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

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Abstract

Background 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. Methods 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. Findings 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). Interpretation 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. Funding Società Prodotti Antibiotici (SPA; Italy), Pfizer, Sigma Tau, and AstraZeneca.

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... Development Stage of CHD Three RCTs enrolled 10,481 patients who had an MI within the previous 3 months (19,21,28), four RCTs enrolled 27,036 patients with confirmed CHD (11,22,23,26), and the other seven studies included 97,774 subjects with high CHD risks (7,12,13,20,24,25,27). If an RCT included subjects with different development stages of CHD and the RCT included the largest number of people at a certain development stage of CHD, then the RCT was included in the corresponding subgroup of the certain development stage of CHD. ...
... Two RCTs applied low doses of omega-3 FA supplementation on 7,338 subjects (22,23), the other eight RCTs applied moderate doses of omega-3 FA supplementation on 87,037 subjects (13,(19)(20)(21)(24)(25)(26)(27), whereas the remaining four RCTs applied high doses of omega-3 FA supplementation on 40,916 subjects (7,11,12,28). To determine the association between omega-3 FA supplementation doses and cardiovascular risk, we conducted a (Figure 6). ...
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Background The clinical benefits of omega-3 fatty acids (FAs) supplementation in preventing and treating coronary heart disease (CHD) remain controversial. Therefore, this study aimed to investigate the clinical benefits of omega-3 FA supplementation, with special attention given to specific subgroups. Methods Randomized controlled trials (RCTs) that compared the effects of omega-3 FA supplementation for CHD vs. a control group and including at least 1,000 patients were eligible for the inclusion in this meta-analysis. The relative risk (RR) of all-cause death, major adverse cardiovascular events (MACEs), cardiovascular death, myocardial infarction (MI), stroke, and revascularization were estimated. We analyzed the association between cardiovascular risk and omega-3 FA supplementation in the total subjects. We focused on the cardiovascular risk compared to omega-3 FA in subgroups with different development stages of CHD, omega-3 FA supplementation application dose, diabetes, and sex. PROSPERO Registration Number: CRD42021282459. Results This meta-analysis included 14 clinical RCTs, including 1,35,291 subjects. Omega-3 FA supplementation reduced the risk of MACE (RR; 0.95; CI: 0.91–0.99; p for heterogeneity 0.27; I ² = 20%; p = 0.03), cardiovascular death (RR; 0.94; CI: 0.89–0.99; p for heterogeneity 0.21; I ² = 25%; p = 0.02), and MI (RR; 0.86; CI: 0.79–0.93; p for heterogeneity 0.28; I ² = 19%; p < 0.01), but had no significant effect on all-cause death, stroke, and revascularization. In the subgroup analysis, omega-3 FA supplementation decreased the incidence of MACE and cardiovascular death in acute patients with MI, the risk of MI and stroke in patients with CHD, and the risk of MI in patients with high-risk CHD. 0.8–1.2 g omega-3 FA supplementation reduced the risk of MACE, cardiovascular death, and MI. It was revealed that gender and diabetes have no significant association between omega-3 FA supplementation and MACE risk. Conclusions Omega-3 FA supplementation had a positive effect in reducing the incidence of MACE, cardiovascular death, MI. Regardless of the stage of CHD, omega-3 FA supplementation can prevent the occurrence of MI. The 0.8–1.2 g omega-3 FA supplementation alleviated CHD risk more effectively than lower or higher doses. Systematic Review Registration https://www.crd.york.ac.uk/prospero/ , identifier CRD42021282459.
... The data used in this study are derived from the GISSI-HF trial: a multicenter, randomized, double-blind, placebo-controlled trial designed to assess the effect of n − 3 polyunsaturated fatty acids in patients with CHF. The detailed protocol and main results of this trial have already been described elsewhere [29] [30]. ...
... Events of interest were also recorded. The entire GISSI-HF trial included 7046 eligible and randomized patients, with the final sample analyzed in [30] and comprised of 6975 patients. ...
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Selecting which explanatory variables to include in a given score is a common difficulty, as a balance must be found between statistical fit and practical application. This article presents a methodology for constructing parsimonious event risk scores combining a stepwise selection of variables with ensemble scores obtained by aggregation of several scores, using several classifiers, bootstrap samples and various modalities of random selection of variables. Selection methods based on a probabilistic model can be used to achieve a stepwise selection for a given classifier such as logistic regression, but not directly for an ensemble classifier constructed by aggregation of several classifi-ers. Three selection methods are proposed in this framework, two involving a backward selection of the variables based on their coefficients in an ensemble score and the third involving a forward selection of the variables maximizing the AUC. The stepwise selection allows constructing a succession of scores, with the practitioner able to choose which score best fits his needs. These three methods are compared in an application to construct parsimonious short-term event risk scores in chronic HF patients, using as event the composite endpoint of death or hospitalization for worsening HF within 180 days of a visit. Focusing on the fastest method, four scores are constructed, yielding out-of-bag AUCs ranging from 0.81 (26 variables) to 0.76 (2 variables).
... [15][16][17][18] At molecular level, we can classify the epidrugs in: "direct epidrugs" [eg, the bromodomain and extra-terminal (BET) protein inhibitor apabetalone]; and repurposed drugs with potential, indirect (non-classical) epigenetic-oriented interference by which they may exert cardioprotective functions [eg, hydralazine, metformin, statins, and sodium-glucose cotransporter-2 inhibitors (SGLT2i)] or nutraceutical compounds [eg, omega-3 polyunsaturated fatty acids (PUFAs)]. Encouraging results are coming from large randomized trials evaluating the putative beneficial effects of combining epidrugs with the conventional therapy in patients with HF. [14][15][16][17][18][19][20][21][22] Our goal is to update on the emerging epigeneticbased strategies which may be useful in the prevention and treatment of HFrEF and HFpEF ( Figure 1). ...
... PUFAs supplementation reduced risk for total mortality and HF hospitalization when added to standard therapy. 19 Furthermore, in the OMEGA-REMODEL trial, high-dose of PUFAs (3.4 g per day) for 6 months post-myocardial infarction reduced infarct size and non-infarct myocardial fibrosis as well as improved ventricular systolic function. 69 ...
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Claudio Napoli,1 Paola Bontempo,2 Vittorio Palmieri,3 Enrico Coscioni,4 Ciro Maiello,5 Francesco Donatelli,6 Giuditta Benincasa1 1Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania “Luigi Vanvitelli”, Naples, 80138, Italy; 2Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, 80138, Italy; 3Department of Cardiac Surgery and Transplantation, Heart Transplantation Unit in Adults of the ‘Ospedali dei Colli Monaldi-Cotugno-CTO’, Naples, Italy; 4Department of Cardiac Surgery, Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d’Aragona, Salerno, Italy; 5Department of Cardiovascular Surgery and Transplants, Monaldi Hospital, Azienda dei Colli, Naples, Italy; 6Chair of Cardiac Surgery, Department of Cardiothoracic Center, Istituto Clinico Sant’Ambrogio, University of Milan, Milan, ItalyCorrespondence: Giuditta BenincasaDepartment of Advanced Medical and Surgical Sciences (DAMSS), University of Campania “Luigi Vanvitelli”, Naples, ItalyTel +390815667916Email giuditta.benincasa@unicampania.itAbstract: Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy (“epidrugs”) is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.Keywords: heart failure, personalized therapy, epidrugs
... Noteworthy, the GISSI-HF study opened new possibilities as the first large scale clinical trial testing omega-3 fatty acids, that when adding 1 g daily to the best medical treatment offered a modest but significant reduction on all-cause mortality and CV hospitalization and proved to be a safe option (Tavazzi et al., 2008a). In a subsequent trial, the reduction seen in inflammatory markers (Moertl et al., 2011), like IL-6 and TNF-α, in the high dose of 4g/d regimen, accompanied by a dosedependent increase of LVEF and improvement of endothelial function, could justify the outcome benefits. ...
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Inflammation has been recognized as a major pathophysiological contributor to the entire spectrum of human heart failure (HF), including HF with reduced ejection fraction, HF with preserved ejection fraction, acute HF and cardiogenic shock. Nevertheless, the results of several trials attempting anti-inflammatory strategies in HF patients have not been consistent or motivating and the clinical implementation of anti-inflammatory treatments for HF still requires larger and longer trials, as well as novel and/or more specific drugs. The present work reviews the different inflammatory mechanisms contributing to each type of HF, the major inflammatory mediators involved, namely tumor necrosis factor alpha, the interleukins 1, 6, 8, 10, 18, and 33, C-reactive protein and the enzymes myeloperoxidase and inducible nitric oxide synthase, and their effects on heart function. Furthermore, several trials targeting these mediators or involving other anti-inflammatory treatments in human HF are also described and analyzed. Future therapeutic advances will likely involve tailored anti-inflammatory treatments according to the patient’s inflammatory profile, as well as the development of resolution pharmacology aimed at stimulating resolution of inflammation pathways in HF.
... In addition, the ESC guidelines state that omega-3 polyunsaturated fatty acid (PUFA) supplementation may be considered to reduce the risk of cardiovascular hospitalisation and death in patients with HF, with a level of evidence B recommendation, class IIb [2] taking into account the results of the GISSI-HF trial. This trial randomised 955 patients to receive a daily dose of 1 g PUFA or placebo and showed that all-cause mortality and the combined end point of all-cause mortality or hospital admission for cardiovascular reasons were lower in the group receiving PUFA [12,98]. The American College of Cardiology and American Heart Association (ACC/AHA) guidelines also state that PUFA supplementation should be considered in these patients, with a level of evidence B recommendation, class IIa [99]. ...
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... Furthermore, increasing the proportion of grass in the diet resulted in a decrease in SFA, whereas MUFA, PUFA (mainly C18:3 n-3), and conjugated linoleic acid (CLA) increased linearly [130]. When fed grass, ruminants produce milk and meat with different profiles of secondary compounds, e.g., CLA and omega 3 [131,132], which have been linked to better human health [133,134], but see [135]. The change in milk FA composition from grass in the diet is also an opportunity to shift not only to a more nutritious source of food, but also to the consumption of nutraceutical diets. ...
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... However, in patients with ischaemic HF, lowering LDL cholesterol with statins has not proven effective (12). The GISSI-HF study, which included patients with ischaemic and non-ischaemic HF, treated with polyunsaturated n-3 fatty acids, showed similar results (13). Increased LDL cholesterol concentrations are thus stenoze. ...
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... Regarding patients with chronic heart failure of NYHA class II-IV, the administration of 1 g n-3 PUFA determines gastrointestinal adverse effect of minor clinical relevance [55]. ...
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Omega-3 (n-3) polyunsaturated fatty acids (PUFA) and their metabolites have long been recognized to protect against inflammation-related diseases including heart disease. Recent reports present conflicting evidence on the effects of n-3 PUFAs on major cardiovascular events including death. While some studies document that n-3 PUFA supplementation reduces the risk for heart disease, others report no beneficial effects on heart disease composite primary outcomes. Much of this heterogeneity may be related to the genetic variation in different individuals/populations that alters their capacity to synthesize biologically active n-3 and omega 6 (n-6) PUFAs and metabolites from their 18 carbon dietary precursors, linoleic acid (LA, 18:2 n-6) and alpha-linolenic (ALA, 18:3, n-3). Here, we discuss the role of a FADS gene-by-dietary PUFA interaction model that takes into consideration dietary exposure, including the intake of LA and ALA, n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in determining the efficacy of n-3 PUFA supplementation. We also review recent clinical trials with n-3 PUFA supplementation and coronary heart disease in the context of what is known about fatty acid desaturase (FADS) gene-by-dietary PUFA interactions. Given the dramatic differences in the frequencies of FADS variants that impact the efficiency of n-3 and n-6 PUFA biosynthesis, and their downstream signaling products among global and admixture populations, we conclude that large clinical trials utilizing “one size fits all” n-3 PUFA supplementation approaches are unlikely to show effectiveness. However, evidence discussed in this review suggests that n-3 PUFA supplementation may represent an important opportunity where precision interventions can be focused on those populations that will benefit the most from n-3 PUFA supplementation.
