Heart and Blood Vessels 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.

It is known that pwCF have lower blood pressure compared to the general population, with a tendency for blood pressure to increase less with age. This is thought to be caused by greatly increased sweat chloride loss. With HEMT initiation, the chloride channels are theoretically fixed and therefore, blood pressure could be increased. There is evidence that the prevalence of hypertension in pwCF has increased, with case series reported in Italy and a US study with a 30% increase in hypertension prevalence in a single CF centre.

Arterial stiffness is also recognised as a highly clinically relevant and independent prognostic biomarker. Arterial stiffness explains the inter-relations between the blood flow and the arterial wall tissue. Arteries become stiffer with ageing and particular diseases, and as in other chronic diseases, increased arterial stiffness and endothelial dysfunction have been reported in CF in a few studies. All of these were, however, conducted prior to the widespread availability of modulator therapy. It is therefore essential to understand the progress of vascular health in people with CF in the HEMT era and identify future research targets. If this is a growing trend, this increase in blood pressure and arterial stiffness will likely increase the risk for CVD morbidity and mortality.

Atherosclerosis is a process underlying many cardiovascular diseases; It is the build-up of fats, cholesterol and other substance at the artery walls. The growth of plaques can occlude or rupture the arteries, causing a cardiovascular event. Atherosclerosis and arterial stiffness often co-exist and exacerbate each other's effects. Atherosclerotic plaques contribute to arterial stiffness by increasing the stiffness of the vessel wall and reducing its ability to expand in response to changes in blood pressure. Conversely, arterial stiffness promotes the development and progression of atherosclerosis by increasing shear stress on the endothelium, a single-cell layer that lines the cardiovascular system, which is responsible for maintaining the tone and health of blood vessels. This promotes endothelial dysfunction.

Endothelial dysfunction can be initiated by exposure to numerous risk factors including hypertension and inflammation, causing damages to the arterial cell wall, and is considered an early marker of atherosclerosis. Dysfunctional endothelial cells exhibit impaired nitric oxide (NO) production, increased expression of adhesion molecules, and enhanced oxidative stress, promoting the adhesion of circulating leukocytes and the infiltration of the low-density lipoprotein cholesterol (LDL-C) into the arterial wall. These processes initiate the inflammatory cascade that drives the formation of atherosclerotic plaques. There is evidence of vascular endothelial dysfunction in children and young adults with CF compared to the normal cohort.

Chronic inflammation is another risk factor of CF which may predispose people to CVD. Other chronic inflammatory diseases such as systemic lupus erythematosus (SLE), HIV infection and rheumatoid arthritis (RA) are associated with increased cardiovascular morbidity and mortality. A recent multinational study suggested that pwCF are already at equivalent CVD risk to those living with HIV, SLE or RA. Some of the pathophysiology relevant to these diseases is shared by CF, for example, NETosis and tumour necrosis factor. They are common inflammatory features of CF and are implicated in atherogenesis and heart failure. More specifically, chronic inflammation diseases are associated with subclinical atherosclerosis prevalence as it contributes to endothelial dysfunction. Inflammation is also key in all stages of atherosclerotic process including vascular lesion formation, which is also exacerbated by other risk factors.

Impaired glycaemic control is another significant risk factor precipitating cardiovascular events; over one-third of people with CF aged 16 and over are being treated with CF diabetes. HEMT has been associated with improved glycaemic control and reduced glycaemic variability; Diabetes, nonetheless, does not appear to be routinely improved. A US study shows an equal proportion of noted deterioration or improvement in glycaemic control after HEMT initiation. Therefore, this well-known risk factor for CVD may continue to be apparent after HEMT.

