Philippe Unger

Exercise stress echocardiography for the study of the pulmonary circulation.

Exercise stress tests have been used for the diagnosis of pulmonary hypertension, but with variable protocols and uncertain limits of normal. The pulmonary haemodynamic response to progressively increased workload and recovery was investigated by Doppler echocardiography in 25 healthy volunteers aged 19–62 yrs (mean 36 yrs). Mean pulmonary artery pressure (P̄pa) was estimated from the maximum velocity of tricuspid regurgitation. Cardiac output (Q) was calculated from the aortic velocity-time integral. Slopes and extrapolated pressure intercepts of P̄pa–Q plots were calculated after using the adjustment of Poon for individual variability. A pulmonary vascular distensibility α was calculated from each P̄pa–Q plot to estimate compliance. P̄pa increased from 14±3 mmHg to 30±7 mmHg, and decreased to 19±4 mmHg after 5 min recovery. The slope of P̄pa–Q was 1.37±0.65 mmHg·min−1·L−1 with an extrapolated pressure intercept of 8.2±3.6 mmHg and an α of 0.017±0.018 mmHg−1. These results agree with those of previous invasive studies. Multipoint P̄pa–Q plots were well described by a linear approximation, from which resistance can be calulated. We conclude that exercise echocardiography of the pulmonary circulation is feasible and provides realistic resistance and compliance estimations. Measurements during recovery are unreliable because of rapid return to baseline.

Reduction of left ventricular diameter and mass after surgical arteriovenous fistula closure in renal transplant recipients.

Background. Left ventricular hypertrophy and dilatation is a frequent finding in kidney transplant recipients, which may be favored by the persistent patency of arteriovenous fistula. The purpose of the current study was to prospectively investigate whether surgical closure of the fistula allows reduction of abnormalities of left ventricular morphology in stable renal transplant patients. Furthermore, we studied the ability of preoperative echocardiographic and noninvasive hemodynamic measurements, including the effects of a temporary occlusion of the fistula, to predict postoperative left ventricular diameter and mass reduction. Methods. Seventeen kidney transplant recipients referred for surgical arteriovenous fistula closure were prospectively studied. Standard echocardiographic parameters, heart rate, and blood pressure were assessed preoperatively at baseline and during an acute pneumatic fistula occlusion. These measurements were repeated 3 to 10 weeks after surgical closure. Six kidney transplant recipients with patent arteriovenous fistulas referred for routine echocardiographic follow-up served as a control group. Results. Surgical fistula closure decreased left ventricular end-diastolic diameter and mass indexes (29.9±2.4 to 27.4±2.1 mm/m2, P <0.001, and 141±37 to 132±39 g/m2, P <0.05, respectively), whereas no changes were seen in controls after a similar delay. Postoperative left ventricular end-diastolic diameter and mass reductions correlated best with the increases in total peripheral resistance (r =0.85, P <0.0001) and mean arterial blood pressure (r =0.64, P =0.006) during pneumatic occlusion, respectively. Conclusions. Surgical closure of arteriovenous fistula reduces left ventricular diameter and mass in kidney transplant recipients. Increases in blood pressure and total peripheral resistance induced by temporary fistula occlusion are the best predictors of these morphological changes.

Bosentan Decreases Pulmonary Vascular Resistance and Improves Exercise Capacity in Acute Hypoxia

