Muscle strength and body composition in adult women with Marfan syndrome.

OBJECTIVE: The purpose of this study was to assess skeletal muscle function and body composition in a group of women with Marfan syndrome compared with matched controls. METHODS: The 21 women who were receiving follow-up for Marfan syndrome at our institution, were free of major cardiovascular disease, and consented to the study performed isokinetic and isometric knee extension and flexion maximal strength tests and had their body composition evaluated using dual-energy X-ray absorptiometry (DEXA). The same assessments were done in 19 matched controls. RESULTS: A significant decrease in lean leg mass with no change in total soft-tissue leg mass was noted in the patients compared with the controls. Peak torque values for the quadriceps and hamstring muscle groups were decreased in the patients, but only quadriceps strength was significantly reduced after normalization for lean leg mass. CONCLUSION: The muscle strength reduction in Marfan patients was not fully explained by a decrease in lean leg mass, suggesting qualitative skeletal-muscle alterations related to abnormal fibrillin expression in muscle connective tissue.

Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period.

OBJECTIVE: To compare compliance with and effectiveness of adaptive servoventilation (ASV) versus continuous positive airway pressure (CPAP) in patients with the central sleep apnoea syndrome (CSA) with Cheyne-Stokes respiration (CSR) and with congestive heart failure in terms of the apnoea-hypopnoea index (AHI), quality of life, and left ventricular ejection fraction (LVEF) over six months. METHODS: 25 patients (age 28-80 years, New York Heart Association (NYHA) class II-IV) with stable congestive heart failure and CSA-CSR were randomly assigned to either CPAP or ASV. At inclusion, both groups were comparable for NYHA class, LVEF, medical treatment, body mass index, and CSA-CSR. RESULTS: Both ASV and CPAP decreased the AHI but, noticeably, only ASV completely corrected CSA-CSR, with AHI below 10/h. At three months, compliance was comparable between ASV and CPAP; however, at six months compliance with CPAP was significantly less than with ASV. At six months, the improvement in quality of life was higher with ASV and only ASV induced a significant increase in LVEF. CONCLUSION: These results suggest that patients with CSA-CSR may receive greater benefit from treatment with ASV than with CPAP.

[Compliance with and acceptability of a new electronic peak flow meter, the PiKo-1]. / Observance et acceptabilité d'un nouveau débitmètre de pointe electronique, le PiKo-1.

BACKGROUND: Monitoring airflow obstruction is an essential component of asthma management. We examined home recording of PEFR using a new electronic peak flow meter in terms of compliance and acceptability in a group of children with asthma. METHODS: Twenty three children (3 with intermittent asthma and 20 with persistent asthma) (average age 10.9 +/- 3.8 [5-18] yrs) were asked to assess their PEFR every day during a period of 5.8 +/- 1.2 [4-8] weeks and record it in a diary card. Patients were not aware that their data was also being stored on the PiKo-1. At the end of the study, the written data were compared to the stored data. A multiple choice questionnaire was given to each subjectto check the acceptability of the PiKo-1. RESULTS: 2 patients were lost to follow up. The compliance (expressed as a percent of the number of recordings that should have been made) was more that 80% for 14/21(67%) patients and less than 45% for 3/21 (14%). Compliance decreased during the study (96% in the first week, 68% during the fifth). 12% of the values were falsified. The PiKo-1 was considered to be small, attractive and useful. Some children found the mouthpiece too small. CONCLUSION: The good results for compliance that we observed might have been due to the short duration of the study. PiKo-1 was well accepted by the subjects. It will be possible to monitor PEFR and forced expiratory volume in the first second of expiration at home using this new device.

Exacerbation of sleep-apnoea related nocturnal blood-pressure fluctuations in hypertensive subjects.

