Physical and emotional stress are recognized triggers of acute coronary syndromes, including ST segment elevation-myocardial infarction (STEMI). We have previously shown that identifiable triggers precede symptoms in over one-third of STEMI patients and inversely correlate with the extent of coronary artery disease (CAD). This study aims to investigate the association between trigger type (physical vs. emotional) and long-term mortality in STEMI patients treated with primary percutaneous coronary intervention (PCI).

This retrospective, single-center observational study included all patients admitted with an STEMI diagnosis from January 2008 to December 2013. Physical and emotional triggers were identified retrospectively from patient records. Mortality data were obtained from the Israeli Ministry of Health.

Of 1345 consecutive STEMI patients treated with primary PCI, mortality data were available for 1267 patients (median age: 61 years). A trigger preceding symptoms onset was identified in 36.5% of patients, with 85% experiencing physical stress and 15% emotional stress. Triggered STEMI patients tended to be younger with fewer comorbidities and lower incidence of multiple vessel CAD compared with nontriggered patients. Notably, emotionally triggered STEMI patients exhibited improved long-term survival compared with those without emotional triggers or with physical triggers. Emotional triggering was identified as an independent predictor of enhanced long-term survival post-PCI compared with physical triggering.

Patients with emotionally triggered STEMI showed less extensive CAD and improved long-term survival following PCI compared with those with physically triggered STEMI. These findings highlight the importance of considering both the presence and type of trigger in the management of STEMI patients and their long-term prognosis.

Patients with chronic kidney disease (CKD) demonstrate accelerated vascular aging which contributes to an increased risk of cardiovascular disease (CVD). Impaired vascular health in CKD is characterized by both functional and structural alterations to the vasculature including hypertension, arterial stiffness, vascular endothelial dysfunction, and autonomic dysfunction. These detriments persist despite pharmacological intervention. Habitual aerobic exercise can be protective of vascular health; however, the feasibility in patients with CKD is low due to numerous barriers to exercise. In this perspective we emphasize the need for novel and non-pharmacological strategies that can rescue vascular health and reduce the development of CVD in patients with CKD, explain the unique barriers to aerobic exercise in CKD, present a novel physical training intervention-high-resistance inspiratory muscle strength training (IMST) that addresses the barriers to exercise, and provide our opinion on why this lifestyle intervention may be particularly efficacious for patients with CKD.

Endothelial cells regulate vascular tone, blood flow, coagulation, and inflammation, with heterogeneous populations serving specific roles throughout the body. In the kidney, endothelial cells maintain vascular integrity and function, contribute to filtration, and support other renal structures. Nitric oxide (NO) is a key signaling molecule that maintains vascular tone and endothelial function. It is synthesized by nitric oxide synthase (NOS) isoforms, with endothelial NOS playing a central role in vascular health. Chronic kidney disease (CKD) is characterized by reduced NO bioavailability, driven by the accumulation of endogenous NOS inhibitors such as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Uremic toxins, oxidative stress, and proinflammatory cytokines contribute to a prothrombotic and proinflammatory state, contributing to endothelial dysfunction and exacerbating cardiovascular (CV) risks in CKD. Biomarkers such as ADMA, SDMA, endothelial microparticles, and soluble adhesion molecules offer insights into vascular health, while invasive or noninvasive diagnostic techniques can assess endothelial function in CKD. Effective management strategies focus on enhancing NO bioavailability, controlling oxidative stress, reducing inflammation, and optimizing dialysis to minimize uremic toxin levels. Emerging therapeutic approaches, including antioxidant therapies and endothelial progenitor cell-based interventions, show promise in preserving vascular function. A multifaceted approach to managing endothelial dysfunction is critical for mitigating CV complications and improving patient outcomes in CKD.

Sumoylation is a post-translational modification that can regulate different physiological functions. Increased sumoylation, specifically conjugation of SUMO2/3 (small ubiquitin-like modifier 2/3), is detrimental to vascular health. However, the molecular mechanism mediating this effect is poorly understood.

We used cell-based assays and mass spectrometry to show that p66Shc is a direct target of SUMO2 and SUMO2 regulates p66Shc function via lysine-81 modification. To determine the effects of SUMO2-p66ShcK81 on vascular function, we generated p66ShcK81R knockin mice and crossbred to LDLr -/- mice to induce hyperlipidemia. Next, to determine p66ShcK81-SUMO2ylation-induced changes in endothelial cell signaling, we performed mass spectrometry followed by Ingenuity Pathway Analysis.

Our data reveal that p66Shc mediates the effects of SUMO2 on endothelial cells. Mass spectrometry identified that SUMO2 modified lysine-81 in the unique collagen homology-2 domain of p66Shc. SUMO2ylation of p66Shc increased phosphorylation at serine-36, causing it to translocate to the mitochondria, a step critical for oxidative function of p66Shc. Notably, sumoylation-deficient p66Shc (p66ShcK81R) was resistant to SUMO2-induced p66ShcS36 phosphorylation and mitochondrial translocation. P66ShcK81R knockin mice were resistant to endothelial dysfunction induced by SUMO2ylation and hyperlipidemia. Ingenuity Pathway Analysis revealed multiple signaling pathways regulated by p66ShcK81-SUMO2ylation in endothelial cells, highlighting Rho-GTPase as a major pathway affected by SUMO2-p66ShcK81.

