Current Vascular Pharmacology - Volume 6, Issue 2, 2008

Peripheral arterial disease (PAD) affects a considerable percentage of the population. A recent large survey including 264,570 patients from 16 countries reported that the prevalence of PAD is 8% (mean age: 54-64 years) [1]. Another population-based study from Sweden including 5,080 subjects aged 60-90 years reported that almost a fifth (18%; 95% confidence interval, 16%-20%) had some form of this disease [2]. PAD is an indicator of systemic atherosclerosis often involving >1 arterial bed (i.e. coronary, cerebrovascular, renal and peripheral arterial systems) [3-6]. Due to the lack of symptoms and physician awareness, PAD often remains undetected and is commonly underdiagnosed [7-9]. The risk factors and medical management of PAD are reviewed elsewhere [10-14]. Among these, smoking deserves special mention because it is the most powerful predictor of PAD [15-17]. Both active [17, 18] and passive [19] cigarette smoking impair flow-mediated endothelium-dependent peripheral arterial vasodilatation (arterial stiffness). Besides PAD, arterial stiffness is also associated with hypertension, obesity, insulin resistance and the metabolic syndrome [20, 21]. Quitting smoking and aggressive risk factor modification (e.g. administering statins, antihypertensive and antiplatelet drugs) can reduce the risk of vascular events and disease progression in patients with PAD [22-26]. Regarding lipids, a recent study on 30,348 elevated-risk primary prevention, coronary heart disease (CHD) and CHD equivalent patients showed that suboptimal lipid levels were associated with up to 45% increased risk for a cardiovascular event (p < 0.05) [27]. However, established and emerging risk factor management, as well as surgical and endovascular procedures are probably still not providing optimal treatment for all patients with PAD [28, 29]. Therefore, new options, like angiogenesis, need to be explored without excluding the established treatment modalities. Furthermore, the interaction between established and novel options need to be identified. Guidelines for the management of PAD were recently published both in Europe [30] and USA [31]. The issue of therapeutic angiogenesis was not addressed as there were not enough evidence-based trials. For patients with critical limb ischemia, there is a growing need for alternative treatment strategies; one option could be angiogenesis by administration of vascular growth factors [32, 33]. Basic fibroblast growth factor (bFGF) levels are elevated in symptomatic PAD patients with critical limb ischemia [34, 35]. This finding, which reflects a physiologic response to limb ischemia, holds implications for the treatment of PAD. The preliminary results from recent animal studies lend further support to this hypothesis [36-38]. In this context, autologous bone marrow mononuclear cells implantation in a PAD patient with critical limb ischemia resulted in an improvement of the ischemic extremity [39]. Bilateral femoral vein plasma concentrations of bFGF and vascular endothelial growth factor (VEGF) were measured before and after the procedure. While plasma VEGF and bFGF concentrations were much greater in the ischemic compared with the non-ischemic leg prior to the implantation, they decreased to the same concentrations as those in the contralateral lower extremity postprocedure [39]. Thus, plasma levels of VEGF and bFGF not only indicate the severity and extent of PAD, but may also predict the effectiveness of the treatment strategy employed for PAD. Positive results for autologous bone marrow mononuclear cells implantation for the treatment of critical limb ischemia have also been reported by other groups [40- 42]. The finding that bone marrow stem cell therapy may induce neovascularization in ischemic myocardium and improve cardiac function further supports this concept [43]. It remains to be determined whether angiogenesis in combination with aggressive risk factor modification offers even better results than either option alone. Current evidence suggests that angiogenesis is a promising additional treatment option for PAD. Future randomised trials may provide more definite results, which will help position angiogenesis in the management of PAD. DECLARATION OF INTEREST This Editorial was written independently; no company or institution supported the authors financially or by providing a professional writer. The authors have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies.

