Mechanism of anthracycline cardiotoxicity

Anthracyclines have several modes of action to interfere with the replication of rapidly proliferating cancer cells. By intercalating with DNA base pairs and stabilising the Topoisomerase (Top) 2α complex after DNA cleavage, they increase DNA breaks and prevent DNA and RNA synthesis.12 Mechanistic understanding of anthracycline cardiomyocyte injury has focused on increased reactive oxygen species (ROS) formation and targeting of Top 2β in cardiomyocytes (figure 1). Iron accumulation within the mitochondria is associated with futile redox cycling and increased ROS production.13 ROS production is harmful but it is uncertain to what degree it is a cause or consequence of anthracycline-mediated cell injury. Inhibition of Top 2β, which is active in quiescent non-proliferating cells including cardiomyocytes, is now thought to be the key mediator of anthracycline-induced cardiotoxicity.14 Inhibition of Top 2β anthracycline in cardiomyocytes causes double-stranded DNA breaks. This is required for activation of the p53-mediated apoptotic cell death pathway and interferes with mitochondrial biogenesis.14 Mice embryonic fibroblasts with the Top 2β deletion are resistant to doxorubicin toxicity15 and conditional knockout mice with the cardiac Top 2β deletion show fewer double-stranded breaks, no decline in LVEF and less mitochondrial dysfunction following doxorubicin treatment.14 The reader is referred to recent reviews for more detailed discussion on the mechanisms of anthracycline cardiotoxicity.16 17

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Figure 1

Mechanism of anthracycline-mediated cell injury and death in cancer cells and cardiomyocytes.  The therapeutic effect of anthracyclines against cancer cells is mediated through inhibition of Top 2α. In cardiomyocytes, Top 2β is inhibited. Top 2 inhibition in both cell types causes accumulation of double-stranded DNA breaks and mitochondrial dysfunction leading to activation of cell death pathways and accumulation of ROS. Early cardiac injury can be detected through quantification of circulating cTnI. The protective activity of DRZ against anthracycline cardiotoxicity is now thought to be largely mediated through inhibition of anthracycline binding to Top 2β. cTnI, cardiac troponin I; DRZ, dexrazoxane; LV, left ventricular; ROS, reactive oxygen species.

Risk markers for anthracycline cardiotoxicity

In addition to cumulative dose, female sex, African-American ancestry, age >65 years or <18 years, renal failure and concomitant exposure of the heart to radiation therapy increase the risk of cardiotoxicity. Pre-existing cardiac diseases associated with myocardial strain including hypertension and valvular disease also increase the risk of heart failure.4

Genetic factors determine individual susceptibility to anthracycline cardiotoxicity. Conditions that increase tissue iron concentration would be expected to enhance cardiotoxicity given the role of anthracycline–iron complexes. Hereditary haemachromatosis is a genetic condition associated with tissue iron overload, and carriers of the haemochromatosis C282Y HFE gene mutation exhibit increased susceptibility to cardiotoxicity.18 Genetic manipulation of anthracycline metabolism and the production of secondary metabolites influence cardiotoxicity. Mice with cardiac-specific overexpression of type 3 carbonyl reductase (CBR3) have increased production of secondary metabolites in response to doxorubicin with consequent rapid onset cardiomyopathy.19 By contrast, deletion of type 1 carbonyl reductase (CBR1) reduces alcohol metabolite production and susceptibility to cardiotoxicity.20 Elevated expression of CBR1 may be responsible for the higher rates of heart failure in anthracycline-treated patients with Down’s syndrome.21 Childhood cancer survivors who were homozygous for a gain-of-function CBR3 allele were more likely to have developed anthracycline cardiotoxicity in one retrospective study.22

Vejpongsa et al proposed that concentrations of Top 2β in peripheral blood leucocytes could be used as a surrogate of cardiac expression and a marker of susceptibility to anthracycline cardiotoxicity. In a small pilot study, patients with low Top 2β concentrations were more resistant to anthracycline cardiotoxicity.23 More recently, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cultured from patients receiving anthracycline chemotherapy were found to mirror the patient-specific sensitivity to cardiotoxicity.24 The hiPSC-CMs from patients who developed LVEF depression exhibited increased cell death and ROS production following in vitro doxorubicin challenge. These findings have to be confirmed in prospective work but illustrate the potential to make precise recommendations about avoiding or titrating anthracycline dosing in susceptible patients.