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Residuabal risk mediated by hypertriglyceridemia among statin-treated individuals is an important clinical and public health challenge. Niacin, fibrates and omega-3 FA are three classes of non-statin agents with demonstrated TG-lowering effects. Randomized controlled trials of niacin and fibrates have been consistently negative, but the trial landscape for two key sources of omega-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is more complex. Clinical trials evaluating omega-3 FA can be differentiated into those that studied mixed formulations (EPA + DHA) and those that studied EPA alone. Those assessing the impact of mixed formulations have not consistently demonstrated CVD risk reduction, whereas trials of EPA alone have been successful. Two recent trials of mixed formulations - STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) and OMEMI (Omega-3 fatty acids in Elderly patients with Myocardial Infarction) – studied contemporarily treated patients with mixed EPA + DHA formulations at higher doses than before and showed no benefit, thus adding valuable information to our overall understanding of this evolving therapeutic class. In this review, we contextualize the findings of STRENGTH and OMEMI within the existing omega-3 FA clinical trial landscape and look ahead to how future trials can inform existing knowledge gaps, particularly with regards to the applicability of these agents within the primary prevention realm.
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Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death globally. Omega-3 polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid and docosahexaenoic acid have been extensively studied as both dietary supplement and pharmaceutical agent for the prevention of ASCVD. Epidemiological and retrospective studies have long shown the inverse relationship of omega-3 PUFA consumption and ASCVD event but results of previous large randomized controlled trials have not consistently shown the same effect. Meta-analysis and a recent clinical trial using a high dose of eicosapentaenoic acid showed convincing protective effects of omega-3 PUFAs on ASCVD. Emerging evidence shows that both chronic inflammation and hypertriglyceridemia increase the risk of atherosclerosis. Amelioration of the inflammatory process and reduction of hypertriglyceridemia provide two mechanisms on the prevention and management of ASCVD, and agents with both of these effects are more potent and desirable. Omega-3 PUFAs exert anti-hypertriglyceridemia effect, ameliorate inflammation, and maintain the resolution of inflammation homeostasis pleiotropically through multiple molecular and cellular mechanisms. This review presents the pathophysiology of atherosclerosis, the mechanisms of omega-3 PUFAs on the reduction of the atherosclerotic risk, and the current clinical utilities of omega-3 PUFAs on the prevention of ASCVD.
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PurposeData on the relationship between omega-3 fatty acid (n-3 FA) therapy with atrial fibrillation (AF) have been inconsistent. We investigate the association between n-3 FA and risk for AF by pooling data from available large, cardiovascular outcome trials.Methods We performed a systematic search on PubMed and Embase for studies on n-3 FA with AF as an outcome measure. Large (≥ 1000 participants) randomized controlled trials with ≥ 1-year follow-up period were included. The association between n-3 FA and risk of AF or stroke was assessed. Mantel–Haenszel random effects model was used to calculate risk ratios (RR) with 95% confidence intervals (CI). We then performed meta-regression to evaluate effect on AF by dose of n-3 FA therapy.ResultsA total of 8 randomized control trials encompassing 83,112 participants were included in the meta-analysis. Of these, five trials assessed a lower dose of n-3 FA (≤ 1 g daily, n = 61,096) while 3 trials assessed a higher dose (> 1 g daily, n = 22,016). In meta-analysis, a significant association was noted between n-3 FA treatment and risk of AF (4.0% vs 3.3%; RR 1.24, 95% CI 1.11–1.38, p = 0.0002). There was a modest but still significant association in the lower dose (n-3 FA ≤ 1 g daily) sub-group (RR 1.12, 95% CI 1.04–1.21, p = 0.004) and stronger association in the higher dose (n-3 FA > 1 g daily) sub-group (RR 1.51, 95% CI 1.26–1.80, p < 0.001; p-interaction between low versus high subgroups = 0.003). There was no increase in stroke risk (RR 1.04, 95% CI 0.90–1.20). Meta-regression demonstrated a significant association between dose of n-3 FA with risk for AF events (log RR 0.103, 95% CI 0.048–0.159, p < 0.001).Conclusion While overall AF event rates were low, n-3 FA treatment is associated with increased risk for AF.
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Heart failure (HF) remains a leading cause of hospitalization and mortality. Marine omega-3 fatty acid supplements (omega-3 s) have shown efficacy in decreasing sudden cardiac death and improving the left ventricle ejection fraction percent (LVEF%). In this review, we evaluated the effect of marine omega-3 fatty acid supplements (omega-3 s) on HF hospitalization, recurrent HF hospitalization, and cardiovascular mortality in patients with heart failure. We found that omega-3 supplementation did not reduce first HF hospitalization or cardiovascular mortality but did significantly reduce recurrent HF hospitalizations, as compared with placebo.
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Objectives To evaluate associations of omega-3 fatty acid (O3-FA) blood levels with cardiometabolic risk markers, functional capacity and cardiac function/morphology in patients with heart failure with preserved ejection fraction (HFpEF). Background O3-FA have been linked to reduced risk for HF and associated phenotypic traits in experimental/clinical studies. Methods This is a cross-sectional analysis of data from the Aldo-DHF-RCT. From 422 patients, the omega-3-index (O3I = EPA + DHA) was analyzed at baseline in n = 404 using the HS-Omega-3-Index ® methodology. Patient characteristics were; 67 ± 8 years, 53% female, NYHA II/III (87/13%), ejection fraction ≥ 50%, E / e ′ 7.1 ± 1.5; median NT-proBNP 158 ng/L (IQR 82–298). Pearson’s correlation coefficient and multiple linear regression analyses, using sex and age as covariates, were used to describe associations of the O3I with metabolic phenotype, functional capacity, echocardiographic markers for LVDF, and neurohumoral activation at baseline/12 months. Results The O3I was below (< 8%), within (8–11%), and higher (> 11%) than the target range in 374 (93%), 29 (7%), and 1 (0.2%) patients, respectively. Mean O3I was 5.7 ± 1.7%. The O3I was inversely associated with HbA1c ( r = − 0.139, p = 0.006), triglycerides-to-HDL-C ratio ( r = − 0.12, p = 0.017), triglycerides ( r = − 0.117, p = 0.02), non-HDL-C ( r = − 0.101, p = 0.044), body-mass-index ( r = − 0.149, p = 0.003), waist circumference ( r = − 0.121, p = 0.015), waist-to-height ratio ( r = − 0.141, p = 0.005), and positively associated with submaximal aerobic capacity ( r = 0.113, p = 0.023) and LVEF ( r = 0.211, p < 0.001) at baseline. Higher O3I at baseline was predictive of submaximal aerobic capacity ( β = 15.614, p < 0,001), maximal aerobic capacity ( β = 0.399, p = 0.005) and LVEF ( β = 0.698, p = 0.007) at 12 months. Conclusions Higher O3I was associated with a more favorable cardiometabolic risk profile and predictive of higher submaximal/maximal aerobic capacity and lower BMI/truncal adiposity in HFpEF patients. Graphic abstract Omega-3 fatty acid blood levels are inversely associated with cardiometabolic risk factors in HFpEF patients. Higher O3I was associated with a more favorable cardiometabolic risk profile and aerobic capacity (left) but did not correlate with echocardiographic markers for left ventricular diastolic function or neurohumoral activation (right). An O3I-driven intervention trial might be warranted to answer the question whether O3-FA in therapeutic doses (with the target O3I 8–11%) impact on echocardiographic markers for left ventricular diastolic function and neurohumoral activation in patients with HFpEF. This figure contains modified images from Servier Medical Art ( https://smart.servier.com ) licensed by a Creative Commons Attribution 3.0 Unported License.
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Background Patients with diabetes mellitus (DM) have a higher prevalence of heart failure (HF) than those without it. Approximately 40 % of HF patients have DM and they tend to have poorer outcomes than those without DM. This study evaluated the impact of insulin therapy on mortality among acute HF patients. Methods A total of 1740 patients from the Korean Acute Heart Failure registry with DM were included in this study. The risk of all-cause mortality according to insulin therapy was assessed using the Cox proportional hazard models with inverse probability of treatment weighting to balance the clinical characteristics (pretreatment covariates) between the groups. Results DM patients had been treated with either oral hypoglycemic agents (OHAs) alone (n = 620), insulin alone (n = 682), or insulin combined with OHAs (n = 438). The insulin alone group was associated with an increased mortality risk compared with the OHA alone group (HR = 1.41, 95 % CI 1.21–1.66]). Insulin therapy combined with OHAs also showed an increased mortality risk (HR = 1.29, 95 % CI 1.14–1.46) compared with the OHA alone group. Insulin therapy was consistently associated with increased mortality risk, regardless of the left ventricular ejection fraction (LVEF) or HF etiology. A significant increase in mortality was observed in patients with good glycemic control (HbA1c < 7.0 %) receiving insulin, whereas there was no significant association in patients with poor glycemic control (HbA1c ≥ 7.0%). Conclusions Insulin therapy was found to be associated with increased mortality compared to OHAs. The insulin therapy was harmful especially in patients with low HbA1c levels which may suggest the necessity of specific management strategies and blood sugar targets when using insulin in patients with HF.
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Fatty acids (FAs) have structural and functional diversity. FAs in the heart are closely associated with cardiac function, and their qualitative or quantitative abnormalities lead to the onset and progression of cardiac disease. FAs are important as an energy substrate for the heart, but when in excess, they exhibit cardio-lipotoxicity that causes cardiac dysfunction or heart failure with preserved ejection fraction. FAs also play a role as part of phospholipids that compose cell membranes, and the changes in mitochondrial phospholipid cardiolipin and the FA composition of plasma membrane phospholipids affect cardiomyocyte survival. In addition, FA metabolites exert a wide variety of bioactivities in the heart as lipid mediators. Recent advances in measurement using mass spectrometry have identified trace amounts of n-3 polyunsaturated fatty acids (PUFAs)-derived bioactive metabolites associated with heart disease. n-3 PUFAs have a variety of cardioprotective effects and have been shown in clinical trials to be effective in cardiovascular diseases, including heart failure. This review outlines the contributions of FAs to cardiac function and pathogenesis of heart diseases from the perspective of three major roles and proposes therapeutic applications and new medical perspectives of FAs represented by n-3 PUFAs.
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Purpose of Review Interest in preventing atherosclerosis and cardiovascular disease extends beyond essential nutrients and dietary patterns. This article reviews the potential for bioactive compounds to play a role in prevention and the recent process in guidance for developing policy for bioactives. Recent Findings A framework for developing recommended intakes of bioactives dietary substances was recently developed and the first guideline expected is for a bioactive targeted for cardiometabolic health. Bioactives target endothelial health, the gut microbiome, serum lipids, blood pressure, inflammation, and oxidative stress. The evidence base is growing and will be enhanced further with the discovery of good biomarkers of exposure and health outcomes. Summary A robust evidence base is essential to develop policy and influence clinical practice for bioactives, an exciting and growing area of research.
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This review presents the results of previously performed epidemiological, experimental and clinical studies indicating the use of ω-3 PUFA (polyunsaturated fatty acids) contributes to reduce the risk of developing cardiovascular diseases. Experimental studies have shown ω-3 PUFA are exhibiting antiarrhythmic effects, improving endothelial function, showing an anti- inflammatory effect, affecting the rheological properties of blood, reducing triglyceride concentrations, and increasing the stability of atheromatous plaque. Wide-scale clinical trials have established high efficacy of ω-3 PUFA in primary and secondary prevention of coronary heart disease. It is found to reduce the risk of ventricular arrhythmias and sudden cardiac death. Also, reduces overall mortality and hospitalization rates due to cardiovascular causes in patients with chronic heart failure. Clinical efficacy among cardiovascular diseases of the prescription drugs ω-3 PUFA standardized by qualitative and quantitative compositions to be studied further in a comparison to the other medications with similar make-up.
