Current Vascular Pharmacology - Volume 19, Issue 5, 2021

IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) was a randomized clinical trial (including 18,144 patients) that evaluated the efficacy of the combination of ezetimibe with simvastatin vs. simvastatin monotherapy in patients with acute coronary syndrome (ACS) and moderately increased low-density lipoprotein cholesterol (LDL-C) levels (of up to 2.6-3.2 mmol/L; 100-120 mg/dL). After 7 years of follow-up, combination therapy resulted in an additional LDL-C decrease [to 1.8 mmol/L, or 70 mg/dL, within the simvastatin (40 mg/day) monotherapy arm and to 1.4 mmol/L, or 53 mg/dL for simvastatin (40 mg/day) + ezetimibe (10 mg/day)] and showed an incremental clinical benefit [composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke; hazard ratio (HR) of 0.936, and 95% CI 0.887-0.996, p=0.016]. Therefore, for very high cardiovascular risk patients “even lower is even better” regarding LDL-C, independently of the LDL-C reducing strategy. These findings confirm ezetimibe as an option to treat very-high-risk patients who cannot achieve LDL-C targets with statin monotherapy. Additional analyses of the IMPROVE-IT (both prespecified and post-hoc) include specific very-high-risk subgroups of patients (those with previous acute events and/or coronary revascularization, older than 75 years, as well as patients with diabetes mellitus, chronic kidney disease or non-alcoholic fatty liver disease). The data from IMPROVE-IT also provide reassurance regarding longer-term safety and efficacy of the intensification of lipid-lowering therapy in very-high-risk patients resulting in very low LDL-C levels. We comment on the results of several (sub) analyses of IMPROVE-IT.

In this second part of the review of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), the findings in relation to patients with stroke, the ACS phenotype, history of coronary artery bypass graft surgery, heart failure, concurrent polyvascular atherosclerotic cardiovascular disease (ASCVD) and diabetes mellitus, and different levels of expression of selected cardiovascular biomarkers, are discussed. The combination therapy was proven safe, and drug discontinuation rates were not increased by adding ezetimibe. Since both statins and ezetimibe are now almost globally generically available, it can be concluded that for secondary prevention of ASCVD, adding ezetimibe to high-intensity statin therapy further reduces low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, cost-effectively.

Background: Having in mind that diabetes mellitus (DM) and obesity are some of the greatest health challenges of the modern era, diabetic cardiomyopathy (DCM) is becoming more and more recognized in clinical practice. Main Text: Initially, DM is asymptomatic, but it may progress to diastolic and then systolic left ventricular dysfunction, which results in congestive heart failure. A basic feature of this DM complication is the absence of hemodynamically significant stenosis of the coronary blood vessels. Clinical manifestations are the result of several metabolic disorders that are present during DM progression. The complexity of metabolic processes, along with numerous regulatory mechanisms, has been the subject of research that aims at discovering new diagnostic (e.g. myocardial strain with echocardiography and cardiac magnetic resonance) and treatment options. Adequate glycaemic control is not sufficient to prevent or reduce the progression of DCM. Contemporary hypoglycemic medications, such as sodium-glucose transport protein 2 inhibitors, significantly reduce the frequency of cardiovascular complications in patients with DM. Several studies have shown that, unlike the above-stated medications, thiazolidinediones and dipeptidyl peptidase-4 inhibitors are associated with deterioration of heart failure. Conclusion: Imaging procedures, especially myocardial strain with echocardiography and cardiac magnetic resonance, are useful to identify the early signs of DCM. Research and studies regarding new treatment options are still “in progress”.

Since the discovery of ischemic pre- and post-conditioning, more than 30 years ago, the knowledge about the mechanisms and signaling pathways involved in these processes has significantly increased. In clinical practice, on the other hand, such advancement has yet to be seen. This article provides an overview of ischemic pre-, post-, remote, and pharmacological conditioning related to the heart. In addition, we reviewed the cardioprotective signaling pathways and therapeutic agents involved in the above-mentioned processes, aiming to provide a comprehensive evaluation of the advancements in the field. The advancements made over the last decades cannot be ignored and with the exponential growth in techniques and applications. The future of pre- and post-conditioning is promising.

