Risk Of Incident Heart Failure Research Articles

Abstract 17586: Physical Activity Associates With a Greater Reduction in Heart Failure Risk Among Individuals With Depression and/or Anxiety

Introduction: Physical activity (PA) has shown a dose-dependent reduction in the incidence of heart failure (HF) by mitigating stress-related neural activity (SNA). Accordingly, we postulated that the impact of PA on HF incidence may be more pronounced in individuals with chronic stress conditions (e.g., depression and/or anxiety) that associate with heightened baseline SNA. Objective: To test whether PA confers a greater reduction in HF incidence among individuals with (vs. without) pre-existing depression and/or anxiety. Methods: Among 48,673 participants (median age 60 years, 40% male) in the Mass General Brigham Biobank, self-reported PA data were collected through a health survey and converted to metabolic equivalent of task minutes per week. Data on incident HF, its subtypes, depression, anxiety, and cardiovascular risk factors were obtained using the International Classification of Disease Codes. Cox regression was employed to assess the association between PA and ten-year HF risk and to examine potential interactions. Results: PA (per each standard deviation) is independently associated with greater reductions in all HF risk among individuals with depression and/or anxiety (standardized hazard ratio [HR] [95% confidence interval (CI)]: 0.735 [0.648, 0.834], p<0.001) compared to those without depression and/or anxiety (0.821 [0.781, 0.864], p<0.001, p-interaction=0.038*). Similar associations were observed between PA and the risk of HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) among those in whom HF could be classified, Fig1. Conclusions: PA is associated with greater reductions in risk of incident HF, including HFpEF and HFrEF, with the greatest reductions in those with pre-existing depression and/or anxiety. These findings highlight the potential for improved cardiovascular benefits linked to PA in individuals with elevated baseline SNA.

Abstract 16389: Inflammatory Chronic Kidney Disease is Associated With Incident Heart Failure: A Pooled Cohort Analysis

Introduction: High sensitivity C-reactive protein (hsCRP), a biomarker of inflammation, can risk stratify patients for cardiovascular disease including heart failure (HF). It is not well established if inflammation increases the risk of HF in patients with chronic kidney disease (CKD) and if hsCRP can be utilized to risk stratify patients with CKD for their risk of incident HF. Aims: We assessed the role of hsCRP in risk stratifying patients with CKD for incident HF. Methods: We studied participants of 3 major epidemiologic cohorts: Atherosclerosis Risk in Communities Study, Multi-Ethnic Study of Atherosclerosis, and Jackson Heart Study. High inflammation was classified as hsCRP >3 mg/L and CKD was classified as estimated glomerular filtration rate <60 mL/min/1.73m2. Participants were stratified into 3 groups: neither CKD nor high inflammation, CKD without high inflammation, or CKD with high inflammation. Cox hazards models adjusted for age, sex, race, body mass index, smoking, alcohol use, diabetes, hypertension, and coronary disease were utilized for analysis. Results: 8,692 participants with 460 incident HF events followed over a median 8.32 years were included in our analysis. Participants with CKD without high inflammation (HR = 1.45; 95% CI 1.14 to 1.85) and CKD with high inflammation (2.05; 1.61 to 2.61) were associated with an increased risk of incident HF compared with participants without CKD or high inflammation (referent, Figure). Furthermore, participants with CKD and a hsCRP >3 mg/L had an increased risk of incident HF (1.41; 1.06 to 1.88) compared with participants with CKD but hsCRP ≤3 mg/L (referent). Conclusions: Patients with CKD and high levels of inflammation carry a 2-fold increased risk of incident HF. In patients with CKD, hsCRP levels >3mg/L may be useful to risk stratify patients with increased risk of developing HF.

