Showing papers in "Current Atherosclerosis Reports in 2001"

The role of fibric acids in atherosclerosis

Abstract: The hypolipidemic fibric acid drugs are peroxisome proliferator-activated receptor a (PPAR alpha) ligands. PPAR alpha activated by fibric acids form heterodimers with the 9-cis retinoic acid receptor (RXR). The PPAR/RXR heterodimers bind to peroxisome proliferator response elements (PPRE), which are located in numerous gene promoters and increase the level of the expression of mRNAs encoded by PPAR alpha target genes. Fibric acids decrease triglyceride plasma levels through increases in the expression of genes involved in fatty acid-beta oxidation. Furthermore, they decrease triglycerides by increasing lipoprotein lipase gene expression and by decreasing apolipoprotein C-III gene expression. Fibric acids increase high-density lipoprotein (HDL) cholesterol partly by increasing apolipoprotein A-I and apolipoprotein A-II gene expression. Fibric acids also reduce vascular wall inflammation and the expression of genes involved in different vascular functions (ie, vasomotricity, thrombosis). Fibric acids are used to treat primary hypertriglyceridemia and mixed hyperlipidemia. Some fibric acid molecules are active in essential hypercholesterolemia. Clinical evidence shows that fibric acids reduce coronary atherosclerosis progression in dyslipidemic patients (eg, bezafibrate, gemfibrozil) and in type 2 diabetic patients (fenofibrate). Gemfibrozil decreases coronary morbidity and mortality in patients with low HDL cholesterol, normal triglycerides,and normal low-density lipoprotein (LDL) cholesterol plasma levels. Further clinical studies are necessary to investigate if fibric acids decrease cardiovascular mortality in type 2 diabetes and in primary prevention of hypertriglyceridemia and hypolipidemia.

Constraint-induced movement therapy to enhance recovery after stroke.

Abstract: A therapeutic approach to rehabilitation of movement after stroke, termed constraint-induced (CI) movement therapy, has been derived from basic research with monkeys given somatosensory deafferentation. CI therapy consists of a family of therapies; their common element is that they induce persons with stroke to greatly increase the use of a more-affected upper extremity (UE) for many hours a day over a 2- to 3-week period. These therapies have significantly improved quality of movement and substantially increased amount of use of a more-affected UE in the activities of daily living in life situations. A number of neuroimaging and transcranial magnetic stimulation studies have shown that the massed practice of CI therapy produces a massive use-dependent cortical reorganization that increases the area of cortex involved in the innervation of movement of the more-affected UE. The intensity and schedule of delivery of this very efficacious therapy is quite different from that of more traditional physical rehabilitation approaches. As a result, to be clinically applicable, the CI therapy approach to rehabilitation will likely require a paradigm shift in the delivery of physical rehabilitation services.

ArePlaque angiogenesis and atherosclerosis

Abstract: Therapeutic angiogenesis trials refer to the stimulation of collateral arterioles and new vascular conduits to perfuse ischemic myocardium and limbs. Atherosclerotic lesions responsible for vascular occlusions themselves are associated with angiogenesis within the vessel wall. Plaque neovascularization is comprised of a network of capillaries that arise from the adventitial vasa vasorum and extend into the intimal layer of atherosclerotic lesions and other types of vascular injury. The functions of these plaque capillaries are proposed to be important regulators of plaque growth and lesion instability. The development of agents that are positive and negative regulators of angiogenesis may have potential therapeutic implications in the progression and acute manifestations of atherosclerosis. This review focuses on the role of plaque angiogenesis in atherosclerosis and discusses the potential therapeutic applications of angiogenesis inhibitors in this disease.

Hyperglycemia and cardiovascular disease.