LVEF and global longitudinal strain

Monitoring change in LVEF remains the basis for identifying cardiotoxicity. The early literature on anthracycline toxicity was informed by radionuclide multigated blood pool imaging scans. This modality is still used widely in UK cancer centres being both reproducible and relatively inexpensive. Echocardiography and cardiac MRI avoid radiation exposure and have the advantage of providing additional information on cardiac structure and function. A recent consensus paper from the ESC proposed a definition of chemotherapy-related cardiotoxicity as an LVEF decrease of >10 percentage points from baseline to a value <53% on repeat confirmatory echocardiographic imaging.25 Current protocols are guided by expert consensus and typically recommend quantification of LVEF prior to starting anthracycline and following completion of chemotherapy with additional on-therapy measurement for patients receiving cumulative doses >200 mg/m² of doxorubicin.4 Baseline LV dysfunction is a strong marker for developing heart failure complications with anthracycline and may be detected more commonly in elderly comorbid patients and those who have received previous cardiotoxic regimes. Postanthracycline LVEF measurement is particularly important in patients with breast cancer who go on to receive trastuzumab, a monoclonal antibody targeting the HER2 epidermal growth receptor which is highly expressed in 15%–20% of breast cancers. Trastuzumab improves survival but in an early study was associated with cardiac dysfunction in 27% and clinical heart failure in 16% of patients receiving prior anthracycline.26 Delaying the initiation of trastuzumab reduced the incidence of systolic dysfunction (7%) and heart failure (0.6%) supporting the concept that delay avoids a period following anthracycline chemotherapy when the myocardium is more vulnerable.27

The development of systolic dysfunction following chemotherapy represents established heart muscle injury with the concomitant risk of progression to clinical congestive cardiac failure. Monitoring LVEF change is therefore a strategy limited to identifying affected patients who may be targeted with subsequent less cardiotoxic regimes and be eligible for heart failure therapy. Advanced imaging protocols and cardiac biomarkers have been investigated to find early on-treatment markers of anthracycline cardiotoxicity that anticipate the development of LVEF fall and heart failure. Global systolic longitudinal myocardial strain (GLS) on echocardiography has emerged as a reproducible indicator of early anthracycline-related myocardial dysfunction and future reduction in LVEF.28 Changes in myocardial velocity and longitudinal strain can be recorded immediately after anthracycline infusion in children.29 A fall in GLS of 15% compared with baseline measurement is considered pathological and an early injury marker which is predictive LV systolic dysfunction.25

Cardiac biomarkers

Evidence of cardiomyocyte injury and death including myofibrillar loss and vacuolisation on endomyocardial biopsy can be seen during therapy with cumulative doses below 200 mg/m².30 The correlation between biopsy grade and LVEF was poor suggesting that cellular-structural changes detectable immediately during therapy precede development of LV dysfunction. Circulating cardiac troponin and B-type natriuretic peptide have been investigated as markers of early myocardial injury. B-type natriuretic peptide is established as a reliable marker of decompensated heart failure and may have a role in the later surveillance of cancer survivors particularly where dyspnoea is a presenting symptom. Cardiac troponin I (cTnI) and cardiac troponin T have shown promise as indicators of muscle injury prior to the onset of LV dysfunction.

Cardinale et al stratified patients receiving anthracycline-containing high-dose chemotherapy regimes according to whether they exhibited increased cTnI concentrations defined by a contemporary assay as >80 ng/L.31Patients were categorised according to whether they had an early on-therapy elevation, late elevation 1 month postchemotherapy or both early and late elevations in cTnI concentration. Of 703 patients, 70% had no early or late elevation in cTnI concentration and the corresponding incidence of cardiotoxicity was low (1%). In the remaining 208 patients, the incidence of cardiac events was 51%. Patients with persistent early and late cTnI concentration increases were at highest risk.

