Somers, Virend K.

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder, characterized by recurrent upper airway obstruction during sleep, resulting in intermittent hypoxia, increased sympathetic activation, and sleep deficiency. Over the past 2 decades, there has been a robust body of evidence to support a strong link between OSA and cardiometabolic diseases. Obesity is an important risk factor for OSA. Observational studies indicate that OSA is a strong risk factor for the development of hypertension and diabetes. Moreover, clinical and experimental studies support a causal role of OSA in hypertension and impairments in glucose metabolism, beyond excess weight. Notably, OSA is particularly underdiagnosed and undertreated in women, which may heighten the cardiometabolic risk. OSA is often overlooked during pregnancy and has been linked to adverse cardiometabolic outcomes in observational studies. In randomized clinical trials, treatment of OSA with continuous positive airway pressure reduces blood pressure in individuals with hypertension, but the beneficial effects of continuous positive airway pressure on glycemic outcomes are less convincing. Inconsistent cardiometabolic response to OSA treatment can be partly explained by failure to consider heterogeneity in OSA and variable continuous positive airway pressure adherence among diverse populations. In this review, we summarize the relationships between OSA and cardiometabolic conditions with a particular focus on obesity, hypertension, and diabetes. We review the current knowledge on the heterogeneity in OSA and discuss potential underlying mechanisms for impairments in blood pressure and glucose metabolism in OSA. We also provide a clinical perspective for OSA management considering current research gaps and emerging approaches for the prevention and treatment of cardiometabolic disease.

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, with its incidence rising due to aging populations, obesity, and advancements in diagnostic modalities. The interplay between sleep disorders and AF is increasingly recognized, with obstructive sleep apnea (OSA) serving as a well-established risk factor. However, emerging evidence implicates additional sleep disturbances—including central sleep apnea, insomnia, and restless legs syndrome—in AF pathogenesis and progression. Despite compelling observational data, interventional studies evaluating the impact of sleep disorder treatment on AF outcomes have yielded mixed results. Although continuous positive airway pressure therapy in patients with OSA mitigates AF recurrence, randomized controlled trials have yet to confirm a definitive causal benefit. This review synthesizes epidemiological, mechanistic, and interventional data linking sleep disorders to AF.