Due to its poor regenerative capacity, the heart is specifically vulnerable to xenobiotic- induced cardiotoxicity, myocardial ischaemia/reperfusion injury and other pathologies. Nuclear factor erythroid-2-related factor 2 (Nrf2) is considered as an essential factor in protecting cardiomyocytes against oxidative stress resulting from free radicals and reactive oxygen species. It also serves as a key regulator of antioxidant enzyme expression via the antioxidant response element, a cis-regulatory element, which is found in the promoter region of several genes encoding detoxification enzymes and cytoprotective proteins. It has been reported that a variety of natural products are capable of activating Nrf2 expression, and in this way, increase the antioxidant potential of cardiomyocytes. In the present review, we consider the cardioprotective activities of natural products and their possible therapeutic potential.

Background: Clopidogrel monotherapy is guideline-recommended in symptomatic peripheral artery disease (PAD). The advent of new antithrombotic strategies prompts an updated analysis of available evidence on antiplatelet therapy for PAD. Methods: We searched MEDLINE, Embase and CENTRAL through January 2019 for randomised controlled trials and observational studies comparing antiplatelet therapies as monotherapy, dual therapy, or combination with anticoagulants. Efficacy (major adverse cardiovascular events, acute or chronic limb ischaemia, vascular amputation, peripheral revascularisation) and safety (all-cause mortality and overall bleeding) outcomes were evaluated via Bayesian network meta-analyses. Results: We analysed 26 randomised controlled trials. Clopidogrel (hazard ratio, HR, 0.78; 95% credible interval [CrI] 0.65-0.93) and ticagrelor (HR 0.80; 95% CrI 0.65-0.98) significantly reduced major adverse cardiovascular events risk compared with aspirin. No significant difference was observed for dual antiplatelet therapy with clopidogrel and aspirin. Vorapaxar significantly reduced limb ischaemia and revascularisation compared with placebo, while dual antiplatelet therapy with clopidogrel and aspirin showed a trend for reduced risk of amputation compared with aspirin (risk ratio 0.68; 95% CrI 0.43-1.04). For all-cause mortality, picotamide, vorapaxar, dipyridamole with aspirin, and ticlopidine showed a significantly lower risk of all-cause mortality vs aspirin. Clopidogrel and ticagrelor showed similar overall bleeding risk vs aspirin, while dual antiplatelet therapy with clopidogrel and aspirin significantly increased bleeding risk. Conclusion: This updated network meta-analysis confirms that clopidogrel significantly decreases the risk of major adverse cardiovascular events compared with aspirin, without increasing bleeding risk. Clopidogrel should remain a mainstay of PAD treatment, at least in patients at higher bleeding risk.

Introduction: Cardiovascular (CV) complications are the most frequent cause of morbidity and mortality in autosomal dominant polycystic kidney disease (ADPKD) patients. In 2017, the Italian Medicines Agency authorised tolvaptan, a vasopressin V2 receptor antagonist, for the treatment of ADPKD, based on the Tolvaptan Phase 3 Efficacy and Safety Study in ADPKD (TEMPO 3: 4), TEMPO 4: 4 and Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) studies. Aim of the Study: The aim of the study was to assess the impact of tolvaptan on CV risk and quality of life, evaluated by nutritional, inflammatory, metabolic, instrumental parameters and psychocognitive tests on ADPKD patients. Methods and Materials: We evaluated 36 patients with ADPKD; 10 patients (7 males, mean age 42.5±7.0 years) treated with tolvaptan and 26 controls (11 males, mean age 36.7±9.1 years). They underwent, at T0, monthly, and at T1 (1 year) clinical, laboratory and instrumental evaluation, in addition to psychocognitive tests. Results: In ADPKD patients treated with tolvaptan, we found at T1, a decrease in carotid intima-- media thickness (p=0.048), epicardial adipose tissue thickness (p=0.002), C-reactive protein (p=0.026), sympathovagal balance during night (p=0.045) and increased flow-mediated dilation (p=0.023) with a reduction in depression (Hamilton and Beck tests, p=0.008 and p=0.002, respectively) compared with controls. Conclusion: These preliminary results suggest that treatment with tolvaptan could improve early atherosclerosis and endothelial dysfunction markers and improve mood in ADPKD patients (probably by acting on endothelial cell and adipocyte V2 receptors).

