Current Vascular Pharmacology - Volume 8, Issue 5, 2010

Atherosclerotic vascular disease remains an enormous public health problem. Cardiovascular risk assessment and hypolipidaemic therapy were greatly advanced during the last 15 years. In fact, hypolipidaemic drugs are consistently among the top ten best-seller drugs worldwide. Although the progress in this field is enormous, there are topics still unresolved. Distinguished authors in the field were invited to give their perspective on current controversies in this supplemental issue of the Current Vascular Pharmacology journal. Biomarkers of kidney function include serum creatinine and more recently estimated glomerular filtration rate (eGFR). These biomarkers and microalbuminuria predict the development of cardiovascular disease (CVD) [1]. Recent analyses indicate that eGFR is a much stronger predictor of CVD than is microalbuminuria. While microalbuminuria indicates endothelial dysfunction and is associated with increased risk for CV events, its level is related more to the level of blood pressure and glycemic control than directly to the pathophysiology of atherosclerosis. Hence, microalbuminuria could be viewed as a biomarker but not as a risk factor for CVD, since risk factors must be an integral part of the disease pathophysiology. Conversely, while microalbuminuria is not of prognostic value to predict chronic kidney disease (CKD) outcomes, increases over time into the albuminuria range clearly indicate presence of kidney disease and are associated with a more rapid decline in kidney function. Kalaitzidis et al. proposes the concomitant evaluation of both biomarkers eGFR and albuminuria to assess kidney function and CVD risk thoroughly. But what happens when the beneficial effect of a treatment adversely affects a biomarker? In this respect the case of fenofibrate is interesting. In the FIELD study, a placebo-controlled study in 9795 patients with type 2 diabetes, fenofibrate over 5 years reduced non fatal cardiovascular events and microvascular events such as albuminuria, the need for laser treatment for proliferative retinopathy or maculopathy and amputations but failed to reduce fatal cardiovascular events [2]. On the other hand, fibrates and in particular fenofibrate, are known to increase homocysteine levels (Hcy), a biomarker associated with an increased risk for CVD, venous thromboembolic events (VTE) and possibly cognitive disorders and bone fractures. It seems that the actual level of a biomarker has a different meaning compared to its changes upon intervention, which seems to be the case with Hcy. The results of all randomized clinical trials reported to date indicate that a reduction of Hcy levels with vitamin B supplements does not improve CVD, recurrence of VTE and cognitive disorders in patients with mild hyperhomocysteinemia, while the increase in Hcy levels with fenofibrate was not associated with adverse cardiovascular outcomes. There is no evidence to recommend measurement of homocysteine in patients receiving a fibrate or to add vitamin B supplements to their treatment. In this issue Foucher et al. suggests that Hcy levels currently represent a risk marker rather than a risk factor, suggesting that the risk factor(s) behind Hcy are awaited to be found. When it comes to hypolidaemic therapy, we focus mainly on statin treatment and its effect on various parameters beyond cholesterol lowering. Pulse wave velocity (PWV) is a method to estimate arterial stiffness. At a given blood pressure, the stiffer the vessel, the less time it takes for the pulse wave to travel the length of the vessel. As a result, PWV is increased with stiffer less compliant arteries. Aortic PWV is considered to be the gold standard of arterial stiffness measurements. Age, blood pressure levels and diabetes mellitus are the major factors associated with increased PWV. Aortic PWV is an independent predictor of both cardiovascular and all-cause mortality in hypertensive patients, and independently predicts mortality in patients with normal renal function or end stage renal failure. By contrast, there is no unanimous opinion concerning the role of dyslipidaemia on PWV, with the majority of the studies reporting no association between lipids and PWV. Statins have been shown to improve the compliance of the vasculature. In this issue we present the available data on the effect of statin administration on arterial stiffness by measuring PWV. Nine eligible randomized controlled trials (RCTs) with 471 participants were found. The most frequent comparison was between fluvastatin against placebo, and the most extensively studied agent was also fluvastatin , while the most frequent indication for statin therapy was hyperlipidaemia (n = 6), with or without other cardiovascular risk factors. Aortic PWV was assessed in 4 studies, with significant reduction (improvement of arterial stiffness) in 2 studies, a nonsignificant change in one study and a significant increase in the other....

