Current Pharmaceutical Design - Volume 23, Issue 46, 2017

Background: Chronic inflammation and immune system activation underlie a variety of seemingly unrelated cardiac conditions including not only atherosclerosis and the subsequent coronary artery disease but also peripheral artery disease, hypertension with target organ damage and heart failure. The beneficial effects of HMG-CoA reductase inhibitors or statins are mainly attributed to their ability to inhibit hepatic cholesterol biosynthesis. Beyond their lipid lowering activity, ample evidence exists in support of their potent anti-inflammatory properties which initiate from the inhibition of GTPase isoprenylation, activating a cataract of secondary pathways and extend to the inhibition and blocking of immune cell activation and interaction. Objective: To summarize the anti-inflammatory mechanisms of statins in clinical and experimental settings in cardiovascular disease. Methods: A systematic search of PubMed and the Cochrane Database was conducted in order to identify the majority of trials, studies, current guidelines and novel articles related to the subject. Results: In vitro, statins have immuno-modulatory and anti-inflammatory effects, and they can exert antiatherosclerotic effects independently of their hypolipidemic actions. In addition, positive results have emerged from mechanistic and experimental studies on the active role of HMG-CoA reductase inhibitors in HF. By extrapolating those data in clinical setting, we further understand how HMG-CoA reductase inhibitors can beneficially affect not only systolic but also diastolic HF. Conclusion: In this review article, we present the basic pathophysiologic data supporting the anti-inflammatory actions of statins in clinical and experimental settings and we link these mechanisms with confirmatory clinical data on the potent non lipid lowering effects of HMG-CoA reductase inhibitors.

Statins are widely established as an important class of medications for primary and secondary prevention of cardiovascular disease. In addition to their lipid-lowering effects, mounting evidence suggests that statins exhibit non-lipid-lowering mediated effects in the cardiovascular system. These so called “pleiotropic” effects are partly due to antioxidant properties of statins. These are mediated by inhibition of the mevalonate pathway, which interferes with small GTP-ase protein prenylation. This, in turn, leads to anti-oxidant effects of statins via a plethora of mechanisms. Statins prevent the activation of the pro-oxidant enzyme NADPH-oxidase by interfering with Rac1 activation and translocation to the membrane, as well as reducing expression of crucial subunits of NADPH-oxidase. Statins also enhance the expression, enzymatic activity and coupling of endothelial nitric oxide synthase (eNOS), through mevalonate-dependent effects. The net result is a restoration of the redox balance in the cardiovascular system, with subsequent anti-atherosclerotic and cardioprotective effects. While the evidence from basic science studies and animal models is strong, more clinical trials are required to establish the relevance of these pleiotropic effects to human cardiovascular disease and potentially lead to expanded indications for statin treatment or alternative therapeutic strategies.

Statins are a group of lipid-lowering medications that have been proven to be efficient in the protection of patients with dyslipidaemia from cardiovascular disease. The beneficial role of statins in both primary and secondary prevention has been well documented in many large randomized clinical trials. This beneficial effect extends to patients with diabetes mellitus. Their safety profile is overall good with mainly mild side effects. However, data indicate that statins may promote new onset diabetes mellitus. We review the current evidence regarding the overall efficacy and safety profile of statins in patients with diabetes mellitus; further we put into a broader perspective the debated diabetogenic effect of these drugs.

Adipose tissue (AT), aside from being an energy storage site, functions as a source of cytokines, adipokines and other vasoactive molecules. Dysfunctional AT contributes to the development of cardiovascular disease by shifting to a pro-oxidant, pro-inflammatory phenotype. Perivascular AT (PVAT) is of particular importance to the development of vascular disease, due to its close proximity to the vascular wall. Molecules released from PVAT can exert both pro- and anti-contractile effects, the balance of which plays a role in controlling vascular tone. Recent evidence supports the existence of reciprocal, two-way interactions between PVAT and the vascular wall. Statins, with their pivotal role in cardiovascular disease prevention, have been shown to exert lipidlowering independent, pleiotropic effects on the vascular wall, some of which may be mediated by modulatory effects on PVAT inflammation and secretome. These effects of statins provide a paradigm for the development of new therapeutic agents aimed at modulating PVAT function, as a novel treatment strategy against cardiovascular disease.

