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Corresponding author at: Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Hondoh 1-1-1, Akita 010-8543, Japan. Tel.: +81 18 884 6110; fax: +81 18 836 2612.
Short-duration adaptive servo-ventilation (ASV) therapy can be effective for heart failure (HF) patients. Albuminuria is recognized as a prognostic marker for HF. We investigated whether short-duration and short-term ASV therapy reduced albuminuria in HF patients.
Methods and results
Twenty-one consecutive HF patients were divided into two groups: those who tolerated ASV therapy (ASV group, n = 14) and those who did not (non-ASV group, n = 7). ASV therapy was administered to enrolled patients for 1 week for 2 h per day (1 h in the morning and 1 h in the afternoon). The urinary albumin to creatinine ratio (UACR), urinary 24 h norepinephrine (NE) excretion, high-sensitivity C-reactive protein (hs-CRP), and plasma brain natriuretic peptide (BNP) levels were measured before and 1 week after ASV therapy. In the ASV group, but not the non-ASV group, the UACR significantly decreased, together with a decrease in urinary NE and hs-CRP levels. There were significant correlations between the changes in UACR and hs-CRP and between the changes in urinary NE and hs-CRP. Multiple linear regression analyses indicated that ASV use was the strongest predictor of decreased UACR.
Conclusion
Albuminuria, urinary NE, and hs-CRP levels reduced in HF patients who could receive short-duration and short-term ASV therapy. Anti-inflammatory effects of ASV therapy may partly mediate the reduction of albuminuria.
Various cardiovascular pathologies are closely associated with albuminuria, which contributes to the progression of heart failure (HF). These include activation of the renin–angiotensin system (RAS) [
Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population.
], as well as renal failure. In the clinic, the urinary albumin to creatinine ratio (UACR) is used as a simple and convenient index to evaluate albuminuria excretion.
We previously showed that adaptive servo-ventilation (ASV) therapy improved cardiac function and prognosis in HF patients, and the effects were apparent in HF patients regardless of sleep-disordered breathing [
]. It is likely that mechanisms underlying HF improvement with ASV therapy involve reductions in sympathetic nerve activity as well as hemodynamic assistance. Elevated sympathetic nerve activity activates the RAS [
], which can cause vascular inflammation and remodeling, where albuminuria was observed. Moreover, we previously found that ASV therapy improved renal function through a reduction of inflammatory responses [
]. Based on these findings, we hypothesize that short-duration ASV therapy may reduce albuminuria in patients with HF.
Methods
Study design
We enrolled 21 consecutive HF patients for ASV therapy from November 2011 to May 2012 who met the following indications: (1) diagnosed with New York Heart Association (NYHA) class II or III stable HF, (2) had left ventricular ejection fraction (LVEF) <55%, and (3) could receive optimized medical treatment for HF. Patients were excluded if they had already experienced another positive airway pressure therapy, could not accept conventional drug therapy, or were admitted 6 months prior to ASV therapy. The study design is summarized in Fig. 1. Enrolled patients were divided into two groups based on the results of an ASV mask-fitting test and a 20 min hemodynamic check during ASV therapy: patients who tolerated ASV therapy (ASV group, n = 14) and those who did not (non-ASV group, n = 7). The day after the fitting tests, patients underwent ASV therapy for 2 h per day: 1 h in the morning from 10 to 11 AM and 1 h in the afternoon from 2 to 3 PM. Physical examination, echocardiographic parameters, plasma brain natriuretic peptide (BNP) levels, high sensitivity C-reactive protein (hs-CRP) levels, 24-h urinary norepinephrine (NE) excretion levels, 24-h creatinine clearance (CCr), and UACR were measured before and 1 week after ASV treatment in the two groups. We evaluated the effects of ASV therapy on albuminuria in stable chronic HF patients. Therefore, at the time of the operation of ASV therapy, patients who had just recovered from acute HF or decompensated HF were excluded from the study. Prescriptions were not changed during the week of ASV therapy. All participants provided informed consent prior to enrollment in the study. This study was approved by the clinical research and ethics committee of the University of Akita.
