5-FU Cardiotoxicity Rescued by Levosimendan: LVEF 28% to 50%

A 48-year-old woman with no prior cardiac history presented with acute decompensated heart failure within 48 hours of completing her first cycle of FOLFOX chemotherapy (5-fluorouracil, oxaliplatin, and leucovorin) as adjuvant treatment for node-positive colon carcinoma. During her sigmoidectomy, 5 of 23 lymph nodes had tested positive, though complete resection was achieved. She was managing her chemotherapy on an outpatient basis when she developed chest pain, anorexia, and vomiting — followed rapidly by acute kidney injury with creatinine rising to 2.0 mg/dL.

On urgent admission, she was tachypneic with progressive desaturation requiring high-flow oxygen. An echocardiogram obtained the following day showed a left ventricular ejection fraction (LVEF) of 28% — a dramatic drop in a woman with no prior cardiac disease. The electrocardiogram demonstrated low-voltage QRS complexes in the peripheral leads, suggesting diffuse myocardial involvement.

Figure 1

ECG showing low voltage in limb leads in 5-FU-induced cardiotoxicity

Low-voltage QRS complexes in the peripheral leads is a nonspecific but important ECG sign in chemotherapy-induced cardiomyopathy. Unlike cardiac amyloidosis — where low voltage is paired with echocardiographic wall thickening — here it reflects diffuse myocardial dysfunction without structural infiltration. Serial ECG normalization (see Figure 3) tracked clinical recovery.

Chest X-ray confirmed bilateral pulmonary congestion that was visibly worse on day 2 compared to day 1. Ischemic heart disease, sepsis, and myocarditis were actively excluded through clinical evaluation, biomarkers, and imaging. The clinical picture was most consistent with 5-FU-induced acute cardiomyopathy.

Figure 2

Serial chest X-rays: congestion and levosimendan-driven resolution

(A) Chest X-ray at admission before ICU transfer — day 1. (B) ICU admission with worsening bilateral pulmonary congestion — day 2. (C) Radiological improvement after starting levosimendan — day 3. (D) Progressive resolution of congestion with levosimendan at 12 mL/hour plus norepinephrine support — day 4. The serial radiographs provide objective documentation of the treatment response and are a useful clinical monitoring tool in this setting.

The patient was transferred to the ICU, where non-invasive mechanical ventilation was initiated and a central venous catheter placed. Levosimendan — a calcium sensitizer with inotropic and vasodilatory properties — was started as an IV bolus followed by a continuous infusion, titrated from 3 to 12 mL/hour over 24 hours with concomitant norepinephrine to prevent hypotension. By day 3, pulmonary congestion was visibly improving on chest X-ray. Creatinine peaked at 4.24 mg/dL on day 3 before trending down. Pro-BNP fell from over 14,700 to 7,310 pg/mL by day 4, and continued its decline to 1,802 pg/mL at discharge. A normal ECG was recorded before discharge.

Figure 3

ECG normalization following clinical resolution of 5-FU-induced heart failure

Return of normal QRS voltage in peripheral leads at the time of clinical recovery. Comparing this tracing to Figure 1 illustrates the reversibility of electrophysiological changes in chemotherapy-induced cardiomyopathy when treated promptly. Monitoring serial ECGs alongside biomarkers provides a low-cost, bedside indicator of myocardial recovery.

Follow-up Doppler echocardiography showed LVEF recovery to 50%. Renal function normalized with creatinine returning to 0.988 mg/dL. The patient was discharged without heart failure symptoms and remained clinically stable and asymptomatic through four weeks of outpatient follow-up.

Figure 4

Mechanisms of action of levosimendan

Levosimendan improves myocardial contractility through calcium sensitization of troponin C — without increasing intracellular calcium or energy consumption, avoiding the pro-arrhythmic risk of traditional inotropes. Its additional mechanisms include opening of mitochondrial ATP-sensitive potassium channels (cardioprotection against ischemia-reperfusion injury), anti-inflammatory and anti-apoptotic effects, and nitric oxide-mediated coronary vasodilation — making it mechanistically distinct from dobutamine or milrinone in the cardio-oncology context. (Figure by authors, CC BY 4.0.)

Discussion

5-Fluorouracil cardiotoxicity is a recognized but underappreciated complication of fluoropyrimidine-based regimens, with cardiovascular event rates ranging from 0% to 34.6% depending on the population studied; severe events including cardiomyopathy occur in 0–2% of cases. The prevailing mechanism is thought to be coronary vasospasm (endothelium-dependent or smooth muscle-dependent), though direct cardiomyocyte toxicity via reactive oxygen species and ferroptosis pathways has also been proposed. The clinical signature — acute cardiomyopathy with markedly reduced LVEF within days of drug exposure in a patient with no prior cardiac history, with no angiographic evidence of obstructive coronary disease — points squarely at the drug. What makes this case instructive is the severity: an LVEF of 28% and pro-BNP exceeding 14,700 pg/mL are markers of profound acute failure that would typically warrant an MCS discussion, yet full recovery was achieved with a calcium sensitizer alone.

Levosimendan's appeal in this setting rests on its mechanism. Unlike dobutamine or milrinone, which increase intracellular calcium and myocardial oxygen demand, levosimendan enhances calcium sensitivity of troponin C — improving contractility without raising calcium load or generating arrhythmogenic signals. This is particularly relevant when the myocardium has already been directly injured by a cardiotoxic drug. The drug's additional anti-inflammatory, antioxidant, and anti-apoptotic properties may further limit ongoing injury. Clinically, the co-administration of norepinephrine to prevent levosimendan's vasodilatory hypotension is a practical management detail that allowed full dose titration in this hemodynamically fragile patient. Case-based literature on levosimendan for chemotherapy-induced cardiomyopathy remains limited, but the growing cardio-oncology evidence base suggests it deserves prospective evaluation, particularly for patients with fluoropyrimidine or anthracycline-induced cardiomyopathy who fail standard inotropic support.