BACKGROUND Altitude exposure is associated with mild pulmonary hypertension and decreased exercise capacity. We tested the hypothesis that pulmonary vascular resistance (PVR) contributes to decreased exercise capacity in hypoxic healthy subjects. METHODS An incremental cycle ergometer cardiopulmonary exercise test and echocardiographic estimation of pulmonary artery pressure (Ppa) and cardiac output to calculate total PVR were performed in 11 healthy volunteers in normoxia and after 1 h of hypoxic breathing (12% O(2)). The measurements were performed in a random order at 1-week intervals after the receiving either a placebo or bosentan, following a double-blind randomized crossover design. Bosentan was administered twice a day for 3 days, 62.5 mg on the first day and 125 mg on the next 2 days. RESULTS Hypoxic breathing decreased the mean (+/- SE) pulse oximetric saturation (Spo(2)) from 99 +/- 1% to 3 +/- 1% and increased the mean PVR from 5.6 +/- 0.3 to 7.2 +/- 0.5 mm Hg/L/min/m(2), together with a decrease in mean maximum O(2) uptake (Vo(2)max) from 47 +/- 2 to 35 +/- 2 mL/kg/min. Bosentan had no effect on normoxic measurements and did not affect hypoxic Spo(2), but decreased PVR to 5.6 +/- 0.3 mm Hg/L/min/m(2) (p < 0.01) and increased Vo(2)max to 39 +/- 2 mL/kg/min (p < 0.01) in hypoxia. Bosentan therapy, on average, restored 30% of the hypoxia-induced decrease in Vo(2)max. Bosentan-induced changes in Ppa and Vo(2)max were correlated (p = 0.01). CONCLUSIONS We conclude that hypoxic pulmonary hypertension partially limits exercise capacity in healthy subjects, and that bosentan therapy can prevent it.

Myocardial homing and coronary endothelial function after autologous blood CD34+ progenitor cells intracoronary injection in the chronic phase of myocardial infarction.

Transcoronary transplantation of progenitor cells has been proposed as a novel therapy for ischemic heart failure. The primary aims were to assess the feasibility of obtaining CD34+ cells from blood without mobilization in chronic conditions and to compare homing with results reported in acute conditions. We also evaluated the effect of CD34+ on endothelial function. In 7 patients with a history of an anterior myocardial infarction (20 ± 2 months), a large amount of CD34+ (18.2 ± 3.0 × 106) were obtained and an intracoronary infusion into the left anterior descending artery via an over-the-wire balloon catheter was performed. Myocardial homing involved 3.2% ± 0.6% of injected cells. Endothelial function studied with increasing doses of bradykinin was not significantly modified after 3 months. In the treated group, compared with 5 nonrandomized control patients with a similar clinical history, the only echocardiographic significant change (2-way analysis of variance) was a decrease in end-systolic volume (P < 0.03). In conclusion, large amounts of CD34+ cells can be obtained from blood, without mobilization, in the chronic phase of myocardial infarction. As reported in the acute situation 1 hour after treatment, intracoronary infusion of CD34+ cells results in myocardial homing of a few percents of the cells. In this small group of patients, no effect of this therapy is detected on the endothelial function and only marginal changes are observed on echocardiographic parameters.

Absence of nitrate tolerance after long-term treatment with ramipril: an endothelium-dependent mechanism.

To determine whether nitrate tolerance is attenuated on aortas isolated from rats treated in the long term with an angiotensin-converting enzyme (ACE) inhibitor, five groups of rats were studied in parallel. Group 1 received ramipril, 1 mg/ kg/day, p.o., for 6 weeks; group 2 received ramipril at the same dose for 4 weeks, and the last 2 weeks, a cotreatment with ramipril plus HOE 140 (a bradykinin B2 antagonist, 500 microg/ kg/day, s.c. injections); group 3 received losartan, 2 mg/kg/day, p.o., for 6 weeks; group 4 received losartan at the same dose, and the last 2 weeks, a cotreatment with losartan plus HOE 140; and group 5 served as control. Rings of thoracic aorta from these groups were studied in organ baths. After nitroglycerin preincubation (10 microM for 30 min) in vitro, the dose-response curves to nitroglycerin were significantly shifted to the right in the control group but not in group 1. This protective effect was partially present in group 3; it was completely abolished in groups 2 and 4. In groups 1 and 3, it also was abolished after nitric oxide synthase (cNOS) inhibition (L-NMMA incubation) or removal of the endothelium. Superoxide anion accumulation (assessed by lucigenin chemiluminescence) was increased by nitroglycerin incubation in the control group but not in groups 1 and 3. After in vivo exposure to nitroglycerin (50 mg/kg subcutaneously twice daily for 4 days), this protection against nitrate tolerance also was observed in groups 1 and 3. Thus long-term ACE inhibition prevents nitrate tolerance by an endothelium-dependent mechanism involving mainly an enhanced NO availability via B2-kinin receptor. This effect on the cNOS pathway seems to attenuate the superoxide anion accumulation induced by nitroglycerin exposure (probably via a downregulation of oxidative enzyme).

