CCCardiol CroatCardiologia CroaticaCardiol. Croat.1848-543X1848-5448Croatian Cardiac SocietyCC 2020 15_11-12_306-1110.15836/ccar2020.306Original Scientific PapersPulse Wave Velocity as a Method of Outcome Monitoring after Renal DenervationBrzina pulsnog vala kao metoda praćenja ishoda renalne denervacijehttps://orcid.org/0000-0002-6988-7303KurjakovićIva1https://orcid.org/0000-0002-3189-1518JugJuraj1https://orcid.org/0000-0001-8446-6120Lovrić BenčićMartina2https://orcid.org/0000-0003-3727-5457VukovićJurica3https://orcid.org/0000-0002-5830-7131PrkačinIngrid13*Medicinski fakultet Sveučilišta u Zagrebu, Zagreb, HrvatskaMedicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, HrvatskaKlinička bolnica Merkur, Zagreb, HrvatskaUniversity of Zagreb School of Medicine, Zagreb, CroatiaUniversity of Zagreb School of Medicine, University Hospital Centre Zagreb, Zagreb, CroatiaUniversity Hospital “Merkur”, Zagreb, CroatiaADDRESS FOR CORRESPONDENCE: Ingrid Prkačin, Klinička bolnica Merkur, Ul. I. Zajca 19, HR-10000 Zagreb, Croatia. / Phone: +385-98-406-218 / E-mail: ingrid.prkacin@gmail.com1120201511-123063110106202024062020250920202020Croatian Cardiac SocietySUMMARY
Resistant hypertension is defined as failure to achieve target blood pressure (BP) in spite of using a minimum of 3 antihypertensive drugs of different classes, one of which must be a diuretic, at optimal tolerated doses. Device-based therapies like renal denervation are indicated in patients in whom pharmacological agents failed to control BP and patients with refractory resistant hypertension have no contraindications for the procedure. Pulse wave velocity is the measure of arterial stiffness which is directly connected to cardiovascular risk and hypertension-mediated organ damage. The aim of this study was to present measurement of arterial stiffness as a noninvasive method of assessing cardiovascular risk in patients with resistant hypertension after renal denervation. This study included 10 patients over the course of 1 to 4 years after renal denervation. Arterial stiffness was measured for patients with a noninvasive method using the Agedio B900 device operating on the principle of oscillometry. This study demonstrates that renal denervation as an additional method of controlling BP has long-term positive effects in addition to lowering BP and vascular stiffness over several years, thus lowering cardiovascular risk. Noninvasive measurement of arterial stiffness could be a novel prognostic marker of the impact of renal denervation on arterial stiffness.
SAŽETAK
Rezistentna hipertenzija definirana je nemogućnošću uspostavljanja ciljnih vrijednosti arterijskoga tlaka (AT) unatoč terapiji koja uključuje tri i više antihipertenzivnih lijekova različitih skupina (od kojih je jedan diuretik) u kombinacijama i optimalnim tolerabilnim dozama. Osim farmakološkog liječenja, bolesnike s refraktornom rezistentnom hipertenzijom upućuje se na postupak denervacije renalnog pleksusa ukoliko ne postoji zapreka. Mjerenjem krutosti žila brzinom pulsnog vala dokazan je marker povišenoga kardiovaskularnog rizika. Cilj istraživanja bio je prikazati vrijednosti mjerenja krutosti krvnih žila kao metodu praćenja ishoda denervacije renalnog pleksusa. Obuhvaćeno je 10 bolesnika koji su bili praćeni nakon denervacije renalnoga pleksusa u vremenu od jedne do četiri godine. Krutost žila mjerena je oscilometrijskim uređajem „Agedio B900“. Istraživanje je pokazalo da denervacija renalnoga pleksusa, kao dodatna metoda kontrole AT-a, ima dugoročne pozitivne učinke povrh sniženja AT-a u smislu sniženja krutosti žila tijekom više godina, čime se snizuje kardiovaskularni rizik. Krutost žila mogući je novi marker praćenja ishoda denervacije renalnog pleksusa.