INTRODUCTION: The increased likelihood of adverse cardiovascular events (CVE) shortly after awakening has been partially attributed to low nitric oxide (NO) production in the early morning. Thus, increasing early morning NO levels to improve vascular function could reduce adverse CVE incidence, especially among older adults as total NO production declines with aging. The increased adverse CVE among post-menopausal women (PMW) are likely due to a steeper decline in their vascular function. As inorganic nitrate increases circulating NO levels for up to 12hrs, our primary hypothesis was to determine if nocturnal inorganic nitrate supplementation improves early morning vascular function relative to a placebo in eight generally healthy adults (6F, 37±5yrs, 26.9±1.8kg/m 2 ). Our secondary hypothesis was that PMW (n=3, 27.1±4.3kg/m 2 ), identified by their age (71±2yrs) and follicle-stimulating hormone levels (72.3±8.0mIU/mL), would show greater improvements in their vascular function compared to younger participants (n=5, 3F, 28±2yrs, 26.8±2.0kg/m 2 ). METHODS: Written informed consent was obtained from all participants before data collection. Participants completed three overnight study visits: Visit 1 was for acclimation with vascular function assessments occurring during Visits 2 and 3. During the latter visits, participants consumed beetroot juice with (6.45mmol) or devoid of (0mmol) inorganic nitrate at 2200 in randomized, cross-over fashion followed by vascular function assessments post-awakening (0630-0800) while participants were supine. Vascular assessments consisted of brachial blood pressure, aortic augmentation index (AIx), carotid-femoral pulse wave velocity (cfPWV), and endothelial function (FMD). Data were compared using a paired-samples t-test (α<0.05). RESULTS: Systolic (125±4 vs. 126±6mmHg, p=0.35) and diastolic (71±2 vs. 72±2mmHg, p=0.32) blood pressure were similar the morning after nitrate and placebo. Additionally, AIx (31±5 vs. 33±6%, p=0.29) and FMD (n=7, 8.8±2.0 vs. 7.6±1.7%, p=0.25) were not different the morning after nitrate and placebo consumption. However, cfPWV was lower the morning following nitrate consumption relative to the placebo (6.3±0.5 vs. 6.9±0.6m/s, p=0.01). A sub-group analysis of PMW showed that both systolic (132±6 vs. 139±9mmHg, p=0.18) and diastolic (70±3 vs. 75±2mmHg, p=0.09) blood pressure tended to be lower following nitrate relative to the placebo whereas AIx (46±1 vs. 50±5%, p=0.31) and FMD (n=2, 8.5±2.7 vs. 6.9±1.6%, p=0.78) did not differ; however, cfPWV was lower the morning after nitrate consumption (7.4±0.9 vs. 8.4±1.1m/s, p=0.02) in PMW but not in the younger participants (5.6±0.4 vs. 6.0±0.3m/s, p=0.23). CONCLUSION: Acute nocturnal inorganic nitrate supplementation lowers aortic stiffness in the early morning, especially among PMW. Although the differences in systolic (7mmHg) and diastolic blood pressure (5mmHg) were not statistically significant, they remain clinically meaningful due to their magnitude. This may suggest a role for nocturnal nitrate supplementation in reducing early-morning adverse CVE among PMW. AHA 24POST1241616 (IMG), NIH K12 AR084222 (JMB), Sleep Research Society 038-JP-23 (JMB), and a grant from Sleep Number Corporation to Mayo Clinic for studies in Aging. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Somali Americans, originating from East Africa, are a fast-growing minority in the United States. Emerging data suggest Somali individuals exhibit increased cardiovascular (CV) risk compared to non-Hispanic White adults. Previous data from our laboratory demonstrated elevated ambulatory arterial stiffness in Somali Americans, as derived from 24-hour blood pressure monitoring. We sought to confirm these vascular stiffness findings via gold-standard applanation tonometry and examine potential sex differences, given that females of African ancestry are at elevated risk of CV disease (CVD). We therefore examined aortic hemodynamics and carotid-femoral pulse wave velocity in male and female Somali Americans. We hypothesized that female Somali Americans would present with greater aortic wave reflection and arterial stiffness compared to males. We further examined the accuracy of prediction of aortic wave reflection from a predominantly White population, when applied to the Somali American population. We utilized applanation tonometry to quantify arterial stiffness in 24 female (age: 27±10 years, BMI: 27±6 kg/m 2 ) and 19 male (age: 22±6 years, BMI: 27±5 kg/m 2 ) Somali Americans without CVD. Each participant arrived in the laboratory at Mayo Clinic, fasted for at least three hours, and did not consume caffeine or exercise for at least 12 hours prior to testing. After 15 minutes of supine rest, duplicate recordings of aortic blood pressure and augmentation index (AIx) were obtained via pulse wave analysis. Similarly, aortic stiffness was quantified via duplicate carotid-femoral pulse wave velocity recordings. Statistical analysis included independent samples t-tests to test for sex differences in aortic hemodynamics, and paired samples t-tests to determine differences between estimated and obtained AIx (α≤0.05). Aortic systolic arterial pressure (111±11 vs. 108±7 mmHg, p=0.295) was similar between female and male Somali Americans. Aortic diastolic arterial pressure (75±7 vs. 67±7 mmHg, p<0.001) and heart rate (67±9 vs. 57±7 beats/min, p<0.001) were higher in female Somali adults. Similarly, AIx (28±14 vs. 19±12%, p=0.045) and AIx normalized to 75 heart beats/minute (24±13 vs. 10±13%, p=0.001) were higher in female Somali Americans. Carotid-femoral pulse wave velocity (5.4±0.9 vs. 5.5±0.8 m/s, p=0.661) was similar between sexes. Estimated AIx (corrected for sex, age, height, and resting heart rate) was markedly lower than observed AIx in both female (13±7 vs. 28±14%, p<0.001) and male (6±5 vs. 19±12%, p<0.001) Somali Americans. These findings, obtained in young, healthy Somali adults are suggestive of elevated CVD risk, evident at an early age. These data are particularly concerning regarding vascular dysfunction in Somali females and suggest that prediction models for arterial stiffness should factor in race to optimize performance. Future work into mechanisms underlying vascular dysfunction in Somali Americans is warranted. Sleep Number Grant to Mayo Clinic and by NIH R01-HL160619, R01-HL169320, T32-DK007013, K12 AR084222, and AHA 24POST1241616. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