Abstract: Diabetes is associated with many microvascular and macrovascular complications. Hyperglycemia plays a pivotal role in the development of microvascular complications, but the actual effect of hyperglycemia on the development and progression of macrovascular complications remains unclear and even somewhat controversial, particularly in type 2 diabetes. Macrovascular complications are increased in individuals with type 2 diabetes long before there is significant hyperglycemia, and in many, but not all, studies a clear association of glucose elevations and macrovascular complications cannot be shown. The complicated nature of metabolic abnormalities in type 2 diabetes and the relative role of these associated conditions in the development of macrovascular disease make definitive conclusions somewhat difficult. In spite of these considerations, there are certain aspects of hyperglycemia associated with macrovascular disease, particularly elevations of postprandial glucoses, and a number of basic mechanisms to explain these associations that could lead to the development of cardiovascular disease. Some of these basic abnormalities include activation of the sorbital pathway, oxidative stress, advanced glycation endproducts (AGE), and AGE precursors. These changes can result in many abnormalities, such as endothelial dysfunction, alteration of protein function, increased cytokine production, and glycosylation of structural proteins. These considerations suggest that hyperglycemia may play an important, but as yet not clearly defined, role in clinical macrovascular disease. Pursuant to this, several major multisite studies are currently underway to clarify the role of hyperglycemia in cardiovascular disease in type 2 diabetes.

Antiatherogenic components of olive oil.

Abstract: Olive oil is the principal source of fat in the Mediterranean diet, which has been associated with a lower incidence of coronary heart disease and certain cancers. Olive oil is characterized by a high proportion of monounsaturated oleic acid, but the main peculiarity of extra-virgin oil is the presence of remarkable quantities of phenolic compounds, notably hydroxytyrosol and oleuropein, that provide high stability and strong taste. Recently, several studies have demonstrated that olive oil phenolics are powerful antioxidants, both in vitro and in vivo, and exert additional potent biologic activities that could partially account for the observed cardioprotective effects of the Mediterranean diet.

Soy proteins and cardiovascular disease

Abstract: The soybean diet is the most potent dietary tool for hypercholesterolemia. The United States Food and Drug Administration recently approved the health claim for its role in reducing the risk of coronary disease. The hypocholesterolemic effect is directly correlated to the patient’s cholesterolemia, with minimal or no reductions occurring at cholesterol of 6 mmol/L or less, and the most benefit occurring in patients with cholesterol of greater than 7 mmol/L. Hypotheses on the mechanism of action include soy fiber, isoflavones (phytoestrogens), and the protein itself. Although there is no evidence for the effect of fiber, studies with ethanol-extracted soy (devoid of isoflavones) indicated a loss of effect, but the extract itself (isoflavone rich) has no hypocholesterolemic activity. In humans, soy protein activates the low-density lipoprotein (LDL) receptor pathway. Recent data suggest that soy protein subunits, particularly 7S, directly activiate LDL receptors in the human liver, thus providing a novel mechanism of plasma cholesterol reduction different from currently available diets and hypolipidemic drugs.

The benefits of niacin in atherosclerosis.

Abstract: Niacin favorably alters all major lipid subfractions at pharmacologic doses. Alone or in combination, it promotes regression of coronary artery disease, decreases coronary events, stroke, and total mortality. Major recent progress in niacin is in four areas. Firstly, recent data indicate that it increases high-density lipoprotein (HDL) and lowers triglycerides and low-density lipoprotein (LDL) by mechanisms different from statins, fibrates, and bile-sequestrants, giving rationale for combination therapy to achieve synergistic effects for complete lipid goal achievement. Secondly, new data on an extended-release preparation of niacin given once nightly indicates that it is as effective and has greater tolerability than immediate-release niacin. Thirdly, preliminary data with a single tablet formulation extended-release niacin and an HMG CoA reductase inhibitor (lovastatin) shows it to be safe and very effective, especially for raising HDL. Finally, emerging evidence indicates that niacin can be used effectively and safely in patients with type 2 diabetes mellitus, who often have low HDL levels.

Recent findings in the study of postprandial lipemia.

Abstract: The study of postprandial metabolism is in the early stages compared with other areas of atherosclerosis research. Recent advances in postprandial research have included improvements in methodology and the investigation of factors that modulate the lipemic response to a meal. Enough studies have now been performed that normal ranges have been identified for blood triacylglycerol (TAG) concentrations that occur after a healthy patient consumes a standardized-mixed meal or a high-fat shake designed to elicit lipemia. Typical postprandial concentrations of other metabolites, such as apolipoproteins B48 and B100 or gastrointestinal hormones (eg, cholecystokinin), have not been studied sufficiently to be able to qualify what represents a standard postprandial response. The method of data analysis is also a key point to consider. Data from children are now becoming available, and the specific effects of ethnicity have just begun to be explored. New areas of study include the effects of different fatty acids (monosaturates or polyunsaturates), the sources of chylomicron lipids (dietary TAG and cholesterol versus that newly synthesized in the body), and the effects of alcoholic beverages consumed with the meal. Variables that can also affect the results of a meal test are under investigation. These include the type of food that is consumed the day before the meal test, the time of day the test is performed, and the palatability of the food. Given solid evidence that delayed postprandial lipemia is an independent risk factor for coronary heart disease, future scientific investigation in the area of post-prandial metabolism is likely to yield discoveries that will significantly contribute to advancements in disease treatment.

