BACKGROUND:High-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 are inflammatory biomarkers associated with cardiovascular disease (CVD) risk. OBJECTIVES:This study aims to examine the associations of hs-CRP and IL-6 with risk of atherosclerotic cardiovascular disease (ASCVD) and incident heart failure (HF) and to evaluate the effect of an intensive lifestyle intervention (ILI) targeting weight loss on IL-6 in type 2 diabetes (T2D). METHODS:Look AHEAD trial participants with T2D and overweight/obesity underwent measurement of hs-CRP (n = 1,902) and IL-6 (n = 1,507) at baseline. Associations of inflammatory biomarkers with risk of ASCVD and incident HF were evaluated using adjusted Cox models. Associations were evaluated among participants with and without CVD history. A generalized linear model compared 1-year change in IL-6 across the ILI and diabetes support and education treatment groups. RESULTS:Median baseline hs-CRP and IL-6 were 4.04 mg/L and 2.07 pg/mL, respectively. After adjusting for demographics, CVD risk factors, and statin use, hs-CRP was not significantly associated with the risk of ASCVD or incident HF. Higher IL-6 was significantly associated with higher risk of incident HF in the overall cohort (HR: 1.43; 95% CI: 1.16-1.75 per 1-SD higher log[IL-6]) with a stronger association among those with no history of CVD (HR: 1.92; 95% CI: 1.38-2.66 per 1-SD higher log[IL-6]; IL-6 × CVD history P interaction < 0.05). The reduction in IL-6 at 1-year was greater with the ILI than with the diabetes support and education (-28.7% vs -11.8%; P = 0.01). CONCLUSIONS:Among adults with T2D and overweight/obesity, IL-6 identified residual inflammatory risk of incident HF, particularly among adults with no CVD history. An ILI targeting weight loss reduced IL-6 over 1-year of follow-up. (Look AHEAD: Action for Health in Diabetes [Look AHEAD]; NCT00017953).
Heart failure (HF) clinical trials increasingly rely on diverse endpoints beyond mortality, including hospitalizations, imaging, hemodynamic status, biomarkers, functional capacity, and patient-reported outcomes. Although statistically significant differences between treatment groups are commonly reported, interpreting whether these changes are clinically meaningful for individual patients remains challenging. This JACC: Heart Failure position statement proposes a pragmatic framework for defining clinically meaningful within-patient change across commonly used HF outcomes by integrating measurement variability, prognostic associations, and patient-anchored evidence where available. Relative and absolute risk reductions should both inform interpretation of clinical events, while imaging, hemodynamic, biomarker, and functional measures require changes exceeding measurement variability and consideration of physiological context. Patient-reported health status measures, particularly the Kansas City Cardiomyopathy Questionnaire, currently have the strongest evidence supporting clinically meaningful thresholds. Many proposed cutpoints remain provisional, reflecting limited validation linking physiological changes to patient-perceived benefit or hard outcomes. Future work should prioritize anchor-based analyses and patient-centered validation to align trial results with shared decision-making.
Background Frailty is common in advanced heart failure (HF) and influences decisions regarding durable left ventricular assist device (LVAD) therapy. Objectives This study aims to characterize the prevalence, prognostic significance, and reversibility of frailty in patients receiving contemporary LVAD therapy. Methods Pooled analysis of HeartMate 3 LVAD recipients from the MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial portfolio and ARIES-HM3 (Antiplatelet Removal and Hemocompatibility Events with the HeartMate 3 Pump) trial. Frailty was quantified using the Rockwood cumulative deficit score and defined as a frailty index (FI) ≥0.21. The authors further stratified frail participants into tertiles of increasing frailty: mildly frail (FI: 0.21-0.324), moderately frail (FI: 0.325-0.39), and severely frail (FI: ≥0.40). The primary outcome was a composite of death, hemocompatibility-related adverse events, renal dysfunction, or right HF. Results Among 2,724 LVAD recipients, 95% met criteria for frailty at baseline. Increasing frailty severity was associated with progressively higher risk of the primary composite outcome and a >6-fold increase in mortality in the most severely frail group than in nonfrail patients (HR: 6.26; 95% CI: 2.32-16.90). Frailty improved substantially after LVAD implantation, with the greatest absolute reductions observed among patients with severe baseline frailty. Recovery to a nonfrail state occurred in 15% of patients by 3 months and was associated with significantly lower subsequent risk of the primary endpoint (rate ratio: 0.53; 95% CI: 0.36-0.79). A multivariable model predicted recovery from frailty with good discrimination (area under the curve: 0.78-0.81). Conclusions Frailty is highly prevalent among patients undergoing LVAD implantation but is often dynamic and partially reversible after restoration of circulatory support. In advanced HF, frailty may reflect physiological vulnerability related to circulatory insufficiency rather than irreversible decline and may represent a modifiable risk state when evaluating candidates for durable mechanical circulatory support.
