Home diagnosis of obstructive sleep apnoea in coronary patients: validity of a simplified device automated analysis.

INTRODUCTION: Our aim was to evaluate a type 3 portable simplified device as a screening tool for obstructive sleep apnoea (OSA) in coronary patients. MATERIALS AND METHODS: In 50 patients selected independently from sleep complaints, we compared the number of respiratory events per hour of valid recording time counted automatically by the device and the number counted manually per hour of sleep on polysomnography performed at home during the same night. RESULTS: Five patients were excluded because of technical failures. Estimated OSA prevalences (95% confidence interval) for apnoea/hypopnoea index (AHI) cut-offs > or = 5, > or = 15, and > or = 30 by polysomnography were 0.93 (0.81-0.98), 0.69 (0.53-0.81), and 0.27 (0.15-0.42), respectively. The device would have correctly diagnosed 75% of patients with severe OSA (AHI > or = 30 by polysomnography) and would have classified the remaining 25% as having moderate OSA. DISCUSSION: This ambulatory device may prove valuable in reducing the costs of diagnosing and managing OSA in coronary patients.

Effects of roflumilast, a phosphodiesterase-4 inhibitor, on hypoxia- and monocrotaline-induced pulmonary hypertension in rats.

Phosphodiesterase type 4 (PDE4) is involved in the hydrolysis of cAMP in pulmonary vascular smooth muscle (PA-SMC) and immune inflammatory cells. Given that intracellular cAMP accumulation inhibits contraction and growth of PA-SMCs as well as inflammatory cell functions, we investigated the effects of the PDE4 inhibitor 3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide (roflumilast), on pulmonary hypertension (PH) in rats. Treatment with roflumilast (0.5 or 1.5 mg x kg(-1) day(-1)) from day 1 to day 21 after monocrotaline (MCT) injection (60 mg x kg(-1) s.c.) attenuated PH development: pulmonary artery pressure, right ventricular hypertrophy, and muscularization of distal vessels on day 21 were decreased compared to control MCT-treated rats. Roflumilast (1.5 mg x kg(-1) day(-1)) also reduced the increases in interleukin-6 and monocyte chemotactic protein-1 mRNAs observed in lung tissue on day 21 without affecting the rise in interleukin-1beta mRNA on days 1 and 21. Roflumilast (1.5 mg x kg(-1) day(-1)) from day 21 to day 42 after MCT reversed established PH, almost normalizing pulmonary artery pressure and structure, and suppressing proliferating cell nuclear antigen-positive cells in pulmonary vascular walls. Treatment with roflumilast similarly attenuated PH development due to chronic hypoxia. Treatment of human PA-SMCs with roflumilast N-oxide, the active metabolite of roflumilast, at concentrations up to 10(-6) M, potentiated PA-SMC growth inhibition induced by prostacyclin (10(-6) M) or interleukin-1beta (10 ng x ml(-1)) but was inactive on its own. In conclusion, the PDE4 inhibitor roflumilast significantly attenuates pulmonary vascular remodeling and hypertension induced by chronic hypoxia or MCT and reverses established PH after MCT administration.

Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents.

Pulmonary hypertension (PH) is a progressive, lethal lung disease characterized by pulmonary artery SMC (PA-SMC) hyperplasia leading to right-sided heart failure. Molecular events originating in pulmonary ECs (P-ECs) may contribute to the PA-SMC hyperplasia in PH. Thus, we exposed cultured human PA-SMC to medium conditioned by P-EC from patients with idiopathic PH (IPH) or controls and found that IPH P-EC-conditioned medium increased PA-SMC proliferation more than control P-EC medium. Levels of FGF2 were increased in the medium of IPH P-ECs over controls, while there was no detectable difference in TGF-beta1, PDGF-BB, or EGF levels. No difference in FGF2-induced proliferation or FGF receptor type 1 (FGFR1) mRNA levels was detected between IPH and control PA-SMCs. Knockdown of FGF2 in P-EC using siRNA reduced the PA-SMC growth-stimulating effects of IPH P-EC medium by 60% and control P-EC medium by 10%. In situ hybridization showed FGF2 overproduction predominantly in the remodeled vascular endothelium of lungs from patients with IPH. Repeated intravenous FGF2-siRNA administration abolished lung FGF2 production, both preventing and nearly reversing a rat model of PH. Similarly, pharmacological FGFR1 inhibition with SU5402 reversed established PH in the same model. Thus, endothelial FGF2 is overproduced in IPH and contributes to SMC hyperplasia in IPH, identifying FGF2 as a promising target for new treatments against PH.

Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats.

BACKGROUND: Progression of pulmonary hypertension (PH) is associated with increased lung expression of the serotonin transporter (5-HTT), which leads to hyperplasia of the pulmonary artery smooth muscle cells (PA-SMCs). Given the postulated causal relation between 5-HTT overexpression and PH, we herein investigated whether the highly selective 5-HTT inhibitor fluoxetine prevented and/or reversed PH induced by monocrotaline (MCT) in rats. Selective 5-HT(1B/1D), 5-HT(2A), and 5-HT(2B) receptor antagonists were used for comparative testing. METHODS AND RESULTS: MCT injection (60 mg/kg SC) was followed by an early peak in lung 5-HTT expression on day 1, which preceded the onset of PH. Established PH on day 15 was associated with a sustained 5-HTT increase. Continued fluoxetine treatment completely prevented PA-SMC proliferation and PH development and also suppressed the late 5-HTT increase, without affecting the early peak. The 5-HT receptor antagonists did not affect PH. Fluoxetine (10 mg . kg(-1) . d(-1) PO) started 3 weeks after MCT injection completely reversed established PH, normalizing PA pressure and structure. MCT-induced PH was also associated with increased expression of various cytokines, but only interleukin-1beta and monocyte chemotactic protein-1 increased at the early phase and stimulated 5-HTT expression by cultured PA-SMCs. CONCLUSIONS: Upregulation of lung 5-HTT induced by MCT appears necessary to initiate the development of pulmonary vascular remodeling, whereas a sustained increase in 5-HTT expression may underlie both the progression and the maintenance of MCT-induced PH. Complete reversal of established PH by fluoxetine provides a rationale for new therapeutic strategies in human PH.

Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study.

AIM: The aim of this long-term prospective study was to evaluate the effect of treating obstructive sleep apnoea (OSA) on the rate of cardiovascular events in coronary artery disease (CAD). METHODS AND RESULTS: We prospectively studied 54 patients (mean age 57.3 +/- 10.1 years) with both CAD (> or = 70% coronary artery stenosis) and OSA (apnoea-hypopnoea index > or = 15). In 25 patients, OSA was treated with continuous positive airway pressure (n=21) or upper airway surgery (n=4); the remaining 29 patients declined treatment for their OSA. The median follow-up was 86.5 +/- 39 months. The two groups were similar at baseline in age, body mass index, smoking history, hypertension, hypercholesterolaemia, diabetes mellitus, number of diseased vessels, left ventricular ejection fraction, and CAD therapy. Treatment of risk factors other than OSA was similar in the two groups. The endpoint (a composite of cardiovascular death, acute coronary syndrome, hospitalisation for heart failure, or need for coronary revascularisation) was reached in 6 (6/25, 24%) and 17 (17/29, 58%) patients with and without OSA treatment, respectively (P<0.01). OSA treatment significantly reduced the risk of occurrence of the composite endpoint (hazard ratio 0.24; 95% confidence interval, 0.09-0.62; p<0.01) and of each of its components. CONCLUSIONS: Our data indicate that the treatment of OSA in CAD patients is associated with a decrease in the occurrence of new cardiovascular events, and an increase in the time to such events.

Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer limits monocrotaline-induced pulmonary vascular remodeling in rats.

