CNIC · Scientific Report 2024

The PESA-Health-CNIC-Santander study builds on the foundation laid by its predecessor, the PESA Study, which began in 2010 under the direction of the CNIC in collaboration with Santander Bank. The original study enrolled 4,184 asymptomatic individuals aged 40 to 55 and aimed to detect subclinical atherosclerosis (SA) long before symptoms appear, while also exploring the factors driving its development and progression.

The continuation of the PESA study, PESA-Health, extends this work by tracking the same participants over an additional 10 years. The new study broadens the scope to include new research areas, such as the links between SA and Alzheimer’s disease or cognitive decline, the role of somatic mutations in aging, and how these mutations may influence cardiovascular events and SA progression.

As in the original PESA study, PESA-Health leverages advanced imaging technologies, including 3D vascular ultrasound of the carotid arteries and aorta, coronary artery calcium quantification via computed tomography, cardiac magnetic resonance, AngioTC, PET, and PET-amyloid analysis. In addition, biosampling is used for for extensive omics analysis, and new substudies are exploring the connection between SA and sleep apnea.

As the CNIC’s flagship study, PESA-Health involves many of the center’s clinical and basic research groups. Findings from the PESA study have already made significant contributions to understanding the origins and progression of atherosclerosis.

PESA-Health launched in February 2020, with 3,496 PESA participants continuing their involvement. By the end of 2024,the first round of visits was completed for 3,300 individuals, and the second round of visits had begun.

Anthracyclines are a widely used class of anticancer drugs, administered to over 3 million of the 4 million new cancer patients diagnosed annually in Europe. While effective, these drugs carry a significant risk: recent data show that >35% of patients treated with anthracyclines develop some form of cardiomyopathy. This trade-off between cancer treatment and chronic heart failure (HF) not only places a heavy psychological burden on cancer survivors but also poses a growing challenge for healthcare systems.

Remote ischemic pre-conditioning (RIPC) offers a potential solution. RIPC is a noninvasive, safe, and cost-effective technique that involves brief, reversible episodes of ischemia (e.g., in an arm) followed by reperfusion. This process can protect remote tissues and organs against injury in future ischemic events. Experimental studies in large animals have shown that 3 to 5 cycles of 5-minute limb ischemia followed by 5-minute reperfusion reduce the size of induced myocardial infarctions. Recent evidence suggests that, to be effective, RIPC must be initiated before the damaging event. Since chemotherapy is a planned procedure, anthracyclineinduced cardiomyopathy provides an ideal setting to test this approach.

RESILIENCE is a multinational, phase II, double-blind, shamcontrolled, randomized controlled trial evaluating the efficacy and safety of RIPC in patients with lymphoma or breast cancer and who are receiving anthracyclines. Eligible patients scheduled to receive ≥240 mg/m² of anthracyclines undergo baseline cardiac magnetic resonance (CMR) imaging and blood tests for high-sensitivity troponin (hsTn) and NTproBNP. Patients with a left ventricular ejection fraction >40% confirmed by CMR are randomized 1:1 to receive either RIPC or a sham procedure.

Nine weeks after completing chemotherapy, patients undergo a final CMR and hsTn/NT-proBNP test. Clinical follow-ups are scheduled for 12, 18, 30, and 42 months until the last patient completes the final CMR.

The RESILIENCE Trial aims to enroll 608 patients across 22 sites in six European countries (Spain, Portugal, France, Germany, the Netherlands, and Denmark). Funded by the European Commission (Grant Agreement-945118-RESILIENCE), the trial began its grant period in June 2021, with patient recruitment starting in 2022. By the end of 2024, three additional hospitals were added, all 22 sites were operational, and 284 participants had been enrolled.

The use of beta-blockers for patients after a myocardial infarction (MI) is largely based on evidence from trials conducted before the reperfusion era. While these drugs have proven benefits for post-MI patients with reduced ejection fraction, their effectiveness for patients with preserved ejection fraction remains unclear. Despite this lack of evidence, over 80% of post-MI patients in this category are prescribed beta-blockers for life.

