Clinical Association of Achilles Tendinopathy and Hypertension Mediated by CaV1.2 Voltage-gated Ca2+ Channel

Abstract

Category: Basic Sciences/Biologics; Hindfoot Introduction/Purpose: The Achilles tendon is subject to acute- and overuse-injuries, which may result in degenerative tendinopathy. Achilles tendinopathy is associated with pain, disability, and functional limitations. While some patients benefit from therapy and conservative measures, many progress to operative intervention. The pathogenic mechanisms of Achilles tendinopathy are largely unknown. Using novel transgenic mouse models with CaV1.2 (a voltage gated calcium channel) wildtype or a gain-of-function mutant channel, we observed potent regulatory effects of increased Ca2+ influx through CaV1.2 on Achilles tendinopathy development. CaV1.2 expression and activity has also been shown to contribute to hypertension amongst other systemic disease. We hypothesized that aberrant CaV1.2 function is a common pathogenic mechanism both hypertension and Achilles tendinopathy. To test this hypothesis, we performed an association study between two diseases. Methods: A case-control study was performed to investigate the association between Achilles tendinopathy and hypertension using TriNetX mulit-center clinical database. We identified Achilles tendinopathy and hypertension patients based on their ICD-10 codes. Chi-squared test, odds ratio (OR) and 95% confidence interval (CI) were used to detect the correlation between these two diseases. To elucidate the role of CaV1.2 in the association of Achilles tendinopathy and hypertension, we performed a retrospective cohort study with the exposure cohort defined as all subjects with hypertension and a calcium channel blocker (CCB) prescription preceding a diagnosed tendinopathy from January 1, 2011 to December 31, 2015. A matched cohort was defined as the subjects with hypertension but on medications other than CCBs. A 7-year follow-up was obtained for the outcome Achilles tendinopathy. Relative risk (RR) and hazard ratio (HR) were used to detect the effect of CCBs and other anti- hypertensives on the development of tendinopathy. Results: We determined that hypertension is more prevalent in patients with Achilles tendinopathy (42.4%) compared to those without (12.6%). The incidence of Achilles tendinopathy is significantly correlated with hypertension (p < 0.0001; OR=3.17, 95%CI=3.11-3.22). Furthermore, hypertension patients on CCBs had a 28% decrease in Achilles tendinopathy risk when compared with hypertensive patients on medications other than CCBs (RR=0.72, 95%CI=0.60-0.86, p< 0.0001). A cox proportional hazards model corroborated the findings, with hypertensive patients on CCBs having 26% decreased incidence of Achilles tendinopathy than patients on other medications (HR=0.74, 95%CI=0.62-0.88, p< 0.0001). In contrast, we found no significant effect of angiotensin-converting enzyme inhibitors (no direct effect on Calcium channel activity) on the incidence of Achilles tendinopathy (HR=0.99, 95%CI=0.88-1.10, p=0.8273). Conclusion: There may be a correlation between Achilles tendinopathy and other common systemic diseases such as hypertension, as well as potential treatment pathways. Our study of the TriNetX clinical database provides evidence that CaV1.2 expression/activity is a potential molecular mechanism underlying Achilles tendinopathy. Additionally, an effect of CCBs in hypertensive patients may be to lower the incidence of Achilles tendinopathy by inhibiting L-type voltage-gated Ca2+ channel (including CaV1.2) signaling in tenocytes. Our finding will provide a rationale for further investigation of this association, including a potential for repurposing FDA-approved generic CCBs to prevent or treat Achilles tendinopathy.