IDH1/2mutations in acute myeloid leukemia patients and risk of coronary artery disease and cardiac dysfunction-a retrospective propensity score analysis

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to leukemia gene mutations and associates with an increased risk for coronary artery disease and poor prognosis in ischemic cardiomyopathy. Two recurrently mutated genes in CHIP and adult acute myeloid leukemia (AML) encode for isocitrate dehydrogenases 1 and 2 (IDH1andIDH2). Global expression of mutantIDH2in transgenic mice-induced dilated cardiomyopathy and muscular dystrophy. In this retrospective observational study, we investigated whether mutantIDH1/2predisposes to cardiovascular disease in AML patients. Among 363 AML patients,IDH1andIDH2mutations were detected in 26 (7.2%) and 39 patients (10.7%), respectively. MutantIDH1patients exhibited a significantly higher prevalence of coronary artery disease (26.1% vs. 6.4%,p = 0.002). Applying inverse probability-weighting analysis, patients withIDH1/2mutations had a higher risk for a declining cardiac function during AML treatment compared toIDH1/2wild type patients [left ventricular ejection fraction pretreatment compared to 10 months after diagnosis: 59.2% to 41.9% (p < 0.001) vs 58.5% to 55.4% (p = 0.27), respectively]. Mechanistically, RNA sequencing and immunostaining in hiPS-derived cardiomyocytes indicated that the oncometabolite R-2HG exacerbated doxorubicin mediated cardiotoxicity. Evaluation ofIDH1/2mutation status may therefore help identifying AML patients at risk for cardiovascular complications during cytotoxic treatment.

Automated summary

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with mutations in leukemia genes like IDH1 and IDH2, which may increase the risk of coronary artery disease in AML patients and lead to a decline in cardiac function during treatment. Mechanistically, the oncometabolite R-2HG exacerbates doxorubicin-induced cardiotoxicity. Evaluation of IDH1/2 mutation status could help identify AML patients at risk for cardiovascular complications during cytotoxic treatment.