This study evaluated the subacute morphologic alterations in renal artery wall and renal nerves in response to catheter-based renal denervation (RDN) in sheep and also compared the efficiency of single-point and multiple-point ablation catheters. Effect of each ablation catheter approved for the clinical use (Symplicity FlexTM, Medtronic, Inc., or EnligHTNTM, St. Jude Medical, INC.) was compared to intact contralateral renal artery in 12 sheep by histopathology and immunohistochemistry evaluation after a 10-day period post-RDN procedure. The safety was verified by extensive evaluation of kidney morphology. Vascular wall lesions and nerve injuries were more pronounced in those animals treated with multi-point EnligHTN catheter when compared with animals treated with single-point Symplicity Flex catheter. However, neither RDN procedure led to complete renal nerve ablation. Both systems, tested in the present study, provided only incomplete renal nerve ablation in sheep. Moreover, no appreciable progression of the nerve disintegration in subacute phase post-RDN procedure was observed. This study further supports the notion that the effectiveness remains fully dependent on anatomical inter-individual variability of the sympathetic nerve plexus accompanying the renal artery. Therefore, new systems providing deeper penetrance to targeted perivascular structure would be more efficient.
We found recently that in Ren-2 transgenic hypertensive rats
(TGR) addition of soluble epoxide hydrolase inhibitor (sEHi) to
treatment with angiotensin-converting enzyme inhibitor (ACEi),
surprisingly, increased the mortality due to heart failure (HF)
induced by creation of the aorto-caval fistula (ACF). Since TGR
exhibit sex-related differences in mortality, we examined here if
such differentiation exists also in the response to the treatment
with ACEi (trandolapril), alone or combined with sEHi [cis-4-[4-
(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid, (c-AUCB)].
ACEi improved survival in males to 74 % (vs. 0 %) and in
females to 65 % (vs. 32 %). ACEi and sEHi combined also
improved the survival in male ACF TGR, however, it was
significantly less (38 %) than after ACEi alone. In contrast, in
females the combined treatment significantly improved the final
survival rate (84 %). There were no significant sex-linked
differences in survival rate in untreated or treated normotensive
Hannover Sprague-Dawley rats. In conclusion, in HF patients
with co-existing hypertension and RAS hyperactivity, the sex may
co-determine the rate of HF progression, and can influence the
effectiveness of the therapeutic measures applied. Therefore, in
the relevant pre-clinical studies the sex-linked differences should
be seriously considered. Our data indicate that TGR might be
an optimal model for such studies.