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IMPORTANCE: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. OBJECTIVE: To investigate the genetics of APs and affiliated arrhythmias. DESIGN, SETTING, AND PARTICIPANTS: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024. EXPOSURES: Sequence variants. MAIN OUTCOMES AND MEASURES: Genome-wide significant association of sequence variants with APs. RESULTS: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response. CONCLUSIONS AND RELEVANCE: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

IMPORTANCE: Pragmatic randomized clinical trials (RCTs) often use multiple data sources to examine clinical events, but the relative contribution of data sources to clinical end-point rates is understudied. OBJECTIVE: To assess the contribution of data sources (electronic health records [EHRs], public/private insurance claims, and/or participant-reported data) to clinical end points among ADAPTABLE participants who had available data. DESIGN, SETTING, AND PARTICIPANTS: The ADAPTABLE study was an open-label, pragmatic RCT from April 2016 through June 2019 conducted in research networks within clinical practice. Participants had existing atherosclerotic cardiovascular disease and available data to analyze. The characteristics of patients by combinations of data source availability were compared to examine the contribution of each of the data sources to end-point ascertainment. Data for this prespecified analysis were examined from January 2022 to June 2023. EXPOSURES: Randomized exposure to 81 mg or 325 mg of aspirin daily. MAIN OUTCOMES AND MEASURES: Number of events for the primary end point (composite of death, hospitalization for myocardial infarction, and hospitalization for stroke) that were contributed by EHR or claims data and then number of events contributed by each additional data source. RESULTS: Of 15 006 participants randomized with at least 1 other source of data available beyond participant-reported data, there were 8756 (58.3%) with participant-reported and EHR data; 4291 (28.6%) with participant-reported, EHR, and claims data; 1412 (9.4%) with EHR-only data; 262 (1.7%) with participant-reported and claims data; 202 (1.3%) with EHR and claims data; and 83 (0.6%) with claims-only data. Participants with EHR-only data were younger (median age, 63.7 years; IQR, 55.8-71.4) compared with the other groups (range, 65.6-71.9 years). Among participants with both EHR and claims data, with or without participant-reported data (n = 4493), for each outcome, most events (92%-100%) were identified in the EHR or in claims data. For all clinical end points, participant-reported data contributed less than 10% of events not otherwise available from claims or EHR data. CONCLUSIONS AND RELEVANCE: In this analysis of a pragmatic RCT, claims and EHR data provided the most clinical end-point data when compared with participant-reported events. These findings provide a framework for collecting end points in pragmatic clinical trials. Further work is needed to understand the data source combinations that most effectively provide clinical end-point data in RCTs.

IMPORTANCE: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood. OBJECTIVE: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis. DESIGN, SETTING, AND PARTICIPANTS: This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023. EXPOSURE: Genotype. MAIN OUTCOMES AND MEASURES: Pericarditis. RESULTS: In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10−16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10−8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein β (encoded by CEBPB). CONCLUSIONS AND RELEVANCE: This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1–blocking drugs.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAMassociate with lower ALT, supporting GPAMas a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

IMPORTANCE: Clinicians recommend enteric-coated aspirin to decrease gastrointestinal bleeding in secondary prevention of coronary artery disease even though studies suggest platelet inhibition is decreased with enteric-coated vs uncoated aspirin formulations. OBJECTIVE: To assess whether receipt of enteric-coated vs uncoated aspirin is associated with effectiveness or safety outcomes. DESIGN, SETTING, AND PARTICIPANTS: This is a post hoc secondary analysis of ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic study of 15 076 patients with atherosclerotic cardiovascular disease having data in the National Patient-Centered Clinical Research Network. Patients were enrolled from April 19, 2016, through June 30, 2020, and randomly assigned to receive high (325 mg) vs low (81 mg) doses of daily aspirin. The present analysis assessed the effectiveness and safety of enteric-coated vs uncoated aspirin among those participants who reported aspirin formulation at baseline. Data were analyzed from November 11, 2019, to July 3, 2023. INTERVENTION: ADAPTABLE participants were regrouped according to aspirin formulation self-reported at baseline, with a median (IQR) follow-up of 26.2 (19.8-35.4) months. MAIN OUTCOMES AND MEASURES: The primary effectiveness end point was the cumulative incidence of the composite of myocardial infarction, stroke, or death from any cause, and the primary safety end point was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage). Cumulative incidence at median follow-up for primary effectiveness and primary safety end points was compared between participants taking enteric-coated or uncoated aspirin using unadjusted and multivariable Cox proportional hazards models. All analyses were conducted for the intention-to-treat population. RESULTS: Baseline aspirin formulation used in ADAPTABLE was self-reported for 10 678 participants (median [IQR] age, 68.0 [61.3-73.7] years; 7285 men [68.2%]), of whom 7366 (69.0%) took enteric-coated aspirin and 3312 (31.0%) took uncoated aspirin. No significant difference in effectiveness (adjusted hazard ratio [AHR], 0.94; 95% CI, 0.80-1.09; P = .40) or safety (AHR, 0.82; 95% CI, 0.49-1.37; P = .46) outcomes between the enteric-coated aspirin and uncoated aspirin cohorts was found. Within enteric-coated aspirin and uncoated aspirin, aspirin dose had no association with effectiveness (enteric-coated aspirin AHR, 1.13; 95% CI, 0.88-1.45 and uncoated aspirin AHR, 0.99; 95% CI, 0.83-1.18; interaction P = .41) or safety (enteric-coated aspirin AHR, 2.37; 95% CI, 1.02-5.50 and uncoated aspirin AHR, 0.89; 95% CI, 0.49-1.64; interaction P = .07). CONCLUSIONS AND RELEVANCE: In this post hoc secondary analysis of the ADAPTABLE randomized clinical trial, enteric-coated aspirin was not associated with significantly higher risk of myocardial infarction, stroke, or death or with lower bleeding risk compared with uncoated aspirin, regardless of dose, although a reduction in bleeding with enteric-coated aspirin cannot be excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve outcomes in this population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02697916

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABOand LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.

We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2and p.R534Q in F5. We also document that F2and F5mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels).

Atrial fibrillation (AF) is associated with a risk for cognitive impairment and dementia, which is more pronounced in patients with a history of clinical stroke. Anticoagulation use and efficacy impact long‐term risk of dementia in AF patients in observational trials. The cognitive decline and dementia in patients with non‐valvular atrial fibrillation (CAF) Trial was a randomized, prospective, open‐label vanguard clinical study with blinded endpoint assessment involving patients with moderate‐ to high‐risk (CHADS2 or CHA2DS2‐Vasc scores of ≥2) non‐valvular AF assigned to dabigatran etexilate or warfarin. The primary endpoint was incident dementia or moderate cognitive decline at 24 months. A total of 101 patients were enrolled [mean age:73.7 ± 6.0 years, male: 54(53.5%)]. Prior stroke and stroke risk factors were similar between groups. Average INR over the study was 2.41 ± 0.68 in the warfarin group. No patient experienced a stroke or developed dementia. Mini‐Mental Status Evaluation, Hachinski Ischemic scale, cognitive subscale of the Alzheimer's Disease Assessment Scale, Disability Assessment for Dementia, Quality of Life Improvement as assessed by Minnesota Living with Heart Failure Scale and the Anti‐Clot Treatment Scale Quality of Life Survey scores did not vary at baseline or change over 2 years. Biomarker analysis indicated a similar efficacy of anticoagulation strategies. Use of dabigatran and well‐managed warfarin therapy were associated with similar risks of stroke, cognitive decline, and dementia at 2 years, suggestive that either strategy is acceptable. The results of this Vanguard study did not support the pursuit of a larger formally powered study. Use of dabigatran and well‐managed warfarin therapy were associated with similar risks of stroke, cognitive decline, and dementia at 2 years, suggestive that either strategy is acceptable.

