Search Results (279)

Hypertensive left ventricular hypertrophy (LVH) is an ominous cardiovascular sequel to chronic hypertension, marked by structural and functional alterations in the heart. Identified as a significant risk factor for adverse cardiovascular outcomes, LVH is typically detected through echocardiography and is characterized by pathological thickening of the left ventricular wall. This hypertrophy results from chronic pressure overload (increased afterload), leading to concentric remodelling, or from increased diastolic filling (preload), contributing to eccentric changes. Apoptosis, a regulated process of cell death, plays a critical role in the pathogenesis of LVH by contributing to cardiomyocyte loss and subsequent cardiac dysfunction. Given the substantial clinical implications of LVH for cardiovascular health, this review critically examines the role of cardiomyocyte apoptosis in its disease progression, evaluates the impact of pharmacological interventions, and highlights the necessity of a comprehensive, multifaceted treatment approach for the prevention and management of hypertensive LVH. Finally, we address the health disparities associated with LVH, with particular attention to the disproportionate burden faced by African Americans and other Black communities, as this remains a key priority in advancing equity in cardiovascular care. Full article

Acute heart failure (AHF) is a clinical syndrome characterized by the sudden onset or rapid worsening of heart failure signs and symptoms, frequently triggered by myocardial ischemia, pressure overload, or cardiotoxic injury. A central component of its pathophysiology is the activation of intracellular signal transduction cascades that translate extracellular stress into cellular responses. Among these, the mitogen-activated protein kinase (MAPK) pathways have received considerable attention due to their roles in mediating inflammation, apoptosis, hypertrophy, and adverse cardiac remodeling. The canonical MAPK cascades—including extracellular signal-regulated kinases (ERK1/2), p38 MAPK, and c-Jun N-terminal kinases (JNK)—are activated by upstream stimuli such as angiotensin II (Ang II), aldosterone, endothelin-1 (ET-1), and sustained catecholamine release. Additionally, emerging evidence highlights the role of receptor-mediated signaling, cellular stress, and myeloid cell-driven coagulation events in linking MAPK activation to fibrotic remodeling following myocardial infarction. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade plays a central role in regulating cardiomyocyte survival, hypertrophy, energy metabolism, and inflammation. Activation of the PI3K/Akt pathway has been shown to confer cardioprotective effects by enhancing anti-apoptotic and pro-survival signaling; however, aberrant or sustained activation may contribute to maladaptive remodeling and progressive cardiac dysfunction. In the context of AHF, understanding the dual role of this pathway is crucial, as it functions both as a marker of compensatory adaptation and as a potential therapeutic target. Recent reviews and preclinical studies have linked PI3K/Akt activation with reduced myocardial apoptosis and attenuation of pro-inflammatory cascades that exacerbate heart failure. Among the multiple signaling pathways involved, glycogen synthase kinase-3β (GSK-3β) has emerged as a key regulator of apoptosis, inflammation, metabolic homeostasis, and cardiac remodeling. Recent studies underscore its dual function as both a negative regulator of pathological hypertrophy and a modulator of cell survival, making it a compelling therapeutic candidate in acute cardiac settings. While earlier investigations focused primarily on chronic heart failure and long-term remodeling, growing evidence now supports a critical role for GSK-3β dysregulation in acute myocardial stress and injury. This comprehensive review discusses recent advances in our understanding of the MAPK signaling pathway, the PI3K/Akt cascade, and GSK-3β activity in AHF, with a particular emphasis on mechanistic insights, preclinical models, and emerging therapeutic targets. Full article

