Search Results (159)

Background and Objectives: Cardiac transplantation is currently the elective treatment choice in end-stage heart failure, and cellular rejection is a predictive factor for morbidity and mortality after surgery. We proposed an evaluation of the clinicopathologic factors involved in the mechanism of rejection. Materials and Methods: This study included 146 patients who underwent transplantation at the Institute of Cardiovascular Diseases and Transplantation in Targu Mures between 2010 and 2023, and we evaluated the function and structure of the myocardium after surgery by using endomyocardial biopsy. Results: Overall, 120 men and 26 women underwent transplantation, with an approximately equal proportion under and over 40 years old (48.6% and 51.4%). Evaluating the degree of acute cellular rejection according to the International Society for Heart and Lung Transplantation classification showed that most of the patients presented with acute cellular rejection (ACR) and antibody-mediated rejection (AMR) grade 0, and most cases of ACR and AMR were reported with mild changes (13% or 10.3% patients). Therefore, the most frequent histopathologic diagnoses were similar to lesions unrelated to rejection (45.2% of patients) and ischemia–reperfusion lesions (25.3% patients), respectively. Conclusions: Although 82.2% of the transplanted cases showed no rejection (ISHLT score 0), non-rejection-related lesion-like changes were present in 45.2% of cases, and because more of the non-rejection-related criteria could be detected, it may be necessary to adjust the grading of the rejection criteria. The histopathologic changes that characterize rejection are primarily represented by the mononuclear inflammatory infiltrate; in our study, inflammatory changes were mostly mild (71.9%), with myocyte involvement in all cases. These changes are associated with and contribute to the maintenance of the rejection phenomenon. Full article

Chronic total occlusions (CTOs), defined as complete coronary artery blockages persisting for over three months, are frequently encountered in up to 25% of coronary angiograms. Although percutaneous coronary intervention (PCI) for CTO remains technically challenging, advancements in guidewires, microcatheters, re-entry devices, and intravascular imaging, along with the expertise of specialized operators, have significantly improved procedural success rates, now exceeding 90% in expert centers. While recent evidence, such as the SYNTAX II study, emphasizes the importance of complete revascularization, over half of CTO cases continue to be managed conservatively with optimal medical therapy (OMT), partly due to the limited high-quality randomized evidence supporting revascularization. Observational studies have demonstrated that successful CTO-PCI is associated with improved angina relief, quality of life, left ventricular function, and possibly long-term survival. Extended observational follow-up, such as the Korean and Canadian registries, suggests long-term reductions in cardiac and all-cause mortality with CTO revascularization. However, randomized controlled trials (RCTs) have primarily shown symptomatic benefit, with no consistent reduction in major adverse cardiac events (MACE) or mortality, likely due to limited sample sizes, short follow-up, and treatment crossovers. Various strategies, including the hybrid algorithm, guide CTO interventions by balancing antegrade and retrograde techniques based on lesion complexity. Imaging modalities such as coronary CT angiography and intravascular ultrasound play a pivotal role in planning and optimizing these procedures. Future innovations, such as real-time fusion imaging of CCTA with coronary angiography, may enhance lesion visualization and guidewire navigation. While current guidelines recommend CTO-PCI in selected symptomatic patients with demonstrable ischemia or viable myocardium, the decision should be individualized, incorporating anatomical feasibility, comorbidities, patient preferences, and input from a multidisciplinary Heart Team. Looking ahead, adequately powered RCTs with extended follow-up are essential to determine the long-term clinical impact of CTO-PCI on hard outcomes such as mortality and myocardial infarction. Full article

