Exploring machine learning strategies for predicting cardiovascular disease risk factors from multi-omic data.

BACKGROUND: Machine learning (ML) classifiers are increasingly used for predicting cardiovascular disease (CVD) and related risk factors using omics data, although these outcomes often exhibit categorical nature and class imbalances. However, little is known about which ML classifier, omics data, or upstream dimension reduction strategy has the strongest influence on prediction quality in such settings. Our study aimed to illustrate and compare different machine learning strategies to predict CVD risk factors under different scenarios. METHODS: We compared the use of six ML classifiers in predicting CVD risk factors using blood-derived metabolomics, epigenetics and transcriptomics data. Upstream omic dimension reduction was performed using either unsupervised or semi-supervised autoencoders, whose downstream ML classifier performance we compared. CVD risk factors included systolic and diastolic blood pressure measurements and ultrasound-based biomarkers of left ventricular diastolic dysfunction (LVDD; E/e' ratio, E/A ratio, LAVI) collected from 1,249 Finnish participants, of which 80% were used for model fitting. We predicted individuals with low, high or average levels of CVD risk factors, the latter class being the most common. We constructed multi-omic predictions using a meta-learner that weighted single-omic predictions. Model performance comparisons were based on the F1 score. Finally, we investigated whether learned omic representations from pre-trained semi-supervised autoencoders could improve outcome prediction in an external cohort using transfer learning. RESULTS: Depending on the ML classifier or omic used, the quality of single-omic predictions varied. Multi-omics predictions outperformed single-omics predictions in most cases, particularly in the prediction of individuals with high or low CVD risk factor levels. Semi-supervised autoencoders improved downstream predictions compared to the use of unsupervised autoencoders. In addition, median gains in Area Under the Curve by transfer learning compared to modelling from scratch ranged from 0.09 to 0.14 and 0.07 to 0.11 units for transcriptomic and metabolomic data, respectively. CONCLUSIONS: By illustrating the use of different machine learning strategies in different scenarios, our study provides a platform for researchers to evaluate how the choice of omics, ML classifiers, and dimension reduction can influence the quality of CVD risk factor predictions.

α-Melanocyte-stimulating hormone alleviates pathological cardiac remodeling via melanocortin 5 receptor.

α-Melanocyte-stimulating hormone (α-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). However, the role of α-MSH and its possible target receptors in the heart remain completely unknown. Here we investigate whether α-MSH could be involved in pathological cardiac remodeling. We found that α-MSH was highly expressed in the mouse heart with reduced ventricular levels after transverse aortic constriction (TAC). Administration of a stable α-MSH analog protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction. In vitro experiments revealed that MC5-R in cardiomyocytes mediates the anti-hypertrophic signaling of α-MSH. Silencing of MC5-R in cardiomyocytes induced hypertrophy and fibrosis markers in vitro and aggravated TAC-induced cardiac hypertrophy and fibrosis in vivo. Conversely, pharmacological activation of MC5-R improved systolic function and reduced cardiac fibrosis in TAC-operated mice. In conclusion, α-MSH is expressed in the heart and protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes. These results suggest that analogs of naturally occurring α-MSH, that have been recently approved for clinical use and have agonistic activity at MC5-R, may be of benefit in treating heart failure.

Association of number of siblings with preclinical markers of cardiovascular disease. The cardiovascular risk in Young Finns study.

To investigate the association of number of siblings with preclinical cardiovascular disease (CVD) markers in adulthood. The sample comprised 2776 participants (54 % female) from the Cardiovascular Risk in Young Finns Study who had CVD risk factor data measured in childhood in 1980 (aged 3-18 years) and markers of preclinical CVD measured in adulthood. Echocardiography was performed in 2011, and carotid intima-media thickness, carotid distensibility, brachial flow-mediated dilatation, and arterial pulse wave velocity were measured in 2001 or 2007. The association between the number of siblings and preclinical CVD was assessed using generalized linear and logistic regression models. Analyses were stratified by sex as associations differed between sexes. Women with 1 sibling had lower E/e'-ratio (4.9, [95%CI 4.8-5.0]) in echocardiography compared with those without siblings (5.1[4.9-5.2]) and those with ≥2 more siblings (5.1[5.0-5.2]) (P for trend 0.01). Men without siblings had the lowest E/A-ratio (1.4[1.3-1.5]) compared with those with 1 sibling (1.5[1.5-1.5]), or ≥2 siblings (1.5[1.5-1.5]) (P for trend 0.01). Women without siblings had highest left ventricular ejection fraction (59.2 %[58.6-59.7 %]) compared with those with 1 sibling (59.1 %[58.8-59.4 %]), or ≥2 siblings (58.4 %[58.1-58.8 %])(P for trend 0.01). In women, brachial flow-mediated dilatation, a measure of endothelial function, was the lowest among participants with ≥2 siblings (9.4 %[9.0-9.8 %]) compared with those with 1 sibling (10.0 %[9.6-10.3 %]) and those without siblings (10.4 %[9.7-11.0 %])(P for trend 0.03). We observed that number of siblings may be associated with increased risk of heart failure in women. As the associations were somewhat inconsistent in males and females, further research is warranted.

