Citations

Introduction: Pathogenic loss-of-function variants in the RBM20 -encoded RNA-binding motif 20 splicing regulator cause a severe form of arrhythmogenic dilated cardiomyopathy (DCM). Erroneous splicing of TTN -encoded titin contributes to the pathogenesis of RBM20 -mediated disease. However, studies exploring the clinical course of RBM20 -mediated arrhythmogenic DCM alone or in comparison to TTN -mediated DCM, the most common familial cause of DCM, are lacking. Methods: The Mayo Clinic Genetic Arrhythmogenic Cardiomyopathy Registry (n=391) was used to identify all patients with a pathogenic/likely pathogenic (P/LP) variant in either RBM20 or TTN . For the purposes of this study, a ventricular arrhythmia (VA) event was defined as sudden cardiac arrest, sustained ventricular arrhythmia, or an appropriate ICD shock and an advanced heart failure (AHF) event was defined as ventricular assist device implantation or heart transplantation. Results: Overall, 40 patients with a P/LP variant in RBM20 (50% female) and 70 patients with a P/LP variant in TTN (43% female) were identified. The prevalence of a cardiac phenotype in patients with RBM20- and TTN -mediated disease was 88% and 83%, respectively. RBM20 patients were more likely to have a family history of sudden cardiac arrest (78% vs 34%; p < 0.0001) and cardiomyopathy (90% vs 61%; p=0.001). No difference in rate of ICD implantation (35% versus 33%) was observed. Interestingly, the prevalence of AHF events (10% vs 6%; p=0.5) and VA events (28% vs 24%; p=0.7) was similar between RBM20 - and TTN -positive patients. However, RBM20 patients were younger than TTN patients at the time of their event (37 ± 18 years vs 50 ± 17; p=0.0004). Time-to-event analysis showed RBM20 patients had an earlier time to AHF event (p=0.05) and time to VA event (p=0.03) than TTN patients. The mean age for AHF events was 25 years for RBM20 patients (N=4) and 47 years for TTN patients (N=4). The mean age for VA events was 29 years for RBM20 patients (N=10) and 42 years for TTN patients (N=14). Conclusions: RBM20 -mediated arrhythmogenic DCM represents a highly penetrant genetic heart disease with potentially life-threatening VAs and end stage heart failure manifestations occurring at a significantly younger age in comparison to TTN -mediated DCM.

Introduction: There is a variation in cardiovascular outcomes between rural and urban hospitals such as higher mortality for AF. Whether such a relationship exists for safety and outcomes of left atrial appendage occlusion (LAAO) device implantation is unknown. Hypothesis: We hypothesized that LAAO procedure in rural hospitals is associated with worse in-hospital outcomes. Methods: A cross-sectional examination of patients who were hospitalized for LAAO procedure was performed in the National Inpatient Sample between 2016 and 2019 to compare in-hospital outcomes in patients admitted to urban vs rural hospitals. ICD 10 PCS code 02L73DK was used to identify hospitalizations with LAAO procedure. The cohort was further stratified into rural and urban hospitals. Chi-square test and multivariate logistic regression were used to analyze the association and statistical analyses were performed using weighted values. Results: A total of 61,390 hospitalizations for LAAO procedures were identified during the study period. From these, 1185 (1.93%) hospitalizations occurred in rural hospitals. Baseline characteristics and inpatient outcomes are shown in Table 1. LAAO in rural hospitalizations was associated with significantly higher in-hospital mortality [OR 2.94 (1.17-7.14), p<0.001*]. This associated persisted even after adjusting for significant baseline characteristics [aOR 3.55 (1.42-8.84), p=0.006*). Conclusions: In-hospital mortality was significantly higher in patients undergoing LAAO in rural hospital. Further studies are needed to validate these findings in a prospective manner.

