Younghoon Kwon

Association of sleep characteristics with atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis

Background Population-based studies have linked measures of sleep disordered breathing to nocturnally occurring atrial fibrillation (AF) episodes. Whether measures of sleep disordered breathing and sleep quality are associated with prevalent AF has not been studied in an unselected population. We investigated the cross-sectional association with prevalent AF of objectively collected prespecified measures of overnight sleep breathing disturbances, sleep stage distributions, arousal and sleep duration. Methods AF prevalence, defined by diagnosis codes, study electrocardiography and sleep study were examined among Multi-Ethnic Study of Atherosclerosis (MESA) participants who underwent polysomnography in the MESA Sleep Study (n=2048). Measurements and main results Higher apnoea hypopnoea index (AHI) was associated with increased odds of AF, although the significance was attenuated after full adjustment for covariates including prevalent cardiovascular disease (OR: 1.22 (0.99 to 1.49) per SD (17/h), p=0.06). Analyses of sleep architecture measures and AF revealed significantly lower odds of AF associated with longer duration of slow wave sleep (OR: 0.66 (0.5 to 0.89) per SD (34 min), p=0.01) which persisted after additionally adjusting for AHI (OR: 0.68 (0.51 to 0.92), p=0.01). Higher sleep efficiency was significantly associated with lower likelihood of AF but the significance was lost when adjusted for AHI. No significant association was present between sleep duration and AF. In a model including AHI and arousal index, the association between AHI and AF was strengthened (AHI: OR 1.49 (1.15 to 1.91) per SD, p=0.002) and a significant inverse association between arousal index and AF was observed (OR 0.65 (0.50 to 0.86) per SD (12/h), p=0.005). Conclusions In a study of a large multiethnic population, AF was associated with AHI severity, and was more common in individuals with poor sleep quality as measured by reduced slow wave sleep time, a finding that was independent of AHI.

Association of Smoking, Alcohol, and Obesity with Cardiovascular Death and Ischemic Stroke in Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS)

Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke and cardiovascular (CV) death. Whether modifiable lifestyle risk factors are associated with these CV outcomes in AF is unknown. Among Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS) participants with incident AF, we estimated the risk of composite endpoint of ischemic stroke or CV death associated with candidate modifiable risk factor (smoking, heavy alcohol consumption, or high body mass index [BMI]), and computed the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) of incorporating each factor into the CHA2DS2-VASc. Among 1222 ARIC (mean age: 63.4) and 756 CHS (mean age: 79.1) participants with incident AF, during mean follow-up of 6.9 years and 5.7 years, there were 332 and 335 composite events respectively. Compared with never smokers, current smokers had a higher incidence of the composite endpoint in ARIC [HR: 1.65 (1.21–2.26)] but not in CHS [HR: 1.05 (0.69–1.61)]. In ARIC, the addition of current smoking did not improve risk prediction over and above the CHA2DS2-VASc. No significant associations were observed with alcohol consumption or BMI with CVD outcomes in AF patients from either cohort. Smoking is associated with an increased risk of ischemic stroke or CV death in ARIC, which comprised mostly middle-aged to young-old (65–74 years), but not in CHS, which comprised mostly middle-old or oldest-old (≥75 years) adults with AF. However, addition of smoking to the CHA2DS2-VASc score did not improve risk prediction of these outcomes.

Obstructive Sleep Apnea and Progression of Coronary Artery Calcium: The Multi‐Ethnic Study of Atherosclerosis Study

Background Obstructive sleep apnea (OSA) is a common condition associated with cardiovascular disease. Its potential effect on progression of subclinical atherosclerosis is not well understood. We tested the hypothesis that self‐reported OSA is associated with progression of coronary artery calcium (CAC). We also evaluated whether traditional cardiovascular risk factors accounted for the association. Methods and Results In the Multi‐Ethnic Study of Atherosclerosis (MESA) prospective cohort, we studied 2603 participants who at baseline (2002–2004) completed a sleep questionnaire and underwent coronary computed tomography (CT) and, then 8 years later (2010–2011), a repeat coronary CT. Participants were categorized by symptoms of habitual snoring or reported physician diagnosis of OSA. At baseline, 102 (3.9%) reported diagnosed OSA; 666 (25.6%) reported diagnosed habitual snoring; and 1835 (70.5%) reported neither habitual snoring nor OSA (“normal”). At baseline, CAC prevalence was highest among those with OSA but similar for those with and without habitual snoring. During 8 years of follow‐up, greater progression of CAC was observed among those with OSA versus normal (mean increase of 204.2 versus 135.5 Agatston units; P=0.01), after accounting for demographics, behaviors, and body habitus. Modest attenuation was observed after adjustment for cardiovascular risk factors (188.7 versus 138.8; P=0.06). CAC progression among habitual snorers was similar to that observed in the normal group. Conclusions OSA was associated with CAC score progression after adjustment for demographics, behaviors, and body mass index. However, the association was not significant after accounting for cardiovascular risk factors, which may mediate the association between OSA and CAC.

