COronary Microcirculation and Troponin Elevation in Septic Shock

Plasma cardiac troponin (cTn) elevation is an indicator of increased mortality in patients with sepsis yet the underlying cause of troponin elevation in sepsis is not known. The COMTESS study investigates whether elevated high-sensitive cardiac Troponin T (hs-cTnT) levels in hemodynamically unstable patients with sepsis can be explained by an underlying coronary artery disease or a process within the coronary microcirculation. Fifty patients with sepsis and with hs-cTnT elevation (\>15 ng/L) will undergo coronary angiography, including an assessment of coronary flow using a method called thermo-dilution to record the index of microcirculatory resistance (IMR) in the left anterior descending artery (LAD). The relationship between IMR and hs-cTnT will subsequently be analysed. It is important to identify the underlying causes of elevated cTn during sepsis to target further research with an aim to improve the survival in patients suffering from this condition.

Severe sepsis and septic shock are frequent primary causes of morbidity and mortality in intensive care units worldwide with a mortality rate of 28.3 - 41.1%. Our research group has previously shown that increasing level of high-sensitive cardiac troponin T (hs-cTnT) taken in sepsis patients is associated with 30-day and one-year mortality. Importantly, our group showed that hs-cTnT is also associated with mortality during the convalescence phase (30-365-day) in sepsis survivors.

Serum cardiac troponin (cTn) measurement is used to detect myocardial injury in patients with acute ischemic heart disease. Cardiac-specific troponins (troponin I and T) are, under normal physiological conditions, only detectable in the blood in small concentrations. In the event of myocyte damage, cardiac-specific troponins I and T enter the systemic circulation and can be detected and measured using modern immunoassay methods. This has led to the use of these biomarkers to identify both the presence and even estimated extent of myocardial injury which can then in turn facilitate an early risk stratification and identification of patients suitable for coronary intervention. Since 2018, the high-sensitive cardiac troponin assays have become the recommended assays for use within the clinical setting. In stark contrast to the treatment of patients with acute myocardial infarction and elevated cTn levels, there are currently no clinical guidelines to help physicians treat, investigate or follow-up sepsis patients with sepsis-related myocardial injury.

The COMTESS study is a pioneering observational prospective clinical study of 50 critically ill sepsis patients with a sampled hs-cTnT \>15 ng/L investigating the relationship between hs-cTnT level and concurrent microvascular dysfunction. Following informed consent, coronary angiography with measurements of coronary flow reserve (CFR), basal resistance index (BRI) and index of microcirculatory resistance (IMR) using thermo-dilution in the left anterior descending artery (LAD) is performed in each patient to ascertain underlying coronary microvascular dysfunction (CMVD). Fractional flow reserve (FFR) will be measured in cases where there is a coronary stenosis in the LAD. A research echocardiography is also performed on day 2-10 to examine right and left ventricular function.

Our primary hypothesis is that increasing level of hs-cTnT is associated with increasing level of CMVD in patients with sepsis and that myocardial injury thus contributes to excess death in sepsis and sepsis-survivors. The mechanisms behind myocardial injury in sepsis are not known. Disturbed sublingual microcirculatory alterations are associated with mortality in septic shock, but whether these alterations in proxy vessels translates to clinically relevant CMVD and myocardial injury in patients with sepsis is not known.

The physiological properties of endothelial cells (ECs) in the microcirculation are dependent on a complex carbohydrate-rich layer covering the EC luminal surface called the glycocalyx. Studies have shown that the disseminated dysfunctional immune response which is the hallmark of sepsis causes glycocalyx and EC injury and widespread coagulopathy leading to microvascular thrombosis. Pro-thrombotic components (e.g., neutrophile extracellular traps \[NETs\], and prothrombin) and components from EC and glycocalyx damage (e.g., Syndecan-1, thrombomodulin) can subsequently be analysed in plasma. Elevated level of Syndecan-1 in sepsis is associated with greater risk of death. Blood samples will be drawn during the coronary angiography for each patient and will be stored in a biobank. Our aim is to investigate if there is an association between plasma level of different microvascular components in relation to IMR level.

Eligibility Criteria:
Inclusion Criteria:

* Patients fulfilling the Sepsis-3 definition of and diagnostic criteria for sepsis or septic shock
* Age 40 - 85 years
* Life expectancy \> 1 year
* hs-cTnT values \>15 ng/L

Exclusion Criteria:

* pregnancy
* previous medical history of coronary artery by-pass grafting
* heart transplant
* previously verified ejection fraction (EF) ≤39% prior to hospital admission
* Hypertrophic cardiomyopathy (Septum \> 15 mm)
* severe aortic stenosis
* amyloidosis or sarcoidosis with myocardial engagement
* estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73m2 prior to hospital admission
* asthma
* infectious endocarditis
* a medical history of abdominal, thoracic, or orthopaedic surgery within the last three months prior to hospital admission.