Cardiogenic Shock, Cardiogenic Shock Post Myocardial Infarction, STEMI - ST Elevation Myocardial Infarction
Conditions
Keywords
acute myocardial infarction with cardiogenic shock
Brief summary
To study the safety and efficacy of fibroblast activation protein (FAP)-targeted allogeneic immunosuppressive chimeric antigen receptor-dendritic cell (CAR-DC) in the treatment of acute myocardial infarction with cardiogenic shock and provide a new method for the treatment of acute myocardial infarction with cardiogenic shock.
Detailed description
Background: Cardiogenic shock following acute myocardial infarction (AMI) remains a major unresolved clinical challenge. Despite advances in urgent revascularization and mechanical circulatory support, short-term mortality remains unacceptably high, approaching 40% within 30 days. Few evidence-based therapies have demonstrated a meaningful survival benefit, highlighting the urgent need for novel, mechanism-driven interventions. Growing clinical and experimental evidence indicates that a dysregulated systemic inflammatory response-manifested by hyperthermia, leukocytosis, and elevated proinflammatory mediators-plays a central role in the pathophysiology and progression of cardiogenic shock. Excessive inflammation exacerbates myocardial dysfunction, promotes multiorgan injury, and impairs recovery, suggesting that targeted immunomodulation may represent a complementary therapeutic strategy in this high-risk population. Dendritic cells (DCs), as professional antigen-presenting cells, occupy a pivotal position at the interface of innate and adaptive immunity and are uniquely suited to orchestrate context-dependent immune responses. In particular, tolerogenic DCs exert potent immunosuppressive effects through regulatory cytokine production, expression of co-inhibitory ligands, antigen-specific suppression of effector T cells, and induction of regulatory T cells. Collectively, these properties render DCs an attractive yet underexplored cellular platform for resolving excessive inflammation and promoting tissue repair in cardiogenic shock with AMI. Purpose: In this prospective clinical study, the investigators engineered a stable, immunosuppressive, and fibrotic lesion-targeted DC therapy, termed immunosuppressive DCs (iCDC). This study was designed to evaluate the safety and preliminary efficacy of allogeneic fibroblast activation protein (FAP)-targeted iCDC therapy in patients with AMI complicated by cardiogenic shock. Study design: This single-center, prospective, concurrent non-randomized controlled clinical trial enrolls patients aged 18-80 years presenting with acute myocardial infarction complicated by cardiogenic shock. Eligible patients are treated with allogeneic FAP-targeted immunosuppressive iCDC therapy. Outcome measure: The primary outcome is the safety of FAP-targeted immunosuppressive iCDC therapy in patients with AMI complicated by cardiogenic shock. Secondary outcomes include 30-day all-cause mortality; hemodynamic parameters following iCDC therapy (systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate); time to hemodynamic stabilization; dose and duration of vasopressor and inotropic support; arterial lactate levels; changes in biomarkers (BNP, CRP, creatinine, ALT, AST, and inflammatory mediators); need for and duration of mechanical ventilation; need for and duration of left ventricular assist device implantation; intensive care unit and total hospital length of stay; left ventricular ejection fraction assessed by echocardiography; SAPS II score; SCAI shock classification; heart failure symptom burden assessed by NYHA functional class and the Kansas City Cardiomyopathy Questionnaire; incidence of major adverse cardiovascular events (MACE), including cardiac death and heart failure hospitalization; and incidence of adverse events.
Interventions
BIOLOGICALFAP allogeneic immunosuppressive CAR-DC
Each subject receive FAP immunosuppressive CAR-DC by intravenous infusion at the first day of shock.
Sponsors
Second Affiliated Hospital, School of Medicine, Zhejiang University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
（patients）: * Age ≥ 18 years and \< 80 years. * Acute ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock, meeting all the following conditions: 1. Post-emergent revascularization (PCI or CABG) 2. Systolic blood pressure \< 90 mmHg for \>30 minutes, or requiring catecholamine support to maintain systolic blood pressure \>90 mmHg 3. Signs of impaired organ perfusion, meeting at least one of the following criteria: 1. Altered mental status 2. Cold, clammy skin and extremities 3. Oliguria, with urine output \<30 mL/h 4. Arterial lactate level \>2 mmol/L * The patient or their legally authorized representative is capable of providing verbal confirmation of understanding the trial risks, benefits, and treatment alternatives associated with receiving immunosuppressive CAR-DC therapy, and provides written informed consent prior to participation in this clinical trial.
Exclusion criteria
（patients）: 1. Acute mechanical complications of infarction (e.g., ventricular septal rupture, acute mitral regurgitation). 2. Cardiac arrest. 3. Hypoxic-ischemic brain injury (cerebral injury with fixed and dilated pupils not attributable to medication). 4. Shock due to other causes (e.g., sepsis, hypovolemia). 5. Resuscitation duration \>30 minutes. 6. Absence of spontaneous cardiac activity. 7. Persistent electrical instability. 8. Active bleeding or contraindications to heparin use. 9. Active autoimmune disease requiring immunosuppressive therapy. 10. History of malignancy. 11. Infection, including: * Active hepatitis B (HBV DNA \>1000 copies/mL by PCR), hepatitis C, syphilis, or HIV infection at screening. * Uncontrolled systemic fungal, bacterial, viral, or other pathogen infections. 12. Pregnant women. 13. Contraindications to the investigational drug or study procedures. Inclusion Criteria（donors）: * Age ≥ 18 years and ≤ 75 years. * Has provided written informed consent. * Hematocrit \>30%, lymphocyte count \>0.5 × 10\^9/L, platelet count \>60 × 10\^9/L. * Pathogen screening results must be negative for HIV (antigen, core antibody, and RNA), HBV (surface antigen and core antibody), HCV, syphilis, CMV, and EBV.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The proportion of subjects with Dose-limiting toxicity (DLT) | in 14 days after injection | The proportion of participants with DLT as assessed by CTCAE v5.0 |
| Incidence of treatment-emergent adverse events (TEAEs) | in 14 days after injection | Incidence of iCDC treatment-emergent adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Systolic blood pressure | 24 hours、48 hours、72 hours、7 days after injection | Systolic blood pressure (mmHg) measured using a calibrated sphygmomanometer under standardized conditions. |
| Diastolic blood pressure | 24 hours、48 hours、72 hours、7 days after injection | Diastolic blood pressure (mmHg) measured using a calibrated sphygmomanometer under standardized conditions. |
| Mean arterial pressure | 24 hours、48 hours、72 hours、7 days after injection | The mean arterial pressure (MAP) is calculated using the following formula: MAP=DBP+1/3(SBP-DBP)；DBP : Diastolic blood pressure，SBP ：Systolic blood pressure |
| Time to hemodynamic stability | From the end of the iCDC infusion to achievement of hemodynamic stability, assessed continuously until ICU discharge (up to 30 days). | Sustained (\> 60 min) systolic blood pressure \>90 mmHg without requirement for catecholamines and without signs of peripheral endorgan hypoperfusion |
| Dose of vasopressors | 24 hours、48 hours、72 hours、7 days after injection | Dose of vasopressors administered to the participant. |
| Duration of vasopressor use | From enrollment to hospital discharge (up to 30 days). | Duration of vasopressor therapy in days treated with vasopressor between enrollment and hospital discharge. A day treated with vasopressor is any day during the hospital period where the patient received a vasopressor. |
| Dose of inotropic drugs | 24 hours、48 hours、72 hours、7 days after injection | Dose of inotropic drugs administered to the participant. |
| Duration of inotropic drugs use | From enrollment to hospital discharge (up to 30 days). | Duration of inotropic drugs therapy in days treated with inotropic drugs between enrollment and hospital discharge. A day treated with inotropic drugs is any day during the hospital period where the patient received inotropic drugs |
| Serum lactate level | The measurement frequency is once every 8 hours for a duration of 48 hours. | Lactate is assessed via arterial blood gas analysis. |
| Change in C-reactive protein (CRP) level from baseline | 24 hours, 72 hours, 7 days，14 days after injection. | Change in serum C-reactive protein concentration compared with baseline. |
| Change in serum creatinine level from baseline | 24 hours, 72 hours, 7 days，14 days after injection. | Change in serum creatinine concentration compared with baseline. |
| Change in ALT (Alanine Aminotransferase) level from baseline | 24 hours, 72 hours, 7 days，14 days after injection. | Change in serum ALT concentration compared with baseline. |
| Change in AST (Aspartate Aminotransferase) level from baseline | 24 hours, 72 hours, 7 days，14 days after injection. | Change in serum AST concentration compared with baseline. |
