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An Overview onHypertension Mediated
https://t.me/medicina_free
Organ Damage
MarcioG.Kiuchi andMarkusP.Schlaich
7
Introduction
Lowering blood pressure (BP) is one of the most effective
means of reducing the risk for cardiovascular events both in
patients with established hypertension and those with additional co-morbidities. Accurate measurement of BP in a clinical setting as well as in an out-of-ofce environment remains
a challenge and is not always an accurate reection of the
overall level of BP and its control with antihypertensive therapy. To this end, hypertension-mediated organ damage, predominantly affecting the heart, the kidneys, and the
vasculature, may serve as a better indicator of the integrated
impact of a given BP burden over time. Similarly, with therapeutic intervention, regression of existing HMOD may be a
better indicator of BP control over time than scattered individual BP readings. Consequently, assessing the effects of a
BP lowering intervention, such as renal denervation (RDN),
on HMOD would shed some light into its medium and
longer- term efcacy beyond BP lowering alone. Here, we
review the currently available evidence to assess the impact
of RDN on HMOD.
M. G. Kiuchi
Dobney Hypertension Centre, Medical School- Royal Perth
Hospital Unit, University of Western Australia,
Crawley, WA, Australia
e-mail: marcio.galindokiuchi@uwa.edu.au
M. P. Schlaich (*)
Dobney Hypertension Centre, Medical School- Royal Perth
Hospital Unit, University of Western Australia,
Crawley, WA, Australia
Departments of Cardiology and Nephrology, Royal Perth Hospital,
Perth, WA, Australia
Neurovascular Hypertension and Kidney Disease Laboratory and
Human Neurotransmitter Laboratory, Baker IDI Heart and
Diabetes Institute, Melbourne, VIC, Australia
e-mail: markus.schlaich@uwa.edu.au
RDN andtheHeart
In hypertension, left ventricular (LV) hypertrophy (LVH) is
initially a useful compensatory process to abnormal loading
conditions. However, it is also the rst step toward the development of overt clinical disease [1–4]. Two studies have
demonstrated that the presence of inappropriately elevated
LV mass (LVM) is associated with a greater risk of cardiovascular (CV) events, either in the presence or in the absence
of traditionally dened LVH [5, 6]. Also, LVH is associated
with an increased rate of CV events and death independent of
other cardiovascular risk factors and, notably, independent of
BP values [7–9]. The reduction of echocardiographically
determined LVM, along with the normalisation of LV geometry during antihypertensive treatment, has been associated
with a decrease in risk for subsequent CV disease [10, 11].
Muiesan etal. demonstrated for the rst time that regression
of echocardiographically determined inappropriate LVM is
associated with an improvement in prognosis [12] (Figs.7.1
and 7.2). Consistently, LVH regression was accompanied by
favourable outcomes [13, 14]. Aside from the improved BP
control, the regression of hypertensive target organ damage
is considered a useful indicator of therapeutic efciency.
Renal denervation (RDN) is a device-based technique to
directly modulate efferent and afferent nerves, which connects both kidneys with central integrative nuclei in the
brain. In resistant hypertensive patients, a marked
BP-lowering effect and a rapid decline in the activity of single muscular sympathetic nerve units were noticed postRDN [15]. Moreover, sympathetic overactivity and RAAS
disruption are likely to benet this population. This may be
reected by regression of hypertension mediated organ damage. Relevant ndings to suport this notion are summarized
below.
In 2012, Brandt et al. showed for the rst time that,
beyond the known effects on reducing blood pressure, RDN
signicantly reduced LV mass and improved diastolic function assessed by echocardiography, which may have important implications for prognosis in patients with resistant
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_7
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4
LVM
LVM
LVM
Event rate (x100 patient-years)
Event free survival (%)
Time to event (months)
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M. G. Kiuchi and M. P. Schlaich
* ††
3.18
3
2
* ††
1.87
ventricular ejection fraction (LVEF) at baseline this improved
signicantly with RDN.Interestingly, in 15 out of 18 patients
in whom the BP response to RDN was less than 10mm Hg,
left ventricular mass index (LVMI) was still signicantly
reduced (Fig.7.3), perhaps highlighting that assessment of
regression of HMOD may be a more accurate measure of
0.81
1
0.97
longer term outcomes after RDN than BP lowering alone.
