The clinical impact of underweight on outcomes in patients undergoing surgical aortic valve replacement (SAVR) remains unclear. This study aimed to investigate the prognostic significance of underweight status in patients undergoing SAVR and to identify key determinants of adverse outcomes within this population. 805 patients underwent SAVR between January 2016 and December 2021 at eight Japanese centers. After excluding 31 patients with missing laboratory data, a total of 774 patients were included. Patients were categorized into underweight group (Body mass index [BMI] < 18.5 kg/m², 79 patients), normal-weight group (BMI 18.5–25 kg/m², 464 patients), and overweight group (BMI ≥25 kg/m², 231 patients). The primary endpoint was all-cause mortality. The median age was 76 years (interquartile range [IQR]: 71–79), and the median BMI was 23.3 kg/m² (IQR: 20.9–25.8). Underweight patients had the highest 5-year mortality, followed by normal-weight and overweight patients (23.5

OBJECTIVE:To assess whether preoperative low-attenuation plaque (LAP) burden is associated with postoperative computed tomography (CT)-detected distal embolism after hybrid aortic arch repair, and to characterize its anatomical distribution and clinical impact. METHODS:In this single-center retrospective cohort, 128 patients who underwent hybrid aortic arch repair (Ishimaru zones 0-2) with paired pre- and postoperative contrast-enhanced CT between 2016 and 2024 were analyzed. Aortic plaque composition was quantified at the aortic arch and mid-descending thoracic aorta; LAP and intermediate-attenuation plaque (IAP) were defined as 0-60 and 61-130 Hounsfield units (HU), respectively. Total LAP and IAP burdens were calculated as the sum of the arch and mid-descending aortic areas. Distal embolism was defined as any new postoperative perfusion defect in the liver, spleen, kidneys, or intestine. Risk factors were assessed using logistic regression, and early and mid-term outcomes were compared between high and low LAP groups. RESULTS:CT-detected distal embolism occurred in 12 of 128 patients (9.4%), most commonly involving the kidneys and spleen. In univariable analysis, female sex, current smoking, peripheral arterial disease, and total LAP burden were associated with distal embolism. In the multivariable model, total LAP burden remained the only independent factor (odds ratio per 10 mm2, 1.18; 95% CI, 1.09-1.30; p < 0.001). Freedom from all-cause mortality was significantly lower in the high LAP group (log-rank p = 0.003). CONCLUSIONS:Preoperative aortic LAP burden was independently associated with CT-detected distal embolism after hybrid aortic arch repair. High LAP burden was associated with increased distal embolism and worse long-term survival, suggesting that LAP-based plaque characterization may improve preoperative embolic risk stratification in complex arch interventions.

Background: Outcomes after isolated tricuspid valve surgery (ITVS) are strongly influenced by advanced right-sided heart failure and hepatorenal dysfunction; however, the prognostic significance of preoperative diuretic burden remains unclear. This study examined whether preoperative diuretic burden is associated with outcomes after ITVS and whether combining it with the model for end-stage liver disease-sodium (MELD-Na) score improves risk stratification. Methods: We retrospectively analyzed 85 patients who underwent ITVS at 16 Japanese hospitals between 2015 and 2024. Diuretic doses were converted to furosemide equivalents. A dose >40 mg/day was defined as high. The primary outcome was 5-year all-cause mortality. The secondary outcome was the composite adverse outcome, which comprised events such as cardiac death, hospitalization for heart failure, and dialysis initiation. Outcomes were compared across four groups defined by diuretic burden and the MELD-Na score. Results: Patients who received a high dose (high-dose group) had higher 5-year cumulative mortality (57.8% vs. 19.4%; P<0.001) and a higher cumulative incidence of the composite adverse outcome (77.5% vs. 31.3%; P<0.001) than those of patients who received a low dose (low-dose group). The MELD-Na score independently predicted mortality [hazard ratio (HR) =1.11; P=0.045]. Combining diuretic burden and the MELD-Na score showed a stepwise gradient, the highest mortality rate, and the highest incidence of the composite adverse outcome in the high-dose group with high MELD-Na scores. The high-dose group with low MELD-Na scores had poorer outcomes than those of the low-dose group with low MELD-Na scores. Conclusions: A higher preoperative diuretic burden is associated with worse outcomes after ITVS. Escalating the diuretic dose to mitigate organ dysfunction does not reliably improve outcomes. Early surgical referral should be considered before dose escalation and organ dysfunction.

