Search Results (661)

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation, playing a critical role in the pathogenesis of various cardiomyopathies, including hypertrophic, dilated, diabetic, ischemic, doxorubicin-induced, and septic cardiomyopathy, as well as myocardial ischemia–reperfusion injury. This article provides a comprehensive narrative review of the molecular mechanisms of ferroptosis—centered on dysregulation of the GPX4/System Xc⁻ axis, iron metabolism, and lipid metabolism—and its role in cardiovascular diseases, with a specific focus on the cardioprotective effects of Traditional Chinese Medicine (TCM). Through a systematic analysis of recent literature, we highlight active components (e.g., baicalin, ginsenoside Rg3, resveratrol, tanshinone IIA), compound formulations (e.g., Qishen Granule, Zhilong Huoxue Tongyu Capsule), and electroacupuncture therapy, which exert effects via multi-target regulation of ferroptosis-related pathways such as Nrf2/HO-1/GPX4, p53/SLC7A11, and PI3K/AKT. Evidence indicates that TCM interventions effectively alleviate cardiomyocyte ferroptosis by activating the Nrf2 antioxidant pathway to upregulate GPX4/SLC7A11, modulating iron metabolism to reduce labile iron pools, and inhibiting ACSL4/ALOX15-mediated lipid peroxidation, with these effects validated in diverse cardiovascular disease models showing improved cardiac function. Targeting ferroptosis offers a novel therapeutic strategy for cardiovascular diseases, and TCM—with its synergistic multi-component, multi-target, multi-pathway advantages—holds significant potential in this context. Future research should prioritize elucidating complex network mechanisms and advancing clinical translation via high-quality studies to provide new theoretical foundations and drug candidates for cardiovascular disease management. Full article

Noonan syndrome (NS) is a paradigmatic rare, genetically heterogeneous, multisystem disorder belonging to the RASopathies family, caused by dysregulated RAS/MAPK signaling. It is characterized by distinctive craniofacial features, postnatal short stature, and a high prevalence of congenital cardiac defects, with pulmonary valve stenosis (PS) and hypertrophic cardiomyopathy (HCM) being the hallmark lesions. First described by Dr. Jacqueline Noonan in 1968, the molecular era began with the discovery of PTPN11 mutations in 2001, revolutionizing diagnosis, risk stratification, and understanding of pathogenesis. Strong genotype–phenotype correlations now guide prognosis and personalized management; for instance, RAF1 and RIT1 variants confer a high risk of severe, early-onset HCM, while PTPN11 is strongly linked to dysplastic PS. Cardiac involvement remains the central determinant of long-term outcomes, requiring continuous surveillance from the prenatal period through adulthood. Management is inherently multidisciplinary, addressing endocrine, hematologic, neurodevelopmental, and oncologic aspects. Recent consensus statements emphasize the critical need for structured transition from pediatric to adult care. Novelty arises from the potential of MEK inhibitors as targeted therapies for severe HCM and lymphatic complications. This review provides a comprehensive update on NS, integrating foundational clinical knowledge with contemporary molecular insights, advanced cardiologic management, and emerging frontiers in therapy and diagnostics, underscoring the necessity of a proactive, lifelong, and personalized care approach. Full article