Fibrates or PPAR alpha agonists, in particular fenofibrate, are known to increase homocysteine levels (Hcy). A 3 to 5 μmol/L increase in Hcy is commonly observed within the first few weeks of fenofibrate treatment; it then persists in plateau when treatment is continued and is reversible upon its cessation. Since its description in 1999, this pharmacological effect attracted a great deal of attention as epidemiological studies in most populations have shown that elevated Hcy levels i.e.Hcy>=15 μmol/L are associated with an increased risk of cardiovascular events (CVD), venous thromboembolic events (VTE) and possibly cognitive disorders and bone fractures. Chronic kidney disease is also associated with elevated Hcy levels and since fenofibrate increases creatinine levels by about 10-12 μmol/L, a relationship between Hcy and creatinine changes has been postulated. Animal studies have shown that the Hcy increase is PPARα dependent but to date animal or human studies have not provided a clear mechanism. In particular, fenofibrate treatment does not change vitamin B levels; however, vitamin B supplements reduce fenofibrate-induced Hcy elevation but not the concomitant cysteine elevation. Similarly, the increase in creatinine with fenofibrate only partially accounts for by a reduction in glomerular filtration rate (GFR) since creatinine production is also increased by 5-10%. In the FIELD study, a placebo-controlled study in 9795 patients with type 2 diabetes, fenofibrate over 5 years reduced non-fatal cardiovascular events and microvascular events such as albuminuria, the need for laser treatment for proliferative retinopathy or maculopathy and amputations but did not reduce fatal events. The increase in Hcy was indeed much larger that what would be explained by creatinine elevation and independent from baseline kidney function. Although baseline Hcy and creatinine levels were associated with subsequent risk of CVD, as suggested by epidemiology, their respective elevation was not. Of interest, after withdrawal of fenofibrate, a potential renoprotective effect was unmasked, as estimated GFR was 5 ml/min/1.73 m2 higher in previous fenofibrate-allocated patients than in previous placebo-allocated patients. There was no suggestion that Hcy elevation was associated with VTE events (which were increased by an unknown mechanism) or bone disorders. In conclusion, the discrepancy between the role of baseline Hcy levels in epidemiology and the absence of effect when altering its levels by either decreasing them with vitamin B supplements or increasing them with fenofibrate, suggests that the risk factor(s) behind homocysteine should be found. Nevertheless, other studies are needed to understand the mechanism and the implications of the moderate homocysteine and creatinine elevations with fenofibrate and other PPARα agonists.

Cardiovascular (CV) disease is the leading cause of morbidity and mortality among people with chronic kidney disease (CKD). CKD has increased over the past decade to become a worldwide public health problem. The definition of a biomarker is a characteristic objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic response to a therapeutic intervention. Thus, biomarkers of kidney function would include serum creatinine and more recently estimated glomerular filtration rate (eGFR). These biomarkers and microalbuminuria, potential biomarker, predict CV events and mortality. Recent analyses of cross-sectional data indicate that eGFR is a much stronger predictor of CV events than is microalbuminuria. While microalbuminuria indicates endothelial dysfunction and is associated with increased risk for CV events, its level is related more to the level of blood pressure and glycemic control than directly to the pathophysiology of atherosclerosis. Hence, microalbuminuria could be viewed as a biomarker but not a risk factor for CV risk since, risk factors must be an integral part of the disease pathophysiology. Conversely, while microalbuminuria is not of prognostic value to predict CKD outcomes, increases over time into the albuminuria range, >200 mg/day, clearly indicate presence of kidney disease and are associated with a more rapid decline in kidney function. Thus, concomitant evaluation of both biomarkers eGFR and albuminuria is recommended to assess kidney function and CV risk thoroughly.

The effect of statin treatment on glucose metabolism and the risk of diabetes remains an issue of controversy. Since statins are drugs commonly prescribed for the prevention of cardiovascular disease even in patients with prediabetes or diabetes, it is of great importance to identify the role of statin treatment on glucose homeostasis. In this review, we have scrutinized available data with regard to the effect of every drug of the class on glycemic outcomes. Experimental data describing mechanisms through which these drugs potentially modify the metabolism of carbohydrates have been described. In order to identify statins which may be preferentially used to improve parameters of glycemic control, studies comparing different agents of this class as to their effect on glucose homeostasis have been discussed. According to experimental studies statin lipophilicity as well as the potential to inhibit 3-hydroxy-3-methylglutarylcoenzyme A reductase should be regarded as prognostic factors of an adverse impact of statin treatment on carbohydrate metabolism. On the other hand, the hypotriglyceridemic capacity, the endothelial-dependent increase in pancreatic islet blood flow, the anti-inflammatory properties along with the capacity of statins to alter circulating levels of several adipokines known to affect glucose homeostasis, including adiponectin, leptin, visfatin and resistin, may beneficially alter glycemic status. In clinical trials, a beneficial, neutral or adverse impact on glycemic control of different populations has been ascribed to various statins. From all drugs of the class pravastatin seems to beneficially affect glucose metabolism and decrease the risk of diabetes. Controversial findings have come to the fore with regard to other statins commonly prescribed in the clinical setting, including rosuvastatin, atorvastatin and simvastatin. More data are needed to clarify the exact role of lovastatin, fluvastatin and the newest statin pitavastatin on carbohydrate metabolism. Comparison trials suggest a potential preferable effect of the hydrophilic statins pravastatin, rosuvastatin and pitavastatin as compared to lipophilic components of the class, including atorvastatin and simvastatin.

