Biomedical subjects
Publications and source records attributed to A Nitenberg.
Coronary microcirculatory is the main target of contrast echocardiography. Coronary flow is one of the parameters which influence the myocardial blood flow but not the only one. Therefore, the knowledge of microcirculatory physiopathology is required in order to analyze datas from contrast echo.
Diabetes mellitus is responsible for abnormalities in the control of endothelium-dependent vascular reactivity observed on both coronary arteries and coronary microvessels. These abnormalities of coronary artery circulation are associated with structural microcirculatory abnormalities even in subjects with angiographically normal coronary arteries. Both these structural and functional abnormalities might be responsible for an inadequate coronary response to an increased myocardial metabolic demand. These could be a key factor in the progressive myocardial alterations and in the physiopathology of diabetic cardiomyopathy. Their role in the genesis of arterial hypertension in diabetic patients remain to be clarified. The main physiopathological mechanisms of endothelial dysfunction are reviewed.
Left ventricular hypertrophy (LVH) is a physiologic process of adaptation of the heart to mechanical load increase. Despite depression of left ventricular contractile performance, mechanical efficiency and ventriculoarterial coupling are preserved in hypertensive patients with LVH. To assess the differences between patients with and without LVH, left ventricular contractile performance and the ventriculoarterial coupling were compared in two groups of hypertensive patients with similar body surface area and arterial pressures, and normal pump function: 30 patients with LVH (group 1) and 23 without LVH (group 2). Left ventricular angiography coupled with simultaneous recording of pressures with a micromanometer were used to determine end-systolic stress-to-volume ratio (ESSVR), end-systolic elastance (Ees), effective arterial elastance (Ea), external work (EW), and pressure-volume area (PVA). Myocardial contractile performance, assessed by Ees normalized by myocardial mass and by ESSVR, was lower in group I than in group 2 (1.23 +/- 0.28 v 1.89 +/- 0.48 mm Hg/mL/100 g, and 3.85 +/- 0.99 v 5.13 +/- 0.56 g/cm2/mL, respectively, both P < .001). Ventriculoarterial coupling evaluated through Ea/Ees ratio, and mechanical efficiency evaluated through EW/PVA ratio, were similar in the two groups (0.53 +/- 0.08 v 0.51 +/- 0.05, and 0.78 +/- 0.03 v 0.80 +/- 0.02, respectively, NS). In conclusion, this study shows that ventriculoarterial coupling and mechanical efficiency are comparable in hypertensive patients with and without LVH. These results suggest that in hypertensive patients, the matching between left ventricular performance and arterial load and the energy transfer are preserved either through left ventricular hypertrophy with moderate depression of myocardial contractile performance or through enhancement of myocardial contractile performance in patients with normal left ventricular mass.
Coronary microcirculation dysfunction may be associated with myocardial perfusion defects on thallium imaging in diabetic patients without coronary artery stenosis. Microvascular coronary adaptation to increased myocardial oxygen demand in response to sympathetic stimulation evoked by the cold pressor test was examined in 22 type 2 diabetic patients with thallium imaging defects and in 15 control subjects. Both the diabetic patients and control subjects had angiographically normal coronary arteries and no other risk factors. Despite a similar increase in the rate-pressure product in the two groups (22.6 +/- 12.4% in diabetic patients and 31.8 +/- 8.2% in control subjects, NS), coronary blood flow increase in the left anterior descending artery (mean flow velocity measured by intracoronary Doppler multiplied by the cross-sectional area measured by digital angiography) was significantly lower in diabetic patients than in control subjects (14.7 +/- 19.8 vs. 75.5 +/- 13.5%, respectively; P = 0.0001). In addition, when there was a positive correlation between the two parameters in control subjects (r = 0.651, P < 0.01), there was no relationship in diabetic patients (r = 0.054). In conclusion, vasodilation of the coronary microcirculation in response to sympathetic stimulation evoked by the cold pressor test is impaired in type 2 diabetic patients without epicardial artery lesions. This microvascular impairment during sympathetic stimulation may explain exercise-induced myocardial perfusion abnormalities observed in these patients and may impair microcirculatory coronary vasodilation during current life stress episodes such as exercise, mental stress, or cold exposition.
