Alain Nitenberg

Coronary Artery Responses to Physiological Stimuli Are Improved by Deferoxamine but not by l-Arginine in Non–Insulin-Dependent Diabetic Patients With Angiographically Normal Coronary Arteries and No Other Risk Factors

BACKGROUNDnAcetylcholine produces coronary artery (CA) constriction in diabetic patients, suggesting an impairment of endothelium-dependent dilation. In diabetes, multiple metabolic abnormalities may inactivate nitric oxide through oxygen free radical production.nnnMETHODS AND RESULTSnTo examine the mechanism of this abnormal response, two physiological tests (ie, a cold pressor test [CPT] and coronary flow increase induced by an injection of 10 mg papaverine [PAP] in the distal left anterior descending CA) were performed before and after either intravenous L-arginine (625 mg/min x 10 minutes) or intravenous deferoxamine (50 mg/min x 10 minutes) in 22 normotensive nonsmoking diabetic patients with angiographically normal CAs and normal cholesterol. Coronary surface areas were measured with quantitative angiography. Before the administration of L-arginine or deferoxamine, CPT induced CA constriction in both groups (-14 +/- 10% and -15 +/- 11%, respectively; each P<.001), and PAP injection in distal LAD did not modify significantly proximal LAD dimensions. In the 10 diabetic patients receiving L-arginine, responses to CPT and PAP were not modified. Conversely, in the 12 patients receiving deferoxamine, CA dilated in response to the two tests (+10 +/- 9% after CPT and +22 +/- 7% after PAP, each P<.001). Intracoronary isosorbide dinitrate, an endothelium-independent dilator, produced similar dilation in the two groups (+47 +/- 19% and +41 +/- 15%, respectively; each P<.001).nnnCONCLUSIONSnThis study shows that (1) responses of angiographically normal CAs to CPT and to flow increase are impaired in diabetic patients; (2) abnormal responses are not improved by L-arginine, suggesting that a deficit in substrate for nitric oxide synthesis is not involved; and (3) deferoxamine restores a vasodilator response to the two tests, suggesting that inactivation of NO by oxygen species might be partly responsible for the impairment of CA dilation in diabetic patients.

Coronary vasodilator reserve in untreated and treated hypertensive patients with and without left ventricular hypertrophy

OBJECTIVESnThis study was initiated to compare the coronary reserve in treated hypertensive patients with and without left ventricular hypertrophy with that in untreated patients.nnnBACKGROUNDnCoronary reserve is impaired in hypertensive patients with left ventricular hypertrophy and normal coronary arteries. Moreover, basal coronary resistance is elevated in hypertensive patients without left ventricular hypertrophy.nnnMETHODSnCoronary reserve was measured with a coronary Doppler catheter before and after a maximally vasodilating dose of intracoronary papaverine (peak/rest flow velocity ratio) in 16 control subjects and 37 hypertensive patients with normal epicardial coronary arteries. Among 20 untreated hypertensive patients, myocardial mass was increased in 11 (group 2a) and normal in 9 (group 2b). Seventeen patients had been treated effectively for at least 1 year; nine (group 3a) had persistent left ventricular hypertrophy, and eight (group 3b) had no left ventricular hypertrophy before treatment. Left ventricular volumes and ejection fraction were normal in all groups.nnnRESULTSnCoronary reserve was moderately reduced in group 2b (3.5 +/- 0.6 vs. 5.2 +/- 0.8 in control subjects, p < 0.001) and markedly diminished in groups 2a and 3a (2.5 +/- 0.5 and 2.7 +/- 0.4, respectively; all p < 0.001 vs. control subjects). In group 3b, coronary reserve was comparable to that of control subjects (5.1 +/- 1.4).nnnCONCLUSIONSnThe reduction in coronary reserve observed in untreated hypertensive patients with normal myocardial mass suggests that structural abnormalities of the coronary microvasculature may occur before left ventricular hypertrophy. Treated patients with normal mass before treatment had a coronary reserve comparable to that of normotensive control subjects, whereas normalization of arterial pressure with persistent left ventricular hypertrophy was associated with a marked impairment of coronary reserve.

