Manuel Sánchez-de-la-Torre

Obstructive sleep apnoea and cardiovascular disease

Obstructive sleep apnoea (OSA) is a common health concern caused by repeated episodes of collapse of the upper airway during sleep. The events associated with OSA lead to brain arousal, intrathoracic pressure changes, and intermittent episodes of hypoxaemia and reoxygenation. These events activate pathways such as oxidative stress, sympathetic activation, inflammation, hypercoagulability, endothelial dysfunction, and metabolic dysregulation that predispose patients with OSA to hypertension and atherosclerosis. OSA is a common cause of systemic hypertension and should be suspected in hypertensive individuals, especially those with resistant hypertension. In patients with OSA, continuous positive airway pressure (CPAP) treatment reduces blood pressure, and its effects are related to compliance and baseline blood pressure. Evidence suggests that OSA is a risk factor for stroke and heart failure. An association between coronary heart disease and OSA seems to be limited to middle-aged men (30-70 years). Cardiac rhythm disorders occur in about half of patients with OSA, but their clinical relevance is still unknown. The association of OSA with cardiovascular risk is mainly based on studies in men, and an association has yet to be established in women. Data on older patients is similarly scarce. Currently, there is not enough evidence to support treatment with CPAP for primary or secondary prevention of cardiovascular disease.

Precision Medicine in Patients With Resistant Hypertension and Obstructive Sleep Apnea: Blood Pressure Response to Continuous Positive Airway Pressure Treatment.

BACKGROUND In patients with resistant hypertension (RH) and obstructive sleep apnea (OSA), the blood pressure response to continuous positive airway pressure (CPAP) treatment is highly variable and could be associated with differential micro-ribonucleic acid (miRNA) profiles. Currently, no available methods exist to identify patients who will respond favorably to CPAP treatment. OBJECTIVES The aim of this study was to identify plasma miRNA profiles that predict blood pressure responses to CPAP treatment. METHODS Cardiovascular system-focused circulating miRNA expression was evaluated in plasma samples using an 84-miRNA array among patients with RH and OSA at baseline and after 3 months of adherent CPAP use. Pathway analysis and miRNA target gene enrichment were performed in silico. Plasma levels of peptides and hormones related to cardiovascular function were also measured. RESULTS The OSA responder group exhibited blood pressure decreases exceeding the observed median (>4.5 mm Hg) after CPAP, which were not present in the nonresponder group (≤4.5 mm Hg) (p < 0.01). Three miRNAs provided a discriminatory predictive model for such a favorable blood pressure response to CPAP (area under the curve: 0.92; p = 0.01). Additionally, CPAP treatment significantly altered a total of 47 plasma miRNAs and decreased aldosterone-to-renin ratios in the responder group (p = 0.016) but not in the nonresponder group. CONCLUSIONS A singular pre-CPAP treatment cluster of 3 plasma miRNAs predicts blood pressure responses to CPAP treatment in patients with RH and OSA. CPAP treatment is accompanied by changes in cardiovascular system-related miRNAs that may potentially influence the risk for cardiovascular disease among patients with OSA and RH. (Effect of Continuous Positive Airway Pressure [CPAP] Treatment in the Control of Refractory Hypertension; NCT00616265).

Free fatty acids and the metabolic syndrome in patients with obstructive sleep apnoea

