1. Νεφρική απονεύρωση και υποστροφή βλαβών στα όργανα στόχους: συστηματική ανασκόπηση και μέτα-ανάλυση
Αθανάσιος Κορδαλής1, Δημήτριος Τσιαχρής1, Παναγιώτα Πιέτρη1, Κωνσταντίνος Τσιούφης2, Χριστόδουλος Στεφανάδης1
1Πρότυπο Κέντρο Καρδιάς και Αγγείων, Ιατρικό Κέντρο Αθηνών
2Α΄ Πανεπιστημιακή Καρδιολογική Κλινική, «Ιπποκράτειο» ΓΝΑ

2. Disclosures
Investigator at the ongoing GSR (Global Symplicity Registry) study.

3. Introduction Hypertension and TOD
Hypertension related target organ damage (TOD) is strongly associated to adverse cardiovascular outcome
Mancia G et al. J Hypertens. 2013;31:1281–-1357
BP reduction is accompanied by organ damage regression and subsequent cardiovascular protection
Tsioufis C et al. J Hypertens. 2009;27(4):744-52
Resistant hypertension (RH) is present in 5-10% of hypertensive patients and is independently associated with adverse cardiovascular prognosis
Tsioufis C et al. J Hypertens. 2014;32(2):415-22

4. Introduction RDN and HTN

5. Objectives
Several prospective observational studies have suggested that renal denervation is associated with a reduction in early TOD.
Based on the above we aimed to evaluate the effect of RDN on target organ damage by pooling currently available data, and to investigate its relation to BP lowering following RDN.

6. Methods Eligibility Criteria
Prospective studies assessing the effect of RDN on pre-specified outcomes of TOD were included.
Inclusion criteria were as follows:
(1) publication in peer-reviewed journals
(2) English language
(3) reporting baseline and follow-up data regarding the outcomes.
No restrictions were imposed regarding the clinical characteristics of study population and the type of catheters used for RDN.
Studies with less than 10 subjects or studies of surgical RDN were excluded.

7. Methods Outcome Measures
Pre-specified outcomes of TOD:
vessels:
central Augmentation Index (AIx)
carotid-femoral pulse wave velocity (PWV)
heart structure and diastolic function:
left ventricular mass index (LVMI)
left atrial volume index (LAVI)
(E/A), (E/Em)
renal:
albumin excretion was not assessed since in an exploratory search a profound heterogeneity of presented measures and values was observed consisting the data ineligible to quantitative analysis

8. Methods Literature search
PubMed, EMBASE and Cochrane Library until January 2017 and by scanning references of selected studies.
Algorithmic search strategy:
“renal denervation” AND
(“target organ damage” or “arterial stiffness” or “augmentation index” or “pulse wave velocity” or “cardiac hypertrophy” or “left ventricular mass” or “left ventricular hypertrophy” or “atrial size” or “diastolic dysfunction”).
Duplication of data from the same cohort was checked by juxtaposing author names, recruiting periods and sample sizes. When more than one study from the same cohort was reporting results on the same outcome, the study with the larger population was selected.

9. Methods Data Synthesis and statistical analysis
Effect size:
for each outcome was algebraically calculated by the outcome measures difference between baseline and follow-up.
Measure of variance (SE of the difference):
when not directly reported, was also calculated. For this calculation the correlation (r) between baseline and follow-up scores was required. Since this information was not available we had to impute it using an approximate value The value of r was set at 0.5, which is considered a conservative estimate for within treatment arm correlation
Sensitivity analyses:
for different levels of r (r=0.35 and r=0.65)
excluding studies with different follow-up duration

10. Flow diagram for study selection
N=712 patients

12. Results LVMI LVMI (BSA) echo: 8 studies (n=250 patients)
follow up duration was 6 months in 7 of them (n=219) and 12 months in one (n=31).
RDN led to a regression of LVMI by gr/m2 at the end of follow up (95% CI to , p<0.001)

13. Results LVMI LVMI (height) echo: 3 studies (n=130 patients)
6 months follow up in all of them
The pooled effect size was also in favor of RDN, estimated at gr/m2.7 (95% CI to , p<0.001)

14. Results LVMI LVMI (BSA) CMR: 5 studies (n=147 patients).
Three of these studies had a follow up duration of 6 months (n=84 patients) while the rest of them had a follow up duration of 12 months (n= 63 patients).
A regression of LVMI by gr/m2 was attributed to the effect of RDN (95% CI to , p=0.024).
Sensitivity analysis after removing the two trials with follow up duration of 12 months revealed a consistency in the estimated effect size [ (95% CI to , p=0.003)]

15. Results LVMI LVMI (height) CMR:
2 studies with a total population of 78 patients
follow up duration of 6 months after RDN
The pooled effect was gr/m2.7 (95% CI to , p=0.003) (Figure 2).

