Impact of multiplex respiratory virus testing on antimicrobial consumption in adults in acute care: a randomized clinical trial.

OBJECTIVES: Inappropriate use of antibiotics is associated with development of antimicrobial resistance. In respiratory infections it is often difficult to differentiate between viral and bacterial infections, and empirical treatment is common. Enhanced viral testing is expected to clarify clinical decision-making and reduce the prescription of antibacterial agents, but the impact of such information on patient care is unclear. METHODS: We conducted a (1:1) randomized controlled clinical trial involving 998 adults with respiratory symptoms, fever, chest pain or poor general condition in the emergency unit of a tertiary hospital. Multiplex PCR results for 496 patients were available in 24 hours (intervention group) and those for the remaining 502 patients were available in 7 days (control group). Our primary outcome measures were the duration of hospitalization and the consumption of antibiotics within 30 days of enrolment. RESULTS: In all, 841 of 998 (84%) patients had respiratory symptoms at study entry. A respiratory virus was detected in 175 (17.5%). The mean duration of hospitalization was 4.2 days (SD 5.4) in the intervention group and 4.1 days (SD 4.9) in the control group (difference 0.1, 95% CI -0.5 to 0.6, p 0.810). The mean days on antibiotics were 11.3 days (SD 12.6) in the intervention group and 10.4 days (SD 11.4) in the control group (difference 0.9, 95% CI -0.6 to 2.4, p 0.235). CONCLUSIONS: Multiplex PCR testing for respiratory viruses with results available within 24 hours did not reduce the consumption of bacterial antibiotics or the length of hospital stay in adults presenting with respiratory symptoms, fever, chest pain or reduced general condition in acute care.

Clostridium difficile infections in teaching hospital in northern Finland.

BACKGROUND: The aim of this study to compare the incidence of Clostridium difficile (CD) infections in the five university hospital districts in Finland based on national register. The clinical findings of CD cases in the Oulu University Hospital (OUH) in one-year cohort were also analyzed. METHODS: The numbers of the CD cases from the national register were used for the hospital district comparison. A retrospective cohort study was conducted among all adult (> 16 years) patients treated in the OUH in 2013, who had positive CD toxin B gene test in stools. The selection of the cohort was based on the data from the OUH microbiology laboratory and the clinical characteristics were collected from hospital records. RESULTS: The incidence of CD findings in 2013 was higher in the OUH district than in the other four university hospital districts: 159 vs. 70 to 84 per 100,000 inhabitants. In 2013, 261 patients had CD infection treated in the OUH. The yearly number of CD cases treated in the OUH in 2009-2016 varied between 221 and 287, and the corresponding proportion of positive CD findings out of all samples taken varied from 10.0 to 17.8%. A recurrent infection was seen in 58 patients (22%) while the all-cause 30 day mortality was 7.3%. CONCLUSIONS: Diagnostic strategies differed nationally, which may explain the differences in CD incidence between the university hospital districts. In the OUH, no increase in the number of CD infections was seen in 2009-2016. Main characteristics of the patient cohort in the OUH were in harmony with earlier literature.

Warfarin-induced calciphylaxis in patients with normal renal function.

WHAT IS KNOWN AND OBJECTIVE: Calciphylaxis is a rare and potentially life-threatening cause of skin necrosis and is poorly recognized by clinicians in non-uraemic patients. CASE DESCRIPTION: We report five cases of warfarin-induced calciphylaxis in patients with normal renal function. In four cases, sodium thiosulphate was successfully used as a treatment. No other predisposing factors besides obesity and warfarin were found in these patients. WHAT IS NEW AND CONCLUSION: Previously only few cases of solely warfarin-induced calciphylaxis have been described. Treatment with sodium thiosulphate has shown promising results, and there is thus a need to improve the recognition of calciphylaxis.

Plasma ghrelin concentrations are positively associated with carotid artery atherosclerosis in males.