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Despite the high prevalence of nutrition disorders in patients with heart failure (HF), major HF guidelines lack specific nutrition recommendations. Because of the lack of standardized definitions and assessment tools to quantify nutritional status, nutrition disorders are often missed in patients with HF. Additionally, a wide range of dietary interventions and overall dietary patterns have been studied in this population. The resulting evidence of benefit is, however, conflicting, making it challenging to determine which strategies are the most beneficial. In this document, we review the available nutritional status assessment tools for patients with HF. In addition, we appraise the current evidence for dietary interventions in HF, including sodium restriction, obesity, malnutrition, dietary patterns, and specific macronutrient and micronutrient supplementation. Furthermore, we discuss the feasibility and challenges associated with the implementation of multimodal nutrition interventions and delineate potential solutions to facilitate addressing nutrition in patients with HF.
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Patients with heart failure (HF) are at high risk for atherosclerotic cardiovascular disease. Studies of atherothrombotic treatments in this population have been disappointing to date. Icosapent ethyl reduced the risk of atherosclerotic cardiovascular disease among a broad array of statin‐treated patients at elevated risk for atherosclerotic cardiovascular disease. Whether the treatment benefits of icosapent ethyl are consistent among those with HF is unknown. REDUCE‐IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) randomized 8179 participants, including 1446 (17.7%) patients with a history of HF (icosapent ethyl, N=703; and placebo, N=743). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. We used Cox regression to estimate the risk of outcomes of participants with and without HF. We estimated the placebo‐controlled change in triglycerides and hs‐CRP (high‐sensitivity C‐reactive protein) from baseline to 2 years. Among 1446 patients with HF, median age was 63.0 years, median body mass index was 31.0 kg/m2, and more were men (69.3%). Icosapent ethyl reduced triglycerides (median reduction, 33.5 mg/dL, or 15.4%; P<0.0001) and hs‐CRP (35.1%; P<0.0001) compared with placebo, similar to patients without HF (P‐interaction>0.90). The treatment effect on the primary end point in patients with HF history (hazard ratio [HR], 0.87; 95% CI, 0.70–1.08) was consistent with the effects observed in patients without HF history (HR, 0.73; 95% CI, 0.65–0.81) (P‐interaction=0.13). In REDUCE‐IT, icosapent ethyl provided similar improvements in triglyceride levels and hs‐CRP as well as similar cardiovascular risk reduction in patients with and without HF. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.
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Aim The “2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure” replaces the “2013 ACCF/AHA Guideline for the Management of Heart Failure” and the “2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.” The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure. Methods A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies, published through September 2021, were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021. Structure Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients’ interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments with high-quality published economic analyses.
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Atherosclerotic cardiovascular disease (ASCVD) and its atherothrombotic complications impose a substantial disease burden in Europe, representing a cost of €210 billion per year for the European Union. Hypertriglyceridemia, a major risk factor for premature ASCVD, is present in more than 20% of the European population, and is a key feature of atherogenic dyslipidemia. Recent findings from the Progression of Early Subclinical Atherosclerosis (PESA) cohort in Spain showed that even in apparently healthy, middle-aged individuals without a history of cardiovascular (CV) risk, elevated triglyceride levels are associated with subclinical atherosclerosis and arterial inflammation. Emerging evidence from epidemiologic and genetic studies supports an independent causative role of triglycerides, triglyceride-rich lipoproteins, and their remnants in this pathology. Icosapent ethyl (IPE) is a highly purified, stable ethyl ester of eicosapentaenoic acid (EPA) that was initially approved by the United States Food and Drug Administration to treat severe hypertriglyceridemia, and subsequently received an expanded indication to reduce the risk of CV events in adult statin-treated patients. Approval was based on the pivotal, randomized, placebo-controlled, double-blind Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), which showed that high-dose IPE (4 g/day) significantly reduced the risk of primary and secondary composite endpoints comprising major CV events and CV death relative to placebo. In 2021, the European Medicines Agency (EMA) approved IPE to reduce the risk of CV events in adult statin-treated patients at high CV risk with elevated triglyceride levels (≥1.7 mmol/L [≥150 mg/dL]) and established CV disease, or diabetes and at least one other CV risk factor. Clinical studies in Europe, which included patients with acute myocardial infarction, coronary artery disease, and those undergoing cardiac rehabilitation, established that 12.5% to 23.3% of these high-risk populations may benefit from treatment with IPE. Such clinical benefit may in part result from the moderate triglyceride-lowering properties of IPE/EPA; equally however, concentrations of atherogenic remnant particle-cholesterol are markedly reduced. Furthermore, IPE/EPA exerts pleiotropic actions beyond its lipid-lowering properties, which include modulation of endothelial function, attenuation of intra-plaque inflammation and oxidative stress, and reduction in macrophage accumulation. Plasma phospholipids, into which EPA is primarily incorporated and transported, appear to serve as precursors for a series of anti-inflammatory metabolites involving the resolvins RvE1 to RvE3, a pathway which may confer cardioprotective benefits. In addition, plaque imaging data from the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) and the Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography (CHERRY) trials show that plaque stabilization may be favorably affected. These factors may act synergistically to stabilize atherosclerotic plaques and reduce CV risk. In addition to robust efficacy data, multiple cost-utility studies across several countries indicate that IPE/EPA is a cost-effective treatment option that is favorably situated relative to some common willingness-to-pay thresholds. This review will evaluate the relevance of hypertriglyceridemia to residual ASCVD burden in statin-treated dyslipidemic patients, the potential of IPE/EPA to reduce the risk of ASCVD and cardiovascular mortality in high-risk patient populations, and the mechanisms which may underlie these effects. Finally, the clinical implications of the EMA label for IPE will be critically appraised in light of the updated 2019 European Society of Cardiology/European Atherosclerosis Society guidelines on the management of dyslipidemia and the recent European Atherosclerosis Society consensus statement on triglyceride-rich lipoproteins and their remnants, together with considerations of its cost-effectiveness across several countries.
Article
Objective Omega-3 supplements are widely used for cardiovascular (CV) protection. We performed an updated meta-analysis for omega-3 and CV outcomes. Methods Random-effects meta-analysis including double-blind RCTs with duration ≥ 1 year, evaluating omega-3 supplements in 4 a priori defined categories (<1, 1, 2, ≥3 of 1g capsules/day) on all-cause mortality, cardiac death, myocardial infarction and stroke, reporting the relative risk (RR) as the measure of interest. Complementary approaches were Trial Sequential Analysis (TSA) and sensitivity analyses for triglycerides, prevention setting, intention-to-treat analysis, eicosapentaenoic acid (EPA), sample size, statin use and study duration. Results Nineteen randomized controlled trials (RCTs) with 97,709 participants were included. Omega-3 supplements were not statistically significantly associated with reduced all-cause mortality, cardiac death, MI, or stroke, with the exception of reduced cardiac mortality only for the equivalent dose of 2 capsules/day (RR 0.55, 95%CI 0.33, 0.90, p=0.0169, I²=0%). TSA reached the required information size only for the lower doses regarding all-cause and cardiac mortality, where they show no significant association. Meta-regression on EPA dose, as well as the majority of sensitivity analyses did not show any statistically significant association. Conclusions Compared to the robust evidence for low doses, higher doses and particularly for the unique type of omega-3 icosapent ethyl ester should be further addressed.
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Background Heterogeneous progression of chronic kidney disease (CKD) toward dialysis advocates improving in renal care management. Diagnosis and staging of CKD relies on estimated glomerular filtration rate (eGFR) and albuminuria. Tubular biomarkers emerged as new predictors of worsening renal function (WRF), due to partial inaccuracy of eGFR and existing WRF in non-proteinuric patients. Active vitamin D is synthesized in renal tubules and participates to mineral adaptation in CKD. Circulating 1,25-dihydroxyvitamin D [1,25(OH) 2 D] was poorly investigated as a biomarker of endocrine tubular function and predictor of WRF. Objective Investigate capability of 1,25(OH) 2 D to predict parathormone (PTH) increase and WRF in CKD stage 3–4. Methods PASCaL-1,25D was an observational, prospective, monocentric study. Primary outcomes were absolute and 20% increase in PTH, and WRF defined as 20% reduction in eGFR or dialysis initiation at 6 months. Results Seventy-one patients completed follow up. Absolute increase in PTH (1–84) was independently predicted by lower 1,25(OH) 2 D levels ( p = 0.0134). No association was detected between 1,25(OH) 2 D and iPTH increase. Higher 1,25(OH) 2 D was associated with reduced risk of WRF at univariate analysis [OR 0.89 (95% CI 0.86–0.93), p = 0.006]. The 1,25(OH) 2 D/PTH (1–84) ratio was associated with non-significant 84% risk reduction for WRF [OR 0.16 (95% CI 0.06–0.41), p = 0.05]. Low 1,25(OH) 2 D reached 100% sensitivity in predicting WRF in CKD stage 3 (AUC 9.909, p < 0.0001) and non-elderly patients (AUC 0.883, p < 0.0001). Machine learning models retained 1,25(OH) 2 D/PTH (1–84) as relevant predictor of WRF together with eGFR and albuminuria. Age influenced interaction between renal and mineral biomarkers. Conclusion 1,25(OH) 2 D deserves attention as biomarker of tubular health, and sensible predictor of WRF on the short run among non-elderly patients affected by stage 3 CKD. The 1,25(OH) 2 D/PTH (1–84) ratio may represent a composite biomarker of tubular reserve/endocrine response to the transition from adaptive to maladaptive equilibrium in CKD-MBD.
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Advanced chronic kidney disease (CKD) frequently aggravates heart failure (HF). However, these patients have inherently been excluded from most HF trials. We aim to provide updated estimates of the representation of patients with advanced CKD and the provision of baseline renal function indices in HF trials with a focused interest on the landmark trials. Updated systematic review was performed from the inception of MEDLINE to 31 December 2019 to identify all chronic HF randomized trials published in the three major cardiology and medical journals, respectively, which included mortality endpoint. The included studies were analysed based on the representativeness of the advanced CKD population and the reporting of baseline renal function. A total of 187 eligible randomized trials with 322,374 participants were included in our analysis. One hundred and six trials (56.7%) had exclusion criteria related to renal function, which remained a continuing trend–55.1% (27/49) from inception-2000, 53.4% (39/73) from 2001–2010 and 61.5% (40/65) from 2011 (P = 0.64). The exclusion criteria, however, have become less restrictive. There was a temporal improvement in the likelihood of HF trials in providing baseline renal function indices (28.6% from inception-2000 versus 53.4% from 2001–2010 and 83.1% from 2011, P < 0.001). Concordant findings were observed in the landmark trials. Patients with advanced CKD remain underrepresented in HF trials in the contemporary era, even though the exclusion criteria have become less restrictive, and the quality of renal function monitoring has improved. The continued underrepresentation of patients with advanced CKD in HF trials merits measured broadening of eligibility in further trial studies.
