Search Results (974)

Endurance exercise is widely recognized for its cardiovascular benefits, including improved longevity and metabolic health. However, excessive endurance training may lead to adverse cardiac adaptations, such as myocardial fibrosis, detected via late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR). This review examines the dual role of myocardial fibrosis in athletes—as a potential risk marker for life-threatening arrhythmias or a benign byproduct of physiological remodeling. While moderate exercise promotes beneficial cardiac hypertrophy, ultra-endurance athletes exhibit a 10–20% increase in ventricular size and mass, alongside elevated cardiac biomarkers post-exercise. Myocardial fibrosis, particularly in the left ventricle (LV), is associated with arrhythmias and sudden cardiac death, especially when presenting as a subepicardial/midmyocardial patchy pattern. Studies report that 22% of athletes with this pattern experienced malignant arrhythmias, underscoring its clinical significance. Conversely, fibrosis may also reflect adaptive remodeling in some cases, complicating its interpretation. The mechanisms underlying fibrosis in athletes remain unclear but may involve repeated cardiac stress, inflammation, or distinct atherosclerotic plaque dynamics. CMR is critical for detecting fibrosis, though differentiating pathological from physiological patterns requires careful clinical correlation. Risk stratification must consider LGE patterns, arrhythmia history, and symptoms. Despite concerns, elite athletes generally exhibit increased longevity, highlighting the complex interplay between exercise benefits and risks. Further research is needed to clarify fibrosis mechanisms, refine diagnostic criteria, and guide management strategies to ensure athlete safety while preserving the advantages of endurance training. Full article

Background: Acromegaly, typically caused by growth hormone (GH)-secreting pituitary adenomas, leads to chronic GH and insulin-like growth factor-1 overproduction, resulting in significant cardiovascular complications, including left ventricular (LV) hypertrophy, myocardial fibrosis, diastolic/systolic LV dysfunction, and frequent valvular disease. Although aortic root dilation has been documented, the morphology and function of the aortic valve annulus (AVA) and its relationship with LV performance remain unexplored. Methods: The present study comprised a total of 31 patients with acromegaly, from which eight subjects were excluded due to inferior image quality. The remaining group of acromegalics consisted of 23 cases (mean age: 54.3 ± 14.5 years, 6 males). Their results were compared to 31 age- and gender-matched healthy subjects (mean age: 50.0 ± 7.4 years, 9 males). Cardiac assessment involved routine two-dimensional Doppler echocardiography and three-dimensional speckle-tracking echocardiography (3DSTE) to quantify basal regional and global longitudinal strains. Detailed planimetric measurements of AVA dimensions and its spatial displacement, called AVA plane systolic excursion (AAPSE), were also obtained. Results: Among 12 patients with inactive acromegaly, 7 patients (58%) showed larger end-systolic AVA area (AVA-A), while 5 patients (42%) had larger end-diastolic AVA-A. Among the 11 patients with active acromegaly, 3 patients (27%) had larger end-systolic AVA-A and 5 patients (45%) had larger end-diastolic AVA-A, while in 3 patients (27%) end-systolic and end-diastolic AVA-A proved to be equal. All end-systolic and end-diastolic AVA dimensions were tendentiously greater in acromegaly, with more pronounced values seen in the presence of an active disease. AAPSE was reduced both in all acromegaly patients and in those with active disease compared to controls. From LV strains, basal and global LV longitudinal strain (LS) and basal LV circumferential strain (CS) were similar when comparing acromegaly patients and those with active and inactive disorder to controls. However, basal and global LV-LS tended to be reduced, while basal LV-CS tended to be increased. Significantly increased global LV-CS were present in active acromegaly patients compared to inactive acromegaly patients and controls Conclusions: Significant aortic valve annular dilation is present in acromegaly, which is associated with its reduced spatial systolic displacement. Full article

