BACKGROUND: Acoramidis achieves near-complete (≥90%) transthyretin stabilization and is approved to reduce cardiovascular-related hospitalization in transthyretin amyloid cardiomyopathy. Its effects on kidney function ar...BACKGROUND: Acoramidis achieves near-complete (≥90%) transthyretin stabilization and is approved to reduce cardiovascular-related hospitalization in transthyretin amyloid cardiomyopathy. Its effects on kidney function are not well characterized. METHODS: Data from randomized phase 2 (N=49) and phase 3 (N=632) studies in transthyretin amyloid cardiomyopathy were included. The estimated glomerular filtration rate (eGFR) slope was generated using a linear spline mixed-effects model. The urinary albumin-to-creatinine ratio was measured longitudinally. Relationships between changes in kidney function and clinical outcomes were explored using Cox proportional hazards models. RESULTS: Acoramidis initiation resulted in a modest acute dip in eGFR that was dose-dependent, reversible, and not associated with adverse kidney-related events. At Day 28, the mean (±SE) dip in eGFR from baseline with acoramidis was 8.5±0.48 mL/min per 1.73 m; the placebo-corrected reduction in the urinary albumin-to-creatinine ratio was 15.5% (95% CI, 0.4%-28.4%; =0.044). The rate of decline in kidney function (chronic eGFR slope) was significantly improved with acoramidis versus placebo (-1.01 versus -3.48 mL/min per 1.73 m per year; <0.001), and the reduction in the urinary albumin-to-creatinine ratio was sustained (13.7% [95% CI, 1.7%-24.2%]; =0.026) over time. Concomitant tafamidis use did not influence the chronic eGFR slope in either arm. Comparing acoramidis versus placebo subgroups with acute eGFR dips ≥ the median (4.89 mL/min per 1.73 m) favored acoramidis for all-cause mortality or cardiovascular-related hospitalization (hazard ratio, 0.42 [95% CI, 0.22-0.78]; =0.006; interaction=0.043) and cardiovascular-related hospitalization (hazard ratio, 0.34 [95% CI, 0.17-0.66]; =0.002, interaction=0.025). Within the placebo arm, eGFR dips portended worse outcomes. CONCLUSIONS: Acoramidis initiation resulted in an acute dip in eGFR and reductions in both the chronic eGFR slope and urinary albumin-to-creatinine ratio versus placebo without adverse kidney-related events. Acoramidis effects on kidney function may be mediated through direct kidney-protective hemodynamic effects. Importantly, the acute dip in eGFR was associated with a reduced risk of adverse clinical outcomes within the first year. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03458130. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03536767. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03860935. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04988386.
Ahn DJ, Attia A, Nakayama T
… +4 more, Narang N, Khush KK, Parker W, Sasaki K
Circ Heart Fail
· 2026 Jun · PMID 42335275
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BACKGROUND: The 2018 heart allocation policy change substantially lowered the priority of candidates supported with durable left ventricular assist devices (LVADs) for heart transplantation. To provide stable candidates...BACKGROUND: The 2018 heart allocation policy change substantially lowered the priority of candidates supported with durable left ventricular assist devices (LVADs) for heart transplantation. To provide stable candidates supported by durable LVADs with a quicker path to transplantation before they suffer complications, the Organ Procurement and Transplantation Network (OPTN) approved a policy stipulating that stable patients supported by durable LVADs for 6 and 8 years will obtain statuses 3 and 2, respectively. METHODS: Using OPTN data, we identified all adult heart transplant candidates with a durable LVAD implanted between October 18, 2018 and May 31, 2025. We estimated the cumulative incidence of LVAD-related complications, treating transplantation and waitlist removal before experiencing complications as competing events. Furthermore, we assessed how the OPTN policy change would impact the status distribution of the waitlist. RESULTS: In our study cohort, 4967 adult patients who were listed for heart transplant received a durable LVAD. Transplant centers submitted 2879 justifications for status upgrades due to LVAD-related complications for 1812 (36.5%) patients. At 6 years after durable LVAD implantation, the cumulative incidence of complications and status upgrades was 42.1% (95% CI, 40.5%-43.8%), and that of transplantation was 36.0% (95% CI, 34.6%-37.6%). Of the 3779 patients who were not censored administratively, only 47 (1.2%) remained on the waitlist by 6 years after durable LVAD implantation. Had the 6- to 8-year OPTN policy change been implemented on June 1, 2025, only 4.7% of the waitlist would have changed statuses instantaneously. CONCLUSIONS: Almost all listed candidates with durable LVADs either experience a complication, status upgrade or are removed from the waitlist within 6 years of obtaining a durable LVAD. The upcoming OPTN policy is unlikely to prevent device complications before granting status upgrades and will likely impact a small percentage of candidates with durable LVADs.