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Background: Currently, with stroke burden increasing, there is a need to explore therapeutic options that ameliorate the acute insult. There is substantial evidence of a neuroprotective effect of marine-derived n-3 polyunsaturated fatty acids (PUFAs) in animal models of stroke, leading to a better functional outcome. Objectives: To assess the effects of administration of marine-derived n-3 PUFAs on functional outcomes and dependence in people with stroke. Search methods: We searched the Cochrane Stroke Trials Register (last searched 31 May 2021), the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 5), MEDLINE Ovid (from 1948 to 31 May 2021), Embase Ovid (from 1980 to 31 May 2021), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; from 1982 to 31 May 2021), Science Citation Index Expanded ‒ Web of Science (SCI-EXPANDED), Conference Proceedings Citation Index-Science - Web of Science (CPCI-S), and BIOSIS Citation Index. We also searched ongoing trial registers, reference lists, relevant systematic reviews, and used the Science Citation Index Reference Search. Selection criteria: We included randomised controlled trials (RCTs) comparing marine-derived n-3 PUFAs to placebo or open control (no placebo) in people with a history of stroke or transient ischaemic attack (TIA), or both. Data collection and analysis: At least two review authors independently selected trials for inclusion, extracted data, assessed risk of bias, and used the GRADE approach to assess the certainty of the body of evidence. We contacted study authors for clarification and additional information on stroke/TIA participants. We conducted random-effects meta-analysis or narrative synthesis, as appropriate. The primary outcome was efficacy (functional outcome) assessed using a validated scale, for example, the Glasgow Outcome Scale Extended (GOSE) dichotomised into poor or good clinical outcome, the Barthel Index (higher score is better; scale from 0 to 100), or the Rivermead Mobility Index (higher score is better; scale from 0 to 15). Our secondary outcomes were vascular-related death, recurrent events, incidence of other type of stroke, adverse events, quality of life, and mood. Main results: We included 30 RCTs; nine of them provided outcome data (3339 participants). Only one study included participants in the acute phase of stroke (haemorrhagic). Doses of marine-derived n-3 PUFAs ranged from 400 mg/day to 3300 mg/day. Risk of bias was generally low or unclear in most trials, with a higher risk of bias in smaller studies. We assessed results separately for short (up to three months) and longer (more than three months) follow-up studies. Short follow-up (up to three months) Functional outcome was reported in only one pilot study as poor clinical outcome assessed with the GOSE (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.36 to 1.68, P = 0.52; 40 participants; very low-certainty evidence). Mood (assessed with the GHQ-30, lower score better) was reported by only one study and favoured control (mean difference (MD) 1.41, 95% CI 0.07 to 2.75, P = 0.04; 102 participants; low-certainty evidence). We found no evidence of an effect of the intervention for the remainder of the secondary outcomes: vascular-related death (two studies, not pooled due to differences in population, RR 0.33, 95% CI 0.01 to 8.00, P = 0.50, and RR 0.33, 95% CI 0.01 to 7.72, P = 0.49; 142 participants; low-certainty evidence); recurrent events (RR 0.41, 95% CI 0.02 to 8.84, P = 0.57; 18 participants; very low-certainty evidence); incidence of other type of stroke (two studies, not pooled due to different type of index stroke, RR 6.11, 95% CI 0.33 to 111.71, P = 0.22, and RR 0.63, 95% CI 0.25 to 1.58, P = 0.32; 58 participants; very low-certainty evidence); and quality of life (physical component, MD -2.31, 95% CI -4.81 to 0.19, P = 0.07, and mental component, MD -2.16, 95% CI -5.91 to 1.59, P = 0.26; 1 study; 102 participants; low-certainty evidence). Adverse events were reported by two studies (57 participants; very low-certainty evidence), one trial reporting extracranial haemorrhage (RR 0.25, 95% CI 0.04 to 1.73, P = 0.16) and the other one reporting bleeding complications (RR 0.32, 95% CI 0.01 to 7.35, P = 0.47). Longer follow-up (more than three months) One small trial assessed functional outcome with both the Barthel Index for activities of daily living (MD 7.09, 95% CI -5.16 to 19.34, P = 0.26), and the Rivermead Mobility Index for mobility (MD 1.30, 95% CI -1.31 to 3.91, P = 0.33) (52 participants; very low-certainty evidence). We carried out meta-analysis for vascular-related death (RR 1.02, 95% CI 0.78 to 1.35, P = 0.86; 5 studies; 2237 participants; low-certainty evidence) and fatal recurrent events (RR 0.69, 95% CI 0.31 to 1.55, P = 0.37; 3 studies; 1819 participants; low-certainty evidence). We found no evidence of an effect of the intervention for mood (MD 1.00, 95% CI -2.07 to 4.07, P = 0.61; 1 study; 14 participants; low-certainty evidence). Incidence of other type of stroke and quality of life were not reported. Adverse events (all combined) were reported by only one study (RR 0.94, 95% CI 0.56 to 1.58, P = 0.82; 1455 participants; low-certainty evidence). Authors' conclusions: We are very uncertain of the effect of marine-derived n-3 PUFAs therapy on functional outcomes and dependence after stroke as there is insufficient high-certainty evidence. More well-designed RCTs are needed, specifically in acute stroke, to determine the efficacy and safety of the intervention. Studies assessing functional outcome might consider starting the intervention as early as possible after the event, as well as using standardised, clinically relevant measures for functional outcomes, such as the modified Rankin Scale. Optimal doses remain to be determined; delivery forms (type of lipid carriers) and mode of administration (ingestion or injection) also need further consideration.
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Many chronic inflammatory processes are linked with the continuous release of inflammatory mediators and the activation of harmful signal-transduction pathways that are able to facilitate disease progression. In this context atherosclerosis represents the most common pathological substrate of coronary heart disease, and the characterization of the disease as a chronic low-grade inflammatory condition is now validated. The biomarkers of inflammation associated with clinical cardiovascular risk support the theory that targeted anti-inflammatory treatment appears to be a promising strategy in reducing residual cardiovascular risk. Several literature data highlight cardioprotective effects of the long-chain omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA). This PUFA lowers plasma triglyceride levels and has potential beneficial effects on atherosclerotic plaques. Preclinical studies reported that EPA reduces both pro-inflammatory cytokines and chemokines levels. Clinical studies in patients with coronary artery disease that receive pharmacological statin therapy suggest that EPA may decrease plaque vulnerability preventing plaque progression. This review aims to provide an overview of the links between inflammation and cardiovascular risk factors, importantly focusing on the role of diet, in particular examining the proposed role of EPA as well as the success or failure of standard pharmacological therapy for cardiovascular diseases.
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Nutrition occupies one of the important places in the programs of prevention and non-drug therapy of CHF and associated diseases. At the same time, the validity of dietary recommendations to patients regarding salt intake, dietary habits and the use of individual nutraceuticals is questionable. The purpose of this review is to present up-to-date data of clinical and experimental studies concerning sodium restriction, the use of various diets, nutraceuticals, and means for correcting intestinal dysbiosis in CHF. Materials and methods : the articles are searched in the databases eLibraryRU and Medline by key terms and their combinations: “heart failure”, “diet”, “sodium restriction”, “nutraceuticals”, “nutrition”, “cardiac cachexia”, “nutritional support”, “salt”, “dietary supplement”, “probiotic”, “prebiotic”, “enteral nutrition” in Russian and English. We select articles containing the results of clinical and experimental studies published from 1997 to 2021. The research data indicate that the pathogenesis of anorexia, malnutrition and “metabolic remodeling” of the myocardium in CHF is based on complex mechanisms determined by stagnant phenomena in the liver, impaired permeability of the edematous intestinal wall, dysbiosis and chronic systemic infl ammation. The recommendations on the consumption of sodium from 2 to 2.5 g/day and table salt from 5 to 6 g/day in patients with CHF are justified. Limitation of fluid intake is relevant only for decompensation of CHF. The use of the Mediterranean and antihypertensive (DASH) diets is recognized by most authors as a promising direction for the prevention and treatment of CHF. The enrichment of the diet of patients with CHF with ω-3 polyunsaturated fatty acids, coenzyme Q10, dietary fibers, polyphenols and saponins is justified. The benefits of enteral nutrition and the complex use of nutraceuticals in order to slow the progression of weight loss, reduce the severity of neurohormonal and pro-inflammatory shifts are shown. Promising trends of research are the creation of personalized diets taking into account the peculiarities of the course of CHF, the nutritional status, the composition of the intestinal microbiota and its metabolites.
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Fish oil is rich in unsaturated fatty acids, i.e., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both of which are widely distributed in the body such as heart and brain. In vivo and in vitro experiments showed that unsaturated fatty acids may have effects of anti-inflammation, anti-oxidation, protecting vascular endothelial cells, thrombosis inhibition, modifying autonomic nerve function, improving left ventricular remodeling, and regulating blood lipid. Given the relevance to public health, there has been increasing interest in the research of potential cardioprotective effects of fish oil. Accumulated evidence showed that fish oil supplementation may reduce the risk of cardiovascular events, and, in specific, it may have potential benefits in improving the prognosis of patients with hypertension, coronary heart disease, cardiac arrhythmias, or heart failure; however, some studies yielded inconsistent results. In this article, we performed an updated systematical review in order to provide a contemporary understanding with regard to the effects of fish oil on cardiovascular diseases.
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Sudden cardiac death (SCD) can be called one of the most important issues of modern cardiology for it is the first and the last sign of heart trouble in 25 % people and occurs in 60 % patients suffering from cardiovascular diseases. Interest to the problem is caused also by the fact that the SCD prevalence tends to increase. Obviously there are ways to take effective measures of prevention aimed at the improvement of the situation. The literature review presents analysis of publications containing topical information about mechanisms and reasons, risk factors and predictors for SCD and covers ways to treat and prevent the disease.
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Animal nutrition plays an important role in the therapy of many diseases, including heart failure. The aim was to assess whether 6 months of feeding an AEP + ADH enriched diet (from fish meat) in dogs suffering from heart failure due to mitral degeneration impacts the dogs’ metabolic profile and clinical status. Twenty small breed dogs were included: 50% were in stage B2 of MMVD and 50%, in stage C according to ACVIM. Dogs were randomly divided into two groups. One group receiving a standard diet, the second one a diet enriched with EPA + DHA (from fish meat). All dogs continued to receive appropriate therapy throughout the study. Control examinations were performed at the start of the study, after 3 and 6 months of appropriate feeding. Examinations included ECG, ECHO, blood hemathology and biochemistry, morphometric measurements, body fat index and subcutaneous fat tissue thickness. Serum samples were analyzed with a high-performance liquid chromatography system. Data were analyzed using the Progenesis QI (PQI, Non-linear Dynamics). The results showed no differences in clinical, cardiological, haematological and biochemical parameters between the two study groups. An effect on the metabolomic profile following a continued diet enriched in DHA + EPA (from fish meat) was more pronounced with time. After 6 months of feeding the diete enriched with DHA + EPA (from fish meat), there was a favorable reduction in glycerophosphocholine and xanthine levels, but an adverse increase in lactate and furvan and a decrease in alanine was not stopped.
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Background The long noncoding RNA LIPCAR (Long Intergenic noncoding RNA Predicting CARdiac remodeling) has emerged as a promising biomarker in cardiac disease and cardiac remodeling. To determine whether LIPCAR levels help for a molecular phenotyping of chronic heart failure (HF) patients, this study assessed the association of LIPCAR with severity of the disease and its progression, and with risk of death or hospitalization in HF patients. Methods LIPCAR was measured in plasma of 967 HF patients with symptomatic heart failure participating in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca - Heart Failure (GISSI-HF) biohumoral sub-study. Results Plasma levels of LIPCAR were significantly associated with functional impairment as assessed by the New York Heart Association (NYHA) class, kidney function as reflected by estimated glomerular filtration rate, and creatinine, hemoglobin and mitral insufficiency. In females, these associations were more marked as compared to males. LIPCAR plasma levels were significantly related to the two cardiac markers, N-terminal pro-B type natriuretic peptide and high-sensitivity cardiac troponin T, but not to inflammatory markers such as high sensitivity C-reactive protein and pentraxin-3, nor to patient reported outcomes such as depression and quality of life. HF patients with high LIPCAR levels univariately showed significantly higher incidence of cardiovascular hospitalizations but not of death; after adjusting for covariates, no significant effects of LIPCAR were found for cardiovascular hospitalizations. Conclusion The circulating long noncoding RNA LIPCAR was increased in HF patients with higher NYHA class, impaired kidney function, and lower hemoglobin, which are indicators of patients’ overall state.