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options.

Tixagevimab–cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab–cilgavimab versus placebo, in patients receiving remdesivir and other standard care.

Graphical Abstract

To apply the practical parsimonious modeling method of the Intermountain Mortality Risk Score in a primary care environment to predict chronic disease (ChrD) onset.

Intermittent fasting may increase longevity and lower cardiometabolic risk. This study evaluated whether fasting modifies clinical risk scores for mortality [i.e., Intermountain Mortality Risk Score (IMRS)] or chronic diseases [e.g., Pooled Cohort Risk Equations (PCRE), Intermountain Chronic Disease score (ICHRON)].

ASCVD/CVD Risk Reduction

CVD Prevention – Primary and Secondary

Depression is a risk factor for cardiovascular (CV) diseases, incident CV events, and mortality. Among individuals who experience a CV diagnosis or event, whether a subsequent diagnosis of depression is associated with a greater risk of mortality is unknown. Among patients with existing coronary artery disease (CAD), this study evaluated the association of a subsequent depression diagnosis with all-cause mortality.

To explore trends in blood pressure (BP) control before and during the COVID-19 pandemic.

This study sought to determine the prevalence of coronary artery–pulmonary artery collaterals in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to correlate their presence with the degree of clot burden. CTEPH is a treatable cause of severe pulmonary hypertension and right heart failure. Bronchopulmonary collateral vessels have been used as a supplementary diagnostic and prognostic tool for this disease. Coronary artery–pulmonary artery collaterals in this population have not been described. The coronary angiograms of 300 consecutive patients with CTEPH evaluated for pulmonary thromboendarterectomy (PTE) between January 1, 2007, and May 1, 2014, were examined. Of these patients, 259 (50% male; mean age, 58.3 ± 10.6 years) had cineangiographic images deemed adequate to definitively assess for the presence of coronary artery–pulmonary artery collaterals and were included in the final analyses. Pulmonary angiogram reports were reviewed for extent of pulmonary artery obstruction. The coronary angiograms of 259 age- and sex-matched control patients were also examined. Among 259 CTEPH patients with definitive imaging, 34 coronary artery–pulmonary artery collaterals were found in 28 patients (10.8%), versus 1 coronary artery–pulmonary artery collateral among control subjects (0.4%; P< 0.001). Compared with CTEPH patients without collaterals, patients with collaterals had a significantly higher prevalence of total occlusion of their right or left main pulmonary artery (P< 0.001) or lobar arteries (P< 0.001). In conclusion, the prevalence of coronary artery–pulmonary artery collaterals in CTEPH patients undergoing coronary angiography for possible PTE is approximately 11%. These vessels are associated with more severe pulmonary artery occlusion.

This study sought to determine the prevalence of coronary artery–pulmonary artery collaterals in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to correlate their presence with the degree of clot burden. CTEPH is a treatable cause of severe pulmonary hypertension and right heart failure. Bronchopulmonary collateral vessels have been used as a supplementary diagnostic and prognostic tool for this disease. Coronary artery–pulmonary artery collaterals in this population have not been described. The coronary angiograms of 300 consecutive patients with CTEPH evaluated for pulmonary thromboendarterectomy (PTE) between January 1, 2007, and May 1, 2014, were examined. Of these patients, 259 (50% male; mean age, 58.3 ± 10.6 years) had cineangiographic images deemed adequate to definitively assess for the presence of coronary artery–pulmonary artery collaterals and were included in the final analyses. Pulmonary angiogram reports were reviewed for extent of pulmonary artery obstruction. The coronary angiograms of 259 age- and sex-matched control patients were also examined. Among 259 CTEPH patients with definitive imaging, 34 coronary artery–pulmonary artery collaterals were found in 28 patients (10.8%), versus 1 coronary artery–pulmonary artery collateral among control subjects (0.4%; P< 0.001). Compared with CTEPH patients without collaterals, patients with collaterals had a significantly higher prevalence of total occlusion of their right or left main pulmonary artery (P< 0.001) or lobar arteries (P< 0.001). In conclusion, the prevalence of coronary artery–pulmonary artery collaterals in CTEPH patients undergoing coronary angiography for possible PTE is approximately 11%. These vessels are associated with more severe pulmonary artery occlusion.

Introduction:Recently there has been a much-needed focus on disparity and inequity in cardiovascular disease (CVD) care. Race, ethnicity, sex, and geography are shown to impact CVD care and outcomes. Perhaps one of the reasons for this is the lack of diversity and representation in CVD research studies, especially in non-sponsored research studies. Here we examine three investigator-initiated clinical CVD trials to describe current enrollment patterns and compare them to the comparable populations.Methods:Three Intermountain Healthcare, internally funded, CVD clinical trials were examined. These studies include a pragmatic trial, a randomized unblinded treatment trial, and a biobanking registry. Basic study characteristics and the comparison populations are shown in Table 1.Results:Demographic comparisons are shown in Table 2. Females were equally or slightly more represented in the studies. Minority races were under-represented in the pragmatic trial and the biobank registry. Rural or frontier counties were under-represented in the pragmatic trial and randomized trial. Hispanic/Latino patients were under-represented in all studies.ConclusionsFemales were well represented in all studies, but other minority groups were under-represented. The largest under-representation was for Hispanic/Latino patients. The reasons and mechanisms that may lead to under-representation and the impact on research results are unknown and deserve further study. While addressing these disparities may increase research costs (e.g., translation costs), future studies will benefit from the development of new resources and processes, and ultimately could lead to better care.

Introduction:When patients (pts) are diagnosed with HFrEF, it is hoped that medical therapy will improve their left ventricular ejection fraction (LVEF). However, which baseline clinical characteristics may predict an improvement in LVEF after medical treatment remains unclear.Methods:Pts with a baseline LVEF ≤35% and a follow-up LVEF ≥180 days later were categorized according to the change in LVEF identified between the baseline and follow-up LVEF’s (Increased [ΔLVEF ≥+10%]; No change [ΔLVEF=-9% to +9%]; Decreased [ΔLVEF ≥-10%]). Baseline characteristics and follow-up death rates were collected. Independent predictors of an improved LVEF were determined by logistic regression.Results:Qualifying HFrEF pts totaled 5,632 and were categorized by ΔLVEF as follows: Increased = 3,074 (54.6%); No change = 2,193 (38.9%); Decreased = 365 (6.5%). Baseline characteristics and independent predictors of an increase in LVEF are shown in the figure. During a median follow-up of 6.2 years, the death rate was 35.3%, 60.0%, and 72.6% (p<0.0001) in patients with an increase, no change, or decrease in LVEF, respectively.Conclusions:In patients diagnosed with HFrEF and initiated on medical therapy, an increase in LVEF predicted a lower death rate. The strongest predictors of an increase in LVEF included female gender, the absence of ASCVD, a low initial BNP, a narrow QRS duration, and the presence of atrial fibrillation, pulmonary hypertension, and statin use. Explanations for these findings remain to be determined.