Statins are an essential part of the management of patients at high vascular risk and are generally well-tolerated. However, statin intolerance will be observed more frequently as more stringent low density lipoprotein cholesterol (LDL-C) targets are pursued in an ever increasing number of patients. We review the management options for high-risk patients intolerant to statin treatment. Potential strategies include switching to a different statin, reducing the frequency of statin administration, substituting statins with other LDL-C-lowering agents (e.g. ezetimibe, colesevelam or nicotinic acid) and combining low-dose statin treatment with other lipid-modifying drugs. A limited number of studies specifically assessed statin-intolerant patients and most were small and of short duration. It is therefore difficult to make evidence-based recommendations for the management of this population. In addition, all treatment options have limitations in terms of safety and/or efficacy.

Objective: Pulse wave velocity (PWV) is a method to estimate arterial stiffness. Statins have been shown to improve the compliance of the vasculature. We present the available data from randomized controlled trials (RCTs) on the effect of statin administration on arterial stiffness by measuring PWV. Methods: We considered all RCTs evaluating PWV following the administration of statins. We searched PubMed up to July 2009. Information regarding the author, journal, year of publication, randomization method, participant characteristics, treatment intervention, PWV assessment, and outcome were recorded independently by two investigators. Results: We found 9 eligible studies with 471 participants. The most frequent comparison was between fluvastatin against placebo, and the most extensively studied agent was also fluvastatin (n = 4 trials, total population = 240). The most frequent indication for statin therapy was hyperlipidaemia (n = 6), with or without other cardiovascular risk factors. Aortic PWV, which is considered to be the most appropriate method for PWV evaluation, was assessed in 4 studies, with significant reduction (improvement of arterial stiffness) in 2 studies, a non-significant change in one study and a significant increase in the other. Peripheral (mainly brachial-ankle) PWV was assessed in the other 5 studies with significant reduction in all except the one multi-arm study where only fluvastatin improved PWV. Conclusions: We cannot safely conclude for the effect of statins on arterial stiffness, as estimated by PWV measurements. This is a poorly investigated field with few RCTs and a limited number of participants. More trials should be carried out to reach more robust conclusions.

A review entitled “Future Challenges for Microsomal Transport Protein Inhibitors” [1] stated (page 281), based upon a manuscript [2] that “A mouse-specific ASO (Isis Pharmaceuticals 147764) demonstrated direct and specific inhibition of MTP in a murine model of hyperlipidemia”. In that same paragraph, it was implied that MTP and apoB ASOs were directly compared in depth in that manuscript [2]. As the primary author of this publication, I would like to point out that those statements are factually incorrect on both counts. As the title of the reference implies, ISIS 147764 is an ASO designed to specifically and selectively inhibit the apoB, not MTP, message. Furthermore, the data clearly show specific inhibition of apoB mRNA and protein. An MTP ASO was only used to demonstrate specificity and selectivity of the apoB drug and data obtained using the MTP ASO were not shown in the cited publication [2]. It was also clearly stated in the manuscript [2] that MTP was not affected by apoB antisense treatment. It would be appreciated if these factual errors were corrected.

Hypertension is a major contributor to vascular morbidity and mortality. Endocrine hypertension (EH) refers to secondary hypertension caused by specific endocrine abnormalities. The significance of EH is that the identification of the underlying disorder and its management may lead to partial or complete normalization of blood pressure. When EH is suspected thorough investigation with biochemical and imaging testing are necessary to establish or exclude mineralocorticoid, catecholamine, glucocorticoid, thyroid, parathyroid or growth hormone disorders as well as rare hereditary syndromes. In addition, it is important to differentiate benign from malignant tumors. The present review provides an update on the pathophysiology and clinical presentation of EH. We also discuss the diagnostic work-ups and therapeutic strategies.

Numerous studies have shown that increased oxidative stress (OxS) is present in diabetic patients. There is evidence that this OxS can be increased before complications associated with diabetes mellitus (DM) occur. However, the role and influence of OxS in the initiation and progression of DM remains the subject of debate. It has been suggested that in DM, OxS is caused by increased production of reactive oxygen species (ROS), and associated with reduction in antioxidant defenses and altered cellular redox status. Acute and chronic OxS which could enhance the development of complications associated with DM. This review considers recent findings on the role of antioxidants in controlling OxS and the incidence of DM with emphasis on animal and human studies.

