Associations of neighborhood sociodemographic environment with mortality and circulating metabolites among low-income black and white adults living in the southeastern United States.

BACKGROUND: Residing in a disadvantaged neighborhood has been linked to increased mortality. However, the impact of residential segregation and social vulnerability on cause-specific mortality is understudied. Additionally, the circulating metabolic correlates of neighborhood sociodemographic environment remain unexplored. Therefore, we examined multiple neighborhood sociodemographic metrics, i.e., neighborhood deprivation index (NDI), residential segregation index (RSI), and social vulnerability index (SVI), with all-cause and cardiovascular disease (CVD) and cancer-specific mortality and circulating metabolites in the Southern Community Cohort Study (SCCS). METHODS: The SCCS is a prospective cohort of primarily low-income adults aged 40-79, enrolled from the southeastern United States during 2002-2009. This analysis included self-reported Black/African American or non-Hispanic White participants and excluded those who died or were lost to follow-up ≤ 1 year. Untargeted metabolite profiling was performed using baseline plasma samples in a subset of SCCS participants. RESULTS: Among 79,631 participants, 23,356 deaths (7214 from CVD and 5394 from cancer) were documented over a median 15-year follow-up. Higher NDI, RSI, and SVI were associated with increased all-cause, CVD, and cancer mortality, independent of standard clinical and sociodemographic risk factors and consistent between racial groups (standardized HRs among all participants were 1.07 to 1.20 in age/sex/race-adjusted model and 1.04 to 1.08 after comprehensive adjustment; all P < 0.05/3 except for cancer mortality after comprehensive adjustment). The standard risk factors explained < 40% of the variations in NDI/RSI/SVI and mediated < 70% of their associations with mortality. Among 1110 circulating metabolites measured in 1688 participants, 134 and 27 metabolites were associated with NDI and RSI (all FDR < 0.05) and mediated 61.7% and 21.2% of the NDI/RSI-mortality association, respectively. Adding those metabolites to standard risk factors increased the mediation proportion from 38.4 to 87.9% and 25.8 to 42.6% for the NDI/RSI-mortality association, respectively. CONCLUSIONS: Among low-income Black/African American adults and non-Hispanic White adults living in the southeastern United States, a disadvantaged neighborhood sociodemographic environment was associated with increased all-cause and CVD and cancer-specific mortality beyond standard risk factors. Circulating metabolites may unveil biological pathways underlying the health effect of neighborhood sociodemographic environment. More public health efforts should be devoted to reducing neighborhood environment-related health disparities, especially for low-income individuals.

Combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction.

Over 2.5 million patients in the USA suffer from heart failure with preserved ejection fraction (HFpEF), and pulmonary hypertension (PH) is present in the majority of these patients. PH represents an adverse prognostic factor in HFpEF and has been identified as a potential therapeutic target to improve symptoms and outcomes. The recognition and investigation of a subset of patients with superimposed pulmonary vascular disease (on top of pulmonary venous hypertension) has led to further subclassification of PH due to left heart disease (PH-LHD) into two categories: isolated post-capillary PH and combined post- and pre-capillary PH (CpcPH). In this review, we (1) describe the evolution of the diagnostic criteria of PH-LHD; (2) identify the diagnostic modalities that can be utilized for the identification of patients with CpcPH-HFpEF; (3) review the literature on the prevalence, clinical characteristics, and prognostic factors of CpcPH-HFpEF; (4) discuss recent and ongoing clinical trials investigating the effectiveness of selective pulmonary vasodilators in PH-LHD; and (5) propose future areas for further investigation of the etiology and pathophysiological mechanisms contributing to the development of CpcPH and highlight important considerations in the design of future trials to promote better characterization of this clinical entity. CpcPH-HFpEF is a distinct subset within HFpEF and one that may respond to targeted therapeutics.

Left Ventricular Wall Stress and Incident Heart Failure in Elderly Community-Dwelling Individuals.

Background: Greater left ventricular (LV) wall stress is associated with adverse outcomes among patients with prevalent heart failure (HF). Less is known about the association between LV wall stress and incident HF. Objectives: The purpose of the study was to identify clinical factors associated with wall stress and test the association between wall stress and incident HF. Methods: We studied 4,601 ARIC (Atherosclerosis Risk In Communities) study participants without prevalent HF who underwent echocardiography between 2011 and 2013. LV end systolic and diastolic wall stress (LVESWS, LVEDWS) were calculated from chamber and wall thickness, systemic blood pressure, and transmitral Doppler E/e' as a surrogate for LV end diastolic pressure. Incident HF was ascertained by International Classification of Diseases (ICD)-9/10 claims for hospitalized HF through December 31, 2016. We used Cox regression to test the association between wall stress and incident HF, adjusted for demographics, traditional cardiovascular risk factors, prevalent coronary artery disease and atrial fibrillation, creatinine, N-terminal pro-B-type natriuretic peptide, troponin, triglycerides, C-reactive protein, LV ejection fraction, and LV mass. Results: The cohort had a median age of 75 years and 58% women, with 18% identifying as Black. Median LVESWS and LVEDWS were 48.8 (25th-75th percentile: 39.3-60.1) and 18.9 (25th-75th percentile: 15.8-22.5) kdynes/cm2, respectively. LVESWS and LVEDWS were modestly related (rho = 0.30, P < 0.001). Over 4.6 years of median follow-up (156 HF events), each 1 kdyne/cm2 greater LVEDWS was significantly associated with higher risk of incident HF (HR: 1.03; 95% CI: 1.01-1.06), while LVESWS was not (HR: 1.00; 95% CI: 0.99-1.01). Conclusions: Among community-dwelling elderly individuals, greater LVEDWS is associated with a higher risk for incident HF.

