If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Impact of N-acetylcysteine on Endothelial Function, B-type Natriuretic Peptide and Renal Function in Patients with the Cardiorenal Syndrome: A Pilot Cross Over Randomised Controlled Trial
Corresponding author at: Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne 8008, Victoria, Australia.
The Alfred Hospital, Commercial Road, Melbourne 8008, Victoria, AustraliaHeart Failure Research Group, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne 8008, Victoria, Australia
Both heart and renal failure are characterised by increased systemic oxidative stress and endothelial dysfunction and occur in the cardiorenal syndrome (CRS). The aim of the present study was to assess the impact of N-acetylcysteine (NAC), a potent antioxidant, on endothelial function, B-type natriuretic peptide (BNP) and renal function in patients with CRS.
Methods
In a double blind, placebo controlled manner, we randomised nine stable outpatients with both heart failure (LVEF < 40% and NYHA class II or III) and renal failure (Cockroft Gault clearance of 20–60 ml/min) to placebo or NAC (500 mg orally twice daily) for 28 days followed by a wash out period (>7 days) and crossover to the other treatment.
Results
Eight patients completed the study and all data (N = 9) was used in the analysis. Mean forearm blood flow improved significantly with NAC with mean ratio of improvement of 1.99 (SEM: ±0.49) for NAC and 0.73 (SEM: ±0.23) for placebo with a p-value of 0.047. There was no significant difference in BNP (p = 0.25), renal function (p = 0.71) or NYHA class (p = 0.5). No deaths occurred during the trial.
Conclusion
In this pilot trial of patients with CRS, NAC therapy was associated with improved forearm blood flow. This may represent a general improvement in endothelial function and warrants further investigation of antioxidant therapy in these patients.
The cardiorenal syndrome (CRS) is a frequent complication in patients with chronic systolic heart failure of various aetiologies. The pathogenesis of the syndrome involves an interplay of several described mechanisms as well as yet poorly understood changes [
Acute Dialysis Quality Initiative (ADQI) consensus group cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative.
Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group.
Endothelial dysfunction, measured by reactive hyperaemia using strain-gauge plethysmography, is an independent predictor of adverse outcome in heart failure.
]. Antioxidant therapy has a possible role in modifying this process. N-acetylcysteine (NAC) has been shown to improve endothelial function in end stage renal failure patients on dialysis with heart failure [
Acetylcysteine reduces plasma homocysteine concentration and improves pulse pressure and endothelial function in patients with end-stage renal failure.
]. We hypothesised that antioxidant therapy with the potent antioxidant N-acetylcysteine would improve markers of endothelial, cardiac and renal function in patients with type 2 CRS.
Methods
Overview of Study Design
We performed a double blind crossover placebo controlled study investigating N-acetylcysteine (NAC) as an adjunctive therapy in patients with type 2 cardiorenal syndrome. We randomised nine stable outpatients with both heart failure (LVEF < 40% and NYHA functional class II or III) and renal failure (Cockroft Gault clearance of 20–60 ml/min) to placebo or NAC (500 mg orally twice daily) for 28 days followed by a wash out period (>7 days) and crossover to the other treatment for 28 days. The patients were recruited from the Heart Failure Clinic at the Alfred Hospital, Melbourne, Australia. The study protocol was approved by the Alfred Hospital Research and Ethics Committee. All study participants provided written informed consent.
Inclusion and Exclusion Criteria
Patients aged 18–75 years of age were eligible to be enrolled in the study. Inclusion criteria included presence of NYHA functional class II or III heart failure with LVEF of <40%. Patients must not have been admitted to a hospital for management of decompensated cardiac failure in the month preceding enrollment. Patients also had to have evidence of chronic renal failure with a glomerular filtration rate (GFR) (as estimated by the Cockroft Gault equation) of >20 ml/min and <60 ml/min (not on any form of dialysis).
Outcome Measures
Primary outcome measures were changes in endothelial function as measured by forearm plethysmography, changes in B-type natriuretic peptide (BNP) levels and change renal function as estimated by the Cockroft and Gault method. These variables were assessed and recorded at baseline, after the first 28 days and then again following the second 28 day period. Secondary outcomes were change in functional status (NYHA class) and death.
Endothelial Function Measurement
Endothelial function was assessed using forearm plethysmography utilising the DE Hokanson Plethysmograph (Bellevue, WA, USA) system of cuffs and transducers and using AD Instruments Chart Version 5 software. The procedure involved having participants rest in bed for 10 min before commencing measurements. The arm was elevated to 30 degrees to facilitate venous return flow. Forearm blood flow (FBF) was then assessed by inflating a pressure cuff around the upper arm to 50 mmHg to occlude venous return and recording the FBF by means of strain gauge plethysmograph around the forearm. This process was then repeated following 5 min of having the upper arm cuff inflated to suprasystolic pressure of 200 mmHg to induce an ischaemic state in the forearm with subsequent hyperaemic response. Forearm plethysmography has previously been validated as a method for assessing endothelial performance [
]. FBF was recorded as ml/min 100 ml−1 (forearm volume). The FBF measurements prior to and following induction of ischaemic reactive hyperaemia were compared and expressed as a percentage change. The flow figure used was a mean of three samples taken after hyperaemia developed. The percentage change after the interventional therapy (NAC or placebo) was compared with pre intervention percentage change by expression as ratio of improvement.
