Two-Dimensional Speckle-Tracking during Dobutamine Stress Echocardiography in the Detection of Myocardial Ischemia in Patients with Suspected Coronary Artery Disease.

BACKGROUND: Two-dimensional speckle-tracking applied to dobutamine stress echocardiography (DSE) may aid in the detection of coronary artery disease (CAD). The aim of this study was to determine the value of strain, strain rate, and postsystolic strain index (PSI) measured by speckle-tracking during DSE in the evaluation of the presence, extent, and severity of myocardial ischemia. METHODS: Fifty patients 63 ± 7 years of age with intermediate probability of CAD were prospectively recruited. All patients underwent DSE, quantitative positron emission tomographic perfusion imaging, and invasive angiography. Regional peak systolic longitudinal strain, strain rate, and PSI were measured at rest, at a dobutamine dose of 20 µg/kg/min, at peak stress, and at early recovery (1 min after stress). Obstructive CAD was defined as >75% stenosis or 40% to 75% stenosis combined with either fractional flow reserve < 0.80 or abnormal findings on myocardial perfusion positron emission tomography. RESULTS: Obstructive CAD was detected in 22 patients and in 36 of 150 coronary arteries. Strain analyses showed the highest reproducibility at rest, at a dobutamine dose of 20 µg/kg/min, and at early recovery. Increased PSI and reduced strain during early recovery were the strongest predictors of obstructive CAD and were associated with the extent, localization, and depth of myocardial ischemia by positron emission tomography. On vessel-based analysis, strain, PSI, and visual analysis of wall motion provided comparable diagnostic accuracy, whereas the combination of strain or PSI with visual analysis provided incremental value over visual analysis alone. CONCLUSIONS: Assessment of systolic or postsystolic strain by speckle-tracking echocardiography during early recovery after DSE can help in the detection of hemodynamically significant coronary stenosis compared with visual wall motion analysis alone.

Reference Values for Echocardiography in Middle-Aged Population: The Cardiovascular Risk in Young Finns Study.

BACKGROUND: Population and sex-specific reference limits produced with modern ultrasound equipment are needed for accurate clinical echocardiography diagnostics. We report a comprehensive set of reference limits of cardiac function and dimensions in a group of young and middle-aged Finnish men and women produced by the recommendations of European Society of Echocardiography and American Society of Cardiology. METHODS AND RESULTS: Cardiac structure and function was studied in a standardized comprehensive echocardiographic examination in 1,079 healthy volunteers without cardiovascular diseases or major known risk factors participating in the population-based Young Finns study (444 men and 635 women, age range 34 and 49 years). We present sex-specific reference values for echocardiographic parameters reflecting cardiac structure (ventricular and atrial dimensions and volumes, left ventricular wall thickness and mass, aortic root) and function. From the 86 measured parameters, only 7 were not statistically significantly different between sexes. CONCLUSION: The Young Finns study provides echocardiographic reference ranges for cardiac structure and function quantification that can be utilized to enhance the accuracy or echocardiography diagnostics. The results emphasize the need for sex-specific assessment for most echocardiographic parameters.

Inhibition of α-adrenergic tone disturbs the distribution of blood flow in the exercising human limb.

