Association between renal sympathetic denervation and arterial stiffness: the ASORAS study

INTRODUCTION

Whereas adequate antihypertensive therapy has demonstrated to reduce cardiovascular risk in hypertensive patients, blood pressure (BP) control is achieved in merely 40% of all patients receiving medical treatment [1–4].

To date, sympathetic renal denervation (RDN) is the most widely studied invasive antihypertensive treatment modality. Six randomized sham-controlled trials demonstrated that RDN significantly lowers systolic ambulatory blood pressure (ABP) by 4–8 mmHg in the absence of major adverse events [5–10]. Yet, about one in three patients does not experience a significant reduction (> 5 mmHg) in systolic ABP following RDN [6,7,10–12]. Previous studies have identified a variety of patient-related and procedure-related predictors as well as pharmacological predictors of response [13–20]. Nevertheless, the reproducibility of these findings is limited, warranting further research on the topic.

Arterial stiffness has emerged as an independent cardiovascular risk factor, which is highly prevalent among hypertensive patients [21,22]. Arterial stiffness hampers the physiological transition of pulsatile flow into steady flow in the microcirculation [23]. Both hypertension and arterial stiffness are strongly related to increased sympathetic activity [24–26]. Arterial wall stiffness can be assessed by measuring pulse wave velocity (PWV), local aortic distensibility (AoD), or by the ambulatory arterial stiffness index (AASI) [27,28].

In previous research, invasively measured PWV, magnetic resonance (MR) AoD and AASI were identified as independent predictors of the BP response to RDN [29–33]. Moreover, reductions in PWV, AoD, and cardiac remodeling were observed post RDN [34–37]. In contrast to the extensively studied role of invasive PWV, little data is available on noninvasively measured arterial stiffness indices in relation to RDN response [32]. Consequently, the aim of this study was to assess effect modification of the BP response following RDN by noninvasive arterial stiffness parameters at baseline, including PWV, in patients with resistant hypertension, as well as to assess how these parameters change over time following RDN.

MATERIALS AND METHODS Study design

This study was a prospective, single-arm pilot study performed in the Erasmus University Medical Center (Rotterdam, The Netherlands).

Study population

Adult patients were eligible when their systolic office blood pressure (OBP) was at least 140 mmHg and mean 24-h systolic ABP was at least 130 mmHg despite the use of three or more antihypertensive drugs (including at least one diuretic). A lower number of antihypertensive drugs was allowed only in case of documented intolerance to three or more classes of antihypertensive drugs. Exclusion criteria were pregnancy, renal artery anatomy ineligible for RDN, estimated glomerular filtration rate (eGFR) less than 45 ml/min per 1.73 m2, known secondary causes of hypertension (except obstructive sleep apnea syndrome) and any contra-indications for MR imaging. Anatomical exclusion criteria involved renal artery diameter less than 4 mm, renal artery length less than 20 mm, renal artery stenosis at least 50%, renal artery aneurysm or previous renal artery intervention. All patients provided written informed consent. The center's local ethics committee approved the study protocol and the study was conducted in accordance with the Declaration of Helsinki.

Blood pressure measurement

Standardized OBP measurement was performed using the Omron M10-IT device (OMRON Healthcare Europe, Hoofddorp, The Netherlands) [38]. Measurements were performed in both arms, and two additional readings were obtained from the arm with the initial highest reading. OBP was calculated as the average of the last two measurements. Twenty-four hour ABP measurements were performed using the Spacelabs 90217A device (Spacelabs Healthcare, Snoqualmie, Washington, USA). AASI was calculated as 1 − the regression slope of diastolic versus systolic ABP measurements, reflecting a parallel relationship between arterial stiffness and AASI increase [28].

