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LE Magazine November 2008

Cardiovascular Health

Current antiplatelet therapies: benefits and limitations.

Antiplatelet therapy is the current criterion standard for the treatment of patients undergoing percutaneous coronary intervention and patients who have acute coronary syndromes. Clopidogrel in combination with aspirin is the current standard of care for reducing cardiovascular events in these patients. However, patients who receive currently available antiplatelet therapy may still develop atherothrombotic events. In addition, despite the clinical benefits achieved with clopidogrel, significant clinical limitations are associated with its use. This article summarizes the current understanding of the benefits and limitations of the commonly used antiplatelet therapies.

Am Heart J. 2008 Aug;156(2 Suppl):S3-9

Variability in response to cardiovascular drugs.

Cardiovascular drugs are characterized by wide inter-individual variability in dose/plasma concentration/ response (therapeutic and/or toxic) relationships. Therefore, some patients achieve good therapeutic response to their drug therapy, while others do not. Also, some patients experience adverse effects, which vary from mild to life-threatening. The source of variability in patients’ response to cardiovascular drugs may be of pharmacokinetic and/or pharmacodynamic origin. Many factors can potentially affect both of them such as genetics, gender, age, disease state, environmental factors like smoking and food, possible drug-drug interactions, and ethnicity (race). Cardiovascular pharmacogenomics is a new field that focus on the roles of genetic polymorphisms in drug metabolizing enzymes and drug targets in development of variable drug response.

Curr Clin Pharmacol. 2006 Jan;1(1):35-46

Statins and peripheral arterial disease: effects on claudication, disease progression, and prevention of cardiovascular events.

Peripheral arterial disease (PAD) of the lower limbs is the third most important site of atherosclerotic disease alongside coronary heart disease (CHD) and cerebrovascular disease (CVD). Best medical treatment is beneficial even in patients who eventually need invasive treatment, as the safety, immediate success, and durability of intervention is greatly improved in patients who adhere to best medical treatment. In recent years, a number of studies have suggested that the ACE-inhibitor ramipril and different statins, together with antiplatelet drugs, reduce cardiovascular morbidity and mortality in PAD. Patients with PAD are really a category of patients with a very high cardiovascular risk burden for fatal and nonfatal cerebrovascular and cardiovascular events; therefore, they need to be treated not only for local problems deriving from arteriopathy (intermittent claudication, rest pain and/or ulcers) but, above all, for preventing vascular events. Statins not only lower the risk of vascular events, but they also improve the symptoms associated with PAD. Statins exert beneficial pleiotropic effects on hemostasis, vasculature and inflammatory markers; there is also evidence that statins improve renal function considering that the plasma creatinine level is considered as an emerging vascular risk factor.

Arch Med Res. 2007 Jul;38(5):479-88

The significance of low HDL-cholesterol levels in an ageing society at increased risk for cardiovascular disease.

In most developed and developing countries, the proportion of the population aged 60 years or more is growing faster than any other age group. Given that the vast majority of cardiovascular events occur in older individuals, new thinking is needed to reduce their risk. Epidemiological studies have shown an increasing prevalence of the metabolic syndrome with age, driven by nutrition inappropriate for a modern sedentary lifestyle. A low level of high-density lipoprotein (HDL)-cholesterol, a component of the atherogenic dyslipidaemia of the metabolic syndrome, has been shown to be an important determinant of coronary risk, which rises in prevalence with increasing age. Thus, raising HDLcholesterol, in addition to lowering the level of low-density lipoprotein (LDL)-cholesterol, seems a plausible approach to reduce cardiovascular risk in an ageing population. Clinical studies have shown that adding nicotinic acid, which raises HDL-cholesterol by 20-25%, to a statin enhances the reduction in progression of atherosclerosis. Results of the ongoing Atherothrombosis Intervention in Metabolic syndrome with low HDL/High triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study are awaited with interest to see whether such theoretical benefit translates into clinical outcome.

Diab Vasc Dis Res. 2007 Jun;4(2):136-42

Statins for the primary prevention of cardiovascular events in older adults: a review of the evidence.