Abstract 18395: Urinary Metals as Novel Risk Factors for Incident Heart Failure and Subtypes in Indigenous Communities in the US: Evidence From the Strong Heart Study

Introduction: Chronic exposure to metals is an independent risk factor for CVD, yet the role of metal exposure on heart failure (HF) and HF subtypes remains understudied. Indigenous communities in the US suffer a high burden of CVD and have been historically exposed to moderate and high levels of environmental metals. In this study we evaluate the prospective association between urinary metal levels and incident HF and HF subtypes in the Strong Heart Study, the largest US cohort of American Indian adults. Hypothesis: We hypothesize that urinary metals are prospectively associated with increased HF risk, and the associations will be different for ejection fraction (EF) <50% and EF >50%. Methods: A total of 2,706 participants (mean (SD) age 56.4(8.1) years, 58% female) with urinary metals available at baseline (1989-1991) were included. Incident HF events were ascertained through 2019 by a physician panel, including classification of HF subtypes (EF50% and EF<50%). Progressively adjusted Cox proportional hazards models were used to identify the risk of incident HF and HF subtypes by an interquartile range (IQR) change in urine metals (Table 1). Results: A total of 444 participants developed HF (90 EF >50%, 127 EF<50%, 227 unclassified). Baseline levels of all metals were higher among participants who developed HF. In fully adjusted models (Model 2), higher levels of urinary cadmium, molybdenum and zinc were significantly associated with HF risk. The associations varied by HF subtype. While no significant associations were identified for those EF≥50%, higher levels of urinary tungsten, molybdenum, and zinc were significantly associated with HF EF<50% risk. Conclusions: We identified an association between baseline urine levels of several essential and non-essential metals and incident HF risk in the Strong Heart Study, with strongest associations for those with EF<50%. These findings can help identify novel modifiable risk factors of HF and inform prevention strategies.

Abstract 15781: Associations Between Hysterectomy and Incident Metabolic Syndrome: The Multi-Ethnic Study of Atherosclerosis (MESA)

Background: Metabolic syndrome is linked to increased risk of incident atherosclerotic cardiovascular disease (CVD), heart failure, and all-cause mortality. Notable associations exist between hysterectomy with bilateral salpingo-oophorectomy and metabolic syndrome. However, there is emerging evidence that even with ovarian conservation, hysterectomy independently increases long-term risk for CVD. Despite these associations, extant literature on the independent link between ovary-sparing hysterectomy and metabolic syndrome is scarce. We, therefore, examined the associations between hysterectomy with ovarian preservation and metabolic syndrome risk in a multi-ethnic cohort. Methods: We studied 1,355 female MESA participants who had data on self-reported history of hysterectomy, oophorectomy, and hystero-oophorectomy and were free of metabolic syndrome and CVD at exam 1 (2000-2002). Metabolic syndrome was defined by the NCEP Adult Treatment Panel III criteria. We used multivariable Cox regression models to evaluate the associations between hysterectomy/oophorectomy subgroups and incident metabolic syndrome from exams 2 (2002-2004) to 6 (2016-2018). Results: The mean ± SD age was 59.0 ± 9.5 years, with 42% White, 27% Black, 19% Hispanic, and 13% Chinese-American participants. 29% and 22% had a history of hysterectomy and oophorectomy, respectively. Over a median follow-up of 10.5 (3.01-17.62) years, there were 750 metabolic syndrome events. Hysterectomy [HR 1.32; 95% CI (1.01-1.73)] and hystero-oophorectomy [1.40 (1.13-1.74)] were strongly associated with metabolic syndrome (Table) . Conclusion: Hysterectomy with ovarian preservation is independently associated with a higher risk of metabolic syndrome. If our findings are confirmed by other studies, screening and preventive strategies focused on females with ovary-sparing hysterectomy and the pathways driving these associations should be explored.

