Abstract
A central iliac arteriovenous anastomosis, termed the “coupler” (ROX Medical), results in a significant reduction in blood pressure (BP) in hypertensive patients. This study assessed functional and hemodynamic changes induced by the device. Twenty‐one patients with resistant and/or uncontrolled hypertension underwent stress echocardiography and cardiopulmonary exercise testing (CPET) at baseline and 6 months post‐coupler implantation. End points were selected to best evaluate cardiac function including Doppler stroke volume (SV), septal and lateral E/E′, and right ventricular systolic velocity S′ (RV S′). CPET VO2 peak demonstrated total cardiopulmonary performance. SV increased from 76.4 SD12.2 mL to 92.1 SD22.7 mL 6 months post‐coupler insertion; P = .002. No changes in RV S′, septal or lateral E/E′, or VO2 peak were observed. Five patients experienced increased diuretic requirement ≥3 times baseline. RV S′ fell from 19.0 SD1.87 cm/s to 16.80 SD3.43 cm/s in these patients (P > .05). A significant increase in SV 6 months post‐coupler insertion was observed. In patients with increased diuretic requirement, the device was associated with a lower RV S′ suggesting occult RV dysfunction as the mechanism of this pre‐specified adverse outcome.
Keywords: advanced echocardiography, cardiopulmonary exercise testing, hypertension, iliac arteriovenous fistula
1. INTRODUCTION
Hypertension is the leading cause of cardiovascular comorbidity and mortality and is a risk factor for coronary heart disease, stroke, chronic kidney disease, and heart failure.1, 2 A central iliac arteriovenous anastomosis has been shown to alter mechanical arterial properties and reduce blood pressure (BP) in patients with resistant and/or uncontrolled hypertension.3 The coupler was first used to treat hypertension in 2012 and adds a low‐resistance, high‐compliance venous segment to the central arterial tree.4, 5, 6 The device is associated with an immediate and significant reduction in BP and reduces the risk of hospitalized hypertensive crises.3
The device has predictable effects on preload (increase) and afterload (significant sustained reduction) which affect cardiac size and volumes.7, 8 Some patients require increased oral diuretics due to volume changes induced by the coupler. Identification of such patients improves their management. The combination of cardiopulmonary exercise testing (CPET) and stress echocardiography (echo) concurrently assesses both exercise performance and functional myocardial changes, filling pressure and symptoms in an objective and reproducible manner.9
In this prospective study of selected patients with resistant and/or uncontrolled hypertension meeting the criteria for coupler insertion, we investigated the hypothesis that insertion of a central iliac arteriovenous anastomosis results in important hemodynamic changes and detailed assessment of these with CPET stress echo predicts patients at risk of increased diuretic requirement post‐coupler insertion.
2. METHODS
2.1. Study design and participants
This study was performed at Eastbourne General Hospital, East Sussex Healthcare NHS Trust, UK, and was approved by the UK national ethics committee. Twenty‐one consecutive participants with resistant and/or uncontrolled hypertension taking part in the ROX Control Hypertension Registry (RH‐03) NCT01885390 were included.10 The rationale and design of the RH‐03 registry have been described previously.10 Inclusion criteria were patients aged 18‐85 years with a diagnosis of resistant or uncontrolled hypertension made on the basis of office and 24‐hour BP monitoring, medical history, and physical examination. Resistant hypertension was defined as patients with established hypertension (diagnosed ≥12 months prior to baseline) on a guideline‐based drug regimen at a stable and a fully tolerated dose, consisting of ≥3 hypertensive medications (including 1 diuretic). Uncontrolled hypertension was defined as patients with hypertension and drug intolerances to antihypertensive medications and unable to take a guideline‐based drug regimen. Patients were excluded if they had any serious medical condition that might have adversely affected the patient's safety, limit the subject's ability to participate in the registry, comply with follow‐up requirements, or impact the scientific integrity of the study. In addition, patients were excluded if found to have a baseline pulmonary capillary mean wedge pressure >15 mm Hg at right heart catheterization. Written informed consent was obtained from all participants. All 21 participants underwent baseline and 6 months post‐coupler stress echo CPET examination.
