Background The role of circulating metabolites in heart failure (HF) mechanisms and their clinical utility remain unclear. We aimed to examine the associations between serum metabolites and incident HF and assess their performance in improving HF risk prediction. Methods A total of 23 571 serum metabolomic spectral variables were measured using untargeted proton nuclear magnetic resonance spectroscopy. Participants from MESA (Multi‐Ethnic Study of Atherosclerosis; discovery cohort) and RS (Rotterdam Study; replication cohort) with metabolomic data and without prevalent HF at baseline were included. Cause‐specific proportional hazards models were used to estimate the associations between metabolomic features and incident HF, with false discovery rate–adjusted P values for multiple comparisons. We further assessed how adjusting for cardiovascular risk factors influenced these associations. Correlations among metabolites were tested. Discriminative performance of risk prediction was evaluated using Harrell’s C‐statistic. Results We included 3942 MESA and 1515 RS participants, with a median of 15 years follow‐up. In MESA, 15 metabolites were significantly associated with incident HF (false discovery rate–adjusted P<0.01), with 5 replicating in RS (false discovery rate–adjusted P<0.05). However, after further adjusting for diabetes or hypertension, observed associations lost statistical significance. Methanol, glucose, proline, and acetoacetate showed significant correlations with fasting glucose (Pearson coefficients, 0.41–0.89). Incorporating the 5 replicated metabolites or all 15 metabolites identified from MESA into PREVENT‐HF (Predicting Risk of Cardiovascular Disease Events–Heart Failure) did not significantly improve C‐statistics in either cohort. Conclusions Fifteen proton nuclear magnetic resonance–measured metabolites were associated with incident HF, but these associations were not independent of diabetes or hypertension. These metabolites provided minimal predictive utility beyond PREVENT‐HF equations.

BACKGROUND:Alternative splicing plays crucial roles in normal heart development and cardiac disease by influencing protein-coding sequences, functional domains, and molecular networks. However, a detailed characterization of the human heart isoform landscape remains incomplete. METHODS:Leveraging long-read single-nucleus RNA sequencing and computational analysis, we dissected full-length isoform heterogeneities, expression patterns, and usage shifts across cell types, cell states, and cardiac conditions of the adult left ventricle. We applied in silico approaches to assess the functional relevance of identified isoforms; validated isoform compositions of representative cardiac genes using reverse transcription quantitative polymerase chain reaction and targeted amplicon sequencing; and developed a web server for interactive navigation of our results. RESULTS:The data revealed that isoform heterogeneity is widespread in the cardiac cellular system, serving as a posttranscriptional buffer mechanism that calibrates the molecule reservoirs in human hearts. In healthy left ventricles, ≈30% of cell type-specific genes were polyform, using multiple isoforms tailored to cell type-specific programs. Among ubiquitously expressed genes, >300 showed differential isoform usage with cell type specificity in normal hearts. Comparisons of cardiomyocytes across conditions uncovered 379 genes with marked isoform usage shifts, most of which are predicted to change protein coding outcomes through direct changes in protein coding sequences and switches between intron retention and non-protein-coding biotypes. In contrast, cell state-specific programs tend to operate on monoform genes associated with changes among cell states. In addition, our data revealed heart failure-associated differential isoform usage events in stromal and immune cell types in the cardiac microenvironment. CONCLUSIONS:We present a comprehensive atlas of splicing isoforms in the normal adult heart and heart failure through long-read single-nucleus RNA sequencing and computational analyses. The results suggest crucial roles of isoforms in buffering core cellular programs and contributing to disease-associated cell states. The full-length details of these cell-specific isoforms serve as an important reference for downstream translational and mechanistic studies and are available on our online data portal at https://github.com/gaolabtools/heart-isoform-atlas.

