Obstructive sleep apnea and its management in patients with atrial fibrillation: An International Collaboration of Sleep Apnea Cardiovascular Trialists (INCOSACT) global survey of practicing cardiologists.

Background: Among international cardiologists it is unclear whether equipoise exists regarding the benefit of diagnosing and managing obstructive sleep apnea (OSA) to improve atrial fibrillation (AF) outcomes and whether clinical practice and equipoise are linked. Methods: Between January 2019 and June 2020 we distributed a web-based 12-question survey regarding OSA and AF management to practicing cardiologists in 16 countries. Results: The United States, Japan, Sweden, and Turkey accounted for two-thirds of responses. 863 cardiologists responded; half were general cardiologists, a quarter electrophysiologists. Responses regarding treating OSA with CPAP to improve AF endpoints were mixed. 33% of respondents referred AF patients for OSA screening. OSA was diagnosed in 48% of referred patients and continuous positive airway pressure (CPAP) was prescribed for 59% of them. Nearly 70% of respondents believed randomized controlled trials (RCTs) of OSA treatment in AF patients were necessary and indicated willingness to contribute to such trials. Conclusions: There was no clinical equipoise among surveyed cardiologists; a majority expressed certainty that combined OSA and AF treatment is superior to AF treatment alone for improving AF outcomes. However, a minority of surveyed cardiologists referred AF patients for OSA testing, and while half of screened AF patients had OSA, CPAP was prescribed in little more than half of them, reflecting the view that better clinical trial evidence is needed to support this practice. Our results underscore the need for larger, multi-national prospective studies of OSA treatment and AF outcomes to inform more uniform society guideline recommendations.

Obstructive Sleep Apnea and Cardiac Arrhythmias: A Contemporary Review.

Obstructive sleep apnea (OSA) is a highly prevalent disorder with a growing incidence worldwide that closely mirrors the global obesity epidemic. OSA is associated with enormous healthcare costs in addition to significant morbidity and mortality. Much of the morbidity and mortality related to OSA can be attributed to an increased burden of cardiovascular disease, including cardiac rhythm disorders. Awareness of the relationship between OSA and rhythm disorders is variable among physicians, a fact that can influence patient care, since the presence of OSA can influence the incidence, prevalence, and successful treatment of multiple rhythm disorders. Herein, we provide a review of this topic that is intentionally broad in scope, covering the relationship between OSA and rhythm disorders from epidemiology and pathophysiology to diagnosis and management, with a particular focus on the recognition of undiagnosed OSA in the general clinical population and the intimate relationship between OSA and atrial fibrillation.

Echocardiography in suspected coronavirus infection: indications, limitations and impact on clinical management.

OBJECTIVES: To describe the use of echocardiography in patients hospitalised with suspected coronavirus infection and to assess its impact on clinical management. METHODS: We studied 79 adults from a prospective registry of inpatients with suspected coronavirus infection at a single academic centre. Echocardiographic indications included abnormal biomarkers, shock, cardiac symptoms, arrhythmia, worsening hypoxaemia or clinical deterioration. Study type (limited or complete) was assessed for each patient. The primary outcome measure was echocardiography-related change in clinical management, defined as intensive care transfer, medication changes, altered ventilation parameters or subsequent cardiac procedures within 24 hours of echocardiography. Coronavirus-positive versus coronavirus-negative patient groups were compared. The relationship between echocardiographic findings and coronavirus mortality was assessed. RESULTS: 56 patients were coronavirus-positive and 23 patients were coronavirus-negative with symptoms attributed to other diagnoses. Coronavirus-positive patients more often received limited echocardiograms (70% vs 26%, p=0.001). The echocardiographic indication for coronavirus-infected patients was frequently worsening hypoxaemia (43% vs 4%) versus chest pain, syncope or clinical heart failure (23% vs 44%). Echocardiography changed management less frequently in coronavirus-positive patients (18% vs 48%, p=0.01). Among coronavirus-positive patients, 14 of 56 (25.0%) died during hospitalisation. Those who died more often had echocardiography to evaluate clinical deterioration (71% vs 24%) and had elevated right ventricular systolic pressures (37 mm Hg vs 25 mm Hg), but other parameters were similar to survivors. CONCLUSIONS: Echocardiograms performed on hospitalised patients with coronavirus infection were often technically limited, and their findings altered patient management in a minority of patients.

Upper Airway Stimulation vs Positive Airway Pressure Impact on BP and Sleepiness Symptoms in OSA.