Atherosclerosis and responses of human isolated coronary arteries to endothelium-dependent and -independent vasodilators.

SUMMARY In canine and porcine coronary arteries, experimental atherosclerosis (induced by endothelial denudation followed by a high-cholesterol diet) potentiates the vasoconstrictor effects of histamine, serotonin, and ergonovine. In isolated human atherosclerotic coronary arteries, only hypersensitivity to histamine has been demonstrated. This discrepancy could be due to several factors. First, the atherosclerotic lesions in human vessels are different from those observed in the animal, since experimental atherosclerosis often corresponds only to the early stage of the disease in humans. Second, the human atherosclerotic coronary arteries were isolated mainly from patients with cardiac failure, a condition that alters the responses of coronary smooth muscle to vasoactive amines. With regard to endothelium-dependent vasodilators, marked attenuations of the relaxations to substance P. bradykinin, and the Ca2+ ionophore A23187 have been described in isolated human atherosclerotic arteries. Acetylcholine elicits variable responses in these preparations and even if the arteries are devoid of atherosclerotic lesions, it often fails to relax them. In addition to this endothelial dysfunction, severely atherosclerotic human coronary vessels exhibit a slightly decreased responsiveness to nitroglycerin and SIN-1 but not to for-skolin. Another abnormality of the smooth muscle is a marked attenuated β-adrenergic relaxation. Thus, atherosclerosis of human coronary vessels induces not only marked alterations in endothelium-dependent responses but also modifies the sensitivity to several endothelium-independent vasodilators.

Effect of atorvastatin therapy and conversion to tacrolimus on hypercholesterolemia and endothelial dysfunction after renal transplantation.

Background. Hypercholesterolemia is a frequent complication in renal transplant patients treated with cyclosporine A (CsA). Whether it is preferable to treat hypercholesterolemia with statins or to switch patients from CsA to tacrolimus (TRL) has not been investigated. Methods. Twelve CsA-treated kidney transplant recipients with hypercholesterolemia were successively crossed over from CsA alone to: CsA plus atorvastatin; TRL alone; and TRL plus atorvastatin. Total cholesterol (C), Low density lipoprotein (LDL)-C, high density lipoprotein (HDL)-C, LDL and HDL alpha-tocopherol content, lag-time of LDL oxidation, plasma levels of oxidized LDL and the percentage of small dense LDL were assayed at the end of each treatment period. Endothelial function was assessed by high resolution ultrasound measurement of flow-mediated brachial artery vasodilatation (FMD). Results. Atorvastatin therapy was more efficient in reducing total cholesterol and LDL-C levels than conversion from CsA to TRL. Combining TRL with atorvastatin further reduced LDL-C levels as compared to TRL alone, but was no more efficient than the CsA-statin combination. Neither atorvastatin therapy nor conversion to TRL significantly changed the proportion of dense LDL, lipoprotein alpha-tocopherol contents or the lag time of LDL oxidation. Addition of atorvastatin to CsA increased FMD from 4.0±1.8% to 6.5±4.0% (P<0.05 vs. CsA). Conversion from CsA to TRL caused a slight improvement in FMD (5.1±2.1%, P<0.05 vs. CsA). Adding atorvastatin to TRL had no detectable effect on FMD (5.5±2.3%, P=NS vs. TRL). Conclusions. Atorvastatin was more efficient in reducing total and LDL cholesterol levels of CsA-treated renal transplant patients than conversion to TRL and significantly improved endothelial dysfunction.

