Summary
Background
Haemodialysis patients often have impaired vascular function that can contribute to mortality. Endothelial-dependent and -independent vascular function can be assessed using the brachial artery reactivity (BAR) technique that measures flow-mediated dilatation (FMD) and the response to glyceryl trinitrate (GTN), respectively.
Aims
The aim of this pilot study was to determine whether BAR measurements in haemodialysis patients were associated with mortality.
Methods
Brachial artery responses to FMD and administration of GTN were assessed in consecutive haemodialysis patients. Patients were then followed up to 18 months after BAR measurements.
Results
Seventeen patients were included in the study. After 18 months of follow-up, patients were divided into two groups: survived ( n = 12) and deceased ( n = 5). Patients who survived had a significantly greater median percentage vasodilatation to GTN than those who died (19.1% vs 8.8%; P = 0.04); and a significantly greater median area under the diameter change–time curve (318 vs 146 mm/s; P = 0.03). However, there were no significant differences between survivors and deceased in median percentage vasodilation to FMD (6.0% vs 4.3%; P = 0.21), time to peak dilation (45 vs 40 s; P = 0.66) or area under the diameter change–time curve (35.5 vs 20 mm/s; P = 0.29).
Conclusion
In this pilot study in a small group of haemodialysis patients, endothelial-independent vasodilatory response to GTN was associated with mortality and was of better prognostic value than the endothelial-dependent response to FMD. This finding needs to be investigated in a larger cohort.
Résumé
Justification
Les patients hémodialysés ont fréquemment une dysfonction vasculaire qui peut être un facteur de surmortalité. La fonction vasculaire endothélium-dépendante et indépendante peut être évaluée par la réactivité de l’artère brachiale (BAR), technique qui mesure la dilatation flux-dépendant (FMD) et la réponse au glycéryl trinitrate (GTN), respectivement.
Objectifs
L’objectif de cette étude pilote était de déterminer si la réactivité de l’artère brachiale chez les patients hémodialysés est associée à une surmortalité.
Méthode
La réponse de l’artère brachiale à la dilatation flux-dépendante et l’administration du glycéryl trinitrate ont été évaluées chez des patients hémodialysés consécutifs. Ces patients ont été suivis pendant 18 mois après détermination des paramètres de réactivité de l’artère brachiale.
Résultats
Dix-sept patients ont été inclus dans l’étude pilote. Après un suivi de 18 mois, les patients ont été divisés en deux groupes : survivants ( n = 12) et décédés ( n = 5). Les patients survivants avaient de façon significative une vasodilatation accrue, en réponse au glycéryl trinitrate, comparativement aux patients décédés (19,1 vs 8,8 % ; p = 0,04) et une médiane de surface sous la courbe diamètre/temps plus élevée (318 vs 146 mm/s : p = 0,03). Cependant, il n’y avait pas de différence significative entre les patients survivants et décédés en ce qui concerne la valeur médiane de la vasodilatation flux-dépendante, exprimée en pourcentage (6,0 % vs 4,3 % ; p = 0,21), le délai d’apparition de la dilatation maximum (45 vs 40 s ; p = 0,66) ou la surface sous la courbe variation de diamètre par rapport au temps (35,5 vs 20 mm/s ; p = 0,29).
Conclusion
Dans cette étude pilote ayant inclus un petit groupe de patients hémodialysés, la vasodilatation endothélium-indépendante en réponse au glycéryl trinitrate est associée à une surmortalité, et à une meilleure valeur prédictive pronostique que la réponse endothélium-dépendante de la dilatation flux-dépendante. Cette observation nécessite une confirmation dans des études prospectives de cohortes.
Background
The ability of arteries to dilate in response to stimuli is an important indicator of underlying vascular disease . Major modulators of vascular dilatation are arterial compliance and endothelial and smooth muscle function. Factors controlling vasodilation include the release of vasoactive compounds from the endothelium and the stiffness of the arteries. In healthy individuals, one of the major mechanisms responsible for vasodilation is the hyperaemic-stimulated release of NO from the endothelium, resulting in vascular smooth muscle relaxation .
The most common non-invasive technique to assess the vasodilatory capacity is the BAR procedure. This technique uses high-resolution ultrasound to measure changes in brachial artery diameter to endogenous production of vasodilatory compounds via FMD. Following FMD, assessment of endothelial-independent vasodilation is performed by administering GTN to generate NO independently from the endothelium. This reflects vascular smooth muscle function and arterial compliance.
Despite a number of studies investigating the prognostic value of FMD , only one has included haemodialysis patients . In this study, data from the dialysis patients were pooled with those of other individuals at risk of cardiovascular events or divided into those with or without CAD. Given the knowledge that some studies , but not all have reported that dialysis patients have impaired BAR, we thought it important to assess the prognostic value of BAR data in haemodialysis patients. Furthermore, most studies have investigated ability of BAR measures to be associated with cardiovascular events rather than mortality . Therefore, the long-term goal is to investigate the whether BAR measures are associated with all-cause mortality in haemodialysis patients. The aim of this pilot study is to collect data to assist in the design of this larger study and to provide data for future meta-analyses on this topic.
Methods
Study population
Haemodialysis patients were recruited from the Launceston General Hospital and the North-West Tasmanian dialysis unit. Consecutive patients attending the dialysis units over a 2-week period who agreed to participate in the study were recruited. All patients were receiving haemodialysis three times a week using a polysulphane membrane dialyser with each session lasting 3 to 4 hours.
