DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress
Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study
BACKGROUND:Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied. METHODS:We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link. RESULTS:Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD. CONCLUSIONS:Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members. REGISTRATION:URL: https://www. CLINICALTRIALS:gov; Unique identifier: NCT03037632.
Risk of post-acute sequelae of SARS-CoV-2 infection associated with pre-coronavirus disease obstructive sleep apnea diagnoses: an electronic health record-based analysis from the RECOVER initiative
STUDY OBJECTIVES/OBJECTIVE:Obstructive sleep apnea (OSA) has been associated with more severe acute coronavirus disease-2019 (COVID-19) outcomes. We assessed OSA as a potential risk factor for Post-Acute Sequelae of SARS-CoV-2 (PASC). METHODS:We assessed the impact of preexisting OSA on the risk for probable PASC in adults and children using electronic health record data from multiple research networks. Three research networks within the REsearching COVID to Enhance Recovery initiative (PCORnet Adult, PCORnet Pediatric, and the National COVID Cohort Collaborative [N3C]) employed a harmonized analytic approach to examine the risk of probable PASC in COVID-19-positive patients with and without a diagnosis of OSA prior to pandemic onset. Unadjusted odds ratios (ORs) were calculated as well as ORs adjusted for age group, sex, race/ethnicity, hospitalization status, obesity, and preexisting comorbidities. RESULTS:Across networks, the unadjusted OR for probable PASC associated with a preexisting OSA diagnosis in adults and children ranged from 1.41 to 3.93. Adjusted analyses found an attenuated association that remained significant among adults only. Multiple sensitivity analyses with expanded inclusion criteria and covariates yielded results consistent with the primary analysis. CONCLUSIONS:Adults with preexisting OSA were found to have significantly elevated odds of probable PASC. This finding was consistent across data sources, approaches for identifying COVID-19-positive patients, and definitions of PASC. Patients with OSA may be at elevated risk for PASC after SARS-CoV-2 infection and should be monitored for post-acute sequelae.
Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry
IMPORTANCE:Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. OBJECTIVE:To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. DESIGN:Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. EXPOSURE:Presence of DCM. MAIN OUTCOMES AND MEASURES:Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). RESULTS:A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). CONCLUSION AND RELEVANCE:Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.
Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection
IMPORTANCE:SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. OBJECTIVE:To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. DESIGN, SETTING, AND PARTICIPANTS:Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. EXPOSURE:SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES:PASC and 44 participant-reported symptoms (with severity thresholds). RESULTS:A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. CONCLUSIONS AND RELEVANCE:A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.
Screening for Dilated Cardiomyopathy in At-Risk First-Degree Relatives
BACKGROUND:Cardiovascular screening is recommended for first-degree relatives (FDRs) of patients with dilated cardiomyopathy (DCM), but the yield of FDR screening is uncertain for DCM patients without known familial DCM, for non-White FDRs, or for DCM partial phenotypes of left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD). OBJECTIVES:This study examined the yield of clinical screening among reportedly unaffected FDRs of DCM patients. METHODS:Adult FDRs of DCM patients at 25 sites completed screening echocardiograms and ECGs. Mixed models accounting for site heterogeneity and intrafamilial correlation were used to compare screen-based percentages of DCM, LVSD, or LVE by FDR demographics, cardiovascular risk factors, and proband genetics results. RESULTS:A total of 1,365 FDRs were included, with a mean age of 44.8 ± 16.9 years, 27.5% non-Hispanic Black, 9.8% Hispanic, and 61.7% women. Among screened FDRs, 14.1% had new diagnoses of DCM (2.1%), LVSD (3.6%), or LVE (8.4%). The percentage of FDRs with new diagnoses was higher for those aged 45 to 64 years than 18 to 44 years. The age-adjusted percentage of any finding was higher among FDRs with hypertension and obesity but did not differ statistically by race and ethnicity (16.2% for Hispanic, 15.2% for non-Hispanic Black, and 13.1% for non-Hispanic White) or sex (14.6% for women and 12.8% for men). FDRs whose probands carried clinically reportable variants were more likely to be identified with DCM. CONCLUSIONS:Cardiovascular screening identified new DCM-related findings among 1 in 7 reportedly unaffected FDRs regardless of race and ethnicity, underscoring the value of clinical screening in all FDRs.
