Search Results (174)

Background: Immune checkpoint inhibitors (ICIs) are a new anti-cancer therapy that have improved survival rates in many aggressive cancers. However, while rare, a significant number of patients develop ICI-induced cardiotoxicity. Clinical manifestations are non-specific and underlying cellular mechanisms remain unknown, making diagnosis and treatment of these ICI-induced cardiac side effects difficult. Exercise has shown protective effects against chemotherapy-induced cardiotoxicity but has not been investigated in combination with ICIs. High-intensity exercise has shown greatest cardioprotective effects in preclinical (animal) models, but human cancer patients prefer low-intensity exercise in the clinical setting. Therefore, the purpose of this study was to further identify the cardioprotective effects of low-intensity exercise as a treatment strategy against ICI-induced cardiotoxicity. Methods: Female mice were randomly selected and separated into four groups: sedentary (SED), sedentary ICI-treated (SED + ICI), low-intensity treadmill-exercised (TM), and low-intensity treadmill-exercised ICI-treated mice (TM + ICI). Mice either underwent a 4-week low-intensity treadmill exercise protocol (TM) or remained sedentary (SED). During the 4 weeks, ICI mice received anti-PD-1 treatment (200 μg/mouse) via intraperitoneal injections twice each week. Echocardiography was performed at baseline and sacrifice to determine changes in cardiac structure and function. At sacrifice, cardiac tissue was collected, weighed, and frozen for further biochemical analysis. Underlying metabolic signaling pathways were assessed via Western Blot, and autophagic flux was analyzed via fluorescent microscopy. Results: Echocardiography at sacrifice revealed significantly decreased fractional shortening as a measure of cardiac function (−20%), 1.5-fold dilation of the left ventricle, and thinning of the posterior cardiac wall at systole and diastole in SED + ICI mice compared to SED controls (p < 0.05), indicative of a phenotype of ICI-induced dilated cardiomyopathy. TM + ICI mice did not show a significant difference in these cardiac structural and functional parameters, suggesting cardioprotective effects of low-intensity exercise. In line with these findings, Western Blot and fluorescent microscopy analyses revealed upregulation of autophagic flux (p < 0.05), as well as dysfunctional metabolic pathways (p < 0.05) in ICI-treated mice compared to non-ICI controls. Low-intensity exercise was associated with regulation of dysfunctional metabolism and autophagy in TM + ICI compared to SED + ICI mice. Conclusions: The clinically relevant ICI treatment protocol used in this study led to significant cardiac dysfunction and remodeling, accompanied by underlying dysfunctional metabolism and autophagy. Low-intensity exercise was capable of regulating abnormal protein synthesis and degradation and protecting against ICI-induced cardiotoxicity. This study adds knowledge to the characterization of still unclear clinical manifestations of ICI-induced cardiotoxicity, underlying signaling pathways that could shed light on potential pharmacological treatment targets, as well as the protective effects of low-intensity exercise as a non-pharmacological treatment strategy. Full article

The Western diet (WD) has been linked to various structural and functional alterations in the left ventricle (LV), but the molecular response of the right ventricle (RV) remains largely unknown. Given the RV’s distinct anatomical and functional characteristics, it is crucial to understand how long-term WD exposure affects RV gene expression, especially in a sex-specific context. Our objective was to perform gene expression profiling of the RV late responses to WD in wild-type mice. Male and female C57BL/6J mice were fed a WD for 125 days from 300 to 425 days of age, and RV tissues were collected at 530 and 640/750 (female/male) days. mRNA sequencing was performed on RV tissues to identify differentially expressed genes (DEGs) between WD-fed and normal diet (ND)-fed groups. Data processing and analysis were conducted using the STAR aligner and DESeq2. WD-induced RV transcriptomic changes were characterized by differential expression of genes associated with cardiac remodeling and transcriptional regulation in both sexes. In females, additional genes showing altered expression were associated with immune response, whereas in males, changes were more limited, primarily involving genes related to circadian rhythm and cardiac remodeling. Echocardiography revealed modest, sex-specific differences: WD-fed females showed a decrease in right-ventricular internal diameter in diastole and a trend toward increased pulmonary trunk diameter, whereas males showed no notable changes. These exploratory results suggest that WD is associated with modest transcriptomic changes in the RV in both sexes, with only minor structural differences observed in females, indicating subtle sex-specific effects after a switch to normal chow. Full article

