This study has one main objective:

a) To assess the impact of two different supervised exercise interventions on cardiorespiratory fitness and markers of subclinical atherosclerosis in patients with Familiar Hipercolesterolemia (FH), and to unravel the underlying mechanisms behind these effects.

The starting hypothesis of the UPPA-FH project anticipates that both exercise interventions will produce a large increase in cardiorespiratory fitness and will improve significant markers of atherosclerosis in patients with FH, with high-intensity interval training program (HIIT) being more efficient than the moderate-intensity continuous training (MICT) modality. The main effects will be mediated by a significant change in the metabolomic signature of the participants. In addition, higher physical activity will be associated with more favorable markers of atherosclerosis progression, as shown through blood and image technique

Familial hypercholesterolemia (FH) is an inherited disorder characterized by high levels of LDL cholesterol and an increased risk of atherosclerosis and premature cardiovascular disease. From a clinical perspective, FH patients require lifelong management and monitoring of their cholesterol levels and may require multiple medications to control their cholesterol levels, leading to increased healthcare utilization and costs. From an economic perspective, the lifetime costs of managing FH can be significant and can include the cost of medications, diagnostic tests, and hospitalizations for cardiovascular events. In Spain, FH represents a heavy burden for the health care system, with direct costs of 37,299,000 €, indirect costs (due to loss of labor productivity) of 50,049,000 €, and an average of 25 years of life lost adjusted for labor productivity. From a public health perspective, FH affects around 25 million people worldwide that are at an increased risk of premature mortality, making FH a significant public health concern.

Hypercholesterolemia is one of the main vascular risk factors (VRF) related to the development of cardiovascular diseases (CVD), mainly myocardial infarction (MI) and stroke, the main causes of global mortality in the past decades. It is important to note that patients with FH present an increased prevalence of CVD at a very early age (44 years on average) and, in comparison to the general population, patients with FH have a 13.2 times higher risk of developing atherosclerotic CVD; specifically, up to 50% of men and 30% of women with FH will suffer an MI before the age of 60. Atherosclerosis is a complex process that involves endothelial dysfunction, inflammation, or oxidative stress. The presence of atherosclerosis can be assessed with positron emission tomography (PET), which has shown a high ability to predict the development of atherosclerotic plaque and cardiovascular events even after the consideration of classic VRF, so it is used as a method of early diagnosis of subclinical atherosclerosis in patients with chronic proinflammatory diseases. Therefore, the use of PET along with various plasma markers of inflammation in patients with FH (including C-reactive protein, [CRP], interleukin 10 [IL10], oxidized LDL [oxLDL], and the intracellular adhesion molecule 1 [ICAM1]), could allow the detection of atherosclerotic disease in the very early stages. Consequently, understanding novel markers that allow early identification of subclinical atherosclerosis, as well as strategies for reducing the VRF associated with FH, are key targets in these patients.

The treatment of hypercholesterolemia is primarily based on pharmacological therapies such as statins, ezetimibe, and monoclonal antibodies, which can decrease LDL cholesterol levels by up to 60%. However, the rate of achieving LDL cholesterol targets set by clinical practice guidelines is low (30-40%) due to poor tolerance to high doses of statins and other reasons. Importantly, new risk factors such as chronic vascular inflammation and oxidative stress are now considered in the etiology of atherosclerotic CVD beyond LDL cholesterol levels. Consequently, new treatment approaches are needed to address the treatment of FH as an important public health concern.

For all the above, unraveling the role of potential protective factors and interventions that might significantly improve the cardiometabolic profile and reduce the risk of morbi-mortality in this population, as well as the mechanisms involved, is of wide clinical and public health interest.

The UPPA-FH project will unravel the role of physical activity and different exercise interventions on critical health markers in men and women with FH and will study the mechanisms by which these effects are produced. For instance, whether the effects of exercise are mediated by changes in the metabolomic signature related to blood lipids will be explored. This will enable i) international institutions to develop clinical guidelines including exercise as a first-line treatment for the management of FH and ii) to unravel (for the first time) the potential mechanisms behind the effects of exercise in this population.

