Omega-3 fatty acids and heart failure.

During the past three decades, the protective role of omega (n)-3 polyunsaturated fatty acids (PUFA), mainly eicosapentaenoic acid and docosahexaenoic acid, in patients with coronary heart disease has been widely reported. The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Heart Failure (GISSI-HF) study, a large-scale clinical trial, recently showed that n-3 PUFA (850-882 mg/d) reduced mortality and admission to the hospital for cardiovascular reasons in patients with chronic heart failure (HF) who were already receiving recommended therapies. The favorable effects of n-3 PUFA in GISSI-HF suggest that marine fish oils could confer protection in HF mainly through their antiarrhythmic action and in part by influencing the mechanisms related to HF progression. This article reviews recent clinical and experimental evidence on the effect of n-3 PUFA in coronary heart disease, with particular attention on HF and its pathophysiologic mechanisms.

Coffee consumption and risk of cardiovascular events after acute myocardial infarction: results from the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevenzione trial.

BACKGROUND: The relation between coffee consumption and cardiovascular disease has been studied extensively, but results are still debated. In addition, little evidence is available on patients with established coronary heart disease. METHODS AND RESULTS: Prospectively ascertained information among 11,231 Italian patients (9584 males and 1647 females) with recent (< or = 3 months) myocardial infarction enrolled in the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevenzione trial was used. Usual dietary habits were assessed at baseline and updated at 0.5 and 1.5 years. Coffee consumption was categorized as never/almost never, < 2 cups per day, 2 to 4 cups per day, and > 4 cups per day. Medication use and fasting glucose were assessed at 0.5, 1, 1.5, 2.5, and 3.5 years. Risk was evaluated with Cox proportional hazards with time-varying covariates. The main outcome measure was the cumulative incidence of cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke). A total of 1167 cardiovascular events occurred during 36,961 person-years of follow-up. After multivariable adjustment for potential confounders in the time-dependent analysis, the relative risk of cardiovascular events across categories of coffee consumption was 1.02 (95% CI 0.87 to 1.20) for < 2 cups per day, 0.91 (95% CI 0.75 to 1.09) for 2 to 4 cups per day, and 0.88 (95% CI 0.64 to 1.20) for > 4 cups per day compared with abstainers (P for trend=0.18). Ultimately, coffee consumption did not change the risk of coronary heart disease events, stroke, and sudden death. CONCLUSIONS: No association between moderate coffee intake and cardiovascular events was observed in post-myocardial infarction patients.

Incidence of new-onset diabetes and impaired fasting glucose in patients with recent myocardial infarction and the effect of clinical and lifestyle risk factors.

