N-3 polyunsaturated fatty acids in heart failure: mechanisms and recent clinical evidence.

Over the past 20 years, there has been significant progress in our knowledge of the pathophysiology of heart failure (HF) with consequent considerable development of both pharmacological and non pharmacological approaches. Despite improved therapeutic strategies, HF still remains burdensome in terms of mortality, quality of life, and hospitalization costs. A new and promising medical treatment to improve survival in HF patients stems from the recent results of the Italian study, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Heart Failure (GISSI-HF). GISSI-HF was a randomized, large scale, double-blind, placebo-controlled trial showing that n-3 PUFA (850-882 mg/d) reduced mortality and admission to the hospital for cardiovascular reasons in patients with chronic heart failure (HF) who were already receiving recommended therapies. The clinical benefit observed in GISSI-HF seemed to be mediated prominently by the antiarrhythmic effects of n-3 PUFA, though an effect on mechanisms related to HF progression cannot be excluded. This article presents the results of GISSI-HF study and reviews the previous clinical evidence on n-3 PUFA and risk of heart failure and discusses in depth the potential mechanisms through which n-3 PUFA treatment can improve clinical outcome in HF patients.

Persistent platelet activation in patients with type 2 diabetes treated with low doses of aspirin.

BACKGROUND: The percentage of diabetic patients who do not benefit from the protective effect of aspirin is larger than in other populations at cardiovascular risk. OBJECTIVE: We compared the ability of aspirin to suppress TxA2 and platelet activation in vivo, in type-2 diabetics vs. high-risk non-diabetic patients. METHODS: Urinary 11-dehydro-TXB2, plasma sCD40 L, and sP-selectin were measured, together with indices of low-grade inflammation, glycemic control, and lipid profile, in 82 patients with type-2 diabetes and 39 without diabetes, treated with low doses of aspirin. RESULTS: Urinary 11-dehydro-TxB2, plasma sCD40L and sP-selectin were significantly higher in diabetics than in controls: [38.9 (27.8-63.3) vs. 28.5 (22.5-43.9) ng mmol(-1) of creatinine, P = 0.02], [1.06 (0.42-3.06) vs. 0.35 (0.22-0.95) ng mL(-1); P = 0.0001], [37.0 (16.8-85.6) vs. 20.0 (11.2-35.6) ng mL(-1), P = 0.0001], respectively. The proportion of individuals with diabetes increased across quartiles of 11-dehydro-TxB2, sCD40L, and sP-selectin, with the highest quartiles of 11-dehydro-TxB2, sCD40L and sP-selectin, including 66%, 93.3%, and 93.3% of individuals with diabetes. Markers of platelet activation positively correlated with indices of glycemic control but not with markers of low-grade inflammation. CONCLUSIONS: Platelet dysfunction associated with insufficient glycemic control, may mediate persistent platelet activation under aspirin treatment.

Electrocardiographic evolutionary changes and left ventricular remodeling after acute myocardial infarction: results of the GISSI-3 Echo substudy.

OBJECTIVES: The aim of this study was to describe the electrocardiographic (ECG) evolutionary changes after an acute myocardial infarction (AMI) and to evaluate their correlation with left ventricular function and remodeling. BACKGROUND: The QRS complex changes after AMI have been correlated with infarct size and left ventricular function. By contrast, the significance of T wave changes is controversial. METHODS: We studied 536 patients enrolled in the GISSI-3-Echo substudy who underwent ECG and echocardiographic studies at 24 to 48 h (S1), at hospital discharge (S2), at six weeks (S3) and six months (S4) after AMI. RESULTS: The number of Qwaves (nQ) and QRS quantitative score (QRSs) did not change over time. From S2 to S4, the number of negative T waves (nT NEG) decreased (p < 0.0001), wall motion abnormalities (%WMA) improved (p < 0.001), ventricular volumes increased (p < 0.0001) while ejection fraction remained stable. According to the T wave changes after hospital discharge, patients were divided into four groups: stable positive T waves (group 1, n = 35), patients who showed a decrease > or =1 in nT NEG (group 2, n = 361), patients with no change in nT NEG (group 3, n = 64) and those with an increase > or =1 in nT NEG (group 4, n = 76). The QRSs and nQ remained stable in all groups. Groups 3 and 4 showed less recovery in %WMA, more pronounced ventricular enlargement and progressive decline in ejection fraction than groups 1 and 2 (interaction time x groups p < 0.0001). CONCLUSIONS: The analysis of serial ECG can predict postinfarct left ventricular remodeling. Normalization of negative T waves during the follow-up appears more strictly related to recovery of regional dysfunction than QRS changes. Lack of resolution and late appearance of new negative T predict unfavorable remodeling with progressive deterioration of ventricular function.

