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Nonplatelet thromboxane generation, stimulated largely by oxidative stress, is a novel mortality risk factor in individuals with coronary artery disease. Though inversely associated with left ventricular ejection fraction (LVEF), a potential role in the pathobiology of heart failure (HF) remains poorly defined. Nonplatelet thromboxane generation and oxidative stress were assessed by measuring urine thromboxane-B(2) metabolites (TXB(2)-M) and 8-isoPGF(2α) by ELISA in 105 subjects taking aspirin and undergoing right heart catheterization for evaluation of HF, valve disease, or after transplantation. Multivariable logistic regression and survival analyses were used to define associations of TXB(2)-M to invasive measures of cardiovascular performance and 4-year clinical outcomes. TXB(2)-M was elevated (>1,500 pg/mg creatinine) in 46% of subjects and correlated with HF severity by New York Heart Association (NYHA) functional class and brain natriuretic peptide level, modestly with LVEF, but not with HF etiology. There was no association of oxidative stress to HF type or etiology but a trend with NYHA functional class. Multiple invasive hemodynamic parameters independently associated with TXB(2)-M after adjustment for oxidative stress, age, sex, and race with pulmonary effective arterial elastance (E(a pulmonary)), reflective of right ventricular afterload, being the most robust on hierarchical analysis. Similar to E(a pulmonary), elevated urinary TXB(2)-M is associated with increased risk of death (adjusted HR = 2.15, P = 0.037) and a combination of death, transplant, or mechanical support initiation (adjusted HR = 2.0, P = 0.042). Nonplatelet TXA(2) thromboxane generation is independently associated with HF severity reflected by invasive measures of cardiovascular performance, particularly right ventricular afterload, and independently predicted long-term mortality risk. NEW & NOTEWORTHY Nonplatelet thromboxane generation in heart failure is independently associated with risk of death, transplant, or need for mechanical support. Measurement of urine thromboxane metabolites using a clinically available assay may be a useful surrogate for invasive measurement of cardiovascular hemodynamics and performance that could provide prognostic information and facilitate tailoring of therapy in patients with heart failure. Inhibiting thromboxane generation or its biological effects is a potential strategy for improving cardiovascular performance and outcomes in heart failure.

Background Recurrent congestion in cardiac amyloidosis (CA) remains a management challenge, often requiring high dose diuretics and frequent hospitalizations. Innovative outpatient strategies are needed to effectively manage heart failure (HF) in patients with CA. Ambulatory diuresis has not been well studied in restrictive cardiomyopathy. Therefore, we aimed to examine the outcomes of an ambulatory diuresis clinic in the management of congestion related to CA. Methods and Results We retrospectively studied patients with CA seen in an outpatient HF disease management clinic for (1) safety outcomes of ambulatory intravenous (IV) diuresis and (2) health care utilization. Forty-four patients with CA were seen in the clinic a total of 203 times over 6 months. Oral diuretics were titrated at 96 (47%) visits. IV diuretics were administered at 56 (28%) visits to 17 patients. There were no episodes of severe acute kidney injury or symptomatic hypotension. There was a significant decrease in emergency department and inpatient visits and associated charges after index visit to the clinic. The proportion of days hospitalized per 1000 patient days of follow-up decreased as early as 30 days (147.3 vs 18.1/1000 patient days of follow-up, P Conclusions We demonstrate the feasibility of ambulatory IV diuresis in patients with CA. Our findings also suggest that use of a HF disease management clinic may reduce acute care utilization in patients with CA. Leveraging multidisciplinary outpatient HF clinics may be an effective alternative to hospitalization in patients with HF due to CA, a population who otherwise carries a poor prognosis and contributes to high health care burden.

Background Cardiovascular disease (CVD) hospitalizations declined worldwide during the COVID-19 pandemic. It is unclear how shelter-in-place orders affected acute CVD hospitalizations, illness severity, and outcomes. Hypothesis COVID-19 pandemic was associated with reduced acute CVD hospitalizations (heart failure [HF], acute coronary syndrome [ACS], and stroke [CVA]), and worse HF illness severity. Methods We compared acute CVD hospitalizations at Duke University Health System before and after North Carolina's shelter-in-place order (January 1-March 29 vs. March 30-August 31), and used parallel comparison cohorts from 2019. We explored illness severity among admitted HF patients using ADHERE ("high risk": >2 points) and GWTG-HF (">10%": >57 points) in-hospital mortality risk scores, as well as echocardiography-derived parameters. Results Comparing hospitalizations during January 1-March 29 (N = 1618) vs. March 30-August 31 (N = 2501) in 2020, mean daily CVD hospitalizations decreased (18.2 vs. 16.1 per day, p = .0036), with decreased length of stay (8.4 vs. 7.5 days, p = .0081) and no change in in-hospital mortality (4.7 vs. 5.3%, p = .41). HF hospitalizations decreased (9.0 vs. 7.7 per day, p = .0019), with higher ADHERE ("high risk": 2.5 vs. 4.5%; p = .030), but unchanged GWTG-HF (">10%": 5.3 vs. 4.6%; p = .45), risk groups. Mean LVEF was lower (39.0 vs. 37.2%, p = .034), with higher mean LV mass (262.4 vs. 276.6 g, p = .014). Conclusions CVD hospitalizations, HF illness severity, and echocardiography measures did not change between admission periods in 2019. Evaluating short-term data, the COVID-19 shelter-in-place order was associated with reductions in acute CVD hospitalizations, particularly HF, with no significant increase in in-hospital mortality and only minor differences in HF illness severity.

More than 80% of adult patients diagnosed with cancer survive long term. Long-term complications of cancer and its therapies may increase the risk of cardiovascular disease (CVD), but prospective studies using adjudicated cancer and CVD events are lacking.The aim of this study was to assess the risk of CVD in cancer survivors in a prospective community-based study.We included 12,414 ARIC (Atherosclerosis Risk In Communities) study participants. Cancer diagnoses were ascertained via linkage with state registries supplemented with medical records. Incident CVD outcomes were coronary heart disease (CHD), heart failure (HF), stroke, and a composite of these. We used multivariable Poisson and Cox regressions to estimate the association of cancer with incident CVD.Mean age was 54 years, 55% were female, and 25% were Black. A total of 3,250 participants (25%) had incident cancer over a median 13.6 years of follow-up. Age-adjusted incidence rates of CVD (per 1,000 person-years) were 23.1 (95% CI: 24.7-29.1) for cancer survivors and 12.0 (95% CI: 11.5-12.4) for subjects without cancer. After adjustment for cardiovascular risk factors, cancer survivors had significantly higher risks of CVD (HR: 1.37; 95% CI: 1.26-1.50), HF (HR: 1.52; 95% CI: 1.38-1.68), and stroke (HR: 1.22; 95% CI: 1.03-1.44), but not CHD (HR: 1.11; 95% CI: 0.97-1.28). Breast, lung, colorectal, and hematologic/lymphatic cancers, but not prostate cancer, were significantly associated with CVD risk.Compared with persons without cancer, adult cancer survivors have significantly higher risk of CVD, especially HF, independent of traditional cardiovascular risk factors. There is an unmet need to define strategies for CVD prevention in this high-risk population.

