Current Vascular Pharmacology - Volume 10, Issue 6, 2012

Dysglycemia as a pre-stage of diabetes mellitus and abdominal obesity are closely interrelated at multiple levels and by a whole array of complex mechanisms, many of which seem to have the potential of causing harm to large blood vessels, in particular to coronary and peripheral vascular segments. Both conditions are associated with elevated circulating concentrations of free fatty acids in conjunction with insulin resistance, oxidative stress, mitochondrial dysfunction, disordered nitric oxide release, and endothelial dysfunction. Oscillating glucose levels seem to be associated with the most of the injury burden to endothelial cells of large blood vessels and also generate some kind of metabolic memory. In addition, the multiple effects of insulin also on the regulation of the vasculature are shifted towards vasoconstriction and proliferation in the context of insulin resistance and the excessively high levels.

The present paper examines major evidences on the correlation between pre-diabetes, diabetes and cardiovascular risk, especially focusing on early and multifactorial treatment strategies holding the potential to delay the occurrence of micro- and macro-vascular complications causing impaired quality of life and reduced survival.

Diabetic dyslipidemia is due to a multiple array of metabolic abnormalities determining a typical phenotype characterized by increased plasma triglycerides, reduced HDL and a preponderance of small, dense LDL. This dyslipidemia, defined as atherogenic dyslipidemia, is thought to be highly responsible for the increased cardiovascular risk in diabetes mellitus. Several lines of evidence indicate that the increased liver production of VLDL is the main underlying defect in atherogenic dyslipidemia. This review will recapitulate the pathophysiological aspects of diabetic dyslipidemia with special focus on the molecular mechanism causing increased liver production of VLDL in diabetic patients. The consequences of atherogenic dyslipidemia on mechanisms of atherogenesis will be also reviewed.

In almost every epidemiological analysis so far performed a strong correlation always emerges between degree of hyperglycemia and risk of both micro- and macrovascular complications. However, whereas lowering plasma glucose levels by intensive treatment has proven to reduce the risk of development of retinopathy, nephropathy and neuropathy, the effect on macrovascular complications has remained quite doubtful. Multiple factors may have concurred to this negative findings including long duration of diabetes, poor pre-existing glycaemic control, potentially inadequate anti-diabetes drugs. Another potential explanation is that, given the high cardiovascular risk of the diabetic patients they were already aggressively treated as far as their cardiovascular risk factors are concerned. The annual mortality in these diabetic cohorts was, indeed, incredibly close to that of the non-diabetic population. These considerations along with the results of multiintervention studies, such as the Steno-2, supports the need for multifactorial intensive needs, definitely including glucose and lipid lowering.

Patients with diabetes and prediabetes are at high risk for micro- and macrovascular complications. A multifactorial management strategy improves their prognosis considerably. Of concern is that these patients often fall between two specialties: cardiovascular medicine and diabetology. Practice guidelines for this patient category have been issued in collaboration between the European Society of Cardiology and the European Association for the Study of Diabetes to ascertain management according to the best available evidence. This article discusses why and for whom such guidelines are important.

Atherosclerosis is a chronic inflammatory disease that is based on the interaction between inflammatory cell subsets and specific cells in the arterial wall. SIRT1 deacetylates histone and non-histone proteins and has been implicated in protective effects of caloric restriction on lifespan and metabolic pathways in yeast, nematodes, and mice. In the vasculature of rodents, SIRT1 mediates vasodilatation through the release of endothelial nitric oxide synthase-derived nitric oxide and scavenges reactive oxygen species. Using a genetic loss-of-function approach, SIRT1 has been shown to interfere with crucial steps of endothelial activation and atherogenesis by suppressing NFκB signaling: Partial SIRT1 deletion in ApoE-/- mice prevented expression of endothelial adhesion molecules thereby hampering the extravasation of circulating monocytes. In monocyte-derived macrophages SIRT1 deletion reduced the expression of the scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (Lox-1) resulting in reduced foam cell formation and atherosclerosis. Moreover, it was reported that SIRT1 regulates the activity of liver X-receptor, thereby promoting ABCA1-driven reverse cholesterol transport in plaque-resident macrophages slowing foam cell formation. Finally, SIRT1 suppressed the expression of endothelial tissue factor, and thus exerted anti-thrombotic properties during induced carotid thrombosis in mice. These findings indicate protective effects of SIRT1 in atherogenesis and thrombosis at an experimental level and highlight the opportunity to translate this concept from bench to bedside. Indeed, SIRT1 activators are available and have been shown to exert beneficial effects at the preclinical level in obesity and type 2 diabetes mellitus (T2DM). SIRT1 activators are currently being evaluated in phase II clinical trials in patients with T2DM. The concept of SIRT1 activation appears a promising strategy for novel therapeutic approaches in patients with atherothrombosis.

