BACKGROUND: Elevated levels of cardiac branched-chain amino acids (BCAAs) and their metabolites, namely branched-chain keto acids (BCKAs), contribute to the development of insulin resistance, contractile dysfunction, and...BACKGROUND: Elevated levels of cardiac branched-chain amino acids (BCAAs) and their metabolites, namely branched-chain keto acids (BCKAs), contribute to the development of insulin resistance, contractile dysfunction, and adverse remodeling in the failing heart. However, there is still confusion about whether BCAA or BCKA mediate these detrimental effects in the failing heart. METHODS: Cardiac-specific mitochondrial branched-chain aminotransferase, the enzyme that converts BCAA into BCKA, knockout (BCAT2) mice underwent a sham or transverse aortic constriction surgery to induce heart failure. Changes in cardiac function and structure were monitored pre- and posttransverse aortic constriction using echocardiography, and metabolic flux through the tricarboxylic acid cycle was measured by perfusing isolated working hearts with radiolabeled energy substrates. Direct effects of BCAA and BCKA on cell hypertrophy were characterized using phenylephrine-induced cell hypertrophy in differentiated cells. RESULTS: Lowering cardiac BCKA levels in BCAT2 failing hearts increases insulin-stimulated glucose oxidation rates via enhancing mitochondrial protein kinase B and pyruvate dehydrogenase complex activities. Increased glucose oxidation rates in BCAT2 failing hearts enhanced cardiac efficiency by decreasing myocardial oxygen consumption rates. However, cardiac BCAA accumulation was associated with excessive stimulation of the mammalian target of rapamycin signaling and aggravation of adverse cardiac remodeling in BCAT2 failing hearts. As a result, the impact of BCAA accumulation offsets the beneficial effects of lowering cardiac BCKA levels on cardiac insulin sensitivity and cardiac efficiency. CONCLUSIONS: Lowering BCKA levels enhances cardiac glucose oxidation and cardiac efficiency by enhancing mitochondrial insulin signaling. BCAA accumulation worsens adverse cardiac remodeling by exacerbating cardiac mammalian target of rapamycin signaling.
BACKGROUND: This study evaluates clinical trends and mid-term waitlist and posttransplant outcomes following the 2018 heart allocation policy change. METHODS: The United Network for Organ Sharing registry was queried to...BACKGROUND: This study evaluates clinical trends and mid-term waitlist and posttransplant outcomes following the 2018 heart allocation policy change. METHODS: The United Network for Organ Sharing registry was queried to analyze adult waitlisted and transplanted patients undergoing isolated heart transplantation. Two analyses were conducted: (1) waitlist and (2) posttransplant outcomes. For the waitlist analysis, candidates were stratified into seasonally matched prepolicy (October 18, 2012-June 30, 2017) and postpolicy (October 18, 2018-June 30, 2023) groups, with a 1-year follow-up period. Waitlist outcomes included 1-year cumulative incidences of transplantation, delisting due to death/clinical deterioration, and all-cause survival from the initial waitlisting. For the posttransplant analysis, recipients were stratified into seasonally matched prepolicy (October 18, 2014-June 30, 2018) and postpolicy (October 18, 2018-June 30, 2020) groups, with a 4-year follow-up period. Posttransplant outcomes included 4-year survival. Propensity score-matching and multivariable Cox regression were used for risk adjustment. RESULTS: Under the 2018 allocation system, there was a continued shift toward the use of older donors, longer graft ischemic times, and shorter waitlist durations. In the waitlist analysis, 30 620 waitlisted candidates were analyzed, with 14 908 (48.7%) listed after the policy change. The postpolicy candidates had a higher 1-year cumulative incidence of transplantation (subhazard ratio, 2.06 [95% CI, 2.00-2.12]; <0.001) and a lower 1-year cumulative incidence of delisting (subhazard ratio, 0.58 [95% CI, 0.53-0.63]; <0.001) compared with the prepolicy candidates. In addition, the postpolicy candidates had significantly improved 1-year survival from initial waitlisting compared with the prepolicy candidates (90.0% versus 86.8%; <0.001). In the posttransplant analysis, 13 712 recipients were analyzed, with 4597 (33.5%) transplanted following the policy change. The 4-year post-transplant survival was similar between the groups (83.3% versus 82.8%; =0.593). Furthermore, the comparable 4-year post-transplant survival persisted in the propensity score-matched comparison and multivariable Cox regression. CONCLUSIONS: Despite the changes in donor and recipient profiles following the 2018 allocation system change, this mid-term reassessment demonstrates its success in significantly improving waitlist survival, while maintaining comparable posttransplant survival.
