A 52-year-old male, current heavy smoker, with no known comorbidities, was diagnosed with stage IV RAS wild-type adenocarcinoma of the rectum, with metastases in the liver and retroperitoneal lymph nodes in April 2022. About 2 weeks prior to the start of chemotherapy, he had been seen by a cardiologist due to asymptomatic ventricular extra systoles seen on routine ECG. At that time echocardiogram was unremarkable with LVEF of 65%; LV had normal end-diastolic diameter (EDD) and end-systolic diameter (ESD) (EDD/ESD-52 mm/33 mm). No disturbances were registered in segmental LV kinetics. LV diastolic function was preserved.
Upon admission to the Department of Oncology, he was started on FOLFOX-6 chemotherapy with planned administration of panitumumab, as per current guidelines. Panitumumab infusion was planned on day 3 of treatment, for technical reasons. He received 85 mg/m2 of oxaliplatin, followed by 400 mg/m2 leucovorin, 400 mg/m2 5-FU i.v.bolus and 2400 mg/m2 continuous infusion of 5-FU over 46 h. Approximately 24 h into the continuous 5-FU infusion he started complaining of pain in the epigastrium that propagated toward the lower third of the sternum and slight nausea, with no shortness of breath, palpitations or dizziness. Infusion of 5-FU was stopped immediately. At this time, panitumumab had not yet been administered.
Upon examination he was hypertensive at 180/100 mmHg, slightly tachycardic with HR of 115/min, afebrile. ECG initially showed peaked T waves with no ST changes (Figure 1A). Initial values of high sensitivity Troponin (Hs-cTn) were in the reference range.
Due to persisting symptoms and evolution of ECG changes he was transferred to cardiac intensive care unit (ICU).
Upon admission to the ICU, the patient continued to complain of pain in the epigastrium spread to the lower third of the sternum, nausea and sweating. Vital signs on admission showed a heart rate of 95 beats/min, arterial blood pressure 110/80 mmHg on both arms, respiration rate 20/min, arterial oxygen saturation 96%. During the examination, the patient was conscious, oriented without focal neurological outbursts and cyanosis. Signs of heart failure (gallop rhythm:present third heart sound) and symptoms of heart failure (dyspnea, tachypnea, orthopnea) with the appearance of late-inspiratory crackles in the lower lung fields were registered.
In the ECG, after 10 h from the initial ECG, an evolution was registered in relation to the previous finding (concave elevation of the ST segment in the inferior and lateral series of leads with frequent single VES) (Figure 1B) and at 15 h from the initial ECG ST elevation is registered in the same series of leads with the appearance of terminally negative T waves (Figure 1C).
On the first therapeutic day, an ECHO of the heart was performed, where an enlarged LV was registered (EDD/ESD LV- 65/51 mm), with the presence of segmental wall motion abnormalities of the LV. Akinesia of the apical and medial third of the left ventricle as well as the basal segment of the interventricular septum was registered, while the remaining segments of the LV were hypokinetic. No signs of left ventricular apex ballooning were observed. Estimated EF using Simpson's Biplane method was 15-20%. There were no signs of valve disease or pericardial effusion. In laboratory analyses, non-significant increase in Hs-cTnT values was registered (12...168...64..12 ng/L; ref. range < 14 ng/L). A slight increase in Hs-cTnT was not accompanied by elevated values of creatinine kinase (CK) (64...40...20 U/L; ref. range 0.0-200 U/L), MB fraction of CK (CK-MB) (2 U/ L; ref. range < 25 U/L) nor lactate dehydrogenase (LDH) [340...328 (ref. value 220-460 U/L)]. Although we knew that Hs-cTnt can be easily elevated in patients with AHF, such as our patient, we suspected that it was an acute coronary syndrome. There was no increase in inflammatory markers (CRP, leukocytes and procalcitonin) as well as nitrogen substances and D-dimer.
