N-terminal pro-B-type natriuretic peptide: an independent marker for coronary artery disease in asymptomatic diabetic patients.

AIMS: To determine whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, a marker for cardiac failure and potentially for the severity of coronary artery disease (CAD), predicts silent myocardial ischaemia (SMI) and silent CAD in asymptomatic high-risk diabetic patients. METHODS: Five hundred and seventeen asymptomatic diabetic patients with > or = 1 additional cardiovascular risk factor but without heart failure were prospectively screened between 1998 and 2008 for SMI, defined as an abnormal stress myocardial scintigraphy, and subsequently for significant (> 70%) angiographic CAD. The 323 patients with interpretable echocardiography and for whom NT-proBNP was measured were included in this analysis. RESULTS: SMI was found in 108 (33.4%) patients, 39 of whom had CAD. NT-proBNP was higher in the patients with CAD than in the patients without CAD [45.0 (1-3199) vs. 20.0 (1-1640) pg/ml; P < 0.0001 median (range)], even after adjustment for confounding factors: age, gender, body mass index, glycated haemoglobin (HbA(1c)), retinopathy, nephropathy, hypertension, echocardiographic parameters (P < 0.05). NT-proBNP in the third tertile (> or = 38 pg/ml) predicted CAD with a sensitivity of 59% and a specificity of 67%. In a multiple logistic regression analysis including NT-proBNP > or = 38 pg/ml, age, body mass index, gender, HbA(1c), hypertension, retinopathy, nephropathy, peripheral occlusive arterial disease, left ventricular systolic dysfunction, dilatation and hypertrophy and Type 1 transmitral flow, NT-proBNP > or = 38 pg/ml was the only significant independent predictor of silent CAD [odds ratio (OR) 3.1 (95% confidence interval 1.3-7.6), P = 0.015]. CONCLUSIONS: NT-proBNP measurement helps to better define asymptomatic diabetic patients with an increased likelihood for CAD, independently of cardiac function and structure.

[Microalbuminuria and urinary albumin excretion: French guidelines]. / Microalbuminurie et excrétion urinaire d'albumine: recommandations pour la pratique clinique.

UNLABELLED: Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hour-urine sample. Values defining microalbuminuria are: - 24-hour urine sample: 30-300 mg/24 hours - Morning urine sample: 20-200 mg/mL or 30-300 mg/g creatinine or 2.5-25 mg/mmol creatinine (men) or 3.5-35 mg/mol (women). - Timed urine sample: 20-200 mug/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans. In diabetic subjects, microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is also a marker of CV and renal risk in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. In non-diabetic subjects, microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of the renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence or elevation of UAE overtime is associated with deleterious outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive subjects with 1 or 2 CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic, non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome as it is in diabetic or hypertensive subjects. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is annually recommended in all subjects with microalbuminuria. MANAGEMENT: in patients with microalbuminuria, weight reduction, sodium restriction (< 6 g/day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of ACEI or ARB are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non-diabetic subjects, any of the five classes of anti-hypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or beta-blockers) can be used.

Microalbuminuria and urinary albumin excretion: French clinical practice guidelines.

Urinary albumin excretion (UAE) may be assayed on a morning urinary sample or a 24 h-urine sample. Values defining microalbuminuria are: 1) 24-h urine sample: 30-300 mg/24 h; 2) morning urine sample: 20-200 mg/ml or 30-300 mg/g creatinine or 2.5-25 mg/mmol creatinine (men) or 3.5-35 mg/mmol (women); 3) timed urine sample: 20-200 mug/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been obtained in humans. IN DIABETIC SUBJECTS: Microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is associated with greater CV and renal risks in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. IN NON-DIABETIC SUBJECTS: Microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence of elevated UAE during follow-up is associated with poor outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive medium-risk subjects with 1 or 2 CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is recommended annually in all subjects with microalbuminuria. MANAGEMENT: In patients with microalbuminuria, weight reduction, sodium restriction (<6 g per day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non-diabetic subjects, any of the five classes of anti-hypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or beta-blockers) can be used.

Postprandial endothelial dysfunction: role of glucose, lipids and insulin.

