Search Results (148)

Primary aldosteronism (PA), the most common cause of secondary hypertension, is increasingly recognized as an independent driver of adverse cardiac remodeling, mediated through mechanisms beyond elevated blood pressure alone. Chronic aldosterone excess leads to myocardial fibrosis, left ventricular hypertrophy, and diastolic dysfunction via mineralocorticoid receptor activation, oxidative stress, inflammation, and extracellular matrix dysregulation. These changes culminate in a distinct cardiomyopathy phenotype, often underrecognized in early stages. Multimodality cardiac imaging, led primarily by conventional and speckle-tracking echocardiography, and complemented by exploratory cardiac magnetic resonance (CMR) techniques such as T1 mapping and late gadolinium enhancement, enables non-invasive assessment of structural, functional, and tissue-level changes in aldosterone-mediated myocardial damage. While numerous studies have established the diagnostic and prognostic relevance of imaging in PA, several gaps remain. Specifically, the relative sensitivity of different modalities in detecting subclinical myocardial changes, the long-term prognostic significance of imaging biomarkers, and the differential impact of adrenalectomy versus medical therapy on cardiac reverse remodeling require further clarification. Moreover, the lack of standardized imaging-based criteria for defining and monitoring PA-related cardiomyopathy hinders widespread clinical implementation. This narrative review aims to synthesize current knowledge on the pathophysiological mechanisms of aldosterone-induced cardiac remodeling, delineate the strengths and limitations of existing imaging modalities, and critically evaluate the comparative effects of surgical and pharmacologic interventions. Emphasis is placed on early detection strategies, identification of imaging biomarkers with prognostic utility, and integration of multimodal imaging into clinical decision-making pathways. By outlining current evidence and highlighting key unmet needs, this review provides a framework for future research aimed at advancing personalized care and improving cardiovascular outcomes in patients with PA. Full article

Background: Sex-related differences in left ventricular (LV) reverse remodeling following ST-segment elevation myocardial infarction (STEMI) remain underexplored. We aimed to investigate predictors of reverse remodeling and its association with clinical outcomes, with a focus on sex-specific differences. Methods: We enrolled 253 STEMI patients (91 women, 28%) and assessed echocardiographic parameters at baseline and six months. LV reverse remodeling was defined as a ≥15% reduction in LV end-diastolic volume (LVEDV). Multivariate logistic regression identified independent predictors of remodeling. Clinical outcomes were evaluated over a median follow-up of 17 months (IQR 14–22 months), including major adverse cardiac events (MACEs). Kaplan–Meier and Cox regression analyses were performed. Results: Reverse remodeling occurred in 43% of patients and was more frequent in men than women (47% vs. 37%, p = 0.04). Male sex (OR 0.30; 95% CI: 0.14–0.65; p < 0.0001) and baseline global work efficiency (GWE) (OR 1.64; 95% CI: 1.45–1.85; p < 0.0001) were independent predictors. Men exhibited greater reductions in LVEDV, greater improvements in LV ejection fraction, and superior myocardial work indices. Over the follow-up, patients with reverse remodeling had significantly lower MACE rates compared to those without (10% vs. 24%, p < 0.01). Cox regression demonstrated that reverse remodeling was associated with a reduced risk of MACEs (HR 0.318; 95% CI: 0.181–0.557; p < 0.0001). Conclusions: LV reverse remodeling after STEMI is associated with improved clinical outcomes and is influenced by sex-specific differences. Baseline myocardial work indices, particularly GWE, are strong predictors of reverse remodeling. Men demonstrated a more favorable remodeling profile and myocardial recovery compared to women. Full article