Exposure to parental smoking and cardiac structure and function in adulthood: the Cardiovascular Risk in Young Finns Study.

BACKGROUND AND AIMS: The relationship between childhood tobacco smoke exposure and cardiac structure and function in midlife is unclear. We investigated the association between parental smoking with cardiac structure and function in adulthood. METHODS: 1250 participants (56.5% female) from the Cardiovascular Risk in Young Finns Study who had data on parental smoking and/or serum cotinine, a biomarker of exposure to tobacco smoke, at baseline 1980 (age 3-18 years) and echocardiography performed in 2011. Parental smoking hygiene (i.e., smoking in the vicinity of children) was categorized by parental smoking and serum cotinine levels in offspring. Dimensions of the left ventricle, diastolic and systolic function, and cardiac remodeling were used as outcomes. Analyses were adjusted for sex, age, and covariates (blood pressure (BP), serum lipids, body mass index, socioeconomic status, smoking (only in adulthood)) in childhood and adulthood. RESULTS: Parental smoking was not associated with systolic or diastolic function in adulthood. Participants exposed to parental smoking (odds ratio (OR) 1.90, 95%CI 1.23-2.92), hygienic parental smoking (OR 1.74, 95%CI 1.12-2.71), and non-hygienic parental smoking (OR 1.88, 95%CI 1.02-3.45) had higher odds of concentric remodeling (relative wall thickness >85th sex-specific percentile without left ventricular hypertrophy). These associations were attenuated after adjustment for child and adult covariates in the non-hygienic parental smoking group. CONCLUSIONS: Exposure to parental smoking in childhood was associated with a higher likelihood of concentric remodeling and thicker left ventricular and interventricular septal walls in midlife, which was not improved by parents who smoked hygienically. Parental smoking was not related to systolic or diastolic function in this relatively young population.

Deep Learning-Based Segmentation of Morphologically Distinct Rat Hippocampal Reactive Astrocytes After Trimethyltin Exposure.

As regulators of homeostasis, astrocytes undergo morphological changes after injury to limit the insult in central nervous system (CNS). Trimethyltin (TMT) is a known neurotoxicant that induces reactive astrogliosis in rat CNS. To evaluate the degree of reactive astrogliosis, the assessment relies on manual counting or semiquantitative scoring. We hypothesized that deep learning algorithm could be used to identify the grade of reactive astrogliosis in immunoperoxidase-stained sections in a quantitative manner. The astrocyte algorithm was created using a commercial supervised deep learning platform and the used training set consisted of 940 astrocytes manually annotated from hippocampus and cortex. Glial fibrillary acidic protein-labeled brain sections of rat TMT model were analyzed for astrocytes with the trained algorithm. Algorithm was able to count the number of individual cells, cell areas, and circumferences. The astrocyte algorithm identified astrocytes with varying sizes from immunostained sections with high confidence. Algorithm analysis data revealed a novel morphometric marker based on cell area and circumference. This marker correlated with the time-dependent progression of the neurotoxic profile of TMT. This study highlights the potential of using novel deep learning-based image analysis tools in neurotoxicity and pharmacology studies.

Fatty liver index and left ventricular mass: prospective associations from two independent cohorts.