Fig. 1Flow diagram of the study design. HF, heart failure; ASV, adaptive servo-ventilation.
Plasma BNP and hs-CRP levels were analyzed from blood samples using standard methods. Albuminuria was analyzed using a spot urine sample. Urinary NE excretion and CCr levels were measured from 24-h urine samples.
Echocardiography
Two-dimensional, M-mode, Doppler echocardiography (iE33; Philips Medical Systems, Andover, MA, USA) was used to evaluate various cardiac parameters in the patients. The LVEF, LV end-systolic volume (LVESV), and LV end-diastolic volume (LVEDV) were estimated from the apical two- and four-chamber views using the modified biplanar Simpson's rule. The sonographers were blinded to the study protocol and were not involved in treating the enrolled patients.
ASV therapy
ASV therapy (AutoSet CS®; ResMed, Sydney, Australia) was initiated in 21 consecutive patients with HF. During the first 20 min of ASV treatment, heart rate (HR), oxygen saturation (SaO2), and blood pressure were monitored every 5 min. ASV therapy was initiated by experienced physicians who were familiar with the ASV device. An expiratory positive airway pressure of 5 cm H2O and inspiratory pressure support between 3 and 10 cm H2O were used. A follow-up assessment was conducted 1 week later. Compliance data were downloaded from the ASV devices and checked 1 week after ASV therapy. In addition, physicians who were familiar with ASV therapy observed and monitored patients every 20 min during the therapy. Enrolled patients were instructed to use the ASV device in bed while resting in a supine position, whether or not they were sleeping.
Statistical analysis
Continuous variables are expressed as means ± standard deviation (SD) except for UACR and BNP data. For continuous and normally distributed data, Student's t-test for comparison between groups or paired t-test for paired sample were used, as appropriate. For non-normally distributed data, a Wilcoxon signed-rank test was used for paired sample, and the Mann–Whitney U test was used when comparing 2 groups. The data of plasma BNP levels and UACR were natural log-transformed. Categorical variables were compared using χ2 analysis and Yate's correction. Correlations were analyzed using Pearson's correlation coefficient. All parameters with p < 0.10 on univariate analysis, baseline ln BNP and age were entered into the multivariate analysis. A p-value of <0.05 indicated statistical significance. All analyses were performed using the Statistical Package for the Social Science Windows ver. 16.0 (SPSS, Chicago, IL, USA).
Results
Baseline characteristics of the enrolled HF patients are shown in Table 1. No significant differences in age, gender, body mass index (BMI), blood pressure, pharmacological data, echocardiographic parameters, or laboratory data were found between the two groups. A total of 14 patients used the ASV device for 2 h during the day (ASV group), while 7 patients could not tolerate ASV therapy (non-ASV group) due to mask intolerance (n = 5) or subjective intolerance of positive airway pressure (n = 2). No significant complications were observed during the 1 week of therapy.
Table 1Baseline characteristics of the enrolled HF subjects.
