Current Vascular Pharmacology - Volume 20, Issue 1, 2022

Contrast-induced Nephropathy (CIN) is animportant complication of iodinated Contrast Medium (CM) administration, being associated with both short- and long-term adverse outcomes (e.g., cardiorenal events, longer hospital stay and mortality). CIN has been mainly studied in relation to cardiac procedures but it can also occur following non-cardiac vascular interventions. This is Part 1 of a narrative review summarizing the available literature on CIN after non-cardiac vascular diagnostic or therapeutic procedures for aortic aneurysm and carotid stenosis. We discuss the definition, pathophysiology, incidence, risk factors, biomarkers and consequences of CIN in these settings, as well as preventive strategies and alternatives to limit iodinated CM use. Physicians and vascular surgeons should be aware of CM-related adverse events and the potential strategies to avoid it. Clearly, more research in this important field is required.

This is Part 2 of a narrative review summarizing the literature on CIN after non-cardiac vascular diagnostic or therapeutic procedures, focusing on Peripheral Artery Disease (PAD) and Renal Artery Stenosis (RAS). Part 1 discussed CIN in relation to aortic aneurysms and carotid stenosis. We comment on the incidence, biomarkers, risk factors and consequences of CIN in patients with PAD or RAS, as well as on strategies to prevent CIN. Future perspectives in the field of CIN in relation to non-cardiac vascular procedures are also considered.

Trimethylamine N-oxide (TMAO) is a gut microbiota metabolite derived from trimethylamine- containing nutrient precursors such as choline, L-carnitine, and betaine, which are rich in many vegetables, fruits, nuts, dairy products, and meats. An increasing number of clinical studies have demonstrated a strong relationship between elevated plasma TMAO levels and adverse cardiovascular events. It is commonly agreed that TMAO acts as an independent risk factor and a prognostic index for patients with cardiovascular disease. Although most animal (mainly rodent) data support the clinical findings, the mechanisms by which TMAO modulates the cardiovascular system are still not well understood. In this context, we provide an overview of the potential mechanisms underlying TMAO-induced cardiovascular diseases at the cellular and molecular levels, with a focus on atherosclerosis. We also address the direct effects of TMAO on cardiomyocytes (a new and under-researched area) and finally propose TMAO as a potential biomarker and/or therapeutic target for diagnosis and treatment of patients with cardiovascular disease.

Patients at High Bleeding Risk (HBR) are a sizable part of the population undergoing Percutaneous Coronary Intervention (PCI) and stent implantation. This population historically lacks standardized definition, thus limiting trial design, data generalizability, and clinical decision-- making. To overcome this limitation, the Academic Research Consortium (ARC) has recently released comprehensive guidelines defining HBR criteria for study design purposes and daily clinical practices. Furthermore, several risk scores have been developed aiming to discriminate against HBR patients and support physicians for clinical decision-making when faced with this complex subset of patients. Accordingly, the first part of this review article will explore guideline-recommended risk scoring as well as ARC-HBR criteria and their relative application for daily clinical practice. The second part of this review article will explore the complex interplay between the risk of bleeding and coronary thrombotic events in patients deemed at HBR. Indeed, several features that identify these patients are also independent predictors of recurrent ischemic events, thus challenging revascularization strategies and optimal antithrombotic therapy. Accordingly, several clinical trials have been conducted to evaluate the safety and efficacy of the new generation of coronary platforms and different antithrombotic strategies for HBR patients to minimize both ischemic and bleeding events. Accordingly, in this part, we discuss current guidelines, trials, and observational data evaluating antithrombotic strategies and stent technologies for patients at HBR.

Background: Heart failure is a major cause of morbidity and mortality globally. By the end of this decade, ∼8 million Americans will have heart failure with an expenditure of $69.8 billion. Objective: In this narrative review, we evaluate the benefits, potential risks and the role of Mineralocorticoid Receptor Antagonists (MRAs) in the management of both Heart Failure with Preserved Ejection Fraction (HFpEF) and Heart Failure with Reduced Ejection Fraction (HFrEF). Methods: We performed a comprehensive literature review to assess the available evidence on the role of MRAs in heart failure using the online databases (PubMed, Embase, Scopus, CINAHL and Google Scholar). Results: Clinical evidence shows that MRAs such as spironolactone and eplerenone reduce mortality and readmissions for patients with HFrEF compared with placebo. Furthermore, one trial reported that MRAs reduce heart failure hospitalization in patients with HFpEF. The American College of Cardiology/American Heart Association Guidelines strongly recommend using MRA in patients with reduced Left Ventricular Ejection Fraction (LVEF) with Class II-IV symptoms, estimated glomerular filtration rate >30 ml/min/1.73 m², and absence of hyperkalemia. Despite this, MRAs are underutilized in the management of heart failure. Conclusions: MRAs improve outcomes in patients with both HFpEF and HFrEF but remain underutilized.

