Community Research and Development Information Service - CORDIS


Project Context and Objectives:
The advancements of critical care medicine are before our eyes, as shown by the improvement in the management of acutely ill patients in the intensive care unit (ICU). However, circulatory shock developed as a consequence of hemorrhage, sepsis or acute cardiac failure is still a poorly understood complication. More importantly, the shortcomings of the treatments against circulatory shock explain the high incidence of multiple organ failure (MOF) and the mortality rate (around 40%) of shock patients.
Shock is defined as inadequate blood flow to tissues, often accompanied by hypotension, tachycardia and a strong inflammatory response, which rapidly compromises organ function through complex biomolecular pathways. In such a framework, protecting heart function is of paramount importance.
The ShockOmics project has the ambitious aim to bring new multi-scale (i.e., from the biomolecular scale up to the level of the global hemodynamics) insight into the understanding of circulatory shock, and proof of concepts for new life saving therapies. This objective requires the cooperation of several branches of the life sciences, ranging from intensive care medicine, molecular (alias “omics”: transcriptomics, proteomics, metabolomics) biology, biomedical engineering, information and communication technology, all integrated in a strictly pipelined and connected work plan.
The goals of ShockOmics address shock biomarkers, with the expectation to improve the early detection of organ damage in shock and in particular acute heart failure. As a secondary outcome, this achievement can improve the monitoring of shock development, prognosis, and the support of clinical decisions in the management of shock patients. Thus, this is also prodromal to the even more challenging goal of designing new therapeutic strategies, for the inhibition of the fatal cascade of events following shock onset..
The hypothesized pathologic processes are addressed first to identify biomarkers, and next to define the therapeutic targets, including inflammation and the effects of protein degradation in the framework of systemic, uncontrolled proteolytic activity, which was shown to take place in a preliminary study on the blood of hemorrhagic shock rats. The specific focus of ShockOmics is on the impairment of heart function and of cardiovascular regulation due both to biomolecular and neuro-vegetative mechanisms.
The overall study design is divided in two phases: a Discovery phase, in which the fundamental molecular cascade of acute heart failure induced by shock will be identified and a Validation phase, in which inhibitors of the identified molecular targets will be tested.
In summary, the full range of “omics” disciplines addressing the shock biomolecular processes is progressively identifying the main pieces of a puzzle, which eventually can contribute to understand the biomolecular pathways, from gene expression, to protein degradation and synthesis, to metabolic alterations, useful both for clinical interpretation and critical discussion of the therapeutic paradigms.

Project Results:
During the first 36 months of ShockOmics, the Consortium completed the analysis on existing biobanks and completed the recruitment of 86 fully eligible patients and their multilevel data collection. RNA sequencing and metabolomics analysis on the patients’ samples were successfully completed. The evaluation of altered expression of key genes in challenged cardiomyoctes, exposed to conditions mimicking either septic or cardiogenic shock, was finalized, using previously established in vitro models.
The following paragraphs summarize the main achievements in ShockOmics, in the different areas covered by the project.
1. “Omics” analysis on samples from existing biobanks
The Consortium established fruitful scientific collaborations with two existing, large shock biobanks (Proteosepsis and Albios), with the aim of performing exploratory proteomics and metabolomics analyses.
Preliminary mass-spectrometry based metabolomics analysis of plasma samples (N=70) from septic shock patients showed:
1) Marked difference of specific metabolites between survivors and non-survivors in a one-week frame post-ICU admission. Some metabolic features are indicative for short-term (28-days) as well as of long-term (90-days) survival rate;
2) Increased kynurenine, that may contribute to hypotension in sepsis, as well as alterations of different lysophosphatidylcholines and phosphatidylcholines species, able to modulate immune and inflammatory responses, that could represent not only a risk factor in septic shock but also important pathophysiologic mechanisms deserving further investigation.
Proteomics analysis on the same plasma samples showed an increase in specific protein abundance when patients at acute phase were compared with the same patient at steady state or with healthy individuals. Such analysis allowed to identify proteins that are promising candidates as biomarkers of the progression of the septic shock. Such results will be validated during the project.

