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Background Hypertriglyceridemia is associated with increased risk of coronary heart disease but the association is often attributed to concomitant metabolic abnormalities. We investigated the epidemiology of primary isolated hypertriglyceridemia (PIH) and associated cardiovascular risk in a population‐based setting. Methods and Results We identified adults with at least one triglyceride level ≥500 mg/dL between 1998 and 2015 in Olmsted County, Minnesota. We also identified age‐ and sex‐matched controls with triglyceride levels <150 mg/dL. There were 3329 individuals with elevated triglyceride levels; after excluding those with concomitant hypercholesterolemia, a secondary cause of high triglycerides, age <18 years or an incomplete record, 517 patients (49.4±14.0 years, 72.0% men) had PIH (triglyceride 627.6±183.6 mg/dL). The age‐ and sex‐adjusted prevalence of PIH in adults was 0.80% (0.72–0.87); the diagnosis was recorded in 60%, 46% were on a lipid‐lowering medication for primary prevention and a triglyceride level <150 mg/dL was achieved in 24.1%. The association of PIH with coronary heart disease was attenuated but remained significant after adjustment for demographic, socioeconomic, and conventional cardiovascular risk factors (hazard ratio [HR], 1.53; 95% CI, 1.06‐2.20; P = 0.022). There was no statistically significant association between PIH and cerebrovascular disease (HR, 1.06; 95% CI, 0.65‐1.73, P = 0.813), peripheral artery disease (HR, 1.27; 95% CI, 0.43‐3.75; P = 0.668), or the composite end point of all 3 (HR, 1.28; 95% CI, 0.92‐1.80; P =0.148) in adjusted models. Conclusions PIH was associated with incident coronary heart disease events (although there was attenuation after adjustment for conventional risk factors), supporting a causal role for triglycerides in coronary heart disease. The condition is relatively prevalent but awareness and control are low.

Purpose The purpose of the present study was to investigate body mass index, multi-morbidity, and COVID-19 Risk Score as predictors of severe COVID-19 outcomes. Patients Patients from this study are from a well-characterized patient cohort collected at Mayo Clinic between January 1, 2020 and May 23, 2020; with confirmed COVID-19 diagnosis defined as a positive result on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays from nasopharyngeal swab specimens. Measures Demographic and clinical data were extracted from the electronic medical record. The data included: date of birth, gender, ethnicity, race, marital status, medications (active COVID-19 agents), weight and height (from which the Body Mass Index (BMI) was calculated, history of smoking, and comorbid conditions to calculate the Charlson Comorbidity Index (CCI) and the U.S Department of Health and Human Services (DHHS) multi-morbidity score. An additional COVID-19 Risk Score was also included. Outcomes included hospital admission, ICU admission, and death. Results Cox proportional hazards models were used to determine the impact on mortality or hospital admission. Age, sex, and race (white/Latino, white/non-Latino, other, did not disclose) were adjusted for in the model. Patients with higher COVID-19 Risk Scores had a significantly higher likelihood of being at least admitted to the hospital (HR = 1.80; 95% CI = 1.30, 2.50; P < .001), or experiencing death or inpatient admission (includes ICU admissions) (HR = 1.20; 95% CI = 1.02, 1.42; P = .028). Age was the only statistically significant demographic predictor, but obesity was not a significant predictor of any of the outcomes. Conclusion Age and COVID-19 Risk Scores were significant predictors of severe COVID-19 outcomes. Further work should examine the properties of the COVID-19 Risk Factors Scale.

There is a need for multimodal strategies to keep research participants informed about study results. Our aim was to characterize preferences of genomic research participants from two institutions along four dimensions of general research result updates: content, timing, mechanism, and frequency. Methods: We conducted a web-based cross-sectional survey that was administered from 25 June 2018 to 5 December 2018. Results: 397 participants completed the survey, most of whom (96%) expressed a desire to receive research updates. Preferences with high endorsement included: update content (brief descriptions of major findings, descriptions of purpose and goals, and educational material); update timing (when the research is completed, when findings are reviewed, when findings are published, and when the study status changes); update mechanism (email with updates, and email newsletter); and update frequency (every three months). Hierarchical cluster analyses based on the four update preferences identified four profiles of participants with similar preference patterns. Very few participants in the largest profile were comfortable with budgeting less money for research activities so that researchers have money to set up services to send research result updates to study participants. Conclusion: Future studies may benefit from exploring preferences for research result updates, as we have in our study. In addition, this work provides evidence of a need for funders to incentivize researchers to communicate results to participants.