Endothelium plays a key role in the regulation of vascular tone and development of atherosclerosis. Endothelial function is impaired early in patients with risk factors and endothelial dysfunction is a strong and independent predictor of cardiovascular events. Because in normal subjects blood concentrations of glucose, lipids and insulin are increased after each meals, and postprandial changes last a long time after the meals, these changes might be of importance in the process of atherosclerosis initiation and development. Experimental and human studies have shown that a transient increase of blood concentrations of glucose, triglycerides and fatty acids, and insulin are able to depress endothelium-dependent vasodilation in healthy subjects and that hyperglycemia, hypertriglyceridemia and hyperinsulinemia are generator of reactive oxygen species at the origin of a cascade of pathophysiological events resulting in the activation of nuclear factor-kappaB. Nuclear factor-kappaB is an ubiquitous transcription factor controlling the expression of numerous genes and is involved in immunity, inflammation, regulation of cell proliferation and growth and apoptosis. These mechanisms may be involved in the development of atherosclerosis in normal subjects when food intake is chronically modified towards glucids and lipids with cumulative effects both on depression of endothelium dependent dilation and oxidative stress.

[Hypertension, endothelial dysfunction and cardiovascular risk]. / Hypertension artérielle, dysfonction endothéliale et risque cardiovasculaire.

Increased blood pressure induces functional and structural changes of the vascular endothelium. Depression of endothelium-dependant vasodilatation is an early manifestation of endothelial dysfunction due to hypertension. It can be demonstrated by pharmacological or physiological tests. Decreased availability of nitric oxide (NO) is a major determinant of the depression of vasodilatation. It may be caused by a reduction in the activity of NO-endothelial synthase (NOSe) related to: 1) a deficit in substrate (L-arginine), 2) an inhibition by asymmetrical dimethylarginine, 3) a deficit in the cofactor tetrahydrobiopterin (BH4). However, the increase in oxidative stress, a producer of superoxide radicals which combine with NO to form peroxynitrates (ONOO-), is the determining factor. It is related to activation of membranous NAD(P)H oxidases initiated by the stimulation of activating mecanosensors of protein C kinase. The message is amplified by oxidation of BH4 which transforms the NOSe into a producer of superoxide radicals. A cascade of auto-amplification loops leading to atherosclerosis and its complications is then triggered. The superoxide radicals and the peroxynitrates oxidise the LDL-cholesterol. They activate the nuclear factor-kappaB which controls the genes stimulating the expression of many proteins: angiotensinogen and AT1 receptors which stimulate the sympathetic system, receptors of oxidised LDL, adhesion and migration factors (ICAM-1, VCAM-1, E-selectin and MCP-1), pro-inflammatory cytokins (interleukines and TNF-alpha), growth factors (MAP kinases), plasminogen activator inhibitor 1. The monocytes and smooth muscle cells produce metalloproteinases and pro-inflammatory cytokins which destabilise the atheromatous plaque and favourise vascular remodelling. Inshort, the endothelial dysfunction due to hypertension plays a role in a complex physiopathological process and is a marker of future cardiovascular events.

Impairment of coronary vascular reserve and ACh-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function.

Evidence is increasing for small-vessel disease and disturbance of endothelium-dependent vasodilation in diabetic patients. The aim of this study was to compare coronary circulation in 11 diabetic patients (6 type I and 5 type II) and 7 control subjects. All patients had normal left ventricular systolic function and angiographically normal coronary arteries. To evaluate the maximal area of coronary microcirculation, coronary vascular reserve was determined by intracoronary Doppler and a maximally vasodilating dose of intracoronary papaverine (peak-to-resting coronary flow velocity ratio). To assess coronary endothelial function responses to stepwise intracoronary infusion of acetylcholine (10(-8) to 10(-5) M coronary estimated concentrations) were analyzed on four different segments in each patient by quantitative angiography. Peak-to-resting coronary flow velocity ratio was lower in diabetic patients than in control subjects (3.9 +/- 0.9 and 5.0 +/- 0.7, respectively, P < 0.02). Acetylcholine did not produce any diameter change at 10(-8) and 10(-7) M, but a progressive diameter reduction was observed at 10(-6) and 10(-5) M (-8.0 +/- 15.2%, P < 0.02 and -24.0 +/- 13.6%, P < 0.001, respectively). In control subjects, a progressive diameter dilation was produced from 10(-8) to 10(-6) M acetylcholine (5.1 +/- 3.4, 12.1 +/- 7.0, and 16.4 +/- 7.3%, respectively, all P < 0.001), and a moderate reduction was observed at 10(-5) M (-4.9 +/- 7.5%, P < 0.02). In the two groups, all segments dilated similarly after intracoronary isosorbide dinitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Impairment of coronary microvascular dilation in response to cold pressor--induced sympathetic stimulation in type 2 diabetic patients with abnormal stress thallium imaging.