OBJECTIVES: Heart disease is the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD). Emerging data have shown that NAFLD may affect subclinical myocardial remodeling, mainly left ventricular hypertrophy; however, evidence from the prospective studies is still lacking. METHODS: Prospective analyses were performed to investigate the association of fatty liver index (FLI) with left ventricular mass (LVM) among 1962 participants from the Bogalusa Heart Study (BHS, 1995-2010) and 1547 participants from the Cardiovascular Risk in Young Finns Study (YFS, 2001-2011) free of cardiovascular diseases (CVD) at baseline. LVM was assessed by two-dimensional guided M-mode echocardiography and indexed (LVMI) to body height (m2.7). Multivariable regression models were applied after adjustment for traditional CVD risk factors. RESULTS: In both cohorts, we observed significant and positive associations between FLI and LVM (BHS: ß=0.59, P < 0.001; YFS: ß=0.41, P < 0.001) and LVMI (BHS: ß=0.14, P < 0.001; YFS: ß=0.09, P < 0.001). In addition, we found that the relationship between FLI and LVMI was stronger in women than men (BHS: P-interaction = 0.01; YFS: P-interaction < 0.01); and the relationship between FLI and LVM/LVMI was stronger in black than white individuals (LVM: P-interaction = 0.02; LVMI: P-interaction = 0.04). Moreover, we found that the associations of FLI with LVM and LVMI were attenuated by high physical activity, especially in BHS (P-interaction = 0.02). CONCLUSION: Our findings from two independent prospective cohorts indicate that FLI is positively associated with LVM/LVMI, independent of traditional cardiovascular risk factors. Such relationships are more pronounced among women and black individuals and are attenuated by high physical activity.

Cardiovascular Risk Factors in Childhood and Left Ventricular Diastolic Function in Adulthood.

BACKGROUND AND OBJECTIVES: Cardiovascular risk factors, such as obesity, blood pressure, and physical inactivity, have been identified as modifiable determinants of left ventricular (LV) diastolic function in adulthood. However, the links between childhood cardiovascular risk factor burden and adulthood LV diastolic function are unknown. To address this lack of knowledge, we aimed to identify childhood risk factors associated with LV diastolic function in the participants of the Cardiovascular Risk in Young Finns Study. METHODS: Study participants (N = 1871; 45.9% men; aged 34-49 years) were examined repeatedly between the years 1980 and 2011. We determined the cumulative risk exposure in childhood (age 6-18 years) as the area under the curve for systolic blood pressure, adiposity (defined by using skinfold and waist circumference measurements), physical activity, serum insulin, triglycerides, total cholesterol, and high- and low-density lipoprotein cholesterols. Adulthood LV diastolic function was defined by using E/é ratio. RESULTS: Elevated systolic blood pressure and increased adiposity in childhood were associated with worse adulthood LV diastolic function, whereas higher physical activity level in childhood was associated with better adulthood LV diastolic function (P < .001 for all). The associations of childhood adiposity and physical activity with adulthood LV diastolic function remained significant (both P < .05) but were diluted when the analyses were adjusted for adulthood systolic blood pressure, adiposity, and physical activity. The association between childhood systolic blood pressure and adult LV diastolic function was diluted to nonsignificant (P = .56). CONCLUSIONS: Adiposity status and the level of physical activity in childhood are independently associated with LV diastolic function in adulthood.

Influence of early-life body mass index and systolic blood pressure on left ventricle in adulthood - the Cardiovascular Risk in Young Finns Study.

BACKGROUND: Increased left ventricular mass (LVM) predicts cardiovascular events and mortality. The objective of this study was to determine whether early-life exposures to body mass index (BMI) and systolic blood pressure (SPB) affects the left ventricular structure in adulthood. METHODS: We used longitudinal data from a 31-year follow-up to examine the associations between early-life (between ages 6-18) BMI and SPB on LVM in an adult population (N = 1864, aged 34-49). The burden of early-life BMI and SBP was defined as area under the curve. RESULTS: After accounting for contemporary adult determinants of LVM, early-life BMI burden associated significantly with LVM (3.61 g/SD increase in early-life BMI; [1.94 - 5.28], p < 0.001). Overweight in early-life (age- and sex-specific BMI values corresponding to adult BMI > 25 kg/m2) associated with 4.7% (2.5-6.9%, p < 0.0001) higher LVM regardless of BMI status in adulthood. Overweight in early-life combined with obesity in adulthood (BMI > 30kg/m2) resulted in a 21% (17.3-32.9%, p < 0.0001) increase in LVM. Higher early-life BMI was associated with a risk of developing eccentric hypertrophy. The burden of early-life SPB was not associated with adult LVM or left ventricular remodeling. CONCLUSIONS: High BMI in early-life confers a sustained effect on LVM and the risk for eccentric hypertrophy independently of adulthood risk factors. KEY MESSAGES Excess in BMI in early-life has an independent effect on LVM and the risk of developing eccentric hypertrophy regardless of overweight status in adulthood. Systolic blood pressure levels in early-life did not have an independent effect on LVM or LV remodeling. The clinical implication of this study is that primary prevention of obesity in early-life may prevent the development of high LVM and eccentric hypertrophy.