BACKGROUND: Individuals with diabetes are at higher risk of myocardial infarction than non-diabetics. However, much less is known about the incidence of, and risk factors for, development of diabetes and impaired fasting glucose in patients who have had a myocardial infarction. We set out to estimate this incidence and investigate whether lifestyle factors such as dietary habits might alter this risk. METHODS: We used prospectively obtained data for 8291 Italian patients with a myocardial infarction within the previous 3 months, who were free of diabetes (determined by medication use, a physician-reported diagnosis, or fasting glucose > or =7 mmol/L) at baseline. Incidence of new-onset diabetes (new diabetes medication or fasting glucose > or =7 mmol/L) and impaired fasting glucose (fasting glucose > or =6.1 mmol/L and <7 mmol/L) were assessed at follow-up at 0.5, 1.0, 1.5, 2.5, and 3.5 years. Baseline data for body-mass index (BMI), other risk factors, dietary habits, and medications were updated during follow-up. A Mediterranean diet score was assigned according to consumption of cooked and raw vegetables, fruit, fish, and olive oil. Associations of demographic, clinical, and lifestyle risk-factors with incidence of diabetes and impaired fasting glucose were assessed with multivariable Cox proportional hazards. FINDINGS: During 26 795 person-years (mean follow-up 3.2 years [SD 0.9]), 998 individuals (12%) developed new-onset diabetes (incidence 37 cases per 1000 person-years). Of the 7533 without impaired fasting glucose at baseline, 2514 (33%) developed new-onset impaired fasting glucose or diabetes (incidence 123 cases per 1000 person-years), rising to 3859 (62%) of 6229 with the lower cutoff for impaired fasting glucose of 5.6 mmol/L (incidence 321 cases per 1000 person-years). Independent risk factors for new-onset diabetes or impaired fasting glucose included older age, hypertension, use of beta-blockers, lipid-lowering medications (protective), and diuretic use. Independent lifestyle risk-factors included higher BMI, greater BMI gain during follow-up, current smoking, a lower Mediterranean dietary score, and wine consumption of more than 1 L/day. Data for physical activity were unavailable, but inability to perform exercise testing was associated with higher incidence of diabetes and impaired fasting glucose. INTERPRETATION: Compared with population-based cohorts, patients with a recent myocardial infarction had a higher annual incidence rate of impaired fasting glucose (1.8 vs 27.5% in our study) and diabetes (0.8-1.6% compared with 3.7%) in this study. Thus, our results indicate that myocardial infarction could be a prediabetes risk equivalent. Smoking cessation, prevention of weight gain, and consumption of typical Mediterranean foods might lower this risk, which emphasises the need for guidance on diet and other lifestyle factors for patients who have had a myocardial infarction.

Reduced Variability to Aspirin Antiplatelet Effect by the Coadministration of Statins in High-Risk Patients for Cardiovascular Disease.

We studied the influence of cardiovascular (CV) risk factors, previous CV events, and cotreatments with preventive medicines, on residual platelet thromboxane (TX)B2 production in 182 patients chronically treated with enteric coated (EC)-aspirin (100 mg/day). The response to aspirin was also verified by assessing arachidonic acid-induced platelet aggregation and urinary 11-dehydro-TXB2 levels. Residual serum TXB2 levels exceeded the upper limit value for an adequate aspirin response in 14% of individuals. This phenomenon was detected at 12 hours after dosing with aspirin. The coadministration of statins (mostly atorvastatin) was an independent predictor of residual serum TXB2 levels, and the percentage of patients with enhanced values was significantly lower in statin users vs. nonusers. We provide evidence in vitro that atorvastatin reduced residual TXB2 generation by increasing the extent of acetylation of platelet COX-1 by aspirin. In conclusion, the coadministration of statins may counter the mechanisms associated with reduced bioavailability of aspirin detected in some individuals with CV disease.

A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology.

BACKGROUND: Various innovative pharmacologic strategies for the treatment of patients with pulmonary hypertension have been tested in recent years. Neither their comparative efficacy on surrogate end points nor the overall impact on mortality have been formally reviewed. METHODS: We did a systematic overview of all randomized trials on the therapeutic yield of prostacyclin and analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension searched in EMBASE, MEDLINE, and CINAHL databases from January 1985 to December 2005. RESULTS: Sixteen trials involving 1962 patients met the inclusion criteria. Up to 80% of the patients were in functional class III/IV with a median walking distance of 330 m at baseline. Overall, experimental treatments were associated with (1) a nonsignificant reduction in all-cause mortality (relative risk 0.70, 95% CI 0.41-1.22), (2) a minor but statistically significant improvement in exercise capacity of 42.8 m (95% CI 27.8-57.8), and (3) an improved dyspnea status by at least one functional class (relative risk 1.83, 95% CI 1.26-2.66). Changes in exercise capacity were not found to be predictive of a survival benefit. CONCLUSIONS: Although confirming the limited benefits in clinical end points documented by each trial, the overview fails to support a significant survival advantage and does not support the predictive power of surrogate end points.

Meta-analysis of effect of statin treatment on risk of sudden death.

