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Changes in renal artery dimensions are associated with response to radiofrequency renal denervation. A series of studies using quantitative angiography and intravascular ultrasound.

Thomas Weber, MD, Associate Professor; Jörg Kellermair, MD; Karen Th. Witberg, RN; Jurgen Ligthart, RT; Robert J. Melder, ScD; Thomas Forstner, MStat; Bernd Eber, MD, Professor

Parameter RRA pre RRA post RRA FU LRA pre LRA FU p-value RRA

vs LRA pre / FU

p-value RRA pre vs post

p-value pre vs FU left / right RA

p-value post vs FU

right RA Mean diameter mm 5.50 (0.56) 4.74 (0.60) 5.54 (0.48) 5.78 (0.57) 5.85 (0.55) <0.001 /

<0.001 <0.001 0.405 /

0.609 <0.001 Minimum diameter

mm 5.03 (0.59) 3.02 (0.76) 4.88 (0.68) 5.29 (0.58) 5.41 (0.5) 0.003 /

<0.001 <0.001 0.197 /

0.144 <0.001 Mean area mm² 24.07 (4.77) 18.63 (4.40) 24.4 (3.98) 26.53 (4.89) 27.2 (4.99) <0.001 /

<0.001 <0.001 0.423 /

0.627 <0.001 Minimum area mm² 20.14 (4.62) 7.60 (3.56) 19.07 (4.84) 22.31 (4.58) 23.24 (4.24) 0.002 /

<0.001

<0.001 0.220 / 0.147

<0.001

Table S1: Changes in QRA parameters induced by RDN in the animal study. RRA … right renal artery; LRA … left renal artery; min … minimal;

pre … pre RDN; post … post RDN; FU … at 7 day follow up. Numbers indicate mean values (standard deviations)

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QRA Parameter Correlation coefficient p-value

Mean diameter post RDN 0.331 0.048

Mean area post RDN 0.342 0.041

Minimum diameter at FU 0.412 0.013

Mean diameter at FU 0.385 0.020

Minimum area at FU 0.411 0.013

Mean area at FU 0.377 0.023

Table S2: Correlations between QRA parameters of right renal artery post RDN and at 7 day FU and NE content of the right kidney, expressed as Bravais-Pearson correlation coefficients.

QRA Parameter p-value

Minimum diameter 0.005

Mean diameter 0.013

Minimum area 0.005

Mean area 0.015

Table S3: P-values, calculated according to

¹

, for the comparison of correlated but non-overlapping correlations-coefficients, indicate differences in

the relationship between NE content and QRA parameters at 7 day FU between the treated (right) and the untreated (left) kidney.

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Men/women 29/14

Age years 61.1 (10.4)

Sum ablation points 9.8 (2.0)

Body height cm 170.0 (8.7)

Body weight kg 91.6 (14.0)

Body mass index kg/m2 31.7 (4.8) Serum creatinine mg/dl 1.1 (0.3)

Estim GFR ml/min 62.5 (10.2)

SBP office mm Hg 172 (21)

DBP office mm Hg 96 (13)

SBP 24h mm Hg 150 (13)

DBP 24h mm Hg 96 (13)

Accessory renal artery right/left 7/9 Normal systolic function 37 (86%) Coronary artery disease 19 (44.2%)

Atrial fibrillation 5 (11.6%)

Diabetes mellitus 23 (53.5%)

Δ 24-hour SBP 1 month mm Hg -8 (16) Δ 24-hour DBP 1 month mm Hg -4 (9) Δ 24-hour SBP 12 months mm Hg -12 (16) Δ 24-hour DBP 12 months mm Hg -6 (8) Number of antihypertensives baseline 4.7 (1.1) Angiotensin receptor blocker 22 (51.2%)

ACE inhibitor 18 (41.9%)

Renin antagonist 2 (4.7%)

Alpha blocker 16 (37.2%)

Betablocker 39 (90.7%)

Thiazide type diuretic 43 (79.1%)

Loop diuretic 4 (9.3%)

Spironolactone 15 (34.9%)

Calcium channel blocker 35 (81.4%) Centrally acting antihypertensive 17 (39.5%) Number of antihypertensive drugs 1 year 4.7 (1.3)

Table S4: Baseline characteristics of the QRA human study

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QRA parameter Mean value Standard deviation

Mean diameter pre RDN mm 5.40 0.86

Mean diameter post RDN mm 5.30 0.91

Δ mean diameter mm -0.10 0.23

Δ mean diameter % -1.97 4.50

Minimum diameter pre RDN mm 4.79 0.78 Minimum diameter post RDN mm 4.32 0.93

Δ minimum diameter mm -0.47 0.44

Δ minimum diameter % -10.25 9.56

Mean area pre RDN mm² 24.15 8.40

Mean area post RDN mm² 23.11 7.97

Δ mean area mm² -1.04 2.64

Δ mean area % -3.95 9.10

Minimum area pre RDN mm² 18.52 6.06

Minimum area post RDN mm² 15.50 6.59

Δ minimum area mm² -3.02 3.05

Δ minimum area % -17.47 17.10

Volume pre RDN mm³ 1244.29 513.83

Volume post RDN mm³ 1194.12 484.94

Δ volume mm³ -50.17 156.87

Δ volume % -3.59 9.38

Table S5: QRA parameters in the human study.

