Young and older patients with acute myocardial infarction: differences in risk factors and angiographic characteristics.

OBJECTIVE: Although coronary artery disease mainly affects older individuals, the incidence of myocardial infarction (MI) among younger adults (<55 years) has increased during the past decade. Young and older MI patients have different underlying pathophysiologic characteristics, atherosclerotic plaque morphology, and risk factor profiles. METHODS: We studied 977 patients (≤55 years old: 322, >55 years old: 655) who were hospitalized for MI in the previous 5 years. Patients' baseline characteristics and daily habits were recorded. Angiographic characteristics and vascular lesions were detected, and further examinations, including flow-mediated dilation (FMD), pulse wave velocity (PWV), and central augmentation index (AIx), were performed. Biomarkers of inflammation (Interleukin-6, Tumor-Necrosis factor-a, Intercellular Adhesion Molecule 1, and Osteopontin) were also tested. RESULTS: The median age in the younger age group was 49 years [interquartile range (IQR: 44-53)] and 66 years (IQR: 61-73) in the older age group. Arterial hypertension was less prevalent in the young compared to the elderly with MI (47.4% vs. 76.2%, p < 0.01). The younger counterparts presented significantly lower rates of diabetes mellitus (19.3% vs. 30.6%, p < 0.01), dyslipidemia (59% vs. 70.8%, p < 0.01), and atrial fibrillation (2.6% vs. 9.7%, p < 0.01) and were more casual smokers (49.3% vs. 23.8%, p < 0.01) compared to older patients with MI. In terms of arterial stiffness, lower PWV [7.3 m/s (IQR: 6.5-8.4 m/s) vs. 9 m/s (IQR: 8-10.8 m/s), p < 0.01] and AIx (20.5 ± 10.8 vs. 25.5 ± 7.8, p < 0.01) were recorded in the young compared to the elderly with MI. Concerning angiographic characteristics, younger patients were more likely to have none or single-vessel disease (55.6% vs. 45.8%, p < 0.02), whereas the older participants more frequently had three or more vessel disease (23.5% vs. 13.6% in the young, p < 0.02). Although significant disparities in blood test results were detected during the acute phase, the great majority of young MI patients were undertreated. CONCLUSION: Younger patients with MI are more likely to be smokers with impaired PWV measures, present with non-obstructive or single-vessel disease, and often remain undertreated. A better knowledge of the risk factors as well as the anatomic and pathophysiologic processes in young adults will help enhance MI prevention and treatment options in this patient population.

Direct Oral Anticoagulants use in Patients with Stable Coronary Artery Disease, Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention.

The investigation for the optimal anticoagulation strategy for patients with stable coronary artery disease, acute coronary syndromes, and undergoing percutaneous coronary intervention constitutes a great challenge for physicians and is a field of extensive research. Although aspirin is commonly recommended as a protective measure for all patients with coronary artery disease and dual antiplatelet therapy for those undergoing procedures, such as percutaneous coronary intervention or coronary artery bypass graft surgery, the risk of recurrent cardiovascular events remains significant. In this context, the shortcomings associated with the use of vitamin K antagonists have led to the assessment of direct oral anticoagulants as promising alternatives. This review will explore and provide a comprehensive analysis of the existing data regarding the use of direct oral anticoagulants in patients with stable coronary artery disease or acute coronary syndrome, as well as their effectiveness in those undergoing percutaneous coronary intervention or coronary artery bypass graft surgery.

Stem Cell-based Therapies in Cardiovascular Diseases: From Pathophysiology to Clinical Outcomes.

Over 20 years of intensified research in the field of stem cells brought about unprecedented possibilities in treating heart diseases. The investigators were initially fascinated by the idea of regenerating the lost myocardium and replacing it with new functional cardiomyocytes, but this was extremely challenging. However, the multifactorial effects of stem cell-based therapies beyond mere cardiomyocyte generation, caused by paracrine signaling, would open up new possibilities in treating cardiovascular diseases. To date, there is a strong body of evidence that the anti-inflammatory, anti-apoptotic, and immunomodulatory effects of stem cell therapy may alleviate atherosclerosis progression. In the present review, our objective is to provide a brief overview of the stem cell-based therapeutic options. We aim to delineate the pathophysiological mechanisms of their beneficial effects in cardiovascular diseases especially in coronary artery disease and to highlight some conclusions from important clinical studies in the field of regenerative medicine in cardiovascular diseases and how we could further move onwards.

