Bernard Cantin

Hyperinsulinemia as an independent risk factor for ischemic heart disease.

BACKGROUND Prospective studies suggest that hyperinsulinemia may be an important risk factor for ischemic heart disease. However, it has not been determined whether plasma insulin levels are independently related to ischemic heart disease after adjustment for other risk factors, including plasma lipoprotein levels. METHODS In 1985 we collected blood samples from 2103 men from suburbs of Quebec City, Canada, who were 45 to 76 years of age and who did not have ischemic heart disease. A first ischemic event (angina pectoris, acute myocardial infarction or death from coronary heart disease) occurred in 114 men (case patients) between 1985 and 1990. Each case patient was matched for age, body-mass index, smoking habits, and alcohol consumption with a control selected from among the 1989 men who remained free of ischemic heart disease during follow-up. After excluding men with diabetes, we compared fasting plasma insulin and lipoprotein concentrations at base line in 91 case patients and 105 controls. RESULTS Fasting insulin concentrations at base line were 18 percent higher in the case patients than in the controls (P<0.001). Logistic-regression analysis showed that the insulin concentration remained associated with ischemic heart disease (odds ratio for ischemic heart disease with each increase of 1 SD in the insulin concentration, 1.7; 95 percent confidence interval, 1.3 to 2.4) after adjustment for systolic blood pressure, use of medications, and family history of ischemic heart disease. Further adjustment by multivariate analysis for plasma triglyceride, apolipoprotein B, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations did not significantly diminish the association between the insulin concentration and the risk of ischemic heart disease (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.3). CONCLUSIONS High fasting insulin concentrations appear to be an independent predictor of ischemic heart disease in men.

Prevalence of dyslipidemic phenotypes in ischemic heart disease (prospective results from the Que´bec cardiovascular study)

In 1985, plasma cholesterol, triglyceride, high-density lipoprotein cholesterol, and plasma apoprotein (apo) B levels were measured in 2,103 men (aged 45 to 76 years) without ischemic heart disease from the Québec city suburbs. Occurrence of a first ischemic event (i.e., angina pectoris, acute myocardial infarction, or coronary-related death) was recorded in 114 men between 1985 and 1990. Men with and without ischemic heart disease were classified as normal or in various dyslipidemic groups according to an established algorithm. Of the 1,989 men who remained free of ischemic events, 50% had a normal lipid profile compared with 32% in men with ischemic heart disease. Although the prevalence of type IIb and IV dyslipidemias was similar in men with and without ischemic heart disease, type IIa (16% vs 10%), hyperapo B-hypertriglyceridemia (12% vs 6%), hyperapo B-normotriglyceridemia (11% vs 7%), and hypoalphalipoproteinemia (18% vs 13%) were more prevalent in men with than without ischemic heart disease. Adjusted odds ratios (ORs) were not increased in type IIb and IV phenotypes, whereas men with type IIa (OR 2.8), with the 2 hyperapo B phenotypes (hyperapo B-normotriglyceridemia, OR 2.7; hyperapo B-hypertriglyceridemia, OR 3.1) or with isolated hypoalphalipoproteinemia (OR 2.2), were at higher risk. The results of this prospective study confirm the importance of both elevated plasma cholesterol and decreased high-density lipoprotein cholesterol levels as risk factors for ischemic heart disease. They also emphasize the high prevalence of an elevated apo B dyslipidemic state in ischemic heart disease.

