Current Vascular Pharmacology - Volume 10, Issue 2, 2012

Diabetes mellitus is a leading health problem both in western societies as well as in developing countries. Diabetes affects more than 200 million people worldwide, with more than 3 million deaths attributed yearly to the disease, and World Health Organization (WHO) predictions expect a double increase of diabetes-related mortality until 2030 [1]. The diabetes-related burden of disease ranges from cardiovascular disease to stroke, kidney disease, visual loss and peripheral neuropathy (with diabetic foot ulcers) [2]. The economic impact of diabetes is enormous; WHO estimates that in the period 2006-2015, China will lose $558 billion in foregone national income due to heart disease, stroke and diabetes alone [1]. Taking into account the importance of diabetes, we invited distinguished authors in the field to give their perspective on current controversies in this supplemental issue of the Current Vascular Pharmacology journal. Heritability is one of the risk factors for both type 1 and type 2 diabetes. Type 2 diabetes mellitus (T2DM) is a complex disease modified by a number of environmental and genetic factors that contribute at varying degrees to the final phenotype and possibly interact with each other. Current approach in genetic epidemiology uses genome-wide association studies (GWAS) which serves to identify the gene targets that have been assessed to-date. It seems that only a minor fraction of the attributed diabetes heritability has been unravelled so far. Ntzani et al. review the current evidence on more than 60 identified loci implicated with T2DM. Despite the increasing numbers of identified genetic markers, a large proportion of the observed T2DM heritability remains unexplained [3, 4]. Larger GWAS on enhanced genotyping platforms, refined ascertainment of the characteristics for the populations under study and additional information from whole-genome sequencing will contribute to a more comprehensive view of the genetic background of the disease, with implications on new targets for drug development, as well as tailored pharmacogenetic approaches. Non-alcoholic fatty liver disease (NAFLD), with a prevalence of 70% among T2DM individuals, is characterized by hepatic steatosis in the absence of excessive alcohol consumption and ranges from steatosis to steatosis with necroinflammation and/or fibrosis (non-alcoholic steatohepatitis, NASH) to cirrhosis and even hepatocellular cancer [5, 6]. NAFLD and NASH are independently associated with higher mortality rates with cardiovascular disease (CVD) being the leading cause of death for these patients [7]. Tziomalos et al. review the current data on pharmacological agents which have been evaluated in NAFLD. Although most studies are small, short-term and yielded unsatisfactory results in terms of efficacy, it seems that vitamin E, metformin and pioglitazone are the most promising agents to date. Lifestyle modification with prevention of obesity is of paramount importance for the reduction of the prevalence of NAFLD in diabetic individuals. The goal for treating hypertension in patients with diabetes is the reduction of macrovascular and microvascular complications. Current guidelines recommend blood pressure (BP) levels < 130/80 mmHg [8]. Retrospective data analyses suggest an association between low BP levels with slower decline in chronic kidney disease (CKD) progression and greater cardiovascular risk reduction in T2DM patients. Kalaitzidis et al. suggest that such recommendations are not supported by appropriately powered prospective outcome trials [9]. Major limitations of most published trials of BP lowering in diabetes is the failure to either target or achieve mean systolic BP levels below 130mmHg. Data from recently published randomized trials do not support BP levels below 130/80 mmHg for all diabetic patients, whereas BP levels < 130/80mmHg are beneficial for stroke risk reduction in high risk patients, as well as for those patients with CKD (GFR <45 ml/min/1.73m2) who have > 500 mg albuminuria.

Objective: Diabetic patients are at risk of macro- and micro-vascular complications, including diabetic nephropathy, and have difficulties in achieving blood pressure (BP) goals. Aliskiren, a direct renin inhibitor, inhibits the first step of the renin angiotensin aldosterone system. We aimed to systematically address the relevant evidence on the effects of aliskiren in diabetic individuals. Methods: We considered randomized controlled trials (RCTs) evaluating aliskiren in diabetic patients. Information was recorded independently by 2 investigators. We were limited to trials published in English. Results: PubMed search retrieved 16 items. After excluding 12, we ended with 4 eligible studies with 1488 participants. Mean baseline BP levels were 143/82 mmHg and median follow up was 2 months. Aliskiren was compared against angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) or aliskiren plus ACE inhibitor/ARB in 2 studies and against placebo in the other 2. The most frequent indication for aliskiren therapy was diabetes plus hypertension and albuminuria. Aliskiren seems to be effective in reducing BP levels, albuminuria in diabetics, either as monotherapy (compared with placebo), or in addition to ACE inhibitors/ARB (compared with monotherapy), without any major safety considerations. Conclusions: There are promising results on the effect of aliskiren in diabetic patients, but the available evidence is limited so far. This is a poorly investigated field with few RCTs and new studies focusing on “hard” outcomes are needed.