BACKGROUND: Ghrelin, a peptide hormone from stomach, stimulates food intake and decreases fat utilization. Ghrelin binds to growth hormone secretagogue receptor (GHSR). GHSR density has been shown to be upregulated in atherosclerotic lesions, but the relationship between ghrelin concentration and atherosclerosis has not yet been studied. We, therefore, characterized the association between ghrelin concentration and carotid artery intima-media thickness (IMT) in a population-based cohort of 1024 middle-aged (40-60 years) men and women. METHODS: Intima-media thickness and the number of atherosclerotic plaques were determined ultrasonographically. Fasting plasma ghrelin concentrations were analysed using RIA-kit (PhoenixPeptide). RESULTS: There was a positive association between mean IMT and ghrelin concentration in the analysis of males before and after adjustments for the traditional risk factors of atherosclerosis [age, systolic blood pressure, LDL cholesterol, body mass index (BMI), and smoking (ancova, P = 0.004 and P = 0.007, respectively)]. However, no such association was found in females (P = 0.985 and P = 0.915). There was no correlation between ghrelin and CRP concentrations or ghrelin and smoking. CONCLUSION: Ghrelin concentrations and carotid artery atherosclerosis are positively associated in males even after adjustment for the commonly recognized risk factors of atherosclerosis. Experimental and prospective studies are warranted to elucidate the role of ghrelin in atherosclerosis.

Levofloxacin does not decrease mortality in Staphylococcus aureus bacteraemia when added to the standard treatment: a prospective and randomized clinical trial of 381 patients.

OBJECTIVES: To study whether levofloxacin, added to standard treatment, could reduce the high mortality and complication rates in Staphylococcus aureus bacteraemia. DESIGN: A prospective randomized multicentre trial from January 2000 to August 2002. SETTING: Thirteen tertiary care or university hospitals in Finland. SUBJECTS: Three hundred and eighty-one adult patients with S. aureus bacteraemia. Patients with meningitis, and those with fluoroquinolone- or methicillin-resistant S. aureus were excluded. INTERVENTIONS: Standard treatment (mostly semisynthetic penicillin) (n = 190) or that combined with levofloxacin (n = 191). Supplementary rifampicin was recommended if deep infection was suspected. MAIN OUTCOME MEASURES: Primary end-points were mortality at 28 days and at 3 months. Clinical and laboratory parameters were analysed as secondary end-points. RESULTS: Adding levofloxacin to the standard treatment offered no survival benefit. Case fatality rates were 14% in both groups at 28 days, and 21% in the standard treatment and 18% in the levofloxacin group at 3 months. Levofloxacin combination did not differ from the standard treatment in the number of complications, time to defervescence, decrease in serum C-reactive protein concentration or length of antibiotic treatment. Deep infection was found in 84% of patients within 1 week following randomization with no difference between the treatment groups. At 3 months, the case fatality rate for patients with deep infection was 17% amongst those who received rifampicin versus 38% for those without rifampicin (P < 0.001, odds ratio = 3.06, 95% confidence intervals = 1.69-5.54). CONCLUSIONS: Levofloxacin combined with standard treatment in S. aureus bacteraemia did not decrease mortality or the incidence of deep infections, nor did it speed up recovery. Interestingly, deep infections in S. aureus bacteraemia appeared to be more common than previously reported.

The negative association between plasma ghrelin and IGF-I is modified by obesity, insulin resistance and type 2 diabetes.

AIMS/HYPOTHESIS: Ghrelin is a natural growth hormone-releasing peptide thought to be involved in the regulation of energy metabolism. The recent studies concerning the association between ghrelin and insulin-like growth factor-I (IGF-I) concentrations have shown either negative correlation or no correlation at all. The aims of this study were to clarify the association between ghrelin and IGF-I concentrations in a large cohort and to characterize whether obesity, insulin resistance and type 2 diabetes affect this association. METHODS: We analysed fasting plasma ghrelin and IGF-I concentrations of 1,004 middle-aged subjects of the population-based OPERA study. Insulin resistance was estimated using QUICKI. RESULTS: IGF-I concentrations were negatively associated with ghrelin concentrations in the analysis of all subjects before (beta=-0.32, p<0.001) and after adjustments for BMI, insulin levels, sex and age (beta=-0.40, p<0.001). The association was particularly strong in males and in the higher BMI tertiles. The degree of association varied in relation to the glycaemic status: no insulin resistance: r(2)=6.5% (p<0.001), insulin resistance without type 2 diabetes: r(2)=21.0% (p<0.001), type 2 diabetes: r(2)=25.4 (p<0.001). IGF-I levels explained larger proportion (r(2)=9.8%) of the variation in ghrelin concentrations compared to fasting insulin concentration (r(2)=3.0%) and BMI (r(2)=1.5%). CONCLUSIONS/INTERPRETATION: There is a negative and independent association between ghrelin and IGF-I concentrations in middle-aged subjects. The interaction between IGF-I and ghrelin is modified by obesity, IR and type 2 diabetes. Further studies are warranted to elucidate the role of ghrelin in the development of these states.

Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects.

BACKGROUND: Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. METHODS AND RESULTS: A meta-analysis was performed on individual patient data from 7 large, population-based studies (each >500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P<0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratio=0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals (P for linearity=0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance (P=0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. CONCLUSIONS: The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy.

Toxic acute hepatitis and hepatic fibrosis after consumption of chaparral tablets.

In this report we describe a young, previously healthy woman who developed severe acute hepatitis after consumption of chaparral tablets, a commonly used herbal product. In this case, the elimination-rechallenge event and the exclusion of other possible aetiologic factors strongly supported true causality between the herbal product and the liver damage. Primary liver biopsy showed severe toxic hepatitis consistent with previous reports of chaparral-induced liver damage. Later, 6 months after the liver function tests had normalized, permanent hepatic fibrosis could still be seen.

Prevalence and prognosis of subjects with Brugada-type ECG pattern in a young and middle-aged Finnish population.

AIMS: The purpose of this study was (1) to determine the prevalence of Brugada syndrome ECG abnormalities ("Brugada sign") in two Finnish populations and (2) to evaluate the natural course of subjects with the "Brugada sign". METHODS AND RESULTS: The study population consisted of 2479 healthy male Air Force applicants (age 18-30 years), and 542 healthy middle-aged subjects (age 40-60 years). All subjects underwent a thorough physical examination and 12-lead ECG in 1980-1990 (first population) and in 1991-1992 (second population). The ECG criteria suggested by the European Society of Cardiology were used to identify subjects with the "Brugada sign". Fifteen (0.61%) subjects in the first population and three subjects in the second population (0.55%) fulfilled the ECG criteria for type 2 or 3 Brugada syndrome, i.e., they had J-point elevation and a saddleback-type ST-segment configuration in the right precordial leads. Type 1 Brugada ECG abnormality (coved ST-segment elevation) was not seen in any subject. No mortality or life-threatening ventricular arrhythmias occurred in either study population during follow-up (19+/-2 years and 11+/-1 years, respectively). CONCLUSION: The benign natural course of the patients with the "Brugada sign" suggests that in asymptomatic subjects without a family history of sudden cardiac death, type 2 or 3 Brugada ECG pattern is a normal variant rather than a specific predictor of life-threatening ventricular arrhythmias.

Increased pulse pressure is associated with reduced baroreflex sensitivity.

Although pulse pressure (PP), heart rate variability (HRV) and baroreflex sensitivity (BRS) have been shown to predict cardiovascular events and mortality in various populations, their relationships have not been clarified. We examined these associations in two separate population-based samples of healthy middle-aged subjects. In population 1, data were obtained from 149 subjects (71 men and 78 women) aged 35-64 (mean 47.7) years, and in population 2, from 214 subjects (88 men and 126 women) aged 40-62 (mean 50.5) years. Increased 24-h ambulatory PP was related to decreased cross-spectral BRS independent of age and gender (beta=-0.28, P<0.001 for population 1; beta=-0.22, P=0.003 for population 2). This association remained significant when 24-h ambulatory diastolic blood pressure, body mass index, smoking and alcohol intake were added as covariates in the multivariate analysis. Increased ambulatory PP was also associated with increased beat-to-beat systolic arterial pressure variability. Associations between ambulatory PP and HRV were not significant after controlling for age and gender. Our results suggest that elevated PP does not affect overall HRV, but it interferes with baroreflex-mediated control of the heart rate. This association may be due to a common denominator, such as arterial stiffness, for PP and BRS.