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The review is devoted to the use of lipid-lowering drugs in certain categories of patients, including patients with acute coronary syndrome, stroke, chronic heart failure, valvular heart disease, atherosclerosis of the central and peripheral arteries, chronic kidney disease, as well as those who will undergo percutaneous coronary intervention. It is noted that in all patients with acute coronary syndrome without contraindications or intolerance it is recommended that high doses statin therapy is initiated or continued as early as possible, regardless of initial values of low-density lipoprotein cholesterol. If the target level of low-density lipoproteins is not achieved after 4-6 weeks with the maximally tolerated statin dose, combination with ezetimibe is recommended, and if this combination is not effective enough, the addition of a proprotein convertase subtilisin/kexin type 9 inhibitors is recommended. The strategy of short pre-treatment or loading (in the case of prior therapy) with high doses of statins should be considered for planned percutaneous coronary intervention or acute coronary syndrome without ST segment elevation. Initiation of lipid-lowering therapy is not recommended in patients with heart failure in the absence of other indications for their use. Lipid-lowering treatments reduce the incidence of stroke in patients enrolled on the basis of carotid atherosclerotic disease. The management of dyslipidaemias in transplant recipients is comparable to what is recommended for patients at high or very high risk of atherosclerotic cardiovascular disease, although more attention is needed regarding the causes of the lipid disturbances and possible side effects due to drug-drug interactions.
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We aimed to investigate the causal effects of n-3 and n-6 polyunsaturated fatty acids (PUFAs) on the risk of coronary artery disease (CAD) through Mendelian randomization (MR) analysis. This MR study utilized a genetic instrument developed from previous genome-wide association studies for various serum n-3 and n-6 PUFA levels. First, we calculated the allele scores for genetic predisposition of PUFAs in individuals of European ancestry in the UK Biobank data (N = 337,129). The allele score-based MR was obtained by regressing the allele scores to CAD risks. Second, summary-level MR was performed with the CARDIoGRAMplusC4D data for CAD (N = 184,305). Higher genetically predicted eicosapentaenoic acid and dihomo-gamma-linolenic acid levels were significantly associated with a lower risk of CAD both in the allele-score-based and summary-level MR analyses. Higher allele scores for linoleic acid level were significantly associated with lower CAD risks, and in the summary-level MR, the causal estimates by the pleiotropy-robust MR methods also indicated that higher linoleic acid levels cause a lower risk of CAD. Arachidonic acid showed significant causal estimates for a higher risk of CAD. This study supports the causal effects of certain n-3 and n-6 PUFA types on the risk of CAD.
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The hemodynamic effects of highly purified eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) have not been evaluated in humans. We therefore conducted a randomized, double-blind, parallel-design intervention study to assess possible separate effects of EPA and DHA on blood pressure, heart rate, and cardiac mechanics. Healthy, nonsmoking men aged 36-56 y (n = 224) were randomly assigned to dietary supplementation with 4 g/d of ethyl ester concentrates of DHA or EPA or 4 g corn oil/d (control). Mean blood pressure at baseline was 122/77 mm Hg and was positively associated with concentrations of serum phospholipid saturated fatty acids. Blood pressure did not change during the intervention. Mean heart rate at baseline was 63.4 beats/min; it decreased 2.2 beats/min in the DHA group (P = 0.006 compared with control), increased 1.9 beats/min in the EPA group (P = 0.04 compared with control), and remained practically unchanged in the control group. In a pooled analysis, changes in heart rate were independent of baseline heart rate and were associated with changes in concentrations of serum phospholipid DHA and docosapentaenoic acid (22:5n-3). Echocardiography in a subsample of 52 men showed improved left ventricular diastolic filling in the marine oil groups compared with the corn oil group (P = 0.02). In contrast, an increase in plasma concentrations of saturated fatty acids was associated with delayed diastolic filling. We conclude that dietary DHA and EPA influence heart rate and that the fatty acid composition of plasma phospholipids may affect cardiac mechanics in humans.
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Sudden death from cardiac causes remains a leading cause of death among patients with congestive heart failure (CHF). Treatment with amiodarone or an implantable cardioverter-defibrillator (ICD) has been proposed to improve the prognosis in such patients. We randomly assigned 2521 patients with New York Heart Association (NYHA) class II or III CHF and a left ventricular ejection fraction (LVEF) of 35 percent or less to conventional therapy for CHF plus placebo (847 patients), conventional therapy plus amiodarone (845 patients), or conventional therapy plus a conservatively programmed, shock-only, single-lead ICD (829 patients). Placebo and amiodarone were administered in a double-blind fashion. The primary end point was death from any cause. The median LVEF in patients was 25 percent; 70 percent were in NYHA class II, and 30 percent were in class III CHF. The cause of CHF was ischemic in 52 percent and nonischemic in 48 percent. The median follow-up was 45.5 months. There were 244 deaths (29 percent) in the placebo group, 240 (28 percent) in the amiodarone group, and 182 (22 percent) in the ICD group. As compared with placebo, amiodarone was associated with a similar risk of death (hazard ratio, 1.06; 97.5 percent confidence interval, 0.86 to 1.30; P=0.53) and ICD therapy was associated with a decreased risk of death of 23 percent (0.77; 97.5 percent confidence interval, 0.62 to 0.96; P=0.007) and an absolute decrease in mortality of 7.2 percentage points after five years in the overall population. Results did not vary according to either ischemic or nonischemic causes of CHF, but they did vary according to the NYHA class. In patients with NYHA class II or III CHF and LVEF of 35 percent or less, amiodarone has no favorable effect on survival, whereas single-lead, shock-only ICD therapy reduces overall mortality by 23 percent.
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The purpose of this paper is twofold: on the one hand, to confirm the positive results on n-3 PUFA from the overall results Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GlSSI)-Prevenzione trial; on the other, to summarize and describe how the results of an important trial can help generate hypotheses either on mechanisms of action or on differential results in particular subgroups of patients, as well as test the pathophysiological hypotheses that have accompanied in the years the story of the hypothesized mechanisms of action of a drug. GISSI-Prevenzione was conceived as a pragmatic population trial on patients with recent myocardial infarction and it was conducted in the framework of the Italian public health system. In GISSI-Prevenzione, 11,323 patients were enrolled in a clinical trial aimed at testing the effectiveness of n-3 polyunsaturated fatty acids (PUFA) and vitamin E. Patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term n-3 PUFA at 1 g daily, but not vitamin E at 300 mg daily, was beneficial for death and for combined death, non-fatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall (-20%), cardiovascular (-30%), and sudden death (-45%). At variance from the orientation of a scientific scenario largely dominated by the "cholesterol-heart hypothesis", GISSI-Prevenzione results indicate n-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction.
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Very-long-chain n-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish are thought to reduce risk of sudden death, possibly by reducing susceptibility to cardiac arrhythmia. To study the effect of supplemental fish oil vs placebo on ventricular tachyarrhythmia or death. The Study on Omega-3 Fatty acids and ventricular Arrhythmia (SOFA) was a randomized, parallel, placebo-controlled, double-blind trial conducted at 26 cardiology clinics across Europe. A total of 546 patients with implantable cardioverter-defibrillators (ICDs) and prior documented malignant ventricular tachycardia (VT) or ventricular fibrillation (VF) were enrolled between October 2001 and August 2004. Patients were randomly assigned to receive 2 g/d of fish oil (n = 273) or placebo (n = 273) for a median period of 356 days (range, 14-379 days). Appropriate ICD intervention for VT or VF, or all-cause death. The primary end point occurred in 81 (30%) patients taking fish oil vs 90 (33%) patients taking placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.64-1.16; P = .33). In prespecified subgroup analyses, the HR was 0.91 (95% CI, 0.66-1.26) for fish oil vs placebo in the 411 patients who had experienced VT in the year before the study, and 0.76 (95% CI, 0.52-1.11) for 332 patients with prior myocardial infarctions. Our findings do not indicate evidence of a strong protective effect of intake of omega-3 PUFAs from fish oil against ventricular arrhythmia in patients with ICDs. clinicaltrials.gov Identifier: NCT00110838.
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Studies on the relation between dietary n-3 fatty acids (FAs) and cardiovascular disease vary in quality, and the results are inconsistent. A systematic review of the literature on the effects of n-3 FAs (consumed as fish or fish oils rich in eicosapentaenoic acid and docosahexaenoic acid or as alpha-linolenic acid) on cardiovascular disease outcomes and adverse events was conducted. Studies from MEDLINE and other sources that were of > or =1 y in duration and that reported estimates of fish or n-3 FA intakes and cardiovascular disease outcomes were included. Secondary prevention was addressed in 14 randomized controlled trials (RCTs) of fish-oil supplements or of diets high in n-3 FAs and in 1 prospective cohort study. Most trials reported that fish oil significantly reduced all-cause mortality, myocardial infarction, cardiac and sudden death, or stroke. Primary prevention of cardiovascular disease was reported in 1 RCT, in 25 prospective cohort studies, and in 7 case-control studies. No significant effect on overall deaths was reported in 3 RCTs that evaluated the effects of fish oil in patients with implantable cardioverter defibrillators. Most cohort studies reported that fish consumption was associated with lower rates of all-cause mortality and adverse cardiac outcomes. The effects on stroke were inconsistent. Evidence suggests that increased consumption of n-3 FAs from fish or fish-oil supplements, but not of alpha-linolenic acid, reduces the rates of all-cause mortality, cardiac and sudden death, and possibly stroke. The evidence for the benefits of fish oil is stronger in secondary- than in primary-prevention settings. Adverse effects appear to be minor.
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The worldwide diversity of dietary intakes of n-6 and n-3 fatty acids influences tissue compositions of n-3 long-chain fatty acids (LCFAs: eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids) and risks of cardiovascular and mental illnesses. We aimed to estimate healthy dietary allowances for n-3 LCFAs that would meet the nutrient requirements of 97-98% of the population. Deficiency in n-3 LCFAs was defined as attributable risk from 13 morbidity and mortality outcomes, including all causes, coronary heart disease, stroke, cardiovascular disease, homicide, bipolar disorder, and major and postpartum depressions. Dietary availability of n-3 LCFAs from commodities for 38 countries and tissue composition data were correlated by best fit to each illness in deficiency risk models. The potential attributable burden of disease ranged from 20.8% (all-cause mortality in men) to 99.9% (bipolar disorder). n-3 LCFA intake for Japan (0.37% of energy, or 750 mg/d) met criteria for uniformly protecting >98% of the populations worldwide. n-3 LCFA intakes needed to meet a tissue target representative of Japan (60% n-3 in LCFA) ranged from 278 mg/d (Philippines, with intakes of 0.8% of energy as linoleate, 0.08% of energy as alpha-linolenate, and 0.06% of energy as arachidonic acid) to 3667 mg/d (United States, with 8.91% of energy as linoleate, 1.06% of energy as alpha-linolenate, and 0.08% of energy as arachidonic acid). With caveats inherent for ecologic, nutrient disappearance analyses, a healthy dietary allowance for n-3 LCFAs for current US diets was estimated at 3.5 g/d for a 2000-kcal diet. This allowance for n-3 LCFAs can likely be reduced to one-tenth of that amount by consuming fewer n-6 fats.