Effect of manual editing of total recording time: Implications for home sleep apnea testing

STUDY OBJECTIVES Type 3 home sleep apnea tests may underestimate the apnea-hypopnea index (AHI) due to overestimation of total sleep time (TST). We aimed to evaluate the effect of manual editing of the total recording time (TRT) on the TST and AHI. METHODS Thirty 15-channel in-home polysomnography studies (AHI 0 to 30 events/h) scored using American Academy of Sleep Medicine criteria were rescored by two blinded polysomnologists after data from electroencephalogram, electrooculogram, and electromyogram were masked. In method 1, periods of probable wakefulness and artifact were manually edited and removed from analysis. Method 2 identified TST as the TRT without manual editing. Paired t-tests were used to compare the TST and AHI between these methods. Sensitivity and specificity of each method were calculated for gold standard AHI cutoffs of ≥ 5 and ≥ 15 events/h. RESULTS TST (mean [standard deviation, SD]) by polysomnography, method 1, and method 2 was 366.0 (70.1), 447.1 (59.0), and 542 (61.9) min, respectively. The corresponding AHI was 12.5 (8.2), 10.8 (7.0), and 9.1 (6.1) events/h, respectively. Compared to polysomnography, both alternative methods overestimated the TST (method 1: mean difference [SD] 81.1 [56.1] min, method 2: 176.0 [89.7] min; both p < 0.001) and underestimated the AHI (method 1: mean difference [SD] -1.6 [3.3], method 2: -3.3 [3.9]; both p < 0.001). The sensitivity was 100% and 70.0% for method 1, and 91.3% and 40.0% for method 2 for identifying sleep-disordered breathing using AHI cutoffs of ≥ 5 and ≥ 15 events/h, respectively. CONCLUSIONS Manual editing of TRT reduces the overestimation of TST and improves the sensitivity for identifying studies with sleep-disordered breathing. COMMENTARY A commentary on this article appears in this issue on page 9.

Effect of sleep-disordered breathing on appropriate implantable cardioverter-defibrillator therapy in patients with heart failure: A systematic review and meta-analysis

Background— Patients with heart failure and reduced ejection fraction are at increased risk of malignant ventricular arrhythmias. Implantable cardioverter-defibrillator (ICD) is recommended to prevent sudden cardiac death in some of these patients. Sleep-disordered breathing (SDB) is highly prevalent in this population and may impact arrhythmogenicity. We performed a systematic review and meta-analysis of prospective studies that assessed the impact of SDB on ICD therapy. Methods and Results— Relevant prospective studies were identified in the Ovid MEDLINE, EMBASE, and Google Scholar databases. Weighted risk ratios of the association between SDB and appropriate ICD therapies were estimated using random effects meta-analysis. Nine prospective cohort studies (n=1274) were included in this analysis. SDB was present in 52% of the participants. SDB was associated with a 55% higher risk of appropriate ICD therapies (45% versus 28%; risk ratio, 1.55; 95% confidence interval, 1.32–1.83). In a subgroup analysis based on the subtypes of SDB, the risk was higher in both central (risk ratio, 1.50; 95% confidence interval, 1.11–2.02) and obstructive (risk ratio, 1.43; 95% confidence interval, 1.01–2.03) sleep apnea. Conclusions— SDB is associated with an increased risk of appropriate ICD therapy in patients with heart failure and reduced ejection fraction.

A case of cerebral venous sinus thrombosis associated with Crohn’s disease: dilemma in management

Inflammatory bowel disease (IBD) is known to increase the risk of venous thromboembolism. Cerebral venous sinus thrombosis (CVST) is a rare but important complication of IBD. Timely diagnosis, particularly in younger patients, requires a high level of suspicion in order to prevent potentially devastating complications such as hemorrhage or venous infarction. The paper presents a 44-year-old Caucasian woman with a previous history of Crohn’s disease and deep venous thrombosis. Magnetic resonance imaging confirmed the diagnosis of CVST. Achieving therapeutic anticoagulation with warfarin was difficult, due to presumed pharmacological interaction between warfarin and 6-mercaptopurine. Clinicians should have a high index of suspicion for CVST when a patient with Crohn’s disease presents with acute headache, and be aware of challenges related to medical management.