Ahn DJ, Nakayama T, Attia A
… +6 more, White M, Eap D, Narang N, Khush KK, Parker WF, Sasaki K
Circ Heart Fail
· 2026 Jun · PMID 42329622
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BACKGROUND: In the US heart allocation system, when transplant centers submit applications for status exceptions to increase waitlist priority, patients obtain the requested status upgrades immediately while their applic...BACKGROUND: In the US heart allocation system, when transplant centers submit applications for status exceptions to increase waitlist priority, patients obtain the requested status upgrades immediately while their applications are sent to the regional review boards (RRBs) and reviewed retrospectively. How often transplants occur during this period is unknown. METHODS: Using the Scientific Registry of Transplant Recipients, we identified all adult heart transplant candidates listed between October 18, 2018, and May 31, 2025, with submitted applications for status exceptions. We assessed (1) the time elapsed between submission of exception applications and their receipt by the RRBs and (2) the rate of heart transplantation during this travel time, stratified by whether the applications were eventually approved or denied. Additionally, we estimated how many listed patients were skipped by candidates who received transplants with exceptions that were ultimately denied. RESULTS: 138 transplant centers submitted status exception requests on behalf of 11 508 adult candidates during the study period, of whom 913 (7.9%) received a denial at least once. The median time from obtaining status upgrades to application receipt by the RRBs was 3 days. Three thousand seven out of 11 508 (26.1%) patients received transplants before the RRBs even received their applications, with 174 (19.1%) among 913 with eventual denials and 2833 (26.7%) among 10 595 with approvals. The cumulative incidence of heart transplantation before application receipt for eventual denials was 19.1% (95% CI, 16.6%-21.7%), and that for approvals was 27.2% (95% CI, 26.4%-28.0%; <0.001) at 2 weeks. Candidates who received transplants despite being denied exceptions bypassed more than 11 thousand potential transplant recipients. CONCLUSIONS: More than 25% of patients with status exception requests receive heart transplants before their applications are even received by their RRBs, raising significant concerns about the fairness of retrospective review of exception requests for the allocation of donor hearts.
Reddy YNV, Frantz RP, Egbe AC
… +15 more, Miranda WR, Asokan AK, Hassoun PM, Hemnes AR, Horn E, Leopold JA, Rischard F, Rosenzweig EB, Hill NS, Erzurum SC, Finet JE, Mukherjee M, Tang WHW, Nair KS, Borlaug BA
Circ Heart Fail
· 2026 Jun · PMID 42318624
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BACKGROUND: Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure-a condition termed unclassified PH. Although hypothesized to re...BACKGROUND: Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure-a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown. METHODS: The current analysis included PVDOMICS participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure. RESULTS: The overall prevalence of unclassified PH in PVDOMICS (n=1046) and the validation cohort (n=1202) was 7.8% (175/2248), which was comparable to the 6.6% (66/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23/159]; =0.006). Increased flow occurred in a minority of unclassified PH from both PVDOMICS (28%; 15/53) and the validation cohort (11%; 13/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)-age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF. CONCLUSIONS: The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02980887.