Introduction: Functional annotation of rare variants is key to the implementation of genomic medicine. We used molecular dynamics (MD) simulations to assess functional consequences of putative pathogenic variants (PVs) in the low-density lipoprotein receptor gene ( LDLR ). LDLR has a multidomain structure with seven LA repeats and local interactions between these repeats influence ligand binding. However, binding and recycling of the receptor-ligand complex require global changes in conformation. Using MD, we investigated the effects of PVs on long-range dynamics and LDL binding. Methods: An LA 4-6 repeat structure was created from a crystal structure of the extracellular domain (PDB: 1N7D). Structures were solvated with a water box containing TIP3P water molecules and simulated using the AMBER software package with the ff14SB forcefield. The wild type (WT) structure was first relaxed using MD; and subsequently PVs D245Y, F181Y and F181G were modeled. Dynamics were simulated for approximately one microsecond. Values for LDL binding for each PV were obtained from a prior study which used a radioisotope uptake assay. Results: WT domains demonstrated a stable conformation based on root mean square deviation. PVs disrupted the normal distribution in all domains significantly (p < 0.0001), broadening it and introducing multiple peaks. Projection along the top principal components (PCs) showed global destabilization with all PVs. The variant with the greatest impact on LDL binding, F181G, adopted a distinct alternate conformation. Comparison between PV and WT subspaces from PCA correlated with LDL binding (R 2 = 0.99, exponential regression). Structural analysis revealed that the LA5 calcium cage is involved in inter-domain salt bridges, which are disrupted in simulations of PVs. Conclusion: MD simulation of LA4-6 repeats in LDLR suggests PVs alter long-range conformational dynamics, and that such dynamics correlate with LDL binding. The impact of PVs on conformational dynamics and binding may be through disruption of interdomain salt bridges that are mediated by the acidic calcium cage. This study demonstrates the potential utility of MD simulations to functionally characterize LDLR variants.

Introduction: Current risk equations for coronary heart disease (CHD) do not take into account family history or cumulative exposure to LDL-C. We modified CHD risk equations for use in familial hypercholesterolemia (FH) patients and developed a decision aid (DA) for FH to facilitate shared decision making (SDM). Methods: Literature review, evidence synthesis and expert input were used to adapt the 30-year Framingham Risk Score (FRS) and 10-year ACC/AHA pooled cohort equations to calculate the CHD risk in individuals with FH aged 20-39 years and ≥40 years, respectively. Based on published data, estimated risk was multiplied by 2 for family history of early CHD or 3 in the presence of a pathogenic variant. Treatment benefit of lipid lowering was estimated based on the ‘cumulative exposure to LDL-C’ model ( JACC 2012; 60 ) using the following equations: Post-treatment 30-yr risk in those aged 20-39 years = Baseline Risk (FRS) x 0.54 delta LDL-C (mmol/L) Post-treatment 10-yr risk in those aged ≥40 years = Baseline Risk (ACC/AHA Pooled Cohort) x 0.72 delta LDL-C (mmol/L) To convey CHD risk and treatment benefit, we developed a DA using an iterative, patient-centered design process for use in FH encounters. Results: Using the DA, providers can discuss baseline CHD risk estimates, lipid lowering drug (LLD) options and the expected post-treatment risk reduction with FH patients. The estimated % LDL-C reduction for each LLD and the predicted risk reduction per mmol/L of LDL-C lowered were obtained from literature review. Lowering LDL-C by 1 mmol/L (39 mg/dL) was associated with a 28% CHD risk reduction over 10 years and a 46% reduction over 30 years ( Eur Heart J 2017; 38 ). We describe 2 examples of estimating CHD risk and treatment benefit in FH cases in Table 1 . Conclusion: We adapted CHD risk prediction equations to account for family history of CHD and presence of a pathogenic FH variant and designed a DA to convey personalized CHD risk estimates and treatment benefit to facilitate SDM with FH patients.

Background: The pathophysiology of lipoprotein (a) [Lp(a)] remains obscure. We conducted a phenome wide analysis study (PheWAS) to identify pleiotropic effects of LPA variants. Methods: Among 51,843 European-ancestry participants (age 58±16 years, 54% female) of the electronic MEdical Records and Genomics (eMERGE) network we assessed whether LPA variants exhibited pleiotropic affects through an electronic health record-based PheWAS. We adjusted significant associations by presence of atherosclerotic cardiovascular disease (ASCVD; defined as a composite of coronary heart disease, cerebrovascular disease, and peripheral artery disease) to determine whether those associations were independent of ASCVD. Results: In PheWAS analysis, we tested 864 phecodes with 36 independent LPA variants. We identified 21 significant associations with non-ASCVD phenotypes including heart failure, aortic valve stenosis, and chronic kidney disease of which 14 were replicated across independent cohorts. The strength of associations between the LPA variant rs10455872 and both heart failure and aortic valve stenosis related phecodes were significantly attenuated after adjustment for ASCVD. However, the association with chronic kidney disease phecode remained independent following adjustment for ASCVD without any attenuation in the estimated odds ratio (Table). Conclusions: LPA genetic variants were associated with aortic valve stenosis, heart failure and chronic kidney disease. The observed association of LPA variant rs10455872 with aortic stenosis and heart failure appear to be partially mediated by ASCVD, while the association with chronic kidney disease appears to be independent of ASCVD. Additional studies are needed to elucidate potential mechanisms by which Lp(a) may contribute to the pathogenesis of non-ASCVD disease phenotypes.

