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BACKGROUND The recent discovery that a combination of noradrenergic and antimuscarinic drugs improved upper airway muscle function during sleep and reduced OSA severity has revitalized interest in pharmacologic therapies for OSA. RESEARCH QUESTION Would 1 week of reboxetine plus oxybutynin (Reb-Oxy) be effective on OSA severity? STUDY DESIGN AND METHODS A randomized, placebo-controlled, double-blind, crossover trial was performed comparing 4-mg reboxetine plus 5-mg oxybutynin (Reb-Oxy) vs placebo in patients with OSA. After a baseline in-laboratory polysomnogram (PSG), patients underwent PSGs after 7 nights of Reb-Oxy and 7 nights of placebo to compare apnea-hypopnea index (AHI), which was the primary outcome. Response rate was based on the percentage of subjects with a ≥ 50% reduction in AHI from baseline. Secondary outcomes included Epworth Sleepiness Scale (ESS) score and psychomotor vigilance test (PVT) values. Home oximetry evaluated overnight oxygen desaturation index (ODI) throughout treatment. RESULTS Sixteen subjects aged 57 [51-61] years (median [interquartile range]) with a BMI of 30 [26-36] kg/m2 completed the study. Reb-Oxy lowered AHI from 49 [35-57] events per hour at baseline to 18 [13-21] events per hour (59% median reduction) compared with 39 [29-48] events per hour (6% median reduction) with placebo (P < .001). Response rate for Reb-Oxy was 81% vs 13% for placebo (P < .001). Although ESS scores were not significantly lowered, PVT median reaction time decreased from 250 [239-312] ms at baseline to 223 [172-244] ms on Reb-Oxy vs 264 [217-284] ms on placebo (P < .001). Home oximetry illustrated acute and sustained improvement in the oxygen desaturation index on Reb-Oxy vs placebo. INTERPRETATION The administration of Reb-Oxy greatly decreased OSA severity and increased vigilance. These results highlight potential possibilities for pharmacologic treatment of OSA. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov; No.: NCT04449133; URL: www.clinicaltrials.gov.

Hypertension control still remains a largely unmet challenge for public health systems. Despite the progress in blood pressure (BP) measurement techniques, and the availability of effective and safe antihypertensive drugs, a large number of hypertensive patients are not properly identified, and a significant proportion of those who receive antihypertensive treatment fail to achieve satisfactory control of their BP levels. It is thus not surprising that hypertension is still a major contributor to disease burden and disability worlwide, even in developed countries. This paper will address current challenges in hypertension management and potential strategies for an improvement in this field. In its first part relevant issues related to hypertension diagnosis will be addressed, in particular how to improve identification of sustained BP elevation and specific BP phenotypes such as white coat and masked hypertension trough the combined use of office and out-of-office BP monitoring techniques. In its second part focus will be on how to improve achievement of hypertension control in treated patients by optimization and simplification of medication regimens, including more efficient selection and titration of antihypertensive drugs and their combinations, aimed at achieving a more consistent 24hBP control; and by favoring a more active patients' and physicians' involvement in hypertension management also through BP telemonitoring and mobile health technologies.

Background The higher cardiovascular variability and the increased prevalence of arrhythmias in patients with obstructive sleep apneas may contribute to their higher rate of fatal events during sleep. In this regard, the use of beta blockers (BB) is debated because they may induce bradyarrhythmias and alter the pattern of heart rate changes induced by apneas. Thus, the aim of our study is to quantify peri‐apneic heart‐rate swings and prevalence of nocturnal bradyarrhythmias in BB‐treated and BB‐naïve patients with obstructive sleep apnea. Methods and Results Our real‐life, retrospective, cohort study analyzed data from patients with obstructive sleep apnea after a basal cardiorespiratory polysomnography. Among 228 eligible participants, we enrolled 78 BB‐treated and 88 BB‐naïve patients excluding those treated with antiarrhythmic drugs or pacemakers, or with uninterpretable ECG traces during polysomnography. In each patient, type and frequency of arrhythmias were identified and peri‐apneic changes of RR intervals were evaluated for each apnea. BB‐treated patients were older and with more comorbidities than BB‐naïve patients, but had similar obstructive sleep apnea severity, similar frequency of arrhythmic episodes, and similar prevalence of bradyarrhythmias. Apnea‐induced heart‐rate swings, unadjusted for age, showed lower RR interval changes in BB‐treated (133.5±63.8 ms) than BB‐naïve patients (171.3±87.7 ms, P =0.01), lower RR interval increases during apneas (58.5±28.5 versus 74.6±40.2 ms, P =0.01), and lower RR interval decreases after apneas (75.0±42.4 versus 96.7±55.5 ms, P Conclusions BB appear to be safe in patients with obstructive sleep apnea because they are not associated with worse episodes of nocturnal bradyarrhythmias and even seem protective in terms of apnea‐induced changes of heart rate.

Aims: Exercise oscillatory ventilation (EOV) is a pivotal cardiopulmonary exercise test parameter for the prognostic evaluation of patients with chronic heart failure (HF). It has been described in patients with HF with reduced ejection fraction (50%, HFpEF), but no data are available for patients with HF with mid-range ejection fraction (40–49%, HFmrEF). The aim of the study was to evaluate the prognostic role of EOV in HFmrEF patients. Methods and results: We analysed 1239 patients with HFmrEF and 4482 patients with HFrEF, enrolled in the MECKI score database, with a 2-year follow-up. The study endpoint was the composite of cardiovascular death, urgent heart transplant, and ventricular assist device implantation. We identified EOV in 968 cases (16% and 17% of cases in HFmrEF and HFrEF,. respectively). HFrEF EOV+ patients were significantly older, and their parameters suggested a more severe HF than HFrEF EOV− patients. A similar behaviour was found in HFmrEF EOV+ vs. EOV− patients. Kaplan–Meier analysis, irrespective of ejection fraction, showed that EOV is associated with a worse survival, and that patients with HFrEF and HFmrEF EOV+ had a significantly worse outcome than the EOV− of the same ejection fraction groups. EOV-associated survival differences in HFmrEF patients started after 18 months of follow-up. Conclusion: Exercise oscillatory ventilation has a similar prevalence and ominous prognostic value in both HFmrEF and HFrEF patients, indicating a group of patients in need of a more intensive follow-up and a more aggressive therapy. In HFmrEF, the survival curves between EOV+ and EOV− patients diverged only after 18 months.