Obesity and metabolic syndrome (MS) occur frequently in patients with obstructive sleep apnoea syndrome (OSAS). We hypothesised that circulating free fatty acids (FFAs) are elevated in OSAS patients independently of obesity. This elevation may contribute to the development of MS in these patients. We studied 119 OSAS patients and 119 controls. Participants were recruited and studied at sleep unit of our institution (Hospital Universitari Son Dureta, Palma de Mallorca, Spain) and were matched for sex, age and body mass index (BMI). The occurrence of MS was analysed by clinical criteria. Serum levels of FFAs, glucose, triglycerides, cholesterol, high-density lipoprotein–cholesterol, aspartate aminotransferase, alanine aminotransferase, &ggr;-glutamyltransferase, C-reactive protein and 8-isoprostanes were determined. Prevalence of MS was higher in OSAS than in the control group (38 versus 21%; p = 0.006). OSAS patients had higher FFAs levels than controls (mean±sd 12.2±4.9 versus 10.5±5.0 mg·dL−1; p = 0.015). Among subjects without MS, OSAS patients (OSAS+ MS-) showed higher levels of FFAs than controls (OSAS- MS-) (11.6±4.7 versus 10.0±4.4 mg·dL−1; p = 0.04). In a multiple regression model, after adjustment for age, sex, BMI and the presence of MS, FFAs were significantly associated with apnoea/hypopnoea index (p = 0.04). This study shows that FFAs are elevated in OSAS and could be one of the mechanisms involved in the metabolic complications of OSAS.

Blood pressure improvement with continuous positive airway pressure is independent of obstructive sleep apnea severity

STUDY OBJECTIVES We sought to perform a patient-level meta-analysis using the individual patient data of the trials identified in our previous study-level meta-analysis investigating the effect of positive airway pressure (PAP) treatment for obstructive sleep apnea (OSA) on blood pressure (BP). DESIGN Patient-level meta-analysis. SETTING N/A. PARTICIPANTS 968 adult OSA subjects without major comorbidities drawn from eight randomized controlled trials. INTERVENTIONS Therapeutic PAP versus non-therapeutic control conditions (sham-PAP, pill placebo or standard care) over at least one week. MEASUREMENTS AND RESULTS The mean reductions in BP between PAP and non-therapeutic control arms were -2.27 mm Hg (95% CI -4.01 to -0.54) for systolic BP and -1.78 mm Hg (95% CI -2.99 to -0.58) for diastolic BP. The presence of uncontrolled hypertension at baseline was significantly associated with a reduction in systolic BP of 7.1 mm Hg and diastolic BP of 4.3 mm Hg after controlling for OSA severity (apnea-hypopnea index, Epworth Sleepiness Scale score, PAP level), patient demographics (age, gender, body mass index, use of antihypertensive medication/s), and measures of PAP efficacy (PAP adherence and treatment duration). CONCLUSIONS OSA patients with uncontrolled hypertension are likely to gain the largest benefit from PAP in terms of a substantial reduction in BP, even after controlling for disease severity.

Long-term adherence to continuous positive airway pressure therapy in non-sleepy sleep apnea patients

OBJECTIVE The effectiveness of continuous positive airway pressure (CPAP) therapy greatly depends on consistent use. However, data regarding adherence in non-sleepy obstructive sleep apnea (OSA) patients are scarce. The aim of this study was to assess long-term adherence and predictors of CPAP compliance in a large sample of non-sleepy OSA patients. METHODS We conducted a prospective, multicenter study comprising 357 non-sleepy patients (Epworth Sleepiness Scale score <11) with moderate-to-severe OSA (apnea-hypopnea index [AHI] of ≥20) who began CPAP therapy between May 2004 and May 2006; follow-up ended in May 2009. Non-compliance was scored as CPAP dropout or average cumulative CPAP use of <4 hours per night. Multivariate Cox regression analysis was performed to identify independent predictors of poor CPAP adherence. RESULTS Patients were followed up for a median of four years (interquartile range [IQR] = 3.0-4.4). At the end of the study period, 230 patients (64.4%) fulfilled the criteria for good CPAP compliance, whereas 127 patients (35.6%) were considered non-compliant. The median CPAP use was five hours per night (interquartile range = 2.18-6.25). Multivariate analysis showed that interactions between the AHI and the percentage of nighttime spent with an O2 saturation of <90% (TC90) (p = 0.010) and between the AHI and hypertension at baseline (p = 0.029) predicted long-term compliance with CPAP. CONCLUSION This study demonstrates that CPAP treatment is feasible in non-sleepy, moderate-to-severe OSA patients. Good CPAP adherence was predicted by greater OSA severity as measured by both the AHI and TC90 and by the presence of hypertension at baseline in patients with higher AHI levels.

