Academic cardiac electrophysiologists' perspectives on sleep apnea care.

PURPOSE: Obstructive sleep apnea syndrome (OSAS) is an important, modifiable risk factor in the pathophysiology of arrhythmias including atrial fibrillation (AF). The purpose of the study was to evaluate cardiac electrophysiologists' (EPs) perception of OSAS. METHODS: We designed a 27-item online Likert scale-based survey instrument entailing several domains: (1) relevance of OSAS in EP practice, (2) OSAS screening and diagnosis, (3) perception on treatments for OSAS, (4) opinion on the OSAS care model. The survey was distributed to 89 academic EP programs in the USA and Canada. While the survey instrument questions refer to the term sleep apnea (SA), our discussion of the diagnosis, management, and research on the sleep disorder is more accurately described with the term OSAS. RESULTS: A total of 105 cardiac electrophysiologists from 49 institutions responded over a 9-month period. The majority of respondents agreed that sleep apnea (SA) is a major concern in their practice (94%). However, 42% reported insufficient education on SA during training. Many (58%) agreed that they would be comfortable managing SA themselves with proper training and education and 66% agreed cardiac electrophysiologists should become more involved in management. Half of EPs (53%) were not satisfied with the sleep specialist referral process. Additionally, a majority (86%) agreed that trained advanced practice providers should be able to assess and manage SA. Time constraints, lack of knowledge, and the referral process are identified as major barriers to EPs becoming more involved in SA care. CONCLUSIONS: We found that OSAS is widely recognized as a major concern for EP. However, incorporation of OSAS care in training and routine practice lags. Barriers to increased involvement include time constraints and education. This study can serve as an impetus for innovation in the cardiology OSAS care model.

Refining Prediction of Atrial Fibrillation-Related Stroke Using the P2-CHA2DS2-VASc Score.

BACKGROUND: In people with atrial fibrillation (AF), periods of sinus rhythm present an opportunity to detect prothrombotic atrial remodeling through measurement of P-wave indices (PWIs)-prolonged P-wave duration, abnormal P-wave axis, advanced interatrial block, and abnormal P-wave terminal force in lead V1. We hypothesized that the addition of PWIs to the CHA2DS2-VASc score would improve its ability to predict AF-related ischemic stroke. METHODS: We included 2229 participants from the ARIC study (Atherosclerosis Risk in Communities) and 700 participants from MESA (Multi-Ethnic Study of Atherosclerosis) with incident AF who were not on anticoagulants within 1 year of AF diagnosis. PWIs were obtained from study visit ECGs before development of AF. AF was ascertained using study visit ECGs and hospital records. Ischemic stroke cases were based on physician adjudication of hospital records. We used Cox proportional hazards models to estimate hazard ratios and 95% CIs of PWIs for ischemic stroke. Improvement in 1-year stroke prediction was assessed by C-statistic, categorical net reclassification improvement, and relative integrated discrimination improvement. RESULTS: Abnormal P-wave axis was the only PWI associated with increased ischemic stroke risk (hazard ratio, 1.84; 95% CI, 1.33-2.55) independent of CHA2DS2-VASc variables, and that resulted in meaningful improvement in stroke prediction. The ß estimate was approximately twice that of the CHA2DS2-VASc variables, and thus abnormal P-wave axis was assigned 2 points to create the P2-CHA2DS2-VASc score. This improved the C-statistic (95% CI) from 0.60 (0.51-0.69) to 0.67 (0.60-0.75) in ARIC and 0.68 (0.52-0.84) to 0.75 (0.60-0.91) in MESA (validation cohort). In ARIC and MESA, the categorical net reclassification improvements (95% CI) were 0.25 (0.13-0.39) and 0.51 (0.18-0.86), respectively, and the relative integrated discrimination improvement (95% CI) were 1.19 (0.96-1.44) and 0.82 (0.36-1.39), respectively. CONCLUSIONS: Abnormal P-wave axis-an ECG correlate of left atrial abnormality- improves ischemic stroke prediction in AF. Compared with CHA2DS2-VASc, the P2-CHA2DS2-VASc is a better prediction tool for AF-related ischemic stroke.