Type-2 diabetes is a complex disease modified by a number of environmental and genetic factors that contribute at varying degrees to the final phenotype and possibly interact with each other. Deciphering the genetic background of the disease serves multiple goals ranging from expanding our knowledge on the disease pathogenesis and identifying future targets for drug development to successfully personalizing clinical disease prediction and prognosis. In the present review, we aimed to systematically appraise the current evidence from genome-wide association studies (GWAS) on type- 2 diabetes, identify the gene targets that have been assessed to-date, and discuss issues that stem from the rapid growth of this literature. Our search identified more than 60 recently identified loci implicated with type-2 diabetes and related traits assessed in populations of European and Asian ancestry. A considerable number of the proposed genes seem to be related to beta-cell development and function, but there are several genes identified as “diabetes-genes” whose underlying pathway linked to diabetes remains poorly understood. Despite the increasing numbers of identified genetic markers, a large proportion of the observed type-2 diabetes heritability remains unexplained; larger GWAS on enhanced genotyping platforms, refined ascertainment of the characteristics of the populations under study and additional information from wholegenome sequencing will contribute to a more comprehensive view of the genetic architecture of the disease. This information is also anticipated to improve the predictive ability of multiple-loci genetic risk scores that will eventually be able to identify disease susceptibility over and above the traditional non-genetic risk factors.

The goal of treating hypertension in patients with diabetes is reduction of macrovascular and microvascular complications. Most current guidelines recommend more aggressive treatment goals with blood pressure (BP) targets of <130/80 mmHg. Retrospective data analyses suggest an association between a lower BP and slower declines in chronic kidney disease (CKD) as well as greater cardiovascular (CV) risk reduction in patients with type 2 diabetes. Such recommendations, however, are not supported by appropriately powered prospective outcome trials. Indeed, several important questions regarding aggressive lowering of BP levels are still unanswered. Major limitations of most existing clinical trials of BP lowering in diabetes is the failure to either target or achieve mean systolic BP values below 130 mmHg. Data from more recent randomized trials that evaluated different levels of BP do not support a BP below 130/80 mmHg as providing further CV risk reduction and compared to levels below 140/90 mmHg. One consistent benefit of a lower BP level, however, is on reduction of cerebrovascular events. There is reasonable evidence that a lower BP level does further slow progression of advanced proteinuric kidney disease such that a BP goal <130/80 mmHg is defensible. This review examines the data for and against aggressive BP lowering in patients with diabetes.

Non-alcoholic fatty liver disease (NAFLD) is a common disorder and its prevalence is expected to increase due to the rising incidence of type 2 diabetes mellitus (T2DM) and obesity. NAFLD is associated with increased mortality rates and cardiovascular disease is the leading cause of death in these patients. The pathogenesis of NAFLD is not completely elucidated but insulin resistance and oxidative stress appear to play a major role. NAFLD is more prevalent and more severe in patients with T2DM. A multitude of pharmacological agents have been evaluated in NAFLD but most studies were small, short-term and yielded unsatisfactory results in terms of efficacy. Patients with T2DM and NAFLD appear to be even less responsive to the evaluated agents. Thus, the optimal management strategy for NAFLD remains unclear. On the other hand, preliminary data suggest that lifestyle intervention can reduce the incidence of NAFLD in overweight or obese patients with T2DM. Accordingly, prevention of obesity and T2DM is of paramount importance for the reduction of the prevalence of NAFLD and of its associated cardiovascular and liver-related complications.