Background/Objectives: Differentiating clinically suspected cardiac amyloidosis from hypertrophic cardiomyopathy (HCM) remains a significant clinical challenge, especially when contrast-enhanced imaging is contraindicated. This study evaluated the potential diagnostic utility of non-contrast cardiac MRI parameters, specifically native T1 and T2 mapping, as supportive indicators in this differential diagnosis. Methods: This retrospective single-center study included 20 patients with clinically suspected amyloidosis (based on combined clinical and echocardiographic assessment), 20 patients with HCM, and 20 healthy controls. Cine imaging and native T1/T2 mapping were analyzed. Myocardial, blood-pool, and liver T1/T2 values, along with morphological parameters, were recorded. N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin levels, when available, were documented retrospectively for descriptive purposes. Receiver operating characteristic (ROC) analyses were performed to assess the discriminatory performance of imaging parameters. Results: Patients in the suspected amyloidosis group demonstrated significantly higher myocardial, blood-pool, and liver T1 values, as well as higher myocardial T2 values, compared with both the HCM and control groups (p < 0.001). Myocardial T1 showed strong discriminatory performance for differentiating suspected amyloidosis from controls (cut-off 1061 ms, AUC = 0.975). In distinguishing suspected amyloidosis from HCM, blood-pool T1 (AUC = 0.900) and myocardial T1 (AUC = 0.938) provided the highest diagnostic performance. Additionally, elevated NT-proBNP (>1000 pg/mL in 93% of tested cases) and troponin levels were observed in the suspected amyloidosis group, consistent with increased myocardial stress. Conclusions: Native T1 and T2 mapping may offer valuable supportive information in differentiating clinically suspected amyloidosis from HCM on non-contrast MRI. Myocardial and blood-pool T1 values appear to provide complementary tissue characterization, which may be particularly useful when gadolinium administration or invasive procedures are not feasible. These findings suggest a role for non-contrast mapping in the diagnostic workup but require further validation in larger, biopsy-confirmed multicenter cohorts. Full article

HCM is the most prevalent cardiac disease in cats and is associated with substantial morbidity and mortality. Among its complications, FATE represents a major adverse clinical outcome. Conventional echocardiographic indices typically assess atrial or ventricular parameters separately and may not fully capture the structural relationship between the LA and LV. The left atrioventricular coupling index (LACI) is a volumetric ratio that combines LA remodeling and LV chamber size at end-diastole into a single structural index. This retrospective, cross-sectional observational study included 91 cats, classified according to ACVIM guidelines into healthy controls (n = 33), asymptomatic HCM (stage B1, n = 14; stage B2, n = 16), symptomatic HCM (stage C, n = 15), and cats with FATE (n = 13). Conventional and two-dimensional speckle-tracking echocardiography were performed, and LACI-ED was calculated as the ratio of LA end-diastolic volume to LV end-diastolic volume. LACI-ED increased progressively with disease severity (p < 0.001), showing the highest values in symptomatic HCM and FATE cases. It correlated positively with LA size and volume (p < 0.01) and inversely with LV GLS (p < 0.01). Exploratory ROC analysis for FATE status yielded limited discriminatory performance for LACI-ED > 150% (AUC = 0.575; 95% CI: 0.402–0.736; sensitivity 46.2%; specificity 84.4%). Although LACI-ED > 150% was associated with higher odds of prevalent FATE (OR = 4.65; 95% CI: 1.405–29.215; p = 0.020), this finding should be interpreted with caution. Pairwise comparisons of ROC curve areas between LACI-ED and conventional echocardiographic parameters (LA/Ao ratio, LA diameter, and LV GLS) revealed no statistically significant differences (all p > 0.05). Although LACI-ED > 150% was associated with higher odds of prevalent FATE (OR = 6.8; p < 0.05), this finding should be interpreted with caution. This cross-sectional study evaluates associations with disease stage and thromboembolic status at the time of examination. The findings suggest that LACI-ED reflects disease severity in feline HCM, whereas its utility for thromboembolic risk assessment appears limited. Full article

Background: Genetic testing in hypertrophic cardiomyopathy (HCM) yields variable positivity rates. Identifying clinical predictors of positive genetic tests could improve pre-test counseling and refine expectations about diagnostic yield. Methods: We analyzed consecutive genotyped HCM probands from a contemporary multicenter cohort across four Italian tertiary centers. Genotype positivity was defined as the presence of ≥1 pathogenic or likely pathogenic variant (ACMG classes 4–5). Multivariable logistic regression identified predictors of genotype positivity. Sensitivity analyses assessed the incremental value of left atrial volume index (LAVI) ≥ 34 mL/m² and the mode of first clinical presentation. Results: Among 274 genotyped probands (median age at diagnosis 54 years; 62% male), 86 (31%) were genotype-positive (38% MYBPC3, 29% MYH7). Age at diagnosis <40 years (OR 2.38, 95%CI 1.26–4.51, p = 0.008), family history of sudden cardiac death/major ventricular arrhythmias (OR 2.34, 95%CI 1.16–4.84, p = 0.019) and family history of non-ischemic cardiomyopathy (OR 1.92, 95%CI 1.04–3.54, p = 0.038), were independently associated with genotype positivity whereas arterial hypertension was inversely associated (OR 0.42, 95%CI 0.23–0.77). Maximal left ventricular wall thickness > 20 mm and gender were not predictive of genotype positivity. Inclusion of LAVI modestly improved the model performance (AUC 0.769, p = 0.016, ΔAUC +0.024; DeLong p = 0.016) but without leading to meaningful patient reclassification. Conclusions: Genotype positivity in HCM links to earlier onset and family history; traditional severity markers and initial presentation may not independently suggest genetic causality. These findings may help shape a personalized approach to genetic counseling in HCM. Full article