BACKGROUND: Positive airway pressure (PAP) and upper airway stimulation (UAS) are approved OSA treatment options. Although the effect of PAP on improvement in BP and daytime sleepiness (defined according to the Epworth Sleepiness Scale [ESS]) has been established, the impact of UAS on BP remains unclear. This study hypothesized that PAP and UAS will confer improvements in BP and daytime sleepiness. METHODS: Clinic-based BP and ESS scores were compared between 517 patients with OSA (apnea-hypopnea index, 15-65) and BMI ≤ 35 kg/m2 initiating PAP therapy (2010-2014) at the Cleveland Clinic and 320 patients with UAS implantation (2015-2017) via an international registry with 2- to 6-month follow-up. Mixed effect models were used to compare outcomes in 201 patients in each arm following propensity matching. RESULTS: PAP showed greater improvement in diastolic BP (mean difference of change between groups, 3.7 mm Hg; P < .001) and mean arterial pressure (mean difference of change between groups, 2.8 mm Hg; P = .008) compared with UAS. UAS showed greater improvement in ESS scores vs PAP (mean difference of change between PAP and UAS groups, -0.8; P = .046). UAS therapy usage was 6.2 h/week greater than PAP-treated patients (95% CI, 3.3-9.0). Results were consistent following adjustment for therapy adherence. CONCLUSIONS: PAP showed greater improvement in BP, potentially reflecting an enhanced ability of PAP to exert beneficial mechanical intrathoracic cardiac and vascular influences. BP measurement error in the UAS group may also have accounted for findings. Greater improvement in sleepiness symptoms was noted with UAS compared with PAP.

Cardiovascular complications of systemic sclerosis: What to look for.

Systemic sclerosis, an autoimmune disease characterized by fibrosis of the skin and various internal organs, is associated with cardiovascular abnormalities including pulmonary hypertension, atherosclerosis, right and left ventricular dysfunction, arrhythmias, conduction defects, pericardial disease, and valvular heart disease. Clinicians caring for patients with this disease should regularly screen for cardiac symptoms, and patients with abnormal findings should be managed in conjunction with a cardiologist to optimally modify cardiovascular risks.

Gasometric gradients between blood obtained from the pulmonary artery wedge and pulmonary artery positions in pulmonary arterial hypertension.

INTRODUCTION: Little is known on the pulmonary gradients of oxyhemoglobin, carboxyhemoglobin and methemoglobin in pulmonary arterial hypertension (PAH). We sought to determine these gradients in group 1 PAH and assess their association with disease severity and survival. METHODS: During right heart catheterization (RHC) we obtained blood from pulmonary artery (PA) and pulmonary artery wedge (PAW) positions and used co-oximetry to test their gasometric differences. RESULTS: We included a total of 130 patients, 65 had group 1 PAH, 40 had pulmonary hypertension (PH) from groups 2-5 and 25 had no PH during RHC. In all groups, PAW blood had higher pH, carboxyhemoglobin and lactate as well as lower pCO2 than PA blood. In group 1 PAH (age 58 ± 15 years, 72% females), methemoglobin in the PAW was lower than in the PA blood (0.83% ± 0.43 vs 0.95% ± 0.50, p = 0.03) and was directly associated with the degree of change in pulmonary vascular resistance (R = 0.35, p = 0.02) during inhaled nitric oxide test. Oxyhemoglobin in PA (HR (95%CI): 0.90 (0.82-0.99), p = 0.04) and PAW (HR (95%CI): 0.91 (0.84-0.98), p = 0.003) blood was associated with adjusted survival in PAH. CONCLUSIONS: Marked differences were observed in the gasometric determinations between PAW and PA blood. The pulmonary gradient of methemoglobin was lower in PAH patients compared to controls and a higher PAW blood methemoglobin was associated with a more pronounced pulmonary vascular response to inhaled nitric oxide. Pulmonary artery and PAW oxyhemoglobin tracked with disease severity and survival in PAH.

Adverse drug reactions in patients with cardiovascular disease.