Introduction: Cardiac resynchronization therapy (CRT) has known benefit for heart failure (HF) with reduced left ventricular ejection fraction (LVEF) and dyssynchrony. However, very little is known about its benefit in infiltrative cardiomyopathies such as cardiac amyloidosis (CA) due to relative rarity of these conditions. Methods: This retrospective case series (2003-2021) comprised patients with HF due to transthyretin wild-type CA with (case) or without (control) CRT implant. Only controls with an indication for CRT or LVEF <40% were included. To further match disease severity, cases were 1:1 matched (propensity score tolerance 0.04) to controls for age, NYHA class, and CA stage (UK Staging). Primary outcome was MACE (major adverse cardiac events) which included stroke, myocardial infarction, HF hospitalization and cardiac mortality during a 3-year follow-up. Loss to follow-up was censored as per last visit date. LVEF and NYHA were noted closest to 1-year follow-up. Survival analysis for MACE was performed with Kaplan-Meier (KM) and multivariable cox regression models. Results: Study Cohort (n=160) had a mean age of 75.5 (SD 7.8) years and 97.5% were males. A majority had NYHA class 2 or 3 (92.3%) and CA stage 2 (42.2.%). Notably, median LVEF at baseline was lower in controls (33.5 vs 36.5; P = .001) and 77.5% of controls had an indication for CRT device. A total of 79 MACE events occurred, most frequent being HF hospitalization (n=45). KM curves were comparable for MACE events in the two groups (log-rank test; P = .059). Even after adjusting, as in table, CRT device was not associated with MACE events (adjusted HR 0.66; 95% CI 0.40-1.09; P = .106). Lastly, change in LVEF ( P = .84) and NYHA ( P = .86) at follow-up was similar in cases vs controls. Conclusions: The findings of this largest yet observational study to examine this question suggest that CRT in patients with transthyretin wild-type CA does not favorably impact outcomes for MACE events, improve LVEF or NYHA functional class.

Background: TITIN truncational variants (TTNtv) is the predominant genetic factor for dilated cardiomyopathy (DCM). Therapeutic development for TTNtv DCM has been confounded by allelic heterogeneity (AH), i.e. while truncations in the C-terminal A-domain (TTNtv-As) are pathogenic, truncations in the N-terminal Z-disc domain (TTNtv-Zs) are largely benign. Molecular mechanisms underlying AH remain elusive, partially because of the lack of an in vivo animal model. Objective: We enquire whether zebrafish is a faithful vertebrate model for deciphering AH in TTNtv DCM and for therapeutic development. Methods and Results: Through comparing phenotypes among a series of ttntv -As and ttntv -Zs in adult zebrafish, we detected DCM-like phenotypes only in ttntv -As but not ttntv -Zs. Similar to human TTNtv DCM and corresponding rodent models, zebrafish ttntv -As manifest decreased ejection fraction, enlarged heart size, myofibril dys-organization, compromised exercise capacity, and dysregulated autophagy. Moreover, we noted exaggerated cardiac senescence at the later stage of the pathogenesis of ttntv DCM. Because AH in autophagy dysregulation was also detected in homozygous ttntv-A zebrafish embryos, we screened autophagy genes and identified ulk1 inhibition that is able to repair the dysregulated autophagy. A similar repairing effect of ulk1 inhibition on dysregulated autophagy was noted in an adult heterozygous ttntv-A model, which is sufficient to attenuate the cardiac senescence and improve cardiac function. Conclusion: Our data suggested adult zebrafish as the first vertebrate model that is able to recapitulate AH in TTNtv DCM patients. Conserved phenotypes including autophagy dysregulation are recapitulated in this lower vertebrate model, while cardiac senescence has been suggested as a novel pathological event. Genetic studies in this animal strongly suggest that repairing autophagy dysregulation is a therapeutic avenue for TTNtv DCM, and identified ulk1 as a candidate therapeutic target gene.