Nifedipine and thallium-201 myocardial perfusion in progressive systemic sclerosis

Heart disease in patients with progressive systemic sclerosis may be due in part to myocardial ischemia caused by a disturbance of the coronary microcirculation. To determine whether abnormalities of myocardial perfusion in this disorder are potentially reversible, we evaluated the effect of the coronary vasodilator nifedipine on myocardial perfusion assessed by thallium-201 scanning in 20 patients. Thallium-201 single-photon-emission computerized tomography was performed under control conditions and 90 minutes after 20 mg of oral nifedipine. The mean (+/- SD) number of left ventricular segments with perfusion defects decreased from 5.3 +/- 2.0 to 3.3 +/- 2.2 after nifedipine (P = 0.0003). Perfusion abnormalities were quantified by a perfusion score (0 to 2.0) assigned to each left ventricular segment and by a global perfusion score (0 to 18) for the entire left ventricle. The mean perfusion score in segments with resting defects increased from 0.97 +/- 0.24 to 1.26 +/- 0.44 after nifedipine (P less than 0.00001). The mean global perfusion score increased from 11.2 +/- 1.7 to 12.8 +/- 2.4 after nifedipine (P = 0.003). The global perfusion score increased by at least 2.0 in 10 patients and decreased by at least 2.0 in only 1. These observations reveal short-term improvement in thallium-201 myocardial perfusion with nifedipine in patients with progressive systemic sclerosis. The results are consistent with a potentially reversible abnormality of coronary vasomotion in this disorder, but the long-term therapeutic effects of nifedipine remain to be determined.

Direct myocardial and coronary effects of enalaprilat in patients with dilated cardiomyopathy: assessment by a bilateral intracoronary infusion technique.

Angiotensin II elicits contractile responses in the coronary arteries and myocardial tissue, which suggests that blockade of the renin-angiotensin system by specific agents should lead to both coronary vasodilation and an alteration of left ventricular inotropism. The present work was designed to delineate--independently from its systemic effects--the intrinsic actions of an angiotensin converting-enzyme inhibitor on the coronary circulation and left ventricular function. To minimize peripheral effects, a bilateral intracoronary infusion of enalaprilat (0.05 mg.min-1, 1 ml.min-1 in each coronary artery) was performed in 16 patients with dilated cardiomyopathy. All patients had normal coronary arteriograms. In 12 patients (group I) the intracoronary infusion of enalaprilat resulted in minimal peripheral changes, with a 5% reduction in the mean aortic pressure (p less than .05) and no significant alteration in indexes of preload, i.e., left ventricular end-diastolic pressure and volume, or of afterload, i.e., left ventricular end-systolic stress and systemic resistances. Myocardial oxygen consumption was also unaffected by the intracoronary infusion of enalaprilat. Coronary vasodilation was demonstrated by a significant elevation of coronary sinus blood flow (+19%, from 181 +/- 73 to 214 +/- 79 ml.min-1, p less than .001) and a reduction of coronary resistance (-18%, from 0.51 +/- 0.17 to 0.41 +/- 0.15 mm Hg.ml-1.min, p less than .001), with a parallel increase in coronary sinus oxygen content and pressure (both p less than .05). Oxygen extraction by the myocardium was reduced (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Multifactorial determinants of reduced coronary flow reserve after dipyridamole in dilated cardiomyopathy

Coronary sinus blood flow (ml/100 g left ventricular [LV] mass/min) and coronary resistance (mean aortic minus LV mean diastolic pressures/coronary sinus blood flow, mm Hg/[ml/100 g/min]) were studied in 7 control patients and in 11 patients with severe dilated cardiomyopathy (DC) and normal coronary arteriograms. Basal coronary sinus blood flow was not different in the 2 groups. After intravenous administration of dipyridamole (0.14 mg/kg/min X 4 min), coronary sinus blood flow and dipyridamole/basal coronary sinus blood flow ratio were significantly (p less than 0.001) lower in the DC group than in the normal group (coronary sinus blood flow 188 +/- 48 vs 408 +/- 58, respectively; blood flow ratio 1.78 +/- 0.35 vs 4.01 +/- 0.56, respectively), and the coronary resistance was higher in the DC group than in the control group (0.39 +/- 0.15 vs 0.22 +/- 0.03, respectively, p less than 0.01). After administration of dipyridamole in patients with DC, no correlation could be found between coronary sinus blood flow and LV mean diastolic, mean aortic or coronary driving pressures, i.e., mean aortic minus LV mean diastolic pressures. Thus, in DC patients, neither an elevated LV diastolic pressure nor a low coronary perfusion pressure can totally account for the restriction of the coronary flow reserve after dipyridamole.