Background and Purpose: An accurate determination of the cardioembolic risk in patients with atrial fibrillation (AF) is crucial to prevent consequences like stroke. Obstructive sleep apnea (OSA) is a known risk factor for both AF and stroke. We aim to explore a possible association between OSA and an increased cardioembolic risk in patients with AF. Methods: We assessed data from the ESADA (European Sleep Apnea Database) cohort where patients with known AF and OSA were included. Parameters of OSA severity and related hypoxia like lowest Sp o 2 and 4% oxygen desaturation index were analyzed. Patients were stratified according to their cardioembolic risk estimated with the CHA 2 DS 2 -VASc score. Results: From the initial cohort of 14 646 patients, a final set of 363 patients were included in the analysis. Indices of hypoxia during sleep were associated with increased CHA 2 DS 2 -VASc score (4% oxygen desaturation index 17.9 versus 29.6 versus 30.5 events/hour and the lowest Sp o 2 81.2 versus 77.8 versus 77.5% for low, moderate, and high cardioembolic risk, respectively, P Conclusions: These results support the potential role of OSA-related hypoxia in the risk for cardioembolic complications such as stroke in patients with AF.

Introduction Positive airway pressure (PAP) treatment modifies blood pressure (BP) in patients with obstructive sleep apnea (OSA). We aimed to explore which factors that influence the BP response to PAP therapy in the European Sleep Apnea Database (ESADA). Methods A total of 2662 OSA patients with PAP therapy ≥90 days were included in the analysis (74% male, age 55±11 years, body mass index 32.3±6.1 kg/m2, 47% hypertensives, apnea-hypopnea index 40±24 events/h, treatment duration 1.0±1.1 years, PAP compliance 5.2±1.9 h/day). Anthropometric data, co-medications and office BP were assessed at baseline and follow-up visit. Results Systolic and diastolic BP were modestly reduced after PAP therapy compared to baseline (133±17 vs. 134±17 mmHg, 78±11 vs. 81±11 mmHg, p2 kg at follow up (−2.0 [−3.7 to −0.4], p=0.016), and use of auto-adjusted PAP (−1.3 [−2.5 to −0.02], p=0.046) were associated with a reduction of systolic BP at follow-up. Conclusions BP reduction following PAP treatment in patients with moderate to severe OSA was modest. We identified several predictors of a favorable BP response including the use of auto adjusted PAP. Our findings suggest that weight reduction strategies in addition to PAP treatment should be considered to obtain adequate BP control in OSA patients. Funding Acknowledgement Type of funding source: Other. Main funding source(s): European Respiratory Society funded Clinical Research Collaboration (2015-2020)

Aims Risk stratification in heart failure (HF) is crucial for clinical and therapeutic management. A multiparametric approach is the best method to stratify prognosis. In 2012, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score was proposed to assess the risk of cardiovascular mortality and urgent heart transplantation. The aim of the present study was to compare the prognostic accuracy of MECKI score to that of HF Survival Score (HFSS) and Seattle HF Model (SHFM) in a large, multicentre cohort of HF patients with reduced ejection fraction. Methods and results We collected data on 6112 HF patients and compared the prognostic accuracy of MECKI score, HFSS, and SHFM at 2- and 4-year follow-up for the combined endpoint of cardiovascular death, urgent cardiac transplantation, or ventricular assist device implantation. Patients were followed up for a median of 3.67 years, and 931 cardiovascular deaths, 160 urgent heart transplantations, and 12 ventricular assist device implantations were recorded. At 2-year follow-up, the prognostic accuracy of MECKI score was significantly superior [area under the curve (AUC) 0.781] to that of SHFM (AUC 0.739) and HFSS (AUC 0.723), and this relationship was also confirmed at 4 years (AUC 0.764, 0.725, and 0.720, respectively). Conclusion In this cohort, the prognostic accuracy of the MECKI score was superior to that of HFSS and SHFM at 2- and 4-year follow-up in HF patients in stable clinical condition. The MECKI score may be useful to improve resource allocation and patient outcome, but prospective evaluation is needed.

Treatment of obstructive sleep apnoea (OSA) has been shown to reduce blood pressure (BP). However, the effect size is modest and treatment of OSA is not recommended as the only treatment target when treating hypertension. The aim of this systematic review and meta-analysis was to identify potential predictors for BP response in patients with OSA undergoing CPAP treatment. A systematic search was conducted in three databases (MEDLINE, Embase and Web of Science) between January 1st 1960 to December 31st 2017 using terms exploring three domains (obstructive sleep apnoea, CPAP, clinical trial) Out of 2445 articles, 59 RCTs were included (n=7,329 subjects) comparing CPAP with control groups. CPAP was associated with a net reduction in systolic BP of -2.12 (95% CI -2.82 to -1.42) mmHg and in diastolic BP of -1.97 (95% CI -2.46 to -1.48) mmHg, favouring treatment of OSA using CPAP (both p-values Younger patients (

