BACKGROUND:Although adeno-associated virus (AAV) gene-replacement therapy is a potentially transformative therapy for severe genetic diseases, its cardiac immunotoxicity may challenge broad clinical use. METHODS:Medical Literature Analysis and Retrieval System Online, Embase, and PubMed databases were searched from January 2005 to March 2025. Studies including patients treated with AAV-replacement therapy were deemed eligible. Prespecified items (type of vector, dose, timing, and clinical significance of the adverse event) were extracted by 2 independent observers. Random-effects models were fitted using restricted maximum likelihood estimation and the method of Hartung, Knapp, Sidik, and Jonkman (International Prospective Register of Systematic Reviews [PROSPERO]. VigiBase and the US Food and Drug Administration Adverse Event Reporting System were searched for the occurrence of myocarditis with commercially available AAV-replacement drugs. RESULTS:Eighty studies including 1939 human patients were analyzed. A total of 734 adverse events were reported over 2122 patient-years of pooled observation. Seventy-one cases of myocarditis were identified. The pooled incidence rate per 100 patient-years was 8.6 (95% CI, 5.8-10.7; I2=63.2%). Events occurred in patients with Duchenne muscular dystrophy, spinal muscular atrophy, and X-linked myotubular myopathy, with recombinant AAVs and adeno-associated virus serotype 8. All received an intravenous dose >1013 vector genomes per kilogram body weight. Myocardial injury peaked in week 1 after injection (90% [95% CI, 85.7%-96.2%]; I2=43.2%), whereas myocarditis occurred mostly after week 2 (55% [95% CI, 48.7%-65.2%]; I2=33.1%), with no cases after the first month. Most myocarditis/myocardial injury did not have a relevant clinical impact (62, 87%), with only 8 (12%) cases having transient left ventricular dysfunction. The latter recovered during the follow-up. The only death occurred in the setting of cytokine-mediated capillary leak syndrome with cardiac dysfunction. Myocarditis occurred in relation to delandistrogene moxeparvovec (1/16 [6%]) and onasemnogene abeparvovec (14/217 [6%]) in the Food and Drug Administration Adverse Event Reporting System and VigiBase. CONCLUSIONS:Immune-mediated myocarditis/myocardial injury after systemic AAV gene therapy occurred in <10 per 100 patient-years (peaking at weeks 1-3) and was usually clinically mild, with a minority showing transient dysfunction. All events followed intravenous doses >1×1013 vector genomes per kilogram body weight, clustered in neuromuscular programs, and were associated with certain recombinant capsids/serotypes. These data support intensive early cardiac monitoring, cautious dose selection, and delivery strategies to minimize systemic exposure. REGISTRATION:URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251046546).

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are strongly linked to heart failure with preserved ejection fraction (HFpEF), yet the mechanisms underlying this association remain unclear because robust integrative preclinical models are lacking and the liver and heart are rarely studied as a coordinated system. Here we show that Alms1 -/- (Foz/Foz) mice fed a Western diet develop MASH with advanced liver fibrosis accompanied by a HFpEF phenotype characterized by left ventricular hypertrophy, impaired cardiomyocyte contractility, reduced β-adrenergic reserve, elevated BNP, and increased mortality despite ejection fraction >50. Liver fibrosis emerged as a strong predictor of cardiac dysfunction. Remarkably, dietary reversal restored hepatic architecture, normalized cardiac function, and improved survival, revealing marked plasticity of the liver-heart axis. Mechanistic analyses revealed coordinated mitochondrial dysfunction, altered substrate utilization, and extracellular matrix remodeling in the left ventricle, with strong concordance to human HFpEF transcriptomic signatures. Ultrastructural studies confirmed mitochondrial injury and sarcomeric disorganization, linking metabolic failure to impaired cardiomyocyte performance. Together, these findings identify mitochondrial dysfunction as a central mediator of MASLD-associated HFpEF and establish the Foz/Foz model as a powerful platform for dissecting liver-to-heart signaling pathways and testing mechanism-based therapeutic strategies.