Antioxidant vitamins and prevention of cardiovascular disease: epidemiological and clinical trial data.

Naturally occurring antioxidants such as vitamin E, beta-carotene, and vitamin C can inhibit the oxidative modification of low density lipoproteins. This action could positively influence the atherosclerotic process and, as a consequence, the progression of coronary heart disease. A wealth of experimental studies provide a sound biological rationale for the mechanisms of action of antioxidants, whereas epidemiologic studies strongly sustain the "antioxidant hypothesis." To date, however, clinical trials with beta-carotene supplements have been disappointing, and their use as a preventive intervention for cancer and coronary heart disease should be discouraged. Only scanty data from clinical trials are available for vitamin C. As to vitamin E, discrepant results have been obtained by the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study with a low-dose vitamin E supplementation (50 mg/d) and the Cambridge Heart Antioxidant Study (400-800 mg/d). The results of the GISSI-Prevenzione (300 mg/d) and HOPE (400 mg/d) trials suggest the absence of relevant clinical effects of vitamin E on the risk of cardiovascular events. Currently ongoing are several large-scale clinical trials that will help in clarifying the role of vitamin E in association with other antioxidants in the prevention of atherosclerotic coronary disease.

Antiarrhythmic mechanisms of n-3 PUFA and the results of the GISSI-Prevenzione trial.

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.

[Congenital cardiopathy in a patient with Sotos syndrome. Description of a case]. / Cardiopatia congenita in paziente con sindrome di Sotos. Descrizione di un caso.

The number of cases of Sotos syndrome or cerebral gigantism described in the literature total more than 200. For 6 of these, cardiac malformations were described. The authors report a case of Sotos syndrome in which malformative alterations of the aortic and mitral valves were simultaneously present.

[A clinical instrumental assessment of professional ex-athletes: the long-term effects on the cardiovascular system]. / Valutazione clinico strumentale di ex-atleti professionisti: ripercussioni a lungo termine sull'apparato cardiovascolare.

BACKGROUND: Although many authors have been interested in the athlete's heart since the 1899, several aspects are still being debated. Among them, the issue concerning long-term morphologic and functional cardiac changes induced by vigorous physical activity can be considered of great importance. The aim of this study was to use Doppler echocardiography to evaluate the association of vigorous physical activity with morphologic and functional cardiac modification. METHODS: A total of 30 healthy ex-professional athletes who had discontinued their activity at least 10 years previously, and 30 healthy subjects without a history of regular physical exercise were recruited for the study. Clinical examination, thorax radiography, routine laboratory tests and ergometric test were performed. Morphologic and functional cardiac modification were evaluated by using Doppler-echocardiography. Data were analysed by performing the Student's t-test for unpaired samples and the Kruskall-Wallis' test. RESULTS: Radiologic and echocardiographic findings showed a complete regression of potential morphologic modifications which had occurred during the period of physical activity. The ergometric data showed both a normal working capacity and a reduced energetic demand. Doppler flow shapes were consistent with a normal pattern, although significantly reduced compared to controls. Doppler data of intracardiac flow showed a reduction of peak flow velocity (PFVA) and acceleration time (AccTA) across the aortic valve, and, across the pulmonary valve, a reduction of peak flow velocity (PFVP), flow velocity integral (FVIP) and acceleration time (AccTP). These data give evidence of a reduction in both left and right systolic ventricular function. In diastole the Doppler flow across mitral valve shows an increase in peak flow velocity E (PFVEM), E velocity--A velocity ratio (E/Am) and deceleration time (DecTM). The Doppler flow across the tricuspid valve shows a reduction in peak flow velocity E (PFVET) and in diastolic slope (slopeT) with an E velocity--A velocity ratio (E/AT) increased. Overall, these findings are consistent with an increase in left ventricular parietal stiffness, while the right ventricular wall shows a reduced active relaxation. Nonetheless, an overall diastole disfunction could not be excluded. CONCLUSIONS: Our findings on ex-professional athletes in resting conditions support a "non pathological" ventricular function modification measured with echocardiographic and Doppler flow methods. The ergometric data showing both a normal working capacity and a reduced energetic demand, and morphology of the Doppler flow shape that is (in absolute) normal would seem to confirm the results. We hope that our data will stimulate future trials on larger populations in order to increase the knowledge of the long-term effects of regular physical activity.