Background: Acute exposure to high altitude (>2500 m) is known to induce a rise in blood pressure (BP) and the appearance of sleep related breathing alterations, in particular central sleep apneas and periodic breathing. Little information is available on whether this is the case in humans also for acute exposure to moderate altitude (between 1500 and 2500 m). Aim of this study was to evaluate the effects of acute exposure of healthy volunteers to moderate altitude on conventional and ambulatory BP as well as on the frequency and severity of breathing alterations during sleep. Methods: Forty-four healthy lowlanders underwent 24-hour ambulatory BP monitoring and nocturnal cardio-respiratory sleep study at sea level and during acute (1–2 days after arrival) exposure to moderate altitude (2035 m, Sestriere, Italy). The key variables investigated included average systolic and diastolic BP and heart rate over daytime, night-time and 24 h, the frequency of obstructive and central apneas/hypopnoeas and the behaviour of oxygen saturation during sleep. Results: Compared to sea level, during moderate altitude exposure mean systolic/diastolic BP increased significantly during daytime (respectively from 125.6 ± 10.9 to 130.6 ± 12.3, p = 0.0032 and from 78.8 ± 6.7 to 81.8 ± 7.7 mmHg, p = 0.0048) and during night-time (respectively from 102.4 ± 12.4 to 107.4 ± 12.7, p = 0.0028, and from 62.0 ± 8.2 to 65.8 ± 8.2 mmHg, p = 0.0014), with no change in nocturnal BP dipping. BP increase was more evident in participants aged over 40 years. Apnea-hypopnea index (AHI) increased from 1.60 (0.40–2.90) to 5.4 (2.90–10.60), p < 0.0001), mainly because of increasing frequency of hypopneas and central apneas, in particular in males aged over 40 years. No association was found between size of BP changes and AHI. Conclusion: Our results indicate that in healthy subjects even exposure to moderate altitude may induce significant, although mild, changes in ambulatory BP and in respiratory patterns during sleep with gender and age-related differences. Further studies are needed to explore the clinical relevance of these findings

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in women.Some authors highlighted that the female risk profile consists of traditional and emerging risk factors. Despite the lower prevalence of type 2 diabetes, years of life lost owing to the disease for women are substantially higher compared with men. In addition, pregnancy complicated by gestational diabetes represents a risk factor for CVD. Women with gestational diabetes have a higher prevalence of coronary artery disease that occur at a younger age and are independent of T2DM.Hypertension is an important cardiovascular risk factor in women. Estrogens and progesterone, known to have an impact on blood pressure levels, have also been proposed to be protective against sleep-disordered breathing. It is very difficult to understand whereas obstructive sleep apnea in women is independently associated with hypertension or if many confounders acting at different stages of the woman lifespan mediate this relation.The cardioprotective effect of physical activity in women of all ages is well known. Women are generally more physically inactive than men. During and after menopause, most women tend to reduce their physical activity levels and together with the reduction in basal metabolic rate, women experience loss of skeletal muscle mass with a negative change in the ratio of fat-to-lean mass.In conclusion, sex differences in the cardiovascular system are because of dissimilarities in gene expression and sex hormones; these result in variations in prevalence and presentation of CVD and associated conditions, such as diabetes, hypertension and vascular and cardiac remodeling.Changes in lifestyle and increase in physical activity could help in prevention of cardiovascular disease in women.

Awareness of the importance of sleep-related disorders in patients with cardiovascular diseases is growing. In particular, sleep-disordered breathing, short sleep time, and low sleep quality are frequently reported by patients with heart failure (HF). Sleep-disordered breathing, which includes obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is common in patients with HF and has been suggested to increase the morbidity and mortality in these patients. Both OSA and CSA are associated with increased sympathetic activation, vagal withdrawal, altered haemodynamic loading conditions, and hypoxaemia. Moreover, OSA is strongly associated with arterial hypertension, the most common risk factor for cardiac hypertrophy and failure. Intrathoracic pressure changes are also associated with OSA, contributing to haemodynamic alterations and potentially affecting overexpression of genes involved in ventricular remodelling. HF treatment can decrease the severity of both OSA and CSA. Indeed, furosemide and spironolactone administration, exercise training, cardiac resynchronization therapy, and eventually heart transplantation have shown a positive effect on OSA and CSA in patients with HF. At present, whether CSA should be treated and, if so, which is the optimal therapy is still debated. By contrast, more evidence is available on the beneficial effects of OSA treatment in patients with HF.

Background and purpose: Both obstructive sleep apnea (OSA) and cardiac organ damage have a crucial role in acute ischemic stroke. Our aim is to explore the relationship between OSA and cardiac organ damage in acute stroke patients. Methods: A total of 130 consecutive patients with acute ischemic stroke were enrolled. Patients underwent full multichannel 24-h polysomnography for evaluation of OSA and echocardiography to evaluate left ventricle (LV) mass index (LV mass/BSA, LV mass/height 2.7), thickness of interventricular septum (IVS) and posterior wall (LVPW), LV ejection fraction and left atrium enlargement. Information on occurrence of arterial hypertension and its treatment before stroke was obtained from patients' history. Results: 61.9% (70) of patients, mostly men (67.1%), with acute stroke had OSA (AHI > 10). Patients with acute stroke and OSA showed a significant increase (P < 0.05) of LV mass index, IVS and LVPW thickness and a significant left atrial enlargement as compared with patients without OSA. LV ejection fraction was not significantly different in stroke patients with and without OSA and was within normal limits. No relationship was found among cardiac alterations, occurrence of OSA and history of hypertension. Conclusion: Acute stroke patients with OSA had higher LV mass and showed greater left atrial enlargement than patients without OSA. This study confirms the high prevalence of OSA in stroke patients, suggesting also an association between OSA and cardiac target organ damage. Our finding of structural LV abnormalities in acute stroke patients with OSA suggests a potential role of OSA as contributing factor in determining both cerebrovascular and cardiac damage, even in absence of clear link with a history of blood pressure elevation.

Background Acute exposure to high‐altitude hypobaric hypoxia induces a blood pressure rise in hypertensive humans, both at rest and during exercise. It is unclear whether this phenomenon reflects specific blood pressure hyperreactivity or rather an upward shift of blood pressure levels. We aimed at evaluating the extent and rate of blood pressure rise during exercise in hypertensive subjects acutely exposed to high altitude, and how these alterations can be counterbalanced by antihypertensive treatment. Methods and Results Fifty‐five subjects with mild hypertension, double‐blindly randomized to placebo or to a fixed‐dose combination of an angiotensin‐receptor blocker (telmisartan 80 mg) and a calcium‐channel blocker (nifedipine slow release 30 mg), performed a cardiopulmonary exercise test at sea level and after the first night's stay at 3260 m altitude. High‐altitude exposure caused both an 8 mm Hg upward shift ( P P P P Conclusions In hypertensive subjects exposed to high altitude, we observed a hypoxia‐driven upward shift and steepening of the blood pressure response to exercise. The effect of the combination of telmisartan/nifedipine slow release outweighed these changes and was associated with better muscle oxygen delivery. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01830530.