Abstract 16482: Proteomic Measures Associated With Leisure-Time Physical Activity and Heart Failure Risk in Late-Life - The Atherosclerosis Risk in Communities Study

Introduction: Leisure-time physical activity (LTPA) is associated with lower heart failure (HF) risk. However, the underlying molecular mechanisms by which LTPA impacts HF risk is unclear. Methods: We evaluated participants at Atherosclerosis Risk in Communities study visits 3 (1993-95) and 5 (2011-13) with plasma proteomics data (Somascan v4) and without HF or stroke. LTPA was assessed by the Baecke questionnaire as metabolic equivalent (MET)-minutes/week. We performed cross-sectional associations of 4,955 proteins with LTPA at visit 3 and then at visit 5 LTPA using multivariable quantile regression models at Bonferroni-corrected significance (p<1e-5, p<0.0004, respectively). We related these proteins to incident HF after visit 3 and then visit 5 using multivariable Cox regression models at Bonferroni-corrected significance (p<0.00086, p<0.003, respectively). Results: Thirty-nine proteins were associated with LTPA at visit 3 (n=10,402; age 60±6 yrs, 54% women; mean 688.6 MET-minutes/week, 773 incident HF events) and visit 5 (n=4,135; 75±5 yrs, 58% women; mean 834.8 MET-minutes/week, 362 events), of which 5 proteins were also associated with incident HF at both visits. Higher levels of THBS2, GABARAP, and BAGE2 were associated with lower LTPA and higher HF risk while higher levels of ART3 associated with higher LTPA and lower risk of incident HF (Figure). PTK7 demonstrated discordant associations with LTPA and HF risk. Levels of THBS2, GABARAP, BAGE2, and ART3 accounted for a significant proportion of the LTPA-HF association (p<0.05). Conclusion: Large-scale proteomics can identify novel biomarkers potentially linking LTPA to HF risk. Further study is needed of THBS2, GABARAP, BAGE2, and ART3, which may link the association of LTPA on HF.

Abstract 13812: Daily Marijuana Use is Associated With Incident Heart Failure: “All of Us” Research Program

Background: With the increasing state-level legalization of marijuana across the United States, its use has increased exponentially, especially among the youth. However, a lot remains unknown concerning its cardiovascular health implications. We sought to assess the association between the frequency of marijuana use and new-onset heart failure (HF). Methods: Using the NIH-sponsored “All of Us” Research Program, we performed a prospective analysis of participants’ survey data and Electronic Health records (EHR). We excluded patients with a baseline EHR diagnosis of HF. Marijuana use was defined as any unprescribed use or if prescribed, use beyond prescribed doses, and was collected using the NM ASSIST instrument. We determined the association between the frequency of marijuana use and incident HF using Cox proportional hazards models adjusted for demographic and socioeconomic factors, diabetes mellitus, hypertension, hyperlipidemia, BMI, alcohol use and smoking status. Results: From a final population of 156,999, there were 2958 events within a median follow-up time of 45 months. Compared to never users, daily marijuana users had an increased risk of incident HF (aHR - 1.34, 95% CI 1.04-1.72). In subgroup analyses, frequency of marijuana use was not associated with incident HFrEF nor HFpEF. There was no evidence of effect modification by age, sex at birth nor smoking status. The relationship was attenuated after addition of coronary artery disease diagnosis as a time varying covariate in our main model (aHR - 1.27, 95% CI 0.99-1.62). Implication: Data on the cardiovascular effects of marijuana use is limited. To our knowledge this is the first prospective analysis on the association of marijuana use and HF. Our study suggests daily marijuana use is associated with HF. More research into the cardiovascular effects of marijuana is needed to enable clinicians provide the public with high quality information on the health implications of marijuana and to guide policies.

Abstract 18857: Association Between Physical Activity and Risk of Incident Cardiovascular Disease in Women With Novel Risk Factors: Evidence From the UK Biobank Cohort