Aortic stenosis (AS) is increasingly recognized as a disease of both the valve and the myocardium. Beyond valvular obstruction, many patients with aortic stenosis develop extra-valvular abnormalities, including left vent...Aortic stenosis (AS) is increasingly recognized as a disease of both the valve and the myocardium. Beyond valvular obstruction, many patients with aortic stenosis develop extra-valvular abnormalities, including left ventricular hypertrophy, diastolic dysfunction, and atrial and pulmonary vascular remodeling, which have emerged as major determinants of symptoms and prognosis. These abnormalities share many similarities with heart failure with preserved ejection fraction (HFpEF), a condition that is also prevalent in the same aging population. Emerging data suggest that AS and HFpEF frequently coexist and interact, compounded by shared cardiometabolic risk factors, producing convergent phenotypes that complicate diagnosis and influence treatment response. Residual HFpEF appears to underlie much of the persistent heart failure burden after aortic valve replacement, while even mild AS portends worse outcomes in patients with HFpEF. Recent studies have shown that HFpEF-directed therapies, such as sodium-glucose cotransporter 2 inhibitors, may benefit selected patients with AS. As both conditions increase in prevalence and valve interventions are offered to increasingly complex patients, a clearer understanding of the ways in which AS and HFpEF overlap and interact is essential. This review integrates epidemiological, pathophysiological, and clinical perspectives to synthesize emerging evidence on the AS-HFpEF overlap and outlines implications for diagnosis, prognosis, and management.
Altered cardiac and systemic metabolism is a hallmark of heart failure (HF). In the failing heart, cardiomyocytes develop alterations in substrate preference, mitochondrial oxidative metabolism, and the shuttling of high...Altered cardiac and systemic metabolism is a hallmark of heart failure (HF). In the failing heart, cardiomyocytes develop alterations in substrate preference, mitochondrial oxidative metabolism, and the shuttling of high-energy phosphates from mitochondria to the cytosol that compromise energetic efficiency and contribute to disease progression. At the systemic level, neurohormonal activation plays a dominant role in HF with reduced ejection fraction, whereas HF with preserved ejection fraction is shaped by the clustering of multiple comorbidities, such as diabetes, obesity and hypertension, which disrupt the physiological crosstalk between the heart and metabolically active organs. This review provides a perspective on cardiac metabolism in HF. We delineate the specific alterations in substrate metabolism that characterize HF with reduced ejection fraction versus HF with preserved ejection fraction, examine the impact of interorgan communication on myocardial function, and highlight how the benefits of emerging HF therapies, including sodium-glucose cotransporter 2 inhibitors and GLP-1 receptor agonists, may be mediated, at least in part, through the restoration of metabolic homeostasis.