Introduction:The clinical spectrum of COVID-19 can range from asymptomatic to severe, with severe resulting in part from an intense inflammatory response. Selective serotonin reuptake inhibitor (SSRI) is the most commonly prescribed class of antidepressants and has anti-inflammatory and anti-platelet effects. Recent studies reported greater survival and lesser COVID severity in patients taking SSRIs, specifically fluoxetine/fluvoxamine. Recently, application was made to the FDA for emergency use of fluvoxamine to prevent severe COVID-19, but it was denied based on insufficient data.Methods:Patients (n=33,088) testing positive for SARS-CoV-2 between March 14, 2020-December 31, 2021 as outpatients were studied. Patients were matched 3:1 by SSRI prescription at the time of a positive test by propensity score (±0.001). Patients were evaluated for COVID-19 hospitalization within 14-days and death within 3-months of positive SARS-CoV-2 test.Results:A total of 8,272 SSRI patients were well-matched to 24,816 no SSRI patients (Table 1). Hospitalization and death were significantly greater in the SSRI group compared to the no SSRI group (Table 1). A total of 2,067 (25.0%) of SSRI patients were taking fluoxetine or fluvoxamine. While attenuated, no SSRI remained associated with a lower 14-day COVID-19 hospitalization risk when compared to fluoxetine or fluvoxamine use, but not with 3-month death (Table 2).Conclusion:This study did not find a lower risk of progression of COVID-19 severity with the use of any SSRI or fluoxetine/fluvoxamine alone. Results from this study support the FDA’s decision to not recommend their use at an early stage of a COVID-19 infection.

Introduction:Artificial Intelligence (AI) algorithms should be evaluated to discern differences in prediction amongst population groups. The Intermountain data science group has developed a software package iEAI, which performs a model evaluation (ME) analysis to detect such meaningful prediction differences. Here we apply this software package to a recently developed cardiac PET/CT stress test-based risk score that predicts 90-day and one-year major adverse cardiac events (including death and myocardial infarction) and revascularization (MACE-Revasc). The results of these analyses will reveal any discrepancies in prediction and help with equity.Methods:5049 patients who had a clinically indicated PET/CT study from January 1, 2018, to December 31, 2018, were considered. The ME analyses were done for gender, age, and race. Precision (or positive predictive value) and recall (or sensitivity) were measured and meaningful differences were those that were statistically significant and had a ratio < 0.85 or >1.25 in magnitude than the reference category (e.g., the largest category).Results:The ME analysis of the PET/CT risk score for MACE-Revasc are shown in the table. For the 90-day PET/CT risk score a recall bias existed for females compared to males (0.49 vs 0.62). There was also bias with improved recall for Native-Hawaiian/ Pacific Islanders compared to Whites (0.87 vs 0.58). For the one-year PET/CT risk score, recall (0.38 vs 0.52) and precision (0.34 vs 0.47) biases were found for females compared to males, and recall biases were found for those aged 50-59 compared to 60-69 (0.34 vs 0.50).Conclusion:Meaningful biases were found in both the PET/CT risk scores for 90-day and One-year MACE-Revasc. As the application of AI in healthcare grows, evaluations like the above should be carried out. Then any detected inequalities could be addressed by refining or redeveloping the risk score models to eliminate biases.

Introduction:There has been considerable discussion regarding the value of follow-up LDL-C measurements in secondary prevention of major adverse cardiac events (MACE). We therefore set out to determine in a large healthcare system whether measurement of LDL-C after an ASCVD event was associated with a difference in MACE during follow-up and whether differences in outcomes could be attributed to differences in statin use.Methods:The Intermountain Enterprise Data Warehouse was searched to identify all adults with a first encounter for ASCVD-including coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD)—between January 1, 1995 and December 31, 2016 who survived the index event and were followed for ≥3 years or until death.Results:Patients (N=68,411) had an average age of 66±14 years; 65% were men; 70.3%, 21.0%, and 8.6% entered with CAD, CVD, and PAD, respectively. A statin was prescribed to 52% of patients during follow-up. A total of 33,698 (49%) did not have and 34,713 (51%) did have a follow-up LDL-C test prior to a subsequent MACE (death, MI, CVA, and revascularization) or end of follow-up. By 3 years, MACE occurred in 14,835 (37.4%) vs. 5,770 (20.1%) of those without vs. with an LDL-C measurement, respectively (Figure top). The multivariable hazard ratio for 3 year MACE based on measuring LDL-C was 0.47. The increased MACE rate associated with not measuring LDL-C was partially mitigated by statin use (Figure bottom). Only 44.7% vs. 58.9% of patients without vs. with LDL-C measurement were taking statins.Conclusion:These data indicate that there is a significant and clinically meaningful difference in MACE based on a follow-up measurement of LDL-C. Statin administration partially, but not completely mitigated the increased MACE rate. While these results are limited in that they are from a retrospective registry, they indicate that LDL-C should be measured, and statin should be administered after an initial ASCVD event.

Introduction:Pragmatic randomized controlled trials (RCT) often use multiple data sources to examine clinical events, but the relative contribution of data sources (patient-reported, electronic health records (EHR), private/public claims data) to clinical endpoint rates is often not examined.Hypothesis:We hypothesized that claims data would contribute the highest number of events relative to other data sources.Methods:The ADAPTABLE study was an open-label, pragmatic RCT that demonstrated no significant difference in major cardiovascular or bleeding events among patients with CV disease randomized to an aspirin dose of 81vs. 325 mg/daily. We assessed the clinical endpoint rates and contribution of clinical endpoints by data source among patients who had EHR, public and private insurance claims data, and/or patient-reported (portal) data.Results:Of 15,076 patients randomized, there were 1,412 patients with EHR-only data; 8,756 with portal and EHR data; and 4,291 patients with portal, EHR, and claims data (Medicare or private). Patients with EHR-only data were younger (63.7 years) compared to the other groups (65.6-71.1 years); and were more likely Black (10.6%) vs. the other groups (6.3%-9.7%), p<0.001. The table demonstrates trial clinical event rates by data source among patients with available portal, EHR, and claims data. Among patients with available portal, EHR, and claims data, Medicare claims data contributed the most events for the composite endpoint (77.5%) and all-cause death (97.3%), while EHR data contributed the most events for MI (74.3%), stroke (74.3%), and major bleed (73.3%).Conclusions:In a large pragmatic trial, Medicare claims data contributed the most clinical events for the primary composite outcome and all-cause death, when compared with other available data sources. Further work is needed to understand the data source combinations that most effectively provide clinical endpoint data in RCTs.