Shared Risk Factors in Cardiovascular Disease and Cancer.

Cardiovascular disease (CVD) and cancer are the 2 leading causes of death worldwide. Although commonly thought of as 2 separate disease entities, CVD and cancer possess various similarities and possible interactions, including a number of similar risk factors (eg, obesity, diabetes mellitus), suggesting a shared biology for which there is emerging evidence. Although chronic inflammation is an indispensable feature of the pathogenesis and progression of both CVD and cancer, additional mechanisms can be found at their intersection. Therapeutic advances, despite improving longevity, have increased the overlap between these diseases, with millions of cancer survivors now at risk of developing CVD. Cardiac risk factors have a major impact on subsequent treatment-related cardiotoxicity. In this review, we explore the risk factors common to both CVD and cancer, highlighting the major epidemiological studies and potential biological mechanisms that account for them.

Abnormal P-Wave Axis and Ischemic Stroke: The ARIC Study (Atherosclerosis Risk In Communities).

BACKGROUND AND PURPOSE: Abnormal P-wave axis (aPWA) has been linked to incident atrial fibrillation and mortality; however, the relationship between aPWA and stroke has not been reported. We hypothesized that aPWA is associated with ischemic stroke independent of atrial fibrillation and other stroke risk factors and tested our hypothesis in the ARIC study (Atherosclerosis Risk In Communities), a community-based prospective cohort study. METHODS: We included 15 102 participants (aged 54.2±5.7 years; 55.2% women; 26.5% blacks) who attended the baseline examination (1987-1989) and without prevalent stroke. We defined aPWA as any value outside 0 to 75° using 12-lead ECGs obtained during study visits. Each case of incident ischemic stroke was classified in accordance with criteria from the National Survey of Stroke by a computer algorithm and adjudicated by physician review. Multivariable Cox regression was used to estimate hazard ratios and 95% confidence intervals for the association of aPWA with stroke. RESULTS: During a mean follow-up of 20.2 years, there were 657 incident ischemic stroke cases. aPWA was independently associated with a 1.50-fold (95% confidence interval, 1.22-1.85) increased risk of ischemic stroke in the multivariable model that included atrial fibrillation. When subtyped, aPWA was associated with a 2.04-fold (95% confidence interval, 1.42-2.95) increased risk of cardioembolic stroke and a 1.32-fold (95% confidence interval, 1.03-1.71) increased risk of thrombotic stroke. CONCLUSIONS: aPWA is independently associated with ischemic stroke. This association seems to be stronger for cardioembolic strokes. Collectively, our findings suggest that alterations in atrial electric activation may predispose to cardiac thromboembolism independent of atrial fibrillation.

Cardio-oncology Related to Heart Failure: Common Risk Factors Between Cancer and Cardiovascular Disease.

There is a growing body of evidence that suggests cancer and cardiovascular disease have a shared biological mechanism. Although there are several shared risk factors for both diseases, including advancing age, gender, obesity, diabetes, physical activity, tobacco use, and diet, inflammation and biomarkers, such as insulinlike growth factor 1, leptin, estrogen, and adiponectin, may also play a role in the biology of these diseases. This article provides an overview of the shared biological mechanism between cancer and cardiovascular disease.

HAS-BLED and CHA2DS2-VASc scores as predictors of bleeding and thrombotic risk after continuous-flow ventricular assist device implantation.

