Nat Commun. 2025 Dec 15;17(1):447. doi: 10.1038/s41467-025-67134-4.Alessia AngelinLiming PeiDouglas Wallace
Ant1-/- and Ant1-/-ND6P25L mitochondrial DNA mutation mice mimic the hypertrophic and dilated cardiomyopathies in patients, respectively
Restoration of just 10% of Ant1 gene expression via gene therapy was sufficient to ameliorate the cardiomyopathies and molecular defects in these mice
Thus, a modest increase in cardiac mitochondrial energetics can have profound benefits on cardiac function and is effective in treating mitochondrial cardiomyopathy in animal models
Individuals with a higher hypertrophic cardiomyopathy polygenic score (PGS) had greater septal thickness and ejection fraction, while a higher dilated cardiomyopathy PGS was linked to larger ventricular diameter and lower EF.
Adding either the HCM or DCM PGS to models that already include age, sex, and monogenic variant status improved both HCM and DCM disease discrimination.
The effect of a pathogenic HCM or DCM variant on disease likelihood was altered by the individual's PGS, indicating that common variant burden can either amplify or dampen the clinical expression of rare pathogenic variants.
JCI Insight. 2026 Feb 3:e194683. doi: 10.1172/jci.insight.194683.
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HongBo WenMaria BasilRajan JainDavid Frank
BRD4 regulates branching morphogenesis & epithelial-mesenchymal crosstalk in the developing lung
BRD4 promotes airway endoderm specification
Inhibition of BRD4 function results in deficits in human ES cell-derived endoderm differentiation, indicating an evolutionally conserved role in mammalian lung development
JAMA Netw Open Published Online: January 15, 2026 2026;9;(1):e2552323. doi:10.1001/jamanetworkopen.2025.52323Wonyoung JungKate KoBonnie Ky
Higher exposure to fine particulate matter ≤2.5 micrometers (PM2.5) and ozone was linked to measurable declines in heart function during breast cancer therapy.
Women in the highest pollution exposure groups had roughly double the risk of developing cancer therapy–related cardiac dysfunction.
Particulate matter ≤10 micrometers (PM10) and NO₂ showed no significant associations, highlighting PM2.5 and ozone as the key environmental cardiotoxicity drivers.
J Thorac Oncol. 2026 Jan 12:103550. doi: 10.1016/j.jtho.2026.01.002. Epub ahead of print. PMID: 41534787.Ivy HanKate KoBonnie Ky
Radiation therapy (RT) caused modest declines in LVEF, global longitudinal strain, circumferential strain, and Ea/Ees post RT, which largely recovered by 12 months.
About 7% of patients developed clinically significant cardiac dysfunction, typically within the first two months of starting RT.
Whole heart V30 was associated with greater LVEF declines, highlighting its importance in RT planning.
JAMA Netw Open. 2025;8(12):e2546201. doi:10.1001/jamanetworkopen.2025.46201
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Congying XiaBonnie Ky
Using N-terminal pro–B-type natriuretic peptide (NT-proBNP) to guide neurohormonal therapy in patients undergoing anthracycline chemotherapy was feasible, well-tolerated, and did not lead to significantly more adverse events compared with usual care.
Patients in the NT-proBNP–guided arm had slightly higher left ventricular ejection fraction (LVEF) at 3 months compared with usual care, suggesting early attenuation of cardiac dysfunction, although this difference diminished over time.
These findings provide support for further study of an NT-proBNP–guided approach to cardioprotection for patients undergoing cancer treatment.
Mol Ther Nucleic Acids . 2025 Nov 10;36(4):102769. doi: 10.1016/j.omtn.2025.102769. eCollection 2025 Dec 9.Xiao WangLauren TestaQiaoli Li
Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disorder caused by variants in ABCC6, which results in widespread calcification of elastic fibers
We developed an LNP-based adenine base editing therapy to correct the recurrent human ABCC6 c.3490C>T (p.R1164X) variant in the liver of variant-humanized mice
Variant correction in the liver was associated with improvement in ABCC6 protein localization, restoration of a blood biomarker of disease, and prevention of multisystemic connective tissue calcification
These results provide proof-of-concept for liver-based genome editing therapies for PXE and provide insight into the liver’s role in the mechanism of multisystemic calcification
Volume 36, Issue 4, 9 December 2025, 102770Xiao WangAidan Quigley
Phenylketonuria (PKU) is an inborn error of metabolism that results in the build up of phenylalanine (Phe) in the blood leading to systemic toxicity.
In this study we identified base editing solutions to correct three of the top five pathogenic variants of PKU.
For two variants we were able to generate mouse models which we subsequently successfully treated with our identified editing solutions.
One of the two mouse models also exhibited elevated blood Phe levels which were ameliorated after treatment with our identified editing solution for that variant.
Obliterative Bronchiolitis (BOS) as a result of chronic rejection or chronic graft-versus-host disease shares pathologic as well as transcriptional features
BOS is characterized by an expanded population of CD8+ tissue resident memory T cells
BOS is also characterized by dysfunctional stromal cells in which there are activated pro- and anti-fibrotic programs
Nature Genetics. Apr. 7, 2025Michael G. LevinScott M. Damrauer
Heart failure is a complex trait affecting over 30 million people worldwide, influenced by both environmental and genetic factors.
Across >2 million individuals, this study identified 176 genetic risk loci for heart failure that clustered into five modules, and confirmed roles for rare loss-of-function variants in TTN, MYBPC3, FLNC, and BAG3, highlighting diverse pathways contributing to heart failure.