Ghrelin Arg51Gln mutation is a risk factor for Type 2 diabetes and hypertension in a random sample of middle-aged subjects.

AIMS/HYPOTHESIS: Experimental studies have suggested that ghrelin, a novel gastrointestinal peptide hormone, could play a role in glucose homeostasis. In addition, ghrelin has been associated with beneficial haemodynamic effects in experimental settings. Since the Arg51Gln mutation changes the carboxyterminal amino acid of the mature hormone and is associated with low ghrelin concentrations, we assessed the hypothesis that Arg51Gln mutation is a risk factor for Type 2 diabetes, impaired glucose tolerance, and hypertension. METHODS: Blood pressure recordings and oral glucose tolerance test were carried out in the hypertensive ( n=519) and control cohorts ( n=526) of our well-defined OPERA study. The genotypes and plasma IGF-I and IGFBP-1 concentrations of 1031 subjects were analysed. RESULTS: The ghrelin 51Gln allele was a risk factor for Type 2 diabetes, and the effect remained significant after adjustment for age, BMI, and study group (OR=2.53, CI: 1.11-5.75, p=0.027). In addition, the 51Gln allele was a risk factor for hypertension (OR=2.63, CI: 1.37-5.08, p=0.003). 51Gln carriers had lower concentrations of IGF-I and higher concentrations of IGFBP-1 compared to non-carriers. CONCLUSION/INTERPRETATION: The ghrelin 51Gln allele could increase the risk for Type 2 diabetes and hypertension. The low IGF-I concentrations in 51Gln carriers suggest that the mechanism might be associated with low GH concentrations.

Endothelial nitric oxide synthase gene Glu298Asp polymorphism and blood pressure, left ventricular mass and carotid artery atherosclerosis in a population-based cohort.

OBJECTIVE: Decreased production of endothelial nitric oxide (NO) is associated with different cardiovascular pathology. We studied the association between the Glu298Asp polymorphism of the NO producing gene, endothelial nitric oxide synthase (eNOS), and hypertension, left ventricular mass (LVM) and carotid artery intima-media thickness (IMT) in a population-based cohort of hypertensive and control subjects. DESIGN: Cross-sectional case-control study. SETTING: District around Oulu University Hospital, Northern Finland. SUBJECTS AND METHODS: The study population consisted of 600 middle-aged hypertensive subjects (300 men and 300 women) and 600 controls (300 men and 300 women) living in the City of Oulu. The hypertensive subjects were randomly selected by age stratification from the Social Insurance Institute register for reimbursement of antihypertensive medication. For each hypertensive subject, an age- and sex-matched control was randomly selected from the national health register. The overall participation rate was 87.8%. In the present study a total of 1024 subjects were screened. Echocardiographic examinations were performed by a trained cardiologist and carotid ultrasonographic examinations by a trained radiologist. RESULTS: The genotype distributions and allele frequencies between the hypertensive and control subjects and the relationship between the Glu298Asp variant and blood pressure, LVM and carotid artery IMT were determined. No differences in genotype distribution or allele frequencies were found between the hypertensive and control groups (the frequency of the Asp allele 0.299 vs. 0.288, respectively). Also, we could not find any association between the eNOS genotype and the measured cardiovascular complications. CONCLUSIONS: The Glu298Asp variant of the eNOS gene does not seem to be a major risk factor for cardiovascular alterations in the general population.

Variation at the cholesteryl ester transfer protein gene in relation to plasma high density lipoproteins cholesterol levels and carotid intima-media thickness.