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.

Epicardial coronary arteries are not adequately sized in hypertensive patients.

OBJECTIVES: This study sought to compare coronary artery dimensions in hypertensive patients and normal subjects. BACKGROUND: Myocardial 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. METHODS: Left 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. RESULTS: Despite 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). CONCLUSIONS: Despite 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.

Size dependence of the end-systolic stress/volume ratio in humans: implications for the evaluation of myocardial contractile performance in pressure and volume overload.

The end-systolic stress/volume ratio is currently recognized as a relatively load-independent index of myocardial contractile performance, but its dependence on ventricular size may limit its value for interpatient comparisons. In this study, the relation between the end-systolic stress/volume ratio and left ventricular end-diastolic volume was angiographically analyzed in 104 patients with normal coronary angiograms. Eighteen patients had a normal ventricle, 24 had aortic stenosis, 18 had aortic regurgitation, 9 had mitral regurgitation and 35 had cardiomyopathy. An inverse relation between the end-systolic stress/volume ratio and left ventricular end-diastolic volume was demonstrated in the normal group (r = 0.72, p less than 0.001); subjects with a larger left ventricle had a reduced index but, presumably, the same degree of contractility as that of subjects with a smaller ventricle. Attempts to normalize values by using end-diastolic volume or body surface area were unsuccessful. A similar inverse relation was demonstrated in the aortic stenosis group (r = 0.48, p less than 0.05), probably because hypertrophy helps to keep wall stress normal or low despite progressive ventricular enlargement in these patients. The end-systolic stress/volume ratio was also inversely related to left ventricular chamber size in patients with volume overload due to aortic regurgitation (r = 0.80, p less than 0.001) and in those with cardiomyopathy (r = 0.84, p less than 0.001). However, at a given left ventricular end-diastolic volume, the end-systolic stress/volume ratio was higher in patients with aortic regurgitation than in those with cardiomyopathy, suggesting better contractile performance for a comparable degree of ventricular dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Doppler echocardiographic measurement of mitral flow volume: validation of a new method in adult patients.

Instantaneous intracardiac flow volumes can be calculated as the product of instantaneous flow velocity and instantaneous orifice area. This was accounted for in a new method of measuring stroke volume and cardiac output in the mitral orifice by pulsed Doppler echocardiography. This method was compared with simultaneous thermodilution in 30 adult patients in sinus rhythm without substantial atrioventricular or pulmonary valve abnormalities. The mitral orifice was assimilated to a conduit with 1) an ellipse-shaped inlet and outlet, 2) the same (and constant) long axis for the inlet and outlet ellipses (that is, the mediolateral anulus diameter measured on apical four chamber views), and 3) a varying outlet short axis (that is, the mitral anteroposterior leaflet separation derived from left parasternal M-mode recordings). This method design avoided the need for a short-axis view of the whole circumference of the mitral outlet orifice, which is difficult to obtain in many adult patients. The mitral flow velocity was recorded from the apex under two-dimensional guidance, within the mitral canal, close to the outlet section. Integration of instantaneous mitral leaflet separation multiplied by instantaneous flow velocity was performed using Simpson's rule. In addition to the proposed "instantaneous orifice area" method (method A), a "mean orifice area" method (method B) was also compared with thermodilution. In this simplified method, mitral flow was the product of mean orifice area and the diastolic mitral velocity integral, both derived from the same recordings as for method A.(ABSTRACT TRUNCATED AT 250 WORDS)

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

OBJECTIVES: This study was initiated to compare the coronary reserve in treated hypertensive patients with and without left ventricular hypertrophy with that in untreated patients. BACKGROUND: Coronary 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. METHODS: Coronary 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. RESULTS: Coronary 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). CONCLUSIONS: The 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.