Background: Iron deficiency in patients with systolic heart failure (HF) was found to be associated with poorer exercise capacity and quality of life. We conducted this systematic review and meta-analysis to assess whether iron supplementation in patients with systolic HF can improve exercise capacity and quality of life. Methods: We searched MEDLINE, and Embase databases from inception to May 2022 to identify the studies that reported the impact of iron therapy including oral and intravenous (IV) iron forms in systolic HF patients with iron deficiency. Outcomes of interest included 1) six minute walk test (6MWT) and 2) Quality of life (QoL) assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ). Data from each study were combined using the random-effects model to calculate weight mean difference (WMD) and 95% confidence interval (CI) Results: Five studies (4 randomized controlled trials and 1 nonrandomized open-label study) with a total of 1,075 patients (610 in the intervention group and 465 in the control group) were included. In the intervention group, 474 patients received IV iron and 136 patients received oral iron therapy. Iron therapy was associated with significant improvement of 6MWT (WMD =22.81, 95% CI 0.47-45.14, p < 0.001) and KCCQ (WMD =4.68, 95%CI 0.43-8.93, p< 0.001). Interestingly, subgroup analysis showed that the main results were driven by IV iron therapy in both 6MWT (WMD =34.68, 95%CI 25.13-44.24, p< 0.001) and KCCQ (WMD =6.78, 95%CI 3.81-9.75, p< 0.001) as there was no significant improvement after oral iron therapy in 6MWT (WMD =0.15, 95% CI -23.86-24.16, p =0.99) and KCCQ (WMD =2.71, 95% CI-1.35-6.78, p =0.19). As shown in Figure 1. Conclusions: Intravenous iron therapy, but not oral iron therapy is associated with improved exercise capacity and QoL in patients with systolic HF.

Introduction: Exercise Stress Echocardiography (ESE) is recommended as a screening tool for the evaluation of Coronary Artery Disease (CAD) in patients with suspected Radiation-Induced Heart Disease (RIHD). Up to now, studies have only evaluated its association with the extent of CAD. Hypothesis Cancer survivors treated with chest Radiotherapy (RT) that undergo an ESE and have a +ESE develop more MACE than those who have -ESE. Methods: A retrospective, descriptive, cohort study was conducted. Patients who had chest RT and underwent ESE with Treadmill Bruce Stress Protocol, from 2000 to 2012, at Mayo Clinic Rochester and Mayo Clinic Health System were included. A univariate analysis was performed to characterize the population. An analysis including Kruskal Wallis and Pearson Chi-Squared tests was completed to identify variables associated with + SE (Table 1). Multivariable Cox Model for MACE was conducted and is shown in Table 2. A time-to-event curve using Kaplan-Meier estimates is shown in Figure 1. Results: We identified 113 patients, with a mean age of 67 years and a median follow-up of 15.1 years. Of those, 99% were female, 98% were breast cancer survivors, 59% had HTN, 14% DM, 11% AFib, 2% COPD, and 12% had a history of MI. All the patients received >3000cGy of Photon RT, and 57% were treated with systemic cancer therapies. A +ESE was seen in 20.3% of the patients with no significant difference in METS achieved compared with patients who had a -ESE. COPD, RT dose, and systemic therapies, specifically doxorubicin, were associated with a +ESE. The cumulative incidence of MACE was higher in the group of +ESE (p=0.029). After adjustment for HTN, DM, smoking history, hyperlipidemia, and prior MI, the HR for MACE associated with a +ESE was 1.97 (1.09-3.59). Conclusion: MACE was more frequent in patients with a +ESE who received chest RT and doxorubicin versus -ESE. These results support the usefulness of ESE in cancer survivors after RT as a cardiovascular screening tool.