Adverse drug reactions (ADRs) occur frequently in modern medical practice, increasing morbidity and mortality and inflating the cost of care. Patients with cardiovascular disease are particularly vulnerable to ADRs due to their advanced age, polypharmacy, and the influence of heart disease on drug metabolism. The ADR potential for a particular cardiovascular drug varies with the individual, the disease being treated, and the extent of exposure to other drugs. Knowledge of this complex interplay between patient, drug, and disease is a critical component of safe and effective cardiovascular disease management. The majority of significant ADRs involving cardiovascular drugs are predictable and therefore preventable. Better patient education, avoidance of polypharmacy, and clear communication between physicians, pharmacists, and patients, particularly during the transition between the inpatient to outpatient settings, can substantially reduce ADR risk.

Obstructive sleep apnea is associated with increased urinary albumin excretion.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with cardiovascular disease through incompletely understood mechanisms. Urinary albumin excretion is a surrogate for endothelial dysfunction and a potent cardiovascular disease risk predictor. We sought to determine whether urinary albumin excretion is increased in subjects with OSA. METHODS: Four hundred ninety-six adults, representing a spectrum of OSA severity, underwent overnight polysomnography and urine collection. OSA severity was assessed using the apnea-hypopnea index (AHI). The primary outcome measure was the adjusted albumin-to-creatinine ratio (aACR). Linear mixed models were used to assess the association between AHI category and aACR, adjusted for confounders and renal dysfunction. RESULTS: Subjects had a mean age of 44 +/- 17 (SD) years and approximately half were men (44%) and African American (56%). The percentages of subjects with mild (AHI 5-14), moderate (AHI 15-29), and severe (AHI > or = 30) OSA were 23%, 15%, and 15%, respectively. The median aACR for the entire sample was 4.3 mg/g (interquartile range: 2.9, 7.5). Adjusted linear mixed-model analyses showed a significant association between AHI category and aACR, with the AHI > or = 30 group having the highest aACR levels (7.87 +/- 1.02 mg/g vs 5.08 +/- 0.41 mg/g for those with AHI < 5; P < 0.006). Similar findings were observed after excluding subjects with renal dysfunction. CONCLUSION: OSA is significantly associated with increased urine albumin excretion, especially among those with more severe disease. These data provide further evidence supporting endothelial dysfunction as a mediating pathway between cardiovascular disease and OSA.

Mouse strain-specific differences in cardiac metabolic enzyme activities observed in a model of isoproterenol-induced cardiac hypertrophy.

1. Alterations in myocardial energy metabolism accompany pressure overload-induced hypertrophy. We previously described a novel model of catecholamine-induced hypertrophy in which A/J mice exhibit more robust cardiac hypertrophy than B6 mice. Accordingly, we assessed the influence of mouse strain on the activities of key myocardial metabolic enzymes and whether there are strain-related metabolic adaptations to short-term, high-dose isoproterenol (ISO) administration. 2. Thirty-nine male mice (19 A/J mice, 20 B6 mice), aged 12-15 weeks, were randomly assigned to receive either ISO (100 mg/kg, s.c.) or vehicle (sterile water) daily for 5 days. On Day 6, all hearts were excised, weighed, freeze clamped and assayed for pyruvate dehydrogenase (PDH), medium chain acyl-CoA dehydrogenase, carnitine palmitoyl transferase I and citrate synthase activities. Plasma fatty acids (FA) were also measured. 3. The ISO-treated A/J mice demonstrated greater percentage increases in gravimetric heart weight/bodyweight ratio than ISO-treated B6 mice (24 vs 3%, respectively; P < 0.001). All enzyme activities were significantly greater in vehicle-treated B6 mice than in A/J mice, illustrating a greater capacity for aerobic metabolism in B6 mice. Administration of ISO reduced PDHa (active form) activity in B6 mice by 47% (P < 0.001), with no significant change seen in A/J mice. Free FA levels were not significantly different between groups; thus, the differences in PDHa were not due to changes in FA. 4. The basal activity of myocardial metabolic enzymes is greater in B6 mice than in A/J mice and ISO alters myocardial PDH activity in a mouse strain-dependent manner. Compared with A/J mice, B6 mice demonstrate less ISO-induced cardiac hypertrophy, but greater activity of key enzymes regulating FA and carbohydrate oxidation, which may protect against the development of hypertrophy. The metabolic adaptations associated with ISO-induced hypertrophy differ from those reported with pressure overload hypertrophy.

Strain-dependent beta-adrenergic receptor function influences myocardial responses to isoproterenol stimulation in mice.

