This systematic review summarized the current evidence of the time-dependent effect of Anth-bc on central aortic stiffness, assessed as AD or central PWV. Results from this meta-analysis suggest that in the short term (at termination of Anth-bc), moderate dose Anth-bc has a clinically meaningful effect on increasing arterial stiffness, with an increase in PWV and a decrease in AD, herewith confirming the results of a recent meta-analysis on this topic [26]. However, we observed smaller effects when measurements were performed at 6-12 months (Figure 2). The risk of bias of the included studies was moderate to high. The quality of the studies included in this review was limited mainly by study design and methodology.
Comparison with other studies
Over the past 10-15 years, an extensive body of literature has been published identifying increased arterial stiffness as a predictor of cardiovascular events and mortality [22, 23, 45]. AD has been found a sensitive parameter of arterial stiffness in patients younger than 50 years, while PWV is the more sensitive parameter after the age of 50 [21]. According to a meta-analysis of general population studies, a 1 m/s increase in PWV, as found in our study, corresponds to an age-, sex-, and risk factor-adjusted risk increase of approximately 14% in total CV events, CV mortality, and all-cause mortality [22]. According to a study by Redheuil et al. who assessed the predictive value of AD for mortality, hard CV events and HF events in 3675 patients without clinical CVD (mean age 61± 10 years),[23] patients included in our meta-analysis had either a not elevated[34, 38] to two-fold increased risk[37, 39] for CV events.
Our meta-analysis suggests that adverse effects of Anth-bc on arterial stiffness may partially be reversible after Anth-bc termination. However, the greater short- comparted to long-term effect is mainly based on the large adverse effect found on AD and PWV in the study by Chaosuwannakit [34], and the slightly positive changes measured at 6 months by Jordan et al. and at 9-12 months by Mizia-Stec et al. Of the four studies that performed two follow-up measurements, one at 3 months (end of Anth-bC) and one at 6 months [35, 39, 40] or 12 months [37], three studies found a further worsening [35, 39, 40], while only the study by Grover and colleagues found an improvement (Figure 2). However, even if partial recovery after the acute adverse effect on arterial stiffness at Anth-bC treatment conclusion was found in some patients, this may not mean that long-term vasculotoxic effects are not be present. Nevertheless, at 5 or 10 years after treatment termination it will be difficult to ascribe increased arterial stiffness to certain chemotherapies, as other treatments, advanced age, cancer itself, or cardiovascular risk factors are known to also play a role. The hypothesis of partial recovery of adverse effects over time will need to be confirmed in longitudinal studies which measure both at completion of Anth-bc and at a later follow-up time. Further, it is clinically important to assess whether partial recovery may be due to cardioprotective treatment of diagnosed cardiotoxic side-effects following cancer therapy.
In our meta-analysis, baseline AD values of three studies were within the range of 1.7±1.3 to 4.1±1.6 mmHg-1,[34, 38, 39] and in the range of reference values in the literature for age-matched, healthy individuals (3.1±1.8 to 4.0±1.6 mmHg-1)[46]. However, baseline AD in the study by Grover et al. was markedly higher (8.1 ± 3.6 mmHg-1). Similarly, values for baseline PWV from the study by Mizia-Stec and colleagues, who measured cfPWV by Doppler echography were noticeably higher (16.7±11.8 m/s) compared to those assessed in the other studies (6.7±0.5 to 6.9±2.3 m/s), which measured aortic arch PWV by CMR [34, 35, 37]. Surface cfPWV has been found to overestimate true aortic PWV by 2-3 m/s,[21] however, this methodological difference cannot explain the almost 10 m/s higher values. However, the unusually high SD of 11 m/s in the study by Mizia-Stec and colleagues raises some doubt about the reliability of their PWV data.
Sources of heterogeneity
Overall, we found high heterogeneity amongst the studies included in the random-effect analyses for AD and PWV that persisted when performing sensitivity and subgroup analyses. Possible reason for the observed heterogeneity could be the clinical diversity of the study populations with various degrees of cardiovascular risk, bias from patient drop-out, or lack of blinding. None of the studies could be found in a trial registry for verification of reported results with study protocol, and none presented a patient flow. In addition, publication bias may be present.