Introduction: Early menopause and complicated pregnancy are associated with a higher risk of cardiovascular diseases (CVD), such as coronary heart disease (CHD) or heart failure (HF). Physical activity (PA) is a modifiable behaviour that typically reduces the risk of CVD; however, it is unclear if this is the case for these novel risk factors. Hypothesis: We hypothesised that PA could moderate the risk of incident CVD in women with novel risk factors. Aims: This study sought to investigate the effect of PA on the risk of incident CVD in women with a history of early menopause and/or complicated pregnancy. Methods: We included 55,930 women (median age 59) with novel risk factors and free from CVD (HF, CHD, arrhythmia, and ischemic stroke) from the UK Biobank Study. Novel risk factors were defined as complicated pregnancy (n=23,627, median age=56), described as a history of any stillbirth or ≥2 miscarriages, gestational diabetes, or hypertensive disorders of pregnancy, and early menopause (n=35,838, median age=60), defined as natural or surgical (bilateral oophorectomy) menopause <47age. Women were categorised into three groups of high (≥1,500 MET-minutes/week), moderate (≥600 MET-minutes/week) and low levels of PA according to their responses to the International Physical Activity Questionnaire (IPAQ). Multivariable Cox proportional hazard models were performed, and the results were adjusted for traditional CVD risk factors such as smoking, alcohol consumption, obesity, diabetes, hypertension, hyperlipidaemia, and cancer. Results: At a median follow-up of 13 years, there were 6636 events. A high level of PA was significantly associated with a lower risk of incident HF (hazard ratio [HR] 0.76, 95% CI[0.63 0.90], n= 1374), arrhythmia (HR 0.79, 95% CI[0.70 0.88], n=2699), and stroke (HR 0.77, 95% CI[0.61 0.97], n=797), compared to low levels of PA. We also observed a significant association between moderate levels of PA and reduced risk of incident arrhythmia (hazard ratio 0.78, 95% CI 0.70 0.87) compared to low levels of PA. Conclusion: High levels of PA can significantly reduce the risk of most incidents of CVD in women with novel risk factors. Thus, higher PA should be strongly encouraged to women with novel risk factors to lower the risk of CVD.

Abstract 16832: Biomarker Enhanced Risk Prediction of Incident Heart Failure in Low-Risk Patients: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Primary prevention strategies to reduce heart failure (HF) burden are urgently warranted. The Pooled Cohort equations to Prevent HF (PCP-HF) risk score is a validated risk tool that integrates readily available parameters obtained in primary care setting to estimate the 10-year risk for incident HF. Although PCP-HF performs well for high-risk individuals, the model’s predictive utility for low-risk individuals may potentially be enhanced by integration of biomarkers. Methods: In this study, the PCP-HF risk score was derived from data collected at visit 5 (2011-2013) of the ARIC cohort study and its 5-year predictive accuracy was investigated using surveillance data up to 2019. Participants with <10% PCP-HF risk probability of incident HF were classified as low-risk. Incremental improvement in predicting incident HF by including laboratory and imaging-based biomarkers in the low-risk population was analyzed by logistic regression, by calculating the area under the curve (AUC) from receiver operating characteristics. Results: Of 4980 study participants with 5 years of follow up, 47% had a low PCP-HF risk score (mean age 73 years, 71% women, 32% Black). Of these, 3% developed HF within 5 years. Compared to those with a high PCP-HF risk score, individuals with low PCP-HF risk score were younger, more often female and Black; had lower left ventricular (LV) mass index and left atrial volume index, higher magnitude of LV global longitudinal strain, and lower levels of NT-proBNP and hs-TnT. On further analysis, the model incorporating laboratory and imaging-based biomarkers exhibited greater predictive accuracy for incident HF compared to the original PCP-HF risk score in this low-risk population (AUC: 0.85 vs 0.62). Conclusion: The integration of laboratory and imaging-based biomarkers with the PCP-HF risk score enhances the predictive accuracy of risk modeling for incident HF, especially in individuals identified as low-risk by the 10-year risk prediction tool.