Vahle B, Weidner S, Tomalka A
… +11 more, Schauer A, Augstein A, Männel A, Barthel P, Friedrich J, Beck G, Labeit S, Bowen TS, Siebert T, Linke A, Adams V
BACKGROUND: Exercise intolerance, promoted by skeletal muscle- and mitochondrial dysfunction, has been identified as a therapeutic target in heart failure with preserved ejection fraction (HFpEF). In the context of mitoc...BACKGROUND: Exercise intolerance, promoted by skeletal muscle- and mitochondrial dysfunction, has been identified as a therapeutic target in heart failure with preserved ejection fraction (HFpEF). In the context of mitochondrial dysfunction, altered cardiolipin integrity has been reported in the myocardium of HFpEF, suggesting Elamipretide, a cardiolipin stabilizing agent, as potential therapeutic approach. The present study investigated cardiolipin dysregulation in the skeletal muscle of HFpEF rats and analyzed the effect of Elamipretide treatment. METHODS: Female zucker fatty spontaneously hypertensive heart failure F1 hybrid lean (n=10, control) and obese rats (n=24, HFpEF) were included. At 20 weeks of age, HFpEF rats were randomized into 2 groups receiving NaCl (n=12) or Elamipretide (n=12) for 12 weeks. Skeletal muscle tissue was collected for whole-muscle force, single-fiber mechanics, mitochondrial respiration, histology and molecular analyses. RESULTS: HFpEF rats exhibited reduced cardiolipin levels (-6.8%, =0.007) and maturation (shown via tafazzin expression), contractile dysfunction, titin hyperphosphorylation, fiber atrophy and increased oxidative stress markers. Elamipretide improved whole muscle (soleus: +8.2%, =0.041, extensor digitorum longus: +10.9%, =0.016) and single-fiber (soleus: +173.2%, <0.001, extensor digitorum longus: +66.0%, =ns) contractile function and titin phosphorylation (soleus: -35.4%, <0.001, extensor digitorum longus: -40.2%, <0.001), while preventing atrophy development (soleus: +49%, =0.001, extensor digitorum longus: +54.8%, <0.001). Improved mitochondrial function, presumably through cardiolipin-mediated improvements in oxidative phosphorylation, could be associated with muscle force and cardiolipin integrity. CONCLUSIONS: Our data highlight cardiolipin stabilization as a key modulator of mitochondrial and contractile function in HFpEF, identifying Elamipretide as a promising therapeutic approach for skeletal muscle dysfunction.
BACKGROUND: Cardiac acute rejection (AR) is a risk factor for poor outcomes; however, there are limited risk prediction models to stratify these patients for death or prolonged left ventricular (LV) dysfunction. We asses...BACKGROUND: Cardiac acute rejection (AR) is a risk factor for poor outcomes; however, there are limited risk prediction models to stratify these patients for death or prolonged left ventricular (LV) dysfunction. We assessed the prognostic utility of percent donor-derived cell-free DNA (%dd-cfDNA) measured at AR diagnosis for predicting adverse outcomes. METHODS: The prospective multicenter GRAFT study (Genomic Research Alliance for Transplantation) enrolled heart transplant recipients and collected serial plasma samples to quantitate %dd-cfDNA. AR was defined as acute cellular rejection, antibody-mediated rejection, as well as biopsy-negative antibody-mediated rejection (donor-specific antibody positivity with LV dysfunction). In the primary analyses, AR was stratified by %dd-cfDNA at diagnosis using a data-driven threshold of 0.15%. Cox regression models assessed the associations between the time-dependent covariates of AR and %dd-cfDNA levels at the AR diagnosis and the outcome of prolonged LV ejection fraction decline (≤50% for ≥90 days) and death. RESULTS: The study included 277 patients and 3218 %dd-cfDNA measurements. Over a median follow-up of 4.9 years (interquartile range, 2.5-5.0), 53 patients experienced the composite outcome of death or prolonged LV dysfunction, and 75 (27%) patients developed AR, including 43 (15%) patients with acute cellular rejection, 18 (7%) with pathological antibody-mediated rejection, and 14 (5%) with donor-specific antibody+/LV dysfunction. AR was associated with an increased risk of the primary composite outcome (hazard ratio, 4.47 [95% CI, 2.42-8.26]; <0.001). When AR was stratified by %dd-cfDNA at diagnosis, patients with %dd-cfDNA ≥0.15% had higher risks of prolonged LV dysfunction, death, and the composite outcome compared with patients who had not developed AR at the same follow-up time (hazard ratio, 6.28 [95% CI, 3.04-13.0]; <0.001 for the composite outcome). In contrast, the risks of death and prolonged LV ejection fraction reduction were not statistically significantly increased among patients who developed AR with %dd-cfDNA <0.15% at diagnosis. CONCLUSIONS: AR with elevated %dd-cfDNA levels at diagnosis is associated with an increased risk of adverse outcomes after heart transplant, offering novel prognostic utility.