Surgical myocardial revascularization, regardless of the technique used, causes ischemia–reperfusion injury (IRI) in the myocardium mediated by inflammation and degradation of the endothelial glycocalyx (EG). We investigated the difference between on-pump and off-pump techniques in terms of the concentration of proinflammatory interleukin (IL)-18 and the EG degradation products syndecan-1 and hyaluronic acid measured by ELISA in the peripheral and cardiac circulation during open heart surgery and in the early postoperative period. The concentration of IL-18, C-reactive protein (CRP), and cardiac troponin T (cTnT) and the leukocyte count increased statistically significantly in revascularized patients at 24 and 72 h after revascularization compared to the beginning of the procedure and was always statistically significantly higher in on-pump patients. Syndecan-1 and hyaluronic acid only increased in on-pump patients 24 and 72 h after revascularization. IL-18 correlated positively with syndecan-1 and CRP only in the pump setting and with the number of leukocytes in both revascularization regimens 24 and 72 h after the surgery. cTnT and hyaluronic acid did not correlate with IL-18. Our results suggest that IL-18 plays an important role in the early inflammatory response in patients during open heart surgery and in the early postoperative period, leading to additional damage to the EG, while it is probably not responsible for myocardial necrosis. It could serve as a biomarker to identify high-risk patients and as a therapeutic target to reduce inflammation and EG degradation. In addition, measurement of IL-18 could help improve the treatment, recovery, and outcomes of patients after heart surgery. Full article

Background/Objectives: The complement system (particularly C5b-9) is an instrumental part of the induction and progression of atherosclerosis. The fluid phase C5b-9, also known as soluble C5b-9 (sC5b-9), is a reliable indicator of terminal complement pathway activation. Response Gene to Complement (RGC)-32 is a C5b-9 effector involved in cell cycle regulation and differentiation, immunity, tumorigenesis, obesity, and vascular lesion formation. RGC-32 regulates the expression of Sirtuin1 (SIRT1), known to delay vascular aging. The aim of this study was to assess the levels of sC5b-9, RGC-32, and SIRT1 in patients with atherosclerotic chronic and acute ischemic coronary syndromes. Methods: We determined the levels of sC5b-9, serum RGC-32, and SIRT1 by enzyme-linked immunosorbent assays (ELISAs) in 41 patients with chronic atherosclerotic coronary syndromes, 36 patients with acute ischemic coronary syndromes, and 21 asymptomatic controls with no history of ischemic heart disease. Results: sC5b-9 was significantly higher in patients with acute coronary syndrome as compared to the control group (p = 0.020, AUC = 0.702). In chronic coronary ischemia patients, serum RGC-32 was correlated with the extension of coronagraphically visualized atherosclerotic lesions (r = 0.352, p = 0.035) as well as with sC5b-9 levels (r = 0.350, p = 0.025). RGC-32 concentration was significantly lower in patients with acute coronary syndrome than in the control group (p = 0.020). We also observed significantly lower serum SIRT1 concentrations in patients with chronic ischemic heart disease than in the control group (p = 0.025). Conclusions: sC5b-9 may function as a possible biomarker for myocardial tissue damage in acute coronary syndrome. In acute coronary syndrome settings, low levels of RGC-32 may indicate a protective, antifibrotic function of RGC-32 in the ischemia-damaged myocardium; however, in stable chronic disease, RGC-32 serum values appear to correlate with the extent of atherosclerotic lesions, suggesting a pro-atherogenic role for RGC-32. Chronic myocardial ischemia decreases SIRT1 protein levels in serum, which underscores the use of SIRT1-modulating drugs in these patients. 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

Mitochondrial ATP-sensitive K+ channels are closely linked to cardioprotection and are potential therapeutic targets during ischemia reperfusion (IR) injury. The renal outer medullary K+ channel isoform 2 (ROMK2) is an ATP-sensitive K+ channel found in the mitochondria of cardiomyocytes. While the germline knockout of ROMK does not mediate myocardial IR injury, the effect of ROMK loss of function on IR injury in the adult myocardium is unknown. By using a selective small molecule inhibitor of ROMK, we paradoxically found that mouse hearts were protected from IR injury after ROMK inhibition compared to vehicle-treated animals. In addition, we found that ROMK inhibition leads to exaggerated mitochondrial uncoupling and increased ROS production. Phosphatidylinositol 4,5-bisphosphate (PIP₂), an activator of ROMK, increased the effect of ATP to hyperpolarize cardiac mitochondrial membrane potential. ROMK inhibition also increased mitochondrial swelling in the absence of ATP. In conclusion, pharmacologic ROMK inhibition protects the murine heart from IR injury and may promote a phenotype of enhanced mitochondrial matrix K+. ROMK may be more important during conditions that promote mitochondrial matrix K+ efflux than influx. Further research to understand its role in mitochondrial K+ handling and as a therapeutic target in IR injury is needed. Full article