In 2009, the International Society for Heart and Lung Transplantation recognized the importance and challenges surrounding generic drug immunosuppression. As experience with generics has expanded and comfort has increased, substantial issues have arisen since that time with other aspects of immunomodulation that have not been addressed, such as access to medicines, alternative immunosuppression formulations, additional generics, implications on therapeutic drug monitoring, and implications for special populations such as pediatrics and older adults. The aim of this consensus document is to address critically each of these concerns, expand on the challenges and barriers, and provide therapeutic considerations for practitioners who manage patients who need to undergo or have undergone cardiothoracic transplantation.

Objectives This study prospectively evaluated endomyocardial biopsies in patients with heart failure with preserved ejection fraction (HFpEF) to identify histopathologic phenotypes and their association with clinical characteristics. Background Myocardial tissue analysis from a prospectively defined HFpEF cohort reflecting contemporary comorbidities is lacking. Methods Patients with HFpEF (EF ≥50%) referred to the Johns Hopkins HFpEF Clinic between August 2014 and September 2018 were enrolled for right heart catheterization and endomyocardial biopsy. Clinical features, echocardiography, hemodynamics, and tissue histology were determined and compared with controls (unused donor hearts) and HF with reduced EF (HFrEF). Results Of the 108 patients enrolled, median age was 66 years (25th to 75th percentile: 57 to 74 years), 61% were women, 57% were African American, 62% had a previous HF hospitalization, median systolic blood pressure was 141 mm Hg (25th to 75th percentile: 125 to 162 mm Hg), body mass index (BMI) was 37 kg/m2 (25th to 75th percentile: 32 to 45 kg/m2), and 97% were on a loop diuretic. Myocardial fibrosis and myocyte hypertrophy were often present (93% and 88%, respectively); however, mild in 71% with fibrosis and in 52% with hypertrophy. Monocyte infiltration (CD68+ cells/mm2) was greater in patients with HFpEF versus controls (60.4 cells/mm2 [25th to 75th percentile: 36.8 to 97.8] vs. 32.1 cells/mm2 [25th to 75th percentile: 22.3 to 59.2]; p = 0.02) and correlated with age and renal disease. Cardiac amyloidosis (CA) was diagnosed in 15 (14%) patients (HFpEF-CA: 7 patients with wild-type transthyretin amyloidosis [ATTR], 4 patients with hereditary ATTR, 3 patients with light-chain amyloidosis, and 1 patient with AA (secondary) amyloidosis), of which 7 cases were unsuspected. Patients with HFpEF-CA were older, with lower BMI, higher left ventricular mass index, and higher N-terminal pro−B-type natriuretic peptide and troponin I levels. Conclusions In this large, prospective myocardial tissue analysis of HFpEF, myocardial fibrosis and hypertrophy were common, CD68+ inflammation was increased, and CA prevalence was 14%. Tissue analysis in HFpEF might improve precision therapies by identifying relevant myocardial mechanisms.

Background Gastrointestinal bleeding (GIB) is common in left ventricular assist device (LVAD) patients. Serotonin release from platelets promotes platelet aggregation, and selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) therapy inhibits the transporter responsible for re-uptake. Methods We reviewed the records of LVAD (HeartMateII™, Abbott Medical, Lake Bluff, IL, USA and Heartware™, Medtronic, Minneapolis, MN, USA) patients at the Medical University of South Carolina and Johns Hopkins Hospital between January 2009 and January 2016. After exclusions, 248 patients were included for analysis. After univariate analysis, logistic regression multivariate analysis was performed to adjust for any demographic, cardiovascular, and laboratory data variables found to be associated with GI bleeding post-LVAD. Results Gastrointestinal bleeding occurred in 85 patients (35%) with 55% of GIBs due to arteriovenous malformations (AVMs). Of the total cohort, 105 patients received an SSRI or SNRI during LVAD support. Forty-four (44) SSRI/SNRI (41.9%) and 41 non-SSRI/SNRI (28.7%) patients had a GIB (RR 1.46, p = 0.03). Twenty-six (26) (24.8%) of the SSRI/SNRI patients had a GIB due to AVMs versus 21 (14.7%) of the non-SSRI/SNRI patients (RR 1.69, p = 0.05). In fully-adjusted multivariate regression analysis, SSRI/SNRI therapy was independently associated with GIB (OR 1.78, p = 0.045). For GIB, the number needed to harm (NNH) was 7.6. Conclusion In conclusion, SSRI/SNRI therapy is independently associated with an increased risk of GIB in LVAD patients.

Background: Patients with heart failure (HF) have multiple coexisting comorbidities. The temporal trends in the burden of comorbidities and associated risk of mortality among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are not well established. Methods: HF-related hospitalizations were sampled by stratified design from 4 US areas in 2005 to 2014 by the community surveillance component of the ARIC study (Atherosclerosis Risk in Communities). Acute decompensated HF was classified by standardized physician review and a previously validated algorithm. An ejection fraction Results: A total of 5460 hospitalizations (24 937 weighted hospitalizations) classified as acute decompensated HF had available ejection fraction data (53% female, 68% white, 53% HFrEF, 47% HFpEF). The average number of comorbidities was higher for patients with HFpEF versus HFrEF, both for women (5.53 versus 4.94; P P P -trendP for interaction by HF type=0.02). The associated mortality risk per 1 higher comorbidity also increased significantly over time for patients with HFpEF and HFrEF, as well ( P for interaction with time=0.002 and 0.02, respectively) Conclusions: The burden of comorbidities among hospitalized patients with acute decompensated HFpEF and HFrEF has increased over time, as has its associated mortality risk. Higher burden of comorbidities is associated with higher risk of mortality, with a stronger association noted among patients with HFpEF versus HFrEF.