Childhood Psychosocial Environment and Adult Cardiac Health: A Causal Mediation Approach.

INTRODUCTION: This study used causal mediation analysis to assess the life-course associations of a favorable childhood psychosocial environment with left ventricular mass and diastolic function in adulthood and the extent to which adult health behaviors mediate these associations. METHODS: The sample included 880 participants (56% women) from the Young Finns Study with data on the childhood environment from 1980, adult health behaviors (smoking, physical activity, diet, and BMI) from 2001 and an echocardiographic assessment of the left ventricular mass (g/m2.7) and diastolic function (E/e' ratio; higher values indicating a lower diastolic function) from 2011. The associations of the childhood environment with the left ventricular mass and E/e' ratio and mediation pathways through health behaviors were assessed using marginal structural models that were controlled for age, sex, and time-dependent confounding by adult socioeconomic position (measured as educational attainment) via inverse probability weighting. The data were analyzed in 2018-2019. RESULTS: The mean age in 2011 was 41 (range 34-49) years. Those above versus below the median childhood score had a 1.28 g/m2.7 lower left ventricular mass (95% CI= -2.63, 0.07) and a 0.18 lower E/e' ratio (95% CI= -0.39, 0.03). There was no evidence for indirect effects from childhood environments to left ventricular outcomes through adult health behaviors after controlling for time-dependent confounding by the adult socioeconomic position (indirect effect ß= -0.30, 95% CI= -1.22, 0.63 for left ventricular mass; ß= -0.04, 95% CI= -0.18, 0.11 for E/e' ratio). The results after multiple imputation were similar. CONCLUSIONS: A favorable childhood environment is associated with more optimal cardiac structure and function in adulthood. After accounting for socioeconomic positions, adult health behaviors explain little of the associations.

Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress.

The intermediate filament (IF) cytoskeleton has been proposed to regulate morphogenic processes by integrating the cell fate signaling machinery with mechanical cues. Signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through the Notch pathway regulates arterial remodeling in response to changes in blood flow. Here we show that the IF-protein vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic forces. Vimentin is important for Notch transactivation by ECs and vimentin knockout mice (VimKO) display disrupted VSMC differentiation and adverse remodeling in aortic explants and in vivo. Shear stress increases Jagged1 levels and Notch activation in a vimentin-dependent manner. Shear stress induces phosphorylation of vimentin at serine 38 and phosphorylated vimentin interacts with Jagged1 and increases Notch activation potential. Reduced Jagged1-Notch transactivation strength disrupts lateral signal induction through the arterial wall leading to adverse remodeling. Taken together we demonstrate that vimentin forms a central part of a mechanochemical transduction pathway that regulates multilayer communication and structural homeostasis of the arterial wall.

Determinants of left ventricular diastolic function-The Cardiovascular Risk in Young Finns Study.

Decreased left ventricular (LV) diastolic function is associated with increased all-cause mortality and risk for a heart failure. The determinants of LV diastolic function have been mainly studied in elderly populations; however, the origin of LV heart failure may relate to the lifestyle factors acquired during the life course. Therefore, we examined biochemical, physiological, and lifestyle determinants of LV diastolic function in 34-49-year-old participants of the Cardiovascular Risk in Young Finns Study (Young Finns Study). In 2011, clinical examination and echocardiography were performed for 1928 participants (880 men and 1048 women; aged 34-49 years). LV diastolic function was primarily defined using E/é-ratio (population mean 4.8, range 2.1-9.0). In a multivariate model, systolic blood pressure (P < 0.005), female sex (P < 0.005), age (P < 0.005), waist circumference (P = 0.024), smoking (P = 0.028), serum alanine aminotransferase (P = 0.032) were directly associated with E/é-ratio, while an inverse association was found for height (P < 0.005). Additionally, a higher E/é-ratio was found in participants with concentric hypertrophy compared to normal cardiac geometry (P < 0.005). Other indicators of the LV diastolic function including E/A-ratio and left atrial volume index showed similarly strong associations with systolic blood pressure and age. In conclusion, we identified systolic blood pressure, waist circumference and smoking as modifiable determinants of the LV diastolic function in the 34-49-year-old participants of the Young Finns Study.