EFNA1 (ephrinA1), a highly expressed tyrosine kinase receptor-ligand in healthy cardiomyocytes, is reduced following myocardial infarction (MI). A single intramyocardial injection of chimeric EFNA1-Fc at the time of ischemia mitigates the injury in both reperfused and non-reperfused mouse myocardium by reducing apoptosis, necrosis, and inflammation. Recently, we have successfully imaged and qualitatively identified endogenous EFNA1 pre- and post-MI using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) coupled with a time-of-flight mass spectrometer (MALDI/TOF MS). Building on our previous work, we are currently focused on understanding and characterizing EFNA1’s role in cardiac tissue by developing an integrated quantitative method to determine endogenous levels of EFNA1 using MALDI-MSI technologies. Herein, we have optimized a method for the relative quantitation of endogenous tryptic EFNA1 peptides detected in the murine heart as compared with routine western blotting. In healthy myocardium, there was approximately 50 ng of endogenous EFNA1 per section of 9.43 mm³ tissue, or roughly 12 pg/µg of homogenized tissue. MALDI-MSI thus provides a tool for determining the anatomical distribution and relative quantitation of endogenous EFNA1 in cardiac tissue. Future applications of these tools will allow us to investigate the dynamic changes in EFNA1 expression profile that occur in pathological states such as myocardial infarction and upon therapeutic treatments. Full article

Myocardial bridging (MB), a congenital variant where a coronary artery segment is tunneled within the myocardium, is increasingly recognized as a contributor to coronary endothelial and vasomotor dysfunction. Beyond the hallmark systolic compression observed on angiography, MB disrupts endothelial integrity, impairs the release of vasoactive substances, and induces vasomotor abnormalities. These effects exacerbate ischemic symptoms and predispose to atherosclerosis in the proximal segment, particularly in conditions such as ischemia/myocardial infarction with nonobstructive coronary arteries. Recent studies underscore MB’s association with coronary vasospasm, microvascular endothelial dysfunction, and adverse cardiovascular outcomes, including sudden cardiac death. These findings highlight the interplay between MB’s structural anomalies and functional impairments, with factors such as the bridge’s length, depth, and orientation influencing its hemodynamic significance. Advances in imaging and coronary physiology assessment, including acetylcholine testing and stress diastolic fractional flow reserve/iFR/RFR, have enhanced diagnostic precision. This review explores the multifaceted impact of MB on coronary physiology, emphasizing its role in endothelial dysfunction and vasomotor regulation. Recognizing MB’s contribution to cardiovascular disease is essential for accurate diagnosis and tailored management strategies aimed at mitigating ischemic risk and improving patient outcomes. Full article

Currently, there are no therapies that prevent the negative myocardial remodeling process that occurs after a heart attack. Injectable hydrogels are a treatment option because they may replace the damaged extracellular matrix and, in addition, can be administered minimally invasively. Reactive oxygen species generated by ischemia-reperfusion damage can limit the therapeutic efficacy of injectable hydrogels. In order to overcome this limitation, grape seed proanthocyanidins were incorporated as antioxidant compounds into a thermosensitive myocardial extracellular matrix hydrogel in this study. For the fabrication of the hydrogel, the extracellular matrix obtained by decellularization of porcine myocardium was solubilized through enzymatic digestion, and the proanthocyanidins were incorporated. After exposing this extracellular matrix solution to 37 °C, it self-assembled into a hydrogel with a porous structure. According to the physicochemical and biological evaluation, the coupling of proanthocyanidins in the hydrogel has a positive effect on the antioxidant capacity, gelation kinetics, in vitro degradation, and cardiomyocyte viability, indicating that the hydrogel coupled with this type of antioxidants represents a promising alternative for potential application in post-infarction myocardial regeneration. Furthermore, this study proposes the best concentrations of proanthocyanidins that resulted in the hydrogels for future studies in cardiac tissue engineering. Full article