Interestingly, the structural and functional cardiac changes
0
Persistence of
appropriate LV M
Regression of
inappropriate
Development of
inappropriate
Persistence of
inappropriate
were partly independent of blood pressure, pointing to a
direct interference modulating the activity of the sympathetic
nervous system. These data corroborate results, previously
reported by Kiuchi etal. [18], which demonstrated a reduc-
Fig. 7.1 Incidence of CV events in relation to previous changes in
LVM appropriateness; patients with persistence, regression, and development of inappropriate LVM and patients with appropriate LVM from
baseline to follow-up. Log-rank test for a trend P=0.003; *P<0.05 vs
inappropriate LVM regression; ††P<0.02 vs appropriate LVM persistence [12]. Reproduced with permission
tion in LVMI, end-diastolic left ventricular internal dimension (LVIDd), left ventricular end-diastolic posterior wall
thickness (PWTd), and end-diastolic interventricular septum
thickness (IVSTd) with RDN.Also, LVEF improved at the
sixth-month post-RDN in 45 resistant hypertensive patients
with chronic kidney disease (CKD).
100
However, Brandt et al. [16] reported that the effect of
RDN on LV mass regression correlated with the degree of
90
80
70
60
myocardial hypertrophy at baseline and was most evident in
patients with LVH at baseline. Although in patients without
LVH, no signicant change of LV mass after RDN occurred,
in the subgroup with LVH at baseline, RDN markedly
reduced LV mass index after 6months of follow-up. In contrast, such as difference based on preoprocedural LVH was
not observed by Kiuchi etal. [18] their cohort. Similarly, no
50
40
persistence of iLVM
regression of iLVM
development of iLVM
appropriate LV M
500
100 150 200 250
difference in the magnitude of the reduction in LVM was
noted in the different CKD stages studied.
Complementarily, Schirmer etal. [19] assessed 66 resistant hypertensive patients and showed that LVMI decreased
and diastolic parameters including E-wave deceleration time,
isovolumetric relaxation time, and E’-wave velocity all
Fig. 7.2 Event-free survival (Kaplan–Meier method) in groups of
patients with persistence, regression, and development of inappropriate
LVM, and in patients with appropriate LVM from baseline to follow-up.
Log-rank Mantel-Cox test between curves of patients with persistence
of inappropriate LVM and curves of patients with regression of inappropriate LVM (P <0.0001) or with persistence of appropriate LVM
(P<0.001), between curves of patients with development of inappropriate LVM and curves of patients with regression of inappropriate
LVM (P =0.03), or of patients with persistence of appropriate LVM
(P=0.045) [12]. Reproduced with permission from [12]
improved. Furthermore, it occurred unrelated to systolic
blood pressure (SBP) reduction or heart rate (HR) 6months
post-RDN.Perhaps, these ndings point to the direct modulation of the SNS activity beyond its impact on BP with
potential impact on the exceedingly high risk of patienst with
resistant hypertension [16, 20].
Doltra etal. prospectively assessed 23 resistant hypertensive patients who had undergone cardiac-MRI and RDN
[21]. RDN led to a decrease in LVMI regardless of the
hypertension who are at exceedingly high cardiovascular
risk [16]. Subsequently, Mahfoud etal. [17] reported on a
series of 72 hypertensive patients, who were further investiagted with cardiac magnetic resonance imaging (MRI).