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Cardiac electric activity is strongly modulated by its environment. Factors modulating this activity include the metabolic state of the myocyte, the availability of oxygen and energy substrates (including plasma fatty acids and glucose), mechanical forces, autonomic tone, and the lipid composition of the cell membrane. Ion channels, exchangers, and pumps act as macromolecular complexes and are regulated by phosphorylation, prenylation, and numerous other signaling pathways. Contemporary changes in diet (including increased caloric content, increased consumption of glucose and omega-6 fatty acids, decreased consumption of omega-3 fatty acids) and an overall decrease in exercise and activity have contributed to an increased incidence of obesity and diabetes in the adult and pediatric population. These trends, in turn, have led to an increased incidence of cardiovascular diseases including atherosclerosis, AF, and congestive heart failure, each of which is associated with increased risk of mortality. SCD due to arrhythmias is a primary cause of increased mortality. Efforts to better understand the links between diet and cardiac rhythm have the potential to improve public health and welfare and to reduce the ballooning costs associated with treating cardiovascular disease. That omega-3 fatty acids have an impact on the fundamental elements (ion channels, exchangers, and modulators) of cardiac electric activity is now indisputable. However, the translation of this understanding into evidence-based public policy guidelines that can decrease the incidence of arrhythmias and SCD still requires significant additional efforts. In this review we have identified a number of concrete areas for investigation that will help to provide some of the information that is required to best meet this goal.
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Patients with systolic heart failure have generally been excluded from statin trials. Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients. A total of 5011 patients at least 60 years of age with New York Heart Association class II, III, or IV ischemic, systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per day. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included death from any cause, any coronary event, death from cardiovascular causes, and the number of hospitalizations. As compared with the placebo group, patients in the rosuvastatin group had decreased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P<0.001) and of high-sensitivity C-reactive protein (difference between groups, 37.1%; P<0.001). During a median follow-up of 32.8 months, the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.83 to 1.02; P=0.12), and 728 patients and 759 patients, respectively, died (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.31). There were no significant differences between the two groups in the coronary outcome or death from cardiovascular causes. In a prespecified secondary analysis, there were fewer hospitalizations for cardiovascular causes in the rosuvastatin group (2193) than in the placebo group (2564) (P<0.001). No excessive episodes of muscle-related or other adverse events occurred in the rosuvastatin group. Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. The drug did not cause safety problems. (ClinicalTrials.gov number, NCT00206310.)
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A recent Cochrane meta-analysis did not confirm the benefits of fish and fish oil in the secondary prevention of cardiac death and myocardial infarction. We performed a meta-analysis of randomized controlled trials that examined the effect of fish-oil supplementation on ventricular fibrillation and ventricular tachycardia to determine the overall effect and to assess whether heterogeneity exists between trials. We searched electronic databases (MEDLINE, EMBASE, The Cochrane Central Register of Controlled Trials, CINAHL) from inception to May 2007. We included randomized controlled trials of fish-oil supplementation on ventricular fibrillation or ventricular tachycardia in patients with implantable cardioverter defibrillators. The primary outcome was implantable cardioverter defibrillator discharge. We calculated relative risk [RR] for outcomes at 1-year follow-up for each study. We used the DerSimonian and Laird random-effects methods when there was significant heterogeneity between trials and the Mantel-Hanzel fixed-effects method when heterogeneity was negligible. We identified 3 trials of 1-2 years' duration. These trials included a total of 573 patients who received fish oil and 575 patients who received a control. Meta-analysis of data collected at 1 year showed no overall effect of fish oil on the relative risk of implantable cardioverter defibrillator discharge. There was significant heterogeneity between trials. The second largest study showed a significant benefit of fish oil (relative risk [RR] 0.74, 95% confidence interval [CI] 0.56-0.98). The smallest showed an adverse tendency at 1 year (RR 1.23, 95% CI 0.92-1.65) and significantly worse outcome at 2 years among patients with ventricular tachycardia at study entry (log rank p = 0.007). These data indicate that there is heterogeneity in the response of patients to fish-oil supplementation. Caution should be used when prescribing fish-oil supplementation for patients with ventricular tachycardia.
Article
Background There is conflicting evidence on the benefits of foods rich in vitamin E (alpha-tocopherol), n-3 polyunsaturated fatty acids (PUFA), and their pharmacological substitutes. We investigated the effects of these substances as supplements in patients who had myocardial infarction. Methods From October, 1993, to September, 1995, 11324 patients surviving recent (less than or equal to 3 months) myocardial infarction were randomly assigned supplements of n-3 PUFA (Ig daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3.5 years. The primary combined efficacy endpoint was death, non-fatal myocardial infarction, and stroke. Intention-to-treat analyses were done according to a factorial design (two-way) and by treatment group (four-way). Findings Treatment with n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary endpoint (relative risk decrease 10% [95% CI 1-18] by two-way analysis, 15% [2-26] by four-way analysis). Benefit was attributable to a decrease in the risk of death (14% [3-24] two-way, 20% [6-33] four-way) and cardiovascular death (17% [3-29] two-way, 30% [13-44] four-way). The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint (14% [1-26]) and for fatal events (20% [5-33]). Interpretation Dietary supplementation with n-3 PUFA led to a clinically important and satistically significant benefit. Vitamin E had no benefit. Its effects on fatal cardiovascular events require further exploration.
Article
GISSI-Prevenzione was conceived as a population, pragmatic trial on patients with recent myocardial infarction conducted in the framework of the Italian public health system. In GISSI-Prevenzione, patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term n-3 PUFA 1 g daily, but not vitamin E 300 mg daily, was beneficial for death and for combined death, non-fatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall, cardiovascular, cardiac, coronary, and sudden death. At variance from the orientation of a scientific scenario largely dominated by the ‘cholesterol-heart hypothesis’, GISSI-Prevenzione results indicate n-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction. As to the relevance and comparability of GISSI-Prevenzione results, up to 5·7 lives could be saved per 1000 patients with previous myocardial infarction treated with n-3 PUFA (1 g daily) per year. Such a result is comparable to that observed in the LIPID trial, where 5·2 lives could be saved per 1000 hypercholaesterolemic, CHD patients treated with pravastatin for 1 year. The choice in favour of a relatively low-dose regimen (1 g capsule daily) more acceptable for long-term treatment in a population of patients following Mediterranean dietary habits, the pattern of effects seen in GISSI-Prevenzione (namely, reduction of overall mortality with no decrease in the rate of non-fatal myocardial infarction), all suggest that it can confidently be said that n-3 PUFA treatment should be considered a recommended new component of secondary prevention. The importance of this combined/additive effect is further suggested by the preliminary analyses (to be submitted in the final form for publication) of the interplay between diet and n-3 PUFA: there is an interesting direct correlation between size of the effect and ‘correctness’ of background diets. It can be anticipated that a conceptual barrier must be overcome: a ‘dietary drug’ should be added to ‘dietary advice’, which remains fundamental to allow this statement to become true in clinical practice.
Article
The effects of dietary supplementation with marine oils on vascular reactivity in human forearm resistance arteries were studied. Healthy male adults (six to nine subjects per group) were given either maxEPA capsules (content: eicosapentaenoic acid, 0.178 g/g; docosahexaenoic acid, 0.116 g/g) at doses of 20, 10, or 5 g/day or placebo capsules at 20 g/day for 28 days. Capsule compliance was confirmed by measurement of platelet membrane incorporation of n-3 fatty acids. Blood pressure was not affected by either maxEPA or placebo. The influence of treatment interventions on forearm vasoconstrictive responses to local infusions of angiotensin II and norepinephrine was examined using venous occlusion plethysmography before and after treatment. Responses to both agonists were significantly suppressed by 20 g/day maxEPA (slopes before and after maxEPA, respectively: angiotensin II, 3.34 and 0.89; norepinephrine, 0.91 and 0.41). When analyzed as difference in area under the dose-response curves, the suppressive effects of maxEPA were clearly dose dependent (angiotensin II: 20 g area reduced by 72%, 10 g by 67%, 5 g by 33%). Similarly, responses to norepinephrine were dose-dependently suppressed by maxEPA (20 g area reduced by 61%, 10 g by 63%, and 5 g by 33%). Placebo had no effect on the responses to either constrictor. The responses to both agonists returned to preoil levels after 2 months' discontinuation of 20 g/day maxEPA. We conclude that the suppressive effects of marine oils on vascular reactivity may, in part, contribute to their cardioprotective influence in humans.
Article
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. 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. 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.
Article
Regular fish consumption is associated with low cardiovascular disease morbidity and mortality. Fish oils modify cardiac membrane phospholipid fatty acid composition with potent antiarrhythmic effects. We tested the effects of dietary fish oil on ventricular hemodynamics and myocardial oxygen consumption (MVO2). Male Wistar rats were fed for 16 weeks on a reference diet rich in n-6 polyunsaturated fatty acids (PUFA), a diet rich in saturated animal fat (SAT), or a diet rich in n-3 PUFA from fish oil. Isolated working hearts were perfused with porcine erythrocytes (40% hematocrit) at 75 mm Hg afterload with variable preload (5 to 20 mm Hg) or with low coronary flow ischemia with maintained afterload, preload, and heart rate, then reperfused. MVO2 was low and coronary perfusion reserve high in n-3 PUFA hearts, and cardiac output increased with workload. The n-3 PUFA reduced ischemic markers-acidosis, K+, lactate, and creatine kinase-and increased contractile recovery during reperfusion. SAT hearts had high MVO2, low coronary perfusion reserve, and poor contractile function and recovery. Dietary differences in MVO2 were abolished by KCl arrest (basal metabolism) or ruthenium red (3.4 micromol/L) but not by ryanodine (1 nmol/L). Fish oil or ryanodine, but not ruthenium red, prevented ventricular fibrillation in reperfusion. Dietary fish oil directly influenced heart function and improved cardiac responses to ischemia and reperfusion. The n-3 PUFA reduced oxygen consumption at any given work output and increased postischemic recovery. Thus, direct effects on myocardial function may contribute to the altered cardiovascular disease profile associated with fish consumption.
Article
Patients with chronic heart failure (CHF) are at high risk of cardiovascular death and recurrent hospital admissions. We aimed to find out whether the use of an angiotensin-receptor blocker could reduce mortality and morbidity. In parallel, randomised, double-blind, controlled, clinical trials we compared candesartan with placebo in three distinct populations. We studied patients with left-ventricular ejection fraction (LVEF) 40% or less who were not receiving angiotensin-converting-enzyme inhibitors because of previous intolerance or who were currently receiving angiotensin-converting-enzyme inhibitors, and patients with LVEF higher than 40%. Overall, 7601 patients (7599 with data) were randomly assigned candesartan (n=3803, titrated to 32 mg once daily) or matching placebo (n=3796), and followed up for at least 2 years. The primary outcome of the overall programme was all-cause mortality, and for all the component trials was cardiovascular death or hospital admission for CHF. Analysis was by intention to treat. Median follow-up was 37.7 months. 886 (23%) patients in the candesartan and 945 (25%) in the placebo group died (unadjusted hazard ratio 0.91 [95% CI 0.83-1.00], p=0.055; covariate adjusted 0.90 [0.82-0.99], p=0.032), with fewer cardiovascular deaths (691 [18%] vs 769 [20%], unadjusted 0.88 [0.79-0.97], p=0.012; covariate adjusted 0.87 [0.78-0.96], p=0.006) and hospital admissions for CHF (757 [20%] vs 918 [24%], p<0.0001) in the candesartan group. There was no significant heterogeneity for candesartan results across the component trials. More patients discontinued candesartan than placebo because of concerns about renal function, hypotension, and hyperkalaemia. Candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for heart failure. Ejection fraction or treatment at baseline did not alter these effects.