BACKGROUND: Cholesteryl ester transfer protein (CETP) plays a major role in lipoprotein metabolism. We have screened the CETP gene for mutations and polymorphisms regulating high density lipoproteins cholesterol (HDL-C) levels and the development of atherosclerosis, and found some polymorphisms (I405V and R451Q) to have minor effects. DESIGN: The purpose of this study was to investigate the combined effect of the several polymorphisms of the CETP gene so far found on HDL-C levels and carotid intima-media thickness (IMT), and, in addition, to study whether the recently found functional polymorphism in the promoter region of the CETP gene (C to A, - 629 relative to the first transcribed nucleotide) explains the previous associations due to linkage disequilibrium. The genotypes were determined in a population sample of 481 men and women. RESULTS: There were no significant differences in plasma CETP activity or carotid IMT between the genotypes of the promoter polymorphism. The women with the CC genotype of the promoter polymorphism had the lowest HDL-C levels (P < 0.001), but no such difference was seen in men. Detected polymorphisms of the CETP gene explained about 8% of the variation in HDL-C in women and about 7 and 10% of the variation in carotid IMT in women and men, respectively. The associations of the promoter, I405V and R451Q-A373P polymorphisms with HDL-C and carotid IMT seemed to be independent of each other. The associations with IMT were independent of total HDL-C levels, suggesting that HDL subfractions may have more effect on IMT. CONCLUSION: The CETP gene locus was found to be polymorphic and its polymorphisms explained a reasonable proportion of the variation in the degree of carotid atherosclerosis.

Effect of hypertension and risk factors on diameters of abdominal aorta and common iliac and femoral arteries in middle-aged hypertensive and control subjects: a cross-sectional systematic study with duplex ultrasound.

There is a general tendency towards atherosclerosis and arterial dilatation in older age, and high blood pressure also tends to increase arterial diameters. The purpose of this study was to examine the effect of hypertension and other cardiovascular risk factors on aortic, common iliac and common femoral artery diameters. The diameters of the abdominal aorta and the iliac and femoral arteries and the extent of echogenic plaques in the aorta and the iliac arteries down to groin level were evaluated with ultrasound in 1007 middle-aged (40-60 years) men (505) and women (502), 496 with arterial hypertension and 511 controls. Twenty-eight subjects were excluded because of poor visualization. Men had significantly larger diameters of the abdominal aorta (mean 21.3+/-2.8 vs. 17.8+/-1.3 mm) and the common iliac (13.4+/-2.0 vs. 12.2+/-1.2) and common femoral arteries (11.0+/-1.4 vs. 9.7+/-0.9) than women (P for all <0.001), but arterial diameter was also related to the subject's size. Atherosclerotic plaques, age and height were associated with the diameter of the abdominal aorta in men, while high body mass index (BMI) had less significance. The diameter of the aorta was larger in hypertensive men aged 56-60 than in controls of the same age. In women, height, BMI and diastolic blood pressure (DBP) were associated with the diameter of the aorta, while systolic blood pressure (SBP) had less and age no effect. Age, plaques, height, BMI, DBP and SBP were associated with the diameters of the common iliac arteries in both genders, while smoking had an inverse correlation. The results on lipid values were inconsistent and an abnormal glucose tolerance test proved nonsignificant. In conclusion, arterial size measured as a diameter related to the subject's size was larger in men. Age, arterial plaques and blood pressure increased arterial diameter significantly. However, the hypertensive disease itself had only a minimal effect. The changes were smaller in women than in men.

Gamma-glutamyl transpeptidase and the metabolic syndrome.