Fifty-ve patients underwent RDN, before and 6 months
after receiving renal denervation and 17 patienst served as
controls. RDN signicantly reduced systolic and diastolic
blood pressure and indexed left ventricular mass, which were
unchanged in the control group. In patients with inpaired left
BP-lowering effect, suggesting that RDN may additionally
reduce interstitial brotic tissue in the myocardium, i.e.
absolute collagen matter. If the observed LVMI regression
was exclusively owing to a reversion of myocyte hypertrophy, extracellular volume fraction would have been expected
to increase [21]. Whether this has a potential effect on the
prognosis and event reduction remains unknown. Besides,
Perlini etal. did previously demonstrate in rodents that interstitial brosis in the myocardium provoked by hypertension
NC
7 An Overview onHypertension Mediated Organ Damage
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Fig. 7.3 Left ventricular
mass index at baseline and
6-month follow-up in patients
undergoing renal denervation
(n=55) and controls (n=17),
depicted as individual
changes and average
values+standard deviation
[17]. Reproduced with
permission from [17]
90
80
70
)
60
1.7
50
LVMI (g/m
40
30
20
0
0
p < 0.001 p = 0.653
RD ontrol
improved with to α-adrenergic blockade or sympathectomy
[22], highlighting the inportance of adrenergic drive in this
context.
More recently, McLellan et al. [23] collected 24-hour
ambulatory-blood-pressure (ABPM), echocardiograms,
cardiac- MRI and performed electrophysiological studies in
14 subjects presenting with resistant hypertension prior to
and 6 months post-RDN. After RDN, the average ABPM
was reduced, while overall conduction velocity rose considerably, and the conduction interval was reduced. Also,
changes in conduction velocity and variations in average
ABPM correlated positively. In an ovine model, those with
chronic hypertension had left atrial remodelling on diverse
time-domains and a strong association between electrophysiologic properties and structure involved in the remodelling
ow. These successive morphological modications were
linked to conduction abnormalities and resulted in greater
atrial brillation inducibility and duration. Immediate antihypertensive therapy commencement may avoid the development of substrates able to maintain atrial brillation [24].
A marked reduction in MRI derived LV mass and diffuse
ventricular brosis was also observed [23], in keeping with
studies discussed above.
Likewise, one hundred consecutive resistant hypertensive
subjects who were subjected to RDN and who experienced an
average ofce systolic BP fall >10mm Hg at the 6month postRDN were studied by Dorr etal. [25]. Cardiac extracellular
matrix and CV brotic tissue reabsorption were assessed by
different pro-peptide types before RDN and at 6-month follow-up through blood biomarkers. A substantial ofce systolic
BP drop was reported 6months post-RDN.At this stage, the
serum levels of pro-peptides were remarkably reduced in comparison to values measured at the baseline in participants with
an intensied collagen turnover, demonstrating substantial
changes comparing patients who had a BP-lowering effect to
those who had not. These results point towards possible benecial effects of RDN on CV brosis in cohorts who have
hypertensive heart disease and cardiac brosis.
Animal studies found sympathetic activation mitigation
by RDN as assessed by renal catecholaminergic content
reduction [26]. Moreover, RDN importantly improved LV
longitudinal strain, reduced end-systolic volume and cardiac
brosis, enhancing cardiac performance. Remarkably, neprilysin activity reduction and brain natriuretic peptide (BNP)
levels increase were shown after RDN [27]. In congestive
HF, the excessive cardiac volume provokes BNP and atrial
natriuretic peptide release, both of which have diuretic and
cardioprotective effects [28, 29]. Heightened neprilysin
activity was uncovered to worsen LV dysfunction, as it enzymatically degrades natriuretic and other bioactive peptides;
and it is related to unfavourable outcomes. Therapeutically,
the HF population have enormously beneted from neprilysin inhibition by sacubitril/valsartan [30]. RDN induced
neprilysin inhibition may, therefore, contribute to its apparent cardioprotective effects.