Zhang X, Davison B, Adamo M
… +16 more, Arrigo M, Biegus J, Chioncel O, Cohen Solal A, Cotter G, Edwards C, Kimmoun A, Lam CSP, Mebazaa A, Metra M, Novosadova M, Pang PS, Sliwa K, Takagi K, Voors AA, Ezekowitz JA
BACKGROUND: Assessment of medication changes in heart failure trials and registries is complex and may not capture the entirety of care. A comprehensive and standardized method is needed. We used different methods to ass...BACKGROUND: Assessment of medication changes in heart failure trials and registries is complex and may not capture the entirety of care. A comprehensive and standardized method is needed. We used different methods to assess the use of guideline-directed medical therapies (GDMT) and verified the association between GDMT intensity score with the STRONG-HF trial (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing of Heart Failure Therapies) clinical outcomes. METHODS: We used data from the STRONG-HF trial to examine the baseline GDMT use for all randomized patients by applying the GDMT intensity score and evaluated its change over time. We also examined their basic adherence, indication-corrected adherence, and dose-corrected adherence, and the association with clinical outcomes up to 180 days. RESULTS: At 90 days, triple therapy indication-corrected use increased from 4.5% to 36% in the usual care group, and from 5.2% to 93.5% in the high-intensity care group (<0.001 between the 2 groups). Triple therapy dose-corrected use increased from 4.5% to 20.5% in the usual care group, and from 3.3% to 77.4% in the high-intensity care group (<0.001). The GDMT intensity score at baseline was <6 in 358 (33%) patients, 6 to 7 in 329 (31%) patients, and >7 in 386 (36%) patients. At 90 days, 88.4% of patients in the high-intensity arm achieved a score >7 versus 14.3% in the usual care arm (<0.0001). The GDMT intensity score was correlated with clinical outcomes at 180 days. CONCLUSIONS: The GDMT intensity score provides a comprehensive description of medication use by means of standardized measurements and is linked to clinical outcomes. Future studies should consider utilizing this as a trial end point. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03412201.