Introduction:Statins traditionally have been contraindicated during pregnancy because of a theoretical risk of teratogenicity. However, emerging evidence to suggest relative safety and potential harm in contraindicating statins in high cardiovascular (CV)-risk pregnancies have led the FDA in 2021 to remove the “Pregnancy Category X” label. This has placed a heavy burden on physician-patient (pt) shared decision making in that statins “should be discontinued in most pregnant patients or consider the ongoing therapeutic needs of the individual pt, particularly those at very high risk for CV events during pregnancy”.Methods:The objective of this study was to describe the current real-world characteristics of pts prescribed a statin during pregnancy and pregnancy outcomes in a large US healthcare system. Pregnant pts taking a statin were identified by a search of the electronic medical records (eMR) of Intermountain Healthcare, a system of 24 hospitals and 215 clinics in Utah, Idaho, and Nevada, between 1997 and 2021, and pregnancy outcomes determined electronically. Statin pts were matched 1:10 by age (+/- 1 y) with non-statin pts. Characteristics and outcomes were determined, and adjusted odds ratios (aOR) were calculated.Results:A total of 63 statin-user pregnancies were matched to 630 controls. Stain pts had more co-morbidities and higher baseline lipids (Table 1). Adverse pregnancy outcomes were more frequent in statin users (Table 2A). However, statin use did not contribute significantly to multivariable risk prediction of miscarriage or congenital anomalies although possibly it did to eclampsia/preeclampsia (Table 2B).Conclusions:In a current real-world US experience, pts prescribed statins during pregnancy had more comorbidities and more adverse outcomes, including fetal anomalies. However, after adjustment, statin use did not contribute to multivariable risk prediction of miscarriage or congenital anomalies.

Introduction:Health, wellness, and healthcare are most effectively and efficiently managed when health status is quantitatively measured. The Intermountain Mortality Risk Score (IMRS) is a well-validated low-cost decision tool calculated from the complete blood count and basic metabolic profile that can be electronically deployed to inform clinician or patient actions. This study evaluated if 3 serial IMRS measurements improved mortality prediction.Methods:In 119,379 Intermountain Healthcare outpatients, inpatients, and emergency patients, baseline (BL) IMRS was calculated in 1999-2005. Of those, the following were excluded: 22,678 who died prior to having 3 IMRS measurements and 38,228 survivors who at 5 years (y) post-BL did not have 3 IMRS. In the study cohort of 58,473 patients, a 1stfollow-up (1F) IMRS was available 1.49±0.79 y post-BL (range 1-4 y), and a 2ndfollow-up (2F) IMRS at 3.75±0.80 y post-BL (range 2-5 y). Patients had 13.4±1.7 y of follow-up after 2F (range: 9.3-18.7 y), with total follow-up post-BL of 17.2±1.5 y (range: 14.3-20.7 y).Results:Overall, 26,693 patients died (45.7%) after 2F. In females, IMRS for decedents vs. survivors was, respectively, 11.3±3.9 vs 6.3±4.0 at BL, 11.1±3.9 vs 5.7±4.0 at 1F, and 12.2±4.2 vs 6.1±4.0 at 2F; differences in males were similar to those results (all p<0.001). Relative risks for IMRS categories are shown in the Table. C-statistics for females were c= 0.815, 0.834, 0.858 for BL, 1F, and 2F, with 0.872 for a sum of the 3 IMRS (results were similar for males, with absolute c 0.06-0.08 lower).Conclusions:IMRS predicted substantial risk differences at each of 3 timepoints, but the IMRS trajectory (including declines in IMRS) revealed by the sequence of IMRS measurements better personalized risk assessment. When risk level and direction are considered together, critical junctures in a person’s health journey may be revealed, empowering earlier or more intensive prevention, diagnostic testing, and interventions.

Introduction:Many clinicians recommend enteric coated aspirin (EC-ASA) to decrease gastrointestinal bleeding (GIB) in secondary cardiovascular (CV) protection even though studies suggest decreased platelet inhibition with EC-ASA compared to uncoated “plain” formulations (P-ASA). ADAPTABLE was a large, pragmatic study, showing no difference in ischemic events or bleeding between 81-mg and 325-mg ASA and provides a large population to assess effectiveness and safety of EC-ASA versus P-ASA in CV patients.Methods:Participants (pts) from ADAPTABLE were re-grouped according to type and dose of reported ASA use at baseline. The primary effectiveness endpoint was the composite of myocardial infarction (MI), stroke, or death from any cause and the primary safety endpoint was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage) analyzed between groups by ASA type and within groups by dose using multivariable Cox proportional hazards.Results:15,076 pts were randomized to 81-mg or 325 -mg ASA were followed for a median of 26.2 months of whom 10,678 reported ASA type at baseline. Of pts reporting ASA type used, 69% used EC-ASA and were slightly older, more likely to be in the 81-mg cohort, be nonsmokers, have slightly more coronary artery disease, and have a slightly lower prior MI rate (Table). No other significant differences between the 2 cohorts were noted. There was no significant difference in the effectiveness or safety outcomes between the EC-ASA and P-ASA cohorts (Table). Within EC-ASA and P-ASA, ASA dose had no effect on effectiveness (interaction p = 0.41) or safety (interaction p = 0.07).Conclusion:Enteric coating did not significantly affect the primary effectiveness or safety endpoints in ADAPTABLE, regardless of ASA dose. More research is needed to confirm whether enteric coated aspirin formulations or newer formulations will improve ischemic and bleeding outcomes in patients with CV disease.

Introduction:Statins play a critical role in primary and secondary ASCVD prevention. Although uncommon, myalgias and abnormal liver function tests (LFTs) may limit statin use. Alcohol consumption also is a common cause of LFT elevations. It is unknown whether or to what extent concurrent alcohol and statin use may alter elevated LFT risk and impact management.Methods:Patients (pts) enrolled in the Intermountain INSPIRE registry who completed a health questionnaire for alcohol and other socioeconomic, dietary, and physical activity data were studied. Demographics, anthropometrics, cardiac risk factors, comorbidities, medication use, and laboratory results were obtained from electronic health records. Associations of alcohol and statin use with high ALT (females, >40 U/L; males, >55 U/L) were tested. Alcohol categories were: non-drinkers (ND; n=2797), moderate drinkers (MD; ≤7 drinks/week, n=980), and heavy drinkers (HD; >7 drinks/week, n=164).Results:High ALT was found in 18.9%, 12.6%, and 10.5% of HD, MD, and ND respectively (p=0.002) and in 11.3% of both statin (n=2154) and non-statin users (n=1787) (p=0.97). After adjustment, HD vs. ND had OR=2.19 (CI: 1.44, 3.33; p<0.001), and MD vs ND had OR=1.09 (CI: 0.86, 1.37; p=0.49). Pts not on statins had high ALT in 15.4% of HD (OR=1.47, CI: 0.73, 2.95; p=0.28) and 12.0% of MD (OR=1.10, CI: 0.79, 1.54; p=0.57) compared to 11.0% of ND. In parallel, pts on statins had high ALT in 21.2% of HD (OR=2.58, 95% CI: 1.52, 4.36; p<0.001) and 13.0% of MD (OR=1.16, CI: 0.85, 1.59; p=0.34) vs. 10.2% of ND. Despite these trends, no formal interaction was found between statin use with HD (p-interaction=0.27) or with MD (p-interaction=0.43). Results for high AST (>40 U/L) and low ALP (<40 U/L) were similar to the ALT findings.Conclusions:In this prospective database, statin use was not associated with abnormal LFT findings, whereas risk was higher with increasing alcohol consumption. Concurrent statin and alcohol use was associated with a modestly elevated risk of abnormal LFT, but the interaction was not significant. Reducing alcohol consumption rather than reducing or discontinuing statins may reverse abnormal LFT while preserving the preventive benefit of statins. This hypothesis deserves further prospective testing.