Objective: Surgical aortic valve replacement in patients with severe aortic stenosis and small annuli remains challenging owing to prosthesis-patient mismatch and the limited feasibility of subsequent valve-in-valve transcatheter aortic valve replacement (ViV-TAVR). The Konno procedure enables annular and left ventricular outflow tract (LVOT) enlargement; however, outcomes in adults remain insufficiently defined. Methods: Between January 2023 and October 2025, 193 patients underwent surgical aortic valve replacement at our institution, of whom 19 (10%) received the Konno procedure for annulus diameter ≤19 mm, high likelihood of prosthesis-patient mismatch, or anticipated ViV-TAVR with estimated high risk of coronary obstruction. Operative results, echocardiographic and electrocardiographic parameters, and computed tomography measurements of the aortic root were assessed before and after surgery. Results: Patients were aged 59 ± 19 years and 84% were women. Bioprostheses were implanted in 12 patients (63%) and mechanical valves in seven (37%), with enlargement permitting prosthesis implantation 2 to 3 sizes larger. Septal myectomy was performed in 6 patients. No in-hospital mortality occurred. Computed tomography demonstrated enlargement of the sinus of Valsalva (+7.0 mm) and sinotubular junction (+6.9 mm), consistent with ViV-TAVR feasibility. Echocardiography confirmed relief of LVOT obstruction; however, right ventricular diameter tended to increase, tricuspid annular plane systolic excursion declined, and QRS duration increased from 90 to 114 milliseconds, indicating intraventricular conduction delay. Conclusions: Konno aortic valve replacement facilitates implantation of larger prostheses, relieves LVOT obstruction, and optimizes root anatomy for future ViV-TAVR. Conduction disturbances and right ventricular functional decline warrant long-term surveillance.

Angiosome-based revascularization may be insufficient in chronic limb-threatening ischemia when microperfusion network is disrupted by atherosclerosis. The woundosome concept, encompassing in-line flow to the wound and microcirculatory status around the wound, provides a more appropriate revascularization framework. A 65-year-old man with bilateral foot ulcers showed patent ankle vessels, yet selective malperfusion of the medial plantar territory corresponded to the ulceration sites. Woundosome-directed bypass to plantar branches was performed bilaterally despite vessel diameters of less than 1 mm, achieving complete wound healing with sustained patency at 1 year. This case demonstrates that woundosome-directed bypass, guided by microperfusion assessment, is essential for wound healing.

Patch augmentation of the right ventricular outflow tract (RVOT) is frequently required in pediatric patients with stenosis or atresia affecting the right ventricle-to-pulmonary artery continuity. However there have been no ideal patch materials for pediatric patients. A 1-month-old infant with pulmonary atresia with an intact ventricular septum underwent surgical pulmonary valvotomy and RVOT reconstruction using a novel hybrid wrap-knitted patch designed for autologous tissue ingrowth. Ten months postoperatively, for recurrent severe pulmonary valve stenosis, the patient underwent repeat RVOT reconstruction. Histological examination of the excised hybrid patch revealed that both surfaces were covered with regenerated tissue composed of smooth muscle cells, blood vessels, and collagen fibers. Transmission electron microscopy confirmed that the regenerated tissue contained feature mature fibroblasts and capillaries, demonstrating sufficient development of regenerated tissue. Histological findings of the hybrid wrap-knit fabric patch excised in redo surgery 10 months after the initial surgery showed potential macrophage-fibroblast interaction, promoting tissue remodeling in the new fabric.

To identify the predictors of all-cause mortality and heart failure (HF) events in patients with ischemic cardiomyopathy (ICM) undergoing isolated coronary artery bypass (CABG) grafting who present with symptomatic HF, and to identify potential stratification variables for future regenerative therapy trials. We retrospectively analyzed data from 90 patients with ICM, left ventricular ejection fraction of ≤ 40