Differences in Cardiac Mechanics and Exercise Physiology Among Heart Failure With Preserved Ejection Fraction Phenomapping Subgroups.

Unsupervised machine learning (phenomapping) has been used successfully to identify novel subgroups (phenogroups) of heart failure with preserved ejection fraction (HFpEF). However, further investigation of pathophysiological differences between HFpEF phenogroups is necessary to help determine potential treatment options. We performed speckle-tracking echocardiography and cardiopulmonary exercise testing (CPET) in 301 and 150 patients with HFpEF, respectively, as part of a prospective phenomapping study (median age 65 [25th to 75th percentile 56 to 73] years, 39% Black individuals, 65% female). Linear regression was used to compare strain and CPET parameters by phenogroup. All indicies of cardiac mechanics except for left ventricular global circumferential strain worsened in a stepwise fashion from phenogroups 1 to 3 after adjustment for demographic and clinical factors. After further adjustment for conventional echocardiographic parameters, phenogroup 3 had the worst left ventricular global longitudinal, right ventricular free wall, and left atrial booster and reservoir strain. On CPET, phenogroup 2 had the lowest exercise time and absolute peak oxygen consumption (VO2), driven primarily by obesity, whereas phenogroup 3 achieved the lowest workload, relative peak oxygen consumption (VO2), and heart rate reserve on multivariable-adjusted analyses. In conclusion, HFpEF phenogroups identified by unsupervised machine learning analysis differ in the indicies of cardiac mechanics and exercise physiology.

Racial and Ethnic Disparities in Ambulatory Heart Failure Ventricular Assist Device Implantation and Survival.

BACKGROUND: Durable left ventricular assist devices (VADs) improve survival in eligible patients, but allocation has been associated with patient race in addition to presumed heart failure (HF) severity. OBJECTIVES: This study sought to determine racial and ethnic differences in VAD implantation rates and post-VAD survival among patients with ambulatory HF. METHODS: Using the INTERMACS (Interagency Registry of Mechanically Assisted Circulatory Support) database (2012-2017), this study examined census-adjusted VAD implantation rates by race, ethnicity, and sex in patients with ambulatory HF (INTERMACS profile 4-7) using negative binomial models with quadratic effect of time. Survival was evaluated using Kaplan-Meier estimates and Cox models adjusted for clinically relevant variables and an interaction of time with race/ethnicity. RESULTS: VADs were implanted in 2,256 adult patients with ambulatory HF (78.3% White, 16.4% Black, and 5.3% Hispanic). The median age at implantation was lowest in Black patients. Implantation rates peaked between 2013 and 2015 before declining in all demographic groups. From 2012 to 2017, implantation rates overlapped for Black and White patients but were lower for Hispanic patients. Post-VAD survival was significantly different among the 3 groups (log rank P = 0.0067), with higher estimated survival among Black vs White patients (12-month survival: Black patients: 90% [95% CI: 86%-93%]; White patients: 82% [95% CI: 80%-84%]). Low sample size for Hispanic patients resulted in imprecise survival estimates (12-month survival: 85% [95% CI: 76%-90%]). CONCLUSIONS: Black and White patients with ambulatory HF had similar VAD implantation rates but rates were lower for Hispanic patients. Survival differed among the 3 groups, with the highest estimated survival at 12 months in Black patients. Given higher HF burden in minoritized populations, further investigation is needed to understand differences in VAD implantation rates in Black and Hispanic patients.

