Somers, Virend K.

Abstract Central sleep apnea, a rare polysomnographic finding in the general population, is prevalent in certain cardiovascular conditions including systolic and diastolic left ventricular dysfunction, atrial fibrillation, coronary artery disease, carotid artery stenosis, stroke, and use of certain cardiac-related medications. Polysomnographic findings of central sleep apnea with adverse cardiovascular impacts include nocturnal hypoxemia and arousals, which can lead to increased sympathetic activity both at night and in the daytime. Among cardiovascular diseases, central sleep apnea is most prevalent in patients with left ventricular systolic dysfunction; a large study of more than 900 treated patients has shown a dose-dependent relationship between nocturnal desaturation and mortality. Multiple small randomized controlled trials have shown mitigation of sympathetic activity when central sleep apnea is treated with nocturnal oxygen, continuous positive airway pressure, and adaptive servoventilation. However, two early randomized controlled trials with positive airway pressure devices have shown either a neutral effect on survival or excess premature mortality in the active treatment arm, compared to untreated central sleep apnea. In contrast, the results of the most recent trial using an advanced adaptive servoventilation device showed improved quality of life and no signal for mortality suggesting that treatment of central sleep apnea was at least safe. In addition to positive airway pressure devices, multiple medications have been shown to improve central sleep apnea, but no long-term trials of pharmacologic therapy have been published. Currently, phrenic nerve stimulation is approved for the treatment of central sleep apnea, and the results of a randomized controlled trial showed significant improvement in sleep metrics and quality of life.

Background: Mitral valve prolapse (MVP) is a common valvular abnormality. Observational studies demonstrate an association between MVP and increased risk of sudden cardiac death from ventricular arrhythmias, coined arrhythmogenic MVP. A genetic component has been postulated but remains under-investigated. Hypothesis: Predicted deleterious variants in Mendelian cardiomyopathy and arrhythmia genes are more frequent in arrhythmogenic MVP (aMVP) compared to non-arrhythmogenic MVP. Aims: To comprehensively phenotype and genotype a single-center aMVP cohort and compare to non-aMVP from two large population-based cohorts and investigate their clinical outcomes. Methods: The aMVP cohort included 46 prospectively enrolled patients from a regional referral center for inherited cardiovascular disease and had undergone multi-modality imaging and clinical gene panel testing. The non-aMVP comparator cohorts included 453 participants from the UK Biobank (UKBB), a prospective cohort of 500,000 UK residents, and 1,418 participants from the National Institutes of Health (NIH) All of Us (AoU), a prospective cohort of 450,000 USA participants. Gene variants were annotated in ANNOVAR. Participants with and without pathogenic/likely pathogenic (P/LP) variants reported on ClinVar with ≥2-star level of evidence were considered genotype positive (G+) and negative (G-) respectively. Results: The demographics for aMVP (age 61.2 ± 12.8 years, 56.5% female) and non-aMVP (UKBB: age 59.8 ± 7.3 years, 50.7% female and AoU: age 65.3 ± 13.4 years, 76.2% female) were comparable. G+ participants were more prevalent in the aMVP cohort 10/46 (21.7%) versus non-aMVP in the UKBB 8/453 (1.8%) and in the AoU 21/1418 (1.5%); p<0.001. The most frequently implicated gene in aMVP was TTN . Of 46 in aMVP cohort, 33 (71%) underwent CMR. G+ participants had a higher frequency of late gadolinium enhancement [6/6 (100%) vs. 14/27 (51.8%), p<0.001] and wall motion abnormalities [3/6 (50%) vs. 1/27 (3.7%), p<0.001] compared to G- participants. The aMVP cohort had significantly more implantable cardioverter defibrillator (ICD) implants compared to non-aMVP cohort [5/46 (10.9%) vs. 1/453 in UKBB (0.2%), p<0.001]. G+ aMVP cohort showed a trend for developing heart failure and ICD implants compared to G- aMVP . Conclusion: P/LP variants in cardiomyopathy and arrhythmia genes are more prevalent in aMVP participants compared to non-aMVP participants. This could be a hitherto unrecognized effect modifier predicting aMVP .