[Influence of chronically-administered enalapril on isotonic and isometric exercise in patients with moderate grade hypertension]. / Influenza dell'enalapril in somministrazione cronica sul lavoro isotonico ed isometrico in pazienti ipertesi di grado lieve-moderato.

We studied 11 patients affected by mild essential hypertension during chronic therapy with enalapril (E). After a pharmacological wash-out the patients were treated with E once a day (10-20 mg) for 4 weeks. Before and after the treatment period the patients were studied by means of the isotonic exercise stress test on the cycloergometer with increments of 25 W every 2 min and by means of the Sustained Handgrip test (SHG) at 70% of maximal capacity for 1 min. During the study period E reduced the blood pressure at rest in all patients without untoward effects. During the isotonic test and particularly during SHG, E reduced systolic and diastolic blood pressure (BP) and the product systolic BP x heart rate. The treatment did not influence the time length of the isotonic exercise stress test. Our results suggest that E does not increase the MVO2 at rest and during different types of exercise: this can be very important because many patients affected by hypertension suffer from ischemic heart disease. E is utilized also in patients with heart failure, some of whom have an hypertensive or ischemic cardiomyopathy.

Heterogeneity of left ventricular remodeling after acute myocardial infarction: results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-3 Echo Substudy.

BACKGROUND: Left ventricular (LV) remodeling after acute myocardial infarction has still to be clarified in the thrombolytic era. METHODS: To evaluate timing and the magnitude and pattern of postinfarct LV remodeling, a subset of 614 patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-3 Echo Substudy underwent serial 2-dimensional echocardiograms at 24 to 48 hours from symptom onset (S1), at hospital discharge (S2), at 6 weeks (S3), and at 6 months (S4) after acute myocardial infarction. RESULTS: During the study period the end-diastolic volume index (EDVi) increased (P <.001) and wall motion abnormalities (%WMA) decreased (P <.001), whereas ejection fraction (EF) remained unchanged. Nineteen percent of patients showed a > 20% increase in EDVi at S2 compared with S1 (severe early dilation), and 16% of patients showed a > 20% dilation at S4 compared with S2 (severe late dilation). Independent predictors of severe in-hospital LV dilation were relatively small EDVi (odds ratio [OR] 0.961, 95% confidence interval [CI] 0.947-0.974, P =.0001) and relatively large %WMA (OR 1.030, 95% CI 1.013-1.048, P =.0005). Similarly, smaller predischarge EDVi (OR 0.975, 95% CI 0. 963-0.987, P =.0001), greater %WMA (OR 1.026, 95% CI 1.008-1.045, P =.0042), and moderate to severe mitral regurgitation (OR 2.261, 95% CI 1.031-4.958, P = 0.0417) independently predicted severe late dilation. Importantly, 92% of the patients with severe early dilation did not have further dilation at S4, and 91% of patients with severe late dilation did not have in-hospital dilation. EF was unchanged over time in patients with early dilation, whereas it significantly decreased in those with late dilation. CONCLUSIONS: Although in-hospital LV enlargement is not predictive of subsequent dilation and dysfunction, late remodeling is associated with progressive deterioration of global ventricular function over time: patients with extensive %WMA and not significantly enlarged ventricular volume before discharge are at higher risk for progressive dilation and dysfunction.