Low-density lipoprotein-cholesterol (LDL-C) lowering remains the main target of hypolipidemic therapy [1]. Statins are the most widely used evidence-based drugs for the management of dyslipidemia and to reduce the risk of cardiovascular (CV) events [2]. The main lipid “target” of statins is LDL-C levels but they also exert variable effects on highdensity lipoprotein-cholesterol (HDL-C) and triglycerides (TG) levels [3]. The recently published Long-term Event Monitoring (LEM) study included 21,139 Japanese patients with hypercholesterolemia (LDL-C = 171, HDL-C = 60 and TG = 166 mg/dl; 4.4, 1.6 and 1.9 mmol/l at baseline). All patients received fluvastatin (mean dose 22.7 ± 6.7 mg/day at study end). Overall, 1.7% (146/8563) and 1.1% (93/8563) of patients aged ≥ 65 years old experienced cardiac and cerebral events, compared with 1.1% (112/10,517) and 0.3% (28/10,517) of patients aged < 65 years old (p = 0.0002 and < 0.0001, respectively). The follow-up period for primary (n = 17,189) and secondary (n = 1,895) prevention was 5 and 3 years, respectively [4]. A post hoc analysis of the LEM study published in this issue of Current Vascular Pharmacology demonstrated that diabetes (DM), hypertension, TG and HDL-C had an impact on cardiac and cerebral events [5]. DM was strongly associated with CV events in both the primary and secondary prevention groups [5]. For primary prevention DM increased the incidence of cardiac events by 2.37-fold and cerebral events by 2.15-fold in patients without complications. For secondary prevention the corresponding increases in risk were 1.59- and 3.79-fold, respectively, in patients with cardiac complications. A surprising finding was that hypertension exerted a significant predictive value for events only in the primary but not in the secondary prevention group [5]. The better control of blood pressure in higher risk patients, mainly in the secondary prevention group, could account, at least in part, for this finding [5]. The role of several lipid profile components on primary or secondary prevention was another surprising finding of the LEM study. Particularly, high TG and low HDL-C levels and not high LDL-C levels were predictors of CV events in the secondary prevention group [5]. Also, in patients without complications, the atherogenic lipid profile (low HDL-C and high TG), but not LDL-C levels, was associated with increased cerebral events [5]. However, it is important to recognize that all patients were on treatment.

Objective: The long-term event monitoring (LEM) study evaluated the lipid-lowering efficacy and safety of fluvastatin in Japanese patients with hypercholesterolemia. The present sub-analysis focused on the impact of risk factors on event prevention. Methods: In the LEM study, patients (n=21,139) who started fluvastatin between 2000/4/1 and 2002/3/31 in Japan were prospectively registered and followed up for 3 years (secondary prevention cohort) or 5 years (primary prevention cohort). Results: Of the patients registered, 19,084 were included in this sub-analysis. The secondary prevention group, demonstrated 8.27- and 2.89-fold higher incidence in cardiac events and cerebral events, respectively compared with the primary prevention group (P<0.001). Complications of cerebrovascular disease demonstrated a 2.22- and 5.29-fold higher incidence in cardiac events and cerebral events (P<0.01 and P<0.001, respectively). Presence of diabetes mellitus (DM) in patients without complication significantly increased the incidence in both cardiac events (2.37) and cerebral events (2.15) as compared with non-DM patients for primary prevention (P<0.001 and P<0.01, respectively). For the secondary prevention, DM patients with complication of cardiac disease showed a significantly higher incidence in both cardiac events (1.59) and cerebral events (3.79) compared with non-DM patients (P<0.05 and P<0.01, respectively). In contrast, DM patients with complications of cerebrovascular disease showed a significantly higher incidence in cerebral events (2.58, P<0.05), but not cardiac events compared with non-DM patients. Similarly, the presence of hypertension significantly increased the incidence in both cardiac (1.64) and cerebral events (1.81) for primary prevention (P<0.01 and P<0.05, respectively). For secondary prevention, hypertension in patients with complication of cardiac or cerebrovascular disease did not affect incidence in both cardiac and cerebral events. In the patients without complication, high triglycerides and low high density lipoprotein cholesterol (HDL-C), but not low density lipoprotein cholesterol (LDL-C), increased cerebral events, while only LDL-C significantly increased cardiac events. For secondary prevention, high triglycerides or low HDL-C, but not LDL-C, significantly increased the relative risk of cardiac events in the patients with complication of cardiac disease. Conclusions: The LEM study, a large-scale prospective study of long-term fluvastatin treatment for hypercholesterolemia in Japanese patients, demonstrated high impact of complications such as DM and hypertension as well as high triglycerides or low HDL-C on cardiac and cerebral events. After long-term statin treatment, the control of other factors rather than LDL-C alone might be important to avoid vascular events.