OBJECTIVE: To analyse the associations between serum gamma-glutamyl transpeptidase activity (GTP) and the components of the metabolic syndrome. DESIGN: Cross-sectional, observational study of hypertensive patients and controls. SETTING: The participating subjects visited the research laboratory of the Department of Internal Medicine, University of Oulu, Oulu, Finland. SUBJECTS: A total of 1045 Caucasians, 40-59 years of age, consisting of 261 drug-treated hypertensive men, 258 drug-treated hypertensive women and 526 age- and sex-matched controls. MAIN OUTCOME MEASURES: The associations between GTP and the cardiovascular risk factors were analysed through multiple regression and logistic methods and by GTP tertiles. The independent effect of GTP on different insulin measures, calculated from the values of 2 h of oral glucose tolerance test, was estimated after concurrent adjustment for age, obesity and alcohol consumption. RESULTS: GTP correlated highly significantly with the components of the metabolic syndrome. The correlation coefficient were 0.33 between GTP and body mass index, 0. 25 between GTP and systolic blood pressure in control men (P = 0. 0001), 0.39 between GTP and triglycerides, and 0.32 between GTP and fasting insulin in hypertensive women (P = 0.0001). The association between GTP and blood pressure remained significant only at upright measurements in controls. All insulin measures had a significant positive association with increasing GTP tertiles in all the study groups (e.g. fasting insulin 8.1 mU L-1 in the lowest and 11.0 mU L-1in the highest tertile in control women, P = 0.0001), with the exception of fasting insulin in control men. In a pooled logistic analysis after adjustment for age, body mass index, alcohol consumption and gender, the independent predictors of the metabolic syndrome were body mass index, uric acid, total cholesterol and GTP (for log-transformed GTP odds ratio 4.0, 95% CI: 2.80-5.69). CONCLUSIONS: There are significant associations between GTP and the components of the metabolic syndrome. Elevated levels of GTP may not always indicate increased alcohol consumption, but may also suggest the existence of the metabolic syndrome with its subsequent deleterious consequences.

Dietary and other non-pharmacological treatments in patients with drug-treated hypertension and control subjects.

OBJECTIVE: To study the nutrient intakes and other lifestyle patterns of drug-treated hypertensives and control subjects. DESIGN: A cross-sectional population-based epidemiological study. SETTING: The participating study subjects visited the research laboratory of the Department of Internal Medicine of the University of Oulu, Oulu, Finland. PARTICIPANTS: A total of 1045 Finnish men and women aged 40-60 years, of whom 716 (69%) completed 7-day food records. MAIN OUTCOME MEASURES: Intakes of energy, protein, total fat, saturated, monounsaturated and polyunsaturated fatty acids, carbohydrate, alcohol, fibre, calcium, magnesium, potassium and sodium were assessed from 7-day food records. The study also included measurements of blood pressure, blood glucose and plasma lipids, and anthropometric variables. Information about alcohol consumption, smoking habits and physical activity was collected by interviewing. RESULTS: Obesity was common amongst the hypertensive subjects, whose body mass indices were significantly higher than those of the control subjects. Only minor differences existed in the energy intake levels and nutrient intakes of the hypertensive and control cohorts, but the control subjects performed more physical activity than the hypertensive subjects. The dietary recommendations concerning the intakes of total and saturated fats, carbohydrate and fibre were poorly met by both the hypertensive and the control subjects. Alcohol consumption was high amongst the hypertensive men, especially amongst the smokers. CONCLUSIONS: Non-pharmacological treatment, including dietary management, of hypertensive patients at high risk for cardiovascular complications seems still to be inadequate. Additional well-focused efforts are needed to intensify the dietary treatment as well as to reduce alcohol consumption and smoking amongst hypertensives.

Baroreflex sensitivity and variants of the renin angiotensin system genes.

OBJECTIVES: Because the renin-angiotensin-aldosterone system (RAS) modifies cardiovascular autonomic regulation, we studied the possible associations between baroreflex sensitivity (BRS) and polymorphism in the RAS genes. BACKGROUND: Wide intersubject variability in BRS is not well explained by cardiovascular risk factors or life style, suggesting a genetic component responsible for the variation of BRS. METHODS: Baroreflex sensitivity as measured from the overshoot phase of the Valsalva maneuver and genetic polymorphisms were examined in a random sample of 161 women and 154 men aged 41 to 61 years and then in an independent random cohort of 29 men and 37 women aged 36 to 37 years. An insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE), M235T variants of angiotensinogen (AGT) and two diallelic polymorphisms in the gene encoding aldosterone synthase (CYP11B2), one in the promoter (-344C/T) and the other in the second intron, were identified by polymerase chain reaction. RESULTS: In the older population, BRS differed significantly across CYP11B2 genotype groups in women (10.1 +/- 4.5, 8.7 +/- 3.8 and 7.1 +/- 3.2 ms x mm Hg(-1) in genotypes -344TT, CT and CC, respectively, p = 0.003 and 11.1 +/- 4.4, 8.9 +/- 4.1 and 7.5 +/- 3.4 ms x mm Hg(-1) in intron 2 genotypes 1/1, 1/2 and 2/2, respectively, p = 0.002), but not in men. No comparable associations were found for BRS with the I/D polymorphism of ACE or the M235T variant of AGT. In the younger population, BRS was even more strongly related to the CYP11B2 promoter genotype (p = 0.0003). The association was statistically significant both in men (p = 0.015) and in women (p = 0.03). CONCLUSIONS: Common genetic polymorphisms in the aldosterone synthase (CYP11B2) gene is associated with interindividual variation in BRS.

