Clinical Research

The PESA-CNIC-Santander study is a long-term endeavor carried out by the CNIC in collaboration with Santander Bank. This study aims to identify the presence of atherosclerosis long before symptoms appear and to understand the cues leading to its development and progression. The study, led by CNIC General Director Valentin Fuster, launched in 2010 and enrolled 4184 asymptomatic individuals between the ages of 40 and 55. Participants undergo serial (every 3 years) imaging and analytical tests, including 3D vascular ultrasound of the carotid arteries, aorta, and iliofemoral arteries to detect atherosclerotic plaques, coronary artery calcium quantification by computed tomography, and biosampling for omics analysis. A subset of 800 participants showing signs of disease are undergoing vascular 18FDG PET/MR and cardiac MR. Several CNIC clinical and basic research groups participate in PESA, which is the Center’s flagship study. The PESA-CNIC-Santander study is already making seminal contributions to our understanding of the origin and progression of atherosclerosis.

In 2019 we have finished the 3 ^rd visit of PESA participants, and now in 2020 the new PESA-Health Initiative will continue and expand the scientific approaches performed taking advantage of the current follow-up of the PESA cohort.

Adherence to treatment after an 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 ongoing SECURE trial (trial identifier NCT02596126) have enrolled around 2500 patients soon after an MI and randomize them to standard treatment or a CNIC Polypill-based strategy. Patients will be followed-up for a minimum of 2 years, and the incidence of major cardiovascular events will be assessed. Trial enrolment was completed by the end of 2019.

This trial has been extended until december 2021, and is now in the Follow-up phase.

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, so far we have recruited 2600 patients, we have completed the first follow up in the 80% of them and the second follow up in the 10 % of them.

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 ‘numbersneeded-to-treat’ (NNT), unnecessary patient risk, wasted resources, and unsustainable costs for health care purchasers. In a relatively low-risk populati on (the PESA-CNIC cohort), we will study whether a personalized worksite based lifestyle interventi on, driven by imaging data (2D and 3D-ultrasound of caroti d 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, parti cipants 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 moti vati onal 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 acti vity, sedentary ti me, 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 producti vity and absenteeism), health care consumpti on, 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 imagingdefined CV risk.

The TANSNIP-PESA Study is ended!!

There is increasing awareness of the association between atherosclerosis and cognitive function, but the mechanisms linking these processes are not fully understood. The Heart-to-Head (H2H) study is testing the hypothesis that extensive subclinical atherosclerosis is associated with subtle cognitive decline and beta-amyloid deposition in the brain. This transatlantic collaboration is framed within an agreement between the CNIC and Mount Sinai Hospital in New York and is led by CNIC General Director Valentin Fuster. In Spain, the H2H project is coordinated between the CNIC and 12 de Octubre Hospital. Other university hospitals (Fundación Jiménez Díaz, Clínico San Carlos, and Gregorio Marañón) participate in the project, which receives funding from the Carlos III Institute of Health through the Proyecto Integrado de Excelencia program. A total of 300 participants are undergoing extensive atherosclerosis phenotyping (multi-territory 3D vascular ultrasound and cardiac computed tomography) and thorough brain imaging (anatomical and functional magnetic resonance imaging and positron emission tomography (PET)-amyloid scan), as well as cognitive function testing.

Recruitment has finished and the follow up visits are being carried out at this moment.

The consequences of valvular heart disease (mitral and aortic) on left ventricular (LV) dimensions, function, and tissue composition are important determinants in the decisión making of patients. Current practice guidelines recommend surgical treatment for patients with significant valvular heart disease when symptoms develop or when LV remodeling or dysfunction occur. Aortic valve stenosis (AS) and mitral regurgitation (MR) are the most prevalent valvulopathies. The transition between asymptomatic to symptomatic or between normal LV dimensions and function to LV dilatation/hypertrophy (LVH) and dysfunction is determined by changes in tissue composition (predominantly cardiomyocyte death, extracellular volume expansion, and fibrosis). Current therapeutic approach (surgical/percutaneous) for severe valvular disease includes the presence of symptoms and/or gross anatomical/functional LV involvement (i.e. significant chamber dilatation of reduced ejection fraction). Many times, when these features appear, it is too late for the surgical/percutaneous approach to completely restore normal cardiac function. Thus, there is a strong need for tools able to early detect myocardial involvement in patients with asymptomatic significant valvular disease to guide treatment before overt deterioration of cardiac function. Cardiac magnetic resonance (CMR) is the gold standard for anatomical and functional cardiac evaluation, including detection of focal areas of fibrosis by late gadolinium enhancement (LGE) after contrast-gadolinium administration. In addition, recent CMR advances (parametric T1/T2 mapping, absolute myocardial perfusion quantification, extracellular volume (a surrogate of diffuse fibrosis) calculation, tagging, ...) allow a very accurate tissue characterization. For focal and diffuse fibrosis evaluation, endovenous contrast use will be needed. We will use gadolinium agent contrast, which is routinely used in clinics with the maximal safety profile. For diffuse fibrosis evaluation, a blood sample is necessary in order to get the hematocrit value. Conversely, echocardiographic (Echo) strain technique is the best imaging modality to study active deformation of the LV myocardium, able to detect impairment of multidirectional strain (active deformation) despite normal preserved LV global function. The 6-minute walking test has been used for the objective evaluation of functional exercise capacity. We will correlate the imaging data with functional data from the 6-minute walking test. CT cardiac scan for calcium is a non invasive way of obtaining information about the presence, location and extent of calcium in the coronary arteries and valves. The amount of calcium detected on a cardiac CT scan, gives us the

calcium score, which is a diagnostic and prognostic tool in patients with aortic stenosis. In this project we propose a multimodality imaging approach (CMR plus strain echocardiography) to better characterize the status of the LV in patients with significant valvular disease. In this project we will focus in 2 specific forms of valve disease: aortic stenosis (paradigm of LV pressure overload), and mitral regurgitation (paradigm of LV volume overload).

