Chahal, C. Anwar A.

Background Sudden cardiac arrest is the leading mode of death in the United States. Epilepsy affects 1% of Americans; yet epidemiological data show a prevalence of 4% in cases of sudden cardiac arrest. Sudden unexpected death in epilepsy (SUDEP) may share features with sudden cardiac arrest. The objective of this study was to report autopsy and genomic findings in a large cohort of SUDEP cases. Methods and Results Mayo Clinic Sudden Death Registry containing cases (ages 0–90 years) of sudden unexpected and unexplained deaths 1960 to present was queried. Exome sequencing performed on decedent cases. From 13 687 cases of sudden death, 656 (4.8%) had a history of seizures, including 368 confirmed by electroencephalography, 96 classified as SUDEP, 58 as non‐SUDEP, and 214 as unknown (insufficient records). Mean age of death in SUDEP was 37 (±19.7) years; 56 (58.3%) were male; 65% of deaths occurred at night; 54% were found in bed; and 80.6% were prone. Autopsies were obtained in 83 cases; bystander coronary artery disease was frequently reported as cause of death; nonspecific fibrosis was seen in 32.6% of cases, in structurally normal hearts. There were 4 cases of Dravet syndrome with pathogenic variants in SCN1A gene. Using whole exome sequencing in 11 cases, 18 ultrarare nonsynonymous variants were identified in 6 cases including CACNB2, RYR2, CLNB, CACNA1H, and CLCN2 . Conclusions This study examined one of the largest single‐center US series of SUDEP cases. Several cases were reclassified as SUDEP, 15% had an ECG when alive, and 11 (11.4%) had blood for whole exome sequencing analysis. The most frequent antemortem genetic finding was pathogenic variants in SCN1A ; postmortem whole exome sequencing identified 18 ultrarare variants.

Post-acute sequelae of SARS-CoV-2 (PASC), or long COVID syndrome, is emerging as a major health issue in patients with previous SARS-CoV-2 infection. Symptoms commonly experienced by patients include fatigue, palpitations, chest pain, dyspnea, reduced exercise tolerance, and “brain fog”. Additionally, symptoms of orthostatic intolerance and syncope suggest the involvement of the autonomic nervous system. Signs of cardiovascular autonomic dysfunction appear to be common in PASC and are similar to those observed in postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. In this review, we report on the epidemiology of PASC, discuss current evidence and possible mechanisms underpinning the dysregulation of the autonomic nervous system, and suggest nonpharmacological and pharmacological interventions to treat and relieve symptoms of PASC-associated dysautonomia.

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti–desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

Introduction: Idiopathic Dilated (DCM) and hypertrophic cardiomyopathies (HCM) are leading causes of sudden cardiac death. The incidence and prevalence of both DCM and HCM were originally estimated in Olmsted County, MN over 1975-1984. Incidence was 6.0 and prevalence was 36.5 per 100,000 person-years, for DCM; with incidence and prevalence rates of 2.5 and 19.7 per 100,000 person-years for HCM. This study aims to determine the incidence and mortality rates of individuals diagnosed with HCM and DCM in Olmsted County, MN from 1984 to 2016. Methods: The Rochester Epidemiology Project is a validated long term medical record linkage system that collects and links medical information for the approximately 145000 residents of Olmsted County, Minnesota. Using this database and the Electronic Health Record systems at Mayo Clinic and Olmsted Medical Center in Rochester, MN, we manually reviewed and validated the medical records of 4440 patients. This cohort includes all patients with any mention of a cardiomyopathy based on ICD and HICDA codes during the period 1984 to 2016. Data were summarized with mean and standard deviation, frequency and percentage and compared between groups using two sample t-test for continuous data and chi-square for proportions. Survival was computed using Kaplan-Meier methods and compared to expected survival based on age and gender. Incidence was computed using Olmsted County population numbers during the time period and adjusted to the US 1980 white population to allow for comparison with the previous study. Results: The calculated crude incidence rate for DCM and HCM are 10.1 and 7.8 per 100,000 respectively. Incidence rates adjusted for comparison to US 1980 white population (age and sex adjusted) are 10.4 (95% CI: 9.3-11.4) and 8.0 (95% CI: 7.1-8.8) per 100,000 person-years, respectively. The observed number of deaths in this cohort (HCM and DCM) was 420 vs 194 expected. Conclusions: Calculated incidence, both crude and adjusted rates are higher than previously estimated rates. The crude incidence rate for HCM is almost 4-fold higher than that for DCM is 2.4 times higher than the original estimate by Codd et al. Individuals with cardiomyopathies were found to have a higher overall mortality rate than the general population with an observed to expected hazard ratio of 1.73 (95% CI 1.49-2.01, p<0.001) for DCM and 1.44 (95% CI 1.21-1.71, p<0.001) for HCM. Our findings suggest that previous studies may have underestimated the true burden of HCM and DCM in the population which has important implications for healthcare provision and cost.