The role of neuronal regulation of human cardiovascular function remains incompletely elucidated, especially during exercise. Here we, by positron emission tomography, monitored tissue-specific blood flow (BF) changes in nine healthy young men during femoral arterial infusions of norepinephrine (NE) and phentolamine. At rest, the α-adrenoceptor agonist NE reduced BF by ~40%, similarly in muscles (from 3.2 ± 1.9 to 1.4 ± 0.3 ml·min(-1)·100 g(-1) in quadriceps femoris muscle), bone (from 1.1 ± 0.4 to 0.5 ± 0.2 ml·min(-1)·100 g(-1)) and adipose tissue (AT) (from 1.2 ± 0.7 to 0.7 ± 0.3 ml·min(-1)·100 g(-1)). During exercise, NE reduced exercising muscle BF by ~16%. BF in AT was reduced similarly as rest. The α-adrenoceptor antagonist phentolamine increased BF similarly in the different muscles and other tissues of the limb at rest. During exercise, BF in inactive muscle was increased 3.4-fold by phentolamine compared with exercise without drug, but BF in exercising muscles was not influenced. Bone and AT (P = 0.055) BF were also increased by phentolamine in the exercise condition. NE increased and phentolamine decreased oxygen extraction in the limb during exercise. We conclude that inhibition of α-adrenergic tone markedly disturbs the distribution of BF and oxygen extraction in the exercising human limb by increasing BF especially around inactive muscle fibers. Moreover, although marked functional sympatholysis also occurs during exercise, the arterial NE infusion that mimics the exaggerated sympathetic nerve activity commonly seen in patients with cardiovascular disease was still capable of directly limiting BF in the exercising leg muscles.

The association between coronary flow reserve and development of coronary calcifications: a follow-up study for 11 years in healthy young men.

AIMS: We studied whether a reduced coronary flow reserve (CFR) in healthy young men independently predicts the presence of coronary artery disease as assessed by coronary artery calcification after 11 years of follow-up. METHODS AND RESULTS: Coronary microvascular dysfunction in early stages of coronary artery disease can be detected as a reduced CFR by positron emission tomography (PET). Seventy-seven healthy, lean, normotensive, non-smoking and non-diabetic men underwent 15-Oxygen ((15)O) water myocardial perfusion PET at rest and during vasodilator stress at the age of 35 ± 4 years at baseline. The subjects were followed-up for 11 ± 1 years and the coronary artery calcium score (CCS) was measured with computed tomography at the end of the follow-up. At the end of the follow-up, 30 (39%) individuals had CCS >0 (average 65 ± 93), but none had clinical symptoms or evidence of ischaemia in stress echocardiography. At baseline, the average CFR was comparable in individuals with CCS >0 and CCS = 0 (4.2 ± 1.4 vs. 4.0 ± 1.2, P = 0.4). Logistic regression analysis showed no associations between CFR, serum glucose, cholesterol levels, systolic blood pressure or body mass index at baseline and CCS at the end of the follow-up (P always >0.05). The presence of CCS (CCS >0) was associated with higher systolic and diastolic blood pressures at the end of the follow-up (137 ± 18 vs. 128 ± 11 mmHg, P = 0.04 and 86 ± 12 vs. 78 ± 11 mmHg, P = 0.01). CONCLUSIONS: Coronary reactivity to vasodilator-induced hyperaemia as assessed by perfusion PET was not predictive of the presence of coronary calcification after 11 years of follow-up in asymptomatic men with very low likelihood of coronary artery disease.

Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) in a population of young adults: relations to cardiovascular risk markers and carotid artery intima-media thickness. The Cardiovascular Risk in Young Finns Study.

OBJECTIVES: The tissue inhibitor of metalloproteinases 4 (TIMP4) is present in significant amounts in human atherosclerotic coronary artery lesions, but its relations with the early pathogenesis of atherosclerotic changes have not been clarified. We studied the associations of circulating TIMP4 with pre-clinical markers of atherosclerosis and traditional cardiovascular risk factors by using longitudinal data on carotid artery intima-media (cIMT) thickness in a population-based cohort of asymptomatic young adult Finns. METHODS: Data on cIMT, plasma TIMP4, lipids, CRP, blood pressure, BMI, smoking status and daily alcohol intake were obtained from 980 24-39 year-old participants in 2001. The 6-year follow-up in cIMT measurements were performed in 2007 for 769 participants. RESULTS: Plasma TIMP4 concentrations (mean ± SD) were 2.3 ± 1.7 ng/mL in men and 2.5 ± 1.8 ng/mL in women. Age, LDL-cholesterol, BMI and systolic blood pressure were directly associated with TIMP4 concentration. In a multivariable model, the independent determinants of TIMP4 included systolic blood pressure (p = 0.008) and daily smoking (p = 0.009), both being inversely associated with TIMP4. These two baseline variables explained 1.5% of the variation in TIMP4. TIMP4 was significantly and inversely associated with cIMT measured 6 years later (beta =- 0.0135, p = 0.01) explaining 0.7% of the variability of cIMT. CONCLUSION: In young apparently healthy adults, circulating TIMP4 concentration was independently and inversely associated with cIMT, a marker of vascular structure and function.