BACKGROUND: Although statins have been demonstrated to be beneficial for secondary prevention in the elderly, their use for primary prevention has not been well described. OBJECTIVE: In this review, we summarize data regarding the efficacy, safety, and current recommendations for statins for the primary prevention of cardiovascular events in older adults. METHODS: This review is based on a computerized literature search of the PubMed database for articles published in the English language from January 1980 to June 2006. Key words searched individually and cross-referenced included: statins, HMG-CoA reductase inhibitors, cholesterol, elderly, aged, cardiovascular disease, primary prevention, risk stratification, and C-reactive protein. This search produced 445 citations; reference lists revealed an additional 12 citations, all of which were screened for relevance to the topic. RESULTS: The existing evidence suggests, but does not confirm, benefit from the use of statins for primary prevention in the elderly subgroup (ie, those aged >65 years). Of the 6 published trials of statins for primary prevention, only 3 included subjects aged >75 years, and subgroup results in older adults are unavailable. Current guidelines recommend statins for individuals based on their assessed cardiovascular risk. CONCLUSIONS: Extension of treatment guidelines should consider an individual’s global risk of coronary heart disease. However, due to the prevalence of subclinical disease in older adults, risk may be higher or otherwise differ with age. In addition, tolerance for and barriers to adherence with long-term medical therapy are important treatment considerations in older adults. Prospective, randomized controlled trials that better define the tolerability, safety, and efficacy of statin therapy in older adults with elevated cholesterol levels and intermediate cardiovascular risk are needed.

Am J Geriatr Pharmacother. 2007 Mar;5(1):52-63

Anti-inflammatory agents and antioxidants as a possible “third great wave” in cardiovascular secondary prevention.

There are 3 important factors that predispose patients to plaque rupture or recurrent events: plaque burden or multiple arterial plaques, the presence of persistent hyperreactive platelets, and ongoing vascular arterial inflammation. Successful therapeutic strategies focus on these predisposing factors, and the use of low-density lipoprotein-lowering medications (principally statins) and antiplatelet agents (principally aspirin) has had a major impact on the occurrence of cardiovascular outcomes and overall mortality over the last 2 decades. However, despite these interventions, a significant number of patients experience recurrent events or progression of disease. Novel compounds are being studied to determine, for example, whether an increase in high-density lipoprotein will provide additional risk reduction; to date, this has not proved to be sufficiently effective. Although early invasive management has been proved to be superior to medical therapy in patients with plaque rupture producing acute coronary syndromes, its superiority in patients with clinically stable obstructive disease has been questioned. Thus, the search for additional agents to improve the outcomes of patients with atherothrombotic disease continues. The importance of inflammation, a potentially critical element in the initiation, progression, and rupture of plaque, has become increasingly evident. In this supplement, the role of inflammation and its principal cause, oxidative stress, are analyzed as potential targets of pharmacologic therapy. The history of anti-inflammatory and antioxidant therapy in cardiovascular disease is critically examined. Finally, the whole process of contemporary drug discovery and development from lead rationale and identification through biologic screening and testing in animals and then humans is explored, using as an example the xanthophyll carotenoids, a class of potent antioxidants currently under investigation.

Am J Cardiol. 2008 May 22;101(10A):4D-13D

Receptor for advanced glycation end products: fundamental roles in the inflammatory response: winding the way to the pathogenesis of endothelial dysfunction and atherosclerosis.

The multiligand receptor for advanced glycation end products (RAGE) of the immunoglobulin superfamily is expressed on multiple cell types implicated in the immune-inflammatory response and in atherosclerosis. Multiple studies have elucidated that ligand-RAGE interaction on cells, such as monocytes, macrophages, and endothelial cells, mediates cellular migration and upregulation of proinflammatory and prothrombotic molecules. In addition, recent studies reveal definitive rules for RAGE in effective T lymphocyte priming in vivo. RAGE ligand AGEs may be formed in diverse settings; although AGEs are especially generated in hyperglycemia, their production in settings characterized by oxidative stress and inflammation suggests that these species, in part via RAGE, may contribute to the pathogenesis of atherosclerosis. In murine models of atherosclerosis, vascular inflammation is a key factor and one which is augmented, in parallel with even further increases in RAGE ligands, in diabetic macrovessels. The findings that antagonism and genetic disruption of RAGE in atherosclerosis-susceptible mice strikingly reduces vascular inflammation and atherosclerotic lesion area and complexity link RAGE intimately to these processes and suggest that RAGE is a logical target for therapeutic intervention in aberrant inflammatory mechanisms and in atherosclerosis.

Ann N Y Acad Sci. 2008 Apr;1126:7-13

Regulation of smooth muscle cells in development and vascular disease: current therapeutic strategies.