2.2. Procedure
Placement of the arteriovenous coupler was accomplished in the cardiac catheterization laboratory in Eastbourne General Hospital under fluoroscopic guidance and has been described in detail previously.3 An 11 F customized venous introducer was placed in the right common femoral vein, and a short 4 F introducer sheath was placed into the right common femoral artery. The coupler delivery system was advanced over a crossing wire from vein to artery, with deployment according to manufacturers' instructions. Finally, a 4‐mm balloon catheter was advanced over the crossing wire within the coupler and the anastomosis was dilated to a final diameter of 4 mm.
2.3. 24‐hour blood pressure assessment
Twenty‐four‐hour BP monitors (Spacelabs Healthcare) were applied to all patients at baseline, day 1, and 3 and 6 months post‐procedure as part of the RH‐03 protocol.10
2.4. Cardiopulmonary exercise testing
Cardiopulmonary exercise testing was performed by two experienced investigators (WE and JZ) 1 week before and 6 months post‐coupler. A semi‐recumbent tilting cycle ergometer (ERG 911 S/L, Schiller) was used. At the start of the test, a 1‐ to 2‐minute rest period was included followed by a 3‐minute unloaded warm‐up period. Exercise protocols were individually determined based on the patient's functional status. Work rate (10, 15 or 20 W) increased every minute until voluntary exhaustion aiming for 8‐10 minutes of exercise. Patients were asked to continue to take their medication as usual. Heart rate (HR), BP, and oxygen saturations were monitored throughout. Oxygen uptake (VO2), carbon dioxide production (VCO2), and ventilation (VE) were continuously measured and derived using a calibrated breath‐by‐breath analyzer (Quark, Cosmed). Patients were verbally encouraged to exercise until maximal exertion. All tests were performed according to exercise testing guidelines.11 VO2 peak was expressed as the highest value from an average of 30 seconds during the final stage of the exercise test.
2.5. Echocardiography protocol
Echocardiography was performed using a GE Vivid 9 platform (Vingmed‐General Electric) equipped with a phased‐array 3.5 MHz transducer. All patients underwent a full British Society of Echocardiography (BSE) minimum dataset echo12 by a BSE accredited physiologist. Two experienced BSE accredited physiologists (blinded to the patient and timing of the scan) performed offline echo measurements for each patient.
Three parameters were prospectively identified to represent the key indicators of cardiac performance: SV to represent cardiac systolic function, E/E′ to represent left atrial pressure and left ventricular (LV) filling, and RV S′ to represent right ventricular systolic function. These parameters were selected in addition as (a) they are readily measured in all patients with a high reproducibility and (b) they represent independent markers of cardiac performance.
2.6. Doppler stroke volume
Stroke volume was calculated by multiplying the cross‐sectional area of the left ventricular outflow tract (LVOT; obtained in the parasternal long axis view) with the velocity time integral (VTI) of the LVOT (obtained in the 5‐chamber view).
2.7. RV systolic velocity S′
For RV S′, the apical 4‐chamber window was used with a tissue spectral Doppler mode region of interest highlighting the right ventricular free wall. The pulsed Doppler sample volume was placed at the tricuspid level of the right ventricular free wall. Tricuspid annular motion was assessed by pulsed tissue Doppler to measure the longitudinal velocity of excursion. This velocity was taken to be the systolic excursion velocity or RV S′.
2.8. Statistical analysis
For each CPET and echo parameter, the difference between the pre‐ and post‐value was calculated in a generalized mixed model, with two observations for each subject (pre and post), linked within patients with generalized random intercept term. The degrees of freedom from the analysis were derived from the number of subjects (rather than observations). The parameterization of the model identified the pre‐ and post‐values. In addition, for each analysis, a post‐treatment identifier for increased diuretic requirement was utilized to identify the interaction between post‐treatment values. This was done separately for each parameter of interest in an exploratory manner, and no multivariable analysis was conducted owing to the modest number of patients included in the study and thus the limited degrees of freedom. A P value of <.05 was considered significant.
