Atherothrombotic Cardiovascular Disease Research Articles

The Role of Statin Therapy for Primary Prevention: What is the Evidence?

Almost one third of annual worldwide mortality is attributed to cardiovascular disease (CVD), making it the leading cause of global death. Dyslipidemia is a well-established risk factor for CVD and plays a pivotal role in the pathogenesis of atherosclerosis. Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lower low-density lipoprotein cholesterol, have emerged as the most effective therapy to date against atherothrombotic CVD. Although their role in secondary prevention of CVD is undisputed, it remains a topic for debate as to how widely they should be used for primary prevention. The Framingham Risk Score and the National Cholesterol Education Program Adult Treatment Panel III guidelines are the cornerstones for the current guidelines for primary prevention statin therapy. Although these guidelines serve as help to evaluate cardiovascular risk and effectively identify many patients who will benefit from statin therapy, there is a growing population of "intermediate-risk" patients who may be undertreated. Additional noninvasive tests may complement the traditional risk scores, potentially expanding the indications for statins.

Effects of Brazilian Cardioprotective Diet Program on risk factors in patients with coronary heart disease: a Brazilian Cardioprotective Diet randomized pilot trial

OBJECTIVE:To evaluate the effectiveness of the Brazilian Cardioprotective Diet Program in reducing blood pressures, fasting glucose levels and body mass indices in patients with established atherothrombotic disease.METHOD:This randomized controlled pilot trial included outpatients who were over 45 years of age with atherothrombotic cardiovascular disease. Group A, who received the Brazilian Cardioprotective Diet Program, had weekly sessions with dietitians. Groups B and C received the usual dietary therapy that is given to patients with cardiovascular diseases as proposed by the Brazilian guidelines. This diet had the same nutrient profile as that given to Group A, but it was customized by the integration of typical Mediterranean foods. The difference between Groups B and C was the number of sessions with the dietitian. Group B received weekly sessions, while group C only had monthly sessions. ClinicalTrials.gov: NCT 01453166.RESULTS:There was a greater reduction in systolic (7.8%) and diastolic (10.8%) blood pressures in Group A compared with Group B (2.3% and 7.3%), and Group C (3.9% and 4.9%, respectively). Fasting glucose decreased by 5.3% and 2% in Groups A and B, respectively. Fasting glucose increased by 3.7% in Group C. The BMIs decreased by 3.5% and 3.3% in Groups A and B, respectively. Group C did not present with any changes in BMI. However, none of these data showed statistical differences between the groups, which is methodologically acceptable in pilot trials.CONCLUSIONS:The Brazilian Cardioprotective Diet Program seems to be more effective in reducing blood pressures, fasting glucose levels, weights and BMIs in patients with previous cardiovascular disease compared with the diet that has been proposed by the Brazilian guidelines.

Variability of fibrinogen measurements in post-myocardial infarction patients

Elevated fibrinogen levels are strongly and consistently associated with incident coronary heart disease (CHD). A possible causal contribution of fibrinogen in the pathway leading to atherothrombotic cardiovascular disease complications has been suggested. However, for implementation in clinical practice, data on validity and reliability, which are still scarce, are needed that are still scarce, especially in subjects with a history of CHD. For the present study, levels of plasma fibrinogen were measured in 200 post-myocardial infarction (post-MI) patients aged 39-76 years, with approximately six blood samples collected at monthly intervals between May 2003 and March 2004, giving a total of 1,144 samples. Inter-individual variability (between-subject variance component, VCb and coefficient of variation, CVb), intra-individual and analytical variability (VCw+a and CVw+a), intraclass correlation coefficient (ICC) and the number of measurements required for an ICC of 0.75 were estimated to assess the reliability of serial fibrinogen measurements. Mean fibrinogen concentration of all subjects over all samples was 3.34 g/l (standard deviation 0.67). Between-subject variation for fibrinogen was VCb = 0.34 (CVb'=17.5%) whereas within-subject and analytical variation was estimated as VCw+a = 0.14 (CVw+a=11.0%). The variation was mainly explained by between-subject variability, shown by the proportion of total variance of 71.3%. Two different measurements were required to reach sufficient reliability, if subjects with extreme values were not excluded. The present study indicates a fairly good reproducibility of serial individual fibrinogen measurements in post-MI subjects.