OBJECTIVE To examine the association between serum metabolites and incident heart failure (HF) and to assess the added value of identified metabolites for 10-year HF risk prediction. Methods: A total of 23,571 serum metabolomic spectral variables were measured using untargeted proton nuclear magnetic resonance ( 1 H NMR) spectroscopy-based method. Participants from Multi-Ethnic Study of Atherosclerosis (MESA) and Rotterdam Study (RS) cohorts with metabolomic profiling data and without prevalent HF at baseline were included. Multivariable Cox proportional hazards models were used to estimate the associations between metabolomic features and incident HF, and we further assessed how adjustment for cardiovascular risk factors attenuated the associations. P values were adjusted for multiple comparisons. Correlations among metabolites were tested. Utility of the metabolites in improving discriminative performance HF risk prediction beyond PREVENT-HF score was assessed using Harrell's c- statistic. Results: A total of 3942 MESA and 1515 RS participants were included, with a median of 15 years follow-up. In MESA, 15 metabolites were significantly associated with incident HF after adjusting for age, sex, race, estimated glomerular filtration rate and lifestyle behaviors, with 5 replicated in RS cohort. However, after further adjusting for diabetes or hypertension, these observed associations lost significance. Several metabolites showed moderate to high correlations with fasting glucose levels. Adding 5 replicated metabolites into the PREVENT-HF score reduced c-statistics in both cohorts, and adding 15 metabolites identified from MESA showed no statistically significant improvements. CONCLUSIONS In 2 cohorts of middle-aged to older adults, 15 1 H NMR measured metabolites were associated with incident HF, but the observed associations were not independent of diabetes or hypertension. Incorporating these metabolites into the PREVENT-HF score did not improve HF risk prediction.

Cardiovascular events, including heart failure and arrhythmias, following chimeric antigen receptor (CAR) T‐cell therapy are increasingly recognized. Although global longitudinal strain (GLS) has demonstrated prognostic utility for other cancer therapy‐related cardiac dysfunction, less is known regarding the association of GLS with adverse cardiac events following CAR T‐cell therapy.

BACKGROUND:Chlorthalidone in chronic kidney disease (CLICK) randomized trial demonstrated a robust reduction in systolic blood pressure (BP) in stage 4 chronic kidney disease (CKD). Here we explore the mechanisms underlying the antihypertensive effect of chlorthalidone.METHODS:In this prespecified analysis, we analyzed the contributions of baseline levels of 24-hour urinary sodium and aldosterone and the changes from baseline to 4 weeks in the multiple mediators reflecting volume status in a causal mediation analysis framework. Baseline levels of these mediators served as covariates. No power calculationfor this analysis was performed.RESULTS:Of the 160 patients randomized, 140 (87.5%) were included in this analysis. Compared to placebo, chlorthalidone within 4 weeks reduced weight -1.5 % (95% CI -2.2 to -0.7) and volume -1.4 % (95% CI -2.2 to -0.6), stimulated plasma renin 40.5% (95% CI 25.4 to 57.4%) and serum aldosterone 40.2% (95% CI 11.7% to 76%), and reduced plasma NT-pro BNP levels -19.4% (95% CI -33.8% to -1.9%). Mediation analysis revealed the following results: for weight change, the total effect on systolic BP was -10.8 mmHg (95% CI -16 to -5.7), of which weight change (indirect effect) accounted for -0.9 mmHg (95% CI -4.2 to 2.5) and BP change independent of weight (direct effect) accounted for -10 mmHg (-15.7 to - 4.2). Thus, the percent mediation was 8.1% (95% CI -22.4 to 38.5). Baseline excretion of 24-hour sodium or aldosterone or any of the changes in the above mediators examined accounted for <2 mmHg BP drop and were not significant for any of the mediators.CONCLUSION:Chlorthalidone improved BP control among patients with advanced CKD independently of baseline urinary sodium, aldosterone, weight loss, or changes in the renin-angiotensin system or NT-pro BNP. (Funded by the National Heart Lung and Blood Institute; CLICK ClinicalTrials.gov number, NCT02841280).