3. RESULTS
Participants had a mean age of 67 years (range 48‐81 years, 43% female). Most had multiple comorbidities (including 48% with paroxysmal atrial fibrillation; Table 1). None of the patient cohort had undergone previous device‐based therapies for hypertension. Indications for coupler insertion were resistant hypertension (in 76% of study participants) and uncontrolled hypertension (in 24%). Patients were taking a mean of 3.19 (median of 3) antihypertensive medications and had a mean of 0.52 (median of 1) drug intolerances each, see Table 1. All patients were taking diuretics at baseline (loop diuretics in 15 and thiazide diuretics in 6). All study participants had a baseline EF of >50% and a pulmonary capillary mean wedge pressure <15 mm Hg at right heart catheterization, per protocol.
Table 1.
Baseline demographics of the study participants
| N (%) | Patient without increased diuretic requirement, N (%) | Patients with increase diuretic requirement, N (%) | P value | |
|---|---|---|---|---|
| Female gender, n (%) | 9 (43) | .058 | ||
| COPD | 2 (9.5) | 2 (13%) | 0.0% | .431 |
| Diabetes | 6 (28.6) | 4 (25%) | 2 (40%) | .541 |
| CVA/TIA | 1 (4.8) | 1 (6.3%) | 0 (0%) | .589 |
| Vascular disease | 5 (23.8) | 3 (19%) | 2 (40%) | .224 |
| Hypercholesterolemia | 9 (42.9) | 7 (44%) | 2 (40%) | .266 |
| Chronic kidney disease | 6 (28.6) | 4 (25%) | 3 (60%) | .241 |
| ACE‐i/ARB | 18 (85.7) | 14 (88%) | 4 (80%) | .416 |
| Beta blocker | 11 (52.4) | 8 (50%) | 3 (60%) | .956 |
| Loop diuretic | 15 (71.4) | 13 (81%) | 3 (60%) | .398 |
| Thiazide diuretic | 6 (28.6) | 3 (19%) | 2 (40%) | .447 |
| Aldosterone antagonist | 4 (19.0) | 2 (13%) | 2 (40%) | .217 |
| Calcium antagonist | 9 (42.9) | 7 (44%) | 2 (40%) | .808 |
| Centrally acting antihypertensive | 5 (23.8) | 4 (25%) | 1 (20%) | .727 |
| Mean number of antihypertensive medications per patient | 3.19 | 2.75 (±0.9) | 3.4 (±1.1) | .185 |
| Median number of antihypertensive medications per patient | 3 | 3 | 3.5 | .354 |
| Mean baseline 24 h‐blood pressure (mm Hg) | 147.6 (±8.9)/80.3 (±9.1) | 145.1 (±5.9)/79.9 (±8.8) | 155.6 (±12.7)/81.6 (±10.7) |
.140 (SBP) .764 (DBP) |
| Mean office blood pressure (mm Hg) | 164.2 (±20.8)/85.6 (±15.0) | 156.6 (±14.1)/86.3 (±15.5) | 191.4 (±14.7)/87.2 (±14.1) |
.003 (SBP) .913 (DBP) |
| Mean heart rate (bpm) | 61.6 (±13.4) | 57.5 (±11.3) | 71.7 (±12.6) | .177 |
| Mean pulmonary capillary wedge pressure (mm Hg) | 9.6 (±3.2) | 10.8 (±2.5) | 7.2 (±3.9) | .114 |
| Mean LVEF (%) | 59.0 (±6.5) | 58.7 (±6.8) | 60.0 (±7.1) | .733 |
| TR Vmax (m/s) | 2.1 (±0.8) | 1.9 (±0.8) | 2.4 (±0.9) | .338 |
| RVSP (+JVP) | 17.3 (±11.9) | 15.0 (±10.2) | 24.8 (±15.0) | .109 |
| LV end diastolic diameter (cm) | 4.6 (±0.5) | 4.6 (±0.5) | 4.6 (±0.9) | .946 |
| Left atrial area (cm2) | 21.9 (±3.9) | 18.0 (±2.0) | 24.2 (2.5) | .011 |
| TAPSE (mm) | 27.1 (±4.0) | 13.2 (±11.2) | 8.8 (12.2) | .57 |
Implantation of the ROX Coupler was successfully performed in all participants with no peri‐procedural complications.