Heart-specific overexpression of transcriptional regulator JDP2 (jun dimerization protein 2) for 5 weeks provokes paroxysmal atrial fibrillation (AF) in mice. We now investigated whether AF and atrial remodeling will be reversible upon termination of JDP2 overexpression, and whether paroxysmal AF converts to permanent AF in the presence of maintained JDP2 overexpression. Cardiac-specific JDP2 overexpression for 5 weeks, resulting in paroxysmal AF, was either continued or repressed via a tet-off system for another 5 weeks. ECGs were recorded weekly. Thereafter, heart and lung weights, and atrial mRNA and protein expression were determined. Extending JDP2 overexpression did not aggravate the AF phenotype, still paroxysmal AF, prolongation of PQ intervals, and atrial hypertrophy were present. This phenotype was completely reversible upon cessation of JDP2 overexpression. A massive downregulation of connexin40 and calcium handling proteins, including SERCA2a, calsequestrin, and ryanodine receptor, was observed in atria after prolonged JDP2 overexpression. In conclusion, atrial remodeling and paroxysmal AF under JDP2 overexpression are not sufficient to maintain or aggravate AF in the absence of JDP2. The comparison of the two groups indicates that the downregulation of calcium proteins and connexins is an important factor in the maintenance of the disease. Full article

Targeting fibrosis in Duchenne muscular dystrophy (DMD)-associated cardiomyopathy is a critical outstanding clinical issue, as cardiac failure remains a leading cause of death despite advances in supportive care. This study evaluates the therapeutic efficacy of CSPG4-targeted chimeric antigen receptor (CAR) T cells in reducing cardiac fibrosis and improving heart function in a preclinical model of the disease. DMD is a progressive genetic disorder characterized by degeneration of skeletal and cardiac muscle. Cardiomyopathy, driven by fibrosis and chronic inflammation, is a leading contributor to mortality in affected patients. Proteoglycans such as CSPG4, critical regulators of extracellular matrix dynamics, are markedly overexpressed in dystrophic hearts and promote pathological remodeling. Current treatments do not adequately target the fibrotic and inflammatory processes underlying cardiac dysfunction. CSPG4-specific CAR-T cells were engineered and administered to dystrophic mice. Therapeutic efficacy was assessed through histological, molecular, and echocardiographic analyses evaluating cardiac fibrosis, inflammation, innervation, and overall function. Treatment with CSPG4 CAR-T cells preserved myocardial integrity, improved cardiac performance, and reduced both fibrosis and inflammatory markers. The therapy also restored cardiac innervation, indicating a reversal of neural remodeling commonly seen in muscular dystrophy-related cardiomyopathy. CSPG4-targeted CAR-T therapy offers a novel, cell-based strategy to mitigate cardiac remodeling in dystrophic hearts. By addressing core fibrotic and inflammatory drivers of disease, this approach represents a significant advancement in the development of precision immune therapies for muscular dystrophies and cardiovascular conditions. Full article

Tricuspid regurgitation (TR) represents a significant, often silently progressing, valvular heart disease with historically suboptimal management due to perceived high surgical risks. Transcatheter tricuspid valve interventions (TTVI) offer a promising, less invasive therapeutic avenue. Central to the success of TTVI is Right Ventricular Reverse Remodelling (RVRR), defined as an improvement in RV structure and function, which strongly correlates with enhanced patient survival. The right ventricle (RV) undergoes complex multi-scale biomechanical maladaptations, progressing from adaptive concentric to maladaptive eccentric hypertrophy, coupled with increased stiffness and fibrosis. Molecular drivers of this pathology include early failure of antioxidant defenses, metabolic shifts towards glycolysis, and dysregulation of microRNAs. Accurate RV function assessment necessitates advanced imaging modalities like 3D echocardiography, Cardiac Magnetic Resonance Imaging (CMR), and Computed Tomography (CT), along with strain analysis. Following TTVI, RVRR typically manifests as a biphasic reduction in RV volume overload, improved myocardial strain, and enhanced RV-pulmonary arterial coupling. Emerging molecular biomarkers alongside advanced imaging-derived biomechanical markers like CT-based 3D-TAPSE and RV longitudinal strain, are proving valuable. Artificial intelligence (AI) and machine learning (ML) are transforming prognostication by integrating diverse clinical, laboratory, and multi-modal imaging data, enabling unprecedented precision in risk stratification and optimizing TTVI strategies. Full article