RDN andtheKidneys
Denervation of the renal efferent nerves and renal afferent
nerves in animal models of CKD has been shown to attenuate hypertension and thus prevent further deterioration of
kidney function [31–34]. Hering etal. reported that RDN in
resistant hypertensive patients caused substantial BP fall and
rapid decrease in the ring properties of single sympathetic
vasoconstrictor bers, which was more pronounced than
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M. G. Kiuchi and M. P. Schlaich
multi-unit MSNA inhibition [15]. The disruption of sympathetic hyperactivity and the interruption of the reninangiotensin- aldosterone system feedback loop may partially
benet this population. In different stages of CKD, the presence of micro- and macro-albuminuria is not only an independent risk factor for cardiovascular events [35, 36], but
also predicts progression of CKD [37]. Along these lines, a
study reported that following RDN, the magnitude of albuminuria as well as the prevalence of micro- and macroalbuminuria was reduced in treatment-resistant hypertensive
patients [38]. Ott etal. analysed the change of renal function
over time before and after RDN amongst patients with CKD
and treatment resistant hypertension. Their ndings suggested that RDN decreases BP and slows or even halts the
decline of renal function in treatment-resistant hypertensive
patients with CKD stages 3 and 4 [39]. Hering etal. reported
that stage 3–4 CKD patients had a sustained reduction in
seated ofce BP measurements post-RDN [40]. Another
important observation from this pilot study was the absence
of further deterioration of renal function in this patient
cohort. Short- and mid-term follow-up of renal function
assessed by plasma and urine testing, as well as
99m
TcMAG- 3 scanning, demonstrated no evidence of aggravation
of renal impairment. Autoregulation of the kidney did not
appear to be adversely affected, as indicated by preserved
renal function despite substantial BP reduction [40]. Kiuchi
et al. presented a series of CKD-resistant hypertensive
patients who were followed up for 2years after RDN.Their
results indicate that RDN (stages 2–4) provided a signicant
reduction in BP and was associated with a long-term increase
in glomerular ltration rate (Fig. 7.4), and a signicant
160
140
)
2
120
100
80
60
40
20
eGFR (mL/min/1.73 m
0
Baseline
(n=30) (n=30) (n=30) (n=30)
Fig. 7.4 Estimated glomerular ltration rate (eGFR) at baseline and at
months 1, 3, 6, 12, 18, and 24 after renal denervation. Values are presented as mean ± standard deviation. *P< 0.0001 vs corresponding
baseline values. At months 18 and 24, patients who required chronic
renal replacement therapy (n= 3) were assigned an eGFR value of 0
[41]. Reproduced with permission from [41]
*
*
Months
*
*
12631
(n=30) (n=30) (n=30)
18 24
decrease in albumin excretion in patients with resistant
hypertension and CKD [41]. While these preliminary data
are encouraging, it merits further investigation in a larger
population.
Delacroix etal. also demonstrated that RDN resulted in
a 22% improvement in eGFR at 6months post-procedure.
Moreover, although not statistically signicant, there was
an 8% improvement in plasma creatinine with a drop in
plasma aldosterone levels in patients with higher baseline
values and a 16% increase in urine creatinine [42]. While it
is challenging to interpret these results owing to the limited
numbers, this data suggests that the improvement in total
blood ow per cardiac cycle post-RDN is probably not due
to local vascular resistance but rather due to more glomerular and tubular function resulting from decreased BP that
potentially resets the renal equilibrium. Furthermore, a
reduced heart rate possibly permits longer transition times
for blood ow through the kidneys enabling longer and better ltration. Similarly, this could be attributed to the
expansion of venous capacitance that likely occurs with
reductions in sympathetic nervous system activity leading
to greater intravascular volume and loading of the ventricle.
In another recent study, Schlaich etal. demonstrated that
end-stage renal disease (ESRD) individuals with poorly
controlled hypertension who received RDN experienced a
sustained systolic BP reduction and a signicant decrease
in MSNA over 12months, supporting the safety of RDN in
these patients [43].