Background: Many patients undergoing durable left ventricular assist device (LVAD) implantation suffer from chronic kidney disease (CKD). Therefore, we investigated the effect of LVAD support on CKD. Methods: A retrospective multicenter cohort study, including all patients undergoing LVAD (HeartMate II (n = 330), HeartMate 3 (n = 22) and HeartWare (n = 48) implantation. In total, 227 (56.8%) patients were implanted as bridge-to-transplantation; 154 (38.5%) as destination therapy; and 19 (4.7%) as bridge-to-decision. Serum creatinine measurements were collected over a 2-year follow-up period. Patients were stratified based on CKD stage. Results: Overall, 400 patients (mean age 53 ± 14 years, 75% male) were included: 186 (46.5%) patients had CKD stage 1 or 2; 93 (23.3%) had CKD stage 3a; 82 (20.5%) had CKD stage 3b; and 39 (9.8%) had CKD stage 4 or 5 prior to LVAD implantation. During a median follow-up of 179 days (IQR 28–627), 32,629 creatinine measurements were available. Improvement of kidney function was noticed in every preoperative CKD-stage group. Following this improvement, estimated glomerular filtration rates regressed to baseline values for all CKD stages. Patients showing early renal function improvement were younger and in worse preoperative condition. Moreover, survival rates were higher in patients showing early improvement (69% vs 56%, log-rank P = 0. 013). Conclusions: Renal function following LVAD implantation is characterized by improvement, steady state and subsequent deterioration. Patients who showed early renal function improvement were in worse preoperative condition, however, and had higher survival rates at 2 years of follow-up.

The pulse amplitude ratio (PAR), the ratio of pulse pressure at the end of the Valsalva maneuver to before the onset, correlates with cardiac filling pressure. We have developed a handheld device that uses finger photoplethysmography to measure PAR and estimate left ventricular end diastolic pressure (LVEDP). Patients hospitalized with heart failure (HF) performed three 10-second trials of a standardized Valsalva maneuver (at 20 mm Hg measured via pressure transducer), while photoplethysmography waveforms were recorded, at admission and discharge. Combined primary outcome was 30-day HF hospitalization, intravenous diuresis, or death. Fifty-two subjects had discharge PAR testing; 12 met the primary outcome. Median PAR on admission was 0.55 (interquartile range: 0.40 to 0.70, n = 48) and on discharge was 0.50 (interquartile range: 0.36 to 0.69). Mean PAR-estimated LVEDP was significantly higher in subjects that had an event (20.2 vs 16.9 mm Hg, p = 0.043). Subjects with PAR-estimated LVEDP >19.5 mm Hg had an event rate hazard ratio of 4.57 (95% confidence interval 1.37, 15.19, p = 0.013) compared with patients with LVEDP 19.5 mm Hg or below, with significantly lower 30-day event-free survival (log-rank p = 0.006). In conclusion, noninvasively estimated LVEDP using the pulse amplitude response to a Valsalva maneuver in patients hospitalized for HF changes with diuresis and identifies patients at high risk for 30-day HF events. Detection of elevated filling pressures before hospital discharge may be useful in guiding HF management to reduce HF events.

Background At the recent 6th World Symposium on Pulmonary Hypertension (PH), the definition of PH was redefined to include lower pulmonary artery pressures in the setting of elevated pulmonary vascular resistance (PVR). However, the relevance of this change to subjects with PH due to left-heart disease as well as the preoperative assessment of heart transplant (HT) recipients is unknown. Methods The United Network for Organ Sharing database was queried to identify adult recipients who underwent primary HT from 1996 to 2015. Recipients were subdivided into those with mean pulmonary artery pressure (mPAP) Results Over the study period, 32,465 patients underwent HT, including 12,257 (38%) with mPAP Conclusions Elevated PVR remains associated with a significant increase in the hazard for 30-day mortality after cardiac transplantation, even in the setting of lower pulmonary artery pressures. These data support the validity of the new definition of pulmonary hypertension.

Introduction: Heart failure (HF) exacerbations are often precipitated by dietary noncompliance, which is common around holidays. We examined whether HF hospitalizations would increase after major national holidays. Methods: The ARIC Study performed surveillance of HF admissions among patients age ≥55 years in 4 US communities from 2005-2014. HF admissions were identified by ICD-9 codes and validated by physician review. For each holiday (H), 4 days before the holiday (H-4 to H-1), and 4 days after the holiday (H+1 to H+4), we compared average daily HF admission rates, hospital length of stay (LOS), 28-day mortality, and 1-year mortality to the remaining days in each holiday’s month using Poisson regression using a complex sampling design. Results: ARIC identified 92,354 HF admissions (weighted). Patients admitted in holiday months were 46% male and 71% white, with average age 75 years. Compared to the holiday months, patients admitted on H were older (78 years, p Conclusions: HF admission rates, hospital LOS, and mortality were similar in the 4 days following a holiday compared to the remainder of each holiday’s month. However, the day before and/or day of a holiday were associated with lower HF admission rates, shorter hospital LOS, and lower 28-day mortality.

Background: The role of checkpoint axes in transplantation has been partially addressed in animal models but not in humans. Occurrence of fulminant myocarditis with allorejection-like immunologic features in patients under anti-PD1 (programmed death cell protein 1) treatment suggests a key role of the PD1/PD-L1 (programmed death ligand 1) axis in cardiac immune homeostasis. Methods: We cross-sectionally studied 23 heart transplant patients undergoing surveillance endomyocardial biopsy. Endomyocardial tissue and peripheral blood mononuclear cells were analyzed by flow cytometry. Multivariate logistic regression analyses including demographic, clinical, and hemodynamic parameters were performed. Murine models were used to evaluate the impact of PD-L1 endothelial graft expression in allorejection. Results: We found that myeloid cells dominate the composition of the graft leukocyte compartment in most patients, with variable T-cell frequencies. The CD (cluster of differentiation) 4:CD8 T-cell ratios were between 0 and 1.5. The proportion of PD-L1 expressing cells in graft endothelial cells, fibroblasts, and myeloid leukocytes ranged from negligible up to 60%. We found a significant inverse logarithmic correlation between the proportion of PD-L1 + HLA (human leukocyte antigen)-DR + endothelial cells and CD8 + T cells (slope, −18.3 [95% CI, −35.3 to −1.3]; P =0.030). PD-L1 expression and leukocyte patterns were independent of demographic, clinical, and hemodynamic parameters. We confirmed the importance of endothelial PD-L1 expression in a murine allogeneic heart transplantation model, in which Tie2 Cre pdl1 fl/fl grafts lacking PD-L1 in endothelial cells were rejected significantly faster than controls. Conclusions: Loss of graft endothelial PD-L1 expression may play a role in regulating CD8 + T-cell infiltration in human heart transplantation. Murine model results suggest that loss of graft endothelial PD-L1 may facilitate alloresponses and rejection.