Background: Stable angina is a debilitating and progressive disease caused by narrowing of the coronary arteries, which in turn affects cardiac perfusion. Statins have a well-established role, modifying symptoms and progression of the disease not only through lipid lowering, but also through pleiotropic effects. Objective: We sought to evaluate the effect of statins in stable angina pectoris Method: We performed a systematic review of the literature searching MEDLINE via Pubmed for all studies which examine the possible effects of statins in stable angina pectoris. Results: Statins have demonstrated favourable modification of both biochemical markers (oxidative stress, inflammatory and coagulation markers/factors) and clinical symptoms (anginal and ischemic) of the disease. These effects have been demonstrated in vitro, ex vivo and in vivo in animals and humans, independently of the lipid lowering effects. Conclusion: With an excellent safety profile and evidence of efficacy in managing patients with stable angina, statins appear an essential part of the therapeutic armoury against atherosclerotic disease.

Background: Atherosclerosis is a systemic, progressive lipid-driven inflammatory disease of the arterial vascular wall leading progressively to plaque development. The vulnerable plaque, the one considered to be the leading cause of cardiovascular events seems to exhibit a large and soft lipid-rich necrotic core covered by a thin and inflamed fibrous cap. Statin treatment is considered as one of the most effective methods for vulnerable plaque stabilization, currently being the principal drug in primary and secondary prevention of cardiovascular disease. Objective: We sought to evaluate the beneficial effect of statins on biological processes involved in the evolution of vulnerable plaques Method: We performed a systematic review of the literature searching MEDLINE via Pubmed for all experimental and human studies implementing statins in vulnerable plaque. Results: Statins seem to have a beneficial role in plaque stabilization and patient outcome. It seems that this effect is mediated by improving endothelial function, decreasing oxidative stress and inflammation, reducing inflammatory activation and inhibiting thrombogenic response. Although these data are quite promising, it remains to be determined the extent of a potent benefit of the pleiotropic effects of statin therapy in clinical setting. Conclusion: Prospective randomized trials should be conducted in order to further elucidate differences among type and dose of statin therapy, duration of treatment and association with LDL levels and clinical outcome.

Background: Patients with acute coronary syndrome (ACS) frequently experience recurrent adverse events from the cardiovascular system comparing to either healthy individuals or individuals with stable coronary artery disease. This is attributed to the inflammatory cascade that is activated during ACS resulting in increased risk for rupture of vulnerable plaques. Objective: Therefore, it is of great importance to avoid recurrent events with treatment aiming at secondary prevention which includes the management of lipid profile besides alteration in the lifestyle and habits. Methods: This review will present current data concerning present status of treatment with statins, and refer to non-statin strategies as well as novel and promising agents for the secondary prevention therapy after ACS. A thorough search of PubMed and the Cochrane Database was conducted in order to identify the majority of trials, studies, current guidelines and novel articles related to the subject. Results: Statins have been proved to play very significant role in the part of secondary prevention since they decrease the burden of atherosclerotic plaques, the risk of adverse events and the need for revascularization in symptomatic patients with CAD. Therefore, they were established and suggested by both European and American guidelines as first-line treatment option for lipid-lowering management. Several clinical trials, meta- analyses and randomized trials strongly recommended the application of early and intensive treatment with statins in patients with ACS. Nevertheless, a vast majority of individuals neither tolerated statins nor achieved the optimal value for LDL-C with the highest tolerated dose of statins resulting in poor clinical outcome. Furthermore, recent clinical trials indicated further benefit of combined treatment of statins with non-statins drugs on the decrease of cardiovascular events as well as progress of coronary artery plaque. Finally, novel agents that are still evaluated with ongoing clinical trials have been turned into a very promising treatment option. Conclusion: In conclusion, statins are established as the first-line treatment for the secondary prevention after acute coronary syndromes in order to avoid the recurrence of thrombotic events. However, the research field on the field of lipid-lowering therapies is still ongoing and very promising for the future.

Peripheral arterial disease (PAD) is a common atherosclertico condition affecting the lower extremities. PAD patients share similar cardiovascular risk factors to coronary artery disease patients and suffer from increased cardiovascular morbidity and mortality. Statins have been widely used in coronary artery disease patients but have been underused in patients with PAD. In the current review, we present data which support the beneficial role of statins in both reducing cardiovascular events and improving symptom-related outcomes in PAD patients. Alongside their lipid lowering effects, their pleiotropic actions are also discussed. Recent guidelines, which strongly recommend the administration of statins in PAD patients, are also presented.