For RDN to become an established treatment of hypertensive CKD, it is most important that renal function is not
adversely affected. Based on the data above, to examine
whether renal nerve function returned in the long-term,
Singh etal. examined vascular contraction to nerve stimulation in renal arteries and determined nerve regrowth by
assessing renal TH (tyrosine hydroxylase), CGRP (calcitonin gene-related peptide), and norepinephrine levels in kidneys at 30 months after RDN. RDN normalised BP in
hypertensive CKD sheep such that BP was similar to that of
the normotensive sheep with intact nerves. Glomerular ltration rate decreased by ~22% in CKD sheep with intact nerves
but increased ~26% in hypertensive CKD-RDN sheep by
30 months (Fig. 7.5). At 30 months, urinary albumin was
~127% and left ventricular mass was ~41% greater in CKD
sheep with intact nerves than control. However, urinary albumin was ~60% less and left ventricular mass was ~40% less
in the CKD sheep that underwent RDN compared with their
intact counterparts (Fig. 7.6). At 30months in CKD-RDN
sheep, neurovascular contraction (~56%), the renal proportion of TH (~50%), CGRP (~67%), and norepinephrine content (~49%) were all less compared to CKD-intact animals;
all these variables were similar between normotensive-intact
and normotensive-RDN groups. RDN provoked a sustained
reduction in BP and enhancements in renal function.
Months after RDN/sham
a
Urinary albumin (µg/ml)
control-intact
control-RDN
CKD-intact
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Fig. 7.5 Mean glomerular
ltration rate (GFR) at
6months of age (before renal
denervation [RDN]/sham) and
at 2, 5, 11, and 30months
after RDN or sham procedure
in normotensive healthy
(control) sheep or sheep with
hypertensive chronic kidney
disease (CKD). * P<0.05,
***P<0.001, ****
P<0.0001 vs. 6months, ##
P<0.01, ####P<0.0001
CKD-intact vs. CKD-RDN
[44]. Reproduced with
permission from [44]
Fig. 7.6 Urinary albumin
and left ventricle mass. (a)
Urinary albumin and (b) left
ventricular (LV) mass in
normotensive healthy
(control) sheep and sheep
with hypertensive chronic
kidney disease (CKD) at 11
and 30 months after renal
denervation (RDN) or sham
(intact) procedure. *P<0.05,
**P<0.01 comparing
control-intact with CKDintact; #P<0.05, ##P<0.01
comparing CKD-RDN with
CKDintact; †P<0.05
comparing effect of age
within CKD-intact [44].
Reproduced with permission
from [44]
400
300
200
100
0
Glomerular
Filtration
Rate
(mI/min/bwt)
pre-RDN/
*
11 months
Months after RDN/sham
3
2
1
0
sham
#
61012
RDN
30 months
30 months post RDN
***
*
##
####
15
control-intact
CKD-intact CKD-RDN
**
21 40
post-RDN/sham
age (months)
control-RDN
*P<0.05, ***P<0.001, ***P<0.0001 vs 6 months
## P<0.01, ####P<0.0001 CKD-intact vs CKD-RDN
b
250
##
200
150
100
LV mass (g)
50
0
11 months
****
####
N=5-7/group
CKD-RDN
†
30 months
#
**
Regrowth of renal nerves and the return of function were
observed in hypertensive CKD-RDN sheep, but levels were
only partially restored [44]. These ndings suggest that RDN
reduces BP in the long-term and is renoprotective and cardioprotective in CKD. In line with clinical studies, these
ndings demonstrate that RDN may improve renal function
in the long-term in CKD and be considered as an exciting
potential approach for treating kidney diseases.
Preservation of renal function is an essential therapeutic
target as it will delay the onset of ESRD and the need for
renal replacement therapy with substantial benets regarding the patient quality of life and healthcare costs. Given
that chronic sympathetic activation leads to the progression
of CKD [45–47] the increase in glomerular ltration rate
(GFR) and renal blood ow (RBF) is likely to be driven by
a reduction in sympathetic ouow after RDN.Another possibility is that sympathetically mediated vasoconstriction
of renal vascular beds over time may be reduced in the
CKD sheep following denervation resulting in an overall
decrease in renal vascular resistance (RVR). This may be
associated with improvements in nitric oxide bioavailability and reduction in oxidative stress-known drivers of CKD
in this model [48].