As the main cause of cardiovascular (CV) disease, arterial hypertension (AH) is one of the leading causes of morbidity and mortality in the world (1). Given its upward epidemiological trend, it is estimated that approximately 1.56 billion people will be suffering from AH by 2025 (2). Resistant arterial hypertension (RAH) is defined as the inability to achieve target arterial pressure (AP) values in patients despite the application of three or more antihypertensive drugs of different classes in adequate and optimally tolerated doses. The basic treatment for patients with RAH includes renin-angiotensin-aldosterone system inhibitors, calcium antagonists, and diuretics, with an emphasis on spironolactone as the fourth antihypertensive drug in the previous fixed combination antihypertensive therapy – primarily a combination of two, and subsequently a combination of three antihypertensives in a single pill (3). Medications such as beta-blockers are recommended as fifth-line drugs, unless they have been already indicated by congestive heart failure or myocardial infarction (3). It is believed that the prevalence of RAH is between 10 and 20% of the hypertensive population. Treatment for RAH is challenging, requiring lifestyle changes and optimal pharmacotherapy with exclusion of other potentially treatable causes as well as additional treatment in refractory cases. Denervation of the renal plexus or renal denervation (RDN) is a minimally invasive endovascular method of selective ablation of afferent and efferent sympathetic nerves of both renal arteries and accessory branches with a radius above 3 mm (due to catheter size) (4). This modulates the tonus of the sympathetic nervous system and reduces AP values. The goal of the treatment is reducing AP values by 10 mmHg. According to the 2018 guidelines for the treatment of hypertension from the European Society of Cardiology and European Society of Hypertension, arterial stiffness is listed as a risk factor in the development of asymptomatic hypertension-mediated organ damage, with >10 m/s pulse wave velocity (PWV) (3). Noninvasive measurement of arterial stiffness and PWV allows the evaluation of CV risk and vascular elasticity as well as monitoring the effectiveness of AP control in patient groups with RAH and hypertensive crisis (5-7). Elevated stiffness is a predictor of total CV mortality and is associated with reduced effectiveness of RDN, so measurement of PWV is recommended to determine which patients will receive the most benefit from a denervation procedure (5).
In this article, we examine whether RDN, as an additional method of AP control, has long-term effects in addition to AP reduction itself in the form of reduction of arterial stiffness over several years.
Patients and Methods
The study included 10 patients with refractory RAH who underwent RDN after secondary potentially treatable AH causes were excluded, medication adherence was confirmed (using blister packs), and if continuous noninvasive arterial pressure (CNAP) AP values were >140/90 mmHg (average 169/94 mmHg), non-dipping in 50%, and there were no anatomical barriers to a RDN procedure. Before the multidisciplinary RDN team reached their decision, all of the patients had multiple hypertensive crises for which they were examined by emergency services. Four female patients were classified as having a hypertensive emergency (acute renal disease, myocardial infarction, stroke, papillary edema) and the rest as hypertensive urgency (AT >180/120 mmHg but with no target organ damage) despite confirmed adherence to taking antihypertensive medication (the average number was six hypertensives). During processing and treatment, the patients’ arterial stiffness was measured (on multiple occasions) and they agreed to participation in a clinical study and signed informed consent. Patients were divided into two groups. The first group included multiple months (up to 12) of RDN outcome monitoring and comprised six patients who underwent measurement of brachial arterial pressure (BAT), central arterial pressure (CAT), and PWV at baseline and one, six, and twelve months after the procedure. The second patient group represented long-term (over multiple years) outcome monitoring for RDN and comprised four patients with BAT, CAT, and PWV values measured two, three, and four years after the procedure (an oscillometric device has only been in use since 2017, so some data for patients on whom RDN was performed before 2017 are not available). Arterial stiffness was measured using the Agedio B900 Pulse Wave Analysis System (Germany) that uses a noninvasive oscillometric method (8). In a single measurement, the device simultaneous provides data on arterial stiffness (PWV in m/s, adjusted according to age group) and CAT (8). The device consists of an upper-arm cuff (of the 3 available sizes, this study used the largest cuffs marked L for large, based on the measurement of the patients’ upper arms), a measurement device, and an iPad that displays the results (8). Measurement lasts several minutes and the device provides two detailed reports, one for the patient and one for the physician. The patient’s report shows patient data on arterial stiffness and a comparison with reference values according to age (which increases patient compliance because they actively participate in creating the next steps of their treatment), whereas the physician’s report presents hemodynamic parameters, the CAT value, mean arterial pressure, and pulse pressure (8). Data used in the present study also included renal function monitoring which was assessed based on estimated glomerular filtration rate (eGFR); data were analyzed using parametric and nonparametric tests (Students t test, Mann-Whitney U test, ANOVA). Spearman rank-order correlation coefficient was calculated to determine associations between variables. The Statistica v.10.0 program was used for statistical data analysis.
ResultsFirst patents group (months-long monitoring)
This group included a total of 6 patients (2 men and 4 women) with an average age of 58.33 (range 50-65 years of age). The median number of drugs being taken for AT was 6 (min. 4, max. 8). Three patients had diabetes (one man). All measured values (systolic BAT, diastolic BAT, systolic and diastolic CAT, PWV, arterial age) were lower at all controls after the follow-up, over a period of 12 months (other than heart frequency and number of medications), as shown in Table 1. The number of medications was not reduced in the first 6 months to objectivize the effect of the RDN procedure.