The present work is addressing the latest advances made in understanding the molecular mechanisms of vascular aging. Increased production of reactive oxygen species (ROS) is the common denominator of vascular aging, endothelial dysfunction and atherosclerosis. ROS are generated by different intracellular molecular pathways. In view of its role in determining the redox state of the cells and their responses to free radicals, mitochondrial p66Shc protein has been regarded as part of a putative transduction pathway relevant to endothelial integrity. Future efforts should translate our knowledge of the mechanisms of aging and its interaction with risk factors into the development of new therapeutic strategies to prevent age-associated cardiovascular disease.

Cardiovascular disease is multidimensional and new ideas are needed to develop the conventional risk factor paradigm that has been based on the Framingham Heart Study since more than 30 years. Traditional risk factors such as hypertension, smoking, hyperlipidemia and diabetes can only explain about 50% of the distribution of coronary heart disease whereas the inclusion of new risk markers or protective markers may increase the explained proportion up to 80% of myocardial infarction risk according to the INTERHEART study. Still there are substantial differences in cardiovascular risk between regions and populations that are hard to explain. Findings in the former Soviet Union geographical area in Eastern Europe could contribute to new and better understanding of cardiovascular risk as a reflection of ageing in general, as populations in these areas not only run a very high cardiovascular risk but also have a shorter mean life expectancy in general. New understanding of the interaction between genes and the environment in prediction of cardiovascular ageing could contribute to the development of more effective preventive strategies.

Arterial aging, characterized by arterial stiffening that is clinically evaluable as aortic pulse wave velocity, is risky for CV events, disability, and loss of cognitive function. Today the only adopted strategy to decrease arterial aging/ arterial stiffness is represented by decreasing BP. Selective antihypertensive drug classes (calcium channel blockers, converting enzyme inhibitors, angiotensin type 1 receptor antagonists) showed a beneficial effect on the arterial wall and on both large and small arteries over and above the reduction in BP levels. Still, the lower the better paradigm seems only to expose older subjects to higher rate of side effects, that via hypotension result in even transient organ hypoperfusion. This vicious circle may be particularly detrimental for cerebral district and, thus, for cognitive impairment onset and progression until dementia.

Loss of normal endothelial function and bioactivity of nitric oxide (NO), associated with increased production of reactive oxygen species (ROS), are characteristics of cardiovascular disease states. There is good experimental evidence that these abnormalities are causally related to cardiovascular disease pathogeneses, and are amenable to therapeutic intervention. However, simple attempts to increase NO levels or reduce “oxidative stress”, for example using nonselective anti-oxidant drugs, have shown no benefit as treatments of cardiovascular disease. Increasing evidence highlights the need to better understand NO and ROS mediated signaling mechanisms in endothelial function, in order to identify more rational and selective therapeutic targets. The NO synthase co-factor, tetrahydrobiopterin (BH4) is a redox active molecule which regulates NO and ROS production by NO synthase and provides an exemplar of redox dependent signaling in the endothelium, with relevance to cardiovascular disease. Loss of endothelial cell BH4 is observed in cardiovascular disease states and results in loss of NO, but increased ROS production by endothelial NO synthase. Genetic mouse models of augmented endothelial cell BH4 synthesis have shown proof of concept that endothelial cell BH4 can alter cardiovascular disease pathogenesis, but clinical trials of BH4 therapy in vascular disease have been limited by systemic oxidation and limited endothelial cell uptake of BH4. In contrast, some existing therapies such as statins appear to exert favourable effects on endothelial cell BH4 and endothelial NO synthase function. Identifying specific redox mechanisms and targets in the endothelium will provide new potential targets for future drug treatments.