So far 34 patients has been included and we have started with the follow up visits (four of them completed).

Pulmonary hypertension (PH) secondary to left heart disease (group PH) is the most common form of PH and currently lacks effective therapy. CNIC researchers have identified a novel therapeutic target for this disease in a large animal model of PH: the β3 adrenergic receptor (Basic Res Cardiol. 2016;111:49). The CNIC is currently leading a phase 2 clinical trial in which group 2 PH patients are randomized to standard therapy vs standard therapy plus a β3 selective agonist (trial identifier NCT02775539 and Nº EudraCT: 2016-002949-32). A total of 80 patients are being recruited in four Spanish hospitals and will be followed under treatment for 4 months. The study endpoints are pulmonary artery hemodynamics and the CMR profile.

The enrollment has been extended until june 2020 to achieve the goal of 80 patients.

Multicenter case-control study. Cases: tako-tsubo patients. Controls: Age/gender/ECG presentationmatched 1) AMI patients, 2) individuals without overt CVD or acute disease. Subestudies/techniques.

1. Psychological (disposition) and neuro-psychological studies to assess personality traits, positive/negative emotions, emotional regulation, resilience and rumination. A) Retrospective disposition psychological study in patients enrolled in the RETAKO registry (Subestudy #1). B) Prospective disposition psychological study early after the index event (Subestudy #2). C) Neuro-psychological and psychological (state) study @ 30 days (Subestudy #6)
2. EEG studies to assess the presence of neuropathohysiological responses. A) Early EEG study after index event to assess sustained atention ability, vigilance and impulsiveness. EEG with Dot probe paradigm (Subestudy #4), and B) EEG structured emotional activation @ 30 days by PPT Paradigm (images) and Cold pressor test (Subestudy #7).
3. Imaging studies to determine brain areas and functional patterns related to this pathophysiology. A) Brain MRI within first 24 hours of index event: structural (T13D), DTI and Resting State (Subestudy #3) and B) fMRI with assessment of emotional valence by visual stimuli to generate emotions @ 30 days (Subestudy #8)
4. Proteomic analysis as a wide screening approach to identify molecules specifically involved in this pathophysiology. Plasma samples from 5 STT cases caused by psychological stress, 5 STT cases caused by physical stress, 5 (matched) controls with ACS, and 5 healthy individuals (Substudy #5).

So far 7 studies have been completed.

Pulmonary hypertension due to left heart disease is a pathophysiological and hemodynamic state which is present in a wide range of clinical conditions that affect left heart structures. Although the pulmonary circulation has traditionally received little attention, it is reasonable to say that today it is a fundamental part of cardiological evaluation. In patients with heart failure, the most important clinical factors are the presence of pulmonary hypertension and right ventricular function. These factors are also essential for determining prognosis and must be taken into account when making some of the most important therapeutic decisions. The pathophysiological process starts passively but later transforms into a reactive process. This latter process, in turn, has one component that can be reversed with vasodilators and another component that is fixed, in which the underlying mechanism is congestive vasculopathy (i.e. essentially medial hypertrophy and pulmonary arterial intimal fibrosis). Currently no specific therapy is available for this type of pulmonary hypertension and treatment is the same as for heart failure itself. The drugs that have been shown to be effective in pulmonary arterial hypertension have generally had a neutral effect in clinical trials. Nevertheless, we are involved in the clinical development of a number of groups of pharmacological compounds that will enable us to make progress in the near future.

So far we have recruited 33 patients and still recruiting

FIS-DTS (Proyecto de Investigación en Salud modalidad Proyectos de Desarrollo Tecnológico en Salud Ref DTS17/00136).

This study has two different protocols:

1) Myocardial study, which includes gadolinium contrast (post-infarction patients, cardiomyopathy, myocarditis,);

2) Study of coronary angiography with MRI without gadolinium contrast (patients undergoing coronary angio-CT by clinical indication).

In this study we will include 150 patients (100 protocol 1, 50 protocol 2) who will undergo MRI studies in two hospitals: Hospital Universitario Rey Juan Carlos (3Tesla MRI), Hospital Universitario de Salamanca (1.5Tesla MRI). Patients will be recruited in both institutions, as well as the Fundación Jiménez Díaz, Hospital Infanta Elena de Valdemoro Hospital, Ruber Juan Bravo University Complex and Quirón Pozuelo University Hospital.

This project is funded by a grant by the ISCiii (FIS-Technological Development (FIS-DTS). During the first year we have validated and improved this technology in the pig model; we have also worked on the reconstruction of the studies so that it is possible to do it in real time in the MRI console itself.