Relationship Between OSA and Hypertension

There is a bidirectional association between OSA and systemic hypertension. The strengths of this relationship appear to be modulated by factors such as age, sex, and somnolence. The 24-h BP circadian pattern also appears to be influenced by OSA. Patients with this syndrome exhibit a high prevalence of nondipping or riser circadian patterns, which are related to clinical and subclinical organ damage in the heart and brain. However, the influence of OSA on nocturnal hypertension development has not yet been clarified. A special area of interest is the recognized relationship between OSA and resistant hypertension. The majority of patients with resistant hypertension suffer OSA. CPAP treatment significantly reduces BP in such patients and could play a clinical role in the management of BP in these patients. Several meta-analyses have demonstrated a concordant mild effect of CPAP on systemic hypertension. This effect is related to CPAP compliance, somnolence status, and baseline BP. The effects of oral appliances on BP in patients with OSA must be evaluated in randomized controlled trials. In the absence of additional data reported by clinical studies on other antihypertensive drug treatments, diuretics, particularly antialdosteronic diuretic agents, should be considered the first-line antihypertensive drug treatment in patients with OSA. By reducing parapharyngeal edema and secondary upper airway obstruction, these drugs appear to improve OSA severity and also to reduce BP.

Role of primary care in the follow-up of patients with obstructive sleep apnoea undergoing CPAP treatment: a randomised controlled trial

Objective To evaluate whether follow-up of patients with obstructive sleep apnoea (OSA) undergoing CPAP treatment could be performed in primary care (PC) settings. Design Non-inferiority, randomised, prospective controlled study. Settings Sleep unit (SU) at the University Hospital and in 8 PC units in Lleida, Spain. Participants Patients with OSA were randomised to be followed up at the SU or PC units over a 6-month period. Main outcomes measured The primary outcome was CPAP compliance at 6 months. The secondary outcomes were Epworth Sleep Scale (ESS) score, EuroQoL, patient satisfaction, body mass index (BMI), blood pressure and cost-effectiveness. Results We included 101 patients in PC ((mean±SD) apnoea–hypopnoea index (AHI) 50.8±22.9/h, age 56.2±11 years, 74% male) and 109 in the SU (AHI 51.4±24.4/h, age 55.8±11 years, 77% male)). The CPAP compliance was (mean (95% CI) 4.94 (4.47 to 5.5) vs 5.23 (4.79 to 5.66) h, p=0.18) in PC and SU groups, respectively. In the SU group, there were greater improvements in ESS scores (mean change 1.79, 95% CI +0.05 to +3.53, p=0.04) and patient satisfaction (−1.49, 95% CI −2.22 to −0.76); there was a significant mean difference in BMI between the groups (0.57, 95% CI +0.01 to +1.13, p=0.04). In the PC setting, there was a cost saving of 60%, with similar effectiveness, as well as a decrease in systolic blood pressure (−5.32; 95% CI −10.91 to +0.28, p=0.06). Conclusions For patients with OSA, treatment provided in a PC setting did not result in worse CPAP compliance compared with a specialist model and was shown to be a cost-effective alternative. Trial registration number Clinical Trials NCT01918449.

The relationship between floppy eyelid syndrome and obstructive sleep apnoea

Purpose To determine the prevalence of eyelid hyperlaxity and floppy eyelid syndrome (FES) in obstructive sleep apnoea (OSA), and the presence of OSA in FES. Participants One-hundred and fourteen patients who had been consecutively admitted for OSA evaluation and 45 patients with FES in which sleep studies were recorded. Methods Subjects underwent eyelid laxity measurement, slit-lamp examination and polysomnography. Results Eighty-nine patients were diagnosed of OSA. Fourteen patients with OSA had FES (16%) and 54/89 (60.67%) had eyelid hyperlaxity. Two of the 25 non-OSA patients had FES (8%) and 8 of 25 (32%) had eyelid hyperlaxity. There was a significantly higher incidence of eyelid hyperlaxity in OSA than in non-OSA patients (p=0.004). Thirty-eight of the 45 patients with FES were diagnosed of OSA (85%) and 65% had severe OSA. Conclusions OSA might be an independent risk factor for eyelid hyperlaxity and severe OSA is common in patients with FES.