Microalbuminuria (MA) is an independent predictor of cardiovascular (CV) morbidity and mortality and for endstage renal disease in patients with diabetes mellitus (DM) or hypertension [1-6]. Furthermore, there is a relationship between albuminuria and CV risk regardless of the presence of DM or hypertension [7-12]. It is well established that MA is associated with proliferative diabetic retinopathy [13]. In subjects without MA or DM, those with increased waist circumference (WC) or metabolic syndrome (MetS) are more likely to develop MA after a 6-year follow-up compared with those with a normal WC or no MetS [14]. In a cohort with type 1 DM, MetS and its components predicted risk but MA was the best single predictor of coronary heart disease (CHD), renal failure and diabetes-related death [15]. The Third National Health and Nutrition Examination Survey reported MA in 6.1% of men and 9.7% of women in the general population in the USA [16]. MA prevalence was 28.8% in patients with previously diagnosed type 1 or 2 DM, 16.0% in those with hypertension and 5.1% in those without DM, hypertension, cardiovascular disease or elevated serum creatinine levels. European studies report a 5% to 7% prevalence of MA in the general population [9, 10]. An increase in urinary albumin excretion (UAE) in “newly-detected hyperglycaemics” was reported in 1961 [17]. However, the term MA was introduced [18,19] to describe a UAE below the detection limit of a standard dipstick, but at a level that was predictive of overt nephropathy in patients with type 1 DM [20]. Currently, MA is defined as UAE between 20 and 200 mg/g (2.5-25 mg/mmol) in men and 30-300 mg/g (3.5-35 mg/mmol) in women, using the urinary albumin-to-creatinine ratio (UACR) in a random urine sample, 30-300 mg/day, if measured in a 24h urine collection or 20-200 μg/min, if measured in a timed (e.g. 4h or overnight) urine collection [21]. Any urinary albumin value below these limits is considered as normal UAE [22]. Because MA is initially intermittent, 2 or 3 specimens should be assessed within a 3-6 month period before considering a patient as having MA [22]. A post-hoc analysis of the Heart Outcomes Prevention Evaluation (HOPE) trial, which included patients with a history of CV disease or DM and at least one vascular risk factor, showed that MA increased the adjusted relative risk (RR) by 1.83 for major CV events, 2.09 for all-cause death and 3.23 for hospitalization for congestive heart failure, with similar RRs for participants with or without DM [8]. For every 0.4 mg/mmol increase in UACR, the adjusted hazard of major CV events increased by 5.9%. The results of the HOPE trial show that any degree of albuminuria is a risk factor for CV events regardless of the presence of DM. This risk increases with the UACR, starting well below the MA cut-off. Similar results were obtained from a post-hoc analysis of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which included patients with hypertension and left ventricular hypertrophy [23]. Among nondiabetic patients, for every 10-fold increase in UACR, the hazard ratios (HR) for the composite endpoint increased by 57%, for CV mortality by 97.7%, for all cause mortality by 75.2%, for stroke by 51% and for myocardial infarction by 45% (p<0.001 for all comparisons). Ratios were similar in diabetic patients, although for myocardial infarction the trend was weaker and not significant. This study showed a prognostic value for UACR at a level below the current definition of MA, whereas the risk for the composite CV endpoint increased continuously as albuminuria increased. A positive dose-response relationship between increasing UAE and mortality was found in 40,548 inhabitants of Groningen, the Netherlands [10]. After adjustment for other wellrecognized CV risk factors, a higher UAE increased the risk of both CV and non-CV death, with a significantly higher rise for CV mortality than for non-CV mortality (p=0.014). A 2-fold increase in UAE was associated with a RR of 1.29 for CV mortality and 1.12 for non-CV mortality. This relationship was already apparent at levels of albuminuria currently considered as normal. In middle-aged nonhypertensive, nondiabetic individuals, those with UACR greater than or equal to the sex-specific median (≥3.9 mg/g for men, ≥7.5 mg/g for women) experi enced a nearly 3-fold risk of CV disease (adjusted HR 2.92, p<0.001) and a borderline significantly increased risk of death (adjusted HR 1.75, p=0.08) compared with those with UACR below the median [11]. MA is associated with lowgrade systemic inflammation [24, 25] and endothelial dysfunction [26-28]. Therefore, it is not surprising that UAE predicts the development of CV events.