Hypertrophic cardiomyopathy (HCM) is a heterogeneous cardiac disease and one of its major challenges is the limited accuracy in stratifying the risk of sudden cardiac death (SCD). Positron emission tomography (PET), through the evaluation of myocardial blood flow (MBF) and metabolism using fluorodeoxyglucose (FDG) uptake, can reveal microvascular dysfunction, ischemia, and increased metabolic demands in the hypertrophied myocardium. These abnormalities are linked to several factors influencing disease progression, including arrhythmia development, ventricular dilation, and myocardial fibrosis. Fibroblast activation can also be evaluated using PET imaging, providing further insights into early-stage myocardial fibrosis. Conflicting findings underscore the need for further research into PET’s role in risk stratification for HCM. If PET can establish a connection between parameters such as abnormal MBF or increased FDG uptake and SCD risk, it could enhance predictive accuracy. Additionally, PET holds significant potential for monitoring therapeutic outcomes. The aim of this review is to provide a comprehensive overview of the most significant data on disease progression, risk stratification, and prognosis in patients with HCM using cardiac PET-CT imaging. Full article

Cardiac ischemia–reperfusion injury (IRI) occurs when blood flow is restored to the myocardium after a period of ischemia, leading to oxidative stress and subsequent myocardial cell damage, primarily due to the accumulation of reactive oxygen species (ROS). In our previous research, we identified that miR-25 is significantly overexpressed in pressure overload-induced heart failure, and its inhibition improves cardiac function by restoring the expression of SERCA2a, a key protein involved in calcium regulation. In this study, we aimed to investigate the role of miR-25 in the context of ischemia–reperfusion injury. We found that miR-25 was markedly upregulated under hypoxic conditions in both in vitro and in vivo models. Through in silico analysis, we identified Sestrin3 (SESN3), an antioxidant protein known for its protective effects against oxidative stress, as a novel target of miR-25. Based on these findings, we hypothesized that inhibiting miR-25 would restore Sestrin3 expression, thereby reducing ROS-induced myocardial cell damage and improving cardiac function. To test this hypothesis, we employed two model systems: a hypoxia/reoxygenation (H/R) stress model using H9c2 myoblasts and a surgically induced ischemia–reperfusion injury mouse model. Our results demonstrated that the use of miR-25 inhibitors significantly improved cardiac function and reduced myocardial damage in both models through the restoration of SESN3 expression. In conclusion, our findings suggest that targeting miR-25 may serve as a novel therapeutic modality to alleviate oxidative damage in the heart. Full article

Epicardial adipose tissue is a unique visceral adipose tissue depot that plays a crucial role in myocardial metabolism. Epicardial adipose tissue is a major source of energy and free fatty acids for the adjacent myocardium. However, under pathological conditions, epicardial fat can affect the heart through the excessive and abnormal influx of lipids. The cardio-lipotoxicity of the epicardial adipose tissue is complex and involves different pathways, such as increased inflammation, the infiltration of lipid intermediates such as diacylglycerol and ceramides, mitochondrial dysfunction, and oxidative stress, ultimately leading to cardiomyocyte dysfunction and coronary artery ischemia. These changes can contribute to the pathogenesis of various cardio-metabolic diseases including atrial fibrillation, coronary artery disease, heart failure, and obstructive sleep apnea. Hence, the role of the cardio-lipotoxicity of epicardial fat and its clinical implications are discussed in this review. Full article