Background Recent advances in wearable technology make continuous cardiorespiratory monitoring possible, with potential applications in assessment of cardiopulmonary patients, healthy subjects and athletes. The aim of the present study was to qualitatively and quantitatively evaluate a new wearable device (Learn Inspire Free Entertain = L.I.F.E.) by embedding in a compression shirt a 12‑lead ECG system and 5 respiratory sensors. Methods Thirty cardiorespiratory patients and ten healthy subjects were studied for 24 h during their usual life activities. In 8 healthy subjects, simultaneous measurements of the device and of an ergo-spirometer were performed during different levels of ventilation in five different body positions. The quality of ECG signals in terms of measurability of heart rate, P wave, QRS complex and ST segment, was analyzed by four expert cardiologists/respiratory physiologists using an arbitrary 1–5 scale. The sum of the respiratory signals was used to calculate the respiratory rate, inspiratory time and relative changes of tidal volume. These parameters were compared to ergo-spirometer measurements. Results Median quality value was >3 for heart rate, QRS complex, ST segment and P wave (except in L3, aVL, aVF, V1 and V2 leads). Median quality of respiratory traces was >4 in patients and between 3 and 4 in healthy subjects. The respiratory monitoring of respiratory rate and inspiratory time was accurate in all body positions. Tidal volumes were underestimated due to a high level of ventilation. Conclusions The L.I.F.E. device provides an accurate continuous monitoring of cardiorespiratory signals during the 24 h both in normal subjects and cardiorespiratory patients.

In heart failure (HF) sleep problems and sleep-related breathing disorders are frequently reported and are associated with poor prognosis. However, only few large clinical studies have investigated this issue in heart failure through breathing pattern analysis by polysomnography. Background: In heart failure (HF) sleep problems and sleep-related breathing disorders are frequently reported and are associated with poor prognosis. However, only few large clinical studies have investigated this issue in heart failure through breathing pattern analysis by polysomnography. Methods and results: 370 HF patients, with either moderate-severe reduced ejection fraction or with clinical decompensation, consecutively referred to 10 participating cardiology centers, have been enrolled in the PROMISES Study, an Italian project aimed at generating a large, multidisciplinary database of anthropometric, clinical, echocardiographic and sleep data, the last derived from overnight unattended cardio-respiratory polysomnography in HF patients. Obstructive sleep apnea was the most frequent form of sleep related breathing disorders observed in our cohort (35.4% with an AHI cutoff of 15). The possible determinants of sleep related breathing disorders were analyzed through stepwise logistic regression analysis and two multivariate models showing that a markedly reduced left ventricular ejection fraction was the most important factor associated with central sleep apneas (OR = 7.7 for AHI cutoff = 15 and LVEF ≤ 35%) together with male gender and increasing age. Conventional risk factors for obstructive sleep apnea did not identify HF patients affected by this condition. Conversely, a greater neck circumference was associated with an increased risk for central apneas. Conclusions: Our paper offers a deeper insight into the features of SRBD and its determinants in HF patients, leading in turn to a better clinical management of these comorbid patients.

BACKGROUND Increasing left ventricular assist device (LVAD) pump speed according to the patient's activity is a fascinating hypothesis. This study analyzed the short-term effects of LVAD speed increase on cardiopulmonary exercise test (CPET) performance, muscle oxygenation (near-infrared spectroscopy), diffusion capacity of the lung for carbon monoxide (D lco ) and nitric oxide (D lno ), and sleep quality. METHODS We analyzed CPET, D lco and D lno , and sleep in 33 patients supported with the Jarvik 2000 (Jarvik Heart Inc., New York, NY). After a maximal CPET (n = 28), patients underwent 2 maximal CPETs with LVAD speed randomly set at 3 or increased from 3 to 5 during effort (n = 15). Then, at LVAD speed randomly set at 2 or 4, we performed (1) constant workload CPETs assessing O2 kinetics, cardiac output (CO), and muscle oxygenation (n = 15); (2) resting D lco and D lno (n = 18); and (3) nocturnal cardiorespiratory monitoring ( n = 29). RESULTS The progressive pump speed increase raised peak volume of oxygen consumption (12.5 ± 2.5 ml/min/kg vs 11.7 ± 2.8 ml/min/kg at speed 3; p = 0.001). During constant workload, from speed 2 to 4, CO increased (at rest: 3.18 ± 0.76 liters/min vs 3.69 ± 0.75 liters/min, p = 0.015; during exercise: 5.91 ± 1.31 liters/min vs 6.69 ± 0.99 liters/min, p = 0.014), and system efficiency (τ = 65.8 ± 15.1 seconds vs 49.9 ± 14.8 seconds, p = 0.002) and muscle oxygenation improved. At speed 4, D lco decreased, and obstructive apneas increased despite a significant apnea/hypopnea index and a reduction of central apneas. CONCLUSIONS Short-term LVAD speed increase improves exercise performance, CO, O2 kinetics, and muscle oxygenation. However, it deteriorates lung diffusion and increases obstructive apneas, likely due to an increase of intrathoracic fluids . Self-adjusting LVAD speed is a fascinating but possibly unsafe option, probably requiring a monitoring of intrathoracic fluids.