Background: Diabetic cardiomyopathy (DCM) is characterized by progressive cardiac dysfunction, metabolic dysregulation, myocardial fibrosis, and mitochondrial impairment. Existing animal models, such as streptozotocin (STZ)-induced models, suffer from high mortality and fail to replicate chronic metabolic dysregulation induced by high-fat diets (HFD), whereas HFD or HFD/STZ-combined rodent models require high maintenance costs. This study aimed to establish a zebrafish HFD-DCM model to facilitate mechanistic exploration and drug discovery. Methods: Eighty wild-type female zebrafish were divided into normal diet (N, 6% fat) and HFD (H, 24% fat) groups and fed the diet for 8 weeks. Metabolic phenotypes were evaluated using intraperitoneal glucose tolerance tests and insulin level analysis. Cardiac function was assessed by using echocardiography (ejection fraction, E peak). Structural, metabolic, and oxidative stress alterations were analyzed by histopathology (H&E, Masson, and Oil Red O staining), molecular assays (RT-qPCR, Western blotting), and mitochondrial structure/function evaluations (respiratory chain activity, transmission electron microscopy, and DHE staining). Results: HFD-fed zebrafish developed obesity, insulin resistance, and impaired glucose tolerance. Echocardiography revealed cardiac hypertrophy, reduced ejection fraction, and diastolic dysfunction. Excessive lipid accumulation, upregulated fibrosis/inflammatory markers, impaired mitochondrial respiration, elevated reactive oxygen species levels, and a disrupted redox balance were observed. Conclusions: We established a female zebrafish HFD model that recapitulates human DCM features, including hypertrophy, metabolic dysregulation, fibrosis, inflammation, and mitochondrial dysfunction. This model offers novel insights into DCM pathogenesis and serves as a valuable platform for mechanistic studies and targeted drug screening. Full article

Introduction: Preeclampsia (PE) is a pregnancy-specific disorder characterized by hypertension and organ dysfunction, affecting 5–8% of pregnancies globally and increasing women’s long-term risk of cardiovascular disease (CVD). This study investigates the association between prior PE and cardiovascular health in postmenopausal women. Methods: A total of 108 postmenopausal women with a history of PE and 100 controls without PE were enrolled. Clinical data, blood pressure readings, and echocardiographic assessments were obtained. Statistical analysis was conducted using SPSS version 20.0. Results: Women with prior PE showed a higher prevalence of eccentric left ventricular hypertrophy (37% vs. 23%, p < 0.02) and diastolic dysfunction (51% vs. 39%, p < 0.003). Maternal history of hypertension was also more common in the PE group (55% vs. 26%, p < 0.003). Obesity was more frequent in the PE group, but did not reach statistical significance (p < 0.09). Conclusions: Prior PE was linked to an increased risk of postmenopausal cardiac abnormalities, including left ventricular hypertrophy and diastolic dysfunction. A maternal history of hypertension was also more common among women with prior PE, suggesting a familial connection; PE should be acknowledged as a significant predictor of long-term cardiovascular risk, requiring lifelong monitoring and preventive measures. Full article

Right heart failure (RHF) is a major cause of morbidity and mortality, often resulting from pulmonary arterial hypertension and characterized by impaired calcium (Ca²⁺) handling and maladaptive remodeling. Phosphodiesterase 9A (PDE9A), a cGMP-specific phosphodiesterase, has been proposed as a potential contributor to RHF pathogenesis by suppressing the cardioprotective cGMP–PKG signaling pathway—a conclusion largely extrapolated from left-sided heart failure models. This review examines existing evidence regarding PDE9A’s role in RHF, focusing on its effects on intracellular calcium cycling, fibrosis, hypertrophy, and contractile dysfunction. Data from preclinical models demonstrate that pathological stress upregulates PDE9A expression in cardiomyocytes, leading to diminished PKG activation, impaired SERCA2a function, RyR2 instability, and increased arrhythmogenic Ca²⁺ leak. Pharmacological or genetic inhibition of PDE9A restores cGMP signaling, improves calcium handling, attenuates hypertrophic and fibrotic remodeling, and enhances ventricular compliance. Early-phase clinical studies in heart failure populations suggest that PDE9A inhibitors are well tolerated and effectively augment cGMP levels, although dedicated trials in RHF are still needed. Overall, these findings indicate that targeting PDE9A may represent a promising therapeutic strategy to improve outcomes in RHF by directly addressing the molecular mechanisms underlying calcium mishandling and myocardial remodeling. Full article