In diabetes, endothelium-dependent dilation of large and small coronary arteries is impaired, which results in a mismatch between myocardial metabolic demand and coronary blood flow. It has been proved that deferoxamine, an iron chelator that inhibits Fenton and Haber-Weiss reactions, restores a normal response to cold pressor test and flow increase in angiographically normal epicardial coronary arteries of diabetic patients. This result suggests that nitric oxide could be inactivated by reactive oxygen species. The aim of this study was to assess the effects of deferoxamine on coronary microcirculation vasomotion when myocardial oxygen demand is increased by sympathetic stimulation elicited by cold pressor test in type 2 diabetic patients. In 17 patients with angiographically normal coronary arteries and without any other coronary risk factors, coronary blood flow has been measured using quantitative angiography and intracoronary Doppler at baseline and during a cold pressor test, before and after intravenous administration of 500 mg deferoxamine. Increase in rate-pressure product, an estimate of myocardial metabolic demand, was similar before and after deferoxamine (+21.1 +/- 8.7% vs +20.5 +/- 8.9%, respectively), but coronary blood flow increase was significantly higher after deferoxamine (+6.3 +/- 12.9% vs +31.8 +/- 16.7%, respectively, p < 0.001), and coronary resistance was increased before deferoxamine and decreased after (+14.8 +/- 21.9% vs -7.9 +/- 10.9%, respectively, p < 0.001). Moreover, before deferoxamine, the negative correlation between coronary blood flow and rate-pressure product changes before deferoxamine (R = 0.518, P < 0.05) was turned in a positive relationship after deferoxamine (r = 0.546, p < 0.05). In conclusion, in type 2 diabetic patients, endothelium-dependent dilation of the coronary microcirculation is restored when iron-catalysed oxidative reactions are inhibited by deferoxamine, which restores the normal matching between myocardial oxygen demand and coronary blood flow.
Restoration of flow-dependent coronary artery dilation by angiotensin-converting enzyme inhibition (ACEI) has been demonstrated in patients with hypertension. The aim of the present study was to evaluate whether dilation of conductance coronary arteries may alter maximal coronary blood flow (CBFmax) and minimal coronary resistance (CRmin) in hypertensive patients with reversible impairment of flow-dependent coronary artery dilation. Thirteen hypertensive patients with angiographically normal coronary arteries and no other risk factors were studied. Cross-sectional areas (CSAs) of proximal and distal left anterior descending (LAD) coronary arteries were determined by quantitative angiography. Coronary flow velocity was recorded in the distal LAD with an intracoronary Doppler catheter. Estimates of coronary blood flow and resistance were calculated at rest and during maximal increase in blood flow induced by papaverine injected in the midportion of the LAD, both before and after ACEI. Flow-dependent dilation of the proximal LAD, abolished before ACEI, was restored after (26.7 +/- 11.2%; p < 0.001). The increase in CSA of the distal LAD exposed to papaverine was significantly higher after ACEI than before (from 33.4 +/- 20.5% to 51.5 +/- 23.4%; p < 0.001). After restoration of proximal LAD flow-dependent dilation, CBFmax was increased by +21.0 +/- 10.3% (p < 0.001), and CRmin was reduced by 19.3 +/- 9.5% (p < 0.001). Thus, dilation of epicardial coronary arteries participates substantially in the coronary resistance in hypertensive patients. Restoration of flow-dependent coronary artery dilation by ACEI may improve the ability of coronary circulation to deliver its maximal myocardial blood flow in hypertensive patients.
In heart transplant recipients (HTR), short-term systolic blood pressure variability is preserved, whereas heart rate variability is almost abolished. Heart period is the sum of left ventricular ejection time (LVET) and diastolic time (DT). In the present time-domain prospective study, we tested the hypothesis that short-term fluctuations in aortic pulse pressure (PP) in HTR were related to fluctuations in LVET. Seventeen male HTR (age 48 +/- 6 yr) were studied 16 +/- 11 mo after transplantation. Aortic root pressure was obtained over a 15-s period using a micromanometer both at rest (n = 17) and following the cold pressor test (CPT, n = 14). There was a strong positive linear relationship between beat-to-beat LVET and beat-to-beat PP in all patients at rest and in 13 of 14 patients following CPT (each P < 0.01). The slope of this relationship showed little scatter both at rest (0.34 +/- 0.07 mmHg/ms) and following CPT (0.35 +/- 0.09 mmHg/ms, P = not significant). Given the essentially fixed heart period, DT varied inversely with LVET. As a result, in 13 of 17 HTR at rest and in 12 of 14 HTR following CPT, there was a negative linear relationship between beat-to-beat PP and DT. In conclusion, our short-term time-domain study demonstrated a strong positive linear relationship between LVET and blood pressure variability in male HTR. We also identified a subgroup of HTR in whom there was a mismatch between PP and DT.