BACKGROUND: The role of checkpoint axes in transplantation has been partially addressed in animal models, but not in humans. Occurrence of fulminant myocarditis with allo-rejection-like immunologic features in patients under anti-PD-1 treatment suggests a key role of the PD1/PD-L1 axis in cardiac immune homeostasis. METHODS: We cross-sectionally studied 23 heart transplant patients undergoing surveillance endomyocardial biopsy. Endomyocardial tissue and peripheral blood mononuclear cells were analyzed by flow cytometry. Multivariate logistic regression analyses including demographic, clinical and hemodynamic parameters were performed. Murine models were used to evaluate the impact of PD-L1 endothelial graft expression in allo-rejection. RESULTS: We found that myeloid cells dominate the composition of the graft leukocyte compartment in most patients, with variable T cell frequencies. The CD4:CD8 T cell ratios were between 0 and 1.5. The proportion of PD-L1 expressing cells in graft endothelial cells, fibroblasts and myeloid leukocytes ranged from negligible up to 60%. We found a significant inverse logarithmic correlation between the proportion of PD-L1(+)HLA-DR(+) endothelial cells and CD8(+) T cells (slope −18.3, 95% CI −35.3/−1.3, P=0.030). PD-L1 expression and leukocyte patterns were independent of demographic, clinical and hemodynamic parameters. We confirmed the importance of endothelial PD-L1 expression in a murine allogeneic heart transplantation model, in which Tie2(Cre)pdl1(fl/fl) grafts lacking PD-L1 in endothelial cells were rejected significantly faster than controls. CONCLUSIONS: Loss of graft endothelial PD-L1 expression may play a role in regulating CD8(+) T cell infiltration in human heart transplantation. Murine model results suggest that loss of graft endothelial PD-L1 may facilitate allo-responses and rejection.

Among the estimated 6.2 million Americans living with heart failure (HF), ≈5%/y may progress to advanced, or stage D, disease. Advanced HF has a high morbidity and mortality, such that early recognition of this condition is important to optimize care. Delayed referral or lack of referral in patients who are likely to derive benefit from an advanced HF evaluation can have important adverse consequences for patients and their families. A 2-step process can be used by practitioners when considering referral of a patient with advanced HF for consideration of advanced therapies, focused on recognizing the clinical clues associated with stage D HF and assessing potential benefits of referral to an advanced HF center. Although patients are often referred to an advanced HF center to undergo evaluation for advanced therapies such as heart transplantation or implantation of a left ventricular assist device, there are other reasons to refer, including access to the infrastructure and multidisciplinary team of the advanced HF center that offers a broad range of expertise. The intent of this statement is to provide a framework for practitioners and health systems to help identify and refer patients with HF who are most likely to derive benefit from referral to an advanced HF center.

Although heart failure (HF) risk and cardiac structure/function reportedly differ according to race and gender, limited data exist in late life when risk of HF is highest.The goal of this study was to evaluate race/gender-based differences in HF risk factors, cardiac structure/function, and incident HF in late life.This analysis included 5,149 HF-free participants from ARIC (Atherosclerosis Risk In Communities), a prospective epidemiologic cohort study, who attended visit 5 (2011-2013) and underwent echocardiography. Participants were subsequently followed up for a median 5.5 years for incident HF/death.Patients' mean age was 75 ± 5 years, 59% were women, and 20% were Black. Male gender and Black race were associated with lower mean left ventricular ejection fraction. Black race was also associated with greater left ventricular wall thickness and concentricity, differences that persisted after adjusting for cardiovascular comorbidities. After adjusting for cardiovascular comorbidities, men were at higher risk for HF and heart failure with reduced ejection fraction (HFrEF) in Black participants compared with White participants (HF: HR of 2.36 [95% CI: 1.37-4.08] vs 1.16 [95% CI: 0.89-1.51], interaction P = 0.016; HFrEF: HR of 3.70 [95% CI: 1.72-7.95] vs 1.55 [95% CI: 1.01-2.37] respectively, interaction P = 0.039). Black race was associated with a higher incidence of HF overall and HFrEF in men only (HF: 1.65 [95% CI: 1.07-2.53] vs 0.76 [95% CI: 0.49-1.17]; HFrEF: HR of 2.55 [95% CI: 1.46-4.44] vs 0.91 [95% CI: 0.46-1.83]). No race/gender-based differences were observed in risk of incident heart failure with preserved ejection fraction.Among older persons free of HF, men and Black participants exhibit worse systolic performance and are at heightened risk for HFrEF, whereas the risk of heart failure with preserved ejection fraction is similar across gender and race groups.

In heart failure with preserved ejection fraction (HFpEF), the occurrence of myocardial fibrosis is associated with adverse outcome. Whether pirfenidone, an oral antifibrotic agent without hemodynamic effect, is efficacious and safe for the treatment of HFpEF is unknown. In this double-blind, phase 2 trial ( NCT02932566 ), we enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated levels of natriuretic peptides. Eligible patients underwent cardiovascular magnetic resonance and those with evidence of myocardial fibrosis, defined as a myocardial extracellular volume of 27% or greater, were randomly assigned to receive pirfenidone or placebo for 52 weeks. Forty-seven patients were randomized to each of the pirfenidone and placebo groups. The primary outcome was change in myocardial extracellular volume, from baseline to 52 weeks. In comparison to placebo, pirfenidone reduced myocardial extracellular volume (between-group difference, −1.21%; 95% confidence interval, −2.12 to −0.31; P = 0.009), meeting the predefined primary outcome. Twelve patients (26%) in the pirfenidone group and 14 patients (30%) in the placebo group experienced one or more serious adverse events. The most common adverse events in the pirfenidone group were nausea, insomnia and rash. In conclusion, among patients with HFpEF and myocardial fibrosis, administration of pirfenidone for 52 weeks reduced myocardial fibrosis. The favorable effects of pirfenidone in patients with HFpEF will need to be confirmed in future trials. In a double-blind, randomized phase 2 trial, treatment of patients with heart failure with preserved ejection fraction (HFpEF) with the oral antifibrotic agent pirfenidone reduced myocardial fibrosis.