Obstructive sleep apnoea syndrome (OSAS) induces marked haemodynamic fluctuations during sleep that might be deleterious to the cardiovascular system. The influence of daytime blood pressure (BP) levels and aging on short-term BP variability during sleep in OSAS patients was investigated. Twenty-nine subjects with newly-diagnosed untreated OSAS were categorised into three groups: normotensive subjects aged <50 yrs (n=10); subjects aged <50 yrs with untreated hypertension (n=8); and normotensive subjects aged >50 yrs (n=11). Beat-by-beat BP was recorded with a Finapres device during polysomnography. The average values+/-SD of apnoea-related BP elevations and the values of the frequency distribution of all BP variations during sleep were assessed to estimate short-term BP variability. Apnoea-related systolic (or diastolic) BP elevations were significantly greater in hypertensives than in normotensives aged <50 yrs (50.3+/-4.88 versus 30.7+/-2.14 mmHg, p<0.001), as was the SD of systolic (or diastolic) BP variations during sleep (19.6+/-2.22 versus 11.1+/-0.73, p<0.001). Short-term BP variability was not significantly increased in normotensive elderly patients. To conclude, the results suggested that systemic hypertension is associated with a greater exacerbation of short-term variability during sleep in obstructive sleep apnoea syndrome patients.

Arterial blood gases during exercise: validity of transcutaneous measurements.

OBJECTIVE: To investigate the validity of transcutaneous measurements of blood gas tensions for the assessment of partial arterial pressure of oxygen (PaO(2)) and carbon dioxide (PaCO(2)) during treadmill exercise. DESIGN: Experimental, self-controlled against a reference standard. SETTING: Lung function laboratory. PATIENTS: Eighty-one patients with various lung diseases. INTERVENTIONS: At rest and at symptom-limited peak exercise, puncture of the radial artery with concurrent transcutaneous measures of blood gases. MAIN OUTCOME MEASURES: Arterial blood samples were analyzed with a radiometer to measure PaO(2) and PaCO(2). A microgas apparatus was used to measure gas tensions transcutaneously. Values obtained transcutaneously (TcPO(2), TcPCO(2)) were compared with those obtained by blood sample. TcPO(2) was adjusted as close as possible to the PaO(2) obtained in the same conditions, with the correction factor of the apparatus. Values obtained transcutaneously were compared with those obtained by blood sample to establish the sensitivity and specificity of the noninvasive method. RESULTS: Mean differences +/- standard deviation between transcutaneous and arterial tension at peak exercise were 0.4 +/- 7.0mmHg and 2.1 +/- 3.3mmHg for PaO(2) and PaCO(2), respectively. The transcutaneous device enabled us to predict a decrease in PaO(2) (>or=2mmHg) from rest to exercise with a sensitivity of 92.1% and a specificity of 90% and an increase in PaCO(2) with a sensitivity of 88% and a specificity of 58.9%. CONCLUSIONS: Although transcutaneous measurement are sufficiently sensitive and specific to detect patients whose PaO(2) decreases during exercise, its precision is not sufficient for gas exchange calculations.

Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension.

Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of primary pulmonary hypertension (PPH). Here we found that PA-SMCs from patients with PPH grow faster than PA-SMCs from controls when stimulated by serotonin or serum and that these effects are due to increased expression of the serotonin transporter (5-HTT), which mediates internalization of indoleamine. In the presence of 5-HTT inhibitors, the growth stimulatory effects of serum and serotonin were markedly reduced and the difference between growth of PA-SMCs from patients and controls was no longer observed. As compared with controls, the expression of 5-HTT was increased in cultured PA-SMCs as well as in platelets and lungs from patients with PPH where it predominated in the media of thickened pulmonary arteries and in onion-bulb lesions. The L-allelic variant of the 5HTT gene promoter, which is associated with 5-HTT overexpression and increased PA-SMC growth, was present in homozygous form in 65% of patients but in only 27% of controls. We conclude that 5-HTT activity plays a key role in the pathogenesis of PA-SMC proliferation in PPH and that a 5HTT polymorphism confers susceptibility to PPH.

Adenovirus-mediated atrial natriuretic protein expression in the lung protects rats from hypoxia-induced pulmonary hypertension.

