Obayashi Y, Kato T, Shiomi H
… +18 more, Nakatsuka K, Kitaoka H, Sakata Y, Dohi K, Tokita Y, Matsushima S, Amano M, Furukawa Y, Tamura T, Hayashida A, Abe H, Ando K, Yuda S, Inoko M, Ono K, Nishimura K, Izumi C, REVEAL-HCM Investigators
BACKGROUND: Mitral regurgitation (MR) is a frequent comorbidity in patients with hypertrophic cardiomyopathy (HCM), which includes distinct subtypes with various characteristics. However, data on the long-term prognostic...BACKGROUND: Mitral regurgitation (MR) is a frequent comorbidity in patients with hypertrophic cardiomyopathy (HCM), which includes distinct subtypes with various characteristics. However, data on the long-term prognostic impact of MR and its progression or regression over time remain limited, particularly across individual HCM subtypes. METHODS: Patients with HCM were retrospectively included from a Japanese multicenter registry and compared by MR severity (moderate or greater versus mild or less) within each subtype: hypertrophic obstructive cardiomyopathy (HOCM), end-stage HCM (ES-HCM), and other HCM (including nonobstructive, midventricular obstruction, and apical HCM). RESULTS: Among 3602 patients (HOCM: n=837; ES-HCM: n=275; other HCM: n=2490), the prevalence of moderate or greater MR was highest in HOCM (36.3%), followed by ES-HCM (21.5%) and other HCM (8.5%). During a median follow-up of 5.3 (interquartile range, 2.1-9.3) years, the cumulative 5-year incidence of all-cause death or heart failure hospitalization was not significantly different between the moderate or greater MR and mild or less MR groups in HOCM (14.6% versus 12.4%; =0.35) or ES-HCM (60.7% versus 54.7%; =0.84). After adjustment for clinical covariates, no significant association was observed in either subtype (HOCM: hazard ratio, 1.13 [95% CI, 0.79-1.60], =0.51; ES-HCM: hazard ratio, 0.84 [95% CI, 0.55-1.28], =0.42). In contrast, in other HCM, moderate or greater MR was significantly associated with the higher 5-year cumulative incidence of all-cause death or heart failure hospitalization (34.2% versus 13.9%, <0.001), which remained significant after adjustment, with a significant interaction (hazard ratio, 1.45 [95% CI, 1.09-1.91], =0.01; =0.02). MR severity improved over time in HOCM, showed no clear change in ES-HCM, and worsened in other HCM (<0.001, 0.46, and <0.001, respectively; <0.001). CONCLUSIONS: In patients with HCM, moderate or greater MR was not associated with worse outcomes in HOCM or ES-HCM, but had significant prognostic implications in other HCM subtypes, suggesting the need for HCM subtype-specific MR management.
Peikert A, Vacca A, Norata GD
… +2 more, Schiattarella GG, Osto E
Circ Heart Fail
· 2026 Mar · PMID 41623119
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Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome affecting ≈32 million individuals worldwide. It accounts for at least half of all heart failure cases and is associated with substanti...Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome affecting ≈32 million individuals worldwide. It accounts for at least half of all heart failure cases and is associated with substantial morbidity and mortality. Although the prevalence of HFpEF increases with age, a substantial proportion of the HFpEF subjects present with cardiometabolic alterations, marking a specific phenogroup of HFpEF. Obesity, diabetes, and hypertension are considered central features in the pathophysiology of HFpEF, driving its development and disease progression by a complex interplay of metabolic-, hemodynamic-, and neurohormonal impairments, resulting in systemic inflammation and immune system dysregulation. Cellular and systemic immunometabolic stress induces vascular endothelial microvascular dysfunction, infiltration of immune cells in the myocardium, and activation of innate and adaptive immune cells in cardiac tissue. The resulting bidirectional crosstalk between systemic and cardiac metabolism influences immune cell reprogramming, sustaining a vicious cycle of cardiac chronic inflammatory response, ultimately leading to adverse structural and functional cardiac remodeling. In this review, we discuss the role of cellular interactions and immunometabolic mechanisms of immune system dysregulation resulting in cardiometabolic HFpEF and elaborate on therapeutic strategies targeting cardiometabolic risk.