Despite significant progress in the prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) is a major public health problem. Statins showed consistent benefits on cardiovascular events, but scant data were available about their effects on SCD. This meta-analysis aimed to assess the effect of statins on SCD. Additional analyses were carried out to evaluate lipid reduction as a possible mediator of the effect. Randomized controlled trials from January 1966 to July 2006 were retrieved by searching the MEDLINE database. Inclusion criteria were outcome focusing on the incidence of SCD, statin treatment compared with placebo or no treatment, randomized design, >or=100 patients enrolled, and follow-up>or=6 months. Data were independently abstracted by 2 investigators using a standardized protocol. Ten randomized controlled trials enrolling a total of 22,275 patients were included in the meta-analysis. Risks of SCD were 3% in patients receiving statins and 3.8% in control patients. Statin treatment was associated with a significant 19% risk reduction for SCD (odds ratio 0.81, 95% confidence interval 0.71 to 0.93, p=0.003). In subgroup analysis, the benefit of statins was independent from the main characteristics of the studies and changes in patient lipid levels during the study. In conclusion, our results suggest that statins decrease the risk of SCD.

Metabolic syndrome and risk of cardiovascular events after myocardial infarction.

OBJECTIVES: We aimed to assess the prevalence and prognostic role of metabolic syndrome (METS) and diabetes in post-myocardial infarction (MI) patients. BACKGROUND: Diabetes is a well known risk factor for patients with previous MI, but glycemic dysmetabolism develops over a protracted period of time. Scanty data are available on the role of METS in patients with previous MI. METHODS: Adjusted Cox's regression models, having diabetes, death, major cardiovascular events (CVE), and hospitalization for congestive heart failure (CHF) during follow-up as outcome events, were fitted on 11,323 patients with prior MI enrolled in the GISSI-Prevenzione Trial. RESULTS: At baseline, 21% and 29% of patients had diabetes mellitus and METS, respectively. The METS patients had a significant (93%) increased risk of diabetes during follow-up. As compared with control subjects, the probability of death and CVE were higher in both METS (+29%, p = 0.002; +23%, p = 0.005) and diabetic patients (+68%, p <0.0001; +47%, p <0.0001), although diabetic but not METS patients were more likely to be hospitalized for CHF (+89%, p <0.0003 and +24%, p = 0.241). Moderate (-6% to -10%) and substantial (>-10%) weight reduction were associated with a significant (18% and 41%, respectively) decreased risk of diabetes. Weight gain was significantly associated with increased risk of diabetes. The risk conferred by METS and diabetes tended to be higher among women. CONCLUSIONS: In patients with MI, METS and diabetes were highly prevalent and are associated with increased risk of death and CVE. Diabetes is also associated with increased risk of hospitalization for CHF. Weight reduction significantly decreased the risk of becoming diabetic in patients with METS.

A clinically practicable diagnostic score for metabolic syndrome improves its predictivity of diabetes mellitus: the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)-Prevenzione scoring.

BACKGROUND: Metabolic syndrome (MS) is associated with late-onset diabetes. However, diagnostic criteria for individual components of MS are based on categorical/arbitrary cut points and, therefore, do not exploit the information yield of each factor. We aimed to generate a diagnostic score for MS (MS-Score), aimed at predicting diabetes by giving appropriate weight to the individual components of MS. METHODS: Of 11,323 patients with prior myocardial infarction and followed up for 3.5 years in the GISSI-Prevenzione study, 3855 subjects with diabetes at baseline or missing information for relevant variables were excluded. A Cox proportional hazards model including age, sex, glycemia, high-density lipoprotein cholesterol, triglycerides, hypertension, and body mass index was fitted to create a diagnostic score. A cutoff point of 28 of the score was the best compromise between sensitivity and specificity for MS diagnosis (MS-Score). The prognostic performance of the MS-Score was compared with that of the diagnostic criteria of MS, as defined by National Cholesterol Education Program Adult Treatment Panel III (MS-ATP). RESULTS: Of 7468 patients, 940 developed diabetes. The risk of getting diabetes significantly and progressively increased in the quintiles of the score reaching > 6-fold higher risk in the last one. The predictive capability of MS-Score was significantly higher than that of the MS-ATP (AUC = 0.650 vs 0.587, sensitivity 67% vs 52%, specificity 63% vs 66%, P = .0002). The MS-Score, but not the MS-ATP, was significantly associated with mortality. CONCLUSION: MS-Score improves the prediction of diabetes development by using the full informative content of individual components for diagnosis of MS.

Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione.

BACKGROUND: Our purpose was to assess the time course of the benefit of n-3 polyunsaturated fatty acids (PUFAs) on mortality documented by the GISSI-Prevenzione trial in patients surviving a recent (<3 months) myocardial infarction. METHODS AND RESULTS: In this study, 11 323 patients were randomly assigned to supplements of n-3 PUFAs, vitamin E (300 mg/d), both, or no treatment (control) on top of optimal pharmacological treatment and lifestyle advice. Intention-to-treat analysis adjusted for interaction between treatments was carried out. Early efficacy of n-3 PUFA treatment for total, cardiovascular, cardiac, coronary, and sudden death; nonfatal myocardial infarction; total coronary heart disease; and cerebrovascular events was assessed by right-censoring follow-up data 12 times from the first month after randomization up to 12 months. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk [RR] 0.59; 95% CI 0.36 to 0.97; P=0.037). The reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months (RR 0.47; 95% CI 0.219 to 0.995; P=0.048). A similarly significant, although delayed, pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths. CONCLUSIONS: The early effect of low-dose (1 g/d) n-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies.

Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids.

BACKGROUND: Sudden death (SD) has a major impact on mortality (M) in patients with left ventricular systolic dysfunction (SyD). In GISSI-Prevenzione, treatment with n-3 polyunsaturated fatty acids (PUFA) reduced M and SD in post-MI patients, but their effect in patients with SyD is unknown. METHODS: 11,323 patients with prior MI and NYHA class < or = II were recruited. After excluding patients with no ejection fraction (EF) measurement (1684), and those with missing data (n=9), 9630 patients were available for analysis. Multivariate Cox regression adjusted models were fitted. RESULTS: Compared to patients with EF > 50%, SyD patients had higher M (12.3% vs. 6.0%) and SD (3.4% vs. 1.4%) rates. PUFA reduced M similarly in patients with (RR 0.76 (0.60-0.96) P=0.02) and without SyD (RR 0.81 (0.59-1.10) P=0.17) (heterogeneity tests P=0.55). In contrast, the effect on SD was markedly asymmetrical: PUFA produced a marked reduction (RR 0.42 (0.26-0.67) P=0.0003) of risk in SyD patients whereas the effect was less evident (RR 0.89 (0.41-1.69) P=0.71) in patients with EF > 50% (heterogeneity tests P=0.07). There was a significant increase in SD with worsening EF (P test for trend=0.02), the benefit on SD in patients with EF < or = 40% being 4-fold higher than in those with EF > 50%. CONCLUSIONS: Increasing SyD is associated with elevated risk of SD and with increasing benefit from PUFA. The effect of PUFA on SD reduction was greater in patients with SyD. Prospective trials testing the effect of PUFA in populations with SyD are required.

[Determinants of late-onset heart failure in myocardial infarction survivors: GISSI Prevenzione trial results]. / Determinantes de insuficiencia cardíaca tardía postinfarto de miocardio: resultados del estudio GISSI Prevenzione.