Caravita S, Liberatore M, Badano LP
… +12 more, Gagliardi MF, De Lorenzo L, Sorropago A, Godino C, Tomaselli M, Lanzarone E, Perego GB, Vachiéry JL, Fudim M, Parati G, Muraru D, Baratto C
Circ Heart Fail
· 2025 Aug · PMID 40600277
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BACKGROUND: The determinants of tricuspid regurgitation (TR) hemodynamic severity remain to be established. We explored the hemodynamic correlates of right atrial (RA) pressure and stroke volume (SV) in patients with and...BACKGROUND: The determinants of tricuspid regurgitation (TR) hemodynamic severity remain to be established. We explored the hemodynamic correlates of right atrial (RA) pressure and stroke volume (SV) in patients with and without TR, and assessed the reliability of the indirect Fick method in relation to TR severity. METHODS: In this observational study, right ventricular (RV) 3-dimensional echocardiography (3DE) was obtained simultaneously with direct Fick right heart catheterization. RVSV and SV were combined to determine the TR regurgitant fraction (RegFr=RVSV-RVSV/RVSV). RA pressures and strain (or 3DE volumes) were combined to derive RA compliance. RESULTS: Out of 74 patients, 61% had moderate or severe TR. TR severity was associated with larger right heart chambers, lower RA compliance, higher values and lower inspiratory decrease of RA pressure, and lower cardiac index (<0.01). In univariate analysis, RA V wave was associated with RegFr (=-0.57) and with ln-transformed RA compliance (=-0.74); SV index was associated with RegFr (=-0.65). The effect of RegFr on V wave was mediated by ln-transformed RA compliance (β, 13.9 [95% CI, 7.6-20.2]). In multivariable analysis, RA V wave remained associated with 1/RA compliance (β, 2.1 [95% CI, 1.4-2.7]), while SV index was associated with RegFr (β, -97.6 [95% CI, -120.1 to -75.0]). The indirect Fick method overestimated cardiac index proportionally to RegFr (<0.01). CONCLUSIONS: SV index is related to TR severity, while the effect of TR on RA V wave is mediated by RA compliance. Respiratory-related changes in RA hemodynamics are associated with TR severity. The indirect Fick method overestimates cardiac index proportionally to TR severity.
Fumagalli C, Zampieri M, Presta R
… +23 more, Pini G, Vetere G, Argirò A, Longhi S, Tini G, Musumeci B, Limongelli G, Palmiero G, Verrillo F, Beltrami M, Bo M, De Ferrari G, Tofani L, Sardu C, Marfella R, Marchionni N, Perfetto F, Olivotto I, Fumagalli S, Maurer MS, Fontana M, Ungar A, Cappelli F
Circ Heart Fail
· 2025 Sep · PMID 40600269
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BACKGROUND: The prevalence of transthyretin cardiac amyloidosis among older adults (often octogenarians) is increasing. We aimed to determine whether age and geriatric syndromes bear any impact on the management and outc...BACKGROUND: The prevalence of transthyretin cardiac amyloidosis among older adults (often octogenarians) is increasing. We aimed to determine whether age and geriatric syndromes bear any impact on the management and outcomes in transthyretin cardiac amyloidosis and assess the risk of ageism. METHODS: In a prospective, multicenter cohort study, 256 patients diagnosed with transthyretin cardiac amyloidosis from March 2021 to March 2024 underwent comprehensive geriatric assessment (CGA). The study evaluated the prevalence and clinical associations of CGAs across different disease stages (National Amyloidosis Centre stage). Key CGA domains included disability, malnutrition, depression, frailty, Short Physical Performance Battery, and cumulative deficits (sum of the single CGA items). Associations of these measures with disease-modifying therapy and overall mortality were analyzed. RESULTS: Median age was 82 years (men: n=223 [87%]; variant: n=19 [7.4%]); 129 (50.3%) patients received disease modifiers. Those ≥85 years had significantly lower odds of receiving disease-modifying therapy even after adjusting for disability, frailty, and cumulative deficits. Over 1.9 (interquartile range, 1.0-2.3) years, 45 (17.6%) patients died. After adjustment for National Amyloidosis Centre stage, diuretics and disease modifiers, CGA domains of disability, malnutrition, Short Physical Performance Battery, frailty, and number of deficits, but not age, were significantly associated with mortality. Assessment of CGA domains improved National Amyloidosis Centre prognostic accuracy. CONCLUSIONS: In a national prospective cohort of patients with transthyretin cardiac amyloidosis, older age was associated with lower prescription of disease modifiers, even among individuals with a low burden of geriatric syndromes. However, when adjusted for geriatric domains, age was not associated with survival, indicating potential ageism. Because some geriatric syndromes may be modifiable, a CGA could enhance risk stratification, reduce age-related bias, and improve outcomes.
