The aim of this consecutive cohort study was to evaluate the echocardiographic phenotype of ACD, establish what impact a delayed diagnosis had on the degree of LV dysfunction, LV dimensions and response to HF treatment. The key findings of this study are threefold: (1) the majority of patients presented with mild LV dysfunction without LV dilatation (2) the echocardiographic phenotype was not different in patients diagnosed with early or late ACD and (3) patients with an early ACD diagnosis and prompt initiation of HF treatment were more likely to have a (partial) recovery of LV function, compared to patients with a late ACD diagnosis.
In contrast to previous studies in which ACD is described as a toxic cause of DCM , we found that LV dilatation was present in only one-fifth of cases at diagnosis and only two patients developed LV dilatation during a median follow-up of 17.7 months. We believe that there are three major reasons for the absence of a DCM-like phenotype. Firstly, many patients received an early diagnosis of ACD due to serial echocardiographic screening at a cardio-oncology clinic. In the past, the diagnosis of ACD was often established upon the development of symptomatic HF, and subclinical changes in LV function were not detected. In these patients, prolonged activation of compensatory mechanisms, including the renin-angiotensin aldosterone system (RAAS), and subsequent LV remodeling, may have led to a more pronounced dilatation of the LV. However, in our study, dilatation was also not present in the majority of patients with a late ACD diagnosis. The second possible reason for the absence of abnormal dimensions could be related to the reduction of cumulative anthracycline dose over the last decades. While doxorubicin doses exceeding > 500 mg/m2 were commonly administered in the past , the maximum cumulative dose of this agent is nowadays restricted to 450 mg/m2 , with a median dose of 329 [200–329] mg/m2 in this study (n = 9 receiving ≥450 mg/m2). It is plausible that these dose restrictions have resulted in an overall milder ACD phenotype. Thirdly, in patients developing LV dysfunction with an LVEF < 45%, HF treatment was promptly initiated, aiming at suppression of RAAS to prevent adverse LV remodeling. The early detection of ACD has shown to be beneficial in one study, where patients with early initiation of therapy were more likely to respond to pharmacological treatment . To our knowledge, our study is the first to validate this time-dependent response to HF treatment. In conclusion, an earlier diagnosis, a restriction in the maximum cumulative anthracycline dose and the initiation of HF treatment might jointly have led to a hypokinetic non-dilated cardiomyopathy rather than DCM . Based upon the results of this study, monitoring of LV function in patients at risk for ACD is recommended to detect subclinical changes in LV function as soon as possible and thereby allow for early initiation of HF treatment in case ACD develops.
We did not find any echocardiographic differences in dimension and function between patients diagnosed early vs. late (Table 2). Furthermore, there were also no discrepancies in LV mass between the two groups. To date, a number of imaging studies have evaluated this parameter in ACD both by CMR [19,20,21] and echocardiography [22, 23]. Currently, CMR is considered as the gold standard for measurements of cardiac structure and volumes . With this technique, three studies found a decrease in LV mass [19,20,21], and an inverse correlation with the anthracycline dose . Furthermore, a lower LV mass was predictive of cardiovascular death, appropriate ICD therapy and HF hospitalization in a multivariate model . However, these findings are contradictory to echocardiographic studies which found an increase in LV mass [22, 23]. Armstrong et al. studied adults who were treated with anthracyclines during childhood. They found a reduced LV mass in nearly half of patients . Comparison of CMR with echocardiography performed within 48 h, revealed that echocardiography overestimated LVEF and LV mass and underestimates LV volumes. The absence of reduced LV masses in our study population could therefore be related to LV mass measurements with echocardiography.
In contrast to our hypothesis, our data does not support the progressive nature of ACD regarding cardiac remodeling. To date, longitudinal imaging studies in patients with ACD are scarce, with a small number of studies performed in pediatric  and adult cancer patients [22, 26]. Lipshultz et al. prospectively followed 115 survivors of childhood acute leukemia with serial echocardiograms during a median follow-up of 11.8 years . The LV contractility initially declined after doxorubicin containing chemotherapy, normalized the next 6 years and subsequently became significantly depressed > 12 years after the cancer diagnosis. In another prospective cohort study among 277 breast cancer patients treated with doxorubicin (36% in combination with trastuzumab) the LVEF decline was not progressive during a median follow-up of 2 years . In a study by Jones et al. in 143 patients that were followed for 2 years, none transitioned to more advanced HF stages . In our study only 5.5% of patients progressed to symptomatic HF. Nevertheless, the presence of asymptomatic LV dysfunction gives an increased risk of ultimately progressing to symptomatic HF. In a meta-analysis evaluating the risk in patients with systolic LV dysfunction due to various etiologies, the incidence of symptomatic HF was 8.4 (95% CI 4.0–12.8) per 100 person-years, compared to 1.04 (95% CI 0.0–2.2) per 100 person-years in the absence of LV dysfunction, equaling a relative risk of 4.6 (95% CI 2.2–9.8) . This meta-analysis illustrates the importance of implementing effective strategies in the pre-symptomatic stages to mitigate the progression rate to symptomatic HF. This progression might also be dependent on the development of other cardiac stressors, such as hypertension, valvular disease, CAD, or the presence of pathogenic variants in cardiomyopathy-associated genes [28, 29]. In the absence of these so called “second-hits”, it is possible that a considerable proportion of patients only develops mild LV dysfunction after anthracycline-containing chemotherapy, that remains stable for years. Larger observational cohort studies, preferably with long-term follow-up can shed more light on the natural course of this specific disease entity. Also, the outcomes of the TITAN-study, which compares intensive cardiac monitoring and -treatment to usual care, will be informative on the added value of early identification of ACD .
Our analysis was restricted to patients that visited the cardio-oncology outpatient clinic. Patients treated with potentially cardiotoxic cancer therapy prior to its launch currently receive cardiological follow-up to screen for long-term cardiovascular complications. It is possible that patients who developed a more severe ACD phenotype presented at the emergency care unit earlier and were never seen in an outpatient clinic setting and therefore were not included in our study. Also, patients deemed to be at low risk for ACD do not receive cardiac screening per protocol at our cardio-oncology service. This may overall lead to an underestimation of ACD in the population of cancer patients treated with anthracyclines.
Furthermore, the current study used patient information collected during standard clinical care. Albeit the follow-up of these patients is standardized to a great extent , there still was heterogeneity in the data. Even though current guidelines recommend to perform cardiac screening prior to treatment , many patients were referred after initiation of anthracycline-treatment, and therefore lacked cardiac baseline assessment. Subtle changes in LV dimensions and –volumes within patients could therefore have been overlooked. In addition, for patients that did not undergo an echocardiography at baseline, pre-existent impaired cardiac function could have been misclassified as ACD. Also, additional testing for other causes of impaired LV function, such as CAD, had not (yet) been performed in a number of patients, leaving uncertainty of the diagnosis of ACD. Nevertheless, this represents only a small subset of our cohort where, from a clinical point of view, ACD was very likely.
Biomarkers, such as troponin or BNP, are not routinely performed at our cardio-oncology clinic and were only available in a limited number of patients. We therefore were unable to include the outcomes of biomarkers in our analysis.