Therapeutic value of renal denervation in cardiovascular disease?

Several experimental and clinical studies have suggested favourable effects with renal denervation (RDN) in hypertension and renal disease. However, controversies exist and additional studies are therefore warranted to validate its therapeutic potential and also to further characterize the underlying mechanism(s). In this context, Lu et al. (2016) investigated the effect of bilateral RDN on cardiac angiogenesis during prolonged pressure overload in a rat model with transverse aortic constriction (TAC). This novel and important study provides additional support for therapeutic effects of RDN, demonstrating that RDN can promote cardiac angiogenesis during pressure overload. (Fig. 1) The prevalence of hypertension is increasing worldwide, which can at least in part be explained by ageing of the population and the rising rates of obesity. Hypertension is very frequent in patients with renal disease and in those with obesity and metabolic dysfunction (e.g. type 2 diabetes mellitus) and is one of the main risk factors for the development of adverse renal and cardiovascular complications. Emerging evidence suggests that increased sympathetic nerve activity can promote or accelerate the development of hypertension and cardiac hypertrophy, and increase the risk of adverse complications (Grassi et al. 2015) (Fig. 1). Several different underlying mechanisms are proposed, including modulation of the renin–angiotensin–aldosterone system (RAAS), activation of the immune cell function and increased oxidative stress (Bohm et al. 2013). In the kidney, the sympathetic efferent nerve fibres are found in close association with the cells of the afferent arteriole and the granular juxtaglomerular cells as well as tubular epithelial cells along the whole nephron and importantly influence renal vascular resistance, renin secretion and tubular processing of, for example, sodium. Renal sensory nerves or afferent nerve fibres are of two principal types: the first kind project from the renal parenchyma to the hypothalamus, and signal renal injury, leading to activation of the systemic sympathetic nervous system. The second type of afferent nerve fibres are pressure-sensitive receptors in the renal pelvis; these are sympathoinhibitory and important in mediating reno-renal reflexes (DiBona & Kopp 1997) (Carlstrom et al. 2015). Previous experimental studies have demonstrated that RDN of efferent sympathetic nerves can blunt renal autoregulatory responses, reduce inappropriate renin release and reduce sodium and water reabsorption in the proximal tubules, thus leading to a leftward shift of the pressure–natriuresis curve. Moreover, reduced firing of afferent sensory nerves can attenuate renal-mediated activation of centrally mediated sympathetic nerve activity (Johns et al. 2011, Carlstrom et al. 2015). Although all of the above-mentioned effects of RDN may contribute to blood pressure lowering, further studies are needed to specifically investigate how RDN influences a cardiac–renal-neuro axis or reno-renal reflexes in models of cardiovascular disease and in patients with hypertension. In this issue of Acta Physiol, the article by Lu et al. provide novel insights regarding how RDN can improve cardiac function and attenuate myocardial fibrosis in rats with prolonged pressure overload. In this article, the authors show that bilateral RDN promote cardiac angiogenesis, via mechanisms that involve regulation of vascular endothelial growth factor (VEGF) and its receptor (VEGFR2) expression, as well as activation of endothelial nitric oxide synthase (eNOS) in the heart. Their results are in agreement with previous observations and clearly suggest that imbalance between cardiomyocyte growth and cardiac angiogenesis may be responsible for the development of chronic heart failure. Despite RDN-mediated reduction in fibrosis in the kidneys from rats with TAC, no significant effect on renal angiogenesis was observed. As commented by the authors, this could possibly be attributed to lower degree of hypoxia in the kidneys or better resistance to hypoxia compared with the heart. It is important to point out that these favourable effects of RDN were independent of any changes in blood pressure, heart rate or total peripheral resistance in this cardiovascular disease model. Accumulating evidence demonstrate a positive link between NADPH oxidase signalling in the heart and development of cardiac hypertrophy and fibrosis (Murdoch et al. 2006). More interestingly, recent publications have reported that RDN can attenuate both cardiac hypertrophy and fibrosis not only in animal models (Wang et al. 2013, Li et al. 2015, Peleli et al. 2016), but also in aged humans (Dorr et al. 2015). Although modulation of cardiac angiogenesis was demonstrated in the study by Lu et al., the authors did not conduct an in-depth investigation of the underlying mechanisms which contribute to RDN-mediated protection of the heart. Several previous studies have suggested that the favourable cardiovascular effects are secondary to attenuated NADPH oxidase expression or activity in the kidney, brain and heart, reduced cardio-renal reflex, lowering of blood pressure or due to modulation of the immune system. It is clear that much work remains; however, the current findings of Lu et al. offer a rationale for applying RDN to boost myocardial angiogenesis as a therapy to prevent the development of heart failure. These aspects are of course not trivial to characterize, but future studies using the TAC model for prolonged pressure overload should consider investigating (1) additional RDN groups with VEGF or eNOS inhibitors to gain more knowledge regarding the causal relation, (2) potential effects on the regulation of immune cell function and oxidative stress and (3) the contribution of efferent and afferent nerves. Between 5 and 15% of all patients diagnosed with hypertension have resistant hypertension, which is defined as systolic blood pressure ≥140 mmHg despite adherence to at least three maximally tolerated doses of antihypertensive medications. Only recently has it been shown that among patients with hypertension, activation of the renal sympathetic outflow is at its highest in drug-resistant hypertension (Grassi et al. 2015). Conflicting results obtained from clinical trials in patients with resistant hypertension (i.e. SYMPLICITY HTN 1-3) have resulted in a global debate regarding the potential therapeutic value of RDN (Krum et al. 2009). Considering the large body of evidence from experimental studies, it is strange that surgical and catheter-based RDN attenuates hypertension in four different mammalian species (rats, dogs, rabbits and pigs), but not humans in the SYMPLICITY HTN-3 trial (Bhatt et al. 2014). In contrast with many experimental models of hypertension where effectiveness of surgical- or chemical-mediated RDN was confirmed (typically by 90–95% reduction in renal noradrenaline content or immunostaining for tyrosine hydroxylase), this was not assessed in the SYMPLICITY HTN-2 and HTN-3 trials. Among clinical studies of endovascular renal denervation, RDN was only confirmed in the SYMPLICITY HTN-1 trial, using measurements of noradrenaline spillover. Although the degree of renal denervation in the SYMPLICITY HTN-1 trial was less than expected (50%), this was sufficient to lower the blood pressure adequately. Retrospective analysis of stored angiographic and procedural records in the SYMPLICITY HTN-3 trial showed that in 74% of patients receiving radio-frequency treatment, not even a single fully circumferential renal artery application was achieved. As it is considered mandatory that such radio-frequency application is achieved bilaterally, it is very unlikely that effective nerve ablation was achieved (Grassi et al. 2015). Further evaluation in rigorously designed clinical trials, which utilize safe and effective methods for RDN, and also assess the degree of accomplished denervation, will be necessary to validate the previously reported benefits of RDN in patients with resistant hypertension. In summary, the interesting and potentially clinically relevant study by Lu et al. brings further knowledge regarding the mechanisms contributing to the observed favourable effects of RDN in an experimental model of cardiovascular disease, but also raises important questions for further investigations. Characterization of the underlying mechanisms requires further study. Furthermore, future clinical investigations are also needed to validate the effects of RDN in patients with uncontrolled hypertension, and to investigate potential therapeutic effects in hypertensive subjects with congestive heart failure. The author declares no conflict of interest. This work was supported by grants from the Swedish Heart and Lung Foundation (ID: 20140448).