Plasminogen activator inhitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study.

AIMS: Hypofibrinolysis displayed by elevated serum plasminogen activator inhibitor 1 (PAI-1) level has been associated with cardiovascular disease (CVD) and its risk factors such as obesity and insulin resistance. However, no studies have examined associations between PAI-1 and CVD risk factors in healthy subjects. We examined associations between serum PAI-1, ultrasound markers of atherosclerosis and CVD risk factors and whether PAI-1 improves prediction of atherosclerosis over known risk factors in a cohort of asymptomatic adults. METHODS: We analyzed PAI-1 and CVD risk factors and assessed carotid intima-media thickness (cIMT), distensibility (CDist) and the presence of a carotid atherosclerotic plaque and flow-mediated dilation (FMD) ultrasonographically for 2202 adults (993 men and 1,209 women, aged 30-45 years) participating in the ongoing longitudinal cohort study, The Cardiovascular Risk in Young Finns Study. High cIMT was defined as >90th percentile and/or carotid plaque and low CDist and low FMD as <20th percentile. RESULTS: In bivariate analyses, PAI-1 correlated directly with cIMT and the risk factors: blood pressure, BMI, waist and hip circumference, alcohol use, total and LDL-cholesterol, triglycerides, glomerular filtration rate, high-sensitivity CRP and glucose (all P<0.005). PAI-1 was higher in men and increased with age. Inverse correlation was observed with CDist, HDL-cholesterol and adiponectin in both sexes, with testosterone and sex hormone binding globulin in men and with creatinine and oral contraceptive use in women (P<0.005). Independent direct associations were observed between PAI-1 and waist circumference, serum triglycerides, insulin, alcohol use and age and inverse with serum creatinine, HDL-cholesterol and adiponectin. PAI-1 did not improve estimation of high cIMT, low CDist and low FMD over conventional risk factors (P for difference in area under curve ≥ 0.37). CONCLUSION: PAI-1 was independently associated with several known CVD risk factors, especially obesity markers, in both men and women. However, addition of PAI-1 to known risk factors did not improve cross-sectional prediction of high cIMT, low CDist and low FMD suggesting that PAI-1 is not a clinically important biomarker in early atherosclerosis.

Associations between serum uric acid and markers of subclinical atherosclerosis in young adults. The cardiovascular risk in Young Finns study.

BACKGROUND AND METHODS: Serum uric acid (SUA) is a suggested biomarker for established coronary artery disease, but the role of SUA in early phases of atherosclerosis is controversial. The relations of SUA with vascular markers of subclinical atherosclerosis, including carotid artery intima-media thickness (cIMT), carotid plaque, carotid distensibility (Cdist) and brachial flow-mediated dilatation (FMD) were examined in 1985 young adults aged 30-45 years. In addition to ordinary regression, we used Mendelian randomization techniques to infer causal associations. RESULTS: In women, the independent multivariate correlates of SUA included BMI, creatinine, alcohol use, triglycerides, glucose and adiponectin (inverse association) (Model R(2) = 0.30). In men, the correlates were BMI, creatinine, triglycerides, C-reactive protein, alcohol use, total cholesterol and adiponectin (inverse) (Model R(2) = 0.33). BMI alone explained most of the variation of SUA levels both in women and men (Partial R(2) âˆ¼ 0.2). When SUA was modeled as an explanatory variable for vascular markers, it directly associated with cIMT and inversely with Cdist in age- and sex-adjusted analysis. After further adjustments for BMI or glomerular filtration rate, these relations were reduced to non-significance. No associations were found between SUA and FMD or the presence of a carotid plaque. Mendelian randomization analyses using known genetic variants for BMI and SUA confirmed that BMI is causally linked to SUA and that BMI is a significant confounder in the association between SUA and cIMT. CONCLUSION: SUA is associated with cardiovascular risk markers in young adults, especially BMI, but we found no evidence that SUA would have an independent role in the pathophysiology of early atherosclerosis.