The REBOOT trial addresses this gap by evaluating the need for beta-blocker therapy in post-MI patients with a left ventricular ejection fraction greater than 40%. This multinational study has enrolled 8,506 patients, who have been randomized to either receive beta-blockers (with the type and dose determined by their physician) or no betablocker treatment. The primary endpoint is a composite of all-cause death, reinfarction, or heart failure admission over a 3-year follow-up period.

Coordinated by the CNIC Clinical Trials Coordination Unit and conducted in collaboration with the Mario Negri Institute of Pharmacological Research in Milan, the trial involves 77 hospitals in Spain and 29 in Italy. This large-scale project has the potential to significantly influence clinical practice.

Patient enrollment began in October 2018 and has now been completed. The trial is currently in the event-adjudication process.

The MRVALVE study uses a multimodality imaging approach (cardiac magnetic resonance [CMR] and strain echocardiography) to better characterize left ventricular (LV) status in patients with significant valvular heart disease (VHD), focusing on aortic valve stenosis (AS) as a model of LV pressure overload and mitral regurgitation (MR) as a model of LV volume overload.

VHD significantly impacts LV dimensions, function, and tissue composition, all of which play a critical role in clinical decisionmaking. Current guidelines recommend surgical treatment for patients with significant VHD when symptoms develop or when there is evidence of LV remodeling or dysfunction. The most common forms of VHD are AS and MR. The progression from asymptomatic to symptomatic disease, or from normal LV function to LV dilatation, hypertrophy, and dysfunction, is driven by changes in tissue composition—primarily cardiomyocyte death, extracellular volume expansion, and fibrosis.

While surgery or percutaneous valve repair or replacement are effective treatments for severe VHD, interventions are typically based on the presence of symptoms or significant LV dysfunction. By the time these features appear, it is often too late to fully restore heart function. This highlights the need for tools for the early detection of myocardial involvement in asymptomatic VHD patients, allowing timely intervention before irreversible damage occurs.

Strain echocardiography, the best imaging modality for evaluating active LV myocardial deformation, can detect impaired multidirectional strain even when overall LV function appears normal. In the MRVALVE study, we correlate imaging data with functional assessments from the 6-minute walking test, which provides an objective measure of exercise capacity. Additionally, cardiac computed tomography is used to assess calcium deposition in the coronary arteries and heart valves, providing a calcium score that serves as both a diagnostic and prognostic tool in AS patients.

To date, 71 patients have been recruited, and all have completed their 1-year follow-up visit.

The MATRIX Project aims to develop innovative treatments for cardiotoxicity caused by certain cancer therapies. This initiative is a joint effort between the CNIC and Fundación Jiménez Díaz University Hospital, building on a collaborative framework established in 2015 to study myocardial diseases.

While significant advances in cancer treatment have improved outcomes for the 4 million new cancer patients diagnosed annually in Europe, these therapies often come with serious side effects. One of the most common is cancer treatment–induced cardiotoxicity (CTiCT), which affects up to 25% of patients treated with anthracyclines or trastuzumab. CTiCT can lead to severe complications, including chronic heart failure or even death, creating a devastating trade-off for cancer survivors.

CTiCT poses a significant challenge, as current therapies are suboptimal. Early detection methods are inadequate, and heart failure treatments are nonspecific. Recent findings from our group suggest that CTiCT is linked to altered mitochondrial dynamics, which triggers metabolic reprogramming in cardiomyocytes.

The MATRIX Project takes a holistic approach to addressing mitochondrial dysfunction in CTiCT. We propose that earlystage CTiCT could be reversed by metabolic reprogramming to alter mitochondrial substrate utilization. Using a novel imaging-based algorithm developed by our team, we aim to detect myocardial damage in patients receiving common anticancer drugs long before traditional clinical parameters show abnormalities. This early detection, currently unavailable, is critical for timely intervention.