The Metabolic Syndrome (MetS) confers a greater risk for both diabetes and cardiovascular diseases. Both insulin resistance and low grade inflammation appear to be pivotal in the pathogenesis of this disorder. The cornerstone of treatment presently is therapeutic lifestyle change with the emphasis on weight loss by diet and exercise. It appears that the evidence base will support statins as first line therapy for the dyslipidemia. Also, there is a limited role for both bile acid sequestrants and fibrates in certain subgroup of patients. It would appear that the Angiotensin converting enzyme inhibitors (ACEs) and angiotensin II receptor blockers (ARBs) are the preferred therapies for hypertension but invariably a combination therapy with additional drugs is required keeping in mind that certain drugs can exacerbate the dyslipidemia and or glycemia of MetS. Whilst metformin appears to be the drug of choice for the dysglycemia, thiazolidinediones (TZDs) like pioglitazone can also be beneficial but recent concern about bladder cancer has resulted in its discontinuation in certain countries in Europe. Metformin therapy has been shown to prevent new onset MetS. Modulating the incretin axis can prove very fruitful. A drug targeting all 3 disorders would be ideal but to date does not exist.

Heart transplantation (HTx) is the treatment of choice for patients with refractory end-stage heart diseases. Although the procedure is considered effective in extending and improving quality of life, the onset of cardiac allograft vasculopathy (CAV) continues to limit the long-term success of HTx. Emerging data indicate that the endothelium plays a significant role in the onset, progression and complication of this multifactorial disease, with both immunologic and nonimmunologic risk factors contributing to its development. Improving our understanding of the integral role of the coronary microcirculation in CAV is of crucial clinical interest since it could provide further insights into the related pathophysiological mechanisms and possible new strategies for CAV prevention and therapy. Assessment of coronary microvasculopathy has been shown to be of predictive value after HTx. Predominant allograft microvascular dysfunction is detectable in 15-20% of patients after HTx. Very recently, stenotic microvasculopathy (detected in biopsy samples) has been characterized as a prognostic factor for long-term survival after HTx. The ability to detect and distinguish changes in epicardial and microvascular function may aid in identifying modifiable factors that lead to CAV. Improved immunosuppressive drugs, including mycophenolate mofetil and proliferation signal inhibitors, as well as statins (in part via immunomodulation), may have a beneficial effect on coronary microcirculation after HTx, although there is still a need to confirm the impact of vasodilators in improving the prognosis of HTx patients. We review the role of coronary microvasculopathy in HTx, its prevention and new potential pharmacological interventions.

Statins are well established drugs for primary and secondary prevention of coronary artery disease (CAD). Despite the well-known ability of statins to lower cholesterol, it is now clear that clinical benefits are also substantially higher than expected and several clinical trials, like JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) have indicated that such clinical effects are independent of cholesterol reduction. These cholesterol-independent actions have been named “pleiotropic effects” and include: anti-oxidation and anti-inflammatory effects, modulation of immune activation, stabilization of atherosclerotic plaque, decreased platelet activation, inhibition of cardiac hypertrophy, reduction of cytokine-mediated vascular smooth muscle cell (VSMC) proliferation and improvement of endothelial function. Recently, additional pleiotropic effects of statins on “cellular senescence” have been seen in different cell types, including endothelial progenitor cells (EPC), endothelial cells (EC), VSMC and chondrocytes. At the molecular level, the effect of statins on cellular senescence could be mediated by their interaction with the telomere/telomerase system. Recent evidence suggests that the anti-aging effects of statins are linked to their ability to inhibit telomere shortening by reducing either directly and indirectly oxidative telomeric DNA damage, as well as by a telomere capping proteins dependent mechanism. In this review, we discuss the pleiotropic effects of statins, focusing on the telomere/telomerase system. We will also present our current findings regarding leukocyte telomere length in very old people with myocardial infarction on statin therapy.

