Search Results (33)

Coronary microvascular obstruction and dysfunction (CMVO) frequently arise following primary percutaneous coronary intervention (PCI), particularly in individuals with myocardial infarction. Despite the restoration of epicardial blood flow, microvascular perfusion might still be compromised, resulting in negative clinical outcomes. CMVO is a complex condition resulting from a combination of ischemia, distal thrombotic embolization, reperfusion injury, and individual susceptibilities such as inflammation and endothelial dysfunction. The pathophysiological features of this condition include microvascular spasm, endothelial swelling, capillary plugging by leukocytes and platelets, and oxidative stress. Traditional angiographic assessments, such as Thrombolysis in Myocardial Infarction (TIMI) flow grade and myocardial blush grade, have limited sensitivity. Cardiac magnetic resonance imaging (CMR) stands as the gold standard for identifying CMVO, while the index of microvascular resistance (IMR) is a promising invasive option. Treatment approaches involve powerful antiplatelet drugs, anticoagulants, and supersaturated oxygen, yet no treatment has been definitively shown to reverse established CMVO. CMVO remains a significant therapeutic challenge in coronary artery disease management. Enhancing the comprehension of its core mechanisms is vital for the development of more effective and personalized treatment strategies. Full article

Secondary dilated cardiomyopathy (DCM) refers to left ventricular dilation and impaired systolic function arising from identifiable extrinsic causes, such as ischemia, hypertension, toxins, infections, systemic diseases, or metabolic disorders. Unlike primary DCM, which is predominantly genetic, secondary DCM represents a diverse spectrum of pathophysiological mechanisms linked to external insults on myocardial structure and function. The increasing prevalence of conditions such as alcohol use disorder, chemotherapy-induced cardiotoxicity, and viral myocarditis underscores the need for heightened awareness and early recognition of secondary DCM. A comprehensive analysis of clinical trial data and observational studies involving secondary dilative cardiomyopathy was conducted, with a focus on mortality, symptom relief, and major adverse events. A systematic literature review was performed using databases, including PubMed, Embase, and ClinicalTrials.gov, following PRISMA guidelines for study selection. Data were extracted on patient demographics, etiology of dilation, trial design, outcomes, and follow-up duration. Advances in diagnostic modalities have refined the ability to identify underlying causes of secondary DCM. For example, high-sensitivity troponin and cardiac magnetic resonance imaging are pivotal in diagnosing myocarditis and differentiating it from ischemic cardiomyopathy. Novel insights into toxin-induced cardiomyopathies, such as those related to anthracyclines and immune checkpoint inhibitors, have highlighted pathways of mitochondrial dysfunction and oxidative stress. Treatment strategies emphasize the management of the causing condition alongside standard heart failure therapies, including RAAS inhibitors and beta-blockers. Emerging therapies, such as myocardial recovery protocols in peripartum cardiomyopathy and immune-modulating treatments in myocarditis, are promising in reversing myocardial dysfunction. Secondary DCM encompasses a heterogeneous group of disorders that require a precise etiological diagnosis for effective management. Timely identification and treatment of the underlying cause, combined with optimized heart failure therapies, can significantly improve outcomes. Future research focuses on developing targeted therapies and exploring the role of biomarkers and precision medicine in tailoring treatment strategies for secondary DCM. Full article

Myocardial oxidative stress increases under conditions of hyperglycemia and ischemia/reperfusion (I/R) injury, leading to cellular damage. Inhibition of oxidative stress is involved in the cardioprotective effects of hydrogen sulfide (H₂S) during I/R and diabetes, and H₂S has the potential to protect the heart. However, the mechanism by which H₂S regulates the level of cardiac reactive oxygen species (ROS) during I/R and hyperglycemic conditions remains unclear. Therefore, the objective of this study was to evaluate the cytoprotective effect of H₂S in primary cardiomyocyte cultures subjected to hyperglycemia, hypoxia–reoxygenation (HR), or both conditions, by assessing the PPAR-α/Keap1/Nrf2/p47phox/NOX4/p-eNOS/CAT/SOD and the PPAR-γ/PGC-1α/AMPK/GLUT4 signaling pathways. Treatment with NaHS (100 μM) as an H₂S donor in cardiomyocytes subjected to hyperglycemia, HR, or a combination of both increased cell viability, total antioxidant capacity, and tetrahydrobiopterin (BH₄) concentrations, while reducing ROS production, malondialdehyde concentrations, 8-hydroxy-2′-deoxyguanosine, and dihydrobiopterin (BH₂) concentrations. Additionally, the H₂S donor treatment increased the expression and activity of PPAR-α, reversed the reduction in the expression of PPAR-γ, PGC-1α, AMPK, GLUT4, Nrf2, p-eNOS, SOD, and CAT, and decreased the expression of Keap1, p47phox and NOX4. Therefore, the treatment with the H₂S donor protects cardiomyocytes from damage caused by hyperglycemia, HR, or both conditions by reducing oxidative stress markers and improving antioxidant mechanisms, thereby increasing cell viability and “cardiomyocyte ultrastructure”. Full article