BACKGROUND: The prevalence and prognostic significance of liver biomarkers in heart failure (HF) with mildly reduced or preserved ejection fraction are uncertain, with both potential hemodynamic and metabolic contributio...BACKGROUND: The prevalence and prognostic significance of liver biomarkers in heart failure (HF) with mildly reduced or preserved ejection fraction are uncertain, with both potential hemodynamic and metabolic contributions to liver dysfunction in these patients. We evaluated the prevalence and prognostic value of liver biomarkers and assessed the effects of the nonsteroidal mineralocorticoid receptor antagonist finerenone on these biomarkers and clinical outcomes in FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure). METHODS: FINEARTS-HF was a randomized, double-blind, placebo-controlled trial that enrolled 6001 patients with left ventricular ejection fraction ≥40%, evidence of structural heart disease, and elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Liver biomarkers examined were total bilirubin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase. RESULTS: Among 5873 patients with available baseline bilirubin measurements, 11.9% had elevated levels (>1.0 mg/dL). Higher bilirubin levels were associated with a greater risk of total worsening HF events and cardiovascular death. Compared with placebo, finerenone rapidly reduced bilirubin and alkaline phosphatase levels (but not transaminase levels), with effects sustained over time. Finerenone reduced the risk of total worsening HF events and cardiovascular death across all bilirubin tertiles (T1 [<0.4 mg/dL], rate ratio 0.94 [95% CI, 0.75-1.17]; T2 [0.5-0.6 mg/dL], 0.83 [0.66-1.05]; T3 [≥0.7 mg/dL], 0.77 [0.62-0.97]), with no significant interaction by bilirubin level (=0.43). Consistent effects were observed for the components of the primary outcome, all-cause death, and improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score. CONCLUSIONS: Baseline bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of finerenone on morbidity and mortality in HF with mildly reduced or preserved ejection fraction. Finerenone reduced bilirubin and alkaline phosphatase, suggesting a possible decongestive effect in HF with mildly reduced or preserved ejection fraction. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626.
Vidula MK, Schurgers LJ, Zhao L
… +19 more, Dib MJ, Zhao M, Wang Z, Ebert C, Salman O, Azzo JD, Zamani P, van Empel V, Richards AM, Doughty R, Javaheri A, Mann DL, Rietzschell E, Kammerhoff K, Schafer P, Seiffert DA, Ramirez-Valle F, Cappola TP, Chirinos JA
Circ Heart Fail
· 2026 Feb · PMID 41603031
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BACKGROUND: MGP (matrix Gla-protein), a known inhibitor of vascular calcification, becomes biologically active by vitamin K-dependent carboxylation. Circulating levels of dpucMGP (dephospho-uncarboxylated matrix Gla-prot...BACKGROUND: MGP (matrix Gla-protein), a known inhibitor of vascular calcification, becomes biologically active by vitamin K-dependent carboxylation. Circulating levels of dpucMGP (dephospho-uncarboxylated matrix Gla-protein), the inactive form of MGP, have been associated with large artery stiffening and reduced skeletal muscle mass in heart failure (HF). Whether dpucMGP is related to adverse outcomes in patients with HF is unknown. METHODS: In this cohort study, we measured plasma dpucMGP among 2247 PHFS (Penn HF Study) participants. We examined the relationship between dpucMGP and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with dpucMGP. We assessed the association between dpucMGP levels and (1) death or HF-related hospital admission; (2) all-cause death. RESULTS: Participants' median age was 61 years (interquartile range, 53-70 years), 64% were male, and 71% were White. dpucMGP exhibited prominent proteomic associations with acute phase response, coagulation, complement system, fibrosis, cell signaling, and metabolic pathways. Greater dpucMGP was associated with older age, renal dysfunction, and warfarin use, whereas Black ethnicity was associated with lower dpucMGP. Increased dpucMGP levels were associated with an increased risk of death or HF-related hospital admission (standardized hazard ratio, 1.23 [95% CI, 1.17-1.28]; <0.0001) and all-cause death (standardized hazard ratio, 1.32 [95% CI, 1.25-1.40]; <0.0001), particularly among participants with nonischemic HF. Associations between dpucMGP and outcomes were dependent on warfarin use, and higher dpucMGP levels were found to mediate the association between warfarin use and adverse outcomes (death [total effect: =0.005; indirect effect: <0.001] and death or HF-related hospital admission [total effect: <0.001; indirect effect: =0.002]). CONCLUSIONS: Higher dpucMGP is associated with multiple biological pathways and with an increased risk for adverse outcomes in HF. Greater dpucMGP levels mediated the relationship between warfarin use and adverse outcomes. Further studies are required to determine the role of therapeutic interventions to reduce dpucMGP levels in this patient population.