At 6‐month follow‐up, five of the 21 patients experienced a suboptimal response to the coupler predefined as an increased diuretic dose requirement ≥ threefold compared with baseline. There were no other changes in medications, throughout the study period.
3.1. Change in blood pressure
See Figure 1. All 21 patients had systolic hypertension and 14 had coexistent diastolic hypertension as per current ACC/AHA guidelines.13 All patients responded to the coupler within 24 hours of implant. There was a significant reduction in systolic BP (SBP; 145.39 ± 6.12 vs 132.22 ± 12.996 mm Hg; P = .001) and diastolic BP (DBP; 79.22 ± 9.039 vs 68.11 ± 9.209 mm Hg; P = .0001) 1 day post‐procedure. There was a significant reduction in 3‐month SBP (149.38 ± 9.179 vs 138.69 ± 15.660 mm Hg; P = .017) and DBP (83.38 ± 7.377 vs 71.92 ± 9.106 mm Hg; P = .0001). There was a significant reduction in 6‐month DBP (80.33 ± 9.063 vs 68.86 ± 11.168 mm Hg; P = .0001), see Figure 1. There was no significant reduction in 6‐month SBP compared with baseline (147.6 ± 8.9 vs 143.1 ± 11.1 mm Hg; P = .106).
Figure 1.
Change in 24‐h BP throughout the study period. Error bars represent the standard error of mean
3.2. Adherence to medications
At each follow‐up visit, adherence to medication was documented. Between 3‐ and 6‐month follow‐up, four patients deviated from their prescribed medication. Two patients stopped taking their medication altogether in view of perceived side effects. Two patients had adjusted their medication as follows: one patient cut their candesartan from 32 to 16 mg in view of dizziness, and one patient stopped their diuretics and doxazosin due to lifestyle intrusion and side effects, respectively.
3.3. Echocardiography
Results are displayed in Table 2a. A significant increase in Doppler SV from 76.4 ± 12.2 mL at baseline to 92.1 ± 22.7 mL at 6 months occurred; P = .002. There were no significant changes in RV S′, septal E/E′, or lateral E/E′.
Table 2.
(a) Echo parameters at baseline and 6 mo post‐ROX Coupler. (b) CPET parameters at baseline and 6 mo post‐ROX Coupler
| Baseline | 6 mo post‐coupler | P value | |
|---|---|---|---|
| (a) | |||
| Doppler SV (mL) | 76.4 (12.2) | 92.1 (22.7) | .002 |
| RV S′ (cm/s) | 17.1 (3.9) | 17.2 (4.0) | .29 |
| Septal E/E′ | 11.1 (3.2) | 10.8 (3.7) | .85 |
| Lateral E/E′ | 13.0 (22.7) | 8.5 (3.8) | .91 |
| (b) | |||
| VO2 Peak | 18.1 (4.7) | 17.0 (4.8) | ns |
| Power (W) | 113.6 (49.9) | 105.8 (57.0) | ns |
| VE/VCO2 | 33.9 (8.5) | 37.1 (6.3) | ns |
3.4. Cardiopulmonary exercise testing
See Table 2b. There was no difference in VO2 peak, power reached, or VE/VCO2 observed in the overall study population.
3.5. Predictors of increased diuretic requirement post‐coupler
See Table 3. There were no significant differences in baseline echo and CPET parameters between those patients requiring increased diuretics and those who did not. Patients with increased diuretic requirement achieved a significantly lower peak power on CPET 6 months post‐coupler implant; −22.50 W (95% CI −36.12 to −8.88 W; P = .003). RV S′ was noted to reduce in patients with increased diuretic requirement (RV S′ reduction of −3.14 cm/s, 95% CI −6.88 to −0.601; P = .096).
Table 3.