Reference values and correlates of right atrial volume in healthy adults by two-dimensional echocardiography.

BACKGROUND: Right atrial (RA) volume is an important parameter in the evaluation of patients with pulmonary hypertension. Aim of this study was to define reference ranges for RA volume by two-dimensional echocardiography (2DE) in healthy adults. METHODS: A total of 596 healthy subjects [mean age 45.7 ± 14.6 years, range 18-88 years; 60.1% women] underwent a transthoracic echocardiography. In addition, a meta-analysis was performed of published studies measuring RA volume in healthy subjects, using 2DE single plane area-length (A-L) and/or method of disks (MOD) at end-systole in apical four-chamber view. RESULTS: In our cohort, RA volume was higher in men than women but did not vary with age. Body surface area (BSA), stroke volume (SV), and tricuspid annular plane systolic excursion (TAPSE) were the only independent variables associated with RA volume (ß coefficient 0.569, 0.123, and 0.131, respectively; all P < .001). In the pooled analysis, normalized RA volume was 25.7 ± 7.0 mL/m2 in men and 21.2 ± 5.8 mL/m2 in women for A-L, 21.6 ± 5.6 mL/m2 in men and 18.2 ± 5.4 mL/m2 in women for MOD (all P values < .0001). The upper limit was about 36 mL/m2 in men and 31 mL/m2 in women for A-L and 31 mL/m2 in men and 27 mL/m2 in women for MOD. CONCLUSIONS: RA volume was found to be higher in men but not influenced by age. It was mainly correlated with larger BSA, indices of preload (SV) and RV longitudinal function (TAPSE). A statistically significant difference was found between A-L and MOD.

Aortic sinus diameter in middle age is associated with body size in young adulthood.

OBJECTIVE: Aortic sinus dilatation can lead to aortic valve regurgitation or even aortic dissection. Our objective was to examine the association between body surface area (BSA) measures from childhood to middle age and aortic sinus diameter in middle age. Understanding the relation of these two clarifies how aortic size is normally determined. METHODS: Cardiovascular Risk in Young Finns Study is a longitudinal study with follow-up of over 31 years (1980-2011). The study comprises information of body composition from multiple time points of 1950 subjects with cardiac ultrasound measurements made in 2011. The association between BSA in different ages and aortic sinus diameter in middle age was analysed by linear regression modelling adjusted with age, sex and diastolic blood pressure. Missing BSA values were derived for each life year (ages 3-33 years) from subject-specific curves for body weight and height estimated from longitudinal measurements using mixed model regression splines. RESULTS: BSA estimates in early 20s are most strongly associated with aortic sinus diameter in middle age. Top association was observed at age 23 years with one SD increase in estimated BSA corresponding to 1.04 mm (0.87-1.21 mm) increase in aortic diameter. Increase in body weight beyond early 20s does not associate with aortic sinus diameter, and the association between middle age BSA and aortic size is substantially weaker (0.74 mm increase (0.58-0.89 mm)). These results were confirmed in a subpopulation using only measured data. CONCLUSION: The association between aortic sinus diameter and BSA is stronger when considering BSA in young adulthood compared with BSA in middle age.

Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure.

BACKGROUND: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. METHODS AND RESULTS: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. CONCLUSIONS: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.

Association of Socioeconomic Status in Childhood With Left Ventricular Structure and Diastolic Function in Adulthood: The Cardiovascular Risk in Young Finns Study.