Background: We recently generated T cell receptor (TCR) transgenic (Tg) mice specific to cardiac myosin heavy chain-α (Myhc-α 334–352) on both myocarditis-resistant (C57BL/6) and susceptible (A/J) genetic backgrounds. We noted that the antigen-specific TCRs were expressed in CD4⁺ and CD8⁺ T cells in both strains, but their responses differed. While the T cells from naïve Tg C57BL/6 mice do not respond to Myhc-α 334–352, whereas those from A/J mice spontaneously respond to the antigen, suggesting their underlying molecular mechanisms might differ. Methods: To investigate the mechanisms of differences in the antigen-responsiveness between the Tg C57BL/6 and A/J mice, we performed bulk RNA sequencing on CD4⁺ and CD8⁺ T cells sorted by flow cytometry. Differentially expressed genes, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, gene set enrichment analysis (GSEA) of GO and KEGG, and transcription factor (TF) network analyses were performed to identify pathways and regulators of immune responses. Results: First, the principal component analysis of the transcriptomic profiles distinguished CD4⁺ from CD8⁺ T cells, which also differed between the two strains. Second, the differentially expressed cytokine and cytotoxicity genes revealed similar patterns between CD4⁺ and CD8⁺ T cells. Importantly, KEGG enrichment analysis revealed downregulated pathways in both CD4⁺ and CD8⁺ T cells that are associated with viral myocarditis, and various autoimmune conditions in C57BL/6 as compared to A/J mice. Similarly, the GSEA of GO revealed negative regulation of heart contraction and positive regulation of cardiac muscle hypertrophy processes were negatively enriched in CD4⁺ T cells of C57BL/6 mice. Finally, by generating the transcription factor (TF) networks, 22 TFs were found common to both CD4⁺ and CD8⁺ T cells, whereas eight TFs were unique to CD4⁺ or CD8⁺ T cells that have a role in T cell activation, tolerance, and T regulatory cells. Conclusions: Our data provide new insights into the transcriptomic profiles that may contribute to the genetic resistance mechanisms for developing cardiac autoimmunity. Full article

Background: PRKAG2-related disease is an autosomal dominant disorder caused by pathogenic variants in the PRKAG2 gene, leading to glycogen accumulation in cardiomyocytes. It is characterized by left ventricular hypertrophy (LVH), ventricular pre-excitation, and conduction disease. Due to the rarity of the condition and the frequent occurrence of private variants, functional or pathological testing is required for definitive pathogenicity classification. Case Presentation: We describe a 22-year-old male referred for evaluation after experiencing exertional dyspnea and a syncopal episode. Family history revealed sudden cardiac deaths and conduction disease requiring pacemaker implantation. The patient exhibited mild LVH on imaging, conduction abnormalities on electrophysiological study, and a heterozygous PRKAG2 variant (c.1643C>T; p.Ser548Leu), classified as likely pathogenic according to ACMG guidelines. Cascade screening identified the variant in three family members, one of whom exhibited a positive phenotype. Endomyocardial biopsy revealed glycogen accumulation, providing histopathological confirmation of PRKAG2-related disease. Conclusions: This case underscores the importance of integrating genetic, clinical, and histopathological data in variant interpretation. Endomyocardial biopsy can provide definitive evidence to reclassify a PRKAG2 variant as pathogenic, thereby guiding management and family screening. Full article

Background/Objectives: Exercise-induced hypertension (EIH) in runners predisposes them to cardiovascular diseases, including myocardial hypertrophy, arrhythmias, and coronary artery disease. Blood flow restriction (BFR) training has been reported to exert non-pharmacological benefits in runners with EIH by improving blood pressure, myocardial workload, and cardiorespiratory fitness. The purpose of this study was to investigate whether changes in myocardial structure and function accompany these effects of BFR training in middle-aged runners with EIH. Methods: Participants who exhibited a maximal systolic blood pressure of ≥210 mmHg during an exercise stress test were assigned either to a BFR training group (BFRTg, n = 15) or to a control group without BFR training (non-BFRTg, n = 14). The BFRTg underwent a two-month BFR training program, performed twice per week for 20 min per session. Cardiac structure and function were evaluated before and after the intervention, and exercise stress test data were obtained from secondary sources of a previous study. Results: Compared with controls, the BFR group showed lower maximal exercise SBP, longer exercise duration, and higher VO_2max. Echocardiography revealed reduced interventricular septal thickness and improved diastolic indices (higher E′/A′, lower E/E′), while systolic function remained unchanged. Conclusions: In conclusion, reductions in septal thickness and improvements in diastolic function induced by blood flow restriction training in runners with exercise-induced hypertension suggest a favorable cardiac adaptation, accompanied by concurrent improvements in exercise blood pressure and cardiorespiratory fitness. Full article