It is important to note that there are potential alternative
explanations, i.e. the increase in GFR may be indicative of
single nephron hyperltration, which in turn due to glomerular hypertension, may herald an accelerated decline in GFR
in the future. However, this hyperltration if associated with
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M. G. Kiuchi and M. P. Schlaich
glomerular hypertrophy or the observed increase in RBF
after RDN and potentially altering the point of glomerular
ultraltration equilibrium, may not cause further glomerular
damage [49]. Indeed, the reduction in albuminuria observed
with RDN in CKD suggests that the improved GFR does not
negatively inuence the integrity of the glomerular basement
membrane. Nevertheless, further investigations into the
exact mechanisms via which RDN improves GFR are
warranted.
RDN andBlood Vessels
Often summarised as pulsatile hemodynamics, arterial stiffness (pulse wave velocity [PWV]), wave reections, and
central (aortic) hemodynamics can be easily quantied noninvasively with good reproducibly [50, 51]. Arterial wave
reections predict cardiovascular events [52–55], independent of brachial BP, and may be more sensitive than brachial
BP to detect antihypertensive drug-induced hemodynamic
changes [56, 57]. Recently, assessment of pulsatile hemodynamics with dedicated brachial cuffs, suitable for 24-hour
ABPM, became commercially available [58, 59].
Wave reections are thought to arise at sites of impedance
change or mismatch along the arterial tree, such as points of
branching, change in lumen diameter (taper) and structural
properties [50]. Multiple small reections, originating from
distributed reection sites, are transmitted back toward the
heart and merge and summate into a single net reected wave
[50]. Wave reections cannot be detected from conventional
(auscultatory or oscillometric) BP measurement, but may be
quantied from pressure waveforms alone, yielding augmentation index (Aix), heart-rate corrected augmentation index
(AIx75) and pressure augmentation (AP), or through combined analysis with ow waveforms, yielding backward
wave amplitude (Pb). As a more sensitive measure of BP,
wave reections provide closer insights into hypertension
associated organ damage [54], cardiac function [60] and the
risk of cardiovascular events [52–54], as compared with brachial BP. Compared with brachial BP, measures of wave
reections are more sensitive to monitor antihypertensive
drug-induced hemodynamic changes [61] as well as changes
of hypertension-mediated organ damage [56, 57]. RDN has
previously been shown to attenuate wave reections in
patients with resistant hypertension [62, 63]. Changes in
AIx75 following RDN, however, were not related to changes
in muscle sympathetic nerve activity (MSNA) [62].
Hering etal. [62] assessed ofce BP and arterial stiffness
using ngertip tonometry-derived augmentation index at
baseline and at 3-month follow-up in 50 consecutive resistant hypertensive patients. Forty patients underwent RDN
and 10 patients served as controls. MSNA was obtained in 20
RDN and 10 non-RDN patients. RDN signicantly reduced
SBP (170±19 vs. 154±25mm Hg; P<0.001) and DBP
(92±15 vs. 84±16mm Hg; P<0.001), augmentation index
(30.6±23.8 vs. 22.7±22.4%; P=0.002), AI@75 corrected
for heart rate (22.4±21.6 vs. 14.4± 20.7; P = 0.002) and
MSNA (80±15 vs. 71±18 bursts/100 heartbeats; P<0.01).
Changes in AI@75 with RDN were unrelated to SBP
(r= 0.043; P= 0.79), and DBP (r =0.092; P =0.57) and
MSNA changes (r= −0.17; P =0.49). No changes in BP,
augmentation index, AI@75 or MSNA were observed in the
non-RDN group. Hence, RDN led to a remarkable and fast
reduction in augmentation index, which appears to be independent of BP and MSNA changes. These ndings suggest a
benecial effect of RDN on arterial stiffness in patients with
resistant hypertersion.