Acetylcholine-induced constriction of angiographically normal coronary arteries is not time dependent in transplant recipients. Effects of stepwise infusion at 1, 6, 12 and more than 24 months after transplantation.

OBJECTIVES: The aim of this study was to evaluate whether acetylcholine may be a useful tool for detection of early angiographically undetectable coronary atherosclerosis in heart transplant recipients. BACKGROUND: Coronary artery disease is the main determinant of long-term prognosis in transplant recipients. Acetylcholine-induced constriction of angiographically normal coronary arteries in heart transplant recipients could be due to early atherosclerosis, and acetylcholine has been proposed for early detection of coronary artery disease. METHODS: The responses of large coronary arteries to stepwise intracoronary infusion of acetylcholine (10(-8) to 10(-5) mol/liter) were compared in five control subjects and in four groups of transplant recipients 1, 6, 12 and > 24 months postoperatively (group 1, n = 6; group 2, n = 7; group 3, n = 6; group 4, n = 6, respectively). All patients had normal coronary arteriographic findings. Vessel dimensions were measured in four segments in each patient. RESULTS: In control subjects, acetylcholine increased diameters significantly at 10(-8), 10(-7) and 10(-6) mol/liter (all p < 0.001 vs. basal value). No significant variation was observed at 10(-5) mol/liter. Intracoronary isosorbide dinitrate increased diameters of all segments (p < 0.001). In transplant recipients, vessel diameters did not vary significantly from baseline at 10(-8) and 10(-7) mol/liter concentrations in groups 1 and 3 and at 10(-8) mol/liter in group 4. Vessels constricted significantly in all the other cases. Comparisons of each group with control subjects showed that responses were significantly different for all concentrations but 10(-8) mol/liter in groups 3 and 4. Intracoronary isosorbide dinitrate elicited coronary vasodilation similar to that of control subjects in all groups of transplant recipients. CONCLUSIONS: This study indicates that the acetylcholine response is persistently abnormal in transplant recipients compared with that in normal control subjects and that this abnormality may not be related simply to the presence of atherosclerosis. Thus, acetylcholine may not be a useful tool for early detection of coronary atherosclerosis in heart transplant recipients.

Coronary artery response to cold-pressor test is impaired early after operation in heart transplant recipients.

OBJECTIVES: The aim of the present study was to evaluate the coronary vasomotor response to the cold-pressor test within 3 months after heart transplantation. BACKGROUND: Normal epicardial coronary arteries dilate in response to sympathetic stimulation evoked by the cold-pressor test. In transplant recipients, abnormal coronary vasomotion has been described shortly after operation. METHODS: Fourteen heart transplant recipients were compared 52 +/- 15 days (mean +/- SD) after operation with 10 control subjects. All had angiographically normal epicardial coronary arteries. Coronary blood flow velocity was measured with a Doppler catheter placed in the proximal left anterior descending coronary artery. Four segments in each patient were analyzed by quantitative coronary angiography to assess the diameter changes during the cold-pressor test and after intracoronary injection of isosorbide dinitrate. RESULTS: Coronary flow velocity increased similarly during the cold-pressor test in control subjects and in transplant recipients, from 7.5 +/- 2.3 to 11.0 +/- 3.9 cm/s and from 10.3 +/- 3.2 to 13.7 +/- 4.8 cm/s (both p < 0.01). In control subjects, 39 of 40 segments analyzed dilated during the cold-pressor test. In transplant recipients, 48 of 56 segments analyzed did not change or constricted. The mean epicardial coronary diameter increased significantly during the cold-pressor test in control subjects (+13 +/- 6%, p < 0.001), whereas it did not change significantly in transplant recipients (-2 +/- 9%, p = NS). In transplant recipients, isosorbide dinitrate elicited coronary vasodilation similar to that in control subjects. CONCLUSIONS: These data indicate that in human transplanted denervated hearts, coronary vasodilation in response to sympathetic stimulation by cold exposure is impaired shortly after operation.