Is Lipoprotein(a) an Independent Risk Factor for Ischemic Heart Disease in Men? The Quebec Cardiovascular Study

OBJECTIVES This study was undertaken to determine whether lipoprotein(a) [Lp(a)] is an independent risk factor for ischemic heart disease (IHD) and to establish the relation of Lp(a) to the other lipid fractions. BACKGROUND Several, but not all, studies have shown that elevated Lp(a) concentrations may be associated with IHD; very few have been prospective. METHODS A 5-year prospective follow-up study was conducted in 2,156 French Canadian men 47 to 76 years old, without clinical evidence of IHD. Lipid measurements obtained at baseline included total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, apoprotein B and Lp(a). During the follow-up period, there were 116 first IHD events (myocardial infarction, angina, death). Adjusted proportional hazards models were used to estimate the relative risk for the different variables. The cohort was also classified according to Lp(a) levels and other lipid risk factor tertiles to evaluate the relation of elevated Lp(a) levels to these risk factors. A cutoff value of 30 mg/dl was used for Lp(a). Risk ratios were calculated using the group with low Lp(a) levels and the first tertile of lipid measures as a reference. RESULTS Lp(a) was not an independent risk factor for IHD but seemed to increase the deleterious effects of mildly elevated LDL cholesterol and elevated total cholesterol and apoprotein B levels and seemed to counteract the beneficial effects associated with elevated HDL cholesterol levels. CONCLUSIONS In this cohort, Lp(a) was not an independent risk factor for IHD but appeared to increase the risk associated with other lipid risk factors.

Triglycerides and HDL-cholesterol as risk factors for ischemic heart disease. Results from the Québec cardiovascular study

The relative importance of reduced plasma high density lipoprotein-cholesterol (HDL-C) levels and elevated plasma triglyceride (TG) concentrations as risk factors for ischemic heart disease (IHD) was examined in a sample of 2177 men from the Québec City suburbs. The sample included 202 men with known IHD. The relationship between HDL-C and TG levels, although significant (r = -0.49, P < 0.0001), was not linear, as most of the variation in HDL-C levels was observed within TG levels below 2.5 mmol/l. Reduced HDL-C (< 0.9 mmol/l) was a prevalent condition in men with IHD (50%) compared to those without IHD (30%). On the other hand 26% and 20% of men with and without IHD, respectively, had elevated TG levels (TG > 2.3 mmol/l). A 2-fold increase in prevalence odds ratio (OR) was observed in men with TG levels > 2.3 mmol/l (95% confidence intervals (CI) [1.2;3.3]). No residual association between elevated TG levels and IHD was found, however, after adjustment for HDL-C concentrations (OR 1.2, 95% CI 0.7;2.1). On the other hand, HDL-C remained a significant predictor of IHD after adjustment for other risk factors (OR 0.3, 95%, CI 0.2;0.6). Men with reduced HDL-C levels were also characterized by a cluster of risk factors such as obesity, diabetes mellitus and hypertension, which may contribute to increase the risk of IHD. Finally, the independent interpretation of cholesterol, TG or LDL-C levels may lead to an inadequate prediction of risk, as a large number of IHD patients showed a cluster of risk factors which included low HDL-C concentrations.

Association of fibrinogen and lipoprotein(a) as a coronary heart disease risk factor in men (The Quebec Cardiovascular Study).

Fibrinogen has been prospectively found to correlate with coronary heart disease (CHD) but a similar association has not been well established for lipoprotein (a) (Lp(a)). Plasma lipids, Lp(a), and fibrinogen levels were measured in 2,125 men (aged 47 to 76 years) who were free of clinical CHD. During a 5-year follow-up period, 116 first CHD events were documented. Men with CHD were older, smoked more, had a higher prevalence of diabetes, and higher levels of systolic blood pressure, cholesterol, low-density lipoprotein cholesterol, Lp(a), and fibrinogen, and lower plasma high-density lipoprotein cholesterol levels. Only fibrinogen levels in the upper tertile of the distribution compared with the lower tertiles were associated with a significant risk of CHD (adjusted risk ratio 2.5; 95% confidence interval [CI] 1.4 to 4.2; p = 0.0010). Such an association was not observed with Lp(a). To assess a possible relation between fibrinogen and Lp(a) to the risk of CHD events, men were assigned to 1 of 4 groups according to fibrinogen median levels and a Lp(a) cut-off level of 300 mg/L: group 1: fibrinogen < 4.05 g/L and Lp(a) < 300 mg/L; group 2: fibrinogen < 4.05 g/L and Lp(a) > or =300 mg/L; group 3: fibrinogen > or =4.05 g/L and Lp(a) < 300 mg/L; and group 4: fibrinogen > or =4.05 g/L and Lp(a) > or =300 mg/L. Using group 1 as a reference, a significant risk ratio was only documented in group 4 (2.5; 95% CI 1.2 to 5.1; p = 0.0132). In this population, high fibrinogen levels associated with high Lp(a) levels significantly increased the risk of CHD.

