Role of the Kallikrein-kinin System in Septic Cardiomyopathy

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

The purpose of this study is to investigate whether there are differential expressions of molecules in the kallikrein-kinin system (KKS) pathway in septic cardiomyopathy, and to analyze their regulatory mechanisms and gene expression changes.

This prospective observational study enrolled 567 critically ill adults within 24 hours of their intensive care unit (ICU) admission across three medical centers in Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology (Wuhan, China)Wuhan, China. Recruitment occurred during two distinct periods: June 2017 to September 2018 and September 2023 to October 2024. Patients were categorized according to Sepsis-3.0 criteria into non-sepsis and sepsis groups. The non-sepsis control group comprised individuals without evidence of infection whose Sequential Organ Failure Assessment (SOFA) scores remained below 2 points. Exclusion criteria included: 1) paraquat poisoning; 2) age under 18 years at diagnosis; 3) acute cardiovascular and cerebrovascular diseases unrelated to inflammation; 4) history of cardiac surgery; 5) pregnancy or breastfeeding; and 6) intellectual or psychological disorders precluding suitable study participation. Within the sepsis cohort, patients meeting the Sepsis-3 criteria who concurrently developed new-onset myocardial injury (troponin elevation exceeding the upper limit of normal, e.g., > 0.05 ng/mL) and/or echocardiographic evidence of myocardial dysfunction (ejection fraction < 50%) or B-type natriuretic peptide (BNP) > 500 pg/mL directly attributable to sepsis. All echocardiographic assessments were performed by accredited sonographers from the Tongji Clinic Echo Lab, with subsequent interpretations conducted by board-certified cardiologists from the same institution.

During the study periods, a total of 652 ICU patients were initially assessed for eligibility. Based on our predefined criteria, 85 patients were excluded: meeting absolute exclusion criteria (n = 18), failing to meet specific strict group definitions (n = 14), declining to participate or missing informed consent (n = 19), lacking baseline plasma samples within 24 hours (n = 16), and having incomplete echocardiographic or core clinical data (n = 18). Ultimately, 567 critically ill patients were enrolled, comprising 417 septic patients (including 104 who developed SIC) and 150 non-septic controls.

Inclusion Criteria:

1. Age >= 18 years old.

2. Admitted to the Intensive Care Unit (ICU) with an anticipated length of stay exceeding 24 hours.

3. Patient or legally authorized representative provides written informed consent prior to enrollment.

4. Categorized into one of the following three mutually exclusive cohorts within 24 hours of ICU admission:

   • Cohort 1 (Non-sepsis Controls): Admitted for definitive non-infectious etiologies (e.g., severe trauma, major non-cardiac surgery) with no clinical or microbiological evidence of infection throughout the ICU stay.
   • Cohort 2 (Sepsis without SIC): Diagnosed with sepsis according to the Sepsis-3 criteria (acute change in SOFA score >= 2 points driven by infection), but with normal cardiac troponin levels and preserved cardiac function.
   • Cohort 3 (Sepsis-Induced Cardiomyopathy, SIC): Diagnosed with sepsis according to the Sepsis-3 criteria, accompanied by new-onset myocardial injury (elevated cardiac troponin above the upper limit of normal) and/or echocardiographic evidence of myocardial dysfunction directly attributable to sepsis.

Exclusion Criteria:

1. Pre-existing severe chronic cardiac conditions, including history of cardiac surgery, severe pre-existing heart failure (NYHA Class III or IV), persistent severe arrhythmias, or known primary cardiomyopathy (e.g., hypertrophic or dilated cardiomyopathy).
2. Acute non-infectious cardiovascular or cerebrovascular events prior to or upon ICU admission, such as acute myocardial infarction (Type 1), acute ischemic/hemorrhagic stroke, or cardiac arrest.
3. Severe end-stage comorbidities, including end-stage renal disease (ESRD) requiring chronic maintenance dialysis prior to this illness, Child-Pugh Class C hepatic cirrhosis, or advanced malignant tumors with a life expectancy < 3 months.
4. History of paraquat poisoning or other toxic ingestions known to directly cause profound myocardial or pulmonary toxicity.
5. Pregnant or breastfeeding women.
6. Indeterminate or ambiguous infectious status (e.g., cases treated with empiric antibiotics for suspected infection but where infection could neither be confirmed nor ruled out), excluded to prevent misclassification bias.
7. Intellectual, psychological, or neurological disorders that preclude necessary clinical examinations or compliance with study procedures.