Background: PLACK syndrome is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in CAST, which encodes calpastatin, an endogenous inhibitor of calpains. The syndrome is classically defined by peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads. Although the phenotype has been largely restricted to dermatological manifestations, emerging reports suggest dilated cardiomyopathy (DCM) as a systemic complication. Methods: We investigated five affected children from three sibships of an extended consanguineous family. Clinical evaluation and genome sequencing (GS) followed by segregation analysis of the targeted mutation test (TMT) were performed. Histopathological examination of an explanted heart was conducted in one child who underwent heart transplantation. Results: All affected children exhibited typical dermatological features of PLACK syndrome. Four developed severe DCM, two of whom required orthotopic heart transplantation. GS, performed in three affected children, identified a novel homozygous frameshift variant in CAST (NM_001750.7:c.1177dup, p.Arg393Profs*4), which segregated with the disease within the family. No additional plausible variants in known cardiomyopathy-associated genes were detected. Histopathological examination of the explanted heart demonstrated hypertrophied cardiomyocytes with nuclear enlargement, hyperchromasia, and fibrosis. Conclusions: Our findings expand the phenotypic spectrum of PLACK syndrome to include severe DCM and suggest CAST deficiency as a novel cause of recessively inherited cardiomyopathy. The favorable short-term outcome following transplantation highlights a potential therapeutic option. Given the possibility of age-dependent penetrance, lifelong cardiac surveillance is for the affected individuals suggested. To emphasize cardiomyopathy as a critical and underrecognized component of the syndrome, we propose the consideration of modifying the acronym to PLACK-C. Full article

Calcium/calmodulin-dependent protein kinase II (CaMKII) comprises multiple isoforms with distinct nuclear variants that exert transcriptional control in a context-dependent manner. Among them, CaMKIIδB and δ9 in the heart, and CaMKIIγ in the nervous system, have emerged as regulators of chromatin dynamics, transcription factor activity, and developmental gene programs. Nuclear localization is driven by splice-dependent nuclear localization sequences, with phosphorylation at defined serine residues modulating import and retention. Evidence supports CaMKII-dependent phosphorylation of class IIa HDACs (Ser467/Ser632 in HDAC4), linking CaMKII to MEF2 activation in cardiac hypertrophy, and interactions with NF-κB and HSF1 further expand its nuclear repertoire. In the nervous system, CaMKIIγ contributes to kinase-dependent gene expression, potentially influencing plasticity and disease susceptibility. While these mechanisms highlight nuclear CaMKII as an isoform-specific regulator of transcription, direct evidence remains elusive, and several CaMKII putative substrates require further validation. This review synthesizes current knowledge on nuclear CaMKII isoforms, emphasizes established mechanistic pathways, and outlines unsolved questions critical for understanding their roles in development, disease progression, and therapeutic targeting. Full article

Background: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) is a frequent but underdiagnosed cause of heart failure with preserved ejection fraction (HFpEF) and left ventricular hypertrophy (LVH). Early identification is essential given the availability of disease-modifying therapies. The T-Amylo and Davies scores are non-invasive tools for estimating ATTR CM probability, but their comparative performance in the same real-world population is not well defined. Objectives: To compare the diagnostic accuracy of T-Amylo and Davies scores in consecutive patients referred for suspected cardiac amyloidosis. Methods: We retrospectively analyzed 81 patients (mean age 76.8 ± 8.3 years, 74% male) who underwent a standardized work-up: ECG, echocardiography with strain, NT-proBNP and troponin, bone scintigraphy, and immunofixation. ATTR CM was diagnosed according to established non-biopsy criteria. Both scores were calculated retrospectively, and sensitivity, specificity, predictive values, accuracy, and agreement were assessed. Results: ATTR CM was confirmed in 28 patients (34.5%). T-Amylo showed higher sensitivity (91.2% vs. 73.5%) and NPV (89.7% vs. 79.1%), while Davies had greater specificity (85.0% vs. 65.0%) and PPV (80.5% vs. 70.8%). Overall accuracy was comparable (T-Amylo 77.0% vs. Davies 79.7%). Agreement between scores was moderate (κ = 0.59). Conclusions: T-Amylo is best suited as a screening tool for suspected ATTR CM, while Davies offers confirmatory value in high-probability cases. Combining these tools in a sequential strategy may optimize diagnostic efficiency, reduce unnecessary testing, and expedite initiation of disease-modifying therapy. Full article

