In the current study, we showed that: 1) new onset DD or worsening of baseline diastolic function are not uncommon after the administration of potentially cardiotoxic chemotherapy; 2) DD occurs early post-chemotherapy before notable changes in EF or GLS are seen; 3) anthracyclines and TKI are associated with increased risk for worsening of DD; 4) patients on ACEi/ARB are less likely to develop early diastolic dysfunction and those on beta-blockers more likely to have improvement of DD; 5) old age and obesity are independent predictors of worsening diastolic function; and 6) none of the patients younger than 50 years developed worsening of diastolic function.
Anthracyclines and monoclonal antibodies based TKI among others have been associated with cardiomyopathy, which may result in heart failure symptoms if undetected or left untreated [5
]. Routine echocardiography prior to and after administration of this regimen has become standard of care. While EF is one of the markers of systolic function, early cardiomyopathy occurs before a visual drop in EF is seen or reported [9
]. Global longitudinal strain with speckle tracking imaging is a more sensitive marker of systolic function and detects subtle change, offering additive value to traditional parameters such as EF [9
]. The role of diastolic parameters as markers for early cardiomyopathy was evaluated several years ago in small studies, and more recently in others [11
]. Indeed, a recent study showed that worsening of diastolic parameters translated into subsequent worsening of systolic function and were indeed a manifestation of chemotherapy-induced cardiotoxicity [15
]. These agents often result in impaired heart relaxation, decreased compliance and elevated filling pressure, hence DD. With the introduction of tissue Doppler imaging, Di Lisi et al. showed a decrease in e’ following chemotherapy [14
Nagelkerke R Square 0.44. ACEi: Angiotensin Converting Enzyme Inhibitors; ARB: Angiotensin Receptor Blocker
In the current study, 17% of patients had worsening of diastolic function within 3 months post-chemotherapy. We have previously shown that diastolic function is indeed dynamic and up to 16% of outpatients may have worsening after a mean follow-up over 1 year; however these patients were not receiving chemotherapy which may explain the faster rate of decline in diastolic function in our cohort. The clinical significance of worsening of diastolic function has been previously established as an independent predictor of new onset heart failure and all-cause mortality and that it bears the same prognosis as worsening of systolic function [22
]. Whether this drop in diastolic function translates into heart failure symptoms needs to be validated on follow-up and in larger studies. It is well accepted that a visual drop in EF is a late manifestation of cardiomyopathy [9
]. The fact that a significant percentage of patients had a drop in diastolic function without any change in EF or GLS underlines the importance to DD as early marker of disease. Although GLS has been shown to be a sensitive marker of early cardiomyopathy, the relatively low number of patients that had GLS measured and recorded is perhaps one of the reasons why no statsitically significant change was detected. Furthermore, most patients with DD had mild relaxation abnormality which is not a surprise given the relatively low cardiovascular co-morbidities of the cohort. However, even grade I DD is associated with increased all-cuase mortality after adjusting for traditional cardiac risk factors, and therefore should not be taken for granted [24
The role of cardio protective medications in patients receiving chemotherapy has been established in several studies. In patients with early manifestation of cardio toxicity, ACEi/ARB and beta blockers have shown promising results in reversing cardiomyopathy and restoring normal systolic function [25
]. An interesting finding of our study is that patients receiving ACEi/ARB for blood pressure control prior to initiation of chemotherapy and throughout its course were less likely to develop worsening of DD. It is interesting to consider the potential mechanism for this finding. Recent studies showed that renin-angiotensin system activation was associated with c-Src up-regulation, Connexin-43 (Cx43) loss, reduced myocyte coupling, and arrhythmia, while ACEi increased Cx53, prevented left ventricular remodelling, and reduced concentrations of circulating angiotensin II and noradrenaline [29
]. On the other hand, administration of beta blockers was associated with improvement in diastolic function. This of course is hypothesis generating at best and needs to be evaluated prospectively in large clinical trials. Whether the initiation of such cardio-protective medications in high risk patients (age >50 years, high body mass index, receiving anthracyclines or TKI) at the beginning of the chemotherapy regimen is indeed associated with lower risk of cardiomyopathy (diastolic and systolic) and whether it translated clinically into lower chance of heart failure and cardiovascular death deserves future investigation. Also, until further large clinical trials are conducted to risk stratify patients receiving chemotherapy regarding cardio toxicity, a bisectional collaboration between the oncologist and cardiologist should occur to identify high risk patients, optimize pharmacological therapy prior and during chemotherapy to prevent deterioration of systolic and diastolic function.
Strengths and limitations
The study was performed prospectively and all clinical variables including comorbidities and medications were retrieved and ascertained at enrolment. The same echocardiographic parameters including left atrial volume index and tissue Doppler were acquired for all patients. Furthermore, grading of diastolic function was done by two blinded level III echocardiography board certified cardiologists using standardized updated guidelines, hence minimizing potential error and bias.
However, we acknowledge several limitations. This is a single tertiary referral centre study of small sample size with referral and selection bias. Only 81 (36%) patients had a follow-up echocardiogram; however, there was no significant difference in baseline diastolic function among those who followed-up and those who did not (p=0.45). The global longitudinal strain was not obtained on many patients because the software was available on one machine (and recently two) only, and an off-line processing workstation was not available. In addition, the cardiac medications were recorded at one time only without the dose and without the knowledge whether patients were compliant with taking them, or whether others started them after enrolment. The cumulative dose of anthracyclines given was also not available. The signs and symptoms of heart failure were not collected nor the NYHA functional classification. The follow-up time between studies was relatively short to notice any significant decrease in systolic performance; yet, there was worsening of diastolic function in a considerable percentage of patients. All patients that developed DD were female with breath cancer, hence narrowing our findings to this subgroup of patients. In addition, the regression model was over fitted given the small number of primary endpoints; a larger study is needed to validate the findings. Finally, there were no hard endpoints collected; this is work in progress and will be prospectively collected at 2 years interval.