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Cardiomyopathy due to Anthracyclines

Anthracycline administration is an important part of treatment for several malignancies, including lung and breast cancer, multiple myeloma, leukemia, and lymphoma. Doxorubicin, epirubicin, idarubicin, sabarubicin and valrubicin, while all potent agents, have the disadvantage of causing a cumulative dose-dependent cardiotoxicity, initially asymptomatic, but potentially irreversible in the end.


Presentation

Three types of anthracycline-induced cardiotoxicity have been described, each of them causing symptoms that depend on the nature of the pathological process. Acute or sub-acute cardiotoxic injury is rare, but it causes patient complaints in less than one week after the first dose has been administered. The individual experiences transient palpitations caused by electrophysiological abnormalities, fatigability- as an expression of underlying myocarditis, develops the clinical signs of pericarditis or those of frank acute left ventricular failure. Sinus tachycardia is frequent in this instance, but palpitations may be also caused by supraventricular, junctional or ventricular tachycardia. Atrial fibrillation and flutter are rare [1]. This type of acute cardiotoxicity is believed to be reversible [2]. Takotsubo stress cardiomyopathy can also be induced by treatment with anthracyclines [3].

Chronic progressive cardiotoxicity can have an early onset or a delayed one. The precocious type causes symptoms within one year of treatment. It has a persistent and progressive character, causing either chronic dilated cardiomyopathy or restrictive cardiomyopathy. The first form is more frequently encountered in adults, while the latter refers to children [4]. The late onset chronic progressive anthracycline cardiotoxicity becomes symptomatic in several years or decades after administration has been stopped. During this time, despite the absence of symptoms, the left ventricular performance gradually declines, making the need for careful monitoring obvious. As delayed heart failure symptoms set in, so may various types of arrhythmia [5]. Decompensation is precipitated by viral infections [6], pregnancy, weightlifting or surgery [7].

Doses of doxorubicin below 240 mg/m2, initially thought to be risk-free, are now known to induce a decline in left ventricular function and its subsequent symptoms [8].

Asymptomatic
  • This is why, even if the patient is asymptomatic, he or she must undergo periodical cardiology evaluations, that should include a clinical examination, an electrocardiogram, and an echocardiogram.[symptoma.com]
Heart Failure
  • The sooner the patient receives heart failure treatment, the better the prognosis is.[symptoma.com]
  • Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial — the Losartan Heart Failure Survival Study ELITE II. ‎[books.google.it]
  • KEYWORDS: Anthracycline; Cardiotoxicity; Chemotherapy; Heart failure[ncbi.nlm.nih.gov]
  • Biological variation of the natriuretic peptides and their role in monitoring patients with heart failure. Eur Heart J. 2004;6(3):355-8. Parthenakis FI, Patrianakos AP, Haritakis CN, Zacharis EA, Nyktari EG, Vardas PE.[revfinlay.sld.cu]
Left Ventricular Dysfunction
  • Other cases of left ventricular dysfunction, such as coronary artery disease must also be taken into consideration and properly analyzed. Stress studies may be appropriate before major procedures.[symptoma.com]

Workup

Anthracycline cardiotoxicity is generally thought to be dose dependent, but early toxicity, defined as acute or sub-acute injury occurs in predisposed individuals regardless of how small the administered dose is. Anthracycline-induced cardiomyopathy evolves with global systolic dysfunction and minimal left ventricular enlargement, accompanied by mild to moderate mitral insufficiency caused by the ventricular remodelation. The easiest way to diagnose these alterations is via echocardiography, a reproducible and widely available method. The systolic dysfunction is assessed by ejection fraction measurement. This can be performed in two manners: the classical, M-mode technique is subject to error if the normal left ventricular geometry is not preserved, and this is the case in patients with left ventricular enlargement. In cases where Simpson's method is applied, it is necessary to determine the end-diastolic and the end-systolic left ventricular volumes in the apical four chambers view (for monoplane Simpson method), and the same parameters in the apical two chambers view (for the biplane Simpson method). The biplane method is considered to be the most accurate, far superior to the M-mode or Teicholz method. Parietal dyssynchrony impairs all echocardiography determination methods, but it may be overruled by other methods, such as cardiac magnetic resonance imaging, cardiac computed tomography, and equilibrium radionuclide angiography. It is important to mention the fact that presence of anemia should be investigated due to the fact that the left ventricle ejection fraction can drop as much as 10% when the hemoglobin returns to normal [9].

Troponin I precociously detects myocardial damage. A rise to a level above 0.5 ng/ml 12-72 hours after treatment predicts a significant decrease of the systolic function 7 months after therapy [10] [11]. Furthermore, a persistent increase has the same significance [12].

Anthracycline-induced cardiotoxicity may demonstrate a genetic predisposition. Gene polymorphisms associated with increased patient sensitivity to anthracyclines refer to NAPD(H) oxidase and the doxorubicin efflux transporters MRP1and MRP2 [13]. Genome-wide studies of this aspect are yet to be conducted.

The electrocardiogram is another useful tool in anthracycline-induced cardiomyopathy. It may reveal abnormalities in 20- 30% of patients [1], including nonspecific ST and T wave changes and decreased QRS voltage in cases with associated pericarditis, QT interval prolongation or supraventricular, junctional or ventricular tachycardia. Late-onset arrhythmia and sudden cardiac death can occur even 15 years after anthracycline administration has been ceased [5].

Other cases of left ventricular dysfunction, such as coronary artery disease must also be taken into consideration and properly analyzed. Stress studies may be appropriate before major procedures.

Ejection Fraction Decreased
  • Furthermore, it seems that enalapril, precociously administered, as soon as myocardial injury has been highlighted by a rise of troponin I, is able to prevent left ventricular ejection fraction decrease.[symptoma.com]

Treatment

Cardiomyopathy due to anthracyclines does not have a specific treatment, but patients respond well to conventional heart failure medication, including digoxin, loop diuretics, and angiotensin-converting enzyme inhibitors, associated with beta-blockers. Carvedilol seems to be the most studied agent from this last category. When associated with enalapril, it seems to induce ejection fraction normalization in almost half of the patients [14]. The sooner the patient receives heart failure treatment, the better the prognosis is. Treatment should be started even if the individual does not have any complaints, but echocardiography reveals diminished left ventricular ejection fraction and it should necessarily include an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker [15]. Furthermore, it seems that enalapril, precociously administered, as soon as myocardial injury has been highlighted by a rise of troponin I, is able to prevent left ventricular ejection fraction decrease [16]. If tolerated, spironolactone can be added, as it has shown clinical benefit.

Ramipril [17] and metoprolol [18] can also be used, as they produce similar results. Heart transplantation is reserved for refractory cases, but it is only routinely performed in few medical centers. The procedure is usually performed in patients who have been disease-free for at least one year [19].

Some patients experience hypotension due to their oncologic disease or its treatment. It has been speculated that this group might benefit more from carvedilol administration, as this agent lowers blood pressure less than ramipril does and diminishes the inappropriate sinus tachycardia [20].

Prognosis

The prognosis of the cardiomyopathy due to anthracyclines is subject to debate. While some claim that it is irreversible, others have demonstrated complete recovery after treatment. However, the common opinion is that prevention is the best strategy and patients receiving anthracyclines should undergo regular cardiology consults. The overall prognosis seems to have improved due to modern therapy and to the fact that the minimum effective dose of anthracyclines is usually prescribed.

Etiology

The etiology of the cardiomyopathy due to anthracyclines is, of course, the use of anthracyclines, such as daunorubicin, doxorubicin. valrubicin, idarubicin, mitoxantrone, and epirubicin. The first drug in this family, daunorubicin, was discovered in the 1950’s [21]. During the next decade, it was proven effective in leukemia and lymphoma treatment [22]. Reports about heart failure following treatment were issued in the 1970's [23] [24].

Epidemiology

Different reports issue different numbers regarding the incidence of anthracycline-induced cardiomyopathy. Doxorubicin was reported to cause this condition in 2.2% of the patients by one study [24] and 5.1% of cases by another one [25]. The explanation for this difference resides in the fact that the first article only diagnosed heart failure based on clinical signs, while the second measured the left ventricle ejection fraction and found it decreased even in some asymptomatic cases. Further studies demonstrated that the greater the dose administered, the more likely the toxicity is to appear [26]. Even doxorubicin doses as low as 240 mg/m2 demonstrated cardiotoxic risk.

As many as 65% of childhood cancer survivors treated with doxorubicin can have echocardiography abnormalities regarding the ejection fraction, years after treatment was stopped [27]. They have a 2.4-fold higher risk of developing congestive heart failure compared to their peers that did not receive anthracyclines [28]. The risk increases to 5.2-fold when doses above 250 mg/m2 are used.

