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The V122I variant in transthyretin (TTR) is the most common amyloidogenic mutation worldwide. The aim of this study is to describe the cardiac phenotype and risk for adverse cardiovascular outcomes of young V122I TTR carriers in the general population.TTR genotypes were extracted from whole-exome sequence data in participants of the Dallas Heart Study. Participants with African ancestry, available V122I TTR genotypes (N = 1818) and either cardiac magnetic resonance imaging (n = 1364) or long-term follow-up (n = 1532) were included. The prevalence of V122I TTR carriers (45 ± 10 years) was 3.2% (n/N = 59/1818). The V122I TTR carriers had higher baseline left ventricular wall thickness (8.52 ± 1.82 vs 8.21 ± 1.62 mm, adjusted P = .038) than noncarriers, but no differences in other cardiac magnetic resonance imaging measures (P.05 for all). Although carrier status was not associated with amino terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline (P = .79), V122I TTR carriers had a greater increase in NT-proBNP on follow-up than noncarriers (median 28.5 pg/mL, interquartile range 11.4-104.1 pg/mL vs median 15.9 pg/mL, interquartile range 0.0-43.0 pg/mL, adjusted P = .018). V122I TTR carriers were at a higher adjusted risk of heart failure (hazard ratio 3.82, 95% confidence interval 1.80-8.13, P.001), cardiovascular death (hazard ratio 2.65, 95% confidence interval 1.14-6.15, P = .023), and all-cause mortality (hazard ratio 1.95, 95% confidence interval 1.08-3.51, P = .026) in comparison with noncarriers.V122I TTR carrier status was associated with a greater increase in NT-proBNP, slightly greater left ventricular wall thickness, and a higher risk for heart failure, cardiovascular death, and all-cause mortality. These findings suggest the need to develop amyloidosis screening strategies for V122I TTR carriers.

Patients with continuous flow destination therapy (DT) left ventricular assist devices (LVAD) comprise a heterogeneous population. We hypothesized that phenotypic clustering of individuals with DT LVADs by their implantation characteristics will be associated with different long-term risk profiles. We analyzed 5,999 patients with continuous flow DT LVADs in Interagency Registry for Mechanically Assisted Circulatory Support using 18 continuous variable baseline characteristics. We Z-transformed the variables and applied a Gaussian finite mixture model to perform unsupervised clustering resulting in identification of 4 phenogroups. Survival analyses considered the competing risk for cumulative incidence of transplant or the composite end point of death or heart transplant where appropriate. Phenogroup 1 (n = 1,163, 19%) was older (71 years) and primarily white (81%). Phenogroups 2 (n = 648, 11%) and 3 (n = 3,671, 61%) were of intermediate age (70 and 62 years), weight (85 and 87 kg), and ventricular size. Phenogroup 4 (n = 517, 9%) was younger (40 years), heavier (108 kg), and more racially diverse. The cumulative incidence of death, heart transplant, bleeding, LVAD malfunction, and LVAD thrombosis differed among phenogroups. The highest incidence of death and the lowest rate of heart transplant was seen in phenogroup 1 (p0.001). For adverse outcomes, phenogroup 4 had the lowest incidence of bleeding, whereas LVAD device thrombosis and malfunction were lowest in phenogroup 1 (p0.001 for all). Finally, the incidence of stroke, infection, and renal dysfunction were not statistically different. In conclusion, the present unsupervised machine learning analysis identified 4 phenogroups with different rates of adverse outcomes and these findings underscore the influence of phenotypic heterogeneity on post-LVAD implantation outcomes.

Background: Obesity and diabetes are associated with a higher risk of heart failure (HF). The interrelationships between different measures of adiposity—overall obesity, central obesity, fat mass (FM)—and diabetes status for HF risk are not well-established. Methods: Participant-level data from the ARIC study (Atherosclerosis Risk in Communities; visit 5) and the CHS (Cardiovascular Health Study; visit 1) cohorts were obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center, harmonized, and pooled for the present analysis, excluding individuals with prevalent HF. FM was estimated in all participants using established anthropometric prediction equations additionally validated using the bioelectrical impedance-based FM in the ARIC subgroup. Incident HF events on follow-up were captured across both cohorts using similar adjudication methods. Multivariable-adjusted Fine-Gray models were created to evaluate the associations of body mass index (BMI), waist circumference (WC), and FM with risk of HF in the overall cohort as well as among those with versus without diabetes at baseline. The population attributable risk of overall obesity (BMI≥30 kg/m 2 ), abdominal obesity (WC>88 and 102 cm in women and men, respectively), and high FM (above sex-specific median) for incident HF was evaluated among participants with and without diabetes. Results: The study included 10 387 participants (52.9% ARIC; 25.1% diabetes; median age, 74 years). The correlation between predicted and bioelectrical impedance-based FM was high ( R 2 =0.90; n=5038). During a 5-year follow-up, 447 participants developed HF (4.3%). Higher levels of each adiposity measure were significantly associated with higher HF risk (hazard ratio [95% CI] per 1 SD higher BMI=1.15 [1.05, 1.27], WC=1.22 [1.10, 1.36]; FM=1.13 [1.02, 1.25]). A significant interaction was noted between diabetes status and measures of BMI ( P interaction=0.04) and WC ( P interaction=0.004) for the risk of HF. In stratified analysis, higher measures of each adiposity parameter were significantly associated with higher HF risk in individuals with diabetes (hazard ratio [95% CI] per 1 SD higher BMI=1.29 [1.14–1.47]; WC=1.48 [1.29–1.70]; FM=1.25 [1.09–1.43]) but not those without diabetes, including participants with prediabetes and euglycemia. The population attributable risk percentage of overall obesity, abdominal obesity, and high FM for incident HF was higher among participants with diabetes (12.8%, 29.9%, and 13.7%, respectively) versus those without diabetes (≤1% for each). Conclusions: Higher BMI, WC, and FM are strongly associated with greater risk of HF among older adults, particularly among those with prevalent diabetes.

To determine the trends in hospitalizations for heart failure (HF), acute myocardial infarction (AMI), and stroke in the United States (US).A retrospective analysis of the National Inpatient Sample weighted data between January 1, 2004 and December 31, 2018 which included hospitalized adults ≥18 years with a primary discharge diagnosis of HF, AMI, or stroke using International Classification of Diseases-9/10 administrative codes. Main outcomes were hospitalization for HF, AMI, and stroke per 1000 United States adults, length of stay, and in-hospital mortality. There were 33.4 million hospitalizations for HF, AMI, and stroke, with most being for HF (48%). After the initial decline in HF hospitalizations (5.3 hospitalizations/1000 US adults in 2004 to 4 hospitalizations/1000 US adults in 2013, P.001), there was a progressive increase in HF hospitalizations between 2013 and 2018 (4.0 hospitalizations/1000 US adults in 2013 to 4.9 hospitalizations/1000 US adults in 2018; P .001). Hospitalization for AMI decreased (3.1 hospitalizations/1000 US adults in 2004 to 2.5 hospitalizations/1000 US adults in 2010, P.001) and remained stable between 2010 and 2018. There was no significant change for hospitalization for stroke between 2004 and 2011 (2.3 hospitalizations/1000 US adults in 2004 vs 2.3 hospitalizations per 1000 US adults in 2011, P = .614); however, there was a small but significant increase in hospitalization for stroke after 2011 that reached 2.5 hospitalizations/1000 US adults in 2018. Adjusted length of stay and in-hospital mortality decreased for HF, AMI, and stroke hospitalizations.In contrast to the trend of AMI and stroke hospitalizations, a progressive increase in hospitalizations for HF has occurred since 2013. From 2004 to 2018, in-hospital mortality has decreased for HF, AMI, and stroke hospitalizations.