Stroke and cognition.

Abstract: Several studies confirm cognitive impairment and dementia to be increased after stroke in the elderly. Although not necessarily involving memory deficits, the frequency of cognitive impairments may occur in up to 30% of stroke survivors at 3 months. This impairment may be confounded by preexisting cognitive decline or dementia. By contrast, cognitive changes and dementia are widely recognized in familial forms of stroke, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Several factors, including type of stroke, recurrent episodes, the site and laterality of the lesion(s), volume of cerebral infarction, medial temporal lobe atrophy, and coexistent neurodegenerative pathology predict the degree of impairment. Aphasia, diabetes mellitus, atrial fibrillation, and depression are listed among other biologic factors that further exacerbate cognition and affect long-term survival. There is no clear consensus whether genetic factors, such as the apolipoprotein E e4 allele or angiotensin converting enzyme gene polymorphisms, modify cognitive changes or stroke outcome. Although several neurotransmitter systems may be affected in post-stroke dementia, the amelioration of cholinergic function is a worthy target.

New developments in the detection of vulnerable plaque.

Abstract: Failure of coronary angiography (luminography) in prediction of future acute coronary syndromes has cast a shadow of doubt over the value of this old gold-standard technique. The fact that angiographically invisible or nonsignificant lesions cause the majority of acute coronary syndromes has driven scientists to develop new diagnostic methods. In this article, we review the ongoing worldwide research on both invasive techniques (such as intravascular angioscopy and colorimetry, ultrasound, thermography, optical coherence tomography, near infrared spectroscopy, Raman spectroscopy, fluorescence emission spectroscopy, elastography, magnetic resonance imaging and spectroscopy, nuclear immunoscintigraphy, electrical impedance imaging, vascular tissue doppler, and shear stress imaging) and noninvasive techniques (such as MRI, contrast-enhanced MRI with and without immunolabeled agents, electron beam computed tomography, multi-slice spiral / helical computed tomography, and nuclear imaging, including positron emission tomography). Each of these techniques and their potential combination holds promise for characterization of plaques responsible for acute coronary syndromes, namely vulnerable plaque.

Cardiovascular disease risk factors and atherosclerosis in children and adolescents.

Abstract: As more is learned about the natural history of the development of atherosclerosis, it is clear that the process that results in morbidity and mortality in adults has its origins in childhood and adolescence. It is also clear that the traditional risk factors, such as hypertension and dyslipidemia, are important in the early stages of the process. It appears that the prevalence and severity of obesity are increasing in children and adolescents in the United States. This trend is associated with increasing blood pressure and the occurrence of type 2 diabetes mellitus in young individuals. These trends may result in increased cardiovascular morbidity and mortality as these overweight pediatric patients become obese adults. Intervention and prevention strategies should be directed at the pediatric population as a whole, as well as at higher-risk individuals. For the latter, it will be necessary to identify those at highest risk. Both nonpharmacologic and pharmacologic approaches may be necessary for treatment of pediatric patients with hyperlipidemia and hypertension. Studies are needed that evaluate the longer-term impact of intervention on cardiovascular risk factors in young patients.

Effect of diet on vascular reactivity: an emerging marker for vascular risk.

Abstract: New technology for studying vascular activity in vivo has shown that the endothelium plays a critical role in the development of atherosclerosis. The healthy endothelium is a metabolically active tissue that exquisitely regulates vascular tone via release of the powerful vasodilator, nitric oxide. Endothelial integrity reduces cell adhesion, lipid deposition, and other early steps in atherogenesis. There is compelling evidence that endothelial function can be altered within hours of eating certain foods, further affirming the role of dietary factors in the prevention and progression of cardiovascular disease. This article reviews recent work on dietary factors (fatty acids, L-arginine, antioxidants, polyphenols, and folic acid) that alter vascular tone, and critically evaluates two noninvasive measures (flow-mediated dilation and total peripheral resistance) for use in dietary intervention trials.