Recently, we showed that compared with the A/J inbred mouse strain, C57BL/6J (B6) mice have an athlete's cardiac phenotype. We postulated that strain differences would result in greater left ventricular (LV) hypertrophy in response to isoproterenol in B6 than A/J mice and tested the hypothesis that a differential response could be explained partly by differences in beta-adrenergic receptor (beta-AR) density and/or coupling. A/J and B6 mice were randomized to receive daily isoproterenol (100 mg/kg sc) or isovolumic vehicle for 5 days. Animals were studied using echocardiography, tail-cuff blood pressure, histopathology, beta-AR density and percent high-affinity binding, and basal and stimulated adenylyl cyclase activities. One hundred twenty-eight mice (66 A/J and 62 B6) were studied. Isoproterenol-treated A/J mice demonstrated greater percent increases in echocardiographic LV mass/body weight (97 +/- 11 vs. 20 +/- 10%, P = 0.001) and in gravimetric heart mass/body weight versus same-strain controls than B6 mice. Histopathology scores (a composite of myocyte hypertrophy, nuclear changes, fibrosis, and calcification) were greater in isoproterenol-treated A/J vs. B6 mice (2.8 +/- 0.2 vs.1.9 +/- 0.3, P < 0.05), as was quantitation of myocyte damage (22.3 +/- 11.5 vs. 4.3 +/- 3.5%). Interstrain differences in basal beta-AR density, high-affinity binding, and adenylyl cyclase activity were not significant. However, whereas isoproterenol-treated A/J mice showed nonsignificant increases in all beta-AR activity measures, isoproterenol-treated B6 mice had lower beta-AR density (57 +/- 6 vs. 83 +/- 8 fmol/mg, P < 0.05), percent high-affinity binding (15 +/- 2 vs. 26 +/- 3%, P < 0.005), and GTP + isoproterenol-stimulated adenylyl cyclase activity (10 +/- 1.1 vs. 5.8 +/- 1.5 pmol cAMP.mg(-1).min(-1)) compared with controls. High-dose, short-term isoproterenol produces greater macro- and microscopic cardiac hypertrophy and injury in A/J than B6 mice. A/J mice, unlike B6 mice, do not experience beta-AR downregulation or uncoupling in response to isoproterenol. Abnormalities in beta-adrenergic regulation may contribute to strain-related differences in the vulnerability to isoproterenol-induced cardiac changes.

Sex influences endothelial function in sleep-disordered breathing.

BACKGROUND: The bases for the association between sleep-disordered breathing (SDB) and cardiovascular disease are poorly understood. Endothelial dysfunction, assessed with brachial artery ultrasonography, may predict cardiovascular risk and represent preclinical vascular disease. We determined whether flow-mediated dilation (FMD) and peak blood flow (PBF) increase after cuff occlusion is altered with SDB. METHODS: 193 participants (58% women) in a cohort study were studied with overnight polysomnography and subsequent brachial artery ultrasonography. SDB was quantified using the apnea-hypopnea index (AHI) and indexes of overnight desaturation and arousal frequency. Two-dimensional and Doppler-velocity measurements of the brachial artery were obtained at baseline and after 5 minutes of upper-arm cuff occlusion. FMD and PBF were defined as the percentage changes from baseline in brachial artery diameter and flow, respectively. RESULTS: In the entire sample, the AHI was inversely associated with both FMD (r = -0.30, P < .001) and PBF (r = -0.20, P < .001). However, sex-stratified univariate analyses showed that these relationships were exclusive to women. Specifically, FMD was significantly lower in women with an AHI > or = 15 than in women with lower AHI scores (P < .005), with no relationship between AHI and FMD in men. Additionally, PBF decreased significantly with increasing AHI (r = -0.29, P = .010) in women alone. Statistical modeling, adjusting for body mass index, age, and other covariates, similarly showed that SDB severity significantly influenced FMD and PBF, with significant interactions between sex and AHI, reinforcing that the associations between SDB severity and endothelial function were stronger in women than in men. CONCLUSIONS: Moderate levels of SBD are associated with impaired conduit and resistance endothelial function in women. Women with SDB may be more vulnerable to early SDB-related cardiovascular disease than are men.

Validation of echocardiographic methods for assessing left ventricular dysfunction in rats with myocardial infarction.