This comprehensive review explores the critical roles of microRNAs (miRNAS) in cardiovascular diseases, emphasizing their regulatory functions in gene expression and their involvement in disease progression. miRNAS are small, evolutionarily conserved non-coding RNAs that regulate gene expression post-transcriptionally and play essential roles in various cardiac conditions, including fibrosis, cardiac remodeling, apoptosis, ischemia/reperfusion injury, hypertrophy, heart failure, arrhythmias, coronary artery disease (CAD), congenital heart diseases (CHDs), cardiomyopathies, and valvular heart disease (VHD). miRNAS are increasingly recognized as sensitive and specific biomarkers for early diagnosis, disease monitoring, and evaluation of therapeutic responses across the cardiovascular disease spectrum. Ischemia/reperfusion injury leads to significant cardiac damage through elevated oxidative stress, mitochondrial dysfunction, and apoptosis. CAD, a major contributor to global morbidity and mortality, is primarily driven by atherosclerosis and chronic inflammation. Cardiac hypertrophy is initially an adaptive response to stress but may progress to heart failure if sustained. Arrhythmias arise from electrical disturbances such as reentry, abnormal automaticity, and triggered activity. Heart failure is a complex and progressive syndrome marked by poor prognosis and increasing global prevalence. VHD involves intricate molecular alterations, including myocardial fibrosis and calcification, which contribute to disease progression and adverse outcomes. Cardiomyopathies—including hypertrophic, dilated, restrictive, and arrhythmogenic forms—are influenced by genetic mutations, systemic diseases, and disrupted molecular signaling. CHDs, the most common congenital malformations, stem from structural abnormalities in cardiac development and remain a major cause of infant morbidity and mortality. Novel therapeutic methods, such as antisense oligonucleotides, miR mimics, and exosome-based delivery mechanisms, demonstrate the translational promise of miRNAs in the realm of personalized cardiovascular medicine. However, issues such as small sample sizes, inconsistent results, interspecies differences, and delivery challenges restrict the clinical application of miRNA-based therapies. This review integrates mechanistic insights, critiques the quality of available evidence, and identifies translational shortcomings. It highlights the diagnostic, prognostic, and therapeutic potential of miRNAs in reshaping cardiovascular disease treatment. Full article

Hypertrophic cardiomyopathy (HCM) is a relatively common global cardiac disease, usually inherited, with complex phenotypes, genetic features, and a natural history. In this study, we constructed atic^−/− zebrafish using the CRISPR/Cas9 gene-editing system and found that atic^−/− zebrafish hearts exhibited HCM symptoms, and atic^−/− zebrafish hearts showed progressive enlargement, eccentric hypertrophy, cardiomyocyte enlargement, and collagen fiber deposition. Echocardiography results also showed that compared with atic^−/− zebrafish hearts, in wild-type zebrafish hearts, the ejection fraction was significantly reduced, shortening fraction was reduced, and ventricular wall thickness was significantly increased. Meanwhile, aerobic exercise intervention in atic^−/− zebrafish showed that aerobic exercise effectively improved the symptoms of HCM and improved cardiac function in atic^−/− zebrafish hearts. Transcriptome sequencing results showed that aerobic exercise improved the symptoms of HCM in atic^−/− zebrafish hearts involving the calcium signaling pathway, Apelin signaling pathway and ECM–receptor interaction. The q-PCR results of key differential genes involved in these pathways further confirmed that aerobic exercise could bring beneficial effects to atic^−/− zebrafish. In conclusion, this study found that the loss of ATIC can lead to hypertrophic cardiomyopathy in zebrafish, and aerobic exercise intervention can effectively improve the hypertrophic pathological characteristics of atic^−/− zebrafish hearts, providing new intervention targets and effective lifestyle interventions for HCM. Full article

Left ventricular hypertrophy (LVH) refers to the pathological thickening of the myocardial wall and is strongly associated with several adverse cardiac outcomes and sudden cardiac death. While the biomechanical drivers of LVH are well established, growing evidence points to a critical role for cardiac and systemic metabolism in modulating hypertrophic remodeling and disease pathogenesis. Despite the efficiency of fatty acid oxidation (FAO), LVH hearts preferentially increase glucose uptake and catabolism to drive glycolysis and oxidative phosphorylation (OXPHOS). The development of therapies to increase and enhance LFCA FAO is underway, with promising results. However, the mechanisms of systemic metabolic states and LCFA dynamics in the context of cardiac hypertrophy remain incompletely understood. Further, it is unknown to what extent cardiac metabolism is influenced by whole-body energy balance and lipid profiles, despite the common occurrence of lipotoxicity in LVH. In this study, we measured whole-body and cellular respiration along with analysis of lipid and glycogen stores in a mouse model of LVH. We found that loss of the cardiac-specific gene, myosin-binding protein C3 (Mybpc3), resulted in depletion of adipose tissue, decreased mitochondrial function in skeletal muscle, increased lipid accumulation in both the heart and liver, and loss of whole-body metabolic flux. We found that supplementation of exogenous LCFAs boosted LVH mitochondrial function and reversed cardiac lipid accumulation but did not fully reverse the hypertrophied heart nor systemic metabolic phenotypes. This study indicates that the LVH phenotype caused systemic metabolic rewiring in Mybpc3^−/− mice and that exogenous LCFA supplementation boosted mitochondrial function in both cardiac and skeletal muscle. Full article