MRI

Patients were scanned on a clinical 1.5T MR imaging system (Discovery MR450 or SIGNA Artist, both GE Healthcare, Milwaukee, Wisconsin, USA) using a dedicated cardiac/anterior array coil. The cardiovascular magnetic resonance (CMR) protocol for left-ventricular (LV) mass, volumes and function involved a retrospectively ECG-gated balanced steady-state free precession (SSFP) cine imaging with breath-holding. A contiguous stack of LV short-axis views was obtained from base to apex. Typical scan parameters were slice thickness 8.0 mm, slice gap 2.0 mm, repetition time/echo time (TR/TE) 3.7/1.6 ms, flip angle 75°, field of view (FOV) 380 × 340 mm, acquired matrix 160 × 192 and 24 phases per cardiac cycle. Functional analysis was performed on short-axis images by manually drawing epicardial and endocardial contours in end-systolic and end-diastolic phase. Papillary muscles were included in the mass and excluded from the volume. LV end-diastolic and end-systolic volume and LV mass were measured. Consequently, these parameters were used to calculate LV stroke volume, ejection fraction and cardiac output. Maximal LV wall thickness was also measured at the short-axis views. Volumes and mass were indexed by body surface area (BSA) as calculated using the formula from Du Bois and Du Bois [39].

Similarly, the protocol for MR-PWV measurement involved a free-breathing, retrospectively ECG-gated 2D phase-contrast flow sequence. The slice plane was positioned at the level of the pulmonary artery perpendicular to the ascending and descending aorta. Typical scan parameters were FOV 420 × 315 mm, matrix size 256 × 256, slice thickness 5.0 mm, flip angle 30°, TR/TE 4.5/2.4 ms, views per segment 1, NEX 2, velocity encoding value 200 cm/s, true temporal resolution ∼11 ms and number of reconstructed phases 100 per cardiac cycle. Aortic arch PWV was calculated by dividing the distance between ascending and descending aorta by the delta time of the systolic wave front [40]. The onset of the systolic wave front was calculated as the time point at the intersection between the tangent of the velocity upslope and the constant diastolic velocity. The length of the aortic segment between the ascending and descending aorta was quantified from a sagittal angulated multislice 3D retrospectively ECG-gated balanced SSFP acquisition during breath-hold. Typical scan parameters were slice thickness 8.0 mm, slice gap – 4.0 mm, TR/TE 2.8/1.3 ms, flip angle 45°, FOV 360 × 290 mm and acquired matrix 192 × 160.

Subsequently, MR-AoD was measured using a retrospectively ECG-gated 2D balanced SSFP sequence during breath-hold. This scan was obtained perpendicular to the ascending aorta at the level of the pulmonary trunk. Typical scan parameters were FOV 420 × 315 mm, matrix size 256 × 192, slice thickness, 8.0 mm, flip angle 45°, TR/TE 3.1/1.4 ms and number of reconstructed phases 24 per cardiac cycle. The ascending aortic contours were manually traced in all phases. MR-AoD was calculated by dividing the difference between the maximum and minimum aortic area (in mm2) by the product of the minimum aortic area and the brachial pulse pressure (in mmHg).

Combined with the CMR, renal artery MR angiography was performed at baseline and throughout follow-up to evaluate the occurrence of any significant renal artery stenosis. The protocol for these measurements has been described previously [41].

CMR analyses were performed using QMass 8.1 software (Medis, Leiden, The Netherlands) for cardiac volumes, mass and function whereas MR-PWV and MR-AoD were assessed using MASS software (LUMC, Leiden, The Netherlands). All analyses were performed by the first author (V.Z.) under supervision of an experienced imaging cardiologist with more than 20 years of MR imaging experience (A.H.).

Transthoracic echocardiography and carotid–femoral pulse wave velocity measurement

TTE was performed and analyzed according to institutional guidelines by a cardiologist specialized in echocardiography (M.G.). Data were obtained on E/e ratio, forward stroke volume index (adjusted for BSA) and valvulo-arterial impedance (Zva).

For CF-PWV, pulse wave transition time was calculated using Doppler ultrasound combined with electrocardiography tracing [42]. The distance used in the calculation was estimated as 80% of the carotid–femoral distance when measured by tape measure [43]. CF-PWV was calculated by dividing the carotid–femoral distance by the pulse wave transition time. All Doppler images were assessed by a single author (V.Z.).

Intervention

RDN procedures were performed under conscious sedation, using fentanyl and midazolam. Unfractionated heparin was administered to achieve an activated clotting time of at least 250 s. After administration of local anesthesia, ultrasound-guided common femoral artery access was achieved and a 6 French sheath was introduced. After engaging the renal arteries, selective angiography was performed to confirm anatomical eligibility for RDN. Patients with eligible renal anatomy consequently underwent radiofrequency ablations in four quadrants of the left and right main renal arteries using the Symplicity Flex single-electrode or Symplicity Spyral multi-electrode radiofrequency RDN system (Medtronic; Minneapolis, USA).

