Search

Sleep-disordered breathing (SDB), characterized by specific underlying physiological mechanisms, comprises obstructive and central pathophysiology, affects nearly 1 billion individuals worldwide, and is associated with excessive cardiopulmonary morbidity. Strong evidence implicates SDB in cardiac arrhythmogenesis. Immediate consequences of SDB include autonomic nervous system fluctuations, recurrent hypoxia, alterations in carbon dioxide/acid-base status, disrupted sleep architecture, and accompanying increases in negative intrathoracic pressures directly affecting cardiac function. Day-night patterning and circadian biology of SDB-induced pathophysiological sequelae collectively influence the structural and electrophysiological cardiac substrate, thereby creating an ideal milieu for arrhythmogenic propensity. Cohort studies support strong associations of SDB and cardiac arrhythmia, with evidence that discrete respiratory events trigger atrial and ventricular arrhythmic events. Observational studies suggest that SDB treatment reduces atrial fibrillation recurrence after rhythm control interventions. However, high-level evidence from clinical trials that supports a role for SDB intervention on rhythm control is not available. The goals of this scientific statement are to increase knowledge and awareness of the existing science relating SDB to cardiac arrhythmias (atrial fibrillation, ventricular tachyarrhythmias, sudden cardiac death, and bradyarrhythmias), synthesizing data relevant for clinical practice and identifying current knowledge gaps, presenting best practice consensus statements, and prioritizing future scientific directions. Key opportunities identified that are specific to cardiac arrhythmia include optimizing SDB screening, characterizing SDB predictive metrics and underlying pathophysiology, elucidating sex-specific and background-related influences in SDB, assessing the role of mobile health innovations, and prioritizing the conduct of rigorous and adequately powered clinical trials.

Background: Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variations to the QT interval in the population., Methods: We performed a genome-wide association study of the QTc in 84 630 UK Biobank participants and created a polygenic risk score (PRS). Among 26 976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed., Results: Fifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1 110 494 common variants was significantly associated with the QTc in TOPMed (ΔQTc /decile of PRS =1.4 ms [95% CI, 1.3 to 1.5]; P =1.1×10 -196 ). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc>480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS)., Conclusions: QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

Obstructive sleep apnea (OSA) is characterized by recurrent complete and partial upper airway obstructive events, resulting in intermittent hypoxemia, autonomic fluctuation, and sleep fragmentation. Approximately 34% and 17% of middle-aged men and women, respectively, meet the diagnostic criteria for OSA. Sleep disturbances are common and underdiagnosed among middle-aged and older adults, and the prevalence varies by race/ethnicity, sex, and obesity status. OSA prevalence is as high as 40% to 80% in patients with hypertension, heart failure, coronary artery disease, pulmonary hypertension, atrial fibrillation, and stroke. Despite its high prevalence in patients with heart disease and the vulnerability of cardiac patients to OSA-related stressors and adverse cardiovascular outcomes, OSA is often underrecognized and undertreated in cardiovascular practice. We recommend screening for OSA in patients with resistant/poorly controlled hypertension, pulmonary hypertension, and recurrent atrial fibrillation after either cardioversion or ablation. In patients with New York Heart Association class II to IV heart failure and suspicion of sleep-disordered breathing or excessive daytime sleepiness, a formal sleep assessment is reasonable. In patients with tachy-brady syndrome or ventricular tachycardia or survivors of sudden cardiac death in whom sleep apnea is suspected after a comprehensive sleep assessment, evaluation for sleep apnea should be considered. After stroke, clinical equipoise exists with respect to screening and treatment. Patients with nocturnally occurring angina, myocardial infarction, arrhythmias, or appropriate shocks from implanted cardioverter-defibrillators may be especially likely to have comorbid sleep apnea. All patients with OSA should be considered for treatment, including behavioral modifications and weight loss as indicated. Continuous positive airway pressure should be offered to patients with severe OSA, whereas oral appliances can be considered for those with mild to moderate OSA or for continuous positive airway pressure-intolerant patients. Follow-up sleep testing should be performed to assess the effectiveness of treatment.

Background: Blacks have a high prevalence of hypertension and uncontrolled blood pressure (BP), each of which may be partially explained by untreated sleep apnea. We investigated the association of sleep apnea with uncontrolled BP and resistant hypertension in blacks., Methods: Between 2012 and 2016, Jackson Heart Sleep Study participants (N=913) underwent an in-home Type 3 sleep apnea study, clinic BP measurements, and anthropometry. Moderate or severe obstructive sleep apnea (OSA) was defined as a respiratory event index ≥15, and nocturnal hypoxemia was quantified as percent sleep time with <90% oxyhemoglobin saturation. Prevalent hypertension was defined as either a systolic BP ≥130 mm Hg or diastolic BP >80mm Hg, use of antihypertensive medication, or self-report of a diagnosis of hypertension. Controlled BP was defined as systolic BP <130 mm Hg and diastolic BP <80 mm Hg; uncontrolled BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with use of 1 to 2 classes of antihypertensive medication; and resistant BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with the use of ≥3 classes of antihypertensive medication (including a diuretic) or use of ≥4 classes of antihypertensive medication regardless of BP level. Multinomial logistic regression models were fit to determine the association between OSA severity and uncontrolled BP or resistant hypertension (versus controlled BP) after multivariable adjustment., Results: The analytic sample with hypertension (N=664) had a mean age of 64.0 (SD,10.6) years, and were predominately female (69.1%), obese (58.6%), and college educated (51.3%). Among the sample, 25.7% had OSA, which was untreated in 94% of participants. Overall, 48% of participants had uncontrolled hypertension and 14% had resistant hypertension. After adjustment for confounders, participants with moderate or severe OSA had a 2.0 times higher odds of resistant hypertension (95% confidence interval [CI], 1.14-3.67). Each standard deviation higher than <90% oxyhemoglobin saturation was associated with an adjusted odds ratio for resistant hypertension of 1.25 (95% CI 1.01-1.55). OSA and <90% oxyhemoglobin saturation were not associated with uncontrolled BP., Conclusion: Untreated moderate or severe OSA is associated with increased odds of resistant hypertension. These results suggest that untreated OSA may contribute to inadequate BP control in blacks.

