Oxidative stress is associated with decreased heart rate variability in patients with chronic kidney disease

Figures & data

Table 1 Time and frequency HRV parameter descriptions⁴²

		Unit	Description
Frequency domain HRV measures
LF	Low frequency power (0.04–0.15 Hz)	ms^2	Correlated to both parasympathetic and sympathetic modulations
HF	High frequency power (0.15–0.4 Hz)	ms^2	Indicator of parasympathetic modulations
LF/HF	Ratio of LF/HF	No units	Indicator of sympathovagal balance
TP	Total Power	ms^2	A global measure of HRV. Calculated from the addition of VLF, LF and HF
Time domain HRV measures
pNN50	Ratio between the number of pairs of adjacent NN intervals differing by more than 50 ms and the total number of NN intervals	%	Reflects high frequency heart rate variations due to parasympathetic modulation
SDNN	Standard deviation of all NN intervals	ms	Indicator of overall HRV
RMSSD	Square root of the mean of the squares of successive R-R interval differences	ms	Reflects high frequency heart rate variations due to parasympathetic modulation. Indicates short-term HRV components

Table 2 Characteristics, medications and biochemical measures of CKD patients

Variable	Normal F2-isoprostanes (n = 62)	Elevated F2-isoprostanes (n = 16)	P value
Demographics
Age (years) (M–W U)	59.8 ± 10.2	56.6 ± 11.8	0.36
Body mass index (kg/m^2)	33.0 ± 6.5	34.0 ± 6.9	0.60
Diabetes status (%)	26 (41.9%)	5 (31.3%)	0.57
eGFR (ml/min/1.73 m^2)	41.1 ± 9.7	40.9 ± 8.1	0.95
eGFR rate of change (ml/min/1.73 m^2)*	0.05 ± 0.5	−0.1 ± 0.1	0.42
Medications
β-Blockers (%)	23 (29.9%)	2 (2.6%)	0.06
ACE-I (%)	31 (40.3%)	5 (6.5%)	0.16
Statins (%)	61 (79.2%)	16 (20.8%)	0.54
Blood biochemistry
Total cholesterol (mmol/l) (M–W U)	4.2 ± 1.0	5.3 ± 1.2	0.01
Triglyceride (mmol/l)	1.7 ± 0.8	2.8 ± 3.1	0.03
HDL (mmol/l) (M–W U)	1.1 ± 0.4	1.6 ± 0.9	<0.01
LDL (mmol/l)	2.6 ± 0.9	2.6 ± 0.9	0.94
Glutathione Peroxidase (GPx) (U/l)	24.6 ± 4.0	23.4 ± 4.8	0.22
Total antioxidant capacity (mmol/l)	1.7 ± 0.2	1.8 ± 0.2	0.64
Albumin (g/l) (M–W U)	38.0 ± 2.6	37.4 ± 4.2	0.85
Haemoglobin (g/l)	132.5 ± 14.5	130.5 ± 15.5	0.63
Phosphate (mmol/l)	1.1 ± 0.2	1.1 ± 0.2	0.73
Magnesium (mmol/l) (M–W U)	0.8 ± 0.1	0.9 ± 0.1	0.50
HOMA-IR (%) (M–W U)	8.7 ± 21.1	7.7 ± 11.3	0.54
HaemoglobinA1c (%) (M–W U)	6.5 ± 1.4	6.2 ± 0.5	0.59
C-Reactive Protein (mg/l)	3.8 ± 3.6	5.2 ± 3.8	0.48

Italicised values are those which are statistically significant (ie. p < 0.05). Normal (<250 pg/ml) and elevated (≥250 pg/ml) plasma F2-isoprostane levels based on previous data from our laboratory.²² (M–W-U) = Mann–Whitney-U test; ACE-I = angiotensin converting enzyme inhibitor; HDL = high density lipoprotein; LDL = low density lipoprotein; HOMA = homeostatic model assessment of insulin resistance. Values are reported as mean ± SD for normally distributed variables, or median (IQR) for not normally distributed or log transformed variables.