BACKGROUND: HAS-BLED and CHA2DS2-VASc scores predict bleeding in patients on anticoagulation and thromboembolic (TE) risk in patients with atrial fibrillation, respectively. We hypothesized that these scores would be predictive of bleeding and TE complications following continuous-flow ventricular assist device (CF-VAD) implantation. METHODS AND RESULTS: Baseline HAS-BLED and CHA2DS2-VASc scores were retrospectively determined for 173 consecutive patients who underwent HeartMate II CF-VAD implantation at a single center from 2005 to 2011. Forty-three patients had bleeding (24.9%) and 22 had TE (12.7%) events over a 290 patient-year follow-up period. The mean ± SD HAS-BLED scores were 2.7 ± 1.0 and 1.9 ± 1.1 (P < .0001) in patients with and without bleeding, respectively. The CHA2DS2-VASc scores were 3.6 ± 1.4 and 2.9 ± 1.5 (P = .03) in patients with and without TE events, respectively. A HAS-BLED score of ≥ 3 was associated with a significantly higher risk of bleeding events compared with a score of <3 (42% vs 15%, respectively; hazard ratio [HR] 3.40, 95% confidence interval [CI] 1.82-6.32; P < .001). A CHA2DS2-VASc score of ≥ 3 was associated with a higher risk of TE events compared with a score of <3 (18% vs 4%, respectively; HR 4.02, 95% CI 1.19-13.6; P = .025). CONCLUSIONS: Baseline HAS-BLED and CHA2DS2-VASc scores of ≥ 3 conferred significantly higher risks of bleeding and TE, respectively, following HeartMate II implantation.

Ventricular ectopy in patients with left ventricular dysfunction: should it be treated?

Ventricular premature complexes (VPCs) are commonly encountered in patients with congestive heart failure (CHF). Frequent ventricular ectopy can be associated with deterioration of cardiac function and may lead to VPC-induced cardiomyopathy. VPC-induced inter- and/or intraventricular dyssynchrony has been postulated as the main mechanism underlying VPC-induced left ventricular dysfunction. For risk stratification, VPCs in the setting of CHF can not be regarded to be a benign arrhythmia as in an apparently healthy subject. However, any potential survival benefits to be derived from suppression of VPCs or nonsustained ventricular tachycardia in CHF may be offset by the negative inotropic and proarrhythmic effects of antiarrhythmic drugs and may be masked by the risk of death that is already high in this subgroup of patients. ß-Blockers are currently considered to be the first-line therapy, with amiodarone as a back-up. Catheter ablation, although invasive and not without procedural risk, avoids the common adverse effects of currently available antiarrhythmic medications. From a standpoint of preventing or reversing left ventricular dysfunction, frequent VPCs should be treated earlier regardless of their site of origin or the presence of associated symptoms, such as palpitations. Catheter ablation may be the preferable approach in selected patients, particularly when ß-blocker therapy has been ineffective or not tolerated.

Assessment of the myogenic stem cell compartment following transplantation of Pax3/Pax7-induced embryonic stem cell-derived progenitors.

An effective long-term cell therapy for skeletal muscle regeneration requires donor contribution to both muscle fibers and the muscle stem cell pool. Although satellite cells have these abilities, their therapeutic potential so far has been limited due to their scarcity in adult muscle. Myogenic progenitors obtained from Pax3-engineered mouse embryonic stem (ES) cells have the ability to generate myofibers and to improve the contractility of transplanted muscles in vivo, however, whether these cells contribute to the muscle stem cell pool and are able to self-renew in vivo are still unknown. Here, we addressed this question by investigating the ability of Pax3, which plays a critical role in embryonic muscle formation, and Pax7, which is important for maintenance of the muscle satellite cell pool, to promote the derivation of self-renewing functional myogenic progenitors from ES cells. We show that Pax7, like Pax3, can drive the expansion of an ES-derived myogenic progenitor with significant muscle regenerative potential. We further demonstrate that a fraction of transplanted cells remains mononuclear, and displays key features of skeletal muscle stem cells, including satellite cell localization, response to reinjury, and contribution to muscle regeneration in secondary transplantation assays. The ability to engraft, self-renew, and respond to injury provide foundation for the future therapeutic application of ES-derived myogenic progenitors in muscle disorders.

Atrial Fibrillation and Hypertension: "Quo Vadis".