Background Chronic Kidney Disease (CKD) and end-stage renal disease (ESRD) are associated with poor outcomes in patients with cardiovascular disease. There is a paucity of contemporary data on in-hospital outcomes and care patterns of atrial fibrillation (AF) associated hospitalizations CKD and ESRD. Methods Outcomes and care patterns were evaluated in GWTG-AFIB database (Jan 2013-Dec 2018), including in-hospital mortality, use of a rhythm control strategy, and oral anticoagulation (OAC) prescription at discharge among eligible patients. Generalized logistic regression models with generalized estimating equations were used to ascertain differences in outcomes. Hospital-level variation in OAC prescription and rhythm control was also evaluated. Results Among 50,154 patients from 105 hospitals the median age was 70 years (interquartile range 61-79) and 47.3% were women. The prevalence of CKD was 36.0% while that of ESRD was 1.6%. Among eligible patients, discharge OAC prescription rates were 93.6% for CKD and 89.1% for ESRD. After adjustment, CKD and ESRD were associated with higher in-hospital mortality (odds ratio [OR] 3.08, 95% confidence interval [CI] 1.57-6.03 for ESRD and OR 2.02, 95% CI 1.52-2.67 for CKD), lower odds of OAC prescription at discharge (OR 0.59, 95% CI 0.44-0.79 for ESRD and OR 0.84, 95% CI 0.75-0.94 for CKD) compared with normal renal function. CKD was associated with lower utilization of rhythm control strategy (OR 0.92, 95% CI 0.87-0.98) with no significant difference between ESRD and normal renal function (OR 1.32, 95% CI 0.79-1.11). There was large hospital-level variation in OAC prescription at discharge (MOR 2.34, 95% CI 2.05-2.76) and utilization of a rhythm control strategy (MOR 2.69, 95% CI 2.34-3.21). Conclusions CKD/ESRD is associated with higher in-hospital mortality, less frequent rhythm control, and less OAC prescription among patients hospitalized for AF. There is wide hospital-level variation in utilization of a rhythm control strategy and OAC prescription at discharge highlighting potential opportunities to improve care and outcomes for these patients, and better define standards of care in this patient population

AIMS To evaluate the performance of the WATCH-DM risk score, a clinical risk score for heart failure (HF), in patients with dysglycaemia and in combination with natriuretic peptides (NPs). METHODS AND RESULTS Adults with diabetes/pre-diabetes free of HF at baseline from four cohort studies (ARIC, CHS, FHS, and MESA) were included. The machine learning- [WATCH-DM(ml)] and integer-based [WATCH-DM(i)] scores were used to estimate the 5-year risk of incident HF. Discrimination was assessed by Harrell's concordance index (C-index) and calibration by the Greenwood-Nam-D'Agostino (GND) statistic. Improvement in model performance with the addition of NP levels was assessed by C-index and continuous net reclassification improvement (NRI). Of the 8938 participants included, 3554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5 years. The WATCH-DM(ml) and WATCH-DM(i) scores demonstrated high discrimination for predicting HF risk among individuals with dysglycaemia (C-indices = 0.80 and 0.71, respectively), with no evidence of miscalibration (GND P ≥0.10). The C-index of elevated NP levels alone for predicting incident HF among individuals with dysglycaemia was significantly higher among participants with low/intermediate (

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.

Background Low cardiorespiratory fitness (CRF), high body mass index, and excess visceral adiposity are each associated with impairment in left ventricular (LV) peak circumferential strain (Ecc), an intermediate phenotype that precedes the development of clinical heart failure (HF). However, the association of regional fat distribution and CRF with Ecc independent of each other and other potential confounders is not known. Methods Participants from the Dallas Heart Study Phase 2 who underwent dual energy X-ray absorptiometry assessment of regional fat distribution, CRF assessment by submaximal treadmill test, and Ecc quantification by tissue-tagged cardiovascular magnetic resonance were included in the analysis. The cross-sectional associations of measures of regional adiposity, namely visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and lower-body fat (LBF) with Ecc after adjustment for CRF and other potential confounders (independent variables) were assessed using multivariable linear regression analysis. Results The study included 1089 participants (55% female, 39% black). In the unadjusted analysis, higher VAT was associated with greater impairment in Ecc. After adjustment for baseline risk factors, CRF, parameters of LV structure and function, and other fat depots such as SAT and LBF, higher VAT remained associated with greater impairment in Ecc (β: 0.19, P = 0.002). SAT and LBF were not significantly associated with Ecc, however, CRF remained associated with Ecc in the fully adjusted model including all fat depots (β: − 0.15, P Conclusions VAT and CRF are each independently associated with impairment in Ecc, suggesting that higher VAT burden and low CRF mediate pathological cardiac remodeling through distinct mechanisms.

OBJECTIVE Evaluate the association between prefrailty and the risk of heart failure (HF) among older adults. DESIGN, SETTING, AND PARTICIPANTS This prospective, community-based cohort study included participants from the Atherosclerotic Risk in Communities study who underwent detailed frailty assessment using Fried Criteria and physical function assessment using the Short Performance Physical Battery (SPPB) score. Individuals with prevalent HF and frailty were excluded. MAIN OUTCOMES AND MEASURES Adjusted association between prefrailty (vs robust), physical function measures (SPPB score, grip strength, and gait speed), and incident HF (overall and HF subtypes, HF with reduced [HFrEF, EF

BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) use hospital readmissions as a performance metric to incentivize hospital care for acute conditions including pneumonia. However, there are limitations to using readmission alone as a hospital performance metric. OBJECTIVE: To characterize 30-day risk-standardized home time (RSHT), a novel patient-centered post-discharge performance metric for acute pneumonia hospitalizations in Medicare patients, and compare hospital rankings based on this metric with mortality and readmissions. STUDY DESIGN: Retrospective, cohort study. PARTICIPANTS: A cohort of Medicare fee-for-service beneficiaries admitted between January 01, 2015 and November 30, 2017. INTERVENTIONS: None. MAIN MEASURES: Risk-standardized hospital-level home time within 30 days of discharge was evaluated as a novel performance metric. Multilevel regression models were used to calculate hospital-level estimates and rank hospitals based on RSHT, readmission rate (RSRR), and mortality rate (RSMR). KEY RESULTS: A total of 1.7 million pneumonia admissions admitted to one of the 3116 hospitals were eligible for inclusion. The median 30-day RSHT was 20.5 days (interquartile range: 18.9–21.9 days; range: 5–29 days). Hospital-level characteristics such as case volume, bed size, for-profit ownership, rural location of the hospital, teaching status, and participation in the bundled payment program were significantly associated with home time. We found a modest, inverse correlation of RSHT with RSRR (rho: −0.233, p< 0.0001) and RSMR (rho: −0.223, p< 0.0001) for pneumonia. About 1/3rd of hospitals were reclassified as high performers based on their RSHT metric compared with the rank on their RSRR and RSMR metrics. CONCLUSION: Home time is a novel, patient-centered, hospital-level metric that can be easily calculated using claims data and accounts for mortality, readmission to an acute care facility, and admission to a skilled nursing facility or long-term care facility after discharge. Utilization of this patient-centered metric could have policy implications in assessing hospital performance on delivery of healthcare to pneumonia patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06712-w.

Supplemental Digital Content is available in the text., The 2017 American College of Cardiology/American Heart Association high blood pressure (BP) guidelines recommend risk assessment of atherosclerotic cardiovascular disease to inform hypertension treatment in adults with elevated BP or low-risk stage I hypertension. The use of coronary artery calcium (CAC) score to guide hypertension therapy has not been adequately evaluated. Participants free of cardiovascular disease were pooled from Multi-Ethnic Study of Atherosclerosis, Coronary Artery Risk Development in Young Adults, and Jackson Heart Study. The risk for incident cardiovascular events (heart failure, stroke, coronary heart disease), by CAC status (CAC-0 or CAC>0) and BP treatment group was assessed using multivariable-adjusted Cox regression. The 10-year number needed to treat to prevent a single cardiovascular event was also estimated. This study included 6461 participants (median age 53 years; 53.3% women; 32.3% Black participants). Over a median follow-up of 8.5 years, 347 incident cardiovascular events occurred. Compared with those with normal BP, the risk of incident cardiovascular event was higher among those with elevated BP/low-risk stage I hypertension and CAC>0 (hazard ratio, 2.4 [95% CI, 1.7–3.4]) and high-risk stage I/stage II hypertension (BP, 140–160/80–100 mm Hg) with CAC>0 (hazard ratio, 2.9 [95% CI, 2.1–4.0]). A similar pattern was evident across racial subgroups and for individual study outcomes. Among those with CAC-0, the 10-year number needed to treat was 160 for elevated BP/low-risk stage I hypertension and 44 for high-risk stage I or stage II hypertension (BP, 140–160/80–100 mm Hg). Among those with CAC>0, the 10-year number needed to treat was 36 and 22, respectively. Utilization of the CAC score may guide the initiation of hypertension therapy and preventive approaches to personalize cardiovascular risk reduction among individuals where the current guidelines do not recommend treatment.