Background: In patients with left ventricular hypertrophy, resting structural parameters alone may not explain exertional symptoms. Hence, we investigate whether combined Cardiopulmonary Exercise Testing- Exercise Stress Echocardiography (CPET-ESE) can provide an integrated functional characterisation of hypertrophic phenotypes. Methods: As a preliminary investigation, this prospective single-centre pilot study enrols 43 patients, categorised into: obstructive hypertrophic cardiomyopathy (n = 19), transthyretin cardiac amyloidosis (n = 15), or preserved-ejection-fraction hypertrophic phenotypes (n = 9). Patients undergo symptom-limited semi-supine CPET-ESE on an electronically braked cycle ergometer with an individualised ramp protocol. Peak effort is defined by symptom limitation and respiratory exchange ratio criteria ($RER\ge 1.05$), while peak VO₂ is defined as the highest 30 s averaged value. Results: Exercise responses differ across phenotypes. Patients with obstructive hypertrophic cardiomyopathy have higher peak VO₂ than the other groups, despite their lower chronotropic reserve. The preserved-ejection-fraction hypertrophic group shows lower peripheral oxygen extraction, whereas transthyretin amyloidosis shows a mixed central and peripheral limitation pattern. Right ventricle–pulmonary artery uncoupling is observed in the latter two groups. Conclusions: The use of CPET-ESE may help describe distinct physiological exercise profiles in hypertrophic phenotypes, but these findings should be considered exploratory. The small, heterogeneous and single-centre cohort precludes definitive mechanistic or predictive conclusions and supports the need for larger validation studies. Full article

The management of obstructive hypertrophic cardiomyopathy (HCM) has been transformed by the advent of cardiac myosin inhibitors (CMIs), such as mavacamten and aficamten. Unlike traditional pharmacotherapy, which primarily addresses symptoms, CMIs target the underlying mechanism of sarcomeric hypercontractility, offering significant reductions in left ventricular outflow tract (LVOT) gradients and improved functional capacity. This review evaluates the evolving role of CMIs in refining surgical candidate selection and postoperative care. Clinically, CMIs function as an in vivo “biological test” to distinguish between dynamic, functional obstruction—often manageable with medication—and fixed anatomical obstruction driven by complex septal or mitral substrates. While clinical trials demonstrate that CMIs can delay or prevent the need for SRT in a significant proportion of patients, surgery remains the definitive solution for those with dominant structural anomalies or drug intolerance. Consequently, the therapeutic paradigm is shifting from a binary “drugs or surgery” approach to a synergistic model. In this framework, CMIs optimize the identification of patients truly requiring structural myectomy while serving as a valuable adjunct for managing residual hypercontractility, ultimately facilitating a personalized, multidisciplinary approach to HCM treatment. Full article