A failure of coronary blood flow to increase during cold pressor test has been shown in patients with coronary atherosclerosis and impaired metabolic coronary vasodilatation in response to atrial pacing has been demonstrated in diabetic patients without significant epicardial artery stenoses. This study was designed to evaluate coronary microvascular adaptation to increased myocardial oxygen demand in response to sympathetic stimulation in diabetic patients with angiographically normal coronary arteries. Microvascular coronary adaptation to increased myocardial oxygen demand due to sympathetic stimulation evoked by the cold pressor test has been examined in 22 type 2 diabetic patients and in 15 control subjects with angiographically normal coronary arteries and no other risk factors. Coronary blood flow was calculated by measuring mean flow velocity in left anterior descending coronary artery by intracoronary Doppler and cross sectional area of the artery by digital angiography. Results show that despite a similar increase in rate-pressure product in the 2 groups (+22.6 +/- 12.4% in diabetic patients and +31.8 +/- 8.2% in control subjects, NS), coronary blood flow increase in left anterior descending artery was significantly lower in diabetic patients than in control subjects (+14.7 +/- 19.8% vs +75.5 +/- 13.5%, respectively, p = 0.0001). In addition, when there was a positive correlation between the 2 parameters in control subjects (R = 0.651, p < 0.01), there was no relationship in diabetic patients (R = 0.054). In conclusion, this study demonstrates that vasodilatation of coronary microcirculation in response to sympathetic stimulation evoked by cold pressor test is impaired in type 2 diabetic patients without epicardial artery lesions. This microvascular impairment during sympathetic stimulation may explain exercise-induced myocardial perfusion abnormalities observed in these patients and may impair microcirculatory coronary vasodilatation during current life stress episodes such as exercise, mental stress or cold exposure.
Smoking-cessation rates may be improved by nicotine-replacement therapy that reduces withdrawal symptoms. However, nicotine may have adverse effects on coronary circulation. The purpose of this study was to examine the short-term effects of nicotine gum chewing on the dimensions of coronary arteries of patients with coronary artery disease and on the response of coronary vessels to sympathetic stimulation caused by the cold pressor test. In 17 patients who were past chronic cigarette smokers, cross-sectional areas of 32 coronary artery stenoses and 32 adjacent apparently normal segments were measured by using quantitative coronary angiography at baseline and after a cold pressor test before and after nicotine gum chewing. The cold pressor test produces an increase in arterial pressure without any change in heart rate. These changes were similar before and after nicotine gum. Before nicotine gum, the cross-sectional area of coronary stenoses and apparently normal segments was significantly and similarly reduced during the cold pressor test (-11+/-12% and -11+/-12%, respectively; both p values <0.0001 vs. baseline). After nicotine gum, baseline cross-sectional area was not modified, and response to the cold pressor test was similar to that observed before nicotine gum (-11+/-18% and -12+/-12%, respectively; both p values <0.0001 vs. baseline). In conclusion, nicotine-replacement therapy by using nicotine gum does not reduce the surface area of normal and diseased coronary segments and does not enhance the constricting effect of sympathetic stimulation produced by the cold pressor test. Thus nicotine gum may be considered a relatively safe drug in patients who need nicotine-replacement therapy to stop smoking.
Left ventricular hypertrophy (LVH) is a recognized independent risk factor for cardiovascular morbidity and mortality. The purpose of this study was to assess the determinants of left ventricular mass index (LVMI), according to the presence or absence of silent myocardial ischaemia (SMI), in diabetic patients with at least two additional risk factors but with no known coronary artery disease. Eighty diabetic patients (14 Type 1 and 66 Type 2) were studied, and LVMI was measured echocardiographically. Three non-invasive tests (the ECG stress test, thallium-201 myocardial scintigraphy with intravenous dipyridamole infusion, and ambulatory 48-h ECG monitoring) were performed on all patients. Forty-five percent of patients had LVH (LVMI > or = 110 g/m2 in men and > or = 106 g/m2 in women). Twenty-six patients (37%) had SMI assessed on at least one of the non-invasive tests, 7 of whom had significant coronary stenoses on angiography. LVMI was significantly higher in patients with coronary stenoses on angiography than in those with SMI but without coronary stenoses or in those without SMI (p < 0.05), and was correlated with systolic blood pressure. In patients free of SMI, LVMI correlated with creatininemia. In patients with SMI and normal coronary arteries on angiography, LVMI correlated with the waist/hip girth ratio, the log urinary albumin excretion rate and the red blood cell filtration index (a rigidity index). This study suggests that LVH is very frequent in diabetic patients and that the main factor contributing to the increase of LVMI differs according to the presence or absence of SMI and coronary stenoses: volume load in patients free of SMI, microcirculatory disorders in those with SMI but with normal coronary arteries, and blood pressure in those with coronary stenoses.