Type 2 diabetes is a heterogeneous disease process with variable trajectories of CVD risk. We aimed to evaluate four phenomapping strategies and their ability to stratify CVD risk in individuals with type 2 diabetes and to identify subgroups who may benefit from specific therapies. Participants with type 2 diabetes and free of baseline CVD in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial were included in this study (N = 6466). Clustering using Gaussian mixture models, latent class analysis, finite mixture models (FMMs) and principal component analysis was compared. Clustering variables included demographics, medical and social history, laboratory values and diabetes complications. The interaction between the phenogroup and intensive glycaemic, combination lipid and intensive BP therapy for the risk of the primary outcome (composite of fatal myocardial infarction, non-fatal myocardial infarction or unstable angina) was evaluated using adjusted Cox models. The phenomapping strategies were independently assessed in an external validation cohort (Look Action for Health in Diabetes [Look AHEAD] trial: n = 4211; and Bypass Angioplasty Revascularisation Investigation 2 Diabetes [BARI 2D] trial: n = 1495). Over 9.1 years of follow-up, 789 (12.2%) participants had a primary outcome event. FMM phenomapping with three phenogroups was the best-performing clustering strategy in both the derivation and validation cohorts as determined by Bayesian information criterion, Dunn index and improvement in model discrimination. Phenogroup 1 (n = 663, 10.3%) had the highest burden of comorbidities and diabetes complications, phenogroup 2 (n = 2388, 36.9%) had an intermediate comorbidity burden and lowest diabetes complications, and phenogroup 3 (n = 3415, 52.8%) had the fewest comorbidities and intermediate burden of diabetes complications. Significant interactions were observed between phenogroups and treatment interventions including intensive glycaemic control (p-interaction = 0.042) and combination lipid therapy (p-interaction

Aims We sought to compare the generalizability and prognostic implications of heart failure with preserved ejection fraction (HFpEF) scores (HFA-PEFF and H2 FPEF score) in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) and Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial participants and matched controls from the Atherosclerosis Risk in Community (ARIC) study. Methods and results Based on the respective scores, the study participants from the TOPCAT (N = 356), RELAX (N = 216), and ARIC (N = 379) studies were categorized as having a low, intermediate, or high likelihood of HFpEF. Age, sex, and race matched controls free of cardiovascular disease who had unexplained dyspnoea were used to evaluate the diagnostic performance. The prognostic value of scores was assessed using multivariable-adjusted Cox regression analyses. The median HFA-PEFF scores in the TOPCAT, RELAX, and ARIC studies were 5.0 [interquartile range (IQR): 5.0-6.0], 4.0 (IQR: 2.0-4.0), and 3.0 (IQR: 2.0-4.0), respectively. The median H2 FPEF scores in the three studies were 5.5 (IQR: 4.0-7.0), 6.0 (IQR: 4.0-7.0), and 3.0 (IQR: 2.0-5.0), respectively. A low HFA-PEFF and H2 FPEF score can rule out HFpEF with high sensitivity (99.5% and 99.6%, respectively) and negative predictive value (95.7% and 98.3%, respectively). A high HFA-PEFF and H2 FPEF score can rule-in HFpEF with good specificity (82.8% and 95.6%, respectively) and positive predictive value (79.9% and 90.4%, respectively). Among TOPCAT participants, the hazard for adverse cardiovascular events per point increase in HFA-PEFF and H2 FPEF score was 1.26 (95% confidence interval: 0.98-1.63) and 1.01 (95% confidence interval: 0.88-1.15), respectively. A higher H2 FPEF score was associated with lower peak oxygen intake in RELAX trial participants (adjusted P = 0.01). Conclusions The HFA-PEFF and the H2 FPEF scores are reliable diagnostic tools for HFpEF. The prognostic utility of HFpEF scores requires further validation in larger rigorously phenotyped populations.

International audience; Background: Prior analyses suggest an association between formula-based plasma volume (PV) estimates and outcomes in heart failure (HF). We assessed the association between estimated PV status by the Duarte-ePV and Kaplan Hakim (KH-ePVS) formulas, and in-hospital and postdischarge clinical outcomes, in the ASCEND-HF trial.Methods and results: The KH-ePVS and Duarte-ePV were calculated on admission. We assessed associations with in-hospital worsening HF, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality. There were 6373 (89.2%), and 6354 (89.0%) patients who had necessary characteristics to calculate KH-ePVS and Duarte-ePV, respectively. There was no association between PV by either formula with in-hospital worsening HF. KH-ePVS showed a weak correlation with N-terminal prohormone BNP, and with measures of decongestion such as body weight change and urine output (r < 0.3 for all). Duarte-ePV was trending toward an association with worse 30-day (adjusted odds ratio 1.07, 95% confidence interval [CI] 1.00-1.15, P = .058), but not 180-day outcomes (adjusted hazard ratio 1.03, 95% CI 0.97-1.09, P = .289). A continuous KH-ePVS of >0 (per 10-unit increase) was associated with improved 30-day outcomes (adjusted odds ratio 0.75, 95% CI 0.62-0.91, P = .004). The continuous KH-ePVS was not associated with 180-day outcomes (adjusted hazard ratio 1.05, 95% CI 0.98-1.12, P = .139).Conclusions: Baseline PV estimates had a weak association with in-hospital measures of decongestion. The Duarte-ePV trended toward an association with early clinical outcomes in decompensated HF, and may improve risk stratification in HF.

Objectives This study investigates the prevalence and prognostic significance of mitral regurgitation (MR) in acute decompensated heart failure (ADHF) patients. Background Few studies characterize the burden of MR in heart failure. Methods The ARIC (Atherosclerosis Risk In Communities) study surveilled ADHF hospitalizations for residents ≥55 years of age in 4 U.S. communities. ADHF cases were stratified by left ventricular ejection fraction (LVEF): Results From 2005 to 2014, there were 17,931 weighted ADHF hospitalizations of which 49.2% had an LVEF Conclusions Patients with ADHF have a significant MR burden that varies with sex and race. In ADHF patients with an LVEF

Background: Studies examining gender-based differences in outcomes of patients experiencing out-of-hospital cardiac arrest have demonstrated that, despite a higher likelihood of return of spontaneous circulation, women do not have higher survival. Methods: Patients successfully resuscitated from out-of-hospital cardiac arrest enrolled in the CCC trial (Trial of Continuous or Interrupted Chest Compressions during CPR) were included. Hierarchical multivariable logistic regression models were constructed to evaluate the association between gender and survival after adjustment for age, gender, cardiac arrest rhythm, witnessed status, bystander cardiopulmonary resuscitation, episode location, epinephrine dose, emergency medical services response time, and duration of resuscitation. Do not resuscitate (DNR) and withdrawal of life-sustaining therapy (WLST) order status were used to assess whether differences in postresuscitation outcomes were modified by baseline prognosis. The analysis was replicated among ALPS trial (Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest) participants. Results: Among 4875 successfully resuscitated patients, 1825 (37.4%) were women and 3050 (62.6%) were men. Women were older (67.5 versus 65.3 years), received less bystander cardiopulmonary resuscitation (49.1% versus 54.9%), and had a lower proportion of cardiac arrests that were witnessed (55.1% versus 64.5%) or had shockable rhythm (24.3% versus 44.6%, P P =0.009) and had WLST (32.8% versus 29.8%, P =0.03). Discharge survival was significantly lower in women (22.5% versus 36.3%, P P =0.005). The association between gender and survival to discharge was modified by DNR and WLST order status such that women had significantly reduced survival to discharge among patients who were not designated DNR (31.3% versus 49.9%, P =0.005; adjusted odds ratio, 0.74 [95% CI, 0.60–0.91]) or did not have WLST (32.3% versus 50.7%, P =0.002; adjusted odds ratio, 0.73 [95% CI, 0.60–0.89]). In contrast, no gender difference in survival was noted among patients receiving a DNR order (6.7% versus 7.4%, P =0.90) or had WLST (2.8% versus 2.4%, P =0.93). Consistent patterns of association between gender and postresuscitation outcomes were observed in the secondary cohort. Conclusions: Among patients resuscitated after experiencing out-of-hospital cardiac arrest, discharge survival was significantly lower in women than in men, especially among patients considered to have a favorable prognosis.

