The CV-CF Study Preclinical Cardiovascular and Metabolic Phenotypes in Paediatric Cystic Fibrosis CFCC Community Conference Program 14 th September 2019 Dr Thomas Saunders
Prof Sarath A/Prof David Ranganathan Armstrong Prof Mark Prof David Oliver Burgner
Improvi ving Life Expectancy in CF
What could d middl dle- and o older-age l e look ok like w e with CF? ? What n new medical issues will a an older p r person with CF face in the future? An And how can we prepare our r kids for r it?
Cardiovascular Disease
Cardiovascular Disease • Stroke • Heart attack • Atherosclerosis
The Classic R Risk F Factors
Inflammation and Atherosclerosis
Ath therosclerosis i is Reversible • Children • Adults • Time • Diet and Exercise • Diet and exercise • Medications: Anti-inflammatories • Good habits
The Argument for CVD in CF
Em Emerging Case R Report rts
Analogous Adult t Conditi tions Coronary Heart Pulmonary Stroke Combined CVD Disease Non-CF Bronchiectasis 1.4x 1.7x COPD 2.5x Idiopathic pulmonary fibrosis 2.3x Chronic Inflammatory HIV 1.5-2.7x Rheumatoid arthritis 1.5-2x SLE 3-50x Psoriasis 1.8x 1.7x Inflammatory Bowel Disease 1.1x 1.3x
Cl Class assical R Risk k Fact actors
Classical R Risk Fact ctors Stephenson A, et al Longitudinal trends in nutritional status and the relation between lung function and BMI in cystic fibrosis: a population-based cohort study, The American Journal of Clinical Nutrition , Volume 97, Issue 4, April 2013, Pages 872–877,
No Non-Clas assi sical al R Risk Fact actors
Non Non-Classical Risk Fact ctors Elevated visceral adipose tissue Recurrent and chronic infection Microvascular changes in CFRD Abnormal endothelium Prothrombotic platelets structure and function High fat diet (trans fats) Abnormal immune cell Low HDL function and types Abnormal cellular lipids E.J. Reverrietal./FreeRadicalBiologyandMedicine76(2014)261–277
The Knowled edge e Ga Gap General Population Ongoing Autopsy studies population studies Preclinical Cardiovascular Phenotypes
The Knowled edge e Ga Gap Inflammatory Disease Population Autopsy studies Preclinical Cardiovascular Phenotypes CUPID VASCFIND Ongoing population studies
The Knowled edge e Ga Gap Cystic Fibrosis Population Autopsy studies Preclinical CV-CF Cardiovascular AtheroCF Phenotypes (Poland)
The CV-CF Study Something New
CV-CF CF • Running in parallel with two similar Victoria studies: • CUPID • VASCFIND • Two large-scale population based studies of the general paediatric populations • CHECKPOINT • BIS • Newly proposed longitudinal CVD in adult CF study in Poland • AtheroCF
Overall Aim To investigate if children with CF are at increased cardiometabolic risk and have underlying mechanisms for targeted prevention
Recru ruitm tment Inclusion Criteria • 150 children with CF 5-18 years old Victorian Paediatric Population Exclusion Criteria • Children with a positive family history of familial dyslipidaemia, or early episodes of coronary artery disease and cerebrovascular diseases in the family • Participants with chronic inflammatory conditions Cystic Fibrosis Controls (450) (150) (apart from CF) • Participants with autoimmune type-1 insulin dependent diabetes, or type-2 diabetes • Cystic fibrosis related diabetes is not an exclusion criteria • Current oral glucocorticoid therapy or other immunosuppressive medications RCH with 229 MCH with 119 CHECKPOIN • Status post organ transplant >5yo CF BIS CUPID >5yo CF T children children • CF participants will not be enrolled during, or within one month following a hospitalization or escalation in care related to their cystic fibrosis (excluding day procedures for line care and medical imaging)
Body M Measur urements • Obesity, BMI, waist-hip ratio and body fat distribution are all known risk factors in adult CVD • Measures of regional adiposity (android vs gynoid) and visceral adiposity strongly correlate with adverse CVD
Ar Arteri rial Wall Thickness • Ultrasound measurement of artery walls • Correlates with pathology examination (gold standard), and the presence of atherosclerosis elsewhere in the body • We know it predicts the occurrence of CVD in adults
The Speed of Y Your Pulse • Reproducible measurement of arterial stiffness. • Faster arterial speeds reflect increased arterial stiffness, and more fatty plaque in the walls • Vessel elasticity reduces with age, precedes hypertension, and predicts cardiovascular events in adults
Retinal Blood Vessels • A measurement of microvascular vessels • Looking for vessels that are larger, more tortuous and have more branching • Elevated indices have been shown to predict the rate and risk of coronary heart disease in adults
Blood ood T Tests • Biomarkers of Inflammation • Breakdown products of: • Fats and cholesterol • Proteins and amino acids • Glucose
Immune S Sys ystem • Cellular aging • Telomeres • Trained Innate Immunity • Hyper-aggressive immune cells
What w we are asking from the families Suitable cases (CF participants) identified through hospital databases and clinician contact. Letter of introduction and information pack provided Participant and/or parent have read the study information pack and are happy to participate OR member of research team may approach potential control participant at CF clinic (or other outpatient department), Day Surgery/Medical Unit, and provide sufficient time to read the study information and are happy to participate Participant attends a study assessment post 6 hour fast (or within one month of routine annual blood tests) Written informed consent obtained by member of research team A complete medical and cardiovascular health history (including family history) will be obtained, alongside height, weight, pubertal status, and adiposity measurements A 16.5ml (~ 3 teaspoons) blood sample will be obtained for batched analysis Non-invasive cardiovascular assessments will be performed including blood pressure, heart rate, pulse wave analysis and velocity, arterial distensibility, and aortic and carotid intima media thickness Retinal photography will be performed A synopsis of outcomes sent to all participants and individual results provided where known (blood pressure, anthropometric measurements, lipid profile)
Why is This Import rtant • Highlight the need for longer term, adult based studies • Help to optimise nutrition in childhood • Help us to understand how inflammation affects the body in CF • Early screening and prevention of atherosclerosis • Important for general health • Reduce adulthood treatment burden • Very important for transplants • Translates to other groups of children with different conditions
Thank you Questions?
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