Purpose: Silent cerebral infarctions are common after aortic arch surgery; however, the predictive value of preoperative computed tomography (CT)-derived plaque characteristics remains unclear. We investigated the incidence, distribution, and risk factors for new cerebral infarction lesions (NCILs) after total aortic arch replacement (TAR), focusing on low-attenuation plaque (LAP, 0-60 Hounsfield units [HU], a surrogate of lipid-rich vulnerable plaque) burden. Methods: Among 82 consecutive TAR patients, 41 underwent both pre- and postoperative brain diffusion-weighted magnetic resonance imaging (MRI). Clinical profiles, CT-derived atheroma grade and plaque attenuation, operative details, and outcomes were compared between NCIL-positive and NCIL-negative groups. The primary multivariable model simultaneously included arch atheroma grade and LAP area, adjusted for age and sex. Results: NCILs were detected in 25/41 patients (61%): 23 silent and 2 symptomatic. All NCILs exhibited embolic imaging features without watershed or hypoperfusion patterns. NCIL-positive patients had significantly greater arch LAP area (63.9 vs. 17.7 mm(2), p <0.01). On multivariable analysis, arch LAP remained the only independent predictor (OR per 10 mm(2), 3.01; 95% confidence interval [CI] 1.50-8.75; p = 0.012), whereas atheroma grade was not. Conclusion: More than half of TAR patients developed MRI-detected, predominantly silent NCILs. Preoperative arch LAP was the sole independent predictor. LAP assessment may refine intraoperative risk stratification and guide tailored neuroprotective strategies.

Background:Atrial functional mitral regurgitation (AFMR) is increasingly prevalent worldwide and is associated with poor clinical outcomes, yet the optimal timing of surgical intervention remains unclear. Although preoperative diuretic dosage may reflect heart failure severity, its prognostic significance after surgery for AFMR has not been fully established. This study investigated the association between preoperative diuretic dosage and postoperative outcomes in patients undergoing surgery for AFMR. Methods:Among 915 patients who underwent mitral valve surgery (MVS) between 2008 and 2023, 85 patients with AFMR were identified and categorized into high-dose (≥40 mg furosemide-equivalent, n=35) and low-dose (<40 mg, n=50) groups based on preoperative diuretic dosage. Ten-year cumulative incidences of all-cause mortality, cardiac mortality, and heart failure readmission were evaluated. Results:Baseline characteristics were comparable between groups in terms of age (78 vs. 75 years, P=0.09), male sex (46% vs. 62%, P=0.19), total bilirubin (1.0 vs. 0.9 mg/dL, P=0.23), ejection fraction (EF; 61% vs. 65%, P=0.20), and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) (5.3% vs. 4.5%, P=0.94). Estimated glomerular filtration rate (eGFR) was lower in the high-dose group (48.3 vs. 58.9 mL/min/1.73 m2, P=0.006). All-cause mortality (51.7% vs. 22.9%, P=0.02), cardiac mortality (47.8% vs. 13.1%, P=0.007), and heart failure readmission (71.1% vs. 52.4%, P=0.005) were significantly higher in the high-dose group over the 10-year follow-up. High-dose diuretic use remained an independent risk factor in multivariable analysis [adjusted hazard ratio (HR) 2.89; 95% confidence interval (CI): 1.01-8.25; P=0.048]. Mortality was particularly higher among patients with renal dysfunction, regardless of dosage, and those with liver dysfunction receiving high-dose diuretics. Conclusions:In AFMR surgery patients, especially with concomitant renal or liver dysfunction, high-dose diuretic use was associated with increased mortality and heart failure readmission.

Background: Right ventricular failure (RVF) is a major adverse event after left ventricular assist device (LVAD) implantation, but its complex mechanisms make accurate prediction challenging. While supervised machine learning (ML) can predict outcomes from complex models, understanding the conclusions is often difficult. This study aimed to develop an interpretable supervised ML model to assess patients’ RVF risk and identify key risk factors. Methods: We analyzed 327 patients from 482 consecutive LVAD implantations performed between June 2010 and January 2024 who underwent preoperative right heart catheterization and echocardiography. RVF was defined as requiring a right ventricular assist device or ≥14 days of postoperative inotropic support. Preoperative clinical and hemodynamic variables were used for risk prediction, and Shapley additive explanation (SHAP) values were used to assess individual risk factors. Results: Thirteen features were selected: sex, age, nonischemic cardiomyopathy, body surface area, aspartate aminotransferase, blood urea nitrogen, left ventricular end-diastolic dimension, left ventricular ejection fraction, cardiac output, right ventricular stroke work index, central venous pressure (CVP)/pulmonary capillary wedge pressure (PCWP), pulmonary pulsatility index (PAPi), and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile. Ensemble learning was the most reliable algorithm, achieving an area under the curve of 0.888 (95% confidence interval [CI], 0.756-0.975) and an accuracy of 0.879 (95% CI, 0.788-0.940). A high-risk group (RVF occurrence rate >20%) had 1-year and 3-year survival rates of 80.7% and 75.3%, respectively, showing a tendency toward worse long-term outcomes compared to the low-risk group (93.2% vs 90.5%; P = .09). SHAP analysis revealed individual patient risk factors and their contributions, most frequently highlighting CVP/PCWP, PAPi, and INTERMACS profile. Conclusions: Supervised ML enables accurate prediction of RVF after LVAD implantation. SHAP values identify individual risk factors, potentially optimizing preoperative conditions.