Extracellular matrix dysregulation is key to the development of pulmonary hypertension (PH), suggesting a pivotal role for the proteases that control matrix remodeling. Both hypoxia- and monocrotaline-induced PH are associated with increased protease activity in the distal and proximal pulmonary arteries. However, the role of proteases is not completely understood. In hypoxic PH, matrix metalloproteinase (MMP) inhibition increased pulmonary vascular remodeling, whereas in monocrotaline PH, serine elastase inhibition reversed pulmonary vascular remodeling. These conflicting effects of protease inhibition may be ascribable to differences across experimental models in either the mechanisms underlying PH or the methods used to inhibit protease activity. In the present study, we investigated the effects of specific MMP inhibition on monocrotaline PH development. To inhibit lung MMP in rats exposed to monocrotaline (60 mg/kg as a single subcutaneous injection), we used intratracheal instillation of the adenovirus-mediated human TIMP-1 gene (Ad.hTIMP-1, 10(8) plaque-forming units) as in our previous study on hypoxic PH. MMP inhibition in lungs was evaluated by in situ zymography. Rats treated with Ad.hTIMP-1 had less severe pulmonary vascular remodeling evidenced by a decreased right ventricular hypertrophy, with decreased muscularization of peripheral pulmonary arteries and increased lung-cell apoptosis compared to controls. No periadventitial collagen accumulation was observed in distal pulmonary arteries, whereas elastin content was significantly increased in Ad.hTIMP-1-treated rats. These data support a deleterious role for proteases in toxic and inflammatory PH and indicate that MMPs may have opposite effects in different PH models.

Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension.

Pulmonary hypertension (PH) results from constriction and remodeling of pulmonary vessels. Serotonin contributes to both phenomena through different signaling pathways. The mitogenic effect of serotonin on pulmonary vascular smooth muscle cells is mediated by the serotonin transporter (5-hydroxytryptamine transporter [5-HTT]), whereas its constricting effect is mediated by 5-HT1B/1D and 5-HT2A receptors. Here, we investigated the respective roles of 5-HTT and 5-HT receptors on the development of chronic hypoxic PH in mice. During exposure to hypoxia (10% O2 for 2 weeks), the animals received one of the specific 5-HTT inhibitors citalopram and fluoxetine (10 mg/kg/day), the selective 5-HT1B/1D receptor antagonist GR127935 (2 and 10 mg/kg/day), or the 5-HT2A receptor antagonist ketanserin (2 mg/kg/day). Mice treated with the 5-HTT inhibitors showed less right ventricle hypertrophy (ratio of right ventricle/left ventricle + septum = 36.7 +/- 2.0% and 35.8 +/- 1.3% in citalopram- and fluoxetine-treated mice, respectively, vs. 41.5 +/- 1.5% in vehicle-treated mice) and less pulmonary vessel muscularization (p < 0.01) than those receiving the vehicle. Neither GR127935 nor ketanserin affected these parameters. These data indicate that 5-HTT plays a key role in hypoxia-induced pulmonary vascular remodeling. The effects of serotonin transporter inhibitors on PH in humans deserve investigation.

Lung overexpression of angiostatin aggravates pulmonary hypertension in chronically hypoxic mice.

Exposure to hypoxia leads to the development of pulmonary hypertension (PH) as a consequence of pulmonary smooth muscle hyperplasia. Hypoxia concomitantly stimulates lung expression of angiogenic factors. To investigate the role of angiogenesis processes in development of hypoxic PH, we examined the effects of lung overexpression of angiostatin, an angiogenesis inhibitor, on development of hypoxic PH and lung endothelial cell (EC) density. Angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molcule driven by the cytomegalovirus promoter (Ad.K3). Comparison was made with a control vector containing no gene in the expression cassette (Ad.CO1). Treatment with Ad.K3 (300 plaque-forming units [pfu]/cell) inhibited cultured human pulmonary artery EC migration by 100% and proliferation by 50%, but was without effects on human pulmonary artery smooth muscle cells. After intratracheal administration of Ad.K3 (109 pfu) to mice, angiostatin protein became detectable in bronchoalveolar lavage fluid. Mice pretreated with Ad.K3 1 d before a 2-wk exposure to hypoxia (10% O2) showed more severe pulmonary hypertension than Ad.CO1-pretreated controls, as assessed by higher right ventricular systolic pressure (36.5 +/- 2.4 versus 30.2 +/- 1.4, respectively), aggravation of right ventricular hypertrophy (P < 0.05), and muscularization of distal vessels (P < 0.01). Lung factor VIII, CD31 immunostaining, as well as eNOS expression were significantly increased after exposure to hypoxia in Ad.CO1-pretreated controls, but decreased in both normoxic and hypoxic animals after treatment with Ad.K3. The results show that inhibition of hypoxia-induced stimulation of lung angiogenic processes aggravates development of hypoxic PH. This suggests that endogenous lung angiogenesis counteracts development of hypoxic PH.

