Effects of renal denervation on short-term blood pressure variability

Evidence from observational studies and post-hoc analysis of randomized clinical trials have indicated a strong independent association between increased blood pressure (BP) variability and cardiovascular outcomes in hypertension. Prospective studies including the Pressioni Arteriose Monitorate e Loro Associazioni study [1,2] have shown that short-term BP variability over a 24-h period independently predicts the development and progression of cardiac, vascular and renal damage, cardiovascular events and mortality. However, BP variability using SD reflects the fluctuation of the BP values, and the magnitude of the SD rise proportionally increases with the mean BP, indicating that ambulatory BP variability does not significantly contribute to risk stratification over and beyond 24-h BP [3]. A report from the International Database of Ambulatory Blood Pressure in relation to Cardiovascular Outcomes included 11 785 patients randomly recruited from 11 populations has described the shortcomings of previous BP variability studies and conclusively established that short-term reading-to-reading BP variability over the 24 h predicted the outcomes [4]. Taken together, these findings strongly support the relevance of BP variability over the 24 h for patients risk stratification and research, and highlights the prognostic use of mean ambulatory BP in clinical practice. Not only 24-h but also visit-to-visit BP variability has been shown to have prognostic relevance [5]. In the Anglo Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm [6], clinic visit-to-visit variability (assessed by SD of BP recordings measured by sphygmomanometer) was found to have prognostic significance for stroke, heart failure, angina and myocardial infarction. The negative impact of visit-to-visit BP variability on patient prognosis was independent of mean office and 24-h SBP, heart rate (HR) and HR variability. Another evidence supporting the prognostic cardiovascular outcomes value of clinic visit-to-visit variability comes from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack trial [7]. More recently, elevated day-to-day home SBP and DBP variability has been associated with the risk for increased cardiovascular death and events in a study with geographically diverse cohorts and long-term follow-up [8]. In the current issue of the Journal, Vogiatzakis et al.[8] report the findings from a meta-analysis of 12 renal denervation (three randomized and nine observational) studies which to date have investigated the impact of the Symplicity catheter-based approach (11 studies) and the EnligHTN multielectrode system (one study) on short-term BP variability in patients with resistant hypertension. Six (n = 524 patients) out of 12 studies investigated the changes in BP variability derived from ambulatory recordings including SD, weighted SD, coefficient of variation and average real variability. The remaining six studies included in the meta-analysis assessed nocturnal dipping pattern after renal denervation. A comprehensive analysis of the eligible studies revealed that the procedure produced no significant changes in the indices of BP variability with the exception for lowering variability in SD of daytime SBP and DBP that was independent of BP reduction per se and background of antihypertensive medication. Three randomized studies and the majority of observational studies in the current meta-analysis showed no improvement in nocturnal dipping status following renal denervation. Although the mechanistic insights underlying BP variability were not provided in studies included in the meta-analysis, the current findings should be interpreted in the context of several limitations. Insufficient renal nerve ablation (e.g. including the Symplicity HTN-3 trial with a large patient cohort), inconsistent antihypertensive drug regimen across studies, changes in medication ranging from 14 to 48% after procedure, a lack of assessment of drug adherence and varying durations of study follow-up (6 weeks–12 months follow-up) could have contributed to the marginal effects of the renal denervation approach on short-term BP variability. Notably, the link between poor antihypertensive medication adherence and increased visit-to-visit BP variability has been previously documented [6,9,10]. Further to this, short-term reading-to-reading [11] and long-term intraindividual visit-to-visit BP variability assessed by the SD of 24-h measure [12] are poorly reproducible. In contrast, both systolic and diastolic average real variability is regarded a more reliable index of beat-to-beat variation and a better predictor of mortality and cardiovascular outcomes [13–15]. Another important mechanism influencing the effectiveness of the procedure is the close association between increased BP variability and arterial stiffness. Previous studies found a significantly better response to renal denervation in patients with lower pulse wave velocity [16] and reduced effect of renal denervation on BP control in patients with isolated systolic hypertension [17]. Despite robust evidence linking increased BP variability to adverse cardiovascular outcomes in hypertensive patients, the impact of BP fluctuations in clinical practice has not yet been established, and therapeutic management of patients with variable BP remains empirical. Major discrepancies exist between visit-to-visit BP variability as calculated by 24 h when compared with clinic measures [18]. Moreover, interindividual (groups) BP variability during treatment merely reflects data obtained from intraindividual visit-to-visit BP variability values. In this context, it appears plausible that future prognostic and treatment efficacy studies will combine the measurements of visit-to-visit clinic, ambulatory and day-to-day home BP variability. The improvement of medication adherence and the use of long-acting antihypertensive drugs can considerably lower diurnal absolute BP levels and variability. The well established relationship between increased muscle sympathetic nerve activity and daytime SBP variability [19,20] suggests that aside from the benefits in BP lowering per se, bilateral ablation of afferent renal sensory nerve fibres originating from the kidney can favourably modulate noradrenergic neurons involved in BP and sympathetic control, thereby stabilizing circadian BP profile. Hopefully, the outcomes of properly designed randomized clinical renal denervation trials on BP variability will be available in the near future. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.