A common missense variant in ICAM1 among African American individuals (rs5491; pK56M) has been associated with risk of heart failure with preserved ejection fraction (HFpEF), but the pathways that lead to HFpEF among those with this variant are not clear. In this analysis of 92 circulating proteins and their associated networks, we identified 7 circulating inflammatory proteins associated with rs5491 among >600 African American individuals. Using weighted coexpression network analysis, 3 protein networks were identified, one of which was associated with rs5491. This protein network was most highly represented by members of the tumor necrosis receptor superfamily. The rs5491 variant demonstrated an inflammatory proteomic profile in a separate cohort of African American individuals. This analysis identifies inflammatory pathways that may drive HFpEF among African American individuals with the ICAM1 pK56M (rs5491) variant.

BACKGROUND:Emulation of the "target trial" (TT), a hypothetical pragmatic randomized controlled trial (RCT), using observational data can be used to mitigate issues commonly encountered in comparative effectiveness research (CER) when randomized trials are not logistically, ethically, or financially feasible. However, cardiovascular (CV) health research has been slow to adopt TT emulation. Here, we demonstrate the design and analysis of a TT emulation using electronic health records to study the comparative effectiveness of the addition of a disease-modifying anti-rheumatic drug (DMARD) to a regimen of methotrexate on CV events among rheumatoid arthritis (RA) patients.METHODS:We used data from an electronic medical records-based cohort of RA patients from Northwestern Medicine to emulate the TT. Follow-up began 3 months after initial prescription of MTX (2000-2020) and included all available follow-up through June 30, 2020. Weighted pooled logistic regression was used to estimate differences in CVD risk and survival. Cloning was used to handle immortal time bias and weights to improve baseline and time-varying covariate imbalance.RESULTS:We identified 659 eligible people with RA with average follow-up of 46 months and 31 MACE events. The month 24 adjusted risk difference for MACE comparing initiation vs non-initiation of a DMARD was -1.47% (95% confidence interval [CI]: -4.74, 1.95%), and the marginal hazard ratio (HR) was 0.72 (95% CI: 0.71, 1.23). In analyses subject to immortal time bias, the HR was 0.62 (95% CI: 0.29-1.44).CONCLUSION:In this sample, we did not observe evidence of differences in risk of MACE, a finding that is compatible with previously published meta-analyses of RCTs. Thoughtful application of the TT framework provides opportunities to conduct CER in observational data. Benchmarking results of observational analyses to previously published RCTs can lend credibility to interpretation.

Metabolic comorbidities, such as obesity and diabetes, are associated with subclinical alterations in both cardiac structure/function and natriuretic peptides prior to the onset of heart failure (HF). Despite this, the exact metabolic pathways of cardiac dysfunction which precede HF are not well-defined. Among older individuals without HF in the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of 47 circulating metabolites measured by H-1-NMR with echocardiographic measures of cardiac structure and function. We then evaluated associations of significant metabolites with circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a separate cohort, we evaluated differences between top metabolites in patients with HF with preserved ejection fraction (HFpEF) and comorbidity-matched controls. Genetic variants associated with top metabolites (mQTLs) were then related to echocardiographic measures and NT-proBNP. Among 3440 individuals with metabolic and echocardiographic data in MESA (62 +/- 10 years, 52% female, 38% White), 10 metabolites broadly reflective of glucose and amino acid metabolism were associated with at least 1 measure of cardiac structure or function. Of these 10 metabolites, 4 (myo-inositol, glucose, dimethylsulfone, carnitine) were associated with higher NT-proBNP and 2 (d-mannose, acetone) were associated with lower NT-proBNP. In a separate cohort, patients with HFpEF had higher circulating myo-inositol levels compared with comorbidity-matched controls. Genetic analyses revealed that 1 of 6 known myo-inositol mQTLs conferred risk of higher NT-proBNP. In conclusion, metabolomic profiling identifies several novel metabolites associated with cardiac dysfunction in a cohort at high risk for HF, revealing pathways potentially relevant to future HF risk.