Endogenous as well as exogenous atrial natriuretic peptide (ANP) attenuates the development of chronic hypoxic pulmonary hypertension (CHPH) in rats. We built a recombinant adenovirus type 5 containing ANP cDNA under the control of the Rous sarcoma virus long terminal repeat (Ad.ANP). The efficiency of this vector in delivering the ANP gene was first examined in rat primary cultures of pulmonary vessel smooth muscle cells (SMCs) in comparison with Ad.beta GAL. Conditioned medium collected from Ad.ANP-infected cells (1000 TCID(50)/cell) contained 5 x 10(9) M immunoreactive ANP and elicited relaxation of isolated rat pulmonary arteries preconstricted with phenylepinephrine. To examine the effects of adenovirus-mediated ANP expression in the CHPH rat lung, Ad.ANP or Ad.beta GAL was administered via the tracheal route. Immunoreactive ANP was detected in bronchoalveolar fluid as early as 4 days and until 10-17 days after Ad.ANP administration (5 x 10(8) TCID(50)). Lung ANP immunostaining was mainly localized in bronchial and alveolar epithelial cells. As compared with Ad.beta GAL-treated controls, rats given Ad.ANP (5 x 10(8) TCID(50)) on the day before a 2-week exposure to hypoxia (10% O(2)) had lower values for pulmonary artery pressure (32.1 +/- 1.93 vs. 35.5 +/- 2 mmHg, p < 0.01) and Fulton's index (0.52 +/- 0.089 vs. 0.67 +/- 0.12, p < 0.001) and less severe right ventricular hypertrophy and distal vessel muscularization. These results suggest that induction of ANP expression in the lung may hold promise in the treatment of pulmonary hypertension.

Dexfenfluramine-associated changes in 5-hydroxytryptamine transporter expression and development of hypoxic pulmonary hypertension in rats.

The appetite suppressant dexfenfluramine, which inhibits neuronal 5-HT uptake and elevates plasma 5-HT levels, has been associated with an increase in the relative risk of developing primary pulmonary hypertension. 5-HT is a mitogen for pulmonary artery smooth muscle cells (PA-SMCs), an effect that depends upon activity of the 5-HT transporter (5-HTT). To investigate the relationship between dexfenfluramine and pulmonary hypertension, we examined 1) the effect of dexfenfluramine on 5-HT uptake by PA-SMCs and the mitogenic response of these cells to 5-HT, and 2) 5-HTT mRNA in lung tissue from normoxic and chronically hypoxic rats during and at discontinuation of a 4-week dexfenfluramine treatment (2 mg/kg/day). In cultured PA-SMCs, dexfenfluramine (10(-6) M) markedly reduced [3H]5-HT uptake and [3H]thymidine incorporation in response to 5-HT (10(-6) M). In lungs from rats exposed to 4-week hypoxia (10% O(2)), 5-HTT mRNA levels were higher than in normoxic rats (233.5 +/- 22.5 versus 121.8 +/- 4.8 amol/mg of RNA, P < 0.05), but were not affected by concomitant treatment with dexfenfluramine. One week after discontinuation of dexfenfluramine, 5-HTT mRNA levels increased substantially, this effect being additive with that of hypoxia (364.0 +/- 13.1 in hypoxic versus 164.2 +/- 10 amol/mg of RNA in normoxic rats). When exposure to 2 weeks of hypoxia followed discontinuation of a 4-week treatment, right ventricular hypertrophy was more severe and muscularization of distal pulmonary arteries more marked (P < 0.01) than in rats pretreated with the vehicle. These data show that, in rats, the increased 5-HTT expression that follows dexfenfluramine discontinuation promotes the development of hypoxic pulmonary hypertension.

Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats.