This study showed that a polygenic risk score can modify the risk of rare pathogenic variants in TTN. Further research is needed to determine if evaluating polygenic background could improve clinical genetic testing and risk stratification for heart failure patients.
Wiley Online Library. Apr. 15, 2025Fawaz NaeemChristopher PetucciDan RaderDan Kelly
Plasma metabolomic and proteomic signatures are identified that are shared as well as distinguish human HFrEF and HFpEF.
Metabolite markers for ketogenic metabolic re-programming were identified as unique signatures in the HFrEF group, possibly related to increased levels of BNP.
Several arginine derivates were elevated in an HFrEF- and HFpEF-distinct manner.
The results set the stage for future studies aimed at assessing selected metabolites as relevant biomarkers to guide HF phenotype-specific therapeutics.
Single-cell RNA sequencing identifies progressive lineage specification from a heterogenous pool of Wnt2+ cardiopulmonary mesodermal progenitor cells (CPPs).
WNT2 plays a critical role in distal lung and capillary maturation and ventricular growth.
J Am Coll Cardiol HF. Mar 29, 2025Payman ZamaniJulio ChirinosKen MarguliesDan Kelly
In participants with Heart Failure with Preserved Ejection Fraction (HFpEF), acute dosing of an exogenous ketone significantly raised plasma ketone levels, decreased systemic carbohydrate utilization, and decreased estimated left ventricular filling pressures at rest and with exercise. However, these changes did not translate into improvements in exercise capacity.
Whether chronic dosing of ketone therapy in HFpEF is beneficial from hemodynamic, ergogenic, and quality of life perspectives remains to be seen.
The impact of ketone utilization on regional fuel substrate utilization warrants further investigation.
The benefits of radiotherapy for cancer patients are well established. Recent advances have improved tumor targeting while minimizing damage to healthy tissues, but side effects remain a challenge.
Both acute and late toxic effects can occur, which can lead to considerable long-term morbidity and adversely affect patients' quality of life.
There is a need to capitalize on the personalized and precise advancements in radiotherapy, such as FLASH radiotherapy, temporal and spatial fractionation, AI and machine learning algorithms.
J Am Heart Assoc. 2025 Mar 7:e039201Rasheed SuleLiming PeiChris Petucci
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Jack Rychik
Using patient liver biopsy samples, researchers at CHOP and UPenn CVI have applied untargeted metabolomics together with integration with their recently published single-cell multiomics to understand Fontan-associated liver disease (FALD).
This comprehensive multiomics analysis reveals new insights into the pathogenesis mechanism of FALD.
Scientific Reports (2025) 15:422Daniel P. KellyJustin Berger
Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. Research is hindered by lack of reproducible, preclinical models.
Combining diet-induced obesity with modest renovascular hypertension via Renin overexpression (aka “HFD-Renin” model) recapitulates the common cardiometabolic phenotype observed in humans, and responds to SGLT2i.
Use of this new model together with orthogonal HFpEF mouse models will aid future preclinical research efforts.
New England Journal of Medicine, November 2024Joseph Rossano
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Breakthrough Gene Therapy: The Phase 1 study of RP-A501 gene therapy assessed safety and efficacy in addressing Danon disease, a rare X-linked cardiomyopathy caused by pathologic variants in the LAMP2 gene
Safety Profile: While some adverse events occurred, including thrombotic microangiopathy and renal failure, all resolved without long-term sequelae.
Encouraging Early Efficacy: Stabilization or improvement in cardiac biomarkers, structure, and function over 24-54 months, with reduced cardiac hypertrophy and biomarker levels.
Future Directions: Encouraged by these results, a global Phase 2 trial is underway to further explore RP-A501’s potential as a transformative treatment for Danon disease.
We have entered an era of accelerated development in HCM therapeutics, fueled by fundamental discovery science and partnerships among academic physicians, scientists, patients, advocacy groups, and the pharmaceutical industry to translate these discoveries to clinical practice.
Represents the largest contribution to non-European ancestry genetics in the US to date, and as such moves the field forward towards a more inclusive future – all the summary statistics are publicly available.
The genetics of health and disease traits are largely similar across populations. Where there are differences, they are largely due to variants that are present in one population that are not present in another.
Circ Res, 2024 Jul 23, PMID: 39041214Justin BergerDaniel P. Kelly
SGLT2 inhibitors – repurposed diabetes drugs – are now standard-of-care heart failure therapy, but how they work in heart failure is unknown.
Genetic inhibition of SGLT2 in mice produces the same pleotropic effect of SGLT2i treatment in humans (blood sugar reduction, mild ketosis, and weight loss) without benefit in heart failure.
SGLT2i improve heart failure in mice lacking SGLT2, proving an independent effect. The mechanism of action remains unknown.
As survivors of childhood cancer age, the growing burden of non-major cardiovascular conditions are strongly associated with future MACE.
Early discovery, secondary prevention through lifestyle modification, low treatment threshold, and high vigilance for the progression of non-MACE conditions should be high-priority targets in survivors.
These results highlight the need for survivor-specific interventional guidelines and trials for the treatment of subclinical cardiovascular disease.
Cardiovascular disease (CVD) is a significant cause of morbidity and mortality in men with prostate cancer; however, data on racial disparities in CVD outcomes are limited.
These results show that black patients are significantly more likely to experience adverse CVD outcomes following systemic ADT compared with their White counterparts.
CV outcomes were largely explained by differences in structural social determinants of health (SDOH) and specifically the socioeconomic status theme as captured by census tract SVI.
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