Infraestructura de Medicina de Precisión asociada a la Ciencia y la Tecnología
The project focuses on patients with Familial Hypercholesterolemia (FH), who have high levels of LDLcholesterol from birth and develop premature cardiovascular disease (onset in the fourth decade of life if left untreated) due to mutations in the LDL receptor. The prevalence of coronary heart disease in heterozygous FH is estimated to be between 3-14 times higher than in the general population, with a great variability that is associated with factors unknown at this time and that we intend to reveal in this project. It is especially necessary to differentiate between patients at high risk of suffering premature clinical events and re-events, from those who have a lower risk, even if they have inherited the same mutation. This risk discrimination based on the knowledge derived from this project (omics and imaging technologies) would make it possible to carry out precision medicine according to the patient’s real risk and prescribe treatments according to this individual risk. Multiple therapeutic approaches for dyslipidemia are being developed at this time, which will need to be prescribed according to clear criteria due to their high cost. This project may help to establish such criteria for rationalisation of expenditure adjusted to the best possible medical treatment of high-risk patients.
Therefore, it is intended to address innovation in medical practice through the integration of new molecular biomarkers (proteins, non-coding RNAs), as well as the use of imaging techniques and polygenic risk score (PRS) to pyrognosically discriminate those FH patients at high risk of suffering premature clinical events, from those at lower risk. The objective is to determine patterns of management of FH patients and their treatment, aimed at improving both their quality of life and reducing health expenditure. We plan to obtain samples after 10 years of clinical evolution from patients in the cohort to evaluate the efficacy of the new biomarkers identified and finally we will evaluate the results with strict criteria of efficacy and cost/benefit before passing them on to the NHS.
The objective of the proposed project is to identify and validate at the clinical-care level biomarkers -omics/imaging that lead to an improvement in the diagnostic and prognostic capacity in patients with FH and thus to the optimization of therapeutic procedures based on a more personalized medicine. Specifically, through a multidisciplinary approach of omics and imaging technologies, it is intended to single out those differential molecular patterns that may act as modifying factors of the clinical phenotype of cardiovascular disease (ASCVD) among subjects with similar genetic mutations of the gene coding for LDLR that cause FH. The newly identified molecules (non-coding RNAs and proteins) will be analyzed in relation to genetic mutations, polygenic risk, plasma lipid parameters (LDL-C, Lp(a), HDL-C), LRLR function markers, and inflammatory markers. In addition, they will be compared with the burden, characteristics, and distribution of subclinical atherosclerotic disease, identified by imaging techniques (CTA) and their potency will be determined to improve the individual risk assessment of ASCVD and the cardiovascular risk stratification obtained from the SAFEHEART equation.
The identification and validation of new biomarkers in the HF population will be carried out based on two key aspects (1) “ASCVD-Resilience” and (2) “gender specificity”.
Recently, we have evidenced in populations aged 65 and 80 years the existence of FH patients who do not present clinical events, however, there is no consistent information that allows us to predict who will be “resilient”. Therefore, a primary OBJECTIVE in this project is to be able to single out FH patients who will have a future with CV disease with precision medicine compared to those who will not suffer from it.
The second key aspect is that in the SAFEHEART cohort there are 52% women, so it will be possible to advance in the characterization by sex of the evolution of atherosclerotic disease. Therefore, the second priority OBJECTIVE is to identify gender differences in genetic and molecular characteristics that will allow progress in the description of protection or resilience patterns.
Thus, based on the biological samples and data from the SAFEHEART cohort, at inclusion and during follow-up, the following three main objectives are proposed:
A.- INNOVATION– A1: To analyze the contribution of the global polygenic risk derived from small variations in the many genes that have been described to participate individually in a moderate way in atherosclerosis. A2: To investigate epigenetic patterns (lncRNAs, miRNAs) in representative subgroups of FH patients with different age ranges, with and without presentation of clinical events of cardiovascular disease (ASCVD) and in comparison with their unaffected relatives. A3: To determine the differential proteomic profile in the subgroups described in A2. A4: Identify the atherosclerotic load by imaging to associate it with the data obtained in A1, A2 and A3 and the lipid profile and inflammatory load.
B.- VALIDATION – B1: To validate the molecular biomarkers selected in objective A (Innovation) in a large population of the SAFEHEART cohort study, in biological samples obtained at inclusion (initial visit, V1) and at 10 years of follow-up (V10 visit), singling out gender and diversity by autonomous communities. B2: To determine whether one or more of the identified molecular biomarkers enhance the power of the SAFEHEART-RE equation in cardiovascular risk stratification. B3: To determine the potency of one or more of the molecular biomarkers selected in the reclassification of cardiovascular risk (medium to high) in the FH population.
C.-TRANSFER / IMPLEMENTATION – C1: Transfer to the National Health System (SNS) the most affordable methodology (molecular biomarker and analysis method) on a cost/benefit basis in order to improve the identification and risk stratification in FH patients.
Familial Hypercholesterolemia (FH) is a hereditary disease, which is transmitted to 50% of the offspring. FH patients have high cholesterol levels from birth, which gives them a high risk of developing premature cardiovascular disease. About 50% of untreated FH patients will have a coronary event by the age of 50. Therefore, early diagnosis and appropriate treatment are critical to preventing premature cardiovascular disease. The testimonies of patients who are members of the Familial Hypercholesterolemia Foundation indicate the scope of the problem. It is a disease that affects families that in many cases have not been diagnosed with FH. As an example, many patients reflect this situation: a patient who is diagnosed for the first time in his family as FH (produced by entering the SAFEHEART cohort) at the age of 40, and describes how his father had a myocardial infarction at the age of 57 with subsequent coronary revascularization surgery, and a grandmother and an uncle (on the paternal side) died of myocardial infarction at 43 and 45 years of age. respectively. Evidence of how the quality of life of FH individuals is very negatively affected by possible premature mortality in the family and by doubts about their own mortality and that of their offspring.
Early detection and evaluation of patients who may be resilient are two key aspects to introduce real changes in the quality of life of FH patients. Social determinants of health have proven to be key in resolving or mitigating hereditary imperatives. Better care as early as possible can reduce the impact of the genetic mutation on patients’ lives. In this Project, with the participation of our clinical groups in twelve autonomous communities, we will also evaluate social aspects that are determinants, such as the environment, education and social inequality within a given community.
FH represents a unique opportunity for the prevention of ischemic heart disease, because the knowledge acquired will be extrapolated to the entire population that suffers the consequences of the progression of the
arteriosclerosis. Cardiovascular disease (CVD) of atherosclerotic origin is, according to WHO (Fact Sheet EURO/03/06), the cause of death in Europe. CVD, including ischemic stroke, is the leading cause of death in adults globally. More than 7 million people suffer a heart attack each year (in Spain there are more than 125000 deaths and more than 5 million hospitalizations due to CVD per year; www.ine.es). In Europe, 45% of all deaths are due to CVD, with 3.3 million deaths per year and a cost of 210 billion euros.
The increase in the prevalence of risk factors is one of the causes of these figures. We need to advance in the knowledge of the molecular/genetic pathological mechanisms responsible for this transformation of a silent disease, such as atherosclerosis, into a clinical manifestation of CVD. This project investigating FH (many FH patients still debut in coronary units without having been diagnosed) will contribute to generating knowledge of general application in CVD.