Herein, we present the European Society for Vascular Surgery Guidelines pertinent to the secondary prevention of cerebrovascular events in patients with carotid artery stenosis including lipid lowering therapy, antiplatelet therapy and other risk factor modification. These recommendations are based on current evidence from clinical trials. There is a need for aggressive prevention treatment in patients with carotid artery disease. We also discuss the diagnosis and grading of carotid artery stenosis.

Herein, we present the European Society for Vascular Surgery Guidelines pertinent to the secondary prevention of cerebrovascular events in patients with carotid artery stenosis including lipid lowering therapy, antiplatelet therapy and other risk factor modification. These recommendations are based on current evidence from clinical trials. There is a need for aggressive prevention treatment in patients with carotid artery disease. We also discuss the diagnosis and grading of carotid artery stenosis.

Cancer chemotherapy is not free of undesirable side effects. With respect to the cardiovascular system, cardiotoxicity is a well-described and potentially lethal side effect of certain chemotherapeutic agents, such as anthracyclines. However, in the last few years, several clinical studies have taken into account the fact that some non-anthracycline chemotherapy treated-patients also have a significantly increased risk of cardiovascular events. The exact mechanism of this toxicity is not known, and several possibilities, including vascular autonomic neuropathy and vascular damage, have been proposed. The aim of the present review was to collate information on the clinical and experimental evidence regarding vascular toxicity for each of the different groups of chemotherapeutic agents. The mechanisms proposed to underlie this toxicity are also discussed.

Atheroma calcification is a common feature of advanced atherosclerosis, however with the advent of CT scanning it has become possible to detect extensive coronary calcification in the absence of flow-limiting lesions. While this phenomenon is known in renal disease, it also exists in some patients with exertional angina. Vascular pathology suggests biomineralisation associated with development of osteoblast-like cells in the arterial wall. While some conventional risk factors are shared with atheroma formation, others such as ethnicity and medications appear more specific to extensive calcification and may mirror those for osteoporosis. Similarly an atherogenic diet can predispose to both conditions while some elements promote or inhibit coronary calcification but not atheroma formation. The immune and endocrine systems contribute to both conditions but not necessarily in the same way, with vitamins D and K more related to calcification than atheroma formation. Finally, statins significantly lower low density lipoprotein (LDL) cholesterol and reduce atheroma formation but are largely powerless against extensive calcification. Although investigations into the exact cause of extensive coronary calcification are in their infancy, early results suggest that it is sufficiently different in nature from atheroma formation to be considered as a separate condition. Further research would yield a greater understanding, which would aid management and the development of specific biomarkers to reduce the cost and radiation risk of CT scanning.

Immunosuppressive drugs (ISDs) have a major impact on the development and progression of cardiac allograft vasculopathy (CAV), the main cause of cardiac allograft loss and a leading cause of death beyond the 1st post-transplant year. The influence of ISDs on the development and progression of CAV is complex. In spite of their high potency to suppress the alloimmune response (prevention of allograft rejection) which plays an essential role in the pathogenesis of CAV, the immunosuppressive regimens which were used in the past were not able to entirely prevent the development of CAV. This can be explained by the fact that several non-alloimmune insults such as brain death, organ preservation, surgical trauma, ischemia-reperfusion, diabetes, hypertension, hyperlipidemia, cytomegalovirus infection etc. are also involved in the development or progression of CAV. Some of these insults are not affected by immunosuppression, whereas others can be even aggravated by certain ISDs, particularly by calcineurin inhibitors (CNIs), but also by glucocorticosteroids and proliferation signal inhibitors (PSIs). Certain ISDs, especially CNIs, also have direct toxic effects on vascular endothelial and smooth muscle cells inducing endothelial dysfunction and proliferation of both smooth muscle cells and fibroblasts which promotes the development and progression of CAV. Other ISDs like PSIs and mycophenolate mofetil appeared able to delay the onset of CAV and reduce its progression, especially by their inhibitory effects on smooth muscle cell migration and proliferation. The present article reviews the data available on the impact of different ISDs and regimens on the development and progression of CAV.

Vitamin D deficiency is a well-established risk factor for bone disease. Emerging data suggest a pleiotropic role of this agent in a variety of functions in humans. Epidemiological studies indicate an inverse association between vitamin D deficiency and the prevalence of cardiovascular disease (CVD), as well as individual cardiometabolic risk factors, such as hypertension, diabetes, dyslipidemia and the metabolic syndrome. Moreover, vitamin D deficiency has been implicated in the atherosclerotic process. This review considers current data regarding the role of vitamin D deficiency in the development of CVD and addresses the effect of supplementation on cardiovascular outcomes.