bims-hafaim 2026-07-12 papers

Issue of 2026–07–12
five papers selected by
Kyle McCommis, Saint Louis University

Immunol Rev. 2026 Jul;340(1): e70128

Emerging Roles for Metabolism in Myocardial Inflammation During Heart Failure.

Metabolic alterations are a hallmark of heart failure and differ across stages. The immune system plays a critical role in cardiac repair and injury during heart failure progression. Metabolic interactions between immune cells and cardiomyocytes are critical for influencing cellular states and cell-cell communications. Understanding these molecular intersections is essential to developing targeted therapies that regulate immunometabolism in the heart. In this review, we provide a comprehensive overview of the metabolic links between immune cells and cardiomyocytes during heart failure and discuss potential treatment strategies.

Keywords: heart failure; immunometabolism; immunotherapies; inflammation; metabolic adaptation; processes; therapeutic approaches

DOI: https://doi.org/10.1111/imr.70128

Eur Heart J Imaging Methods Pract. 2026 Aug;4(3): qyag110

Cardiac energetics in health and disease: a meta-analysis.

Jonathan J H Bray, John A Henry, Archit Singhal, Takanayi Mureyi, Liam S Couch, Mahmood Ahmad, Ladislav Valkovič, Stefan Neubauer, Andrew J M Lewis, O J Rider.

Aims: The cardiac phosphocreatine-to-ATP ratio (PCr/ATP) is the principal non-invasive biomarker of myocardial energetic status and is measured by phosphorus magnetic resonance spectroscopy (31P-MRS). However, studies of cardiac energetics are typically from single centres with relatively small numbers of patients, leading to unknown generalizability.
Methods and results: Here, we use systematic review and meta-analysis of all available studies reporting cardiac PCr/ATP ratios to show pooled reference values across populations (databases searched: Embase, Medline, CENTRAL). We collected data on differing methodological factors to enable adjustment. We included 176 studies comprising 7843 individual participant magnetic resonance examinations between 1987 and 2025. The pooled PCr/ATP ratio was 1.96 for healthy volunteers (n = 2988), 1.54 for heart failure with reduced ejection fraction (n = 575; a 21% reduction), and 1.60 for heart failure with preserved ejection fraction (n = 146; an 18% reduction) with further reductions seen across other disease states including valvular disease and diabetes. Methodological factors, including field strength, sequence type, and voxel location significantly, influenced measurements, though adjustment had minimal effect on pooled estimates. Body mass index and natriuretic peptides negatively correlated with PCr/ATP, whilst left ventricular systolic function showed positive correlation.
Conclusion: This comprehensive meta-analysis provides reference PCr/ATP values across cardiac conditions, implicating energetic impairment as a common pathway spanning myocardial diseases of diverse aetiology, and suggests that methodological heterogeneity does not fully account for the observed between-group differences.
Registration: PROSPERO (CRD420251081946).

Keywords: MRS; PCr/ATP; cardiac energy metabolism; energetics; magnetic resonance imaging; phosphorus spectroscopy

DOI: https://doi.org/10.1093/ehjimp/qyag110

J Mol Cell Cardiol. 2026 Jul 09. pii: S0022-2828(26)00103-3. [Epub ahead of print]

RBP1 attenuates pathological cardiac hypertrophy via Wnt3a/β-catenin signaling.

Qinfeng Hu, Hui Ni, Xiaoce Dai, Chengjiang Jin, Meixiang Xiang, Hong Ma.

