Somers, Virend K.

Background Obstructive sleep apnea (OSA) is characterized by repetitive intermittent hypoxia and reoxygenation during sleep, and is a risk factor for cardiometabolic diseases including hypertension and diabetes. The renin‐angiotensin system (RAS) is an important cardiovascular and metabolic regulator playing key roles via angiotensin peptides. Recent studies demonstrate that all components of the RAS, including enzymes responsible for AngII generation, such as angiotensin converting enzyme (ACE) and chymase, are present in adipose tissue. Furthermore adipose tissue significantly contributes to systemic levels of AngII, thereby potentiating development of hypertension in obesity. Given that OSA patients are mostly obese, the localized effects of RAS in adipose tissue are likely an important mediator of OSA‐related hypertension. This study sought to investigate the effects of intermittent hypoxia (IH), a hallmark of OSA, on Ang II generation pathways in preadipocytes. Methods/Results RAS plays an important role in adipose tissue via its action on preadipocytes. Therefore, we examined the effects of IH in primary cultures of human white preadipocytes (HWP). HWP cells were exposed to repeated cycles of 30 min‐21% O 2 (normoxic) and 30 min‐1% O 2 (hypoxic) at 37°C for 24 hours. Cells grown in continuous normoxic conditions were used as controls. mRNA and protein expression of ACE, chymase, renin, AT1, and AT2 receptors were investigated by semi‐quantitative RT‐PCR and Western blot, respectively. Ang II secretion was examined by enzyme‐linked immunosorbent assay in condition medium. Results IH upregulated ACE (P=0.04) and chymase (P=0.05) expression while the expression of renin (P=0.94), AT1R (P=0.30), and AT2R (P=0.58) receptors did not change in HWP. Additionally, IH increased Ang II secretion in conditioned media (P=0.01). Conclusions This is the first study to demonstrate intermittent hypoxia‐mediated upregulation of Ang II generating enzymes ACE and chymase, along with increased AngII secretion in HWP. Together, our data strongly support the role of IH in upregulating RAS via increases in AngII. These studies suggest a role for adipose tissue and RAS in OSA related pathophysiology. Support or Funding Information NIH R01 grant (#HL65176); Becari C. is supported by grant from CNPq‐Brazil (# 203802/2014‐4).

Background Decreases in estrogen are shown to increase body fat in men. However, obese men have high levels of estrogen and the effects of weight gain on estrogen have not been previously investigated. The objective of this study was to investigate the relationship between regional fat depots and estrogen during modest weight in healthy men. Methods We investigated the effects of overfeeding in 25 healthy men (30 ± 7 years, 24.7 ± 3.1 kg/m 2 ). Changes in regional fat depot during weight gain were assessed using dual‐energy X‐ray absorptiometry and abdominal computed tomography scans. Participants gained approximately 5% body weight in 8 weeks. Estrone (E1), 17β‐estradiol (E2) and sex hormone binding globulin (SHBG) were measured at baseline and after weight gain. Results Overfeeding was accompanied by 3.9 ± 1.3 kg weight gain. These increases in weight resulted from increases in total body fat mass (18.3 ± 8.5 vs. 21.7 ± 8.8 kg, p<0.001) while the fat free mass did not change (58.4 ± 8.6 vs. 58.9 ± 8.7 kg, p=0.15). E1 (32.28 ± 14.25 vs. 33.44 ± 12.29 pg/mL, p=0.56) and E2 (25.04 ± 8.3 vs. 26.52 ± 7.8 pg/mL, p=0.28) did not change after weight gain. However, weight gain resulted in decreased SHBG (22.8 ± 10.5 vs. 20.8 ± 11.1 nmol/l, p=0.036) and increased E2/SHBG ratio (1.4 ± 1.0 vs 1.63 ± 1.0, p=0.027). The changes in E2/SHBG ratio, a surrogate marker of bioavailable E2, was positively associated with increases in abdominal fat mass (p=0.048, rho=0.39) and increases in visceral fat mass (p=0.049, rho=0.39). Conclusion Modest weight gain in healthy men does not alter circulating E1 and E2 levels. However weight gain results in decreased SHBG and increased free E2 (E2/SHBG ratio). The increased E2/SHBG ratio suggesting a pro‐estrogen effect is associated with increases in visceral fat mass during weight gain. Our study therefore suggests a complex relationship between abdominal fat gain and free E2 in men which may conceivably predispose to feminizing characteristics in obese men. Support or Funding Information PS is supported by AHA Grant 11SDG7260046 and NIH grant DK81014. NC is supported by AHA grant AHA 13POST16420009. MDJ is supported by NIH grants DK45343 and DK40484. VKS is supported by NIH Grants HL73211, and DK81014. This study was made possible by a grant from NCRR (1UL1 RR024150).