ASV-group
Non-ASV-group
p-value
N = 14
N = 7
Age (years)
59.6 ± 8.3
67.5 ± 9.4
0.070
Male sex, n (%)
10 (71.4)
4 (57.1)
0.638
BMI (kg/m2)
27.7 ± 4.9
27.6 ± 7.1
0.551
Hypertension, n (%)
8 (57.1)
6 (85.7)
0.337
Diabetes mellitus, n (%)
6 (42.9)
4 (57.1)
0.660
Dyslipidemia, n (%)
7 (50.0)
2 (28.5)
0.642
Underlying heart disease, n (%)
Ischemic heart disease
6 (42.9)
2 (28.5)
0.525
Cardiomyopathy
3 (21.4)
1 (14.3)
0.694
Valvular heart disease
2 (14.3)
2 (28.5)
0.186
Others
3 (21.4)
2 (28.5)
0.717
Heart rhythm disorder, n (%)
Atrial fibrillation
6 (42.9)
3 (42.9)
0.681
Pacing
5 (35.7)
2 (28.6)
0.743
Blood pressure (mmHg)
Systolic
108.5 ± 20.0
110.7 ± 11.2
0.601
Diastolic
57.5 ± 7.4
55.4 ± 7.0
0.389
Medication, n (%)
ACEIs/ARBs
14 (100.0)
7 (100.0)
1.000
β-Blockers
13 (92.8)
6 (85.7)
0.599
Loop diuretics
14 (100.0)
7 (100.0)
1.000
Aldosterone antagonists
12 (85.7)
7 (100.0)
0.293
Statins
11 (78.5)
5 (71.4)
0.717
Ca antagonists
8 (57.1)
4 (57.1)
1.000
Laboratory data
24-h CCr (mL/min)
63.8 ± 28.4
58.5 ± 26.1
0.709
UACR (mg/gCr)
27.4 (24.2–40.1)
25.5 (24.1–44.8)
0.157
Ln UACR
3.31 (3.18–3.68)
3.24 (3.18–3.80)
0.157
Urinary NE (μg/day)
219.1 ± 76.6
204.0 ± 107.2
0.502
Plasma BNP (pg/mL)
430.8 (205.3–829.3)
270.1 (221.0–440.0)
0.502
Ln BNP
6.07 (5.32–6.71)
5.60 (5.39–6.09)
0.502
hs-CRP (mg/dL)
0.29 ± 0.28
0.28 ± 0.33
0.681
Echocardiography data
LVEF (%)
34.5 ± 12.8
38.5 ± 10.3
0.550
LVEDV (mL)
223.7 ± 71.0
202.9 ± 68.0
0.478
LVESV (mL)
154.8 ± 74.3
128.0 ± 58.7
0.455
Values are reported as mean ± standard deviation except for UACR, BNP data (median [quartile 1 to quartile 3]). HF, heart failure; ASV, adaptive servo-ventilation; BMI, body mass index; ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; CCr, creatinine clearance; UACR, urinary albumin to creatinine ratio; NE, norepinephrine; BNP, brain natriuretic peptide; hs-CRP, high-sensitivity C-reactive protein; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume.
Table 2 shows the changes in physical, echocardiographic, and laboratory data for each group. Echocardiography data including LVEF and LVEDV were not changed in either group. There was a significant decrease in plasma BNP in the ASV group [−36.8 ± 25.9% (583.4 ± 292.9 to 414.6 ± 584.1 pg/mL)] compared to the non-ASV group [2.9 ± 39.4% (328.7 ± 209.4 to 311.2 ± 202.6 pg/mL), p = 0.011]. However, there were no differences in the physical findings between the groups, including HR, blood pressure, and BMI.
Table 2Changes of physical, echocardiographic, and laboratory data of enrolled HF patients with or without ASV therapy.
ASV-group (n = 14)
Non-ASV-group (n = 7)
Before
After 1 week
p-value
Before
After 1 week
p-value
Physical findings
Heart rate (/min)
70.2 ± 12.1
67.2 ± 11.0
ns
61.3 ± 5.5
62.0 ± 4.4
ns
Blood pressure
Systolic (mmHg)
108.5 ± 20.0
106.1 ± 16.2
ns
110.7 ± 11.2
114.9 ± 8.6
ns
Diastolic (mmHg)
57.5 ± 7.4
54.4 ± 7.3
ns
55.4 ± 7.0
56.1 ± 4.3
ns
BMI (kg/m2)
26.5 ± 3.4
26.4 ± 2.8
ns
25.4 ± 2.3
25.6 ± 1.9
ns
Echocardiographic data
LVEF (%)
34.5 ± 12.8
35.0 ± 13.7
ns
38.5 ± 10.3
37.0 ± 11.8
ns
LVEDV (mL)
223.7 ± 71.0
216.1 ± 71.9
ns
202.9 ± 68.0
199.6 ± 62.5
ns
LVESV (mL)
154.8 ± 74.3
147.7 ± 76.6
ns
128.0 ± 58.7
129.9 ± 60.7
ns
Laboratory data
24-h CCr (mL/min)
63.8 ± 28.4
59.7 ± 27.0
ns
58.5 ± 26.1
61.4 ± 34.7
ns
UACR (mg/gCr)
31.5 ± 10.3
23.7 ± 10.2
0.023
32.1 ± 14.2
40.2 ± 17.9
ns
Urinary NE (μg/day)
219.1 ± 76.6
139.9 ± 63.2
0.005
204.0 ± 107.2
213.6 ± 114.1
ns
Plasma BNP (pg/mL)
583.4 ± 292.9
414.6 ± 584.1
0.002
328.7 ± 209.4
311.2 ± 202.6
ns
hs-CRP (mg/dL)
0.29 ± 0.28
0.22 ± 0.25
0.002
0.28 ± 0.33
0.25 ± 0.31
ns
HF, heart failure; ASV, adaptive servo-ventilation; BMI, body mass index; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; CCr, creatinine clearance; UACR, urinary albumin to creatinine ratio; NE, norepinephrine; BNP, brain natriuretic peptide; hs-CRP, high-sensitivity C-reactive protein.