We investigated whether pro-resolving lipid mediators of the lipoxin family can attenuate fibrosis and inflammation in muscle LIM protein knockout (MLP ko ) mice, a model of dilated cardiomyopathy (DCM). Male and female MLP ko mice received either vehicle or a mix of lipoxin-A 4 and lipoxin-B 4 three times per week for six weeks. Cardiac function was assessed using echocardiography, and fibrosis and DCM-associated cardiac signaling was evaluated through histology, immunofluorescence and immunoblot analyses. Flow cytometry and RNA sequencing (RNAseq) was performed to identify changes in cardiac gene expression and characterize macrophage subpopulations, respectively. Flow cytometry showed increased inflammatory CD11c + M1-like macrophages and reduction of CD206 + M2-like macrophages in MLP ko hearts compared to wild-type controls. Lipoxin treatment partially reversed the macrophage imbalance and showed mild improvements in cardiac physiology in MLP ko males. RNAseq analyses revealed sex-dependent alterations in the expression of pro-fibrotic and inflammation-related genes, suggesting changes in extracellular matrix (ECM) integrity and composition, and to the adaptive immune response. Intriguingly, several ECM proteins showed unexpected localizations at cardiac intercalated disks, which are known to be involved in DCM etiology. Further analysis identified lipoxin-dependent reduction in the DCM-associated expression of intercalated disk components only in lipoxin-treated MLP ko males. Lipoxins also modulated key cardiac signaling pathways in a sex-specific manner, including Erk1/2 and PKCα-linked Ankrd1/Carp1, which is associated with DCM development in MLP ko mice. While lipoxins do not directly reverse cardiac dysfunction or fibrosis in MLP ko mice, they may provide sex-specific protective effects by modulating DCM-related cardiac signaling pathways and by influencing immune-cell populations.

Glycogen storage diseases (GSDs) are a heterogeneous group of rare and often under-recognized causes of inherited cardiomyopathy characterized by pathological glycogen or autophagic vacuole accumulation of debris within various tissues, including the heart. These diseases often present as phenocopies of sarcomeric hypertrophic cardiomyopathy, though they may also manifest with dilated or mixed phenotypes. Key GSDs with cardiomyopathy include Pompe disease (GSD IIa), Danon disease (IIb), Cori/Forbes disease (GSD III), Andersen disease (GSD IV), Tarui disease (GSD VII), phosphorylase kinase deficiency (GSD IX), glycogenin-1 deficiency (GSD XV), and PRKAG2 syndrome, each presenting unique clinical trajectories. Accurate diagnosis requires integration of clinical red flags, multimodality cardiac imaging, and electrocardiography, alongside definitive diagnostic tools like enzyme screening, genetic testing, and endomyocardial biopsy. There is a dearth of evidence regarding specific treatment of each unique GSD cardiomyopathy, but emerging therapeutics across the spectrum of GSDs aim to address this need. This review covers current knowledge on the spectrum of GSD-related cardiomyopathies, discussing pathophysiology, diagnosis, and evolving treatment strategies.