Chronic hypoxic pulmonary hypertension (PH) is associated with vasoconstriction and structural remodeling of pulmonary vessels including narrowing of the arterial lumen and loss of distal functional arteries. To test whether lung overexpression of the angiogenic factor vascular endothelial growth factor (VEGF) is beneficial in hypoxic PH, recombinant adenovirus encoding the human VEGF 165 gene under the control of a cytomegalovirus promoter (Ad. VEGF) or control vector containing no gene in the expression cassette (Ad.Null) was administered intratracheally to rats. With Ad. VEGF (10(8) plaque-forming units [pfu]), VEGF protein was present in bronchoalveolar lavage fluid as early as 2 d and until 17 d after gene transfer, but was not detected in serum. Only small patchy areas of mononuclear cells without cell damage, edema, or hemorrhage were observed on lung histology with no significant change in lung permeability. In rats pretreated with Ad.VEGF (10(8) pfu) 2 d before a 2-wk exposure to hypoxia (10% O(2)), lower values versus Ad. Null-pretreated controls were found for pulmonary artery pressure (25 +/- 1 versus 30 +/- 2 mm Hg, P < 0.05), right ventricular over left ventricular-plus-septum weight (0.37 +/- 0.01 versus 0.47 +/- 0. 02, P < 0.001), normalized wall thickness of 50- to 200-microm vessels (P < 0.001), and muscularization of distal vessels (P < 0. 001). Pretreatment with Ad.VEGF (10(8) pfu) increased endothelial nitric oxide synthase activity in lung tissue and partially restored endothelium-dependent vasodilation in isolated lungs from chronically hypoxic rats, as assessed by improvement of ionophore A23187-induced vasodilation and attenuation of endothelin-1 (300 pmol)-induced vasoconstriction, an effect abolished in the presence of nitro-L-arginine methylester. We conclude that adenoviral-mediated VEGF overexpression in the lungs attenuates development of hypoxic PH, in part by protecting endothelium-dependent function.

Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats.

Chronic hypoxic pulmonary hypertension (PH) results from persistent vasoconstriction, excess muscularization, and extracellular matrix remodeling of pulmonary arteries. The matrix metalloproteinases (MMPs) are a family of proteinases implicated in extracellular matrix turnover and hence in smooth muscle and endothelial cell migration and proliferation. Because MMP expression and activity are increased in PH, we designed the present study to investigate whether inhibition of lung MMPs in rats subjected to chronic hypoxia (CH) contributes to or protects against vascular remodeling and PH. To achieve lung MMP inhibition, rats exposed to 10% O(2) for 15 days were treated with either doxycycline (20 mg/kg per day by gavage starting 2 days before and continuing throughout the CH period) or a single dose of recombinant adenovirus (Ad) for the human tissue inhibitors of metalloproteinases-1 (hTIMP-1) gene (Ad.hTIMP-1, 10(8) plaque-forming units given intratracheally 2 days before CH initiation). Control groups either received no treatment or were treated with an adenovirus containing no gene in the expression cassette (Ad.Null). Efficacy of hTIMP-1 gene transfer was assessed both by ELISA on bronchoalveolar lavages and by hTIMP-1 immunofluorescence on lung sections. MMP inhibition in lungs was evaluated by in situ zymography and gelatinolytic activity assessment using [(3)H]gelatin. Rats treated with either doxycycline or Ad.hTIMP-1 had higher pulmonary artery pressure and right heart ventricular hypertrophy more severe than their respective controls. Worsening of PH was associated with increased muscularization and periadventitial collagen accumulation in distal arteries. In conclusion, our study provides compelling evidence that MMPs play a pivotal role in protecting against pulmonary artery remodeling.

Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene.