Arterial Stiffness (AS) describes the rigidity of the arterial walls. Epidemiological studies have shown that increased AS is an independent predictive marker of Cardiovascular (CV) morbidity and mortality in both pregnant and non-pregnant women. Preeclampsia (PE), a form of pregnancy-induced hypertension, affects approximately 5% of pregnancies worldwide. Preeclamptic women have a higher risk of CV Disease (CVD), mainly because PE damages the heart’s ability to relax between contractions. Different pharmacological approaches for the prevention of PE have been tested in clinical trials (e.g., aspirin, enoxaparin, metformin, pravastatin, and sildenafil citrate). In current clinical practice, only low-dose aspirin is used for PE pharmacoprevention. However, low-dose aspirin does not prevent term PE, which is the most common form of PE. Compromised vascular integrity precedes the onset of PE and therefore, AS assessment may constitute a promising predictive marker of PE. Several non-invasive techniques have been developed to assess AS. Compared with normotensive pregnancies, both Carotid-Femoral Pulse Wave Velocity (cfPWV) and Augmentation Index (AIx) are increased in PE. In view of simplicity, reliability, and reproducibility, there is an interest in oscillometric AS measurements in pregnancies complicated by PE.

Background: Takayasu arteritis (TAK) is a rare autoimmune vasculitis that predominantly affects the aorta and its major branches, including the coronary arteries. Information is limited regarding sex-specific differences in coronary artery involvement among TAK patients. Objective: To assess the differences in coronary angiographic findings and long-term outcomes between male and female TAK patients with coronary artery involvement. Methods: This retrospective cohort study included 87 TAK patients, grouped by sex, who underwent coronary angiography. General characteristics, clinical features, coronary angiographic findings, and therapeutic strategies were obtained from medical records. Major Adverse Cardiac Events (MACE), including death from any cause, myocardial infarction, repeated coronary artery revascularization, and rehospitalization due to unstable or progressive angina or heart failure occurring during follow-up, were also recorded. Results: A total of 207 coronary lesions with stenosis were found in 87 TAK patients. The prevalence of ostial coronary lesions was lower in men than in women (9.1 vs. 23.9%, p=0.031). We observed less moderate stenosis (6.8 vs. 22.7%, p=0.018) and more severe stenosis or occlusion (70.5 vs. 46.0%, p=0.004) in the coronary lesions of male TAK patients. During the up to 7-year follow- up, death from any cause was greater in men than in women (21.4 vs. 1.5%, p=0.003); no other significant differences in MACE occurrence were observed between sexes. Conclusion: Among TAK patients with coronary artery involvement, males tend to have more serious coronary stenosis and a higher risk for long-term mortality than females.

Background and Aim: Negatively charged nanoliposomes have a strong attraction towards plasma lipoprotein particles and can thereby regulate lipid metabolism. Here, the impact of such nanoliposomes on dyslipidaemia and progression of atherosclerosis was investigated in a rabbit model. Methods: Two sets of negatively-charged nanoliposome formulations including [Hydrogenated Soy Phosphatidylcholine (HSPC)/1,2-distearoyl-sn-glycero-3- phosphoglycerol (DSPG)] and [1,2- Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC)/1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPG)/Cholesterol] were evaluated. Rabbits fed a high-cholesterol diet were randomly divided into 3 groups (n=5/group) intravenously administrated with HSPC/DSPG formulation (DSPG group; 100 mmol/kg), DMPC/DMPG formulation (DMPG group; 100 mmol/kg), or the normal saline (control group; 0.9% NaCl) over a 4-week period. The atherosclerotic lesions of the aortic arch wall were studied using haematoxylin and eosin staining. Results: Both DSPG and DMPG nanoliposome formulations showed a nano-sized range in diameter with a negatively-charged surface and a polydispersity index of <0.1. After 4 weeks administration, the nanoliposome formulations decreased triglycerides (-62±3% [DSPG group] and -58±2% [DMPG group]), total cholesterol (-58±9% [DSPG group] and -37±5% [DMPG group]), and lowdensity lipoprotein cholesterol (-64±6% [DSPG group] and -53±10% [DMPG group]) levels, and increased high-density lipoprotein cholesterol (+67±28% [DSPG group] and +35±19% [DMPG group]) levels compared with the controls. The nanoliposomes showed a significant decrease in the severity of atherosclerotic lesions: mean values of the intima to media ratio in DMPG (0.96±0.1 fold) and DSPG (0.54±0.02 fold) groups were found to be significantly lower than that in the control (1.2±0.2 fold) group (p<0.05). Conclusion: Anionic nanoliposomes containing [HSPC/DSPG] and [DMPC/DMPG] correct dyslipidaemia and inhibit the progression of atherosclerosis.

