Current Vascular Pharmacology - Volume 17, Issue 3, 2019

Cardiovascular diseases secondary to atherosclerosis are the primary causes of early death and disability worldwide and dyslipidaemia represents one of the most important modifiable risk factors. Among lipid abnormalities that define it, low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy, since multiple randomized controlled trials have shown the positive impact of its reduction on atherosclerosis development. For their ability to lower LDL-C levels, statins are the most studied drugs in cardiovascular disease prevention, of proven utility in slowing the progression or even determining regression of atherosclerosis. In addition, they have ancillary proprieties, with positive effects on the mechanisms involved in the development of atherosclerosis and cardiovascular morbidity and mortality, the so-called “pleiotropic mechanisms”. Although sharing the same mechanism of action, the different chemical and pharmacological characteristics of each kind of statins affect their absorption, bioavailability, plasma protein binding properties, excretion and solubility. In this overview, we analysed pharmacokinetic and pharmacodynamic mechanisms of this class of drugs, specifying the differences among the molecules, along with the economic aspects. Detailed knowledge of characteristics and differences of each kind of available statin could help the physician in the correct choice, based also on patient's clinical profile, of this essential tool with a demonstrated high cost-effectiveness both in primary than in the secondary prevention of cardiovascular disease.

Statins, 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, have been used for decades for the prevention of coronary artery disease and stroke. They act primarily by lowering serum cholesterol through the inhibition of cholesterol synthesis in the liver, which results in the upregulation of low-density lipoprotein receptors in the liver. This results in the removal of low-density lipoproteincholesterol. Studies have suggested that statins may demonstrate additional effects that are independent of their effects on low-density lipoprotein-cholesterol. These have been termed “pleiotropic” effects. Pleiotropic effects may be due to the inhibition of isoprenoid intermediates by statins. Isoprenoid inhibition has effects on the small guanosine triphosphate binding proteins Rac and Rho which in turn effects nicotinamide adenine dinucleotide phosphate oxidases. Therefore, there are changes in endothelial nitric oxide synthase expression, atherosclerotic plaque stability, pro-inflammatory cytokines and reactive oxygen species production, platelet reactivity, and cardiac fibrosis and hypetrophy development. Recently, statins have been compared to the ezetimibe and the recently published outcomes data on the proprotein convertase subtilisin kexin type 9 inhibitors has allowed for a reexamination of statin pleiotropy. As a result of these diverse effects, it has been suggested that statins also have anti-arrhythmic effects. This review focuses on the mechanisms of statin pleiotropy and discusses evidence from the statin clinical trials as well as examining the possible anti-arrhythmic effects atrial fibrillation and ventricular tachyarrhythmias.

Elderly patients represent a rising social problem, due to the exponential growth of persons in these age groups and their atherothrombotic burden. The management of this population still raises several challenges, requiring a balance between elevated cardiovascular risk, clinical complexity, frailty and co-morbidities. Statins represent the main pillar in cardiovascular prevention, lowering serum cholesterol and reducing mortality and ischemic events, especially in high-risk patients. Yet, elderly patients have often been excluded from major clinical trials of statins, thus limiting the experience with these drugs in advanced age. Moreover, important barriers to the use of statins in the elderly exist due to potential risks attributed to altered metabolism, comorbidities, polypharmacy and drug-drug interactions and financial constraints. This situation has led to a “statin paradox”, since high-risk elderly patients, that would most benefit from the use of statins, may be undertreated with these drugs in real life. The vague indications provided by guidelines mean that this issue is still debated, especially regarding primary prevention. Nevertheless, the benefits in outcome offered by statins cannot be neglected. Efforts should be made in order to focus on the importance of statin use in the elderly and to provide clinicians with adequate tools for case by case decisions.