Blood pressure and pulse wave velocity values in the first group of patients.
The average systolic CAT value before RDN was 159 mmHg, whereas the values were lower in all the subsequent measurements as follows: 129.00 mmHg (1 month, p<0.001), 134.17 mmHg (6 months, p<0.0001), and 125.66 (12 months, p<0,0001). The average diastolic CAT value before RDN was 104 mmHg, which was lowered in subsequent measurements as follows: 89.33 mmHg (1 month, p=0.03), 93.83 mmHg (6 months, p=0.04), and 88.17 mmHg (12 months, p=0.02). Average arterial age before RDN was 9 years above the average for the age of the patients, whereas subsequent measurements showed a reduction as follows: 4.00 years (1 month, p<0.01), 5.67 years (6 months, p<0.005), and 4.67 years (12 months, p<0.005). PWV values can be compared between patients since they were all in a similar age group (50-65 years of age). The difference in PWV values was evident, and there was a reduction in both diabetic and nondiabetic patients (long-term p=0.093). Although not statistically significant, there was a gradual improvement in renal function over the 12 months (eGFR 56.61 vs 68.75 mL/min/1.73m2 after 12 months, p=0.35).
Second patient group (years-long monitoring)
The four patients in the second group were women with an average age of 61.75 years (range 50-70 years of age), half of which had diabetes. Given that the patients were of similar age and the same sex, data can be compared regarding the long-term outcomes for RDN (no data available from before the RDN procedure). The average systolic CAT value 2 years after RDN was 259 mmHg and in subsequent measurements as follows: 133.25 mmHg after 3 years (p=0.6437) and 120.75 mmHg after 4 years (p=0.0538). The average diastolic CAT value 2 years after RDN was 85.25 mmHg and in subsequent measurements as follows: 91.25 mmHg after 3 years (p=0.3515) and 79.75 mmHg after 4 years (p=0.1187). The average PWV value 2 years after RDN was 9.92 m/s; 9.87 m/s after 3 years (p=0.9669); and 9.32 m/s after 4 years (p=0.5469). Average arterial age 2 years after RDN was 5.5 years higher than the reference value for the patient age, and changed over subsequent measurements as follows: after 3 years arterial age was 6 years (6=0.8089), and 4 years after RDN the average arterial age was 4 years higher compared with reference values (p=0.1536). Every year of follow-up was compared with the previous one. Variables were analyzed with a nonparametric test to determine Spearman coefficient values for the association between changes in systolic and diastolic pressure and changes in PWV. The values were as follows: systolic CAT vs PWV: r=0.7043, p<0.001; diastolic CAT vs PWV: r=0.4406, p<0.05; systolic CAT vs diastolic CAT: 0.5592, p<0.01. Over several years of monitoring renal function at baseline and before RDN, the mean value was eGFR 60.61 vs 64.85 mL/min/1.73m2 four years after the RDN procedure.
Discussion
As an additional method of treatment for RAH, renal plexus denervation (RDN) is a procedure that has caused numerous controversies in recent years. Initially, the SYMPLICITY HNT-1 and HNT-2 showed that RDN was a safe and effective method of reducing office AP values by 27/17 mmHg after 12 months and 32/12 mmHg after 6 months (a weakness of the study was that 24 h ambulatory blood pressure monitoring (ABPM) was not used) (4). However, the SYMPLICITY HNT-3 study that followed the effect of RND using ABPM caused some doubts because a rection in AP values of 10 or more mmHg was not demonstrated (4). The study itself received a number of criticisms that were primarily associated with the radiofrequency energy delivery procedure (which varied in the study between one or more ablated points). After that study, the RDN method was improved by perfecting the catheter, which is of a spiral shape and relivers radiofrequency energy to the endoluminal part of the renal artery in a single touch, not just at one point (as in SYMPLICITY HNT-3) but at 4 points of contact (the success of RDN depends on the number of ablation points) (4). Due to the lack of randomized studies, the previous 2018 ESH guidelines did not recommend RDN as a regular additional method of AP control in patients with refractory resistant arterial hypertension (5). Recently published results of the Global SYMPLICITY Registry from 2019 that includes 1742 patients monitored for 3 years after RDN demonstrated the safety and effectiveness of the procedure with significantly reduced brachial pressure values, which indicate a trend towards stability with preserved renal function (9). Additional studies after the publication of the lastest ESH guidelines (in June 2018) have confirmed the effectiveness and safety of RDN not only in patients with RAH but also in other groups of hypertonic patients (10).
