Renaud Tamisier

Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea.

RATIONALEnRandomized controlled trials (RCTs) have shown that continuous positive airway pressure (CPAP) treatment of obstructive sleep apnea (OSA) reduces blood pressure (BP). CPAP treatment has never been compared with antihypertensive medications in an RCT.nnnOBJECTIVESnTo assess the respective efficacy of CPAP and valsartan in reducing BP in hypertensive patients with OSA never treated for either condition.nnnMETHODSnIn this 8-week randomized controlled crossover trial, 23 hypertensive patients (office systolic BP/diastolic BP: 155 ± 14/102 ± 11 mm Hg) with OSA (age, 57 ± 8 yr; body mass index, 28 ± 5 kg/m(2); apnea-hypopnea index, 29 ± 18/h) were randomized first to either CPAP or valsartan (160 mg). The second 8-week period consisted of the alternative treatment (crossover) after a 4-week washout period.nnnMEASUREMENTS AND MAIN RESULTSnOffice BP and 24-hour BP were measured before and at the end of the two active treatment periods. Twenty-four-hour mean BP was the primary outcome variable. There was an overall significant difference in 24-hour mean BP between treatments: the change in 24-hour mean BP was -2.1 ± 4.9 mm Hg (P < 0.01) with CPAP, and -9.1 ± 7.2 mm Hg with valsartan (P < 0.001), with a difference of -7.0 mm Hg (95% confidence interval, -10.9 to -3.1 mm Hg; P < 0.001). The difference was significant not only during daytime but also during nighttime: the change in nighttime mean BP with CPAP was -1.3 ± 4.6 mm Hg (not significant), and -7.4 ± 8.4 mm Hg with valsartan (P < 0.001), with a difference of -6.1 mm Hg (P < 0.05) (95% confidence interval, -10.8 to -1.4 mm Hg).nnnCONCLUSIONSnIn an RCT, although the BP decrease was significant with CPAP treatment, valsartan induced a fourfold higher decrease in mean 24-hour BP than CPAP in untreated hypertensive patients with OSA. Clinical trial registered with www.clinicaltrials.gov (NCT00409487).

Mechanisms of cardiac dysfunction in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is associated with cardiovascular morbidity and mortality, largely as a result of myocardial anomalies. Numerous mechanisms cause OSA-related myocardial damage. The majority are initiated as a result of OSA-induced, chronic, intermittent hypoxia. The most-important mechanisms that lead to myocardial damage are increased sympathetic activity, endothelial dysfunction, systemic inflammation, oxidative stress, and metabolic anomalies. All these mechanisms promote the development of hypertension, which is common in patients with OSA. Hypertensive cardiomyopathy and coronary heart disease, as well as obesity-related, diabetic, and tachycardia-induced cardiomyopathies, are also associated with OSA. Left ventricular hypertrophy, myocardial fibrosis, atrial dilatation, and left ventricular systolic and diastolic dysfunction in patients with OSA explain the association of the disease with these clinical outcomes. The gold-standard treatment for OSA, nasal continuous positive airway pressure (CPAP), might improve cardiac symptoms and hemodynamic parameters in patients with the disease. However, large clinical trials are required to improve our understanding of the cardiac consequences of OSA, and determine the effect of treatment, particularly CPAP, on myocardial damage in symptomatic patients and primary prevention of cardiovascular disorders.

Masked hypertension in obstructive sleep apnea syndrome.