Background The prevalence of excessive daytime sleepiness (EDS) in the general population is reported to be 9 to 28 percent. Various social and biological factors have been reported to contribute to the development of EDS, such as cardiovascular disease, metabolic disorders as well as socioeconomic status. Medically, EDS is associated with poorer prognosis in patients with sleep disorders. However, whether sleepiness is an independent negative prognostic indicator in patients without sleep apnea is poorly understood. Objective To evaluate the relationship between self‐reported excessive daytime sleepiness (assessed by Epworth Sleepiness Scale) and the risk of all‐cause mortality in patients without obstructive sleep apnea (OSA). Methods We performed a retrospective cohort study in a large registry of patients seen at the Mayo Clinic Center for Sleep Medicine between November 17 th , 2009 and April 15 th , 2017. All patients received a diagnostic polysomnography and had completed Epworth Sleepiness Scale (ESS). The primary outcome of all‐cause mortality risk was computed using the Kaplan‐Meier analysis and Cox‐proportional hazard model with age, sex, body mass index (BMI), baseline comorbidities and sleep measurements as confounders. Results A total of 2746 non‐OSA patients were identified. The overall median age (IQR) was computed as 53 (40, 63) with 45% of patients identifying as males. The median follow‐up time was approximately 2.3 years. In a univariate analysis, daytime sleepiness was associated with the female sex, younger age and higher BMI. No significant differences were observed in vascular related diseases between sleepy and non‐sleepy patients. EDS was not significantly associated with all‐cause mortality with an adjusted hazard ratio of 1.23 (95% CI 0.86, 1.76; p =0.257). In addition, there was no significant association of EDS and the risk of all‐cause mortality even after stratifying by sex, age and BMI in non‐OSA patients. Conclusion EDS is not associated with all‐cause mortality in non‐OSA patients. Further prospective studies are needed to confirm this finding. Support or Funding Information This research was supported by NIH HL65176 and NIH HL114024. Kaplan–Meier survival curve of 8 years all‐cause mortality of non‐OSA patients with and without excessive daytime sleepiness (EDS) at baseline. image Kaplan–Meier survival curve of 8 years all‐cause mortality of non‐OSA patients with and without excessive daytime sleepiness (EDS) at baseline. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Background Aortic stenosis (AS) affects, and is associated with significant comorbidity and mortality, including sudden cardiac death (SCD) from unknown mechanisms. However, it is difficult to predict which patients with AS will suffer a SCD event. Anemia and low iron are known risk factors for mortality in heart failure populations and AS. We hypothesized that anemia in patients with AS is associated with increased risk of SCD. Purpose Understand the relationship and prognostic implications between anemia and SCD in patients with severe AS. Methods and Results We selected 8,144 of 10,850 patients with severe AS (mean transvalvular gradient ≥40 mmHg or peak velocity ≥4 m/s or calculated valve area < 1 cm 2 ) from the Mayo Clinic Aortic Stenosis Registry, which includes all consecutive patients with severe AS over the time period January 1 st , 1983 to September 30 th , 2015. Subjects in this analysis (median age 76 years and 57% male) were diagnosed starting in 1995 and had hemoglobin (Hb) measurements within one year of diagnosis and prior to intervention. The mean Hb level was 12.8 (± 1.9) g/dL. The prevalence of anemia (Hb<13.0g/dL for men, <12.0g/dL for women) was 40%, 14% microcytic, 20% macrocytic, with the remainder normocytic. Of the 8,144 patients, a total of 4,440 died (10‐year survival 39%; and 240 were confirmed as SCD events [10 year cumulative incidence 4%]). Anemia was associated with increased all‐cause mortality (HR 1.87, 95% CI 1.76–1.99, P=<0.001) and increased SCD events (HR 1.58, 95% CI 1.22–2.06, P=<0.001) in patients with severe AS. Every SD decrease in Hb (1.9 g/dL) was associated with an increased risk of SCD (HR 1.42, 95% CI 1.24–1.62, P<0.001). Conclusions Anemia is highly prevalent in patients with severe aortic stenosis and is independently associated with increased all‐cause mortality, and more specifically with increased SCD risk. Possible mechanisms include anemia aggrevating myocardial hypoxia, increasing propensity for arrhythmia and abnormal Bezold‐Jarisch reflex mismatch. Anemia may be a useful prognostic marker and a potential therapeutic target in patients with severe AS. Support or Funding Information CAAC is supported by AHA17POST33400211 and NIH HL134885. This study was supported by a grant from the Department of Cardiovascular Medicine, Mayo Clinic Rochester. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Ramadan fasting is observed by most of the 1.8 billion Muslims around the world. It lasts for 1 month per the lunar calendar year and is the abstention from any food and drink from dawn to sunset. While recommendations on ‘safe’ fasting exist for patients with some chronic conditions, such as diabetes mellitus, guidance for patients with cardiovascular disease is lacking. We reviewed the literature to help healthcare professionals educate, discuss and manage patients with cardiovascular conditions, who are considering fasting. Studies on the safety of Ramadan fasting in patients with cardiac disease are sparse, observational, of small sample size and have short follow-up. Using expert consensus and a recognised framework, we risk stratified patients into ‘low or moderate risk’, for example, stable angina or non-severe heart failure; ‘high risk’, for example, poorly controlled arrhythmias or recent myocardial infarction; and ‘very high risk’, for example, advanced heart failure. The ‘low-moderate risk’ group may fast, provided their medications and clinical conditions allow. The ‘high’ or ‘very high risk’ groups should not fast and may consider safe alternatives such as non-consecutive fasts or fasting shorter days, for example, during winter. All patients who are fasting should be educated before Ramadan on their risk and management (including the risk of dehydration, fluid overload and terminating the fast if they become unwell) and reviewed after Ramadan to reassess their risk status and condition. Further studies to clarify the benefits and risks of fasting on the cardiovascular system in patients with different cardiovascular conditions should help refine these recommendations.

