"We explore new therapeutic strategies aimed at correcting structural alterations of the myocardium in patients with heart failure."
DR. ARANTXA GONZÁLEZ MIQUEO RESEARCHER. HEART FAILURE RESEARCH GROUP
The Heart Failure Research Group focuses its research on the characterization of the main structural alterations of the myocardium that underlie its functional deterioration in order to understand the pathophysiological basis and identify new molecular targets involved in this pathology.
We also seek to identify non-invasive circulating biomarkers that allow us to establish a more precise diagnosis in each patient, facilitating the establishment of a personalized therapeutic strategy that improves the efficacy of treatment.
Our projects have a clear translational focus, thanks to the close collaboration with physicians from the Universidad de Navarra Clinic and other prestigious national and international centers. Our researchers are linked to IdiSNA and CIBERCV, participating in several collaborative projects; they are involved in multinational projects in the field of European Union research programs, having established stable collaborations with several high-level research groups.
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Objectives of the Heart Failure Group
To deepen in the pathophysiological mechanisms that mediate the histocellular alterations involved in the myocardial remodeling that occurs in chronic heart failure and its co-morbidities, with a special focus on the study of the extracellular matrix and fibrosis.
Establish noninvasive biomarker profiles (molecular and imaging) that reflect histocellular alterations in cardiac tissue and/or relevant pathophysiological mechanisms in each patient, for better individualized stratification of patients with heart failure.
To validate new molecular targets in order to develop innovative pharmacological interventions to prevent or reverse myocardial damage in chronic heart failure.
FROM THE LABORATORY TO THE CLINIC
Circulating biomarkers of myocardial fibrosis
Our group has identified circulating biomarkers that reflect not only the amount of myocardial fibrosis but also its physicochemical properties (stiffness and resistance to degradation) that have been shown to have prognostic utility in patients with chronic heart failure, being associated with an increased risk of new hospitalizations, development of complications such as atrial fibrillation or even with an increased risk of death from cardiovascular causes.
In clinical trials, these biomarkers have been useful for monitoring the antifibrotic efficacy of some drugs and for identifying those patients who will respond better to certain treatments.
Lines of research
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.
- 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).
- 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.
- To validate the PCP/PCPE-1 system as a therapeutic target for the treatment of myocardial fibrosis in pressure overload models.
- To assess the impact of GrE and increased extracellular matrix stiffness on cardiac cell behavior.
- To identify new molecular mediators and/or biomarkers involved in the development of diffuse myocardial fibrosis.
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.
- 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).
- To evaluate the contribution of endothelial dysfunction and inflammation in the development of fibrosis in cellular studies.
- To analyze the anti-fibrotic potential of new drugs used in the treatment of chronic heart failure (e.g. iSGLT2, finerenone...).
- To study the association of chronic heart failure with preserved ejection fraction and brain involvement using circulating and imaging biomarkers that reflect microvascular alterations.
- 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.
- 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.
- 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...).
- 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.
- 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.
- 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.
- 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).
- To validate the pathophysiological relevance of targets identified in the analysis of the transcriptome of EVs in cellular and animal models.
- 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.
- 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.
Meet the research team
Scientific activity of the
Heart Failure Research Group
Latest scientific publications
- The combination of PICP blood levels and LGE at CMR provides additional prognostic information in idiopathic Dilated Cardiomyopathy Apr 30, 2021 | Magazine: European Journal of Heart Failure
- Urinary peptides in heart failure: a link to molecular pathophysiology Apr 21, 2021 | Magazine: European Journal of Heart Failure
- Spironolactone effect on the blood pressure of patients at risk of developing heart failure: an analysis from the HOMAGE trial Apr 2, 2021 | Magazine: European Heart Journal - Cardiovascular Pharmacotherapy
- Inner ear drug delivery through a cochlear implant: Pharmacokinetics in a Macaque experimental model Mar 19, 2021 | Magazine: Hearing Research