Heart Failure

PI: Begoña Salazar

Diffuse myocardial fibrosis, or exaggerated accumulation of collagen in the myocardium, plays a key role in the development and progression of chronic heart failure. The enzymatic systems involved in the processing of collagen fibers emerge as key mechanisms of the process.

In this regard, 2 relevant systems have recently been identified in the axis of the formation of mature collagen fibers: 1) carboxy-terminal procollagen proteinase (PCP) with its enhancer PCPE-1, which processes the passage from immature procollagen to collagen capable of forming fibers; and 2) lysyl oxidase (LOX), the main enzyme responsible for collagen cross-linking, a process that facilitates the formation of collagen fibers and their deposition.

In recent years it has been shown that myocardial fibrosis is characterized not only by an increase in the quantity of collagen but also by alterations in its quality, such as an increase in the degree of collagen cross-linking (GrE).

This process, as already mentioned, is mainly mediated by enzymes of the LOX family, and conditions the formation of insoluble collagen fibers, which are more rigid and more resistant to degradation.

Patients with a malignant fibrosis phenotype characterized by severe deposition of highly cross-linked collagen fibers have an increased risk of hospitalization or death from cardiovascular causes, as well as an increased risk of complications associated with heart failure such as atrial fibrillation.

Objectives

1. To deepen in the impact of the different myocardial fibrosis phenotypes in the development and evolution of chronic heart failure and its associated pathologies in patients with heart failure at different stages of evolution and in experimental models (animals and cell cultures).
2. To analyze the relevance of collagen synthesis (PCP/PCPE-1-LOX) and degradation (matrix metalloproteinases or MMPs) systems in patients with heart failure of different etiology and in models of pressure overload.
3. To validate the PCP/PCPE-1 system as a therapeutic target for the treatment of myocardial fibrosis in pressure overload models.
4. To assess the impact of GrE and increased extracellular matrix stiffness on cardiac cell behavior.
5. To identify new molecular mediators and/or biomarkers involved in the development of diffuse myocardial fibrosis.

PI: Arantxa González Miqueo

Heart failure with preserved ejection fraction is a very heterogeneous pathology in which non-cardiac systemic co-morbidities such as hypertension, diabetes or chronic kidney disease play a key role.

Available therapies, more focused on mitigating symptoms than treating the underlying pathophysiological mechanisms, have not demonstrated a significant improvement in the prognosis of these patients.

From a mechanistic perspective, in recent years, systemic inflammation has been described as causing myocardial endothelial dysfunction, microvascular alterations and increased leukocyte infiltration, which trigger myocardial remodeling (including the development of myocardial fibrosis) and subsequent functional deterioration in patients with heart failure with preserved ejection fraction. 

These pathophysiological mechanisms are also involved in other complications associated with this syndrome that affect the brain, such as cognitive impairment or the generation of cardioembolic thrombi, which is one of the main causes of ischemic stroke.  

Therefore, this project focuses on analyzing the association between microvascular alterations, inflammation and the development of myocardial fibrosis, as well as its impact on cardiac function and the development and progression of heart failure with preserved ejection fraction.

Likewise, we seek to deepen in the pathophysiological mechanisms common with brain pathologies such as cognitive impairment or cardio-embolic thrombus formation.

Objectives

1. To characterize microvasculature alterations, inflammation and myocardial fibrosis phenotype in patients with heart failure with preserved ejection fraction and associated cardiac pathologies (e.g. atrial fibrillation).
2. To evaluate the contribution of endothelial dysfunction and inflammation in the development of fibrosis in cellular studies.
3. To analyze the anti-fibrotic potential of new drugs used in the treatment of chronic heart failure (e.g. iSGLT2, finerenone...).
4. To study the association of chronic heart failure with preserved ejection fraction and brain involvement using circulating and imaging biomarkers that reflect microvascular alterations.
5. To evaluate the role of atrial myopathy (inflammation, endothelial dysfunction and fibrosis) in the development of cardioembolic thrombus and ischemic stroke.