Feline hyperthyroidism is the most frequent endocrinopathy in adult and senior cats, frequently leading to cardiac changes characterised by a hypertrophic cardiomyopathy (HCM) phenotype, which may partially reverse with appropriate treatment. However, the structural and molecular alterations in the myocardium can persist and closely resemble those observed in hypertrophic cardiomyopathy. Despite this clinical overlap, protein expression patterns in the hearts of hyperthyroid cats remain poorly understood. This study aimed to evaluate the myocardial expression of desmin, a key contractile protein, as well as calreticulin and interleukin-10 proteins involved in cardiac remodelling and response to injury. Left ventricular samples were obtained from 16 hyperthyroid cats, 12 cats with HCM, and 10 healthy controls. Immunohistochemical staining was performed to assess the expression patterns of the selected proteins. Our findings revealed that, despite median left ventricular dimensions not being significantly different from ones observed in healthy animals, cats with hyperthyroidism exhibited similar alterations in desmin and interleukin-10 expression to those seen in HCM-affected cats. These changes were associated with cardiomyocyte degeneration and coronary artery narrowing, suggesting a shared pathway of myocardial injury independent of the primary disease. Full article

Background/Objectives: Surgical aortic valve replacement effectively relieves left ventricular afterload and promotes reverse remodeling in patients with severe aortic stenosis. The Perceval prosthesis offers a hybrid approach, combining complete annular decalcification with sutureless deployment. This design allows for reduced operative times and potentially larger effective orifice areas. However, comparative data with conventional stented bioprosthetic valves remain limited, particularly regarding reverse remodeling, hemodynamic performance, and long-term clinical outcomes. Methods: In this retrospective cohort study, 115 patients underwent aortic valve replacement with either the Perceval valve (n = 44) or conventional stented bovine pericardial valves (n = 71). Results: The Perceval group showed a 100% procedural success rate with no in-hospital mortality, significantly shorter cardiopulmonary bypass and cross-clamp times, larger effective orifice areas, and a lower incidence of patient–prosthesis mismatch. Both groups demonstrated favorable left ventricular mass regression and reverse remodeling. The rates of paravalvular leakage, permanent pacemaker implantation, and redo aortic valve replacement were comparable between groups. Multivariate Cox regression identified the follow-up indexed left ventricular mass as an independent predictor of major adverse cardiac and cerebral events. Conclusions: In this study, the Perceval valve was associated with promising hemodynamic characteristics and procedural efficiencies, particularly in cases with small aortic annuli and during minimally invasive procedures. The valve was associated with reverse ventricular remodeling and clinical outcomes that appeared similar to those of conventional stented bioprostheses. These observations suggest it may represent a potential alternative option for surgical aortic valve replacement in appropriate clinical scenarios. However, randomized control trials are needed to confirm these associations. Full article

Purpose: Although biomarkers of myocardial fibrosis and inflammation have been proposed as potential modulators of response to cardiac resynchronization therapy (CRT), their clinical utility and interaction with echocardiographic parameters remain incompletely understood. This study aims to assess the dynamic changes in these biomarkers, their relationship with echocardiographic variables, and their association with structural response to CRT. Methods: We retrospectively evaluated 86 consecutive patients referred for CRT with symptomatic heart failure, left ventricular (LV) ejection fraction ≤ 35%, QRS width ≥ 130 ms and LBBB morphology. We measured sST-2, Gal-3, NTpro-BNP and eGFR at baseline and after 1 year of CRT. An echocardiographic reduction of LV end-systolic volume ≥ 15% was used to define a patient as a responder to CRT. Results: The mean baseline and follow-up values of Gal-3 (responders: 24.1 [16.8;32] ng/mL, non-responders: 30 [20;39.3] ng/mL, p = 0.03) and sST2 (responders: 28.5 [20;36] ng/mL, non-responders: 34.5 [25;37.7] ng/mL, p = 0.03) were lower in responders than non-responders. Responders showed a significant reduction between baseline and follow-up values of ΔGal-3 (−12.1% vs. −2.5%, p = 0.04), ΔsST2 (−30.8% vs. 2.2%, p < 0.001), ΔNT-proBNP (−16.4% vs. 5.2, p = 0.04) and ΔeGFR (6.7 ± 24.3% vs. -6.3 ± 27.9%, p = 0.03). At the multivariate analyses, baseline Gal-3 [cut-off: 38.5 ng/mL, AUC: 0.63, p = 0.03, (OR 7.13 [1.12;45.41], p = 0.03), together with TAPSE > 17.5 mm (OR 10.86 [3.15;37.44], p < 0.001) significantly correlated with the structural response to CRT in several prediction models. Among echocardiographic parameters, TAPSE remained the strongest predictive factor of positive response to CRT at the univariate and multivariate analyses. Conclusions: In patients with heart failure and reduced ejection fraction undergoing CRT, Gal-3 and TAPSE are significantly associated with a positive structural response to CRT. Full article

Fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and organ dysfunction. It is a major contributor to chronic diseases affecting various organs, with limited therapeutic options available. Among the different forms of fibrosis, cardiac fibrosis is particularly relevant due to its impact on cardiovascular diseases (CVDs), which remain the leading cause of morbidity and mortality worldwide. This process is driven by activated cardiac fibroblasts (CFs), which promote ECM accumulation in response to chronic stressors. Epigenetic mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, are key regulators of fibroblast activation and fibrotic gene expression. Enzymes such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs) have emerged as potential therapeutic targets, and epigenetic inhibitors have shown promise in modulating these enzymes to attenuate fibrosis by controlling fibroblast function and ECM deposition. These small-molecule compounds offer advantages such as reversibility and precise temporal control, making them attractive candidates for therapeutic intervention. This review aims to provide a comprehensive overview of the mechanisms by which epigenetic regulators influence cardiac fibrosis and examines the latest advances in preclinical epigenetic therapies. By integrating recent data from functional studies, single-cell profiling, and drug development, it highlights key molecular targets, emerging therapeutic strategies, and current limitations, offering a critical framework to guide future research and clinical translation. Full article

Background/Objectives: Cardiac resynchronization therapy (CRT) with fusion pacing (“LV only”), also known as fusion-CRT (f-CRT), represents a feasible alternative to cardiac resynchronization therapy (CRT) with biventricular pacing (BiVP), not only in cases of BiVP failure, but also as a primary therapy option due to its potential benefits over traditional CRT. Fusion pacing may be particularly beneficial in selected patients and understanding the structural and functional differences between responders could guide future optimization strategies. This study provides a descriptive comparison between super-responders (SRs) and non-super-responders (NSRs) undergoing fusion-CRT. Methods: Patients with RA/LV-only pacing systems or biventricular CRT systems operating predominantly in LV-only pacing mode due to intrinsic RV conduction were included. A follow-up protocol was conducted for all patients at 6 months and then annually. Data from the most recent follow-up were used for statistical analysis. Super-responders (SRs) were those with substantial reverse remodeling, quantified by a ≥30% reduction in LVESV and a stable LVEF of ≥45% at follow-up. Although SRs were defined based on these reverse remodeling criteria, separate analyses of additional echocardiographic parameters (e.g., left atrial dimensions) were performed to independently assess the broader impact of fusion-CRT on cardiac structure and function. Results: Among 71 patients, 55 were non-super-responders (NSRs) and 16 were super-responders (SRs), with a mean follow-up of 43.2 months. SRs were predominantly female and had smaller left ventricular (LV) dimensions: LVEDd (6.30 cm vs. 6.80 cm, p = 0.02), LVEDV (185 mL vs. 240 mL, p = 0.03), LVESV (132.5 mL vs. 175 mL, p = 0.03), and a higher LVEF (p = 0.03). The follow-up LVEF was positively correlated with changes in LVESV (ρ = 0.557, p < 0.001), but not with NYHA class changes (ρ = 0.184, p = 0.125). Larger baseline LV and left atrial (LA) volumes were associated with a reduced follow-up LVEF (LVESV: ρ = −0.426, p < 0.001; LVEDV: ρ = −0.394, p < 0.001; LAv: ρ = −0.374, p = 0.001). Both groups showed improvement in the NYHA class (p < 0.001, p = 0.007). MR improved significantly in SRs (p = 0.02) and worsened slightly in NSRs (p = 0.13), while TR worsened significantly in the NSRs group (p = 0.03). Conclusions: Our findings highlight key differences in clinical and echocardiographic parameters between SRs and NSRs following fusion-CRT. These observations may contribute to a better understanding of response patterns and inform future prospective studies aiming to optimize patient selection and timing of therapy. Full article