Objective: Non-adherence to antihypertensive agents leads to reduced blood pressure (BP) control. Data supporting the correlation of adherence with arterial stiffness (AS) are few. Furthermore, the causal relationship between AS and cognitive dysfunction (CO/DY) has not been clearly established. It is suggested that angiotensin II receptor blockers (ARBs) exhibit the lowest discontinuation rate among antihypertensive drugs. Design and Methods: We followed up with patients receiving monotherapy with irbesartan. CO/DY was assessed with the Mini-Mental State Examination (MSE) and other tests. Results: Patients [n=77; mean age: 56±11 years; 39 men (50.6%)] were followed-up for 16.1±10.9 months. At the end of follow up, significant reductions were observed in mean peripheral systolic BP (135±117 vs 153±11 mmHg; p<0.005), mean peripheral diastolic BP (85±11 vs 95±10 mmHg; p<0.005), mean central systolic BP (130±11 vs 142±12 mmHg; p<0.005) as well as in mean central diastolic BP (85±8 vs 95±97 mmHg; p<0.005). AS indices [carotid-femoral pulse wave velocity and augmentation index] also improved significantly: 7.7±1.4 vs 8.2±1.4 m/sec (p<0.005), and 29.1±8.3 vs 32.3±9.1 (p<0.005), respectively. At the end of the study, a significant improvement was observed in the MMSE test (29.7±0.7 vs. 29.2±0.9; p<0.02), as well as a significant reduction in 24h urine albumin (94±82 vs. 204±112 mg/24h, p<0.005). The level of adherence was high in 60/77 (77.9%), medium in 9/77 (11.6%) and low in 8/77 (10.38%) patients. Conclusion: Hypertensive patients receiving mono-therapy with an ARB showed reduced AS, cognitive improvement, significant reductions in BP (peripheral and central) and decreased 24h urinary albumin excretion.

Background: Non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), are major health problems worldwide. Genetics may play a role in the pathogenesis of NAFLD/NASH. Aims: To investigate the prevalence of NAFLD/NASH in 5,400 military personnel and evaluate the effect of treatment with 3 statins on NAFLD/NASH using 2 non-invasive scores [NAFLD Activity Score (NAS); Fibrosis-4 score (FIB-4)]. Methods: During the mandatory annual medical check-up, military personnel underwent a clinical and laboratory evaluation. Participants with NAFLD/NASH were randomized into 4 groups (n=151 each): diet-exercise, atorvastatin, rosuvastatin, or pitavastatin for 1 year (i.e., until the next routine evaluation). Results: From all the participants, 613 had NAFLD/NASH (prevalence 11.3 vs 39.8% in the general population, p<0.001), and a total of 604 consented to participate in the study. After a year of treatment, the diet-exercise group showed no significant changes in both scores (NAS 4.98 baseline vs. 5.62, p=0.07; FIB-4 3.42 vs. 3.52, p=0.7). For the atorvastatin group, both scores were reduced (NAS 4.97 vs 1.95, p<0.001, FIB-4 3.56 vs 0.83, p<0.001), for rosuvastatin (NAS 5.55 vs 1.81, p<0.001, FIB-4 3.61 vs 0.79, p<0.001), and for pitavastatin (NAS 4.89 vs 1.99, p<0.001, FIB-4 3.78 vs 0.87, p<0.001). Conclusion: Atorvastatin, rosuvastatin, and pitavastatin have a beneficial and safe effect in NAFLD/NASH patients as recorded by the improvement in the NAS (representing NAFLD activity) and FIB-4 (representing liver fibrosis) scores. Since both those with and without NAFLD/- NASH shared several baseline characteristics, genetics may play a role in the pathogenesis of NAFLD/NASH and its treatment with statins.