Although the impressive progression of modern diagnostic opportunities and therapeutic options, cardiovascular diseases still represent the leading causes of morbidity and mortality, worldwide. Beyond the effective pharmacological treatment of major cardiovascular disease or sequelae, however, cardiovascular diseases developing in adult individuals are largely preventable. The substantial failure to prevent cardiovascular disease in the 20th century generation is mostly linked to the ineffective use, as well as to the underuse of available preventive strategies. As a consequence, preventive strategies should be encouraged at both individual and population level, to substantially improve healthy status of the general population and reduce the burden of cardiovascular diseases in Western and Developing Countries.

The need of early, preclinical detection of disease is given by the fact that in 50% of patients dying due to coronary death, mortality is neither heralded by cardiac symptoms nor diagnosis make .The risk during life of suffering of consequences of atherosclerosis can be efficiently assessed through the Framingham risk score (among several other global risk scores). Global risk scores although originally formulated to give a numerical estimate of the risk, give generally a rough categorization of the patient into a low, (0-10%) intermediate (10%-20%) or high (>20%) risk. Furthermore the boarders between intermediate and low or high risk are frequently not uniform. Although global risk score evaluation are considered efficient tools in medical practice, over- or underestimation of risk has been reported in several studies. These are the mean reason why many investigators embarked during the last two decades in an effort to discover newer predictive markers. Among them few have passed the threshold of a rigorous assessment of their predictive power including analysis not only of statistical association but also of calibration, discrimination, and reclassification.

All coronary patients should be advised and have the opportunity to access a comprehensive cardiovascular prevention and rehabilitation programme, addressing all aspects of lifestyle - smoking cessation, healthy eating and being physically active - together with more effective management of blood pressure, lipids and glucose. To achieve the clinical benefits of a multidisciplinary and multifactorial prevention programme we need to integrate professional lifestyle interventions with effective risk factor management, and evidence based drug therapies, appropriately adapted to the medical, cultural, and economic setting of a country. The challenge is to engage and motivate cardiologists, physicians and health professionals to routinely practice high quality preventive cardiology in hospital and community, and a health care system which invests in prevention.

Low high-density lipoprotein (HDL) cholesterol levels are associated with an increased risk of coronary artery disease and myocardial infarction. Experimental studies have identified several potential anti-atherogenic properties of HDL, including promotion of macrophage cholesterol efflux, endothelial nitric oxide stimulation, anti-inflammatory and anti-thrombotic effects. These observations have lead to the important question of whether raising of HDL can reduce cardiovacular risk. Notably, recent studies have suggested that vascular effects of HDL can be highly heterogenous and are altered in patients with coronary disease or diabetes, that has been referred to as “HDL dysfunction”. Moreover, studies using gene-targeted mice have indicated that genetic modifications leading to a similar increase of HDL cholesterol levels can either reduce (i.e. apoA1 transgene overexpression) or accelerate (i.e. SR-B1 deficiency) atherosclerosis, depending on the molecular target. These findings therefore suggest that HDL cholesterol levels alone are likely not sufficient as a readout for the vascular effects of HDL-targeted therapeutic interventions, since both, the vascular effects of on-treatment HDL as well as the underlying molecular mechanism used to elevate HDL cholesterol levels may represent critical determinants of the overall vascular effects of therapeutic interventions raising HDL-cholesterol levels. In summary, low HDL cholesterol plasma levels remain associated with an increased cardiovascular risk. However, the above findings suggest that careful clinical trial programms are needed to determine, which HDL raising therapeutic interventions may indeed exert vasoprotective effects.

