has been approved by the FDA as an oral drug for the treatment of Chronic
Myeloid Leukemia ( CML ), gastrointestinal stromal tumors (GISTs) and hypereosinophilic
syndrome. Although imatinib is well tolerated, the incidence of edema and
dyspnea are reported to be as high as 66 and 16%, respectively. Imatinib-induced cardiotoxicity is a very
uncommon adverse event <1% 1-11. A 53-year-old male with history of Chronic Myeloid Leukemia ( CML ) on Imatinib for the past 5 years. He presented with symptoms of exertional dyspnea, poor exercise performance, fatigue, and leg swellings. Chest X ray revealed cardiomegaly, and pulmonary edema. Electrocardiogram showed normal sinus rhythm, no ischemic changes. Cardiac enzymes were normal. 2D Echocardiogram showed ejection fraction EF of 35%, normal pulmonary systolic pressure, no wall motion abnormality, with normal valvular function .
In our case report, we highlight the association between Imatinib use and
congestive heart failure, which may need discontinuing the medication and
prompt treatment of congestive heart failure.
Congestive Heart Failure, Mitochondrial dysfunction, Chronic
is a revolutionary drug for the treatment of CML by targeting ABL; it
efficiently inhibits BCR-ABL+ CML cells, blocks phosphorylation and
induces apoptotic cell death
Myocardial tissue homeostasis depends
largely on mitochondrial function; therefore, impairment in mitochondrial
function eventually leads to cardiomyocyte and endothelial cell death and
consequent cardiovascular dysfunction. Several chemical compounds and drugs
have been known to alter cardiac mitochondrial function, which can account both
for the toxicological and pharmacological properties of these substances 17-23.
A 53-year-old male with history of
Chronic Myeloid Leukemia ( CML ) on
Imatinib for the past 5 years as maintenance therapy. He presented with
symptoms of exertional dyspnea,
paroxysmal nocturnal dyspnea, poor exercise performance, fatigue, and leg
signs: Blood pressure was 123/74 mmHg, pulse rate 96 beats/ min regular,
temperature 98.0 F ( 36.7 C ) Tympanic, respiratory rate 20, SpO2 94% on room
showed normal sinus rhythm, no ST, T wave changes.
radiograph showed evidence of cardiomegaly, and pulmonary edema.
Tow dimensional Echocardiogram showed ejection fraction EF of 35%, normal pulmonary systolic
pressure, otherwise unremarkable.
Labs: WBC 4,600 /microL, Hemoglobin Hgb 11.9 g/dl, HCT 34.7 %, MCV 83
fL, Platelets 210,000 /microL, INR 1.0, PTT 25s, Glucose 101 mg/dl, Urea 13
mg/dl, S. Creatinine 0.9 mg/dl, GFR 97 mL/min/1.73 m2 ,
Sodium 133 meq/L, Potassium 4.2 meq/L, S. Troponin I 0.01- 0.041– 0.01 ng/ml,
BNP 6450 pg/ml.
diagnosis of acute heart failure was made and imatinib discontinued. He was
prescribed comprehensive therapy including oxygen, diuretics and vasodilators according to the ACC/AHA guidelines for the diagnosis and management of
heart failure in adults. Patient was
sent home on Carvedilol 3.125 mg po BID,
Lisinopril 5 mg po daily, and Furosemide 40 mg po daily.
follow up after 3 months revealed patient’s symptoms and signs of heart failure
had resolved and findings of biochemical tests, chest X-ray film and
echocardiogram were all consistent with recovery, where repeat 2D
Echocardiogram showed EF of 55%.
Chronic myeloid leukemia (CML) is a
myeloproliferative disorder caused by an acquired mutation of hematopoietic
stem cells. This mutation results in a reciprocal translocation between
chromosomes 9 and 22 termed the Philadelphia chromosome (t9;22q34;q11) and
generates a novel fusion gene, BCR-ABL, which encodes tyrosine kinase. Imatinib
mesylate (Gleevec), a small-molecule inhibitor of multiple tyrosine kinases,
selectively prevents phosphorylation of BCR-ABL and inhibits downstream
signaling and growth of BCR-ABL–positive cells 3-9.
Cardiomyocytes utilize an enormous
amount of adenosine triphosphate (ATP), being in a constant energy-consuming
contractile state. To maintain constant ATP production, malfunctioning
mitochondria are constantly replaced by newly synthetized organelles by
processes involving mitochondrial biogenesis and replication and
autophagy/mitophagy . These processes work in a tightly regulated manner, with
mitochondrial fusion and fission allowing the dynamic formation and remodeling
of a reticulated mitochondrial network . Since mitochondria are responsible for
the production of ATP, agents that interfere with the physiological myocardial
mitochondrial function are expected to induce depletion of ATP pool.
Eventually, these processes may lead to subsequent myocardial dysfunction 12-19.
BNP is a cardiac neurohormone that is
secreted by membrane granules in the cardiac ventricles in response to
ventricular volume overload and pressure overload. BNP concentrations are
reflective of LV diastolic filling pressures and increased in patients with symptomatic LV
dysfunction. In the present case, the concentration of BNP was 6450 pg/mL,
reflecting deterioration in cardiac function and Systolic heart failure. After
withdrawal of imatinib, not only were the symptoms relieved, but also the BNP
concentration decreased significantly, which implied that systolic heart
failure in this patient was imatinib-related 7-13.
summary, imatinib therapy uncommonly causes heart failure and mainly occurs in
elderly patients with preexisting cardiovascular conditions. Our case
demonstrates imatinib induced cardiotoxicity in young patient with no
preexisting cardiovascular disease. We recommend that when patients develop
symptoms of congestive heart failure, should be monitored closely and treated
aggressively with standard medical therapy, including diuretics, and
vasodilators. In addition, imatinib mesylate should be discontinued or the
dosage reduced 17-21.
effect of imatinib on the heart is dose, time, and age dependent. This is clinically important as imatinib
treatment is life long and that cardiac damage can be cumulative, that
eventually causes congestive heart failure 6,7,8.
conclude that imatinib is an uncommon cause of cardiotoxicity with incidence
< 1%, and that the cardiovascular adverse events that occur are manageable when recognized and treated. Imatinib remains a potential cardiotoxin, and the cardiac consequences of its long-term use remain unknown. We recommend treatment of risk factors for cardiovascular disease in imatinib treated patients according the American Heart Association guidelines for the prevention and treatment of heart failure, along with frequent monitoring of signs/symptoms of heart failure.