Background. Gestational diabetes mellitus (GDM) induces maternal hyperglycemia, which may alter fetal cardiac structure and function, increasing short- and long-term cardiovascular risks. Purpose. To systematically review the evidence on the fetal cardiac structural and functional effects of GDM, to explore the diagnostic role of novel imaging and biochemical biomarkers, and to summarize the long-term cardiovascular complications associated with GDM. Materials and Methods. A systematic search of PubMed, Scopus, and Cochrane Library was conducted according to the PRISMA guidelines. All studies comparing cardiac outcomes in GDM and non-GDM pregnancies were included. Data on myocardial hypertrophy, diastolic and systolic function, imaging modalities, and biomarkers were extracted and qualitatively synthesized. Results. A total of twelve eligible studies were identified. Fetal cardiac hypertrophy and diastolic and early systolic dysfunction are common among GDM pregnancies and can be detected by dual-gate Doppler and speckle-tracking echocardiography. Abnormalities are observed in indices such as the myocardial performance index, E/A, E/e′ ratios, and global longitudinal and circumferential strain in fetuses and may persist in the neonatal period. Alterations may be more pronounced for the right ventricle compared to the left. Septal hypertrophy is associated with elevated umbilical cord pro-brain natriuretic peptide. The risk of early-onset cardiovascular disease in the progeny of diabetic mothers is 29% higher, as evidenced by population-based cohort data. Conclusions. GDM is linked to fetal cardiac remodeling and an increased long-term cardiovascular risk. Early detection and customized interventions to reduce adverse outcomes may be achieved by integrating advanced echocardiographic techniques and biomarkers into prenatal surveillance. Full article

When blood flow to a part of the myocardial muscle is reduced or blocked, it leads to tissue ischemia in that region. Myocardial infarction (MI) occurs when the ischemic insult is of sufficient duration in time to induce cardiomyocyte death and subsequent activation of the innate immune response. MI initiates a complex cascade of cellular and molecular events within the left ventricle. Inflammatory cells rapidly infiltrate the infarcted area to remove necrotic tissue, setting the stage for reparative wound healing processes. Over the ensuing days, various cell populations—including leukocytes, fibroblasts, and endothelial cells—are attracted to the infarcted site by inflammatory cytokines and chemokines. The activated cells at the site of injury contribute to tissue remodeling and scar formation through the deposition of extracellular matrix components, particularly collagen. While scar formation is essential for structural stabilization of the infarct region to replace the loss of cardiomyocytes, scar tissue also increases myocardial stiffness and impairs cardiac contractile function. This review summarizes our knowledge regarding cellular dynamics, inflammatory signaling, and cardiac remodeling that govern MI healing. We identify the current gaps in the field and provide a foundational resource for those seeking to understand the biological underpinnings of cardiac repair following MI. Full article