Article
Although previous data suggested that only doses of 4 g/day or higher of n-3 polyunsaturated fatty acids (PUFA) have had a beneficial effect in the prevention of atherosclerosis and cardiovascular diseases, the GISSI-Prevenzione Study in a 3-year trial showed that 1 g/day reduced total and cardiovascular mortality in over 11,000 post-infarction patients. The aim of this study was to investigate the time course and the extent of incorporation of n-3 fatty acids in plasma and blood cells after 1 g/day of n-3 PUFA, the dose effective in the GISSI-Prevenzione in comparison with higher doses. Thirty-six healthy volunteers were given 1, 2 and 4 g/day of n-3 PUFA ethyl esters for 12 weeks, followed by a 4-week washout. Blood was collected at weeks 0, 1, 2, 4, 8, 12 and 16 and used for lipid profile analysis and measurement of fatty acid composition in plasma phospholipids, platelets and mononucleates. Total n-3 PUFA increased by 2.0-, 2.2- and 2.9-fold versus baseline after 12-week treatment with 1, 2 and 4 g respectively. A statistically significant raise of total n-3 PUFA was seen in platelets and mononucleates. Among individual n-3 PUFA, 22:5 n-3 was enriched early and dose dependently in plasma phospholipids, platelets and mononucleates; the raise of 22:6 n-3 was less marked especially in platelets and mononucleates. One gram per day of n-3 PUFA induces fast (within 1 week) and striking changes in blood composition of PUFA that may well explain their beneficial effects against cardiovascular diseases.
Article
Results from observational studies on fish consumption and risk of stroke are inconsistent. We quantitatively assessed the relationship between fish intake and incidence of stroke using a meta-analysis of cohort studies. We searched the Medline and Embase databases (1966 through October 2003) and identified 9 independent cohorts (from 8 studies) that provided a relative risk (RR) and corresponding 95% CI for total or any type of stroke in relation to fish consumption. Pooled RR and 95% CI of stroke were estimated by variance-based meta-analysis. Compared with those who never consumed fish or ate fish less than once per month, the pooled RRs for total stroke were 0.91 (95% CI, 0.79 to 1.06) for individuals with fish intake 1 to 3 times per month, 0.87 (95% CI, 0.77 to 0.98) for once per week, 0.82 (95% CI, 0.72 to 0.94) for 2 to 4 times per week, and 0.69 (95% CI, 0.54 to 0.88) for > or =5 times per week (P for trend=0.06). In stratified analyses of 3 large cohort studies with data on stroke subtypes, the pooled RRs across 5 categories of fish intake were 1.0, 0.69 (95% CI, 0.48 to 0.99), 0.68 (95% CI, 0.52 to 0.88), 0.66 (95% CI, 0.51 to 0.87), and 0.65 (95% CI, 0.46 to 0.93) for ischemic stroke (P for trend=0.24); and 1.0, 1.47 (95% CI, 0.81 to 2.69), 1.21 (95% CI, 0.78 to 1.85), 0.89 (95% CI, 0.56 to 1.40), and 0.80 (95% CI, 0.44 to 1.47) for hemorrhagic stroke (P for trend=0.31). These results suggest that intake of fish is inversely related to risk of stroke, particularly ischemic stroke. Fish consumption as seldom as 1 to 3 times per month may protect against the incidence of ischemic stroke.
Article
Results from observational studies on fish consumption and coronary heart disease (CHD) mortality are inconsistent. A meta-analysis of cohort studies was conducted to examine the association between fish intake and CHD mortality. Studies were included if they provided a relative risk (RR) and corresponding 95% CI for CHD mortality in relation to fish consumption and the frequency of fish intake. A database was developed on the basis of 11 eligible studies and 13 cohorts, including 222 364 individuals with an average 11.8 years of follow-up. Pooled RR and 95% CI for CHD mortality were calculated by using both fixed-effect and random-effect models. A linear regression analysis of the log RR weighted by the inverse of variance was performed to assess the possible dose-response relation. Compared with those who never consumed fish or ate fish less than once per month, individuals with a higher intake of fish had lower CHD mortality. The pooled multivariate RRs for CHD mortality were 0.89 (95% CI, 0.79 to 1.01) for fish intake 1 to 3 times per month, 0.85 (95% CI, 0.76 to 0.96) for once per week, 0.77 (95% CI, 0.66 to 0.89) for 2 to 4 times per week, and 0.62 (95% CI, 0.46 to 0.82) for 5 or more times per week. Each 20-g/d increase in fish intake was related to a 7% lower risk of CHD mortality (P for trend=0.03). These results indicate that fish consumption is inversely associated with fatal CHD. Mortality from CHD may be reduced by eating fish once per week or more.
Article
The GISSI Heart Failure project is a large-scale, randomized, double-blind study designed to investigate the effects of n-3 polyunsaturated fatty acids and rosuvastatin on mortality and morbidity in patients with symptomatic heart failure. Patients with New York Heart Association classes II to IV heart failure, already receiving optimized recommended therapy, will be recruited in a nation-wide network of more than 300 cardiology and internal medicine services to be randomly allocated to treatment with n-3 polyunsaturated fatty acids (1 g daily) or the corresponding placebo. Patients with no clear indication or contraindication to cholesterol-lowering therapy will be further randomized to receive low-dose rosuvastatin (10 mg daily) or placebo. According to data available in heart failure registries, it is expected that 70% of the patients will be suitable to enter both components of the trial, which assume the same co-primary endpoints: (a) 15% reduction of all-cause mortality and (b) 20% reduction of all-cause mortality or cardiovascular hospitalizations. The trial is event-driven and will continue either until at least 1252 deaths have been recorded or a reduction of all-cause mortality will satisfy the significance boundaries, which have been established to stop the study. The recruitment of the planned sample size of approximately 7000 patients randomized in the n-3 PUFA trial is expected to be completed within 18 months from the trial start. As of February 29, 2004, 4624 heart failure patients have been included in the trial. The GISSI-HF project, with its protocol articulated into two independent randomization schemes, has the aim and the power to verify the hypothesis that n-3 polyunsaturated fatty acids and rosuvastatin can favorably modify the prognosis of patients with symptomatic heart failure.
Article
Approximately 20 years ago, the Italian cardiology community realized the scientific importance and the potential impact on clinical practice of the new concept of evidence-based medicine and launched (without funds) a national megatrial, the Gruppo Italiano por lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) study. In the following 20 years, 4 GISSI trials have been carried out, and a fifth is underway. The conceptual process that followed this experience shaped the role of the medico-scientific society that sponsored these trials as an active player in research, with the public health as the common target. This process of getting together was founded on the basic principle that active participation can be much more effective and rewarding than education (a passive process). Accordingly, further studies were undertaken dealing with clinical epidemiology, observational outcome research introduced complementarily to develop lines of clinical investigation along 2 mainstreams: ischemic heart disease and heart failure. The original decision to directly sponsor countrywide research projects in critical and relevant areas of care had broader implications not only for the role of scientific societies, but more generally for the nurture of independent research, which is today widely recognized to be at risk. The articulation among experimental, observational, and evaluative protocols in which all caring physicians are allowed to be producers and authors and not simply users of knowledge can favor a cultural continuity that minimizes the risk of parallelisms and gaps between research and care.
Article
Our aim was to investigate the relation between fish consumption and incidence of congestive heart failure (CHF). The incidence and health burden of CHF are rising, particularly in older persons. Although n-3 fatty acids have effects that could favorably influence risk of CHF, the relation between fish intake and CHF incidence is unknown. Among 4,738 adults age > or =65 years and free of CHF at baseline in 1989-90, usual dietary intake was assessed using a food frequency questionnaire. In a participant subsample, consumption of tuna or other broiled or baked fish, but not fried fish, correlated with plasma phospholipid n-3 fatty acids. Incidence of CHF was prospectively adjudicated. During 12 years' follow-up, 955 participants developed CHF. In multivariate-adjusted analyses, tuna/other fish consumption was inversely associated with incident CHF, with 20% lower risk with intake 1 to 2 times/week (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.64 to 0.99), 31% lower risk with intake 3 to 4 times/week (HR = 0.69, 95% CI = 0.52 to 0.91), and 32% lower risk with intake > or =5 times/week (HR = 0.68, 95% CI = 0.45 to 1.03), compared with intake <1 time/month (p trend = 0.009). In similar analyses, fried fish consumption was positively associated with incident CHF (p trend = 0.01). Dietary long-chain n-3 fatty acid intake was also inversely associated with CHF (p trend = 0.009), with 37% lower risk in the highest quintile of intake (HR = 0.73, 95% CI = 0.57 to 0.94) compared with the lowest. Among older adults, consumption of tuna or other broiled or baked fish, but not fried fish, is associated with lower incidence of CHF. Confirmation in additional studies and evaluation of potential mechanisms is warranted.
Article
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. 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. 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%. 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.
Article
The effect of fish oil on heart rate (HR), a major risk factor for sudden death, is not well established. We calculated this effect in a meta-analysis of randomized, double-blind, placebo-controlled trials in humans. Randomized trials of fish oil that evaluated HR were identified through MEDLINE (1966 through January 2005), hand-searching of references, and contact with investigators for unpublished results. Two investigators independently extracted trial data. A pooled estimate was calculated from random-effects meta-analysis. Predefined stratified meta-analyses and meta-regression were used to explore potential heterogeneity. Of 197 identified articles, 30 met inclusion criteria. Evidence for publication bias was not present. In the overall pooled estimate, fish oil decreased HR by 1.6 bpm (95% CI, 0.6 to 2.5; P=0.002) compared with placebo. Between-trial heterogeneity was evident (Q test, P<0.001). Fish oil reduced HR by 2.5 bpm (P<0.001) in trials with baseline HR > or =69 bpm (median) but had little effect (0.04-bpm reduction; P=0.56) in trials with baseline HR <69 bpm (P for interaction=0.03). Fish oil reduced HR by 2.5 bpm (P<0.001) in trials with duration > or =12 weeks but had less effect (0.7-bpm reduction; P=0.27) in trials with duration <12 weeks (P for interaction=0.07). HR reduction with fish oil intake did not significantly vary by fish oil dose (range, 0.81 to 15 g/d), type of HR measure, population age, population health, parallel versus crossover design, type of control oil, or study quality by Delphi criteria (P for interaction >0.25 for each). In randomized controlled trials in humans, fish oil reduces HR, particularly in those with higher baseline HR or longer treatment duration. These findings provide firm evidence that fish oil consumption directly or indirectly affects cardiac electrophysiology in humans. Potential mechanisms such as effects on the sinus node, ventricular efficiency, or autonomic function deserve further investigation.
Article
The long-chain n-3 fatty acids in fish have been demonstrated to have antiarrhythmic properties in experimental models and to prevent sudden cardiac death in a randomized trial of post-myocardial infarction patients. Therefore, we hypothesized that these n-3 fatty acids might prevent potentially fatal ventricular arrhythmias in high-risk patients. Four hundred two patients with implanted cardioverter/defibrillators (ICDs) were randomly assigned to double-blind treatment with either a fish oil or an olive oil daily supplement for 12 months. The primary end point, time to first ICD event for ventricular tachycardia or fibrillation (VT or VF) confirmed by stored electrograms or death from any cause, was analyzed by intention to treat. Secondary analyses were performed for "probable" ventricular arrhythmias, "on-treatment" analyses for all subjects who had taken any of their oil supplements, and "on-treatment" analyses only of those subjects who were on treatment for at least 11 months. Compliance with double-blind treatment was similar in the 2 groups; however, the noncompliance rate was high (35% of all enrollees). In the primary analysis, assignment to treatment with the fish oil supplement showed a trend toward a prolonged time to the first ICD event (VT or VF) or of death from any cause (risk reduction of 28%; P=0.057). When therapies for probable episodes of VT or VF were included, the risk reduction became significant at 31%; P=0.033. For those who stayed on protocol for at least 11 months, the antiarrhythmic benefit of fish oil was improved for those with confirmed events (risk reduction of 38%; P=0.034). Although significance was not achieved for the primary end point, this study provides evidence that for individuals at high risk of fatal ventricular arrhythmias, regular daily ingestion of fish oil fatty acids may significantly reduce potentially fatal ventricular arrhythmias.