Aims Non‐alcoholic fatty liver disease leads to progressive liver fibrosis and appears to be a frequent co‐morbid disease in heart failure with preserved ejection fraction (HFpEF). It is well known that liver fibrosis severity predicts future liver‐related morbidity and mortality, but its impact on outcomes in patients with HFpEF remains unknown. This analysis aimed to describe the prevalence of liver fibrosis, as assessed using surrogate biomarkers, in patients with HFpEF and the association of such biomarkers in predicting clinical outcomes in these patients. Methods and results Patients with HFpEF from TOPCAT Americas were included in the analysis. The non‐alcoholic fatty liver disease fibrosis score (NFS) and fibrosis‐4 (FIB‐4) scores were calculated using a combination of clinical characteristics and laboratory parameters. Risk of advanced fibrosis was classified as low, intermediate, and high. For the 1423 with sufficient data, we used Cox regression analysis to test the association between the risk of fibrosis severity and the combined primary endpoint of all cardiovascular death, aborted cardiac arrest, and hospitalization for heart failure. Advanced fibrosis, as determined by high fibrosis scores, was present in 37.57% by the NFS and 8.02% by the FIB‐4. Higher risk of advanced hepatic fibrosis was associated with older age. In unadjusted models, the risk of advanced fibrosis was associated with the primary cardiovascular outcome [NFS high vs. low, hazard ratio (HR) 1.709 (95% confidence interval, CI 1.238–2.358, P = 0.0011) and FIB‐4 high vs. low, HR 1.561 (95% CI 1.139–2.140, P = 0.0056)]. After multivariable adjustment, this association was diminished [NFS high vs. low, HR 1.349 (95% CI 0.938–1.939, P = 0.1064) and FIB‐4 high vs. low, HR 1.415 (95% CI 0.995–2.010, P = 0.0531)]. Conclusions Our study suggests that advanced liver fibrosis, as estimated by fibrosis risk scores, may not be uncommon in patients with HFpEF, and there appears to be a limited independent association between liver fibrosis risk scores and clinical outcomes related to heart failure events.

Background The burden of amyloidosis among hospitalized patients is increasing over time. However, amyloidosis remains an underdiagnosed cause of heart failure (HF) hospitalization among older adults. Objectives We investigated the prevalence and prognostic implications of amyloidosis among patients hospitalized with HF. Methods All hospitalizations for primary diagnosis of HF between January 1, 2010, and August 31, 2015, identified in the Nationwide Readmissions Database were categorized into those with and without a secondary diagnosis of amyloidosis. HF hospitalizations with amyloidosis were then matched in a 3:1 fashion to HF hospitalizations without amyloidosis using the year of admission, discharge quarter, age, sex, and Charlson comorbidity index. Primary outcomes were inpatient mortality and 30-day readmission. Multivariable logistic regression was used to estimate the association between HF with amyloidosis and clinical outcomes. Results Of 1,593,360 HF hospitalizations that met inclusion criteria, 2,846 (0.18%) had HF with a secondary diagnosis of amyloidosis and were matched to 8,515 hospitalizations for HF without amyloidosis. Hospitalizations for HF with amyloidosis were associated with higher prevalence of kidney disease (56% vs. 45%), malignancy (20% vs. 4%), and higher inpatient mortality (6% vs. 3%) as compared with HF without amyloidosis. In adjusted analyses, HF with amyloidosis was associated with higher odds of in-hospital mortality (odds ratio: 1.46; 95% confidence interval [CI]: 1.17 to 1.82), 30-day readmission (odds ratio: 1.17; 95% CI: 1.05 to 1.31), and longer mean length of stay (least-squares mean difference: 1.46; 95% CI: 1.12 to 1.80). Conclusions In patients hospitalized with decompensated HF, presence of amyloidosis was associated with higher risk of inpatient mortality and 30-day readmission., Central Illustration

Aims Patients with obesity and ischaemic heart failure may counter‐intuitively have better outcomes compared with patients with normal body weight due to an ‘obesity paradox’. This study sought to determine if body mass index (BMI) impacts the treatment effects or safety outcomes of the treatment of ischaemic heart failure with coronary artery bypass grafting (CABG). Methods and results We obtained and reviewed the Surgical Treatment of Ischaemic Heart Failure (STICHES) data for 1212 patients. We categorized obesity by the World Health Organization (WHO) classes to define baseline characteristics and test for treatment interactions for the primary and secondary STICHES outcomes by treatment groups. While CABG decreased the risk of death, there was no evidence of treatment interaction by BMI per 5 kg/m2 (P = 0.83) or WHO obesity class. For the overall cohort, there was no interaction by WHO obesity class for the cumulative incidence of death in either the medical therapy or CABG plus medical therapy (P‐interaction = 0.90). There was a non‐significant trend for higher BMI and a lower risk of death [hazard ratio 0.92, 95% confidence interval (CI) 0.85–1.00, P = 0.051]. Increasing body size (per 5 kg/m2) was associated with return to the operating room (odds ratio 2.48, 95% CI 1.45–4.26, P

Natriuretic peptides (NPs, B-type natriuretic peptide /BNP and NT-proBNP) are universally used biomarkers with established cut-points to aid in the diagnosis of heart failure (HF). It has been demonstrated that an inverse relationship exists between obesity, defined by the body mass index (BMI), and NPs, such that the application of NPs to diagnostic algorithms in HF remains challenging in overweight and obese patients. Some have advocated that lowering the cut-offs for NPs or using a correction for high BMI may improve the diagnostic accuracy in obese individuals. The inverse relationship of NPs with high BMI is present in both HF with reduced (HFrEF) and with preserved (HFpEF) ejection fraction, although levels tend to be higher in HFrEF. Nevertheless, data from several studies have shown that the prognostic value of NPs is preserved across BMI classes, and that increasing circulating levels of NPs correlate with adverse outcomes including all-cause mortality and HF hospitalizations. While NPs can still be used in diagnosis of HF in obese individuals, lower thresholds and the clinical context should be utilized in decision making. Additionally, given the validated prognostic value even in obesity, NPs can be employed in risk-stratification of individuals with obesity and HF, although there remains limited evidence about use in those with severe obesity (BMI >40 kg/m2).

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: A malignant subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk. Methods: Participants (n=15 710) without prevalent cardiovascular disease were pooled from 3 population-based cohort studies, the ARIC Study (Atherosclerosis Risk in Communities), the DHS (Dallas Heart Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). Participants were classified into 3 groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT (high sensitivity cardiac troponin-T) Results: Over the 10-year follow-up period, HF occurred in 512 (3.3%) participants, with 5.2% in black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women versus white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI, 2.1–3.5) in those with malignant LVH and 0.9 (95% CI, 0.6–1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding population attributable fraction, were intermediate and similar among black women and white men and lowest among white women. Conclusions: A higher prevalence of malignant LVH may in part explain the higher risk of HF among blacks versus whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower HF risk and mitigate racial disparities.