One of the regenerative medicine approaches for severe heart failure (HF) involves enhancing the inherent regenerative capacity, with mesenchymal stem cells (MSCs) being a crucial element. High mobility group box 1 (HMGB1) has been reported to promote the mobilization of MSCs from the bone marrow and contribute to tissue repair. We hypothesized that cardiac function would improve through this mechanism in a porcine ischemic cardiomyopathy (ICM) model and analyzed its effectiveness using various imaging modalities, histological analyses, and RT-PCR. Echocardiography revealed an increased left ventricular (LV) ejection fraction and reduced LV end-systolic volume. Cardiac magnetic resonance imaging with late gadolinium enhancement demonstrated improved regional LV strain and a smaller scarred myocardial zone. A pressure wire study in the coronary arteries showed enhanced coronary flow reserve and resistive reserve ratio. Histological analysis exhibited a smaller cardiomyocyte diameter, reduced fibrosis area, and an increased number of CD31-positive endothelial cells. RT-PCR analysis indicated elevated levels of pro-angiogenic, anti-fibrotic, and anti-inflammatory factors such as SDF1, HGF, FGF2, and TGFb3. These findings suggested that HMGB1 fragment activated a self-tissue repair pathway, leading to improved cardiac function. The less-invasive intravenous administration of the HMGB1 fragment highlights its potential as a regenerative therapy for severe HF.

Inferior phrenic artery aneurysms (IPAAs) are extremely rare, with only 17 reported cases. Most were diagnosed following ruptured, and developed secondary to trauma, surgery, or pancreatitis. We report a case of an asymptomatic unruptured IPAA treated endovascularly. A 73-year-old man without a history of laparotomy, trauma, or pancreatitis had a 6.8-mm saccular IPAA identified incidentally on computed tomography angiography during a comprehensive health checkup. Coil embolization was successfully performed without complications. Given the rarity of IPAAs, a gold standard therapy has not been established. However, endovascular therapy appears to be a safe and effective treatment option.

Once an esophago–airway fistula develops during chemoradiotherapy for cT4b esophageal cancer, further curative treatment is often precluded. We describe a robotic technique for closure of a large esophago–left main bronchial fistula using a pedicled autologous pericardial patch reinforced with a latissimus dorsi muscle flap. A 66-year-old woman with squamous cell carcinoma of the middle to upper thoracic esophagus invading the left main bronchus developed a fistula after definitive chemoradiotherapy. After temporary airway stenting, salvage surgery was performed in the semi-prone position under single-lung ventilation and CO₂ pneumothorax. Following thoracic esophagectomy, a horseshoe-shaped pedicled pericardial patch was created robotically, flipped cranially, and sutured to the bronchial defect. A right latissimus dorsi muscle flap was then introduced into the right thoracic cavity through a second intercostal opening and robotically fixed over the repair. To our knowledge, this is the first report of this robotic technique.

