Juha Virolainen

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

BACKGROUND Aldosterone 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. METHODS AND RESULTS A 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). CONCLUSIONS Genetic 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.

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.

Relationship of electrocardiographic repolarization measures to echocardiographic left ventricular mass in men with hypertension.

Objective Arterial hypertension often leads to an increase in left ventricular mass (LVM). Marked left ventricular hypertrophy (LVH) is associated with potentially arrhythmogenic ventricular repolarization abnormalities, which may contribute to the increased risk of sudden cardiac death in this disorder. We studied whether electrocardiographic repolarization changes are already detectable in mild LVM increase associated with hypertension. Methods In 220 men (mean age 51 ± 6 years) attending the GENRES hypertension study, we measured QT intervals (QTend and QTpeak), T-wave peak to T-wave end (TPE) intervals, and novel T-wave morphology parameters (principal component analysis ratio, T-wave morphology dispersion, total cosine R-to-T, and T-wave residuum) from a digital standard 12-lead electrocardiogram, and related them to echocardiographically determined LVM. Results In this group of moderately hypertensive men, the mean LVM index (LVMI; LVM divided by body surface area) was 99 ± 19 g/m2, with only 18% of the subjects showing evidence of echocardiographic LVH (LVMI > 116 g/m2). LVMI correlated significantly with QT intervals (r = 0.16–0.21, P = 0.018–0.002), TPE intervals (r = 0.23–0.27, P < 0.001), and T-wave morphology parameters (r = 0.22–0.39, P < 0.001). Except for the QTpeak interval, the relationship between LVMI and electrocardiographic repolarization parameters was independent in multivariate analyses. Conclusion Altered electrocardiographic ventricular repolarization, indicating reduced repolarization reserve and possibly increased repolarization heterogeneity, is already present in hypertensive men with only mild LVM increase. At a population level, this may carry important risk implications for the large group of hypertensive patients.

Prevalence and predictors of audible physiological third heart sound in a population sample aged 36 to 37 years.

BACKGROUND A physiological third heart sound (S3) is common in youth but allegedly very rare after the age of 40 years. The mechanism of its disappearance is not known. The aim of this work was to study the prevalence and predictors of physiological S3 in a population-based sample of persons approaching 40 years of age. METHODS AND RESULTS A random sample of 120 persons born in 1954 was invited; 93 (42 men) entered the study. Their physical activity, alcohol and tobacco consumption, and salt intake were quantified by diary follow-up. The presence of an S3 was determined by auscultation and confirmed by phonocardiography. Left ventricular (LV) size, mass, and systolic function were assessed by M-mode echocardiography and LV filling by Doppler velocimetry of transmitral flow. An audible S3 was detected in 22 subjects, 1 of whom had heart disease. The prevalence of physiological S3 was 23.1%. Subjects with physiological S3 had a lower body mass index (22.3 +/- 2.8 versus 24.6 +/- 4.1 kg/m2 [mean +/- SD], P = .005), lower heart rate (63 +/- 7 versus 68 +/- 10 beats per minute, P = .015), higher peak early diastolic transmitral velocity (67 +/- 10 versus 58 +/- 8 cm/s, P = .002), and higher acceleration of early diastolic velocity (717 +/- 148 versus 622 +/- 122 cm/s2, P = .012) than those without S3. No differences were noted in the lifestyle characteristics, blood pressure, or LV mass and systolic function. Body mass index and peak early diastolic transmitral velocity were independent predictors of physiological S3 in logistic regression analysis. CONCLUSIONS Nearly one fourth of persons approaching their forties still have an audible physiological S3. The presence of S3 is predicted by leanness and a high early diastolic LV inflow velocity; the disappearance of S3 is unlikely to be secondary to increasing blood pressure and relative LV hypertrophy, as is widely presented, but reflects a more primary age-related alteration of LV early diastolic function.

Evolution of heart rate variability in cardiac transplant recipients: a clinical study.

Koskinen P, Virolainen J, Koskinen Pk, Häyry P, Kupari M (Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, and Transplantation Laboratory, University of Helsinki, Helsinki, Finland). Evolution of heart rate variability in cardiac transplant recipients: a clinical study. J Intern Med 1996; 239: 443–9.