In 2004, approximately 9 million people worldwide experienced a stroke, with the majority being ischemic in nature. While the prognosis for recovery can be good, long-term survival and functional outcome can be improved. Stroke survivors are at an increased risk for recurrent stroke and other ischemic vascular events and face significant cross-risk for atherothrombotic conditions affecting the coronary and peripheral vascular beds. As such, the secondary prevention of ischemic events in patients with stroke has focused on the treatment of atherosclerosis as a whole, with antiplatelet therapy playing a key role. There is some controversy regarding optimal antiplatelet therapy following stroke. The appropriate use of specific agents, the impact of stroke type and proper dosing, and other questions stem from an incomplete understanding of the issues, variability in clinical trial data, diversity in patient demographics, and differences in antiplatelet regimens. This review evaluates the clinical evidence for antiplatelet therapy in patients that have suffered an ischemic stroke, with an emphasis on balancing the benefits of a particular antiplatelet regimen with its attendant risk profile. The critical assessment of emerging trial data and its impact on existing treatment guidelines may aid in choosing the most appropriate antiplatelet regimen for comprehensive secondary prevention following stroke.

Several lines of evidence suggest a detrimental effect of aldosterone excess on the development of metabolic alterations. Glucose metabolism derangements due to aldosterone action are frequently observed not only in patients with primary aldosteronism but also in patients with obesity. A contribution to the hyperaldosteronism observed in obese subjects can be attributed, at least in part, to the action of still unidentified adipocyte-derived factor. Aldosterone, through genomic and non-genomic actions contributes to induce several abnormalities: pancreatic fibrosis, impaired beta cell function, as well as reduced skeletal muscle and adipose tissue insulin sensitivity. Oxidative stress, systemic inflammation, together with these metabolic alterations may explain the appearance of the cardiometabolic syndrome and the progression of cardiovascular and renal diseases, in the presence of inappropriate aldosterone levels. The biological actions of aldosterone are mediated by mineralocorticoid receptor (MR), although MR can be activated through an aldosteroneindependent fashion. Besides salt-water homeostasis, MR activation promotes inflammation, endothelial dysfunction, cardiovascular remodelling and affects adipose tissue differentiation and function. Clinical and experimental studies have shown that MR blockade is able to suppress inflammation, to improve endothelium- dependent vasorelaxation, but most interestingly, to improve pancreatic insulin release as well as insulin-mediated glucose utilization. These actions indicate MR antagonists as a useful therapeutic tool able not only to reduce cardiovascular risk and renal damage, but also to improve metabolic sequaelae.

Although infective endocarditis (IE) is not the most frequent infection seen in intravenous (IV) drug abusers (IVDAs), health care providers should always regard it as a possible diagnosis in this population. Many researchers have tried to elucidate the clinical, epidemiologic, immunologic and pathogenetic aspects of this entity. Right-sided endocarditis accounts for almost 10% of all IE episodes and has been most commonly interrelated with IV use of illicit substances. On the other hand, recent reports have proposed that left-sided valve participation is seen more often now than in the past. While, our progress in medicine, new diagnostic criteria and especially modern imaging techniques have broadened our ability to recognize IE, there are still some gray areas regarding right-sided IE. Our aim is to comprehensively review the clinical features and complications and also the possible pathogenetic and immunologic mechanisms implicated in IE patients who are injecting illicit substances.

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most widely prescribed therapeutic class of drugs worldwide, with established clinical benefits both in terms of improving serum lipid profiles and reducing cardiovascular events and mortality. Although statins have a favorable risk-to-benefit ratio, they have the potential to cause adverse events which can result in muscular inflammation (myositis), muscle breakdown (rhabdomyolysis) and, ultimately, kidney failure. While the incidence of rhabdomyolysis is approximately 3.4 cases per 100,000 person-years with standard-dose statin therapy, the risk of developing the condition increases substantially at higher therapeutic doses. This effect may be exacerbated by prescribing statins in combination with certain other medications because drug-drug interactions increase statin exposure by interacting with enzymes that would normally be involved in their metabolism and clearance. Co-administration of drugs that inhibit the cytochrome P450 (CYP) enzymes responsible for metabolizing statins, or that interact with the organic anion-transporting polypeptides (OATPs) responsible for statin uptake into hepatocytes, substantially increases the risk of developing myotoxicity. Such effects vary among statins according to their metabolic profile. For example, pitavastatin, a novel statin approved for the treatment of hypercholesterolemia and combined (mixed) dyslipidemia, is not catabolized by CYP3A4, unlike other lipophilic statins, and may be less dependent on the OATP1B1 transporter for its uptake into hepatocytes before clearance. Such differences in drug-drug interaction profiles among available statins offer the possibility of reducing the risk of myotoxicity among high-risk patients.