Results of pre‐specified models by outcome
| Name | Post | Increased diuretic requirement (baseline) | Increased diuretic requirement × Post |
|---|---|---|---|
| VO2 peak | −0.588 (95% CI −2.123 to 0.948; P = .433) | −1.909 (95% CI −6.912 to 3.094; P = .434) | −2.213 (95% CI −5.359 to 0.934; P = .157) |
| Power | −2.500 (95% CI −9.145 to 4.145; P = .441) | −29.425 (95% CI −84.735 to 25.885; P = .279) | −22.500 (95% CI −36.118 to −8.882; P = .003) |
| VE/VCO2 | 2.488 (95% CI −1.469 to 6.444; P = .203) | 1.594 (95% CI −7.079 to 10.268; P = .704) | 2.812 (95% CI −5.857 to 11.481; P = .504) |
| RV S′ | 0.938 (95% CI −0.890 to 2.765; P = .296) | 2.563 (95% CI −1.672 to 6.797; P = .221) | −3.138 (95% CI −6.883 to 0.608; P = .096) |
| Doppler SV | 17.013 (95% CI 7.304 to 26.721; P = .002) | −0.459 (95% CI −20.427 to 19.508; P = .962) | −4.175 (95% CI −24.072 to 15.721; P = .665) |
| E/E′ lateral | −0.117 (95% CI −2.157 to 1.924; P = .906) | 2.911 (95% CI −1.047 to 6.868; P = .140) | −1.690 (95% CI −5.872 to 2.492; P = .408) |
| E/E′ septal | −0.171 (95% CI −2.073 to 1.732; P = .853) | 0.142 (95% CI −3.643 to 3.926; P = .938) | −0.631 (95% CI −4.530 to 3.269; P = .739) |
3.6. Safety
There were no procedural‐related adverse events throughout the 6‐month study duration.
4. DISCUSSION
The study was designed to test the hypothesis that implantation of a central iliac arteriovenous anastomosis results in important hemodynamic changes and detailed assessment of these with CPET stress echo predicts patients at risk of increased diuretic requirement post‐coupler insertion. The trial partly met its primary effectiveness end point, with a statistically significant increase in SV observed post‐coupler in the overall population.
Central arteriovenous shunts have previously been shown to increase venous return activating the Starling mechanism to increase SV and cardiac output.14, 15, 16 The finding is thus consistent with this physiology. In addition, the reduction in aortic pressure in systole predicts a reduction in afterload.6 By reducing the pressure against which the heart must work to eject blood during systole, an increase in SV should result. It is likely that a combination of these factors results in the increase in SV observed. The SV does not increase to a significant degree in patients with increased diuretic requirement because these patients cannot accommodate the increased preload induced by the coupler.
Tricuspid annular motion can be assessed by pulsed tissue Doppler to measure the longitudinal velocity of excursion. This velocity has been termed the RV S′ or systolic excursion velocity. RV S′ has been shown to be highly reproducible and was the chosen echo parameter for assessment of right heart function.17 RV S′ should increase due to the extra circulatory volume imposed upon the right ventricle by coupler insertion. A nonsignificant increase in RV S′ was observed in the overall study population consistent with this hypothesis. A larger trial is justified to confirm this finding.