(1) Background: The characteristics of rare diseases (RDs) vary considerably—not only between different disease types but also between individual patients with the same condition. In the Roma community, we analyzed the most frequent rare genetic disorders related to the founder effect. (2) Methods: This retrospective study, conducted between January 2019 and January 2025 at the Clinical Genetics and Metabolics Outpatient Clinic in Košice, included 61 patients aged from infancy to 25 years diagnosed with hypomyelinating leukodystrophy 14, pontocerebellar hypoplasia type 1B, neuronal ceroid lipofuscinosis 7, or TMEM70 deficiency. (3) Results: This study includes the largest known cohort of patients with hypomyelinating leukodystrophy 14 caused by the UFM1 c.-273_-271delTCA mutation, predominantly affecting males (n = 17). The disorder is severe, with most patients dying before one year of age, and is characterized by inspiratory stridor, axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly. In a separate group with pontocerebellar hypoplasia type 1B, six Roma patients (three males, three females) shared the same EXOSC3 mutation. Diagnosis occurred at an average age of 8.8 months, and most children did not survive beyond three years. Common features included microcephaly, severe hypotonia, and spastic quadriplegia. Thirteen children from eight families were diagnosed with neuronal ceroid lipofuscinosis 7, all carrying the same MFSD8 mutation. Symptoms typically began with psychomotor regression between ages 3 and 4, along with intellectual disability and seizures, which were more frequent in males. The mean age at diagnosis was 4.5 years, and eight children died before age nine. Finally, 25 patients with TMEM70 deficiency associated with Roma ancestry were identified, predominantly females, with a mean age of 9.95 years and the oldest patient aged 25. Four children died due to severe metabolic crises. Common findings included intellectual disability, global hypotonia, hypertrophic cardiomyopathy, epilepsy, and failure to thrive. (4) Conclusions: Most rare diseases are genetic and carry high morbidity and mortality, with no targeted therapies currently available. Their increased prevalence in the Roma population reflects founder effects and high consanguinity. Prenatal and newborn screening, along with voluntary carrier testing for couples, is essential for proactive health management. Full article

Background: Fibroblast growth factor-23 (FGF23) is a key regulator of phosphate homeostasis and an emerging biomarker in cardiovascular disease. Emerging data suggest that FGF23 may also contribute to the pathophysiology of myocardial infarction (MI), but existing studies have largely focused on non-acute stages. To address this gap, we investigated early FGF23 regulation by characterizing serum concentration kinetics over the first 24 h following MI, using both a clinical MI model (TASH) and a cohort of patients with ST-elevation myocardial infarction (STEMI). Methods: Circulating FGF23 concentrations (cFGF23; RU/mL) were determined by C-terminal ELISA in patients with preserved renal function (eGFR > 30 mL/min/1.73 m²). TASH (transcoronary septal ablation) was carried out in patients with hypertrophic obstructive cardiomyopathy (n = 38). Venous serum samples were taken at baseline (pre-TASH) and at 30′, 60′, 2 h, 4 h and 24 h post-TASH. For the STEMI cohort (n = 18), serum was sampled immediately before and 3 h after coronary recanalization. All samples were processed using standardized procedures prior to analysis. Changes over time were assessed using the Friedman test with Bonferroni-corrected pairwise Wilcoxon comparisons. Results: FGF23 concentrations changed significantly over time after TASH (Friedman test, p < 0.000001, Kendall’s W = 0.518). Baseline FGF23 was 28.9 (19.4–71.0) RU/mL and increased significantly at 30′ (68.2 (36.2–178.7) RU/mL, adjusted p < 0.0001 **) after TASH. Concentrations remained elevated at 60′ (54.8 (31.6–118.3) RU/mL; adjusted p = 0.0019 *), returned to baseline at 2 h (30.9 (20–71.2) RU/mL; adjusted p = 1.0 vs. baseline) and decreased significantly below baseline at 4 h (24 (12.13–37.5) RU/mL, adjusted p = 0.0215 *). By 24 h, FGF23 had returned to baseline levels (28.8 (12.8–57.3) RU/mL; adjusted p = 1.0 vs. baseline). Although concentrations were numerically higher than at the 4 h nadir, this recovery did not reach statistical significance (adjusted p = 0.136 vs. 4 h). In STEMI patients, a non-significant decrease was observed from baseline (27 (15.5–35.75) RU/mL) to 3 h after recanalization (15.5 (6.75–34.25) RU/mL; p = 0.074, effect size r = 0.422). In an exploratory normalized analysis, the decline reached significance (p = 0.0241). Conclusions: The triphasic kinetics of circulating FGF23 in TASH patients—characterized by an early rise, transient undershoot, and a recovery toward baseline with a continuing upward trend—are consistent with a dynamic release-and-clearance pattern following myocardial injury. These findings are hypothesis-generating and warrant further investigation in larger cohorts with additional biomarkers to elucidate the source, regulation, and potential functional significance of FGF23 in the acute phase of myocardial infarction. Full article

