at these locations. The presented studies are based on our validated methodology for the three-dimensional fusion of intravascular ultrasound (IVUS) and X-ray angiography, introducing a novel approach for IVUS segmentation that incorporates a robust, knowledge-based cost function and a fully optimal, three-dimensional segmentation algorithm. Our first study shows that circumferential plaque distribution depends on local vessel curvature in the majority of vessels. The second study analyzes the correlation between plaque distribution and wall shear stress in a set of 48 in vivo vessel segments. The results were conclusive for both studies, with a stronger correlation of circumferential plaque thickness with local curvature than with wall shear stress. The inverse relationship between local wall shear stress and plaque thickness was significantly more pronounced (p<0.025) in vessel cross sections exhibiting compensatory enlargement (positive remodeling) without luminal narrowing than when the full spectrum of disease severity was considered. The inverse relationship was no longer observed in vessels where less than 35% of vessel cross sections remained without luminal narrowing. The findings of this study confirm, in vivo, the hypothesis that relatively lower wall shear stress is associated with early plaque development.