Aims:Right ventricular (RV) function is a key factor in the diagnosis and prognosis of heart disease. However, current advanced computed tomography (CT)-based assessments rely on semi-automated segmentation of the RV blood pool and manual delineation of the RV free and septal wall boundaries. These steps are time-consuming and prone to inter- and intra-observer variability. Methods and results:We developed and evaluated a fully automated pipeline consisting of two deep learning methods to automate volumetric and regional strain analysis of the RV from contrast-enhanced, electrocardiogram (ECG)-gated cineCT images. The Right Heart Blood Segmenter (RHBS) is a 3D high-resolution configuration of nnU-Net to define the endocardial boundary, while the Right Ventricular Wall Labeler (RVWL) is a 3D point cloud-based deep learning method to label the free and septal walls. We trained our models using a diverse cohort of patients with different RV phenotypes and tested them in an independent cohort of patients with aortic stenosis undergoing TAVR. Our approach demonstrated high accuracy in both cross-validation and independent validation cohorts. RHBS and RVWL both yielded Dice scores of 0.96 and accurate volumetry metrics. RVWL achieved high Dice scores (>0.90) and high accuracy (>93%) for wall labelling. The combination of RHBS + RVWL provided an accurate assessment of free and septal wall regional strain, with a median cosine similarity value of 0.97 in the independent cohort. Conclusion:A fully automated 3D cineCT-based RV regional strain analysis pipeline has the potential to significantly enhance the efficiency and reproducibility of RV function assessment, enabling the evaluation of large cohorts and multi-centre studies.

BACKGROUND:Evaluating regional variations in right ventricular (RV) performance can be challenging, particularly in patients with significant impairments due to the need for 3D spatial coverage with high spatial resolution. ECG-gated cineCT can fully visualize the RV and be used to quantify regional strain with high spatial resolution. However, strain is influenced by loading conditions. Myocardial work (MW)-measured clinically as the ventricular pressure-strain loop area-is considered a more comprehensive metric due to its independence of preload and afterload. In this study, we sought to develop regional RV MW assessments in 3D with high spatial resolution by combining cineCT-derived regional strain with RV pressure waveforms from right heart catheterization (RHC). PURPOSE:Regional MW is not measured in the right ventricle (RV) due to a lack of high spatial resolution regional strain (RS) estimates throughout the ventricle. We present a cineCT-based approach to evaluate regional RV performance and demonstrate its ability to phenotype three complex populations: end-stage LV failure (HF), chronic thromboembolic pulmonary hypertension (CTEPH), and repaired tetralogy of Fallot (rTOF). METHODS:Forty-nine patients (19 HF, 11 CTEPH, 19 rTOF) underwent cineCT and RHC. RS was estimated as the regional change in the endocardial surface from full-cycle ECG-gated cineCT and combined with RHC pressure waveforms to create regional pressure-strain loops; endocardial MW was measured as the loop area. Detailed, 3D mapping of RS and MW enabled spatial visualization of strain and work strength, and phenotyping of patients. RESULTS:HF patients demonstrated more overall impaired strain and work compared to the CTEPH and rTOF cohorts. For example, the HF patients had more akinetic areas (median: 9%) than CTEPH (median: < 1%, p = 0.02) and rTOF (median: 1%, p < 0.01) and performed more low work (median: 69%) than the rTOF cohort (median: 38%, p < 0.01). The CTEPH cohort had more impairment in the septal wall; < 1% of the free wall and 16% of the septal wall performed negative work. The rTOF cohort demonstrated a wide distribution of strain and work, ranging from hypokinetic to hyperkinetic strain and low to medium-high work. Impaired strain (-0.15 ≤ RS) and negative work were strongly-to-very strongly correlated with RVEF (R = -0.89, p < 0.01; R = -0.70, p < 0.01, respectively), while impaired work (MW ≤ 5 mmHg) was moderately correlated with RVEF (R = -0.53, p < 0.01). CONCLUSION:Regional RV MW maps can be derived from clinical CT and RHC studies and can provide patient-specific phenotyping of RV function in complex heart disease patients.