Introduction Heart failure (HF) caused by pressure overload remains as one of the leading causes of morbidity and mortality worldwide, which can manifest itself in a wide range of clinical scenarios. Current therapeutic strategies are limited to lifestyle changes, pharmacological measures, and devices aimed at supporting heart function. This poses a challenge in the search for new strategies for disease management. Macrophages, constituting nearly 10 % of non-myocyte cells in a healthy heart are considered a means to fill this gap due to their pleiotropic phenotype, which extends beyond the well-known functions of phagocytosis and antigen presentation. In this study, we evaluated the efficacy of bone marrow mononuclear cell (BMNC)-derived macrophages (BMNC-Mφ) in treating a mouse model of transverse aortic constriction (TAC). Methods In in vitro experiments, BMNC were polarized into BMNC-Mφ using a previously established protocol. We then performed transcriptomic analysis to confirm BMNC-Mφ marker genes compared to BMNC. BMNC-Mφ phenotypes were further validated by flow cytometry and RT-qPCR. In in vivo experiments, all mice underwent TAC surgery (day 0). On days 7 and 14 post-TAC, mice in the experimental and control groups received intravenous injections of approximately 3 × 106 BMNC-Mφ or PBS, respectively. Heart function was assessed weekly by transthoracic echocardiography at baseline and 7, 14, 21, and 28 days post-TAC. Additionally, we monitored in vivo transcriptome dynamics over time using time-resolved deep RNA sequencing profiles of heart tissues from healthy, 1 day post-TAC, 8 days post-TAC, and 16 days post-TAC mice. Time-course transcriptomic profiling was followed by histological analysis of excised hearts on day 28. Results BMNC-Mφ showed phenotype similar to that of resident cardiac macrophages, with increased expression of key anti-inflammatory macrophage markers, including Igf1, Arg1, Retnla, Ang2, Anxa2, and others. In vivo application of BMNC-Mφ further confirmed their potential to mitigate adverse cardiac remodeling in TAC model. Mice receiving BMNC-Mφ better tolerated mechanical stress, as reflected in preserved LV function (LVEF [52.3 % vs. 45.6 %, p = 0.0152], LVFS [22.6 % vs. 19.2 %, p = 0.0208], and LVIDs [2.65 mm vs. 3.2 mm, p = 0.0261]), as well as structure (fibrosis area [5.6 % vs. 10.67 %, p < 0.01]). In addition, BMNC-Mφ promoted angiogenesis (2120.4 ± 25.5 per mm2 vs. 1512.4 ± 34 per mm2, p < 0.05) and controlled cardiomyocyte growth, which was seen in the smaller short-axis diameter of cardiomyocytes in BMNC-Mφ-treated group (17.2 ± 0.18 μm vs. 19.45 ± 0.46 μm, p < 0.05). Conclusion The main conclusion drawn from our results is that BMNC-Mφ improved or at least preserved LV function and architecture through metabolic recovery, immunosuppression, organized cell cycle/proliferation, and fibrosis modulation.

Pathological remodeling after myocardial infarction (MI) involves multifactorial mechanisms, highlighting the need for combinatorial therapeutic strategies. Synthetic mRNAs offer design flexibility and represent a modality particularly suitable for such approaches. To investigate this, five genes (Hgf, Igf1, Pdgfb, Cxcl12, and Tgfβ1) were selected from a model in which extracellular vesicles secreted by human iPSC‐derived cardiomyocytes restored cardiac function. Synthetic mRNAs encoding these genes were delivered via polyplex nanomicelles by direct myocardial administration in mice with MI‐induced heart failure. Nanomicelles have been shown to provide stable encapsulation, enhanced local expression, and prolonged persistence. This treatment promoted angiogenesis via the PI3K–Akt–ETV4 axis, suppressed fibrosis via inhibition of the JNK/FOXO3 pathway, and enhanced repair by activating ERK signaling, together yielding multifaceted benefits, including tissue regeneration, improved contractility, and extended survival. These findings establish the therapeutic potential of multigene mRNA cocktail therapy for post‐MI heart failure and mark an important step toward developing new interventions for diseases characterized by complex remodeling.

Myocardial ischemia-reperfusion (I/R) injury causes cardiomyocyte death and cardiac dysfunction in part through ferroptosis. Brown adipocytes (BAs) have emerged as endocrine regulators with cardioprotective potential, yet their involvement in ferroptosis modulation during I/R injury remains unclear. Here, we engineered BA sheets and transplanted them onto the ischemic myocardium in a rat I/R model to evaluate therapeutic efficacy. BA sheets transplantation significantly improved cardiac function, reduced infarct size and fibrosis, and mitigated adverse remodeling while enhancing angiogenesis. In vitro, conditioned medium derived from BA sheets promoted cardiomyocyte survival, preserved contractile performance, and inhibited apoptosis and ferroptosis under hypoxia/reoxygenation stress. Mechanistically, these effects were mediated by the activation of the NRG4-ErbB4 axis and its downstream PI3K/AKT and NRF2/HO-1 antioxidant signaling pathways. Our findings demonstrate that engineered BA sheets exert potent cardioprotection against myocardial I/R injury by suppressing ferroptosis in an NRG4-ErbB4-dependent manner, supporting their promise as a therapeutic strategy for ischemic heart disease.