High-sensitivity cTnI (hs cTnI) blood testing allows accurate quantification of circulating cTnI in most healthy people. Application of hs cTnI testing doubles the diagnosis of myocardial infarction in women with chest pain by defining a lower gender-specific reference range.32 Initial studies with hs cTnI monitoring in anthracycline-treated patients have shown promise.28 33 A combination of GLS measurement and hs cTnI testing had a 93% sensitivity and 91% negative predictive value for future cardiotoxicity in 81 patients with breast cancer receiving anthracycline chemotherapy followed by trastuzumab.28 This study used limited cTnI measurements at baseline, 3 months after completion of anthracycline therapy and three monthly until completion of trastuzumab therapy. The optimal timing of cardiotoxicity surveillance using cTnI measurement has not been defined and we have observed cumulative increases in cTnI concentrations with hs cTnI testing following sequential cycles of anthracycline in patients with breast cancer (Henriksen et al unpublished data). It is likely that small changes following the first cycles of anthracycline hold valuable predictive information.

Evidence is lacking with respect to how changes in cTnI concentration profiles and advanced measures of cardiac function such as GLS should be used to inform patient care. Despite this, many centres have adopted these measurements into anthracycline monitoring protocols and the European Society of Medical Oncology has published guidance for cTnI monitoring in patients exposed to anthracycline.34 The ongoing UK multicentre Cardiac CARE study (ISRCTN24439460) will stratify anthracycline-treated patients according to on-therapy hs cTnI concentration profiles. Patients exhibiting high-risk profiles will be randomised to cardioprotection therapy with candesartan and carvedilol to examine whether LVEF decline can be prevented.

Anthracycline derivatives and infusion protocols

Reducing the cumulative anthracycline dose limits cardiotoxicity and contemporary treatment protocols use high-dose regimes (>400 mg/m²) less frequently for this reason. Ratios for dose conversion between anthracycline derivatives are based on equivalent haematological toxicity.35 A correlation between haematological and cardiac toxicity is assumed but difficult to prove. There is some evidence to indicate lower rates of heart failure in epirubicin versus doxorubicin-treated patients with no difference in anti-cancer response. A Cochrane systematic review concluded that there was insufficient evidence to indicate clinically important differences in cardiotoxicity between anthracycline derivatives at equivalent tumoricidal doses.36 A subsequent analysis of almost 16 000 childhood cancer survivors found that daunorubicin was associated with less cardiotoxicity than doxorubicin.37 Continuous infusion rather than bolus administration is associated with lower cardiac concentrations in mice38 and less cardiotoxicity in patients with adult sarcoma and lymphoma39 but not in children with acute lymphoblastic leukaemia.18 Liposomal encapsulation of anthracyclines modifies tissue distribution without compromising tumoricidal efficacy.40 Differences between vessel permeability in the myocardium with tight capillary junctions and fragile cancer vasculature are thought to result in preferential uptake within cancer tissue.40 Liposomal encapsulated doxorubicin is associated with lower rates of clinical heart failure and subclinical changes in LV function.36 It is expensive and within the USA its use is restricted to ovarian cancer, AIDS-related Kaposi’s sarcoma and multiple myeloma after failure of at least one initial treatment.16

Dexrazoxane

Dexrazoxane (DRZ) has proven protective activity against anthracycline cardiotoxicity by minimising or completely preventing LVEF fall and reducing cardiac marker release.36 41 DRZ is taken up rapidly by the myocardium following infusion and competes with ATP-binding sites on Top 2β. DRZ binding to Top 2β is now thought to be the main mechanism of protective action by producing a configuration change which prevents complex formation with anthracycline and in so doing reduces cardiotoxicity.15 42 Concerns about mitigating the anti-tumoricidal activity of anthracyclines and a signal for increased secondary malignancies in childhood lymphoma and leukaemia following DRZ use43 44 have led to a recommendation for restricted use in adults with metastatic breast cancer receiving higher cumulative anthracycline dose. Recent reviews have questioned the evidence for secondary malignancies following DRZ and have called for a review of the guidelines to recommend more widespread application.16 17 A reappraisal of early data together with further analysis of outcomes from DRZ-treated patients <18 years old has led to an extended indication in paediatric patients receiving cumulative doses >300 mg/m².45

Angiotensin inhibition and β-blockade for treatment and prevention of cardiotoxicity: heart failure and asymptomatic decline in LVEF

Patients developing heart failure during or following anthracycline treatment should be treated according to guidelines from the European Society of Cardiology. Involvement of a cardio-oncologist specialist is recommended when heart failure or significant decline of LVEF is noted during chemotherapy as careful decision making is required with respect to further exposure to cardiotoxic cancer treatment. Depending on the gain from further cancer therapy, it is sometimes possible to continue treatment with the support of ACE inhibition (ACEi) and β-blockade. Liposomal anthracycline or DRZ may also be considered in this setting if available.4