The transcriptional regulation of MYH6 and MYH7 genes has been extensively investigated in healthy versus failing hearts; however, their expression dynamics in healthy human hearts across age and sex, particularly in the context of cardiovascular risk factors such as hypertension, remain poorly characterised. This study aimed to carry out a reanalysis of MYH6 and MYH7 transcript levels in a large cohort of non-failing human left ventricular samples, stratified by sex, age, and hypertensive status. Furthermore, we examined how age and sex influence gene expression differences between non-failing and failing hearts, the latter affected by dilated cardiomyopathy (DCM). Normalised expression values for MYH6 and MYH7 transcripts from both healthy and failing left ventricles were extracted using the GEO2R online analysis tool from the publicly available RNA-sequencing library GSE141910. This library provides transcriptomic profiles of left ventricular (LV) tissue from both healthy individuals and patients with cardiomyopathies. The Mann–Whitney U test was employed for pairwise comparisons between different groups stratified by sex, age, and hypertensive status. Statistical analysis demonstrates sex-specific differences in MYH6 and MYH7 expression in healthy left ventricles, with postmenopausal females (aged > 50 years) with hypertension emerging as a distinct group. Conversely, in end-stage DCM hearts, the expression levels of both myosin genes seemed to be primarily influenced by disease-related pathophysiological mechanisms rather than by sex or age. Comparison between healthy and failing hearts revealed a consistent and significant downregulation of MYH6 in all comparisons, irrespective of sex or age. On the other hand, MYH7 expression exhibited greater variability, particularly among males, with age and hypertensive status influencing its expression. The results underscore the importance of considering age, sex, and comorbidities in interpreting cardiac gene expression patterns and highlight potential regulatory divergence in contractile gene expression during cardiac remodelling. Full article

Although experimental evidence indicates that mitochondrial collapse is a common effect of both Chagas disease and post-ischemic heart failure and that cardiac anatomy and function are partially restored by stem cell therapy, the responsible molecular mechanisms are still under debate. Gene expression data from our publicly accessible transcriptomic dataset obtained by profiling the left ventricle myocardia of mouse models of Chagas disease and post-ischemic heart failure were re-analyzed from the perspective of the Genomic Fabric Paradigm. In addition to the regulation of the gene expression levels, we determined the changes in the strength of the homeostatic control of transcript abundance and the remodeling of the gene networks responsible for the mitochondrial respiration. The analysis revealed that most of the mitochondrial genes assigned to the five complexes of the respiratory chain were significantly downregulated by both Chagas disease and ischemia but exhibited outstanding recovery of the normal expression levels following direct injection of bone-marrow-derived stem cells. However, instead of regaining the original expression control and gene networking, the treatment induced novel mitochondrial arrangements, suggesting that multiple transcriptomic topologies might be compatible with any given physiological or pathological state. This study confirmed several established mechanisms and identified novel gene expression signals, especially Cox4i2, Cox6b1, Cox7b, Ndufb11, and Tmem186, that warrant further investigations. Their broad rescue with cell therapy underscores mitochondria as a convergent, tractable target for cardiac repair. Full article

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

Training not only enhances the athletic performance of horses but also improves cardiac structure and function, strengthens cardiovascular adaptability, and reduces the risk of cardiovascular diseases. However, the consequences of training on equine cardiac structure and function remain unclear. This study investigated the morphological, functional, genetic, and metabolic changes in the hearts of Yili horses divided into three groups: high athletic performance (agility group, AG), low athletic performance (ordinary group, OG), and untrained (untrained group, UN). The results showed remodeling of the cardiac structure and physiological adaptations in AG and OG compared to UN groups, with differences between AG and OG primarily in the left ventricle. To explore the molecular mechanisms underlying these phenotypic changes, transcriptomic and metabolomic analyses (particularly GO and KEGG pathway analyses) were performed to assess differences in gene expression and metabolite levels among the three groups. Our results show that miR-1842, miR-671, miR-106b and miR-18a were differentially expressed in the trained groups (AG group and OG group) compared with the control group that did not receive training. These regulatory factors would regulate PFKFB3 to affect the glycolytic activity mediated by HIF-1, there by promoting glycolysis and changing lactate level. This, in turn, would positively feedback to stabilize HIF-1, thus forming a closed loop for the reprogramming of myocardial energy metabolism. In the AG group, positive effects of cAMP signaling were noticeable. In conclusion, our findings offer new insights into physiological cardiac remodeling in Yili horses by highlighting genetic and metabolomic changes resulting from exercise training. Full article

