Serum Biomarkers of Myocardial Remodeling and Coronary Dysfunction in Early Stages of Hypertrophic Cardiomyopathy in the Young.

Hypertrophic cardiomyopathy (HCM) remains the leading cause of sudden cardiac death in the young. Early markers for HCM are important to identify individuals at risk. The aim of this study was to investigate novel serum biomarkers reflecting myocardial remodeling, microfibrosis, and vascular endotheliopathy in the early stages of familial HCM in young patients. Twenty-three HCM patients, 16 HCM-risk individuals, and 66 controls (median 15 years) underwent echocardiography and serum analysis for cathepsin S, endostatin, myostatin, type I collagen degradation marker (ICTP), matrix metalloproteinase (MMP)-9, vascular endothelial growth factor receptor (VEGFR)-1, and vascular and intercellular adhesion molecules (VCAM, ICAM). In a subset of the population, global myocardial perfusion was performed by magnetic resonance imaging. Cathepsin S (p = 0.0009), endostatin (p < 0.0001), MMP-9 (p = 0.008), and VCAM (p = 0.04) were increased in the HCM group and correlated to left ventricular mass index and mitral E/e' (p < 0.01). In the HCM-risk group, myostatin was decreased (p = 0.004), whereas ICAM was increased (p = 0.002). Global perfusion was decreased in the HCM group (p < 0.05) versus controls. Endostatin and mitral E/e' correlated inversely to myocardial perfusion (p ≤ 0.05). This is the first study demonstrating adverse changes in biomarkers reflecting myocardial matrix remodeling, microfibrosis, and vascular endotheliopathy in early stage of hypertrophic cardiomyopathy in the young.

MYBPC3 hypertrophic cardiomyopathy can be detected by using advanced ECG in children and young adults.

INTRODUCTION: The conventional ECG is commonly used to screen for hypertrophic cardiomyopathy (HCM), but up to 25% of adults and possibly larger percentages of children with HCM have no distinctive abnormalities on the conventional ECG, whereas 5 to 15% of healthy young athletes do. Recently, a 5-min resting advanced 12-lead ECG test ("A-ECG score") showed superiority to pooled criteria from the strictly conventional ECG in correctly identifying adult HCM. The purpose of this study was to evaluate whether in children and young adults, A-ECG scoring could detect echocardiographic HCM associated with the MYBPC3 genetic mutation with greater sensitivity than conventional ECG criteria and distinguish healthy young controls and athletes from persons with MYBPC3 HCM with greater specificity. METHODS: Five-minute 12-lead ECGs were obtained from 15 young patients (mean age 13.2years, range 0-30years) with MYBPC3 mutation and phenotypic HCM. The conventional and A-ECG results of these patients were compared to those of 198 healthy children and young adults (mean age 13.2, range 1month-30years) with unremarkable echocardiograms, and to those of 36 young endurance-trained athletes, 20 of whom had athletic (physiologic) left ventricular hypertrophy. RESULTS: Compared with commonly used, age-specific pooled criteria from the conventional ECG, a retrospectively generated A-ECG score incorporating results from just 2 derived vectorcardiographic parameters (spatial QRS-T angle and the change in the vectorcardiographic QRS azimuth angle from the second to the third eighth of the QRS interval) increased the sensitivity of ECG for identifying MYBPC3 HCM from 46% to 87% (p<0.05). Use of the same score also demonstrated superior specificity in a set of 198 healthy controls (94% vs. 87% for conventional ECG criteria; p<0.01) including in a subset of 36 healthy, young endurance-trained athletes (100% vs. 69% for conventional ECG criteria, p<0.001). CONCLUSIONS: In children and young adults, a 2-parameter 12-lead A-ECG score is retrospectively significantly more sensitive and specific than pooled, age-specific conventional ECG criteria for detecting MYBPC3-HCM and in distinguishing such patients from healthy controls, including endurance-trained athletes.

Effects of ketogenic diet on vascular function.

BACKGROUND: Ketogenic diet is a well-established treatment in children with difficult to treat epilepsy. Very little is known about the long-term effects on vascular atherogenic and biochemical processes of this high-fat and low carbohydrate and protein diet. METHODS: We evaluated 26 children after one year and 13 children after two years of ketogenic diet. High resolution ultrasound-based assessment was used for carotid artery intima-media thickness (cIMT), carotid artery distensibility and carotid artery compliance. Blood lipids including high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol, (LDL-C), total cholesterol (TC), apolipoprotein A (apoA), apolipoprotein B (apoB) and high-sensitivity C-reactive protein (hsCRP) were analysed. RESULTS: A gradual decrease in carotid distensibility and an increase in LDL-C, apoB and the TC:LDL-C and LDL-C:HDL-C ratios were seen at three and 12 months of KD-treatment. These differences were not significant at 24 months. cIMT, BMI and hsCRP did not show any significant changes. CONCLUSIONS: The initial alterations in lipids, apoB and arterial function observed within the first year of KD-treatment appear to be reversible and not significant after 24 months of treatment.