Collectively, our work reveals SUMO2-p66Shc signaling as a fundamental regulator of vascular endothelial function. We discovered that p66ShcK81 is an upstream modification regulating p66Shc signaling and mediates hyperlipidemia-induced endothelial dysfunction and oxidative stress.

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.

Evidence suggests bovine dairy products may have neutral or beneficial effects on cardiometabolic health, despite being a source of saturated fat. The dairy matrix, the structure and combination of protein, fat, and other nutrients, and how they interact with each other, is purported to be responsible for these beneficial health effects. Whether this relationship extends to endothelial function, as assessed by flow mediated dilation (FMD), remains to be elucidated.

Three electronic databases (PubMed, Embase and Cochrane Central) were searched from inception until 5th September 2024. This review included randomised controlled trials (RCT) investigating any bovine dairy intervention which considered endothelial function using FMD in humans with a non-dairy or alternative dairy control.

Of 4,220 records identified, 18 reports from 11 RCT including 508 (53.3% male) participants, examined endothelial function by FMD and were eligible for evidence synthesis. Eight papers reported an improvement, nine reported no effect and one reported a decrease in FMD. The greatest effects were found in those with impaired health at baseline, with whey protein and high dairy intakes observed to be most beneficial.

Bovine dairy intake has neutral or beneficial effects on cardiometabolic health. This review demonstrates that this relationship extends to endothelial function as assessed by FMD. Whey protein and high dairy intakes may be most effective, although further high quality RCT in this area are warranted.

Coronary circulation plays an essential role in delivering oxygen and metabolic substrates to satisfy the considerable energy demand of the heart. This article reviews the history that led to the current understanding of coronary physiology, beginning with William Harvey's revolutionary discovery of systemic blood circulation in the 17th century, and extending through the 20th century when the major mechanisms regulating coronary blood flow (CBF) were elucidated: extravascular compressive forces, metabolic control, pressure-flow autoregulation, and neural pathways. Pivotal research studies providing evidence for each of these mechanisms are described, along with their clinical correlates. The authors describe the major role played by researchers in the 19th century, who formulated basic principles of hemodynamics, such as Poiseuille's law, which provided the conceptual foundation for experimental studies of CBF regulation. Targeted research studies in coronary physiology began in earnest around the turn of the 20th century. Despite reliance on crude experimental techniques, the pioneers in coronary physiology made groundbreaking discoveries upon which our current knowledge is predicated. Further advances in coronary physiology were facilitated by technological developments, including methods to measure phasic CBF and its regional distribution, and by biochemical discoveries, including endothelial vasoactive molecules and adrenergic receptor subtypes. The authors recognize the invaluable contribution made by basic scientists toward the understanding of CBF regulation, and the enormous impact that this fundamental information has had on improving clinical diagnosis, decision-making, and patient care.

Morning-time heart attacks are associated with an ablation in the sleep-time dip in blood pressure, the mechanism of which is unknown. The epigenetic changes are the hallmark of sleep and circadian clock disruption and homocystinuria (HHcy). The homocystinuria causes ablation in the dip in blood pressure during sleep. Interestingly, HHcy is generated during the epigenetic gene turning off and turning on (i.e., imprinting) by methylation of the DNA promoter. The mitochondrial sulfur metabolism by 3-mercaptopyruvate sulfur transferase (3MST), ATP citrate lyase (ACYL), and epigenetic rhythmic methylation are regulated by folate 1-carbon metabolism (FOCM), i.e., the methionine (M)-SAM-SAH-Hcy, adenosine, and uric acid cycle. Epigenetic gene writer (DNMT), gene eraser (TET/FTO), and editor de-aminase (ADAR) regulate the rhythmic, i.e., reversible methylation/demethylation of H3K4, H3K9, H4K20, m6A, and m5C. The mitochondrial ATP citrate cycle and creatine kinase (CK) regulate chromatin transcription, maturation, and accessibility as well as muscle function. The transcription is regulated by methylation. The maturation and accessibility are controlled by acetylation. However, it is unclear whether a high fat dysbiotic diet (HFD) causes dysrhythmic expression of the gene writer, eraser, and editor, creating hyperuricemia and cardiac and renal dysfunction. We hypothesized that an HFD increases the gene writer (DNMT1) and editor (ADAR), decreases the eraser (TET/FTO), and increases uric acid to cause chronic diseases. This increases the levels of H3K4, H3K9, H4K20, m6A, and m5C. Interestingly, the DNMT1KO mitigates. Further, the DNMT1KO and ADAR inhibition attenuate HFD-induced NGAL/FGF23/TMPRSS2/MMP2, 9, 13, and uric acid levels and improve cardiac and renal remodeling. Although the novel role of nerve endings by the Piezo channels (i.e., the combination of ENaC, VDAC, TRPV, K+, and Mg2+ channels) in the interoception is suggested, interestingly, we and others have shown mechanisms independent of the nerve, by interoception, such as the cargo of the exosome in denervation models of heart failure. If proper and appropriate levels of these enzymes are available to covert homocysteine to hydrogen sulfide (H2S) during homocystinuria, then the H2S can potentially serve as a newer form of treatment for morning heart attacks and renal sulfur transsulfuration transport diseases.