Hypertension is one of the most well-established risk factors for atrial fibrillation. Longstanding untreated hypertension leads to structural remodeling and electrophysiologic alterations, causing an atrial myopathy that forms a vulnerable substrate for the development and maintenance of atrial fibrillation. Hypertension-induced hemodynamic, inflammatory, hormonal, and autonomic changes all appear to be important contributing factors. Furthermore, hypertension is also associated with several atrial fibrillation-related comorbidities. As such, hypertension may represent an important target for therapy in atrial fibrillation. Clinicians should be aware of the pitfalls of blood pressure measurement in atrial fibrillation. While the auscultatory method is preferred, the use of automated devices appears to be an acceptable method in the ambulatory setting. There are pathophysiologic basis and emerging clinical evidence suggesting the benefit of renin-angiotensin system inhibition in risk reduction of atrial fibrillation development, particularly in patients with left ventricular hypertrophy or left ventricular dysfunction. A better understanding of hypertension's pathophysiologic link to atrial fibrillation may lead to the development of novel therapies for the primary prevention of atrial fibrillation. Finally, future studies are needed to address the strategies of optimal blood pressure to minimize the risk of atrial fibrillation-related complications.

Association of Ventricular Arrhythmias With Dementia: The Atherosclerosis Risk in Communities (ARIC) Study.

OBJECTIVE: We performed a cross-sectional analysis to determine whether nonsustained ventricular tachycardia (NSVT) and premature ventricular contractions (PVCs) were associated with dementia in a population-based study. METHODS: We included 2,517 (mean age 79 years, 26% Black) participants who wore a 2-week ambulatory continuous ECG recording device in 2016 to 2017. NSVT was defined as a wide-complex tachycardia ≥4 beats with a rate >100 bpm. We calculated NSVT and PVC burden as the number of episodes per day. Dementia was adjudicated by experts. We used logistic regression to assess the associations of NSVT and PVCs with dementia. RESULTS: The mean recording time of the Zio XT Patch was 12.6 ± 2.6 days. There were 768 (31%) participants with NSVT; prevalence was similar in White and Black participants. There were 134 (6.5%) dementia cases (5% in White, 10% in Black participants). After multivariable adjustment, there was no overall association between NSVT and dementia; however, there was a significant race interaction (p < 0.001). In Black participants, NSVT was associated with a 3.67 times higher adjusted odds of dementia (95% confidence interval [CI] 1.92-7.02) compared to those without NSVT, whereas in White participants NSVT was not associated with dementia (odds ratio [95% CI] 0.64 [0.37-1.10]). In Black participants only, a higher burden of PVCs was associated with dementia. CONCLUSIONS: Presence of NSVT and a higher burden of NSVT and PVCs are associated with dementia in elderly Black people. Further research to confirm this novel finding and to elucidate the underlying mechanisms is warranted.

Clinical Outcomes and Characteristics With Dofetilide in Atrial Fibrillation Patients Considered for Implantable Cardioverter-Defibrillator.

BACKGROUND: Dofetilide is one of the only anti-arrhythmic agents approved for atrial fibrillation (AF) in patients with reduced left ventricular ejection fraction (LVEF). However, postapproval data and safety outcomes are limited. In this study, we assessed the incidence and predictors of LVEF improvement, safety, and outcomes in patients with AF with LVEF ≤35% without prior implantable cardioverter defibrillator, cardiac resynchronization therapy, or AF ablation. METHODS: An analysis of 168 consecutive patients from 2007 to 2016 was performed. Incidences of adverse events, drug continuation, implantable cardioverter defibrillator and cardiac resynchronization therapy implantation, LVEF improvement (>35%) and recovery (≥50%), AF recurrence, and AF ablation were determined. Multivariable regression analysis to identify predictors of LVEF improvement/recovery was performed. RESULTS: The mean age was 64±12 years. Dofetilide was discontinued before hospital discharge in 46 (27%) because of QT prolongation (14%), torsades de pointe or polymorphic ventricular tachycardia/fibrillation (6% [sustained 3%, nonsustained 3%]), ineffectiveness (5%), or other causes (3%). At 1 year, 43% remained on dofetilide. Freedom from AF was 42% at 1 year, and 40% underwent future AF ablation. LVEF recovered (≥50%) in 45% and improved to >35% in 73%. Predictors of LVEF improvement included presence of AF during echocardiogram (odds ratio, 4.22 [95% CI, 1.71-10.4], P=0.002), coronary artery disease (odds ratio, 0.35 [95% CI, 0.16-0.79], P=0.01), left atrial diameter (odds ratio, 0.52 per 1 cm increase [95% CI, 0.30-0.90], P=0.01), and LVEF (odds ratio, per 1% increase, 1.09 [95% CI, 1.02-1.16], P=0.006). The C statistic was 0.78. CONCLUSIONS: In patients with LVEF ≤35%, who are potential implantable cardioverter defibrillator candidates, treated with dofetilide as an initial anti-arrhythmic strategy for AF, drug discontinuation rates were high, and many underwent future AF ablation. However, most patients had improvement in LVEF, obviating the need for primary prevention implantable cardioverter defibrillator.