Baseline examinations and follow-up

Patients had a preprocedural baseline visit and were followed up through clinical visits at 1, 3, 6 and 12 months after the index procedure. Evaluation of any adverse events and medication regimen, physical examination, OBP measurements and laboratory testing were performed during each visit. ABP was measured at all visits except for the 1-month visit. TTE (including CF-PWV measurement) and MR imaging (including CMR, MR-AoD/MR-PWV measurement and renal artery MR angiography) were performed at baseline and at 6-month and 12-month follow-up (Fig. 1).

F1FIGURE 1:

Study flowchart. BP, blood pressure; PWV, pulse wave velocity.

Endpoints

The primary efficacy endpoint was the temporal evolution of mean 24-h systolic ABP throughout 1-year post RDN, based on repeated measurements at baseline, 3, 6 and 12 months of follow-up. Effect modification of the primary efficacy endpoint was studied for a predefined set of baseline covariates, consisting of: vascular stiffness parameters (MR-PWV, MR-AoD, CF-PWV, AASI), CMR LV parameters (LV mass index, maximal LV wall thickness), TTE parameters (E/e ratio, forward stroke volume index, Zva), clinical parameters (age, sex, BMI, eGFR), baseline OBP [including heart rate and isolated systolic hypertension (ISH)] and ABP (mean 24-h, daytime, nighttime), antihypertensive drug defined daily doses (DDD) and procedural parameters (device type, number of ablations).

Secondary efficacy endpoints were temporal evolution of vascular stiffness parameters (MR-PWV, MR-AoD, CF-PWV, AASI), CMR LV parameters (LV mass index, maximal LV wall thickness, LV end-diastolic and end-systolic volume index, LV stroke volume index, LV ejection fraction, cardiac output), TTE parameters (E/e ratio, forward stroke volume index, Zva), BP outcomes (mean 24-h systolic and diastolic ABP, daytime systolic and diastolic ABP, nighttime systolic and diastolic ABP, systolic OBP, diastolic OBP, heart rate) and antihypertensive drug outcomes (number of drugs, DDDs, antihypertensive load index) throughout 1 year of follow-up.

The primary safety endpoint was a composite endpoint, consisting of cardiovascular death, major procedural bleeding, acute kidney injury and renal artery stenosis (whichever occurred first) up until 6 months of follow-up.

Secondary safety endpoints consisted of the individual items of the primary safety endpoint, all cardiovascular adverse events and renal function (eGFR) up until 1-year post procedure.

Statistical analysis

Continuous variables were reported as mean ± standard deviation (SD) or median (25th to 75th percentile) for normally and non-normally distributed variables, respectively. Non-normally distributed BP values were reported in both ways to allow for comparison to previous literature. Normality was assessed using the Shapiro–Wilcoxon test and quantile–quantile plots. Categorical variables were reported as number of patients and corresponding percentages.

The primary efficacy endpoint was assessed using linear mixed-effects models with the temporal evolution of mean 24-h systolic ABP throughout 1 year of follow-up as the dependent variable and a fixed effect for time as the independent variable. Random intercepts were used to account for repeated measurements within patients, and random slopes for time were additionally included when they significantly improved the model fit (as measured with the likelihood ratio test). Results were presented as the regression coefficient for time, which can be interpreted as the annual change in the primary efficacy endpoint (mean 24-h systolic ABP) throughout 1 year post RDN [including the corresponding 95% confidence interval (CI) and P value].

Effect modification of the primary efficacy endpoint was studied by adding the effect modifier of interest and the interaction term [time × effect modifier] to the linear mixed-effects model. The regression coefficient for the interaction term was reported (including the corresponding 95% CI and P value). This coefficient can be interpreted as the additional change in mean 24-h systolic ABP over time following RDN for a one unit or level increase in the evaluated baseline effect modifier (continuous or categorical, respectively). Effect modifiers significant at alpha-level 0.20 in univariable analyses were subsequently included in multivariable linear mixed-effects models, thereby displaying corrected measures of effect. Only one interaction term was fitted per multivariable model, to preserve interpretability of the regression coefficients. To avoid collinearity, only one (surrogate) measure of arterial wall stiffness, SBP and DBP was entered in each model.

