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Cardiovascular Risk Factors And Signs Of Subclinical Atherosclerosis In The Heinz Nixdorf Recall Study: In Reply

We thank Dr. Zimmermann for pointing out that the sleep apnea syndrome is a cardiovascular risk factor.

The goal of the Heinz Nixdorf Recall Study is to determine the predictive value of coronary calcification (an indicator of subclinical atherosclerosis) for cardiovascular morbidity and mortality. Other indicators of subclinical atherosclerosis, such as intimal-medial thickness and plaque formation in the carotid artery and the ABI index for peripheral arterial occlusive disease, were looked at as well. In addition to the ECG and the stress ECG, anthropometric and psychosocial factors were analyzed.

Obstructive sleep apnea (OSA) elevates cardiovascular risk independently of other, often associated risk factors such as advanced age, obesity, and metabolic disorders (1–3). Large-scale epidemiological studies have shown that OSA is of particular importance as an independent risk factor for arterial hypertension (2, 3). Thus, according to published guidelines, a work-up of arterial hypertension should include screening for sleep apnea.

In the second phase of the Heinz Nixdorf Recall Study, which is currently in progress in cooperation with Prof. Teschler of the Ruhrlandklinik in Essen (Germany), due attention was paid to these facts and nocturnal respiratory monitoring was performed.

Because logistical difficulties prevented the performance of complete polysomnography – the gold-standard test for OSA – in all of the study subjects, a simple screening test of breathing during sleep was carried out (Apnea Link, Resmed, Sydney, Australia). Dr. Wessendorf and colleagues recently presented the initial findings: in the patient collective of the Heinz Nixdorf Recall Study, OSA was a frequent comorbidity, and its severity was correlated with the age, body-mass index, and waist-hip ratio of the patient. These results are in accordance with those in the published literature on the subject. An initial analysis has also shown an association with coronary calcification; we are currently studying the question whether this is true independently of other risk factors.DOI: 10.3238/arztebl.2008.0294b

Prof. Dr. Med. Raimund Erbelfor the Investigator Group of the Heinz Nixdorf Recall StudyKlinik für KardiologieUniversitätsklinikum EssenWestdeutsches Herzzentrum EssenHufelandstr. 5545122 Essen, Germanyerbel@uk-essen.De

Conflict of interest statementProf. Erbel has received support for the setting up of a scientific meeting from the Siemens company, Erlangen, Germany.

Atherosclerosis Progression And Temporal Inverse Allocation Model. (IMAGE)

Caption

Over a 9-year follow-up period from adolescence to young adulthood, elevated lipid and dyslipidemia levels were associated with worsening subclinical atherosclerosis. However, using a temporal inverse allocation model recently developed for simulating treatment intervention, the study revealed that an attempt at lowering cholesterol in young adulthood may be too late and ineffective in stopping atherosclerosis progression. Age 17 years appears to be the golden opportunity to treat and stop atherosclerosis progression in a general population of asymptomatic adolescents

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About The Lab

Dr Bacha's laboratory at the Children's Nutrition research Center (CNRC) investigates the risk factors and mechanisms underlying the pathogenesis of the metabolic complications related to childhood obesity and insulin resistance with a focus on youth-onset type 2 diabetes, cardiovascular disease risk and subclinical atherosclerosis. Her lab utilizes state of the art methodology to understand the pathophysiology of these nutrition related diseases in children and adolescents, so that more targeted prevention and intervention strategies can be implemented. 

Glucose and Insulin Metabolism- Prediabetes and Type 2 Diabetes in YouthEarlier work by Dr. Bacha focused on understanding the relationship of adiposity to insulin resistance and characterizing the risk factors for type 2 diabetes in youth. Her work on the pathophysiological mechanisms of prediabetes and type 2 diabetes contributed to the current understanding of the pathophysiology of the disease in children, and the importance of the defect in beta cell function to the pathogenesis and the rapid progression of type 2 diabetes and its complications in childhood.  Dr. Bacha has been a longterm investigator in the TODAY study and its long-term post-intervention follow-up TODAY 2. This project investigated the natural history of type 2 diabetes in children, therapeutic options and longitudinal follow-up post participation in the study. 

Currently Dr. Bacha's laboratory is pursuing the use metabolomics to uncover biomarkers of beta cell function and cardiovascular disease in youth with type 2 diabetes.

A new study aims to characterize the pathogenesis of youth-onset prediabetes and type 2 diabetes to better identify youth at risk for the disease.

Endothelial Dysfunction and Subclinical Atherosclerosis:Dr Bacha's work aimed to delineate the cardiovascular complications related to childhood obesity, insulin resistance and type 2 diabetes, and to identify adequate biomarkers of subclinical atherosclerosis in youth, and their determining factors. She utilized different methodologies to measure vascular function including pulse wave velocity and intima media thickness, and coronary artery calcifications (CAC), as early biomarkers of subclinical atherosclerosis. Her work demonstrated that different aspects of subclinical atherosclerosis appear to be differentially modulated, adiposity being the major determinant of CAC, hyperglycemia for intima media thickness, and leptin and insulin sensitivity for arterial stiffness.  She also demonstrated that peripheral endothelial function is a biomarker of vascular health modulated by insulin sensitivity in youth. In addition, work in her lab showed that non-alcoholic fatty liver disease in youth is associated with multi-organ insulin resistance and significant endothelial dysfunction directly related to the hepatic fat content. This was independent of visceral adiposity or glycemia. Ongoing work is focusing on understanding thee determinants of cardiac autonomic dysfunction in youth across the glycemic spectrum.

In the TODAY study, she also described evidence of early cardiac injury in relation to obesity and high blood pressure in youth-onset type 2 diabetes and contributed to work showing rapid progression of cardiovascular disease risk in youth with type 2 diabetes.  

A recent project aims to understand the role of the advanced glycation endproducts (AGEs), and their receptor as biomarkers of microvascular and macrovascular disease in youth-onset type 2 diabetes.

Sleep, Circadian Dysregulation and Energy MetabolismHer work included evaluation of the perturbations in energy metabolism related to obesity across the glycemia spectrum in youth, and the relationship of sleep dysfunction and circadian dysregulation to energy homeostasis and glucose metabolism in children. She showed reduced metabolic flexibility in the setting of severe insulin resistance in youth across the glycemic spectrum (JCI Insights 2021). She also investigated the relationship of sleep parameters (actigraphy) to physical activity and energy metabolism. These studies showed that delayed sleep timing is an important factor in determining physical activity in children. Reduced sleep duration was related to increased sedentary behaviors and less time spent in light physical activity. Moreover, she utilized indirect calorimetry and the doubly labelled water measures of energy expenditure, and showed that shorter sleep duration was associated with lower basal metabolic rate after accounting for age, sex, fat mass and lean mass. 

Bone Health A new area of investigation in the Bacha laboratory focuses on Bone Health in Children. She is utilizing high resolution peripheral quantitative computed tomography (HRpQCT) to measure bone micro-architecture and strength, along with assessment of body composition, glucose metabolism, physical activity and nutrition to better understand the factors that may interfere with adequate bone formation in childhood and adolescence, a critical time for bone growth and lifelong bone health.

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