Interleukin-6 Signaling in Atherosclerosis: From Molecular Mechanisms To Clinical Outcomes.

Interleukin-6 (IL-6) is a cytokine centrally involved in several immune responses and it has been recognized as a driver of enhanced atherothrombotic risk. Immunity and inflammation are intrinsically involved in atherosclerosis progression. This generated 'inflammation hypothesis', which is now validated in large-scale clinical trials. Abundant evidence supports the distinctive role of IL-6 in coronary artery disease. The focus on this cytokine stems from epidemiological studies linking high plasma concentrations of IL-6 with greater risk for adverse cardiovascular events, genetic studies which implicate a causative role of IL-6 in atherosclerosis and murine data which support the involvement of IL-6 in various pathophysiological cascades of atherothrombosis. The fact that high IL-6 levels are equivalent to increased cardiovascular risk created an unmet need to address those who are at 'residual inflammatory risk'. Moreover, the opposing effects of IL-6 underlined the importance of deciphering specific signaling cascades, which may be responsible for different effects. Finally, murine data and some small clinical trials highlighted the possibility of reversing the pro-atherogenic effects of IL-6 by directly targeting it. While IL-1 blockage was proved effective, it is reasonable to examine if moving more downstream in the inflammation cascade could be more selective and effective than other anti-inflammatory therapies. In the present review, we examine the role of IL-6 as a biomarker of 'residual inflammatory risk', its vital role in the pathophysiology of atherosclerosis progression and the possibility of targeting it to stall coronary artery disease progression.

Novel Concepts in the Management of Angina in Coronary Artery Disease.

Coronary artery disease remains a condition with high prevalence and detrimental effects on the quality of life of affected individuals. Its most frequent manifestation, stable angina pectoris, may be challenging to manage despite the available antianginal pharmacotherapy and adequate risk factor control, especially in subjects not amenable to revascularization. In the direction of refractory angina pectoris, several approaches have been developed over the years with varying degrees of success. Among the most recognized techniques in managing angina is enhanced external counterpulsation, which utilizes mechanical compression of the lower extremities to increase blood flow to the heart. Moving to coronary sinus reduction, it leads to an increase in coronary sinus backward pressure, ultimately augmenting myocardial blood flow redistribution to ischemic regions and ameliorating chronic angina. Clinical trial results of the above-mentioned techniques have been encouraging but are based on small sample sizes to justify their widespread application. Other interventional approaches, such as transmyocardial laser revascularization, extracorporeal shockwave myocardial revascularization, and spinal cord stimulation, have been met with either controversial or negative results, and their use is not recommended. Lastly, angiogenic therapy with targeted intramyocardial vascular endothelial growth factor injection or CD34+ cell therapy may be beneficial and warrants further investigation. In this review, we summarize the current knowledge in the field of angina management, highlighting the potential and the gaps in the existing evidence that ought to be addressed in future larger-scale, randomized studies before these techniques can be safely adapted in the clinical practice of patients with refractory angina pectoris.

Adhesion Molecules as Prognostic Biomarkers in Coronary Artery Disease.

Atherosclerosis is a progressive disease, culminating in the production of atherosclerotic plaques in arteries through intricate pathophysiological processes. The progression of this disorder is based on the effect of triggering factors -mainly hyperlipidemia, diabetes mellitus, arterial hypertension, and smoking- on the endothelium. Coronary artery disease (CAD) is an atherosclerotic disease with a higher prevalence among individuals. Pro- and anti-inflammatory cytokines are the main contributors to atherosclerotic plaque formation. CAD and its manifestations multifactorial affect patients' quality of life, burdening the global healthcare system. Recently, the role of adhesion molecules in CAD progression has been recognized. Physicians delve into the pathophysiologic basis of CAD progression, focusing on the effect of adhesion molecules. They are proteins that mediate cell-cell and cell-extracellular matrix interaction and adhesion, driving the formation of atherosclerotic plaques. Several studies have assessed their role in atherosclerotic disease in small cohorts and in experimental animal models as well. Furthermore, several agents, such as nanoparticles, have been introduced modifying the main atherosclerotic risk factors as well as targeting the endothelial inflammatory response and atherosclerotic plaque stabilization. In this review, we discuss the role of adhesion molecules in atherosclerosis and CAD progression, as well as the potential to be used as targeting moieties for individualized treatment.

