Prospective observational study investigating genomic determinants of outcome from cardiogenic shock (GOlDilOCS)
Lead Research Organisation:
Barts Health NHS Trust
Department Name: Intensive Care
Abstract
What is being done?
We will study patients with a life-threatening condition called cardiogenic shock. This type of shock happens when the heart is suddenly unable to pump sufficient blood around the body to meet the needs of vital organs such as the brain, lungs, liver and kidney, thereby impairing their ability to function normally. Cardiogenic shock is often a consequence of a sudden and unexpected event, for example a heart attack Our study is aimed at understanding how the body responds to the inadequate blood supply caused by cardiogenic shock and to find out how and why this response varies from one patient to another. Our long-term goal is to improve survival from cardiogenic shock by developing a better understanding of which patients will benefit from specific treatments and how we can ensure that the right patients are getting the right treatment at the right time. We also hope to identify new targets for drug treatment aimed at modifying the body's response to cardiogenic shock.
Why is this needed?
Every year across Europe over 50000 patients are diagnosed with cardiogenic shock. Despite improvements in how we deliver care to patients with acute heart problems, death rates from cardiogenic shock have remained unacceptably high at between 30% and 50% for the last two decades. Current treatments use drugs and mechanical pumps to temporarily restore or replace the function of the heart, to "buy-time" for the heart to recover. Most of the patients who die, do so due to failure of other vital organs, often despite some recovery of heart function. We believe that in many cases death is a consequence of inflammation caused by a dysfunctional response of the immune system to the initial insult. Of those who survive, 30% will suffer the effects of long-term heart damage (heart failure), as well as the consequences of critical illness, including extreme weakness, fatigue, depression, chronic ill health with repeated hospital attendances and admissions, being unable to return to work and a poor quality of life.
How will this be done?
We believe that a dysregulated and inappropriate immune response to cardiogenic shock results in widespread inflammation, organ failure and often death. Further we think that the nature and drivers of the patient response to cardiogenic shock differ between individuals. We will take a novel approach to studying cardiogenic shock by measuring the levels of gene activity and mediators of inflammation in blood from patients with this condition. Using these data, we will:
- better understand the reasons why people develop cardiogenic shock and die from it
- identify why there is variation between patients in severity of disease and the response to current therapies
- work out which patients are likely to benefit most from current and new treatments and why
- work with doctors undertaking clinical trials of new treatments for cardiogenic shock to use the knowledge gained from this study to improve the design of such trials
Where will the work be done?
The work will be undertaken at Queen Mary University London, the University of Oxford and the Wellcome Sanger Institute using blood samples from patients in the UK and Germany.
When will this work take place?
We will complete this work between 2022 and 2025.
We will study patients with a life-threatening condition called cardiogenic shock. This type of shock happens when the heart is suddenly unable to pump sufficient blood around the body to meet the needs of vital organs such as the brain, lungs, liver and kidney, thereby impairing their ability to function normally. Cardiogenic shock is often a consequence of a sudden and unexpected event, for example a heart attack Our study is aimed at understanding how the body responds to the inadequate blood supply caused by cardiogenic shock and to find out how and why this response varies from one patient to another. Our long-term goal is to improve survival from cardiogenic shock by developing a better understanding of which patients will benefit from specific treatments and how we can ensure that the right patients are getting the right treatment at the right time. We also hope to identify new targets for drug treatment aimed at modifying the body's response to cardiogenic shock.
Why is this needed?
Every year across Europe over 50000 patients are diagnosed with cardiogenic shock. Despite improvements in how we deliver care to patients with acute heart problems, death rates from cardiogenic shock have remained unacceptably high at between 30% and 50% for the last two decades. Current treatments use drugs and mechanical pumps to temporarily restore or replace the function of the heart, to "buy-time" for the heart to recover. Most of the patients who die, do so due to failure of other vital organs, often despite some recovery of heart function. We believe that in many cases death is a consequence of inflammation caused by a dysfunctional response of the immune system to the initial insult. Of those who survive, 30% will suffer the effects of long-term heart damage (heart failure), as well as the consequences of critical illness, including extreme weakness, fatigue, depression, chronic ill health with repeated hospital attendances and admissions, being unable to return to work and a poor quality of life.