OBJECTIVES Long-term left ventricular assist device (LVAD) support can cause accelerated progression of aortic insufficiency (AI). The MOMENTUM trial has led to increased use of the HeartMate 3 (HM3) LVAD, due to greater hemocompatibility. However, the differential effect on the rate of progression of AI during HM3 support versus HeartMate 2 (HM2) has not been extensively studied. This analysis compares the rates of progression to moderate or severe AI (MSAI) comparing a cohort of patients supported with the HM2 versus HM3. METHODS A retrospective review was performed on all consecutive patients implanted with HM2 or HM3 between May 2005 and June 2020. Follow-up time was limited to the first 6 years after LVAD implantation. Demographics and 4005 echocardiograms were assessed for 536 HM2 and 300 HM3 patients. The primary end point was progression to MSAI. Univariable and multivariable Cox proportional hazard regression and landmark analyses were performed. RESULTS Progression to MSAI was greater in the HM2 (17%) versus HM3 (9.9%) cohort. On the univariable analysis, the hazard ratio for HM3 was 0.581 (95% confidence interval 0.370–0.909, P = 0.02) whereas on multivariable analysis hazard ratio was 0.624 (95% confidence interval 0.386–1.008, P = 0.0537). Preoperative AI, female sex and body surface area CONCLUSIONS Current practice strategies achieved low rates of progression to MSAI. Preoperative AI, female sex and body surface area

Background Heart failure (HF) imposes significant burden on patients and caregivers. Longitudinal data on caregiver health‐related quality of life (HRQOL) and burden in ambulatory advanced HF are limited. Methods and Results Ambulatory patients with advanced HF (n=400) and their participating caregivers (n=95) enrolled in REVIVAL (Registry Evaluation of Vital Information for VADs [Ventricular Assist Devices] in Ambulatory Life) were followed up for 24 months, or until patient death, left ventricular assist device implantation, heart transplantation, or loss to follow‐up. Caregiver HRQOL (EuroQol Visual Analog Scale) and burden (Oberst Caregiving Burden Scale) did not change significantly from baseline to follow‐up. At time of caregiver enrollment, better patient HRQOL by Kansas City Cardiomyopathy Questionnaire was associated with better caregiver HRQOL ( P =0.007) and less burden by both time spent ( P P =0.0007) of caregiving tasks. On longitudinal analyses adjusted for baseline values, better patient HRQOL ( P =0.034) and being a married caregiver ( P =0.016) were independently associated with better caregiver HRQOL. Patients with participating caregivers (versus without) were more likely to prefer left ventricular assist device therapy over time (odds ratio, 1.43; 95% CI, 1.03–1.99; P =0.034). Among patients with participating caregivers, those with nonmarried (versus married) caregivers were at higher composite risk of HF hospitalization, death, heart transplantation or left ventricular assist device implantation (hazard ratio, 2.99; 95% CI, 1.29–6.96; P =0.011). Conclusions Patient and caregiver characteristics may impact their HRQOL and other health outcomes over time. Understanding the patient‐caregiver relationship may better inform medical decision making and outcomes in ambulatory advanced HF.

BACKGROUND Pericardial adipose tissue (PAT) is associated with adverse cardiovascular outcomes in those with and without established heart failure (HF). However, it is not known whether PAT is associated with adverse outcomes in patients with end-stage HF undergoing left ventricular assist device (LVAD) implantation. This study aimed to evaluate the associations between PAT and LVAD-associated outcomes. METHODS AND RESULTS We retrospectively measured computed tomography-derived PAT volumes in 77 consecutive adults who had available chest CT imaging prior to HeartMate 3 LVAD surgery between October 2015 and March 2019 at Duke University Hospital. Study groups were divided into above-median (≥219 cm3) and below-median (

Introduction: Circulating metabolome profiling holds promise in predicting HF risk, but its prediction performance among older adults is not well established. Hypothesis: We hypothesize that metabolic signatures are associated with the risk of HF and its subtypes (HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)), and they can improve HF risk prediction beyond established risk factors. Methods: We measured 828 serum metabolites among 4,030 African and European Americans free of HF from the Atherosclerosis Risk in Communities (ARIC) study visit 5 (2011-2013). We regressed incident HF on each metabolite using Cox proportional hazards models. A metabolite risk score (MRS) was derived by summing individual metabolite levels weighted by beta coefficients estimated from least absolute shrinkage and selection operator (LASSO) regularized regressions. We regressed incident HF, HFpEF and HFrEF on the MRS. Harrell’s C-statistics were calculated to evaluate risk discrimination. We replicated the association between MRS and HF in 3,697 independent ARIC participants with metabolite measured at visit 1 (1987-1989). Results: Among 4,030 participants, the mean (SD) age was 76 (5) years. Adjusting for HF risk factors, 302 metabolites were associated with incident HF (false discovery rate < 0.05). One SD increase of the MRS, constructed from 51 metabolites selected by LASSO, was associated with two to three-fold high risk of HF, HFpEF and HFrEF in the fully adjusted models ( Table ). Five-year risk prediction analysis showed that C statistics improved from 0.850 to 0.884 by adding MRS over ARIC HF risk factors, kidney function and NT-proBNP (ΔC (95%CI) = 0.034 (0.017,0.052)). In the replication analysis, a more parsimonious MRS constructed using 15 metabolites, was associated with incident HF ( Table ). Conclusions: We identified a metabolic signature that was associated with the risk of HF and improved HF risk prediction. Our findings may shed light on pathways in HF development and at-risk populations.

Cancer survivors might have an excess risk of cardiovascular disease (CVD) resulting from toxicities of cancer therapies and a high burden of CVD risk factors. We sought to evaluate the association of cancer survivorship with subclinical myocardial damage, as assessed by elevated high-sensitivity cardiac troponin T (hs-cTnT) test results. We included 3,512 participants of the Atherosclerosis Risk in Communities Study who attended visit 5 (2011–2013) and were free of CVD (coronary heart disease, heart failure, or stroke). We used multivariate logistic regression to evaluate the cross-sectional associations of survivorship from any, non-sex-related, and sex-related cancers (e.g., breast, prostate) with elevated hs-cTnT (≥14 ng/L). Of 3,512 participants (mean age, 76 years; 62% women; 21% black), 19% were cancer survivors. Cancer survivors had significantly higher odds of elevated hs-cTnT (OR = 1.26, 95% CI: 1.03, 1.53). Results were similar for survivors of non-sex-related and colorectal cancers, but there was no association between survivorship from breast and prostate cancers and elevated hs-cTnT. Results were similar after additional adjustments for CVD risk factors. Survivors of some cancers might be more likely to have elevated hs-cTnT than persons without prior cancer. The excess burden of subclinical myocardial damage in this population might not be fully explained by traditional CVD risk factors.