AIMS: We sought to describe the baseline characteristics of PARALLAX (a randomized controlled trial of sacubitril/valsartan vs. individualized medical therapy in heart failure [HF] with mildly reduced and preserved ejection fraction [HFpEF]); compare PARALLAX to recent HFpEF trials; and examine the clinical characteristics associated with quality of life (QOL) and 6-minute walk distance (6MWD). METHODS AND RESULTS: A total of 2566 patients with HF and left ventricular ejection fraction (LVEF) >40% were randomized, of whom 96% had an LVEF ≥ 45%. Multivariable linear regression was used to determine characteristics associated with Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and 6MWD. Mean age was 73±8 years, 51% were female, and comorbidities were common. Of the QOL measures tested in PARALLAX, the SF-36 physical functioning score was most closely correlated with 6MWD (R=0.41, P

Background: Socioeconomic disadvantage is a strong determinant of adverse outcomes in patients with heart failure. However, the contribution of community-level economic distress to adverse outcomes in heart failure may differ across races and ethnicities. Methods: Patients of self-reported Black, White, and Hispanic race and ethnicity hospitalized with heart failure between 2014 and 2019 were identified from the Medicare MedPAR Part A 100% Files. We used patient-level residential ZIP code to quantify community-level economic distress on the basis of the Distressed Community Index (quintile 5: economically distressed versus quintiles 1–4: nondistressed). The association of continuous and categorical measures (distressed versus nondistressed) of Distressed Community Index with 30-day, 6-month, and 1-year risk-adjusted mortality, readmission burden, and home time were assessed separately by race and ethnicity groups. Results: The study included 1 611 586 White (13.2% economically distressed), 205 840 Black (50.6% economically distressed), and 89 199 Hispanic (27.3% economically distressed) patients. Among White patients, living in economically distressed (versus nondistressed) communities was significantly associated with a higher risk of adverse outcomes at 30-day and 1-year follow-up. Among Black and Hispanic patients, the risk of adverse outcomes associated with living in distressed versus nondistressed communities was not meaningfully different at 30 days and became more prominent by 1-year follow-up. Similarly, in the restricted cubic spline analysis, a stronger and more graded association was observed between Distressed Community Index score and risk of adverse outcomes in White patients (versus Black and Hispanic patients). Furthermore, the association between community-level economic distress and risk of adverse outcomes for Black patients differed in rural versus urban areas. Living in economically distressed communities was significantly associated with a higher risk of mortality and lower home time at 1-year follow-up in rural areas but not urban areas. Conclusions: The association between community-level economic distress and risk of adverse outcomes differs across race and ethnic groups, with a stronger association noted in White patients at short- and long-term follow-up. Among Black patients, the association of community-level economic distress with a higher risk of adverse outcomes is less evident in the short term and is more robust and significant in the long-term follow-up and rural areas.

Background Nonalcoholic fatty liver disease (NAFLD) and heart failure (HF) are increasing in prevalence. The independent association between NAFLD and downstream risk of HF and HF subtypes (HF with preserved ejection fraction and HF with reduced ejection fraction) is not well established. Methods and Results This was a retrospective, cohort study among Medicare beneficiaries. We selected Medicare beneficiaries without known prior diagnosis of HF. NAFLD was defined using presence of 1 inpatient or 2 outpatient claims using International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD‐9‐CM ), claims codes. Incident HF was defined using at least 1 inpatient or at least 2 outpatient HF claims during the follow‐up period (October 2015–December 2016). Among 870 535 Medicare patients, 3.2% (N=27 919) had a clinical diagnosis of NAFLD. Patients with NAFLD were more commonly women, were less commonly Black patients, and had a higher burden of comorbidities, such as diabetes, obesity, and kidney disease. Over a mean 14.3 months of follow‐up, patients with (versus without) baseline NAFLD had a significantly higher risk of new‐onset HF in unadjusted (6.4% versus 5.0%; P Conclusions Patients with NAFLD are at an increased risk of incident HF, with a higher risk of developing HF with preserved ejection fraction versus HF with reduced ejection fraction. The persistence of an increased risk after adjustment for clinical and demographic factors suggests an epidemiological link between NAFLD and HF beyond the basis of shared risk factors that requires further investigation.

Background: Bedside evaluation of congestion is a mainstay of heart failure (HF) management. Whether detected physical examination signs have changed over time as obesity prevalence has increased in HF populations, or if the associated prognosis differs for HF with reduced or preserved ejection fraction (HFrEF or HFpEF) is uncertain. Methods: From 2005 to 2014, the ARIC study (Atherosclerosis Risk in Communities) conducted adjudicated hospital surveillance of acute decompensated HF. We analyzed trends in physical examination findings, imaging signs, and symptoms related to congestion, both over time and by obesity class, and associated 28-day mortality risks. Results: Of 24 937 weighted hospitalizations for acute decompensated HF (mean age 75 years, 53% women, 32% Black), 47% had HFpEF. The prevalence of obesity increased from 2005 to 2014 for both HF types. With increasing obesity category, detected edema increased, while jugular venous distension decreased, and rales remained stable. Detected edema also increased over time, for both HF types. Associations between 28-day mortality and individual signs and symptoms of congestion were similar for HFpEF and HFrEF; however, the adjusted mortality risk with all 3 (edema, rales, and jugular venous distension) versus P for interaction by HF type =0.02. Conclusions: In patients hospitalized with acute decompensated HF, detected physical examination findings differ both temporally and by obesity. Combined findings from the physical examination are more prognostic of 28-day mortality for patients with HFpEF than HFrEF.

Aim: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) associate with structural heart disease and heart failure risk in individuals without known cardiovascular disease (CVD). However, few data are available regarding whether factors influencing levels of these two biomarkers are similar or distinct. We performed serial measurement of NT-proBNP and hs-cTnT in a contemporary multiethnic cohort with extensive phenotyping, with the goal of identifying their respective biological determinants in a population without known or suspected CVD. Methods: We evaluated 1877 participants of the Dallas Heart Study who had NT-proBNP and hs-cTnT measured and were free from clinical CVD at the each of its two examinations (2000–2002 and 2007–2009). Variables collected included demographic and risk factors, high-sensitivity C-reactive protein, body composition via dual-energy x-ray absorptiometry, coronary artery calcium by computed tomography, and cardiac dimensions and function by cardiac MRI. Linear regression was used to identify associations of these factors with each biomarker at baseline and with changes in biomarkers over follow-up. Results: NT-proBNP and hs-cTnT were poorly correlated at baseline (Spearman rho 0.083, p = 0.015), with only moderate correlation between change values (rho 0.18, p

Current risk prediction tools do not include physical activity (PA) or cardiorespiratory fitness (CRF), despite their robust association with adverse cardiovascular disease (CVD) events and their potential as targets for preventive interventions. PA and CRF are each associated with cardiovascular (CV) morbidity and mortality, independent of traditional risk factors. Improvement in CRF is associated with reduced risk of atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). Risk prediction tools have been developed for ASCVD, and more recently for HF, to refine CVD risk assessment and inform CVD prevention strategies. Attempts have been made to incorporate PA and CRF into available CVD risk prediction models. Inclusion of PA and CRF into established CVD risk assessment models improves CVD risk prediction incremental to established CVD risk prediction tools, suggesting PA and CRF are markers of CVD risk and targets for CVD prevention.

Introduction Sodium–glucose cotransporter 2 (SGLT2) inhibitors have been shown to slow the decline of kidney function in outcome trials, but the biological mediator(s) underlying the therapeutic benefit are not well established. Purpose We performed a post-hoc analysis exploring potential mediators of the effects of the SGLT2 inhibitor ertugliflozin on the VERTIS CV exploratory kidney composite outcome (sustained 40% decrease from baseline in estimated glomerular filtration rate [eGFR], chronic kidney replacement therapy or kidney death). Methods In VERTIS CV, 8246 participants with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease were randomised to placebo, ertugliflozin 5 mg or 15 mg (pooled for analyses, as prospectively planned), and were followed for a mean of 3.5 years. The hazard ratio (HR; 95% confidence interval) for the pre-specified exploratory kidney composite outcome was 0.66 (0.50, 0.88). Cox regression models were used to evaluate covariates that were significantly differentially changed from baseline with ertugliflozin treatment as candidate mediators, with a mediator identified as a covariate when added to an unadjusted model of randomised treatment assignment a) yielded a larger hazard ratio; and b) the mediator retained P100%. Results Of 22 covariates significantly changed by ertugliflozin, nine were identified as potential mediators (Table). The covariates with a high percentage of mediation were those related to changes in blood erythrocytes (haemoglobin, haematocrit and red blood cell mass), with average changes in haemoglobin having the highest percentage of mediation (61.8%). Serum uric acid was associated with a mediation of 29.4% and 50.0% for the early and average post-randomisation effect periods, respectively. Early changes in glycated haemoglobin had a large mediation (50%), but the average change during the trial was not significant. Average change in serum albumin had a large mediation (29.4%). Average changes in body weight and systolic blood pressure had percentages of mediation of 41.2% and 14.7%, respectively. Conclusion Multiple factors may be involved in the reduction of the kidney composite outcome observed with ertugliflozin. In the short-term, changes in glycaemia had a high mediation effect. Over the long-term, changes suggestive of haemoconcentration and/or haematopoiesis (natriuresis-related effects), showed the highest percentage of mediation, followed by changes in serum uric acid and body weight (glucosuria-related effects). Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA in collaboration with Pfizer Inc., New York, NY, USA