How will this be done?
We believe that a dysregulated and inappropriate immune response to cardiogenic shock results in widespread inflammation, organ failure and often death. Further we think that the nature and drivers of the patient response to cardiogenic shock differ between individuals. We will take a novel approach to studying cardiogenic shock by measuring the levels of gene activity and mediators of inflammation in blood from patients with this condition. Using these data, we will:
- better understand the reasons why people develop cardiogenic shock and die from it
- identify why there is variation between patients in severity of disease and the response to current therapies
- work out which patients are likely to benefit most from current and new treatments and why
- work with doctors undertaking clinical trials of new treatments for cardiogenic shock to use the knowledge gained from this study to improve the design of such trials
Where will the work be done?
The work will be undertaken at Queen Mary University London, the University of Oxford and the Wellcome Sanger Institute using blood samples from patients in the UK and Germany.
When will this work take place?
We will complete this work between 2022 and 2025.
Technical Summary
Mortality from cardiogenic shock (CS) has remained at 30-50% over the last two decades. A more comprehensive understanding of the pathobiology of CS, specifically the heterogeneity of the host response, is needed to guide development of targeted therapies and inform clinical trial enrolment.
Objective
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.
Design
This is a prospective observational cohort study across 5 cardiac centres. 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.
Methods
Blood samples will be collected at presentation, 24 hours, and 5 days to generate a biobank for initial focused genetic, transcriptomic and inflammatory mediator profiling, and for future multi-modal deep phenotyping. Clinical data will be retrieved from patient records and transcribed into an electronic case report form. Inter-individual heterogeneity in whole blood gene expression will be analysed using unsupervised hierarchical cluster analysis. Gene expression and inflammatory mediator profiles, and their evolution, will be correlated with clinical endpoints including survival. Enrichment of biological pathways and functions, and upstream regulators will be determined. Context- specific regulatory genetic variants involving gene networks central to the pathogenesis of CS will be identified.
Impact
These data will enable a personalised medicine approach and inform clinical trial design in CS.
Objective
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.
Design
This is a prospective observational cohort study across 5 cardiac centres. 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.
Methods
Blood samples will be collected at presentation, 24 hours, and 5 days to generate a biobank for initial focused genetic, transcriptomic and inflammatory mediator profiling, and for future multi-modal deep phenotyping. Clinical data will be retrieved from patient records and transcribed into an electronic case report form. Inter-individual heterogeneity in whole blood gene expression will be analysed using unsupervised hierarchical cluster analysis. Gene expression and inflammatory mediator profiles, and their evolution, will be correlated with clinical endpoints including survival. Enrichment of biological pathways and functions, and upstream regulators will be determined. Context- specific regulatory genetic variants involving gene networks central to the pathogenesis of CS will be identified.
Impact
These data will enable a personalised medicine approach and inform clinical trial design in CS.
Publications
Buckel M
(2023)
Extending the 'host response' paradigm from sepsis to cardiogenic shock: evidence, limitations and opportunities
in Critical Care
Leadbeater P
(2024)
Comparative before-after study of fever prevention versus targeted temperature management following out-of-hospital cardiac arrest
in Resuscitation Plus
Thomson RJ
(2023)
In perspective: the patient at the heart of research in acute cardiovascular care.
in European heart journal. Acute cardiovascular care
Warren A
(2024)
Cardiogenic shock: all hail the RCT, long live the registry
in Critical Care
Warren A
(2023)
EPidemiology Of Cardiogenic sHock in Scotland (EPOCHS): A multicentre, prospective observational study of the prevalence, management and outcomes of cardiogenic shock in Scotland
in Journal of the Intensive Care Society