Coronary artery spasm (CAS) is a reversible vasoconstriction of normal or atherosclerotic epicardial coronary arteries with a subsequent reduction in myocardial blood flow, leading to myocardial ischemia, myocardial infarction, severe arrhythmias, or even sudden death. It is an entity that should be recognized based on a particular clinical presentation. Numerous differences exist between CAS and obstructive coronary disease in terms of mechanisms, risk factors, and therapeutic solutions. The gold standard for CAS diagnosis is represented by transitory and reversible occlusion of the coronary arteries at spasm provocation test, which consists of an intracoronary administration of Ach, ergonovine, or methylergonovine during angiography. The pathophysiology of CAS is not fully understood. However, the core of CAS is represented by vascular smooth muscle cell contraction, with a circadian pattern. The initiating event of this contraction may be represented by endothelial dysfunction, inflammation, or autonomic nervous system unbalance. Our study explores the intricate balance of these factors and their clinical relevance in the management of CAS. Full article

N6-methyladenosine (m6A) is the most prevalent internal chemical modification in eukaryotic messenger RNA (mRNA), significantly impacting its lifecycle through dynamic and reversible processes involving methyltransferase, demethylase, and binding proteins. These processes regulate mRNA stability, splicing, nuclear export, translation, and degradation. Programmed cell death (PCD), a tightly controlled process encompassing apoptosis, pyroptosis, ferroptosis, autophagy, and necroptosis, plays a crucial role in maintaining cellular homeostasis, tissue development, and function. Recently, m6A modification has emerged as a significant research area due to its role in regulating PCD and its implications in cardiovascular diseases (CVDs). In this review, we delve into the intricate relationship between various PCD types and m6A modification, emphasizing their pivotal roles in the initiation and progression of CVDs such as myocardial ischemia-reperfusion (I/R), atherosclerosis (AS), pulmonary hypertension (PH), cardiomyopathy, doxorubicin (Dox)-induced cardiotoxicity (DIC), heart failure (HF), and myocardial infarction (MI). Our findings underscore the potential of elucidating the roles of m6A and PCD in CVD to pave new pathways for prevention and treatment strategies. Full article

Acute and chronic coronary artery disease (CAD) are interconnected, representing two facets of the same condition. Chronic CAD exhibits a dynamic nature, manifesting as stable or acute ischemia, or both. Myocardial ischemia can be transient and reversible. The genesis of CAD involves diverse anatomical and functional mechanisms, including endothelial dysfunction, arteriolar remodeling, capillary rarefaction, and perivascular fibrosis, though no single factor explains its heterogeneity. Chronic CAD is often stable but may present as symptomatic or asymptomatic (e.g., in diabetes) and affect various coronary compartments (epicardial or microcirculation). This complexity necessitates a reappraisal of our approach, as pathophysiological mechanisms vary and often overlap. A comprehensive exploration of these mechanisms using advanced diagnostic techniques can aid in identifying the dynamic processes underlying CAD. The disease may present as obstructive or non-obstructive, stable or unstable, underscoring its diversity. The primary source of CAD lies in the arterial wall, emphasizing the need for research on its components, such as the endothelium and vascular smooth muscle cells, and factors disrupting arterial homeostasis. Shifting focus from arterial luminal status to the arterial wall can provide insights into the genesis of atheromatous plaques, enabling earlier interventions to prevent their development and progression. Full article

Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and H9c2 cell lines, we established a chemical hypoxia model by treating cells with cobalt chloride (CoCl₂) to simulate low-oxygen conditions. We found that CoCl₂ treatment significantly upregulated the expression of hypoxia-inducible factor 1 alpha (HIF-1α) in cardiomyocytes, indicating the successful induction of hypoxia. Subsequent morphological and biochemical analyses revealed that hypoxia altered cardiomyocyte morphology disrupted the cytoskeleton, and caused cellular damage, accompanied by increased lactate dehydrogenase (LDH) release and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity, indicative of oxidative stress. Lentivirus-mediated TPM3 overexpression attenuated hypoxia-induced morphological changes, cellular damage, and oxidative stress imbalance, while TPM3 knockdown exacerbated these effects. Furthermore, treatment with the HDAC1 inhibitor MGCD0103 partially reversed the exacerbation of hypoxia-induced injury caused by TPM3 knockdown. Protein–protein interaction (PPI) network and functional enrichment analysis suggested that TPM3 may modulate cardiac muscle development, contraction, and adrenergic signaling pathways. In conclusion, our findings highlight the therapeutic potential of TPM3 modulation in mitigating hypoxia-associated cardiac injury, suggesting a promising avenue for the treatment of ischemic heart disease and other hypoxia-related cardiac pathologies. Full article

Introduction: Ischemic conditionings (ICon) were intensively investigated and several protective signaling pathways were identified. Previously, we have shown the role of matrix metalloproteinases (MMP) in myocardial ischemia/reperfusion injury (MIRI) and the cardioprotective role of biglycan (BGN), a small leucine-rich proteoglycan in vitro. Here, we hypothesized that cardiac MMP and BGN signaling are involved in the protective effects of ICon. Methods: A reverse target-microRNA prediction was performed by using the miRNAtarget™ 2.0 software to identify human microRNAs with a possible regulatory effect on MMP and BGN, such as on related genes. To validate the identified 1289 miRNAs in the predicted network, we compared them to two cardioprotective miRNA omics datasets derived from pig and rat models of MIRI in the presence of ICons. Results: Among the experimentally measured miRNAs, we found 100% sequence identity to human predicted regulatory miRNAs in the case of 37 porcine and 24 rat miRNAs. Upon further analysis, 42 miRNAs were identified as MIRI-associated miRNAs, from which 24 miRNAs were counter-regulated due to ICons. Conclusions: Our findings highlight 24 miRNAs that potentially regulate cardioprotective therapeutic targets associated with MMPs and BGN in a highly translatable porcine model of acute myocardial infarction. Full article

Succinate dehydrogenase inhibition with malonate during initial reperfusion reduces myocardial infarct size in both isolated mouse hearts subjected to global ischemia and in in situ pig hearts subjected to transient coronary ligature. However, the long-term effects of acute malonate treatment are unknown. Here, we investigated whether the protective effects of succinate dehydrogenase inhibition extend to a reduction in scar size and adverse left ventricular remodeling 28 days after myocardial infarction. Initially, ten wild-type mice were subjected to 45 min of left anterior descending coronary artery (LAD) occlusion, followed by 24 h of reperfusion, and were infused during the first 15 min of reperfusion with saline with or without disodium malonate (10 mg/kg/min, 120 μL/kg/min). Malonate-treated mice depicted a significant reduction in infarct size (15.47 ± 3.40% of area at risk vs. 29.34 ± 4.44% in control animals, p < 0.05), assessed using triphenyltetrazolium chloride. Additional animals were then subjected to a 45 min LAD ligature, followed by 28 days of reperfusion. Treatment with a single dose of malonate during the first 15 min of reperfusion induced a significant reduction in scar area, measured using Picrosirius Red staining (11.94 ± 1.70% of left ventricular area (n = 5) vs. 23.25 ± 2.67% (n = 9), p < 0.05), an effect associated with improved ejection fraction 28 days after infarction, as determined using echocardiography, and an attenuated enhancement in expression of the pro-inflammatory and fibrotic markers NF-κB and Smad2/3 in remote myocardium. In conclusion, a reversible inhibition of succinate dehydrogenase with a single dose of malonate at the onset of reperfusion has long-term protective effects in mice subjected to transient coronary occlusion. Full article

