Abstract Background Growing evidence suggests that a comorbidity-driven systemic pro-inflammatory state, including activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, contributes to the pathogenesis of HFpEF. The anti-inflammatory drug colchicine, traditionally used for gout treatment, inhibits NLRP3 activity through its well-known microtubule-disassembling properties. However, its potential to ameliorate diastolic dysfunction remains insufficiently explored. Purpose Building on our previous demonstration of colchicine's cardioprotective effect in a murine model of high-grade inflammation, Coxsackievirus B3-induced myocarditis, we now aimed to examine its impact on inflammation, fibrosis, and cardiac function in a mouse model of low-grade inflammation, Angiotensin II (AngII)-induced diastolic dysfunction with elevated filling pressure. Methods Six-week-old male C57BL/6J mice received daily subcutaneous injections of AngII (1.1 mg/kg BW) for 14 days according to Murdoch et al. (2014). Colchicine (5 µmol/kg BW) was given orally on day 1 (+Col d1) or day 7 (+Col d7). Controls received water. Cardiac function was assessed by invasive pressure–volume analysis and echocardiography. Myocardial stiffness was determined from passive force in isolated cardiomyocytes. Titin phosphorylation and fibrosis were evaluated by Western blot and immunohistochemistry, respectively. Systemic and LV inflammation were assessed using flow cytometry, ELISA, and qPCR of inflammasome markers. Results AngII infusion resulted in increased left ventricular end-diastolic pressure (LVEDP), reduced fractional shortening (FS) and cardiac output (CO), as well as elevated passive tension in isolated cardiomyocytes, with no overt fibrosis observed compared to controls. These functional changes were associated with reduced phosphorylation of the titin N2B segment and were accompanied by systemic inflammasome activation, as indicated by increased proportions of splenic NLRP3+, ASC+, caspase-1+ and IL-1β+ immune cells, along with elevated circulating S100A8/9 levels. In turn, treatment with colchicine after 1 and 7 days restored LVEDP, FS and CO to control levels, reduced passive myocardial stiffness and normalised titin N2B phosphorylation. Furthermore, colchicine attenuated systemic inflammasome activation without inducing adverse structural or functional effects. LV expression of the AngII receptor type 1 and components of the NLRP3 inflammasome was not affected in any group. Conclusion Colchicine effectively reversed AngII-induced diastolic dysfunction, involving amelioration of sarcomere compliance and suppression of systemic NLRP3 inflammasome activation. These findings identify colchicine as a promising therapeutic strategy to mitigate inflammation-driven myocardial stiffness and preserve diastolic function, highlighting its translational relevance for HFpEF.
Purpose The effect of pulmonary hemodynamics on outcomes after the implantation of the HeartMate 3 left ventricular assist device (HM3-LVAD) is still not fully understood, although some studies indicate positive results. We conducted an analysis using the EUROMACS international database, which includes many patients from various sites across Europe. Methods We identified adults who underwent HM3-LVAD implantation from the EUROMACS Database of the European Association of Cardiothoracic Surgery from January 2018 through April 2024. We excluded those with previous cardiac surgery, undergoing concomitant cardiac procedures, on an IABP or ECMO, and those with missing hemodynamic data. Based on the pre-transplant hemodynamic profile, patients were categorized into: Group 1 with a mean pulmonary artery PA pressure (mPAP) < 20 mmHg and a pulmonary vascular resistance (PVR) < 2 WU; Group 2 with a mPAP > 20 mmHg and a PVR < 2 WU; and Group 3 with a PVR > 2 WU. We compared 1- and 2-year mortality rates, major bleeding, and right ventricular (RV) failure after adjusting for factors in the HM3 Survival Risk Score. Results 632 individuals were identified: 47 (7.4%) in group 1, 144 (22.8%) in group 2, and 441 (69.8%) in group 3. Groups differed in age, gender, body mass index, race, and pre-LVAD use of some medications. Post-implant 1-year and 2-year death rates were 14.1% (n=89) and 18.7% (n=118), respectively while 16.0% (n=103) experienced a major bleed. After adjusting for factors in the HM3 Risk Score, no differences were seen in the odds of 1-year death when group 1 (Odds Ratio [OR] 1.09, 95% confidence interval [CI] 0.46-2.59) and group 2 (OR 0.61, 95% CI 0.61-1.86) were compared with group 3 (Figure). Similar results were seen for 2-year mortality (group 1 vs. group 3, p = 0.561; group 2 vs group 3, p = 0.330) and major bleeding (group 1 vs. group 3, p = 0.476; group 2 vs group 3, p = 0.958) with no difference between the groups. While, compared with group 3, group 1 increased the odds of late (>14 days) RV failure, no other differences in late or early (14 days) failure were seen. Conclusions In this retrospective study, elevated PA pressure and/or resistance did not affect the mortality and bleeding rates up to 2 years after HM3-LVAD implantation in adults enrolled in the EUROMACS database.