BACKGROUND: In patients with acute heart failure, the addition of hydrochlorothiazide (HCTZ) to furosemide increased the diuretic response in the CLOROTIC trial (Combining Loop with Thiazide Diuretics for Decompensated H...BACKGROUND: In patients with acute heart failure, the addition of hydrochlorothiazide (HCTZ) to furosemide increased the diuretic response in the CLOROTIC trial (Combining Loop with Thiazide Diuretics for Decompensated Heart Failure). The aim of this subanalysis was to evaluate the incidence and risk factors for hypokalemia, and its impact on mortality and readmissions. METHODS: This is a post hoc analysis of the CLOROTIC trial that randomized 230 patients with acute heart failure and volume overload to receive HCTZ or placebo in addition to intravenous furosemide. The incidence and risk factors for the development of hypokalemia (K <3.5 mmol/L) and its association with 30- and 90-day mortality and readmissions were analyzed. The Monte Carlo simulation method was applied to predict the development of hypokalemia. RESULTS: The incidence of hypokalemia was significantly higher in the HCTZ group (compared with the placebo group) at 48 and 96 hours after randomization, and at discharge (<0.001). In a multivariate analysis, the following variables were independently associated with the development of hypokalemia: baseline K values (OR per 0.1 units, 0.82 [95% CI, 0.76-0.87]; <0.001), treatment with HCTZ (OR, 4.90 [95% CI, 2.50-9.90]; <0.001), and treatment with a mineralocorticoid receptor antagonist at baseline (OR, 0.42 [95% CI, 0.20-0.84]; =0.017). There was no association between the development of hypokalemia and 30- and 90-day mortality and readmissions. The Monte Carlo simulation method predicted in patients treated with furosemide alone a higher risk of hypokalemia when baseline K values are ≤3.7 mmol/L. When HCTZ is added to furosemide, the risk of hypokalemia is present with higher baseline K values (≤4.3 mmol/L). CONCLUSIONS: Adding HCTZ to intravenous furosemide increases the risk of hypokalemia a especially when baseline K is ≤4.3 mmol/L and when patients are not treated with a mineralocorticoid receptor antagonist. In patients treated with furosemide and HCTZ, it is advisable to add potassium supplements or a mineralocorticoid receptor antagonist. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01647932.
BACKGROUND: The use of donation after circulatory death (DCD) donors for heart transplantation (HT) is increasing in the United States. Whether sex differences exist in DCD HT utilization and outcomes is unknown. METHODS...BACKGROUND: The use of donation after circulatory death (DCD) donors for heart transplantation (HT) is increasing in the United States. Whether sex differences exist in DCD HT utilization and outcomes is unknown. METHODS: Adults listed for HT at DCD centers between January 1, 2019 (first US DCD HT) and September 15, 2023, in the Organ Procurement and Transplantation Network Registry were included. Differences in listing for DCD HT by sex were investigated using multivariable logistic regression. The impact of listing for DCD HT (modeled as a time-varying covariate) on waitlist outcomes including the rate of HT waitlist removal for death or clinical deterioration was assessed using multivariable competing risk analyses. Annual trends in DCD HT and 2-year survival after DCD HT by sex were also investigated. RESULTS: A total of 9807 individuals were listed at DCD centers during the study period. Listing for DCD HT was less common among women after multivariable adjustment (odds ratio, 0.84 [95% CI, 0.76-0.92]; <0.001). Listing for DCD HT was associated with an adjusted increased rate of HT (hazard ratio, 1.85 [95% CI, 1.75-1.95]; <0.001) and a lower risk of waitlist removal for death or clinical deterioration (hazard ratio, 0.57 [95% CI, 0.45-0.73]; <0.001) for both men and women; these protective effects were not different between sexes (interaction terms: transplant, =0.55; delisting, =0.91). During the study period, women made up 26% to 29% of donation after brain death transplants, but only 18% to 20% of DCD transplants. Survival at 2 years after DCD HT was similar between sexes (87% for women and 88% for men; log-rank =0.37). CONCLUSIONS: Women were less likely to be listed for DCD HT and makeup proportionally less DCD transplants compared with men. Being listed for DCD HT improved waitlist outcomes in both sexes. One-year survival after DCD HT was similar by sex. As DCD HT expands, additional measures to ensure equitable access are imperative.