Secondary efficacy endpoints were analyzed using a similar approach as in the primary efficacy endpoint. For a subset of secondary efficacy endpoints, consisting of vascular stiffness, CMR LV and TTE endpoints, exploratory analyses were performed in case of a significant change throughout 1 year of follow-up. For these particular variables, correlation analyses between the change in mean 24-h systolic ABP and the change in the variable of interest were performed. Correlation was assessed using scatterplots and repeated measures correlation coefficients (rrm) [44].

The primary and secondary safety endpoints were assessed by presenting the number of events (percentages) for adverse event data. Renal function (eGFR) was analyzed using a similar approach as in the primary efficacy endpoint.

The current pilot study was considered exploratory and has, therefore, not been powered to detect any predetermined effect size. Unless stated otherwise, two-tailed P values less than 0.05 were considered statistically significant. Statistical analyses were performed using R 4.1.1 with the nlme package to perform linear mixed-effects models [45,46].

RESULTS Study population

Between May 2013 and April 2019, 30 patients were enrolled. Mean age was 62.5 ± 10.7 years and 15 (50.0%) patients were female. Patients had a mean BMI of 29.4 ± 4.4 kg/m2 and median eGFR was 89.1 [74.3–109.5] ml/min per 1.73 m2. Mean 24-h ABP was 146.7/80.8 ± 13.7/12.0 and OBP was 172.4/94.6 ± 18.7/16.0 mmHg while patients were on 5.0 ± 2.4 DDDs of antihypertensive drugs. ISH was observed in 13 (43.3%) patients. Median MR-PWV was 6.8 [6.1–11.0] m/s, whereas mean CF-PWV was 8.5 ± 2.1 m/s (Table 1).

TABLE 1 - Baseline characteristics Variable Patients (n = 30) Clinical parameters  Female sex [n (%)] 15 (50.0)  Age (years), mean ± SD 62.5 ± 10.7  BMI (kg/m2), mean ± SD 29.4 ± 4.4  Body surface area (m2), mean ± SD 2.0 ± 0.3  Estimated glomerular filtration rate (ml/min per 1.73 m2), median [25th to 75th percentile] 89.1 [74.3–109.5] Smoking status  Current smoker [n (%)] 6 (20.0)  Ever smoker [n (%)] 11 (36.7) Medical history  Stroke and/or transient ischemic attack [n (%)] 3 (10.0)  Myocardial infarction [n (%)] 6 (20.0)  Coronary revascularization [n (%)] 9 (30.0)  Diabetes mellitus type 2 [n (%)] 12 (40.0) Ambulatory blood pressure  Mean 24-h SBP (mmHg), mean ± SD/median [25th–75th percentile] 146.7 ± 13.7/144.5 [137.0–152.8]  Mean 24-h DBP (mmHg), mean ± SD 80.8 ± 12.0  Daytime SBP (mmHg), mean ± SD/median [25th–75th percentile] 149.8 ± 15.5/145.0 [137.3–157.5]  Daytime DBP (mmHg), mean ± SD 83.7 ± 12.8  Nighttime SBP (mmHg), mean ± SD 138.5 ± 14.9  Nighttime DBP (mmHg), mean ± SD 74.8 ± 13.6  Ambulatory arterial stiffness index, mean ± SD 0.53 ± 0.13 Office blood pressure  SBP (mmHg), mean ± SD 172.4 ± 18.7  DBP (mmHg), mean ± SD 94.6 ± 16.0  Heart rate (beats per minute), median [25th–75th percentile] 67.5 [60.0–75.5]  Isolated systolic hypertension [n (%)] 13 (43.3) Antihypertensive drug treatment – summary measures  Defined daily doses, mean ± SD 5.0 ± 2.4  Antihypertensive load index, median [25th–75th percentile] 2.2 [1.8–3.2]  Total number of drugs, mean ± SD 3.4 ± 1.3  Intolerance to ≥ 3 classes of antihypertensive drugs [n (%)] 4 (13.3) Antihypertensive drug treatment – individual classes  Thiazide diuretic [n (%)] 23 (76.7)  Angiotensin-converting enzyme inhibitor [n (%)] 5 (16.7)  Angiotensin receptor blocker [n (%)] 23 (76.7)  Calcium channel blocker [n (%)] 23 (76.7)  Aldosterone antagonist [n (%)] 6 (20.0)  Alpha antagonist [n (%)] 10 (33.3)  Vasodilator [n (%)] 4 (13.3)  Direct renin inhibitor [n (%)] 1 (3.3) Cardiovascular magnetic resonance imaging  LV mass index (g/m2), mean ± SD 66.8 ± 15.4  Maximal wall thickness (mm), mean ± SD 12.3 ± 2.7  LV end-diastolic volume index (ml/m2), median [25th–75th percentile] 74.3 [69.9–86.9]  LV end-systolic volume index (ml/m2), median [25th–75th percentile] 28.6 [24.0–33.1]  LV ejection fraction (%), mean ± SD 62.5 ± 7.7  LV stroke volume index (ml/m2), mean ± SD 48.4 ± 6.8  Cardiac output (l/min), median [25th–75th percentile] 6.3 [5.6–7.3] Echocardiography   E/é ratio, mean ± SD 14.6 ± 5.2  Forward stroke volume index (ml/m2), mean ± SD 41.2 ± 10.2  Valvulo-arterial impedance (mmHg/ml/m2), mean ± SD 4.6 ± 1.2 Vascular parameters  MR-pulse wave velocity (m/s), median [25th–75th percentile] 6.8 [6.1–11.0]  MR-aortic distensibility (10–3/mmHg), median [25th–75th percentile] 1.4 [0.9–1.8]  CF-pulse wave velocity (m/s), mean ± SD 8.5 ± 2.1 Procedural characteristics  Procedure time (minutes), median [25th–75th percentile] 58.5 [48.5–70.0]  Contrast volume used (ml), median [25th–75th percentile] 70.0 [50.0–120.0]  Radiofrequency renal denervation device   Symplicity Flex [n (%)] 11 (36.7)   Symplicity Spyral [n (%)] 19 (63.3)  Total number of emissions bilaterally, median [25th–75th percentile] 17.5 [10.0–23.8]   Right renal emissions, median [25th–75th percentile] 6.0 [5.0–11.0]   Left renal emissions, median [25th–75th percentile] 9 [5.0–12.8]