Vascular function is impaired by conditions such as hypertension, dyslipidemia, and diabetes as well as coronary risk factors including age, smoking, obesity, menopause and physical inactivity. Measurement of vascular function is useful not only for assessment of atherosclerosis itself but also in many other aspects such as understanding the pathophysiology, assessing treatment efficacy, and predicting prognosis of cardiovascular events. It is therefore important to accurately assess the extent of vascular function. A variety of vascular function assessments are currently used in clinical practice, including flow-mediated vasodilation, reactive hyperemia index, strain-gauge pulse plethysmographs, pulse wave velocity, augmentation index, intima media thickness, and chemical biomarkers. However, it is also true that there is no gold standard method for measuring vascular function in humans. To use vascular function effectively, it is necessary to understand the measurement-related pitfalls.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death globally despite advances in preventive therapies. Understanding of the initiation and progression of atherosclerosis, the interplay between lipoproteins, endothelial dysfunction, inflammation, and immune responses is critical to treating this disease. The development of vulnerable coronary plaques prone to thrombosis, can lead to acute coronary syndromes, for these reasons, the potential plaque stabilization and regression through pharmacological interventions, particularly lipid-lowering agents like statins and PCSK9 inhibitors is crucial. The imaging techniques such as intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT) play a key role in assessing plaque composition and guiding interventional therapeutic strategies. Clinical evidence supports the efficacy of intensive lipid-lowering therapy in inducing plaque regression, with studies demonstrating reductions in plaque volume and improvements in plaque morphology assessed by IVUS, OCT and NIRS. While pharmacological interventions show promise in promoting plaque regression and stabilization, their impact on long-term cardiovascular events requires further investigation. Multimodality imaging and comprehensive outcome trials are proposed as essential tools for elucidating the relationship between plaque modification and clinical benefit in coronary atherosclerosis. The stabilization or regression of atherosclerotic plaque might serve as the phenomenon linking the reduction in LDL-C levels to the decrease in cardiovascular events. Overall, this review emphasizes the ongoing efforts to advance our understanding of ASCVD pathophysiology and optimize therapeutic approaches for improving patient outcomes.

Coronary artery disease (CAD) is more prevalent in men than in women, with endothelial dysfunction, prodromal to CAD, developing a decade earlier in middle-aged men. We investigated the molecular basis of this dimorphism ex vivo in arterial segments discarded during surgery of CAD patients. The results reveal a lower endothelial relaxant sensitivity in men, and a senescence-associated inflammaging transcriptomic signature in endothelial cells. In women, cellular metabolism and endothelial maintenance pathways are conserved. This suggests that senolytic therapies to reduce risk of cardiovascular events in women with CAD may not be as effective as in men.

Coronary microvascular dysfunction (CMD) involves functional or structural abnormalities of the coronary microvasculature resulting in dysregulation of coronary blood flow (CBF) in response to myocardial oxygen demand. This perfusion mismatch causes myocardial ischemia, which manifests in patients as microvascular angina (MVA). CMD can be diagnosed non-invasively via multiple imaging techniques or invasively using coronary function testing (CFT), which assists in determining the specific mechanisms involving endothelium-independent and dependent epicardial and microcirculation domains. Unlike traditional coronary artery disease (CAD), CMD can often occur in patients without obstructive atherosclerotic epicardial disease, which can make the diagnosis of CMD difficult. Moreover, MVA due to CMD is more prevalent in women and carries increased risk of future cardiovascular events. Successful treatment of symptomatic CMD is often patient-specific risk factor and endotype targeted. This article aims to review newly identified mechanisms and novel treatment strategies for managing CMD, and outline sex-specific differences in the presentation and pathophysiology of the disease.

Endothelial cells (ECs) are a multifaceted component of the vascular system with roles in immunity, maintaining tissue fluid balance, and vascular tone. Dysregulation or dysfunction of ECs can have far-reaching implications, leading pathologies ranging from cardiovascular diseases, such as hypertension and atherosclerosis, ischemia, chronic kidney disease, blood-brain barrier integrity, dementia, and tumor metastasis. Recent advancements in regenerative medicine have highlighted the potential of stem cell-derived ECs, particularly from induced pluripotent stem cells, to treat ischemic tissues, as well as models of vascular integrity. This review summarizes what is known in the generation of ECs with an emphasis on tissue-specific ECs and EC subphenotypes important in the development of targeted cell-based therapies for patient treatment.

Intracoronary acetylcholine (ACH) testing is clinically useful to diagnose the presence of the coronary vasomotor disorders coronary endothelial dysfunction and coronary epicardial/microvascular spasm. In Western countries, continuous intracoronary injection of ACH for 2-3 minutes without a pacemaker is the usual method, while rapid injection of ACH for 20-30 seconds with a pacemaker is the traditional procedure in Japan. Coronary microvascular spasm is often observed in Western populations, whereas coronary epicardial spasm is frequently seen in Japanese subjects. Methodological differences between Western and Japanese protocols may lead to the opposite prevalence of coronary vasomotor disorders. This article discusses the optimal method for diagnosing endothelial dysfunction and epicardial/microvascular spasm based on previous reports, and compares intracoronary ACH testing performed by Western cardiologists with that by Japanese physicians.