Hypoxia is a well-recognized stimulus for pulmonary blood vessel remodeling and pulmonary hypertension development. One mechanism that may account for these effects is the direct action of hypoxia on the expression of specific genes involved in vascular smooth muscle cell (SMC) proliferation. Previous studies demonstrated that the serotonin (5-hydroxytryptamine; 5-HT) transporter (5-HTT) mediates the mitogenic activity of 5-HT in pulmonary vascular SMCs and is overexpressed during hypoxia. Thus, 5-HT-related mitogenic activity is increased during hypoxia. Here, we report that mice deficient for 5-HTT (5-HTT(-/-)) developed less hypoxic pulmonary hypertension and vascular remodeling than paired 5-HTT(+/+) controls. When maintained under normoxia, 5-HTT(-/-)-mutant mice had normal hemodynamic parameters, low blood 5-HT levels, deficient platelet 5-HT uptake, and unchanged blood levels of 5-hydroxyindoleacetic acid, a metabolite of 5-HT. After exposure to 10% O(2) for 2 or 5 weeks, the number and medial wall thickness of muscular pulmonary vessels were reduced in hypoxic 5-HTT(-/-) mice as compared with wild-type paired controls. Concomitantly, right ventricular systolic pressure was lower and right ventricle hypertrophy less marked in the mutant mice. This occurred despite potentiation of acute hypoxic pulmonary vasoconstriction in the 5-HTT(-/-) mice. These data further support a key role of 5-HTT in hypoxia-induced pulmonary vascular SMC proliferation and pulmonary hypertension.

Induction of cardiac nitric oxide synthase 2 in rats exposed to chronic hypoxia.

Induction of nitric oxide synthase (NOS2, also designated as iNOS) in the heart is known to occur in response to various stimuli. It is not known, however, whether in vivo hypoxia leads to cardiac NOS2 induction. We thus investigated the effects of normobaric hypoxia (10% O(2)for 8, 15 and 21 days) on NOS2 protein expression and enzyme activity in rat right ventricle (RV) and left ventricle (LV). Chronic hypoxia induced RV hypertrophy: the RV weight to body weight ratio was increased by 45% upon 15 days of exposure, with no change thereafter and no change in left ventricular (LV) weight. Treatment of hypoxic rats with l -NAME for 1 month decreased pulmonary artery pressure and RV hypertrophy compared to hypoxic non-treated rats. NOS2 activity detected by [(3)H]l -arginine to [(3)H]l -citrulline conversion increased in RV during hypoxia, with a maximum at 15 days (+161% of control rats P<0.05), whereas it increased less (by 60%) in LV. In parallel, after 15 days of hypoxia there was a three-fold increase in NOS2 protein abundance detected by Western blotting using an isoform-specific antibody in the RVs (two-fold increase in the LV). Immunochemistry with the specific antibody demonstrated the expression in cardiomyocytes isolated from both ventricles of normoxic and hypoxic rats. Protein kinase C (PKC) content and activity was unchanged in LV of hypoxic rats, but increased in RV as compared with normoxic rats. These results clearly show that, in the heart, NOS2 is upregulated by hypoxia with an expression in cardiomyocytes of both ventricles. In addition, NOS2 is more inducible in the right hypertrophied ventricle than in the left non-hypertrophied hypoxic ventricle.

Effect of celiprolol treatment in hypertensive patients with sleep apnea.

The effects of a beta-blocker, celiprolol, on sleep and arterial blood pressure (BP) were evaluated during a single-blind study in seven hypertensive patients with sleep apnea. Diurnal ambulatory BP measurements with an automatic cuff-inflation device and polysomnography with simultaneous Finapres BP recording were performed separately on consecutive days at the end of two 21-day treatment periods involving placebo followed by celiprolol (200 mg/day). Age was 59 +/- 2.5 yr (m +/- sem) and body mass index 33.2 +/- 2.3 kg. m-2. Diurnal ambulatory BP was significantly lower with celiprolol than with placebo (systolic 139 +/- 4 vs 152 +/- 5 mmHg, diastolic 86 +/- 2 vs 96 +/- 2 mmHg). The apnea-hypopnea index was similar under celiprolol and placebo (48 +/- 7.4 vs 53 +/- 7.8, respectively), as were the total sleep time and percent of duration of the different sleep stages. Individual average BP values were significantly lower during REM sleep under celiprolol but remained similar under celiprolol and placebo in the other sleep stages. Variability of nocturnal BP (assessed by the SD of distribution of BP variations) was not affected by celiprolol. In conclusion, celiprolol which decreased daytime BP, did not affect sleep pattern or respiratory disturbances, or nocturnal BP variability related to apnea.

