Jaume Marrugat

BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)). INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. FUNDING: US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

BACKGROUND: Virgin olive oils are richer in phenolic content than refined olive oil. Small, randomized, crossover, controlled trials on the antioxidant effect of phenolic compounds from real-life daily doses of olive oil in humans have yielded conflicting results. Little information is available on the effect of the phenolic compounds of olive oil on plasma lipid levels. No international study with a large sample size has been done. OBJECTIVE: To evaluate whether the phenolic content of olive oil further benefits plasma lipid levels and lipid oxidative damage compared with monounsaturated acid content. DESIGN: Randomized, crossover, controlled trial. SETTING: 6 research centers from 5 European countries. PARTICIPANTS: 200 healthy male volunteers. MEASUREMENTS: Glucose levels, plasma lipid levels, oxidative damage to lipid levels, and endogenous and exogenous antioxidants at baseline and before and after each intervention. INTERVENTION: In a crossover study, participants were randomly assigned to 3 sequences of daily administration of 25 mL of 3 olive oils. Olive oils had low (2.7 mg/kg of olive oil), medium (164 mg/kg), or high (366 mg/kg) phenolic content but were otherwise similar. Intervention periods were 3 weeks preceded by 2-week washout periods. RESULTS: A linear increase in high-density lipoprotein (HDL) cholesterol levels was observed for low-, medium-, and high-polyphenol olive oil: mean change, 0.025 mmol/L (95% CI, 0.003 to 0.05 mmol/L), 0.032 mmol/L (CI, 0.005 to 0.05 mmol/L), and 0.045 mmol/L (CI, 0.02 to 0.06 mmol/L), respectively. Total cholesterol-HDL cholesterol ratio decreased linearly with the phenolic content of the olive oil. Triglyceride levels decreased by an average of 0.05 mmol/L for all olive oils. Oxidative stress markers decreased linearly with increasing phenolic content. Mean changes for oxidized low-density lipoprotein levels were 1.21 U/L (CI, -0.8 to 3.6 U/L), -1.48 U/L (-3.6 to 0.6 U/L), and -3.21 U/L (-5.1 to -0.8 U/L) for the low-, medium-, and high-polyphenol olive oil, respectively. LIMITATIONS: The olive oil may have interacted with other dietary components, participants' dietary intake was self-reported, and the intervention periods were short. CONCLUSIONS: Olive oil is more than a monounsaturated fat. Its phenolic content can also provide benefits for plasma lipid levels and oxidative damage. International Standard Randomised Controlled Trial number: ISRCTN09220811.

BACKGROUND: The aim of this study was to analyze 28-day case fatality trends between 1978 and 1993 among hospitalized acute myocardial infarction (AMI) patients in the REGICOR registry, Gerona, Spain, and relate them to thrombolytic and antiplatelet drug use and changes in patient characteristics. METHODS AND RESULTS: A total of 2053 consecutive patients 25 to 74 years of age with a first Q-wave AMI admitted to the reference hospital between 1978 and 1993 were registered. Clinical characteristics and patient management were recorded. Four 4-year periods were considered: 1978 to 1981, 1982 to 1985 (prethrombolytic therapy), 1986 to 1989 (thrombolytic and antiplatelet drugs introduced), and 1990 to 1993 (thrombolytic and antiplatelet drugs used routinely). The end point was death at 28 days. Case fatality at 28 days decreased 6% per year between 1978 and 1993. A logistic model adjusted for comorbidity and severity showed the last 3 periods to present a steep decrease in the OR of death at 28 days: 0.86 (95% CI, 0.52 to 1.41), 0.59 (95% CI, 0.35 to 0.99), and 0.40 (95% CI, 0.24 to 0.69), respectively, compared with the first period. After 1986, 85.7% of the 112 lives saved could be attributed to the use of antiplatelet and thrombolytic drugs. Adjusted relative risk reduction was 56.0% for antiplatelet drugs, 34.1% for thrombolytic drugs, and 77.9% for the 2 combined. CONCLUSIONS: Our results strongly suggest that new therapies introduced since 1986 have contributed to the decrease in 28-day case fatality of patients admitted with a first Q-wave AMI. This decrease could be attributable mainly to the use of antiplatelet and thrombolytic drugs. These findings should encourage the routine use of thrombolytic and antiplatelet drugs and particularly their combination in the acute phase of AMI.

Questionnaires are frequently used for measuring physical activity. The aim of this study was to validate the Spanish version of the Minnesota Leisure Time Physical Activity Questionnaire (MLTPAQ) in Spanish men. Healthy men (n = 187) aged 20-60 years were recruited. The MLTPAQ was administered to assess the quantity (total activity metabolic index) and quality (heavy, moderate, and light) of physical activity performed in the last year, quarter, month, and week. Fitness was assessed with an exercise test. Spearman's correlation coefficients between the total activity metabolic index and exercise test duration, time to maximal theoretical heart rate, and caloric intake were 0.57, 0.46, and 0.40, respectively. The intraclass correlation coefficients between the total activity metabolic indexes in the last year and in the last quarter, month, and week were 0.62, 0.46, and 0.35, respectively. In multiple linear regression, the heavy, moderate, and light activity metabolic index, age, body mass index, and basal heart rate explained 40% of the variability of time to the maximum theoretical heart rate. The Spanish version of the MLTPAQ is a valid instrument to measure the quantity and quality of physical activity performed in the last year (also in periods shorter than 1 year) by Spanish men aged 20-60 years. Only heavy physical activity is related to cardiorespiratory fitness.