Statistical Analysis
The ratio of improvement for FBF with NAC and placebo were expressed with an attendant standard error of the mean (SEM) and the ratio of improvement of each group was compared using Student's t-test. Student's t-test was also used to compare changes in Cockroft Gault GFR, BNP and NYHA class between NAC and placebo treatment.
Results
Eight patients completed the study and all data (n = 9) was used in the final analysis. Baseline characteristics of the study participants are shown in Table 1. As shown in Figure 1, Figure 2, mean forearm blood flow improved significantly with NAC versus placebo with a mean ratio of improvement from baseline of 1.99 (SEM: ±0.49) for NAC versus 0.73 (SEM: ±0.23) for placebo (p = 0.047).
Table 1Baseline Patient Characteristics.
Number of patients
9
Male
88.9% (n = 8)
Mean age (±SD)
60.4 (±8.9) years
Mean LVEF (±SD)
25.4 (±7.86)%
Mean Cockroft Gault GFR (±SD)
43.9 (±7.11) ml/min
Mean B type natriuretic peptide (±SD)
1250.67 (±860.2)
Mean systolic blood pressure (±SD)
104.44 (±25.2) mmHg
Mean diastolic blood pressure (±SD)
65.9 (±4.64) mmHg
Mean weight (±SD)
90.26 (±10.62) kg
Ischaemic cardiomyopathy
44.44% (n = 4)
Non Ischaemic cardiomyopathy
55.56% (n = 5)
Treatment with beta blockers
88.89% (n = 8)
Treatment with ACE inhibitor or angiotensin II receptor blocker
There was no significant difference in the response of BNP or Cockroft and Gault estimated GFR (eGFR) to placebo versus NAC. The mean change in BNP with placebo was −7.53% (SEM: ±6.87) and was −5.74% (SEM: ±11.1) for NAC (p = 0.25). The mean change in eGFR with placebo was 1.95% (SEM: ±4.72) and was 0.26% (SEM: ±5.17) for NAC (p = 0.71). This data is also shown in Figure 3, Figure 4. Mean change in NYHA class did not vary between NAC or placebo (mean improvement in NYHA class of 0.11% (SEM: ±0.26) for both placebo and NAC, p = 0.5). No deaths occurred during the trial.
Figure 3Per cent change in BNP with placebo vs NAC.
The above results demonstrate a potential beneficial effect of antioxidant therapy with NAC on endothelial function in patients with type 2 CRS. This effect was shown in stable outpatients typical of patients with type 2 CRS. The ability to demonstrate a significant improvement in this primary outcome measure, despite our small sample size, likely indicates the potent potential effect of NAC on endothelial function in this patient population.
Endothelial dysfunction is well recognised as a feature of the pathophysiology at play in heart failure [
Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death.
]. Berrazueta and colleagues recently demonstrated a correlation between the degree of endothelial dysfunction in patients with heart failure and worsening prognosis utilising a forearm plethysmography technique similar to that employed by our group [
Endothelial dysfunction, measured by reactive hyperaemia using strain-gauge plethysmography, is an independent predictor of adverse outcome in heart failure.
NAC is a potent antioxidant molecule with the potential to mediate important effects on endothelial function via its impact on reactive oxygen species at the endothelial cell membrane [
]. Endothelial availability of nitric oxide (NO) is reduced in patients with cardiac failure and it is likely that this plays a key role in the pathogenesis of endothelial dysfunction in this patient group [
The modification of this process of increased NO breakdown by NAC likely explains, at least in part, the mechanism by which endothelial function was improved by NAC within our study. However, oxidative stress has numerous other deleterious potential mechanisms by which endothelial function can be impaired [
]. NAC also has the potential to modulate these relationships, given its overall antioxidant effect and findings may also reflect this.
The key limitation of the current study is the small sample size. It may be partly for this reason that our pilot study did not demonstrate any significant effect on BNP, eGFR or NYHA class. More importantly, the small sample also meant that our study was underpowered to detect clinically meaningful changes in these parameters.
Our results add to a growing body of literature regarding the possible application of antioxidant therapies in patients with chronic heart failure. More specifically, our study suggests a possible role for NAC in the treatment of CRS. The significant improvement in endothelial function seen in this patient population in our study warrants further investigation.
Disclosures
This research was funded by a grant from the Alfred Hospital Small Projects Fund.
Acute Dialysis Quality Initiative (ADQI) consensus group cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative.
Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group.
Endothelial dysfunction, measured by reactive hyperaemia using strain-gauge plethysmography, is an independent predictor of adverse outcome in heart failure.
Acetylcysteine reduces plasma homocysteine concentration and improves pulse pressure and endothelial function in patients with end-stage renal failure.
Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death.
01339-X&id=gr1.jpg){kind=link}
01339-X&id=gr2.jpg){kind=link}
01339-X&id=gr3.jpg){kind=link}
01339-X&id=gr4.jpg){kind=link}