Effects of time and previous acute rejection episodes on coronary vascular reserve in human heart transplant recipients.

OBJECTIVES: This study examined whether previous rejection episodes may have deleterious effects on coronary vascular reserve of heart transplant recipients months after transplantation. BACKGROUND: Coronary reserve has been demonstrated to be within the normal range in long-term transplant patients without previous episodes of rejection. Conversely, acute rejection is associated with a dramatic reduction of coronary reserve, which is rapidly restored after therapy. METHODS: Coronary flow velocity was measured by intracoronary Doppler catheter before and after a maximally vasodilating dose of intracoronary papaverine in 16 control subjects and in 59 transplant patients classified into three groups with respect to time after transplantation: 1 to 6 months (group 1, n = 17), 7 to 18 months (group 2, n = 22) and > 18 months (group 3, n = 20). Coronary vascular reserve was evaluated through peak/rest coronary flow velocity ratio and minimal coronary vascular resistance index. All patients had normal findings on left ventricular angiography and coronary arteriography and a normal left ventricular mass. RESULTS: Arterial pressure was normal in all groups. Heart rate in the three groups of transplant patients, mean aortic pressure in groups 1 and 2, left ventricular systolic pressure in group 2 and rate-pressure product in groups 1 and 2 were higher than in control subjects. Average number of rejection episodes per patient was similar in the three groups of patients (group 1, 2.4 +/- 1.4; group 2, 2.5 +/- 1.9, and group 3, 2.1 +/- 1.3). Results showed no difference between each group of transplant patients and control subjects for peak/rest coronary flow velocity ratio (control subjects, 5.2 +/- 0.8; group 1, 5.3 +/- 1.5; group 2, 4.9 +/- 1.2, and group 3, 4.4 +/- 1.6) and for minimal coronary vascular resistance index (control subjects, 0.18 +/- 0.03; group 1, 0.18 +/- 0.04; group 2, 0.20 +/- 0.06, group 3, 0.23 +/- 0.11). In addition, patients with zero or one rejection episode had similar values of peak/rest coronary flow velocity ratio and minimal coronary vascular resistance index (4.3 +/- 1.3 and 0.23 +/- 0.10, respectively, n = 22) as did those with one or two rejection episodes (5.1 +/- 1.5 and 0.19 +/- 0.07, respectively, n = 24), and those with four or more episodes (5.2 +/- 1.4 and 0.19 +/- 0.05, respectively, n = 13). CONCLUSIONS: This study showed that coronary vascular reserve remains within normal range and is independent from the number of previous episodes of rejection until late after transplantation in human heart transplant patients with angiographically normal coronary arteries.

[Endothelial dysfunction in patients with diabetes: identification, pathogenesis and treatment]. / Dysfonction endothéliale chez les patients diabétiques. Mise en évidence, potentiel pathogène, quels traitements?

Cardiovascular diseases are the leading cause of morbidity and mortality in people with diabetes. Vascular abnormalities can be observed long before atherosclerosis develops and in sites not usually prone to atherosclerosis. These vascular abnormalities are known to be due to endothelial dysfunctions, one of the most frequent of which is depressed endothelium-dependent dilation. In patients with diabetes, this is mainly linked to decreased bioavailability of nitric oxide. Although inactivation of tetrahydrobiopterin, a co-factor of NO-synthase, may depress nitric oxide production, the latter is more likely due to the inactivation of nitric oxide by superoxide anions: enhanced oxidative stress increases their production in people with diabetes. Moreover, hyperglycemia directly activates oxidative stress, which in turn depresses endothelium-dependent vasodilation. Glycemia and oxidative stress are positively correlated in people with diabetes. However, while depression of endothelium-dependent dilation may be a visible functional manifestation of oxidative stress, the oxidative stress itself is mainly responsible for the cascade of endothelial events that play a key role in development of vascular atherosclerosis and its complications. Especially important among these events are the activation of NF-kappaB and the oxidation of LDL-cholesterol. Although antioxidants provide short-term improvement of endothelial function in humans, all studies of the effectiveness of preventive antioxidant therapy have been disappointing. Control of hyperglycemia thus remains the best way to improve endothelial function and to prevent atherosclerosis and other cardiovascular complications of diabetes.