The rat infarct model is widely used in heart failure research, but few echocardiographic indexes of left ventricular (LV) function are validated in this model. Accordingly, the objective of this study was to validate a 13-segment LV wall motion score index (WMSI) and the myocardial performance index (MPI) in infarcted rats. Twenty-nine male Wistar rats underwent left coronary artery ligation or sham operation and were evaluated with two-dimensional and Doppler flow echocardiography 8 wk later. After echocardiography, invasive indexes were obtained using a high-fidelity catheter. WMSI and MPI were correlated with the invasive and noninvasive measurements of LV function. WMSI and MPI significantly correlated directly with end-diastolic pressure (r=0.72 and 0.42 for WMSI and MPI, respectively) and the time constant of isovolumic relaxation (r=0.68 and 0.48) and inversely with peak rate of rise of LV pressure (+dP/dt; r=-0.68 and -0.50), peak rate of decline in LV pressure (r=-0.57 and -0.44), LV developed pressure (r=-0.58 and -0.42), area fractional shortening (r=-0.85 and -0.53), and cardiac index (r=-0.74 and -0.74). Stepwise linear regression analyses revealed that LV end-diastolic pressure, +dP/dt, area fractional shortening, and cardiac index were independent determinants of WMSI (r=0.994) and that cardiac index and +dP/dt were independent determinants of MPI (r=0.781). We conclude that the 13-segment WMSI and MPI are reproducible and correlate strongly with established echocardiographic and invasive indexes of systolic and diastolic function. These findings support the use of WMSI and MPI as indexes of global LV function in the rat infarction model of heart failure.

Vascular reactivity in heart failure: role of myosin light chain phosphatase.

Congestive heart failure (CHF) is a clinical syndrome, which is the result of systolic or diastolic ventricular dysfunction. During CHF, vascular tone is regulated by the interplay of neurohormonal mechanisms and endothelial-dependent factors and is characterized by both central and peripheral vasoconstriction as well as a resistance to nitric oxide (NO)-mediated vasodilatation. At the molecular level, vascular tone depends on the level of regulatory myosin light chain phosphorylation, which is determined by the relative activities of myosin light chain kinase and myosin light chain phosphatase (MLCP). The MLCP is a trimeric enzyme with a catalytic, a 20-kDa and a myosin targeting (MYPT1) subunit. Alternative splicing of a 3' exon produces leucine zipper positive and negative (LZ+/-) MYPT1 isoforms. Expression of a LZ+ MYPT1 has been suggested to be required for NO-mediated smooth muscle relaxation. Thus, we hypothesized that the resistance to NO-mediated vasodilatation in CHF could be attributable to a change in the relative expression of LZ+/- MYPT1 isoforms. To test this hypothesis, left coronary artery ligation was used to induce CHF in rats, and both the dose response relationship of relaxation to 8-Br-cGMP in skinned smooth muscle and the relative expression of LZ+/- MYPT1 isoforms were determined. In control animals, the expression of the LZ+ MYPT1 isoform predominated in both the aorta and iliac artery. In CHF rats, LVEF was reduced to 30+/-5% and there was a significant decrease in both the sensitivity to 8-Br-cGMP and expression of the LZ+ MYPT1 isoform. These results indicate that CHF is associated with a decrease in the relative expression of the LZ+ MYPT1 isoform and the sensitivity to 8-Br-cGMP-mediated smooth muscle relaxation. The data suggest that the resistance to NO-mediated relaxation observed during CHF lies at least in part at the level of the smooth muscle and is a consequence of the decrease in the expression of the LZ+ MYPT1 isoform.

Detection of endothelial dysfunction with brachial artery ultrasound scanning.

The role of the endothelium in human disease recently has become the focus of intense scientific investigation. Impaired endothelial function is associated with a number of disease states, including cardiovascular disease (CVD) and its major risk factors. Endothelial dysfunction precedes overt vascular disease by years and may itself be a potentially modifiable CVD risk factor. Although no gold standard for the measurement of endothelial function exists, the measurement of flow-mediated dilation (FMD) in the brachial artery, assessed with Doppler ultrasonography, is the most studied method and shows the most promise for clinical application. It is a well-tolerated, noninvasive, and low-risk procedure. Brachial artery FMD after transient vascular occlusion may serve as an index of nitric oxide bioavailability, and its impairment correlates with coronary arterial abnormalities. These factors, with the wide availability of vascular ultrasound scanning in clinical practice, make brachial artery FMD an attractive screening tool for endothelial dysfunction. Present limitations of this procedure include the lack of a consensus definition of normal FMD and the variability among centers in both procedural technique and image analysis. However, these limitations are likely to be overcome with increasing experience and advances in technology, and with further refinements, the measurement of brachial artery FMD will likely become the clinical technique of choice for the evaluation of endothelial disease.