BACKGROUND:Precision therapies for dilated cardiomyopathy (DCM) are lacking despite diverse manifestations and clinical trajectories based on underlying etiology. DCM-associated pathogenic variants in cardiac beta-myosin heavy chain (MYH7) and titin (TTN) can impair the function/availability of cardiac myosin. Danicamtiv is a novel investigational small molecule that selectively enhances cardiac myosin function. OBJECTIVES:The study sought to translationally evaluate danicamtiv in the setting of myosin dysfunction, from in vitro assessments to a clinical trial exploring its safety and efficacy in DCM due to MYH7 or TTN variants, or other causes (either positive or negative genetic results). METHODS:The danicamtiv effects on DCM-variant cardiac myosin enzyme activity and skinned left ventricular (LV) fiber force generation were assessed in vitro. A phase 2a, baseline-controlled, open-label trial enrolled individuals with DCM into cohorts by variants (MYH7 or TTN) or other causes. In the week of treatment period (TP)1, participants received oral danicamtiv 25 mg twice daily with dose adjustment in TP2 to 10 or 50 mg twice daily. The primary endpoint was safety/tolerability; secondary endpoints included echocardiography-assessed changes in cardiac structure/function. RESULTS:In vitro, danicamtiv increased the activity of wild-type and DCM myosin, increasing force production in cardiac fibers. Forty-one participants were enrolled in the trial (mean age 49.6 ± 13 years; mean baseline LV ejection fraction 33.4% ± 8.0%). Twelve had MYH7 variants, 14 had TTN variants, and 15 had other cause DCM. Treatment-emergent adverse events were reported in 22 (53.7%) of 41 participants (all mild or moderate; 1 discontinuation); an asymptomatic increase in cardiac troponin was detected in 3 participants in the other causes cohort. After TP2, the MYH7 and TTN cohorts showed improvements from baseline in LV ejection fraction (MYH7: 8.8% [95% CI: 5.03%-12.64%]; TTN: 5.9% [95% CI: 2.59%-9.28%]) but less in the other causes cohort (4.4% [95% CI: -0.90% to 9.73%]). CONCLUSIONS:Selective in vitro enhancement of cardiac myosin motor function and myofilament force generation by danicamtiv prompted clinical evaluation. A short course of danicamtiv was generally well tolerated in participants with DCM. Echocardiography outcomes were consistent with a danicamtiv-induced enhancement of myosin function/availability; MYH7 and TTN cohorts generally had the most favorable responses in contractile function. (Exploratory Study of Danicamtiv in Patients With Primary Dilated Cardiomyopathy Due to Genetic Variants or Other Causalities; NCT04572893).

Donor-derived cell-free DNA (dd-cfDNA) is a promising biomarker of acute rejection (AR) after heart transplantation (HTx). dd-cfDNA, measured as a fraction of total cfDNA, can be affected by changes in total cfDNA whereas dd-cfDNA quantity can mitigate this impact. This study investigated the performance of a 2-threshold algorithm (2TA) that combines dd-cfDNA fraction (dd-cfDNA%) and donor-quantity score (DQS). A total of 808 plasma samples were prospectively collected for dd-cfDNA testing from 187 adult HTx patients with contemporaneous endomyocardial biopsies. cfDNA was analyzed by a single nucleotide polymorphism-based next-generation sequencing workflow; dd-cfDNA% and DQS were measured using the sequencing reads and single nucleotide polymorphism genotypes. Both dd-cfDNA% and DQS were significantly higher in AR than in non-AR samples (P < 10-14). Considering samples exceeding either dd-cfDNA% = 0.26% or DQS = 18 copies/mL as positive, the 2TA demonstrated 86.5% sensitivity and 83.6% specificity for AR detection and an area under the curve of 0.881. Compared to dd-cfdNA% alone, performance improved with a mean net reclassification index of 16.4% (standard deviation: 4.0%; P = .015) and a 37.3% reduction in the number of the false positive cases compared to the previously established cutoff of 0.15%. Combining dd-cfDNA fraction and quantity estimate in a 2TA may improve AR detection accuracy in HTx recipients compared with dd-cfDNA% alone.