Background To date, at least 20 different amyloidogenic proteins have been documented. Growing evidence suggests that despite being part of the universal amyloid proteome, apolipoprotein A-IV can be amyloidogenic, accounting for less than 1% of cases. Case summary A 75-year-old woman was admitted for paroxysmal nocturnal dyspnoea and intermittent exertional shortness of breath and was found to be in acute heart failure. The patient underwent intravenous diuretic therapy and was discharged after decongestion. She then underwent a battery of outpatient tests to determine aetiology of her heart failure. Cardiac magnetic resonance imaging showed severe concentric left ventricular hypertrophy and diffuse late gadolinium enhancement, concerning for amyloidosis, but serologic evaluation for amyloidogenic light chain (AL) amyloidosis was negative. Tc 99m pyrophosphate (PYP) scan showed Grade 2 uptake at 1 h that was only moderately suggestive of transthyretin (TTR) amyloidosis. She ultimately received a right heart catheterization and endomyocardial biopsy, which showed apolipoprotein A-IV amyloid deposition within Congo red-positive areas of the endomyocardial specimen. The patient continues to report dyspnoea on exertion but has avoided additional heart failure admissions with intensification of her diuretic regimen. Discussion In this case, nuclear PYP scan to evaluate for TTR amyloidosis demonstrated focal PYP uptake, but endomyocardial biopsy demonstrated apolipoprotein A-IV deposition without evidence of TTR amyloidosis. Our case increases knowledge of this rare form of amyloidosis, suggests that it may result in false positive nuclear PYP results, and highlights the importance of its evaluation, particularly in circumstances in which investigations do not reveal definitive evidence of AL or TTR amyloidosis.

We thank the authors for their interest in our work and for their letter highlighting the importance of diversity in research studies. We agree with the call for greater diversity in prospective cohorts to mirror the diversity of the current population of the United States. Longitudinal data from cohorts such as those studied in the Lifetime Risk Pooling Project in our analysis offer the opportunity to examine long-term outcomes associated with key risk factors such as fasting glucose levels. Of the 6 National Heart, Lung, and Blood Institute (NHLBI) cohorts included in our study, 1 began enrollment in 1948 (Framingham Heart Study), 1 in 1971 (Framingham Offspring Study), and 3 included the years 1985–1989 (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adult Study and Cardiovascular Health Study). The Multi-Ethnic Study of Atherosclerosis began enrollment in 2000 and, in fact, included Hispanic and Chinese Americans. Another Reminder of Health Care Disparities in Clinical Medicine: Lack of Representative Research DatabasesJournal of Cardiac FailureVol. 29Issue 10PreviewWe read with great interest the work recently published by Sinha et al.1 These investigators studied the competing cumulative risk for developing first cardiac event described as atherosclerotic cardiovascular disease, heart failure, or noncardiac death.1 Data were stratified according to race and sex with regard to prespecified fasting plasma glucose parameters.1 According to their analysis, middle-aged and older Black women were more likely to have a heart failure event as their first cardiovascular disease event, whereas adults from the other race–sex groups had an atherosclerotic cardiovascular disease event as their first cardiovascular disease event. Full-Text PDF