| Change in Interleukin-6 (IL-6) levels from baseline | 24 hours, 72 hours, 7 days，14 days after injection. | Change in serum Interleukin-6 (IL-6) levels compared with baseline. |
| Need for mechanical ventilation | From the end of the drug infusion until ICU discharge (up to 30 days). | Need for mechanical ventilation is defined as requiring invasive or non-invasive positive pressure ventilation for at least 1 hour due to respiratory failure. |
| Duration of mechanical ventilation | From the initiation of mechanical ventilation until ICU discharge (up to 30 days). | Duration of mechanical ventilation is defined as the total number of hours from the initiation of invasive or non-invasive ventilation until the last successful extubation |
| Requirement for left ventricular assist device implantation | From the end of iCDC infusion through study completion (up to 30 days). | Requirement for left ventricular assist device implantation is defined as the need for implantation of a left ventricular assist device as bridge-to-transplant or destination therapy in patients with cardiogenic shock or end-stage heart failure who fail to maintain adequate end-organ perfusion despite optimized medical therapy. |
| Duration of left ventricular assist device use | From left ventricular assist device implantation through study completion (up to 30 days). | Duration of left ventricular assist device use is defined as the total time from completion of device implantation until device removal, patient death, or the study cutoff date, whichever occurs first. |
| Simplified Acute Physiology Score II | Daily from ICU admission through ICU discharge (up to 30 days). | The Simplified Acute Physiology Score II (SAPS II) is a validated severity-of-disease scoring system used to assess the physiological status of critically ill patients. The score ranges from 0 to 163, with higher scores indicating greater disease severity and a worse prognosis. SAPS II will be calculated based on the worst physiological values recorded during each 24-hour period. |
| time to recovery from cardiogenic shock | From the end of iCDC infusion to recovery from cardiogenic shock, assessed continuously until ICU discharge (up to 30 days). | Time to recovery from cardiogenic shock is defined as the duration from the end of the single study drug infusion to the achievement of predefined criteria for hemodynamic stability and improvement in end-organ perfusion. |
| length of stay at the intensive care unit | From ICU admission until ICU discharge (up to 30 days). | Length of stay in the ICU is defined as the total time from ICU admission until ICU discharge. |
| Length of hospital stay; | From hospital admission until hospital discharge or death (up to 30 days). | Total hospital length of stay is defined as the total calendar days from patient admission registration until final discharge or death, whichever occurs first. |
| Left ventricular ejection fraction (LVEF) | 1 month after injection | The difference of LVEF from baseline. LVEF will be assessed by echo. |
| SCAI Shock Classification | 3 days、7 days、14 days after injection | The SCAI shock classification is a standardized, five-stage system (from A to E) used to categorize the severity of cardiogenic shock based on clinical, hemodynamic, and biomarker criteria. |
| assessment of heart failure symptom | 1 month after injection | The difference of heart failure symptom, which will be assessed by NYHA grading and KCCQ score. |
| Incidence of major adverse cardiovascular events (MACE) | 1 month after injection | Incidence of Cardiac death, readmission due to heart failure. |
| Change in B-type natriuretic peptide (BNP) level from baseline | 7 days，14 days，30 days after injection. | Change in serum B-type natriuretic peptide concentration compared with baseline. |
| incidence of adverse events | From the end of the drug infusion through study completion，up to 30 days. | Incidence of adverse events of heart, nerve system, mental system, digestive system and immune system. |
| All-cause mortality | 30 days after injection | All-cause mortality at 30 days after iCDC treatment |
Countries
China
Contacts
CONTACTJiamin Li, MD
PRINCIPAL_INVESTIGATORXinyang Hu, PhD
Second Affiliated Hospital, School of Medicine, Zhejiang University, China
Outcome results
None listed