Background/Objectives: Dilated cardiomyopathy (DCM) is a prevalent and life-threatening heart muscle disease often caused by titin (TTN) truncating variants (TTNtv). While TTNtvs are the most common genetic cause of heritable DCM, the precise downstream regulatory mechanisms linking TTN deficiency to cardiac dysfunction and maladaptive fibrotic remodeling remain incompletely understood. This study aimed to identify key epigenetic regulators of TTN-mediated gene expression and explore their potential as therapeutic targets, utilizing human patient data and in vitro models. Methods: We analyzed RNA sequencing (RNA-seq) data from left ventricles of non-failing donors and cardiomyopathy patients (DCM, HCM, PPCM) (GSE141910). To model TTN deficiency, we silenced TTN in human iPSC-derived cardiomyocytes (iPSC-CMs) and evaluated changes in cardiac function genes (MYH6, NPPA) and fibrosis-associated genes (COL1A1, COL3A1, COL14A1). We further tested the effects of TMP-195, a class IIa histone deacetylase (HDAC) inhibitor, and individual knockdowns of HDAC4/5/7/9. Results: In both human patient data and the TTN knockdown iPSC-CM model, TTN deficiency suppressed MYH6 and NPPA while upregulating fibrosis-associated genes. Treatment with TMP-195 restored NPPA and MYH6 expression and suppressed collagen genes, without altering TTN expression. Among the HDACs tested, HDAC5 knockdown was most consistently associated with improved cardiac markers and reduced fibrotic gene expression. Co-silencing TTN and HDAC5 replicated these beneficial effects. Furthermore, the administration of TMP-195 enhanced the modulation of NPPA and COL1A1, though its impact on COL3A1 and COL14A1 was not similarly enhanced. Conclusions: Our findings identify HDAC5 as a key epigenetic regulator of maladaptive gene expression in TTN deficiency. Although the precise mechanisms remain to be clarified, the ability of pharmacological HDAC5 inhibition with TMP-195 to reverse TTN-deficiency-induced gene dysregulation highlights its promising translational potential for TTN-related cardiomyopathies. Full article

Background: The mitral valve apparatus is a complex system that requires sufficient function of all involved structures. Previous studies have demonstrated that ventricular remodeling can cause displacement of subannular structures, including the papillary muscles, which in turn promotes the development of mitral regurgitation. Furthermore, in such cases, annuloplasty alone is often insufficient to restore optimal valve function. Instead, additional reconstruction of the subannular apparatus is associated with improved clinical outcomes. Our study aimed to analyze the topography of the papillary muscles in the mitral valve complex and their relevance for mitral valve function. Methods: In 148 patients who underwent both cardiac computed tomography (CT) and echocardiography, the position of the papillary muscles within the left ventricle was assessed. CT scans were evaluated in end-diastolic four-chamber view, two-chamber view, and short-axis view. CT analysis involved determining the position of the papillary muscles based on a modified left ventricular segmentation scheme, which subdivided the original segments into “a” and “b” subsegments in a counterclockwise manner. Furthermore, the midventricular diameter, ventricular length, as well as the angle between the papillary muscle (PM) and the left ventricular wall, were measured. Comorbidities were assessed. The presence of mitral regurgitation (MR) and ejection fraction was determined based on echocardiographic data. Echocardiography was conducted either as part of initial cardiological assessments or during follow-up examinations. For detailed statistical analysis, the patients were divided into the following groups: control group, MR-only group, coronary heart disease (CHD)-only group, and combined CHD and MR subgroup. Results: Mitral regurgitation was significantly correlated with age (p < 0.001) and hypertension (r = 0.1900, p = 0.0208), and in the MR-only subgroup, additionally with atrial fibrillation (r = 0.2426, p = 0.0462). The length (p < 0.001) and internal diameter (p < 0.001) of the left ventricle were significantly larger in men than in women. Different positions of the papillary muscles were identified. Segment 7a was significantly correlated with MR in the combined CHD and MR subgroup. In normal-sized ventricles, patients with MR and papillary muscle in 12a (p = 0.0095) or 10a (p = 0.0460) showed a significantly larger angle than patients without MR (overall dataset). Conclusions: Assessment of papillary muscle position is essential in diagnosing mitral regurgitation and should guide the consideration of subannular repair during surgical treatment. Full article