Left ventricular hypertrophy (LVH) is a physiological process of adaptation of the heart to mechanical load increase. Despite depression of left ventricular (LV) contractile performance, work efficiency is preserved and ventriculoarterial coupling is almost normal in hypertensive patients with LVH. To assess the differences between patients with and without LVH, LV contractile performance, the ventriculoarterial coupling and mechanical efficiency were compared in 2 groups of hypertensive patients with similar body surface area and arterial pressures, 23 without LVH (group 1) and 30 with LVH (group 2) and compared to data of 20 normotensive subjects. Left ventricular angiography coupled with simultaneous recording of pressures with micromanometer were used to determine end-systolic stress-to-volume ratio (ESSVR), end-systolic elastance (Ees), effective arterial elastance (Ea), external work (EW) and pressure-volume area (PVA). Left ventricular contractile performance assessed by Ees/100 g myocardial mass and EESVR were lower in group 2 than in group 1 (1.23 +/- 0.28 vs 1.89 +/- 0.48 mmHg/mL/100 g and 6.22 +/- 1.07 vs 9.56 +/- 0.97 g/cm2/mL/m2, respectively, both p < 0.0001, control subjects: 1.47 +/- 0.41 and 6.97 +/- 1.22, respectively). Ventriculoarterial coupling evaluated through Ea/Ees ratio (0.51 +/- 0.05 in group 1 vs 0.53 +/- 0.08 in group 2, 0.49 +/- 0.09 in control subjects), and work efficiency evaluated through EW/PVA ratio (0.80 +/- 0.02 in group 1 vs 0.78 +/- 0.03 in group 2, 0.80 +/- 0.03 in control subjects), were similar in the 2 groups and were comparable to control subject values. In conclusion, this study shows that ventriculoarterial coupling and work efficiency are comparable in hypertensive patients with and without LVH. These results suggest that in patients without LVH the matching between left ventricle and arterial receptor is preserved through an enhancement of myocardial contractility which is energetically costly. Conversely, LVH seems to be a useful adaptation which minimizes the energetical cost of high pressure generation.
BACKGROUND: Acetylcholine 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. METHODS AND RESULTS: To 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). CONCLUSIONS: This 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.
Contractile performance of hypertrophied left ventricle may be depressed in arterial hypertension. Ventriculoarterial coupling is impaired when myocardial contractile performance is reduced and when afterload is increased. The left ventricular contractile performance and the ventriculoarterial coupling were evaluated in 30 hypertensive patients with moderate left ventricular hypertrophy and 20 control subjects. Left ventricular angiography coupled with the simultaneous recording of pressures with a micromanometer were used to determine end-systolic stress/volume index, the slope of end-systolic pressure-volume relationship, ie, end-systolic elastance, effective arterial elastance, external work, and pressure-volume area. In hypertensive patients, left ventricular contractile performance, as assessed by end-systolic elastance/ 100 g myocardial mass, was depressed (4.35 +/- 1.13 v 5.21 +/- 1.89 mm Hg/mL/100 g in control subjects P < .02), when end-systolic stress-to-volume ratio was comparable in the two groups (3.85 +/- 0.99 g/cm2/mL in hypertensive patients versus 3.51 +/- 0.77 g/cm2/mL in control subjects). Ventriculoarterial coupling, evaluated through effective arterial elastance/end-systolic elastance ratio, was slightly higher in hypertensive patients (0.53 +/- 0.08 v 0.48 +/- 0.09 mm Hg/mL in control subjects, P < .05), and work efficiency (external work/pressure-volume area) was similar in the two groups (0.78 +/- 0.04 mm Hg/mL in hypertensive patients versus 0.80 +/- 0.03 mm Hg/mL in control subjects). This study shows that despite a slight depression of left ventricular contractile performance, work efficiency is preserved and ventriculoarterial coupling is almost normal in hypertensive patients with left ventricular hypertrophy. Thus, it appears that left ventricular hypertrophy might be a useful means of preserving the match between left ventricle and arterial receptor with minimal energy cost.