Interaction between hydralazine and nitrovasodilators in vascular smooth muscle

The combination of hydralazine and nitrates has been shown to provide long-term benefit in congestive heart failure, despite a nitrate dosage that should induce tolerance. To assess the interactions between hydralazine and nitroglycerin, aortic rings were isolated from male Wistar rats. In rings precontracted with phenylephrine, hydralazine incubation (10 μM and 0.1 mM) potentiated the responses to nitroglycerin (p < 0.05) but not to sin-1 (a direct activator of guanylate cyclase), 8-bromocyclic guanylate monophosphate, and forskolin (an adenylate cyclase activator). In similar conditions, the incubation of isoniazid (0.1 mM, used as a pyridoxal-sequestering agent without direct vasoactive properties) also potentiated the dose-response curve to nitroglycerin (p < 0.05). In aortas isolated from rats rendered nitrate tolerant in vivo (50 mg/kg subcutaneously twice daily during 4 days), hydralazine partially attenuated tolerance (p < 0.05). Our results suggest that the observed interaction between hydralazine and nitroglycerin may involve an inhibition of pyridoxal-dependent reactions, such as the catabolism of methionine and cysteine. This may enhance the availability of sulfhydryl-containing compounds, and therefore potentiate the responses to nitroglycerin.

Prevention of cyclosporine A-induced vascular toxicity by pentoxifylline.

To determine whether an in vivo treatment with pentoxifylline (PTX) can prevent the vascular toxicity of cyclosporine A (Cx), three groups of rats were studied in parallel. The first group received daily injections of Cx (20 mg/kg intramuscularly) and pentoxifylline (80 mg/kg intraperitoneally) for 7 days, the second group was treated with Cx only, and the third group served as control (vehicle treatment). Cx serum levels were similar in groups 1 and 2. In thoracic aortic rings isolated from Cx group (group 2), the concentration-response curves to phenylephrine were potentiated: there was a significant leftward shift (p < 0.001 vs. control) in the EC50 values and an increase in the maximal responses (p < 0.05). After mechanical removal of the endothelium or inhibition of endothelium-derived relaxing factor formation (incubation with NG-monomethyl-L-arginine, L-NMMA), this enhanced responsiveness to phenylephrine persisted. In preparations from the same group (group 2), the endothelium-dependent relaxations to acetylcholine (ACh) were decreased whereas the endothelium-independent relaxations to nitroprusside (NTP 0.01–10 nM) and forskolin (1 nM) were slightly attenuated but without changes in the maximal response. In the group cotreated with Cx and PTX (group 1), the responses to ACh, NTP, and forskolin were not different from controls whereas the greater responsiveness to phenylephrine was only partially attenuated. In vivo cotreatment with PTX may prevent the endothelial dysfunction and the functional changes in smooth muscle cells induced by Cx.

Endothelial function of internal mammary artery in patients with coronary artery disease and in cardiac transplant recipients

The objective of this study was to examine the endothelial function of internal mammary artery in patients with coronary artery disease and in heart transplant recipients. Therefore the response of this artery to increasing concentrations of acetylcholine (1, 10, 20 microg/min for 2.5 minutes each) was assessed in 6 patients in a control group, 16 patients with coronary artery disease (CAD group) matched for risk factors with 16 heart graft recipients (who underwent transplantation for nonischemic heart failure), and 12 patients with coronary artery disease and peripheral vascular disease (PVD group). Diameters of proximal and middle segments of internal mammary artery were measured by quantitative angiography. The responses to the first concentration of acetylcholine were attenuated in these three groups compared with the control group. At the highest concentration of acetylcholine the diameter increase was similar in the control and CAD groups, whereas the responses remained significantly impaired in the transplant and PVD groups. However, after selective infusion of L-arginine (30 mg/min for 11 minutes), the precursor of endothelium-derived nitric oxide, was performed, the responses to acetylcholine were restored in these two latter groups. Endothelin plasma levels were significantly enhanced in the PVD group, which exhibited the most severe impairment in acetylcholine-induced vasodilation. Thus some patients with CAD, mainly those with advanced atherosclerosis, and cardiac transplant recipients exhibit internal mammary artery endothelial dysfunction, and this abnormality seems reversible.