There was, however, a nonsignificant reduction in RV S′ in the patients requiring increased diuretics. The mechanism of increased diuretic requirement is likely due to patients who are unable to cope with the increased volume load on the right heart. However, those who accommodate the increased right heart volume loading do not require increased diuretic use. In the majority of conditions resulting in right heart dysfunction, reducing excessive preload with diuretics is key to reducing RV dilatation and free wall tension and optimizing contractility.18
E/E′ is the most reproducible echo parameter for estimation of LV filling pressure19 and is proportional to left atrial pressure. No significant differences between lateral or septal E/E′ were observed post‐coupler. This negative finding is important because an increase in preload predicts an increase in E/E′20, 21 and implicates the importance of a reduction in afterload post‐coupler.22 In addition, with increased right heart filling pressures and reduced arterial stiffness the E/E′ is expected to decrease.23
VO2 peak is determined by cellular oxygen demand and equates to maximal rate of O2 transport. No significant change in this end point was observed confirming no detrimental effect of the iliac anastomosis upon this critical CPET parameter. VO2 peak has been shown to have high prognostic value in cardiac patients and healthy individuals.24 This negative finding provides reassurance that the described significant increase in SV does not cause detrimental effects to the rate of O2 transport.25
The minute ventilation/carbon dioxide production (VE/VCO2) slope reflects the increase in ventilation in response to CO2 production and thus shows increased ventilatory drive.26 Changes in the VE/VCO2 slope may be induced by increased chemoreceptors, the peripheral ergoreceptor response, the ventilator dead‐space, and also by the muscle mass engaged in exercise.27 No significant differences in the VE/VCO2 slope were seen in the overall population confirming that the iliac anastomosis does not adversely impact ventilatory efficiency28 as seen in heart failure patients.29
The power reached during CPET is an objective measure of the amount of work done during the test.30 The power reached on the cycle ergometer did not change pre‐ and post‐coupler. This is despite a degree of diversion of lower limb arterial blood flow. Potentially, a vascular steal syndrome could arise with this device as has been reported in between 5% and 15% of brachio‐cephalic/basilic fistulae used for hemodialysis.31 The findings that there were no significant changes in power reached are reassuring. The reason for this is that the diversion of blood flow induced by the coupler is small (0.8 L/min) compared with arterial capacity (approximately 5 L/min),32 and the increased SV would tend to ameliorate this change in leg perfusion. However, significant reduction in power was noted in patients with increased diuretic requirement. This confirms that this predefined clinical adverse effect is an important outcome measure in patients who have a suboptimal response to the coupler. In addition, the baseline power reached on the CPET was almost 30 W less for the patients who required significant increases in diuretic dose. Although specific research is still needed to confirm the importance of a stepwise multiparametric interpretation of CPET,33 this suggests that patients with lower baseline exercise capacity might have a greater risk of right heart decompensation post‐coupler insertion.
There was a nonsignificant reduction in SBP at 6 months. The most likely explanation is nonadherence to medication between 3 and 6 months documented in 4/21 (19%) of patients. Strict adherence to medications would have probably maintained SBP <140 mm Hg in patients with both combined and isolated systolic hypertension as observed in larger patient cohorts.34, 35
4.1. Study limitations
It was not possible within the study protocols to provide a control group which may have helped delineate which CPET, and echo parameters were most important prognostically.
Five patients (24%) experienced a change in medication with a significant increase in diuretic dose required for clinical reasons and may have affected the echo and CPET parameters studied in these patients. However, keeping drug therapy unchanged would be unethical in this cohort.
5. CONCLUSIONS
Stroke volume significantly increases in hypertensive patients treated with a coupler. SV does not significantly increase in the patients with increased diuretic requirement, probably as these patients cannot accommodate the increased preload induced by the device. Likewise, right ventricular function did not augment in this population. Despite this, the coupler was not associated with any significant change in exercise performance. A mechanism of reduced recruitability of the right and left ventricles was shared by patients requiring increased diuretics. This study confirms the overall safety of the coupler in the studied population at 6 months and its neutral impact on exercise performance in severely hypertensive patients.
CONFLICT OF INTEREST
NS has received an unrestricted research grant from ROX Medical, California, USA; WE has nothing to disclose; JvZ has nothing to disclose; NF has nothing to disclose; GL has nothing to disclose; and SF has nothing to disclose.
AUTHOR CONTRIBUTION
W Eysenck did the conception and design, the echo CPET studies, the analysis and interpretation of data and drafted the manuscript. J van Zalen did the echo CPET studies and helped draft the manuscript. N Freemantle provided essential statistical support. G Lloyd provided essential cardiac imaging and CPET expertise. S Furniss revised the manuscript critically for important intellectual content and final approval of the manuscript submitted. N Sulke did the conception and design and interpretation of data and revised the manuscript critically for important intellectual content and final approval of the manuscript submitted.
Eysenck W, van Zalen J, Freemantle N, Lloyd G, Furniss S, Sulke N. The hemodynamic effects of a central iliac arteriovenous anastomosis at 6 months in patients with resistant and uncontrolled hypertension. J Clin Hypertens. 2019;21:1399–1405. 10.1111/jch.13646
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