Discussion

Acute anthracycline-cardiotoxicity affects less than 1% of patients and is manifested by paroxysmal arrhythmia, pericardial exudate, left ventricular dysfunction, and episodically sudden cardiac death and can be fatal. ^{Reference Sadurska7}

Our patient developed acute cardiotoxicity post-second dose of daunorubicin (cumulative dose of 120 mg/m²). Although cardiomyopathy correlates strongly with a cumulative dose of anthracyclines; lower doses (<300 mg/m²) have also been implicated. ^{Reference Fraschini, Galbiati and Capra8} There is probably no completely safe dose, and even the lowest dose can induce severe cardiotoxicity, suggesting an important role of individual susceptibility to anthracyclines. ^{Reference Sadurska7,Reference Kremer, van der Pal and Offringa9}

Genetic variation may contribute to individual susceptibility. ^{Reference Chow, Leger and Bhatt10,Reference Chow, Antal, Constine and Gardner11} The RARG S427L variant (rs2229774) is highly associated with paediatric patients. If validated, genetic predictors of ACT could be incorporated as part of clinical risk predictors and screening algorithms. ^{Reference Chow, Leger and Bhatt10} Further independent studies are needed to confirm these findings in a cohort of patients with AML.

In our patient, notable risk factors included very young age, uncontrolled hypertension, and sepsis contributing to the acute cardiac decompensation, aggravating the cardiotoxicity.

Very young age (<4 years) at diagnosis and treatment with anthracycline-based therapy has been correlated with increased risk of cardiac disease. ^{Reference Kremer, van der Pal and Offringa9,Reference Blanco, Sun and Landier Chen12} Expert panels recommend close monitoring for young patients who receive anthracyclines. ^{Reference Rathe, Carlsen and Oxhøj13,Reference Fulbright14}

It is known that cardiotoxicity may be induced or increased by risk factors for cardiovascular diseases with a higher risk for hypertension when compared to other factors. ^{Reference Sadurska7,Reference Vyskočil, Petráková and Jelínek15} The combination of exposure to anthracyclines and hypertension genetic susceptibility loci puts this subgroup of individuals at greater risk of developing cardiotoxicity. ^{Reference Hildebrandt, Monica and Wu16}

Patients with AML have a higher sepsis incidence. ^{Reference Malik, Cardenas-Turanzas and Gaeta17} Sepsis-induced myocardial dysfunction (SIMD) is considered to be a major risk associated with sepsis. ^{Reference Vallabhajosyula, Jentzer and Geske18} SIMD could further contribute to the severity of cardiac dysfunction after anthracycline exposure.

Markers of necrosis as T-troponin, I-troponin, and CKMB are elevated very early after the first administration of anthracyclines, ^{Reference Sadurska7} and were noted in our patient. In nearly 50% of children receiving moderate dose anthracyclines, subclinical troponin elevations related to myocardial injury has been seen. ^{Reference Lipshultz, Miller and Scully19}

Besides treatment of the underlying sepsis, prompt identification and treatment of cardiac failure and hypertension with discontinuation of further anthracycline exposure contributed to complete recovery in our patient. Treatments included diuresis, afterload reduction, beta-adrenoceptor antagonists, and improving myocardial contractility.

The Scottish Intercollegiate Guidelines Network (SIGN) has developed a long-term follow-up of survivors of childhood cancer guidelines. They recommend echocardiograms at regular intervals during treatment with anthracyclines and every 3 years thereafter in patients who have received a modest dose. ^{Reference Fulbright14}