Cardiovascular disease (CVD) and its complications are a leading cause of death worldwide. Endothelial dysfunction plays a crucial role in the initiation and progression of CVD, serving as a pivotal factor in the pathogenesis of cardiovascular, metabolic, and other related diseases. The regulation of endothelial dysfunction is influenced by various risk factors and intricate signaling pathways, which vary depending on the specific disease context. Despite numerous research efforts aimed at elucidating the mechanisms underlying endothelial dysfunction, the precise molecular pathways involved remain incompletely understood. This review elucidates recent research findings on the pathophysiological mechanisms involved in endothelial dysfunction, including nitric oxide availability, oxidative stress, and inflammation-mediated pathways. We also discuss the impact of endothelial dysfunction on various pathological conditions, including atherosclerosis, heart failure, diabetes, hypertension, chronic kidney disease, and neurodegenerative diseases. Furthermore, we summarize the traditional and novel potential biomarkers of endothelial dysfunction as well as pharmacological and nonpharmacological therapeutic strategies for endothelial protection and treatment for CVD and related complications. Consequently, this review is to improve understanding of emerging biomarkers and therapeutic approaches aimed at reducing the risk of developing CVD and associated complications, as well as mitigating endothelial dysfunction.

The coronary circulation plays a crucial role in balancing myocardial perfusion and oxygen demand to prevent myocardial ischemia. Extravascular compressive forces, coronary perfusion pressure, and microvascular resistance are involved to regulate coronary blood flow throughout the cardiac cycle. Autoregulation of the coronary blood flow through dynamic adjustment of microvascular resistance is maintained by complex interactions among mechanical, endothelial, metabolic, neural, and hormonal mechanisms. This review focuses on the neural mechanism. Anatomy and physiology of the coronary arterial innervation have been extensively investigated using animal models. However, findings in the animal heart have limited applicability to the human heart as cardiac innervation is generally highly variable among species. So far, limited data are available on the human coronary artery innervation, rendering multiple questions unresolved. Recently, the clinical entity of ischemia with non-obstructive coronary arteries has been proposed, characterized by microvascular dysfunction involving abnormal vasoconstriction and impaired vasodilation. Thus, measurement of microvascular resistance has become a standard diagnostic for patients without significant stenosis in the epicardial coronary arteries. Neural mechanism is likely to play a pivotal role, supported by the efficacy of cardiac sympathetic denervation to control symptoms in patients with angina. Therefore, understanding the coronary artery innervation and control of microvascular resistance of the human heart is increasingly important for cardiologists for diagnosis and to select appropriate therapeutic options. Advancement in this field can lead to innovations in diagnostic and therapeutic approaches for coronary artery diseases.

Habitual betel quid chewing, a tobacco product, is a leading cause of oral cancer in Asia-Pacific countries where this practice is most prevalent. However, it is not well understood whether betel quid chewing is also a cause of adverse cardiovascular outcomes. To address this gap, we conducted a systematic literature review of peer-reviewed published studies evaluating the association between habitual betel quid use on the risk of adverse cardiovascular outcomes.

We searched PubMed for studies assessing the correlation between betel quid chewing and cardiovascular health. We included studies if (i) they included human subjects; (ii) were peer-reviewed articles in indexed journals; and (iii) were in English. We extracted data from eligible studies and stratified them by geographical location, study designs and cardiovascular outcomes. Finally, we did a narrative synthesis of the data to identify adverse cardiovascular outcomes associated with chronic betel quid use.

We reviewed data from 19 studies that met the inclusion criteria. Habitual betel quid chewing was associated with hypertension, atherosclerosis, inflammation and ischaemic heart disease. In addition, betel quid use was a risk factor for arrhythmias. Interestingly, betel quid use was an independent risk factor for cardiovascular disease in women. Long-term betel quid consumption was associated with higher risks for all-cause mortality and increased overall cardiovascular risk.

Habitual betel quid chewing is an important cardiovascular risk factor in populations where the practice is prevalent.

Background and Objectives: Myocardial bridging (MB) is still not yet considered a significant finding in Indonesia both radiographically and clinically. Hence, this article aims to assess the prevalence of MB using multi-detector computed tomography (MDCT) and look at factors contributing to stenosis amongst patients with MB. Materials and Methods: This study is cross-sectional in a single centre, with consecutive sampling, looking at all patients who underwent a multi-detector computed tomography (MDCT) scan from February 2021 until February 2023. GraphPad Prism version 9.0.0 for Windows (GraphPad Software, Boston, MA, USA) was used to analyse the results. Results: There are 1029 patients with an MB, yielding a prevalence of 44.3% (95%CI 42.3-46.4). The left anterior descending vessel is the most commonly implicated, with 99.6%. Among those with stenosis, the middle portion of the bridging vessel is the most common site of stenosis (n = 269), followed by the proximal portion (n = 237). The severity of stenosis is more often moderate, with 30-50% (n = 238). Females (odds ratio [OR] of 1.8, 95%CI 1.4-2.3; p-value < 0.0001), older age (t-value 5.6, p-value < 0.0001), symptomatic patients (OR 1.4, 95% CI 1.1-1.9; p-value = 0.013), and higher mean coronary artery calcium score (t-value 11.3, p-value < 0.0001) are more likely to have stenosis. The degree of stenosis is significantly higher in the proximal stenosis group than in the middle stenosis group (t-value 27, p-value < 0.0001). Conclusions: Our research demonstrates that MB may prevent atheromatosis of the coronary segment distal to the MB and predispose the development of atherosclerosis in the section proximal to the bridge.