BACKGROUND: The impact of treating OSA on renal function decline is controversial. Previous studies usually included small samples and did not consider specific effects of different CPAP modalities. The aim of this study was to evaluate the respective influence of fixed and autoadjusting CPAP modes on estimated glomerular filtration rate (eGFR) in a large sample of patients derived from the prospective European Sleep Apnea Database cohort. METHODS: In patients of the European Sleep Apnea Database, eGFR prior to and after follow-up was calculated by using the Chronic Kidney Disease-Epidemiology Collaboration equation. Three study groups were investigated: untreated patients (n = 144), patients receiving fixed CPAP (fCPAP) (n = 1,178), and patients on autoadjusting CPAP (APAP) (n = 485). RESULTS: In the whole sample, eGFR decreased over time. The rate of eGFR decline was significantly higher in the subgroup with eGFR above median (91.42 mL/min/1.73 m(2)) at baseline (P < .0001 for effect of baseline eGFR). This decline was attenuated or absent (P < .0001 for effect of treatment) in the subgroup of patients with OSA treated by using fCPAP. A follow-up duration exceeding the median (541 days) was associated with eGFR decline in the untreated and APAP groups but not in the fCPAP group (P < .0001 by two-way ANOVA for interaction between treatment and follow-up length). In multiple regression analysis, eGFR decline was accentuated by advanced age, female sex, cardiac failure, higher baseline eGFR, and longer follow-up duration, whereas there was a protective effect of fCPAP. CONCLUSIONS: fCPAP but not APAP may prevent eGFR decline in OSA.

Objective:Acute exposure to high/moderate altitude (HMA) induces increase in ambulatory blood pressure (BP), which may be particularly pronounced during the night, leading to reduced nocturnal BP dipping. Occurrence of central sleep apneas (CSA) is also typical for HMA exposure. Aim of this study wa

Background: Hypertension and severe obstructive sleep apnea (OSA)may independently contribute to left ventricular diastolic dysfunction. However, scanty data is available on this issue in hypertensives withmild.moderate OSA. Methods and results:Weperformed polysomnography, echocardiography and 24 h ambulatory blood pressure monitoring in 115 treated essential hypertensives with suspicion of OSA. After exclusion of severe/treated OSA and/or cardiovascular disease patients, mild.moderate OSA (5 ≥ apnoea/hypopnoea index b 30 events·h-1) was diagnosed in 47.3% of the remaining 91 patients, while 52.7% were free of OSA. Transmitral early (E) and late (A) peak flow velocities were assessed in 69 patients, and mitral annular velocity (E′) in 53. Compared to non- OSA, mild.moderate OSA heart rate was higher (p =0.031) while E/A was lower (p = 0.001) without differences in 24 h mean systolic and diastolic blood pressures (125.36 ± 12.46/76.46 ± 6.97 vs 128.63 ± 11.50/77.70 ± 7.72 mm Hg, respectively, NS). Patients with E′ > 10 cm/s and E/A > 0.8 showed a lower mean SpO2 than subjects with normal diastolic function (p = 0.004; p > 0.001). In a logistic regression model age, mean SpO2, daytime heart rate and nocturnal diastolic blood pressure fall were associated with altered relaxation pattern, independently from BMI and gender. Conclusions: In controlled hypertensives mild.moderate OSA may be associated with early diastolic dysfunction, independently from age, gender andmean blood pressure and in the absence of concentric left ventricular hypertrophy. Moreover nocturnal hypoxia may be a key factor in determining early diastolic dysfunction, under the synergic effects of hypertension and mild.moderate OSA.

BACKGROUND OSA is associated with an increased risk of cardiovascular morbidity. A driver of this is metabolic dysfunction and in particular type 2 diabetes mellitus (T2DM). Prior studies identifying a link between OSA and T2DM have excluded subjects with undiagnosed T2DM, and there is a lack of population-level data on the interaction between OSA and glycemic control among patients with diabetes. We assessed the relationship between OSA severity and T2DM prevalence and control in a large multinational population. METHODS We performed a cross-sectional analysis of 6,616 participants in the European Sleep Apnea Cohort (ESADA) study, using multivariate regression analysis to assess T2DM prevalence according to OSA severity, as measured by the oxyhemoglobin desaturation index. Patients with diabetes were identified by previous history and medication prescription, and by screening for undiagnosed diabetes with glycosylated hemoglobin (HbA1c) measurement. The relationship of OSA severity with glycemic control was assessed in diabetic subjects. RESULTS T2DM prevalence increased with OSA severity, from 6.6% in subjects without OSA to 28.9% in those with severe OSA. Despite adjustment for obesity and other confounding factors, in comparison with subjects free of OSA, patients with mild, moderate, or severe disease had an OR (95% CI) of 1.33 (1.04-1.72), 1.73 (1.33-2.25), and 1.87 (1.45-2.42) ( P P CONCLUSIONS Increasing OSA severity is associated with increased likelihood of concomitant T2DM and worse diabetic control in patients with T2DM.

Blood pressure (BP) is characterized by marked fl uctuations occurring within the 24 h as a result of complex interactions between behavioral, environmental, humoral, and neural central or refl ex infl uences. Signifi cant BP variations also occur over more prolonged periods of time (i.e. between days, weeks, months, seasons and even years), not as a random phenomenon but as a result of several interacting factors yet not completely identifi ed. Depending on the method and time interval considered for measurement, the clinical signifi cance and prognostic implications of different types of BP variability (BPV) may substantially differ. Either in the short or in the long term, BPV has been associated with development, progression and severity of cardiac, vascular and renal organ damage and with an increased risk of cardiovascular events and mortality, independently adding to cardiovascular risk, over and above the contribution of elevated mean BP levels. The present paper provides a review on the main methods currently employed for assessment of BPV as well as on the mechanisms, clinical interpretation and prognostic signifi cance of different types of BPV, addressing the question on whether BPV should be a target for antihypertensive treatment for the current prevention of cardiovascular disease.

