Genomic Determinants of Outcome in Cardiogenic Shock

Official title

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

Overview

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

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.

Interventions

• Other Observational study
  Blood sampling and clinical data collection

Primary outcome measures

• 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 [Time frame: through study completion, an average of 5 days]

Secondary outcome measures (6)

• Identify transcriptomic (and chemokine/cytokine) signatures at presentation that elucidate the pathobiology of CS and examine their subsequent evolution. [Time frame: through study completion, an average of 5 days]
• Correlate recently identified clinical phenotypes of CS with transcriptomic and inflammatory mediator signatures. [Time frame: through study completion, an average of 5 days]
• Identify transcriptomic and chemokine/cytokine signatures at presentation that improve prognostic accuracy in patients with CS [Time frame: 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. [Time frame: through study completion, an average of 5 days]
• Identity novel therapeutic targets that might modulate the dysfunctional immune response to CS - "drug discovery" [Time frame: 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. [Time frame: through study completion, an average of 5 days]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Study design

Observational model

Cohort

Study locations

United Kingdom · 1 center

• Barts Health NHS trust — London

Publications

• Maslove DM, Tang B, Shankar-Hari M, Lawler PR, Angus DC, Baillie JK, Baron RM, Bauer M, Buchman TG, Calfee CS, Dos Santos CC, Giamarellos-Bourboulis EJ, Gordon AC, Kellum JA, Knight JC, Leligdowicz A, McAuley DF, McLean AS, Menon DK, Meyer NJ, Moldawer LL, Reddy K, Reilly JP, Russell JA, Sevransky JE, Seymour CW, Shapiro NI, Singer M, Summers C, Sweeney TE, Thompson BT, van der Poll T, Venkatesh B PMID 35715504
• Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, Rautanen A, Gordon AC, Garrard C, Hill AV, Hinds CJ, Knight JC. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med. 2016 Apr;4(4):259-71. doi: 10.1016/S2213-2600(16)00046-1. Epub 2016 Feb 23. PMID 26917434
• Toma A, Dos Santos C, Burzynska B, Gora M, Kiliszek M, Stickle N, Kirsten H, Kosyakovsky LB, Wang B, van Diepen S, Epelman S, Szekely Y, Marshall JC, Billia F, Lawler PR. Diversity in the Expressed Genomic Host Response to Myocardial Infarction. Circ Res. 2022 Jun 24;131(1):106-108. doi: 10.1161/CIRCRESAHA.121.318391. Epub 2022 May 9. No abstract available. PMID 35534922
• Cano-Gamez K, Burnham KL, Goh C, Allcock A, Malick ZH, Overend L, Kwok A, Smith DA, Peters-Sengers H, Antcliffe D; GAinS Investigators; McKechnie S, Scicluna BP, van der Poll T, Gordon AC, Hinds CJ, Davenport EE, Knight JC, Webster N, Galley H, Taylor J, Hall S, Addison J, Roughton S, Tennant H, Guleri A, Waddington N, Arawwawala D, Durcan J, Short A, Swan K, Williams S, Smolen S, Mitchell-Inwang PMID 36322631

Identifiers

NCT: NCT05728359 · 290406

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