Introduction: Hypertrophic cardiomyopathy (HCM) is a common myocardial disease worldwide and is associated with heart failure symptoms and sudden cardiac death. In a subset of patients, it may produce dynamic left ventricular outflow tract obstruction (LVOTO) and systolic anterior motion (SAM)-related mitral valve dysfunction through drag forces and altered mitral–septal geometry. In contrast, subaortic stenosis caused by a subaortic membrane is an uncommon congenital lesion that may lead to fixed subvalvular LVOTO in adulthood. The coexistence of these entities is rare and can substantially complicate diagnosis and management. Case presentation: A 51-year-old woman with HCM, paroxysmal atrial fibrillation, and heart failure presented with acute decompensation and cardiogenic shock. After initial hemodynamic stabilization and cardioversion for atrial fibrillation with rapid ventricular response, multimodality imaging with transthoracic and transesophageal echocardiography, coronary computed tomography angiography, and cardiac magnetic resonance demonstrated dual LVOTO, with a dynamic component related to HCM/SAM physiology and a fixed component caused by an elongated subaortic membrane, accompanied by severe SAM-related mitral regurgitation. Echocardiography showed a resting peak LVOT gradient of 49 mmHg, increasing to 85 mmHg with the Valsalva maneuver. After exclusion of obstructive coronary artery disease and evaluation for selected phenocopies, the patient underwent septal myectomy, subaortic membrane resection, and adjunctive mitral valve plication. Early postoperative echocardiography showed reduction in the maximum provoked LVOT gradient to 38 mmHg and improvement of mitral regurgitation from severe to mild. At 3-month follow-up, she remained in sinus rhythm, improved to New York Heart Association functional class II, and had no documented readmissions for heart failure. Conclusions: Combined fixed and dynamic LVOTO due to concomitant subaortic membrane and HCM is exceedingly rare. Accurate diagnosis requires a high index of suspicion and a multimodality imaging strategy to define the obstructive mechanisms and support mechanism-based surgical management and avoid incomplete treatment when a coexisting fixed lesion is present. Full article

Background: RASopathies represent a clinically and genetically diverse group of syndromes resulting from germline mutations in genes regulating the RAS/mitogen-activated protein kinase (MAPK) signaling cascade. Methods: The aim of this study was to describe the clinical features and genetic variants identified in patients with genetically confirmed Noonan syndrome (NS) in a limited cohort from Romania. A total of 25 patients with positive genetic testing for NS-associated genes were included. Genetic testing was performed primarily using next-generation sequencing. Results: A total of twenty-six variants were identified in twenty-five patients, as one patient carried two pathogenic variants in the PTPN11 gene (c.188A>G and c.922A>G). Of these variants, twenty-four (92.31%) were classified as pathogenic and two (7.69%) as variants of uncertain significance (VUS). Pathogenic variants were found in different genes, including PTPN11, LZTR1, SOS1, and RAF1, with PTPN11 being the most frequently affected gene. Males predominated (17/25), with a male-to-female ratio of approximately 2:1. Two patients inherited the pathogenic variant from an affected parent. Cardiovascular involvement was present in 21 patients (84%), with pulmonary valve stenosis (PVS) being the most common finding (48%), followed by hypertrophic cardiomyopathy (16%). Additional cardiac anomalies included atrial septal defect, valvular regurgitation, dysplastic valves, coarctation of the aorta, and sinotubular junction narrowing. Short stature was observed in 64% of patients, and craniofacial dysmorphism was present in 96%. Cutaneous, ectodermal, dental, ophthalmologic, and auditory manifestations were variably observed. Conclusions: Although based on a limited cohort from Romania, this study provides insights into clinical features suggestive of NS. Our findings highlight the genetic heterogeneity of NS and emphasize the importance of comprehensive genetic testing for confirming diagnosis, guiding clinical management, and supporting family counseling. Full article

