Renal denervation: a blunt weapon against isolated systolic hypertension?

This editorial refers to ‘Reduced blood pressure-lowering effect of catheter-based renal denervation in patients with isolated systolic hypertension: data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry’†, by F. Mahfoud et al., on page 93. Role of isolated systolic hypertension in the pathogenesis of resistant hypertension. Renal denervation is more effective in counteracting the steady rather than the pulsatile component of blood pressure. DBP, diastolic blood pressure; MBP, mean blood pressure; PP, pulse pressure; SBP, systolic blood pressure. A preliminary report suggested that renal denervation might reduce carotid–femoral pulse wave velocity (PWV) at least in part independently of BP reduction,6 though other data demonstrated a blunted BP-lowering effect of renal denervation in ISH resistant hypertensive patients in comparison with those with combined systo-diastolic hypertension.7 In this issue of the journal, Mahfoud and co-authors confirmed in a larger cohort of 1103 patients, obtained by pooling data from the SYMPLICITY HTN-3 trial and the Global SYMPLICITY Registry, that renal denervation is less effective in individuals with ISH in comparison with those with combined resistant hypertension.8 Of note, this was demonstrated both for office and for 24 h BP values. This finding reminds us about the importance of identification of pathophysiological mechanisms underlying hypertension development for establishing an effective treatment. Indeed, most of the individuals with uncontrolled hypertension actually have ISH, especially those over 60 years of age.2 When large artery stiffness is the main mechanism sustaining hypertension, the hypertension specialist has few really effective therapeutic options. All antihypertensive drugs currently approved and used for treatment of hypertension were designed to reduce peripheral vascular resistance or cardiac output, thus having a major impact on the steady component of BP (mean and diastolic BP) rather than on the pulsatile component (PP and systolic BP), though high-dose renin–angiotensin system (RAS) blockers seem also to have BP-independent destiffening properties.9 Unfortunately, the present study suggests that interventions targeting adrenergic overactivation, such as renal denervation, suffer the same limitation, and thus they can hardly be an answer to the problem of uncontrolled systolic hypertension, which is by far the most common form of resistant hypertension. Though a marked sympathetic activation is present in true resistant hypertension, as demonstrated by the use of the microneurographic technique,10 and the functional component of arterial stiffness is conceivably under sympathetic control,11 targeting the sympathetic nervous system in the presence of extensive vascular structural alterations is probably ineffective. Furthermore, whether renal denervation is actually able to induce a sustained reduction in adrenergic tone is still controversial. There is an ongoing debate on the direction of the cause–effect relationship between arterial stiffenss and hypertension, and in particular ISH.4 As already mentioned, arterial stiffness is likely to precede and promote hypertension.3 On the other hand, a wide PP might accelerate the rupture of elastin lamellae in large arteries, amplyfing the age-related stiffening process; furthermore, the excessive pressure pulsatility might exert irreversible damage by barotrauma in the capillaries in the parenchymal organs, such as the brain and the kidney. The development of chronic kidney disease in turn makes hypertension more difficult to control, perpetuating refractoriness to treatment and reduced BP response to renal denervation.12 At this stage, the role of functional mechanisms such as sympathetic inhibition in individuals with such extensive vascular and renal organ damage, such as those with ISH, is obviously marginal, as the study of Mahfoud and co-authors suggest.8 An interesting and novel finding of this article is that a reduced antihypertensive effect is not a feature of ageing per se, but specifically of ISH, regardless of age. This fact is of clinical relevance, since ISH is associated with an increased cardiovascular mortality even in young adults in comparison with high-normal BP individuals, as recently demonstrated in the Chicago Heart Association Detection Project in Industry, a large population study following up ∼27 000 young adults for 31 years.13 Interestingly, the risk is only slightly increased in men, possibly because of the increased prevalence of spurious systolic hypertension in the male sex. The latter condition probably has a totally different pathophysiology from ISH, being related to increased PP amplification from the centre to the periphery rather than to increased aortic stiffness.14 In young women, in which PP amplification occurs to a lesser extent than in men, ISH is less prevalent but is associated with a higher risk of cardiovascular events.13 Future studies should investigate which is the best approach to reduce cardiovascular risk in this subset of the hypertensive population. In conclusion, the findings of the present study underline the importance of the knowledge of the pathophysiology of hypertension for the development of effective treatments and confirm once again the strong and urgent need for novel therapeutic approaches targeting arterial stiffness to reduce BP and its global burden. Conflict of interest: none declared.