Emerging research highlights the complex interrelationships between sleep-disordered breathing and cardiovascular disease, presenting clinical and research opportunities as well as challenges. Patients presenting to cardiology clinics have a high prevalence of obstructive and central sleep apnea associated with Cheyne-Stokes respiration. Multiple mechanisms have been identified by which sleep disturbances adversely affect cardiovascular structure and function. Epidemiological research indicates that obstructive sleep apnea is associated with increases in the incidence and progression of coronary heart disease, heart failure, stroke, and atrial fibrillation. Central sleep apnea associated with Cheyne-Stokes respiration predicts incident heart failure and atrial fibrillation; among patients with heart failure, it strongly predicts mortality. Thus, a strong literature provides the mechanistic and empirical bases for considering obstructive sleep apnea and central sleep apnea associated with Cheyne-Stokes respiration as potentially modifiable risk factors for cardiovascular disease. Data from small trials provide evidence that treatment of obstructive sleep apnea with continuous positive airway pressure improves not only patient-reported outcomes such as sleepiness, quality of life, and mood but also intermediate cardiovascular end points such as blood pressure, cardiac ejection fraction, vascular parameters, and arrhythmias. However, data from large-scale randomized controlled trials do not currently support a role for positive pressure therapies for reducing cardiovascular mortality. The results of 2 recent large randomized controlled trials, published in 2015 and 2016, raise questions about the effectiveness of pressure therapies in reducing clinical end points, although 1 trial supported the beneficial effect of continuous positive airway pressure on quality of life, mood, and work absenteeism. This review provides a contextual framework for interpreting the results of recent studies, key clinical messages, and suggestions for future sleep and cardiovascular research, which include further consideration of individual risk factors, use of existing and new multimodality therapies that also address adherence, and implementation of trials that are sufficiently powered to target end points and to support subgroup analyses. These goals may best be addressed through strengthening collaboration among the cardiology, sleep medicine, and clinical trial communities., (© 2017 American Heart Association, Inc.)

Background: Risk factors for obstructive sleep apnea (OSA) and the development of subsequent cardiovascular (CV) complications differ by sex. We hypothesize that the relationship between OSA and high-sensitivity troponin T (hs-TnT), cardiac structure, and CV outcomes differs by sex., Methods and Results: Seven hundred fifty-two men and 893 women free of CV disease participating in both the Atherosclerosis Risk in the Communities and the Sleep Heart Health Studies were included. All participants (mean age, 62.5 ± 5.5 years) underwent polysomnography and measurement of hs-TnT. OSA severity was defined by using established clinical categories. Subjects were followed for 13.6 ± 3.2 years for incident coronary disease, heart failure, and CV and all-cause mortality. Surviving subjects underwent echocardiography after 15.2 ± 0.8 years. OSA was independently associated with hs-TnT among women (P=0.03) but not in men (P=0.94). Similarly, OSA was associated with incident heart failure or death in women (P=0.01) but not men (P=0.10). This association was no longer significant after adjusting for hs-TnT (P=0.09). Among surviving participants without an incident CV event, OSA assessed in midlife was independently associated with higher left ventricle mass index only among women (P=0.001)., Conclusions: Sex-specific differences exist in the relationship between OSA and CV disease. OSA, assessed in midlife, is independently associated with higher levels of concomitantly measured hs-TnT among women but not men, in whom other comorbidities associated with OSA may play a more important role. During 13-year follow-up, OSA was associated with incident heart failure or death only among women, and, among those without an incident event, it was independently associated with left ventricular hypertrophy only in women., (© 2015 American Heart Association, Inc.)

Background: Insomnia complaints are common in older adults and may be associated with mortality risk. However, evidence regarding this association is mixed. Thus, we prospectively examined whether men with insomnia symptoms had an increased risk of mortality during 6 years of follow-up., Methods and Results: A prospective cohort study of 23,447 US men participating in the Health Professionals Follow-Up Study and free of cancer, reported on insomnia symptoms in 2004, were followed through 2010. Deaths were identified from state vital statistic records, the National Death Index, family reports, and the postal system. We documented 2025 deaths during 6 years of follow-up (2004-2010). The multivariable-adjusted hazard ratios of total mortality were 1.25 (95% confidence interval [CI], 1.04-1.50) for difficulty initiating sleep, 1.09 (95% CI, 0.97-1.24) for difficulty maintaining sleep, 1.04 (95% CI, 0.88-1.22) for early-morning awakenings, and 1.24 (95% CI, 1.05-1.46) for nonrestorative sleep, comparing men with those symptoms most of the time with men without those symptoms, after adjusting for age, lifestyle factors, and presence of common chronic conditions. Men with difficulty initiating sleep and nonrestorative sleep most of the time had a 55% (hazard ratio, 1.55; 95% CI, 1.19-2.04; P-trend=0.01) and 32% (hazard ratio, 1.32; 95% CI, 1.02-1.72; P-trend=0.002) increased risk of cardiovascular disease mortality, respectively, relative to men without those symptoms., Conclusion: Some insomnia symptoms, especially difficulty initiating asleep and nonrestorative sleep, are associated with a modestly higher risk of mortality.

Background: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation., Methods and Results: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism., Conclusions: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.