The endothelium is a continuous layer of cells that coats the interior walls of arteries, capillaries, and veins. It has an essential regulatory role in hemostatic function, vascular tone, inflammation, and platelet activity. Endothelial dysfunction is characterized by a shift to a proinflammatory and prothrombic state, and it could have a bidirectional relationship with heart failure (HF). Due to neurohormonal activation and shear stress, HFrEF may promote endothelial dysfunction, increase ROS synthesis, and reduce nitric oxide production. Different studies have also shown that endothelium function is damaged in HFpEF because of a systemic inflammatory state. Some clinical trials suggest that drugs that have an effect on endothelial dysfunction in patients with HF or cardiovascular disease may be a therapeutic option. The aim of this review is to highlight the pathogenetic correlation between endothelial dysfunction and heart failure and the related potential therapeutic options.

Non-obstructive coronary artery disease (NO-CAD) constitutes a heterogeneous group of conditions collectively characterized by less than 50% narrowing in at least one major coronary artery with a fractional flow reserve (FFR) of ≤0.80 observed in coronary angiography. The pathogenesis and progression of NO-CAD are still not fully understood, however, inflammatory processes, particularly atherosclerosis and microvascular dysfunction are known to play a major role in it. Chemokine fractalkine (FKN/CX3CL1) is inherently linked to these processes. FKN/CX3CL1 functions predominantly as a chemoattractant for immune cells, facilitating their transmigration through the vessel wall and inhibiting their apoptosis. Its concentrations correlate positively with major cardiovascular risk factors. Moreover, promising preliminary results have shown that FKN/CX3CL1 receptor inhibitor (KAND567) administered in the population of patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), inhibits the adverse reaction of the immune system that causes hyperinflammation. Whereas the link between FKN/CX3CL1 and NO-CAD appears evident, further studies are necessary to unveil this complex relationship. In this review, we critically overview the current data on FKN/CX3CL1 in the context of NO-CAD and present the novel clinical implications of the unique structure and function of FKN/CX3CL1 as a compound which distinctively contributes to the pathomechanism of this condition.

Cardiovascular diseases (CVDs) are a leading global cause of mortality and are primarily driven by atherosclerotic coronary artery disease. Their pathogenesis involves multi-factorial mechanisms, among which low-density lipoprotein (LDL) plays a causative role. Recent ESC/EAS guidelines advocate for a shift toward new risk estimation algorithms that better emphasize non-fatal cardiovascular events, lifetime risk prediction, and tailored pharmacological approaches, including statin + ezetimibe and triple therapy, in specific cases. Intensive lipid-lowering therapy has been shown to be pivotal, especially in post-acute coronary events. Intracoronary imaging has revealed insights into the composition of plaque and demonstrated the significant regression that can be achieved through the use of statins such as rosuvastatin and atorvastatin. The positive effects of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors, particularly alirocumab and evolocumab, on plaque regression, have been demonstrated. Inclisiran, which targets PCSK9 gene expression, significantly reduces LDL cholesterol. The associated challenges include hesitancy to prescribe intensive regimens and limited treatment adherence, highlighting the need for pharmacological combinations to improve therapeutic outcomes.

Despite improvements in contemporary medical and surgical therapies, cardiovascular disease (CVD) remains a significant cause of worldwide morbidity and mortality; more specifically, ischemic heart disease (IHD) may affect individuals as young as 20 years old. Typically managed with guideline-directed medical therapy, interventional or surgical methods, the incurred cardiomyocyte loss is not always completely reversible; however, recent research into various stem cell (SC) populations has highlighted their potential for the treatment and perhaps regeneration of injured cardiac tissue, either directly through cellular replacement or indirectly through local paracrine effects. Different stem cell (SC) types have been employed in studies of infarcted myocardium, both in animal models of myocardial infarction (MI) as well as in clinical studies of MI patients, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), Muse cells, multipotent stem cells such as bone marrow-derived cells, mesenchymal stem cells (MSCs) and cardiac stem and progenitor cells (CSC/CPCs). These have been delivered as is, in the form of cell therapies, or have been used to generate tissue-engineered (TE) constructs with variable results. In this text, we sought to perform a narrative review of experimental and clinical studies employing various stem cells (SC) for the treatment of infarcted myocardium within the last two decades, with an emphasis on therapies administered through thoracic incision or through percutaneous coronary interventions (PCI), to elucidate possible mechanisms of action and therapeutic effects of such cell therapies when employed in a surgical or interventional manner.