Background: Additional data are needed to define the optimal listing strategy and peri-transplant management for adults with congenital heart disease (ACHD). In this study, we evaluated the perioperative management and 1-year outcomes for 30 patients who underwent orthotopic heart transplantation (OHT) for ACHD. Methods: We conducted a single-center retrospective case series of all patients who received an OHT at our institution for ACHD from January 1, 2017 through June 30, 2024. Descriptive statistical analyses were used to illustrate the baseline characteristics, peri-transplant management, and 1-year outcomes of participants. Results: Seventeen (56.7%) patients received a heart-only transplant, 4 (13.3%) had a heart-lung transplant, 8 (26.7%) had a heart-liver transplant, and 1 (3.3%) had a heart-liver-kidney transplant. Embolization of aortopulmonary and venous collateral vessels before transplantation was performed in 12 (80%) Fontan patients, with a median of 2 procedures per patient. Twenty-eight (93.3%, n = 30) patients were alive at 90 days, and 26 (92.9%, n = 28) were alive at 1 year. Conclusions: This cohort of ACHD patients had a 92.9% 1-year survival rate, consistent with other high-volume centers in the United States. In this paper, we discuss our institutional practices that address barriers to transplant for ACHD patients, such as early referral for transplant, indications for listing, pretransplant embolization of collateral vessels, and multiorgan transplant.

Introduction The efficacy of statin therapy in improving cardiac allograft vasculopathy (CAV)-free survival in heart transplant (HTx) recipients is well established. Drug interactions with calcineurin inhibitors is a major barrier to statin utilization and uptitration. Patients are frequently on a fixed statin dose regardless of comorbidities or lipid profile. Purpose: The aim of this study is to describe differences in statin regimen, lipid profile and CAV development between HTx recipients with high and low pre-HTx cardiovascular (CV) risk. Methods This single-center, retrospective study included all HTx recipients from 2019-2020 with survival ≥1 year, 2 lipid panels, and ≥1 intravascular ultrasound (IVUS) assessment. Recipient demographics, IVUS and medication data, and lipid profile prior to HTx and annually post-HTx were collected. Patients were categorized as high-CV risk if indication for HTx was ischemic heart disease, patient had a history of diabetes, and/or pre-HTx A1C was ≥6.5. All other patients were categorized as low CV risk. Severe CAV was defined as Stanford classification ≥4 on IVUS. Results Of 87 HTx recipients included, 43 (49%) were considered high-risk and more likely to be male (Table 1). At baseline, high-intensity statin use was more prevalent in high-risk patients, but by year 2, there was no difference in statin intensity between groups (Table 1). There was no difference in baseline lipid profiles; however, by year 2, LDL-C, HDL-C, and non-HDL-C at year 1 and non-HDL-C was higher in high-risk patients (Table 1). Severe CAV developed in 37 (43%) patients within the first 2 years post-HTx, with a trend (RR 1.5, p=0.1) toward increased risk in the high-risk CV group (22, 51%) compared to the low-risk CV group (15, 34%). Conclusions Downgrading of statin intensity after HTx was observed in high-risk patients, with a trend towards higher risk for CAV in this group. Further studies assessing individualized statin regimens informed by pre-HTx CV risk and post-HTx lipid trends on CAV development are needed.

Background Left ventricular assist device (LVAD) implantation is a life-saving therapy for end-stage heart failure, but right ventricular failure (RVF) remains a major complication. Current RVF risk models are limited. We hypothesized that pathogenic/likely pathogenic (P/LP) variants increase intrinsic RV vulnerability and post-LVAD RVF risk. Methods and Results In a single-center retrospective study of 136 adults undergoing LVAD implantation in 2018-2024, 87% were male, 65% non-White, and 68% had non-ischemic cardiomyopathy. Genetic testing was completed in 48 (35%), identifying P/LP variants in 19%. Patients with P/LP variants had higher early RVF rates (89% vs. 38% vs. 15%, p<0.01) and longer hospitalizations (84 vs. 31 vs. 24 days, p=0.02) than those with variants of uncertain significance or negative results. Outcomes did not differ by ischemic versus non-ischemic etiology. Conclusions P/LP variants were associated with early RVF, suggesting that genetic testing may inform RVF risk stratification and perioperative management.