Chronic volume/pressure overload-induced heart failure augments oxidative stress and activates matrix metalloproteinase which causes endocardial endothelial-myocyte (EM) uncoupling eventually leading to decline in myocardial systolic and diastolic function. The elevated levels of homocysteine (Hcy), hyperhomocysteinemia (HHcy), are associated with decline in cardiac performance. Hcy impairs the EM functions associated with the induction of ventricular hypertrophy leading to cardiac stiffness and diastolic heart failure. Hcy-induced neurological defects are mediated by the NMDA-R (N-methyl-D-aspartate (NMDA) receptor) activation. NMDA-R is expressed in the heart. However, the role of NMDA-R on cardiac function during HHcy is still in its infancy. The blockade of NMDA-R attenuates NMDA-agonist-induced increase in the heart rate. Hcy increases intracellular calcium and activates calpain and calpain-associated mitochondrial (mt) abnormalities have been identified in HHcy. Mitochondrial permeabilization and uncoupling in the pathological setting is fueled by redox stress and calcium mishandling. Recently the role of cyclophilin D, a component of the mitochondrial membrane permeability transition pore, has been identified in cardiac-ischemia. Mechanisms underlying the potentiation between NMDA-R activation and mitochondrial defects leading to cardiac dysfunction during HHcy remain to be elucidated. This review addresses the mitochondrial mechanism by which Hcy contributes to the decline in mechano-electrical function and arrhythmogenesis via agonizing NMDA-R. The putative role of mitochondrial MMP activation, protease stress and mitochondrial permeability transition in cardiac conduction during HHcy is discussed. The review suggests that Hcy increases calcium overload and oxidative stress in the mitochondria and amplifies the activation of mtMMP, causing the opening of mitochondrial permeability transition pore leading to mechano-electrical dysfunction.

Chronic kidney disease (CKD), and particularly kidney failure, is associated with accelerated atherosclerosis and approximately a 20-fold increased risk of cardiovascular death. The majority of these patients die from complications directly attributed to atherosclerosis and their life expectancy is decreased. Established risk factors are involved in the pathogenesis of this phenomenon. Age, gender, smoking, hypertension, dyslipidaemia and diabetes mellitus are among the established risk factors. Inflammation, qualitative lipid disorders (e.g. small dense low density lipoprotein), vascular calcification and oxidative stress represent emerging risk factors. The precise mechanism of atherosclerosis in patients with kidney failure is not yet known. CKD might represent a clinical model of atherogenesis. Thus, the evidence obtained from investigating “renal” atherogenesis could be of interest in improving our understanding of this disease process in the non-renal population. We review the relationship between “renal” and non-renal atherosclerosis focusing on pathogenesis, risk factors and clinical events and how they interact with treatment options. Overall, the “later” stages of CKD may eventually be considered as a coronary heart disease equivalent condition.

Ischaemic preconditioning, a response to brief sublethal episodes of ischaemia leading to a pronounced protection against subsequent lethal ischaemia, is mimicked by some pharmacological agents. Halogenated anaesthetics alone exhibit cardioprotective properties at therapeutic doses, independent of their anaesthetic and haemodynamic effect, leading to the concept of anaesthetic preconditioning. Only recently has research turned to clinical application of preconditioning protocols, and anaesthetic preconditioning has indeed been demonstrated in randomised clinical trials conducted in patients undergoing cardiac surgery - mostly coronary artery bypass graft. Most of these trials demonstrate cardiac protection by assessing postprocedural release of cardiac troponin or early postoperative cardiac function. Few studies focus on clinical outcomes, and none demonstrates an advantage in terms of mortality or cardiac morbidity. A recent meta-analysis, pooling data regarding the use of desflurane and sevoflurane, found significant reductions of inhospital mortality, myocardial infarction rate, intensive care unit and hospital stay, time on mechanical ventilation and incidence of long term cardiac events. In conclusion, the use of desflurane and sevoflurane appears to yield a better outcome, in terms of mortality and cardiac morbidity, in patients undergoing cardiac surgery. A definitive demonstration of this concept represents a difficult task because of the low mortality rate in modern cardiac surgery and because of the number of interfering factors. Whether these cardioprotective properties also exist in non-coronary surgery settings is still controversial owing to the scarce available data.