Cardiac hypertrophy represents a central manifestation of hypertension-mediated organ damage (HMOD), which consists of structural and functional changes as a response to sustained pressure overload. Oxidative stress and inflammation play central roles in the development of cardiac hypertrophy, contributing to myocardial remodeling in association with mechanical stress and neurohormonal activation. The imbalance between the production of reactive oxygen species and antioxidant defense mechanisms is associated with the activation of signaling pathways and the expression of genes involved in the development and progression of cardiac fibrosis and hypertrophy. Oxidative stress is also related to mitochondrial dysfunction, redox-sensitive transcription factors, post-translational modifications, and epigenetic modulation. Novel therapeutic strategies can target these molecular pathways, reducing the impact of hypertension on HMOD. Type-2 sodium glucose transporter inhibitors were shown to restore mitochondrial bioenergetics, reducing oxidative stress, and suppressing inflammation. Also, glucagon-like peptide-1 receptor agonists reduce ROS generation and stabilize mitochondrial structure and function. In addition, vericiguat, which represents an approach targeted to restore nitric oxide-soluble guanylate cyclase signaling, might represent a valuable therapeutic approach, working to prevent and slow the progression of cardiac hypertrophy before the development of heart failure. In this review we will describe the pathophysiological mechanisms associated with cardiac hypertrophy and discuss the recent innovative therapeutic strategies with potential implications for prevention and management. Full article

Background: Aging and the female sex are considered risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Unlike other risk factors, such as hypertension, obesity, or diabetes, they do not represent therapeutic targets. Methods: In a recently developed two-hit murine HFpEF model (angiotensin II + high-fat diet; MHS), we studied the relative contributions of the biological sex, aging, and gonadal hormones to cardiac remodeling and function. We aimed to reproduce a frequent HFpEF phenotype in mice characterized by aging, hypertension, the female sex, menopause, and metabolic alterations. Using the MHS mouse model, we studied cardiac remodeling and function in C57Bl6/J mice of both sexes, young (12 weeks) and old (20 months), that were gonadectomized (Gx) or not. Results: We observed that in mice, aging was associated with body weight gain, cardiac hypertrophy (CH), left ventricle (LV) concentric remodeling, and left atrial (LA) enlargement. Diastolic parameters such as E and A wave velocities were modulated by aging but only in females. Submitting young and old mice to MHS for 28 days induced the expected HFpEF phenotype consisting of CH, LV wall thickening, LA enlargement, and diastolic dysfunction with a preserved EF except for old males, in which it was significantly reduced. Young mice were Gx at five weeks, and old mice at six months (over a year before MHS). Gx increased myocardial fibrosis in MHS females and helped preserve the EF in males. Conclusions: Our results suggest that MHS has sex-specific effects on old mice, and the loss of gonadal hormones significantly impacts the observed heart failure phenotype. Full article

Mitochondria play a central role in energy metabolism and continuously adapt through dynamic processes such as fusion and fission. When the balance between these processes is disrupted, it can lead to mitochondrial dysfunction and increased oxidative stress, contributing to the development and progression of various cardiometabolic diseases (CMDs). Their role is crucial in diabetes mellitus (DM), since their dysfunction drives β-cell apoptosis, immune activation, and chronic inflammation through excessive ROS production, worsening endogenous insulin secretion. Moreover, sympathetic nervous system activation and altered dynamics, contribute to hypertension through oxidative stress, impaired mitophagy, endothelial dysfunction, and cardiomyocyte hypertrophy. Furthermore, the role of mitochondria is catalytic in endothelial dysfunction through excessive reactive oxygen species (ROS) production, disrupting the vascular tone, permeability, and apoptosis, while impairing antioxidant defense and promoting inflammatory processes. Mitochondrial oxidative stress, resulting from an imbalance between ROS/Reactive nitrogen species (RNS) imbalance, promotes atherosclerotic alterations and oxidative modification of oxidizing low-density lipoprotein (LDL). Mitochondrial DNA (mtDNA), situated in close proximity to the inner mitochondrial membrane where ROS are generated, is particularly susceptible to oxidative damage. ROS activate redox-sensitive inflammatory signaling pathways, notably the nuclear factor kappa B (NF-κB) pathway, leading to the transcriptional upregulation of proinflammatory cytokines, chemokines, and adhesion molecules. This proinflammatory milieu promotes endothelial activation and monocyte recruitment, thereby perpetuating local inflammation and enhancing atherogenesis. Additionally, mitochondrial disruptions in heart failure promote further ischemic injury and excessive oxidative stress release and impair ATP production and Ca²⁺ dysregulation, contributing to cell death, fibrosis, and decreased cardiac performance. This narrative review aims to investigate the intricate relationship between mitochondrial dysfunction and CMDs. Full article