ABSTRACTBackgroundLate gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) imaging is a well‐established indicator of myocardial fibrosis in hypertrophic cardiomyopathy (HCM). However, its association with electrocardiographic (ECG) abnormalities and the risk of atrial fibrillation (AF) remains uncertain.ObjectivesTo investigate the association between the presence and burden of LGE with ECG characteristics, including precordial voltage, depolarization and repolarization abnormalities, and the incidence of AF in adults with HCM.MethodsWe conducted a retrospective cohort study of 144 adults with HCM with CMR and 12‐lead ECG within 30 days of each other. LGE was quantified as a percentage of LV mass and categorized as absent, < 5%, or ≥ 5%. ECG parameters, including QRS voltage, repolarization abnormalities, and LVH criteria, were analyzed. Incident AF was assessed during a median follow‐up of 6.6 years.ResultsLGE was present in 96 (67%) patients, with 21 (22%) having ≥ 5% LGE. There were no significant differences in precordial voltage between patients with and without LGE across Sokolow‐Lyon, Cornell, and Romhilt‐Estes criteria. However, T‐wave inversion was more common in leads I (41% vs. 19%, p = 0.009), aVL (50% vs. 31%, p = 0.033), and V4 (41% vs. 23%, p = 0.035) in patients with LGE. Patients with ≥ 5% LGE had a significantly lower median LVEF (64% vs. 74%, p = 0.003). Additionally, LGE presence was not associated with an increased risk of incident AF (HR 1.8, 95% CI 0.6–5.3, p = 0.308).ConclusionIn contrast to pediatric HCM, LGE is associated with specific ECG repolarization abnormalities, particularly T‐wave inversion in lateral leads, but does not significantly affect precordial voltage in adults.

Abstract Introduction Poor sleep quality is bidirectionally associated with cardiovascular and neurocognitive disorders. Preclinical data implicate nitric oxide (NO) in the onset, and maintenance, of sleep. Acute inorganic nitrate supplementation increases NO bioavailability via serial reduction for &gt;12hrs. We tested if objective (Aim 1) or subjective (Aim 2) sleep quality was better following acute, pre-sleep nitrate supplementation relative to a placebo. Methods Seven non-shift working adults (4F/3M, 40±8yrs, 25.8±1.6kg/m2) with no history of sleep, cardiovascular, or neurocognitive disorders completed three overnight polysomnography (PSG) visits with time in bed standardized to 2200-0600hrs. Visit 1 was for acclimation and screening for sleep-disordered breathing. On Visits 2 and 3, participants consumed beetroot juice containing (6.45mmol) or devoid of (0mmol) inorganic nitrate at 2200 using a randomized, cross-over study design. PSG-derived outcomes included slow-wave (SWS) and rapid eye-movement (REM) sleep, sleep efficiency, and wake after sleep onset (WASO). Subjective sleep quality assessments were administered in-laboratory including a 0-10 scale, the Stanford Sleepiness Scale (SSS), and performance with mental arithmetic shortly after awakening. Results No participant demonstrated evidence for sleep-disordered breathing (apnea-hypopnea index = 1.7±0.9events/hr). Total sleep time (TST, 434±17 vs. 412±19min), sleep efficiency (89±3 vs. 85±4%), as well as SWS duration (75±10 vs. 66±9min) and percent of TST (17±2 vs. 16±2%) were higher after nitrate relative to the placebo (p&lt; 0.05 for all). WASO (47±16 vs. 62±19min, p&lt; 0.05) was lower after nitrate versus placebo and no differences were seen in REM sleep duration (131±23 vs. 117±12min, p=0.45) nor percent of TST (30±5 vs. 29±3%, p=0.80). Neither the 0-10 scale (6.7±0.5 vs. 6.8±0.6units, p=0.84), SSS (2.6±0.4 vs. 2.5±0.3units, p=0.68), or arithmetic performance (82±3 vs. 81±5% correct, p=0.85) differed post-nitrate compared to post-placebo. Conclusion These data suggest that acutely increasing nocturnal NO levels via pre-sleep inorganic nitrate supplementation improves objective indices of sleep quality in healthy adults. However, greater amounts of nitrate or prolonged supplementation (weeks) may be needed to improve perceived sleep quality. Support (if any) The National Institutes of Health (K12 AR084222 to JMB, R01s HL160619 and HL65176 to VKS), Sleep Research Society Foundation (CDA 038-JP-23 to JMB), and the American Heart Association (24POST1241616 to IMG).