Multiple thromboses at multiple sites

Hyperhomocysteinemia is a significant independent, usually heritable, prothrombotic risk factor for atherothrombotic cardiovascular, cerebrovascular, and peripheral vascular disease. We report a 42-year-old woman who had multiple embolic events.

The usefulness of antiplatelet prescriptions for the identification of patients with atherothrombosis in primary care: a Dutch cross‐sectional study

Patients with atherothrombotic cardiovascular disease (ACD) should receive specific treatments, including lipid-lowering medication. In order to optimize treatment for patients with ACD in primary care, an efficient method to identify all these patients is needed. We aimed to assess which method serves best to identify all patients with ACD in Dutch primary care: morbidity records, antiplatelet prescribing records or a combination of these. In a cross-sectional study in 45 Dutch general practices, computerized medical records of all patients with any cardiovascular disease, cardiovascular symptoms or cardiovascular medication were analysed. Of the 7280 patients with a recorded indisputable indication for antiplatelet therapy, 4715 (64.8%) could be identified by means of antiplatelet prescriptions. Of the patients with a recorded indisputable indication for antiplatelets but without any antiplatelet prescription, 28.9% received a vitamin K antagonist. Of the 8718 patients with antiplatelet therapy, 5697 (65.3%) could be identified by means of a recorded indisputable or possible indication for antiplatelet therapy. Female patients, patients younger than 60 years old and patients having a recorded diagnosis of angina pectoris or diabetes had a higher risk to be missed by antiplatelet prescribing records. Morbidity records and prescribing records should be used both in order to identify all patients with ACD in primary care. Patients who use antiplatelet prescriptions but do not have a recorded ACD deserve extra attention, because they are either treated without a good indication for antiplatelet therapy (overtreatment) or need a correction of their morbidity records.

Telmisartan

Telmisartan (Micardis®, Pritor®), a well established angiotensin type 1 receptor antagonist, is indicated in the EU for the reduction of cardiovascular morbidity in patients with manifest atherothrombotic cardiovascular disease (CVD) or type 2 diabetes mellitus with documented target organ damage, as well as for the treatment of hypertension. In the pivotal ONTARGET trial, which enrolled ACE inhibitor-tolerant patients at high vascular risk, telmisartan 80 mg once daily added to existing, proven therapy was noninferior to ramipril 10 mg once daily (the gold standard cardioprotective ACE inhibitor) in terms of CVD prevention. Moreover, telmisartan was better tolerated than ramipril, as reflected in, for example, lower incidences of permanent treatment discontinuations due to cough and angioedema. The placebo-controlled TRANSCEND and PRoFESS studies provided supporting evidence for the (time-dependent) effectiveness of telmisartan in preventing cardiovascular events, although the drug appeared to have neither a beneficial nor a harmful impact on cardiovascular mortality. The TRANSCEND trial also demonstrated that telmisartan was well tolerated in ACE inhibitor-intolerant patients at high vascular risk. On the basis of these findings, telmisartan can be considered an effective treatment option for CVD prevention in patients at high vascular risk. Consideration may be given to prescribing the drug as an alternative to ramipril in patients who are able to tolerate ACE inhibitors and, potentially, instead of ramipril in patients who are unable to tolerate ACE inhibitors.