Although a myocardial infarction occurs roughly every minute in the U.S. alone, medical research has yet to unlock the key to fully enabling post-hypoxic myocardial regeneration. Thymosin beta-4 (TB4), a short, secreted peptide, was shown to possess a beneficial impact regarding myocardial cell survival, coronary re-growth and progenitor cell activation following myocardial infarction in adult mammals. It equally reduces scarring, however, the precise mechanisms through which the peptide assists this phenomenon have not been properly elucidated. Accordingly, the primary aim of our study was to identify novel molecular contributors responsible for the positive impact of TB4 during the remodeling processes of the infarcted heart. We performed miRNA profiling on adult mice hearts following permanent coronary ligation with or without systemic TB4 injection and searched for targets and novel mechanisms through which TB4 may mitigate pathological scarring in the heart. Our results revealed a significant increase in miR139-5p expression and identified ROCK1 as a potential target protein aligned. Real-time PCR, Western blot and immunostaining on adult mouse hearts and human cardiac cells revealed the peptide indirectly or directly modulates ROCK1 protein levels both in vivo and in vitro. We equally discovered TB4 may reverse or inhibit fibroblast/myofibroblast transformation and the potential downstream mechanisms by which TB4 alters cellular responses through ROCK1 are cell type specific. Given the beneficial effects of ROCK1 inhibition in various cardiac pathologies, we propose a potential utilization for TB4 as a ROCK1 inhibitor in the future. Full article

Pulmonary hypertension (PH) is a progressive disorder characterized by obstructive changes in the pulmonary vasculature, leading to increased pulmonary vascular resistance (PVR), right ventricular (RV) strain, and eventual RV failure (RVF). Despite advancements in medical therapy, PH remains associated with significant morbidity and mortality, particularly in children. RVF is a clinical syndrome resulting from complex structural and functional remodeling of the right heart, leading to inadequate pulmonary circulation, reduced cardiac output, and elevated venous pressure. Management paradigms for pediatric PH diverge significantly from those in adults, particularly due to the predominance of congenital heart disease (CHD) and the dynamic nature of pediatric cardiovascular and pulmonary development. CHD remains a principal driver of PH in children, and its associated pathophysiology demands a nuanced approach. In patients with unrepaired left-to-right shunts, elevated pulmonary blood flow can lead to progressive pulmonary vascular remodeling and increased PVR. The postoperative persistence or progression of PH may occur if irreversible vascular changes have already developed. Current PH treatments primarily focus on reducing PVR, yet distinguishing between therapeutic approaches that target the pulmonary vasculature and those aimed at improving RV function remain challenging. In pediatric patients with progressive PH despite optimal therapy, additional targeted interventions may be necessary to mitigate RV dysfunction and disease progression. This review provides a comprehensive analysis of the mechanisms underlying RVF in PH, incorporating insights from clinical studies in adults and experimental models, while highlighting the unique considerations in children. Furthermore, it explores current pharmacological and interventional treatment strategies, emphasizing the need for novel therapeutic approaches aimed at directly reversing RV remodeling. Given the complexities of RV adaptation in pediatric PH, further research into disease-modifying treatments and innovative interventions is crucial to improving long-term outcomes in affected children. Full article