Introduction:Recent interest has focused on STEMI patients (pts) without standard modifiable risk factors (SMuRF-less), noting that they are surprisingly common (14-27%). These studies have reported them to have a worse, or at best similar, in-hospital/short-term prognosis. However, relatively little attention has been paid to the prevalence and prognosis of SMuRF-less patients with non-ST elevation myocardial infarction (NSTEMI). The aim of our study was to identify the proportion and outcomes of SMuRF-less NSTEMI pts in a large US healthcare population.Methods:Pts with NSTEMI between 2001-2021 presenting to Intermountain Healthcare catheterization laboratories were included. SMuRF included a clinical diagnosis of, or treatment for, hypertension, hyperlipidemia, diabetes, and/or smoking. 60-day and long-term major adverse cardiovascular event (MACE) outcomes were defined as death, myocardial infarction, and heart failure hospitalization and were tested using Cox proportional hazard regression.Results:NSTEMI pts totaled 8196, of which1458 (17.8%) were SMuRF-less. SMuRF-less pts were younger, more frequently male, had fewer comorbidities, and were slightly less likely to have PCI/CABG than NSTEMI pts with SMuRF (Table 1). 60-day MACE for SMuRF-less pts were lower (adj HR 0.55, p<0.0001), and this persisted for long-term MACE outcomes (adj HR 0.64, p<0.0001) and for each of its components (Table 2).Conclusions:In this large US healthcare population, SMuRF-less NSTEMI presentation, as with STEMI presentation, was found to be common (17.8%). However, unlike STEMI reports, short- and long-term outcomes were generally more favorable for SMuRF-less status. Further studies to increase understanding of risk factors and preventive measures for NSTEMI in SMuRF-less pts are indicated.

Introduction:Patients are at high risk for a recurrent cardiovascular (CV) event in the first year following acute coronary syndrome (ACS). Low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for recurrent CV events. Despite the availability of lipid-lowering therapies (LLT), many patients fail to achieve guideline recommended LDL-C <70 mg/dL in the year post-ACS. Early LDL-C evaluation and LLT intensification after recent ACS may reduce recurrent CV event risk. In prior phase III trials, inclisiran plus maximally tolerated statin therapy effectively reduced LDL-C in patients with established ASCVD. As patients with an ACS within 3 months of screening were excluded from these trials, the efficacy of inclisiran in these patients is unknown.Objective:To assess the LDL-C-lowering effect of inclisiran with usual care vs usual care alone in patients with recent ACS and LDL-C ≥70 mg/dL, despite statin therapy.Methods:VICTORION-INCEPTION (NCT04873934) is a phase IIIb, randomized, parallel-group, open-label, multicenter, US-based trial enrolling eligible patients to receive inclisiran plus usual care or usual care (Figure). Concomitant LLT and routine LDL-C assessment is at the discretion of the managing physician to mimic real-world clinical practice. The primary endpoints are percent change from baseline in LDL-C and proportion of patients achieving LDL-C <70 mg/dL. Key secondary endpoints include absolute change from baseline in LDL-C by visit, proportion of patients reaching pre-specified LDL-C targets, other plasma lipids, adherence to background LLT, and safety and tolerability of inclisiran. Exploratory endpoints include patient-reported outcomes and healthcare resource utilization.Conclusions:VICTORION-INCEPTION, an ongoing trial planned to complete in early 2024, will assess the effectiveness of inclisiran plus usual care for the management of patients with elevated LDL-C post-ACS despite receiving statin therapy.

Abstract Genetic deficiency of the dystrophin-glycoprotein complex causes hereditary dilated cardiomyopathy. Enteroviruses can also cause cardiomyopathy and we have recently described a potential molecular mechanism for enterovirus-induced dilated cardiomyopathy. The coxsackieviral protease 2A proteolytically cleaves and functionally impairs dystrophin. Additionally, during infection with coxsackievirus B3, the dystrophin-glycoprotein complex becomes disrupted and the sarcolemmal integrity is lost. This review article discusses the importance of the dystrophin cleavage for the development of increased sarcolemmal permeability and potential pathways for mechanisms by which the dystrophin cleavage during coxsackieviral infection may contribute to dilated cardiomyopathy. Zusammenfassung Ein Gendefekt des Dystrophin-Glykoprotein-Komplexes ist eine Ursache der hereditären dilatativen Kardiomyopathie. Enteroviren können gleichfalls eine Kardiomyopathie verursachen. Wir haben vor kurzem einen möglichen molekularen Mechanismus für die enterovirusinduzierte dilatative Kardiomyopathie beschrieben. Die Protease 2A der Coxsackie-Viren spaltet proteolytisch Dystrophin, sodass die Funktion von Dystrophin gravierend beeinträchtigt wird. Zusätzlich wird bei einer Infektion mit Coxsackie-Virus B3 der Dystrophin-Glykoprotein-Komplex aufgebrochen, was mit einem Verlust der sarkolemmalen Integrität einhergeht. In dieser Übersichtsarbeit wird die Bedeutung der Dystrophin-Spaltung für die Permeabilitätssteigerung des Sarkolemms ebenso diskutiert wie potentielle Mechanismen, über die die Dystrophinspaltung zur Entstehung einer dilatativen Kardiomyopathie während einer Coxsackie-Virusinfektion beiträgt.

Enteroviruses such as Coxsackievirus B3 can cause dilated cardiomyopathy through unknown pathological mechanism(s). Dystrophin is a large extrasarcomeric cytoskeletal protein whose genetic deficiency causes hereditary dilated cardiomyopathy. In addition, we have recently shown that dystrophin is proteolytically cleaved by the Coxsackievirus protease 2A leading to functional impairment and morphological disruption. However, the mechanism of dystrophin cleavage and the exact cleavage site remained to be identified. Antibody epitope mapping of endogenous dystrophin indicated protease 2A-mediated cleavage at the site in the hinge 3 region predicted by a neural network algorithm (human, amino acid 2434; mouse, amino acid 2427). Using site-directed mutagenesis, peptide sequencing, and fluorescence resonance energy transfer assays with recombinant dystrophin, we demonstrate that this putative site in mouse and human dystrophin is a direct substrate for the Coxsackieviral protease 2A both in vitroand in vivo. The substrate analogue protease inhibitor z-LSTT-fmk was designed based on the dystrophin sequence that interacts with the protease 2A and was found to have an IC50of 550 nmin vitro. Dystrophin is the first cellular substrate of the enteroviral protease 2A that was identified using by a bioinformatic approach and for which the cleavage site was molecularly mapped within living cells.

Background:Dealing with statin intolerance represents a major clinical challenge. Controlled clinical trials suggest that a large percentage of statin intolerance may be due to a “nocebo effect”, wherein adverse reactions are linked to pill ingestion irrespective of actual pill content (e.g., SAMSON trial). We tested whether statin intolerance was associated with intolerance to other medications in a large real-world experience. We hypothesized that statin intolerance would be associated with multiple drug intolerances.Methods:We searched Intermountain Healthcare medical records between January 2002 and February 2021 for patients (pts) with a listed intolerance or allergy to 1 or more statins. We compared these to a control group of randomly selected pts not exposed to statins but taking one or more other oral medications. A second control group included all patients taking and tolerating statin therapy. We compared the number of recorded drug allergies/intolerances in the statin intolerant group with those in the 2 control groups.Results:Characteristics of patients in the 3 groups are shown in the Table. On average, statin intolerant patients had 3.64 additional listed drug allergies/intolerances (beyond statins), compared to 1.31 in non-statin exposed controls and 1.81 in the statin tolerant population (both p<.001).Conclusion:In this large real-world experience, statin intolerance was strongly associated with intolerance to multiple other medications. Although some patients may have a true intolerance to multiple medications, including statins, patients with multiple drug intolerances may also suffer from a generalized nocebo effect. In either case, noting a patient’s tendency toward multiple drug intolerances can alert clinicians to an increased intolerance risk when initiating a statin and can lead to preemptive medical and educational interventions aimed at reducing this risk.