Association of high sensitive C-reactive protein (hsCRP) with established cardiovascular risk factors in the Indian population

IntroductionInflammation, the key regulator of C-reactive protein (CRP) synthesis, plays a pivotal role in atherothrombotic cardiovascular disease.MethodsHigh sensitivity CRP (hsCRP) analysis was carried out in randomly selected 600 individuals from the sentinel surveillance study in Indian industrial population (SSIP). The hsCRP was measured quantitatively by turbid metric test using kits from SPINREACT, Spain. We analyzed the association between hsCRP and traditional CVD risk factors in this sub-sample.ResultsComplete risk factor data and CRP levels were available from 581/600 individuals. One half (51.2%) of the study subjects were males. Mean age of the study group was 39.2 ± 11.2 years. The Pearson correlation coefficients were in the range of 0.12 for SBP (p = 0.004) to 0.55 for BMI (p < 0.001). The linear regression coefficients ranged from 0.01 for SBP, PG and TC (p < 0.001) to 0.55 for logeTAG (p < 0.001) after adjustment for age, sex and education. The mean of logehsCRP significantly increased (P < 0.001) from individuals with ≤1 risk factors (-0.50) to individuals with three or more risk factors (0.60). In the multivariate model, the odds ratios for elevated CRP (CRP ≥ 2.6 mg/dl) were significantly elevated only in females in comparison to males (1.63, 95% CI; 1.02-2.58), overweight individuals in comparison to normal weight individuals (3.90, 95% CI; 2.34-6.44, p < 0.001), and abdominal obese individuals (1.62, 95% CI; 1.02-2.60, p = 0.04) in comparison to non-obese individuals.ConclusionClinical measurements of adiposity (body mass index and abdominal obesity) correlate well and can be surrogate for systemic inflammatory state of individuals.

Novel HDL-directed pharmacotherapeutic strategies.

The burden of atherothrombotic cardiovascular disease remains high despite currently available optimum medical therapy. To address this substantial residual risk, the development of novel therapies that attempt to harness the atheroprotective functions of HDL is a major goal. These functions include the critical role of HDL in reverse cholesterol transport, and its anti-inflammatory, antithrombotic, and antioxidant activities. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights have fueled the development of HDL-targeted drugs, which can be classified among four different therapeutic approaches: directly augmenting apolipoprotein A-I (apo A-I) levels, such as with apo A-I infusions and upregulators of endogenous apo A-I production; indirectly augmenting apo A-I and HDL-cholesterol levels, such as through inhibition of cholesteryl ester transfer protein or endothelial lipase, or through activation of the high-affinity niacin receptor GPR109A; mimicking the functionality of apo A-I with apo A-I mimetic peptides; and enhancing steps in the reverse cholesterol transport pathway, such as via activation of the liver X receptor or of lecithin-cholesterol acyltransferase.

2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Executive Summary

2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Executive Summary

The SHAPE Paradigm

Atherosclerosis is a chronic immunoinflammatory disease trigerred by lipoprotein retention in the subendothelium and produces its most serious manifestations by triggering arterial thrombosis when the plaque ruptures or erodes.1 Atherothrombotic cardiovascular disease remains the leading cause of death in the West and is achieving similar dubious distinction in developing countries.2 Atherosclerosis begins at a young age, but it remains clinically silent for a long time and the majority of clinical manifestations occur later in life. Despite considerable progress, regrettably 50% of life-threatening acute cardiovascular events occur in previously asymptomatic individuals. Identifying individuals at risk for future cardiovascular events affords an opportunity for risk reduction and thus remains a major imperative for healthcare professionals. In 2006 the SHAPE (Society for Heart Attack Prevention and Education) Task Force introduced an algorithm incorporating noninvasive screening for subclinical atherosclerosis to augment risk factor–based risk stratification in asymptomatic subjects between the ages of 45 to 75 in men and 55 to 75 in women, excluding those at very low risk or at high risk.3 In June 2009, the Texas Governor Rick Perry signed off on the Texas Heart Attack Prevention Bill introduced by Rep Rene Oliveira, mandating health-benefit plans to cover noninvasive screening for subclinical atherosclerosis. This bill grew out of the 2006 SHAPE Task Force guidelines and became effective September 1, 2009; an earlier version of the bill had been rejected in 2007. This generated a mixed reaction from healthcare professionals and others, much of which played out in the media. The critics argued that such an action is inappropriate because: (1) the SHAPE guidelines were created by an ad hoc group and had not been explicitly endorsed by the American College of Cardiology (ACC) or the American Heart Association (AHA), and (2) SHAPE guidelines are not based on randomized clinical …