Cholesteryl ester transfer protein gene polymorphisms are associated with carotid atherosclerosis in men.

BACKGROUND: The cholesteryl ester transfer protein (CETP) is involved in the reverse cholesterol transport and is therefore a candidate gene for atherosclerosis. DESIGN: The prevalences of the I405V and the R451Q polymorphisms were studied in a population sample of 515 men and women. Genotypes were determined by PCR and carotid atherosclerosis by ultrasonography as the mean intima-media thickness (IMT) of the carotid arteries. RESULTS: The Q451 allele was associated with significantly lower intima media thickness in men (P = 0.001). The Q451 allele was, in our earlier study, associated with high plasma CETP activity in men. The VV405 genotype was associated with lower plasma CETP activity compared with the II405 genotype (P < 0.01 for the difference). In the general linear model general factorial procedure the interaction between alcohol consumption and the I405V genotype on IMT was significant (P = 0.013) in men, and when the interaction term was taken into the model the I405V genotype also significantly affected IMT (P = 0.008). The VV405 genotype seems to be most harmful for men with the highest alcohol consumption. CONCLUSIONS: We describe two polymorphisms of the CETP gene associated with intima media thickness in men. A significant interaction was found between alcohol consumption and the I405V genotype on IMT.

Heart rate variability and progression of coronary atherosclerosis.

Low heart rate (HR) variability is associated with increased risk of cardiovascular morbidity and mortality, but the causes and mechanisms of this association are not well known. This prospective study was designed to test the hypothesis that reduced HR variability is related to progression of coronary atherosclerosis. Average HR and HR variability were analyzed in 12-hour ambulatory ECG recordings from 265 qualified patients participating in a multicenter study to evaluate the angiographic progression of coronary artery disease in patients with prior coronary artery bypass surgery and low high-density lipoprotein cholesterol concentrations (<1.1 mmol/L). Participants were randomized to receive a placebo or gemfibrozil therapy. The progression of coronary atherosclerosis was estimated by quantitative, computer-assisted analysis of coronary artery stenoses from the baseline angiograms and from repeated angiograms performed an average of 32 months later. The progression of focal coronary atherosclerosis of the patients randomized to placebo therapy was more marked in the tertile with the lowest standard deviation of all normal to normal R-R intervals (SDNN, 74+/-13 ms; mean decrease in the per-patient minimum luminal diameter -0.17 mm; 95% confidence interval [CI], -0.23 to -0.12 mm) than in the middle tertile (SDNN, 107+/-7 ms; mean decrease -0.05 mm; 95% CI, -0.08 to -0.01 mm) or highest tertile (SDNN, 145+/-25 ms; mean change 0.01 mm; 95% CI, -0. 04 to 0.02 mm) (P<0.001 between the tertiles). This association was abolished by gemfibrozil. SDNN was lower (P<0.001) and minimum HR was faster (P<0.01) in the patients with marked progression than in those with regression of focal coronary atherosclerosis. In multiple regression analysis including HR variability, minimum HR, demographic and clinical variables, smoking, blood pressure, glucose, lipid measurements and lipid-modifying therapy, progression of focal coronary atherosclerosis was independently predicted by the SDNN (beta=0.24; P=0.0001). Low HR variability analyzed from ambulatory ECG predicts rapid progression of coronary artery disease. HR variability provided information on progression of focal coronary atherosclerosis beyond that obtained by traditional risk markers of atherosclerosis.