Stroke is the third most common cause of death in women and a major cause of disability. Stroke occurs in older age in women compared with men. High premenopausal estrogen concentrations in women are thought to be protective against stroke and cardiovascular disease. Estrogens are essential for normal reproductive function and they exert complex and diverse non reproductive actions on multiple tissues such as neuroprotective effects, vasodilatation, improved vascular reactivity, antithrombotic effects and lipid lowering effects. After menopause estrogen concentrations are depleted and in the past estrogen replacement therapy was considered as a potential protective agent against both cardiovascular disease and stroke. Although the use of hormone therapy was originally associated with a reduction in the risk of heart disease by about 50% in observational studies, the results regarding stroke have been less clear. In order to investigate the effect of hormone therapy on stroke risk, randomized controlled trials of cardio-and/or cerebrovascular- disease prevention in women with established heart disease have been designed. The Heart Estrogen- Progestin Replacement Study included stroke as secondary outcome. This study did not show any differences in myocardial infarction (MI) or coronary death (HR 0.99; 95%CI 0.80-1.22) and in stroke rate. In another study, the Women Estrogen Stroke Trial, 17 beta estradiol 1 mg/placebo was administered to women with previous ischemic stroke or transient ischaemic attack (TIA) having a mean age 71. No differences in stroke rate (RR 1.1; 95% CI 0.8-1.4) and in mortality rate (RR 1.2; 95% CI 0.8-1.8) were found, while a trend showing an increased rate of fatal strokes (RR 2.9; 95% CI 0.9-9.0) and for more severe non-fatal strokes (% patients with final National Institutes of Health Stroke Scale (NIHSS) 0-1: 19 % vs. 33%; p = 0.12) was observed. The Women's Health Initiative, a primary prevention study, where conjugated equine estrogen (CEE) plus medroxyprogesterone acetate/placebo was utilized, was stopped because of an excess in breast cancer and increased stroke rates (RR 1.4; 95% CI 1.1-1.8). Recently, a meta-analysis including 39,769 women participating in 28 trials has been published. Twelve studies were of secondary prevention and the overall stroke rate was 2%. In the hormone replacement therapy (HRT) arm there was a 29% increased rate of ischemic stroke (Number Needed to Harm, NNH:147). Furthermore, a 56% increased rate of death or dependency after stroke and a tendency of more fatal stroke were observed. Additionally, a higher stroke risk was reported in the first year of treatment. Conclusions: There seems to be no indication for hormone replacement therapy in the prevention of stroke in women. Further studies are needed to discover why estrogens have different effects on the heart and brain. Conventional risk-factors which could increase the risk of estrogen therapy need to be identified and as well as more restrictive inclusion and exclusion criteria such as coagulation parameters and intimal thickness should be adopted before new randomized trials are started.

This review considers the evidence showing that statins can prevent first or recurrent stroke or improve its outcome in subjects at moderate or high risk for cardiovascular disease (CVD). Data are reviewed according to trial design (observational or prospective) and baseline CVD risk. Two (ASCOT, CARDS) out of five primary CVD prevention statin trials showed a considerable reduction in stroke rates. In two (MIRACL and PROVE IT) out of five acute coronary syndrome trials, the prevention of first stroke was significant. Most secondary prevention trials (4S, CARE, LIPID, HPS, GREACE and TNT) showed a beneficial effect of statins in stroke prevention. Finally, SPARCL, the only secondary stroke prevention trial in subjects without overt coronary heart disease (CHD), showed a significant reduction in total and ischaemic (fatal and nonfatal) stroke rate, although a small but significant increase in nonfatal haemorrhagic stroke was noted. There was also a significant reduction in CHD-related events. The possible mechanisms responsible for statin-associated stroke prevention are discussed. The evidence suggests the need to consider early and long-term statin treatment (with substantial low-density lipoprotein cholesterol reduction) in all patients at high risk of any type of major vascular event, without discriminating CHD from stroke. Thus, statins may be beneficial to both the heart and the brain.