Does elevated C-reactive protein cause human atherothrombosis? Novel insights from genetics, intervention trials, and elsewhere

To evaluate evidence from human epidemiology, mechanistic studies, animal studies, human genetics, and human intervention trials to address whether elevated C-reactive protein (CRP) causes human atherothrombotic cardiovascular disease. Human epidemiology demonstrates that elevated CRP levels are associated with increased risk of atherothrombosis. Mechanistic and animal studies provide evidence both for and against a causal relationship of CRP with atherothrombosis. Human genetics demonstrate that genetic variation in the CRP gene is associated with lifelong increased CRP levels, but not with increased risk of atherothrombosis. A human intervention trial in healthy people with low LDL cholesterol and elevated CRP demonstrated that aggressive statin treatment caused reductions of 50% in LDL cholesterol, 37% in CRP, 50% in atherothrombotic cardiovascular events, 20% in total mortality, and 45% in venothrombotic events. Importantly, the maximal atherothrombotic treatment benefits were obtained in those who achieved the lowest levels of both LDL cholesterol and CRP. Given the data available in mid-2009, elevated CRP per se does not seem to cause atherothrombotic cardiovascular disease, which questions whether CRP-reducing agents will prevent these diseases. However, inflammation per se possibly contributes to atherothrombotic and venothrombotic disease, and CRP measurement may be used in risk assessment and treatment monitoring in atherothrombotic cardiovascular disease.

Adipocytokines, Sex Hormones, and Cardiovascular Risk Factors in Postmenopausal Women: Factor Analysis of the Rancho Bernardo Study

Steroid sex hormones modulate the expression of adipocytokines implicated in the pathogenesis of athero-thrombotic cardiovascular disease. We used exploratory factor analysis to search for latent associations between circulating sex steroid hormones, adipocytokines, and cardiovascular risk factors in a well-characterized cohort of postmenopausal women. Among participants in the Rancho Bernardo community study we identified 515 Caucasian women with a mean age of 74+/-8 years and mean body mass index of 24.2+/-3.7 kg/m(2). All had intact ovaries and none was using estrogen therapy. We constructed models aiming for structural clarity and high loading of variables on individual factors. Total adiponectin loaded with major lipid subfractions (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and fasting triglycerides) and with sex hormone-binding globulin. Leptin loaded with central obesity (waist circumference) and fasting insulin levels. Neither adipocytokine loaded with total or bioavailable testosterone or with estradiol or dehydroepiandrosterone sulfate. Sex hormones consistently loaded together on a separate factor; this co-segregation was not influenced by body mass index. Exclusion of women with diabetes did not alter these observations. In conclusion, we identified evidence of latent associations between adipocytokines and a range of cardiovascular risk factors in postmenopausal women. Our results suggest that cardiovascular risk in older women may be modulated through a hitherto unrecognized association between adiponectin, lipid subfractions, and sex hormone bioavailability.

Quo Vadis: Whither Homocysteine Research?

Four decades of research on the link between hyperhomocysteinemia and cardiovascular disease has led to a crossroads. Several negative studies on the role of homocysteine-lowering B-vitamin therapy in reducing the risk of atherothrombotic cardiovascular disease have dampened enthusiasm for this important field of research. In this review, we assess the present state of homocysteine research and suggest potential avenues that would help to clarify the purported link between the plasma homocysteine level and cardiovascular risk. We address several questions raised by the findings of various basic, epidemiological and clinical studies and attempt to construct a framework that we believe will allow us to address the fundamental unresolved issues in this controversial area, specifically focusing on the risk of coronary vascular disease and cardiac failure. This review should allow researchers to deconstruct this complex field into separate areas that, when addressed adequately, may lead to findings that elucidate the overall link between hyperhomocysteinemia and cardiovascular disease and allow the design of appropriate clinical trials.