Background: Sleep disordered breathing (SDB) is frequently observed in patients with cardiovascular disease, and is associated with intermittent hypoxia, sympathetic activation, oxidative stress, and endothelial dysfunction, all of which may facilitate the development and progression of cardiovascular disease. Objectives: We sought to determine the prevalence, subtypes, and clinical implications of comorbid SDB in patients with hypertrophic cardiomyopathy (HCM). Methods: In this prospective observational study, patients with HCM without prior diagnosis of SDB were recruited to undergo inpatient polysomnography between May 1 st 2018 and October 31 st 2022. Electrocardiographic and echocardiographic parameters, cardiac biomarkers, and symptoms were comparatively assessed in patients with and without comorbid SDB. Patients were assessed for the development of major adverse cardiovascular events (MACE) during follow-up (median 29, range 3-57 months). Results Among 154 participants, 91 (59.1%) were diagnosed with SDB of whom 38 (41.8%) had mild, 22 (24.2%) moderate, 18 (19.8%) severe obstructive sleep apnea, and 13 (14.3%) had central sleep apnea. SDB was associated with greater left ventricular mass (median [IQR]) (128 [107, 161] vs. 109 [96, 134] g/m 2 , p =0.034) and E/e’ ratio (12.5 [10, 15] vs. 10.0 [8.3, 14.5], p =0.039). Patients with HCM over the age of 50 years, with body mass index ≥ 30kg/m 2 , who described their sleep as “poor” were at particularly high risk of having comorbid SDB, as were those who were diabetic, hypertensive, or described greater exertional limitation (NYHA Class ≥II 53% vs. 27%, p =0.005). Importantly, subjects with SDB had elevated baseline Troponin T levels (14 ng/L vs 11 ng/L, p =0.030), and further substantial overnight troponin increases following untreated apneic sleep (2.1ng/L vs 0.2ng/L, p =0.009). Finally, patients with comorbid SDB experienced a significantly higher proportion of incident adverse cardiovascular events (MACE hazard ratio 5.3, 95% CI, 1.6, 17.2, p =0.006) than those without SDB. Conclusions: We report a particularly high burden of previously undiagnosed SDB in patients with HCM, particularly in older, heavier, male patients. Undiagnosed SDB in HCM is not benign and is associated with symptom progression, comorbidity, and a poorer prognosis, particularly in the case of central sleep apnea. These important new findings provide rationale for heightened vigilance and routine screening for SDB in patients with HCM.

Introduction: Sleep duration is now recognized as an important determinant of cardiovascular (CV) health. Recently, the CV implications of day-to-day variability in sleep duration have become apparent, with irregular sleep duration associated with increased risk of CV disease, including hypertension. However, the relationship between sleep duration variability and ambulatory blood pressure (BP) patterns in the general population or in patients with CV disease is unknown. Research Questions: We sought to investigate whether irregular sleep duration is associated with aberrant ambulatory BP or heart rate (HR) profiles in patients undergoing cardiac rehabilitation (CR). Methods: We recruited a sample of 42 patients with coronary artery disease enrolled in CR at Mayo Clinic Rochester. Participants underwent 24-hour ambulatory BP monitoring and sleep assessment including one week of wrist actigraphy and sleep diary prior to entering CR. Twenty-four hour, awake, and asleep averages were calculated for systolic BP, diastolic BP, and HR. Nocturnal dipping and morning surge were also computed for BP and HR. Sleep regularity was quantified by SD of actigraphy-derived sleep duration and irregular sleep duration was defined as SD >1 hour. Chi-square tests and Mann-Whitney U tests were used to compare groups. Results: Thirty-six participants (22% females, median age [25 th ,75 th IQR] 66.5 [61,75.8] years, body mass index 31.7 [26.9,35.1] kg/m 2 ) had valid actigraphy and ambulatory BP recordings. We found sleep duration SD >1 hour in 36% of them. Demographics and average sleep duration were similar between those with irregular and regular sleep duration (all Ps>0.11). Twenty-four-hour, awake and asleep HR values were comparable between groups (all Ps>0.26). Participants with irregular sleep duration exhibited lower nocturnal HR dipping (9.2 [3.1,11.6] % vs 12.9 [8.9,18.2] %, P=0.019) than their counterparts with regular sleep. Morning HR surge was also attenuated in patients with irregular sleep duration (3 [-1,9] bpm vs 10 [7,14] bpm, P=0.006). Ambulatory SBP and DBP measures did not differ significantly between groups (all Ps>0.17). Conclusions: High day-to-day variability in sleep duration is linked to blunted nocturnal dipping and morning surge in HR in patients with coronary artery disease enrolled in CR. Because altered ambulatory HR profile predicts unfavorable CV outcomes, evaluation of sleep patterns in the CR setting may yield important prognostic information.