Background: Cardiac toxicity (CT) is a rare late effect of anthracycline therapy for breast cancer (BC). Statins may attenuate the CT of anthracyclines. Myocardial strain can detect subclinical CT before ejection fraction (EF) declines. Global longitudinal strain (GLS) ≥-19% and relative change (RelΔ) in GLS≥11% predict future decline in EF. We conducted a pilot study to evaluate the effect of simvastatin on GLS in BC patients receiving anthracyclines. Methods: We enrolled women with stage I-III BC planning doxorubicin/cyclophosphamide (AC) x 4. Women with heart disease or taking a statin were excluded. Participants were randomized 1:1 to simvastatin 40 mg daily x 24 weeks (wk) + AC or to AC alone. We performed echo with strain 5 times: baseline (BL), pre-AC#2, 1-3 wk after AC#4, 24 wk after AC #1 and 52 wk after AC#1. The primary endpoint was the mean absolute change (|Δ|) in GLS from BL to 1-3 wk after AC#4. Secondary endpoints included RelΔ in GLS, feasibility and safety. We used two-sample t-tests to compare mean changes in GLS and Fisher's exact test to compare dichotomized GLS values. The study closed early due to loss of staff. Results: Of 31 patients, 15 (48%) received simvastatin+AC. Mean age was 46 years; 71% pre-menopausal, 61% white and 32% black. There were no significant differences in BL cardiovascular risk factors between the arms. After AC, 3 HER2+ patients received trastuzumab. There were no grade 3-4 AEs with simvastatin. Common grade 1-2 AEs included myalgia (20%), elevated AST (27%) and elevated ALT (53%). One patient in the AC arm died from heart failure with low EF 2 months after having a normal echo 1-3 wk after AC#4. The rate of missing echos was 14%. Of 133 completed echos, 124 (93%) were evaluable for GLS. Mean GLS was 60% at all times in both arms. Among 27 patients evaluable for the primary endpoint, there was no significant difference in mean |Δ| in GLS from BL to 1-3 wk after AC#4 between the arms (Simvastatin+AC: 0.42%; AC: 1.11%, p=0.57). In addition, there were no differences in the mean|Δ| in GLS from BL to any other time between the arms (all p>0.1). The proportion of patients with GLS0.05). The proportion of patients with RelΔ in GLS≥11% from BL was lower in the simvastatin+AC arm than in the AC arm pre-AC#2 (13% vs 19%), 1-3 wk after AC#4 (20% vs 44%) and 24 wk after AC#1(27% vs 31%) (all p>0.05). Conclusion: Simvastatin did not result in a statistically significant difference in the mean |Δ| in GLS from BL to 1-3 wk after AC#4. However, the study was underpowered due to small sample size and there was a suggestion of reduced CT with simvastatin. Co-administration of simvastatin and AC was safe and serial echocardiographic strain monitoring was feasible. Further studies are needed to evaluate the cardioprotective effect of statins on strain in BC patients receiving anthracyclines. Citation Format: Smith KL, Griffin JM, Tsai H-L, Leathers M, Hays A, Lu D-Y, Zhang Z, Rosner GL, Russell SD, Connolly RM, Jelovac D, Visvanathan K, Wolff AC, Stearns V, Abraham T. Effect of simvastatin on cardiac strain in breast cancer patients receiving anthracycline therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-09.

Background: Previous literature has suggested a potential diuretic sparing effect as early as 6 months following sacubitril-valsartan initiation in patients with heart failure with reduced ejection fraction (HFrEF); however, whether this effect manifests earlier after initiation is unclear. Objective: To evaluate the acute diuretic-sparing effects of sacubitril-valsartan. Methods: This was a single-center, retrospective analysis of outpatients with HFrEF initiated on sacubitril-valsartan with follow up within 90 ± 30 days and a concomitant loop diuretic prescription. The primary outcome was the percent of patients with an increase, decrease or no change in loop diuretic total daily dose (TDD). Key secondary outcomes included change in loop diuretic TDD (mg furosemide equivalents) and hospital admissions or emergency department (ED) visits. Results: A total of 145 patients were included (overall cohort) with 120 continuing sacubitril-valsartan at follow up (on-treatment cohort). In the on-treatment cohort, 20% (n = 24) had a reduction in loop diuretic TDD and 10% had an increase (n = 12). Median change in loop diuretic TDD was unchanged from baseline to follow up (p 0.13). In patients on >80 mg TDD of furosemide at baseline (n = 9), mean change was-53 ± 44 mg (p 0.006). Hospitalizations (6.2%) and ED visits (0.7%) for heart failure were infrequent. Conclusion: Patients may require a loop diuretic dose reduction within 2-3 months following sacubitril-valsartan initiation. This diuretic-sparing effect appears larger in those on higher baseline loop diuretic doses, and closer follow up may be warranted for these patients.

Background: After heart transplantation, endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive, and its conventional histological interpretation has limitations. This is a validation study to assess the performance of a sensitive blood biomarker—percent donor-derived cell-free DNA (%ddcfDNA)—for detection of AR in cardiac transplant recipients. Methods: This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data were collected to define AR, its 2 phenotypes (acute cellular rejection [ACR] and antibody-mediated rejection [AMR]), and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range [IQR]) for AR, AMR, and ACR with controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis. Results: The study included 171 subjects with median posttransplant follow-up of 17.7 months (IQR, 12.1–23.6), with 1392 EMBx, and 1834 %ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (IQR, 0.03%–0.21%) by 28 days. Also, %ddcfDNA increased again with AR compared with control values (0.38% [IQR, 0.31–0.83%], versus 0.03% [IQR, 0.01–0.14%]; P Conclusions: We found that %ddcfDNA detected AR with a high area under the receiver operator characteristic curve and negative predictive value. Monitoring with ddcfDNA demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in patients with heart transplant and paves the way for a clinical utility study. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02423070.

OBJECTIVES: The purpose of this study was to examine whether peak oxygen uptake (pVO2) and other cardiopulmonary exercise test (CPET)-derived variables could predict intermediate-term mortality in stable continuous flow LVAD recipients. BACKGROUND: pVO2 is a cornerstone in the selection of patients for heart transplantation, but the prognostic power of pVO2 obtained in patients treated with a left ventricular assist device (LVAD) is unknown. METHODS: We collected data for pVO2 and outcomes in adult LVAD recipients in a retrospective, multicenter study and evaluated cutoff values for pVO2 including: 1) values above or below medians; 2) grouping patients in tertiles; and 3) pVO2 ≤14 ml/kg/min if the patient was not treated with beta-blockers (BB) or pVO2 ≤12 ml/kg/min if the patient was taking BB therapy. RESULTS: Nine centers contributed data from 450 patients. Patients were 53 ± 13 years of age; 78% were male; body mass index was 25 ± 5 kg/m2 with few comorbidities (stroke: 11%; diabetes: 18%; and peripheral artery disease: 4%). The cause of heart failure (HF) was most often nonischemic (66%). Devices included were the HeartMate II and 3 (Abbott); and Heartware ventricular assist devices Jarvik and Duraheart (Medtronic). The index CPET was performed at a median of 189 days (154-225 days) after LVAD implantation, and mean pVO2 was 14.1 ± 5 ml/kg/min (47% ± 14% of predicted value). Lower pVO2 values were strongly associated with poorer survival regardless of whether patients were analyzed for absolute pVO2 in ml/kg/min, pVO2 ≤12 BB/14 ml/kg/min, or as a percentage of predicted pVO2 values (P ≤ 0.001 for all). For patients with pVO2 >12 BB/14 and ventilation/carbon dioxide relationship (VE/VCO2) slope