European Journal of Heart FailureVolume 25, Issue 1 p. 95-97 Invited Editorial Loop diuretic management after sacubitril/valsartan initiation in heart failure with preserved ejection fraction: deceptively simple or more than meets the eye? Arjun Sinha, Arjun Sinha Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USASearch for more papers by this authorRavi B. Patel, Corresponding Author Ravi B. Patel [email protected] Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Corresponding author. Division of Cardiology, Northwestern University Feinberg School of Medicine, 676 North Saint Clair Street, Suite 600, Chicago, IL 60611, USA. Email: [email protected]Search for more papers by this author Arjun Sinha, Arjun Sinha Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USASearch for more papers by this authorRavi B. Patel, Corresponding Author Ravi B. Patel [email protected] Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Corresponding author. Division of Cardiology, Northwestern University Feinberg School of Medicine, 676 North Saint Clair Street, Suite 600, Chicago, IL 60611, USA. Email: [email protected]Search for more papers by this author First published: 29 November 2022 https://doi.org/10.1002/ejhf.2750 The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology. doi: 10.1002/ejhf.2703 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, et al. PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019; 381: 1609–20. 10.1056/NEJMoa1908655 CASPubMedWeb of Science®Google Scholar 2Solomon SD, Vaduganathan M, Claggett BL, Packer M, Zile M, Swedberg K, et al. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure. Circulation. 2020; 141: 352–61. 10.1161/CIRCULATIONAHA.119.044586 PubMedWeb of Science®Google Scholar 3Vaduganathan M, Claggett BL, Desai AS, Anker SD, Perrone SV, Janssens S, et al. Prior heart failure hospitalization, clinical outcomes, and response to sacubitril/valsartan compared with valsartan in HFpEF. J Am Coll Cardiol. 2020; 75: 245–54. 10.1016/j.jacc.2019.11.003 CASPubMedWeb of Science®Google Scholar 4 Chatur S, Claggett BL, Vardeny O, Jering K, Desai AS, Pfeffer MA, et al. Sacubitril/valsartan and loop diuretic requirement in heart failure with preserved ejection fraction in the PARAGON-HF trial. Eur J Heart Fail. 2023; 25: 87–94. 10.1002/ejhf.2703 CASPubMedWeb of Science®Google Scholar 5Vardeny O, Claggett B, Kachadourian J, Desai AS, Packer M, Rouleau J, et al. Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail. 2019; 21: 337–41. 10.1002/ejhf.1402 CASPubMedWeb of Science®Google Scholar 6Maddox TM, Januzzi JL, Allen LA, Breathett K, Butler J, Davis LL, et al. 2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021; 77: 772–810. 10.1016/j.jacc.2020.11.022 PubMedWeb of Science®Google Scholar 7McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al.; PARADIGM-HF Investigators and Committees. 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JACC Heart Fail. 2020; 8: 70–80. 10.1016/j.jchf.2019.07.005 PubMedWeb of Science®Google Scholar 11Bayés-Genís A, Barallat J, Galán A, de Antonio M, Domingo M, Zamora E, et al. Soluble neprilysin is predictive of cardiovascular death and heart failure hospitalization in heart failure patients. J Am Coll Cardiol. 2015; 65: 657–65. 10.1016/j.jacc.2014.11.048 CASPubMedWeb of Science®Google Scholar 12Mustafa NH, Jalil J, Zainalabidin S, Saleh MSM, Asmadi AY, Kamisah Y. Molecular mechanisms of sacubitril/valsartan in cardiac remodeling. Front Pharmacol. 2022; 13:892460. 10.3389/fphar.2022.892460 CASPubMedWeb of Science®Google Scholar 13Nguyen TTL, Wang M, Liu D, Iyer S, Gonzalez Bonilla HM, Acker N, et al. Proteomic biomarkers of sacubitril/valsartan treatment response in heart failure with preserved ejection fraction: molecular insights into sex differences. 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Femoral atherosclerotic plaques are less inflammatory than carotid plaques histologically, but limited cell-level data exist regarding comparative immune landscapes and polarization at these sites. We investigated intraplaque leukocyte phenotypes and transcriptional polarization in 49 patients undergoing femoral (n = 23) or carotid (n = 26) endarterectomy using single-cell RNA-Seq (scRNA-Seq; n = 13), flow cytometry (n = 24), and IHC (n = 12). Comparative scRNA-Seq of CD45+-selected leukocytes from femoral (n = 9; 35,265 cells) and carotid (n = 4; 30,655 cells) plaque revealed distinct transcriptional profiles. Inflammatory foam cell–like macrophages and monocytes comprised higher proportions of myeloid cells in carotid plaques, whereas noninflammatory foam cell–like macrophages and LYVE1-overexpressing macrophages comprised higher proportions of myeloid cells in femoral plaque (P < 0.001 for all). A significant comparative excess of CCR2+ macrophages in carotid versus plaque was observed by flow cytometry in a separate validation cohort. B cells were more prevalent and exhibited a comparatively antiinflammatory profile in femoral plaque, whereas cytotoxic CD8+ T cells were more prevalent in carotid plaque. In conclusion, human femoral plaques exhibit distinct macrophage phenotypic and transcriptional profiles as well as diminished CD8+ T cell populations compared with human carotid plaques