Patients with lower limb and pelvic trauma, or undergoing major orthopaedic surgery represent one of the highest risk groups for the development of venous thromboembolism (VTE). A significant number of pharmacological and mechanical agents have been used for the prophylaxis and treatment of VTE. Fondaparinux is a relative new pharmacological agent that selectively binds to antithrombin, and represents a new class of synthetic selective inhibitors of activated factor X. Eleven percent of the fondaparinux-related English language literature, between 2001 and 2007, refers to orthopaedic trauma, and was the sample assessed for this critical analysis review. The clinical studies evaluating the safety, efficacy, and financial implications associated with lower limb orthopaedic trauma show that fondaparinux has comparable results with the well-established use of enoxaparin. However, the scientific community has raised several issues regarding mostly fondaparinux's safety, timing of its 1st dose, bleeding side effects, duration of administration and lack of a reliable reversing agent. Further trials are necessary focusing on the safety and efficacy of this drug mostly in relation to clinical relevant outcomes and to different fields of trauma surgery (pelvis, long bone fractures and polytrauma patients).

Stroke is the third most common cause of death worldwide following ischemic heart disease and cancer and the number one condition associated with permanent disability. In Western countries, the yearly incidence of stroke is ∼ 0.2% of the population and the number of stroke-related death is expected to double over the next 30 years. Studies from the Netherlands and Scotland showed that stroke accounted for 3% to 5% of their total health care resources. For 2006, the estimated direct and indirect cost of stroke in the United States was ∼ 60 billion. Significant stenosis of the internal carotid artery is responsible for 10% to 20% of all strokes or transient ischemic attacks. Large-scale randomized clinical trials have established the superiority of carotid endarterectomy (CEA) over medical management in patients with high-grade stenosis of the internal carotid artery, particularly among symptomatic patients. Although percutaneous carotid revascularization has been performed since the early eighties, the enthusiasm has long been tempered by the fear of cerebral embolism. Following the introduction of emboli protection devices (EPD) around the year 2000, the number of procedures performed worldwide has grown exponentially. We review the available studies on carotid stenting and discuss appropriate use of this procedure. Emphasis is also placed on optimal long-term pharmacotherapy in patients with carotid stenosis.

Hemodialysis (HD) patients are commonly affected by secondary hyperparathyroidism (SHPT), in which 3 well-known factors are usually involved: hypocalcemia, hyperphosphatemia and calcitriol deficiency. Classically, high parathyroid hormone (PTH) levels cause bone-associated diseases, such as osteitis fibrosa and renal osteodystrophy, but more recently it has been demonstrated the link between SHPT and a systemic toxicity, with a major role in determining cardio-vascular disease, including arterial calcification, endocrine disturbances, compromised immune system, neurobehavioral changes, and altered erythropoiesis. Treatment with calcitriol (CT), the active form of vitamin D, reduces parathyroid hormone (PTH) levels, but may result in elevations in serum calcium (Ca) and phosphorus (P), increasing the risk of cardio-vascular calcification in the HD population. Several new vitamin D analogs have been developed and investigated with the rationale to treat SHPT with a reduced risk of hypercalcemia and hyperphosphatemia in HD patients. Paricalcitol (1,25-dihydroxy-19-nor-vitamin D2, 19- Nor-D2) is a vitamin D analog that suppresses PTH secretion with minimal increases on serum calcium and phosphate levels. It was demonstrated that paricalcitol prevents vascular calcification in experimental models of renal failure, compared with calcitriol. Furthermore, 19-Nor-D2 is the first analog approved for use in HD patients and is available for i.v. and oral administration, commonly 3 times weekly after HD. The purpose of the present review is to analyze the pathogenesis and treatment of SHPT in HD patients, and the role of paricalcitol in the prevention of arterial calcification.