Introduction:The use of statins in patients (pts) with heart failure (HF) is controversial. In patients without HF, statins reduce the risk of atherosclerotic cardiovascular disease (ASCVD), including HF-related events. In contrast, no benefit was observed in statin-treated HF pts in the CORONA and GISSI-HF trials. However, issues with generalizability may limit the applicability of these trial results in clinical practice. Therefore, we analyzed the impact of statin therapy in systolic HF pts in a large real-world experience.Methods:We searched Intermountain Healthcare medical records for pts with a diagnosis of HF and a reported ejection fraction of <=40%. We compared outcomes (MACE=death, MI, stroke) at a median of 4.5 years follow-up in those who were and were not prescribed a statin. Statin use was defined as use at or after a HF diagnosis but prior to 60-days before MACE or end of follow-up. Cox hazard regression analysis was used to determine hazard ratios.Results:A total of 15,010 pts were studied. Baseline demographics and outcomes are shown in the Table. Statin use was associated with more frequent ASCVD risk factors yet a lower MACE risk during follow-up. Benefit was similar for primary and secondary prevention pts and for prior and new statin prescriptions. By time-varying hazard ratio (HR) analysis, the longer the pt was on a statin, the greater the reduction in risk of MACE (p<0.0001).Conclusion:These results suggest a potential benefit of selective statin use in the real-world management of HF pts with ASCVD or at high-ASCVD risk. These novel observations deserve validation in additional real-world experiences.

Background:The COVID-19 pandemic has affected nearly every aspect of daily life. The interpersonal loss due to quarantining and social distancing, compounded with societal disruption has negatively affected mental health. Once established, mental health conditions can become chronic with having subsequent effects on additional risk factors and disease incidence, such as cardiovascular disease (CVD).Methods:Patients who completed a PHQ-9 in a primary care setting in the year prior to the COVID pandemic (Mar 1, 2019 to Feb 29, 2020) and during the COVID pandemic (Mar 1, 2020 to Apr 20, 2021) were studied. Patients were stratified into 2 groups: no depression/no longer depressed and remained depressed/became depressed. Patients were assessed for follow-up emergency department (ED) visits for anxiety and chest pain (CP) after PHQ-9 completion during the pandemic.Results:A total of 4,633 patients were studied, with 2,848 (61.5%) being never/no longer depressed and 1,785 (38.5%) remaining/became depressed. PHQ-9 scores during the pandemic were higher than prior to the pandemic among those depressed. A total of 2,171 (46.6%) received a COVID test, with more depressed patients tested compared to non-depressed (Table), but with positivity for SARS-CoV-2 (n=362 [16.7%]) being similar (p=0.18). The table shows baseline characteristics and outcomes. Depression was associated with increased ED visits for anxiety (Table). Those with depression, visited the ED at 3.5 times and 2.7 times greater rate for anxiety and anxiety with CP compared to non-depressed, respectively.Conclusions:Depression was highly prevalent among patients who receive routine primary care, with depressive symptoms increasing during the pandemic. Since depression and anxiety are associated with an increased risk of CVD and associated risk factors, identifying and treating patients early who exhibit such symptoms will be important in reducing the risk of future CVD and risk factor incidence.

Background:Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor remains standard treatment for patients undergoing PCI, and clopidogrel remains the most used agent. Many patients (pts) are genetically resistant to clopidogrel and may not receive its full benefit. However, the use of platelet function testing to provide individualized management of P2Y12 inhibitor therapy remains controversial. Therefore, we analyzed the impact of the use of platelet function testing after PCI in a large real-world experience.Methods:We searched Intermountain Healthcare medical records for pts who underwent PCI followed by DAPT. We compared 1-year outcomes (MACE=death, MI, stroke; and repeat revascularization and major bleeding) in those who did, or did not, receive P2Y12 platelet function testing within 90 days. Cox hazard regression analysis was used to determine multivariable hazard ratios.Results:A total of 11,561 pts were included, of which 650 (5.6%) received P2Y12 platelet function testing. Baseline demographics, discharge P2Y12 inhibitor and outcomes are shown in the Table.Conclusion:In this real-world analysis of patients undergoing PCI, a small proportion of the patients received P2Y12 platelet function testing. Platelet function testing was associated with increased utilization of prasugrel or ticagrelor and a statistically lower incidence of 1-year MACE (10.8% vs. 12.4%, adjusted odds ratio = 0.69, p=0.03), with a very low incidence of major bleeding. Further investigation regarding the potential benefits of individualized management of DAPT therapy through P2Y12 platelet function testing may be justified.

Background:In the presence of comorbid conditions, COVID-19 infections are known to require more advanced treatment, poorer outcomes and have longer-term sequelae. New-onset atrial fibrillation (AF) during COVID-19 infection has been associated with worse cardiovascular outcomes but not mortality. However, it remains unclear whether a prior history (hx) of atrial fibrillation is a cardiovascular risk factor predicting a worse outcome in COVID-19 patients. As such, we examined, using propensity matching accounting for possible confounders, the need for advanced treatment and subsequent major cardiovascular events (MACE) in patients with a prior hx of AF with COVID-19 infection.Methods:From March 2020 to May 2021, patients testing positive for SARS-CoV-2 with a prior AF diagnosis (n=3119) were propensity matched for age, gender, race/ethnicity, prior coronary artery disease (CAD), prior heart failure (HF), prior stroke and hypertension to non-AF SARS-CoV-2 positive patients. Cox hazard regression analysis with multivariable adjustment was used to determine risk of subsequent MACE (all-cause death, myocardial infarction, HF and stroke).Results:Baseline characteristics, treatments, and outcomes stratified by AF status are shown in the Table. While the groups had similar baseline characteristics, AF COVID-19 patients were more likely to require hospitalization, ICU care, and ventilator support. Consistent with our hypothesis, composite MACE event rates were higher in the AF patients (HR=1.60, p<0.0001) secondary to increases in heart failure and all-cause mortality rates.Conclusions:These data support AF as a cardiovascular risk factor predicting worse outcomes in COVID-19 patients. Specifically, AF increases the need for advanced treatments such as hospitalization, ICU care and ventilator support resulting in an increase in subsequent heart failure and all-cause mortality.