Acetylcholine-induced coronary vasoconstriction in young, heavy smokers with normal coronary arteriographic findings

PURPOSEnCigarette smoking is a major coronary risk factor. Acetylcholine dilates coronary arteries in normal subjects, but acetylcholine-induced coronary constriction has been reported in patients with normal coronary arteriographic findings and other risk factors for coronary artery disease. The purpose of the present study was to evaluate the epicardial coronary artery response to acetylcholine in young, heavy smokers.nnnSUBJECTS AND METHODSnResponses to stepwise infusion of acetylcholine (10(-8)M, 10(-7)M, 10(-6)M, and 10(-5)M) into the left coronary artery were studied in five young, heavy smokers and in five age-matched nonsmokers. All subjects were normotensive and had normal left ventricular function and coronary arteriographic findings. Levels of serum cholesterol, triglycerides, and low-density lipoprotein levels were within normal ranges. Vessel dimensions were measured on four different segments in each subject, with quantitative digital-substracted arteriography.nnnRESULTSnIn smokers, no change was produced at the 10(-8) M and 10(-7) M concentrations of acetylcholine, but progressive diameter reduction was observed at 10(-6) M and 10(-5) M acetylcholine (-26.6% +/- 13.6%, p < 0.001; -42.2% +/- 9.5%, p < 0.001, respectively). In nonsmokers, a progressive diameter dilation was produced from 10(-8) M to 10(-6) M acetylcholine (+5.3% +/- 3.6%, p < 0.001; +12.4% +/- 6.5%, p < 0.001; +15.9% +/- 6.9%, p < 0.001, respectively), and no change was observed at 10(-5) M acetylcholine. In the two groups, all segments dilated after infusion of intracoronary isosorbide dinitrate.nnnCONCLUSIONnThe abnormal coronary vasoconstriction induced by acetylcholine in young, heavy smokers with angiographically normal coronary arteries suggests an endothelial vasodilator dysfunction. This mechanism may contribute to the pathogenesis of coronary artery disease in cigarette smokers.

Loss of Flow-Dependent Coronary Artery Dilatation in Patients With Hypertension

BACKGROUNDnAbnormal endothelium-dependent coronary response to acetylcholine has been shown in patients with essential hypertension. We tested the hypothesis that flow-dependent dilatation, which has been shown in normal human coronary arteries, is impaired in hypertensive patients.nnnMETHODS AND RESULTSnThe coronary vasomotor response to maximal increase of blood flow induced by papaverine was studied in 10 control subjects and in 14 hypertensive patients with no other risk factors and angiographically normal coronary arteries. After the injection of papaverine in the midportion of the left anterior descending coronary artery (LAD), the diameter of the proximal LAD (LAD1) was measured by quantitative angiography, whereas that of the proximal circumflex artery (LCx) served as control segment. Estimates of coronary blood flow in the distal LAD (LAD2) were calculated by intracoronary Doppler flow velocity measurements. An increase in LAD2 blood flow of 521 +/- 41% (P < .001) in control subjects was associated with a 17.0 +/- 3.3% dilatation of the LAD1 (P < .001) and with no significant change in the diameter of the LCx. In hypertensive patients, despite a comparable increase in LAD2 blood flow of 406 +/- 32% (P < .001), the LAD1 failed to dilate (-0.4 +/- 0.6%, NS). The dilative response to isosorbide dinitrate was similar in control subjects and hypertensive patients (30.0 +/- 4.1%, P < .001 and 21.9 +/- 1.9%, P < .001, respectively).nnnCONCLUSIONSnThus, the flow-mediated coronary dilatation is lost in hypertensive patients, and this may impair normal dilatation observed in response to an increase in myocardial metabolic demand.

Coronary flow and resistance reserve in patients with chronic aortic regurgitation, angina pectoris and normal coronary arteries