Cardiac Allograft Vasculopathy by Intravascular Ultrasound in Heart Transplant Patients: Substudy From the Everolimus Versus Mycophenolate Mofetil Randomized, Multicenter Trial

OBJECTIVES A pre-planned substudy of a larger multicenter randomized trial was undertaken to compare the efficacy of everolimus with reduced-dose cyclosporine in the prevention of cardiac allograft vasculopathy (CAV) after heart transplantation to that of mycophenolate mofetil (MMF) with standard-dose cyclosporine. BACKGROUND CAV is a major cause of long-term mortality following heart transplantation. Everolimus has been shown to reduce the severity and incidence of CAV as measured by first year intravascular ultrasound (IVUS). MMF, in combination with cyclosporine, has also been shown to have a beneficial effect in slowing the progression of CAV. METHODS Study patients were a pre-specified subgroup of the 553-patient Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial who underwent heart transplantation and were randomized to everolimus 1.5 mg or MMF 3 g/day. IVUS was performed at baseline and at 12 months. Evaluable IVUS data were available in 189 patients (34.6%). RESULTS Increase in average maximal intimal thickness (MIT) from baseline to month 12 was significantly smaller in the everolimus 1.5 mg group compared with the MMF group (0.03 mm vs. 0.07 mm, p < 0.001). The incidence of CAV, defined as an increase in MIT from baseline to month 12 of greater than 0.5 mm, was 12.5% with everolimus versus 26.7% with MMF (p = 0.018). These findings remained irrespective of sex, age, diabetic status, donor disease, and across lipid categories. CONCLUSIONS Everolimus was significantly more efficacious than MMF in preventing CAV as measured by IVUS among heart-transplant recipients after 1 year, a finding, which was maintained in a range of patient subpopulations. CV surgery: transplantation, ventricular assistance, cardiomyopathy.

Survival with painless strongly positive exercise electrocardiogram

To determine the prognosis of patients with painless strongly positive exercise electrocardiogram, the 6-year cumulative survival rate was computed for 298 medically treated patients who terminated their exercise test with or without angina. All had horizontal or downsloping ST depression greater than or equal to 2 mm during a treadmill exercise test according to the standardized multistage Bruce protocol. Of the 298 patients, 119 terminated the exercise test because of dyspnea or fatigue and 179 stopped because of angina. Among the 119 patients without angina, there were 18 deaths, 16 from coronary artery disease (CAD), of which 8 occurred suddenly. Among the 179 patients with exercise-induced angina, 36 died, 33 from CAD, of which 13 were sudden deaths. The overall 6-year survival rate was 85 +/- 3% for patients without angina and 80 +/- 3% in those with angina (p less than 0.05). However, patients without angina achieved a significantly longer duration of exercise and had higher maximal heart rate and systolic blood pressure during exercise. In both groups, survival decreased with decreasing duration of exercise. In patients without angina, the 6-year survival rate was 97 +/- 3% in those achieving stage IV (greater than or equal to 541 s), 87 +/- 4% in stage III (361 to 540 s), 64 +/- 13% in stage II (181 to 360 s) and 60 +/- 15% in stage I (less than or equal to 180 s).(ABSTRACT TRUNCATED AT 250 WORDS)