Background: Statins are effective for primary and secondary prevention of atherosclerotic cardiovascular disease. They also have systemic anti-inflammatory and immunomodulating properties suggesting potential utility for improving clinical outcomes for a wide range of diseases. The literature provides data suggesting benefit in patients with comorbidities associated with contrast-induced nephropathy (CIN), chronic obstructive pulmonary disease (COPD), pneumonia, head injury, neurological disease (e.g. Alzheimer's and Parkinson's disease), prostate cancer, nuclear cataract and spinal cord injury. This systematic review evaluates the current evidence supporting the potential benefit of statins outside their customary role of attenuating cardiovascular risk reduction. Methods: The electronic databases MEDLINE, EMBASE, and clinicaltrials.gov were searched for studies published January 2000 - March 2018 reporting comorbidity reduction associated with statin use. Results: Fifty-eight publications that satisfied our selection criteria (based on the PRISM guidance for systematic reviews) were selected and included case-control, cohort, cross-sectional and observational studies as well as systematic reviews and meta-analyses. Ten studies addressed statin use and incidence of CIN after coronary imaging; 8 addressed statin use in patients with COPD; 14 addressed statin use and comorbidity reduction associated with head injury and/or a neurological disease disorder; 5 addressed the association between statin use and nuclear cataract; 9 addressed the association between statin use and prostate/colorectal cancer; 9 studies addressed the role of statin use in treating infections; and 3 addressed the association between statin use and spinal cord injury related survival rate. Conclusion: Overall, the literature supports beneficial pleiotropic effects of statin use in contrastinduced nephropathy, head injury, Alzheimer's and Parkinson's disease, nuclear cataract, prostate cancer, infection management, and spinal cord injury. Further investigation is warranted, and randomized clinical trials are needed to confirm the clinical utility suggested by the reported studies included in this meta-analysis.

Curcumin is a naturally occurring polyphenol isolated from Curcuma longa that has various pharmacological activities, including, anti-inflammatory, anti-oxidant and anti-cancer properties. The anticancer effect of curcumin is attributed to activation of apoptotic pathways in cancer cells, as well as inhibition of inflammation and angiogenesis in the tumour microenvironment and suppression of tumour metastasis. Angiogenesis, which is the formation of new blood vessels from pre-existing ones, is a fundamental step in tumour growth and expansion. Several reports have demonstrated that curcumin inhibits angiogenesis in a wide variety of tumour cells through the modulation of various cell signaling pathways which involve transcription factors, protein kinases, growth factors and enzymes. This review provides an updated summary of the various pathways and molecular targets that are regulated by curcumin to elicit its anti-angiogenic activity.

The non-traditional cardiovascular (CV) risk factors that appear to be of most clinical interest include: apolipoprotein A (ApoA), apolipoprotein B (ApoB), high-sensitivity C-Reactive protein (hsCRP), homocysteine, interleukin 1 (IL1), lipoprotein (a) [Lp(a)], the density of low-density lipoprotein (LDL) particles, the LDL particle number, tissue/tumor necrosis factor-α (TNF-α) and uric acid. These non-traditional risk factors may be of value in adding further confirmation and attention to suspected significant CV risk. They can also provide a better understanding of current concepts of atherogenesis (e.g. various potential mechanisms associated with inflammation) as an etiology and in guiding current plus future therapies. In the mid-20th century, atherosclerosis and CV disease were considered mechanistic occurrences with essentially no attention to possible metabolic and molecular etiologies. Therefore, the only treatments then centered around mainly surgical procedures to try to improve blood flow, first with peripheral arterial disease (PAD) and later coronary artery disease (CAD). Now, failure to treat CV risk factors, especially where there is good evidence-based medicine, as in the case of statins for high CV risk patients, is considered medical negligence. Nevertheless, many problems remain to be solved regarding atherosclerosis prevention and treatment.

Background: Chronic total occlusion (CTO) of a coronary artery is defined as an occluded segment with no antegrade flow and a known or estimated duration of at least 12 weeks. Objective: We considered the current literature describing the indications and clinical outcomes for denovo CTO- percutaneous coronary intervention (PCI), and discuss the role of CTO-PCI and future directions for this procedure. Methods: Databases (PubMed, the Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL were searched and relevant studies of CTO-PCI were selected for review. Results: The prevalence of coronary artery CTO's has been reported to be ~ 20% among patients undergoing diagnostic coronary angiography for suspected coronary artery disease. Revascularization of any CTO can be technically challenging and a time-consuming procedure with relatively low success rates and may be associated with a higher incidence of complications, particularly at non-specialized centers. However, with an increase in experience and technological advances, several centers are now reporting success rates above 80% for these lesions. There is marked variability among studies in reporting outcomes for CTO-PCI with some reporting potential mortality benefit, better quality of life and improved cardiac function parameters. Anecdotally, properly selected patients who undergo a successful CTO-PCI most often have profound relief of ischemic symptoms. Intuitively, it makes sense to revascularize an occluded coronary artery with the goal of improving cardiovascular function and patient quality of life. Conclusion: CTO-PCI is a rapidly expanding specialized procedure in interventional cardiology and is reasonable or indicated if the occluded vessel is responsible for symptoms or in selected patients with silent ischemia in whom there is a large amount of myocardium at risk and PCI is likely to be successful.