Effectiveness of the Family Heart Talk Communication Tool in Improving Family Member Screening for Dilated Cardiomyopathy: Results of a Randomized Trial
BACKGROUND:Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive. METHODS:booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive the day after proband enrollment and not enrolled on the same day as the proband. RESULTS:=0.90). CONCLUSIONS: REGISTRATION/BACKGROUND:URL: https://www. CLINICALTRIALS/RESULTS:gov; Unique identifier: NCT03037632.
Cluster-Randomized Trial Comparing Ambulatory Decision Support Tools to Improve Heart Failure Care
BACKGROUND:Mineralocorticoid receptor antagonists (MRA) are under-prescribed for patients with heart failure with reduced ejection fraction (HFrEF). OBJECTIVE:To compare effectiveness of two automated, electronic health record (EHR)-embedded tools vs. usual care on MRA prescribing in eligible patients with HFrEF. METHODS:BETTER CARE-HF (Building Electronic Tools To Enhance and Reinforce CArdiovascular REcommendations for Heart Failure) was a three-arm, pragmatic, cluster-randomized trial comparing the effectiveness of an alert during individual patient encounters vs. a message about multiple patients between encounters vs. usual care on MRA prescribing. We included adult patients with HFrEF, no active MRA prescription, no contraindication to MRA, and an outpatient cardiologist in a large health system. Patients were cluster-randomized by cardiologist (60 per arm). RESULTS:The study included 2,211 patients (alert: 755, message: 812, usual care [control]: 644), with average age 72.2 years, average EF 33%, who were predominantly male (71.4%) and White (68.9%). New MRA prescribing occurred in 29.6% of patients in the alert arm, 15.6% in the message arm, and 11.7% in the control arm. The alert more than doubled MRA prescribing compared to control (RR: 2.53, 95% CI: 1.77-3.62, p<0.0001), and improved MRA prescribing compared to the message (RR: 1.67, 95% CI: 1.21-2.29, p=0.002). The number of patients with alert needed to result in an additional MRA prescription was 5.6. CONCLUSIONS:An automated, patient-specific, EHR-embedded alert increased MRA prescribing compared to both a message and usual care. Our findings highlight the potential for EHR-embedded tools to substantially increase prescription of life-saving therapies for HFrEF. (NCT05275920).
Corrigendum to "Vascular endothelium as a target for perfluroalkyl substances (PFAs)" [Environ. Res. 212 (2022) 1-4/11339]
Physician preferences for revascularization in patients with ischemic cardiomyopathy: Defining equipoise from web-based surveys
BACKGROUND/UNASSIGNED:The optimal revascularization approach in patients with heart failure with reduced ejection fraction (HFrEF) and ischemic heart disease ("ischemic cardiomyopathy") is unknown. Physician preferences regarding clinical equipoise for mode of revascularization and their willingness to consider offering enrollment in a randomized trial to patients with ischemic cardiomyopathy have not been characterized. METHODS/UNASSIGNED:We conducted two anonymous online surveys: 1) a clinical case scenario-based survey to assess willingness to offer clinical trial enrollment for a patient with ischemic cardiomyopathy (overall response rate to email invitation 0.45 %), and 2) a Delphi consensus-building survey to identify specific areas of clinical equipoise (overall response rate to email invitation 37 %). RESULTS/UNASSIGNED:< 0.0001). In 17 scenarios (11.8 %), there was no difference in CABG or PCI appropriateness ratings, suggesting clinical equipoise in these settings. CONCLUSIONS/UNASSIGNED:Our findings demonstrate willingness to consider offering enrollment in a randomized clinical trial and areas of clinical equipoise, two factors that support the feasibility of a randomized trial to compare clinical outcomes after revascularization with CABG vs. PCI in selected patients with ischemic cardiomyopathy, suitable coronary anatomy and co-morbidity profile.