Abstract Multiple guidelines exist for the management of aortic stenosis (AS). We systematically reviewed current guidelines and recommendations, developed by national or international medical organizations, on management of AS to aid clinical decision-making. Publications in MEDLINE and EMBASE between 1 June 2010 and 15 January 2021 were identified. Additionally, the International Guideline Library, National Guideline Clearinghouse, National Library for Health Guidelines Finder, Canadian Medical Association Clinical Practice Guidelines Infobase, and websites of relevant organizations were searched. Two reviewers independently screened titles and abstracts. Two reviewers assessed rigour of guideline development and extracted the recommendations. Of the seven guidelines and recommendations retrieved, five showed considerable rigour of development. Those rigourously developed, agreed on the definition of severe AS and diverse haemodynamic phenotypes, indications and contraindications for intervention in symptomatic severe AS, surveillance intervals in asymptomatic severe AS, and the importance of multidisciplinary teams (MDTs) and shared decision-making. Discrepancies exist in age and surgical risk cut-offs for recommending surgical aortic valve replacement (SAVR) vs. transcatheter aortic valve implantation (TAVI), the use of biomarkers and complementary multimodality imaging for decision-making in asymptomatic patients and surveillance intervals for non-severe AS. Contemporary guidelines for AS management agree on the importance of MDT involvement and shared decision-making for individualized treatment and unanimously indicate valve replacement in severe, symptomatic AS. Discrepancies exist in thresholds for age and procedural risk used in choosing between SAVR and TAVI, role of biomarkers and complementary imaging modalities to define AS severity and risk of progression in asymptomatic patients.

Abstract Background Orthotopic heart transplant (OHT) is indicated in 1–8% of patients with myocarditis. However, national trends in the utilization of transplantation and outcomes in myocarditis across the United States are not well established. Purpose Our objective was to study the trends and baseline characteristic of myocarditis patients undergoing heart transplant in the United States using Healthcare Cost and Utilization Project (HCUP) National (nationwide) Inpatient Sample (NIS) from 1999 to 2014. Methods Using NIS data, we identified patients older than 18 years with myocarditis using codes ICD9 codes of 422.0 and 422.9. Among these patients, we identified those who underwent cardiac transplantation using ICD9 procedure codes 37.5 and 33.6. We presented categorical data as percentages and continuous data as mean or median as appropriate. Results We identified a total of 62,264 hospitalizations for myocarditis from 1999–2014. 430 (0.69%) myocarditis patients underwent OHT which consisted of 0.82% of all 29990 cardiac transplants identified in the same period. The trends in OHT for myocarditis is as shown in Figure 1. The mean age was 32.9±2.4 years and 51.1% (n=219) were females. 235 (54.6%) were Caucasians and 60 (13.9%) were Hispanic. Majority of the transplants were performed at medium (16%) and large sized hospitals (80.4%). Cardiac transplants were mainly done at teaching hospitals (98.9%). Further, with regards to the geographical distribution of transplant procedure, most were done in the West (37.2%) followed by South (25.3%), Northeast (21.4%) and Mid-west (16%) of the United States. Private insurance was the major payor source which covered 245 (58%) patients followed by Medicaid covering 112 (26%) patients. A total of 26 (6%) myocarditis patients died during the same hospitalization for OHT. In terms of discharge following OHT in myocarditis 85.8% (n=369) were discharged home and 8.1% (n=35) to short term hospitalization. The average length of stay for OHT for myocarditis was 64.3±6.3 days. Also, the mean cost of hospitalization for heart transplant in myocarditis when adjusted for inflation was 789,566±93,108 dollars. In-patient mortality following OHT was not significantly different in large sized hospital compared to small and medium sized hospitals (7.6% vs 5.7%, p=0.54). However, the cost of hospitalization was significantly lesser in small and medium sized hospitals (588,363±154,349 vs 826,864±106,110 dollars, p&lt;0.0001). Conclusions Only a small percentage of OHT is done for myocarditis with high proportion done in female when compared to OHT for other etiologies. Further studies need to be done to compare long term outcomes of heart transplant in myocarditis. Funding Acknowledgement Type of funding source: None