Introduction The prevalence and outcomes of polyvascular disease (PVD) in patients admitted with acute decompensated heart failure (ADHF) have not been previously reported, nor is it known whether associations differ for heart failure (HF) with reduced vs. preserved ejection fraction (HFrEF vs HFpEF, respectively). Purpose To investigate the relationship between atherosclerotic involvement of multiple arterial territories and mortality in patients hospitalized with ADHF. Methods The Atherosclerosis Risk in Communities (ARIC) study conducted hospital surveillance of adjudicated heart failure in 4 US areas from 2005–2014, with events verified by physician review. Medical histories were abstracted from the hospital record. PVD was defined by coexisting disease in ≥2 arterial beds, identified by prevalent coronary artery disease, peripheral arterial disease, and cerebrovascular disease. Mortality hazards of PVD vs. no PVD were analyzed separately for HFpEF and HFrEF, with adjustment for age, race, sex, year of admission and geographic region. All analyses were weighted by the inverse of the sampling probability. Results Of 24,936 ADHF hospitalizations (52% female, 32% Black, mean age 75 years), 19% had PVD (22% among HFrEF hospitalizations, 17% among HFpEF hospitalizations), Figure 1. There was an increasing trend in 1-year mortality with 0, 1 and ≥2 arterial bed involvement, both for patients with HFrEF (29% to 32% to 38%; P-trend=0.0006) and HFpEF (26% to 32% to 37%; P-trend Conclusion Patients hospitalized with ADHF and coexisting PVD have an increased risk of death, irrespective of HF type. Clinical attention should be directed toward PVD, with secondary prevention strategies enacted to improve the prognosis of this vulnerable population. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institutes of Health Distributions of arterial diseaseTrends in 1-year mortality outcomes

Background Frailty is conceptualized as an accumulation of deficits in multiple areas and is strongly associated with the prognosis of heart failure (HF). However, the social domain of frailty is less well investigated. We prospectively evaluated the clinical characteristics and prognostic impact of social frailty (SF) in elderly patients with HF. Methods and Results FRAGILE‐HF (prevalence and prognostic value of physical and social frailty in geriatric patients hospitalized for heart failure) is a multicenter, prospective cohort study focusing on patients hospitalized for HF and aged ≥65 years. We defined SF by Makizako’s 5 items, which have been validated as associated with future disability. The primary end point was a composite of all‐cause death and rehospitalization because of HF. The impact of SF on all‐cause mortality alone was also evaluated. Among 1240 enrolled patients, 825 (66.5%) had SF. During the 1‐year observation period after discharge, the rates of the combined end point and all‐cause mortality were significantly higher in patients with SF than in those without SF (Log‐rank test: both P

IMPORTANCE: Elevated high-sensitivity cardiac troponin T (hscTnT) and N-terminal pro–B-type natriuretic peptide (NTproBNP) levels are associated with risk of heart failure (HF) and mortality among individuals in the general population. However, it is unknown if this risk is modifiable. OBJECTIVE: To test the hypothesis that elevated hscTnT and NTproBNP levels would identify individuals with the greatest risk for mortality and HF and the largest benefit associated with intensive systolic blood pressure (SBP) lowering. DESIGN, SETTING, AND PARTICIPANTS: This is a nonprespecified post hoc analysis of the multicenter, prospective, randomized clinical Systolic Blood Pressure Intervention Trial (SPRINT), conducted from October 20, 2010, to August 20, 2015. A total of 9361 patients without diabetes with increased risk for cardiovascular disease were randomized to receive intensive vs standard SBP lowering. Statistical analysis was performed on an intention-to-treat basis from September 30, 2019, to July 29, 2021. INTERVENTIONS: Participants were randomized to undergo intensive (

Objectives The aim of this study was to evaluate the association between age and invasive cardiovascular hemodynamics during upright exercise among healthy adults. Background The marked age-related decline in maximal exercise oxygen uptake (peak VO2) may contribute to the high burden of heart failure among older individuals and their greater severity of exertional symptoms. However, the mechanisms underlying this decline are not well understood. Methods A total of 104 healthy community-dwelling volunteers age 20 to 76 years well screened for cardiovascular disease underwent exhaustive upright exercise with brachial and pulmonary artery catheters; radionuclide ventriculography; and expired gas analysis for the measurement of peak VO2, cardiac output, left ventricular stroke volume, end-diastolic volume, end-systolic volume, ejection fraction, pulmonary capillary wedge pressure, and arteriovenous oxygen difference. Results Over a 5.5-decade age range, there was a 40% decline in peak VO2 due primarily to reduced peak exercise cardiac output; peak arteriovenous oxygen difference was unaffected by age. The lower age-related exercise cardiac output was related to lower peak exercise heart rate and stroke volume. Aging was also associated with lower peak exercise ejection fraction, indicating reduced inotropic reserve. Peak exercise end-diastolic volume was lower with aging despite similar left ventricular filling pressure, suggesting age-related reduced diastolic compliance limiting the use of the Frank-Starling mechanism to compensate for reduced chronotropic and inotropic reserves. These age relationships were unaffected by sex. Conclusions The age-related decline in exercise capacity among healthy persons is due predominantly to cardiac mechanisms, including reduced chronotropic and inotropic reserve and possibly reduced Frank-Starling reserve. Peak exercise left ventricular filling pressure and arteriovenous oxygen difference are unchanged with healthy aging.

The updated scientific statement by the American Heart Association has defined resistant hypertension (HTN;RH) as uncontrolled blood pressure (BP) ≥ 130/80 mmHg, despite concurrent use of 3 anti-HTN drug classes comprising a calcium channel blocker, a blocker of renin-angiotensin system, and a thiazide diuretic, preferably chlorthalidone. Using the updated BP criteria, the prevalence of RH in the United States is found to be modestly increased by approximately 3–4% among treated population. Meta-analysis of observational studies have demonstrated that pseudo-RH from white coat HTN or medication nonadherence is as much common as the truly RH. Thus, screening for pseudo-resistance in the evaluation of all apparent RH is of utmost importance as diagnosis of white-coat HTN requires no treatment, while medication nonadherence would benefit from identifying and targeting barriers to adherence.

Background: Risk for atherosclerotic cardiovascular disease was a novel consideration for antihypertensive medication initiation in the 2017 American College of Cardiology/American Heart Association Blood Pressure (BP) guideline. Whether biomarkers of chronic myocardial injury (high-sensitivity cardiac troponin T ≥6 ng/L] and stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥100 pg/mL) can inform cardiovascular (CV) risk stratification and treatment decisions among adults with elevated BP and hypertension is unclear. Methods: Participant-level data from 3 cohort studies (Atherosclerosis Risk in Communities Study, Dallas Heart Study, and Multiethnic Study of Atherosclerosis) were pooled, excluding individuals with prevalent CV disease and those taking antihypertensive medication at baseline. Participants were analyzed according to BP treatment group from the 2017 American College of Cardiology/American Heart Association BP guideline and those with high BP (120 to 159/ Results: The study included 12 987 participants (mean age, 55 years; 55% women; 21.5% with elevated high-sensitivity cardiac troponin T; 17.7% with elevated NT-proBNP) with 825 incident CV events over 10-year follow-up. Participants with elevated BP or hypertension not recommended for antihypertensive medication with versus without either elevated high-sensitivity cardiac troponin T or NT-proBNP had a 10-year CV incidence rate of 11.0% and 4.6%, with a 10-year number needed to treat to prevent 1 event for intensive BP lowering of 36 and 85, respectively. Among participants with stage 1 or stage 2 hypertension recommended for antihypertensive medication with BP Conclusions: Elevations in high-sensitivity cardiac troponin T or NT-proBNP identify individuals with elevated BP or hypertension not currently recommended for antihypertensive medication who are at high risk for CV events. The presence of nonelevated biomarkers, even in the setting of stage 1 or stage 2 hypertension, was associated with lower risk. Incorporation of biomarkers into risk assessment algorithms may lead to more appropriate matching of intensive BP control with patient risk.