Prognosis in patients with a strongly positive exercise electrocardiogram

In patients with a strongly positive exercise electro-cardiogram, the workload achieved during the test allows the identification of subsets with good or poor survival rates. To determine whether the same criteria also predict acute ischemic heart events such as unstable angina and myocardial infarction, fatal and nonfatal acute manifestations were documented in 241 patients medically treated during an 8-year follow-up. All patients had a Bruce protocol treadmill exercise test with ST-segment depression greater than or equal to 2 mm and coronary angiographic studies. There were 52 deaths; of these 44 were due to coronary artery disease. There were 41 episodes of unstable angina and 21 myocardial infarcts documented as first morbid events. As expected, survival improved with increased workload achieved; patients terminating their exercise at stage I (5.1 METs) had an 8-year survival rate of 45 +/- 9% while those reaching stage IV or more (10 METs) had a survival rate of 93 +/- 6%. In a multivariate analysis, the duration of exercise and the number of narrowed coronary arteries and of left ventricular segment abnormalities correlated significantly with survival. In contrast, nonfatal acute events occurred in about 20 to 35% of patients whatever the stage of the exercise test. Furthermore, neither variables during the exercise test nor angiographic findings predicted nonfatal events. Thus, although the workload achieved did identify patients with different mortality rates, it failed to predict subsets of patients with different morbid event rates.

Does correction of the friedewald formula using lipoprotein(a) change our estimation of ischemic heart disease risk? The Quebec Cardiovascular Study

BACKGROUND LDL-cholesterol is usually calculated using the Friedewald formula. This calculation method does not take into account the presence of Lp(a), which is associated with LDL-cholesterol. Dahlen has suggested that the Friedewald formula should be modified to account for Lp(a) associated cholesterol. This study was undertaken to determine if correction of the Friedewald formula would result in a better evaluation of ischemic heart disease (IHD) risk. METHODS 2222 men free from IHD were prospectively followed for 5 years for the appearance of myocardial infarction, coronary insufficiency or coronary death. At the baseline evaluation all had a complete fasting lipid profile which included Lp(a) determinations. LDL-cholesterol levels were calculated from total cholesterol, total triglycerides and HDL-cholesterol using the Friedewald formula and also using the Dahlen modification of the Friedewald formula. RESULTS During the follow-up there were 89 first IHD events. Both types of LDL-cholesterol calculations showed that the last tertile of the LDL-cholesterol distribution in comparison to the first tertile, doubles the relative risk (RR: 2.15; 95% confidence limits: 1.23-3.75) using the Friedewald formula (RR: 2.18; 95% confidence limits: 1.25-3.81) using the Dahlen modification. Lp(a) levels were not an independent predictor of IHD risk. CONCLUSION Modification of the Friedewald formula to account for Lp(a) levels does not improve our evaluation of IHD risk.

Alterations in erythrocyte membrane lipid composition and fluidity in primary lipoprotein lipase deficiency

Lipid composition of plasma lipoproteins and erythrocyte ghost membranes has been studied in 16 healthy normolipidaemic subjects and in 16 patients affected by primary lipoprotein lipase deficiency, resulting in severe chylomicronaemia and in cholesterol-depleted low-density lipoproteins and high-density lipoproteins. A significant decrease in membrane cholesterol/phospholipid ratio was observed in lipoprotein lipase deficient patients compared to controls (3.27 +/- 0.33 vs. 3.95 +/- 0.50, mean +/- S.D.; P less than 0.0001). There was also an increase in the erythrocyte membrane phosphatidylcholine/sphingomyelin ratio in lipoprotein lipase deficient patients compared to controls (1.53 +/- 0.10 vs. 1.05 +/- 0.13; P less than 0.0001) due to a concurrent increase in phosphatidylcholine and decrease in sphingomyelin relative concentrations in these patients. Erythrocyte ghost membrane fluidity was determined by fluorescence anisotropy and found to be higher in membranes from lipoprotein lipase deficient patients. This increase in membrane fluidity can be attributed in part to changes in membrane cholesterol and phospholipid concentrations in response to abnormal plasma lipoprotein composition.