Background: Coronavirus Disease 2019 (COVID-19) is associated with Coagulopathy (CAC) and Venous Thromboembolism (VTE). These are well-reported complications of COVID-19 infection. Earlier publications have shown that CAC and thromboembolism are predictors of mortality among COVID-19 patients with severe disease. Materials and Methods: A prospective study was conducted in the Intensive Care Unit (ICU) where all confirmed COVID-19 patients were enrolled and followed until death or ICU discharge. CAC, VTE, along with all comorbidities, were recorded. Predictors of mortality were determined by univariate and multivariate regression. Results: Among 261 patients with COVID-19, 48.3% survived and 51.7% died. CAC was present in 53.2% and 76.3% of the survivors and non-survivors, respectively (p<0.001); 89 patients (31.4%) had VTE (p=0.36) and 11 patients (4.2%) had arterial thrombosis (p=0.76) among survivors and nonsurvivors. Age between 71-80 years (p=0.009), male gender (p=0.045), CAC (p<0.001), comorbidities like chronic kidney disease (CKD, p=0.013), chronic obstructive pulmonary disease (COPD, p=0.001) and asthma (p=0.046), were significant predictors of mortality. Conclusion: A severe complication of COVID-19 is CAC, such as sepsis-induced coagulopathy, overt disseminated-coagulopathy and VTE. Old age, various comorbidities (e.g., COPD, CKD, or asthma), CAC, VTE (pulmonary embolism) and coagulation parameters with critical severity score (D-dimers, platelets, prothrombin time) and the SOFA (Sequential Organ Failure Assessment) score were significant predictors of mortality among COVID-19 patients.

Background: Epicardial Adipose Tissue (EAT) surrounds the epicardium and can mediate harmful effects related to Coronary Artery Disease (CAD). Objective: We explored the regional differences between adipose stores surrounding diseased and non-diseased segments of coronary arteries in patients with advanced CAD. Methods: We enrolled 32 patients with known CAD who underwent coronary artery bypass graft (CABG) surgery. Inflammatory mediators were measured in EAT biopsies collected from a region of the Left Anterior Descending Artery (LAD) with severe stenosis (diseased segment) and without stenosis (non-diseased segment). Results: Mean age was 64.3±11.1 years, and mean EAT thickness was 7.4±1.9 mm. Dyslipidemia was the most prevalent comorbidity (81% of the patients). Out of a total of 11 cytokines, resistin (p=0.039), matrix metallopeptidase 9 (MMP-9) (p=0.020), C-C motif chemokine ligand 5 (CCL-5) (p=0.021), and follistatin (p=0.038) were significantly increased in the diseased compared with the non-diseased EAT segments. Indexed tumor necrosis factor-alpha (TNF-α), defined as the diseased to non-diseased cytokine levels ratio, was significantly correlated with increased EAT thickness both in the whole cohort (p=0.043) and in a subpopulation of patients with dyslipidemia (p=0.009). Treatment with lipid-lowering agents significantly decreased indexed TNF-α levels (p=0.015). No significant alterations were observed in the circulating levels of these cytokines with respect to CAD-associated comorbidities. Conclusion: Perivascular EAT is a source of cytokine secretion in distinct areas surrounding the coronary arteries in patients with advanced CAD. Adipocyte-derived TNF-α is a prominent mediator of local inflammation.

Background: Venous Thromboembolism (VTE) is common among patients with severe Coronavirus Disease 2019 (COVID-19). Anticoagulation in hospitalized COVID-19 patients has been associated with survival benefit; however, the optimal thromboprophylaxis strategy has not yet been defined. Objective: To identify published guidance reports by national and international societies regarding thromboprophylaxis strategies in COVID-19 patients in different settings (outpatients, hospitalized, post-discharge). Methods: A systematic review of the literature (Pubmed/EMBASE) was conducted independently by two investigators. Results: Among 1942 initially identified articles, 33 guidance documents were included: 20 published by national and 13 by international societies. These documents provide recommendations mainly for hospitalized (97% of reports) and post-discharge (75%) COVID-19 patients, and less so for outpatients (34%). Thrombotic and bleeding risk stratification prior to any treatment decision is the cornerstone of all suggested thromboprophylaxis strategies; 81% of the documents recommend thromboprophylaxis for all hospitalized patients with a prophylactic dosage of low molecular weight heparin irrespective of VTE risk. Intermediate or therapeutic dose intensity is recommended in high VTE risk patients by 56% and 28% of documents, respectively. Mechanical thromboprophylaxis is suggested in case of high bleeding risk or contraindication to pharmacological thromboprophylaxis (59% of documents). Extended pharmacological thromboprophylaxis is recommended for patients with high VTE risk after hospital discharge (63% of documents). For non-hospitalized outpatients, 28% of documents recommend pharmacological thromboprophylaxis for high VTE risk. Conclusion: The current guidance identifies thromboprophylaxis in COVID-19 patients, especially during hospitalization, as of major importance for the prevention of VTE. Recommendations are derived from limited evidence from observational studies.