Concurrent Negative-Pressure Pulmonary Edema (NPPE) and Takotsubo Syndrome (TTS) after Upper Airway Obstruction.

Upper airway obstruction is a potentially life-threatening emergency often encountered in the acute care, perioperative, and critical care settings. One important complication of acute obstruction is negative-pressure pulmonary edema (NPPE). We describe two cases of acute upper airway obstruction, both of which resulted in flash pulmonary edema complicated by acute hypoxic respiratory failure. Though NPPE was suspected, these patients were also found to have Takotsubo syndrome (TTS). Neither patient had prior cardiac disease, and both subsequently had a negative ischemic workup. Because TTS is a condition triggered by hyperadrenergic states, the acute airway obstruction alone or in combination with NPPE was the likely explanation for TTS in each case. These cases highlight the importance of also considering cardiogenic causes of pulmonary edema in the setting of upper airway obstruction, which we suspect generates a profound catecholamine surge and places patients at increased risk of TTS development.

Withdrawal Notice: Atrial Fibrillation and Hypertension: "Quo Vadis"

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Increased baseline ECG R-R dispersion predicts improvement in systolic function after atrial fibrillation ablation.

Background: Atrial fibrillation (AF) is associated with left ventricular (LV) systolic dysfunction which may improve after AF ablation. We hypothesised that increased ventricular irregularity, as measured by R-R dispersion on the baseline ECG, would predict improvement in the left ventricular ejection fraction (LVEF) after AF ablation. Methods: Patients with LVEF <50% at two US centres (2007-2016), having both a preablation and postablation echocardiogram or cardiac MRI, were included. LVEF improvement was defined as absolute increase in LVEF by >7.5%. Multivariable logistic regression (restricted to echocardiographic/ECG variables) was performed to evaluate predictors of LVEF improvement. Results: Fifty-two patients were included in this study. LVEF improved in 30 patients (58%) and was unchanged/worsened in 22 patients (42%). Those with versus without LVEF improvement had an increased baseline R-R dispersion (645±155 ms vs 537±154 ms, p=0.02, respectively). The average baseline heart rate in all patients was 93 beats per minute. After multivariable logistic regression, increased R-R dispersion (OR 1.59, 95% CI 1.00 to 2.55, p=0.03) predicted LVEF improvement. Conclusions: Increased R-R dispersion on ECG was independently associated with improved systolic function after AF ablation. This broadens the existing knowledge of arrhythmia-induced cardiomyopathy, demonstrating that irregular electrical activation (as measured by increased R-R dispersion on ECG) is associated with a cardiomyopathy capable of improving after AF ablation.

Relation of the CHA2DS2-VASc Score to Risk of Thrombotic and Embolic Stroke in Community-Dwelling Individuals Without Atrial Fibrillation (From The Atherosclerosis Risk in Communities [ARIC] Study).