Zhang J, Zanella F, Ellis MW
… +16 more, Bradford WH, Gutierrez-Lara EJ, Wang TM, Fujita K, Duron C, Karakikes I, Lyon RC, Mezzano V, Roberts JD, Carromeu C, Gu Y, Martin JL, Muotri AR, Scheinman MM, Peterson KL, Sheikh F
Circ Heart Fail
· 2026 Apr · PMID 41582809
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BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a fatal genetic heart disease primarily caused by mutations in desmosomal genes, leading to impaired cell-cell adhesion, ventricular arrhythmias, and progressive heart f...BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a fatal genetic heart disease primarily caused by mutations in desmosomal genes, leading to impaired cell-cell adhesion, ventricular arrhythmias, and progressive heart failure. Although gene therapy for specific ACM populations shows promise, it remains unclear whether mutation-agnostic pathways dysregulated across desmosomal mutations could be exploited for therapeutic intervention in this genetically broad and severe population. The reduction in expression of the ventricular gap junction protein Cx43 (connexin-43) is a common molecular alteration underlying desmosomal junctional deficits and arrhythmias, suggesting a potential common underlying mechanism and a therapeutic target for ACM. We hypothesized that restoration of Cx43 expression could be a mutation-agnostic intervention for ACM. METHODS: We exploited adeno-associated-viral-mediated gene therapy to restore the gap junction protein, Cx43, in genetic mouse models and human stem cell models of ACM, harboring loss or mutations in desmosomal genes, including (desmoplakin), (plakophilin-2), and (desmoglein-2). RESULTS: Administration of AAV-Cx43 (adeno-associated-viral-mediated connexin-43) gene therapy alleviated the severe biventricular dilatation, contractile dysfunction, and arrhythmias, while prolonging lifespan in 2 severe desmosomal ACM mouse models, either harboring loss and a prevalent human mutation. Viral-mediated restoration of Cx43 could also alleviate physiological deficits in ACM human induced pluripotent stem cell-derived cardiomyocytes harboring and mutations. Mechanistically, Cx43 targets desmosomal protein expression and relocalization to the cell junction to support their mechanical stabilization and coupling. CONCLUSIONS: By using mouse and human models of desmosomal ACM harboring different mutational backgrounds, we show the sufficiency of Cx43 gene therapy and its restoration to modify and alleviate ACM deficits. These data suggest that noncanonical functions of Cx43, including mechanical modulation and reassembly of the desmosome, are a therapeutic target with the potential to treat diverse ACM populations.
Odutayo A, Bhatt DL, Sridhar VS
… +16 more, Szarek M, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Lopes RD, Scirica BM, Ray KK, Davies MJ, Banks P, Girard M, Verma S, Udell JA, Pitt B, Steg PG, Cherney DZI
Circ Heart Fail
· 2026 Mar · PMID 41569429
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BACKGROUND: The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America heart failure (HF) classification incorporates cardiac biomarkers to identify early risk of HF. The HF stage...BACKGROUND: The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America heart failure (HF) classification incorporates cardiac biomarkers to identify early risk of HF. The HF stages may also guide the prognosis and management of cardiovascular and kidney-related events. METHODS: SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) was a randomized trial in diabetes with kidney disease comparing sotagliflozin versus placebo on cardiovascular death, HF hospitalizations, and urgent HF visits. SCORED participants were grouped by HF stage post hoc. Stage A: no HF, normal biomarkers (NT-proBNP [N-terminal pro-B-type natriuretic peptide] <125 pg/mL; high sensitivity cardiac troponin T [hs-cTnT] <14 ng/L), and normal cardiac structure/function. Stage B (pre-HF): no HF but elevated NT-proBNP, hs-cTnT, or abnormal cardiac structure/function. Stage C/D: symptomatic HF. End points include the primary composite (cardiovascular death and HF-related events), major adverse cardiovascular events, and kidney-related composites (≥50% decline in estimated glomerular filtration rate, kidney failure, or kidney death). Using competing-risk proportional hazards models, we examined the association between HF stage and these end points, and the effect of sotagliflozin versus placebo by HF stage. RESULTS: There were 741 patients (7%) in stage A, 6560 (62%) in stage B (pre-HF), and 3283 (31%) in stage C/D (established HF). The median NT-proBNP and hs-cTnT increased with HF stage. Increasing HF stage was associated with a 2- to 4-fold increase in the primary outcome/major adverse cardiovascular events in the placebo group. The kidney-specific composite was 5-fold higher in stage B (pre-HF) versus stage A but similar in stages B and C/D. The effect of sotagliflozin versus placebo was similar, irrespective of HF stage (primary outcome: hazard ratio, 0.74 [95% CI, 0.63-0.88]; =1.00), with higher absolute benefit in each HF stage (-trend=0.002). The absolute benefit for the kidney-specific end point was comparable for stages B and C/D. CONCLUSIONS: Increasing HF stage is associated with a higher risk of HF, major adverse cardiovascular events, and kidney events. Asymptomatic stage B (pre-HF) increased cardiovascular and renal events by >2- and 5-fold, respectively. The benefits of sotagliflozin are consistent, irrespective of HF stage.