Introduction: The COVID-19 pandemic imposed significant constraints to delivery of cardiac rehabilitation (CR) with many programs relying on delivery of home-based cardiac rehabilitation (HBCR). We sought to compare the effects of HBCR vs conventional center-based CR (CBCR) on clinical metrics, health-related quality of life, and modifiable risk factors in CR patients. Methods: Retrospective cohort study comparing 511 HBCR patients (March 2020-April 2021; COVID-19 pandemic) and 765 age and sex matched CBCR patients (Jan 2018-Jan2020; immediately pre-pandemic) from the Mayo Clinic Health System. We assessed changes in clinical outcomes before and after CR. HBCR included 12 sessions (one in-person assessment + weekly education and exercise monitoring phone/video calls). Conventional CBCR included 36 sessions (3 sessions per week for 12 weeks). Continuous data were described as mean±SD, and comparisons of change between groups were assessed with linear regression adjusting for baseline value, in complete cases. Results: HBCR and CBCR patients were 65±14 yrs old (68% male) and 65±14 yrs old (67% male) respectively. HBCR patients demonstrated greater improvement in exercise days/week whereas CBCR patients had greater improvement in exercise min/day. HBCR patients had greater improvement in blood glucose with a trend towards greater improvement in non-HDL cholesterol. Both groups demonstrated similar improvement on nutrition, depression, health-related quality of life surveys and total, LDL and HDL cholesterol, as well as HbA1c between the groups. Conclusions: Collecting clinical metrics during the COVID-19 pandemic proved challenging due to the initial closure of out-patient services. For patients in whom data was captured, HBCR appears to be similarly effective at improving several intermediate outcomes compared to CBCR. HBCR may be an effective alternative for improving clinical outcomes in patients who are unable to participate in CBCR.

Introduction: Many center-based cardiac rehabilitation programs were forced to close during the pandemic resulting in a programmatic shift to delivering cardiac rehabilitation remotely in the home-based setting. This study examined sex differences in the change of exercise frequency and exercise capacity in patients participating in home-based cardiac rehabilitation (HBCR) during the COVID-19 pandemic. Methods: Retrospective cohort study of 567 HBCR patients between March 2020 and May 2021. Patients who completed the Duke Activity Status Index questionnaire before and after HBCR were included. We calculated the number of reported exercise days/ week, exercise min/day, and VO 2 peak estimated. Patients were divided into two groups according to sex (Male/Female). Continuous data are described as mean±SD and baseline data compared with a two-sample t-test. The delta change from pre-post between groups also are compared with a two-sample t-test. Results: Of 567 HBCR patients, 118 patients completed both pre and post HBCR questionnaires (Male, n=82, 66±12 yo vs Female, n=36, 65±12 yo, p=0.80). There were no differences between groups for baseline exercise days/week or exercise min/day pre HBCR (4.0±2.8 vs 4.1±3.0 days, p=0.87; 22±20 vs 18±20 min, p=0.33); however, VO 2 peak at baseline HBCR was higher in males than females (22.3±8.1 vs 18.9±5.9 ml/kg/min, p<0.05). Both groups improved exercise days/week (4.0±2.8 to 5.7±1.5 vs 4.1±3.0 to 5.7±1.4 days, p<0.05 for both), exercise min/day (22±20 to 40±15 vs 18±20 to 37±21 min, p<0.05 for both), and VO 2 peak (22.3±8.1 to 27.8±8.0 vs 18.9±5.9 to 22.7±6.5, ml/kg/min, p<0.05 for both). In addition, there was no significant difference for the delta change of the three outcomes between groups (1.7±2.7 vs 1.6±2.5 days; 18±19 vs 19±18 min; 5.5±6.5 vs 3.8±4.5 ml/min/kg, p>0.05 for all). Conclusions: Female patients entering HBCR during the COVID-19 pandemic demonstrated lower exercise capacity compared to males; however, both female and male patients increased exercise frequency (days/week and min/day) and exercise capacity (estimated VO 2 peak) similarly after attending HBCR during the COVID-19 pandemic.