The plasma levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Traditional HDL-raising therapies, like fibrates, PPAR-γ agonists, and nicacin, among others, are associated with undesirable side effects, limited efficacy, or have not yet been shown to improve morbidity and mortality on top of statins in clinical outcome trials. A novel pharmacological target for raising circulating HDL-C levels is the cholesterol ester transfer protein (CETP), an enzyme that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. Four pharmacological small-molecule inhibitors of CETP, i.e. torcetrapib (Pfizer), dalcetrapib (JTT-705; Roche), anacetrapib (Merck), and evacetrapib (Eli Lilly) have been developed. Notwithstanding a marked increase in HDL, torcetrapib was associated with an increase in all-cause mortality in the ILLUMINATE trial and raised safety concerns related to the off-target effects of CETP inhibition. Most recently, development of dalcetrapib was abruptly stopped due to a lack of clinically meaningful efficacy. Thus, it will be of utmost importance to demonstrate that the remaining CETP inhibitors in development not only increase HDL-C levels in plasma, but also improve HDL-function in patients with coronary disease or an acute coronary syndrome.

Among patients with atherothrombosis, including coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD), patients with PAD generally have the worse prognosis. The Reduction of Atherothrombosis for Continued Health (REACH) Registry characterized the atherothrombotic risk factor profile, and evaluated treatment intensity and cardiovascular events among different atherothrombotic patient populations worldwide. Two thirds of PAD patients had polyvascular disease, defined as symptomatic involvement of more than one vascular bed. The risk factor profile in patients with CAD, CVD and PAD was very much similar. However, optimal risk factor control by medical treatment and lifestyle interventions was least accomplished in PAD patients. Furthermore, PAD patients and patients with polyvascular disease showed the highest cardiovascular event rates. Of note, therapeutic strategies are similar for all atherothrombotic disease categories, irrespective of the presence of polyvascular disease. Therefore, it is of the utmost importance to achieve optimal risk factor control, particularly for PAD patients and for those with polyvascular disease, in order to prevent future cardiovascular events.

Multisite artery or polyvascular disease is common. In the REACH registry, 15.9% of patients with either established atherosclerotic arterial disease or at least 3 risk factors for atherothrombosis had symptomatic polyvascular disease. History of risk factors and known co-morbidities, as well as a thorough physical examination, are mandatory in the initial screening and diagnostic work-up. Various non-invasive imaging techniques (duplex ultrasound, computed tomography angiography, magnetic resonance angiography) can be used for the identification of the polyvascular patient. Digital subtraction angiography is now used almost exclusively in association with endovascular procedures. Appropriate implementation of each technique is based on international guidelines and a multidisciplinary discussion for each case. The presence of co-existing disease in a different vascular bed is associated with a higher risk of recurrent symptoms and complications in the first site. In this context, accumulating evidence suggests that arterial biomarkers, such as arterial stiffness (pulse wave velocity), central blood pressures, wave reflections indices, ankle-brachial index, carotid intimamedia thickness, as well as vasculogenic erectile dysfunction, can predict cardiovascular morbidity and mortality beyond classical risk factors and prediction models. An important pending question is whether identification of multisite arterial disease may improve clinical outcomes in patients who are already in secondary prevention programs. Such screening of asymptomatic multisite artery disease in patients with known CVD would be of paramount importance if it is ultimately proven with hard evidence that it should lead to a different management from the one proposed for CVD patients without multisite artery disease.

Multisite artery disease (MSAD) affects 15% to 30% of patients with clinically manifest atherosclerosis, and has a relevant negative impact on prognosis. However, studies specifically focused on MSAD are very few, and available evidence is scarce. Importantly, patients with MSAD require an integrated management, possibly by a “Vascular Team” composed of the different specialists involved in the treatment of atherosclerosis. A multi-disciplinary, patient-centered approach is mandatory to deal with the variety of clinical scenarios and comorbidities found in MSAD patients. The risk/benefit ratio for multi-site arterial revascularization should always be carefully assessed in MSAD patients, taking into account the additional risks of interventions in this subset of patients. Many therapeutic options have been proposed for multisite revascularization, but little evidence is currently available to support specific recommendations. Percutaneous revascularization of the different arterial districts, when feasible, appears promising because of the lower operative morbidity and mortality.