Role of VEGF-B in the lung during development of chronic hypoxic pulmonary hypertension.

Angiogenic factors exert protective effects on the lung. To investigate the effect of VEGF-B, a factor coexpressed in the lung with VEGF-A, we assessed chronic hypoxic pulmonary hypertension in VEGF-B knockout mice (VEGF-B-/-) and in rats with lung overexpression of VEGF-B induced by adenovirus transfer. No significant difference in pulmonary hemodynamics, right ventricular hypertrophy, distal vessel muscularization, or vascular density was found between VEGF-B-/- and control mice after 3 wk of hypoxia. When overexpressed, VEGF-B(167) or VEGF-B(186) had protective effects similar to those of human VEGF-A(165). Lung endothelial nitric oxide synthase (eNOS) expression was increased by 5 days of hypoxia or VEGF-A adenovirus vector (Ad.VEGF-A) overexpression, whereas VEGF-B(167) or VEGF-B(186) had no effect. With hypoxia or normoxia, the wet-to-dry lung weight ratio was increased 5 days after Ad.VEGF-A administration compared with control (Ad.nul), Ad.VEGF-B(167), or Ad.VEGF-B(186). Endogenous VEGF-B does not counteract the development of hypoxic pulmonary hypertension. However, when overexpressed in the lung, VEGF-B can be as potent as VEGF-A in attenuating pulmonary hypertension, although it has no effect on eNOS expression or vascular permeability.

Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension?

Investigations on the effects of serotonin (5-HT) and the serotonin transporter (5-HTT) on the pulmonary circulation are of special interest because of the reported increased risk of primary pulmonary hypertension (PPH) in patients who used some appetite suppressants that interfere with 5-HT. In addition to its vasoactive effects, 5-HT exerts mitogenic and comitogenic effects on pulmonary artery smooth muscle cells (PASMCs). These mitogenic and comitogenic effects require 5-HT internalization by the high-affinity 5-HTT, which can be competitively inhibited by specific drugs such as fluoxetine and paroxetine. In a recent study, we showed that hypoxia increases the rate of 5-HTT gene transcription in PASMCs and potentiates the growth-promoting effect of 5-HT on these cells. An increase in the levels of 5-HTT messenger ribonucleic acid was observed in smooth-muscle cells from remodeled pulmonary arteries in rats subjected to long-term hypoxia. Two series of especially relevant data further support the idea that 5-HT plays a key role in PASMC proliferation in vivo: (1) treatments that increase plasma 5-HT levels aggravate pulmonary hypertension in rats subjected to long-term hypoxia, and this effect can be prevented by combined simultaneous treatment with 5-HTT inhibitors; and (2) knockout mice with disruption of the 5-HTT gene exhibit lesser degree of hypoxic pulmonary hypertension and pulmonary vascular remodeling than control mice despite increased hypoxic pulmonary vasoconstriction. These observations indicate that 5-HTT expression, activity, or both in PASMCs contribute to pulmonary vascular remodeling and that the inducing effects of some appetite suppressants on pulmonary hypertension may be related to possible effects of these drugs on 5-HTT expression, activity, or both.