CF, carotid–femoral; LV, left ventricular; MR, magnetic resonance; SD, standard deviation.


Procedural characteristics

Median procedural time was 58.5 [48.5–70.0] minutes in which 17.5 [10.0–23.8] emissions were performed bilaterally. Eleven patients (36.7%) were treated with the Symplicity Flex radiofrequency RDN device whereas 19 patients (63.3%) were treated with the Symplicity Spyral radiofrequency RDN device (Table 1).

Primary efficacy endpoint

Mean 24-h systolic ABP decreased with −8.4 mmHg/year (95% CI −14.5 to −2.3; P = 0.007) post RDN (Table 3). Baseline CF-PWV was identified as an independent effect modifier of the change in mean 24-h systolic ABP post RDN (+2.7 mmHg/year in mean 24-h systolic ABP per m/s increase in baseline CF-PWV; 95% CI 0.3–5.1; P = 0.03) after correction for age, sex, BMI and heart rate. Similarly, variables that emerged as independent effect modifiers were daytime diastolic ABP (−0.4 mmHg/year per mmHg; 95% CI −0.8 to 0.0; P = 0.03), age (+0.6 mmHg/year per year of age; 95% CI 0.2–1.0; P = 0.006), female sex (−14.0 mmHg/year as compared with male; 95% CI −23.1 to −5.0; P = 0.003) and BMI (+1.2 mmHg/year per kg/m2; 95% CI 0.1–2.2; P = 0.04). MR-PWV did not emerge as a significant effect modifier (+1.1 mmHg/year per m/s increase in baseline MR-PWV; 95% CI −0.1 to 2.3; P = 0.07) (Table 2 and Fig. 2). Similar findings were observed in univariable analyses. None of the other evaluated baseline covariates, including RDN device type, demonstrated any effect modification (Supplemental Table 1, https://links.lww.com/HJH/C120).