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Responder Non-Responder ^p-value

Responder a (minus 5 mm Hg 24-hour SBP OR DBP) 28 11

Δ minimum diameter mm -0.58 (0.47) -0.21 (0.28) 0.02

Δ minimum diameter % -12.5 (10.3) -5.2 (6.8) 0.094

Δ minimum area mm² -3.8 (3.1) -0.9 (2.2) 0.009

Δ minimum area % -21.8 (17.6) -7.2 (14.2) 0.02

Responder b (minus 5 mm Hg 24-hour SBP) 26 13

Δ minimum diameter mm -0.61 (0.48) -0.21 (0.26 0.01

Δ minimum area mm² -4.0 (3.2) -0.9 (2.0) 0.003

Δ minimum area % -22.9 (17.7) -7.3 (13.1) 0.008

Responder c (minus 10 mm Hg 24-hour SBP) 20 19

Δ minimum area mm² -4.1 (3.6) -2.0 (2.4) 0.04

Δ minimum area % -23.4 (19.8) -12.2 (14.1) 0.05

Responder d (minus 5 mm Hg 24-hour DBP) 19 20

Δ minimum area mm² -3.9 (3.5) -2.1 (2.6) 0.07

Δ minimum area % -24.2 (19.8) -11.5 (13.3) 0.02

Responder e (minus 10 mm Hg 24-hour DBP) 13 26

Δ minimum area mm² -4.5 (3.7) -2.2 (2.6) 0.03

Δ minimum area % -28.2 (21.0) -12.4 (13.6) 0.007

Table S6: Responder status to RDN at one year, based on different blood pressure changes, and QRA parameters (human study)

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QRA parameter Δ SBP 1 Mon Δ DBP 1 Mon Δ SBP 12 Mon Δ DBP 12 Mon Mean diameter post RDN mm 0.39* 0.40*

Δ mean diameter mm 0.33*

Δ mean diameter % 0.33*

Minimum diameter post RDN mm 0.34* 0.42^#

Δ minimum diameter mm 0.39* 0.46^$

Δ minimum diameter % 0.35* 0.46^$ 0.46^$

Mean area post RDN mm² 0.36* 0.37*

Δ mean area mm² Δ mean area %

Minimum area post RDN mm² 0.37*

Δ minimum area mm² 0.42^#

Δ minimum area % 0.32* 0.43^# 0.46^$

Volume post RDN mm³ 0.40* 0.37* 0.40*

Table S7: Relationships between QRA measurements post RDN, their changes pre/post RDN, and changes in mean 24-hour blood pressures. Only

statistically relevant relationships are shown. ... p<0.05,*

^#

... p<0.01,

^$

... p<0.005

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Gender men/women 10/7

Age years 61.9 (12.4)

Body height cm 171.2 (9.2)

Body weight kg 96.8 (12.2)

Body mass index kg/m² 33.1 (4.7)

Serum creatinine mg/dl 1.05 (0.27)

HbA1c % 7.02 (1.41)

Diabetes n (%) 11 (64.7)

Accessory renal artery right/left 3/2

Coronary artery disease n (%) 4 (23.5%)

Atrial fibrillation n (%) 3 (17.6%)

Office SBP baseline mm Hg 168 (18)

Office DBP baseline mm Hg 96 (15)

24-hour SBP baseline mm Hg 152 (12)

24-hour DBP baseline mm Hg 88 (11)

Δ 24-hour SBP 1 month mm Hg -11 (11) Δ 24-hour DBP 1 month mm Hg -6 (9) Δ 24-hour SBP 12 month mm Hg -18 (15) Δ 24-hour DBP 12 month mm Hg -9 (10)

Catheter type: Flex / Spyral 9 / 8

Number ablation points n 11.8 (3.8)

Procedure time minutes 65.9 (9.4)

Number antihypertensive drugs n 5.5 (1.1)

Angiotensin receptor blocker n (%) 13 (75.5%)

ACE inhibitor n (%) 4 (23.5%)

Renin antagonist n (%) 0 (0%)

Alpha blocker n (%) 5 (29.4%)

Betablocker n (%) 16 (94.1%)

Thiazide type diuretic n (%) 17 (100%)

Loop diuretic n (%) 2 (11.8%)

Spironolactone n (%) 11 (64.7%)

Calcium channel blocker n (%) 15 (88.2%)

Centrally acting antihypertensive n (%) 11 (64.7%)

Number antihypertensive drugs 1 year 5.2 (1.6)

Table S8: Baseline characteristics of the patients in the IVUS study

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Independent variables Coefficient Std. Error rpartial p-value

Δ Minimum lumen area mm² 0.53 0.19 0.64 0.018

Table S9: Multiple regression model to predict the change in 24-hour SBP at 1 month (coefficient of determination R

²

= 0.46) - IVUS study.