Heart failure (HF) imposes a significant burden on public health, affecting over 56.19 million people worldwide. Right ventricular (RV) dysfunction may occur in HF patients due to various factors, including adverse interventricular interactions, ischemic heart disease, and HF-correlated pulmonary hypertension. Additionally, the deterioration of RV function plays a critical role in the progression of HF, regardless of left ventricular (LV) systolic function, suggesting an unfavorable outcome. Throughout the progression of HF and increasing afterload, the right ventricle undergoes adaptive remodeling to preserve adequate cardiac output. Right ventricular-pulmonary artery (RV-PA) coupling integrates the dynamic adaptation of RV systolic function to afterload and has been considered a stronger predictor of HF prognosis than other conventional parameters. Thus, accurate evaluations of RV-PA coupling are significant in the clinical diagnosis and management of HF patients, along with prognostic speculation. In this review, we summarize the basic principles and measurements of RV-PA coupling and focus on its clinical significance across each subtype of HF. Full article

Background/Objectives: Dilated cardiomyopathy (DCM), defined as dilation and contractile dysfunction of the left or both cardiac ventricles, remains the most common category of primary myocardial disease worldwide. It is the most prevalent cause of chronic heart failure and the most common indication for cardiac transplantation in young subjects. Accumulating evidence increasingly highlights the substantial genetic defects underlying DCM. Nevertheless, the genetic ingredients accountable for DCM in a major percentage of patients remain indefinite. Methods: A multigenerational pedigree suffering from DCM and a total of 276 healthy volunteers employed as controls were recruited from the Chinese Han-ethnicity population. A whole-exome sequencing (WES) assay followed by a Sanger sequencing analysis of the genomic DNAs from the available family members was implemented. Functional characterization of the identified genetic variant was completed by dual-luciferase analysis. Results: A new heterozygous variation in the ETS1 (erythroblast transformation-specific 1) gene, NM_005238.4:c.447T>G;p.(Tyr149*), was identified by WES and validated by Sanger sequencing analysis to co-segregate with DCM in the whole DCM family. This nonsense ETS1 variant was not found in 276 control subjects. Functional examination elucidated that Tyr149*-mutant ETS1 lost the ability to transactivate its downstream target genes CLDN5 (claudin 5) and ALK1 (activin receptor-like kinase 1), two genes crucial for cardiovascular embryonic development and postnatal structural remodeling. Conclusions: The present investigation reveals ETS1 as a new gene predisposed to human DCM and indicates ETS1 haploinsufficiency as an alternative molecular pathogenesis underlying DCM, providing a potential molecular target for genetic counseling and early diagnosis as well as personalized prophylaxis of DCM. Full article