For end-stage CTiCT, where mitochondrial dysfunction may be irreversible, we propose that replenishing the myocardium with healthy mitochondria through in-vivo mitochondrial transplantation could offer a radical new therapeutic option.

The MATRIX Project has broad translational potential, including the development of new therapeutic approaches, early diagnostic technologies, and insights into the basic mechanisms of CTiCT.

Patient recruitment began in 2020, and as of February 2025, 56 participants have been enrolled.

Acute myocarditis is challenging to diagnose due to its varied clinical presentation and the lack of rapid, accessible, and accurate diagnostic tools. Symptoms can range from atypical chest pain (resembling pericarditis or angina) to dyspnea, fatigue, palpitations, syncope, and, in severe cases, sudden death or shock. Early diagnosis is further complicated by the nonspecific results obtained with standard tests, such as ECG, echocardiography, and laboratory tests.

Currently, diagnosing acute myocarditis typically requires invasive procedures like endomyocardial biopsy or advanced imaging techniques like cardiovascular magnetic resonance, which are not universally available. This highlights the urgent need for new, noninvasive diagnostic approaches.

Dr. Martín Fernández’s research group has made significant progress in this area by identifying a novel microRNA in mice and humans with myocarditis. Their work, published in the New England Journal of Medicine (2021: 27;384(21):2014- 2027), demonstrates that the human homolog (hsa-miRChr8: 96) can effectively distinguish myocarditis patients from those with myocardial infarction.

The MYOCARDITIS-CNIC Registry, a collaborative initiative between the CNIC and Hospital Virgen de la Arrixaca, aims to build on these findings. Several Spanish hospitals, including Hospital de la Princesa and Clínica Universitaria de Navarra, are participating in the registry by collecting clinical data and biological samples from patients presenting to emergency departments with signs of myocarditis. This registry will provide critical insights into the early stages of myocarditis and help validate potential clinical biomarkers for early diagnosis.

To date, 75 participants have been enrolled in the registry.

Arterial hypertension can cause damage to the cerebral vascular system, even when blood pressure effectively controlled. Current treatments for hypertension focus on managing blood pressure and preventing damage to target organs, such as the brain. Remote ischemic preconditioning (RIPC), a technique first shown to protect organs like the heart and brain in animal models 30 years ago, has since been adapted for use in human patients. RIPC involves inflating and deflating a blood pressure cuff on the arm through four cycles of 5 minutes each. The brief ischemia induced in the arm can protect distant organs, including the brain, from future ischemic damage.

Our research group has contributed significantly to this field, with recent studies demonstrating that RIPC can improve cognitive performance and cerebral vascular function in patients with vascular dementia.

The PRECOGNITIVE study is a proof-of-concept randomized trial involving 45 women with hypertension and evidence of target organ damage, such as left ventricular hypertrophy. Participants are divided into 3 groups:

1. The RIPC group undergo the RIPC procedure, with the cuff inflated to 20 mmHg above their systolic blood pressure.
2. The RIPC-Sham group follow the same procedure, but the cuff will only be inflated to 50 mmHg, insufficient to induce ischemia.
3. The control group do not receive any cuff therapy.

The study aims to determine whether RIPC has a significant protective effect on the cerebral vasculature in hypertensive patients without significant cognitive impairment. Outcomes will be assessed using comprehensive neurocognitive tests and noninvasive imaging techniques, including echocardiography, noncontrast brain magnetic resonance imaging, and transcranial Doppler ultrasound.

As of the end of 2024 15 patients have been recruited.

Heart failure (HF) is one of the most significant health challenges in modern societies, placing a heavy burden on healthcare systems. To develop new therapies, it is essential to understand the mechanisms underlying the development and progression of HF.

The heart is the body’s most energy-demanding organ relative to its size. Under normal conditions, it primarily relies on fatty acid beta-oxidation, which generates about 60% of the ATP needed for cardiac function. Carbohydrate metabolism via the Krebs cycle provides the second-largest energy source, while other nutrients, such as amino acids, contribute less than 1%.