Plasma levels of neuropeptides and metabolic hormones, and sleepiness in obstructive sleep apnea

BACKGROUND Obstructive sleep apnea (OSA) is related to obesity and metabolic disorders. The main clinical symptoms are excessive daytime sleepiness (EDS) and snoring. However, not all patients with OSA manifest EDS. Hypocretin-1, neuropeptide Y, leptin, ghrelin and adiponectin are implicated in both metabolic and sleep regulation, two conditions affected by OSA. We hypothesized that levels of these peptides may be related to EDS in OSA patients. METHODS We included 132 patients with EDS, as defined by an Epworth Sleepiness Scale (ESS) score ≥ 13 (mean ± SD, 15.7 ± 2.3) and 132 patients without EDS as defined by an ESS score ≤ 9 (6.5 ± 1.9). All patients had an apnea-hypopnea index (AHI) ≥ 20 h(-1). Both groups were matched for gender (males; 83.3% vs. 85.6%), age (50.15 ± 11.2 yrs vs. 50.7 ± 9.9 yrs), body mass index (BMI) (31.8 ± 5.6 kg m(-2) vs. 32.1 ± 4.8 kg m(-2)), and apnea-hypopnea index (AHI) (45.5 ± 19.1 h(-1) vs. 43 ± 19.2 h(-1)). RESULTS OSA patients with EDS showed significantly higher plasma hypocretin-1 levels (p < 0.001) and lower plasma ghrelin levels (p < 0.001) than OSA patients without EDS. There were no statistically significant differences in neuropeptide Y (p = 0.08), leptin (p = 0.07) and adiponectin (p = 0.72) between the two groups. In the multiple linear regression model ESS score was associated with plasma levels of hypocretin-1, ghrelin and total sleep time. CONCLUSION Our study shows that EDS in patients with OSA is associated with increased circulating hypocretin-1 and decreased circulating ghrelin levels, two peptides involved in the regulation of body weight, energy balance, sympathetic tone and sleep-wake cycle. This relationship is independent of AHI and obesity (two key phenotypic features of OSA).

Vitamin D status and parathyroid hormone levels in patients with obstructive sleep apnea.

Background: Vitamin D insufficiency and high levels of parathyroid hormone (PTH) appear to be emerging risk factors for metabolic syndrome (MS), diabetes and cardiovascular disease, conditions that occur frequently in patients with obstructive sleep apnea syndrome (OSAS). Objectives: This study examined whether serum concentrations of 25-hydroxyvitamin D [25(OH)D] and PTH were associated with the presence of MS, diabetes and hypertension among an OSAS population. Methods: A total of 826 patients (635 men and 191 women) with newly diagnosed OSAS were studied. The occurrence of the MS was analyzed according to the National Cholesterol Education Program Adult Treatment Panel III clinical criteria. Serum levels of 25(OH)D, PTH, glucose, triglycerides, cholesterol, HDL cholesterol, creatinine and uric acid were determined. Results: In 55.3% of the men and in 63.2% of the women, the serum 25(OH)D level was less than 30 ng/ml (insufficient status). After adjusting for age, sex and seasonality, there was a significant trend of decreasing odds for diabetes [odds ratio (OR) 0.55, 95% confidence interval (CI) 0.33-0.94, ptrend = 0.038] and MS (OR 0.34, 95% CI 0.21-0.56, ptrend < 0.001) with increasing vitamin D levels. Higher PTH levels were associated with a higher prevalence of obesity (OR 2.05, 95% CI 1.06-3.09, ptrend < 0.001) and hypertension (OR 1.83, 95% CI 1.01-3.05, ptrend = 0.049). Conclusions: These data suggest an inverse association of 25(OH)D with diabetes and MS and a positive association of PTH with obesity and hypertension among patients with OSAS. Based on our observational study, the causative nature of the associations cannot be established. These findings require further examination in prospective studies including clinical trials.