Introduction: There is a need for innovative solutions to better screen and diagnose the 7 million patients with chronic heart failure. A key component of assessing these patients is monitoring fluid status by evaluating for the presence and height of jugular venous distension (JVD). We hypothesize that video analysis of a patient’s neck using machine learning algorithms and image recognition can identify the amount of JVD. We propose the use of high fidelity video recordings taken using a mobile device camera to determine the presence or absence of JVD, which we will use to develop a point of care testing tool for early detection of acute exacerbation of heart failure. Methods: In this feasibility study, patients in the Duke cardiac catheterization lab undergoing right heart catheterization were enrolled. RGB and infrared videos were captured of the patient’s neck to detect JVD and correlated with right atrial pressure on the heart catheterization. We designed an adaptive filter based on biological priors that enhances spatially consistent frequency anomalies and detects jugular vein distention, with implementation done on Python. Results: We captured and analyzed footage for six patients using our model. Four of these six patients shared a similar strong signal outliner within the frequency band of 95bpm – 200bpm when using a conservative threshold, indicating the presence of JVD. We did not use statistical analysis given the small nature of our cohort, but in those we detected a positive JVD signal the RA mean was 20.25 mmHg and PCWP mean was 24.3 mmHg. Conclusions: We have demonstrated the ability to evaluate for JVD via infrared video and found a relationship with RHC values. Our project is innovative because it uses video recognition and allows for novel patient interactions using a non-invasive screening technique for heart failure. This tool can become a non-invasive standard to both screen for and help manage heart failure patients.

Background Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure hospitalizations, with limited data on predictors of mortality by sex and race. We evaluated for differences in predictors of all‐cause mortality by sex and race among hospitalized patients with HFpEF in the ARIC (Atherosclerosis Risk in Communities) Community Surveillance Study. Methods and Results Adjudicated HFpEF hospitalization events from 2005 to 2013 were analyzed from the ARIC Community Surveillance Study, comprising 4 US communities. Comparisons between clinical characteristics and mortality at 1 year were made by sex and race. Of 4335 adjudicated acute decompensated heart failure cases, 1892 cases (weighted n=8987) were categorized as HFpEF. Men had an increased risk of 1‐year mortality compared with women in adjusted analysis (hazard ratio [HR], 1.27; 95% CI, 1.06–1.52 [ P =0.01]). Black participants had lower mortality compared with White participants in unadjusted and adjusted analyses (HR, 0.79; 95% CI, 0.64–0.97 [ P =0.02]). Age, heart rate, worsening renal function, and low hemoglobin were associated with increased mortality in all subgroups. Higher body mass index was associated with improved survival in men, with borderline interaction by sex. Higher blood pressure was associated with improved survival among all groups, with significant interaction by race. Conclusions In a diverse HFpEF population, men had worse survival compared with women, and Black participants had improved survival compared with White participants. Age, heart rate, and worsening renal function were associated with increased mortality across all subgroups; high blood pressure was associated with decreased mortality with interaction by race. These insights into sex‐ and race‐based differences in predictors of mortality may help strategize targeted management of HFpEF.

Background Left ventricular assist devices (LVADs) generate electromagnetic interference that causes high‐frequency noise artifacts on 12‐lead ECGs. We describe the causes of this interference and potential solutions to aid ECG interpretation in patients with LVAD. Methods and Results Waveform data from ECGs performed before and after LVAD implantation were passed through a fast Fourier transform to identify LVAD‐related changes in the spectral profile. ECGs recorded in 9 patients with HeartMate II, HeartMate 3, and HeartWare LVADs were analyzed to identify the LVAD model‐specific spectral patterns. Waveform data were then passed through digital low‐pass and bandstop filters and redisplayed to evaluate the effect of filtering on LVAD‐related electromagnetic interference. The spectral profile of patients with HeartMate II and HeartMate 3 LVADs demonstrated a prominent signal at the device‐specific frequency of impeller rotation. In patients with the HeartMate 3 LVAD, 2 additional peaks were observed at the frequencies equivalent to the LVAD's artificial pulsatility rotational speeds. Patients with HeartWare devices demonstrated a prominent signal peak at a frequency equal to double their LVAD's set rotational speed. Applying a low‐pass filter to a value below the observed frequency peak from the LVAD significantly improved the waveform tracing and quality of the ECG. Applying a speed‐specific bandstop filter to remove the observed LVAD frequency peak also improved the clarity of the ECG without compromising physiological high‐frequency signal components. Conclusions LVADs create impeller rotational speed‐specific electromagnetic interference that can be ameliorated by application of low‐pass or bandstop filters to improve ECG clarity.

Background Heart failure with preserved ejection fraction ( HF p EF ) constitutes half of hospitalized heart failure cases and is commonly associated with obesity. The role of natriuretic peptide levels in hospitalized obese patients with HF p EF , however, is not well defined. We sought to evaluate change in NT ‐pro BNP (N‐terminal pro‐B‐type natriuretic peptide) levels by obesity category and related clinical outcomes in patients with HF p EF hospitalized for acute heart failure. Methods and Results A total of 89 patients with HF p EF hospitalized with acute decompensated heart failure were stratified into 3 obesity categories: nonobese ( body mass index [BMI] 2 , 19%), obese ( BMI 30.0–39.9 kg/m 2 , 29%), and severely obese ( BMI ≥40.0 kg/m 2 , 52%), and compared for percent change in NT ‐pro BNP during hospitalization and clinical outcomes. Clinical characteristics were compared between patients with normal NT ‐pro BNP (≤125 pg/ mL ) and elevated NT ‐pro BNP . Admission NT ‐pro BNP was inversely related to BMI category (nonobese, 2607 pg/ mL [interquartile range, IQR: 2112–5703]; obese, 1725 pg/ mL [IQR: 889–3900]; and severely obese, 770.5 pg/ mL [IQR: 128–1268]; P NT ‐pro BNP with diuresis (−64.8% [95% CI, −85.4 to −38.9] versus obese −40.4% [95% CI, −74.3 to −12.0] versus nonobese −46.9% [95% CI, −57.8 to −37.4]; P =0.03). Nonobese and obese patients had significantly worse 1‐year survival compared with severely obese patients (63% versus 76% versus 95%, respectively; P NT ‐pro BNP (13%) were younger, with higher BMI , less atrial fibrillation, and less structural heart disease than those with elevated NT ‐proBNP. Conclusions In hospitalized patients with HF p EF , NT ‐pro BNP was inversely related to BMI with the largest decrease in NT ‐pro BNP seen in the highest obesity category. These findings have implications for the role of NT ‐pro BNP in the diagnosis and assessment of treatment response in obese patients with HF p EF .