Background Ambulatory blood pressure (BP) monitoring (ABPM) detects subjects with normal clinic but high ambulatory 24-h BP, that is, masked hypertension. Methods One hundred and thirty newly diagnosed obstructive sleep apnea syndrome (OSAS) patients, free of recognized cardiovascular disease were included (111 men, age = 48 ± 1 years, BMI = 27.6 ± 0.4 kg/m2, respiratory disturbance index (RDI = 42 ± 2/h). Clinic BP, 24-h ABPM, baroreflex sensitivity (BRS), echocardiography and carotid intima–media thickness (IMT) were assessed. Results Forty-one patients (31.5%) were normotensive, 39 (30.0%) exhibited masked hypertension, four (3.1%) white-coat hypertension and 46 (35.4%) hypertension. Significant differences were found between normotensive, masked hypertensive and hypertensive patients in terms of BRS (10.5 ± 0.8, 8.0 ± 0.6 and 7.4 ± 0.4 ms/mmHg, respectively, P < 0.001), carotid IMT (624 ± 17, 650 ± 20 and 705 ± 23 μm, respectively, P = 0.04) and left ventricular mass index (37 ± 1, 40 ± 2 and 43 ± 1 g/height2.7, respectively, P = 0.003). A clinic systolic BP more than 125 and a diastolic BP more than 83 mmHg led to a relative risk (RR) of 2.7 and a 90% positive predictive value for having masked hypertension. Conclusion Masked hypertension is frequently underestimated in OSAS and is nearly always present when clinic BP is above 125/83 mmHg.

Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity

Chronic intermittent hypoxia (CIH) is thought to be responsible for the cardiovascular disease associated with obstructive sleep apnea (OSA). Increased sympathetic activation, altered vascular function, and inflammation are all putative mechanisms. We recently reported (Tamisier R, Gilmartin GS, Launois SH, Pepin JL, Nespoulet H, Thomas RJ, Levy P, Weiss JW. J Appl Physiol 107: 17-24, 2009) a new model of CIH in healthy humans that is associated with both increases in blood pressure and augmented peripheral chemosensitivity. We tested the hypothesis that exposure to CIH would also result in augmented muscle sympathetic nerve activity (MSNA) and altered vascular reactivity contributing to blood pressure elevation. We therefore exposed healthy subjects between the ages of 20 and 34 yr (n = 7) to 9 h of nocturnal intermittent hypoxia for 28 consecutive nights. Cardiovascular and hemodynamic variables were recorded at three time points; MSNA was collected before and after exposure. Diastolic blood pressure (71 +/- 1.3 vs. 74 +/- 1.7 mmHg, P < 0.01), MSNA [9.94 +/- 2.0 to 14.63 +/- 1.5 bursts/min (P < 0.05); 16.89 +/- 3.2 to 26.97 +/- 3.3 bursts/100 heartbeats (hb) (P = 0.01)], and forearm vascular resistance (FVR) (35.3 +/- 5.8 vs. 55.3 +/- 6.5 mmHg x ml(-1) x min x 100 g tissue, P = 0.01) all increased significantly after 4 wk of exposure. Forearm blood flow response following ischemia of 15 min (reactive hyperemia) fell below baseline values after 4 wk, following an initial increase after 2 wk of exposure. From these results we conclude that the increased blood pressure following prolonged exposure to CIH in healthy humans is associated with sympathetic activation and augmented FVR.

Obstructive sleep apnoea and metabolic syndrome: put CPAP efficacy in a more realistic perspective

Non-communicable Diseases, mainly cardiovascular diseases, cancer, diabetes and chronic respiratory diseases, are responsible for two-thirds of the 57 million annual deaths worldwide.1 Obesity and obstructive sleep apnoea (OSA) are among the key players involved in non-communicable diseases. Several studies have reported an independent association of OSA with the different components of the metabolic syndrome, particularly hypertension, insulin resistance and abnormal lipid metabolism.2 Both OSA and metabolic syndrome are associated with an increase risk in cardiovascular disease. Hence, rapidly accumulating data from both epidemiological and clinical studies3 have suggested that OSA is independently associated with alterations in glucose metabolism and with an increased risk of developing type 2 diabetes. Indeed, recent reports have indicated that more than 50% of patients with type 2 diabetes have OSA. Multiple mechanistic pathways contribute to the deteriorated plasma glucose/insulin homeostasis in OSA, the number one being sympathetic over activity,4 due to sleep fragmentation and intermittent hypoxia (figure 1). Independently of autonomic nervous system activation, in animal models intermittent hypoxia contributes to decreased glucose utilisation in oxidative muscle fibres.5 Intermittent hypoxia also seems to be responsible for increased beta-cell proliferation and cell death, the latter being due to oxidative stress.6 In fat tissue, chronic intermittent hypoxia (CIH) the hallmark of OSA exacerbate adipose tissue inflammation and lead to a dysregulated production of adipocytokines which may contribute to insulin resistance and could trigger non-alcoholic fatty liver disease (figure 1). We have demonstrated in morbid obesity that CIH is strongly associated with higher systemic inflammation (IL-6) and more severe fibrotic or inflammatory liver injuries.7 Visceral fat releases free fatty acids in the portal vein leading to accumulation of hepatic fat and development of hepatic insulin resistance. Regarding lipid abnormalities, intermittent hypoxia leads to an increase in serum cholesterol, to an up-regulation …

Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans

Recurrent and intermittent nocturnal hypoxia is characteristic of several diseases including chronic obstructive pulmonary disease, congestive heart failure, obesity-hypoventilation syndrome, and obstructive sleep apnea. The contribution of hypoxia to cardiovascular morbidity and mortality in these disease states is unclear, however. To investigate the impact of recurrent nocturnal hypoxia on hemodynamics, sympathetic activity, and vascular tone we evaluated 10 normal volunteers before and after 14 nights of nocturnal sustained hypoxia (mean oxygen saturation 84.2%, 9 h/night). Over the exposure, subjects exhibited ventilatory acclimatization to hypoxia as evidenced by an increase in resting ventilation (arterial Pco(2) 41.8 +/- 1.5 vs. 37.5 +/- 1.3 mmHg, mean +/- SD; P < 0.05) and in the isocapnic hypoxic ventilatory response (slope 0.49 +/- 0.1 vs. 1.32 +/- 0.2 l/min per 1% fall in saturation; P < 0.05). Subjects exhibited a significant increase in mean arterial pressure (86.7 +/- 6.1 vs. 90.5 +/- 7.6 mmHg; P < 0.001), muscle sympathetic nerve activity (20.8 +/- 2.8 vs. 28.2 +/- 3.3 bursts/min; P < 0.01), and forearm vascular resistance (39.6 +/- 3.5 vs. 47.5 +/- 4.8 mmHg.ml(-1).100 g tissue.min; P < 0.05). Forearm blood flow during acute isocapnic hypoxia was increased after exposure but during selective brachial intra-arterial vascular infusion of the alpha-blocker phentolamine it was unchanged after exposure. Finally, there was a decrease in reactive hyperemia to 15 min of forearm ischemia after the hypoxic exposure. Recurrent nocturnal hypoxia thus increases sympathetic activity and alters peripheral vascular tone. These changes may contribute to the increased cardiovascular and cerebrovascular risk associated with clinical diseases that are associated with chronic recurrent hypoxia.

Sustained muscle sympathetic activity after hypercapnic but not hypocapnic hypoxia in normal humans

Exposure to hypercapnic hypoxia (asphyxia), but not hyperoxic hypercapnia, results in increased sympathetic activity that persists after exposure. To determine the contribution of CO2 to the post-hypoxia sympathoexcitation, we exposed 12 normal volunteers to hypocapnic and hypercapnic hypoxia (SaO2 approximately 85%) for 20 min each on different days. We measured plethysmographic forearm blood flow, muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP), and heart rate. MSNA increased during both exposures but remained elevated for 15 min only after asphyxia. Following asphyxia, MAP returned to pre-exposure values, but after hypocapnic hypoxia MAP decreased below baseline for 15 min. There were sustained decreases in heart rate after hypocapnic, but not hypercapnic hypoxia. Forearm vascular resistance (FVR) decreased below baseline during both exposures, reached its highest value above baseline after asphyxia and then declined. After hypocapnic hypoxia FVR rose to baseline after exposure. Hemodynamics are differently altered by hypercapnic relative to hypocapnic 20 min hypoxia, while only hypercapnic hypoxia produces sustained elevation of MSNA during recovery.