Fig. 2A depicts the relative change in UACR in patients before and 1 week after ASV therapy. There are significant differences between the groups [ASV group: −19.6 ± 30.0% (31.5 ± 10.3 to 23.7 ± 10.2 mg/gCr); non-ASV group: 24.8 ± 27.1% (32.1 ± 14.2 to 40.2 ± 17.9 mg/gCr); p = 0.003]. The relative changes in 24-h urinary NE excretion levels are shown in Fig. 2B. Urinary NE excretion significantly decreased in the ASV group [−28.1 ± 22.8% (219.1 ± 76.6 to 139.9 ± 63.2 μg/day)] compared to the non-ASV group [1.4 ± 29.5% (204.0 ± 107.2 to 203.6 ± 114.1 μg/day), p = 0.037]. Fig. 2C shows the change in hs-CRP after therapy. It also changed significantly more in the ASV group [−33.4 ± 24.9% (0.29 ± 0.28 to 0.22 ± 0.25 mg/dL)] than in the non-ASV group [6.8 ± 45.3% (0.28 ± 0.33 to 0.25 ± 0.31 mg/dL), p = 0.044]. Fig. 2D shows the relative change in 24-h CCr after therapy. It was −5.5 ± 13.1% (63.8 ± 28.4 to 59.7 ± 26.9 mL/min) in the ASV group and −0.2 ± 17.7% (58.5 ± 26.1 to 61.4 ± 34.7 mL/min) in the non-ASV group, although the differences were not statistically significant (p = 0.263).
Fig. 2Relative change in (A) the urinary albumin to creatinine ratio (UACR), (B) urinary norepinephrine (NE), (C) high-sensitivity C-reactive protein (hs-CRP), and (D) 24-h creatinine clearance (CCr) in heart failure patients with or without ASV therapy. ASV, adaptive servo-ventilation.
Correlations between the changes in UACR and hs-CRP are shown in Fig. 3. The change in UACR was significantly correlated with the change in hs-CRP in the enrolled 21 HF patients (r = 0.726, R2 = 0.368, p = 0.004). Fig. 4 shows the correlations between the relative change in urinary NE excretion and hs-CRP in patients with and without ASV therapy. Significant correlations were found between the two parameters (r = 0.499, R2 = 0.275, p = 0.015). Moreover, the change in UACR was significantly correlated with the change in urinary NE excretion (r = 0.476, R2 = 0.226, p = 0.029). We conducted multiple linear analyses, including ASV use, baseline ln BNP, and age, in the enrolled 21 HF patients. This analysis showed that ASV use was the strongest parameter indicating reduced UACR (coefficient = −0.694, SE = 6.745, p = 0.001, Table 3).
Fig. 3Correlations between a relative change in the urinary albumin to creatinine ratio (UACR) and high-sensitivity C-reactive protein (hs-CRP) level in heart failure patients. Black circle = non-ASV group; gray circle = ASV group. ASV, adaptive servo-ventilation.
