Somers, Virend K.

Importance Sleep disordered breathing (SDB) is a well-established contributor to cardiovascular morbidity, mediated by intermittent hypoxemia, autonomic dysregulation, and endothelial dysfunction. Patients with hypertrophic cardiomyopathy (HCM) may be especially at risk for SDB, but the clinical impact of SDB in this population remains unclear. Objective To define the prevalence and subtypes of SDB in HCM and examine their association with echocardiographic parameters and cardiac biomarker expression. Design, Setting, and Participants A prospective cohort study was conducted between April 18, 2018, and January 15, 2024, at a single tertiary referral center specializing in HCM care. Adults with HCM (left ventricular wall thickness ≥15 mm or pathogenic variants) were recruited from an institutional registry. Patients diagnosed with SDB or current pregnancy were excluded. Patients underwent polysomnography, with comparative assessment of echocardiographic, electrocardiographic, and biomarker indices. Observers were blinded to polysomnographic results. Data analysis was performed from April 11, 2024, to July 25, 2024. Exposures SDB classified via polysomnography using apnea-hypopnea index thresholds, with subtypes including obstructive sleep apnea and central sleep apnea and with event severity, hypoxemia, and sleep architecture disruption quantified. Main Outcomes and Measures Echocardiographic indices, cardiac biomarker expression, functional status, apnea-hypopnea index, and overnight hypoxemia. Results Among 154 patients (median [IQR] age, 60 [48-68] years; 102 [66.2%] male), 91 (59.1%) were diagnosed with SDB. Those with SDB, compared with those without SDB, had higher left ventricular mass index (median [IQR], 128 [107-161] vs 109 [96-134] g/m 2 ; P = .03), E/e′ ratio (median [IQR], 12.5 [10.0-15.0] vs 10.0 [8.3-14.5]; P = .04), and baseline troponin-T level (median [IQR], 0.013 [0.009-0.022] vs 0.011 [0.007-0.015] ng/mL [to convert to micrograms per liter, multiply by 1]; P = .04) and greater overnight troponin-T level increases (change in median [IQR], 0.0021 [−0.0029 to 0.0062] vs 0.0002 [−0.0022 to 0.0026] ng/mL; P = .02). New York Heart Association class II or III symptoms were more common in those with SDB (48 [52.7%] vs 17 [27.0%]; P = .005). Hypertension and diabetes were more prevalent among patients with SDB than without SDB (hypertension: 67 [73.6%] vs 36 [57.1%]; P = .03; diabetes: 14 [15.4%] vs 3 [4.8%]; P = .04), whereas rates of atrial fibrillation and prior myectomy did not differ significantly between groups. Conclusions and Relevance This study suggests that undiagnosed SDB is highly prevalent in patients with HCM and that SDB is associated with adverse myocardial remodeling, greater diastolic dysfunction, and elevated troponin-T levels, indicating subclinical myocardial injury. SDB may contribute to HCM pathophysiology and symptom burden, supporting the rationale for randomized clinical trials to determine the impact of treating SDB on symptoms and clinical outcomes in patients with HCM.

Abstract Autonomic neural control of the cardiovascular system is formed of complex and dynamic processes able to adjust rapidly to mitigate perturbations in hemodynamics and maintain homeostasis. Alterations in autonomic control feature in the development or progression of a multitude of diseases with wide‐ranging physiological implications given the neural system's responsibility for controlling inotropy, chronotropy, lusitropy, and dromotropy. Imbalances in sympathetic and parasympathetic neural control are also implicated in the development of arrhythmia in several cardiovascular conditions sparking interest in autonomic modulation as a form of treatment. A number of measures of autonomic function have shown prognostic significance in health and in pathological states and have undergone varying degrees of refinement, yet adoption into clinical practice remains extremely limited. The focus of this contemporary narrative review is to summarize the anatomy, physiology, and pathophysiology of the cardiovascular autonomic nervous system and describe the merits and shortfalls of testing modalities available. © 2023 American Physiological Society. Compr Physiol 13:4493‐4511, 2023.

Abstract Aldosterone, a hormone synthesized by the adrenal glands, plays a pivotal role in regulating both blood pressure and electrolyte balance and may contribute to long term cardiovascular risk. Recent findings suggest that adipose tissue might serve as a source for aldosterone production and secretion. Patients suffering from obstructive sleep apnea (OSA) often exhibit elevated blood pressure levels and increased cardiovascular risk. Therefore, we sought to investigate whether increased aldosterone synthesis in fat tissue could contribute to the increase in hypertension and cardiovascular disease in OSA patients. To address this, we conducted a comparative analysis of adipocyte aldosterone level in OSA patients versus Age and BMI matched healthy individuals. Our data revealed no significant differences in aldosterone content between the two groups. Further examination involved measuring the expression of the key enzyme CYP11B2 responsible for aldosterone synthesis. We observed comparable expression levels of CYP11B2 in both the OSA and control groups. To corroborate these findings, we isolated stromal vascular fraction (SVF) from human fat tissues. The SVF cells were cultured in preadipocyte medium and subjected to normoxia and intermittent hypoxia (IH), mimicking OSA conditions as per established protocol. Subsequent analysis of aldosterone levels in cell lysates and conditioned medium revealed no significant differences. Similarly, in vitro examination of CYBP11B2 expression was not different in normoxic versus IH conditions. In conclusion, our study did not discern significant differences in adipocyte aldosterone production and secretion between patients with OSA and matched control subjects, nor in human preadipocytes under normoxic versus IH conditions.

