Clinical Research

The PESA-Health-CNIC-Santander study is the natural continuation of the long-term endeavor started in 2010 with the PESA Study, carried out by the CNIC in collaboration with Santander Bank. Within PESA-Health, the PESA participants enrolled in 2010 (4184 asymptomatic individuals between the ages of 40 and 55 years at enrollment) will be actively followed up over an additional 10 years.

The original aim of the study was to identify the presence of subclinical atherosclerosis (SA) long before symptoms appear and to understand the cues leading to its development and progression. PESA-Health will expand these objectives to new areas, such as the correlation of SA with Alzheimer’s and cognitive diseases, the acquisition of somatic mutations during aging, and the correlation of these mutations with increasing cardiovascular event rates and SA progression. PESA-Health will continue to take advantage of state-of-the-art imaging technologies, including 3D vascular ultrasound of the carotid arteries and aorta, coronary artery calcium quantification by computed tomography, cardiac magnetic resonance, AngioTC, NaF PET, PET-amyloid analysis, and biosampling for omics analysis. In addition, new state-of-the-art sub studies have been added, including the relationship between sleep apnea and SA.

PESA-Health is the CNIC’s flagship study, and several CNIC clinical and basic research groups participate in it. The PESA study is already making seminal contributions to our understanding of the origin and progression of atherosclerosis.

The PESA-Health-CNIC-Santander study welcomed its first participant in February 2020, taking advantage of the follow-up of the PESA cohort to continue and expand the scientific approaches performed. By the end of 2021, 3481 participants have shown their interest continuing their participation, and more than 1300 participants have performed the first visit of PESA-H.

More information: http://www.estudiopesa.org

The MATRIX Project aims to develop new and innovative treatments for cardiac toxicity associated with some cancer treatments. MATRIX will be jointly run at the CNIC and Fundación Jiménez Díaz (FJD) University Hospital within a collaborative framework established in 2015 to study myocardial diseases. Great advances in the treatment of cancer—a disease with 4 million new diagnoses every year in Europe—sometimes come with a 'toll' to pay in the form of major adverse effects. One of the most common adverse effects is myocardial toxicity, which affects up to 25% of patients treated with the common anticancer drugs anthracyclines or trastuzumab. The cardiotoxic effects of these drugs can be very serious and condemn the cancer survivor to chronic heart failure or even death from this complication.

Cancer treatment-induced cardiotoxicity (CTiCT) can result in severe heart failure. The trade-off between cancer and chronic heart failure places an immense personal burden on patients, with physical and psychological consequences. Current therapies for CTiCT are suboptimal, featuring poor early detection algorithms and nonspecific heart failure treatments. Our recently published results and additional preliminary data indicate that CTiCT is associated with altered mitochondrial dynamics, triggering cardiomyocyte metabolic reprogramming. MATRIX adopts a holistic approach to tackling mitochondrial dysfunction in CTiCT. We propose that early-stage CTiCT could be reverted by metabolic reprogramming to shift mitochondrial substrate utilization. By refining a novel imaging-based algorithm recently developed by our group, we will achieve very early detection of myocardial damage in patients treated with commonly prescribed cancer therapies, long before clinically used parameters become abnormal. Such early detection, not available currently, is crucial for early therapeutic intervention. We also hypothesize that in end-stage CTiCT, mitochondrial dysfunction has passed a no-return point, and the failing heart will only be rescued by a strategy to replenish the myocardium with fresh healthy mitochondria. This can be achieved with the radical new therapeutic option of in-vivo mitochondrial transplant. The MATRIX project has broad translational potential, including a new therapeutic approach to a clinically relevant condition, the development of technology for early diagnosis, and advances in knowledge of basic disease mechanisms.Patient recruitment began in 2020.

Adherence to treatment after acute myocardial infarction (MI) is essential for efficient secondary prevention. Despite this, many post-MI patients abandon prescribed medication. To address this issue, CNIC researchers and FERRER laboratories developed a “polypill” including three key drugs prescribed to post-MI patients (aspirin, an ACE-inhibitor, and a statin). Having demonstrated that prescription of the CNIC Polypill significantly increases treatment adherence among post-MI patients (J Am Coll Cardiol. 2014; 64:2071-82), CNIC researchers are now leading a multinational randomized clinical trial supported by the H2020 program.

The SECURE trial (trial identifier NCT02596126) has enrolled 2499 patients in 7 European countries (Spain, Italy, Germany, Czech Republic, France, Poland and Hungary) soon after an MI and randomized them to standard treatment or a CNIC Polypill-based strategy. Patients have been followed-up for a minimum of 2 years, and the incidence of major cardiovascular events is being assessed. Trial has completed its follow-up phase by the end of October 2021 and the grant has finished by December 2021. Now the partners are analyzing its results, and publication of the results is expected within 2022.

In addition, the SECURE Trial has maintained contact with the other trials funded within the same call of H2020, publishing a paper on barriers and potential solutions on trials working with the elderly population (Age Ageing. 2021 Nov 10;50(6):1988-1996).