Background: Little is known about the effects of cardiovascular drugs at high altitude. Objective: To assess 24-h blood pressure (BP) and heart rate (HR) during short-term altitude exposure in healthy normotensive persons treated with carvedilol or nebivolol. Methods: Participants were randomized in double-blind to placebo, nebivolol 5 mg once daily or carvedilol 25 mg b.i.d. Tests were performed at sea level (baseline and after 2 weeks treatment) and on second to third day at altitude (Monte Rosa, 4559 m), still on treatment. Data collection included conventional BP, 24-h ambulatory BP monitoring (ABPM), oxygen saturation (SpO2), Lake Louise Score and adverse symptoms score. Results: Twenty-four participants had complete data (36.4 ± 12.8 years, 14 men). Both beta-blockers reduced 24-h BP at sea level. At altitude 24-h BP increased in all groups, mainly due to increased night-time BP. Twenty-four-hour SBP at altitude was lower with carvedilol (116.4 ± 2.1 mmHg) than with placebo (125.8 ± 2.2 mmHg; P < 0.05) and intermediate with nebivolol (120.7 ± 2.1 mmHg; NS vs. others). Rate of nondipping increased at altitude and was lower with nebivolol than with placebo (33 vs. 71%; P = 0.065). Side effects score was higher with carvedilol than with placebo (P = 0.04), and intermediate with nebivolol. SpO2 at altitude was higher with placebo (86.1 ± 1.2%) than with nebivolol (81.7 ± 1.1%; P = 0.07) or carvedilol (81.1 ± 1.1%; P = 0.04). Conclusions: Both carvedilol and nebivolol partly counteract the increase in BP at altitude in healthy normotensive individuals but are associated with a lower SpO2. Carvedilol seems more potent in this regard, whereas nebivolol more effectively prevents the shift to a nondipping BP profile and is better tolerated. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Objective:To explore the effects of BB on nocturnal peri-apnoeic heart rate variability (HRV) and on arrhythmias in OSA patients.Design and method:Arrhythmias and increased cardiovascular V are highly prevalent in patients with obstructive sleep apneas (OSA), possibly resulting in fatal events, as s

AimsIt is unknown whether subclinical high-altitude pulmonary oedema reduces spontaneously after prolonged altitude exposure. Continuous positive airway pressure (CPAP) removes extravascular lung fluids and improves haemoglobin oxygen saturation in acute cardiogenic oedema. We evaluated the presence of pulmonary extravascular fluid increase by assessing CPAP effects on haemoglobin oxygen saturation under acute and prolonged altitude exposure.Methods and resultsWe applied 7 cm H2O CPAP for 30 min to healthy individuals after acute (Capanna Margherita, CM, 4559 m, 2 days permanence, and

Aims Previous studies investigating the effect of hypoxia on left ventricle focused on its global function, an approach that may not detect a selective dysfunction of subendocardial layers that are most sensitive to an inadequate oxygen supply. In the HIGHCARE study, aimed at exploring the effects of high altitude hypoxia on multiple biological variables and their modulation by an angiotensin receptor blocker, we addressed the effects of hypobaric hypoxia on both systolic and diastolic left ventricular geometry and function, focusing on echocardiographic assessment of left ventricle twist to indirectly examine subendocardial left ventricular systolic function. Methods and results In 39 healthy subjects, physiological and echocardiographic variables, including left ventricular twist and a simplified torsion-to-shortening ratio (sTSR), were recorded at sea level, at 3400 m, and at 5400 m altitude (Mount Everest base camp). Both left ventricular twist and sTSR were greater at 5400 m than at sea level (12.6° vs. 9.6° and 0.285 vs. 0.202, P < 0.05 for both), were linearly related to the reduction in arterial oxygen partial pressure ( P < 0.01 for both), and were associated with significant changes in LV dimensions and contractility. No effects of angiotensin receptor blockade were observed on these variables throughout the study. Conclusion Our study, for the first time, demonstrates an increase in left ventricular twist at high altitude in healthy subjects exposed to high altitude hypoxia, suggesting the occurrence of subendocardial systolic dysfunction in such condition.

Central sleep apnea (CSA) is reported in advanced heart failure (HF) [(1)][1]. At least 3 factors have been suggested to play a pivotal role in CSA pathogenesis, specifically hyperventilation, which is the likely consequence of an enhanced stimulation of intrapulmonary receptors; low cardiac output

Background: Patients with obstructive sleep apnea (OSA) are characterized by deranged cardiovascular variability, a well-established marker of cardiovascular risk. While long-term treatment with continuous positive airway pressure leads to a significant improvement of cardiovascular variability, little is known of the possibility of achieving the same results with other therapeutic approaches. The aim of our study was to investigate the responses of autonomic indexes of neural cardiac control to another type of OSA treatment based on an oral jawpositioning appliance. Methods: In 10 otherwise healthy subjects with OSA (OSA ) and in 10 subjects without OSA (OSA ) we measured heart rate, BP, and indices of autonomic cardiac regulation derived from time-domain and spectral analysis of R-R interval (RRI), before and after 3 months of treatment with the oral device. High-frequency (HF) power of RRI was taken as an index of parasympathetic cardiac modulation, and the ratio between low-frequency (LF) and HF RRI powers as an indirect marker of the balance between sympathetic and parasympathetic cardiac modulation. Results: At baseline, in comparison with OSA subjects, OSA subjects displayed a significantly lower RRI variance (p < 0.02) and reduced HF RRI powers (p < 0.001). After 3 months of treatment with the oral device, the OSA group showed a marked reduction in apnea-hypopnea index (p < 0.001), a lengthening in RRI and a significant increase in its variance (p < 0,02), an increased HF RRI power (from 134 26 to 502 48 ms2, p < 0.001), and a reduction in LF/HF RRI power ratio (from 3.11 0.8 to 1.5 0.5). As a result of these changes, after the 3-month treatment there were no more significant differences between the two groups in these parameters. In both OSA and OSA groups, body weight, heart rate, and BP did not change over time. Conclusions: Three months of treatment with a specific oral jaw-positioning appliance improves cardiac autonomic modulation in otherwise healthy patients with OSA of mild degree.