A critical review of peripheral arterial tone and pulse transit time as indirect diagnostic methods for detecting sleep disordered breathing and characterizing sleep structure

Purpose of review Sympathetic activity varies continuously across sleep stages. During rapid eye movement sleep, sympathetic tone increases substantially but is highly variable. Microarousals are associated with momentary bursts of sympathetic activity. Abnormal respiratory events progressively elevate sympathetic activity in proportion to the severity of oxyhemoglobin desaturation. These phenomena imply that cardiovascular markers of sympathetic activity such as peripheral arterial tone (PAT) and pulse transit time could be indirect tools for diagnosing sleep disordered breathing and characterizing sleep structure and fragmentation. Recent findings Measurement of variations in PAT coupled with pulse rate accelerations and desaturations in oximetry can be used to diagnose sleep apnea. Good agreement between both manually and automatically analyzed PAT recordings and polysomnography has been demonstrated during in-laboratory or at-home studies. Numerous validation studies against esophageal pressure have demonstrated that pulse transit time is the best noninvasive method for measurement of respiratory effort. Pulse transit time and PAT are sensitive techniques for arousal recognition, particularly in children and infants. There are specific sleep stage-dependent PAT patterns that allow for the recognition of rapid eye movement sleep and, in the case of nonrapid eye movement sleep, the separation of lighter stages from deeper, slow wave sleep. Elevated nocturnal sympathetic activity as documented by PAT attenuations is linked with chronically elevated blood pressure in humans. Summary Cardiovascular markers of autonomic control during sleep permit not only the diagnosis of obstructive sleep apnea and estimation of sleep structure but are also linked with the prevalence of daytime hypertension.

Chronic intermittent hypoxia modulates nNOS mRNA and protein expression in the rat hypothalamus

Exposure to chronic intermittent hypoxia (CIH) as observed in obstructive sleep apnea (OSA) elicits a sustained elevation of sympathetic activity and arterial blood pressure. Our overall hypothesis is that intermittent hypoxia might increase sympathetic activity, in part by altering neuronal nitric oxide synthase (nNOS) expression in the hypothalamus, where nitric oxide is sympathoinhibitory. In this study, we begin investigation of this hypothesis by testing the more specific hypothesis that the CIH alters nNOS expression in regions of the hypothalamus associated with cardiovascular regulation. To test the effect of CIH on NOS expression we subjected male Sprague-Dawley rats to cyclic intermittent hypoxia for 8h/day, for 35 days. Experimental rats showed an increase in systemic blood pressure. In situ hybridization and immunohistochemistry were performed on hypothalamic sections, respectively. The CIH rats displayed significantly lower levels of both nNOS mRNA and protein in the paraventricular hypothalamic nucleus (PVN) with different changes in the subareas of the PVN. There was a decreased level of nNOS mRNA and protein in the subfornical organ and the periventricular hypothalamic nucleus of the CIH rats, but no significant change in the supraoptic nucleus or the lateral hypothalamic area. This work suggests that examination of central regulation of sympathetic activity may help elucidate the mechanisms of hypertension after CIH.

Comments on Point: Counterpoint: Hypobaric hypoxia induces/does not induce different responses from normobaric hypoxia.

112:1788-1794, 2012. ; J Appl Physiol Joshua C. Weavil, Peter Bartsch and Charles F. Nelatury Samuel Verges, Patrick Levy, Eric M. Snyder, Bruce D. Johnson, Jonathon L. Stickford, Y. Millet, Benjamin D. Levine, James H. Wessel III, Bernard Wuyam, Renaud Tamisier, MacInnis, Michael S. Koehle, Thomas Rupp, Marc Jubeau, Stephane Perrey, Guillaume Laymon, Jack A. Loeppky, Matiram Pun, Kai Schommer, Mary C. Vagula, Martin J. S. Chapman, Johnny Conkin, Hugo Nespoulet, Darren P. Casey, Bryan J. Taylor, Abigail Olivier Girard, Michael S. Koehle, Jordan A. Guenette, Samuel Verges, Robert F. normobaric hypoxia induces/does not induce different responses from Comments on Point:Counterpoint: Hypobaric hypoxia