2. Clinical study
The Consortium succeeded in defining a shared clinical protocol to allow the multiscale analysis of blood samples and hemodynamic data from subjects with circulatory shock.
86 patients (shock and controls) were recruited in three intensive care units and hemodynamic signals were downloaded from the bedside monitors every day for up to seven days from shock diagnosis by means of dedicated software. Blood samples from shock patients are collected at: i) T1<16 hours from T0; ii) T2=48 hours after T0; iii) T3=day 7 or before discharge or discontinuation of therapy in case of fatal outcome; iv) T4=day 100.
3. In vitro studies
After defining the most appropriate cell model for the functional evaluation of challenging stimuli (i.e. a two-step model, with cardiomyocytes differentiated from H9C2 cell line used for initial screening and primary cardiomyocytes used for validation) and the most appropriated detrimental stimuli and experimental conditions to mimic septic, hemorrhagic and septic shocks, the Consortium has characterized the effects of challenging stimuli: identification of the most significant gene expression alterations, which are key in the onset of the inflammatory response to shock and the evaluation of the contribution of the cellular microenvironment to the challenging stimuli previously identified.
The last part of the project will be devoted to the definition of optimal targets to test specific inhibitors, according to the findings of WP6, and the results of “omics” analyses

4. “Omics” analyses on samples collected in the clinical study
mRNA and smallRNA sequencing has been completed on all samples collected during the clinical study. The first differential expressed genes analysis of RNA data has been performed on a subset of septic shock patients. The same analyses are currently ongoing in the whole sample.
The plasma metabolome was profiled from all patients enrolled in the ShockOmics project by mass-spectrometry target strategy. An explorative analysis has been carried out on a subset of septic shock patients for which 131 metabolite concentrations were measured at ICU admission and 48 hours after, with the aim to investigate whether circulating metabolites can be associated with organ dysfunction index.

5. Animal experiments
A. Preliminary experiments on rat model of hemorrhagic shock has been performed by a shot gun and label free proteomic approach. The data at the protein and peptide level showed a sizable increase of circulating peptides and proteins in shock in comparison to control, with a strong indication that the increased chymotryptic activity in shock could be responsible for the detected proteolytic activity. The same rat model of hemorrhagic shock and its control were used for a preliminary transcriptome profiling of blood. Genes involved in apoptosis, immune response and response to stress were differentially expressed.
B. The Consortium finalized the protocol for animal studies, which are underway. The use of large animal models was brought to a minimum, thanks to the use of several different experimental approaches, in parallel (i.e. samples from biobanks, in vitro studies, observational clinical study). However, complex models as swine model of shock are necessary as only such model can truly simulate the organ interaction, multiorgan failure syndrome, systemic inflammation and ensuing acute heart failure as well as collection of myocardial tissue for analysis at the end of the experiment.

6. Hemodynamic analysis
The final structured database of annotated waveforms was created and all signals recorded from the patients enrolled in the clinical study were pre-processed with a uniformed format. Data modelling is underway.

Potential Impact:
The relevance of shock, and consequently of its associated pathologies (such as acute heart failure), is demonstrated by several evidences. Trauma resulting from accidental injuries is the leading cause of death in individuals aged 1–44 yr in the United States of America, and hemorrhagic shock, for instance, affects 36–39% of trauma victims.
The scientific and clinical relevance of the topic of this proposal is also clear considering indications and campaigns from important medical societies: a) the American Heart Association has indicated resuscitation as one of the areas of highest interest for translational cardiovascular research; b) the European Society of Critical Care Medicine and the Society of Critical Care Medicine have inspired the “Surviving Sepsis Campaign”, with the objective of working towards satisfying the demands of critical care physicians for accepted definition and treatments of sepsis, and for much needed advancements in its cure
The costs of hemorrhagic shock in US have been estimated to spam from $51,000, for a trauma-patient with uncomplicated shock, to $321,000 for a severe hemorrhagic shock with MOF.
Besides the relevance of the acute cardiovascular illness per se, the social and financial costs of the disease are evident also considering the long term impact on shock survivors, who have displayed a high two year mortality (44.9%) in the case of septic shock and a lower quality of life even 1.5 years after their ICU discharge.
For all these reasons, it appears evident that the expected advancements in the therapy of shock would have very significant social and economical implications.
The ever-increasing costs of healthcare delivery in the Western world makes the development of evidence-based therapies, grounded in this case on strong patho-physiological evidence of the sepsis cascade following trauma, surgery, anesthesia, etc., more than ever timely and urgent.
More specifically to ensure this broader impact occur in practice, ShockOmics will purse the following impacts as a consequence of the expected outcomes of this proposal.
1) A new technology for the timely identification/recognition of circulating biomarkers of pathogens potentially responsible for acute heart failure and hemodynamic instability
2) A new protocol for the timely and efficient delivery of therapy to prevent the evolution of systemic inflammation in shock towards acute heart failure and hemodynamic instability;
3) Software and hardware platforms for the integration of new, systems biology based, multiscale models for the analysis of hemodynamic stability in critical care monitors;
4) Open source tools for the simulation and analysis of the patho-physiology of acute heart failure and hemodynamic instability in shock;
5) Accessibility to the ShockOmics database;
In addition, ShockOmics is characterized by a strong involvement of research intensive SMEs, which will be the key actors in the implementation of the aforementioned impacts and for the measures needed to examine their potential commercialization.

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