In HF, however, the heart undergoes a metabolic shift, switching from fatty acids to glucose as its main energy source. This phenomenon, known as the metabolic switch, was initially thought to be a protective adaptation. However, recent evidence from animal and human studies shows that glucose metabolism produces 4-5 times less ATP than fatty acid metabolism, suggesting that this switch is harmful and contributes to the decline in cardiac contractile function.

Our group has demonstrated that the metabolic switch plays a key role in the progression of HF secondary to idiopathic dilated cardiomyopathy (IDCM). In mouse models, a diet rich in fatty acids reversed the metabolic switch and improved the IDCM phenotype. Similar results were observed in pigs, which have a metabolism comparable to humans.

Before conducting a clinical trial in patients with IDCM, it is critical to determine the prevalence of the metabolic switch in this population. This is the primary goal of the MACADAMIA study, an observational project involving a small cohort of IDCM patients. Using advanced imaging techniques—including transthoracic echocardiography with myocardial strain analysis, cardiac magnetic resonance (CMR), and positron emission tomography/computed tomography (PET/CT) with the radiotracer 18FDG—the study aims to characterize the metabolic profile of these patients without any intervention.

As of February 2025, 28 patients have been recruited. In the medium to long term, we plan to conduct a clinical trial in IDCM patients who exhibit the metabolic switch. Patients will be randomized to receive either a diet rich in fatty acids or a normal diet, and will be assessed for changes in cardiac function (by CMR) and metabolism (by PET/CT).

Tafamidis is a medication used to treat transthyretin cardiac amyloidosis (ATTR-CM), a rare and life-threatening disease caused by the buildup of of transthyretin amyloid fibrils in the heart. Clinical trials have demonstrated that Tafamidis reduces mortality and cardiovascular hospitalizations in patients with ATTR-CM, prompting its recent approval for use in Spain. However, clinical trials can have limitations, and their results may not always reflect real-world clinical outcomes.

Advances in diagnostic techniques have enabled earlier detection of ATTR-CM, resulting in a shift in patient profiles and improved prognoses compared with the population studied in the original clinical trial. This raises questions about the effectiveness and safety of Tafamidis in contemporary patients. The ATTRACKING CNIC study aims to address this uncertainty by evaluating Tafamidis in a real-world, unselected cohort of ATTR-CM patients.

OBJECTIVES:

1. To characterize the real-world population of ATTR-CM patients in Spain prescribed 61mg Tafamidis.
2. To assess the safety of Tafamidis in a diverse, real-world Spanish cohort with ATTR-CM.
3. To compare the real-world clinical impact of Tafamidis therapy with the results of the ATTR-ACT clinical trial.

Study Design

PATTRACKING CNIC is a prospective, multicenter, nonrandomized observational trial involving patients diagnosed with ATTR-CM who are starting daily treatment with 61 mg Tafamidis.

As of February 2025, contracts have been signed with 22 hospitals, and 195 participants have been recruited.

Pulmonary vein isolation (PVI) is the cornerstone of catheterbased ablation for patients with persistent atrial fibrillation (AF). However, over the past 20 years, the success rate of PVI in achieving long-term rhythm control for persistent AF has been suboptimal. Even with treatment, only about 40% of patients remain free of AF (without antiarrhythmic drugs) at 12 months post-ablation, highlighting the challenges of managing this condition.

To address this issue, our group has developed a computational tool that helps interventional electrophysiologists identify specific atrial regions, called driver regions, which are associated with the long-term persistence of AF. Using a conventional electroanatomic mapping system and multielectrode catheters, these regions can be pinpointed with novel signal processing algorithms. These algorithms, which are openly available to the scientific community (Quintanilla JG et al. Circ Res. 2019;125:609-27), analyze individual atrial signals to detect frequency and amplitude modulations (iFM and iAM) during fibrillatory activity. This allows for the precise localization of rotational activity and the identification of the leading drivers of persistent AF.