E vidence is available that the frequency and severity of arterial hypertension, and, in general, of cardiovascular diseases, bear a relationship with sleep disorders and, more specifically, with sleep duration [1,2]. Indeed, on the one side patients with cardiovascular diseases often complain of a number of sleep disturbances, including sleep fragmentation, insomnia, and breathing disorders during sleep. On the other side, patients with sleep complaints seem to be more frequently affected by cardiovascular problems. Given such a complex bidirectional relationship between these phenomena, it is therefore often difficult to determine which is the cause and which is the effect between cardiovascular problems and sleep disorders. Sleep-related breathing disorders, and, in particular, obstructive sleep apnea (OSA) syndrome, formerly named Pickwickian syndrome [3], are among the most common problems occurring during sleep in the general population, with at least 4% of middle-aged men and 2% of middle-aged women being affected in the developed world, its prevalence is increasing in parallel with the increasing prevalence of obesity [4–6]. A number of studies have shown OSA to be strictly related to the presence of hypertension and to represent an independent risk factor for the development of a high blood pressure (BP) condition [5,6]. Evidence of a relationship between arterial hypertension and excessive daytime somnolence has also been provided [7,8], whereas sleep fragmentation and a reduction in nocturnal sleep duration have been identified as factors majorly responsible for the increased sympathetic activity and the occurrence of elevated BP levels extending during daytime [9,10]. Given the large number of papers demonstrating the complex and multiple links relating sleep disorders and sleep duration with the occurrence of high BP levels, it is somehow surprising that only limited evidence has been up

Aim Many hypertensive subjects travel to high altitudes, but little is known on ambulatory blood pressure (ABP) changes and antihypertensive drugs' efficacy under acute and prolonged exposure to hypobaric hypoxia. In particular, the efficacy of angiotensin receptor blockers in this condition is unknown. This may be clinically relevant considering that renin–angiotensin system activity changes at altitude. The HIGHCARE-HIMALAYA study assessed changes in 24 h ABP under acute and prolonged exposure to increasing altitude and blood pressure-lowering efficacy and safety of an angiotensin receptor blockade in this setting. Methods and results Forty-seven healthy, normotensive lowlanders were randomized to telmisartan 80 mg or placebo in a double-blind, parallel group trial. Conventional and Ambulatory BPs were measured at baseline and on treatment: after 8 weeks at sea level, and under acute exposure to 3400 and 5400 m altitude, the latter upon arrival and after 12 days (Mt. Everest base camp). Blood samples were collected for plasma catecholamines, renin, angiotensin, and aldosterone. In both groups, exposure to increasing altitude was associated with: (i) significant progressive increases in conventional and 24 h blood pressure, persisting throughout the exposure to 5400 m; (ii) increased plasma noradrenaline and suppressed renin–angiotensin–aldosterone system. Telmisartan lowered 24 h ABP at the sea level and at 3400 m (between-group difference 4.0 mmHg, 95% CI: 2.2–9.5 mmHg), but not at 5400 m. Conclusion Ambulatory blood pressure increases progressively with increasing altitude, remaining elevated after 3 weeks. An angiotensin receptor blockade maintains blood pressure-lowering efficacy at 3400 m but not at 5400 m.

AIMS Heart failure is a widespread syndrome involving several organs, still characterized by high mortality and morbidity, and whose clinical course is heterogeneous and hardly predictable.In this scenario, the assessment of heart failure prognosis represents a fundamental step in clinical practice. A single parameter is always unable to provide a very precise prognosis. Therefore, risk scores based on multiple parameters have been introduced, but their clinical utility is still modest. METHODS In this review, we evaluated several prognostic models for acute, right, chronic, and end-stage heart failure based on multiple parameters. In particular, for chronic heart failure we considered risk scores essentially based on clinical evaluation, comorbidities analysis, baroreflex sensitivity, heart rate variability, sleep disorders, laboratory tests, echocardiographic imaging, and cardiopulmonary exercise test parameters. RESULTS What is at present established is that a single parameter is not sufficient for an accurate prediction of prognosis in heart failure because of the complex nature of the disease. However, none of the scoring systems available is widely used, being in some cases complex, not user-friendly, or based on expensive or not easily available parameters. CONCLUSION We believe that multiparametric scores for risk assessment in heart failure are promising but their widespread use needs to be experienced.

There is evidence of an important mutual interaction between sleep disorders and cardiovascular problems. Patients with cardiovascular diseases often complain of several sleep disturbances such as sleep fragmentation, insomnia and breathing disorders during sleep. On the contrary, patients with sleep disorders are more frequently affected by cardiovascular problems. Such a reciprocal interaction makes it often difficult to determine which is the cause and which is the effect between these conditions. Sleep-related breathing disorders, particularly obstructive sleep apnoea syndrome (OSAS), formerly named Pickwickian syndrome, are highly prevalent in the general population, OSAS affecting at least 4% of middle-aged men and 2% of middle-aged women in the developed world, with its prevalence increasing in parallel with the growing prevalence of obesity. Individuals with OSAS are also characterized by a worsened quality of life and by excessive daytime somnolence, and are at an increased risk of road traffic and workplace accidents when compared with nonapnoeic individuals [1–3]. From a public health viewpoint, also the reported increased risk of cardiovascular morbidity and mortality associated with a diagnosis of obstructive sleep apnoea (OSA) is of particular importance [4,5]. OSA is associated with a higher prevalence of hypertension, in particular resistant hypertension, myocardial infarction, cardiac arrhythmias, congestive heart failure and stroke. Indeed, untreated severe OSA confers a three-fold increased risk of death from cardiovascular causes [1,2,6]. Prevalence of hypertension in OSA patients ranges from 35 to 80% and appears to be influenced by OSA severity. In fact, more than 60% of individuals with respiratory disturbance index greater than 30 were found to be hypertensive. Conversely, approximately 40% of hypertensive patients are diagnosed with OSA. Finally, when focussing on patients with resistant hypertension, OSA prevalence is significantly higher, reaching 83% [7]. Given this background, and the relevant interaction between OSA and cardiovascular disorders, it is evident that strategies for OSA treatment also play a key role in cardiovascular diseases prevention.

infarction, ventricular arrhythmias and sudden death, which reach a maximum in the early morning after awakening [3]. Other cardiovascular effects of sleep follow cyclic changes during the night, being associated with the occurrence of specific sleep stages. In fact, physiological sleep is composed by a phase of nonrapid eye movements (NREM), with a predominant parasympathethic tone, followed by a rapid eye movement (REM) phase, with autonomic tone similar to the awake phase. The sequence of NREM/REM phases repeats cyclically, with four or five cycles occurring every night, REM phases appearing longer at the end than at the beginning of sleep. The associated cyclic changes of autonomic tone influence importantly heart rate, blood pressure, cardiac output and peripheral resistance. Circadian variations and cyclic changes in sleep stages probably interact with each other.