Baseline 24-hour SBP and catheter type did not reach statistical relevance.

Independent variables Coefficient Std. Error rpartial p-value

Δ Minimum lumen area mm² 0.37 0.15 0.61 0.028

Table S10: Multiple regression model to predict the change in 24-hour DBP at 1 month (coefficient of determination R

²

= 0.57) - IVUS study.

Baseline 24-hour DBP and catheter type did not reach statistical relevance.

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Flex system Spyral system p-value

n 9 8

Gender men/women 4/5 6/2 0.52

Age years 63.2 (11.1) 60.5 (14.3) 0.67

Body height cm 169.2 (10.3) 173.5 (7.8) 0.35

Body weight kg 95.9 (16.0) 97.8 (12.9) 0.79

Body mass index kg/m² 33.4 (4.0) 32.7 (5.6) 0.75

Serum creatinine mg/dl 1.08 (0.28) 1.03 (0.27) 0.70

HbA1c % 7.04 (1.26) 7.0 (1.64) 0.95

Diabetes n (%) 6 (66.7%) 5 (62.5 %) 0.93

Accessory renal artery right/left 1/2 2/0 0.92

Coronary artery disease n (%) 3 (33.3 %) 1 (12.5 %) 0.47 Atrial fibrillation n (%) 2 (22.2 %) 1 (12.5 %) 0.74

Office SBP baseline mm Hg 169 (17) 168 (21) 0.91

Office DBP baseline mm Hg 103 (12) 89 (14) 0.04

24-hour SBP baseline mm Hg 154 (12) 151 (13) 0.66

24-hour DBP baseline mm Hg 90 (12) 86 (9) 0.57

Δ 24-hour SBP 1 month mm Hg -14 (13) -8 (7) 0.31

Δ 24-hour DBP 1 month mm Hg -8 (10) -5 (7) 0.47

Number ablation points n 9 (2) 15 (3) 0.0003

Number antihypertensive drugs n 5.4 (1.0) 5.4 (1.2) 0.92 Angiotensin receptor blocker n (%) 6 (66.7%) 7 (87.5%) 0.71

ACE inhibitor n (%) 3 (33.3%) 1 (12.5%) 0.42

Alpha blocker n (%) 1 (11.1%) 4 (50%) 0.19

Betablocker n (%) 9 (100%) 7 (87.5%) 0.85

Thiazide type diuretic n (%) 9 (100%) 8 (100%) 1.0

Loop diuretic n (%) 1 (11.1%) 1 (12.5%) 0.94

Spironolactone n (%) 7 (77.8%) 4 (50%) 0.58

Calcium channel blocker n (%) 8 (88.9%) 7 (87.5%) 0.98 Centrally acting antihypertensive n (%) 6 (66.7%) 5 (62.5%) 0.93

Table S11: Baselines characteristics and blood pressure response in the two treatment groups.

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Parameter Pre RDN overall Pre RDN Flex Pre RDN Spyral p-value Lumen volume mm³ 791.3 (280.2) 674.4 (278.2) 922.8 (231.8) 0.07 Vessel volume mm³ 1020.7 (342.8) 890.8 (348.9) 1166.7 (288.9) 0.10 Wall volume mm³ 229.4 (75.5) 216.4 (84.3) 243.9 (66.7) 0.47 Minimum lumen area mm² 23.5 (5.4) 22.9 (5.3) 24.2 (5.7) 0.63 Minimum vessel area mm² 31.4 (5.7) 31.0 (5.5) 31.7 (6.3) 0.81 Minimum wall area mm² 5.7 (1.1) 5.9 (1.2) 5.4 (1.0) 0.38 Maximum wall area mm² 12.6 (3.0) 13.1 (3.4) 12.1 (2.6) 0.38

Table S12: IVUS parameters pre RDN in the two treatment groups

Parameter Δ % overall group Δ % Flex Δ % Spyral p-value

Lumen volume -8.9 (10.4) -14.1 (11.4) -3.1 (4.9) 0.02

Vessel volume -5.6 (9.4) -10.4 (10.3) -0.2 (4.2) 0.02

Wall volume 6.9 (11.0) 2.9 (12.2) 11.4 (8.1) 0.11

Minimum lumen area -10.5 (13.9) -16.3 (15.7) -3.9 (8.1) 0.06

Minimum vessel area -6.8 (12.2) -13.6 (12.4) 0.8 (6.2) 0.009

Minimum wall area 5.3 (10.6) 6.3 (13.2) 4.3 (7.5) 0.71

Maximum wall area 14.1 (21.1) 8.7 (24.5) 20.1 (15.8) 0.28

Table S13: Changes in IVUS parameters following RDN in the two treatemt groups

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