Patients with preload-dependent conditions are at high risk of hemodynamic instability from both hypovolemia and hypervolemia. In hypovolemic states, the presence of third spacing may be misleading and obscure true intravascular volume status. Therefore, management of critically ill patients should be guided by a thorough understanding of physiology and pathophysiology to appropriately address hemodynamic derangements. Overreliance on rigid protocols and protocol-driven care without adequate clinical judgment may, in some cases, adversely affect patient outcomes. Herein, we present a case of hypovolemia-induced hypotension in the setting of third spacing and concentric left ventricular hypertrophy. Full article

Cardiac amyloidosis (CA) remains underrecognized due to overlapping features with other cardiovascular conditions, including hypertrophic cardiomyopathy and hypertensive heart disease. Certain ‘red flag’ features across the clinical and imaging spectrum help identify CA. However, these features are often absent, subtle, or inconsistently recognized, particularly in early disease, and are atypical phenotypes. This leads to frequent delays in diagnosis and presentation at advanced stages. Artificial intelligence (AI) offers a promising approach to detect subtle disease signatures by integrating multimodal and longitudinal data beyond human pattern recognition. AI-enhanced electrocardiography has emerged as a scalable screening tool, demonstrating high diagnostic performance and enabling earlier detection. In parallel, echocardiographic AI has evolved toward video-based analysis, improving standardization and reducing inter-reader variability. Similarly, AI applications in cardiac magnetic resonance and nuclear scintigraphy allow for automated quantification and more reproducible assessment of amyloid burden. Beyond diagnosis, emerging models support disease phenotyping, risk stratification, and treatment monitoring. This review synthesizes current applications of AI across multimodal testing in the evaluation and diagnosis of CA. Full article

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease in the general population, with a variable phenotypic expression and symptomatology. Atrial fibrillation (AF) is the most common arrhythmia identified among patients diagnosed with HCM. Treatment of both AF and HCM has continuously evolved over time, leading to a significant improvement in the prognosis and life expectancy of symptomatic patients. Numerous studies have demonstrated that the risk of developing this arrhythmia correlates with atrial morphological, functional and electrical remodeling, a process known as atrial myopathy. Once a first episode of AF is diagnosed, permanent anticoagulation is required among patients diagnosed with HCM, regardless of the CHA₂ DS₂-VA score. Additionally, atrial cardiomyopathy is associated with an increased thromboembolic risk, independent of AF presence, in patients with stable sinus rhythm, in the context of atrial mechanical and endothelial dysfunction. This article aims to evaluate the current scientific evidence and treatment approaches in patients diagnosed with HCM. Full article

Background/Objectives: Variants of MYPN, encoding a sarcomeric protein myopalladin, are associated with different types of cardiomyopathies and myopathies. However, the molecular mechanisms of MYPN-associated pathologies are still poorly understood. Methods: In this study, we generated induced pluripotent stem cells (iPSCs) from a hypertrophic cardiomyopathy patient carrying a novel p.N989I (c.2966A>T) variant of MYPN and used iPSC-derived cardiomyocytes to examine the impact of the variant on biophysical characteristics and transcriptomic profile. Results: No significant changes in parameters of calcium transients, sodium current and action potential were found in iPSC-derived cardiomyocytes with the p.N989I (c.2966A>T) variant of MYPN compared to non-isogenic cells from an unrelated healthy donor. At the transcriptomic level, MYPN-N989I cardiomyocytes demonstrated an upregulation of genes linked to cell cycle, mitotic spindle, microtubule cytoskeleton organization, and myogenic program genes. Downregulation of sarcomeric, Z-disc- and cell junction-associated genes, as well as genes involved in ATP synthesis, oxidative phosphorylation, and the SRF-signaling pathway, was also revealed. Conclusions: Our data suggest that the p.N989I (c.2966A>T) variant of MYPN plays a dual role in hypertrophic cardiomyopathy pathogenesis, disrupting not only sarcomeric and cytoskeletal organization but also the regulation of the muscle gene program. Full article