Background Obstructive sleep apnea (OSA) increases the risk for metabolic and cardiovascular disease. Telomere shortening has been linked to hypertension, diabetes mellitus, and cardiovascular diseases such as stroke and myocardial infarction. Because these conditions are highly prevalent in sleep apnea, we hypothesized that telomere length (TL) would be reduced in patients with OSA. Methods Genomic DNA was isolated from circulating leukocytes in 176 subjects (42.8 ± 13.8 years, 22.7 % women) who had undergone overnight polysomnographic evaluation. Of these individuals, 92 subjects had an Apnea Hypopnea Index (AHI) >5 events/hour and were classified as OSA patients. TL was measured using a quantitative PCR where a telomere to single copy gene ratio is determined and represented as number of base pairs (bp). The effect of OSA on TL was determined by comparing a control group (no OSA) (AHI<5, n=92) with patients with mild OSA (≥ 5 AHI <15, n=25), and those with moderate to severe OSA (AHI ≥15, n=59) in unadjusted and age‐adjusted models. Results Compared to control subjects, mild and moderate to severe OSA subjects were older: 48.9 ± 11.2 vs. 36.0 ± 11.2 years (p<0.001) and 50.8 ± 13.1 vs. 36.0 ± 11.2 years (p<0.001), respectively. Statistical models examining the effects of OSA severity on TL showed a J‐shaped curve : longer TL in moderate to severe OSA (4867 ± 221 bp) and controls (4820 ± 160 bp), and the shortest TL in mild OSA (4742 ± 155 bp). The mean TL in moderate to severe OSA was significantly longer than in mild OSA (p=0.0048). These effects were more pronounced after adjustment for age, when we observed significant differences in mean TL between moderate to severe OSA and mild OSA (p=0.0036) and between moderate to severe OSA and the control group (p=0.0379) (). However, the mean TL between control subjects and subjects with mild OSA was not different. Conclusion Moderate to severe OSA patients had longer TL compared with mild OSA and control group. This association was independent of age. Even though OSA is associated with increased cardiovascular risk, telomere lengthening in subjects with moderate to severe OSA suggests the presence of protective compensatory mechanisms to prevent telomere shortening in OSA. On the other hand, the existence of longer telomere in subjects with moderate and severe OSA may also indicate triggering of molecular mechanisms which may contribute to cancer development. Further studies are needed to explain the role of hypoxia in telomere dynamics in OSA, and the interactions between telomere length and increased longevity reported in older patients with OSA. Support or Funding Information NIH R01 grant (#HL65176); Singh P. is supported by AHA scientist development grant (11SDG7260046). Becari C. is supported by grant from CNPq‐Brazil (# 203802/2014‐4).

AbstractBackgroundCardiac tamponade (CT) can be a complication following invasive cardiac procedures. We assessed CT following common cardiac electrophysiology (EP) procedures to facilitate risk prediction of associated morbidity and in‐hospital mortality.MethodsPatients who underwent various EP procedures in the cardiac catheterization lab (ablations and device implantations) were identified using the International Classification of Diseases, Ninth and Tenth Edition, Clinical Modification (ICD‐9‐CM and ICD‐10‐CM, respectively) from the Nationwide Inpatient Sample (NIS) database. Patient demographics, presence of comorbidities, CT‐related events, and in‐hospital death were also abstracted from the NIS database.ResultsThe frequency of CT‐related events in patients with EP intervention from 2010 to 2017 ranged from 3.4% to 7.0%. In‐hospital mortality related to CT‐related events was found to be 2.2%. Increasing age was the only predictor of higher mortality in atrial fibrillation (AF) ablation and cardiac resynchronization therapy (CRT) groups (OR [95% CI]: AF ablation = 11.15 [1.70–73.34], p = .01; CRT = 1.41 [1.05–1.90], p = .02).ConclusionsIn the real‐world setting, CT‐related events in EP procedures were found to be 3.4%–7.0% with in‐hospital mortality of 2.2%. Older patients undergoing AF ablation were found to have higher mortality.