Increased pulse wave velocity has been shown to be a marker of elevated CV risk in patients receiving antihypertensive therapy, especially those with RAH (6). Arterial stiffness is an independent marker which is directly proportional to endothelial dysfunction and development of pre-clinical atherosclerosis (11). In choosing patients for RDN, it is recommended to determine arterial stiffness by measuring PWV, which is a predictor of total and CV mortality and if elevated (measured by invasive methods) is associated with poorer response to RDN (5). In this study, we found a reduction in PWV values after RND measured using a noninvasive oscillometric method (first group), but no data is available on long-term outcomes regarding comorbidity and cardiovascular mortality, i.e. conclusions can be made only indirectly. In the second group in the present study, we observed beneficial long-term outcomes over a period of four years in patients who underwent RDN. The “p” value between follow-up AP pressure measurements and PWV values was mostly not statistically significant, which indicates the long-term efficacy of RDN in treating RAH and contradicts the common assumption that RDN has a “best before date” and that pressure once again starts being poorly regulated after approximately 12 months. Analysis of the association between changes in central systolic and diastolic pressure and changes in PWV found a stronger association with systolic (r=0.7043) than diastolic AP (r=0.4406). During the course of both the months-long and the year-long RDN outcome monitoring, no deterioration of renal function was observed and it remained stable throughout or even improved, although not statistically significantly.
Although this study included only a small number of patients, the data that has been obtained is significant and indicate the need for further research on larger samples with monitoring of long-term effects of RDN on slowing down target organ damage and total mortality.
Conclusion
The positive effects of RDN were found to include long-term AP stability in the monitoring period that lasted up to 4 years. Pulse wave velocity is an established marker of elevated CV risk and a promising predictor for the procedure as well as an RDN outcome marker. Further studies with a larger number of participants are needed to determine the significance of PWV reduction regarding comorbidities and CV mortality after a RDN procedure.
LITERATURECareyRMCalhounDABakrisGLBrookRDDaughertySLDennison-HimmelfarbCRAmerican Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension. Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council. Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. . 2018 November;72(5):e53–90. 10.1161/hyp.000000000000008430354828EttehadDEmdinCAKiranAAndersonSGCallenderTEmbersonJBlood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. . 2016 March 5;387(10022):957–67. 10.1016/S0140-6736(15)01225-826724178WilliamsBManciaGSpieringWAgabiti RoseiEAziziMBurnierMESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. . 2018 September 1;39(33):3021–104. 10.1093/eurheartj/ehy33930165516KjeldsenSENarkiewiczKBurnierMOparilS. Renal denervation achieved by endovascular delivery of ultrasound in RADIANCE-HTN SOLO or by radiofrequency energy in SPYRAL HTN-OFF and SPYRAL-ON lowers blood pressure. . 2018 August;27(4):185–7. 10.1080/08037051.2018.148617829936868OkonTRöhnertKStiermaierTRommelKPMüllerUFenglerKInvasive aortic pulse wave velocity as a marker for arterial stiffness predicts outcome of renal sympathetic denervation. . 2016 August 5;12(5):e684–92. 10.4244/EIJV12I5A11027497368JakopovićMMIvoševićAStankovićMPrkačinI. Cardiovascular Outcomes and Potential Long-term Benefits of Renal Denervation in Patients with Resistant Hypertension. . 2018;13(9-10):277–82. 10.15836/ccar2018.277BilinovacLKurjakovićIVukovićJJugJLovrić BenčićMPrkačinI. Oscillometric Measurement of Pulse Wave Velocity in Hypertensive Crisis. . 2020;15(1-2):22–6. 10.15836/ccar2020.22Agedio B900 Pulse Wave Analysis System. (Internet, 22.4.2020) available: https://www.hiberniamedical.ie/product/agedio-b900-pulse-wave-analysis-systemMahfoudFBöhmMSchmiederRNarkiewiczKEwenSRuilopeLEffects of renal denervation on kidney function and long-term outcomes: 3-year follow-up from the Global SYMPLICITY Registry. . 2019 November 1;40(42):3474–82. 10.1093/eurheartj/ehz11830907413Mahfoud F, Azizi M, Ewen S, Pathak A, Ukena C, Blankestijn P, et al. Proceedings from the 3rd European Clinical Consensus Conference for clinical trials in device-based hypertension therapies. Eur Heart J. 2020 Apr 21;41(16):1588-99. https://doi.org/10.1093/eurheartj/ehaa121VamsiVAchappaBKamathPKulkarniVPrkacinI. Are pulse wave velocity and arterial stiffness markers for early pre-clinical atherosclerosis detection in resistant hypertensive patients?2020;23(1):27–31.