Abstract 17003: Associations of SGLT2 Inhibitor-Related Plasma Proteins With Incident Heart Failure: The Atherosclerosis Risk in Communities Study

Introduction: The mechanisms by which SGLT2 inhibitors reduce heart failure (HF) hospitalization is unclear. Data from EMPEROR-Reduced and two pilot clinical trials identified 288 plasma proteins modifiable by SGLT2 inhibitors. Methods: Among participants in the community-based ARIC study who were free of HF and had aptamer-based proteomic measurements (SomaLogic, Boulder, CO) at Visit 2 (mid-life, n=10,983; 1991-1993) and Visit 5 (late-life, n=4,321; 2011-2013), we studied the association of these 288 SGLT2 inhibitor-related proteins with incident HF after Visit 2 (1149 incident HF events) and Visit 5 (453 events) using multivariable Cox proportional hazards regression models, cardiometabolic traits using multivariable linear regression and Mendelian randomization to assess for potential causal effects. Results: The mean age was at 57±6 at Visit 2 and 76±5 at Visit 5 and 55% were women. Of 288 plasma proteins reported to be modulated by SGLT2 inhibition, 39 associated with incident HF after both Visit 2 and Visit 5: 24 with HFpEF [LVEF>50%], 2 with HFrEF, and 8 with both ( Figure ). These proteins also associated with plasma glucose levels, hematocrit and urine albumin-to-creatinine ratio and were enriched with immune signaling pathways and the fatty acid binding pathway. Two sample Mendelian randomization suggested causal effects of higher IGFBP1, lower CHRDL1 and higher B2M on higher incident HF risk (P<0.05). Conclusions: Proteins impacted by SGLT2 inhibition and associated with risk of HF suggest glucose metabolism, erythropoiesis and kidney damage as potential contributors to the effect of SGLT2 inhibitors on HF outcomes.

Autoantibodies against the chemokine receptor 3 predict cardiovascular risk.

Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.

Right ventricular free wall and four-chamber longitudinal strain in relation to incident heart failure in the general population.

Right ventricular free wall (RVFWLS) and four-chamber longitudinal strain (RV4CLS) are associated with adverse events in various patient populations including patients with heart failure (HF). We sought to investigate the prognostic value of RVFWLS and RV4CLS for the development of incident HF in participants from the general population. Participants from the 5th Copenhagen City Heart Study (2011-2015) without known chronic ischaemic heart disease or HF at baseline were included. RVFWLS and RV4CLS were obtained using two-dimensional speckle-tracking echocardiography from the right ventricular (RV)-focused apical four-chamber view. The primary endpoint was incident HF. Among 2740 participants (mean age 54 ± 17 years, 42% male), 43 (1.6%) developed HF during a median follow-up of 5.5 years (IQR 4.5-6.3). Both RVFWLS and RV4CLS were associated with an increased risk of incident HF during follow-up independent of age, sex, hypertension, diabetes, body mass index and tricuspid annular plane systolic excursion (TAPSE), (HR 1.06, 95%CI 1.00-1.11, P = 0.034, per 1% absolute decrease and HR 1.14, 95%CI 1.05-1.23, P = 0.001, per 1% absolute decrease, respectively). Left ventricular ejection fraction (LVEF) modified the association between RV4CLS and incident HF (P for interaction = 0.016) such that RV4CLS was only of prognostic importance among those with LVEF < 55% (HR 1.21, 95%CI 1.11-1.33, P < 0.001 vs. HR 0.94, 95%CI 0.80-1.10, P = 0.43 in patients with LVEF ≥ 55%). In participants from the general population, both RVFWLS and RV4CLS were associated with a greater risk of incident HF independent of important baseline characteristics and TAPSE, and LVEF modified the relationship between RV4CLS and incident HF.

Circulating neutrophil-related proteins associate with incident heart failure and cardiac dysfunction: The ARIC study.