The primary goal of the TAILOR-AF study is to use iAM/ iFM mapping to identify and ablate the leading drivers of AF in patients who continue to experience symptomatic recurrences of persistent AF despite undergoing 2 or more PVI procedures. Secondary objectives include analyzing blood biomarkers, atrial imaging parameters, and phenotypic features in the surface electrocardiograms associated with advanced atrial remodeling. In patients undergoing minimally invasive thoracoscopy-guided ablation of leading drivers, tissue samples from the left atrial appendage will also be collected to study the molecular mechanisms underlying AF maintenance.

As of the end of 2024, 22 patients had been enrolled in the study.

SIR-CVT is a non-interventional project with two primary objectives:

1. To evaluate risk factors and current practice management practices for cardiovascular (CV) toxicity in patients with solid organ cancer receiving immune checkpoint inhibitors (ICI) for approved indications.
2. To validate the human homolog of miR-721 as a biomarker for the early diagnosis of immunotherapy-induced myocarditis in these patients.

The study also addresses several secondary objectives:

• Identifying clinical, electrocardiographic, imaging, laboratory, and genetic markers for the early diagnosis of ICI-related myocarditis.
• Identifying markers for the early detection of other ICIrelated adverse CV effects unrelated to myocarditis.
• Evaluating the relationship between previous chemotherapy regimens and ICI-related CV risk.
• Investigating the pathogenic mechanisms underlying myocarditis induced by immune checkpoint blockade (antiPD-L1/PD1 and anti-CTLA4).
• Assessing the impact of CV monitoring on patient quality of life and perceived quality of care.

The study involves of a baseline visit, after which patients are managed according to standard clinical protocols, including the frequency of follow-up visits. Participants will be followed until death, loss to follow-up, or the final visit 12 months after enrollment. All data collected will be used exclusively for research purposes.The study involves of a baseline visit, after which patients are managed according to standard clinical protocols, including the frequency of follow-up visits. Participants will be followed until death, loss to follow-up, or the final visit 12 months after enrollment. All data collected will be used exclusively for research purposes.

As of February 2025, two patients have been enrolled and have undergone cardiac magnetic resonance and ultrasound imaging studies at the CNIC.

Atherosclerosis, the buildup of plaque in arteries, is the leading cause of cardiovascular diseases. This condition develops gradually as cholesterol, fat, blood cells, and other substances accumulate in the arterial walls, causing them to narrow and reducing blood flow to vital organs. Atherosclerosis contributes significantly to global morbidity and mortality, often beginning early in life and affecting multiple vascular systems.

To address this major health challenge, the CNIC and the Rigshospitalet in Copenhagen have launched Phase 1 of the REACT project (Reversal of Early Atherosclerosis through Personalized Curative Treatment), funded by the Novo Nordisk Foundation. The primary goal of this phase is to determine the prevalence of asymptomatic (silent) atherosclerosis in a diverse, European-ancestry population across a wide age range (18–69 years). This will be achieved using advanced biomedical imaging techniques and circulating biomarkers, alongside traditional risk factors.

The REACT project focuses on early detection of atherosclerosis through a combination of imaging techniques, including vascular ultrasound (3DVUS), calcium scoring, and angiography, as well as biomarker analysis. The first phase is a prevalence study involving 16,000 participants (8,000 in Spain and 8,000 in Denmark). This study will provide a detailed understanding of how common asymptomatic atherosclerosis is at different ages and help develop a more precise risk evaluation algorithm than those currently in use.

The findings from Phase 1 will inform the design of Phase 2, a randomized clinical trial that will assess whether early intervention—guided by imaging and including lifestyle changes, non-pharmacological approaches, and lipidlowering treatments—can reduce atherosclerotic plaque burden or even lead to regression or cure. The first participant was recruited on December 30, 2024, and the goal is to enroll all 8,000 participants within 18 months. This initiative will create a unique resource for future basic and clinical research.