Brain "embolism" detected by magnetic resonance imaging during percutaneous mitral balloon commissurotomy.

PURPOSE: The common finding of thrombi between the bifoil balloons when they were extracted after mitral dilation prompted us to look for evidence of minor brain embolisms using the sensitive technique of BMRI (brain magnetic resonance T2-weighted imaging). METHODS: BMRI was performed within 48 hr before and after a percutaneous mitral balloon commissurotomy (PMBC) in each of the 63 patients in this study. RESULTS: There was evidence (hyperintensity foci: HI) of a previous asymptomatic brain embolism in 38 of 63 patients before PMBC and a new HI appeared in 18 of 63 patients after the procedure. New HI signals were found exclusively in the white matter in 8 of 18 patients and in only 3 of 18 were HI signs larger than 1 cm. One patient, with an HI signal > 1 cm in the thalamus and another < 1 cm in the brain stem, presented diplopia accompanied by other minor clinical signs. The differences in HI rate among four subgroups (1, older vs younger than 43 years; 2, sinus rhythm vs atrial fibrillation; 3, echo score < 8 vs > 8; 4, patients from western countries vs the others) were not statistically significant, probably because the number of patients in each subgroup was low. Patients in atrial fibrillation had slightly more (not significant) HI before PMBC (15/20, 75%) than patients in sinus rhythm (23/43, 53%), but after PMBC their HI frequencies were similar (atrial fibrillation: 5/20, 25%; sinus rhythm: 13/43, 30%). CONCLUSION: Brain microembolism is frequent during PMBC, but is often anatomically limited and free from clinical signs in most cases. Brain embolism seems to be related mainly to the procedure itself and not the features of the patient.

Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells. Relationship with the mitogenic action of serotonin.

-The increased delivery of serotonin (5-hydroxytryptamine, 5-HT) to the lung aggravates the development of hypoxia-induced pulmonary hypertension in rats, possibly through stimulation of the proliferation of pulmonary artery smooth muscle cells (PA-SMCs). In cultured rat PA-SMCs, 5-HT (10(-8) to 10(-6) mol/L) induced DNA synthesis and potentiated the mitogenic effect of platelet-derived growth factor-BB (10 ng/mL). This effect was dependent on the 5-HT transporter (5-HTT), since it was prevented by the 5-HTT inhibitors fluoxetine (10(-6) mol/L) and paroxetine (10(-7) mol/L), but it was unaltered by ketanserin (10(-6) mol/L), a 5-HT2A receptor antagonist. In PA-SMCs exposed to hypoxia, the levels of 5-HTT mRNA (measured by competitive reverse transcriptase-polymerase chain reaction) increased by 240% within 2 hours, followed by a 3-fold increase in the uptake of [3H]5-HT at 24 hours. Cotransfection of the cells with a construct of human 5-HTT promoter-luciferase gene reporter and of pCMV-beta-galactosidase gene allowed the demonstration that exposure of cells to hypoxia produced a 5.5-fold increase in luciferase activity, with no change in beta-galactosidase activity. The increased expression of 5-HTT in hypoxic cells was associated with a greater mitogenic response to 5-HT (10(-8) to 10(-6) mol/L) in the absence as well as in the presence of platelet-derived growth factor-BB. 5-HTT expression assessed by quantitative reverse transcriptase-polymerase chain reaction and in situ hybridization in the lungs was found to predominate in the media of pulmonary artery, in which a marked increase was noted in rats that had been exposed to hypoxia for 15 days. These data show that in vitro and in vivo exposure to hypoxia induces, via a transcriptional mechanism, 5-HTT expression in PA-SMCs, and that this effect contributes to the stimulatory action of 5-HT on PA-SMC proliferation. In vivo expression of 5-HTT by PA-SMC may play a key role in serotonin-mediated pulmonary vascular remodeling.