BACKGROUND:Primary graft dysfunction (PGD) remains the leading cause of early mortality after heart transplantation and limits broader adoption of donation after circulatory death (DCD) hearts. Ex vivo heart perfusion (EVHP) provides a human platform to characterize molecular features associated with graft performance. OBJECTIVES:This study examines the circulating proteome during EVHP to determine potential markers or modulators of PGD in DCD hearts. METHODS:The authors prospectively studied 37 human DCD hearts supported on EVHP. Perfusate was sampled at initiation (0-2 hours) and termination (3-6 hours) and profiled using a high-throughput proteomic platform (SOMAScan 11K). Ten PGD cases were propensity-matched to 10 non-PGD controls. Differential protein abundance and pathway enrichment analyses were performed. RESULTS:At EVHP initiation, PGD hearts demonstrated enrichment of senescence-associated pathways (normalized enrichment score [NES]: 1.93; q < 0.01). By EVHP termination, proteomic profiles more clearly separated PGD from non-PGD hearts. PGD hearts exhibited broader proteomic remodeling, with 1,242 increased proteins (742 unique; q < 0.05) and 745 decreased proteins (619 unique; q < 0.05). Protein abundance was more dynamically associated with perfusion time in PGD hearts (33 proteins; median |ρ| = 0.78; q < 0.05) than in non-PGD hearts (3 proteins; median |ρ| = 0.83; q < 0.05). Pathway analysis revealed enrichment of apoptotic (NES: 1.75; q < 0.05) and catabolic programs (NES: 1.42; q < 0.05), with concurrent activation of inflammatory pathways (NES: 1.68; q < 0.05) in hearts destined to have PGD. CONCLUSIONS:PGD is defined less by baseline differences than by divergent proteomic trajectories during EVHP. Early enrichment of senescence-associated pathways is followed by coordinated activation of apoptotic and catabolic programs. These findings position EVHP as a physiological window for identifying molecular signatures of graft dysfunction and suggest an opportunity for targeted intervention in DCD donor hearts.
BACKGROUND:Safe and effective decongestion remains an important therapeutic goal in patients hospitalized for heart failure. OBJECTIVES:The authors evaluated the effect of dapagliflozin on multiple clinically relevant measures of congestion among patients hospitalized for heart failure. METHODS:This was a prespecified analysis of DAPA ACT HF-TIMI 68 (Dapagliflozin Effect on Cardiovascular Events in Acute Heart Failure-Thrombolysis in Myocardial Infarction 68), a randomized, placebo-controlled trial evaluating in-hospital initiation of dapagliflozin on clinical outcomes through 2 months. The authors assessed placebo-adjusted changes from baseline in modified EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure) Composite Congestion Score (CCS), body weight, mean daily loop diuretic dose (furosemide 40 mg intravenous [IV] equivalents), and body weight adjusted for mean daily loop diuretic dose (diuretic efficiency) at 1 week, 1 month, and 2 months using linear mixed-effects models for repeated measures. RESULTS:At randomization, 12%, 63%, and 24% had no congestion (CCS 0), mild-to-moderate congestion (CCS 1-3), and severe congestion (CCS 4-9), respectively. Compared with placebo, dapagliflozin improved all decongestion-related endpoints by 1 week, including CCS (least squares mean difference [LSMD]: -0.18; 95% CI: -0.33 to -0.04; P = 0.011), body weight (LSMD: -0.60 kg; 95% CI: -0.95 to -0.26; P < 0.001), mean daily loop diuretic dose (LSMD: -0.12 furosemide 40-mg IV equivalents; 95% CI: -0.22 to -0.02; P = 0.014), and diuretic efficiency (LSMD: -0.93 kg/furosemide 40 mg IV equivalents; 95% CI: -1.61 to -0.25; P = 0.008). These improvements were sustained through 2 months, with progressive increases in diuretic efficiency through 2 months (LSMD: -1.99 kg/furosemide 40 mg IV equivalents; 95% CI: -3.19 to -0.78; P < 0.001). CONCLUSIONS:In-hospital initiation of dapagliflozin led to modest but significant improvements across multiple measures of congestion within 1 week that were sustained through 2 months. Diuretic efficiency progressively improved through 2 months. (Dapagliflozin Effect on Cardiovascular Events in Acute Heart Failure-Thrombolysis in Myocardial Infarction 68 [DAPA ACT HF-TIMI 68]; NCT04363697).
BACKGROUND:The MAPLE-HCM trial demonstrated the superiority of monotherapy with aficamten vs metoprolol at improving clinical endpoints in obstructive hypertrophic cardiomyopathy (oHCM). The impact of pretrial use of standard-of-care (SOC) medications, including beta-blockers (BBs), was unknown. OBJECTIVES:The aim of this study was to evaluate the efficacy of aficamten by pretrial medical therapy. METHODS:Participants were randomized to aficamten (5-20 mg/d) or metoprolol (50-200 mg/d) for 24 weeks. Exercise capacity and other efficacy endpoints were examined by pretrial medical therapy: 1) BB-no: participants not receiving any BB therapy at screening; 2) BB-yes: participants on BB at screening, regardless of duration of exposure; and 3) SOC-no: participants without SOC therapy for ≥12 months before screening. Groups 1 and 3 overlapped, as all SOC-no participants were also included in the BB-no group. RESULTS:A total of 175 patients were randomized. At screening, 52 participants were BB-no, 123 BB-yes, and 22 SOC-no. The overall mean age was 58 years; 41.7% of patients were women. The mean left ventricular outflow tract gradient was 47 mm Hg at rest and 74 mm Hg after the Valsalva maneuver. Aficamten demonstrated consistent benefits across multiple efficacy endpoints compared with metoprolol, independent of pretrial medical therapy. Aficamten improved exercise capacity (peak oxygen uptake) compared with metoprolol: BB-no: +3.1 mL/kg/min (95% CI: 1.8-4.5 mL/kg/min; P < 0.001); BB-yes: +1.9 mL/kg/min (95% CI: 0.9-2.8 mL/kg/min; P < 0.001) (P for interaction = 0.133); and SOC-no: +4.1 mL/kg/min (95% CI: 2.2-6.0 mL/kg/min; P < 0.001). CONCLUSIONS:Aficamten was superior to metoprolol regardless of BB use at screening or prior SOC medications. This supports the primary study results and suggests no confounding by BB resistance. Consequently, aficamten can be considered an early treatment option independent of prior SOC history. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM [MAPLE-HCM; NCT05767346).