Extracellular Matrix Remodeling Biomarkers in Coronary Artery Disease.

Atherosclerosis and one of its most serious consequences, coronary artery disease, are important sources of morbidity and mortality globally, necessitating early detection and treatment. Considering their complex pathophysiology, including several harmful processes, a comprehensive approach to diagnosis, prognosis, and therapy is very desirable. Extracellular matrix remodeling is a major component of this dangerous cascade, including the cleavage of constituents (collagen, elastin, proteoglycans) and the propagation or exacerbation of the inflammatory response. Several extracellular matrix degradation indicators have been hypothesized to correlate with the existence, severity, and prognosis of coronary artery disease. The potency of matrix metalloproteinases, notably collagenases and gelatinases, has been the most thoroughly investigated in clinical studies. Stromelysins, matrilysins, transmembrane matrix metalloproteinases, collagen and laminin turnover indicators, as well as fibronectin, have also been studied to a lesser level. Among the most well-studied markers, MMP-1, MMP-2, MMP-8, and MMP-9 have been found increased in patients with cardiovascular risk factors such as metabolic syndrome, its components (obesity, dyslipidemia, diabetes mellitus), and smoking. Increasing concentrations are detected in acute coronary syndromes compared to stable angina pectoris and healthy control groups. It should also be stressed that those extracellular matrix biomarkers may also be detected in high concentrations in other vascular pathologies such as peripheral artery disease, carotid artery disease, aortic aneurysms, and dissections. Despite the advances gained, future research should focus on their importance and, more crucially, their added utility as biomarkers in identifying persons at risk of developing overt coronary artery disease. At the same time, determining the prognosis of coronary artery disease patients using such biomarkers may be important for their adequate care.

The impact of SGLT2 inhibitors on inflammation: A systematic review and meta-analysis of studies in rodents.

BACKGROUND: Inhibition of sodium-glucose cotransporter-2 (SGLT2) has received remarkable attention due to the beneficial effects observed in diabetes mellitus, heart failure, and kidney disease. Several mechanisms have been proposed for these pleiotropic effects, including anti-inflammatory ones. Our systematic review and meta-analysis aimed to assess the effect of SGLT2 inhibition on inflammatory markers in experimental models. METHODS: A literature search was conducted to detect studies examining the effect of SGLT2 inhibitors on inflammatory markers [interleukin-6 (IL-6), C reactive protein (CRP), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1)]. Consequently, a meta-analysis of the included studies was performed, assessing the differences in the levels of the inflammatory markers between the treatment groups as its primary outcome. Moreover, risk of bias, sensitivity analysis and publication bias were evaluated. RESULTS: The systematic literature review yielded 30 studies whose meta-analysis suggested that treatment with an SGLT2 inhibitor resulted in decreases of IL-6 [standardized mean difference (SMD): -1.56, 95% CI -2.06 to -1.05), CRP (SMD: -2.17, 95% CI -2.80 to -1.53), TNF-α (SMD: -1.75, 95% CI -2.14 to -1.37), and MCP-1 (SMD: -2.04, 95% CI -2.91 to -1.17). The effect on CRP and TNF-α was of lesser magnitude in cases of empagliflozin use. Moderate-to-substantial heterogeneity and possible publication bias were noted. The findings remained largely unaffected after the sensitivity analyses, the exclusion of outlying studies, and trim-and-fill analyses. CONCLUSION: The present meta-analysis suggests that SGLT2 inhibition results in reduction of inflammatory markers in animal models, further validating the suggested anti-inflammatory mechanism of action.

Genetic Predisposition and Inflammatory Inhibitors in COVID-19: Where Do We Stand?

Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and the resulting coronavirus disease-19 (COVID-19) have led to a global pandemic associated with high fatality rates. COVID-19 primarily manifests in the respiratory system as an acute respiratory distress syndrome following viral entry through the angiotensin-converting enzyme-2 (ACE2) that is present in pulmonary epithelial cells. Central in COVID-19 is the burst of cytokines, known as a "cytokine storm", and the subsequent widespread endothelial activation, leading to cardiovascular complications such as myocarditis, arrhythmias, and adverse vascular events, among others. Genetic alterations may play an additive, detrimental role in the clinical course of patients with COVID-19, since gene alterations concerning ACE2, major histocompatibility complex class I, and toll-like receptors may predispose patients to a worse clinical outcome. Since the role of inflammation is quintessential in COVID-19, pharmacologic inhibition of various signaling pathways such as the interleukin-1 and -6, tumor necrosis factor-alpha, interferon gamma, Janus kinase-signal transducer and activator of transcription, and granulocyte-macrophage colony-stimulating factor may ameliorate the prognosis following timely administration. Finally, frequently used, non-specific anti-inflammatory agents such as corticosteroids, statins, colchicine, and macrolides represent additional therapeutic considerations.

A Systematic Review and Meta-Analysis on the Efficacy and Safety of Direct Oral Anticoagulants in Patients with Peripheral Artery Disease.

BACKGROUND: PAD is a significant cause of morbidity and mortality affecting over 200 million people worldwide. Current guidelines recommend at least a single antiplatelet or anticoagulant agent in symptomatic PAD and lifelong antithrombotic treatment after a revascularization procedure. The aim of this systematic review and meta-analysis was to investigate the efficacy and safety of direct oral anticoagulants (DOACs) in patients with peripheral artery disease (PAD). PAD is a significant cause of morbidity and mortality affecting over 200 million people worldwide. METHODS: The present systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Risk ratios (RR) were calculated using the random effects model. RESULTS: Overall, 10 studies were included in this systematic review and meta-analysis. In 4 studies, 14,257 patients with PAD were enrolled and they were assigned to receive either aspirin (ASA)+/- clopidogrel (N = 5,894) or DOAC+/- anti-platelet (e.g., ASA, clopidogrel) (n = 8,363). Non DOAC users were found to have higher reintervention rates (RR 1.12; 95% CI 1.01-1.24; P = 0.025) compared to DOAC users. No statistically significant difference was observed between the 2 groups, in terms of major bleeding (RR 0.78; 95% CI 0.50-1.23; P = 0.285), all-cause mortality (RR 0.98; 95% CI: 0.83-1.16; P = 0.818) and cardiovascular mortality (RR: 0.99; 95% CI: 0.73-1.333; P = 0.946) mortality. In addition, two real-world studies comparing DOAC with warfarin showed decreased rates of major cardiovascular events in the DOAC group. CONCLUSION: DOAC use alone or combined with an anti-platelet agent could be associated with lower re-intervention rates, without increasing the risk for adverse bleeding events. However, this study failed to detect any difference in terms of all-cause mortality, MACEs and MALEs between DOAC users and DOAC naïve patients. Future studies are needed to better determine the efficacy and safety of DOACs in patients with PAD.

Inflammation in Coronary Microvascular Dysfunction.

Chronic low-grade inflammation is involved in coronary atherosclerosis, presenting multiple clinical manifestations ranging from asymptomatic to stable angina, acute coronary syndrome, heart failure and sudden cardiac death. Coronary microvasculature consists of vessels with a diameter less than 500 µm, whose potential structural and functional abnormalities can lead to inappropriate dilatation and an inability to meet the required myocardium oxygen demands. This review focuses on the pathogenesis of coronary microvascular dysfunction and the capability of non-invasive screening methods to detect the phenomenon. Anti-inflammatory agents, such as statins and immunomodulators, including anakinra, tocilizumab, and tumor necrosis factor-alpha inhibitors, have been assessed recently and may constitute additional or alternative treatment approaches to reduce cardiovascular events in atherosclerotic heart disease characterized by coronary microvascular dysfunction.

Transcervical carotid artery revascularization: A systematic review and meta-analysis of outcomes.