Background: Return of incidental genetic findings is recommended for pathogenic/likely pathogenic (P/LP) variants in Mendelian arrhythmia genes. The extent to which these variants are associated with arrhythmia phenotypes in unselected populations is unknown. Objective: Assess the impact of return of results (RoR) of P/LP variants in 4 arrhythmia genes in research participants not selected for cardiovascular disease. Methods: The cohort included 24,410 participants from the Electronic Medical Records and Genomics Network. Rare variants (minor allele frequency <1%) in KCNE1 , KCNH2 , KCNQ1 , and SCN5A were identified and classified according to ACMG guidelines. Arrhythmia phenotypes extracted from electronic health records (EHRs) included atrial fibrillation/flutter (AF/AFL), conduction system disease, long QT syndrome (LQTS), ventricular tachycardia/fibrillation (VT/VF), and premature ventricular contractions (PVCs). P/LP carriers’ phenotypes were compared to non-carriers using logistic regression adjusted for demographic covariates and site. Participants with P/LP variants were informed of their results and the impact of this RoR was assessed after 1 year of follow-up clinical care. Results: The participants included 53.7% females and 72.5% white individuals, with a median age of 57 years. 71 participants had a heterozygous P/LP variant in one of the 4 genes. LQTS diagnoses were associated with P/LP carrier status for all 4 genes ( KCNE1 OR 22.8, p=1.0e-4; KCNH2 OR 35.1, p=1.8e-7; KCNQ1 OR 27.3, p=3.6e-18; SCN5A OR 5.6, p=0.02). Carriers of SCN5A P/LP variants were also more likely to have PVCs (OR 4.3, p=0.003). Sensitivity analyses showed the associations predated the RoR. EHRs included a diagnosis of LQTS or Brugada Syndrome in 11/71 (16%) pre-RoR, and 16 more were diagnosed after RoR (27/71, 38%). A total of 47/71 (66%) participants had a documented arrhythmia phenotype 1 year after RoR, although 20 of these participants were not diagnosed with an inherited arrhythmia syndrome. Conclusion: Inherited arrhythmia diagnoses could be established in nearly half of participants with P/LP variants. These data indicate that return of incidental P/LP variants in these genes may facilitate the early diagnosis of arrhythmias.

Background Patients from various countries may have unique patterns of using complementary and alternative medicine (CAM) and unique reasons for using it. Objective Our objective was to assess the use of CAM among patients from the Gulf region attending the Executive and International Health Program of the Department of General Internal Medicine at Mayo Clinic in Rochester, Minnesota. Methods This cross-sectional survey was administered to all patients who were from the Gulf region and were undergoing outpatient evaluation in the Executive and International Health Program. After their initial medical evaluation by a physician, the patients were invited to anonymously complete the modified International Complementary and Alternative Medicine Questionnaire. Results The survey was completed by 69 patients (41 women, 27 men; mean age, 45.4 years). The most frequently seen providers for CAM treatments were physicians (71.0% of patients), spiritual healers (29.0%), and chiropractors (20.3%). CAM treatments most frequently received from a physician were massage therapy (51.0%), hijama (38.8%), spiritual healing (24.5%), and acupuncture or herbs (16.3%). The most frequently used dietary supplements were ginger (42.0%), bee products (30.4%), and garlic (27.5%). The most common self-help therapies were prayers for health (68.1%), meditation (15.9%), and relaxation techniques (11.6%). CAM therapy, including visits to CAM providers, was used by 92.8% of patients. CAM was mainly used to improve well-being and long-term health conditions rather than for acute illnesses. Conclusion The use of CAM was high among our patients from the Gulf region, and the CAM therapies used by this population differed from the ones used by US patients. Physicians providing care to patients from the Gulf region should be aware of how the use of CAM may affect the care needs of these patients.

As genomic sequencing expands to screen larger numbers of individuals, offering genetic counseling to everyone may not be possible. One approach to managing this limitation is for a genetic counselor to communicate clinically actionable results in person or by telephone, but report other results by mail. We employed this approach in a large genomic implementation study. In this paper, we describe participants’ experiences receiving genomic screening results by mail. We conducted 50 semi-structured telephone interviews with individuals who received neutral genomic screening results by mail. Most participants were satisfied receiving neutral results by mail. Participants generally had a good understanding of results; however, a few participants had misunderstandings about their genomic screening results, including mistaken beliefs about their disease risk and the comprehensiveness of the test. No one reported plans to alter health behaviors, defer medical evaluations, or take other actions that might be considered medically problematic. Reporting neutral results by mail is unlikely to cause recipients distress or generate misunderstandings that may result in reduced vigilance in following recommended preventive health strategies. Nonetheless, some individuals may benefit from additional genetic counseling support to help situate their results in the context of personal concerns and illness experiences.