Background/Objectives: Heart failure (HF) with reduced ejection fraction (EF) has, in more than 50% of cases, an ischemic etiology and continues to be associated with increased mortality and morbidity despite all the progress registered in the field of medical therapy and interventional revascularization. Myocardial revascularization is extensively used in clinical practice based on the traditional concept that it can improve myocardial function and outcome in ischemic HF. This review is aimed at presenting current knowledge regarding revascularization in patients with chronic ischemic HF and reduced EF. Methods: The impact of revascularization on symptomatology, left ventricle reverse remodeling, major adverse cardiac events (MACEs), and the role of complete revascularization and of percutaneous interventional revascularization in chronic total occlusion (PCI-CTO) were analyzed. The best therapeutic strategies, revascularization and/or optimal medical therapy (OMT), are debated in different categories of patients, in order to identify who will benefit more from revascularization strategies. Results: Based on the long-term results of the STICH trial incorporated in the guidelines with a class I-b recommendation, coronary artery bypass graft (CABG) remains the main modality of revascularization for prognostic improvement in ischemic HF with multivessel disease. But real-life patients are usually old with multiple comorbidities and high surgical risk. In this category, the Heart Team opinion is required to evaluate the probability of complete revascularization and to choose between percutaneous coronary intervention (PCI) and CABG according to clinical status and coronary anatomy. Conclusions: However, until further studies are available, the results of the REVIVED-BCIS2 trial encourage OMT over PCI in patients with ischemic cardiomyopathy. The available randomized controlled trials (RCTs) showed improved angina and quality of life in PCI-CTO versus OMT, but the effect on MACEs was not demonstrated. Full article

Background: Arteriovenous fistulas (AVFs) may contribute to cardiac remodeling and consequently to an increased risk of heart failure and cardiovascular mortality in patients with end-stage kidney disease (ESKD). We aimed to assess cardiac changes following AVF creation and identify potential parameters associated with cardiac remodeling. Methods: In our prospective, single-center study, ESKD patients without significant pre-existing cardiac disease underwent 2D and 3D echocardiographic evaluation before and after AVF creation, along with AVF flow measurement. Cardiac remodeling was assessed using 3D indexed left and right ventricular end-diastolic volumes (LVEDVi, RVEDVi), while systolic function was assessed using longitudinal strain and 3D ejection fraction. Results: We included 20 patients (18 men; median age 73.5 years [IQR: 67–77]) with a mean AVF flow of 1140 ± 345 mL/min. At a median of 8.2 months (IQR: 7.3–9.3) following AVF creation, significant biventricular dilatation was observed: LVEDVi increased from 89 ± 14 to 97 ± 21 mL/m² (p < 0.05) and RVEDVi from 80 ± 15 to 91 ± 18 mL/m² (p < 0.05), while the systolic function of both ventricles did not change significantly. The right ventricle showed the most pronounced remodeling and it was independently associated with volume overload (p = 0.003) and elevated left ventricular filling pressure (p = 0.030), but not with AVF flow. Conclusions: Moderate AVF flow was associated with cardiac remodeling, primarily affecting the right ventricle. Fluid overload and left ventricular filling pressure were key factors associated with right ventricular remodeling, underscoring the need for careful fluid management and vascular access planning in ESKD patients. Full article

Background/Objectives: Nelumbo nucifera Gaertn. (lotus) seeds have traditionally been used to treat hypertension, though their mechanisms remain unclear. This study investigated the antihypertensive effects of lotus seed extract (LSE) and its mechanisms in rats with N^ω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Methods: Male Sprague Dawley rats received L-NAME (40 mg/kg/day) in drinking water and were treated orally with LSE (5, 10, or 100 mg/kg/day), captopril (5 mg/kg/day), or a combination of LSE and captopril (2.5 mg/kg/day each) for 5 weeks. Hemodynamic parameters and histological changes in the left ventricle and aorta were assessed. Mechanistic studies included measurements of plasma nitric oxide (NO) metabolites, malondialdehyde (MDA), superoxide dismutase (SOD) activity, angiotensin II (Ang II), angiotensin-converting enzyme (ACE) activity, and protein expression via western blot. Results: L-NAME elevated systolic blood pressure and induced cardiovascular remodeling, oxidative stress, and renin-angiotensin system activation. LSE treatment reduced blood pressure, improved antioxidant status, increased NO bioavailability, and downregulated gp91^phox and AT₁R expression. The combination of low-dose LSE and captopril produced stronger effects than LSE alone, with efficacy comparable to captopril. Conclusions: These findings suggest that LSE exerts antihypertensive effects via antioxidant activity and inhibition of the renin-angiotensin system, supporting its potential as an adjunct therapy for hypertension. Full article