Neutrophil activity contributes to adverse cardiac remodelling in experimental acute cardiac injury and is modifiable with pharmacologic agents like colchicine. Neutrophil activity-related plasma proteins known to be affected by colchicine treatment were measured at Visit 3 (1993-1995) and Visit 5 (2011-2013) of the ARIC cohort study. A protein-based neutrophil activity score was derived from 10 candidate proteins using LASSO Cox regression. Associations with incident heart failure (HF) and with cardiac function using Cox proportional hazards regression and linear regression models, respectively. The mean ages at Visits 3 and 5 were 60 ± 6 and 75 ± 5 years, respectively, and 54% and 57% were women, respectively. Each 1-standard deviation increase in the neutrophil activity score was associated with a higher risk of incident HF in mid-life (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.25-1.37) and late-life (HR 1.23, 95% CI 1.14-1.34), with a higher HR for HF with preserved than reduced ejection fraction (HR 1.30, 95% CI 1.16-1.47 vs. HR 1.13, 95% CI 0.98-1.30). Higher neutrophil activity was associated with greater left ventricular end-diastolic volume index, mass index and diastolic and systolic dysfunction. Plasma proteins related to neutrophil function associate with incident HF in mid- and late-life and with adverse cardiac remodelling. Therapies that modify these proteins, such as colchicine, may represent promising targets for the prevention or treatment of HF.

Incident Cardiovascular Disease Risk among Older Asian, Native Hawaiian and Pacific Islander Breast Cancer Survivors.

Cardiotoxicity among breast cancer survivors is associated with chemotherapy and radiation therapy. The risk of cardiovascular disease (CVD) among Asian, Native Hawaiian and Pacific Islander (ANHPI) breast cancer survivors in the United States is unknown. We used the SEER-Medicare linked database to estimate the risk of CVD among older breast cancer survivors. International Classification of Disease diagnosis codes were used to identify incident CVD outcomes. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CI) comparing ANHPI with Non-Hispanic White (NHW) patients with breast cancer for CVD, and among ANHPI race and ethnicity groups. A total of 7,122 ANHPI breast cancer survivors and 21,365 NHW breast cancer survivors were identified. The risks of incident heart failure and ischemic heart disease were lower among ANHPI compared with NHW breast cancer survivors (HRheart failure, 0.72; 95% CI, 0.61-0.84; HRheart disease, 0.74; 95% CI, 0.63-0.88). Compared with Japanese patients with breast cancer, Filipino, Asian Indian and Pakistani, and Native Hawaiian breast cancer survivors had higher risks of heart failure. ischemic heart disease and death. Among ANHPI breast cancer survivors, risk factors for heart failure included older age, higher comorbidity score, distant cancer stage and chemotherapy. Our results support heterogeneity in CVD outcomes among breast cancer survivors among ANHPI race and ethnicity groups. Further research is needed to elucidate the disparities experienced among ANHPI breast cancer survivors. Filipino, Asian Indian and Pakistani, and Native Hawaiian patients with breast cancer had higher risks of heart failure, ischemic heart disease and death among ANHPI patients with breast cancer.

Iodine-Induced Hypothyroidism and Long-Term Risks of Incident Heart Failure.

Background Although most individuals can adapt to a large iodine load and remain euthyroid, hypothyroidism can develop after iodine exposure. Hypothyroidism is associated with adverse cardiovascular consequences, including heart failure. This study was performed to investigate the relationships between iodine-induced hypothyroidism and incident heart failure. Methods and Results This cohort study of the US Veterans Health Administration (1998-2021) included adults aged ≥18 years with a serum thyroid-stimulating hormone (thyrotropin) <60 days of iodine contrast administration, and <1 year of a baseline normal serum thyroid-stimulating hormone. Cox proportional hazards regression ascertained risk of incident heart failure following iodine-induced hypothyroidism, adjusting for age, sex, race and ethnicity, body mass index, and history of coronary heart disease, dyslipidemia, diabetes, and hypertension. Of 45 470 veterans (mean±SD age, 61.1±14.1 years; 88% men), 3361 (7.4%) developed iodine-induced hypothyroidism. Heart failure developed in 5685 (12.5%) individuals over a median follow-up of 3.6 years (interquartile range, 1.9-7.2 years). Adjusted for risk factors, iodine-induced hypothyroidism was associated with increased risk of heart failure, compared with those who remained euthyroid after iodine exposure (adjusted hazard ratio [HR], 1.11 [95% CI, 1.01-1.22]). Women were at greater risk than men (adjusted HR: women, 1.65 [95% CI, 1.13-2.40]; men, 1.08 [95% CI, 0.98-1.19]; P for interaction, 0.02). Conclusions In the largest US study of this topic, hypothyroidism following iodine exposure was associated with an increased risk of incident heart failure, particularly in women. These findings support the need for further research to address the clinical significance of this issue, including the possible sex-specific risks of incident heart failure in more diverse data sets and study populations.