Takotsubo syndrome (TTS) is a clinical condition characterized by temporary regional wall motion anomalies and dysfunction that extend beyond a single epicardial vascular distribution. Various pathophysiological mechanisms, including inflammation, microvascular dysfunction, direct catecholamine toxicity, metabolic changes, sympathetic overdrive-mediated multi-vessel epicardial spasms, and transitory ischemia may cause the observed reversible myocardial stunning. Despite the fact that TTS usually has an acute coronary syndrome-like pattern of presentation, the absence of culprit atherosclerotic coronary artery disease is often reported at coronary angiography. However, the idea that coronary artery disease (CAD) and TTS conditions are mutually exclusive has been cast into doubt by numerous recent studies suggesting that CAD may coexist in many TTS patients, with significant clinical and prognostic repercussions. Whether the relationship between CAD and TTS is a mere coincidence or a bidirectional cause-and-effect is still up for debate, and misdiagnosis of the two disorders could lead to improper patient treatment with unfavourable outcomes. Therefore, this review seeks to provide a profound understanding of the relationship between CAD and TTS by analyzing potential common underlying pathways, addressing challenges in differential diagnosis, and discussing medical and procedural techniques to treat these conditions appropriately. Full article

While reperfusion, or restoration of coronary blood flow in acute myocardial infarction, is a requisite for myocardial salvage, it can paradoxically induce a specific damage known as ischemia/reperfusion (I/R) injury. Our understanding of the precise pathophysiological molecular alterations leading to I/R remains limited. In this study, we conducted a comprehensive and unbiased time-course analysis of post-translational modifications (PTMs) in the post-reperfused myocardium of two different animal models (pig and mouse) and evaluated the effect of two different cardioprotective therapies (ischemic preconditioning and neutrophil depletion). In pigs, a first wave of irreversible oxidative damage was observed at the earliest reperfusion time (20 min), impacting proteins essential for cardiac contraction. A second wave, characterized by irreversible oxidation on different residues and reversible Cys oxidation, occurred at late stages (6–12 h), affecting mitochondrial, sarcomere, and inflammation-related proteins. Ischemic preconditioning mitigated the I/R damage caused by the late oxidative wave. In the mouse model, the two-phase pattern of oxidative damage was replicated, and neutrophil depletion mitigated the late wave of I/R-related damage by preventing both Cys reversible oxidation and irreversible oxidation. Altogether, these data identify protein PTMs occurring late after reperfusion as an actionable therapeutic target to reduce the impact of I/R injury. Full article

The inhibition of mammalian target of rapamycin (mTOR) with rapamycin (RAPA) provides protection against myocardial ischemia/reperfusion (I/R) injury in diabetes. Since interactions between transcripts, including long non-coding RNA (lncRNA), microRNA(miRNA) and mRNA, regulate the pathophysiology of disease, we performed unbiased miRarray profiling in the heart of diabetic rabbits following I/R injury with/without RAPA treatment to identify differentially expressed (DE) miRNAs and their predicted targets of lncRNAs/mRNAs. Results showed that among the total of 806 unique miRNAs targets, 194 miRNAs were DE after I/R in diabetic rabbits. Specifically, eight miRNAs, including miR-199a-5p, miR-154-5p, miR-543-3p, miR-379-3p, miR-379-5p, miR-299-5p, miR-140-3p, and miR-497-5p, were upregulated and 10 miRNAs, including miR-1-3p, miR-1b, miR-29b-3p, miR-29c-3p, miR-30e-3p, miR-133c, miR-196c-3p, miR-322-5p, miR-499-5p, and miR-672-5p, were significantly downregulated after I/R injury. Interestingly, RAPA treatment significantly reversed these changes in miRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated the participation of miRNAs in the regulation of several signaling pathways related to I/R injury, including MAPK signaling and apoptosis. Furthermore, in diabetic hearts, the expression of lncRNAs, HOTAIR, and GAS5 were induced after I/R injury, but RAPA suppressed these lncRNAs. In contrast, MALAT1 was significantly reduced following I/R injury, with the increased expression of miR-199a-5p and suppression of its target, the anti-apoptotic protein Bcl-2. RAPA recovered MALAT1 expression with its sponging effect on miR-199-5p and restoration of Bcl-2 expression. The identification of novel targets from the transcriptome analysis in RAPA-treated diabetic hearts could potentially lead to the development of new therapeutic strategies for diabetic patients with myocardial infarction. Full article

