The Effect of Gender and Sex Hormones on Cardiovascular Disease, Heart Failure, Diabetes, and Atrial Fibrillation in Sleep Apnea

Hegner, Philipp; Lebek, Simon; Maier, Lars S.; Arzt, Michael; Wagner, Ştefan

doi:10.3389/fphys.2021.741896

Cited by 7 publications

(4 citation statements)

References 89 publications

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“…For example, as similarly reported in our recent meta-analysis investigating the vascular impact of IH in rodents [ 24 ], among the 92 studies included in our analysis, only one used female animals, whereas 87 used male animals, and four did not report animal sex. This represents an important limitation of preclinical studies in regards to recent literature highlighting the effect of sex on OSA-associated cardiovascular dysfunctions [ 50 ]. Along the same lines, most of the animal studies included in our meta-analysis were conducted in healthy and young rodents, in the absence of any comorbidities.…”

Section: Discussionmentioning

confidence: 99%

Cardiac consequences of intermittent hypoxia: a matter of dose? A systematic review and meta-analysis in rodents

et al. 2022

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AimIntermittent hypoxia (IH) is considered to be a major contributor to obstructive sleep apnoea-related cardiovascular consequences. The present meta-analysis aimed to assess the effects of IH on cardiac remodelling, function and infarct size after myocardial ischaemia across different rodent species and IH severities.Methods and resultsRelevant articles from PubMed, Embase and Web of Science were screened. We performed a random effect meta-analysis to assess the effect of IH on myocardium in rodents by using standardised mean difference (SMD). Studies using rodents exposed to IH and outcomes related to cardiac remodelling, contractile function and response to myocardial ischaemia–reperfusion were included. 5217 articles were screened and 92 were included, demonstrating that IH exposure induced cardiac remodelling, characterised by cardiomyocyte hypertrophy (cross-sectional area: SMD=2.90, CI (0.82–4.98), I2=94.2%), left ventricular (LV) dilation (LV diameter: SMD=0.64, CI (0.18–1.10), I2=88.04%), interstitial fibrosis (SMD=5.37, CI (3.22–7.53), I2=94.8) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelling: SMD=6.70, CI (2.96–10.44), I2=95.9). These structural changes were accompanied by a decrease in LV ejection fraction (SMD=−1.82, CI (−2.52–−1.12), I2=94.22%). Importantly, most of the utilised IH protocols mimicked extremely severe hypoxic disease. Concerning infarct size, meta-regression analyses highlighted an ambivalent role of IH, depending on its severity. Indeed, IH exposure with inspiratory oxygen fraction (FIO2) <7% was associated with an increase in infarct size, whereas a reduced infarct size was reported for FIO2 levels above 10%. Heterogeneity between studies, small study effect and poor reporting of methods in included articles limited the robustness of the meta-analysis findings.ConclusionThis meta-analysis demonstrated that severe IH systematically induces cardiac remodelling and contractile dysfunction in rodents, which might trigger or aggravate chronic heart failure. Interestingly, this meta-analysis showed that, depending on stimulus severity, IH exhibits both protective and aggravating effects on infarct size after experimental ischaemia–reperfusion procedures.

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Section: Discussionmentioning

confidence: 99%

Cardiac consequences of intermittent hypoxia: a matter of dose? A systematic review and meta-analysis in rodents

et al. 2022

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“…We performed several secondary analyses: (1) sensitivity analysis of hypopnea definition used, that is, 3% desaturation or arousal compared with 4% desaturation; (2) stratification by prescribed PAP therapy; (3) stratification by sleep study type; (4) sensitivity analysis excluding patients on supplemental oxygen; and (5) investigating ETCO 2 in the subset of patients with central sleep apnea, that is, central apnea index ≥5. Finally, we tested interaction terms between each hypoxia measure and age, 21 sex, 37 , 38 race, 39 , 40 or BMI 41 , 42 given their roles as potential effect modifiers, and between hypoxia measures and hypertension on the biologic basis that hypoxia can lead to endothelial 7 and vascular dysfunction, 43 thus increasing risk for AF. 44 …”

Section: Methodsmentioning

confidence: 99%

Sleep‐Disordered Breathing, Hypoxia, and Pulmonary Physiologic Influences in Atrial Fibrillation