Heart failure risk in patients with atrial fibrillation treated with catheter ablation vs antiarrhythmic drugs

Atrial fibrillation (AF) increases heart failure (HF) risk. Whereas the risk of HF-related hospitalization and mortality are known in the setting of AF, the impact of AF treatment on HF development is understudied. The purpose of this study was to compare HF incidence among AF patients treated with antiarrhythmic drugs (AADs) vs catheter ablation (CA). AF patients with 1 prior AAD usage were identified in 2014-2022 Optum Clinformatics database. Patients were classified into 2 cohorts: those receiving CA vs those receiving a different AAD prescription. The 2 cohorts were matched on sociodemographic and clinical covariates using propensity score matching technique. Cox regression model was used to compare incident HF risk in the 2 cohorts. Subgroup analyses were performed by race/ethnicity, sex, AF subtype, and CHA2DS2-VASc score. After matching, 9246 patients were identified in each cohort (AAD and CA). Patients receiving CA had a 57% lower risk of incident HF than those treated with AADs (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.40-0.46). Subgroup analysis by race/ethnicity depicted similar results, with non-Hispanic White (HR 0.43; 95% CI 0.40-0.46), non-Hispanic Black (HR 0.46; 95% CI 0.35-0.60), Hispanic (HR 0.53; 95% CI 0.40-0.70), and Asian (HR 0.46; 95% CI 0.24-0.92) patients treated with CA (vs AAD) having significantly lower risk of HF, respectively. The effect size of CA remained significant in subgroups defined by sex, AF subtypes, and CHA2DS2-VASc score. AF patients receiving CA had ∼57% lower risk of developing HF than those receiving AAD. The lower risk of HF associated with CA vs AAD persisted across different race/ethnicity, sex, AF subtypes, and CHA2DS2-VASc score.

MMP-2 Associates With Incident Heart Failure and Atrial Fibrillation: The ARIC Study.

MMP (matrix metalloproteinase)-2 participates in extracellular matrix regulation and may be involved in heart failure (HF), atrial fibrillation (AF), and coronary heart disease. Among the 4693 ARIC study (Atherosclerosis Risk in Communities) participants (mean age, 75±5 years; 42% women) without prevalent HF, multivariable Cox proportional hazard models were used to estimate associations of plasma MMP-2 levels with incident HF, HF with preserved ejection fraction (≥50%), HF with reduced ejection fraction (<50%), AF, and coronary heart disease. Mediation of the association between MMP-2 and HF was assessed by censoring participants who developed AF or coronary heart disease before HF. Multivariable linear regression models were used to assess associations of MMP-2 with measures of left ventricular and left atrial structure and function. Compared with the 3 lower quartiles, the highest MMP-2 quartile associated with greater risk of incident HF overall (adjusted hazard ratio, 1.48 [95% CI, 1.21-1.81]), incident HF with preserved ejection fraction (1.44 [95% CI, 1.07-1.94]), incident heart failure with reduced ejection fraction (1.48 [95% CI, 1.08-2.02]), and incident AF (1.44 [95% CI, 1.18-1.77]) but not incident coronary heart disease (0.97 [95% CI, 0.71-1.34]). Censoring AF attenuated the MMP-2 association with HF with preserved ejection fraction. Higher plasma MMP-2 levels were associated with larger left ventricular end-diastolic volume index, greater left ventricular mass index, higher E/e' ratio, larger left atrial volume index, and worse left atrial reservoir and contractile strains (all P<0.001). Higher plasma MMP-2 levels associate with diastolic dysfunction, left atrial dysfunction, and a higher risk of incident HF and AF. AF is a mediator of MMP-2-associated HF with preserved ejection fraction risk.