Importance: Increased left ventricular (LV) mass and diastolic dysfunction are associated with cardiovascular disease. Prospective data on effects of childhood socioeconomic status (SES) on measures of LV structure and function are lacking. Objective: To examine whether family SES in childhood was associated with LV mass and diastolic function after adjustment for conventional cardiovascular disease risk factors in childhood and adulthood. Design, Setting, and Participants: The analyses were performed in 2016 using data gathered in 1980 and 2011 within the longitudinal population-based Cardiovascular Risk in Young Finns Study. The sample comprised 1871 participants who reported family SES at ages 3 to 18 years and were evaluated for LV structure and function 31 years later. Exposures: Socioeconomic status was characterized as annual income of the family and classified on a 3-point scale. Main Outcomes and Measures: Left ventricular mass indexed according to height at the allometric power of 2.7 and the E/e' ratio describing LV diastolic performance at ages 34 to 49 years. Results: The participants were aged 3 to 18 years at baseline (mean [SD], 10.8 [5.0] years), and the length of follow-up was 31 years. Family SES was inversely associated with LV mass (mean [SD] LV mass index, 31.8 [6.7], 31.0 [6.6], and 30.1 [6.4] g/m2.7 in the low, medium, and high SES groups, respectively; differences [95% CI], 1.7 [0.6 to 2.8] for low vs high SES; 0.8 [-0.3 to 1.9] for low vs medium; and 0.9 [0.1 to 1.6] for medium vs high; overall P = .001) and E/e' ratio (mean [SD] E/e' ratio, 5.0 [1.0], 4.9 [1.0], and 4.7 [1.0] in the low, medium, and high SES groups, respectively; differences [95% CI], 0.3 [0.1 to 0.4] for low vs high SES; 0.1 [-0.1 to 0.3] for low vs medium; and 0.2 [0 to 0.3] for medium vs high; overall P < .001) in adulthood. After adjustment for age, sex, and conventional cardiovascular disease risk factors in childhood and adulthood, and participants' own SES in adulthood, the relationship with LV mass (differences [95% CI], 1.5 [0.2 to 2.8] for low vs high SES; 1.3 [0 to 2.6] for low vs medium; and 0.2 [-0.6 to 1.0] for medium vs high; P = .03) and E/e' ratio (differences [95% CI], 0.2 [0 to 0.5] for low vs high SES; 0.1 [-0.1 to 0.4] for low vs medium; and 0.1 [0 to 0.3] for medium vs high; P = .02) remained significant. Conclusions and Relevance: Low family SES was associated with increased LV mass and impaired diastolic performance more than 3 decades later. These findings emphasize that approaches of cardiovascular disease prevention must be directed also to the family environment of the developing child.

Ideal cardiovascular health in childhood-Longitudinal associations with cardiac structure and function: The Special Turku Coronary Risk Factor Intervention Project (STRIP) and the Cardiovascular Risk in Young Finns Study (YFS).

BACKGROUND: Ideal cardiovascular health (CVH), defined by the American Heart Association, is associated with incident cardiovascular disease in adults. However, association of the ideal CVH in childhood with current and future cardiac structure and function has not been studied. METHODS AND RESULTS: The sample comprised 827 children participating in the longitudinal Special Turku Coronary Risk Factor Intervention Project (STRIP) and The Cardiovascular Risk in Young Finns Study (YFS). In STRIP, complete data on the seven ideal CVH metrics and left ventricular (LV) mass measured with echocardiography were available at the age of 15 (n=321), 17 (n=309) and 19 (n=283) years. In YFS, the cohort comprised children aged 12-18years (n=506) with complete ideal CVH metrics data from childhood and 25years later in adulthood, and echocardiography performed in adulthood. In STRIP, ideal CVH score was inversely associated with LV mass during childhood (P=0.036). In YFS, childhood ideal CVH score was inversely associated with LV mass, LV end-diastolic volume, E/e' ratio, and left atrium end-systolic volume in adulthood (all P<0.01). In addition, improvement of the ideal CVH score between childhood and adulthood was inversely associated with LV mass, LV end-diastolic volume, E/e' ratio, and left atrium end-systolic volume (all P≤0.03). CONCLUSIONS: Childhood ideal CVH score has a long-lasting effect on cardiac structure and function, and the association is evident already in childhood. Our findings support targeting the ideal CVH metrics as part of primordial prevention of cardiovascular diseases.

Systemic Dosing of Thymosin Beta 4 before and after Ischemia Does Not Attenuate Global Myocardial Ischemia-Reperfusion Injury in Pigs.