INTRODUCTION AND OBJECTIVES: Improvement in the early phase of myocardial infarction (MI) is associated with a higher rate of late complications, including late-onset heart failure (LHF). The factors predicting LHF are not well understood. Our aims were to identify the factors predicting LHF and to determine the survival rate in these patients. PATIENTS AND METHOD: The GISSI-Prevenzione trial involved 11,323 low-risk patients (NYHA class < or = II) who had had a recent MI (< 3 months). It was a multicenter, open-label, clinical trial of the efficacy of treatment with polyunsaturated fatty acids, vitamin E, both, or neither. Patients with heart failure at baseline and those whose ejection fraction was unknown (n = 2908) were excluded from the present analysis. Late-onset heart failure was defined prospectively as hospital admission due to heart failure. A Cox regression model adjusted for major covariates was used for risk analysis. RESULTS: The study included 8415 patients. During 3.5 years of follow-up, 192 (2.3%) developed LHF. The risk of LHF could be predicted from readily available parameters: age (per year; RR=1.07; 95% CI, 1.05-1.09), ejection fraction (per 1% increment; RR=0.96; 95% CI, 0.94-0.97), heart rate (> or = 74 beats/min; RR=1.62; 95% CI, 1.21-2.16), white blood cell count (> or = 8900 per ml; RR=1.42; 95% CI, 1.05-1.94), diabetes (RR=1.62; 95% CI, 1.17-2.24), hypertension (RR=1.76; 95% CI, 1.33-2.34), peripheral artery disease (RR=2.11; 95% CI, 1.32-3.37), and reinfarction (RR=2.09; 95% CI, 1.28-3.39). LHF was associated with poor survival: (RR=2.34; 95% CI, 1.63-3.36). CONCLUSIONS: The risk of LHF in post-MI patients can be predicted from readily available parameters. LHF was associated with a poor prognosis.

n-3 PUFAs in cardiovascular disease.

Many large, randomised clinical trials and some meta-analyses have shown that treatment with n-3 polyunsaturated fatty acids (n-3 PUFAs) is associated with consistent benefits on cardiovascular (CV) events, primarily due to a reduction of coronary and CV deaths in patients with coronary heart disease. At variance with such evidence, some clinical trials and meta-analyses showing a neutral effect of n-3 PUFAs have been recently published, raising concern about the consistency of the evidence on the CV benefits of n-3 PUFAs. Several methodological and clinical aspects of these recent trials deserve to be considered. Indeed, the low rate of events or the overoptimistic expectations of the benefit of n-3 PUFAs used for sample size calculation led to an inadequate statistical power of several studies. The improvement of background medical therapy, serum baseline levels of n-3 PUFAs, and different doses and/or treatment duration might have downplayed the benefit of n-3 PUFAs. Similarly to old drugs shown to be effective some years ago, it is possible that the benefits of treatment with n-3 PUFAs are not as great in a modern CV prevention strategy so rich in many effective drugs compared with past trials testing CV drugs when less effective therapies were available.

n-3 PUFAs and heart failure.

The risk of death of patients with heart failure (HF) is still too high in daily clinical practice despite the many progress that have occurred in the diagnosis and treatment of this syndrome that significantly reduce the mortality of these patients. Results of the GISSI-HF trial, the first and only large-scale clinical trial to date assessing the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) in HF patients, showed that treatment of 100 patients saved almost 2 lives and prevented almost 2 cardiovascular hospitalisations, indicating that beneficial cardiovascular effects of n-3 PUFAs observed in other populations might also apply to patients with HF. Treatment with n-3 PUFAs may be considered as a new option to add to the shortlist of evidence-based life-prolonging therapies for HF, as suggested by the recent guidelines of the European Society of Cardiology. However, further large clinical trials are undoubtedly needed to give adequate answers to still open questions on the treatment of HF.

Uric acid: a cardiovascular risk factor in patients with recent myocardial infarction.