Post-stroke epilepsy.

Abstract: Seizures occur in about 10% of stroke patients. Hence, stroke is the most common cause of seizures and epilepsy in the elderly population. Five percent are early-onset seizures (peak onset within the first day after the stroke) and another 5% are late-onset seizures (peak onset within 6 to 12 months after the stroke). Epilepsy (ie, recurrent seizures) develops in 3% to 4% of the stroke patients (in about one third of the patients with early-onset seizures and about one half of the patients with late-onset seizures). There is a strong positive correlation between stroke severity and the risk of post-stroke seizures; the risk is very low in mild strokes. Seizures are more common in hemorrhagic stroke and in stroke with cortical involvement. Whether this is due to the hemorrhagic component or the cortical involvement per se, or a reflection of more severe strokes among patients with hemorrhagic strokes and lesions involving cortical structures, is not clear. The influence of seizures on outcome is still a matter of controversy. Although epileptic seizures are considered easy to control, this is not supported by evidence from randomized controlled trials.

Body weight-supported treadmill training after stroke.

Abstract: Gait rehabilitation is a major aspect of neurologic rehabilitation. This review focuses on locomotor therapy by treadmill stimulation with partial body weight support (BWS), which has become a very promising treatment concept over the past few years. It enables severely affected patients to follow modern aspects of motor learning, favoring a task-specific approach. Initially two therapists assist the movement, placing the paretic limbs and controlling the trunk movements. As compared with overground walking, patients walked more symmetrically, less spastically, and more efficiently on the treadmill with BWS. Several clinical controlled studies have shown its potential in patients after stroke, who regained walking ability faster in the acute or in the chronic stage. Controlled multicenter trials comparing locomotor and conventional therapy will be the next step. Also, the use of BWS during overground walking could be incorporated into the locomotor treatment program of less affected stroke patients. An electromechanical gait trainer relieving the strenuous effort of the therapists and controlling the trunk in a phase-dependent manner is a new technical alternative for severe stroke patients.

Atherogenesis and the arginine hypothesis.

Abstract: In patients who have elevated levels of plasma ADMA, a relative deficiency of L-arginine has been found to contribute to the pathophysiology of athersclerosis, causing vasoconstriction, and accelerating atherogenesis. This finding—that there is a relative deficiency of L-arginine in atherosclerotic disease—is a breakthrough that will open new avenues of therapy.

The role of chemokines in atherosclerosis

Abstract: Recruitment of mononuclear leukocytes and the migration, growth, and activation of the multiple cell types within atherosclerotic lesions are critical features of the chronic inflammatory and fibroproliferative response central to atherosclerosis. Attraction of leukocyte to tissues is controlled by chemokines, whose presence is well documented in atherosclerotic lesions. Studies using knockout and transgenic murine models have demonstrated that chemokine receptor/ligand interactions are of crucial importance in the development of atherosclerosis. Beyond their chemotactic effect on mononuclear leukocytes, chemokines may also interfere with smooth muscle cell migration and growth, as well as platelet activation and other well-defined features of the atherosclerotic process. There is no doubt that the identification of chemokines as important vascular signals has provided insights into our understanding of basic cellular and molecular mechanism of atherosclerosis. Thus, there is evidence that chemokine receptor/ligands could be identified as potential new targets for therapeutic intervention to prevent or control atherosclerosis in the near future.

Gene-diet interaction and plasma lipid response to dietary intervention

Abstract: Research in the field of gene-diet interactions as determinants of plasma lipid response to dietary interventions has accumulated a substantial body of evidence during the past decade. Several candidate genes have shown some promise as potential markers of individual dietary responsiveness. Among the best characterized are the APOE, APOA4, APOB, APOC3, and LPL loci. Other genes are being continuously incorporated to this most interesting search. However, in very few cases has consensus been achieved about the usefulness of genetic markers as clinically significant predictors of dietary response. The increased ability to generate genotypic information, in combination with the knowledge from the human genome project and more comprehensive experimental designs, will dramatically improve our capacity to answer many of our current questions. It will also help to prove that knowledge of an individual's genetic background will facilitate more precise dietary counseling and intervention, and more efficacious primary and secondary coronary heart disease prevention.