Cardiovascular Risk Factors in Non-Diabetic Hemodialysis Patients: A Comparative Study

Patients on hemodialysis (HD) are prone to atherosclerotic cardiovascular complications. In an attempt to determine the significance of several atherosclerotic and thrombogenic parameters as risk factors for atherothrombotic cardiovascular disease (CVD) in these patients, we compared two groups of non-diabetic HD patients matched for age and sex, selected according to the absence (group 1, n = 30) or presence (group 2, n = 30) of symptomatic atherothrombotic vascular disease affecting the coronary, cerebral, or peripheral arteries. Duration of HD, primary renal disease (PRD), presence of hypertension, EPO treatment, and smoking habits were recorded. Serum total cholesterol (TC), triglycerides (TG), HDL-C, LDL-C, TC/HDL-C ratio, lipoprotein(a) (Lp(a)), fibrinogen (FG), plasminogen (PLG), fibronectin (FN), and hematocrit (HCT) were measured pre-HD in a midweek session. The same blood parameters were also assessed in twenty matched clinically healthy subjects (controls). None of the blood parameters differed between groups 1 and 2, except for serum Lp(a) and FN, which were higher in group 2 (p = 0.005 and p = 0.041, respectively). Both groups were not different regarding PRD, duration of HD, and EPO treatment, but the presence of hypertension and smoking habits were more common in group 2 (p = 0.008 and p = 0.045, respectively). Moreover, multiple stepwise logistic regression analysis with Lp(a), FN, hypertension, and smoking showed that the presence of hypertension (p = 0.016) and the Lp(a) (p = 0.027) and FN (p = 0.024) levels, but not smoking, were independent predictors for the presence of atherothrombotic CVD. Our results suggest that hypertension, abnormal lipid particles, and thrombogenic proteins may contribute to the high prevalence of CVD in HD patients.

A Relationship between the Obstructive Sleep Apnea Syndrome and the Erythrocyte Sedimentation Rate

ObjectivesThe erythrocyte sedimentation rate (ESR) is a marker for inflammation, and it has been identified as a risk factor for atherothrombotic cardiovascular disease. The aim of this study was to determine the relationship between the plasma ESR level and nocturnal oxygen desaturation or other polysomnographic variables and to examine the role of obesity in patients with obstructive sleep apnea syndrome (OSAS).MethodsThis retrospective study included 72 patients with a diagnosis of OSAS who underwent overnight polysomnography and routine blood tests between July and December of 2005. We compared the plasma ESR level with the sum of all the polysomnographic variables and divided the patient group into obese and non-obese patients.ResultsThe mean ESR level was 8.45 mm/hr. There was a significant difference in the ESR level between genders (P<0.001). A significant correlation was found between the percentage of time spent at a SpO2 below 90% and the ESR level in the obese group (BMI ≥25, N=43, P=0.012). In addition, the ESR levels had a positive correlation with age in the obese group (P=0.002). However, there was no significant correlation with the percentage of time spent at a SpO2 below 90% in the whole group of patients and in the non-obese group (BMI <25, N=29). The ESR level showed no correlation with the other polysomnographic variables.ConclusionThe duration of deoxygenation in obese patients with OSAS may be associated with the ESR level which is an independent predictor of cardiovascular disease.