Coronary no-reflow (CNR) is a frequent phenomenon that develops in patients with ST-segment elevation myocardial infarction (STEMI) following reperfusion therapy. CNR is highly dynamic, develops gradually (over hours) and persists for days to weeks after reperfusion. Microvascular obstruction (MVO) developing as a consequence of myocardial ischemia, distal embolization and reperfusion-related injury is the main pathophysiological mechanism of CNR. The frequency of CNR or MVO after primary PCI differs widely depending on the sensitivity of the tools used for diagnosis and timing of examination. Coronary angiography is readily available and most convenient to diagnose CNR but it is highly conservative and underestimates the true frequency of CNR. Cardiac magnetic resonance (CMR) imaging is the most sensitive method to diagnose MVO and CNR that provides information on the presence, localization and extent of MVO. CMR imaging detects intramyocardial hemorrhage and accurately estimates the infarct size. MVO and CNR markedly negate the benefits of reperfusion therapy and contribute to poor clinical outcomes including adverse remodeling of left ventricle, worsening or new congestive heart failure and reduced survival. Despite extensive research and the use of therapies that target almost all known pathophysiological mechanisms of CNR, no therapy has been found that prevents or reverses CNR and provides consistent clinical benefit in patients with STEMI undergoing reperfusion. Currently, the prevention or alleviation of MVO and CNR remain unmet goals in the therapy of STEMI that continue to be under intense research. Full article

Background: Myocardial perfusion imaging via single-photon emission computed tomography (SPECT MPI) is a well-established method of diagnosing coronary artery disease (CAD). The purpose of this study was to assess the role of SPECT MPI in predicting major cardiovascular events. Methods: The study population was composed of 614 consecutive patients (mean age: 67 years, 55% male) referred for SPECT MPI due to symptoms of stable CAD. The SPECT MPI was performed using a single-day protocol. We conducted a follow-up on all patients at 12 months via a telephone interview. Results: The majority of our patients (78%) presented findings suggestive of reversible ischemia, fixed defects or both. Extensive perfusion defects were found in 18% of the population, while LV dilation was found in 7%. During the 12-month follow-up, 16 deaths, 8 non-fatal MIs and 20 non-fatal strokes were recorded. There was no significant association of SPECT findings with the combined endpoint of all-cause death, non-fatal MI and non-fatal stroke. The presence of extensive perfusion defects was an independent predictor of mortality at 12 months (HR: 2.90, 95% CI: 1.05, 8.06, p = 0.041). Conclusions: In a high-risk patient population with suspected stable CAD, only large reversible perfusion defects in SPECT MPI were independently associated with mortality at 1 year. Further trials are needed to validate our findings and refine the role of SPECT MPI findings in the diagnosis and prognosis of cardiovascular patients. Full article

Although Polygonum orientale L. (PO) has a beneficial effect on treatment of myocardial ischemia (MI), its mechanism remains unclear. This study aimed to explore the pharmacological mechanism of PO against MI through MAPK signaling pathways. Firstly, the therapeutic effect of PO was evaluated for treatment of MI mice. Using Western blot and immunohistochemistry, the influence of PO on MAPK signaling pathways and cell apoptosis was investigated. Subsequently, one key pathway (ERK) of MAPK signaling pathways was screened out, on which PO posed the most obvious impact. Finally, an inhibitor of ERK1/2 was utilized to further verify the regulatory effect of PO on the MAPK/ERK signaling pathway. It was found that PO could reduce the elevation of the ST segment; injury of heart tissue; the activity of LDH, CK, NOS, cNOS and iNOS and the levels of NO, BNP, TNF-α and IL-6. It is notable that PO could significantly modulate the protein content of p-ERK/ERK in mice suffering from MI but hardly had an effect on p-JNK/JNK and p-p38/p38. Additionally, the expressions of bax, caspase3 and caspase9 were inhibited in heart tissue in the PO-treated group. To evaluate whether ERK1/2 inhibitor (PD98059) could block the effect of PO on treatment of MI, both PO and PD98059 were given to mice with MI. It was discovered that the inhibitor indeed could significantly reverse the regulatory effects of PO on the above indicators, indicating that PO could regulate p-ERK/ERK. This study provides experimental evidence that PO extenuates MI injury, cardiomyocyte apoptosis and inflammation by activating the MAPK/ERK signaling pathway. Full article