Herbs and atherosclerosis

Abstract: It is now widely accepted that atherosclerosis is a complex multicellular process involving oxidation of cholesterol and the intracellular accumulation of oxidized cholesterol. This accumulation causes a cascade of inflammatory processes, resulting in an unstable atherosclerotic plaque that ultimately bursts, causing myocardial infarction. Botanical dietary supplements (herbs) can ameliorate this process and prevent cardiovascular disease at many steps in the process. Many herbs have antioxidant activity and can reduce low-density lipoprotein oxidation. Some phytosterols found in botanicals can inhibit cholesterol absorption. After a brief review of herbs being promoted for achieving and maintaining healthy cholesterol levels, the evidence and future prospects for Chinese red yeast rice, the main component of dietary supplements with HMG-CoA reductase inhibiting activity, are discussed in detail. Initial phase II clinical trials are highly encouraging. This herb is likely to be able to directly impact the process of atherosclerosis, but large-scale clinical trials are needed to assess the public health potential of this herbal supplement.

The renin angiotensin system as a risk factor for coronary artery disease

Abstract: The renin angiotensin system was demonstrated to play a significant role in the genesis of hypertension and regulation of vascular tone over 100 years ago. The early investigations were subsequently expanded to implicate the renin angiotensin system in a variety of physiologic processes that may play a significant role in the initiation and progression of atherosclerosis. The renin angiotensin system modulates vascular structure and left ventricular hypertrophy via a number of trophic effects. Elevated levels of angiotensin II are associated with the generation of oxidative stress, and may thus play a significant role in the earliest phases of atherosclerosis. The role inflammation plays in atherosclerosis is amplified by the renin angiotensin system via the effects on adhesion molecules, growth factors, and chemoattractant molecules, which modulate the migration of inflammatory cells into the subendothelial space. The effects of angiotensin II, which may be at least partially genetically mediated, have been implicated in epidemiologic and clinical studies as a risk factor for the development of atherosclerosis. This review centers on the potential role that the renin angiotensin system plays as a risk factor for the development of atherosclerosis, and the role of converting enzyme inhibition or angiotensin receptor blockade as a mechanism to decrease the initiation, progression, and clinical consequences of the atherosclerotic process.

Did the antioxidant trials fail to validate the oxidation hypothesis

Abstract: Most clinical trials on antioxidants using vitamin E or β-carotene have failed to note any significant change in cardiovascular endpoints. The results of these studies have been interpreted as a setback for the oxidation hypothesis. An analysis of the hypothesis and the trials, however, points out major misconceptions about the hypothesis and unjustified outcome expectations. Wrong selection of patient population, endpoints that are incompatible with the hypothesis, poor choice of antioxidants, and lack of inclusion of biochemical markers of oxidative stress and markers of vascular response are some of the contributors to the “failure” of these trials.

Biologic effect and molecular regulation of vascular apoptosis in atherosclerosis.

Abstract: Apoptosis, a form of genetically programmed cell death, plays a key role in regulation of cellularity of the arterial wall. During atherogenesis, deregulated apoptosis may cause abnormalities of arterial morphogenesis, wall structural stability, and metabolisms. Many biophysiologic and biochemical factors, including mechanical forces, reactive oxygen and nitrogen species, cytokines, growth factors, oxidized lipoproteins, etc. may influence apoptosis of vascular cells. The Fas/Fas ligand/caspase death-signaling pathway, Bcl-2 protein family/mitochondria, the tumor suppressive gene p53, and the proto-oncogene c-myc may be activated in atherosclerotic lesions and mediate vascular apoptosis during the development of atherosclerosis. Abnormal expression and dysfunction of these apoptosis-regulating genes may attenuate or accelerate vascular cell apoptosis and affect the integrity and stability of plaques. Clarification of the molecular mechanism that regulates apoptosis may help design a new strategy for treatment of atherosclerosis and its major complication, the acute vascular syndromes.

Innovative approaches to comprehensive cardiovascular disease risk reduction in clinical and community-based settings

Abstract: We have developed, tested, and successfully implemented an affordable, evidence-based, comprehensive cardiovascular disease risk-reduction program for use in primary and secondary prevention settings. The program is administered at hospitals, physician practices, cardiac rehabilitation programs, work sites, shopping malls, and health clubs. The program is also delivered from a call center using the telephone and the Internet. Program staff are guided by a computerized participant management and tracking system. Lifestyle management interventions are based on several behavior change models, primarily social learning theory, the stages of change model, and single concept learning theory. Typically, the program is administered entirely by non-physician healthcare professionals whose services are integrated with the care provided by the participants' physicians. Outcome data have documented the clinical effectiveness of this innovative approach.