Transcatheter mitral valve implantation (TMVI) using an anchoring system at the left ventricular (LV) apex has developed as treatment option for high-surgical risk patients with severe mitral regurgitation (MR). The aim of this study was to compare TMVI with LV apical anchoring to traditional approaches, focusing on their impact on reverse remodeling and outcomes. Data of consecutive patents who underwent TMVI with TENDYNE prosthesis and TMVI as valve-in-valve and valve-in-ring procedures between 2015 and 2024 were compared regarding post-procedural changes in LV end-diastolic volume index (LVEDVI), left atrial volume index (LAVI), LV ejection fraction (LVEF), LV sphericity index (LVSI) and LVOT-obstruction based on cardiac computed tomography (CCT). Changes in mitral valve pressure gradient (MV MPG) and presence of paravalvular leakage (PVL) were assessed echocardiography. We analyzed data of patients who underwent TMVI with TENDYNE prosthesis (Group 1, n=26, mean age 77±7, 50% women) and TMVI as valve-in-valve and valve-in-ring procedures (Group 2, n=29, mean age 71±10, 41% women). LV EDVI decreased stronger in Group 1 (125±34 vs 102±31 ml/m2, p<0.001) then in Group 2 (101±26 vs 95±32ml/m2, p=0.155). Postprocedural reduction in LAVI was significant in both Groups (103 vs 85 ml/m2, p<0.001) and (85 vs 78 ml/m2, p=0.031). LVSI changes were stronger in Group 1 (0.5±0.1 vs 0.7±0.5, p=0.057) than in Group 2 (0.4±0.1 vs 0.4±0.5, p=0.248). LV EF decreased slightly in both Groups (42 vs 38%, p=0.003) and (55 vs 52%, p=0.003). MV MPG reduction was more pronounced in Group 1 (3.5±1.2 vs 6.9±3.2mmHg, p<0.001). LVOT obstruction was observed in 4 patients in Group 1 and in 7 patients in Group 2. The 30d mortality rate was numerically higher in Group 1 - 5/26 (19%) compared to Group 2 - 1/29 (3%) but without statistical significance (p=0.090). We observed more favorable valve hemodynamics and LV reverse remodeling after TENDYNE procedure than after traditional procedures, however with more spherical shape of the LV. 30-day mortality did not differ significantly between both groups. Larger multicenter studies are needed to investigate the impact of LV geometric changes induced by different TMVI procedures on the long-term clinical outcomes.
Abstract Background Hereditary arrhythmia syndromes such as catecholaminergic polymorphic ventricular tachycardia (CPVT) are rare but potentially fatal causes of sudden cardiac death in the young. Despite advances in genetic testing, many patients remain undiagnosed due to variants of uncertain significance and inconclusive stress testing. iPSC-derived cardiomyocytes enable direct visualization of patient-specific calcium-handling abnormalities, but manual analysis is time-consuming and limits clinical translation. Purpose To address these limitations, this project developed and validated an automated machine-learning framework using confocal calcium-imaging data from patient-derived iPSC-cardiomyocytes. A hierarchical diagnostic approach—from species classification to major cardiac pathologies and genotype identification—demonstrated model sensitivity to interspecies, disease-related, and mutation-specific calcium-handling differences. Methods A curated multi-species dataset (>600 line-scan recordings from human, rabbit, rat, mouse, and pig cardiomyocytes with heart failure, myocardial infarction, or CPVT3) was analyzed. Conventional models (Random Forest, SVM, XGBoost) were trained on manually extracted calcium-transient features, while a ResNet-18 network was fine-tuned on raw microscopy data from whole line-scan images using transfer learning. Performance was evaluated by weighted F1-score (wF1) with stratified 10-fold cross-validation and bootstrapped 95% confidence intervals. Model interpretability was assessed using SHAP values and Grad-CAM. Results Conventional machine-learning models using manually extracted calcium-transient features achieved wF1 = 0.79 ± 0.02 (species), 0.83 ± 0.01 (pathology), and 0.83 ± 0.04 (genotype). The ResNet-based approach applied to compressed microscopy data reached comparable or higher performance, improving species (wF1 = 0.68 ± 0.03 → 0.90 ± 0.08) and pathology (wF1 = 0.80 ± 0.02 → 0.87 ± 0.12) classification using alternative heads, while genotype prediction rose from wF1 = 0.87 ± 0.05 to 1.00 ± 0.00, suggesting potential overfitting. External validation on a limited dataset for species yielded wF1 = 0.50 ± 0.02 (random wF1 = 0.32, internal wF1 = 0.68 ± 0.03). Grad-CAM indicated model focus on calcium transients, and SHAP analyses highlighted the decay phase as most informative, suggesting that targeted analysis may further increase performance. Conclusion Deep-learning models trained directly on raw microscopy images were non-inferior to, and partly outperformed, conventional feature-based algorithms, distinguishing biological and pathological states and detecting CPVT mutations via calcium-signaling patterns. This marks a first step toward an automated and scalable diagnostic pipeline for hereditary arrhythmia syndromes. External validation on a subset of species data confirmed robustness across laboratories, while CPVT and genotype results remain exploratory pending independent validation datasets.