Physical activity and physical fitness are strong markers of health that are positively and strongly associated with survival in the general population and in patients with CVD. However, the role of physical activity on markers of atherosclerosis progression, inflammation, endothelial function, and other CVD risk factors in patients with FH has not been explored and would provide a framework for targeted physical activity promotion interventions. Similarly, CRF is associated with a better lipid profile, lower rates of pro-atherosclerotic VRF (hypertension, diabetes), and less subclinical atherosclerosis in different populations and is associated with a lower risk of death from all causes and a lower risk of death from cardiovascular diseases (CVD). CRF has also been shown to be a better predictor of mortality than other traditional vascular risk factors (VRF), such as hypercholesterolemia, hypertension, smoking, or type 2 diabetes. In men with hypercholesterolemia, higher cardiorespiratory fitness (CRF) is associated with up to 45% lower risk of CVD mortality, independent of other clinical risk factors, which underscores the importance of CRF in the primary prevention of CVD in patients with hypercholesterolemia. Therefore, exploring the value of CRF as a marker of health in patients with familial hypercholesterolemia (FH) and how exercise interventions can improve CRF is of high scientific and clinical value.

Although exercise interventions can reduce inflammation, oxidative stress and improve endothelial function in different populations and is a cost-effective therapy with similar benefits to pharmacological treatment in reducing CV and all-cause mortality, its effects in patients with FH have not been addressed before. The UPPA-FH will unravel the role of high-intensity interval training (HIIT) versus moderate-intensity continuous training (MICT) on cardiorespiratory fitness and the course of atherosclerosis in men and women with FH. These interventions have proved to be effective in improving CRF and improve CVD risk factors, and HIIT has been shown to be a time-efficient intervention that increases adherence due to the limited amount of time needed and the clinically relevant benefits in patients with and without CVD. HIIT protocols also improve anthropometric, metabolic, and vascular function in people with type 1 diabetes, type 2 diabetes, coronary disease, obesity, or the general population. Furthermore, HIIT has been shown to be safe in patients with high CV risk, such as those with coronary disease and heart failure, when developed in supervised environments.

Unlocking how physical activity and fitness impact the development of atherosclerosis and the unique metabolomic signature of men and women with FH is a key goal of this proposal. But we're not stopping there. The UPPA-FH project goes one step further to uncover the specific effects of different exercise interventions and regimens on key health markers for FH, such as cardiorespiratory fitness and atherosclerosis, and to understand the underlying mechanisms for these benefits. This proposal has the potential to make breakthrough discoveries that will pave the way for future interventions and for developing clinical guidelines, including exercise recommendations for FH patients, which are currently lacking.

The novelty of this proposal relies on discovering the extent to which exercise can improve key health parameters in FM patients, which is currently unknown. The clinical guidelines for these patients lack specific information on physical activity and exercise, which limits the ability of the health care system to benefit this population. Based on evidence on many similar populations, it can be affirmed that exercise has a huge potential to improve critical markers in patients with FH. Another novelty of the UPPA-FH study is to unravel the mechanisms underlying the effects of exercise, including inflammatory markers, oxidative stress and the metabolomic signature. Finally, also a novelty of this study will be to address the safety of moderate and high intensity exercise in this special population of high CV risk by providing detailed information about the adverse effects of the interventions; the lack of adverse effects reporting in exercise trials is a very common issue that this study will clearly address. All in all, through a highly collaborative y multidisciplinary research approach team and design, this study will contribute to improve the current management of FH patients, and will allow to understand the reasons why exercise is beneficial in this genetic condition.

Inclusion criteria:

• Individuals with a diagnosis of genetic FH.
• > 18 years old.
• Minimum follow-up of 1 year in the Vascular Risk Clinic of the Virgen de las Nieves University Hospital (HUVN).
• Clinical and treatment stability.
• Non-pathological angio-TAC of coronary arteries in the 5 years prior to the study (for participants >45 years old).

Exclusion criteria:

• Inability to read, understand and sign the informed consent.
• Contraindications to exercise.
• History of clinical CVD (ischemic heart disease, stroke, and/or peripheral arterial disease).