Heinzinger,

Thompson,

Milinovich

et al. 2023

JAHA

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Background We leverage a large clinical cohort to elucidate sleep‐disordered breathing and sleep‐related hypoxia in incident atrial fibrillation (AF) development given the yet unclear contributions of sleep‐related hypoxia and pulmonary physiology in sleep‐disordered breathing and AF. Methods and Results Patients who underwent sleep studies at Cleveland Clinic January 2, 2000, to December 30, 2015, comprised this retrospective cohort. Cox proportional hazards models were used to examine apnea hypopnea index, percentage time oxygen saturation <90%, minimum and mean oxygen saturation, and maximum end‐tidal carbon dioxide on incident AF adjusted for age, sex, race, body mass index, cardiopulmonary disease and risk factors, antiarrhythmic medications, and positive airway pressure. Those with spirometry were additionally adjusted for forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second/forced vital capacity. This cohort (n=42 057) was 50.7±14.1 years, 51.3% men, 74.1% White individuals, had median body mass index 33.2 kg/m 2 , and 1947 (4.6%) developed AF over 5 years. A 10‐unit apnea hypopnea index increase was associated with 2% higher AF risk (hazard ratio [HR], 1.02 [95% CI, 1.00–1.03]). A 10‐unit increase in percentage time oxygen saturation <90% and 10‐unit decreases in mean and minimum oxygen saturation were associated with 6% (HR, 1.06 [95% CI, 1.04–1.08]), 30% (HR, 1.30 [95% CI, 1.18–1.42]), and 9% (HR, 1.09 [95% CI, 1.03–1.15]) higher AF risk, respectively. After adjustment for spirometry (n=9683 with available data), only hypoxia remained significantly associated with incident AF, although all coefficients were stable. Conclusions Sleep‐related hypoxia was associated with incident AF in this clinical cohort, consistent across 3 measures of hypoxia, persistent after adjustment for pulmonary physiologic impairment. Findings identify a strong role for sleep‐related hypoxia in AF development without pulmonary physiologic interdependence.

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“…Over the past few decades, sleep-disordered breathing (SDB) has emerged as a highly prevalent disease that currently affects about one billion patients worldwide ( Benjafield et al, 2019 ). SDB is frequently associated with various cardiovascular disorders, such as hypertension ( Pengo et al, 2020 ), heart failure with reduced or preserved ejection fractions (HFrEF/HFpEF) ( Arzt et al, 2016 ; Lebek et al, 2021 ; Wester et al, 2023 ; Hegner et al, 2024 ), and arrhythmias like atrial fibrillation ( Gami et al, 2004 ; Hegner et al, 2021a ; Hegner et al, 2021b ; Mehra et al, 2022 ), which may lead to subsequent strokes ( Arzt et al, 2005 ). The interactions between SDB and these cardiovascular disorders can substantially contribute to patient morbidity and mortality while also posing economic challenges ( Gami et al, 2004 ; Arzt et al, 2005 ; Arzt et al, 2016 ; Benjafield et al, 2019 ; Pengo et al, 2020 ; Lebek et al, 2021 ; Mehra et al, 2022 ; Wester et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

CaMKIIδ-dependent dysregulation of atrial Na+ homeostasis promotes pro-arrhythmic activity in an obstructive sleep apnea mouse model

Hegner,

Ofner,

Schaner

et al. 2024

Front. Pharmacol.

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BackgroundObstructive sleep apnea (OSA) has been linked to various pathologies, including arrhythmias such as atrial fibrillation. Specific treatment options for OSA are mainly limited to symptomatic approaches. We previously showed that increased production of reactive oxygen species (ROS) stimulates late sodium current through the voltage-dependent Na+ channels via Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ), thereby increasing the propensity for arrhythmias. However, the impact on atrial intracellular Na+ homeostasis has never been demonstrated. Moreover, the patients often exhibit a broad range of comorbidities, making it difficult to ascertain the effects of OSA alone.ObjectiveWe analyzed the effects of OSA on ROS production, cytosolic Na+ level, and rate of spontaneous arrhythmia in atrial cardiomyocytes isolated from an OSA mouse model free from comorbidities.MethodsOSA was induced in C57BL/6 wild-type and CaMKIIδ-knockout mice by polytetrafluorethylene (PTFE) injection into the tongue. After 8 weeks, their atrial cardiomyocytes were analyzed for cytosolic and mitochondrial ROS production via laser-scanning confocal microscopy. Quantifications of the cytosolic Na+ concentration and arrhythmia were performed by epifluorescence microscopy.ResultsPTFE treatment resulted in increased cytosolic and mitochondrial ROS production. Importantly, the cytosolic Na+ concentration was dramatically increased at various stimulation frequencies in the PTFE-treated mice, while the CaMKIIδ-knockout mice were protected. Accordingly, the rate of spontaneous Ca2+ release events increased in the wild-type PTFE mice while being impeded in the CaMKIIδ-knockout mice.ConclusionAtrial Na+ concentration and propensity for spontaneous Ca2+ release events were higher in an OSA mouse model in a CaMKIIδ-dependent manner, which could have therapeutic implications.

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The Effect of Gender and Sex Hormones on Cardiovascular Disease, Heart Failure, Diabetes, and Atrial Fibrillation in Sleep Apnea

Cited by 7 publications

References 89 publications

Cardiac consequences of intermittent hypoxia: a matter of dose? A systematic review and meta-analysis in rodents

Cardiac consequences of intermittent hypoxia: a matter of dose? A systematic review and meta-analysis in rodents

Sleep‐Disordered Breathing, Hypoxia, and Pulmonary Physiologic Influences in Atrial Fibrillation

CaMKIIδ-dependent dysregulation of atrial Na+ homeostasis promotes pro-arrhythmic activity in an obstructive sleep apnea mouse model

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