POSSIBLE CONTRIBUTION OF PERI-VASCULAR ADIPOSE THROMBO-INFLAMMATION TO CARDIAC AUTONOMIC NEUROPATHY: MODULATION BY RIVAROXABAN

Abstract

Cardiac autonomic neuropathy (CAN) is an early occurrence in type 2 diabetes (T2D) patients that represents a silent cause of cardiovascular mortality and morbidity. The pathophysiology of CAN is poorly understood however, the high prevalence of CAN in patients newly diagnosed with T2D suggests that its pathophysiology is rooted in an earlier stage of metabolic derangement, possibly being prediabetes. Our laboratory recently showed that prediabetes is associated with localized perivascular adipose tissue (PVAT) inflammation with a paracrine cardiovascular involvement, and sympathovagal imbalance leading to parasympathetic CAN. Literature reported that adipose inflammation is also associated with a rise in thrombin and factor Xa activity. Moreover, factor Xa-driven protease-activated receptor stimulation exacerbates inflammation provoking a continuous cycle.

In this present study, we intend to examine whether suppression of factor Xa activity in a prediabetic rat model will ameliorate the localized PVAT inflammation. This will be associated with improved cardiac autonomic function, as well as reversal of cardiovascular structural abnormalities.

A non-obese prediabetic rat model was used. Sprague-Dawley rats were fed a mild hypercaloric diet for twelve weeks to induce PVAT inflammation. In vivo invasive hemodynamic measurement of the baroreflex sensitivity showed reduced parasympathetic activity in prediabetic rats that was reversed by rivaroxaban treatment. After sacrifice, PVAT inflammation was observed as an increased interleukin-1 expression, adipocyte hypertrophy, and increased oxidative stress, ameliorated by rivaroxaban treatment. Similarly, increased cardiac and brainstem oxidative stress were noted in prediabetic rats where only cardiac oxidative stress was reversed by rivaroxaban treatment.

Rivaroxaban was shown to have no effect on the brainstem oxidative stress indicating that any vagal insult is presumably peripheral in nature. Moreover, rivaroxaban treatment revealed that CAN can be ameliorated by direct effects on the cardiovascular system and AT releasing factor Xa, or indirectly by affecting macrophages expressing PARs.

In conclusion, rivaroxaban showed promising results in interrupting thrombo-inflammation and ameliorating adipose tissue inflammation which eventually might have improved the baroreceptor sensitivity and mitigated CAN.