Introduction: The COVID-19 pandemic resulted in the closure of many center-based cardiac rehabilitation programs leading many institutions to rely on home-based cardiac rehabilitation (HBCR) to provide critical secondary cardiovascular disease prevention and rehabilitation. The impact of age on the change of exercise frequency and exercise capacity as a result of HBCR during the COVID-19 pandemic remains unknown. Methods: Retrospective cohort study of 567 HBCR patients between March 2020 and May 2021. Patients who completed the Duke Activity Status Index questionnaire at enrollment and completion of HBCR were included. We calculated the number of reported exercise days/week , exercise min/day, and VO 2 peak estimated. Patients were divided into two groups according to age (Younger<65 y.o; Older≥65 y.o). Continuous data are described as mean ±SD and baseline data compared with a two-sample t-test. The delta change from pre-post between groups also are compared with a two-sample t-test. Results: Of 567 HBCR patients, 118 patients completed both pre and post HBCR questionnaires (Younger, n=54, 56±8 years old vs Older, n=64, 74±7 y.o, p<0.05). Both groups improved exercise days/week (4.4±2.8 to 5.8±1.3 vs 3.8±2.9 to 5.6±1.6 days, p<0.05 for both), exercise min/day (21±20 to 41±17 vs 20±20 to 37±17 min, p<0.05 for both), and VO 2 peak (20.5±7.1 to 27.6±8.0 vs 21.9±8.1 to 25.1±7.7 ml/min/kg, p<0.05 for both). The delta change for exercise days/week and exercise min/day were not significantly different between groups (1.4±2.7 vs 1.9±2.7 days and 19±19 vs 17±18 min, p>0.05); however, the Younger patients significantly increased their VO 2 peak more than the older patients (7.1±6.1 vs 3.2±5.3 ml/min/kg, p<0.05). Conclusions: During the COVID-19 pandemic, exercise frequency (days/week and min/day) and exercise capacity (estimated VO2peak) increased in all patients participating in HBCR. With this, the increase in estimated exercise capacity was greater in younger patients compared with older patients. These findings suggest that additional work is needed to explore factors potentially limiting improvement and strategies to maximize improvement in exercise capacity in older patients participating in HBCR.

Background: The communities in which people live affect their health. We aimed to determine whether neighborhood characteristics are associated with outcomes in patients with atrial fibrillation (AF) in a Midwest community. Methods: Patients with incident AF from 2013-2017 from a 27-county region who survived >90 days after their diagnosis were identified (N=14,725). Patient addresses were linked to publicly-available data on population density (rural-urban commuting area; RUCA) and neighborhood socioeconomic status (area deprivation index; ADI). Patients were followed for ischemic stroke or transient ischemic attack (TIA), heart failure (HF), dementia/delirium, and all-cause death through 2021. Cox regression determined risk of outcomes by RUCA category (urban, micropolitan, small rural, isolated) and ADI quartile after adjustment for age, sex, race/ethnicity, and CHA2DS2-VASc score. Results: After excluding persons missing race/ethnicity (n=46), RUCA (n=1,465), and ADI (n=1,640), 13,233 patients with AF (mean age 73.8 years, 57% men) remained. After a median follow-up of 4.7 years, 5,989 patients died; 582 experienced a stroke/TIA, 4,122 (of 9,156 patients at risk) developed HF, and 1,758 (of 12,154 patients at risk) developed dementia/delirium. Persons living in isolated areas (HR 1.14, 95% CI 1.05-1.24) and the highest ADI quartile (HR 1.59, 95% CI 1.37-1.85) experienced the greatest risk of death (Figure). A trend toward an increased risk of HF was observed for the 2 highest ADI quartiles (p-trend <0.01), although the estimates did not reach statistical significance. The risk of other outcomes did not differ by RUCA or ADI category. Conclusion: Patients with AF residing in isolated areas and neighborhoods with greater area deprivation experience increased risks of death. Additional research is needed to better understand how neighborhood characteristics influence treatment, co-morbid conditions, and other outcomes in patients with AF.