Background:As SARS-CoV-2 vaccines are being administered on an unprecedented scale, it is critical to carefully assess risks to aid clinicians in the early detection and treatment of potential side effects. Here we examine increases in the risk of pericarditis following SARS-CoV-2 vaccination.Methods:We examined pericarditis cases from December 15, 2020, to April 15, 2021 seen within Intermountain Healthcare, an integrated healthcare system. Pericarditis was defined by at least two of the following criteria: chest pain, EKG changes, pericardial effusion, and pericardial rub; excluded cases secondary to non-infectious causes (e.g., AF ablation). We determined vaccination within 60 days prior to pericarditis diagnosis using Intermountain and Utah Department of Health vaccination information. Rates of pericarditis per 10 million patient days for vaccinated patients compared to unvaccinated patients were compared. We also examined a case-crossover design with 4 control dates for each pericarditis case.Results:Of the 29 identified pericarditis cases, 13 (44.8%) had a SARS-Cov-2 vaccination within 60 days before the onset of pericarditis. During the same period, 743,774 individuals in the Intermountain Healthcare system had received at least one dose of the SARS-CoV-2 vaccine. Thus, 1.7 per 100,000 vaccinated individuals were diagnosed with acute pericarditis. Within a 60-day post-vaccination window, the rate of acute pericarditis per 10-million patient-days was 3.90 in the vaccinated group and 0.84 in the unvaccinated group. Thus, there was a 4.49 times higher rate of acute pericarditis in vaccinated patients compared to the unvaccinated individuals (p=0.0002). Case-crossover analysis showed the odds of acute pericarditis was 3.33 higher (95% CI: 1.29, 10.14) in the vaccinated versus the unvaccinated group (p=0.01).Conclusions:We found acute pericarditis to be a rare post-SARS-CoV-2 vaccination event, but the risk was significantly higher than in comparable unvaccinated subjects. This risk of pericarditis post-SARS-CoV-2 vaccine is eclipsed by the risk of contracting COVID-19 and its associated, commonly seen severe outcomes. Nevertheless, clinicians should be informed of this risk to facilitate earlier recognition and treatment.

Introduction:Intermittent fasting reduces weight and cardiometabolic risk factors. In the WONDERFUL Trial (NCT02770313), intermittent fasting reduced homeostatic model assessment of insulin resistance (HOMA-IR) and the Metabolic Syndrome Score (MSS), with insulin having the largest decline. The red cell distribution width (RDW) measures the dispersion of red blood cell size, is strongly predictive of mortality and major adverse events, and may be a biomarker of general health. This post hocstudy of subjects from the WONDERFUL Trial examined the interactive effect of intermittent fasting and baseline RDW on changes in insulin, glucose, HOMA-IR, and MSS.Methods:Subjects aged 21-70 years who had pre-diabetes, diabetes, or ≥1 other metabolic syndrome factor and modestly elevated LDL-C were enrolled if they were not taking anti-diabetic or statin medications and were free of chronic diseases (N=71; n=38 intermittent fasting, n=33 controls). Subjects were randomized to 24-hour water-only fasting (twice-weekly for 4 weeks followed by once-weekly for 22 weeks) or ad libitumeating (control) for 26 weeks.Results:Age averaged 49.1±11.1 years and 64.8% were female. Change scores stratified by RDW size distribution (RDW-SD) are shown in the Table. Results were similar when the RDW coefficient of variation (RDW-CV) was used. Intermittent fasting did not change RDW-SD (1.27±9.6 fL vs. control: -0.37±1.76 fL, p=0.34) or RDW-CV (-0.15%±0.55% vs. control: -0.11%±0.45%, p=0.76) over the 26-week trial.Conclusions:Compared to controls, intermittent fasting significantly decreased insulin more in subjects with higher baseline RDW than those with RDW ≤median. This differential effect may also apply to changes in HOMA-IR, glucose, and MSS. These findings should be validated and expanded in larger studies since RDW may identify people who would derive the most cardiometabolic benefit from engaging in intermittent fasting.

Introduction:Intermittent fasting decreases cardiometabolic risk factors, heart failure (HF) risk, and type 2 diabetes risk. Sodium-glucose transport 2 (SGLT-2) inhibitors reduce diabetes and HF risk and a study of canagliflozin reported that it raised galectin-3 levels (Januzzi 2017). Previously in the WONDERFUL trial (NCT02770313), intermittent fasting caused declines in the Metabolic Syndrome Score (MSS) and homeostatic model assessment of insulin resistance (HOMA-IR). This study evaluated intermittent fasting’s effects on galectin-3 in a post hocanalysis of the WONDERFUL Trial.Methods:People aged 21-70 years were enrolled who had ≥1 metabolic syndrome feature or type 2 diabetes, were free of anti-diabetic and statin medications, and had elevated LDL-C. Subjects had 26-week galectin-3 data (N=67; n=36 intermittent fasting, n=31 controls). Subjects were randomized to a 24-hour water-only fasting intervention (fasting twice per week for 4 weeks, then once each week for 22 weeks) or a parallel control arm (ad libitumeating). This study evaluated the 26-week galectin-3 change score and other changes in HF biomarkers.Results:At 26 weeks, the galectin-3 change score was increased in intermittent fasting (0.575±2.63 ng/mL) vs control (-0.624±2.79 ng/mL; p=0.021). Changes in galectin-3 were inversely correlated with HOMA-IR change score (r= -0.288, p=0.018) and MSS change score (r= -0.238, p=0.052). Changes in galectin-3 at 4 weeks (intermittent fasting: 0.345±2.68 ng/mL; control: -0.465±3.18 ng/mL; p=0.27) and 13 weeks (fasting: 0.917±4.96; control: -0.097±2.83 ng/mL; 0.15) were not significantly different. B-type natriuretic peptide went down in intermittent fasting (-0.328±12.29 pg/mL) but this was not significant compared to controls (15.50±75.34 pg/mL, p=0.23). Other HF biomarkers were unchanged.Conclusions:Water-only 24-hour intermittent fasting increased galectin-3. This rise in galectin-3 was correlated with declining HOMA-IR and MSS and may be similar to reported effects of SGLT-2 inhibitors. Increased galectin-3 may be an adaptive response that could prevent chronic disease by decreasing inflammation, ameliorating insulin resistance, or modifying related mechanisms.

Introduction:Mitochondrial DNA copy number (mtDNA-CN) is associated with cardiovascular disease (CVD) and mortality. Here we examine, in a high-risk CVD population, the association with prevalent coronary artery disease (CAD) and subsequent major adverse events (MACE) at 1-,5- and 10-year follow-up of mtDNA-CN.Methods:Consecutive subjects (n=2267) consenting to a blood sample drawn for the Intermountain INSPIRE biorepository at the time of a coronary angiogram from July 1994 to Sept 2003 were included. The mtDNA-CN was determined by multiplexed real-time polymerase chain reaction coamplifying a stable site of mt D- Loop and a region of a single copy genomic β-2-microglobulin gene(β2M). MtDNA-CN is given as the ratio of Mt to β2M DNA. The presence of severe CAD (>70% stenosis) was analyzed using multivariate logistic regression. The subsequent MACE (including all-cause mortality and non-fatal MI) outcomes were studied using multivariate Cox proportional hazard regression.Results:The average age of subjects was 62.3 ± 13.8, 35% were female, and 50% had prior CAD. Over half (55%) had severe CAD at the angiogram. As the mtDNA-CN increased, severe CAD decreased (58% for 1stquartile vs. 51% for 4thquartile). After adjustment for baseline differences, subjects with mtDNA-CN in the 1stquartile were 1.31 times more likely to have severe CAD than subjects with mtDNA-CN in the 4thquartile (95% CI: 1.01, 1.71; p=0.04). A total of 902(39.8%) had a subsequent MACE event within 10-years (193[8.5%] in 1-year and 548[24.2%] in 5-years). There was no association between mtDNA-CN and 1-year MACE. However, mtDNA-CN was associated with 5-year (p=0.006) and 10-year (p=0.003) MACE. After adjustment, subjects with mtDNA-CN in the 1stquartile were at 1.29 increased risk of 10-year MACE than subjects with mtDNA-CN in the 4thquartile (95% CI: 1.07, 1.56; p=0.008).Conclusions:In a coronary angiographic population, mtDNA-CN was associated with severe CAD and the risk of subsequent long-term MACE. These findings suggest that mtDNA-CN could be used as a clinical biomarker for risk. Moreover, understanding the factors impacting mtDNA-CN may also help in the prevention of secondary CVD outcomes.