Background/Objectives: A 43-year-old male presented with neurological symptoms and asymptomatic cardiac dysfunction, left ventricular hypertrophy, and impaired global longitudinal strain with apical sparing, associated with elevated NT-proBNP. Methods: Multimodality imaging (bone scintigraphy and cardiac magnetic resonance) revealed cardiac amyloid deposition. Genetic testing confirmed variant transthyretin amyloidosis (ATTR) with mixed phenotype. Results: Treatment with tafamidis 20 mg for stage I polyneuropathy, available at that moment, was initiated with good neurological outcome. Three years later, cardiac function deteriorated, following a moderate COVID-19 infection, with heart failure symptoms and reduced ventricular and atrial functions. For progressive ATTR cardiomyopathy, we intensified therapy to tafamidis free acid 61 mg, associated with SGLT2 inhibitor, spironolactone, and furosemide with subsequent improvements of symptoms and stabilization of imaging findings. Conclusions: This case emphasizes the importance of multimodal imaging in early detection, monitoring, and guiding individualized management in ATTR cardiomyopathy. Full article

Background and Objectives: Nonischemic cardiomyopathies comprise a wide spectrum of heart muscle disorders characterized by different morphological, functional, and tissue abnormalities. Cardiovascular magnetic resonance (CMR) represents the gold standard imaging modality for assessing cardiac morphology, systolic function, and tissue characterization, thereby aiding in early diagnosis, precise phenotyping, and tailored treatment. The aim of this review is to provide an up-to-date overview of CMR techniques for studying myocardial perfusion and their applications to nonischemic cardiomyopathy, not only to rule out an underlying ischemic aetiology but also to investigate the pathophysiological characteristics of microcirculatory dysfunction in these patients. Materials and Methods: We performed a structured review of the literature focusing on first-pass gadolinium perfusion sequences, stress protocols, and emerging pixel-wise perfusion mapping approaches. Studies were selected to illustrate the methods for image acquisition, post-processing, and quantification of myocardial blood flow (MBF) and myocardial perfusion reserve (MPR), as well as to highlight associations with clinical endpoints. Results: First-pass CMR perfusion imaging reliably detects diffuse and regional microvascular dysfunction across cardiomyopathies. Semi-quantitative parameters (e.g., upslope, MPRI) and quantitative MBF mapping (mL/g/min) have demonstrated that impaired perfusion correlates with disease severity, extent of fibrosis, and adverse outcomes, including heart failure hospitalization, arrhythmias, and mortality. Novel automated pixel-wise mapping enhances reproducibility and diagnostic accuracy, distinguishing coronary microvascular dysfunction from balanced three-vessel disease. Microvascular dysfunction—present in approximately 50–60% of dilated cardiomyopathy (DCM), 40–80% of hypertrophic cardiomyopathy (HCM), and >95% of cardiac amyloidosis (CA) patients—has emerged as a key driver of adverse outcomes. Perfusion defects appear early, often preceding overt hypertrophy or fibrosis, and provide incremental prognostic value beyond conventional CMR metrics. Conclusions: CMR represents a powerful tool for detecting myocardial perfusion abnormalities in nonischemic cardiomyopathies, improving phenotyping, risk stratification, and personalized management. Further standardization of quantitative perfusion techniques will facilitate broader clinical adoption. Full article