Childhood asthma management guided by repeated FeNO measurements: a meta-analysis.

The fraction of exhaled nitric oxide (FeNO) has gained interest as a non-invasive tool to measure airway inflammation in asthma since it reflects allergic inflammation. Recent controlled clinical studies have, however, questioned its role in the management of asthma in children. To assess the clinical value of FeNO in paediatric asthma management, a meta-analysis was performed on the controlled studies of childhood asthma management guided by repeated FeNO measurements, and relevant publications on the confounders of FeNO were reviewed. The data suggests that utilising FeNO to tailor the dose of inhaled corticosteroids in children cannot be recommended for routine clinical practice since there is a danger of excessive inhaled corticosteroid doses in children without meaningful changes in clinical outcomes. Many disease and non-disease related factors (most importantly atopy, height/age and infection) affect FeNO levels which can easily confound the interpretation.

Progressive external ophthalmoplegia in southwestern Finland: a clinical and genetic study.

BACKGROUND: Progressive external ophthalmoplegia (PEO) is a common phenotype of mitochondrial disease. Molecular etiologies include sporadic, large-scale deletions in mitochondrial DNA (mtDNA), multiple mtDNA deletions secondary to autosomal dominant or recessive mutations and mtDNA point mutations. METHODS: We studied the prevalence and clinical and genetic characteristics of PEO in a defined population in southwestern Finland. A total of 620 patients were first identified from the patient registry at the Turku University Hospital over an 18-year period. The medical records of these patients were scrutinized, and those with clinical features compatible with PEO were ascertained. RESULTS: We identified 10 patients with possible PEO. The patients were examined clinically, and DNA was analyzed for mtDNA deletions and for the m.3243A>G and m.8344A>G mtDNA point mutations. The ANT1, PEO1, POLG1 and POLG2 genes were sequenced. We confirmed the clinical diagnosis of PEO in 6 patients. Large-scale mtDNA deletions were detected in 3 out of 6 PEO patients and mutations in the POLG1 gene in 1 out of 6. We did not find any mutations in the ANT1, PEO1 or POLG2 genes. CONCLUSIONS: Our results suggest that molecular investigation of patients with PEO, either sporadic or familial, should start with an analysis for mtDNA deletions, followed by an analysis of the POLG1 gene.

Plasma osteopontin is not associated with vascular markers of subclinical atherosclerosis in a population of young adults without symptoms of cardiovascular disease. The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: Osteopontin is used as a biomarker for measuring the severity of atherosclerosis, but the role of osteopontin in the pathogenesis of atherosclerosis is not clear. METHODS: The distribution and determinants of osteopontin were studied in a randomized cohort of 1,817 young adults (aged 30­45 years) without clinical symptoms of atherosclerosis. RESULTS: The mean ± SD osteopontin concentration was 60.7 ± 15.6 µg/mL in men and 51.7 ± 16.0 µg/mL in women. In multivariable models the correlates of osteopontin explained 6.9% (Model R² of the total variation in osteopontin in men, including CRP (ß = 3.02, p < 0.0001), SHBG (ß = 0.21, p < 0.0001), total cholesterol (ß = − 1.78, p = 0.002), age (ß = − 0.26, p = 0.02) and alcohol use (ß = 0.57, p = 0.04) and of these CRP had the greatest influence (Partial R² = 2.1%). In women, multivariable correlates of osteopontin included CRP (ß = 2.90, p < 0.0001), total cholesterol (ß = − 1.99, p = 0.002), insulin (ß = − 1.76, p = 0.001), physical activity (ß = 0.66, p = 0.03), adiponectin (ß = 0.25, p = 0.008) and diastolic blood pressure (ß = 0.14, p = 0.003). These five variables explained 6.7% (Model R²) of the total variation in osteopontin, with CRP (Partial R² = 2.7%) having the greatest influence. Osteopontin was not associated with carotid intima-media thickness, carotid elasticity, brachial endothelial function or the presence of a carotid plaque in either sex. CONCLUSION: We found no evidence of association between osteopontin levels and early vascular markers of atherosclerosis in asymptomatic young adults, suggesting that osteopontin is not implicated in the preclinical atherosclerotic changes in vascular structure and function.