Background Hyperlipidemia is a major cardiovascular disease (CVD) risk factor, but there are limited data on its mortality trends in CVD over time. We assessed annual hyperlipidemia‐related CVD mortality trends in the United States, including the COVID‐19 pandemic's impact. Methods and Results Mortality data were obtained from the Centers for Disease Control and Prevention repository between 1999 and 2020 among patients ≥15 years old, using International Classification of Diseases, Tenth Revision ( ICD‐10 ) codes for hyperlipidemia (E78.0–E78.5) and CVD (I00–I99). Age‐adjusted mortality rates (AAMRs) per 1 000 000 population were standardized to the 2000 US population. Log‐linear regression models were used to evaluate mortality shifts. Average annual percentage change from 1999 to 2019 was used to project 2020 AAMRs, estimating pandemic‐attributed excess deaths. From 1999 to 2020, 483 155 hyperlipidemia‐related CVD deaths occurred. Despite a general CVD mortality decline, hyperlipidemia‐related CVD AAMRs rose from 36.33 in 1999 to 99.77 in 2019. Ischemic heart diseases (AAMR 49.39) were the leading cause, whereas hypertension had the highest mortality increase (average annual percentage change +10.23%). Mortality rates were higher in men (AAMR 104.87) and non‐Hispanic (AAMR 82.49), and rural populations (AAMR 89.98). Highest mortality was observed in Black populations (AAMR 84.35), those ≥75 years old (AAMR 646.45), and Western US regions (AAMR 96.88). During the first pandemic year, deaths exceeded projections by 10.55%, with notable increases among ages 35 to 75 (14.23%), Hispanic (17.96%), Black (14.82%), and urban (11.68%) groups. Conclusions Hyperlipidemia‐related CVD mortality has risen over the past 2 decades, further heightened by the COVID‐19 pandemic, with higher impact on men, Black Americans, the older population, and rural residents. Further study is needed to understand contributing factors and mitigate disparities.

Abstract Study Objectives The majority of patients with insomnia exhibit abnormal sleep in objective testing (e.g. decreased sleep duration, decreased slow wave sleep [SWS]). Previous studies have suggested that some of these objective measures of poor sleep, such as decreased sleep duration, are associated with a higher risk of hypertension in insomnia. We examined the relationship between SWS and morning and evening blood pressure (BP) levels in patients with clinically diagnosed insomnia. Methods A total of 229 normal sleepers and 1378 insomnia patients were included in this study. Insomnia was defined based on standard diagnostic criteria with symptoms lasting ≥6 months. All participants underwent in-laboratory polysomnography. Patients were classified into quartiles of percent SWS. Evening and morning hypertension were defined using BP measurements taken in the evening before and in the morning after polysomnography, respectively. Multivariable logistic regression models were used to assess the relationship between insomnia, SWS, and hypertension. Results Insomniacs with &lt;3.5% SWS (OR 3.27, 95% confidence intervals [CI]: 1.31 to 7.66) and those with 3.5%–10.2% SWS (OR 2.38, 95% CI: 1.28 to 5.91) had significantly greater odds of morning hypertension compared to normal sleepers. No associations were seen in insomnia with 10.2%–15.8% SWS and with &gt;15.8% SWS. Significant effect modifications by sex (p = .043) were found, as decreased SWS was associated with morning hypertension only in men. Odds of evening hypertension were not significantly associated with SWS. Conclusions Decreased SWS is associated with morning hypertension in a dose-dependent manner in insomnia, especially in men.