Coronary vasomotor disorders (CVD) are characterized by transient hypercontraction of coronary vascular smooth muscle cells, leading to hypercontraction of epicardial and/or microvascular coronary circulation. CVDs play a relevant role in the pathogenesis of ischemia, angina and myocardial infarction with non-obstructive coronary arteries. Invasive provocative testing with intracoronary Acetylcholine (ACh) administration is the gold standard tool for addressing CVD, providing relevant therapeutic and prognostic implications. However, safety concerns preclude the widespread incorporation of the ACh test into clinical practice. The purpose of this review is to shed light on the pathophysiology underlying CVD and on the clinical role of the ACh test, focusing on safety profile and prognostic implications. We will also discuss contemporary evidence on the management of CVD and the role of the ACh test in driving a personalized approach of patients with CVD.

Atherosclerosis and solid organ chronic rejection are pervasive chronic disease states that account for significant morbidity and mortality in developed countries. Recently, a series of shared molecular pathways have emerged, revealing biological parallels from early stages of development up to the advanced forms of pathology. These shared mechanistic processes are inflammatory in nature, reflecting the importance of inflammation in both disorders. Vascular inflammation triggers endothelial dysfunction and disease initiation through aberrant vasomotor control and shared patterns of endothelial activation. Endothelial dysfunction leads to the recruitment of immune cells and the perpetuation of the inflammatory response. This drives lesion formation through the release of key cytokines such as IFN-y, TNF-alpha, and IL-2. Continued interplay between the adaptive and innate immune response (represented by T lymphocytes and macrophages, respectively) promotes lesion instability and thrombotic complications; hallmarks of advanced disease in both atherosclerosis and solid organ chronic rejection. The aim of this study is to identify areas of overlap between atherosclerosis and chronic rejection. We then discuss new approaches to improve current understanding of the pathophysiology of both disorders, and eventually design novel therapeutics.

Vasospastic angina (VSA) refers to chest pain experienced as a consequence of myocardial ischaemia caused by epicardial coronary spasm, a sudden narrowing of the vessels responsible for an inadequate supply of blood and oxygen. Coronary artery spasm is a heterogeneous phenomenon that can occur in patients with non-obstructive coronary arteries and obstructive coronary artery disease, with transient spasm causing chest pain and persistent spasm potentially leading to acute myocardial infarction (MI). VSA was originally described as Prinzmetal angina or variant angina, classically presenting at rest, unlike most cases of angina (though in some patients, vasospasm may be triggered by exertion, emotional, mental or physical stress), and associated with transient electrocardiographic changes (transient ST-segment elevation, depression and/or T-wave changes). Ischaemia with non-obstructive coronary arteries (INOCA) is not a benign condition, as patients are at elevated risk of cardiovascular events including acute coronary syndrome, hospitalization due to heart failure, stroke and repeat cardiovascular procedures. INOCA patients also experience impaired quality of life and associated increased healthcare costs. VSA, an endotype of INOCA, is associated with major adverse events, including sudden cardiac death, acute MI and syncope, necessitating the study of the most effective treatment options currently available. The present literature review aims to summarize current data relating to the diagnosis and management of VSA and provide details on the sequence that treatment should follow.

Heart failure (HF) is a clinical syndrome consisting of typical symptoms and signs due to structural and/or functional abnormalities of the heart, resulting in elevated intracardiac pressures and/or inadequate cardiac output. The vascular system plays a crucial role in the development and progression of HF regardless of ejection fraction, with endothelial dysfunction (ED) as one of the principal features of HF. The main ED manifestations (i.e., impaired endothelium-dependent vasodilation, increased oxidative stress, chronic inflammation, leukocyte adhesion, and endothelial cell senescence) affect the systemic and pulmonary haemodynamic and the renal and coronary circulation. The present review is aimed to discuss the contribution of ED to HF pathophysiology-in particular, HF with preserved ejection fraction-ED role in HF patients, and the possible effects of pharmacological and non-pharmacological approaches. For this purpose, relevant data from a literature search (PubMed, Scopus, EMBASE, and Medline) were reviewed. As a result, ED, assessed via venous occlusion plethysmography or flow-mediated dilation, was shown to be independently associated with poor outcomes in HF patients (e.g., mortality, cardiovascular events, and hospitalization due to worsening HF). In addition, SGLT2 inhibitors, endothelin antagonists, endothelial nitric oxide synthase cofactors, antioxidants, and exercise training were shown to positively modulate ED in HF. Despite the need for future research to better clarify the role of the vascular endothelium in HF, ED represents an interesting and promising potential therapeutic target.

Age is a key risk factor for cardiovascular disease, including atherosclerosis. However, pathophysiological disease processes in the arteries are not an inevitable feature of aging. Large cohort studies with arterial phenotyping along with clinical and demographic data are essential to better understand factors related to the susceptibility or resilience to age-related vascular pathophysiology in humans. This review explores the mechanisms by which vascular structure and function alters with age, and how these changes relate to cardiovascular pathophysiology and disease. Features of vascular aging in the coronary arteries have historically been difficult to quantify pre-mortem due to their size and location. However, non-invasive imaging modalities including CT Coronary Angiogram are now being used to assess coronary vascular age, and further advances in imaging analysis such as the CT Fat Attenuation Index will help provide further measurement of features associated with coronary vascular aging. Currently, markers of vascular aging are not used as therapeutic targets in routine clinical practice, but non-pharmacological interventions including aerobic exercise and low salt diet, as well as anti-hypertensives have been demonstrated to reduce arterial stiffness. Advances in imaging technology, both in acquisition and advanced analysis, as well as harmonisation of measurements for researchers across the globe will be invaluable in understanding what constitutes healthy vascular aging and in identifying features of vascular aging that are associated with coronary artery disease and its adverse outcomes. Assessing such images in large cohorts can facilitate improved definitions of resilient and susceptible phenotypes to vascular aging in the coronary arteries. This is a critical step in identifying further risk factors and biomarkers within these groups and driving forward the development of novel therapies aimed at slowing or stopping age-related vascular changes in the coronary arteries.