Background: Individuals with prediabetes and diabetes are at increased risk of atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). Whether ASCVD or HF is more likely to occur first in these populations within different race-sex groups is unknown.Objective: To determine the competing risk for the first cardiovascular event by subtype in Black and white men and women with prediabetes and diabetes.Methods: Individual-level data from adults without ASCVD or HF were pooled from 6 popula-tion-based cohorts. We estimated the competing cumulative incidences of ASCVD, HF and noncardiovascular death as the first event in middle-aged (40-59 years) and older (60-79 years) adults, stratified by race and sex, with normal fasting plasma glucose (FPG < 100 mg/ dL), prediabetes (FPG 100-125 mg/dL) and diabetes (FPG > 126 mg/dL or on antihyperglyce-mic agents) at baseline. Within each race-sex group, we estimated risk the adjusted hazard ratio of ASCVD, HF and noncardiovascular death in adults with prediabetes and diabetes rela-tive to adults with normoglycemia after adjusting for cardiovascular risk factors.Results: In 40,117 participants with 638,910 person-years of follow-up, 5781 cases of incident ASCVD and 3179 cases of incident HF occurred. In middle-aged adults with diabetes, compet-ing cumulative incidence of ASCVD as a first event was higher than HF in white men (35.4% vs 11.6%), Black men (31.6% vs 15.1%) and white women (24.3% vs 17.2%) but not in Black women (26.4% vs 28.4%). Within each group, the adjusted hazard ratio of ASCVD and HF was significantly higher in adults with diabetes than in adults with normal FPG levels. Findings were largely similar in middle-aged adults with prediabetes and older adults with prediabetes or diabetes.Conclusions: Black women with diabetes are more likely to develop HF as their first CVD event, whereas individuals with diabetes from other race-sex groups are more likely to present first with ASCVD. These results can inform the tailoring of primary prevention therapies for either HF-or ASCVD-specific pathways based on individual-level risk. (J Cardiac Fail 2023;29:246-254)

Background:Home dialysis utilization is lower among veterans than in the general US population. Several sociodemographic factors and comorbidities contribute to peritoneal dialysis (PD) underutilization. In 2019, the Veterans Health Administration (VHA) Kidney Disease Program Office convened a PD workgroup to address this concern.Observations:The PD workgroup was explicitly concerned by the limited availability of PD within the VHA, which frequently requires veterans to transition kidney disease care from US Department of Veterans Affairs medical centers (VAMCs) to non-VHA facilities when they progress from chronic kidney disease to end-stage kidney disease, causing fragmentation of care. Since the administrative requirements and infrastructure of VAMCs vary, the workgroup focused its deliberations on synthesizing a standard process for evaluating the feasibility and establishing a new PD program within any individual VAMC. A 3-phased approach was envisioned, beginning with ascertainment of prerequisites, leading to an examination of the clinical and financial feasibility through the process of data gathering and synthesis, culminating in a business plan that translates the previous 2 steps into an administrative document necessary for obtaining VHA approvals.Conclusions:VAMCs can use the guide presented here to improve therapeutic options for veterans with kidney failure by establishing a new or restructured PD program.