Lu R, Nalbandian A, Akita K
… +5 more, Teruya S, Bampatsias D, Santos AM, Maurer MS, Shimada YJ
Circ Heart Fail
· 2026 Feb · PMID 41569308
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BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) causes a restrictive cardiomyopathy resulting in heart failure (HF). Signaling pathways associated with ATTR-CM are not well defined. The purpose of this study w...BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) causes a restrictive cardiomyopathy resulting in heart failure (HF). Signaling pathways associated with ATTR-CM are not well defined. The purpose of this study was to identify signaling pathways that are dysregulated in ATTR-CM compared with controls. METHODS: This was a case-control study of cases with ATTR-CM, internal controls with hypertensive left ventricular hypertrophy, and external controls with HF. For model development, ATTR-CM cases were age- and sex-matched with internal controls with hypertensive left ventricular hypertrophy. Plasma proteomics profiling of 7289 proteins was conducted. A sparse partial least squares discriminant analysis was performed to develop a proteomics-based discrimination model from 70% of the data (ie, the training set), and the discriminative ability was tested in the remaining 30% of the data (ie, the internal test set). External validation using HF controls was also conducted. Pathway analysis of significantly (ie, univariable <10) dysregulated proteins was executed. Signaling pathways with a false discovery rate <0.05 were declared positive. RESULTS: The analysis included 169 cases and 220 controls. A total of 211 discriminant proteins were identified in the training set from the proteomics-based model developed to distinguish ATTR-CM cases from 170 internal controls with hypertensive left ventricular hypertrophy. The area under the receiver-operating characteristic curve to discriminate ATTR-CM in the test set from 50 external controls with HF was 0.89 (95% CI, 0.82-0.96). The sensitivity was 0.90 (95% CI, 0.75-0.97), and the specificity was 0.86 (95% CI, 0.72-0.96). Pathway analysis revealed the PI3K-Akt (phosphoinositide-3-kinase-protein kinase) pathway and its related pathways (eg, JAK-STAT [Janus kinase-signal transducer and activator of transcription]) were dysregulated. Dysregulation of previously identified pathways, such as the complement and coagulation cascade pathways, was also observed. CONCLUSIONS: This study reveals a distinct proteomic profile of ATTR-CM compared with controls with HF, and elucidates both novel and known signaling pathways that are differentially regulated in ATTR-CM.
Echouffo-Tcheugui JB, Ndumele CE, Chen J
… +19 more, Rooney MR, Walker KA, Schlosser P, Matsushita K, Grams ME, Ballantyne CC, Hoogeveen RC, Boerwinkle E, Yu B, Shah AM, Dubin RF, Deo R, Ren Y, Rotter JI, Taylor KD, Post WS, Ganz P, Selvin E, Coresh J
Circ Heart Fail
· 2026 Mar · PMID 41569286
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BACKGROUND: To investigate the proteomic signatures of heart failure (HF) in diabetes. The underlying mechanisms of the elevated risk of HF in diabetes are unknown. METHODS: In 10 189 ARIC study (Atherosclerosis Risk in...BACKGROUND: To investigate the proteomic signatures of heart failure (HF) in diabetes. The underlying mechanisms of the elevated risk of HF in diabetes are unknown. METHODS: In 10 189 ARIC study (Atherosclerosis Risk in Communities) participants free of HF (mean age 57±7 years, 56% women, 22% Black adults, 14% with diabetes), we conducted discovery and internal validation for the associations of 4955 plasma proteins with HF by diabetes status. We performed (1) Cox regression to identify proteins associated with HF by diabetes status, (2) external validation in the MESA study (Multi-Ethnic Study of Atherosclerosis, n=5233, 633 with diabetes), and (3) pathway analyses for identified proteins. RESULTS: Over 24 years in ARIC, there were 2417 HF events (605 among individuals with diabetes). In 993 individuals with diabetes in the discovery sample, 19 proteins were associated with HF (<10), 12 proteins replicated in the internal validation sample (<0.05/19). Six of the internally validated proteins replicated in MESA (false discovery rate, q<0.05). Five proteins were specifically associated with HF in those with diabetes: 4 are novel (inactive tyrosine-protein kinase 7, chondroadherin, leucine-rich repeat, and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 and fibulin-5) and 1 is the previously known (cartilage intermediate layer protein 2). NPPB (N-terminal pro-BNP) was associated with HF in those with and without diabetes. Pathways over-represented among proteins associated with diabetes-related HF were lipid metabolism, inflammation, and brown adipose tissue (false discovery rate, q<0.05). CONCLUSIONS: We identified 5 proteomic markers (4 novel) uniquely related to HF risk among individuals with diabetes and not among those without diabetes.