Type 2 diabetes is a significant risk factor for cardiovascular disease, particularly coronary heart disease, heart failure, and diabetic cardiomyopathy. Diabetic cardiomyopathy, characterized by heart dysfunction in the absence of coronary artery disease or hypertension, is triggered by various mechanisms, including hyperinsulinemia, insulin resistance, and inflammation. At the cellular level, increased insulin resistance leads to an imbalance in lipid and glucose metabolism, causing oxidative stress, mitochondrial dysfunction, and excess production of reactive oxygen species (ROS). This disrupts normal heart function, leading to fibrosis, hypertrophy, and cardiac remodeling. In diabetic patients, the excessive accumulation of fatty acids, advanced glycation end products (AGEs), and other metabolic disturbances further contribute to endothelial dysfunction and inflammatory responses. This inflammatory environment promotes structural damage, apoptosis, and calcium-handling abnormalities, resulting in heart failure. Additionally, diabetes increases the risk of arrhythmias, such as atrial fibrillation, which worsens cardiac outcomes. New insights into these molecular mechanisms have led to improvements in diabetes management, focusing on mitigating complications and understanding the cellular processes involved. Recent therapeutic advances, such as SGLT-2 inhibitors, have shown promise in addressing the energy imbalance and cardiac dysfunction seen in diabetic cardiomyopathy, offering new hope for better cardiovascular outcomes. Full article

Excessive activity of the hormone angiotensin II (AngII) is known to contribute to the pathogenesis of multiple cardiovascular diseases, including atherosclerosis, vascular remodeling, and hypertension, primarily through inducing gene expression changes. In this study, we identified LMCD1 (LIM and cysteine-rich domains 1, also known as Dyxin), primarily recognized as a transcription co-factor involved in various oncogenic processes, cardiac hypertrophy, and vascular remodeling, as a potential key factor in AngII-mediated effects in vascular smooth muscle cells (VSMCs). We demonstrated that AngII upregulates LMCD1 expression in primary rat VSMCs through type 1 angiotensin receptor (AT1-R) activation, leading to calcium signaling and p38 MAPK pathway activation. Additionally, we also demonstrated in A7r5 vascular smooth muscle cells that LMCD1 protein overexpression results in enhanced cell proliferation and cell migration. Our findings provide insights into the mechanisms by which AngII mediates changes in LMCD1 expression. The elevated expression of LMCD1 enhanced the cell proliferation and migration in VSMCs in vitro experiments, suggesting that LMCD1 may be an important factor in vascular remodeling and the pathogenesis of severe cardiovascular diseases. These results raise the possibility that LMCD1 could be a promising pharmacological target in the cardiovascular dysfunctions associated with AT1-R overactivation. Full article

Hypertension-induced cardiac remodeling is a complex process driven by interconnected molecular and cellular mechanisms that culminate in hypertensive myocardium, characterized by ventricular hypertrophy, fibrosis, impaired angiogenesis, and myocardial dysfunction. This review discusses the histomorphometric changes in capillary density, fibrosis, and mast cells in the hypertensive myocardium and delves into the roles of key regulatory systems, including the apelinergic system, vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathways, and nitric oxide (NO)/nitric oxide synthase (NOS) signaling in the pathogenesis of hypertensive heart disease (HHD). Capillary rarefaction, a hallmark of HHD, contributes to myocardial ischemia and fibrosis, underscoring the importance of maintaining vascular integrity. Targeting capillary density (CD) through antihypertensive therapy or angiogenic interventions could significantly improve cardiac outcomes. Myocardial fibrosis, mediated by excessive collagen deposition and influenced by fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta (TGF-β), plays a pivotal role in the structural remodeling of hypertensive myocardium. While renin–angiotensin–aldosterone system (RAAS) inhibitors show anti-fibrotic effects, more targeted therapies are needed to address fibrosis directly. Mast cells, though less studied in humans, emerge as critical regulators of cardiac remodeling through their release of pro-fibrotic mediators such as histamine, tryptase, and FGF-2. The apelinergic system emerges as a promising therapeutic target due to its vasodilatory, anti-fibrotic, and cardioprotective properties. The system counteracts the deleterious effects of the RAAS and has demonstrated efficacy in preclinical models of hypertension-induced cardiac damage. Despite its potential, human studies on apelin analogs remain limited, warranting further exploration to evaluate their clinical utility. VEGF signaling plays a dual role, facilitating angiogenesis and compensatory remodeling during the early stages of arterial hypertension (AH) but contributing to maladaptive changes when dysregulated. Modulating VEGF signaling through exercise or pharmacological interventions has shown promise in improving CD and mitigating hypertensive cardiac damage. However, VEGF inhibitors, commonly used in oncology, can exacerbate AH and endothelial dysfunction, highlighting the need for therapeutic caution. The NO/NOS pathway is essential for vascular homeostasis and the prevention of oxidative stress. Dysregulation of this pathway, particularly endothelial NOS (eNOS) uncoupling and inducible NOS (iNOS) overexpression, leads to endothelial dysfunction and nitrosative stress in hypertensive myocardium. Strategies to restore NO bioavailability, such as tetrahydrobiopterin (BH₄) supplementation and antioxidants, hold potential for therapeutic application but require further validation. Future studies should adopt a multidisciplinary approach to integrate molecular insights with clinical applications, paving the way for more personalized and effective treatments for HHD. Addressing these challenges will not only enhance the understanding of hypertensive myocardium but also improve patient outcomes and quality of life. Full article