BACKGROUND: Pathological cardiac hypertrophy is a central driver of heart failure, yet targeted therapies remain lacking. This study aimed to investigate the role of retinoid homeostasis in cardiac hypertrophy, focusing on retinol-binding protein 1 (RBP1), the primary intracellular regulator of retinol homeostasis. We sought to elucidate the effects and underlying mechanisms of RBP1 in cardiac hypertrophy.
METHODS: Cardiac retinol and all-trans retinoic acid (atRA) levels were quantified using LC-MS. A mouse model of pressure overload-induced cardiac hypertrophy was established via transverse aortic constriction (TAC) surgery. Cardiac-specific overexpression of RBP1 was achieved by intravenous injection of an adeno-associated virus 9 (AAV9) vector carrying RBP1 under the control of the cardiac troponin T (cTnT) promoter. An in vitro hypertrophy model was established by treating rat neonatal cardiomyocytes (NRCMs) with phenylephrine (PE). Gain- and loss-of-function approaches were applied to evaluate the effect of RBP1 on cardiomyocyte hypertrophy. Transcriptomic changes upon RBP1 knockdown in PE-treated NRCMs were analyzed by RNA sequencing. To dissect the signaling pathways involved, the retinoic acid receptors (RARs) inhibitor AGN193109 and the Wnt signaling agonist Wnt3a were administered. A dual-luciferase reporter assay was performed to evaluate whether atRA regulates Wnt3a promoter activity.
RESULTS: Retinol metabolism was impaired in mice subjected to TAC. Supplementation of atRA sufficiently ameliorated cardiac hypertrophy. RBP1 was upregulated in both hypertrophied myocardium and isolated cardiomyocytes. Cardiac-specific RBP1 overexpression effectively restored myocardial retinol and atRA pools and alleviated cardiac hypertrophy and fibrosis in TAC mice. RBP1 expression was significantly upregulated in PE-induced hypertrophic NRCMs. Knockdown of RBP1 in NRCMs aggravated hypertrophy, whereas its overexpression attenuated hypertrophy induced by PE stimulation. RNA sequencing analyses indicated that RBP1 knockdown disrupted retinol and retinoic acid metabolic processes. Pharmacological inhibition of atRA signaling using AGN193109 (AGN) partially reversed the protective effect of RBP1 overexpression on cardiomyocyte hypertrophy, indicating that the anti-hypertrophic effect of RBP1 is partially dependent on atRA signaling. Further analyses demonstrated that RBP1 inhibits cardiomyocyte hypertrophy by suppressing Wnt3a/β-catenin signaling. Mechanistically, atRA partially reversed Wnt3a/β-catenin activation induced by RBP1 knockdown, whereas AGN partially abolished the inhibitory effect of RBP1 overexpression on this pathway, indicating that RBP1 regulates Wnt3a/β-catenin signaling in an atRA-dependent manner. Moreover, luciferase reporter assays demonstrated that atRA suppressed Wnt3a promoter activity via retinoic acid response elements (RAREs) within its promoter region.
CONCLUSIONS: RBP1 is upregulated in hypertrophic myocardium and exerts a protective role against cardiac hypertrophy. These results suggest that RBP1 may serve as a potential therapeutic target for cardiac hypertrophy and heart failure, offering a promising strategy to prevent and regress cardiac hypertrophy through RBP1/atRA/Wnt3a/β-catenin signaling.

Keywords: Cardiac hypertrophy; RBP1; Retinol metabolism; Wnt signaling

DOI: https://doi.org/10.1016/j.yjmcc.2026.07.008

Mol Cell Biol. 2026 Jul 07. 1-11

Gasdermin D Inhibition Attenuates Mitochondrial Damage and Cardiomyocyte Pyroptosis in Heart Failure with Preserved Ejection Fraction.

Linlin Chen, Zhiming Jiang, Cheng Li, Hao He, Yulian Yin, Dong Li.