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Coronary vasodilator responses to pharmacological (acetylcholine) and physiological (cold pressor test and flow dependent dilation) stimuli are impaired in hypertensive patients. The ability of angiotensin-converting enzyme inhibitors to restore normal coronary responses in hypertension and the potential mechanisms involved are examined. In spontaneously hypertensive rats, angiotensin-converting enzyme inhibitors prevent impairment of endothelial-dependent relaxation of arterial rings in response to acetylcholine; in dogs, intracoronary infusion of an angiotensin-converting enzyme inhibitor dilates epicardial arteries and enhances coronary blood flow. In hypertensive patients with normal coronary arteries, intravenous administration of the angiotensin-converting enzyme inhibitor perindoprilat changes constriction of coronary arteries to dilation in response to the cold pressor test, and the absence of flow-dependent dilation becomes a normal response. In addition, maximal coronary blood flow induced by papaverine is enhanced by angiotensin-converting enzyme inhibition and minimal coronary resistance is reduced. It is concluded that both animal and human studies have demonstrated that angiotensin-converting enzyme inhibitors may acutely reverse the abnormalities of coronary vasomotion in arterial hypertension. However, not all the mechanisms responsible are fully understood and further studies are needed, particularly to determine the exact role of nitric oxide, bradykinin and oxygen-derived free radicals.
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BACKGROUND: In heart transplants, left ventricular function may be impaired in the absence of rejection or graft atherosclerosis. Matching between left ventricle and arterial receptor, i.e., ventriculoarterial coupling, and left ventricular efficiency have never been studied. METHODS: Left ventricular pressure-volume loops and single beat analysis were used to determine effective arterial elastance (Ea) and the slope of the end-systolic pressure-volume relation (end-systolic elastance; Ees). Left ventricular efficiency was evaluated by determination of external work (EW), pressure-volume area (PVA), coronary blood flow (continuous thermodilution), and myocardial oxygen consumption (MVO2). Measurements were made at baseline in 11 control subjects and 9 heart transplant recipients (HTX) without rejection and were repeated after phenylephrine in the latter group. RESULTS: At baseline, Ees, Ees/Ea, and work efficiency (EW/PVA) were lower in HTX than in control subjects (2.51+/-0.87 vs. 3.70+/-1.15 mmHg/ml/m2, P<0.01; 0.96+/-0.21 vs. 1.47+/-0.31, P<0.001; and 0.53+/-0.08 vs. 0.59+/-0.09, P<0.01, respectively). Energy conversion efficiency (PVA/MVO2) and mechanical efficiency (EW/ MVO2) were higher in HTX (0.58+/-0.08 vs. 0.45+/-0.14, P<0.001; and 0.31+/-0.05 vs. 0.26+/-0.06, P<0.001, respectively). In HTX, phenylephrine infusion increased Ees, Ea, EW, PVA, and MVO2 without modifying Ees/Ea, EW/PVA, PVA/MVO2, and EW/MVO2. CONCLUSIONS: In heart transplants, (1) left ventricular contractility is moderately depressed; (2) elevation of energy conversion efficiency compensates for the decrease in work efficiency, allowing normal mechanical efficiency; and (3) alpha 1 adrenergic stimulation does not impair ventriculoarterial coupling and mechanical efficiency.
Seven normotensive untreated patients with obstructive sleep apnea (OSA) and five control subjects without OSA were compared. Patients with cardiac dilation, chronic airflow limitation, liver and kidney disease, or diabetes mellitus were excluded. Change in pressure-heart rate relation to alpha-adrenergic stimulation (P-HRR), extracellular volume (ECV), and plasma volume (Vp) were measured during daytime. Plasma atrial natriuretic peptide (ANP), plasma renin and aldosterone concentrations were obtained at 1 hour intervals during the night. A mean apnea/hypopnea index (AHI) of 52.2 +/- 23.9/h and a mean lowest arterial oxygen saturation (SaO2) of 61.2 +/- 19.3% (mean +/- SD) were determined from polysomnographic monitoring in the patient group. Release of ANP was significantly higher during sleep in OSA patients than in control subjects (P < .01), with a maximum concentration between 4 and 6 AM in the former. Daytime ECV was significantly higher (P < .05) and Vp significantly lower (P < .05) in OSA patients. Night maximum concentration of ANP (max ANP) was negatively related to AHI (P < .05). P-HRR was negatively related to AHI (P < .05) and positively related to max ANP (P < .05). In conclusion, OSA syndrome alters hormonal system control of body fluid compartment regulation. The decreased response in night max ANP secretion in the most severe OSA patients could be explained by the smaller Vp observed in these patients, decreasing atrial and ventricular pressure loading. Furthermore, alteration of P-HRR, correlated to AHI and max ANP, strengthens the hypothesis that patients who develop hypertension are those in whom the protective mechanism of ANP release failed.