Objectives This study sought to assess the prevalence of frailty, its associations with physical function, quality of life (QoL), cognition, and depression and to investigate more efficient methods of detection in older patients hospitalized with acute decompensated heart failure (ADHF). Background In contrast to the outpatient population with chronic HF, much less is known regarding frailty in older, hospitalized patients with ADHF. Methods Older hospitalized patients (N = 202) with ADHF underwent assessment of frailty (using Fried criteria), short physical performance battery (SPPB), 6-min walk test (6-MWT) distance, quality of life (QoL using the Kansas City Cardiomyopathy Questionnaire), cognition (using the Montreal Cognition Assessment), and depression (using the Geriatric Depression Screen [GDS]). The associations of frailty with these patient-centered outcomes were assessed by using adjusted linear regression models. Novel strategies to identify frailty were examined. Results A total of 50% of older, hospitalized patients with ADHF were frail, 48% were pre-frail, and 2% were non-frail. Female sex, burden of comorbidity, and prior HF hospitalization were significantly associated with higher likelihood of frailty. Frailty (vs. pre-frail status) was associated with a significantly worse SPPB score (5 ± 2.2 vs. 7 ± 2.4, respectively), 6-MWT distance (143 ± 79 m vs. 221 ± 99 m, respectively), QoL (35 ± 19 vs. 46 ± 21, respectively), and more depression (GDS score: 5.5 ± 3.5 vs. 4.2 ± 3.3, respectively) but similar cognition. These associations were unchanged after adjustment for age, sex, race, total comorbidities, and body mass index. Slow gait speed plus low physical activity signaled frailty status as well (C-statistic = 0.85). Conclusions Ninety-eight percent of older, hospitalized patients with ADHF are frail or pre-frail. Frailty (vs. pre-frail status) is associated with worse physical function, QoL, comorbidity, and depression. The simple 4-m walk test combined with self-reported physical activity may quickly and efficiently identify frailty in older patients with ADHF.

Frailty, a syndrome characterized by an exaggerated decline in function and reserve of multiple physiological systems, is common in older patients with heart failure (HF) and is associated with worse clinical and patient-reported outcomes. Although several detailed assessment tools have been developed and validated in the geriatric population, they are cumbersome, not validated in patients with HF, and not commonly used in routine management of patients with HF. More recently, there has been an increasing interest in developing simple frailty screening tools that could efficiently and quickly identify frail patients with HF in routine clinical settings. As the burden and recognition of frailty in older patients with HF increase, a more comprehensive approach to management is needed that targets deficits across multiple domains, including physical function and medical, cognitive, and social domains. Such a multidomain approach is critical to address the unique, multidimensional challenges to the care of these high-risk patients and to improve their functional status, quality of life, and long-term clinical outcomes. This review discusses the burden of frailty, the conceptual underpinnings of frailty in older patients with HF, and potential strategies for the assessment, screening, and management of frailty in this vulnerable patient population.

Aim To identify distinct phenotypic subgroups in a highly-dimensional, mixed-data cohort of individuals with heart failure (HF) with preserved ejection fraction (HFpEF) using unsupervised clustering analysis. Methods and results The study included all Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) participants from the Americas (n = 1767). In the subset of participants with available echocardiographic data (derivation cohort, n = 654), we characterized three mutually exclusive phenogroups of HFpEF participants using penalized finite mixture model-based clustering analysis on 61 mixed-data phenotypic variables. Phenogroup 1 had higher burden of co-morbidities, natriuretic peptides, and abnormalities in left ventricular structure and function; phenogroup 2 had lower prevalence of cardiovascular and non-cardiac co-morbidities but higher burden of diastolic dysfunction; and phenogroup 3 had lower natriuretic peptide levels, intermediate co-morbidity burden, and the most favourable diastolic function profile. In adjusted Cox models, participants in phenogroup 1 (vs. phenogroup 3) had significantly higher risk for all adverse clinical events including the primary composite endpoint, all-cause mortality, and HF hospitalization. Phenogroup 2 (vs. phenogroup 3) was significantly associated with higher risk of HF hospitalization but a lower risk of atherosclerotic event (myocardial infarction, stroke, or cardiovascular death), and comparable risk of mortality. Similar patterns of association were also observed in the non-echocardiographic TOPCAT cohort (internal validation cohort, n = 1113) and an external cohort of patients with HFpEF [Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial cohort, n = 198], with the highest risk of adverse outcome noted in phenogroup 1 participants. Conclusions Machine learning-based cluster analysis can identify phenogroups of patients with HFpEF with distinct clinical characteristics and long-term outcomes.

Author(s): Patel, Kershaw V; Mauricio, Rina; Grodin, Justin L; Ayers, Colby; Fonarow, Gregg C; Berry, Jarett D; Pandey, Ambarish | Abstract: AimsThe relationship between resting stroke volume (SV) and prognostic markers in heart failure with preserved ejection fraction (HFpEF) is not well established. We evaluated the association of SV index (SVI) at rest with exercise capacity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in stable patients with HFpEF.Methods and resultsParticipants enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial with available data on SVI by the Doppler method were included in this analysis (n = 185). A low-flow state defined by resting SVI l 35 mL/m2 was present in 37% of study participants. Multivariable adjusted linear regression analysis suggested that higher resting heart rate, higher body weight, prevalent atrial fibrillation, and smaller left ventricular (LV) end-diastolic dimension were each independently associated with lower SVI. Patients with low-flow HFpEF had lower systolic blood pressure and smaller LV end-diastolic dimension. In multivariable adjusted linear regression models, lower SVI was significantly associated with lower peak oxygen consumption (peak VO2 ) and higher NT-proBNP levels at baseline, and greater decline in peak VO2 at 6 month follow-up independent of other confounders. Resting LV ejection fraction was not associated with peak VO2 and NT-proBNP levels.ConclusionsThere is heterogeneity in the resting SVI distribution among patients with stable HFpEF, with more than one-third of patients identified with the low-flow HFpEF phenotype (SVI l 35 mL/m2 ). Lower SVI was independently associated with lower peak VO2 , higher NT-proBNP levels, and greater decline in peak VO2 . These findings highlight the potential prognostic utility of SVI assessment in the management of patients with HFpEF.

Highlights •Ticagrelor is a cornerstone of antithrombotic therapy after ACS, but its effectiveness is limited by nonadherence. •Premature ticagrelor discontinuation occurs in 25% of patients and is related to adverse events. •The most frequent adverse events of ticagrelor are bleeding and dyspnea. •Appropriate patient selection, early follow-up, patient education, and appropriate bleeding prophylaxis can mitigate ticagrelor nonadherence.

Background The Wake‐Up T2MI Registry is a retrospective cohort study investigating patients with type 2 myocardial infarction (T2MI), acute myocardial injury, and chronic myocardial injury. We aim to explore risk stratification strategies and investigate clinical characteristics, management, and short‐ and long‐term outcomes in this high‐risk, understudied population. Methods From 1 January 2009 to 31 December 2010, 2846 patients were identified with T2MI or myocardial injury defined as elevated cardiac troponin I with at least one value above the 99th percentile upper reference limit and coefficient of variation of 10% (>40 ng/L) and meeting our inclusion criteria. Data of at least two serial troponin values will be collected from the electronic health records to differentiate between acute and chronic myocardial injury. The Fourth Universal Definition will be used to classify patients as having (a) T2MI, (b) acute myocardial injury, or (c) chronic myocardial injury during the index hospitalization. Long‐term mortality data will be collected through data linkage with the National Death Index and North Carolina State Vital Statistics. Results We have collected data for a total of 2205 patients as of November 2018. The mean age of the population was 65.6 ± 16.9 years, 48% were men, and 64% were white. Common comorbidities included hypertension (71%), hyperlipidemia (35%), and diabetes mellitus (30%). At presentation, 40% were on aspirin, 38% on β‐blockers, and 30% on statins. Conclusion Improved characterization and profiling of this cohort may further efforts to identify evidence‐based strategies to improve cardiovascular outcomes among patients with T2MI and myocardial injury.