Patients who develop asymptomatic decline in LVEF reaching criteria for cardiotoxicity should be considered for guideline-based heart failure treatment either with ACEi/angiotensin receptor blockade (ARB) alone or in combination with β-blockade.4 Of 226 patients who developed cardiotoxicity following anthracycline-based chemotherapy and received treatment with enalapril or enalapril and β-blocker in combination, 11% exhibited complete recovery of LVEF, 18% had no recovery and the remainder exhibited partial LVEF recovery to baseline over a period of 5-year echocardiographic follow-up.11 Early initiation within 6 months of anthracycline therapy and combined enalapril and carvedilol treatment were associated with greater LVEF recovery and a return to baseline in 42% of patients.46 These non-randomised observational data lack a control group but do illustrate the potential for recovery over time from anthracycline toxicity.

Primary prevention with β-blockade, ACEi and ARBs

β-Blockade, ACEi and ARBs have been evaluated in randomised controlled trials for prevention of anthracycline-induced cardiotoxicity (table 2). The treatment approach in most primary prevention studies involves administering cardioprotective medication to all anthracycline-treated patients. This ensures that benefits from early cardioprotection are realised but necessitates overtreatment in the sense that only a minority of patients will develop cardiotoxicity. A further consequence of non-selective treatment is the dilution of effect from cardioprotection which may be missed in small studies. The recent Prevention of cardiac dysfunction during adjuvant  breast cancer therapy (PRADA) study was placebo controlled and used cardiac MRI to quantify LVEF change in patients with breast cancer.47 Candesartan initiated prior to anthracyline chemotherapy was associated with protection against early decline in LVEF.

However, the overall LVEF % point fall in the placebo group was only 2.6. PRADA randomised 130 patients and illustrates the challenge of identifying treatment effect with non-selective randomization in a contemporary breast cancer population receiving lower cumulative anthracycline doses (56% received <300 mg/m²). Cardinale’s group randomised 114 patients with an early cTnI concentration increase within 72 hours of chemotherapy to enalapril or placebo. There was no change in LVEF in enalapril-treated patients at baseline versus 12 months (LVEF% mean±SD; 61.9±2.9 vs 62.4±3.5) whereas control untreated subjects had significant LVEF decline (62.8±3.4 vs 48.3±9.3).48

Smaller randomised trials with carvedilol,49 nebivolol50 and carvedilol and enalapril in combination51 have demonstrated similar protection from LVEF decline following anthracycline compared with untreated patients. Information about the durability of treatment effect is limited owing to short (<6 months) follow-up in these studies. Most primary prevention studies have investigated either β-blockade or ACEi/ARB rather than combined therapy. Arguably, the latter is the logical approach if the goal is to maximise cardioprotection by transferring the established additive effect that combination therapy has in the setting of heart failure with systolic dysfunction.

The need to better understand the relationship between LVEF decline and late development of heart failure, in anthracycline-treated patients, is illustrated by two studies with seemingly conflicting results. Patients with lymphoma receiving doxorubicin and randomised to either metoprolol or enalapril had no difference in LVEF following a median 31-month follow-up compared with untreated control patients.52 By contrast, a retrospective evaluation of new symptomatic heart failure in 920 anthracycline-treated patients with breast cancer found that incidental β-blocker prescription was associated with reduced heart failure incidence over a median follow-up period of 38 months (HR 0.2; 95% CI 0.1 to 0.7).53 Ongoing studies (table 3) will help better define the primary prevention role of these medications. Key questions include (1) how long ACEi and β-blockers should be continued following LVEF recovery and (2) to what degree these medications prevent future heart failure presentations.

Primary prevention with statins

Statin administration is associated with protection from anthracycline cardiotoxicity in animal models. The preclinical evidence and possible mechanism involving modulation of Rho GTPase has been the subject of a recent detailed review.54 Incidental statin prescription was linked with lower incident heart failure in anthracycline-treated patients with breast cancer in a retrospective analysis.55 Further prospective randomised studies are needed to understand whether this is a statin-mediated effect or a result of concomitant prescription of other cardioprotective medications including β-blockers and ACEi.