The CV-CF Study Preclinical Cardiovascular and Metabolic Phenotypes - - PowerPoint PPT Presentation

The CV-CF Study

CFCC Community Conference Program 14th September 2019 Dr Thomas Saunders

Preclinical Cardiovascular and Metabolic Phenotypes in Paediatric Cystic Fibrosis

Prof Sarath Ranganathan Prof Mark Oliver A/Prof David Armstrong Prof David Burgner

Improvi ving Life Expectancy in CF

What could d middl dle- and o

• lder-age l

e look

• k 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

• Adults
• Diet and Exercise
• Medications: Anti-inflammatories
• Children
• Time
• Diet and exercise
• Good habits

The Argument for CVD in CF

Em Emerging Case R Report rts

Analogous Adult t Conditi tions

Pulmonary Coronary Heart Disease Stroke Combined CVD

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

E.J. Reverrietal./FreeRadicalBiologyandMedicine76(2014)261–277

Recurrent and chronic infection Abnormal endothelium structure and function Microvascular changes in CFRD High fat diet (trans fats) Low HDL Abnormal cellular lipids Abnormal immune cell function and types Elevated visceral adipose tissue Prothrombotic platelets

The Knowled edge e Ga Gap

General Population

Autopsy studies Ongoing population studies Preclinical Cardiovascular Phenotypes

The Knowled edge e Ga Gap

Autopsy studies Ongoing population studies Preclinical Cardiovascular Phenotypes CUPID VASCFIND

Inflammatory Disease Population

The Knowled edge e Ga Gap

Autopsy studies Preclinical Cardiovascular Phenotypes

Cystic Fibrosis Population

CV-CF

AtheroCF (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

To investigate if children with CF are at increased cardiometabolic risk and have underlying mechanisms for targeted prevention Overall Aim

Recru ruitm tment

Inclusion Criteria

• 150 children with CF 5-18 years old

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

(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

• Status post organ transplant
• 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)

Victorian Paediatric Population Cystic Fibrosis (150)

RCH with 229 >5yo CF children MCH with 119 >5yo CF children

Controls (450) BIS CUPID CHECKPOIN T

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
• ccurrence 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

• od 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?