An expanding number of therapies are now indicated for comorbidity management in heart failure with preserved ejection fraction (HFpEF). Whether comorbidity burdens differ for patients with HFpEF who are hospitalized for acute decompensated heart failure (ADHF) versus those with chronic stable heart failure (CSHF) who are hospitalized for other causes is uncertain. Since 2005, the Atherosclerosis Risk in Communities (ARIC) study has conducted adjudicated community surveillance of hospitalized heart failure. Hospitalized ADHF and CSHF were sampled identically, using prespecified discharge codes and demographic strata, but were differentiated by signs or symptoms of acute or worsening heart failure upon physician review of the medical record. HFpEF was defined by an ejection fraction ≥50%. All events were weighted by the inverse of the sampling probability for statistical analyses. From 2005 to 2014, 13,706 weighted (2,936 unweighted) hospitalizations (mean age 77 years, 64% women, 29% Black) were sampled among patients with HFpEF and adjudicated ADHF (86%) or CSHF (14%). Comorbidity prevalence was high both for ADHF and CSHF hospitalizations, irrespective of gender. Women hospitalized with ADHF versus CSHF had greater prevalence of hypertension (89% vs 84%) diabetes mellitus (48% vs 39%) and renal disease (85% vs 74%). Echocardiographic features such as left ventricular hypertrophy and valvular abnormalities were more common with ADHF than CSHF, for both genders. However, the 28-day and 1-year mortality risk were comparable for ADHF and CSHF. In conclusion, hospitalized patients with HFpEF have a high comorbidity burden and risk of death, irrespective of the cause of hospitalization.

Background Diabetes is associated with abnormalities in cardiac remodeling and high risk of heart failure (HF). Objectives The purpose of this study was to evaluate the prevalence and prognostic implications of diabetes with cardiomyopathy (DbCM) among community-dwelling individuals. Methods Adults without prevalent cardiovascular disease or HF were pooled from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], CHS [Cardiovascular Health Study], CRIC [Chronic Renal Insufficiency Cohort]). Among participants with diabetes, DbCM was defined using different definitions: 1) least restrictive: ≥1 echocardiographic abnormality (left atrial enlargement, left ventricle hypertrophy, diastolic dysfunction); 2) intermediate restrictive: ≥2 echocardiographic abnormalities; and 3) most restrictive: elevated N-terminal pro-B-type natriuretic peptide levels (>125 in normal/overweight or >100 pg/mL in obese) plus ≥2 echocardiographic abnormalities. Adjusted Fine-Gray models were used to evaluate the risk of HF. Results Among individuals with diabetes (2,900 of 10,208 included), the prevalence of DbCM ranged from 67.0% to 11.7% in the least and most restrictive criteria, respectively. Higher fasting glucose, body mass index, and age as well as worse kidney function were associated with higher risk of DbCM. The 5-year incidence of HF among participants with DbCM ranged from 8.4%-12.8% in the least and most restrictive definitions, respectively. Compared with euglycemia, DbCM was significantly associated with higher risk of incident HF with the highest risk observed for the most restrictive definition of DbCM (HR: 2.55 [95% CI: 1.69-3.86]; least restrictive criteria HR: 1.99 [95% CI: 1.50-2.65]). A similar pattern of results was observed across cohort studies, across sex and race subgroups, and among participants without hypertension or obesity. Conclusions Regardless of the criteria used to define cardiomyopathy, DbCM identifies a high-risk subgroup for developing HF.

Background Heart failure (HF) poses a major public health burden in the United States. We examined the burden of out‐of‐pocket healthcare costs on patients with HF and their families. Methods and Results In the Medical Expenditure Panel Survey, we identified all families with ≥1 adult member with HF during 2014 to 2018. Total out‐of‐pocket healthcare expenditures included yearly care‐specific costs and insurance premiums. We evaluated 2 outcomes of financial toxicity: (1) high financial burden—total out‐of‐pocket healthcare expense to postsubsistence income ratio of >20%, and (2) catastrophic financial burden with the ratio of >40%—a bankrupting expense defined by the World Health Organization. There were 788 families in the Medical Expenditure Panel Survey with a member with HF representing 0.54% (95% CI, 0.48%–0.60%) of all families nationally. The overall mean annual out‐of‐pocket healthcare expenses were $4423 (95% CI, $3908–$4939), with medications and health insurance premiums representing the largest categories of cost. Overall, 14% (95% CI, 11%–18%) of families experienced a high burden and 5% (95% CI, 3%–6%) experienced a catastrophic burden. Among the two‐fifths of families considered low income, 24% (95% CI, 18%–30%) experienced a high financial burden, whereas 10% (95% CI, 6%–14%) experienced a catastrophic burden. Low‐income families had 4‐fold greater risk‐adjusted odds of high financial burden (odds ratio [OR] , 3.9; 95% CI, 2.3–6.6), and 14‐fold greater risk‐adjusted odds of catastrophic financial burden (OR, 14.2; 95% CI, 5.1–39.5) compared with middle/high‐income families. Conclusions Patients with HF and their families experience large out‐of‐pocket healthcare expenses. A large proportion encounter financial toxicity, with a disproportionate effect on low‐income families.

Background Patient‐reported outcomes may be discordant to severity of illness as assessed by objective parameters. The frequency of this discordance and its influence on clinical outcomes in patients with heart failure is unknown. Methods and Results In HF‐ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), participants (N=2062) had baseline assessment of health‐related quality of life via the Kansas City Cardiomyopathy Clinical Summary score (KCCQ‐CS) and objective severity by cardiopulmonary stress testing (minute ventilation [V E ]/carbon dioxide production [VCO 2 ] slope). We defined 4 groups by median values: 2 concordant (lower severity: high KCCQ‐CS and low V E /VCO 2 slope; higher severity: low KCCQ‐CS and high V E /VCO 2 slope) and 2 discordant (symptom minimizer: high KCCQ‐CS and high V E /VCO 2 slope; symptom magnifier: low KCCQ‐CS and low V E /VCO 2 slope). The association of group assignment with mortality was assessed in adjusted Cox models. Symptom magnification (23%) and symptom minimization (23%) were common. Despite comparable KCCQ‐CS scores, the risk of all‐cause mortality in symptom minimizers versus concordant–lower severity participants was increased significantly (hazard ratio [HR], 1.79; 95% CI, 1.27–2.50; P P =0.18, respectively). Conclusions Severity of illness by patient report versus cardiopulmonary exercise testing was frequently discordant. Mortality tracked more closely with the objective data, highlighting the importance of relying not only on patient report, but also objective data when risk stratifying patients with heart failure.

Background: Visceral/ectopic fat is a modifiable cardiovascular (CV) risk factor. Liraglutide, a glucagon like peptide 1 receptor agonist, reduces weight and CV events compared with placebo. We investigated its effects on body fat distribution in a high-risk population with overweight/obesity. Methods: In this double blind, single center trial, we randomly assigned individuals ≥35 years with BMI ≥30 kg/m2 or ≥27 kg/m2 with metabolic syndrome to receive liraglutide or placebo for 40 wks in addition to reduced calorie diet and increased physical activity. Participants underwent a 6-minute neck to knee MRI scan for fat distribution at randomization and end of treatment. The primary outcome was relative percent change in visceral adipose tissue volume. Secondary endpoints included changes in adipose distribution and other biomarkers of CV risk. Results: Of 185 randomized participants, 128 completed the study and were included in the mITT analysis. The cohort was 92% female, 38% Black, and 24% Hispanic with mean age 50 yrs and BMI 38 kg/m2 with median follow up 36 wks. Liraglutide significantly reduced visceral and ectopic fat and inflammation compared with placebo (Table). Conclusions: Liraglutide reduced visceral/ectopic fat measured by MRI in adults with overweight/obese at high CV risk, with proportionally greater effects seen in the abdominal viscera and liver. Disclosure I. Neeland: Consultant; Self; Merck & Co., Inc. S. P. Marso: Consultant; Self; Novo Nordisk, Other Relationship; Self; Abbott Vascular, ASAHI Intecc, Boston Scientific Corporation. C. Ayers: None. A. Pandey: None. P. H. Joshi: Research Support; Self; Amgen Inc., AstraZeneca, NASA, Novartis AG, Novo Nordisk. Funding Novo Nordisk