Heart failure with reduced ejection fraction due to ischemic cardiomyopathy remains a significant clinical challenge. Electrical conduction delays exacerbate symptoms by causing uncoordinated contractions, reducing pumping efficiency, and increasing mortality. Right ventricular pacing further worsens dyssynchrony, while resynchronization therapy improves outcomes but has a high non-responder rate. Given these limitations, bundle branch pacing engages the heart’s conduction system, restoring synchronized contraction and enhancing cardiac function. This review examines the impact of left-bundle-branch-block-induced dyssynchrony, the role of advanced imaging in assessing ventricular function, and the clinical outcomes of bundle branch pacing in heart failure patients. Specifically, we explore the mechanical and hemodynamic effects of left bundle branch block, imaging techniques for dyssynchrony evaluation, and the comparative benefits of bundle branch pacing versus resynchronization therapy. Conduction delays impair function, increase myocardial stress, and worsen clinical outcomes. Advanced imaging plays a critical role in patient selection, identifying those most likely to benefit from conduction system pacing. By restoring electrical coordination, bundle branch pacing enhances ventricular function, reduces hospitalizations, and promotes reverse remodeling. It offers similar or superior benefits to conventional resynchronization therapy, regulates stress hormones, reduces oxidative damage, and improves calcium handling. Bundle branch pacing represents a significant advancement in heart failure management, but careful patient selection remains crucial. Future research should focus on optimizing implantation techniques and validating long-term benefits through large-scale clinical trials. Full article

Cardiac fibrosis is a scarring event that occurs in the myocardium in response to multiple cardiovascular disorders, such as acute myocardial infarction (AMI), ischemic cardiomyopathy, dilated cardiomyopathy, hypertensive heart disease, inflammatory heart disease, diabetic cardiomyopathy, and aortic stenosis. Fibrotic remodeling is mainly sustained by the differentiation of fibroblasts into myofibroblasts, which synthesize and secrete most of the extracellular matrix (ECM) proteins. An increase in the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in cardiac fibroblasts is emerging as a critical mediator of the fibrogenic signaling cascade. Herein, we review the mechanisms that may shape intracellular Ca²⁺ signals involved in fibroblast transdifferentiation into myofibroblasts. We focus our attention on the functional interplay between inositol-1,4,5-trisphosphate (InsP₃) receptors (InsP₃Rs) and store-operated Ca²⁺ entry (SOCE). In accordance with this, InsP₃Rs and SOCE drive the Ca²⁺ response elicited by G_q-protein coupled receptors (G_qPCRs) that promote fibrotic remodeling. Then, we describe the additional mechanisms that sustain extracellular Ca²⁺ entry, including receptor-operated Ca²⁺ entry (ROCE), P2X receptors, Transient Receptor Potential (TRP) channels, and Piezo1 channels. In parallel, we discuss the pharmacological manipulation of the Ca²⁺ handling machinery as a promising approach to mitigate or reverse fibrotic remodeling in cardiac disorders. Full article

Uremic cardiomyopathy, characterized by diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis, is a common cardiovascular complication of chronic kidney disease (CKD). Men are at a higher risk for cardiovascular and renal diseases, compared to age-matched, pre-menopausal women. We aimed to investigate the influence of sex on the severity of uremic cardiomyopathy through the characterization of functional and molecular indices of myocardial remodeling in a rat model. CKD was induced by a 5/6 nephrectomy in 9-week-old male and female Wistar rats. Serum and urine tests, transthoracic echocardiography, left ventricular (LV) histology, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were performed at week 8 or 9. Moreover, LV alterations were also tested in permeabilized cardiomyocytes (CMs) by force measurements and Western immunoblotting. CKD resulted in the development of a more severe uremic cardiomyopathy in male rats—including LVH, LV diastolic dysfunction, and fibrosis—than in female rats, where only LVH was observed. A uremic cardiomyopathy was also associated with a decrease in maximal Ca²⁺-activated force (F_max) in CMs of male rats. Additionally, increases in CM Ca²⁺-independent passive stiffness (F_passive) and decreases in cardiac myosin-binding protein C (cMyBP-C) phosphorylation levels were significantly larger in male than female rats. In conclusion, a uremic cardiomyopathy involved cardiac remodeling in both sexes. Nevertheless, male rats exhibited more pronounced signs of macroscopic and microscopic alterations than their female counterparts, illustrating a sex-dependent component of uremic cardiomyopathy. Full article