Background: Numerous studies indicate that statins have multiple beneficial actions (known as ‘pleiotropic actions’) on cardiovascular system through the improvement of endothelial dysfunction, inflammation, oxidative stress, excessive arterial thrombosis, and stabilization of the atherosclerotic plaque. Aortic disease primarily consists of aortic valve stenosis, aortic valve regurgitation, aneurysm disease, and genetic disorders such as Marfan syndrome, bicuspid aortic valve and aortic coarctation. Many studies have revealed the cardioprotective actions of statins in aortic disease. Objective: Our aim was to present current data concerning the value of treatment with statins in aortic diseases. Methods: A thorough search of PubMed and the Cochrane Database was conducted to identify the studies and novel articles related to the use of statins in aortic disease. Results: Numerous studies in animals and humans indicate a beneficial effect of treatment with statins in the previous conditions apart from a few conflicting data. Conclusion: There is a need of further investigation in this field, especially for the estimation of the optimal type and dose of statins required in each clinical condition of aortic disease.

Calcific aortic stenosis (AS) is the most common form of valvular heart disease in Europe and North America. It is a progressive disease with a prolonged period of asymptomatic latency which eventually leads to critical left ventricular outflow tract obstruction necessitating surgical replacement of the valve. Statins are lipidlowering drugs with a robust evidence base demonstrating clinical benefit in atherosclerotic coronary artery disease. There has therefore been significant interest in the potential benefit of statins in AS. Initial animal, retrospective and non-randomized prospective studies suggested a beneficial effect of statins in AS. However, the outcomes of 3 major randomized controlled clinical trials consistently failed to demonstrate any significant benefit of lipid-lowering therapy on progression or clinical outcomes in AS. Consequently, statin therapy should not be recommended if the sole purpose is prevention of AS progression and there is no other indication for lipidlowering therapy. However, recent data have suggested that lipoprotein(a) (Lp(a)) may play a previously unknown but critical role in the progression of AS. Lp(a) is not significantly modified by statin therapy and there is therefore significant emerging interest in targeted reduction of Lp(a) with novel therapeutic agents such as PCSK9 inhibitors and antisense oligonucleotides.

Background: Statins are a well-established class of drugs in both preventing coronary events and treating cardiovascular atherosclerotic disease, however their use in heart failure is still in debate. Objectives: To establish whether statins' pleiotropic actions in endothelium, inflammation, remodeling of the heart and anti-arrhythmic potential may be in favorable of heart failure patients. Methods: We proceed to literature search of English bibliography under the terms heart failure, statins, 3- hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Results: Various experimental and clinical trials on the use of statins in the different subtypes of heart failure according to the ejection fraction of the left ventricle have been conducted to conclude whether statins should be part of their patients' treatment. The evidence shows that the subgroup of patients with ischemic heart disease and those with preserved ejection fraction seems to have better results from the use of statins although randomized control trial in the total heart failure population did not show any benefit in mortality. Conclusion: Statins may be beneficial to left ventricle systolic and diastolic performance of heart failure patients however their result in mortality cannot be established based on current evidence.

Chronic kidney disease (CKD) is associated with dyslipidemia and increased cardiovascular risk. This elevated risk for cardiovascular events exists even in the largest subpopulation with milder stages of CKD, prior to the development of significant reductions in renal excretory function. Statin therapy is a critical component of primary and secondary cardiovascular prevention efforts for at-risk patients. Efficacy in the CKD population, however, has appeared less robust across the spectrum of CKD, particularly in hemodialysis patients. This article will review the current state of knowledge on statin therapy in CKD, effects on renal outcomes, safety in this population and alternative lipid therapies.

Contrast-induced nephropathy (CIN) is a type of acute kidney injury associated with intravascular administration of iodinated contrast, usually reversible. Contrast agents are an essential component of invasive and noninvasive coronary angiography. These agents have been modified over time to enhance patient safety and tolerability, but adverse reactions still occur. CIN has been variably defined, as a rise in serum creatinine of 0.5 mg/dl, or a 25% increase in serum creatinine above baseline within 24-72 hours after the procedure. The incidence of CIN varies based on the definition used and risk profile of the patients. CIN is rare among patients with normal renal function at baseline. In low-risk patients, CIN occurs in 1-5%, whereas in higher-risk populations, the incidence can be as high as 30%. CIN is also associated with a 5- to 20-fold increased risk of other early adverse events including in-hospital myocardial infarction, target vessel occlusion, and early mortality. The main prevention strategies are adequate intravenous hydration before, during and after the procedure as well as restriction of contrast load with maximum volume approximately no more than three times the serum creatinine clearance. Recent observational and small prospective randomized trials demonstrate the reduction of CIN incidence with HMG-CoA enzyme inhibitors. In this systematic review and meta-analysis we explore the effects of statin administration in prevention of CIN.