Chronic venous disease (CVeD) is a highly prevalent condition in the general population, and it has a significant impact on quality of life. While it is usually manifested by obvious signs, such as varicose veins and venous ulcers, other symptoms of the disease are less specific. Among the other symptoms, which include heaviness, swelling, muscle cramps and restless legs, pain is the symptom that most frequently compels CVeD patients to seek medical aid. However, there is a substantial discrepancy between pain severity and clinically detectable signs of CVeD, questioned by several opposing studies. Further evaluation is needed to clarify this subject, and to analyse whether pain development predicts objective CVeD progression. General management of CVeD starts with advising lifestyle changes, such as lowering body mass index and treating comorbidities. However, the mainstay of treatment is compression therapy, with the additional use of pharmacological substances. Venoactive drugs proved to be the drugs of choice for symptom alleviation and slowing the progression of CVeD, with micronized purified flavonoid fraction being the most effective one. Interventional therapy is reserved for advanced stages of the disease.

Background: Recent data advocate adoption of a more intensive treatment strategy for management of blood pressure (BP). Objective: We investigated whether the overall effects of the Systolic Blood Pressure Intervention Trial (SPRINT) are applicable to cardiovascular disease (CVD) patients. Methods: In a post hoc analysis we analyzed data from SPRINT that randomly assigned 9361 individuals to a systolic BP (SBP) target of <120 mmHg (intensive treatment) or <140 mmHg (standard treatment). 1562 patients had clinically evident CVD (age=70.3±9.3 years, 24% females) at study entry and were followed for 3.1 years. Further, we assessed the effect of low (<150 mmHg) baseline SBP on outcome. Results: In CVD patients, there was no benefit from the intensive treatment regarding all endpoints, except for a marginally significant benefit on all-cause mortality (hazard ratio [HR]: 0.67; 95% confidence interval [CI], 0.45 to 1.00; p=0.0509). Further, while there was no increase in serious adverse events (SAE) in the intensive group, there was increased risk for study-related SAE, acute renal failure and electrolyte abnormalities. In patients with low baseline SBP there was a beneficial effect on allcause mortality (HR: 0.56; 95% CI: 0.33 to 0.96; p=0.033), but with greater stroke incidence (HR: 2.94; 95% CI: 1.04 to 8.29; p=0.042). Conclusion: We confirm the beneficial effect of the intensive strategy in SPRINT study on all-cause mortality and the harmful effect on specific adverse outcomes in patients with CVD. However, in patients with low baseline SBP stroke may increase.

Background: Oestradiol is an important regulatory factor with several positive effects on the cardiovascular (CV) system. We evaluated the molecular mechanism of the in vivo effects of oestradiol on the regulation of cardiac inducible nitric oxide (NO) synthase (iNOS) expression and activity. Methods: Male Wistar rats were treated with oestradiol (40 mg/kg, intraperitoneally) and after 24 h the animals were sacrificed. The concentrations of NO and L-Arginine (L-Arg) were determined spectrophotometrically. For protein expressions of iNOS, p65 subunit of nuclear factor-ΚB (NFΚB-p65), Ras homolog gene family-member A (RhoA), angiotensin II receptor type 1 (AT1R), insulin receptor substrate 1 (IRS-1), p85, p110 and protein kinase B (Akt), Western blot method was used. Coimmunoprecipitation was used for measuring the association of IRS-1 with the p85 subunit of phosphatidylinositol- 3-kinase (PI3K). The expression of iNOS messenger ribonucleic acid (mRNA) was measured with the quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of the tissue was used to detect localization and expression of iNOS in heart tissue. Results: Oestradiol treatment reduced L-Arg concentration (p<0.01), iNOS mRNA (p<0.01) and protein (p<0.001) expression, level of RhoA (p<0.05) and AT1R (p<0.001) protein. In contrast, plasma NO (p<0.05), Akt phosphorylation at Thr308 (p<0.05) and protein level of p85 (p<0.001) increased after oestradiol treatment. Conclusion: Our results suggest that oestradiol in vivo regulates cardiac iNOS expression via the PI3K/Akt signaling pathway, through attenuation of RhoA and AT1R.