Short-term electrophysiological effects of losartan, bisoprolol, amlodipine, and hydrochlorothiazide in hypertensive men

Background and aim. Hypertension-induced left ventricular structural remodelling associates with repolarization abnormalities. We investigated if antihypertensive drugs can modulate ventricular repolarization. Methods. A total of 183 hypertensive men received for 4 weeks drugs (losartan 50 mg, bisoprolol 5 mg, amlodipine 5 mg, hydrochlorothiazide (HCTZ) 25 mg) in a randomized order, separated by 4-week placebo periods. Electrocardiograms (ECG) were recorded at the end of placebo and drug periods. Measurements of repolarization duration (QT intervals), repolarization heterogeneity (T-wave peak to T-wave end (TPE) intervals), and T-wave morphology (T-wave principal component analysis (PCA) ratio, T-wave morphology dispersion (TMD), and total cosine R-to-T (TCRT)) during each drug were compared to placebo measurements. Results. Losartan and bisoprolol shortened maximum and mean rate-adjusted QT intervals as well as mean TPE interval, decreased TMD, and increased TCRT. Losartan also shortened precordial maximum TPE interval and decreased PCA ratio. Amlodipine had no repolarization effects, whereas HCTZ prolonged precordial maximum TPE interval and mean TPE interval. Conclusion. Losartan and bisoprolol have beneficial short-term ECG repolarization effects. Amlodipine seems to have no repolarization effects. HCTZ seems to prolong the ECG TPE interval, potentially reflecting increased repolarization heterogeneity. These findings show that antihypertensive drugs may relatively rapidly and treatment-specifically modulate ECG markers of ventricular repolarization.

Age-dependent increase in aortic stiffness during negative intrathoracic pressure in healthy subjects ☆

Abstract An acute reduction in intrathoracic pressure increases the transmural pressure of the thoracic aorta and cardiac chambers and thus left ventricular systolic wall stress as well. 1 Forced inspiration against airway resistance (Mueller maneuver) has therefore been advocated as an afterload challenge to the left ventricle. 2 The stiffness of the ascending aorta is another important determinant of left ventricular afterload and depends on the structure of the aortic wall and on the degree of aortic distention. 3 In theory, negative intrathoracic pressure could increase left ventricular systolic load also by augmenting the stiffness of the proximal aorta through increased distention, but no direct data are available. In the present study, we measured aortic stiffness at rest and during the Mueller maneuver using 2-dimensional echocardiography of the proximal aorta together with continuous noninvasive blood pressure monitoring. To assess whether age-related changes in the aorta modify the effect of negative intrathoracic pressure, we compared the responses between groups of young and middle-aged healthy subjects.

Resection and Patch Repair of a Large Saccular Coronary Artery Aneurysm at the Left Main Bifurcation

Coronary artery aneurysm is a rare condition with primarily conservative treatment. Here, we present a case of saccular left main coronary aneurysm with a successful patch repair and discuss the indications for operative treatment.

Respiratory variation of heart rate and systolic arterial pressure in adults with atrial septal defect

Abstract Heart rate (HR) variation with respiration (sinus arrhythmia) is believed to be minimal or absent in adults with atrial septal defect (ASD), but there is no valid proof. 1 Therefore (and because the way an interatrial communication modifies sinus arrhythmia is of physiologic interest), we studied short-term HR variation in time and frequency domains in adult patients with ASD, and in age- and sex-matched healthy subjects. The variation of noninvasively recorded systolic arterial pressure also was quantified.

Perioperative Myocardial Infarction in Non-Cardiac Surgery Patients: A Prospective Observational Study

Background and Aims: Perioperative myocardial infarction is an underdiagnosed complication causing morbidity, mortality, and considerable costs. However, evidence of preventive and therapeutic options is scarce. We investigated the incidence and outcome of perioperative myocardial infarction in non-cardiac surgery patients in order to define a target population for future interventional trials. Material and Methods: We conducted a prospective single-center study on non-cardiac surgery patients aged 50 years or older. High-sensitivity troponin T and electrocardiograph were obtained five times perioperatively. Perioperative myocardial infarction diagnosis required a significant troponin T release and an ischemic sign or symptom. Perioperative risk calculator was used for risk assessment. Results: Of 385 patients with systematic ischemia screening, 27 patients (7.0%) had perioperative myocardial infarction. The incidence was highest in vascular surgery—19 of 172 patients (11.0%). The 90-day mortality was 29.6% in patients with perioperative myocardial infarction and 5.6% in non–perioperative myocardial infarction patients (p < 0.001). Perioperative risk calculator predicted perioperative myocardial infarction with an area under curve of 0.73 (95% confidence interval: 0.64–0.81). Conclusion: Perioperative myocardial infarction is a common complication associated with a 90-day mortality of 30%. The ability of the perioperative risk calculator to predict perioperative myocardial infarction was fair supporting its routine use.