Fig. 4Correlations between relative changes in norepinephrine (NE) and high-sensitivity C-reactive protein (hs-CRP) in heart failure patients. Black circle = non-ASV group; gray circle = ASV group. ASV, adaptive servo-ventilation.
This study demonstrated the effects of short-duration and short-term ASV therapy on albuminuria in HF patients. We determined that the UACR, urinary NE excretion, and hs-CRP levels were significantly reduced in the ASV group but not in the non-ASV group. Significant correlations were found between changes in hs-CRP and UACR. Moreover, the change in hs-CRP was significantly correlated with the change in urinary NE and was the strongest predictor of reduced UACR.
Increased urinary albumin excretion is attributed to endothelial dysfunction, which may be an important prognostic marker in patients with HF [
]. One possible cause of albuminuria in HF patients may be vascular inflammation induced by increased sympathetic nerve activity. Elevated sympathetic nerve activity activates the RAS system [
], and leads to vascular remodeling events such as vasoconstriction, proliferation of vascular smooth muscle cells, and vascular inflammation. The present study showed that ASV-mediated changes in hs-CRP levels were significantly correlated with the changes in UACR in HF patients (Fig. 3), implying that anti-inflammatory effects of ASV therapy may be partly associated with decreased urinary albumin excretion. In addition, multiple linear regression analyses showed that ASV use was the strongest parameter predicting a decrease in UACR (Table 3), which supports the idea that the polymodal effects of ASV therapy, such as anti-inflammatory effects and hemodynamic support, may contribute to reduced UACR in HF patients.
ASV therapy has been established as a non-pharmacological intervention for HF patients with sleep-disordered breathing, such as central apnea [
]. Because ASV therapy can produce deep and regular respiratory conditions, it may reduce sympathetic nerve activity. The present study showed that 24-h urinary NE excretion levels significantly decreased in ASV-treated patients (Fig. 2B). These results confirm that ASV therapy can reduce sympathetic nerve activity by providing respiratory support.
Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease.
]. In the present study, the relative change in 24-h urinary NE was significantly correlated with the change in hs-CRP levels in the HF patients (Fig. 4), indicating that the reduction of sympathetic nerve activity by ASV therapy may be associated with anti-inflammatory actions.
We previously showed that short-duration ASV can be an alternative approach for HF patients who cannot tolerate long-duration ASV therapy [
‘A single night’ beneficial effects of adaptive servo-ventilation on cardiac overload, sympathetic nervous activity, and myocardial damage in patients with chronic heart failure and sleep-disordered breathing.
] demonstrated that single-night ASV significantly reduced urinary and serum NE levels. In addition, the fact that the reduction of sympathetic nerve activity, inflammation, and UACR were shown even in short-duration and short-term daytime ASV therapy provides the rationale for the beneficial effects of short-duration ASV therapy on HF.
A recent study has shown that improvements in cardiac function could directly reduce excretion of urinary albumin [
]. The present study provided the result that short-duration and short-term daytime ASV therapy could reduce plasma BNP levels together with the reduction in UACR, indicating that hemodynamic support provided by ASV therapy could be partly associated with the reduction in urinary albumin excretion.
There were some limitations to this study due to the observational study design and small number of patients. Randomized trials will be needed to clarify the effects of ASV therapy on albuminuria in HF patients. In this study, because we could not evaluate 24-h urine test for albumin, the measurement of urinary albumin may be inaccurate. Furthermore, we did not demonstrate a direct relationship between RAS inhibition and the reduction in albuminuria. Finally, we did not assess inflammatory cytokine levels.
In conclusion, urinary albumin, urinary NE excretion, and hs-CRP levels were reduced in HF patients who could receive short-duration and short-term ASV therapy, where anti-inflammatory effects of ASV therapy may partly mediate the reduction in albuminuria.
Conflict of interest
The authors declare no conflicts of interest.
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‘A single night’ beneficial effects of adaptive servo-ventilation on cardiac overload, sympathetic nervous activity, and myocardial damage in patients with chronic heart failure and sleep-disordered breathing.
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