Potential modulators of vasculotoxicity
Vasculotoxicity is likely to be modulated by age, the effect of cumulative Anth-bc dose, the individual cardiovascular risk factor profile, additional chemo- and radiotherapies, and cardioprotective medication. Two of the included studies in this analysis excluded patients with CV comorbidities and coronary artery disease (CAD)[36, 39] with one of them including patients with younger mean age compared to the other studies (44 vs 51 years) [39]. Both studies showed smaller effects of Anth-bc on AD and PWV, suggesting that, similar to cardiotoxicity, vascular toxicity may be more pronounced in older patients with preexisting CV risk factors or CV disease. It is well established that cumulative Anth-bc dose plays an important role in the development of cardiotoxicity [12]. While Chaosuwannakit et al. found an association between cumulative Anth-bc dose and worsening of AD (r= 0.34, p= 0.02), Drafts et al. could not confirm these findings (p=0.6). In this meta-analysis, studies with moderate Anth-bc-dose (between 200-450mg/m2) show either a much (ratio of 2.2) or somewhat increased arterial stiffness (ratio of 1.1-1.4) or a decrease (ratio of 0.8-1.0, see Figure 2) leading to non-significant regression (r= 0.07, p= 0.0612). However, this may not be interpreted as a non-existing dose-response relationship but rather be a consequence of the large heterogeneity between the included studies.
Most of our studies investigated the relation between blood pressure and vascular injury.[34-37, 39] Grover et al. found a higher increase in arterial stiffness in patients with higher systolic BP. A higher PWV at baseline and greater increase over time with higher systolic BP was also found by Drafts et al., and Daskalaki et al. found decreased AD to be associated with higher systolic BP. Contrarily, Mizia-Stec and colleagues did not find any relationship between the diagnosis of systemic hypertension and Anth-bc induced changes in PWV. However, none of the studies adjusted changes in arterial stiffness for changes in BP, which has a direct impact on PWV.[47] As blood pressure tends to be decreased with Anth-bc,[48] the increase in arterial stiffness measured by PWV found in this and the previous meta-analysis[26] may be underestimated [47].
None of our studies found a significant effect of additional chemotherapies,[34, 35] however, the small sample sizes may have precluded the detection of such associations. Future studies are warranted to gain more insight into the effect of age, cumulative Anth-bc dose, the presence of cardiovascular risk factors and the addition of co-medication on vascular function.
Strengths and limitations
Subgroup analyses of different time points has allowed the detection of a potential (partial) reversibility of adverse effects by Anth-bc on arterial stiffness. Another strength of this meta-analysis is the inclusion of studies assessing central arterial stiffness only. This is important since central (i.e. aorta and carotid arteries) and peripheral (i.e. brachial or femoral) arteries differ in their passive and active contractile properties [49]. In contrast to a recent meta-analysis on the same topic, using p-values of repeat measure analyses provided us with a higher power to detect significant results due to a more efficient adjustment for confounders.
A limitation of our study was that all included studies were observational and expectedly did not include a truly comparable control group of cancer patients. This greatly limits the value of a meta-analysis [32]. Therefore, the effect of cancer itself, presence of CV risk factors or other confounding treatments and comorbidities could not be identified. Secondly, they were based on small numbers of participants, which explains the large CIs of some of the studies. It should further be noted, that due to the limited number of the included studies, short-term effects of Anth-bc are greatly driven by the study from Chaosuwannakit and colleagues and smaller effects were observed in sensitivity analyses when their study was removed, however heterogeneity persisted (Supplement Figure 3). Studies did not report Anth-bc duration, making it difficult to estimate the follow-up time after Anth-bc termination for the various cancer patients. Unfortunately, none of included studies were able to provide individual patient data.
Clinical implications
The adverse effect of Anth-bc on arterial stiffness likely applies to the whole vasculature and expands beyond the myocardium. Several reviews highlighted the importance of arterial stiffness in the prediction of all-cause cardiovascular outcomes [22, 27-29]. Therefore, non-invasive assessment of arterial stiffness may be used for detection of early cardiovascular injury in asymptomatic patients at risk during treatment and effects of cardio-/vasculo-protective treatments. Further, prospective longitudinal studies should measure arterial stiffness before, immediately after treatment termination, as well as preferably at several follow-up times in order to assess long-term consequences of Anth-bc on arterial stiffness and potential alleviating effects of cardioprotective medication or spontaneous recovery.