Anticancer Therapy-Related Increases in Arterial Stiffness: A Systematic Review and Meta-Analysis

Abstract

Background Cardio-oncology is a clinical discipline focused primarily on the early detection of anticancer therapy-related cardiomyopathy. However, there is growing evidence that the direct adverse consequences extend beyond the myocardium to affect the vasculature, but this evidence remains limited. In addition, there remains a paucity of clinically based strategies for monitoring vascular toxicity in these patients. Importantly, arterial stiffness is increasingly recognized as a surrogate end point for cardiovascular disease and may be an important vascular outcome to consider. Therefore, the aim of this systematic review and meta-analysis was to summarize evidence of increased arterial stiffening with anticancer therapy and evaluate the effect of treatment modifiers. Methods and Results A total of 19 longitudinal and cross-sectional studies that evaluated arterial stiffness both during and following anticancer therapy were identified using multiple databases. Two separate analyses were performed: baseline to follow-up (12 studies) and control versus patient groups (10 studies). Subgroup analysis evaluated whether stiffness differed as a function of treatment type and follow-up time. Standard mean differences and mean differences were calculated using random effect models. Significant increases in arterial stiffness were identified from baseline to follow-up (standard mean difference, 0.890; 95% CI, 0.448-1.332; P<0.0001; mean difference, 1.505; 95% CI, 0.789-2.221; P≤0.0001) and in patient versus control groups (standard mean difference, 0.860; 95% CI, 0.402-1.318; P=0.0002; mean difference, 1.437; 95% CI, 0.426-2.448; P=0.0052). Subgroup analysis indicated differences in arterial stiffness between anthracycline-based and non-anthracycline-based therapies (standard mean difference, 0.20; 95% CI, 0.001-0.41; P=0.048), but not follow-up time. Conclusions Significant arterial stiffening occurs following anticancer therapy. Our findings support the use of arterial stiffness as part of a targeted vascular imaging strategy for the identification of early cardiovascular injury during treatment and for the detection of long-term cardiovascular injury into survivorship.

Keywords: arterial stiffness; cancer therapy; cardiotoxicity; pulse wave velocity; vascular toxicity.

Figure 1. Flow chart of selection process of eligible studies.

Flow through of the identification and selection of studies included in the systematic review and meta‐analysis. Aod indicates aortic distensibility; and PWV, pulse wave velocity.

Figure 2. Determination of arterial stiffness.

A, Pulse wave velocity can be calculated by dividing the distance (L) between 2 arterial sites by the difference in transit time (Δt) of pressure wave obtained via applanation tonometry or velocity wave obtained via Doppler ultrasonography (illustrated here) arrival between those sites. B, Carotid β stiffness can be calculated from B‐mode and M‐mode visualizations of the common carotid artery. From this image, maximal and minimal carotid diameters over the cardiac cycle can be determined by tracing the region of interest (red boundaries). C/Upper, Pulse wave velocity can be calculated from phase‐contrast cardiovascular magnetic resonance images of the aorta by dividing the distance between the ascending and descending thoracic aorta by the transit time of the flow wave computed on the basis time difference of the velocity–time curve at 2 different regions (blue line). C/Lower, Aortic distensibility can be calculated from phase contrast cardiovascular magnetic resonance imaging of the thoracic aorta. From these images, maximum and minimum aortic areas over the cardiac cycle can determined by tracing the region of interest (red boundaries). C, Reprinted from Chaosuwannakit et al30 with permission. Copyright ©2010, American Society of Clinical Oncology.

Figure 3. SMD results from longitudinal studies.

Forest plot illustrating the effect size for each of the 12 longitudinal studies reporting arterial stiffness with anticancer chemotherapy. Overall effect favored greater arterial stiffness following anticancer treatment compared with pretreatment (SMD, 0.890; 95% CI, 0.447–1.332; z=3.95; P≤0.0001).1, 14, 15, 24, 25, 26, 27, 28, 29, 30, 31, 32 SMD indicates standard mean difference.

Figure 4. Standard mean difference results from cross sectional studies.

Forest plot illustrating the effect size for each of the 10 cross‐sectional studies reporting arterial stiffness with anticancer chemotherapy. Overall effect favored greater arterial stiffness following anticancer treatment compared with matched healthy control participants (standardized mean difference, 0.860; 95% CI, 0.402–1.318; z=3.68; P=0.0002).2, 30, 31, 32, 33, 34, 35, 36, 37, 38