Eculizumab-Induced Acute Heart Failure Decompensation: A Novel Cardiotoxic Signal in Complement-Mediated TMA
核心洞察
A 45-year-old woman with complement-mediated thrombotic microangiopathy (搜索) developed recurrent acute heart failure decompensation (搜索) within hours of each eculizumab infusion.
The reproducible "on-off-rechallenge" pattern, including recurrence after a reduced 0.6 g dose, strongly suggested eculizumab as a precipitating trigger rather than an incidental association.
Cardiac decompensation resolved upon permanent discontinuation of eculizumab, with NT-proBNP declining from 35,000 pg/mL to 25,000 pg/mL and resolution of orthopnea.
A 45-year-old woman with clinically suspected complement-mediated thrombotic microangiopathy (搜索) (TMA) developed recurrent, life-threatening episodes of acute heart failure decompensation (搜索) temporally linked to eculizumab infusion, according to a case report published in Infection and Drug Resistance. The reproducible pattern—occurring within hours of each administration and resolving upon drug discontinuation—raises the possibility of a previously underappreciated cardiotoxic signal associated with this cornerstone therapy for atypical hemolytic uremic syndrome (搜索) (aHUS).
The patient presented with acute altered mental status, vomiting, involuntary limb movements, and urinary incontinence. Cranial computed tomography revealed lacunar infarcts in bilateral periventricular regions. Laboratory findings included microangiopathic hemolytic anemia with schistocytes on peripheral smear, severe thrombocytopenia (nadir 21 × 10⁹/L), acute kidney injury requiring intermittent hemodiafiltration, and markedly elevated complement activation markers. Although a positive direct antiglobulin test (IgG and C3d) suggested coexisting autoimmune hemolytic anemia, the constellation of schistocytes, thrombocytopenia, renal infarcts on CT, and elevated C5b-9 fulfilled diagnostic criteria for complement-mediated TMA.
Clinical Course and the "On-Off-Rechallenge" Phenomenon
Following the first dose of eculizumab (1.2 g), the patient exhibited a favorable hematological response with platelet count rising to 90 × 10⁹/L by day 10. However, after the second dose on day 14, a spontaneous breathing trial failed due to tachycardia (120–140 bpm) and tachypnea (20–34 breaths/min), coinciding with a twofold rise in NT-proBNP.
The third dose on day 22 precipitated acute tachycardia (130–140 bpm), tachypnea (30–40 breaths/min), and elevated blood pressure (148/92 mmHg). Bedside echocardiography revealed left heart enlargement, impaired left ventricular systolic function (LVEF approximately 53%), mild mitral regurgitation, and a trivial pericardial effusion.
Given the recurrent temporal association, the scheduled fourth dose was withheld. Over the subsequent 30 days, septic shock resolved, urine output improved to 1,000–2,000 mL per day, and antihypertensive therapy was successfully de-escalated from intravenous nicardipine to oral amlodipine and terazosin.
A shared decision was made to administer a reduced dose of eculizumab (0.6 g) on day 41. Approximately five hours post-infusion, the patient developed acute respiratory distress with chest tightness, dyspnea, and oxygen desaturation (SpO₂ fluctuating between 80% and 89%). Bibasilar moist rales were audible, and bedside thoracic ultrasound revealed a left-sided pleural effusion with a maximum depth of 75 mm. After five hours of intensive cardiorespiratory support, symptoms improved.
Following multidisciplinary consultation, eculizumab was permanently discontinued. NT-proBNP levels declined from 35,000 pg/mL to 25,000 pg/mL, with resolution of orthopnea and shortness of breath. At transfer to the nephrology department on day 58, the patient remained alert and oriented with no recurrence of neurological symptoms, blood pressure controlled at 125/78 mmHg, and serum creatinine at 369 µmol/L with ongoing renal replacement therapy.
Mechanistic Hypotheses and the "Two-Hit" Model
The authors propose a "two-hit" model to explain the observed cardiotoxicity. The patient had evidence of myocardial injury prior to eculizumab initiation—elevated hs-cTnI (peak 1,701.8 pg/mL) and NT-proBNP (4,284 pg/mL on admission), reflecting severe anemia (hemoglobin 39 g/L), sepsis-related inflammation, and possible TMA-related microvascular ischemia. This pre-existing cardiac vulnerability constituted the "first hit," with eculizumab serving as the "second hit" precipitating acute decompensation.
Potential mechanisms include abrupt complement blockade disrupting vascular tone regulation leading to acute afterload mismatch, or eculizumab triggering a pro-inflammatory cascade through altered anaphylatoxin (C5a) signaling. The rapid symptomatic improvement with heart failure management and recurrence upon rechallenge argue against irreversible cytotoxicity and favor a functional, hemodynamic mechanism.
Alternative Explanations Considered
The authors systematically evaluated competing explanations. Volume overload was deemed unlikely given that decompensation occurred within hours of infusion—too rapid for significant positive fluid balance—and the patient was receiving continuous renal replacement therapy with strict ultrafiltration. Underlying cardiac pathology was not supported by the absence of prior cardiac history and the prompt reversibility of symptoms. While hypertension was present during episodes (up to 160–170/100–110 mmHg), it alone could not explain the reproducible, infusion-linked pattern, as heart failure resolved when eculizumab was withheld despite persistent hypertensive susceptibility.
Clinical Implications
The authors recommend that baseline cardiac assessment, including echocardiography and BNP or NT-proBNP measurement, be considered prior to initiating eculizumab, particularly in patients with known cardiac risk factors or critical illness. Close monitoring of vital signs, oxygen saturation, and clinical signs of pulmonary congestion during and for at least 24 hours after infusion is advised. Notably, the recurrence after dose reduction suggests that simply lowering the dose may not mitigate risk in susceptible individuals.
The report also underscores the need for an international registry to track severe adverse events associated with complement inhibitors, which would help identify risk factors and incidence rates for such complications.
Limitations
As a single-case report with multiple confounding factors inherent to critical illness—including severe anemia, sepsis, acute kidney injury, hypertension, and hemodynamic instability—causality cannot be definitively established. Genetic analysis of complement factors was not performed, and renal biopsy was precluded by severe thrombocytopenia. The case is best characterized as clinically suspected complement-mediated TMA with features consistent with aHUS, rather than genetically proven aHUS. The adverse event was formally reported to the national pharmacovigilance authority in accordance with pharmacovigilance regulations.