In view of the clinical picture, ECG changes as well as the findings of echocardiography, the patient underwent cardiac catheterization, which did not register angiographically significant narrowing of the large blood vessels of the heart. Coronary artery vasospasm was not visualized during coronary angiography. Considering the findings of the coronary angiography, a working diagnosis of myocardial infarction without obstruction of the blood vessels of the heart was made:MINOCA.
In order to establish/exclude the diagnosis, the patient underwent in the second act automated intravascular ultrasound (IVUS) system, pull/back interrogation (0.5 mm/s) of all three coronary arteries. IVUS showed normal trilaminar appearance of vessel wall and absence of atherosclerotic disease. In addition, signs of plaque rupture, plaque erosion or thrombus were not found in either of all three coronary arteries (Figure 2).
Medical treatment continued (coronary vasodilators, calcium channel blockers, ACE- inhibitors, beta-blockers, low-molecular-weight heparin, diuretics with the use of antiarrhythmic:amiodarone) in the ICU, where he was monitored all the time. Rapid evolutionary changes on daily basis were still registered in the ECG, and on the 2nd day of therapy negative T waves were registered in the inferior and lateral leads (Figure 1D) while, on the 5th day of therapy, a normal ECG was registered (Figure 1E).
During the next 7 days, control echocardiographic examinations were performed on several occasions. Given that we still did not have a clear diagnosis, in order to eliminate the differential diagnostic dilemma between myocardial infarction without changes in the blood vessels of the heart (MINOCA) and toxic cardiomyopathy caused by 5-FU, the patient underwent CMR. It was performed on the seventh therapeutic day from the onset of symptoms according to ESC recommendations. Cardio magnetic resonance should have considered the presence of scar in the endocardium/myocardium, the presence of micro- vascular obstructions, the presence of hemorrhage in the myocardium, myocardial edema and the detection of the so-called "gray zone":the zone at risk or to prove signs of the presence of dilated cardiomyopathy caused by 5-FU.
Examination of the heart was performed in standard planes using functional True FISP sequences and TSE morphological sequences in three planes without contrast medium application, as well as after contrast application with IR sequence and T1 and T2 maps using Modified Look Locker inversion recovery (MOLLI) sequence. Reduced LV systolic function was registered (EF 40%); LV was dilated (EDD/ESD- 62/47 mm), normal wall thickness, enlarged EDV (202 ml; ref 77-195 ml) and ESV (121 ml; ref 19-72 ml), overall hypo contractile without segmental LV wall abnormalities.
Post-contrast, a smaller linear zone of late gadolinium accumulation (LGE) was observed:septal fibrosis intramyocardially in the basal part of the septum with inhomogeneous opacification of the entire myocardium, primarily as part of the post-therapeutically altered myocardium (cardio toxicity). No signs of localized edema or necrosis of LV were registered. According to radiologists and CMR findings, changes in the myocardium first correspond to changes in cardiotoxicity (Figure 3).
During hospitalization, a drop in TnT was registered in the laboratory with the normalization of natriuretic peptides.
Transthoracic echocardiography (TTE) on the fifth day of admission revealed an enlarged LV (EDV 182 ml, ESV 113 ml), severely hypokinetic, with depressed EF (30%) and spontaneous contrast within the cavity. Global longitudinal function was significantly reduced (GLS-9.5%) with prominent mechanical dispersion (PSD 80.5 ms), detected by 2D speckle tracking echocardiography.
Thirteen days after, TTE confirmed the presence of enlarged LV (EDV 168 ml, ESV 71 ml), but with significantly better LV EF (58%), improved global longitudinal function (-17.6%), and significantly more synergic intraventricular contractions (PSD 44.6 ms) (Figure 4).
The patient was discharged home in good general condition. Frequent check-ups by a cardiologist are advised. Further oncological treatment was advised based on the opinion of the cardiology-oncology council (Supplementary Figure 1).