Abstract Introduction Cardiovascular disease (CVD) remains the leading cause of death in the United States. We previously showed a high prevalence of obstructive sleep apnea (OSA) among former National Football League (NFL) players. Further, we hypothesized that post-career OSA impacts CVD risk among retired professional athletes, even though these former NFL players are often near peak physical fitness for a significant portion of their lifespan. The Living Heart Foundation Heart-Obesity-Prevention-Education Group aimed to provide an in-depth health assessment for CVD risk factors among former NFL players to examine the role of OSA on blood pressure (BP) and echocardiographic measurements. Methods Forty-three former NFL players completed an at-home sleep study and outpatient health assessment to determine CVD risk including office BP and transthoracic echocardiogram (TTE) measurements. Seated BP readings were made in triplicate, TTE measurements, including ejection fraction, left atrial size, left ventricular size and thickness, and ascending aortic diameter, were obtained in 17 former NFL players without OSA (age: 46±10 years, BMI: 32±5 kg/m2, apnea-hypopnea index: 3±1 events/hour) and 26 with OSA (age: 51±9 years, BMI: 33±5 kg/m2, apnea-hypopnea index: 17±12 events/hour). Independent sample t-tests were utilized to determine differences in blood pressure and TTE measurements between OSA and non-OSA groups (α=0.05). Results Systolic BP was similar in non-OSA vs. OSA groups (131±12 vs. 135±16 mmHg, p=0.443), while diastolic BP was higher in former NFL players with OSA (78±8 vs. 86±9 mmHg, p=0.007). Ejection fraction, left atrial size, left ventricular size, and left ventricular thickness were similar between groups (p&gt;0.05 for all). However, ascending aortic diameter was modestly larger in former NFL players with OSA (3.3±0.19 vs. 3.5±0.40 cm, p=0.048). Conclusion These findings suggest OSA may be a primary driver of increased BP and increased aortic diameter in former NFL players, and impact cardiac structural health, suggesting augmented CVD risk in former NFL players. Future work is warranted to investigate impact of race and player position on OSA-mediated CVD risk in retired NFL players. Support (if any) NFL Players Association, NIH T32-DK007013, and the American Heart Association (24POST1241616)

Abstract Background: Obstructive sleep apnea (OSA) is associated with obesity and cardiovascular risk. Results from the SURMOUNT-OSA studies demonstrated significant reduction of a number of cardiometabolic risk measures in participants with OSA and obesity following treatment with tirzepatide. Objectives: Systematically analyze all tirzepatide treatment related changes of cardiometabolic risk measures in SURMOUNT-OSA studies and investigate to what extent these changes were mediated by reductions in weight and/or OSA-related measures. Methods: The SURMOUNT-OSA master protocol comprised two 52-week, randomized, double-blind, placebo-controlled Phase 3 studies. Study 1 (N=234) and 2 (N=235) included participants with moderate-to-severe OSA and obesity, who at screening reported not using, or using positive airway pressure (PAP) therapy, respectively. The design and rationale of the studies have been published previously (1). The current analysis investigated the association of treatment with tirzepatide or placebo with SURMOUNT-OSA pre-specified cardiometabolic risk measures including blood pressure, and levels of high-sensitivity C-reactive protein (hsCRP), HDL-C, non-HDL-C, triglycerides, fasting insulin. Further analyses included change in HOMA-IR with tirzepatide compared to placebo, and mediation analysis to determine the proportion of observed changes attributable to reductions in body weight, apnea-hypopnea index (AHI) and sleep apnea-specific hypoxic burden (SASHB). Results: In Study 1, participants experienced greater difference in change from baseline with tirzepatide compared to placebo in SBP (-7.9 mmHg; 95% CI -11.0 to -4.9; p<0.001), and DBP (-3.2 mmHg; 95% CI -5.4 to -1.0; p=0.005) at 48 weeks, and hsCRP (-28.9±8.2%; p=0.003), HDL-C (7.2±2.1%; p<0.001), non-HDL-C (-13.0±3.1%; p<0.001), triglycerides (-32.2±3.7%; p<0.001), fasting insulin (-41.4±5.0%; p<0.001), and HOMA-IR (-48.0±4.9%; p<0.001) at 52 weeks. In Study 2, participants experienced greater differences in change from baseline following tirzepatide compared to placebo in SBP (-4.3 mmHg; 95% CI -7.3 to -1.2; p=0.007) at 48 weeks, and hsCRP (-45.1±8.0%; p<0.001), HDL-C (10.0±2.8%; p<0.001), non-HDL-C (-14.3±2.5%; p<0.001), triglycerides (-31.5±3.7%; p<0.001), fasting insulin (-45.4±5.4%; p<0.001), and HOMA-IR (-54.8±5.0%; p<0.001) at 52 weeks. Statistically significant independent mediation effect of changes in OSA metrics was observed on hsCRP, HOMA-IR and triglycerides. In addition, the combination of changes in weight and OSA metrics, but not weight or OSA improvements alone, had a significant mediation effect on non-HDL-C. There was no significant mediation effect of weight or OSA metrics observed on DBP. Conclusions: In the SURMOUNT-OSA program trials, tirzepatide appeared to have significant cardiometabolic benefits for patients with moderate-to-severe OSA and obesity. Based on the mediation analysis, treating both sleep-disordered breathing and obesity is likely required to optimize cardiometabolic benefits for patients with OSA and obesity.

AbstractThe intricate role of the autonomic nervous system (ANS) in regulating cardiac physiology has long been recognized. Aberrant function of the ANS is central to the pathophysiology of cardiovascular diseases. It stands to reason, therefore, that neuroscience‐based cardiovascular therapeutics hold great promise in the treatment of cardiovascular diseases in humans. A decade after the inaugural edition, this White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology and pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases. image