The use of cardiopulmonary bypass (CPB) and aortic cross-clamping causes myocardial ischemia-reperfusion injury (I-RI) and can lead to reduced postoperative cardiac function. We investigated whether this injury could be attenuated by thymosin beta 4 (TB4), a peptide which has showed cardioprotective effects. Pigs received either TB4 or vehicle and underwent CPB and aortic cross-clamping for 60 min with cold intermittent blood-cardioplegia and were then followed for 30 h. Myocardial function and blood flow was studied by cardiac magnetic resonance and PET imaging. Tissue and plasma samples were analyzed to determine the amount of cardiomyocyte necrosis and apoptosis as well as pharmacokinetics of the peptide. In vitro studies were performed to assess its influence on blood coagulation and vasomotor tone. Serum levels of the peptide were increased after administration compared to control samples. TB4 did not decrease the amount of cell death. Cardiac function and global myocardial blood flow was similar between the study groups. At high doses a vasoconstrictor effect on mesentery arteries and a vasodilator effect on coronary arteries was observed and blood clot firmness was reduced when tested in the presence of an antiplatelet agent. Despite promising results in previous trials the cardioprotective effect of TB4 was not demonstrated in this model for global myocardial I-RI.

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.

Subtle increases in heart size persist into adulthood in growth restricted babies: the Cardiovascular Risk in Young Finns Study.

BACKGROUND AND OBJECTIVES: Impaired fetal growth is associated with increased cardiovascular morbidity and mortality in adulthood. We sought to determine whether adults born with intrauterine growth restriction have primary maladaptive changes in cardiac structure. METHODS: Study participants were adults (34-49 years) who attended the 31-year follow-up of the Cardiovascular Risk in Young Finns Study (longitudinal cohort). Transthoracic echocardiograms and demographic and cardiovascular risk surveys were completed for 157 adults born small for gestational age (SGA, birth weight <10th population centile) and 627 born average for gestational age (average for gestational age (AGA), birth weight 50th-90th population centile). RESULTS: Those born growth restricted had subtly enlarged hearts with indexed left ventricular (LV) end-systolic and end-diastolic diameters slightly greater in the SGA individuals than the AGA group (LVESD 18.7 mm/m(2) SGA vs 18.1 mm/m(2) AGA, p<0.01; LVEDD 27.5 mm/m(2) SGA vs 26.6 mm/m(2) AGA, p<0.01); LV base-to-apex length (47.4 mm/m(2) SGA vs 46.0 mm/m(2) AGA, p<0.01); LV basal diameter (26.4 mm/m(2) SGA vs 25.7 mm/m(2) AGA, p<0.01); and right ventricular base-to-apex length (40.1 mm/m(2) SGA vs 39.2 mm/m(2) AGA, p=0.02). LV stroke volume was greater in those born AGA (74.5 mL SGA vs 78.8 mL AGA, p<0.01), with no significant difference in cardiac output (5 L/min SGA vs 5.2 L/min AGA, p=0.06), heart rate, diastolic indices or sphericity index. CONCLUSIONS: Adults born SGA have some statistically significant but subtle changes in cardiac structure and function, which are less marked than have been described in childhood, and are unlikely to play a pathogenic role in their elevated cardiovascular risk.

A polymorphism in the protein kinase C gene PRKCB is associated with α2-adrenoceptor-mediated vasoconstriction.

OBJECTIVES: α2-Adrenoceptors (α2-AR) mediate both constriction and dilatation of blood vessels. There is considerable interindividual variability in dorsal hand vein (DHV) constriction responses to α2-AR agonist activation. Genetic factors appear to contribute significantly to this variation. The present study was designed to identify the genetic factors contributing toward the interindividual variability in α2-AR-mediated vascular constriction induced by the selective α2-AR agonist dexmedetomidine. METHODS: DHV constriction responses to a local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable for constriction was log-transformed dexmedetomidine ED50. A genome-wide association study (GWAS) of 433 378 single-nucleotide polymorphisms (SNPs) was carried out for determining the sensitivity of DHV responses in 64 healthy Finnish individuals. Twenty SNPs were selected on the basis of the GWAS results and their associations with the ED50 of dexmedetomidine were tested in an independent North American study population of 68 healthy individuals. RESULTS: In both study populations (GWAS and replication samples), the SNP rs9922316 in the gene for protein kinase C type ß was consistently associated with dexmedetomidine ED50 for DHV constriction (unadjusted P=0.00016 for the combined population). CONCLUSION: Genetic variation in protein kinase C type ß may contribute toward the interindividual variation in DHV constriction responses to α2-AR activation by the agonist dexmedetomidine.