AimsWe assessed the haemodynamic changes induced by exposure to high altitude hypoxia and the effects on them of acetazolamide, a drug prescribed to prevent and treat mountain sickness.Methods and resultsIn 42 subjects (21 males, age 36.8 ± 8.9 years) randomized to double blind acetazolamide 250 mg b.i.d. or placebo, pulse wave velocity and pulse wave parameters were assessed (PulsePen) at baseline; after 2-day treatment at sea level; within 6 h and on 3rd day of exposure to high altitude. Exposure to high altitude significantly increased diastolic (P < 0.005) and mean blood pressure (BP) (P < 0.05, after prolonged exposure) in placebo but not in the acetazolamide group. Therefore, subjects on acetazolamide showed significantly lower values of diastolic (P < 0.005) and mean BP (P < 0.05) at altitude. Furthermore, they also showed significantly lower values of systolic BP (P < 0.05). Pulse wave velocity did not change at high altitude, while the augmentation index, normalized for a theoretical heart rate of 75 b.p.m., significantly increased (P < 0.05) under placebo, but not under acetazolamide. In a multivariate model, unadjusted augmentation index at high altitude was not affected by BP changes, while significant determinants were heart rate and gender.ConclusionAcute exposure to high altitude induced a rise in brachial BP and changes in pulse waveform-derived parameters, independent from changes in mean BP and partly counteracted by treatment with acetazolamide. The impact of acetazolamide on the haemodynamic alterations induced by hypobaric hypoxia may be considered among the beneficial effects of this drug in subjects prone to mountain sickness.Clinical Trial Registration: EudraCT Number: 2010-019986-27

Blood pressure (BP) is characterized by marked short-term fluctuations occurring within a 24 h period (beat-to-beat, minute-to-minute, hour-to-hour, and day-to-night changes) and also by long-term fluctuations occurring over more-prolonged periods of time (days, weeks, months, seasons, and even years). Rather than representing 'background noise' or a randomly occurring phenomenon, these variations have been shown to be the result of complex interactions between extrinsic environmental and behavioural factors and intrinsic cardiovascular regulatory mechanisms. Although the adverse cardiovascular consequences of hypertension largely depend on absolute BP values, evidence from observational studies and post-hoc analyses of data from clinical trials have indicated that these outcomes might also depend on increased BP variability (BPV). Increased short-term and long-term BPV are associated with the development, progression, and severity of cardiac, vascular, and renal damage and with an increased risk of cardiovascular events and mortality. Of particular interest are the findings from post-hoc analyses of large intervention trials in hypertension, showing that within-patient visit-to-visit BPV is strongly prognostic for cardiovascular morbidity and mortality. This result has prompted discussion on whether antihypertensive treatment should be targeted not only towards reducing mean BP levels but also to stabilizing BPV with the aim of achieving consistent BP control over time, which might favour cardiovascular protection.

Awareness, treatment, and control of hypertension are characterized by different prevalence according to sex and race. Although women demonstrate higher rates of awareness and treatment of hypertension as compared with men, they are less frequently controlled with the administered antihypertensive treatment. 1 Moreover, as shown in the same survey, non-Hispanic black women compared with their non-Hispanic white and Mexican American counterparts, were characterized by higher rates of hypertension awareness, treatment and control. 1 Despite these epidemiologic observations, hypertension remains still nowadays largely uncontrolled, despite improved treatment, a condition occurring also in women and defined as the hypertension paradox by Chobanian. 2 Such a paradox requires more efforts to address a number of yet unmet needs in this field. First, the commonly recommended but largely neglected lifestyle modifications should be more effectively promoted. Second, the doctor’s time spent with the patients has to be improved, both quantitatively and qualitatively. Finally, the issue of inadequate hypertension control should also be revisited through a patient-centric approach. This approach might be particularly important in postmenopausal women because of the accelerated age-related increase in the incidence of hypertension, in the progress of arterial stiffening, and in the rate of fatal cardiovascular events, especially after the age of 65 years. 1 In the present issue of The Journal of Clinical Hypertension, Doner Lotenberg and colleagues 3 describe the results obtained by mapping the journey of postmenopausal women going through the steps required to diagnose and manage a high blood pressure (BP) condition. Authors, through analysis of an online survey, examined the experiences in this regard of 300 postmenopausal women with at least 6-year lasting hypertension. These data were extracted from a structured questionnaire focusing on hypertension diagnosis and monitoring, on hypertension treatment, and on long-term disease management. The main findings of the present study 3 confirm the low adherence of these women to treatment, the inadequate rate of lifestyle intervention counseling by health care providers, and the limited use of home BP monitoring to measure routinely out-of-office BP levels, especially in the elderly. Additionally, the finding that the diagnosis of hypertension was made in the majority of women (77%) during a check-up or a sick visit also demonstrates that prehypertension is not regularly searched. This omission to follow the increasing BP changes with aging are partially driven by the inadequacy of educational programs focusing on regular BP measurements and by the widespread belief that prehypertensive BP levels should generally be overlooked. The authors also report that a high clinical suspicion of hypertension or the identification of patients with prehypertension should be corroborated by out-of-office BP measurements (eg, measurements in pharmacies, grocery stores, or health clubs) that are more easily accessible in the general population setting than measurements by physicians.