Introduction:Adults <40-yrs (20-39) may have elevated cardiovascular risk based on higher LDL-C (e.g., ≥160 mg/dL). We sought to compare the risk of MACE (all-cause death, MI, ischemic stroke, heart failure hospitalization, and peripheral vascular disease [PVD]) in adults <40-yrs and LDL-C ≥160 to 189 compared with LDL-C <160 mg/dL.Hypothesis:Adults <40-yrs with LDL-C ≥160-189 mg/dL are minimally addressed in the current cholesterol management guidelines but may have a higher risk of MACE compared to other healthy controls.Methods:Patients (pts) from 20- 39 yrs of age with at least three lipid labs and outpatient primary care encounters at Intermountain Healthcare, a large integrated healthcare system, prior to January 2010 and an LDL-C measurement between January and December of 2020 (n=14,570) were included and followed for MACE until June 2021. Pts with LDL-C >190 or <160 on statin in 2010 but previously ≥160 were excluded. Pts were identified using MDClone (ADAMS self-service analytics platform). Outcome of interest was MACE during 10-yr follow-up, LDL-C was stratified as ≥160-189 vs <160 mg/dL. Baseline characteristics were compared by either a chi-squared or t-test, as appropriate. Multivariate logistic regression was used to identify the role of LDL-C as a predictor of outcome. A p-value of <0.05 was considered statistically significant.Results:Baseline characteristics are presented in the Table. MACE for LDL-C ≥160-189 mg/dL was not statistically significant compared to LDL-C <160 (OR 1.28, 95% CI 0.94 - 1.74, p<0.115).Conclusions:The risk of 10-yr MACE in adults <40 yrs of age with LDL-C ≥160-189 mg/dL did not confer a statistically significant elevated risk. Our findings are consistent with current guidelines that statin therapy is not mandated in these individuals.

Studies from both in vivo and in vitro model systems have provided an initial skeleton of the potential signaling pathways that might regulate cardiac genes during growth and hypertrophy. One of the first detectable changes in cardiac gene expression is the activation of a program of immediate early gene expression, which is distinct for the hypertrophic response, and is conserved in multiple models of both in vivo and in vitro hypertrophy. Diverse and distinct hormonal stimuli have been documented to activate several features of the hypertrophic response, including several autocrine and paracrine factors. Although the signaling mechanisms that link these factors with the activation of cardiac gene expression are unclear, recent studies suggest that the activation of protein kinase C may represent one of the most proximal common events in this signaling cascade. The activation of cardiac target genes induces a program of embryonic gene expression, including the atrial natriuretic factor (ANF) gene. The cissequences that mediate cardiac‐specific and inducible expression of an embryonic marker gene (ANF) can be segregated by studies in both cultured cell models and in vivo models of hypertrophy in transgenic mice, suggesting that specific sets of regulatory elements may exist for inducible expression of this class of cardiac gene responses. However, the induction of a constitutively expressed contractile protein gene (MLC‐2) is mediated by a set of conserved elements that regulate both cardiac‐specific and inducible expression. Finally, a subset of cardiac muscle genes appears to be noninducible during in vivo or in vitro hypertrophy in myocardial cells, demonstrating specificity of transcriptional activation during the hypertrophic process. The development of a bona fide in vivo pressure overload model of hypertrophy in a small animal model that can be genetically manipulated, such as the in vivo murine model recently described, should allow a rigorous analysis of the role of these specific signaling mechanisms in the activation of the responses of cardiac genes during the hypertrophic process in vivo.—Chien, K. R.; Knowlton, K. U.; Zhu, H.; Chien, S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J.5: 3037‐3046; 1991.

ABSTRACTInfection of cells by picornaviruses of the rhinovirus, aphthovirus, and enterovirus groups results in the shutoff of host protein synthesis but allows viral protein synthesis to proceed. Although considerable evidence suggests that this shutoff is mediated by the cleavage of eukaryotic translation initiation factor eIF4G by sequence-specific viral proteases (2A protease in the case of coxsackievirus), several experimental observations are at variance with this view. Thus, the cleavage of other cellular proteins could contribute to the shutoff of host protein synthesis and stimulation of viral protein synthesis. Recent evidence indicates that the highly conserved 70-kDa cytoplasmic poly(A)-binding protein (PABP) participates directly in translation initiation. We have now found that PABP is also proteolytically cleaved during coxsackievirus infection of HeLa cells. The cleavage of PABP correlated better over time with the host translational shutoff and onset of viral protein synthesis than did the cleavage of eIF4G. In vitro experiments with purified rabbit PABP and recombinant human PABP as well as in vivo experiments withXenopusoocytes and recombinant XenopusPABP demonstrate that the cleavage is catalyzed by 2A protease directly. N- and C-terminal sequencing indicates that cleavage occurs uniquely in human PABP at482VANTSTQTM?GPRPAAAAAA500, separating the four N-terminal RNA recognition motifs (80%) from the C-terminal homodimerization domain (20%). The N-terminal cleavage product of PABP is less efficient than full-length PABP in restoring translation to a PABP-dependent rabbit reticulocyte lysate translation system. These results suggest that the cleavage of PABP may be another mechanism by which picornaviruses alter the rate and spectrum of protein synthesis.

ABSTRACTApoptosis is a central host defense mechanism to eliminate virus-infected cells. Activation of NF-?B suppresses apoptosis following some types of stimulation in vitro. To test the physiological importance of this pathway in vivo, we studied murine encephalomyocarditis virus (EMCV) infection in mice and cell lines defective in NF-?B1 (p50) signaling. As previously reported, we find that all p50 knockout (p50 -/-) mice survive an EMCV infection that readily kills normal mice. By introducing the p50 mutation into interferon (IFN) type I receptor knockout (IFNRI -/-) mice, we find that this resistance is not mediated by IFN-ß as previously thought. While no IFNRI -/- mice survive, the double-knockout mice survive 60% of the time. The survival is tightly linked to the animals’ ability to clear the virus from the heart in vivo. Using murine embryonic fibroblasts (MEF) derived from wild-type, p50 -/-, and p65 -/- embryos, we found that NF-?B is not required for the replication cycle of EMCV. However, during these experiments we observed that p50 -/- and p65 -/- MEF infected with EMCV undergo enhanced, premature cytotoxicity. Upon examination of this cell death, we found that EMCV infection induced both plasma membrane and nuclear changes typical of apoptosis in all cell lines. These apoptotic processes occurred in an accelerated and pronounced way in the NF-?B-defective cells, as soon as 6 h after infection, when virus is beginning to be released. Previously, only the RelA (p65) subunit of NF-?B has been shown to play a role in suppressing apoptosis. In our studies, we find that p50 is equally important in suppressing apoptosis during EMCV infection. Additionally, we show that suppression of apoptosis by NF-?B1 is required for EMCV virulence in vivo. The attenuation in p50 -/- mice can be explained by rapid apoptosis of infected cells which allows host phagocytes to clear infected cells before the viral burst leading to a reduction of the viral burden and survival of the mice.