Kehr D, Salatzki J, Seger B
… +15 more, Varadi K, Birkenstock J, Schlegel P, Gao E, Koch WJ, Katus HA, Frey N, Riffel J, André F, Peppel K, Jungmann A, Busch M, Pfannkuche H, Ritterhoff J, Most P
Circ Heart Fail
· 2025 Jul · PMID 40534567
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BACKGROUND: Guided by long-term safety data for AAV5 (adeno-associated virus 5) in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieves therapeutic efficacy in dysf...BACKGROUND: Guided by long-term safety data for AAV5 (adeno-associated virus 5) in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieves therapeutic efficacy in dysfunctional human-sized hearts, using a clinically applicable mode of administration and vector dosages. METHODS: AAV-mediated cardiac gene transfer in pigs was performed by percutaneous catheter-based retrograde intravenous vector delivery, and vector genome and transgene expression levels determined by reverse transcription-polymerase chain reaction and immunoblotting. Postmyocardial infarction (MI) cardiac dysfunction porcine and murine models were generated by coronary catheter-based occlusion and ligation, respectively. The study end points left ventricular ejection fraction and left ventricular MI size, were measured by cardiac magnetic resonance imaging and echocardiography. Bulk myocardial RNA-sequencing and weighted gene correlation network analysis were used to link study end points to molecular pathway mechanisms. Safety was assessed by clinical chemistry, blood count and ECG. RESULTS: In a first biodistribution study, AAV5 (1×10 vector genomes; vgs) with the reporter gene () achieved broad and homogenous transduction of healthy pig hearts 30 days after catheter-based retrograde intravenous vector delivery without toxicity. Both its myocardial and extra-cardiac distribution patterns were advantageous compared with AAV9- and AAV6-. Using AAV5 with the cardioprotective human gene (; 1×10 vgcs) by catheter-based retrograde intravenous vector delivery in a subsequent therapy study in post-MI pigs prevented left ventricular MI extension and improved left ventricular ejection fraction after 3 months without clinical toxicity. Weighted gene correlation network analysis linked novel antiinflammatory actions and cardioprotective signaling mechanisms by hS100A1 to study end point improvements, which was confirmed in a post-MI mouse model. CONCLUSIONS: Providing the clinically relevant proof of concept for AAV5 to effectively transduce healthy and dysfunctional human-sized hearts, its clinical long-term safety, scalable producibility, and low preexisting immunity in humans may predestine AAV5 as an effective and safe gene carrier for a prevalent disease such as chronic heart failure, using therapeutic genetic effectors such as or others.