Platelet-endothelial interactions in atherosclerosis.

Abstract: The pathogenesis of atherosclerosis, the leading cause of morbidity and mortality in the United States, is multifactorial. Many factors that have been shown to influence the development of atherosclerosis also affect the function of the endothelium through soluble or cell-cell interactions. Among these, interactions between platelets and endothelial cells have only recently begun to receive systematic study. This article reviews recent evidence showing how the interaction between platelets and endothelial cells may play a important role in the pathogenesis of atherosclerosis, suggesting an underappreciated potential locus for pharmacologic intervention.

Clinical trial evidence for the cardioprotective effects of omega-3 fatty acids.

Abstract: The notion that marine omega (ω)-3 fatty acids might have beneficial cardiovascular effects was first suggested by epidemiologic studies in Greenland Inuits published in the late 1970s. These simple observations spawned hundreds of other studies, the confluence of which strongly suggests a true cardioprotective effect of ω-3 fatty acids. The strongest confirmation has come from the publication of three randomized clinical trials, all of which reported benefits to patients with preexisting coronary artery disease. The most convincing of these was the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI)-Prevezione study, in which 5654 patients with coronary artery disease were randomized to either ω-3 fatty acids (850 mg/d) or usual care. After 3.5 years, those taking the ω-3 fatty acids had experienced a 20% reduction in overall mortality and a 45% decrease in risk for sudden cardiac death. These findings support the view that relatively small intakes of ω-3 fatty acids are indeed cardioprotective, and suggest that they may operate by stabilizing the myocardium itself.

Effects of the glycemic index of foods on serum concentrations of high-density lipoprotein cholesterol and triglycerides.

Abstract: The role of carbohydrates in cardiovascular disease prevention has garnered increasing attention due to accumulating evidence showing deleterious effects of low-fat, high-carbohydrate diets on serum triglycerides and high-density lipoprotein (HDL) cholesterol. Researchers argue that classifying carbohydrates based on their capacity for increasing blood glucose (termed the glycemic index ) is a useful tool for elucidating the effects of carbohydrate-rich foods on glucose and lipid metabolism. Several epidemiologic reports show that lower dietary GI is associated with lower serum triglycerides and higher HDL cholesterol. Results from intervention studies show that substituting low-GI for high-GI foods in a low-fat, high- carbohydrate diet lowers serum triglycerides by 15% to 25%. The available evidence to date suggests that the glycemic index of foods will be an important factor in future dietary prevention research.

Genes and environment in type 2 diabetes and atherosclerosis in aboriginal Canadians.

Abstract: The incidence of coronary heart disease (CHD) among aboriginal people in northern Ontario has tripled over the past 20 years. This is inextricably linked to the remarkably high prevalence of type 2 diabetes in these native communities. Approximately 40% of the Oji-Cree of northern Ontario have typical obesity-related type 2 diabetes, which represents a drastic increase from virtually unreportable levels 50 years ago. The Oji-Cree have a private mutation in the HNFIA gene, namely G319S, which is absent from other ethnic groups and aboriginal populations. The most compelling reasons that HNFIA S319 is a diabetes-susceptibility allele are its consistent statistical association with the presence and severity of diabetes. Also, HNFIA S319 has specificity and positive predictive values of 97% and 95%, respectively, for the development of diabetes in the Oji-Cree by 50 years of age. This makes the HNFIA G319S genotype the most specific predictive genetic test for diabetes in any human population. HNFIA S319 has all the attributes of a thrifty allele in the Oji-Cree. It is possible that the recent increase in CHD in the aboriginal people of northern Ontario is the result of the expression of diabetes susceptibility due to HNFIA S319 as a consequence of rapid changes in environment and lifestyle.

Genetic determinants of plasma triglycerides: impact of rare and common mutations.