Immune profiling of murine cardiac leukocytes identifies triggering receptor expressed on myeloid cells 2 as a novel mediator of hypertensive heart failure.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodelling. METHODS AND RESULTS: Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. A modified single-cell sequencing approach, cellular indexing of transcriptomes and epitopes by sequencing, of cardiac immune cells reveals an altered abundance and transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including up-regulation of Trem2, which has been recently implicated in obesity and atherosclerosis. The role of Trem2 in hypertensive heart failure, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy, diastolic dysfunction, renal injury, and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls. Moreover, Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programmes and increased expression of pro-inflammatory cytokines. Furthermore, we found that plasma levels of soluble TREM2 are elevated in DOCA-salt treated mice and humans with heart failure. CONCLUSIONS: Together, our data provide an atlas of immunological alterations that can lead to improved diagnostic and therapeutic strategies for HFpEF. We provide our dataset in an easy to explore and freely accessible web application making it a useful resource for the community. Finally, our results suggest a novel cardioprotective role for Trem2 in hypertensive heart failure.

Depressive Symptoms and Incident Heart Failure Risk in the Southern Community Cohort Study.

OBJECTIVES: This study aims to examine whether greater frequency of depressive symptoms associates with increased risk of incident heart failure (HF). BACKGROUND: Depressive symptoms associate with adverse prognosis in patients with prevalent HF. Their association with incident HF is less studied, particularly in low-income and minority individuals. METHODS: We studied 23,937 Black or White Southern Community Cohort Study participants (median age: 53 years, 70% Black, 64% women) enrolled between 2002 and 2009, without prevalent HF, receiving Centers for Medicare and Medicaid Services coverage. Cox models adjusted for traditional HF risk factors, socioeconomic and behavioral factors, social support, and antidepressant medications were used to quantify the association between depressive symptoms assessed at enrollment via the Center for Epidemiologic Studies Depression Scale (CESD-10) and incident HF ascertained from Centers for Medicare and Medicaid Services International Classification of Diseases-9th Revision (ICD-9) (code: 428.x) and ICD-10 (codes: I50, I110) codes through December 31, 2016. RESULTS: The median CESD-10 score was 9 (IQR: 5 to 13). Over a median 11-year follow-up, 6,081 (25%) participants developed HF. The strongest correlates of CESD-10 score were antidepressant medication use, age, and socioeconomic factors, rather than traditional HF risk factors. Greater frequency of depressive symptoms associated with increased incident HF risk (per 8-U higher CESD-10 HR: 1.04; 95% CI: 1.00 to 1.09; P = 0.038) without variation by race or sex. The association between depressive symptoms and incident HF varied by antidepressant use (interaction-P = 0.03) with increased risk among individuals not taking antidepressants. CONCLUSIONS: In this high-risk, low-income, cohort of predominantly Black participants, greater frequency of depressive symptoms significantly associates with higher risk of incident HF.

Reduced Circumferential Strain in Athletes with Prior COVID-19.

Purpose: To characterize global and segmental circumferential systolic strain (CS) measured by cardiac MRI in athletes after SARS-CoV-2 infection. Materials and Methods: This retrospective observational cohort study included 188 soldiers and collegiate athletes referred for cardiac MRI after SARS-CoV-2 infection (C19+) between July 2020 and February 2021 and a control group of 72 soldiers, collegiate, and high school athletes who underwent cardiac MRI from May 2019 to February 2020, prior to the first SARS-CoV-2 case detected in our region (C19-). Global and segmental CS were measured by feature tracking, then compared between each group using unadjusted and multivariable- adjusted models. Acute myocarditis was diagnosed according to the modified Lake Louise criteria and the location of pathologic late gadolinium enhancement (LGE) was ascertained. Results: Among the 188 C19+ athletes (median age, 25 years [IQR, 23-30]; 131 men), the majority had mild illness. Global CS significantly differed between C19+ and C19- groups, with a median of -24.0 (IQR -25.8, -21.4) versus. -25.0 (-28.0, -22.4), respectively (p = .009). This difference in CS persisted following adjustment for age, sex, body mass index, heart rate, and systolic blood pressure ß coefficient 1.29 [95% CI: 0.20, 2.38], p = .02). In segmental analysis, the basal- and mid- inferoseptal, septal and inferolateral segments were significantly different (p < .05), which had a higher frequency of post-COVID late gadolinium enhancement. The global and segmental differences were similar after exclusion of athletes with myocarditis. Conclusion: Among athletes, SARS-CoV-2 infection was associated with a small but statistically significant reduced CS.

Management of neurogenic orthostatic hypotension in the heart failure patient.

Neurogenic orthostatic hypotension (nOH) is a common comorbidity in patients with neurodegenerative diseases. It is associated with an increased risk of falls, incident cardiovascular disease, and all-cause mortality. There are over 5 million individuals in the U.S. with heart failure (HF) with an associated 50% mortality rate at 5 years. The prevalence of nOH and HF increase with age and, as the population continues to age, will be increasingly common comorbid conditions. Thus, the effective management of these conditions has important implications for public health. The management of orthostatic hypotension in the context of congestive heart failure is challenging due to the fact that the fundamental principles of management of these disease states are in opposition to each other. In this review, we will discuss the principles of management of nOH and HF and outline strategies for the effective treatment of these comorbid conditions.