Pekka Koskinen

Associations Between Human Aldosterone Synthase (CYP11B2) Gene Polymorphisms and Left Ventricular Size, Mass, and Function

BACKGROUNDnAldosterone has direct and indirect effects on the heart, and genetic variations in aldosterone synthesis could therefore influence cardiac structure and function. Such variations might be associated with polymorphisms in the gene encoding aldosterone synthase (CYP11B2), the enzyme catalyzing the last steps of aldosterone biosynthesis.nnnMETHODS AND RESULTSnA Finnish population sample of 84 persons (44 women) aged 36 to 37 years was studied by M-mode and Doppler echocardiography to assess left ventricular size, mass, and function. Subjects were genotyped through the use of the polymerase chain reaction for two diallelic polymorphisms in CYP11B2: one in the transcriptional regulatory region (promoter) and the other in the second intron. In multiple regression analyses, the CYP11B2 promoter genotype predicted statistically significant variations in left ventricular end-diastolic diameter (beta=.40, P<.0001), end-systolic diameter (beta=.33, P=.0009), and mass (beta=.17, P=.023). These effects were independent of potentially confounding factors, including sex, body size, blood pressure, physical activity, smoking, and ethanol consumption. Genotype groups also differed in a measure of left ventricular diastolic function, the heart rate-adjusted atrial filling fraction (P=.018). Increased dietary salt, which is known to predict increased left ventricular mass, had this effect only in association with certain CYP11B2 genotypes (P<.001).nnnCONCLUSIONSnGenetic variations in or near the aldosterone synthase (CYP11B2) gene strongly affect left ventricular size and mass in young adults free of clinical heart disease. These polymorphisms may also influence the response of the left ventricle to increases in dietary salt.

Short-term heart rate variability and factors modifying the risk of coronary artery disease in a population sample

Heart rate (HR) variability is impaired in chronic coronary artery disease (CAD), but the mechanism is not fully resolved. This study was aimed at assessing whether HR variability is influenced by the risk factors of CAD. Of a random sample of 120 subjects born in 1954, 88 (41 men and 47 women) could be included in the analyses. No subject had clinical heart disease. The subjects physical activity, alcohol consumption and smoking were quantified by 2-month diary follow-up. Serum lipids and insulin were measured. The tests of HR variability included power spectral analysis and calculation of the root-mean-square difference of RR intervals at rest under controlled respiration. HR variability indexes were asymmetrically distributed and strongly HR-dependent, and therefore, all statistical tests were performed on log-transformed data adjusted to the population mean HR. Multiple regression analyses showed independent inverse relations between the root-mean-square RR difference and low-density lipoprotein (LDL) cholesterol (beta = -0.22; p = 0.008), and between the total RR-interval power and LDL cholesterol (beta = -0.25; p = 0.007), as well as smoking (beta = -0.19; p = 0.035). In women, alcohol use influenced the RR-interval root-mean-square difference (beta = 0.31; p = 0.015), total power (beta = 0.33; p = 0.017) and high-frequency power (beta = 0.26; p = 0.056). It is concluded that short-term HR variability is related inversely to LDL cholesterol and smoking in the population, and directly to alcohol use in women.(ABSTRACT TRUNCATED AT 250 WORDS)

The Helsinki Heart Study: an 8.5-year safety and mortality follow-up

Abstract. Objectives. Earlier monitoring of all symptoms, hospital admissions, cancer diagnoses and causes of death during gemfibrozil treatment had raised some suspicions which called for further follow‐up.

The Helsinki Heart Study: Central Findings and Clinical Implications

This paper describes the central findings and discusses the clinical implications of the Helsinki Heart Study. This was a controlled primary prevention trial to test the hypothesis that using gemfibrozil to lower the concentrations of serum low density lipoprotein (LDL) and very low density lipoprotein (VLDL) and to raise that of high density lipoprotein (HDL) protects subjects against coronary heart disease.

Polymorphisms of the gene encoding cholesterol ester transfer protein and serum lipoprotein levels in subjects with and without coronary heart disease

SummaryWe determined TaqI-A, TaqI-B and EcoNI genotypes at the cholesteryl ester transfer protein (CETP) locus in 111 healthy volunteers and in 187 hyperlipidemic men of whom 72 had suffered a myocardial infarction. There were no significant differences in the allele distributions at these polymorphic loci either between the population sample and the hyperlipidemic subjects, or between patients with and without previous myocardial infarction. To detect the associations between the CETP polymorphisms and serum lipid and apoprotein levels, we determined the serum concentrations of total cholesterol, triglycerides, high density lipoprotein (HDL)-cholesterol, apoA-I, apoA-II and apoB in the subjects studied and correlated them to the 3 RFLPs. No significant differences were observed in the serum levels of apoproteins and lipid parameters between subjects with different genotypes in any of these polymorphic CETP loci, either in the population sample or in hyperlipidemic men. Multivariate analyses did not reveal a significant independent role for any of the 3 polymorphisms in determining serum HDL-cholesterol or apoA-I levels after adjusting for triglyceride and low density lipoprotein cholesterol concentrations. This was evident for the group of healthy volunteers and for hyperlipidemic subjects, including those who had survived a myocardial infarction. We conclude that, in Finns, the CETP RFLPs are not useful markers for the risk of coronary heart disease.

Cytomegalovirus infection-enhanced allograft arteriosclerosis is prevented by DHPG prophylaxis in the rat.