Biomarkers have a well-defined role in the diagnosis and management of chronic heart failure, but their role in patients with left ventricular assist devices and cardiac transplant is uncertain. In this review, we summarize the available literature in this patient population, with a focus on clinical application. Some ubiquitous biomarkers, for example, natriuretic peptides and cardiac troponin, may assist in the diagnosis of left ventricular assist device complications and transplant rejection. Novel biomarkers focused on specific pathological processes, such as left ventricular assist device thrombosis and profiling of leukocyte activation, continue to be developed and show promise in altering the management of the advanced heart failure patient. Few biomarkers at this time have been assessed with sufficient scrutiny to warrant broad, universal application, but encouraging limited data and large potential for impact should prompt ongoing investigation.

Background Greater physical activity ( PA ) is associated with lower heart failure ( HF ) risk. However, it is unclear whether this inverse association exists across all subgroups at high risk for HF , particularly among those with preexisting atherosclerotic cardiovascular disease. Methods and Results We followed 13 810 ARIC (Atherosclerosis Risk in Communities) study participants (mean age 55 years, 54% women, 26% black) without HF at baseline (visit 1; 1987–1989). PA was assessed using a modified Baecke questionnaire and categorized according to American Heart Association guidelines: recommended, intermediate, or poor. We constructed Cox models to estimate associations between PA categories and incident HF within each high‐risk subgroup at baseline, with tests for interaction. We performed additional analyses modeling incident coronary heart disease as a time‐varying covariate. Over a median of 26 years of follow‐up, there were 2994 HF events. Compared with poor PA , recommended PA was associated with lower HF risk among participants with hypertension, obesity, diabetes mellitus, and metabolic syndrome (all P CI , 0.74–1.13 [ P interaction=0.02]). Recommended PA was associated with lower risk of incident coronary heart disease (hazard ratio, 0.79; 95% CI , 0.72–0.86), but not with lower HF risk in those with interim coronary heart disease events (hazard ratio, 0.90; 95% CI , 0.78–1.04 [ P interaction=0.04]). Conclusions PA was associated with decreased HF risk in patients with hypertension, obesity, diabetes mellitus, and metabolic syndrome. Despite a myriad of benefits in patients with atherosclerotic cardiovascular disease, PA may have weaker associations with HF prevention after ischemic disease is established.

Introduction: Patients with HF have multiple co-existing CV and non-CV comorbidities. The temporal trends in the burden of co-morbidities and associated risk of mortality among patients with acute decompensated HF (ADHF) is not well-established. Methods: HF related hospitalizations were captured in the ARIC surveillance cohort study across 4 US communities 2005 to 2014 using ICD-9 codes. HF hospitalizations were adjudicated using validated algorithm to identify ADHF with reduced ejection fraction (HFrEF, ejection fraction Results: Of the 22,805 hospitalizations sampled between 2005-2004, 8914 were classified as ADHF corresponding to 41,146 weighted hospitalizations for ADHF (53% HFrEF, 47% HFpEF). The burden of CV co-morbidities remained stable while that of and that of non-CV comorbidities increased significantly over time among patients with HFpEF and HFrEF. The overall burden of CV co-morbidities was not significantly associated with risk of mortality among patients with HFrEF and HFpEF. In contrast, greater burden of non-CV comorbidities was significantly associated with higher risk of in-hospital, 28-day, and 1-year mortality for both HFpEF and HFrEF. Among patients with HFrEF, the risk of mortality associated with higher burden of non-CV comorbidities did not change over time. In contrast, for HFpEF, there was a significant temporal decline in the non-CV burden associated risk of in-hospital mortality and an increase in the risk of 1-year mortality over time. Conclusion: The burden of non-CV co-morbidities among patients with ADHF has increased over time. Higher burden of non-CV comorbidities was associated with higher risk of mortality, with stable temporal associations in HFrEF and an increasing risk over time for 1-year mortality for HFpEF.

Introduction: Obesity is disproportionately prevalent in black populations and strongly associated with heart failure with preserved ejection fraction (HFpEF). An “obesity paradox” or lower mortality risk with obesity, has been reported in HFpEF populations. Whether racial differences exist in the temporal trends and outcomes of obesity is uncertain. Methods: Hospitalizations for acute decompensated heart failure (ADHF) were sampled from 2005-2014 by the ARIC Study Community Surveillance and classified by physician review. BMI was calculated using the admission height and weight. Associations between obesity and 1-year all-cause mortality were analyzed with multivariable Cox regression. Results: There were 10,147 weighted hospitalizations for ADHF with ejection fraction ≥50% (64% female, 74% white). Overall, black patients had a higher mean BMI than white patients (34 vs. 30 kg/m 2 ; P P P = 0.003 and P = 0.002) while remaining stable for black patients. Within BMI groups (18.5-24, 25-30, 30-35, 35-40, and ≥40 kg/m 2 ) a U-shaped mortality risk was observed, with the lowest risk among patients with a BMI of 30-35 kg/m 2 ( Figure ). When defining obesity by a BMI cutpoint ≥30 kg/m 2 , the “obesity paradox” was apparent in 2005-2009 for white obese vs. non-obese patients (HR = 0.58, 95% CI: 0.38 - 0.80), but attenuated by 2010-2014 (HR = 1.11; 95% CI: 0.80 - 1.48); P for interaction =0.006. Among black patients, there was no survival benefit for a BMI ≥30 kg/m 2 in 2005-2009 (HR = 1.15; 95% CI; 0.65 - 2.02) or 2010-2014 (HR = 1.06; 95% CI: 0.68 - 1.66). Conclusion: In this decade-long community surveillance of HFpEF patients hospitalized with ADHF, obesity and mean BMI were stable for black patients but steadily increased for white patients. A BMI ≥30 kg/m 2 was initially associated with better survival among white patients but the association dissipated as obesity and mean BMI increased over time.