Patient records were assessed for risk factors associated with CVD and those with an arteriovenous fistula in both right and left arms were excluded. None of the patients were smokers (defined as smoking ≥ one cigarette per day for > 1 year within the last 5 years). Full lipid profiles (total, LDL and HDL cholesterol and triglycerides) were conducted on all patients in the week prior to testing following a 12-hour fast.
Each patient provided written informed consent. The Statewide Tasmanian Human Scientific Ethics Committee approved the study and it was carried out in accordance with the declaration of Helsinki (2000) of the World Medical Association.
Brachial artery reactivity and carotid artery intima media thickness
All testing procedures have been explained in a previous study . The repeatability of the BAR protocol and the measurement of IMT was determined in a separate study where six healthy subjects had their IMT measured and were assessed for their vasodilatory response to RH and GTN on two occasions separated by 24 hours. The mean absolute differences between the 2 days were 1.7% for RH, 2.1% for GTN and 1.2% for IMT.
Biochemical analyses
Measurements were carried out in the NATA-accredited pathology laboratory at the Launceston General Hospital. Total cholesterol, HDL cholesterol and triglycerides were measured with an automated analyser (Olympus Au600 Clinical Chemistry Analyser, Mishima Olympus Co. Ltd, Japan). LDL cholesterol was calculated using the Friedewald equation LDL = total cholesterol–HDL cholesterol–(triglycerides/2.2). CRP was determined by measuring the absorbance of insoluble aggregates formed when antihuman CRP antibodies were added to patient samples.
Follow-up
Eighteen months after the baseline measurements, research staff in the dialysis units confirmed deaths via medical records. At this time, the remaining patients were still attending the units, allowing confirmation of survival.
Data analysis
As this was a pilot study, a sample size calculation was not performed. To determine AUC, individual responses to RH and GTN were plotted using PRISM (v2, GraphPad Software, San Diego, CA, USA), converted to TIFF files, and AUC was determined using Analytical Imaging Station software (Imaging Research, St Catherine’s, Canada) as previously described .
Patients were followed for 18 months and then divided into two groups: survived and deceased. A two-sample Wilcoxon rank-sum (Mann-Whitney) test was used to compare variables between these groups. These analyses showed that the response of the brachial artery to GTN was different between groups. This prompted the use of Cox proportional multivariable regression to assess the independence of GTN or RH to dilate the brachial artery and investigate the association with mortality. Furthermore, a Cox proportional hazards model was used to compare GTN dilation with variables selected based on previous evidence of their association with mortality in haemodialysis patients: age, CRP, carotid IMT and supine pulse pressure . SPSS version 11.0.0 (Chicago, IL, USA) was used for all statistical methods. A P value of < 0.05 was considered statistically significant.
Results
In total, 17 patients (13 male, four female) were included in this study. Of these, 16 patients had previously been diagnosed with hypertension, five had type 2 diabetes and 11 were diagnosed with atherosclerosis (either angiographically determined or with a documented vascular incident). Five of the 17 patients died within the 18-month follow-up period due to withdrawal from dialysis ( n = 3) and MI ( n = 2). There were a total of 16 cardiovascular events (including the two deaths from MI), and 13 of these occurred in individuals who had survived 18 months.
Table 1 shows clinical and biochemical characteristics of the patients. There were no significant differences in any of the biochemical parameters between the patients who died within 18 months of the BAR measures and those who survived.
| All patients | Survived > 18 months | Died within 18 months | P | |
|---|---|---|---|---|
| ( n = 17) | ( n = 12) | ( n = 5) | ||
| Age (years) | 60 (23–78) | 60 (23–76) | 68 (52–78) | 0.09 |
| Male/female | 13/4 | 10/2 | 3/2 | 0.90 |
| Time on dialysis (months) | 25.5 (1.5–60.5) | 24.8 (1.5–60.5) | 34.0 (7.0–41.0) | 1.00 |
| Standing SBP (mmHg) | 130 (105–160) | 130 (105–160) | 132 (112–150) | 0.49 |
| Standing DBP (mmHg) | 75 (54–100) | 78 (60–100) | 72 (54–80) | 0.31 |
| Standing pulse pressure (mmHg) | 52 (15–85) | 50 (15–85) | 62 (47–78) | 0.25 |
| Supine SBP (mmHg) | 142 (108–172) | 136 (108–172) | 142 (138–170) | 0.43 |
| Supine DBP (mmHg) | 80 (60–100) | 80 (60–100) | 80 (76–98) | 0.75 |
| Supine pulse pressure (mmHg) | 58 (30–110) | 54 (30–110) | 62 (56–80) | 0.31 |
| Total cholesterol (mmol/L) | 4.5 (2.8–6.4) | 4.5 (3.0–6.4) | 4.6 (2.8–5.3) | 0.96 |
| LDL cholesterol (mmol/L) | 2.1 (1.3–4.0) | 2.1 (1.3–4.0) | 2.6 (1.6–3.1) | 1.00 |
| HDL cholesterol (mmol/L) | 1.1 (0.7–2.1) | 1.1 (0.7–2.1) | 1.2 (0.7–1.9) | 0.49 |
| LDL/HDL ratio | 2.1 (1.2–4.3) | 2.2 (1.2–4.3) | 2.0 (1.6–2.4) | 0.67 |
| Triglycerides (mmol/L) | 1.7 (0.6–4.9) | 1.7 (0.8–4.9) | 1.4 (0.6–1.8) | 0.22 |
| CRP (mg/L) | 13 (1–155) | 14 (1–155) | 8 (2–136) | 0.29 |
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