16. Results LAVI LAVI echo Five studies (n=194 patients)
Four studies had a follow up duration of 6 months (n=163) while one study followed up the patients for 12 months (n=31).
The pooled estimator found no effect of RDN on LAVI [ ml/m2 (95% CI to 1.268, p=0.266)].
Sensitivity analysis for the follow up duration was interesting as it revealed a regression of LAVI [ ml/m2 (95% CI to , p<0.001)] after excluding the only study with follow up duration of 12 months (representing the 24.93% of weight in the initial analysis).

17. Results Diastolic Function
E/A
was reported at baseline and after RDN in 7 studies (n=258 patients).
All but one of these studies had a follow up duration of 6 months (n=227)
Application of random effect models didn’t reveal a difference in E/A before and after RDN [0.043 (95% CI to 0.117, p=0.252)]
Sensitivity analysis after excluding the study with 12 months follow up confirmed the absence of difference.

18. Results Diastolic Function
E/Em
was reported as an outcome variable in 9 studies (n=286 patients).
The follow up duration was 6 months in 7 of them (n=238) and 12 months in 2 (n=48).
The pooled effect was in favor of RDN revealing a reduction of in E/E’ (95% CI to , p=0.024).

19. Results Augmentation Index -PWV
Four studies were reporting results regarding AIx before and after RDN (n=186 patients).
The follow up duration was 6 months in three of them (n=146 patients) and 3 months in one (n= 40 patients).
The pooled effect size of RDN on AIx was (95% CI to , p<0.001)
Sensitivity analysis after excluding the only study with 3 months follow up was confirmatory of the initial result.

20. Results Augmentation Index -PWV
Pulse wave velocity
Four studies (n= 158).
The follow up duration was 6 months in all of them
RDN treatment reduced PWV by m/s (95% CI to , p<0.001)

21. Results SBP-DBP
. In 12 studies reporting data on systolic blood pressure (n= 473 patients) RDN led to a decrease of mmHg (95% CI to , p<0.001). Diastolic blood pressure data were reported in 11 studies (n= 363 patients) and a decrease of 9.8 mmHg was noted (95% CI to -7.34, p<0.001

22. Results Meta-regression Analysis
Baseline BP and achieved BP difference after RDN regressed over:
Echo LVMI:
baseline systolic BP (b= -0.95, p=0.21)
BP difference during follow up (b=0.19, p=0.38)
This was also the case for baseline diastolic BP (b= -0.01, p=0.98) and achieved diastolic BP difference (b= -0.23, p=0.81)
We conducted the same analysis for the rest of the outcomes showing a positive effect of RDN on organ damage (i.e. E/Em, Aix, PWV) (p>0.1 for all)

23. Discussion
The effect of RDN on CMR-assessed LV mass was less pronounced mostly due to the more precise and reproducible assessment of cardiac mass using CMR and the blinded investigation
Besides inducing LV mass regression, RDN significantly improved cardiac functional parameters expressed by a decrease in LV filling pressures as indicated by a reduced E/Em and LA size (in sensitivity analysis), along with the unaffected by RDN transmitral inflow ratio E/A
The latter, per se, represents the least objective index to assess diastolic function, as there is a significant overlay of E/A values across the spectrum of diastolic dysfunction
A global assessment of E/A in combination with tissue Doppler velocities and LA size is mandatory to reveal increased pressures
From a pathophysiologic point of view, the fact that cardiac alterations are not only a result of BP reduction, suggests a direct role of reduced sympathetic nervous system activity in patients after RDN.

24. Limitations
Metaanalysis of observational studies, hence vulnerable to systematic bias and inability to control for confounding factors
Imputed correlation of measured outcomes between baseline and follow up. However, sensitivity analysis using different levels of imputed correlation was confirmatory of the main analysis.
The majority of the studies had small sample size and several differences in methodology (type of catheters used, technical aspects of ablation, antihypertensive medication, adherence control).
The variability in quantification and presentation of measured outcomes (use of multiple imaging modalities, not indexed values or indexed to different variables) was substantial leading to multiple analyses with small number of studies.
Follow up duration of the included studies was limited to 12 months, so no conclusions regarding the long term effect of RDN on TOD regression can be drawn.
Due to presented aggregate data, it was not possible to control for the effect of established protective medication on pooled effect

25. Conclusions
RDN improves LV structure and function as indicated by a significant decrease in LVM (echo or CMR-assessed) and a decrease in E/Em.
Central hemodynamics and arterial stiffness are improved in patients with RH after RDN
RDN induces cardiovascular damage regression besides BP lowering
New studies that include as end-points, not only BP levels, but also surrogates of target organ damage are necessary towards this direction.