Circulation time measurement from sleep studies in patients with obstructive sleep apnea.

INTRODUCTION Lung to finger circulation time (LFCT) can be estimated from polysomnography (PSG) in the presence of an apneic event by using oxygen as an indicator and a finger as the site of detection. The purpose of this study was to refine the methodology of LFCT measurement and to compare LFCT in patients with obstructive sleep apnea (OSA) with and without heart failure (HF). METHODS In a retrospective manner, 10 LFCT measurements per patient were made from the PSG in 171 consecutive patients with a diagnosis of OSA who were divided into two groups: (a) those with a clinical history of underlying HF (N = 42) and (b) those without HF (N = 129). Mean values were compared between the two groups. We also examined associations of LFCT with various factors in each group and the combined group separately using multiple regression analysis. RESULTS Gender and age were significantly associated with LFCT in patients with OSA alone. Use of β-blockers was associated with LFCT in the group with OSA with HF. Among the entire cohort, HF, β-blocker, gender, and age were found to be significantly associated with LFCT. The presence of HF was the strongest predictor of a prolonged LFCT (adjusted mean LFCT: OSA only = 18.5 [95% CI: 17.2-19.7 sec] vs. OSA with HF = 26.1 [95% CI: 24.3-28.0 sec], p < 0.0001). CONCLUSION LFCT can be reliably measured and is prolonged in patients with OSA and underlying HF. LFCT based on PSG may be a useful marker for detection of coexisting HF in patients with OSA.

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.

Telangiectasia and Pulmonary Arterial Hypertension Following Treatment With Trastuzumab Emtansine: A Case Report

Trastuzumab emtansine (T-DM1) is a Food and Drug Administration-approved novel agent for the treatment of HER-2 positive advanced breast cancer. We report a case of pulmonary arterial hypertension (PAH) that we attribute to the use of T-DM1. A 43-year-old woman with stage IV breast cancer presented with dyspnea on exertion. After excluding other secondary causes of pulmonary hypertension, a diagnosis of moderately severe PAH was made based on right heart catheterization. History revealed that the patient had been on T-DM1 before presentation. During T-DM1 treatment, the patient experienced hereditary hemorrhagic telangiectasia-like symptoms consisting of spider angiomata-skin lesions, epistaxis, and hematochezia, which resolved with discontinuation of T-DM1. Temporal associations of T-DM1 use with the development of PAH in the patient, and the reported association between hereditary hemorrhagic telangiectasia and PAH via genetic linkage, led us to suspect T-DM1 as the cause of PAH.

Association between sleep disordered breathing and electrocardiographic markers of atrial abnormalities: the MESA study

Aims Electrocardiographic (ECG) markers of left atrial (LA) abnormalities have been linked to increased risk of atrial fibrillation (AF). Sleep disordered breathing (SDB) has been associated with increased risk of AF. We aimed to examine the association of ECG markers of LA abnormalities with SDB. Methods and results 1546 participants (mean age 67.2 years, 53.4% women, and 63.3% non-whites) from the Multi-Ethnic Study of Atherosclerosis Exam 5 Sleep ancillary study were included in this analysis. ECG markers of LA abnormalities (P wave terminal force in V1 (PTFV1), maximum P wave duration, PR interval and heart rate corrected PR interval) were measured from resting standard digital ECG tracings using standardized processing. Linear and logistic regression analyses were utilized to examine the cross-sectional associations of measures of SDB (apnea hypopnea index [AHI] and % time spent with oxygen saturation <90% [%SpO290]) with each ECG marker. In a multivariable analysis adjusting for demographics, cardiovascular risk factors, and comorbidities, AHI was associated with greater PTFV1 but not with other ECG markers of LA abnormalities. A 1-SD increase of AHI (16.6/hr) was associated with higher levels of PTFV1 (175.1 µV.ms, 95% confidence interval [95%CI] 75.4, 274.7) and higher odds of abnormally elevated PTFV1 (≥4000 µV.ms) (Odds Ratio: 1.21 [95%CI 1.05, 1.39]). No association was found between %SpO290 and ECG markers of LA abnormalities. Conclusion Severity of SDB, as measured by AHI, is associated with subclinical LA disease, as indicated by PTFV1. PTFV1 may be an important ECG marker linking SDB and AF.