Article
Fish intake is associated with improved cardiovascular health, including a lower risk of arrhythmic death, atrial fibrillation, and heart failure. However, the physiologic effects that may produce these cardiovascular benefits are not well-established. We investigated the cross-sectional associations between a usual dietary intake of fish during the previous year and cardiac structure, function, and hemodynamics as determined by physical examination and 2-dimensional, Doppler, and M-mode transthoracic echocardiography among 5,073 older adults enrolled in the Cardiovascular Health Study. On multivariate-adjusted analyses, consumption of tuna or other broiled or baked fish was associated with a lower heart rate (p < 0.001), lower systemic vascular resistance (p = 0.002), and greater stroke volume (p < 0.001). Tuna/other fish intake was also associated with a higher E/A ratio (p = 0.004), a measure of more normal diastolic function. In contrast, fried fish or fish sandwich (fish burger) intake was associated with left ventricular wall motion abnormalities (p = 0.02), a reduced ejection fraction (p < 0.001), lower cardiac output (p = 0.04), a trend toward a larger left ventricular diastolic dimension (p = 0.07), and higher systemic vascular resistance (p = 0.003). In conclusion, in this large population-based study, the intake of tuna or other broiled or baked fish was associated with improved cardiac hemodynamics, but fried fish intake was associated with structural abnormalities indicative of systolic dysfunction and potential coronary atherosclerosis. These findings suggest potential specific physiologic mechanisms that may, in part, account for the effects of fish intake on cardiovascular health.
Article
n-3 Fatty acids have important visual, mental, and cardiovascular health benefits throughout the life cycle. Biodistribution, interconversion, and dose response data are reviewed herein to provide a basis for more rational n-3 dose selections. Docosahexaenoic acid (DHA) is the principal n-3 fatty acid in tissues and is particularly abundant in neural and retinal tissue. Limited storage of the n-3 fatty acids in adipose tissue suggests that a continued dietary supply is needed. A large proportion of dietary alpha-linolenic acid (ALA) is oxidized, and because of limited interconversion of n-3 fatty acids in humans, ALA supplementation does not result in appreciable accumulation of long-chain n-3 fatty acids in plasma. Eicosapentaenoic acid (EPA) but not DHA concentrations in plasma increase in response to dietary EPA. Dietary DHA results in a dose-dependent, saturable increase in plasma DHA concentrations and modest increases in EPA concentrations. Plasma DHA concentrations equilibrate in approximately 1 mo and then remain at steady state throughout supplementation. DHA doses of approximately 2 g/d result in a near maximal plasma response. Both dietary DHA and EPA reduce plasma arachidonic acid concentrations. Tissue contents of DHA and EPA also increase in response to supplementation with these fatty acids. Human milk contents of DHA are dependent on diet, and infant DHA concentrations are determined by their dietary intake of this fatty acid. We conclude that the most predictable way to increase a specific long-chain n-3 fatty acid in plasma, tissues, or human milk is to supplement with the fatty acid of interest.
Article
Fish (finfish or shellfish) may have health benefits and also contain contaminants, resulting in confusion over the role of fish consumption in a healthy diet. We searched MEDLINE, governmental reports, and meta-analyses, supplemented by hand reviews of references and direct investigator contacts, to identify reports published through April 2006 evaluating (1) intake of fish or fish oil and cardiovascular risk, (2) effects of methylmercury and fish oil on early neurodevelopment, (3) risks of methylmercury for cardiovascular and neurologic outcomes in adults, and (4) health risks of dioxins and polychlorinated biphenyls in fish. We concentrated on studies evaluating risk in humans, focusing on evidence, when available, from randomized trials and large prospective studies. When possible, meta-analyses were performed to characterize benefits and risks most precisely. Modest consumption of fish (eg, 1-2 servings/wk), especially species higher in the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduces risk of coronary death by 36% (95% confidence interval, 20%-50%; P<.001) and total mortality by 17% (95% confidence interval, 0%-32%; P = .046) and may favorably affect other clinical outcomes. Intake of 250 mg/d of EPA and DHA appears sufficient for primary prevention. DHA appears beneficial for, and low-level methylmercury may adversely affect, early neurodevelopment. Women of childbearing age and nursing mothers should consume 2 seafood servings/wk, limiting intake of selected species. Health effects of low-level methylmercury in adults are not clearly established; methylmercury may modestly decrease the cardiovascular benefits of fish intake. A variety of seafood should be consumed; individuals with very high consumption (> or =5 servings/wk) should limit intake of species highest in mercury levels. Levels of dioxins and polychlorinated biphenyls in fish are low, and potential carcinogenic and other effects are outweighed by potential benefits of fish intake and should have little impact on choices or consumption of seafood (women of childbearing age should consult regional advisories for locally caught freshwater fish). For major health outcomes among adults, based on both the strength of the evidence and the potential magnitudes of effect, the benefits of fish intake exceed the potential risks. For women of childbearing age, benefits of modest fish intake, excepting a few selected species, also outweigh risks.
Article
n-3 Polyunsaturated fatty acids are assumed to play an important role in the prevention and treatment of atherosclerosis. Endothelial nitric-oxide synthase (eNOS) is responsible for cardiovascular homeostasis involving in regulation of vascular function, and the subcellular localization is critical for its activation. Here we determined the effect of docosahexaenoic acid (DHA, 22:6 n-3) on distribution of eNOS and its activity. DHA treatment markedly altered lipid environment of caveolae microdomains, which was coincided with selective displacement of caveolin-1 and eNOS from caveolae. Akt was not detected in caveolae fractions and CaM was distributed in both of caveolin-1-enriched membranes and non-caveolar fractions, whose distribution was unaffected by DHA. These data demonstrated for the first time that DHA altered caveolae microenvironment not only by modifying membrane lipid composition, but also by changing distribution of major structural proteins. DHA-induced alterations in caveolae lipid/protein environment may be an important mechanism in the development of pathogenesis of atherosclerosis.
Article
Fish and omega-3 fatty acid consumption reduce risk of cardiac death, but mechanisms are not well established. Heart rate variability (HRV) predicts cardiac death and reflects specific electrophysiological pathways and influences. We hypothesized that habitual consumption of fish and marine omega-3 fatty acids would be associated with more favorable HRV, elucidating electrophysiological influences and supporting effects on clinical risk. In a population-based cohort of older US adults, we evaluated cross-sectional associations of usual dietary fish and omega-3 consumption during the prior year and ECG-derived (n=4263) and 24-hour Holter monitor-derived (n=1152) HRV. After multivariable adjustment, consumption of tuna or other broiled/baked fish was associated with specific HRV components, including indices suggesting greater vagal predominance and moderated baroreceptor responses (eg, higher root mean square successive differences of normal-to-normal intervals [P=0.001]; higher normalized high-frequency power [P=0.008]; and lower low-frequency/high-frequency ratio [P=0.03]) and less erratic sinoatrial node firing (eg, lower Poincaré ratio [P=0.02] and higher short-term fractal scaling exponent [P=0.005]) but not measures of circadian fluctuations (eg, 24-hour standard deviation of normal-to-normal intervals). Findings were similar for estimated dietary consumption of marine omega-3 fatty acids. For magnitudes of observed differences in HRV comparing the highest to lowest category of fish intake, differences in relative risk of cardiac death during 10.8 years of follow-up ranged from 1.1% (for difference in standard deviation of normal-to-normal intervals) to 5.9% and 8.4% (for differences in Poincaré ratio and short-term fractal scaling exponent) lower risk. Habitual tuna/other fish and marine omega-3 consumption are associated with specific HRV components in older adults, particularly indices of vagal activity, baroreceptor responses, and sinoatrial node function. Cellular mechanisms and implications for clinical risk deserve further investigation.
Writing committee—Luigi Tavazzi (GVM Hospitals of Care and Research, Cotignola, Italy)
  • Maria Grazia Gianni
  • Roberto Franzosi
  • Latini
  • Aldo
  • Roberto Maggioni
  • Gian Luigi Marchioli
  • Maurizio Nicolosi
  • Porcu
GISSI-HF Study Group Steering committee—Luigi Tavazzi (Chairman), Gianni Tognoni (Co-Chairman), Maria Grazia Franzosi, Roberto Latini, Aldo P Maggioni, Roberto Marchioli, Gian Luigi Nicolosi, Maurizio Porcu. Writing committee—Luigi Tavazzi (GVM Hospitals of Care and Research, Cotignola, Italy), Aldo P Maggioni (ANMCO Research Centre, Florence, Italy), Roberto Marchioli (Consorzio Mario Negri Stud, S Maria Imbaro, Italy), Simona Barlera (Istituto Mario Negri, Milan, Italy), Maria Grazia Franzosi (Istituto Mario Negri, Milan, Italy), Roberto Latini (Istituto Mario Negri, Milan, Italy), Donata Lucci (ANMCO Research Centre, Florence, Italy), Gian Luigi Nicolosi (AO S Maria Angeli, Pordenone, Italy), Maurizio Porcu (AO Brotzu-S Michele, Cagliari, Italy), Gianni Tognoni (Consorzio Mario Negri Stud, S Maria Imbaro, Italy).
Clinical monitoring—Martina Ceseri, Gianluca Alongi
  • Fulvio Camerini
  • Jay
  • Adriano Cohn
  • Bertram Decarli
  • Peter Pitt
  • Sleight
  • Philip
  • Daniele Poole-Wilsonsecretary )
  • Franco Bertoli
  • Claudio Cobelli
  • Antonietta Fresco
  • Giacomo Ledda
  • Cristina Levantesi
  • Franco Opasich
  • Gianfranco Rusconi
  • Fabio Sinagra
  • Alberto Turazza
  • Antonio Atzori
  • Filippo Bambi
  • Desiree Bastarolo
  • Francesca Bianchini
Data and safety monitoring board—Salim Yusuf (Chairman), Fulvio Camerini, Jay N Cohn, Adriano Decarli, Bertram Pitt, Peter Sleight, Philip A Poole-Wilson. Primary endpoint committee—Enrico Geraci (Chairman), Marino Scherillo (Co-Chairman), Gianna Fabbri (Coordinator), Barbara Bartolomei (Secretary), Daniele Bertoli, Franco Cobelli, Claudio Fresco, Antonietta Ledda, Giacomo Levantesi, Cristina Opasich, Franco Rusconi, Gianfranco Sinagra, Fabio Turazza, Alberto Volpi. Clinical monitoring—Martina Ceseri, Gianluca Alongi, Antonio Atzori, Filippo Bambi, Desiree Bastarolo, Francesca Bianchini, Iacopo Cangioli, Vittoriana Canu, Concetta Caporusso, Gabriele Cenni, Laura Cintelli, Michele Cocchio, Alessia Confente, Eva Fenicia, Giorgio Friso, Marco Gianfriddo, Gianluca Grilli, Beatrice Lazzaro, Giuseppe Lonardo, Alessia Luise, Rachele Nota, Mariaelena Orlando, Rosaria Petrolo, Chiara Pierattini, Valeria Pierota, Alessandro Provenzani, Velia Quartuccio, Anna Ragno, Chiara Serio, Alvise Spolaor, Arianna Tafi, Elisa Tellaroli. Subprojects—Stefano Ghio, Elisa Ghizzardi (Ventricular Remodeling–Echo), Roberto Latini, Serge Masson (Biohumoral), Maria Grazia Franzosi, Lella Crociati (Genetic), Maria Teresa La Rovere (Arrhythmic and Autonomic Pattern–Holter monitoring), Ugo Corrà (Exercise Capacity), Paola Di Giulio (Quality of Life and Depression), Andrea Finzi 29 Hibbeln JR, Nieminen LRG, Blasbalg TL, Riggs JA, Lands WEM. Healthy intakes of n 3 and n 6 fatty acids: estimations considering worldwide diversity. Am J Clin Nutr 2006; 83 (suppl): 1483S–93S.