Recent hospital-based cohort studies found the CHA2DS2-VASc score to be associated with ischemic stroke in individuals without atrial fibrillation (AF). Our aim was to determine the distribution of embolic and thrombotic strokes and association with the CHA2DS2-VASc score, among community-dwelling individuals without AF. We included participants from the Atherosclerosis Risk in Communities (ARIC) Study who attended visit 4 (1996 to 1998) and had no previous AF, stroke, or anticoagulant use (n = 10,671). During follow-up through 2008, incident AF cases (n = 760) and participants who started warfarin were censored. Incident AF was ascertained from study electrocardiograms and hospital discharge diagnosis codes, and stroke was physician-adjudicated. After 10 years of follow-up, 280 ischemic strokes were identified, of which 146 were thrombotic and 57 embolic. The hazard ratios (95% confidence intervals [CI]) for thrombotic stroke were 1 (reference), 1.71 (1.13 to 2.59), 2.92 (1.91 to 4.45), 3.22 (1.70 to 6.11), and 1.25 (0.17 to 9.09), with CHA2DS2-VASc scores of 0 to 1, 2, 3, 4, and ≥5, respectively. The hazard ratios (95% CI) for embolic stroke were 1 (ref), 4.91 (2.10 to 11.5), 7.07 (2.93 to 17.0), 14.8 (5.50 to 39.6), and 15.2 (3.16 to 73.3), with CHA2DS2-VASc scores of 0 to 1, 2, 3, 4, and ≥5, respectively. A receiver-operating characteristic model had a C-statistic of 0.65 for ischemic stroke, 0.61 for thrombotic stroke, and 0.71 for embolic stroke. In conclusion, in community-dwelling individuals without AF, the CHA2DS2-VASc score can assess ischemic stroke risk and has good discriminatory capacity for embolic stroke.

Sleep, sleep apnea and atrial fibrillation: Questions and answers.

Sleep apnea (SA) is a common sleep disorder increasingly recognized as a risk for cardiovascular disease. Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with significant morbidity and mortality. An increasing number of investigations in recent years have linked SA to AF. In this review, we aim to provide a critical overview of the existing evidence in a question and answer format by addressing the following: What is the prevalent association between the two conditions (separating nocturnally detected AF episodes from AF as a prevalent condition)? Is SA a risk factor for incident AF? Is SA a risk factor for recurrence of AF following cardioversion/catheter-based ablation? What is the association between SA and AF in patients with heart failure? Are there signature electrocardiographic markers of AF found in patients with SA? Are there electrophysiology-based studies supporting the link between SA and AF? What other sleep characteristics (beyond SA) are found in patients with AF? What is the impact of SA treatment on AF? What is the effect of AF treatment on sleep? Finally, we address unsolved questions and suggest future directions to enhance our understanding of the AF-SA relationship.

Atrial Fibrillation and Objective Sleep Quality by Slow Wave Sleep.

BACKGROUND: Self-reported poor sleep quality has been suggested in patients with AF. Slow wave sleep (SWS) is considered the most restorative sleep stage and represents an important objective measure of sleep quality. The aim of this study was to compare quantity of SWS between patients with and without AF. METHODS AND RESULTS: We included patients with and without a documented history of AF by reviewing clinically indicated polysomnography data from a single sleep center. Patients on medications with potential influence on sleep architecture were excluded. Logistic regression was performed to determine the association between AF and SWS time (low vs. high) adjusting for age, gender, body mass index, and sleep apnea. In a 2:1 case-control set-up, a total of 205 subjects (139 with AF, 66 without AF) were included. Mean age was 62 (SD: 14.3) years and 59% were men. Patients with AF had lower SWS time (11.1 vs. 16.6 min, p=0.02). In multivariable analysis, prevalent AF was associated with low SWS independent of sleep apnea and other potential confounders (OR 2.5 [1.3, 5.0], p=0.006). Limiting the analysis to patients whose total sleep time was greater than 4 hours (by excluding N=31) resulted in more robust results (OR 3.9 [1.7, 9.7]. p=0.002). CONCLUSION: AF is associated with more impaired sleep quality as indicated by lower quantity of SWS. More studies are needed to explore the mechanistic interactions between AF and sleep.