Background/Objectives: Fabry disease (FD) is a rare X-linked disease caused by the deficient activity of the enzyme α-galactosidase A. Cardiac involvement is particularly critical, often determining the disease prognosis. Epidemiological data on FD in Portugal are limited and inconsistent, highlighting the need for targeted screening. The F-CHECK study aimed to determine the prevalence of FD through the systematic screening of a Portuguese cohort of patients with unexplained cardiomyopathies. Methods: This multicenter observational study (NCT05409846) assessed the prevalence and clinical characteristics of FD in a Portuguese cohort (n = 409) of patients from 10 central hospitals who presented with unexplained cardiomyopathies, including idiopathic hypertrophic cardiomyopathy (HCM), left ventricular hypertrophy, dilated-phase HCM, and dilated cardiomyopathy with late gadolinium enhancement in the inferolateral segment. Screening was performed using dried blood spot assays to measure α-galactosidase A activity and/or by GLA gene sequencing in whole-blood samples. Results: FD was diagnosed in 14 patients, corresponding to a prevalence of 3.4%. FD diagnosis was significantly associated with systemic manifestations such as acroparesthesias (p = 0.027) and angiokeratomas (p = 0.003), as well as an increased risk of prior arrhythmic events (p = 0.021) and cerebrovascular disease (p = 0.016). Most FD patients (57%) presented a non-founder mutation in the GLA gene; however, they were pathogenically relevant. Conclusions: The observed 3.4% prevalence highlights the importance of systematic FD screening among Portuguese patients with unexplained cardiomyopathy, extending beyond classic hypertrophic presentations to dilated forms. Specific clinical signs, electrocardiogram findings, and cardiac imaging features can serve as valuable indicators to guide targeted genetic testing for FD. Full article

Chronic kidney disease (CKD) cardiac impairment is manifested as cardio-renal syndrome type 4 (CRS-IV). The kidneys and heart are highly dependent on mitochondria; thus, bioenergetics and redox and biogenesis alterations are critical in CKD and heart damage. Most previous studies have focused on the advanced stage of CRS-IV, but mitochondrial impairment onset in the early stages and its pathological pathways are poorly understood. In this work, we characterized mitochondrial bioenergetics, biogenesis and redox impairment in both tissues in the early stages after CKD and analyzed their relationship with CRS-IV in a CKD model with 5/6 nephrectomy (NX). We found the first cardiac mitochondrial alterations 10 days after surgery, together with an increase in plasma cardio-renal connectors, derived from renal mitochondrial damage. Oxidative phosphorylation capacity decreased and uncoupling led to oxidative stress, inflammation, cardiac hypertrophy and ejection fraction reduction, triggering CRS-IV. N-acetylcysteine (NAC) administration prevented mitochondrial alterations in both organs and heart damage. Interestingly, the protective effects of NAC correlated with SIRT1/3-PGC-1α pathway overactivation. These results suggest that mitochondrial biogenesis induction and redox regulation protection in the early stages after renal damage serve as a strategy to prevent bioenergetic alterations in the kidneys and heart, preventing inflammation and CRS-IV development. Full article

The relationship of diabetes mellitus (DM) with cardiovascular mortality and morbidity has been widely established. Diabetic cardiomyopathy (DBCM) has been increasingly recognized as the development of cardiac dysfunction accompanied by heart failure (HF) symptoms in the absence of obvious causes like coronary artery disease (CAD), hypertension (HTN) or valvular diseases. The objective of this review is to critically appraise the role of echocardiography in the diagnosis and prognostic stratification of DBCM. Echocardiography remains the first-line imaging modality due to its availability, repeatability, non-invasive nature and ability to assess structural and functional changes. Classical echocardiographic indices such as left ventricular hypertrophy and systolic and diastolic dysfunction assessment provide valuable information but they lack sensitivity, often remaining normal until advanced stages of DBCM. Recently developed echocardiographic modalities, including strain imaging, myocardial work indices and left atrial strain, may allow for earlier detection of subclinical myocardial dysfunction, having important prognostic implications. However, these advanced modalities require high imaging quality, expertise and standardization, being subject to technical and physio-logical limitations. Stress echocardiography, particularly exercise-based protocols, is an increasingly recognized, valuable tool for unmasking exertional abnormalities in filling pressures, myocardial reserve and pulmonary pressures that are not evident at rest. Until now, stress echocardiography requires validation in large cohorts to assess its prognostic power. This review highlights the importance of timely recognition of DBCM, underscores the advantages and disadvantages of current echocardiographic approaches and outlines future perspectives in multimodality imaging to improve patient outcomes. Full article