Pregnancy-induced physiological hypertrophic preconditioning attenuates pathological myocardial hypertrophy by activation of FoxO3a.

Previous studies show a woman's pregnancy is correlated with post-reproductive longevity, and nulliparity is associated with higher risk of incident heart failure, suggesting pregnancy likely exerts a cardioprotection. We previously reported a cardioprotective phenomenon termed myocardial hypertrophic preconditioning, but it is unknown whether pregnancy-induced physiological hypertrophic preconditioning (PHP) can also protect the heart against subsequent pathological hypertrophic stress. We aimed to clarify the phenomenon of PHP and its mechanisms. The pluripara mice whose pregnancy-induced physiological hypertrophy regressed and the nulliparous mice underwent angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Echocardiography, invasive left ventricular hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. Silencing or overexpression of Foxo3 by adeno-associated virus was used to investigate the role of FoxO3a involved in the antihypertrophic effect. Compared with nulliparous mice, pathological cardiac hypertrophy induced by Ang II infusion, or TAC was significantly attenuated and heart failure induced by TAC was markedly improved in mice with PHP. Activation of FoxO3a was significantly enhanced in the hearts of postpartum mice. FoxO3a inhibited myocardial hypertrophy by suppressing signaling pathway of phosphorylated glycogen synthase kinase-3β (p-GSK3β)/β-catenin/Cyclin D1. Silencing or overexpression of Foxo3 attenuated or enhanced the anti-hypertrophic effect of PHP in mice with pathological stimulation. Our findings demonstrate that PHP confers resistance to subsequent hypertrophic stress and slows progression to heart failure through activation of FoxO3a/GSK3β pathway.

Evaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events

Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events. We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance. The mean (±SD) eGFR was 70 (±16) mL/min/1.73m2; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke. Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD. This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr.Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr.Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).

Predicting Risk of Incident Heart Failure Among Type 2 Diabetic Patients Using the WATCH-DM Risk Score

Predicting Risk of Incident Heart Failure Among Type 2 Diabetic Patients Using the WATCH-DM Risk Score

Incident Heart Failure Risk Reclassification With Race-Independent Estimated Glomerular Filtration Rate: A National Heart, Lung, and Blood Institute Pooled Cohorts Analysis

This study compared the predictive value of the race-independent creatinine- and cystatin C-based estimated glomerular filtration rate (eGFRcr-cys) and the race-dependent creatinine-based eGFR (eGFRcr) for incident heart failure (HF). This study combined the participant-level data from ARIC (Atherosclerosis Risk in Communities) (visit 4) and MESA (Multi-Ethnic Study of Atherosclerosis) (visit 1) to calculate eGFRcr-cys and eGFRcr. The primary outcome of the study was adjudicated incident HF over a follow-up period of 10 years. Multivariable Cox models were used to assess the risk of incident HF with the quartiles of eGFRcr-cys and eGFRcr. Among 15,615 individuals (median age: 62 [57-68] years; 55.0% females; 23.9% Black), the median eGFRcr-cys and eGFRcr were 91.4 (79.4, 102.0) mL/min/1.73m2 and 84.7 (72.0, 94.7) mL/min/1.73m2, respectively. Compared with the fourth quartile of eGFRcr-cys, the hazard ratio for incident HF was 1.02 (95% CI:0.80-1.30) in the third quartile, 1.02 (95% CI:0.80-1.30) in the second quartile, and 1.47 (95% CI:1.16-1.86) in the first quartile. Compared with the 4th quartile of the eGFRcr, the risk of incident HF was similar in the 3rd (HRadj:0.90 [95% CI:0.73-1.12]), 2nd (HRadj: 0.96 [95% CI:0.77-1.20]), and 1st (HRadj:1.15 [95% CI:0.93-1.44]) quartiles. C-statistics were similar for the multivariable-adjusted Cox models for incident HF using eGFRcr (0.80 [0.79-0.81]) and eGFRcr-cys (0.80 [0.79-0.82]). The eGFRcr and eGFRcr-cys had comparable predictive values for incident HF.