The prescription of beta-blockers to patients after an MI is based on evidence from trials performed in the pre-reperfusion era. While there is solid evidence for their benefit in post-MI patients with reduced ejection fraction, such evidence is lacking for patients with preserved ejection fraction. Despite this, more than 80% of post-MI patients in this category are prescribed beta-blockers for the rest of their lives. REBOOT (tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion) is a multinational trial that will enroll 8600 post-MI patients with a left ventricular ejection fraction above 40%. Patients will be randomized to beta-blocker therapy (type and dose decided by the attending physician) or to no treatment.

The primary endpoint is the composite of all-cause death, reinfarction, or heart failure admission during 3-year follow-up. This trial is coordinated by the CNIC Clinical Trials Coordination Unit and is run in close collaboration with the Mario Negri Institute of Research in Milan. More than 70 hospitals in Spain and more than 20 in Italy participate in this large- scale project that will have a major impact on clinical practice.

The first patients were enrolled in October 2018, and 5771 had been recruited by the end of 2021. The first follow-up assessment has been completed in 84% of patients, the second follow-up in 58% and the third follow-up in 3.5%.

Existing tools for characterizing atherosclerosis and determining the risk of its complications are inadequate. These deficiencies limit effective management across the spectrum of this disease, and therefore opportunities are lost for early, cost-effective interventions in sub-clinical disease, while high-risk populations with manifest disease are administered treatments almost indiscriminately. This leads to high ‘numbers needed-to-treat’ (NNT), unnecessary patient risk, wasted resources, and unsustainable costs for health care purchasers. In a relatively low-risk population (the PESA-CNIC cohort), we will study whether a personalized worksite based lifestyle intervention, driven by imaging data (2D and 3D-ultrasound of carotid and ilio-femoral arteries, and coronary artery calcification) results in changes in behavior, improved control of risk factors, and reduced progression of subclinical atherosclerosis plaque burden (SAPB). TANSNIP is a randomized control trial (RCT) including middle–aged bank employees from the PESA cohort, strati fi ed by SAPB (high SABP n=260; low SABP n= 590). Within each stratum, participants are randomized 1:1 to join a lifestyle program or receive standard care. The program consists of three elements: (1) 12 personalized lifestyle counseling sessions using motivational interviewing (MI) over a 30-month period; (2) a wrist-worn physical activity tracker, and (3) a sit-stand workstation. The primary outcome measure is a composite score of blood pressure (BP), physical activity, sedentary time, body weight, diet, and smoking (the adapted FUSTER-BEWAT score), measured at baseline and at 1-, 2-, and 3-year follow-up. Secondary outcomes are individual changes in lifestyle behaviors and specific changes in anthropometric measures, blood biomarkers, self-rated health, work-related outcomes (including work productivity and absenteeism), health care consumption, program process measures, and cost measures at different measurement points.

The expectation is that individual awareness of CVD risk stratification in the intervention group will lead to a reduction in the prevalence of CV risk factors related to lifestyle and an increase in physical activity compared with the control group. A second rationale is that the level of compliance with the comprehensive 3-year worksite-based lifestyle intervention will be higher among participants with a high imaging defined CV risk.

The TANSNIP-PESA Study is ended. The analysis is now complete, and the TANSNIP-PESA Study has sent a publication that is currently under peer-review.

The alarming increase of unhealthy lifestyles in adolescents threatens our society. Early and effective health promotion strategies are desperately needed, as well as non-invasive tools to detect individuals showing very early stages of subclinical disease who may benefit from more intensive prevention approaches. The main objectives of this project are:

1. to identify early adverse vascular and cardiac subclinical changes in adolescents using cardiovascular magnetic resonance (CMR), and their association with different lifestyle patterns
2. to evaluate the efficacy of a school-based intervention to promote cardiovascular health among adolescents, and its impact on vascular and cardiac imaging parameters
3. to provide reference ranges for cardiac and vascular structure and function in adolescents using CMR

The EnIGMA project, funded by the Fondo de Investigación Sanitaria - Instituto de Salud Carlos III (PI19/01704),  takes advantage of an already running cluster-randomized controlled trial in which we successfully recruited 24 public secondary schools (n=1326 adolescents) in Spain in 2017, to perform state-of-the-art CMR imaging of the heart and thoracic aorta in adolescents aged 15-17 years. In this trial, schools were 1:1:1 randomized to receive a short-term (2-year) or a long-term (4-year) educational program to promote health, or the usual curriculum (control). Participants’ assessments scheduled at baseline, and after 2 and 4 years include anthropometry, bioelectrical impedance, blood pressure, glucose and lipid profile, accelerometers, and lifestyle questionnaires. For this project, a subset of participants (n=123, age- and sex-matched) have underwent a multi-territory multi-parametric CMR imaging study. This unique setting will allow studying associations between health factors and behaviors, and early imaging markers of subclinical disease.