Brandt etal. [63] evaluated 110 patients who underwent
bilateral RDN. Radial artery applanation tonometry and
pulse wave analysis were used to derive central aortic pressure and hemodynamic indices at baseline and 1, 3, and
6months after ablation. Ten patients with resistant hypertension who did not undergo RDN served as controls. RDN signicantly reduced mean central aortic BP from 167/92mm
Hg to 149/88mm Hg, 147/85mm Hg, and 141/85mm Hg at
1, 3, and 6 months (p < 0.001), respectively. Aortic pulse
pressure decreased from 76.2 ± 23.3 mm Hg to
61.5±17.5mm Hg, 62.7±18.1mm Hg, and 54.5±15.7mm
Hg 1, 3, and 6months after RDN (p<0.001), respectively.
Six months after RDN aortic augmentation and augmentation index were signicantly reduced by −11 mm Hg
(p<0.001) and−5.3% (p<0.001), respectively. Carotid to
femoral pulse wave velocity showed a signicant reduction
from 11.6±3.2m/s to 9.6±3.1m/s at 6months (p<0.001).
Consistently, ejection duration and aortic systolic pressure
load were signicantly diminished, indicating improvement
of cardiac work load by RDN.No signicant changes were
obtained in control patients. Besides the known RDN
lowering- effect on brachial BP, Brandt etal. [63] showed this
approach signicantly improved arterial stiffness and central
hemodynamics, which might have important prognostic
implications in patients with resistant hypertension at high
cardiovascular risk.
Mortensen etal. [64] submited 21 hypertenseve patients
(systolic peripheral BP ≥150 mm Hg) to RDN. After
6 months, peripheral systolic BP was reduced by 6.1%
(P < 0.05) while central systolic pressure was reduced by
7.0% (P<0.05). Subgroup analysis showed that in responders, peripheral systolic BP was reduced by 16.1% (P<0.01)
while central systolic pressure was reduced by 18.3%
(P < 0.01). Arterial stiffness improved signicantly. AIx
improved by 9.5% (P<0.05). In responders, AIx improved
by 19.2% (P<0.02). PWV was high at baseline (10.8m/s)
and improved by 10.4% (P < 0.05). In responders, PWV
improved by 13.7% (P<0.05). Multivariate analysis showed
that short-term effects on PWV were BP-related, whereas
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during follow-up, improvement of PWV becomes
BP-unrelated. So, these ndings may lead to a better cardiovascular outcome.
Ott etal. [65] treated 94 resitant hypertensive patients by
catheter-based RDN approach. Ambulatory BP, including
central pressures, hemodynamics, and arterial stiffness were
measured at baseline and 3, 6, 12months after RDN by an
oscillometric device. At 3, 6, and 12-month follow-ups, brachial ambulatory BP was reduced (P for all <0.001).
Consistently, central ambulatory BP was reduced (P for all
<0.001). Ambulatory assessed averaged daytime pulse wave
velocity improved after RDN (P<.05). Total vascular resistance decreased (P for all < .01). In patients with resistant
hypertension, RDN improved brachial and central ambulatory BP, arterial stiffness, and total vascular resistance, indicating an improvement of cardiovascular outcome.
On the other hand, in the ReSET trial [66], which was a
randomised, sham-controlled and double-blinded trial, central BP, carotid-femoral PWV, and heart rate variability
(HRV) were obtained at baseline and after 6months postRDN.Fifty-three patients (77% of the ReSET-cohort) were
included in this substudy. The groups were similar at baseline (SHAM/RDN): n = 27/n = 26; 78/65% males; age
59 ± 9/54 ± 8 years (mean ± SD); systolic brachial BP
158±18/154±17mm Hg; systolic 24-hour ambulatory BP
153 ± 14/151 ± 13 mm Hg. Changes in PWV (0.1 ± 1.9
(SHAM) vs. −0.6±1.3 (RDN) m/s), systolic C-BP (−2±17
(SHAM) vs. −8±16 (RDN) mm Hg), diastolic C-BP (−2±9
(SHAM) vs. −5±9 (RDN) mm Hg), and augmentation index
(0.7±7.0 (SHAM) vs. 1.0±7.4 (RDN) %) were not signicantly different after 6months. Changes in HRV-parameters
were also not signicantly different. Baseline HRV or PWV
did not predict BP-response after RDN.Due to this results,
the authors concluded that in a sham-controlled setting, there
were no signicant effects of RDN on arterial stiffness, central BP and HRV.