Patients with obstructive sleep apnea (OSA) have a heightened risk of developing cardiovascular diseases, namely hypertension. While seminal evidence indicates a causal role for sympathetic nerve activity in the hypertensive phenotype commonly observed in patients with OSA, no studies have investigated potential sex differences in the sympathetic regulation of blood pressure in this population. Supporting this exploration are large-scale observational data, as well as controlled interventional studies in healthy adults, indicating that sleep disruption increases blood pressure to a greater extent in females relative to males. Furthermore, females with severe OSA demonstrate a more pronounced hypoxic burden (i.e., disease severity) during rapid eye movement sleep when sympathetic nerve activity is greatest. These findings would suggest that females are at greater risk for the hemodynamic consequences of OSA and related sleep disruption. Accordingly, the purpose of this review is three-fold: (1) to review the literature linking sympathetic nerve activity to hypertension in OSA, (2) to highlight recent experimental data supporting the hypothesis of sex differences in the regulation of sympathetic nerve activity in OSA, and (3) to discuss the potential sex differences in peripheral adrenergic signaling that may contribute to, or offset, cardiovascular risk in patients with OSA.

Background Obstructive sleep apnea (OSA) is common in heart failure with preserved ejection fraction (HFpEF). However, current evidence is equivocal regarding the potential benefits of treating OSA with positive airway pressure (PAP) therapy in HFpEF. This study assessed the association between adherence to PAP therapy and health care resource use in patients with OSA and HFpEF. Methods and Results Administrative insurance claims data linked with objective PAP therapy usage data from patients with OSA and HFpEF were used to determine associations between PAP adherence and a composite outcome including hospitalizations and emergency room visits. One‐year PAP adherence was based on an adapted US Medicare definition. Propensity score methods were used to create groups with similar characteristics across PAP adherence levels. The study cohort included 4237 patients (54.0% female, mean age 64.1 years); 40% were considered adherent to PAP therapy (30% intermediate adherent, 30% nonadherent). In the matched cohort, PAP‐adherent patients had fewer health care resource use visits than nonadherent patients, a 57% decrease in hospitalizations, and a 36% decrease in emergency room visits versus the year before PAP initiation. Total health care costs were lower in adherent patients than nonadherent patients ($12 732 versus $15 610, P <0.001). Outcomes for intermediately adherent patients were most similar to those for nonadherent patients. Conclusions Treating OSA with PAP therapy in patients with HFpEF was associated with a reduction in health care resource use. These data highlight the importance of managing concomitant OSA in patients with HFpEF, and the need for strategies to enhance PAP adherence in this population.

Introduction: Cardiovascular complications are the main contributors towards morbidity and mortality in hemochromatosis. Iron overload can cause arrhythmias and heart failure (HF). There is a paucity of data on haemochromatosis and the burden of HF and its sequalae. Hypothesis: To determine characteristics of HF patients with and without haemochromatosis, and in-hospital outcomes (mortality, length of stay (LOS), mechanical circulatory support, and cardiac transplantation). Methods: Patients with HF, with and without hemochromatosis, were identified from the Nationwide Inpatient Sample Database. Results: Between 2016-2019, 2,940 (0.06%) of 4,823,994 HF patients had hemochromatosis. The hemochromatosis cohort was younger (mean age, 68 vs 71 years), predominantly men (63% vs 52%), White (77% vs 64%), and had less cardiovascular comorbidity burden (coronary artery disease (41% vs 51%), atrial fibrillation (45% vs 46%), hypertension (20% vs 24%), hyperlipidaemia (44% vs 53%), diabetes (42% vs 49%) and obesity (18% vs 25%), compared with HF patients without hemochromatosis (p<0.01 for all). However, hemochromatosis patients had a higher concomitant third degree atrio-ventricular block (1.2% vs 0.7%), ventricular tachycardia (7.8% vs 5.4%), ventricular fibrillation (0.5% vs 0.3%), chronic liver disease (24% vs 6%) and anemia (51% vs 37%) [p<0.01]. The hemochromatosis patients had a higher mean LOS (6.1 vs 5.4 days, p<0.01), need for mechanical circulatory support (0.9% vs 0.6%, p<0.01) and cardiac transplantation (0.2% vs 0.1%, p<0.01). Mortality (2.0% vs 2.7%, p=0.09) was comparable between the groups. Conclusion: Despite younger age and lower burden of cardiovascular comorbidities, patients with hemochromatosis had a higher burden of arrhythmias, need for mechanical circulatory support and cardiac transplantation and a higher LOS. This warrants the need to devise early management strategies for HF patients with hemochromatosis.