BACKGROUND: To date uric acid (UA) is not considered a cardiovascular risk factor, although evidence about a relationship between UA and cardiovascular diseases has been reported. METHODS: Information from 10,840 patients enrolled in the GISSI-Prevenzione trial was used to evaluate the relationship between UA and risk for total mortality and cardiovascular events (CVE). UA levels were categorized in quintiles, as ≤ 4.5 (Q1), 4.6 to 5.3 (Q2), 5.4 to 6.0 (Q3), 6.1 to 6.8 (Q4) and >6.8 (Q5) mg/dL. Multivariable analysis was used to estimate the relative risks (HR) of outcome measures across categories of UA. The analysis of the area under the receiver operating characteristic curve (AUC), the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI) tests were used to evaluate the incremental prognostic information of UA. RESULTS: During 36,802 person-years of follow-up, 974 deaths and 1120 cardiovascular events occurred. We found a statistically significant association between high UA and total mortality [HR, P value]: Q1 [reference category, 1.00]; Q2 [1.13, 0.267]; Q3 [1.06, 0.619]; Q4 [1.23, 0.063]; Q5 [1.63, <0.0001], test for trend P<0.0001. Similar results were obtained for cardiovascular events [HR, P value]: Q1 [reference category, 1.00]; Q2 [1.12, 0.271]; Q3 [1.19, 0.094]; Q4 [1.25, 0.031]; Q5 [1.38, 0.002], test for trend P=0.0009. The prognostic accuracy of prediction models for CVE was significantly increased by adding UA to classical cardiovascular risk factors (AUC P=0.0041; NRI P=0.0004; IDI P<0.0001). CONCLUSION: High UA may be considered a risk factor for death and CVE.

Wine consumption and risk of cardiovascular events after myocardial infarction: results from the GISSI-Prevenzione trial.

BACKGROUND: To evaluate the association of wine intake with incident cardiovascular events (CVE) and total mortality after myocardial infarction (MI). METHODS: We used prospectively ascertained information among 11,248 Italian patients with recent MI enrolled in the GISSI-Prevenzione Trial. Usual wine consumption has been categorised as never/almost never, up to 0.5L/day, and >0.5L/day. Multiple imputation was used for missing values at baseline and during follow-up. We assessed adjudicated cumulative incidence of major CVE during 3.5years of follow-up and total mortality at long-term follow-up (7.3years), respectively. Multivariate Cox proportional hazards models were fitted to estimate hazard ratios (HR) first using data at baseline and then updated using time-varying covariates. RESULTS: During 37,021 person-years of follow-up, 1168 CVE occurred. Moderate wine intake at baseline was associated with significantly reduced risk of CVE (adjusted HR 0.87; 95% CI 0.76-0.99) as compared with non-drinkers. In time-updated analyses, results were virtually the same, though they were barely statistically not significant (adjusted HR 0.88; 95% CI 0.77-1.00). Wine intake was associated with lower risk of total mortality. In time-updated adjusted analyses, patients with wine consumption up to 0.5L/day (HR 0.83; 95% CI 0.74-0.92) and >0.5L/day (HR 0.77; 95% CI 0.63-0.94) had lower mortality compared with non-drinkers (P for trend=0.0003). CONCLUSIONS: Among patients with established heart disease, moderate consumption of wine seems to be associated with lower incidence of CVE and total mortality as compared with non drinkers.

Why Do We Still Need Large Scale Clinical Trial: The Case of n-3 PUFA.

After the first reports about a protective effect on coronary heart disease (CHD) published more than 40 years ago, wide interest in the therapeutic use of n-3 polyunsaturated fatty acids (n-3 PUFA) aroused. Since then, many studies and meta-analyses have reported a significantly reduced risk of CHD and CV death due to fish and n-3 PUFA intake. Some of the overviews reported a significant reduction of risk of sudden cardiac death, all-cause death, and nonfatal CV events. On the other side, recent clinical trials had mixed findings, raising concern about the consistency of the evidence on n-3 PUFA. We critically reviewed recent large clinical trials reporting data on the antiarrhythmic effects of n-3 PUFA in different clinical settings, i.e., patients with CHD, heart failure, with implantable cardioverter defibrillator, and at risk of atrial fibrillation, in order to summarize the results which are available up to date and possibly give "substantiated" fuel to the debate on the conflicting results of n-3 PUFA.

Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane.

Diabetes mellitus is associated with platelet hyperactivity, which leads to increased morbidity and mortality from cardiovascular disease. This is coupled with enhanced levels of thromboxane (TX), an eicosanoid that facilitates platelet aggregation. Although intensely studied, the mechanism underlying the relationship among hyperglycemia, TX generation, and platelet hyperactivity remains unclear. We sought to identify key signaling components that connect high levels of glucose to TX generation and to examine their clinical relevance. In human platelets, aldose reductase synergistically modulated platelet response to both hyperglycemia and collagen exposure through a pathway involving ROS/PLCγ2/PKC/p38α MAPK. In clinical patients with platelet activation (deep vein thrombosis; saphenous vein graft occlusion after coronary bypass surgery), and particularly those with diabetes, urinary levels of a major enzymatic metabolite of TX (11-dehydro-TXB2 [TX-M]) were substantially increased. Elevated TX-M persisted in diabetic patients taking low-dose aspirin (acetylsalicylic acid, ASA), suggesting that such patients may have underlying endothelial damage, collagen exposure, and thrombovascular disease. Thus, our study has identified multiple potential signaling targets for designing combination chemotherapies that could inhibit the synergistic activation of platelets by hyperglycemia and collagen exposure.

Uses and benefits of omega-3 ethyl esters in patients with cardiovascular disease.

Much evidence on the favorable effects of omega-3 ethyl esters on cardiovascular morbidity and mortality has been obtained in studies performed in healthy subjects and in different clinical settings. Here the clinical effects of omega-3 ethyl ester administration in patients with previous myocardial infarction or heart failure are reviewed, together with a discussion of underlying mechanisms of action. The pharmacokinetic and pharmacodynamic properties of omega-3 ethyl esters, as well as evidence concerning their safety and tolerability, are also reported.

Effect of n-3 polyunsaturated fatty acids and rosuvastatin in patients with heart failure: results of the GISSI-HF trial.

Epidemiological, experimental studies and post hoc analyses of randomized trials suggested that n-3 polyunsaturated fatty acids (PUFA) and statins could be beneficial in chronic heart failure. Two double-blind, placebo-controlled, randomized clinical trials investigated the efficacy and safety of n-3 PUFA 1 g daily (R1) and rosuvastatin 10 mg daily (R2) in patients with heart failure. In total, 6975 and 4574 patients were randomized in R1 and R2, respectively; the main reason for excluding patients from R2 being the open-label administration of statin treatment. Primary end points were death, and death or admission to hospital for cardiovascular reasons. n-3 PUFA, but not rosuvastatin, significantly decreased the two coprimary end points: 56 and 44 patients needed to be treated with n-3 PUFA for a median duration of 3.9 years to avoid one death or one cumulative event. Both drugs were safe and were tolerated. A simple and safe treatment with n-3 PUFA provides a beneficial advantage in patients with heart failure in a context of usual care.

Efficacy of n-3 polyunsaturated fatty acids according to clinical characteristics of patients with recent myocardial infarction: insights from the GISSI-Prevenzione trial.

The GISSI-Prevenzione trial established the efficacy of n-3 polyunsaturated fatty acids (PUFAs) for reducing mortality in patients after recent myocardial infarction. The generalisability of such results to clinical practice could vary according to other individual patient characteristics. We analysed the GISSI-Prevenzione database to assess whether other major risk factors, comorbidities, dietary habits, or medications could interact with the efficacy of n-3 PUFA treatment to reduce total mortality. We found no evidence that concomitant disease states, habits, or interventions altered the therapeutic benefit of n-3 PUFA consumption in survivors of recent myocardial infarction.