Diabetic cardiomyopathy (DCM) begins with a subclinical stage featuring cardiac hypertrophy, fibrosis, and disrupted signaling. These changes, especially fibrosis and stiffness, often lead to clinical heart failure. The mechanism involves metabolic dysregulation, oxidative stress, and inflammation, leading to cardiac damage and dysfunction. During the progression of the disease, the myocardium senses surrounding mechanical cues, including extracellular matrix properties, tensile tension, shear stress, and pressure load, which significantly influence the pathological remodeling of the heart through mechanotransduction. At the molecular level, the mechanisms by which mechanical cues are sensed and transduced to mediate myocardial mechanical remodeling in DCM remain unclear. The mechanosensitive transcription factors YAP and TAZ fill this gap. This article reviews the latest findings of how YAP and TAZ perceive a wide range of mechanical cues, from shear stress to extracellular matrix stiffness. We focus on how these cues are relayed through the cytoskeleton to the nucleus, where they trigger downstream gene expression. Here, we review recent progress on the crucial role of YAP and TAZ mechanotransduction in the pathological changes observed in DCM, including myocardial fibrosis, hypertrophy, inflammation, mitochondrial dysfunction, and cell death. Full article

Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiovascular disease. In general, obstructive hypertrophic cardiomyopathy (HOCM) is more closely related to severe clinical symptoms and adverse clinical outcomes. Therefore, it is necessary to explore the possible causes of HOCM, which may help physicians better understand the disease and effectively control and manage the progression of the disease. In recent years, the discovery of lactylation has provided scholars with a new direction to explore the occurrence of diseases. In cardiovascular diseases, this post-translational modification can exacerbate cardiac dysfunction, and it can also promote the cardiac repair process after myocardial infarction. In this study, we used the myocardial tissue of mice carrying the Myh7 V878A gene mutation site for protein lactylation detection. Through a further analysis of the enriched pathways using KEGG enrichment, GO enrichment, and Wiki Pathways enrichment, we found that the enriched pathways with lactylation modifications in the HOCM mice mainly included the fatty acid oxidation pathway, the tricarboxylic acid cycle pathway, the adrenergic signaling pathway in cardiomyocytes, and the cardiomyocyte hypertrophy pathway. Among the above pathways, significant changes in lactylation occurred in proteins including Acads, Acaa2, Mdh2, Myl2, and Myl3. We used the COIP experiment to verify the omics results and the ELISA assay to verify the function of the enzymes. We found that a decrease in lactylation modifications also led to a decrease in enzyme function. The abnormalities of these proteins not only lead to abnormalities in energy metabolism in the myocardial tissue of HOCM but also may affect myocardial contractility, resulting in the impaired contractile function of HOCM. The results of this study lay a preliminary theoretical foundation for further exploring the pathogenesis of HOCM. Full article