Kordalis etal. [67] performed a meta-analysis including 4 studies in which results regarding AIx before and
after RDN (n=186 patients) were reported. The followup duration was 6 months in three studies (n = 146
patients) and 3 months in one study (n = 40 patients).
There was no heterogeneity among the reviewed trials
(I2=0%, Q=1.52, P=0.677). The pooled effect size of
RDN on AIx was −7.05 (95% CI -9.12 to −4.98, P<0.001;
baseline mean −48.98, 14.39% reduction) (Fig. 7.7).
Sensitivity analyses after excluding the only study with
3months follow-up was conrmatory of the initial result.
Kordalis et al. [67] also asseded PWV measurements
before and after RDN that were reported in four studies
(n=158). The follow-up duration was 6months in all of
them, whereas the study of Baroni etal. [68] was reporting measurements both in 6 and 12months. The outcome
of 6months was used in the meta-analysis for homogeneity reasons. The variation in effect size attributable to heterogeneity was moderate (I2 = 53.2%, Q = 6.42,
P = 0.093). RDN treatment reduced PWV by 1.54 m/s
(95% CI −2.16 to −0.92, P < 0.001; baseline
mean= 11.35 m/s, 13.57% reduction) (Fig. 7.7). In this
meta-analysis, central hemodynamics and arterial stiffness, were improved in resistant hypertensive patients
after RDN [69, 70]. In concordance with cardiac HMOD
regression, the reduction in PWV and AIx was independent from BP-lowering effect suggesting a RDN-related
reduction of both total body (measured by MSNA) and
renal sympathetic activity (measured by norepinephrine
spillover) [71]. AIx is a composite measure of the magnitude (e.g. vasoconstriction of peripheral blood vessels,
which is under control of sympathetic system) and the
Fig. 7.7 Forest plots of indices of arterial stiffness. (a) Forest plot
demonstrating the changes in AIx among prospective studies following
RDN. (b) Forest plot demonstrating the changes in PWV among pro-
spective studies following RDN. AIx augmentation index, CI condence interval, ES effect size, PWV pulse wave velocity, RDN renal
denervation [67]. Reproduced with permission from [67]
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M. G. Kiuchi and M. P. Schlaich
timing of wave reection, which itself is affected by an
earlier return of the pulse wave as a result of an increased
PWV because of arterial stiffness. RDN affected pulse
wave reection via a reduction in peripheral resistance,
also resulting in a reduction of central BP [69, 70]. In
addition to RDN-induced reduction of vasoconstrictive
factors, improvement in endothelial function and intramural vascular remodeling processes may have additionally
contributed to reduction in arterial stiffness and wave
reections [15]. In analogy with antihypertensive strategies that target the renin–angiotensin system and improve
arterial stiffness, modication of sympathetic tone by
RDN may induce favorable structural and functional
alterations independent of BP lowering [72].
Conclusion andFuture Research Directions
Hypertension mediated organ damge is an important predictor of CV events in patients with elevated BP and regressin
of HMOD has been associated with improved outcomes CV
[1–9]. While BP lowering per se is expected to facilitate
regression of HMOD to some extent, the data provided above
is reassuring in that it demonstrates that RDN induced BP
lowering indeed is associated with regressin of LVH, reduction of microalbuminuria, reduced progression of the decline
of eGFR, and benecial hemodynamic and vascular changes.
The demonstration of HMOD regression with RDN even in
the absence of signifcant BP changes points to the potential
additional benet of lowering of sympathetic nerve activity,
which in itself may have salutary effects on HMOD.Further
studies in larger cohorts of patienst with various degrees of
elevated BP and longer term adequately designed studies
using established markers of HMOD will be required to substantiate the notion of long term organ protection with RDN,
that may at least in part be due to factors beyond BP lowering
alone.
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