TABLE 2 - Multivariable analysis of baseline effect modifiers of change over time in mean 24-h systolic ambulatory blood pressure post renal denervation Baseline covariates Change in mean 24-h systolic ABP post renal denervation in mmHg/year (95% CI) P value Clinical parameters  Age (years) 0.6 (0.2–1.0) 0.006  Female sex (as compared with male) −14.0 (−23.1 to −5.0) 0.003  BMI (kg/m2) 1.2 (0.1–2.2) 0.04 Office blood pressure  Heart rate (beats per minute) −0.2 (−0.4 to 0.0) 0.08 Ambulatory blood pressure  Mean 24-h DBP (mmHg) −0.3 (−0.7 to 0.0) 0.08  Daytime SBP (mmHg) −0.2 (−0.5 to 0.1) 0.17  Daytime DBP (mmHg) −0.4 (−0.8 to 0.0) 0.03 Vascular parameters  MR-pulse wave velocity (m/s) 1.1 (−0.1 to 2.3) 0.07  CF-pulse wave velocity (m/s) 2.7 (0.3–5.1) 0.03

All models contained fixed effects for time, age, sex, BMI, heart rate and the variable of interest, as well as an interaction term [time × variable of interest]. Random effects were used to account for repeated measurements of the variable of interest within patients. The regression coefficient for this interaction term was presented (including CIs and P values). For continuous effect modifiers, the additional change in mmHg/year post renal denervation was presented per increase of one unit in the effect modifier. For categorical effect modifiers, the additional change in mmHg/year post renal denervation was presented as compared to a given reference level of the effect modifier. ABP, ambulatory blood pressure; CI, confidence interval; MR, magnetic resonance imaging; US, ultrasound.


F2FIGURE 2:

Mean 24-h ambulatory blood pressure over time post renal denervation for different levels of baseline effect modifiers. ABP, ambulatory blood pressure.

Secondary efficacy endpoints

Throughout follow-up, significant reductions were observed in LV mass index (−2.3 g/m2 per year; 95% CI −4.0 to −0.5; P = 0.01), LV stroke volume index (−2.1 ml/m2 per year; 95% CI −4.1 to −0,1; P = 0.04) and Zva (−0.5 mmHg/ml per m2 per year; 95% CI −1.0 to −0.1; P = 0.01). Furthermore, reductions were observed in mean 24-h diastolic ABP (−5.7 mmHg/year; 95% CI −8.4 to −3.0; P < 0.001), systolic OBP (−9.0 mmHg/year; 95% CI −16.2 to −1.7; P = 0.02) and diastolic OBP (−8.0 mmHg/year; 95% CI −11.7 to −4.4; P < 0.001), daytime systolic ABP (−8.4 mmHg/year; 95% CI −15.7 to −1.1; P = 0.02) and diastolic ABP (−5.9 mmHg/year; 95% CI −9.7 to −2.2; P = 0.003), nighttime systolic ABP (−7.5 mmHg/year; 95% CI −12.0 to −2.9; P = 0.002) and diastolic ABP (−4.6 mmHg/year; 95% CI −7.9 to −1.4; P = 0.005) throughout 1 year of follow-up. No changes over time were observed in other secondary outcomes (Table 3). The change in mean 24-h systolic ABP was correlated with the change in LV mass index between baseline and 6 and 12-month follow-up (rrm = 0.45; P = 0.02) (Fig. 3).