Heart failure with preserved ejection fraction (HFpEF) represents the most prevalent subtype of heart failure globally, with its underlying pathogenesis remaining incompletely elucidated. Pyroptosis and mitochondrial dysfunction have been implicated in HFpEF progression. In addition, gasdermin D (GSDMD) has been shown to mediate both mitochondrial dysfunction and pyroptosis, yet the specific regulatory mechanisms involved in HFpEF remain to be elucidated. In this study, we found that HFpEF mouse models exhibited elevated blood glucose and blood pressure, impaired diastolic cardiac function, upregulated serum NT-proBNP, increased heart weight-to-tibia length (HW/TL) ratio, reduced exercise tolerance, obvious myocardial structural damage, excessive mitochondrial ROS accumulation, increased mitochondrial GSDMD-N expression, mitochondrial morphological abnormalities, and activated myocardial pyroptosis pathway. Treatment with GI-Y2 significantly ameliorated these changes. Collectively, GSDMD contributes to HFpEF progression by promoting mitochondrial damage and cardiomyocyte pyroptosis.

Keywords: GI-Y2; GSDMD; HFpEF; mitochondrial damage; pyroptosis

DOI: https://doi.org/10.1080/10985549.2026.2693284

JACC Heart Fail. 2026 Jul 07. pii: S2213-1779(26)00318-5. [Epub ahead of print] 103218

Effects of Tirzepatide in Obesity-Related HFpEF by Sex: A Prespecified Secondary Analysis From the SUMMIT Trial.

SUMMIT Trial Group

BACKGROUND: The SUMMIT trial showed that the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide decreased risk of cardiovascular death or worsening heart failure (HF) in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Women outnumber men with HFpEF, and there are sexual dimorphisms in the relationships between body fat and pathophysiology that could influence response to tirzepatide.
OBJECTIVES: This study aims to compare baseline characteristics and effects of tirzepatide on primary and other endpoints in women and men with obesity-related HFpEF.
METHODS: In the SUMMIT trial, 731 patients with NYHA functional class II-IV HFpEF and body mass index (BMI) ≥30 kg/m2 were randomly assigned to tirzepatide (n = 364) or placebo (n = 367). The primary outcomes were time to cardiovascular death or worsening HF and change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) at 52 weeks. Key secondary outcomes included changes in 6-minute walk distance (6MWD), C-reactive protein, and body weight at 52 weeks. Baseline characteristics and effects of tirzepatide on primary and secondary endpoints were contrasted by sex.
RESULTS: Compared with men (n = 338, 46.2%), women with obesity-related HFpEF (n = 393, 53.8%) had greater BMI, waist to height ratio (WHtR), symptom severity (higher NYHA functional class, lower KCCQ-CSS), and poorer exercise capacity (lower 6MWD), whereas men had greater left ventricular remodeling and paracardiac fat. Greater baseline BMI or WHtR were correlated with lower KCCQ-CSS and 6MWD in women and men, with no interaction, but higher WHtR was associated with poorer kidney function exclusively in women (interaction P = 0.043). The effect of tirzepatide on the risk of worsening HF or cardiovascular death did not differ in women and men (HR: 0.66 and 0.61, respectively, interaction P = 0.81), with no heterogeneity of effect on KCCQ-CSS at 52 weeks (8.1- and 5.5-point placebo-corrected improvement, respectively, interaction P = 0.43) or 6MWD (18 m and 15 m placebo-corrected improvement, respectively, interaction P = 0.76). Among patients randomized to tirzepatide, decreases in body weight on treatment were more strongly associated with improvements in KCCQ-CSS in women than men (interaction P = 0.0058).
CONCLUSIONS: Compared with men, women with obesity-related HFpEF have greater adiposity, symptom severity, and poorer exercise capacity but lower left ventricular mass and paracardiac fat deposition. Despite these differences, tirzepatide resulted in consistent benefits across multiple domains of HF severity that did not differ by sex. (A Study of Tirzepatide [LY3291876] in Participation With Heart Failure With Preserved Ejection Fraction [HFpEF] and Obesity [SUMMIT]; NCT04847557).

Keywords: clinical trial; heart failure; heart failure with preserved ejection fraction; obesity; pathophysiology; sex differences; tirzepatide; women

DOI: https://doi.org/10.1016/j.jchf.2026.103218