Abstract Purpose: Cardiovascular health disparities are present in African Americans, but it remains unknown whether this phenomenon affect Somali Americans. Study of Somali Americans is warranted due to distinct genetic and cultural differences from African Americans of western African ancestry. Orthostatic hemodynamic responses have implications for cardiovascular risk, especially among African American females. We sought to examine race and sex differences in systolic (SAP) and diastolic (DAP) arterial pressure and heart rate (HR) responsiveness to standing. We hypothesized that SAP, DAP, and HR change from supine to standing position would be higher in Somali Americans. Methods: We studied blood pressure and HR responsiveness in 139 (70 Somali; age: 29±10 years, 69 White; age: 31±9 years) participants. Supine SAP, DAP, and HR were measured after at least five minutes of supine rest, and again after one minute of standing. SAP, DAP, and HR change was compared between groups. Results: ΔSAP and ΔDAP were similar between groups (race × sex: p>0.05). However, HR responsiveness to orthostasis varied between race and sex comparisons (race×sex: p=0.011). Somali females exhibited an augmented HR response to orthostasis compared to White females (Δ19±13 vs. 11±9 beats/min, p=0.005) and Somali males (Δ19±13 vs. 12±9 beats/min, p=0.020). Conclusion: ΔHR to standing is augmented in young female Somali Americans. These findings highlight an early potential impairment in hemodynamic regulation that may heighten future cardiovascular risk. Further work is warranted to identify the potential autonomic nervous system underpinnings that may contribute to potentiated orthostatic responses and cardiovascular risk in Somali American females. Clinical Trial Registration: www.clinicaltrials.gov; unique identifier, NCT04124848; NCT05411029; NCT03308578.

Abstract Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer’s disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5–0.9 Hz) and delta (1–3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by −0.0082 (95% CI: −0.0143; −0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.

AbstractBackgroundCardiac tamponade or pericardial tamponade (PT) can be a complication following invasive cardiac procedures.MethodsPatients who underwent various procedures in the cardiac catheterization lab (viz. coronary interventions) were identified using the International Classification of Diseases, Ninth and Tenth Edition, Clinical Modification (International classification of diseases [ICD]‐9‐Clinical modification [CM] and ICD‐10‐CM, respectively) from the Nationwide Inpatient Sample (NIS) database. Patient demographics, presence of comorbidities, PT‐related events, and in‐hospital death were also abstracted from the NIS database.ResultsThe frequency of PT‐related events in the patients undergoing CI from 2010 to 2017 ranged from 3.3% to 8.4%. Combined in‐hospital mortality/morbidity of PT‐related events were higher with increasing age (odds ratio [OR] [95% CI]: chronic total occlusion (CTO) = 1.19 [1.10‐1.29]; acute coronary syndrome (ACS) = 1.21 [1.11‐1.33], both p < 0.0001) and female sex (OR [95%CI]: CTO = 1.70 [1.45‐2.00]; ACS = 1.72 [1.44‐2.06], both p < 0.0001). In‐hospital mortality related to PT‐related events was found to be 8.5% for coronary procedures. In‐hospital mortality was highest amongst the patients undergoing percutaneous transluminal coronary angioplasty (PTCA) for ACS (ACS vs. non‐CTO PTCA vs. CTO PTCA: 15.7% vs. 10.4% and 14.4%, p < 0.0001 and ACS vs. non‐CTO PTCA vs. CTO PTCA: 12.1% vs. 8.1% and 5.6%, p = 0.0001, respectively).ConclusionsIn the real‐world setting, PT‐related events in CI were found to be 3.3%−8.4%, with in‐hospital mortality of 8.5%. The patients undergoing PTCA for ACS were found to have highest mortality. Older patients undergoing CTO PTCA independently predicted higher mortality.