Left ventricular hypertrophy has been found to be associated with a reduction of coronary vascular reserve, which could be responsible for episodes of myocardial ischemia. To evaluate coronary flow and resistance reserve in patients with chronic aortic regurgitation, coronary sinus blood flow and coronary resistance were measured before and after an intravenous dipyridamole infusion (0.14 mg/kg per min X 4 min) in eight control subjects and eight patients with aortic regurgitation, exertional angina pectoris and normal coronary arteriograms. Coronary flow reserve, evaluated by the dipyridamole/basal coronary sinus blood flow ratio, and coronary resistance reserve, evaluated by the basal/dipyridamole coronary resistance ratio, were both significantly reduced in patients with aortic regurgitation (1.67 +/- 0.40 versus 4.03 +/- 0.52 in control subjects, p less than 0.001 and 1.71 +/- 0.50 versus 4.38 +/- 0.88 in control subjects, p less than 0.001, respectively). In patients with aortic regurgitation, basal coronary sinus blood flow was higher than in control subjects (276 +/- 81 versus 105 +/- 24 ml/min, respectively, p less than 0.001) and basal coronary resistance was lower (0.31 +/- 0.13 versus 0.95 +/- 0.17 mm Hg/ml per min, respectively, p less than 0.001), but coronary blood flow and resistance after dipyridamole were not significantly different in the two groups (461 +/- 159 versus 418 +/- 98 ml/min in control subjects, 0.19 +/- 0.11 versus 0.22 +/- 0.04 mm Hg/ml per min in control subjects, respectively). These data demonstrate that coronary reserve is severely reduced in patients with chronic aortic regurgitation and exertional angina.(ABSTRACT TRUNCATED AT 250 WORDS)

Epicardial coronary arteries are not adequately sized in hypertensive patients

OBJECTIVESnThis study sought to compare coronary artery dimensions in hypertensive patients and normal subjects.nnnBACKGROUNDnMyocardial oxygen demand at rest and corresponding coronary blood flow are the main determinants of large coronary artery dimensions in humans. Coronary diameters are increased in aortic valve disease.nnnMETHODSnLeft main, proximal and distal left anterior descending and proximal circumflex coronary artery diameters were measured by quantitative angiography in 10 control subjects (group 1) and 26 untreated hypertensive patients, 12 without (group 2a) and 14 with (group 2b) left ventricular hypertrophy. All patients had normal cholesterol levels and angiographically normal coronary arteries. Measurements were made at baseline and after 2 mg of intracoronary isosorbide dinitrate to obtain maximal dimensions of vessels. Coronary flow velocity was measured in the distal left anterior descending coronary artery by Doppler ultrasound.nnnRESULTSnDespite a higher rate-pressure product in hypertensive patients, all segment diameters were slightly but not significantly higher at baseline in group 2b than in groups 1 and 2a. Diameters were similar in the three groups after isosorbide dinitrate. Conversely, coronary flow velocity was significantly higher in hypertensive patients than in group 1 either at baseline (10.4 +/- 2.2 [mean +/- SD] cm/s [group 2a] and 12.8 +/- 2.4 cm/s [group 2b] vs. 6.5 +/- 2.0 cm/s [group 1], all p < 0.001) or after isosorbide dinitrate (6.8 +/- 2.8 cm/s [group 2a] and 7.8 +/- 2.1 cm/s [group 2b] vs. 3.7 +/- 0.8 cm/s [group 1], p < 0.01 and p < 0.001, respectively).nnnCONCLUSIONSnDespite an elevated myocardial oxygen demand, maximal dimensions of large coronary arteries are not increased in hypertensive patients, resulting in an elevated coronary flow velocity that may increase longitudinal shear stress at the endothelial surface. This elevated flow velocity might be an important determinant in the pathogenesis of atherosclerosis in hypertensive patients.

Effects of Midazolam on the Coronary Circulation in Patients with Coronary Artery Disease

The effects of midazolam on coronary sinus blood flow (CSBF), myocerdial oxygen consmption (MVO2), and myocardial laclate balance were investigated in eight patients with stable coronary artery disease undergoing cardiac catheterization. Coronary sinus blood flow was measured by continuous thermodilution. Arterial and coronary sinus blood were analyzed for oxygen and lactate content. The determinants of left ventricular (LV) performance were obtained from the cardiac output measured by thermodilution and from left heart catheterization data. All data were obtained before, and 5 and 15 min after midazolam, 0.2 mg kg−1 iv. Sleep was induced in all patients after administration of midazolam and persisted throughout the entire study period. Mean aortic and LV end-diastolic pressure were decreased from control values (−15 and −44%, respectively), as well as cardiac index and stroke index (−10 and −15%, respectively), Heart rate increased moderately (+8%), while no change in systemic vascular resistance and maximum velocity of shortening (Vmax) were observed, Midazolam administration was followed by a decrease of CSBF (−24%) and of MVO2, (−26%). Coronary vascular resistance did not change, but coronary sinus oxygen tension increased slightly, suggesting a mild alteration in normal autoregulation. However, no evidence of myocardial ischemia occurred, as judged by the absence of changes in the: 1) ECG, 2) myocardial lactate extraction, and 3) relaxation time constant. These results suggest tht midazolam may be used safely in patients with coronary artery disease