Background and Objectives: The majority of cardiac surgical procedures are performed using cardiopulmonary bypass and cardioplegia-induced cardiac arrest. Cardiac arrest and reperfusion may lead to ischemia-reperfusion injury of the myocardium. The aim of this study was to investigate whether gradual reperfusion with a slow increase in oxygen partial pressure leads to a reduction in reperfusion injury. Materials and Methods: Fifty patients undergoing elective cardiac surgery were included in this prospective randomized study. Patients in the hyperoxemic (control) group received conventional reoxygenation (paO₂ 250–300 mmHg). Patients in the normoxemic (study) group received gradual reoxygenation (1st-minute venous blood with paO₂ 30–40 mmHg, 2nd-minute arterial blood with paO₂ 100–150 mmHg). Periprocedural blood samples were taken serially, and markers of myocardial injury were analyzed. In addition, the influence of gradual reoxygenation on hemodynamics, inflammation, and the overall perioperative course was evaluated. Results: There was a trend toward higher CK levels in the hyperoxemia group without statistical significance; however, CK-MB and troponin T levels did not show any statistical difference between the two groups. Potassium concentrations in the coronary sinus were significantly higher in the hyperoxemia group at 3 and 8 min after opening of the aortic cross-clamp (6.88 ± 0.87 mmol/L vs. 6.30 ± 0.91 mmol/L and 5.87 ± 0.73 mmol/L vs. 5.43 ± 0.42 mmol/L, respectively; p = 0.03 and p = 0.02). All other measurements did not show a statistical difference between the two groups. Conclusions: The use of gradual reperfusion in cardiac surgery with cardiopulmonary bypass and cardiac arrest is safe. However, it does not reduce ischemia-reperfusion injury compared to standard hyperoxemic reperfusion. Full article

This article aims to analyze the relationship between non-obstructive coronary artery disease (NOCAD) and atrial fibrillation (AF), exploring the underlying pathophysiological mechanisms and implications for clinical management. NOCAD and AF are prevalent cardiovascular conditions that often coexist, yet their interrelation is not well understood. NOCAD can lead to ischemic necrosis of cardiomyocytes and their replacement with fibrous tissue, sustaining focal ectopic activity in atrial myocardium. Atrial fibrillation, on the other hand, the most common sustained cardiac arrhythmia, is able to accelerate atherosclerosis and increase oxygen consumption in the myocardium, creating a mismatch between supply and demand, and thus promoting the development or worsening of coronary ischemia. Therefore, NOCAD and AF seem to be a complex interplay with one begets another. Full article

Sensory neurons densely innervate the myocardium. The role of their sensing and response to acute and prolonged ischemia is largely unclear. In a cellular model of ischemia-reperfusion injury, the presence of sensory neurons increases cardiomyocyte survival. Here, after the exclusion of classical neurotransmitter release, and measurement of cytokine release, we modified the experiment from a direct co-culture of primary murine cardiomyocytes and sensory neurons to a transfer of the supernatant. Sensory neurons were exposed to ischemia and the resulting conditioned supernatant was transferred onto cardiomyocytes. This approach largely increased the tolerance of cardiomyocytes to ischemia and reperfusion. Towards the identification of the mechanism, it was demonstrated that after ten-fold dilution, the conditioned solution lost its protective effect. The effect remained after removal of extracellular vesicles by ultracentrifugation, and was not affected by exposure to protease activity, and fractionation pointed towards a hydrophilic agent. Solutions conditioned by HEK293t cells or 3T3 fibroblasts also increase cardiomyocyte survival, but to a lower degree. A metabolomic search identified 64 at least two-fold changed metabolites and lipids. Many of these could be identified and are involved in essential cellular functions. In the presented model for ischemia-reperfusion, sensory neurons secrete one or more cardioprotective substances that can improve cardiomyocyte survival. Full article