Given that CVD risk factors are becoming more prevalent, it is not unreasonable to assume people with Cystic Fibrosis are at risk of developing cardiovascular disease. I have evaluated the QRISK3 score, a general population CVD risk prediction tool, in the Merseyside and North Wales adult CF population with CF diabetes and found that a 1-year post-HEMT initiation was associated with over 20% relative increase in 10-year CV risk. This was the first study of QRISK in the post-modulator era. QRISK has previously performed sub-optimally in other inflammatory conditions but to date, no studies have evaluated its performance in CF. To address the above uncertainties on vascular risk profiles in pwCF, a more in depth understanding of vascular health is needed to determine the actual cardiovascular health in pwCF. A priority is to evaluate the atherosclerosis development in pwCF, which can be demonstrated by endothelial dysfunction and arterial stiffness. Common inflammatory disease listed above have their own modifying score on QRISK3 and we predict CF should have their own modifying score as those common inflammatory disease.

To date there is little to no identification of overall cardiovascular disease risk in pwCF following the advent of HEMT. Despite the transformative impact of HEMT on pulmonary function and life expectancy in CF patients, there remains a critical gap in understanding the potential cardiovascular implications of these therapies. Given the emergence of new risk factors associated with HEMT, such as significant weight gain and alterations in blood pressure dynamics, there is an urgent need for early and thorough assessment of markers indicative of cardiovascular health in this population. This could include blood pressure, arterial stiffness, endothelial dysfunction, weight/BMI, inflammatory profiles, and diabetes/blood lipid profiles. By integrating these multidimensional assessments into routine clinical care for individuals with CF, healthcare providers can proactively identify and manage cardiovascular risk factors, thus promoting optimal cardiovascular health outcomes in this population.

STUDY:

This study involves three parts (WP1, WP2, WP3). Work Package 1: Cross-sectional analysis of CV health in PwCF and age- and sex-matched control Work Package 2: Longitudinal analysis of CV health in PwCF and age-matched control Work Package 3: Evaluation of the relationship between CVD risk prediction tools and CV health in pwCF

WORK PACKAGE 1 AND 2

The following will be assessed:

* Arterial stiffness (PWV) * Endothelial-mediated function (FMD) * Blood-borne biomarkers

* Full blood count (FBC) * Renal function * Glycated haemoglobin (HbA1c) * Full lipid profile

* Total Cholesterol * High-density lipoprotein cholesterol (HDL-C) * Low--density lipoprotein cholesterol (LDL-C) * Triglycerides * Inflammatory markers

* C-Reactive Protein (CRP) * Creatine Kinase-MB (CKMB) * Resting blood pressure, measured at supine and upright position * Sweat Chloride levels * Height and weight (for BMI measurement) * Body Composition QRISK3 related data will be collected as well (https://qrisk.org/three/index.php). This includes the following additional clinical information - ethnicity, angina or heart attack in a 1st degree relative \<60; history of migraines, rheumatoid arthritis, systemic lupus erythematosus or severe mental illness; taking atypical antipsychotic medication, diagnosis of, or treatment for erectile dysfunction.

Participants will be reminded not to use any short-acting bronchodilators for at least 6 hours, not to have any high fat diet for at least 12 hours, no alcohol and exercise for at least 24 hours and no vitamin supplements for at least 72 hours before attending for assessment. Following baseline measurements, participants will have all measurements repeated at 12 months. Participants will have routine care as managed by their general practitioner and the Cystic Fibrosis team.

MEASUREMENT OF ARTERIAL STIFFNESS Arterial stiffness will be assessed using Pulse Wave Velocity (PWV) and Augmentation Index (AIx)-two widely validated non-invasive markers of large artery stiffness and wave reflection, respectively.

Pulse wave velocity (PWV) will be estimated using an IEM Mobil-O-Graph, which analyses oscillometric pulse waveforms recorded at the brachial artery. Using the ARC

• Incidence of cardiovascular events (MI, angina, stroke, TIA or cardiac death) [Срок оценки: at 12 months]
• Change in Arterial Stiffness Assessed by Pulse Wave Velocity (PWV) [Срок оценки: at start and at 12 months]
• Change in Arterial Stiffness Assessed by Augmentation Index (AIx) [Срок оценки: at start and at 12 months]
• QRISK3 scores [Срок оценки: at start and at 12 months]