The occurrence and development of atherosclerotic cardiovascular disease, which can result in severe outcomes, such as myocardial infarction, stroke, loss of limb, renal failure, and infarction of the gut, are strongly associated with injury to the intimal component of the arterial wall whether via the inside-out or outside-in pathways. The role of injury to the tunica media as a pathway of atherosclerosis initiation is an underresearched area. This review focuses on potential pathways to vessel wall injury as well as current experimental and clinical research in the middle-aged and elderly populations, including the role of exercise, as it relates to injury to the tunica media.

A database search using PubMed and Google Scholar was conducted for research articles published between 1909 and 2023 that focused on pathways of atherogenesis and the impact of mechanical forces on wall injury. The following key words were searched: wall injury, tunica media, atherogenesis, vascular aging, and wall strain. Studies were analyzed, and the relevant information was extracted from each study.

A link between high mechanical stress in the arterial wall and reduced vascular compliance was found. The stiffening and calcification of the arterial wall with aging induce high blood pressure and pulse pressure, thereby causing incident hypertension and cardiovascular disease. In turn, prolonged high mechanical stress, particularly wall strain, applied to the arterial wall during vigorous exercise, results in stiffening and calcification of tunica media, accelerated arterial aging, and cardiovascular disease events. In both scenarios, the tunica media is the primary target of mechanical stress and the first to respond to hemodynamic changes. The cyclical nature of these impacts confounds the results of each because they are not mutually exclusive.

The role of stress in the tunica media appears to be overlooked despite its relevance, and further research into new primary preventive therapies is needed aside from cautioning the role of vigorous exercise in the elderly population.

The vascular endothelium is a multifunctional cellular system which directly influences blood components and cells within the vessel wall in a given tissue. Importantly, this cellular interface undergoes critical phenotypic changes in response to various biochemical and hemodynamic stimuli, driving several developmental and pathophysiological processes. Multiple studies have indicated a central role of the endothelium in the initiation, progression, and clinical outcomes of cardiac disease. In this review we synthesize the current understanding of endothelial function and dysfunction as mediators of the cardiomyocyte phenotype in the setting of distinct cardiac pathologies; outline existing in vivo and in vitro models where key features of endothelial cell dysfunction can be recapitulated; and discuss future directions for development of endothelium-targeted therapeutics for cardiac diseases with limited existing treatment options.

The formation of atherosclerotic plaques is one of the main sources of cardiovascular disease. In addition to known risk factors such as dyslipidemia, diabetes, obesity, and hypertension, endothelial dysfunction has been shown to play a key role in the formation and progression of atherosclerosis. Peroxisome proliferator-activated receptor-gamma (PPARγ), a transcription factor belonging to the steroid superfamily, is expressed in the aorta and plays a critical role in protecting endothelial function. It thereby serves as a target for treating both diabetes and atherosclerosis. Although many studies have examined endothelial cell disorders in atherosclerosis, the role of PPARγ in endothelial dysfunction is still not well understood. In this review, we summarize the possible mechanisms of action behind PPARγ regulatory compounds and post-translational modifications (PTMs) of PPARγ in the control of endothelial function. We also explore the potential use of endothelial PPARγ-targeted agents in the prevention and treatment of atherosclerosis.

There is a great need for new approaches early in drug discovery that have the potential to improve clinical translation of compound-mediated cardiovascular effects. Current approaches frequently rely on in vivo animal models or in vitro tissue bath preparations, both of which are low throughput and costly. An in vitro surrogate screen for blood pressure using primary human cells may serve as a higher throughput method to quickly select compounds void of this secondary pharmacology and potentially improve late-stage drug development outcomes.

In this study, we investigated 10 compounds with published in vivo blood pressure effects in a commercially available collagen contraction assay and evaluated rat, human, and canine (aortic) vascular smooth muscle cells (VSMCs). The aim of this study was to evaluate consistency between species and test their ability to predict the effects of known human vasodilators and constrictors. VSMCs were embedded at the same cell density in a collagen matrix which then floated freely in media containing test compounds. Collagen discs contracted faster than vehicle treated controls when incubated with a constrictor, and slower in the presence of a dilator.

Rat VSMCs responded as predicted of a VSMC-only culture to 9 out of 10 compounds. Human VSMCs responded as predicted to 8 out of 10 compounds, and canine VSMCs responded to 7 out of 10 compounds.

Our results suggest that rat VSMCs predict 90% of the effects of known vasoactive compounds in the collagen contraction assay while human and canine VSMCs were slightly less predictive (80% and 70%, respectively). Although blood pressure regulation is a multi-faceted and complex process, our data suggests the collagen smooth muscle contraction assay is useful as a qualitative early screen of compounds that act directly on smooth muscle cells of the arterial vasculature.