PI: Susana Ravassa

Chronic heart failure is a heterogeneous syndrome, the end result of diverse pathophysiological mechanisms and different histocellular alterations.

In order to design personalized therapeutic strategies aimed at correcting the predominant alterations in each patient, it is necessary to have precise biomarkers that allow early diagnosis, better risk stratification in patients and monitoring of the effects of therapy. 

Since obtaining endomyocardial biopsies is not feasible on a large scale, circulating and imaging biomarkers are a useful tool for the analysis of large patient populations. In recent years we have defined a panel of biomarkers of myocardial remodeling that includes markers of fibrosis (PICP and CITP:MMP-1), cardiomyocyte damage and stress (NT-proBNP and hs-TnT) and inflammation (IL-18, sST-2, galectin-3).

Similarly, advances in cardiac magnetic resonance have allowed the development of new parameters to assess microvascular alterations and diffuse myocardial fibrosis.

This project focuses on analyzing the diagnostic and therapeutic usefulness of the panel of biomarkers of myocardial remodeling and identifying new molecular biomarkers to define molecular profiles corresponding to the different phenotypes of patients with chronic heart failure.

Objectives

1. To establish a profile of circulating and cardiac imaging biomarkers that reflect the different aspects of myocardial remodeling. Biomarkers already identified will be combined with new biomarkers under development, derived from proteomic studies and characterization of non-coding RNAs.
2. To assess the diagnostic and prognostic utility of the panel of biomarkers of myocardial remodeling in patients with chronic heart failure of different etiologies and different associated pathologies (atrial fibrillation, chronic kidney disease...).
3. To analyze the usefulness of the myocardial remodeling biomarker panel for monitoring the effects of therapy in patients with chronic heart failure and associated pathologies.
4. To use the myocardial remodeling biomarker panel to detect cardiovascular sequelae in patients with cardiotoxicity induced by chemotherapeutic agents or in patients infected with Sars-CoV-2.

PI: Mª Ujué Moreno Zulategui

In recent years it has been demonstrated that extracellular vesicles (EVs) are actively released in response to tissue damage, so that the analysis of both their number and content can provide valuable information both in terms of the identification of new biomarkers and new pathophysiological mechanisms. In fact, it has been proposed that EVs may act as mediators by transferring their content (proteins, non-coding RNAs or mRNAs) to target cells in a paracrine or endocrine manner.

The optimization of massive sequencing technologies (NGS) for serum and plasma studies has allowed the characterization of the transcriptome of EVs present in plasma, as well as the analysis of circulating non-coding RNAs.

This approach will make it possible to establish molecular profiles associated with the different phenotypes of chronic heart failure, which may also be pathophysiological mediators, and to lay the foundations for the identification of new therapeutic targets.

Objectives

1. To characterize the cellular origin (endothelial, platelet, cardiomyocyte, leukocyte) of plasma EVs in patients with chronic heart failure of different etiologies and at different stages of evolution.
2. To identify new biomarkers by analyzing the transcriptome (mRNA-Seq) of plasma EVs in patients with chronic heart failure and their associated co-morbidities (chronic kidney disease, atrial fibrillation).
3. To validate the pathophysiological relevance of targets identified in the analysis of the transcriptome of EVs in cellular and animal models.
4. To evaluate the transcriptome of endothelial-derived EVs to assess the implication of microvascular alterations as a common causal mechanism in chronic heart failure with preserved ejection fraction and cognitive impairment.
5. To establish new biomarkers based on the analysis of the serum microRNA-ome in patients with chronic heart failure of different etiologies and at different stages of evolution.

PI: Susana Ravassa

One class of chemotherapy drugs (anthracyclines) is used in cancer treatment to improve patient survival. However, their use is restricted due to their cardiotoxic effects, making cardiovascular toxicity one of the most serious complications of cancer treatment.

Objectives:

Early identification of patients who are candidates for developing cardiotoxicity with systemic therapies in order to prevent pharmacological prevention or modify treatment in the future and avoid this complication in the medium to long term.