Coronary artery constriction caused by the cold pressor test in human hypertension.

Hypertensive patients with angiographically normal coronary arteries may have myocardial ischemia when metabolic demand increases. Abnormal epicardial coronary artery vasomotion in response to sympathetic stimulation may contribute to ischemia in such patients. We studied the vasomotor response of smooth coronary arteries to a cold pressor test in 10 hypertensive patients without other risk factors and in 9 control subjects. Vessel dimensions were measured by quantitative angiography, and blood flow was calculated using an intracoronary Doppler catheter in the left anterior descending coronary artery. In response to cold pressor stimulation, arteries of control subjects dilated 13.0 +/- 5.9% (P < .001), and they constricted 8.2 +/- 8.5% in hypertensive patients (P < .001). Rate-pressure product increased from 9466 +/- 1677 to 12,547 +/- 2367 beats per minute (bpm).mm Hg in control subjects (P < .001) and from 13,720 +/- 1823 to 17,353 +/- 2037 bpm.mm Hg in hypertensive patients (P < .001). Coronary blood flow velocity and blood flow increased 51 +/- 26% (P < .05) and 87 +/- 27% (P < .001), respectively, in control subjects and 68 +/- 52% (P < .05) and 36 +/- 33% (P < .01) in hypertensive patients. At peak cold pressor test, despite a significant higher rate-pressure product in hypertensive patients, blood flow was similar in both groups, suggesting an uncoupling between myocardial metabolic demand and supply. Thus, hypertension impairs the vasodilator response of angiographically normal coronary arteries to a cold pressor test. This abnormal response may be due to enhanced catecholamine reactivity and/or impairment of endothelial flow-mediated vasodilator response.

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

PURPOSE: Cigarette 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. SUBJECTS AND METHODS: Responses 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. RESULTS: In 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. CONCLUSION: The 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.

Reversibility by dipyridamole of thallium-201 myocardial scan defects in patients with sarcoidosis.

PURPOSE: In order to clarify the significance of anginal pain and myocardial thallium-201 scan defects in cardiac sarcoidosis, the pharmacologic effect of dipyridamole on myocardial perfusion was assessed by planar thallium-201 myocardial scintigraphy in patients with sarcoidosis. PATIENTS AND METHODS: Thallium-201 myocardial scintigraphy was performed at rest and after 0.56 mg/kg intravenous dipyridamole during four minutes in 16 patients with sarcoidosis. The myocardial scan (45-degree and 70-degree left anterior oblique, and anterior views) was divided into 15 segments. Results were evaluated by the number of segmental defects and with a global perfusion score (from 0 to 60) by a semi-quantitative index depending on the size and severity of myocardial thallium-201 defects. RESULTS: Thirteen of the 16 patients showed partial or total reversion of their thallium-201 defects on redistribution scanning either at rest or after dipyridamole. The mean (+/- SD) number of myocardial perfusion defects that were present in all the patients decreased from 5.31 +/- 1.78 at rest to 3.25 +/- 2.52 after redistribution (p less than 0.001) and to 2.19 +/- 2.10 after dipyridamole (p less than 0.001). The mean global perfusion score increased from 53.2 +/- 3.0 at rest to 56.2 +/- 2.9 after redistribution (p less than 0.001) and to 57.2 +/- 2.7 after dipyridamole (p less than 0.001). A significant correlation (r = 0.82, p less than 0.001) was found between the increase of global perfusion score on redistribution and after dipyridamole. CONCLUSION: The reversibility of myocardial scan defects is a common finding in sarcoidosis. It makes unlikely the role of scar fibrosis or extensive confluent granulomas as a mechanism for such defects. The effect of dipyridamole suggests the presence of reversible disorders lying at the coronary microvascular level.

Ventriculoarterial coupling and left ventricular efficiency in heart transplant recipients.

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.