OBJECTIVE: Carotid artery stenosis is considered a determinant factor for cerebrovascular events, estimated to be the cause of 10% to 20% of all ischemic strokes. Transcervical carotid artery revascularization (TCAR) has been offered as an alternative to transfemoral carotid artery stenting and carotid endarterectomy to treat carotid artery stenosis. METHODS: We performed a systematic review and meta-analysis of prospective and retrospective studies reporting the outcomes of patients who had undergone TCAR for carotid artery stenosis. The incidence of periprocedural adverse events was calculated. RESULTS: A total of 45 studies with 14,588 patients met the predefined eligibility criteria and were included in the present meta-analysis. The technical success rate was 99% (95% confidence interval [CI], 98%-99%). The reasons for technical failure included an inability to cross the lesion and/or failure to deploy the stent. Access site complications occurred in 2% of all cases (95% CI, 1%-2%; 30 studies). Overall, the incidence of cranial nerve (CN) injuries was very rare, with only 33 of 8994 patients experiencing neurologic deficits attributed to CN involvement. Bleeding complications were reported by 20 studies and occurred in 2% (95% CI, 1%-3%) of all cases. The overall periprocedural all-cause mortality and stroke rate was 0.5% and 1.3%, respectively. In-stent restenosis was observed in 4 of 260 patients (1.5%; 7 studies), and early (30-day) reocclusion or acute thrombosis of the target lesion occurred in 12 of 1243 patients (∼1%; 11 studies). CONCLUSIONS: The results from the present study have provided significant evidence that TCAR is a very promising and safe carotid revascularization approach with favorable technical success rates associated with low periprocedural stroke and CN injury rates.

Revascularization approaches in patients with radiation-induced carotid stenosis: an updated systematic review and meta-analysis.

BACKGROUND: Ionizing radiation remains a well-known risk factor of carotid artery stenosis. The survival rates of head and neck cancer patients undergoing radiotherapy have risen owing to medical advancements in the field. As a consequence, the incidence of carotid artery stenosis in these high-risk patients has increased. AIMS: In this study we sought to compare the outcomes of carotid endarterectomy (CEA) vs carotid artery stenting (CAS) for radiation-induced carotid artery stenosis. METHODS: This study was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Eligible studies were identified through a comprehensive search of PubMed, Scopus and Cochrane Central until July 2020. A random-effects model meta-analysis was conducted, and odds ratios (ORs) were calculated. The I-square statistic was used to assess for heterogeneity. RESULTS: Seven studies and 201 patients were included. Periprocedural stroke, myocardial infarction (MI), and death rates were similar between the two revascularization approaches. However, the risk for cranial nerve (CN) injury was higher in the CEA group (OR, 7.40; 95% CI, 1.58-34.59; I2 = 0%). Analysis revealed no significant difference in terms of long-term mortality (OR, 0.41; 95% CI, 0.14-1.16; I2 = 0%) and restenosis rates (OR, 0.69; 95% CI, 0.29-1.66; I2 = 0%) between CEA and CAS after a mean follow-up of 40.5 months. CONCLUSIONS: CAS and CEA appear to have a similar safety and efficacy profile in patients with radiation-induced carotid artery stenosis. Patients treated with CEA have a higher risk for periprocedural CN injuries. Future prospective studies are warranted to validate these results.

Abdominal aortic aneurysms and abdominal wall hernias - a systematic review and meta-analysis.

Background: Abdominal wall hernias (AWHs) share common epidemiological characteristics with abdominal aortic aneurysms (AAAs), typically presenting in male population and older ages. Prior reports have associated those two disease entities. Our objective was to perform a systematic review and meta-analysis and examine whether AAA rates are higher among patients with AWH vs controls and whether the incidence of AWH was higher among patients with AAA vs patients without AAA. Methods: We performed a systematic review and meta-analysis according to the PRISMA guidelines. The Medline database was searched up to July 31, 2020. A random effects meta-analysis was performed. Results: In total, 17 articles and 738,972 participants were included in the systematic review, while 107,578 patients were eligible for the meta-analysis. Among four studies investigating the incidence of AAA in patients with hernias, AAA was more common in patients with hernias, compared to patients without hernias. [OR: 2.53, 95% CI: 1.24-5.16, I2=81.6%]. Among thirteen studies that compared patients with known AAA vs no AAA, the incidence of hernias was higher in patients with AAA, compared with patients without AAA [OR: 2.27, 95% CI: 1.66-3.09, I2=84.6%]. Conclusions: Our study findings indicate that a strong association between AWH and AAA exists. AWHs could therefore be used as an additional selection criterion for screening patients for AAA, apart from age, gender, family history and smoking.