Brain "embolism" detected by magnetic resonance imaging during percutaneous mitral balloon commissurotomy.

PURPOSE: The common finding of thrombi between the bifoil balloons when they were extracted after mitral dilation prompted us to look for evidence of minor brain embolisms using the sensitive technique of BMRI (brain magnetic resonance T2-weighted imaging). METHODS: BMRI was performed within 48 hr before and after a percutaneous mitral balloon commissurotomy (PMBC) in each of the 63 patients in this study. RESULTS: There was evidence (hyperintensity foci: HI) of a previous asymptomatic brain embolism in 38 of 63 patients before PMBC and a new HI appeared in 18 of 63 patients after the procedure. New HI signals were found exclusively in the white matter in 8 of 18 patients and in only 3 of 18 were HI signs larger than 1 cm. One patient, with an HI signal >1 cm in the thalamus and another <1 cm in the brain stem, presented diplopia accompanied by other minor clinical signs. The differences in HI rate among four subgroups (1, older vs younger than 43 years; 2, sinus rhythm vs atrial fibrillation; 3, echo score <8 vs >8; 4, patients from western countries vs the others) were not statistically significant, probably because the number of patients in each subgroup was low. Patients in atrial fibrillation had slightly more (not significant) HI before PMBC (15/20, 75%) than patients in sinus rhythm (23/43, 53%), but after PMBC their HI frequencies were similar (atrial fibrillation: 5/20, 25%; sinus rhythm: 13/43, 30%). CONCLUSION: Brain microembolism is frequent during PMBC, but is often anatomically limited and free from clinical signs in most cases. Brain embolism seems to be related mainly to the procedure itself and not the features of the patient.

Effect of DMPPO, a phosphodiesterase type 5 inhibitor, on hypoxic pulmonary hypertension in rats.

1. Cyclic guanosine 3'-5'-monophosphate (cyclic GMP) is the second messenger of important physiologically active mediators controlling the pulmonary vascular tone. To potentiate the effects of cyclic GMP on the pulmonary vasculature, we used DMPPO, a new selective PDE-5 inhibitor, and examined its action in a rat model of hypoxic pulmonary hypertension. 2. Levels of cyclic GMP measured during baseline conditions at 5 and 60 min of perfusion were similar in the perfusate of isolated lungs from normoxic and chronically hypoxic rats and did not differ with time. Pretreatment with DMPPO (1 microM) induced a larger increase in cyclic GMP concentration in the perfusate from chronically hypoxic rat lungs (31+/-36 at 5 min to 1821+/-83 pmol ml(-1) at 60 min) than in normoxic rat lungs (329+/-20 to 1281+/-127 pmol ml(-1), P<0.05). 3. In isolated lungs preconstricted with U-46619, pretreatment with DMPPO (1 microM) potentiated the vasodilator effects of atrial natriuretic peptide (100 pM-10 nM) and sodium nitroprusside (1 pM 10 nM), but did not alter vasodilation to isoproterenol. 4. In conscious rats previously exposed to 15 days hypoxia and studied under 10% O2, DMPPO (0.01, 0.05 and 0.1 mg kg(-1), i.v. bolus) caused a dose-dependent decrease in pulmonary arterial pressure (Pap) with no change in systemic artery pressure (Sap) and cardiac output. 5. Continuous infusion of DMPPO (0.1 mg kg(-1) h(-1) i.v. by osmotic pumps) in rats exposed to 10% O2 during 2-weeks reduced the Pap (P<0.05) and the degree of muscularization of pulmonary vessels at the alveolar wall (P<0.01) and alveolar duct levels (P<0.05) despite no significant change in right ventricular hypertrophy. 6. These results suggest that cyclic GMP phosphodiesterase inhibition may selectively dilate pulmonary circulation during chronic hypoxia.