Cardiopulmonary involvement in Fabry's disease.

BACKGROUND: Fabry's disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipid in different tissues, including endothelial and smooth-muscle cells and cardiomyocytes. OBJECTIVES: There is controversial data on cardiopulmonary involvement in Fabry's disease, because many reports are based on small and selected populations with Fabry's disease. Furthermore, the aetiology of cardiopulmonary symptoms in Fabry's disease is poorly understood. METHODS: We studied cardiopulmonary involvement in seventeen patients with Fabry's disease (20-65 years, 6 men) using ECG, bicycle stress, cardiac magnetic resonance imaging, spirometry, diffusing capacity and pulmonary high-resolution computed tomography (HRCT) tests. Cardiopulmonary symptoms were compared to observed parameters in cardiopulmonary tests. RESULTS: Left ventricular hypertrophy (LVH) and reduced exercise capacity are the most apparent cardiac changes in both genders with Fabry's disease. ECG parameters were normal when excluding changes related to LVH. Spirometry showed mild reduction in vital capacity and forced expiratory volume in one second (FEV I), and mean values in diffusing capacity tests were within normal limits. Generally, only slight morphological pulmonary changes were detected using pulmonary HRCT, and they were not associated with changes in pulmonary function. The self-reported amount of pulmonary symptoms associated only with lower ejection fraction (P < 0.001) and longer QRS-duration (P = 0.04) of all measured cardiopulmonary parameters, whereas cardiac symptoms have no statistically significant association with any of these parameters. CONCLUSION: LVH and reduced exercise capacity are the most apparent cardiopulmonary changes in Fabry's disease but they have only a minor association to cardiopulmonary symptoms.Therefore, routine cardiopulmonary evaluation in Fabry's disease using echocardiography is maybe enough when integrated to counselling for aerobic exercise training.

Ambulatory blood pressure: associations with coronary heart disease in the aged Finnish population.

BACKGROUND AND AIMS: Ambulatory blood pressure (ABP) has been shown to be a better predictor of cardiovascular events than clinical blood pressure (BP) in middle-aged and older populations. This study studied the association of various components of ABP (daytime, night-time, 24-hour ABP) in the presence of coronary heart disease (CHD) in an older Finnish population. METHODS: This cross-sectional, observational, population-based study was carried out in The Lieto Health Centre, Finland, in 1998-99. The study population consisted of 502 subjects (237 men, 265 women) aged 64-87 years. ABP measurements for 24 hours, daytime (awake) and night-time (asleep), were made. Resting electrocardiograms (ECG) were recorded. A person was considered to have CHD if at least one of the following criteria was met: (I) history of coronary by-pass surgery or coronary angioplasty, (II) diagnosis of CHD in previous medical records, (III) ischemia-related changes on ECG. RESULTS: CHD increased by 30% with a 10 mmHg increase in night-time systolic blood pressure (SBP) (OR 1.30, 95% Cl 1.15-1.47). When ambulatory 24-hour and daytime SBP values were each entered separately into the multivariate model, 24-hour SBP, but not daytime SBP, was associated with CHD. CONCLUSIONS: The most important information gained from 24-h BP monitoring in subjects with CHD is night-time BP. Night-time BP may provide new information about the CHD risk which is not identified in common clinical diagnoses of hypertension. ABP measurements should be made to confirm sufficient control of night-time BP, especially SBP, in older people with CHD.