The Art of Primary Prevention and Risk Assessment

See related article, pages 730–736. The paradigm that homocysteine is associated with atherosclerotic disease has been discussed since the 1960s. Since then, large observational studies and meta-analyses showed a strong relationship between homocysteine and cardiovascular risk. However, several recent trials using homocysteine-lowering therapies for secondary prevention failed to show beneficial effects in patients with prior stroke or known coronary artery disease.1–3 These trials showed no advantage of either folic acid and/or vitamin B complex therapy on “hard” end points such as mortality or cardiovascular events. Thus, the “homocysteine hypothesis” for atherothrombotic disease became controversial. Kaul et al4 stated in a recent review that it remains unclear whether a causal relationship exists between homocysteine and cardiovascular risk, or if homocysteine is related to other confounding risk factors or is a marker of existing disease burden. This discussion is now continued and refuelled with a new study published in this issue of Stroke . Hodis and coworkers present a work that assesses homocysteine-lowering therapy as primary prevention in patients without preexisting cardiovascular disease. The goal was to show a reducing effect of a high-dose combination of B-vitamins on progression of carotid intima media thickness …

Paraoxonase and Coronary Heart Disease Risk

Organophosphates were first synthesized in the 1930s as insecticides1 and were subsequently shown to have direct neurotoxic effects in mammals, as well. The neurotoxicity is derived from their ability to inhibit acetylcholinesterase by covalently modifying the active-site serine group in the enzyme. Mazur2 first demonstrated the presence of an organophosphate-hydrolyzing enzyme in mammalian tissue, an observation that ultimately led to the identification of a human paraoxonase in serum in 1953.3 Paraoxonase—so named because of its ability to hydrolyze the toxic metabolite of parathion, paraoxon—was also shown early after its identification to manifest arylesterase activity, an effect that was underappreciated until the enzyme was found to play a role in modulating vascular oxidant stress many years later. Article see p 147 The paraoxonase story is a good example of the power of language to mislead. There is no teleological reason for mammals to have evolved an enzyme that can hydrolyze synthetic organophosphates; yet, paraoxonase was isolated in an effort to understand the endogenous metabolism of these exogenous neurotoxins. The enzymatic activity for which the enzyme is named is screened by using synthetic substrates without regard for the native substrate or its role in human (patho)biology. This focus on one aspect of the enzyme’s function, overemphasized by its denotation, delayed an appreciation of other potential—and perhaps more relevant—roles. In 1991, Mackness et al4 showed that paraoxonase …

Selective Serotonin Reuptake Inhibitors Influence Agonist-Induced Platelet Aggregation. Preliminary Results from Comorbidity of Depression and Cardiovascular Disease Study

Selective serotonin reuptake inhibitors (SSRI) are a first-line treatment option for depressive illnesses, anxiety and obsessive-compulsive disorders with a favorable risk benefit ratio and side effects. They selectively inhibit neuronal reuptake of serotonin and result in depleted serotonin stores in the dense bodies of platelets. It is hypothesized that depressive illnesses cause platelet activation and endothelial dysfunction, which could be modulated by the use of SSRIs. In order to validate this hypothesis an institutional-based co morbidity of depression and cardiovascular study is undertaken. Patients with depression (n=25) and healthy control (n=25) are recruited in this study. Males and females between the ages of 20 and 65 years meeting the DSM-IV criteria for major depressive disorder served as the inclusion criteria for the study. The exclusion criteria included patients with heart disease, diabetes, lipid disorders, history of smoking, pregnant and lactating women, psychosis, schizoaffective illnesses and presence of other Axis I diagnosis with the exception of generalized anxiety disorder. Blood samples were collected at baseline and then 4 and 8 weeks following treatment with Escitaloprim, an SSRI. Preliminary results from the agonist-induced platelet aggregation showed varying degrees of inhibition of collagen, ADP, arachidonic acid and epinephrine-induced platelet aggregation as shown in the table below.Agonist induced platelet aggregation profileAveraged % aggregationTimeCollagenAAADPEpinephrineSalineBaseline71.5± 22.464.1± 35.148.15± 30.955.65± 29.26.9± 4.5Week 463.4± 19.567.1± 25.133± 26.737.375± 25.89.375± 7.8Week 874.7± 21.355.71± 36.152.4± 3150.4± 32.35± 3.9While a number of patients showed an inhibition of ADP (2.5μM) and epinephrine (10μg/ml) and collagen (380μg/ml), however, other patients showed an inhibition of collagen-induced platelet aggregation. These results indicate that patients treated with SSRIs may have inhibition of platelet activation and aggregation, which may have an impact in the prevention of atherothrombotic cardiovascular disease. SSRIs might increase the bleeding tendency in some patients by inhibiting platelet aggregation. However, when the SSRIs are given in combination with other drugs patients may have a propensity for bleeding complications due to drug-drug interactions. Further large-scale trials are warranted to validate these results.

Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial

Several epidemiological and experimental studies suggest that n-3 polyunsaturated fatty acids (PUFA) can exert favourable effects on atherothrombotic cardiovascular disease, including arrhythmias. We investigated whether n-3 PUFA could improve morbidity and mortality in a large population of patients with symptomatic heart failure of any cause. We undertook a randomised, double-blind, placebo-controlled trial in 326 cardiology and 31 internal medicine centres in Italy. We enrolled patients with chronic heart failure of New York Heart Association class II-IV, irrespective of cause and left ventricular ejection fraction, and randomly assigned them to n-3 PUFA 1 g daily (n=3494) or placebo (n=3481) by a concealed, computerised telephone randomisation system. Patients were followed up for a median of 3.9 years (IQR 3.0-4.5). Primary endpoints were time to death, and time to death or admission to hospital for cardiovascular reasons. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00336336. We analysed all randomised patients. 955 (27%) patients died from any cause in the n-3 PUFA group and 1014 (29%) in the placebo group (adjusted hazard ratio [HR] 0.91 [95.5% CI 0.833-0.998], p=0.041). 1981 (57%) patients in the n-3 PUFA group and 2053 (59%) in the placebo group died or were admitted to hospital for cardiovascular reasons (adjusted HR 0.92 [99% CI 0.849-0.999], p=0.009). In absolute terms, 56 patients needed to be treated for a median duration of 3.9 years to avoid one death or 44 to avoid one event like death or admission to hospital for cardiovascular reasons. In both groups, gastrointestinal disorders were the most frequent adverse reaction (96 [3%] n-3 PUFA group vs 92 [3%] placebo group). A simple and safe treatment with n-3 PUFA can provide a small beneficial advantage in terms of mortality and admission to hospital for cardiovascular reasons in patients with heart failure in a context of usual care.

Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis

The key initiating process in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins. Local biological responses to these retained lipoproteins, including a chronic and maladaptive macrophage- and T-cell-dominated inflammatory response, promote subsequent lesion development. The most effective therapy against atherothrombotic cardiovascular disease to date--low density lipoprotein-lowering drugs--is based on the principle that decreasing circulating apolipoprotein B lipoproteins decreases the probability that they will enter and be retained in the subendothelium. Ongoing improvements in this area include more aggressive lowering of low-density lipoprotein and other atherogenic lipoproteins in the plasma and initiation of low-density lipoprotein-lowering therapy at an earlier age in at-risk individuals. Potential future therapeutic approaches include attempts to block the interaction of apolipoprotein B lipoproteins with the specific subendothelial matrix molecules that mediate retention and to interfere with accessory molecules within the arterial wall that promote retention such as lipoprotein lipase, secretory sphingomyelinase, and secretory phospholipase A2. Although not the primary focus of this review, therapeutic strategies that target the proatherogenic responses to retained lipoproteins and that promote the removal of atherogenic components of retained lipoproteins also hold promise. The finding that certain human populations of individuals who maintain lifelong low plasma levels of apolipoprotein B lipoproteins have an approximately 90% decreased risk of coronary artery disease gives hope that our further understanding of the pathogenesis of this leading killer could lead to its eradication.