Vascular smooth muscle cells (SMCs) exhibit extensive phenotypic diversity and rapid growth during embryonic development, but maintain a quiescent, differentiated state in adult. The pathogenesis of vascular proliferative diseases involves the proliferation and migration of medial vascular SMCs into the vessel intima, possibly reinstating their embryonic gene expression programs. Multiple mitogenic stimuli induce vascular SMC proliferation through cell cycle progression. Therapeutic strategies targeting cell cycle progression and mitogenic stimuli have been developed and evaluated in animal models of atherosclerosis and vascular injury, and several clinical studies. Recent discoveries on the recruitment of vascular progenitor cells to the sites of vascular injury suggest new therapeutic potentials of progenitor cell-based therapies to accelerate re-endothelialization and prevent engraftment of SMC-lineage progenitor cells. Owing to the complex and multifactorial nature of SMC regulation, combinatorial antiproliferative approaches are likely to be used in the future in order to achieve maximal efficacy and reduce toxicity.

Expert Rev Cardiovasc Ther. 2006 Nov;4(6):789-800

Paraoxonases and cardiovascular diseases: pharmacological and nutritional influences.

PURPOSE OF REVIEW: To summarize the new articles published in the last year on paraoxonases, including their expression in cardiovascular diseases, and regulation by pharmacological and nutritional means. RECENT FINDINGS: The elucidation of the crystal structure of the paraoxonase 1 (PON1) gene, obtained by directed evolution, shows that it consists of a six-bladed beta-propeller with a unique active site. PON1 is present in HDL but also in lipoprotein-deficient serum, in VLDL and in chylomicrons. PON1 protects lipids in lipoproteins, in macrophages and in erythrocytes from oxidation. Cellular PON2 and PON3 were also shown to reduce oxidative stress. Beyond its antioxidative properties, PON1 possesses additional antiatherogenic properties against macrophage foam cell formation: attenuation of cholesterol and oxidized lipids influx, inhibition of macrophage cholesterol biosynthesis and stimulation of macrophage cholesterol efflux. The PON1 gene is regulated by Sp1 and protein kinase C, whereas the PON2 gene in macrophages is regulated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. PON1 activity and mass are both reduced in cardiovascular diseases and the hypocholesterolemic drugs, statins, increase serum PON1 activity (by reducing oxidative stress, or by upregulating hepatic PON1 expression). Expression of cellular PON2, like PON1, was upregulated by statins. Nutritional antioxidants, such as polyphenols, increase PON1 mRNA expression and activity, by an aryl hydrocarbon receptor-dependent mechanism. SUMMARY: The elucidation of PON1 structure and its active center has enabled a better understanding of its mechanism of action, including its physio-pathological substrate(s). Some drugs and nutrients including dietary antioxidants and polyphenols considerably increase the activities of paraoxonases which, in turn, can reduce oxidative stress and atherosclerosis development.

Curr Opin Lipidol. 2005 Aug;16(4):393-9

Dietary approach to attenuate oxidative stress, hypertension, and inflammation in the cardiovascular system.

Imbalance between production and scavenging of superoxide anion results in hypertension by the inactivation of nitric oxide, and the increased oxidative stress from the resultant peroxynitrite that is produced promotes inflammatory processes such as atherosclerosis. Induction of phase 2 proteins promotes oxidant scavenging. We hypothesized that intake of dietary phase 2 protein inducers would ameliorate both hypertension and atherosclerotic changes in the spontaneously hypertensive stroke-prone rat. For 5 days/week for 14 weeks, we fed rats 200 mg/day of dried broccoli sprouts that contained glucoraphanin, which is metabolized into the phase 2 protein-inducer sulforaphane (Group A), sprouts in which most of the glucoraphanin was destroyed (Group B), or no sprouts (Group C). After 14 weeks of treatment, no significant differences were seen between rats in Groups B and C. Rats in Group A had significantly decreased oxidative stress in cardiovascular and kidney tissues, as shown by increased glutathione (GSH) content and decreased oxidized GSH, decreased protein nitrosylation, as well as increased GSH reductase and GSH peroxidase activities. Decreased oxidative stress correlated with better endothelial-dependent relaxation of the aorta and significantly lower (20 mm Hg) blood pressure. Tissues from Groups B and C had considerable numbers of infiltrating activated macrophages, indicative of inflammation, whereas animals in Group A had few detectable infiltrating macrophages. There is interest in dietary phase 2 protein inducers as means of reducing cancer incidence. We conclude that a diet containing phase 2 protein inducers also reduces the risk of developing cardiovascular problems of hypertension and atherosclerosis.

Proc Natl Acad Sci U S A. 2004 May 4;101(18):7094-9

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