Markku Kupari

Prevalence of aortic valve abnormalities in the elderly: An echocardiographic study of a random population sample

OBJECTIVES This study was undertaken to elucidate the prevalence of aortic valve abnormalities in the elderly. BACKGROUND The age of persons treated actively for valve disorders is increasing. More information is needed about the prevalence of aortic valve disease in old age. METHODS Randomly selected men and women in the age groups 75 to 76, 80 to 81 and 85 to 86 years (n = 501) participating in the Helsinki Ageing Study were studied with imaging and Doppler echocardiography. Additionally, 76 persons 55 to 71 years of age were included. The systolic aortic valve area was calculated by the continuity equation. The velocity ratio (peak velocity in the left ventricular outflow tract/peak velocity across the aortic valve) was a supplementary criterion for aortic stenosis. Valve regurgitation and cusp calcification were assessed visually. RESULTS Evaluation of the aortic valve was possible in 552 persons (96%). Mild calcification was found in 222 (40%) and severe calcification in 72 (13%). Two persons (0.4%) had an aortic valve prosthesis. Critical native valve stenosis (calculated aortic valve area < or = 0.8 cm2 and velocity ratio < or = 0.35) was found in 12 persons (2.2%). Six of these were symptomatic and potentially eligible for valvular surgery. All persons with aortic valve stenosis were in the three oldest age groups. The prevalence of critical aortic valve stenosis was 2.9% (95% confidence interval 1.4% to 5.1%) in the group 75 to 86 years of age. Aortic regurgitation, mostly mild, was found in 29% of the entire study cohort. CONCLUSIONS Calcific aortic valve stenosis constitutes a significant health problem in the elderly. Only a minority of those with potentially operable aortic valve stenosis undergo surgery.

Congestive heart failure in old age: prevalence, mechanisms and 4‐year prognosis in the Helsinki Ageing Study

Objective. To examine the prevalence, underlying diseases, abnormalities of left ventricular function and prognosis in congestive heart failure (CHF) of old age.

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.

Natural history of aortic valve stenosis of varying severity in the elderly.

In a population sample of 501 persons aged 75 to 86 years, Doppler echocardiography uncovered moderate or severe aortic valve stenosis in 8.8% of women and 3.6% of men. Severe aortic valve stenosis predicted a four-fold-age- and sex-adjusted risk of death within 4 years of diagnosis, and mortality tended to be increased also with moderate lesions; mild aortic valve stenosis had a favorable outcome.

Cardiac Sarcoidosis and Giant Cell Myocarditis as Causes of Atrioventricular Block in Young and Middle-Aged Adults

Background—Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) may present as high-degree atrioventricular block (AVB), but their proportion of the causal spectrum of AVB is not well-known. We investigated the prevalence of biopsy-verified CS and GCM in young and middle-aged adults undergoing pacemaker (PM) implantation for AVB. Methods and Results—We used the PM registry of Helsinki University Central Hospital to identify all patients aged 18 to 55 years who underwent PM implantation for AVB between January 1999 and April 2009 and reviewed their medical records. In total, 133 patients had either second- or third-degree AVB as an indication for PM. Of them, 61 had a known cause for AVB, and they were excluded from further analyses. Among the remaining 72 patients with initially unexplained AVB, biopsy-verified CS or GCM was found in 14 (19%) and 4 (6%) patients, respectively. The majority (16/18, 89%) were women. Among the adult patients aged <55 years, the prevalence of CS and GCM combined was 14% (95% CI, 7.7% to 19.3%) of the whole AVB population and 25% (95% CI, 15% to 35%) of those with an initially unexplained AVB. Over an average of 48 months of follow-up, 7 (39%) of 18 patients with CS or GCM versus 1 of the 54 patients in whom AVB remained idiopathic, experienced either cardiac death, cardiac transplantation, ventricular fibrillation, or treated sustained ventricular tachycardia (P<0.001). Conclusions—CS and GCM explain ≥25% of initially unexplained AVB in young and middle-aged adults. These patients are at high risk for adverse cardiac events.