BACKGROUNDnMajor risk factors for accelerated allograft arteriosclerosis include humoral and cellular immune response, hyperlipidemia, and viral infections. We demonstrated earlier that rat cytomegalovirus (RCMV) infection doubles smooth muscle cell proliferation and intimal thickening of rat aortic allografts. In this study, the effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) on RCMV-enhanced rat allograft arteriosclerosis are investigated.nnnMETHODS AND RESULTSnAortic allografts from the DA to the WF rat strain were used. The recipients were inoculated with 10(5) plaque-forming units of RCMV 1 day after transplantation. Two groups of RCMV-infected rats were treated with DHPG with an initial dose of 20 mg/kg IP and a maintenance dose of 10 mg/kg IP twice a day for a period of 14 days. In the DHPG prophylaxis group (n = 22), the drug administration started 1 day before infection, and in the DHPG treatment group (n = 17), 7 days after infection. One group of infected rats was left untreated (n = 21). The grafts were removed 7 and 14 days and 1, 3, and 6 months after transplantation. In the DHPG prophylaxis group, no virus could be recovered by plaque assays. In the treatment group, 50% of rats were virus-positive at 1 month and 40% at 3 months. DHPG prophylaxis prevented the infiltration of inflammatory cells and their proliferation in the adventitia of RCMV-infected recipients (P < .01), with a 60% reduction in the interleukin-2 receptor expression (P < .05) and a 30% decrease in major histocompatibility complex class II expression (P = NS). DHPG prophylaxis did not significantly alter the levels of insulin-like growth factor-1, epidermal growth factor, platelet-derived growth factor-BB, transforming growth factor-beta 1, acidic fibroblast growth factor, and basic fibroblast growth factor messages in the allograft vascular wall. Early media necrosis was reduced. Arteriosclerotic alterations and proliferation of smooth muscle cells were both reduced 50% to 70% by DHPG prophylaxis (P < .05 at 3 months). The responses in the DHPG treatment group were quite similar but less impressive and statistically nonsignificant.nnnCONCLUSIONSnWe consider it likely that DHPG inhibits arteriosclerotic alterations primarily by reducing the infectious virus and thereby the inflammatory response in the allograft vascular wall; another possibility is a direct antiproliferative effect on smooth muscle cell replication. A dose-dependent inhibitory effect of DHPG on smooth muscle cell replication was recorded in an in vitro study.

Leukocytes as a coronary risk factor in a dyslipidemic male population

The role of an elevated serum leukocyte count (WBC) as a coronary risk factor was investigated using a nested case-control design in dyslipidemic middle-aged men (n = 420) participating in the Helsinki Heart Study, a coronary primary prevention trial. Baseline WBC was significantly higher, 6.93 (2.11) x 10(9)/L in subjects with cardiac events, than in controls, 6.26 (1.88) x 10(9)/L; p less than 0.002. This association was time-dependent, however, since the difference was not significant for events occurring during the second half of the 5-year study. Using nonsmokers in the lowest WBC tertile as the reference sample, the relative risks in the highest WBC tertile were 1.86 (95% confidence intervals [CI] 0.81 to 4.28) for nonsmokers and 3.07 (95% CI 2.23 to 8.19) for smokers. Logistic regression analysis including smoking in the model disclosed an independent contribution of elevated WBC to coronary heart disease. We conclude that elevated leukocyte count was a coronary risk factor even in this dyslipidemic population.

The Helsinki Heart Study: coronary heart disease incidence during an extended follow‐up

Abstract. Objectives. To confirm that coronary heart disease (CHD) can be prevented by gemfibrozil treatment and to estimate the long‐term effect of the treatment.

Effect of gemfibrozil on the concentration and composition of serum lipoproteins A controlled study with special reference to initial triglyceride levels

We investigated the modulating effect of serum total triglycerides on the lipid composition of various lipoproteins, and on the response to gemfibrozil treatment. This placebo controlled study was conducted blind in 60 participants of the Helsinki Heart Study. An inverse relationship was observed between cholesterol content in all lipoprotein fractions and serum total triglyceride level. Gemfibrozil, in addition to changing the absolute amounts of lipoprotein lipids, also normalized the qualitative abnormalities associated with hypertriglyceridemia. Gemfibrozil increased the level of HDL-cholesterol with the main effect on HDL3-subfraction. The observed reduction in LDL-cholesterol was dependent on the initial triglyceride level.

Seasonal variation in high density lipoprotein cholesterol

We investigated the seasonal variation in high density lipoprotein cholesterol (HDL) in 142 dyslipidemic (non-HDL-cholesterol > or = 5.2 mmol/l) middle-aged men in the placebo group of the Helsinki Heart Study over the 5-year trial period. A seasonal pattern was found in HDL fluctuation, with a 4.5% drop during mid-winter (5-year mean 1.192 +/- 0.265 mmol/l) compared with a stable level (5-year mean 1.248 +/- 0.281 mmol/l) during the rest of the year (P < 0.001). A less pronounced seasonal variation in HDL was observed in 85 subjects receiving gemfibrozil. Although affecting pretrial HDL level in cross-sectional analyses, age, alcohol consumption, dietary adherence, physical activity and serum triglycerides had no influence on the seasonality of HDL variation. Smoking had a slight attenuating effect on the variation pattern. Pretrial HDL was influenced by relative weight, but there was also an inverse relationship between HDL and body weight variations, i.e. the annual drop in HDL coincided with the annual peak in body weight. However, seasonal HDL variation was not directly reflected in the annual variation in CHD incidence.