HomeCirculation: Genomic and Precision MedicineVol. 16, No. 6Hypertrophic Cardiomyopathy Secondary to RAF1 Cysteine-Rich Domain Variants No AccessResearch ArticleRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessResearch ArticleRequest AccessFull TextHypertrophic Cardiomyopathy Secondary to RAF1 Cysteine-Rich Domain Variants Dominic E. Fullenkamp, Ryan M. Jorgensen, Desiree F. Leach, Arjun Sinha, Isabella M. Salamone, Jamie R. Johnston, Lisa M. Dellefave-Castillo, Lubna Choudhury, Elizabeth M. McNally and Lisa D. Wilsbacher Dominic E. FullenkampDominic E. Fullenkamp https://orcid.org/0000-0001-7627-7119 Center for Genetic Medicine (D.E.F., I.M.S., J.R.J., L.M.D.-C., E.M.M.), Northwestern University, Chicago, IL. Division of Cardiology, Department of Medicine (D.E.F., A.S., L.M.D.-C., L.C., E.M.M., L.D.W.), Northwestern University, Chicago, IL. , Ryan M. JorgensenRyan M. Jorgensen Feinberg Cardiovascular and Renal Research Institute (R.M.J., D.F.L., L.D.W.), Northwestern University, Chicago, IL. , Desiree F. LeachDesiree F. Leach Feinberg Cardiovascular and Renal Research Institute (R.M.J., D.F.L., L.D.W.), Northwestern University, Chicago, IL. , Arjun SinhaArjun Sinha Division of Cardiology, Department of Medicine (D.E.F., A.S., L.M.D.-C., L.C., E.M.M., L.D.W.), Northwestern University, Chicago, IL. , Isabella M. SalamoneIsabella M. Salamone Center for Genetic Medicine (D.E.F., I.M.S., J.R.J., L.M.D.-C., E.M.M.), Northwestern University, Chicago, IL. , Jamie R. JohnstonJamie R. Johnston https://orcid.org/0000-0002-3563-640X Center for Genetic Medicine (D.E.F., I.M.S., J.R.J., L.M.D.-C., E.M.M.), Northwestern University, Chicago, IL. , Lisa M. Dellefave-CastilloLisa M. Dellefave-Castillo https://orcid.org/0000-0001-6044-0559 Center for Genetic Medicine (D.E.F., I.M.S., J.R.J., L.M.D.-C., E.M.M.), Northwestern University, Chicago, IL. Division of Cardiology, Department of Medicine (D.E.F., A.S., L.M.D.-C., L.C., E.M.M., L.D.W.), Northwestern University, Chicago, IL. , Lubna ChoudhuryLubna Choudhury https://orcid.org/0000-0003-4039-8490 Division of Cardiology, Department of Medicine (D.E.F., A.S., L.M.D.-C., L.C., E.M.M., L.D.W.), Northwestern University, Chicago, IL. , Elizabeth M. McNallyElizabeth M. McNally https://orcid.org/0000-0002-1221-719X Center for Genetic Medicine (D.E.F., I.M.S., J.R.J., L.M.D.-C., E.M.M.), Northwestern University, Chicago, IL. Division of Cardiology, Department of Medicine (D.E.F., A.S., L.M.D.-C., L.C., E.M.M., L.D.W.), Northwestern University, Chicago, IL. and Lisa D. WilsbacherLisa D. Wilsbacher Correspondence to: Lisa D. Wilsbacher, MD, PhD, Simpson-Querrey Biomedical Research Center, 8-404 303 E, Superior St., Chicago, IL 60611. Email: E-mail Address: [email protected] https://orcid.org/0000-0002-3676-0680 Division of Cardiology, Department of Medicine (D.E.F., A.S., L.M.D.-C., L.C., E.M.M., L.D.W.), Northwestern University, Chicago, IL. Feinberg Cardiovascular and Renal Research Institute (R.M.J., D.F.L., L.D.W.), Northwestern University, Chicago, IL. Department of Pharmacology, Feinberg School of Medicine (L.D.W.), Northwestern University, Chicago, IL. Originally published31 Oct 2023https://doi.org/10.1161/CIRCGEN.123.004262Circulation: Genomic and Precision Medicine. 2023;16FootnotesFor Sources of Funding and Disclosures, see page 582.Correspondence to: Lisa D. Wilsbacher, MD, PhD, Simpson-Querrey Biomedical Research Center, 8-404 303 E, Superior St., Chicago, IL 60611. Email: lisa.wilsbacher@northwestern.eduReferences1. 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AbstractAimsCirculating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)].Methods and resultsPeripheral blood immune cell subsets were measured in adults from the Multi‐Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0 ± 10.4 years with 51% women, and in the CHS cohort, it was 79.6 ± 4.4 years with 62% women. In the meta‐analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95% CI 0.83–0.99), P = 0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95% CI 0.62–0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF.ConclusionsWe observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population‐based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation.