Left Ventricular Ejection Fraction and Cardiotoxicity: Is Our Ear Really to the Ground?

Abstract

The cardiotoxicity of anthracyclines has been studied extensively, yet many uncertainties persist. A vast number of reports address not only the clinical features of anthracycline-related cardiac toxicity, but also mechanistic considerations, ultrastructural changes, risk factors, prevention, treatment options, and, more recently, interactions with other potentially cardiotoxic agents. Despite extensive information, the ability to make firm conclusions about the overall prognosis and management of patients who have been exposed to anthracyclines is problematic. There are several reasons for the ongoing interest in treatment-related cardiotoxicity: (1) anthracyclines, even after three decades, continue to play a prominent role in the treatment of a wide variety of both hematologic and solid tumors; (2) cardiotoxicity can be a devastating and sometimes fatal event; (3) given that the purported mechanisms for oncologic effect and cardiotoxicity are different in the case of anthracyclines but conceptually linked in the case of trastuzumab, it remains intriguing to attempt to maintain oncologic benefits while mitigating the potential devastation of cardiotoxicity; and (4) the effect of anthracycline on the heart is a cumulative dose-related phenomenon, making this entity more predictable than some other forms of cancer treatment-related cardiotoxicity. It is now well established that anthracycline cardiotoxicity is a cumulative dose-related effect, suggesting that each administration constitutes additive or sequential damage. Once damage has progressed beyond a threshold level, myocyte injury is probably irreversible and additional exposure constitutes added stress and further damage. The heart, however, has substantial reserves, making it virtually impossible to appreciate subclinical damage with the usual methods employed to evaluate these patients. These are all facts regarding anthracyclines that have been appreciated for decades. So why, then, does this subject remain so much in the forefront? Why are there still enigmas and confusion regarding anthracycline cardiotoxicity? The answers to these questions, at least in part, are related to the broad group of newer agents often administered in combination with anthracyclines that have resulted in novel interactions that are now being investigated and only partially understood. Many recent examples of cancer therapy are highly influenced by cardiotoxicity, and certainly cardiac concerns may dictate future choices. The enigmas and confusion surrounding anthracyclines are, to a large extent, related to inherent weaknesses in how we define and measure cardiotoxicity. Both in the management of individual patients and in virtually all of the clinical trials that have considered cardiotoxicity, the predominant parameter for cardiac dysfunction has been an abnormality or a serial decrease in left ventricular (LV) contractility. This is determined principally by estimating the chamber dimensions or volume and calculating the left ventricular ejection fraction (LVEF). The measurements are obtained by either cardiac ultrasound or nuclear imaging techniques. The derived value is compared with institutional norms, or in the case of follow-up studies, with the patient’s previous, pretreatment, or serial determinations. Decreases in LVEF usually are deemed to be related to the offending agent and, equally problematic, unchanged values are often equated to a lack of cardiotoxicity. Neither of these assumptions regarding LVEF is necessarily valid. It is not adequately appreciated that the normal heart has tremendous recruitable contractile ability, and that for the LV to exhibit a decrease in ejection fraction (EF), the myocardium must have undergone sufficient damage so as to exceed its ability to compensate. Thus, a decreased EF after treatment is a marker for advanced myocyte damage; it is an imperfect marker that is influenced by nonanthracycline cardiac stressors and volume status on one hand, and significant interpretative variation on the other. There is convincing evidence that myocyte damage occurs with anthracyclines at much lower cumulative dosages than can be appreciated by declines in the LVEF values. The most compelling is that cardiac biopsy changes occur at cumulative dosages far below those usually associated with EF decreases. Anthracycline damage may well start at the time of initial exposure in susceptible patients, and each subsequent dose represents an incremental stress. Considerable efforts have been expended in identifying risk factors for anthracycline toxicity and in seeking ways to protect the myocardium from anthracycline damage. These toxicity risk factors can be thought of as stressors that impair myocardial reserve, or additive factors that augment the effects of prior damage, or both. These include advanced age and prior cardiac disease, such as hypertension, on which initial LV myocardial damage builds. As a result, the threshold for clinicall