Abstract: Raised plasma triglyceride (TG) levels are an independent risk factor for coronary artery disease (CAD), and thus understanding the genetic and environmental determinants of TG levels are of major importance. TG metabolism is a process for delivering free fatty acids for energy storage or b-oxidation, and involves a number of different hydrolytic enzymes and apolipoproteins (apo). The genes encoding these proteins are, therefore, candidates for determining plasma TGs. Although rare mutations in lipoprotein lipase (LPL), the major TG-hydrolyzing enzyme, and apo CII (APOC2), its essential activator, result in extremely high plasma TG levels, their low frequency means they have little impact upon TG levels in the general population. Common mutations in LPL, apo CIII (APOC3), and apo E (APOE) have the strongest effect on plasma TG levels at the population level. In addition, environmental factors such as diet, obesity, and smoking interact with genetic determinants of TG to produce a modulating high-risk environment.

Botulinum toxin for the management of muscle overactivity and spasticity after stroke.

Abstract: Stroke is a major cause of disability involving the arm and leg. This disability results from the upper motoneuron syndrome (UMN) evident after stroke. It is commonly associated with spasticity and muscle overactivity, which can lead to abnormal limb posturing that interferes with active and passive function. The origin of limb deformity in patients with UMN is based on the concept of unbalanced agonist and antagonist muscle forces acting across joints. In the past decade, botulinum toxin A (BTX-A) a new medication that modifies muscle force and, hence, can treat muscle imbalance, has become available and has renewed interest in the management of muscle overactivity and spasticity after stroke. A reduction in muscle tone, painful spasms, and improved functionality can be obtained. Research and clinical reports support the concept that chemodenervation with BTX-A is an excellent intervention for treating focal muscle overactivity and spasticity secondary to stroke. Many muscles differing in size, shape, and location have been injected, and clinical effectiveness is particularly notable in elbow flexors, ankle plantar flexors, and smaller limb muscles, such as intrinsics of the hand and wrist. Smaller muscles are readily accessible for injection and require smaller amounts of toxin.

Combination lipid-altering therapy: An emerging treatment paradigm for the 21st century

Abstract: For the care of an expanding segment of the US population with multiple coronary risk factors, combination lipid-altering therapy is emerging as a treatment imperative. The most recent National Cholesterol Education Program’s consensus guidelines emphasize long-term global coronary heart disease (CHD) risk status, designate patients with CHD risk equivalents (eg, diabetes, peripheral arterial disease, 20% or more 10-year absolute CHD risk) for aggressive lipid-altering therapy, and deem the metabolic syndrome (eg, obesity, insulin resistance, hypertension, elevated triglycerides, low levels of high-density lipoprotein cholesterol, small dense low-density lipoprotein particles) as a secondary target for intervention. With the advancing age of the US population and the high prevalence of diabetes, the metabolic syndrome, and CHD, increasing numbers of patients will require a more balanced metabolic attack attainable only through combination lipid-altering regimens. Many of these patients, as well as persons at heightened risk for cardiovascular disease because of a range of heritable conditions (eg, familial hypercholesterolemia, familial combined hyperlipidemia), will undoubtedly require binary or ternary regimens involving statins in concert with niacin, fibric-acid derivatives, or bile acid resins. Such approaches enable the clinician to exploit the complementary effects of these agents, allowing them to be administered at low, optimally tolerable doses that are consistent with superior efficacy and a lower risk of adverse events as compared with escalating doses of monotherapy.

The use of statins in acute coronary syndromes: the mechanisms behind the outcomes.

Abstract: Lipid-lowering drugs, in particular statin treatments, have been shown to reduce the incidence of initial and recurrent coronary heart disease (CHD) events within several years of initiating therapy. This effect can be clinically detected within the first 1 to 2 years in randomized trials. Recent observational and clinical trial data suggest that lipid-lowering therapy initiated at the time of an acute coronary event can reduce recurrent events, and possibly all-cause mortality, in a much shorter period of time. The possible mechanisms by which this benefit occurs include the effect of reduced lipoprotein levels, as well as an independent effect of statins on endothelial function. Statins improve endothelial-dependent flow-mediated vasodilation by increasing the bioavailability of nitric oxide. They stabilize the plaque by modulating the inflammatory response within the vessel wall. They also decrease clot formation by decreasing the adherence of platelets to the ruptured plaque and by acting on the extrinsic coagulation cascade pathway. This review examines these effects of statins and lipoproteins on vascular function, as well as the clinical evidence supporting early treatment in acute coronary syndromes.