Respiratory infection recurrence and passive smoking in early atherosclerosis in children and adolescents with type 1 diabetes.

BACKGROUND: Optimal glucose control in juvenile type 1 diabetes mellitus is necessary but not sufficient to reduce the burden of cardiovascular events in later life. This emphasizes the importance of searching for other possible risk factors associated with diabetes. We investigated whether recurrent episodes of acute respiratory infections and exposure to tobacco smoke could influence vascular phenotypes for early atherosclerosis in children and adolescents with type 1 diabetes. MATERIALS AND METHODS: Common carotid artery elasticity and intima-media thickness along with circulating markers of lipid, inflammatory and glycaemic profiles were investigated in up to 98 children and adolescents with type 1 diabetes. The number of clinically manifest acute respiratory tract infections (RTI) during the past year, and the degree of exposure to environmental tobacco smoke (ETS), were assessed by separate questionnaires. RESULTS: Carotid artery compliance (CAC) was decreased in patients with high (>or= 4/year; n = 22) recurrence of RTI compared to the remaining patients (n = 40; P < 0.05). In a multivariate analysis, the number of RTI during the past year and HbA(1C) were independently associated with decreased CAC (P < 0.05 for both). The inverse relationship between RTI recurrence and CAC was strengthened by frequent exposure to ETS. CONCLUSIONS: High recurrence of respiratory infections in young type 1 diabetics is associated with increased stiffening of the carotid artery particularly in those often exposed to tobacco smoke.

Arterial endothelial injury due to infection in childhood: ticking bomb or innocent bystander?

Atherosclerosis is regarded as a chronic disease that begins in early life. While the main underlying mechanism of atherosclerosis is nowadays unequivocally attributed to a low-grade inflammatory reaction, the spectrum of aetiological conditions is far from being fully elucidated. Both viruses and bacteria have been suggested to intervene at various stages of atherosclerosis development, although a clear pathogenic link between infection and atherosclerosis remains debatable. As one key event in atherogenesis involves a perturbation of the protective mechanisms normally posed by the arterial endothelium, a number of studies have enquired into the possible detrimental effects of microbes and their components on the endothelial cells. This review aims to scrutinize the current literature in this regard, and to suggest several possible directions for future studies.

Endothelial dysfunction after repeated Chlamydia pneumoniae infection in apolipoprotein E-knockout mice.

BACKGROUND: Arterial relaxation is largely regulated by endothelial nitric oxide (NO). Its diminished activity has been associated with incipient atherosclerosis. We investigated the endothelium-dependent relaxation of aorta in apolipoprotein E-knockout (apoE-KO) mice exposed to single or repeated Chlamydia pneumoniae inoculation. METHODS AND RESULTS: Forty-eight apoE-KO mice, 8 weeks old, were inoculated intranasally with C pneumoniae (n=24) or saline (n=24) every 2 weeks over a 6-week period. Twenty mice (10 infected and 10 controls) were killed at 2 weeks and 6 weeks, respectively, after the first inoculation. The smooth muscle tone of aortic rings was measured in vitro at both time points. The norepinephrine-precontracted thoracic aortic rings were successively exposed to methacholine in the absence and presence of N:(G)-nitro-L-arginine methyl ester (L-NAME) and diclofenac. The methacholine-induced relaxation was attenuated in the infected mice at 6 weeks in both the absence and presence of L-NAME (P:<0.05 and P:<0.01, respectively). When administered together with L-NAME, diclofenac enhanced the relaxation of the L-NAME-pretreated aortas in infected mice at 2 weeks (P:<0.05) but not in noninfected mice. The relaxation response from infected mice tended to differ in the same manner at 6 weeks (P:<0.1). No intimal thickening was detected at either time point. CONCLUSIONS: C pneumoniae impairs arterial endothelial function, and the NO pathway is principally involved. Cyclooxygenase-dependent vasoconstricting products may also account for the infection-induced impaired relaxation. These findings further support the role of C pneumoniae infection in atherosclerosis development.