Epirubicin causes cardiac toxicity in 0.7% of patients [29]. Clinical signs of heart failure usually appear in 1 to 3 months after treatment was stopped, with limits varying between 9 and 192 days [30].

Sex distribution
Age distribution

Pathophysiology

Anthracyclines cause either one of two types of cardiotoxicity. Type I is irreversible and characterized by cardiomyocyte necrosis or apoptosis. Type II, on the other hand, is reversible, as the cells become dysfunctional, but are still viable. Long-term cardiotoxicity is considered to be type I. The mechanism of the cardiac injury involves free radicals. Doxorubicin is reduced by NADH dehydrogenase, giving birth to a semiquinone radical that reacts with molecular oxygen, forming the superoxide radical [31]. Reactive oxygen species are also formed via a Fenton reaction based on the doxorubicin-iron complex [32].

Other toxicity mechanisms have also been described, including cytochrome C release into the cytosol [33] and downregulation of the expression of the antiapoptotic proteins [34]. Furthermore, doxorubicin induces DNA double-strand breaks via topoisomerase-II (Top2) enzyme [35]. Finally, the last cardiomyopathy due to anthracyclines pathophysiology hypothesis involves dysregulation of cardiomyocyte autophagy [36].

Prevention

Prevention of anthracyclines induced cardiomyopathy relies on dose reduction and diminishing the oxidative stress. This is achieved by administering doxorubicin in a PEGylated liposomal form. This ensures selective uptake of the agent in malignant cells and reduces cardiotoxicity even if doses above 500 mg/m2 are needed [37]. Probucol is an antioxidant that has proven effective in animal models [38], as has carvedilol administration [39], as opposed to vitamin E. Dexrazoxane, an iron chelating agent, also prevents left ventricular ejection fraction decrease [40], as may enalapril [16].

The clinician must balance the risk of anthracycline toxicity and the therapeutic benefit. This is a difficult decision in cases where toxicity has already set in, but the patient needs to continue treatment for his malignancy. These patients should definitely receive cardioprotective agents, such as carvedilol or angiotensin-converting enzyme inhibitors. In cases where toxicity is not obvious, close monitoring is needed.

Mediastinal irradiation, young age (especially under 4 years old), female sex and arterial hypertension seem to represent risk factors for anthracycline cardiotoxicity, as toxic effects appear at lower doses in these instances. Therefore, these patients must benefit from even closer monitoring.

Summary

Anthracyclines are important therapeutic agents, but their use is limited by their cardiotoxic effect. Toxicity sets in within one week, within one year or many years after treatment, depending on the underlying pathophysiological process. Patients may be asymptomatic, may complain about fatigability and palpitations in the precocious form of the disease and gradually develop all signs and symptoms of chronic heart failure in progressive cases. All patients receiving anthracycline therapy should undergo cardiology evaluations before, during and after treatment, including an electrocardiogram and an echocardiogram. The latter method effectively detects left ventricular ejection fraction drop and accurately characterizes wall motion and other abnormalities. A precocious rise of troponin I levels predicts systolic dysfunction 7 months after therapy. Treatment implies standard heart failure therapy, but two therapeutic classes, beta-blockers (carvedilol in particular) and angiotensin-converting enzyme inhibitors should absolutely be administered. Prevention of the cardiomyopathy due to anthracyclines relies on carefully balancing the benefit of anthracyclines administration and the risk associated with their use in predisposed individuals and on overall dose reduction.

Patient Information

Anthracyclines are potent chemotherapeutic agents, but their use is associated with toxic effects. Some of the cells that the heart is made of, the cardiomyocytes suffer after being exposed to these agents, especially in predisposed individuals. Patients may have no complaints or symptoms including fatigability, palpitations, difficulty breathing or peripheral edema may set in after a variable amount of time. This is why, even if the patient is asymptomatic, he or she must undergo periodical cardiology evaluations, that should include a clinical examination, an electrocardiogram, and an echocardiogram. In some cases, more sophisticated imaging methods, such as cardiac magnetic resonance imaging, cardiac computed tomography, and equilibrium radionuclide angiography are deemed necessary. One increased blood test, troponin I, can predict heart failure 7 months after anthracycline exposure. Heart failure treatment should be initiated as soon as symptoms occur and in some cases even if the patient seems healthy, but his echocardiogram is abnormal. While some believe the damage to the heart is irreversible, others have demonstrated a significant improvement with therapy. In extreme cases, heart transplantation is feasible in certain medical centers.

References

Article

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Last updated: 2018-06-21 17:28