This study evaluates the potential therapeutic effects of anthocyanin-rich Prunus cerasus (sour cherry) extract (PCE) on atherosclerosis-associated cardiac dysfunction, described by the impairment of the NO-PKG (nitric oxide-protein kinase G) pathway and the antioxidant capacity. Initially, a rabbit model of atherosclerotic cardiovascular disease was established by administering a cholesterol-rich diet, enabling the examination of the impact of 9 g/kg PCE on the pre-existing compromised cardiovascular condition. After that, the animals were divided into four groups for 12 weeks: the (1) untreated control group; (2) PCE-administered healthy rabbits; (3) hypercholesterolemic (HC) group kept on an atherogenic diet; and (4) PCE-treated HC group. Dyslipidemia, impaired endothelial function, and signs of diastolic dysfunction were evident in hypercholesterolemic rabbits, accompanied by a reduced cardiac expression of eNOS (endothelial nitric oxide synthase), PKG, and SERCA2a (sarco/endoplasmic reticulum calcium ATPase 2a). Subsequent PCE treatment improved the lipid profile and the cardiac function. Additionally, PCE administration was associated with elevated myocardial levels of eNOS, PKG, and SERCA2a, while no significant changes in the vascular status were observed. Western blot analysis further revealed hypercholesterolemia-induced increase and PCE-associated reduction in heme oxygenase-1 expression. The observed effects of anthocyanins indicate their potential as a valuable addition to the treatment regimen for atherosclerosis-associated cardiac dysfunction.

Vascular aging represents a collection of structural and functional changes in a blood vessel with advancing age, including increased stiffness, vascular wall remodeling, loss of angiogenic ability, and endothelium-dependent vasodilation dysfunction. These age-related alterations may occur earlier in those who are at risk for or have cardiovascular diseases, therefore, are defined as early or premature vascular aging. Vascular aging contributes independently to cardio-cerebral vascular diseases (CCVDs). Thus, early diagnosis and interventions targeting vascular aging are of paramount importance in the delay or prevention of CCVDs. Here, we review the direct assessment of vascular aging by examining parameters that reflect changes in structure, function, or their compliance with age including arterial wall thickness and lumen diameter, endothelium-dependent vasodilation, arterial stiffness as well as indirect assessment through pathological studies of biomarkers including endothelial progenitor cell, lymphocytic telomeres, advanced glycation end-products, and C-reactive protein. Further, we evaluate how different types of interventions including lifestyle mediation, such as caloric restriction and salt intake, and treatments for hypertension, diabetes, and hyperlipidemia affect age-related vascular changes. As a single parameter or intervention targets only a certain vascular physiological change, it is recommended to use multiple parameters to evaluate and design intervention approaches accordingly to prevent systemic vascular aging in clinical practices or population-based studies.

Vasospastic angina (VSA) occurs at rest and on exertion, with transient electrocardiographic ischemic changes. VSA presents with spontaneous coronary artery spasm (CAS); it has been associated with stable angina, acute coronary syndromes, and sudden cardiac death. CAS can be identified in normal arteries or non-obstructive coronary atherosclerosis, but is also prevalent in patients with coronary artery disease. The diagnosis is made with invasive coronary reactivity testing with provocation using acetylcholine (Ach). Epicardial spasms can be visualized through coronary angiography as a reversible epicardial vessel narrowing, while the diagnosis of microvascular spasm can be made when angina symptoms and ECG changes happen following intracoronary Ach without epicardial spasm. Identification of CAS allows for risk stratification and specific therapies targeting endothelial dysfunction and paradoxical vascular smooth muscle cell constriction. Therapies include calcium channel blockers as monotherapy or in a combination of a dihydropyridine and non-dihydropyridine. Short-acting nitrates offer acute symptomatic relief but long-acting nitrates should be used sparingly. This current update on invasive evaluation of VSA discusses unified Ach protocols.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including alpha-linolenic acid (ALA) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are "essential" fatty acids mainly obtained from diet sources comprising plant oils, marine blue fish, and commercially available fish oil supplements. Many epidemiological and retrospective studies suggested that ω-3 PUFA consumption decreases the risk of cardiovascular disease, but results of early intervention trials have not consistently confirmed this effect. In recent years, some large-scale randomized controlled trials have shed new light on the potential role of ω-3 PUFAs, particularly high-dose EPA-only formulations, in cardiovascular prevention, making them an attractive tool for the treatment of "residual" cardiovascular risk. ω-3 PUFAs' beneficial effects on cardiovascular outcomes go far beyond the reduction in triglyceride levels and are thought to be mediated by their broadly documented "pleiotropic" actions, most of which are directed to vascular protection. A considerable number of clinical studies and meta-analyses suggest the beneficial effects of ω-3 PUFAs in the regulation of blood pressure in hypertensive and normotensive subjects. These effects occur mostly through regulation of the vascular tone that could be mediated by both endothelium-dependent and independent mechanisms. In this narrative review, we summarize the results of both experimental and clinical studies that evaluated the effect of ω-3 PUFAs on blood pressure, highlighting the mechanisms of their action on the vascular system and their possible impact on hypertension, hypertension-related vascular damage, and, ultimately, cardiovascular outcomes.