Background Genetic testing is recommended in the evaluation of transthyretin amyloid cardiomyopathy (ATTR-CM) with the goal of improving diagnosis and facilitating cascade genetic testing of at-risk family members. This has become increasingly important with the availability of targeted therapeutics. However, utilization of genetic testing in ATTR-CM has been slow. Methods In this single-center qualitative study, we conducted semi-structured interviews with 10 participants (either with ATTR-CM or at-risk family members). Interviews were recorded, transcribed, and analyzed using deductive and inductive approaches. Baseline genetic proficiency was evaluated using a validated Genetics Knowledge Questionnaire. Results Four common themes emerged from the patient interviews around genetic testing. Utilization of genetic testing predominantly depended on a trusted non-genetic provider’s recommendation. Attitudes toward genetic testing were overall positive with cited benefits of increasing disease knowledge and protecting family members. Patients considered genetic testing to be an easy process, but it was often associated with psychological distress, especially among asymptomatic at-risk family members. Pretest counseling with informed consent and discussion of insurance discrimination risks (disability, life) was important to patients but often inadequate. Participants had a median score of 88% on the Genetics Knowledge Questionnaire. Conclusions In this qualitative study, we found that patients with ATTR-CM and at-risk family members viewed genetic testing positively but emphasized the importance of provider recommendation, emotional support, informed consent, and disclosure of potential insurance discrimination risks. These findings highlight key patient-centered priorities to guide the implementation of genetic testing into clinical cardiology practice.

BACKGROUND:Carney complex, a familial syndrome caused by germline PRKA1A mutation, predisposes to recurrent cardiac myxomas. In refractory cases, orthotopic heart transplantation (OHT) can be considered for assumed curative treatment of recurrent myxoma. CASE SUMMARY:We present a case of recurrent cardiac myxoma arising from residual native right atrial tissue in a woman with Carney complex 26 years after OHT for recurrent myxoma. DISCUSSION:To our knowledge, this represents the first reported case of recurrent cardiac myxoma after OHT in a patient with Carney complex. Surgical ablation of remaining atrial tissue during OHT for myxoma may reduce the risk of recurrence, and lifelong surveillance after myxoma resection in Carney complex may be indicated. TAKE-HOME MESSAGE:This case highlights a rare genetic syndrome that can cause recurrent cardiac myxomas. If OHT is performed in the context of Carney complex, attention to surgical and surveillance strategies to prevent and detect recurrence is key.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and represents a leading cause of morbidity and mortality. HCM is a sarcomeric disease characterized by genetically determined defects in sarcomere proteins, leading to left ventricular hypertrophy, hypercontractility and diastolic dysfunction. The phenotypic spectrum of the disease is heterogeneous, ranging from mild forms that can remain stable and asymptomatic for many years, through to childhood-onset, severe cases that can result in progressive heart failure and ventricular arrhythmias. Multi-imaging techniques including echocardiography and cardiac magnetic resonance are pivotal for diagnostic and prognostic assessment in HCM. For decades, therapeutic approaches were limited to invasive septal reduction therapies and nonspecific pharmacological treatment for heart failure. In the last 10 years, however, an in-depth understanding of the pathological mechanisms of HCM has led to the development of targeted therapies, such as myosin inhibitors, which have proven to be safe and effective in improving functional capacity and reducing symptoms. Innovative therapeutic approaches, such as gene therapies that aim to target the genetic variants underpinning the condition, are currently under investigation. Hypertrophic cardiomyoapthy is a condition in which the left ventricle of the heart becomes thickened. In this Primer, Argirò and colleagues discuss the epidemiology, pathogenetic mechanisms, diagnosis and management of hypertrophic cardiomyoapthy and describe how the disease can affect patient quality of life.