Cardiovascular Health in People With Cystic Fibrosis

Background:

Cystic fibrosis (CF) is an autosomal recessive disorder characterised by a chloride ion transport defect, leading to dehydrated epithelial secretions, resulting in an inflammatory/infection cycle. This manifests itself most obviously in the lungs but affects multiple organ sites.

Before the development of Cystic Fibrosis Transmembrane Receptor (CFTR) modulators, the mainstay of disease was supportive with a focus on airway clearance, aggressive treatment and prevention of infection and optimisation of nutrition and other common co-morbidities like cystic fibrosis diabetes (CFD) . As a result of the introduction of highly effective modulator therapies (HEMT), overall wellbeing and prognostic outlook has improved significantly. These recent step-changes in prognostic outlook come after small but persistent improvements over the last three decades, such that prior to the introduction of CFTR modulator therapy, the median life expectancy had reached approximately 50 years of age, but now expected it to be longer. The latest HEMT in the market is Elexacaftor/Tezacaftor/Ivacaftor (ETI). Licensed in 2020, it is a ground-breaking development of treatment. About 90% of people with CF worldwide are eligible for the medication according to their genotypes, drastically improving these people's intra- and extra-pulmonary outcomes.

Cardiovascular disease (CVD) is the leading cause of death globally [5]. CVD prevention is essential as there are modifiable risk factors that can be controlled and reducing the occurrence of cardiovascular disease morbidity and mortality. Although people with CF possess numerous traditional CVD risk factors, including a high-fat-high-calorie diet and CF diabetes, historically very few cases are presented with cardiovascular disease in CF. PwCF were considered not at high risk of CVD development because of the shorter life expectancy, low body mass index (BMI) and low blood pressure. However, the risk profile is changing rapidly for people receiving ETI and there are concerns there is likely to be a "wave" of CVD in people living with CF in the coming decade. Some of the rationale for these concerns are set out below.

PwCF were generally considered at risk of malnutrition and being underweight and were therefore recommended to have a high-energy, low-nutrient dietary intake. The introduction of ETI improves nutritional absorption, and as a consequence the weight and BMI are also improved. Unlike lung function improvements that often peaked within eight weeks of ETI initiation, clinical trial data and real-world studies show that increased weight and BMI do not stop increasing. In clinical trials of HEMT, rapid weight gain was commonly observed, and the mean BMI increased by 1.04 kg/m2 in just 24 weeks. The ongoing study showed progressive weight gain continuing two years after HEMT initiation, with the mean BMI increased by 1.6kg/m2. In adults, the mean BMI is around 25, suggesting that approximately half of pwCF receiving HEMT are overweight. Data shows that despite reducing dietary energy intake, BMI has not proportionally decreased, which suggests that metabolic changes also have a significant role in weight and BMI in pwCF on ETI.