Long waiting times for donor organs in pediatric patients have increased the need for mechanical circulatory support as a bridge to heart transplantation. We report the case of a one-year-old boy with Barth syndrome who presented with cardiogenic shock due to severe biventricular heart failure. Emergency biventricular assist device support using centrifugal pumps was initiated. Under severe pulmonary hypertension and pulmonary regurgitation, the right ventricular assist device outflow was temporarily directed to the left atrium to optimize left ventricular preload. As pulmonary hemodynamics improved, the right ventricular assist device outflow was redirected to the pulmonary artery, allowing evaluation of native pulmonary circulation and subsequent right ventricular assist device weaning. After recovery of end-organ function, the left ventricular assist device was converted to a Berlin Heart EXCOR 76 days after biventricular assist device implantation. The patient remained stable on Berlin Heart EXCOR support for 374 days and subsequently underwent successful heart transplantation. This case highlights the importance of early right ventricular assist device support and strategic management of right ventricular assist device outflow to optimize left ventricular assist device performance in pediatric patients with severe pulmonary hypertension. Such an approach may facilitate successful bridge-to-candidacy and eventual heart transplantation in high-risk pediatric patients.

BACKGROUND:This study aimed to compare the 5-year outcomes of patients who underwent isolated transcatheter aortic valve replacement (TAVR) vs patients who underwent isolated surgical aortic valve replacement (SAVR) from the Evolut Low Risk trial. METHODS:In the Evolut Low Risk trial, 1414 low-risk patients with severe aortic stenosis underwent TAVR using a self-expanding, supraannular CoreValve, Evolut R, or PRO bioprosthesis (Medtronic) or SAVR. This post hoc analysis excluded 250 patients, those with concomitant procedures (eg, percutaneous coronary intervention and coronary artery bypass grafting) and those who experienced crossover between treatment arms. The 5-year clinical and echocardiographic outcomes are reported. RESULTS:A total of 1164 patients underwent an isolated procedure (667 TAVR, 497 SAVR). At 5 years, the composite of all-cause mortality or disabling stroke was similar between the isolated groups (15.5% TAVR, 14.6% SAVR; P = .84). All-cause mortality (13.5% TAVR, 12.8% SAVR; P = .85) and cardiovascular mortality (6.9% TAVR, 8.3% SAVR; P = .36) were also comparable. New permanent pacemaker implantation was higher with TAVR (27.3% vs 8.9%; P < .001). The 5-year rate of aortic valve reintervention was 3.0% for TAVR and 2.2% for SAVR (P = .51). Moderate or greater paravalvular regurgitation occurred in 0.5% of TAVR patients and none of the SAVR patients (P = .52) at 5 years. CONCLUSIONS:This post hoc analysis of the Evolut Low Risk trial in patients undergoing isolated TAVR or SAVR demonstrates similar rates of all-cause mortality, reintervention, and moderate or greater paravalvular regurgitation at 5 years, supporting Evolut TAVR as a suitable treatment option in carefully selected low-risk patients undergoing isolated valve replacement.

Dilated cardiomyopathy (DCM) is the most prevalent pediatric cardiomyopathy and has a poor prognosis. Although heart transplantation is the only curative option, the severe donor shortage in Japan underscores an urgent need for alternative therapies. Here, we generated induced pluripotent stem cell (iPSC) lines from two unrelated children with the same TNNT2-R151W mutation. We then investigated the cellular characteristics of the cardiomyocytes derived from these iPSC lines (R151W iPSC-CMs) and evaluated their contractile function in pillar-based engineered heart tissue (EHT). We also assessed the therapeutic potential of overexpressing wild-type TNNT2 in patient-derived iPSCs (wtTNNT2-OE-iPSCs). R151W-iPSC-CMs exhibited pronounced sarcomere disarray, attenuated Ca 2+ transient amplitude, prolonged time to peak, and delayed decay tau. These characteristics are indicative of failing myocardium and were restored in wtTNNT2-OE-iPSC-CMs. Pillar-based EHT assays revealed a substantial decrease in contractile force in R151W-EHTs compared to wtTNNT2-OE-EHTs, which is suggestive of the systolic dysfunction observed clinically in DCM. Collectively, these results provide the first functional evidence that the TNNT2-R151W mutation leads to pediatric DCM by causing sarcomere insufficiency and disturbances in Ca 2+ handling. Our patient-specific iPSC-EHT platform faithfully recapitulates key features of pediatric DCM and could offer a robust system for mechanistic studies and drug testing. Furthermore, phenotypic rescue upon overexpression of wild-type TNNT2 suggests that this allele is amenable to a gene replacement approach aimed at restoring wild-type function in TNNT2-mutant cardiomyopathies.