Genomic Determinants of Outcome in Cardiogenic Shock

Study Overview
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Brief Summary
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The aim of this project is to understand the heterogeneity of both the immune consequences and treatment responses in CS. We will explore this heterogeneity through identification of transcriptomic sub-phenotypes and their association with outcomes, including therapeutic responses.

Detailed Description
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This is a prospective observational cohort study in 8-10 cardiac centres across Europe. We will recruit patients presenting with acute myocardial infarction (AMI) and CS who are supported medically (n=100); with extracorporeal membrane oxygenation (n=50); and with the Impella Device (n=50). We will also enrol patients who present with either AMI and no evidence of CS (n=50) or CS due to non-ischaemic pathologies (e.g. myocarditis: n=50) as comparators. The recruitment target is 300 patients.

Official Title
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Prospective Observational Study Investigating Genomic Determinants of Outcome From Cardiogenic Shock (GOlDilOCS)

Conditions
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Cardiogenic Shock

Intervention / Treatment
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* Other: Observational study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All of the following are required for inclusion following screening: Willing to provide informed consent or appropriate consent from a nominated consultee or personal consultee Presentation within 24 hours of onset of ACS symptoms. CS can only be secondary to ACS (Type 1 MI STEMI or N-STEMI) or myocarditis Planned or completed revascularisation of culprit coronary artery CS will be defined by: Systolic blood pressure <90 mmHg for at least 30 minutes A requirement for a continuous infusion of vasopressor or inotropic therapy to maintain systolic blood pressure > 90 mmHg. Clinical signs of pulmonary congestion, plus signs of impaired organ perfusion with at least one of the following manifestations: altered mental status. cold and clammy skin and limbs. oliguria with a urine output of less than 30 ml per hour. elevated arterial lactate level of >2.0 mmol per litre. Exclusion Criteria: Any of the inclusion criteria not met and: Unwilling to provide informed consent. Echocardiographic evidence (recorded within 90 mins of end of PCI procedure) of mechanical cause for CS: eg ventricular septal defect, LV-free wall rupture, ischaemic mitral regurgitation. Age <18 and ≥80 years. Shock from another cause (sepsis, haemorrhagic/hypovolaemic shock, anaphylaxis, etc). Significant systemic illness Known dementia of any severity Comorbidity with life expectancy <12 months. Out-of-hospital cardiac arrest (OHCA) and any of the following: No return of spontaneous circulation (ongoing resuscitation effort) pH <7 Without bystander CPR within 10 minutes of collapse Arterial lactate level of <2.0 mmol per litre.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cardiogenic shock and MI<br>Patients presenting with acute myocardial infarction and cardiogenic shock who are supported medically (ie. inotropes +/- intra aortic balloon pump only). N=50 | Other: Observational study<br>* Blood sampling and clinical data collection<br>|
| Cardiogenic shock and MI wtih ECMO<br>Patients presenting with acute myocardial infarction and cardiogenic shock who are supported medically with ECMO (+/- LV unloading device). N=50 | Other: Observational study<br>* Blood sampling and clinical data collection<br>|
| Cardiogenic shock and MI wtih Impella<br>Patients presenting with acute myocardial infarction and cardiogenic shock who are supported medically with Impella. N=50 | Other: Observational study<br>* Blood sampling and clinical data collection<br>|
| MI without cardiogenic shock<br>Patients presenting with acute myocardial infarction and cardiogenic shock as a control comparator | Other: Observational study<br>* Blood sampling and clinical data collection<br>|
| Non ischemic Cardiogenic Shock ie myocarditis<br>Patients presenting with myocarditis and cardiogenic shock as a control comparator | Other: Observational study<br>* Blood sampling and clinical data collection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary aim is to better understand the heterogeneity of the immune consequences and treatment responses in CS through identification of transcriptomic sub-phenotypes and their association with in-hospital mortality | This will be achieved through bloods sample collection, analysis and linked to the patient's clinical diagnosis and outcome. | through study completion, an average of 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify transcriptomic (and chemokine/cytokine) signatures at presentation that elucidate the pathobiology of CS and examine their subsequent evolution. | Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed. | through study completion, an average of 5 days | 
| Correlate recently identified clinical phenotypes of CS with transcriptomic and inflammatory mediator signatures. | Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed. | through study completion, an average of 5 days | 
| Identify transcriptomic and chemokine/cytokine signatures at presentation that improve prognostic accuracy in patients with CS | Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed. | through study completion, an average of 5 days | 
| Investigate inter-individual heterogeneity in the dynamic transcriptomic response to CS through an eQTL mapping approach and identify context- specific regulatory genetic variants involving gene networks central to the pathogenesis of CS. | Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed. | through study completion, an average of 5 days | 
| Identity novel therapeutic targets that might modulate the dysfunctional immune response to CS - drug discovery | Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed. | through study completion, an average of 5 days | 
| Determine the extent to which the signatures and drivers of a dysfunctional immune response in CS are shared with other critical illness syndromes. | Bloods samples will be collected from patients during their hospital stay and corresponding analysis performed. | through study completion, an average of 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ACS,, Cardiogenic Shock, ECMO, Impella, Gene Expression, Endotype