Abstract Introduction Voluntary sleep curtailment decreases insulin sensitivity. However, molecular mechanisms underlying impaired insulin signaling are not completely understood. To gain molecular insights, we examined the transcription of known cellular insulin-signaling regulators in adipose tissue obtained from subjects undergoing experimental sleep restriction. Methods Nineteen healthy subjects (males: 11; age: 19 - 36 years; BMI: 24.5 ± 3.6 kg/m2) underwent a normal (9 hours/night) and a restricted sleep (4 hours/night) sequence in a random order. Each inpatient stay included a screen visit followed by 4 days of acclimation and 9 days of experimental phase consisting of a controlled sleep opportunity. Eucaloric diet was provided to ensure weight maintenance. Abdominal fat sample was obtained at the screen and end of the experimental phase. mRNA was quantified by RT-PCR. Fasting morning blood draws were obtained at the end of acclimation and experimental phases. Mixed models were used for analysis. Results mRNA expression did not differ in normal and restricted sleep condition for SOCS3 [changes in normal Vs. restricted sleep, 0.02 (0.11, -0.01) Vs. 0.01 (0.12, -0.07), p=0.33], PTEN [-0.22 (0.18, -0.39) Vs. -0.10 (0.21, -0.20), p=0.22], PTB1B [-0.003 (0.04, -0.07) Vs. -0.01 (0.06, -0.06), p=0.74] and Cav-1 [-2.45 (0.78, -8.39) Vs. -6.31 (1.68, -8.29), p=0.34]. Further, transcription of insulin-receptor also did not change [0.01 (0.07, -0.06) Vs. -0.03 (0.09, -0.07), p=0.92]. However, within group analysis show significant decreases in Cav-1 mRNA only during sleep restriction (normal: p=0.09; restricted: p=0.003). Importantly, restricting sleep duration was associated with lowering of insulin (0.6 ± 1.9 Vs. -1.6 ± 1.7 uIU/ml; p=0.003), no change in glucose (-1.5 ± 3.8 Vs. -3.7 ± 4.12 mg/dl, p=0.06) and improvement in HOMA-IR index (0.12 ± 0.44 Vs -0.42 ± 0.43, p=0.002). Conclusion Chronic sleep restriction does not alter the transcription of cell-signaling regulators in abdominal adipose tissue. Moreover, restricting sleep duration without increasing calorie intake did not seem to decrease insulin sensitivity as determined by HOMA-IR. Support NIH grants HL114676, Mayo Clinic CCaTS UL1 TR002377; AHA grant 13POST16420009 to NC

Abstract Introduction Sleep disordered breathing (SDB) is associated with adverse cardiovascular outcomes and decreased cardiorespiratory fitness (CRF). The risk of long-term major adverse cardiovascular events (MACE) when SDB and decreased CRF co-occur has not been determined. Methods We included consecutive patients that underwent a symptom-limited cardiopulmonary exercise test followed by first-time diagnostic polysomnography within 6 months. Patients were stratified based on the presence of moderate-severe SDB (apnea/hypopnea index ≥15/hour) and decreased CRF defined as <70% predicted peak oxygen consumption (VO2). MACE was a composite outcome of myocardial infarction (MI), coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), stroke/transient ischemic attack (TIA) and death. Cox-proportional hazard models adjusting for factors known to influence CRF and MACE were constructed. Results Of 498 included patients (60±13 years, 28.1% female), 175 (35%) had MACE (MI=17, PCI=14, CABG=13, stroke=20, TIA=12, deaths=99) at a median follow-up of 8.7 years (interquartile range=6.5-10.3 years). After adjusting for age, sex, beta-blockers, systemic hypertension, diabetes mellitus, coronary artery disease, cardiac arrhythmia, chronic obstructive pulmonary disease, smoking and positive airway pressure (PAP) usage, decreased CRF alone (HR=1.91, 95%CI=1.15-3.18, p=0.012), but not SDB alone (HR=1.26, 95%CI=0.75-2.13, p=0.389) was associated with increased risk of MACE. Those with SDB and decreased CRF had increased risk of MACE compared to patients with decreased CRF alone (HR=1.85, 95%CI=1.21-2.84, p<0.005) after accounting for these confounders; the risk was attenuated after additionally adjusting for adequate adherence to PAP (HR=1.85, 95%CI=0.99-3.05, p=0.05). Conclusion The incidence of MACE, including mortality, was high in this sample. Moderate-severe SDB with concurrent decreased CRF was associated with higher risk of MACE than decreased CRF alone. These results highlight the importance of including CRF in the risk assessment of patients with SDB, and conversely, that of screening for SDB in patients with low peak VO2. Support None.