Introduction: Arrhythmias commonly occur during clinical exercise stress testing (EST), however there are limited data on prognostic significance, particularly differences between individuals with minor versus significant arrhythmia burden. Hypothesis: We hypothesized that significant but not minor arrhythmia burden during EST would be predictive of future all-cause mortality. Methods: Adults who underwent clinically indicated EST at Mayo Clinic Rochester between September 1993 and April 2017 were included and followed-up until March 2021 using the National Death Index to ascertain survival status. Expert clinician coding pertaining to arrhythmia burden during EST were used to group individuals (see Table 1 ). Cox proportional hazard models adjusted for known predictors of exercise-induced arrhythmias, were used to test the association of arrhythmia burden with all-cause mortality. Results: A total of 30796 individuals were included (age: 55±14yrs; female: 36%; Table 1 ). Mean follow-up was 8.8±3.6yrs, with a total of 2516 deaths. Arrhythmia during EST was associated with all-cause mortality compared with no arrhythmia (HR: 1.72; 95% CI: 1.58-1.88; p<0.001), however significant arrhythmia showed greater association compared with minor arrhythmia (HR: 2.07; 95% CI: 1.81-2.38; p<0.001). Both minor and significant arrhythmia during EST were significant predictors of all-cause mortality compared with no arrhythmia ( Figure, Table 2 ), however, after model adjustments, only significant arrhythmia was associated with all-cause mortality (HR: 1.40; 95% CI: 1.21-1.63; p<0.001) ( Table 2 ). Conclusions: After multivariate adjustment, significant arrhythmia burden during EST showed a 40% increased future risk of all-cause mortality, Conversely, adjusting for age and sex attenuated the effect of minor arrhythmia burden during EST on incidence of death. These results highlight the clinical significance of arrhythmia burden during exercise testing.

Introduction: Obstructive sleep apnea (OSA) is common in heart failure, although the impact of OSA treatment remains unclear. We assessed the association between adherence to positive airway pressure (PAP) therapy and healthcare resource utilization in patients with OSA and heart failure with reduced ejection fraction (HFrEF). Methods: Administrative insurance claims data linked with objective PAP therapy usage data from patients with OSA and HFrEF were used to measure the association of PAP adherence and a composite clinical outcome of hospitalization and emergency room (ER) visits. US Medicare defines PAP compliance as usage of the device for at least 4 hours/night for 70% of nights in a consecutive 30-day period over 90 days. PAP adherent patients met these criteria for all 4 90-day periods, while PAP non-adherent patients did not meet these criteria for any 90-day period over one year. Propensity score methods were used to create well matched groups with differing PAP adherence levels. Results: The study cohort consisted of 3,182 eligible patients (69.9% male, mean age 59.7 years) of whom 39% were considered adherent to PAP therapy (29% intermediate-adherent, 31% non-adherent). In the year after PAP prescription, after propensity score matching, PAP adherent patients had fewer hospital visits than non-adherent patients, driven by a 24% reduction in ER visits for adherent patients (Table 1a). These results remained consistent with inverse probability weighting and furthermore showed there were no statistically significant differences between intermediate-adherent and non-adherent patients for any outcome (Table 1b). Conclusions: Treating OSA with PAP therapy in patients with HFrEF is associated with a reduction in the composite outcome of hospitalization and ER visits, driven primarily by a reduction in ER visits. Consistent adherence to PAP therapy is required to realize these benefits.