Factors influencing Doppler indexes of left ventricular filling in healthy persons

Ninety-three healthy persons aged 11 to 91 years were studied to assess the factors influencing Doppler indexes of left ventricular (LV) diastolic filling. The effects of physical activity, alcohol consumption and smoking were tested in addition to those of age, sex, heart rate, body mass index, blood pressure, left atrial diameter, and LV end-diastolic diameter, wall thickness, mass and fractional shortening. The data were fitted stepwise into multiple linear regression models both in the total population and in 3 groups aged less than 40, 40 to 60 and greater than 60 years. In the total population, age explained 45 to 68% of the variation in the peak early and late diastolic velocities, their ratio, deceleration of the early velocity, atrial filling fraction and peak filling rate normalized to mitral stroke volume. With advancing age--and with increases in either body mass index, heart rate, diastolic blood pressure or LV mass--the indexes of early filling decreased, whereas with regular modest use of alcohol or regular aerobic exercise they increased (p less than 0.05 for all). In the middle-aged subjects, gender explained 32 to 57% of the variation in the peak atrial velocity, early to atrial peak velocity ratio and atrial filling fraction; the peak velocity ratio measured 1.4 +/- 0.3 (mean +/- standard deviation) in men vs 1.0 +/- 0.2 in women (p less than 0.001). In conclusion, many constitutional and physiologic factors and even life-style can influence the Doppler indexes of LV filling. This demonstrates the exquisite sensitivity of the method but indicates also that individual measurements must be interpreted with caution.

Free Fatty Acid Kinetics and Oxidation in Congestive Heart Failure

To characterize fuel utilization of patients with congestive heart failure (CHF), we measured serum free fatty acid (FFA), counterregulatory hormone concentrations, whole body substrate oxidation rates (indirect calorimetry), and the turnover and oxidation rates of FFA ([1-(14)C]-palmitate infusion) in 7 patients with CHF and in 7 cardiac patients without CHF after an overnight fast. Plasma glucose and serum insulin concentrations were comparable, whereas serum FFA, blood ketone body, and fasting blood lactate (p <0.05 for all) concentrations were significantly increased in patients with CHF compared to those without CHF. Fasting plasma norepinephrine (p <0.05), serum cortisol (p <0.01), and growth hormone (p <0.01) concentrations were also higher in patients with CHF than in those without CHF. Rates of energy expenditure at rest (62 +/- 2 vs 56 +/- 1 J x kg(-1) x min(-1), p <0.05), FFA turnover (6.5 +/- 0.5 vs 5.0 +/- 0.4 micromol x kg(-1) x min(-1), p <0.05), and oxidation (2.0 +/- 0.2 vs 1.5 +/- 0.1 micromol x kg(-1) x min(-1)], p <0.05) were significantly higher in patients with CHF than in control subjects. In univariate analysis, the left ventricular ejection fraction was inversely correlated and the plasma norepinephrine concentration positively correlated with both energy expenditure at rest, FFA turnover, and the FFA oxidation rate. In multivariate analysis, the plasma norepinephrine concentration was the most significant predictor of increased FFA oxidation rate. We conclude that release of FFAs to the circulation and their subsequent oxidation are increased in patients with severe CHF after an overnight fast. These changes might reflect stress hormone-induced lipolysis and accompanying stimulation of serum FFA oxidation via mass action.

Relation of aortic stiffness to factors modifying the risk of atherosclerosis in healthy people.

To identify factors predicting aortic stiffness, we studied the modulus of elasticity of the thoracic aorta in relation to sex, obesity, blood pressure, physical activity, smoking, ethanol consumption, salt intake, and serum lipid and insulin levels in 55 healthy people born in 1954. A transverse cine magnetic resonance image of the thoracic aorta was made, and the modulus of elasticity was determined as brachial artery cuff pulse pressure/aortic strain, where strain was determined as the ratio of pulsatile aortic luminal area change to the diastolic luminal area. The average of measurements made in the ascending and descending aorta was used as the elastic modulus of the thoracic aorta. Habitual physical activity, smoking, and alcohol use were quantified by 2-month prospective daily recording and salt intake by 7-day food records. The aortic elastic modulus ranged from 100 to 2091 10(3) dyne/cm2 (median, 390 10(3) dyne/cm2). In multiple regression analyses, log10 aortic elastic modulus was related directly to mean blood pressure (standardized coefficient [beta] = .37, P = .002), serum high-density lipoprotein cholesterol (beta = .36, P = .012), square root of daily energy expenditure in physical activity (beta = .33, P = .005), and log10 serum insulin (beta = .27, P = .047) and inversely to serum low-density lipoprotein cholesterol (beta = -.26, P = .035). A relation to salt intake was also observed, but the regression slope was dependent on mean blood pressure (P = .005 for interaction). These data suggest that many modifiable constitutional and lifestyle characteristics may contribute to the stiffness of the thoracic aorta.