TABLE 3 - Change in outcome measures during 1 year after renal denervation Variable Modelled change post renal denervation per year (95% CI) P value Ambulatory blood pressure  Mean 24-h systolic blood pressure (mmHg) −8.4 (−14.5 to −2.3) 0.007  Mean 24-h diastolic blood pressure (mmHg) −5.7 (−8.4 to −3.0) <0.001  Daytime systolic blood pressure (mmHg) −8.4 (−15.7 to −1.1) 0.02  Daytime diastolic blood pressure (mmHg) −5.9 (−9.7 to −2.2) 0.003  Nighttime systolic blood pressure (mmHg) −7.5 (−12.0 to −2.9) 0.002  Nighttime diastolic blood pressure (mmHg) −4.6 (−7.9 to −1.4) 0.005  Ambulatory arterial stiffness index (subset of patients; n = 20) 0.0 (−0.1 to 0.0) 0.17 Office blood pressure  Systolic blood pressure (mmHg) −9.0 (−16.2 to −1.7) 0.02  Diastolic blood pressure (mmHg) −8.0 (−11.7 to −4.4) <0.001  Heart rate (beats per minute) −1.8 (−5.1 to 1.5) 0.28 Antihypertensive drug treatment  Defined daily doses 0.0 (−0.4 to 0.3) 0.79  Antihypertensive load index 0.0 (−0.2 to 0.2) 0.94  Total number of drugs 0.0 (−0.2 to 0.3) 0.75 Vascular parameters  MR-pulse wave velocity (m/s) 0.1 (−1.9 to 2.1) 0.92  MR-aortic distensibility (10–3/mmHg) 0.0 (−0.4 to 0.4) 0.84  CF-pulse wave velocity (m/s) 0.5 (−0.6 to 1.5) 0.37 Cardiovascular magnetic resonance  LV mass index (g/m2) −2.3 (−4.0 to −0.5) 0.01  Maximal wall thickness (mm) 0.1 (−0.5 to 0.7) 0.74  LV end-diastolic volume index (ml/m2) −2.5 (−5.9 to 1.0) 0.16  LV end-systolic volume index (ml/m2) −0.4 (−2.8 to 2.0) 0.75  LV stroke volume index (ml/m2) −2.1 (−4.1 to −0.1) 0.04  LV ejection fraction (%) −1.2 (−2.9 to 0.5) 0.17  Cardiac output (l/min) −0.5 (−1.2 to 0.1) 0.10 Echocardiography   E/é ratio −1.0 (−2.5 to 0.5) 0.19  Forward stroke volume index (ml/m2) 1.0 (−1.6 to 3.6) 0.45  Valvulo-arterial impedance (mmHg/ml/m2) −0.5 (−1.0 to −0.1) 0.01

LV, left ventricular; MR, magnetic resonance; SD, standard deviation; US, ultrasound.


F3FIGURE 3:

Correlation between change in mean 24-h ambulatory blood pressure and (a) change in left ventricular mass index, (b) left ventricular stroke volume index and (c) valvulo-aortic impedance (Zva) at 6 and 12 months post renal denervation. ABP, ambulatory blood pressure; LV, left ventricular; r rm, repeated measures correlation.

Primary and secondary safety endpoints

The primary safety endpoint of this study occurred in two (6.7%) patients. One patient (3.3%) died one-and-a-half months after the procedure, most likely because of a cardiac arrhythmia. Another patient (3.3%) had a retroperitoneal bleeding, which required no additional intervention. This patient received intravenous fluid therapy as well as one unit of packed red blood cells and was discharged from the hospital after 4 days in good clinical condition. No newly acquired renal artery stenosis and renal failure occurred within 1 year after the index procedure. Within 1 year of follow-up, four patients (13.3%) presented with a hypertensive emergency and two patients (6.7%) had a stroke or transient ischemic attack. Coronary revascularization was performed in two patients (6.7%), of which one (3.3%) presented with a myocardial infarction (Table 4). Renal function (eGFR) remained stable throughout 1-year post RDN (−4.3 ml/min per 1.73 m2 per year; 95% CI –10.6 to 2.0; P = 0.18).

TABLE 4 - Safety endpoints Clinical endpoint Patients (n = 30) Primary safety endpoint (cardiovascular death, major procedural bleeding, acute kidney injury or renal artery stenosis at 6 months) [n (%)] 2 (6.7)  Cardiovascular death at 6 months [n (%)] 1 (3.3)  Major procedural bleeding [n (%)] 1 (3.3)  Newly acquired renal artery stenosis and/or repeat renal artery intervention at 6 months [n (%)] 0 (0.0)  Acute kidney injury at 6 months [n (%)] 0 (0.0) Secondary safety endpoints (12 months)  Cardiovascular death [n (%)] 1 (3.3)  Newly acquired renal artery stenosis and/or repeat renal artery intervention [n (%)] 0 (0.0)  Development of renal failure or requirement of dialysis [n (%)] 0 (0.0)  Hospitalization for hypertensive emergency [n (%)] 4 (13.3)  Stroke or transient ischemic attack [n (%)] 2 (6.7)  Myocardial infarction [n (%)] 1 (3.3)  Coronary revascularization [n (%)] 2 (6.7)
DISCUSSION

This single-center pilot study aimed to evaluate th

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