Lewsey SC, Samuel TJ, Schär M
… +8 more, Sourdon J, Goldenberg JR, Yanek LR, Lai S, Steinberg AM, Bottomley PA, Gerstenblith G, Weiss RG
Circ Heart Fail
· 2025 Jul · PMID 40534551
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BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a systemic process with contributions from peripheral factors, including skeletal muscle (SM). Age-associated SM loss and impaired energy metabolism o...BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a systemic process with contributions from peripheral factors, including skeletal muscle (SM). Age-associated SM loss and impaired energy metabolism occur without heart failure, but the relative importance of changes in SM quantity versus metabolic quality in patients with HFpEF for exercise intolerance (EI) or outcomes has not been studied. We hypothesized that EI and subsequent clinical outcomes across the adult lifespan in patients with HFpEF are related to impaired SM energy metabolism rather than age-associated SM loss. METHODS: Patients with HFpEF (n=64; aged 34-86 years) with left ventricular ejection fraction ≥50% were stratified by age in a prospective study. They underwent 3T magnetic resonance imaging to measure calf muscle quantity and P magnetic resonance spectroscopy to measure muscle high-energy phosphate metabolism during plantar flexion exercise. RESULTS: Older patients with HFpEF exhibited more severe EI, less calf muscle, faster exercise-induced high-energy phosphate decline, and worse SM energetics at fatigue than younger patients. EI correlated closely with muscle metabolic quality, not quantity. Neither magnetic resonance imaging exercise time, 6-minute walk distance, nor peak oxygen uptake at cardiopulmonary exercise testing on cardiopulmonary bicycle exercise testing correlated with calf SM area. In contrast, the 6-minute walk distance or peak oxygen uptake at cardiopulmonary exercise testing were inversely related to rapid exercise-induced high-energy phosphate decline and worse SM energetic profile at fatigue. Rapid exercise-induced high-energy phosphate decline and lower ATP at fatigue were associated with increased cardiovascular death or heart failure hospitalizations in univariate analysis over a median of 39.3 months. CONCLUSIONS: EI in older patients with HFpEF is closely linked to age-associated abnormalities in SM energy metabolism, namely, rapid exercise-induced energetic decline and worse energetic profile at fatigue, and not SM quantity. Abnormal SM energy metabolism is associated with worse outcomes in patients with HFpEF in unadjusted analysis. These findings support SM energy metabolism as a barometer of systemic HFpEF severity and the pursuit of new SM metabolic modulators to reduce disabling EI and possibly adverse outcomes in patients with HFpEF.
Masood IR, Wang L, Stanley HM
… +10 more, Edwards JJ, Ahmed H, Lin KY, Wittlieb-Weber CA, O'Connor MJ, Rossano JW, O'Malley S, Paridon SM, Tam VW, Edelson JB
Circ Heart Fail
· 2025 Jul · PMID 40534547
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BACKGROUND: Restricting certain patients with hypertrophic cardiomyopathy (HCM) from exercise likely has negative cardiovascular effects and has not been shown to reduce the risk of sudden cardiac death. Promoting exerci...BACKGROUND: Restricting certain patients with hypertrophic cardiomyopathy (HCM) from exercise likely has negative cardiovascular effects and has not been shown to reduce the risk of sudden cardiac death. Promoting exercise in children with HCM is complex and requires knowledge of the environmental factors that impact exercise capacity in children with HCM. METHODS: This retrospective, cross-sectional analysis includes children with HCM who underwent exercise stress testing at a single, children's tertiary-care center between 2000 and 2023. Addresses from contemporaneous exercise stress testing were accessed and geocoded to census tracts. The child opportunity index was the primary exposure of interest. Granular neighborhood measures including the walkability index, rural-urban commuting area codes, index of concentration at the extremes, and uniform crime reporting rates were measured. The primary outcome measure was peak oxygen consumption. Linear regression and multivariable analyses were performed. RESULTS: A total of 155 patients were identified who met inclusion criteria, 23% (n=35) of whom were female. The mean age at the time of exercise stress testing was 15.8±3.1 years. More than half of the included patients were from a high or very high child opportunity index (30%, n=46, and 35%, n=54, respectively). Most patients lived in urban environments (rural-urban commuting area codes score, 1 or 2, 96.7%, n=150). The mean peak oxygen consumption was 2159±906 mm/min, and the adjusted peak oxygen consumption was 35.5±9.3 mL/kg per min. A multivariate model adjusting for disease severity, age at diagnosis of HCM, race, and accounting for collinearity showed that low child opportunity index, higher levels of urbanization, and lower concentration of neighborhood wealth were independently associated with lower peak oxygen consumption. CONCLUSIONS: Our study identified previously unrecognized environmental determinants of exercise capacity in children with HCM, with lower child opportunity index, increased urbanization, and lower neighborhood wealth independently associated with lower exercise performance. Programs designed to increase physical activity levels and exercise performance in children with HCM should account for neighborhood and economic factors.