Aortic valve stenosis: an active atheroinflammatory process.

Purpose of review To summarize the current understanding of the pathobiology of aortic valve stenosis and portray the major advances in this field. Recent findings Stenotic aortic valves are characterized by atherosclerosis-like lesions, consisting of activated inflammatory cells, including T lymphocytes, macrophages, and mast cells, and of lipid deposits, calcific nodules, and bone tissue. Active mediators of calcification and cells with osteoblast-like activity are present in diseased valves. Extracellular matrix remodeling, including collagen synthesis and elastin degradation by matrix metalloproteinases and cathepsins, contributes to leaflet stiffening. In experimental animals, hypercholesterolemia induces calcification and bone formation in aortic valves, which can be inhibited by statin treatment. The potential of statins to retard progression of aortic valve stenosis has also been recognized in clinical studies; however, further prospective trials are needed. Angiotensin II-forming enzymes are upregulated in stenotic valves. Angiotensin II may participate in profibrotic progression of aortic valve stenosis and may serve as a possible therapeutic target. Summary Recent findings regarding the interaction of inflammatory cells, lipids, mediators of calcification, and renin–angiotensin system in stenotic valves support the current opinion of aortic valve stenosis being an actively regulated disease, potentially amenable to targeted molecular therapy. Evidence from prospective clinical studies is eagerly awaited.

Blood ketone bodies in congestive heart failure

OBJECTIVES The present study was designed to assess whether blood ketone bodies are elevated in congestive heart failure (CHF) and whether ketonemia is related to the hemodynamic and neurohumoral abnormalities of CHF. BACKGROUND In CHF, consumption of the bodys fat stores may become abnormally high, contributing to the development of cardiac cachexia. Increased mobilization of free fatty acids could, in theory, augment ketogenesis, but whether patients with CHF are prone to ketosis remains unknown. METHODS Forty-five patients with chronic CHF (mean age [+/- SD] 57 +/- 13 years) and 14 control subjects free of CHF (mean age 53 +/- 13 years) underwent invasive and noninvasive cardiac studies and determination of blood ketone bodies (acetoacetate plus beta-hydroxybutyrate), circulating free fatty acids, glucose, lactate, insulin, glucagon, growth hormone, cortisol, norepinephrine, N-terminal proatrial natriuretic peptide, tumor necrosis factor-alpha and interleukin-6 after an overnight fast. RESULTS Patients with CHF had elevated blood ketone bodies (median 267 mumol/liter, range 44 to 952) compared with control subjects (median 150 mumol/liter, range 31 to 299, p < 0.05). In the total study group, blood ketone bodies were related to pulmonary artery wedge pressure (r5 = 0.45, p < 0.001), left ventricular ejection fraction (r3 = -0.37, p < 0.01), right atrial pressure (r3 = 0.36, p < 0.01) and circulating concentrations of free fatty acids (r5 = 0.52, p < 0.001), glucose (r5 = -0.39, p < 0.001), norepinephrine (r3 = 0.45, p < 0.001), growth hormone (r5 = 0.30, p < 0.05) and interleukin-6 (r3 = 0.27, p < 0.05). In multivariate analysis, left ventricular ejection fraction, serum free fatty acids and serum glucose were independent predictors of ketonemia. CONCLUSIONS Blood ketone bodies are elevated in CHF in proportion to the severity of cardiac dysfunction and neurohormonal activation. This may be at least partly attributable to increased free fatty acid mobilization in response to augmented neurohormonal stimulation. Additional studies are needed to identify the detailed mechanisms and clinical implications of CHF ketosis.