*eGFR rate of change = change in eGFR from baseline to 12 months (from LANDMARK III study) divided by 12 (months in a year).

Table 3 Heart rate variability parameters of all and patients not on beta-blockers

Heart rate variability – all patients	Normal F2-isoprostanes (n = 62)	Elevated F2-isoprostanes (n = 16)	P value
Mean RR (ms)	895.0 ± 167.9	837.5 ± 114.8	0.20
Mean HR (1/min)	69.5 ± 13.4	73.0 ± 10.4	0.33
STD HR (1/min)	2.2 ± 0.8	1.8 ± 0.7	0.10
SDNN (ms^2)	29.3 ± 13.2	20.9 ± 8.8	0.02
RMSSD (ms^2)	18.9 ± 10.7	15.1 ± 8.3	0.19
Very low frequency (ms^2)	530.8 ± 656.7	212.4 ± 159.3	0.04
Low frequency (ms^2)	318.7 ± 580.9	106.4 ± 128.3	0.04
High frequency (ms^2)	405.4 ± 1556.1	108.4 ± 105.3	0.40
Total power (ms^2)	1254.8 ± 2588.7	427.2 ± 289.6	0.09
LF:HF (ms^2)	2.5 ± 2.5	1.8 ± 1.5	0.10
NN50 (count) (M–W U)	10.8 ± 20.7	4.2 ± 7.0	0.14
pNN50 (count) (M–W U)	3.5 ± 7.3	1.2 ± 2.0	0.13
Heart rate variability – patients not on beta-blockers	Normal F2-isoprostanes (n = 39)	Elevated F2-isoprostanes (n = 14)	P value
Mean RR (ms)	876.6 ± 148.6	846.4 ± 100.9	0.49
Mean HR (1/min)	69.4 (14.9)	74.2 (15.2)	0.61
STD HR (1/min)	2.2 ± 0.9	1.7 ± 0.7	0.04
SDNN (ms^2)	29.5 ± 14.4	19.8 ± 6.9	0.02
RMSSD(ms^2)	17.9 (14.3)	13.8 (15.3)	0.40
Very low frequency (ms^2) (M–W-U)	266.9 (657.9)	152.0 (202.2)	0.08
Low frequency (ms^2) (M–W-U)	179.2 (277.8)	47.9 (82.2)	<0.01
High frequency (ms^2)	91.7 (189.9)	70.1 (163.2)	0.41
Total power (ms^2)	759.7 (1179.4)	387.0 (431.6)	0.10
LF:HF(ms^2)	1.7 (2.4)	1.5 (2.2)	0.05
NN50 (count)	4.0 (16.3)	0.0 (8.0)	0.61
pNN50 (count)	1.2 (4.8)	0.0 (2.2)	0.50

Normal (<250 pg/ml) and elevated (≥250 pg/ml) plasma F2-isoprostane levels based on previous data from our laboratory.²² (M–W-U) = Mann–Whitney-U test; RR = r–r interval; HR = heart rate; STD HR = standard deviation of heart rate; SDNN = standard deviation of all NN intervals; RMSSD = square root of the mean of the squares of successive R–R interval differences; NN50 = the number of successive N–N intervals greater than 50 ms; pNN50 = ratio between the number of pairs of adjacent NN intervals differing by more than 50 ms and the total number of NN intervals. Values are reported as mean ± SD for normally distributed variables, or median (IQR) for not normally distributed or log transformed variables.

Table 4 The association between plasma F2-isoprostanes and HRV parameters in all patients and those not on beta-blockers

	r value	P value
HRV – all patients
Mean RR (ms)	−0.20	0.08
Mean HR (1/min)	0.18	0.12
STD HR (1/min)	−0.25	0.03
SDNN (ms^2)	−0.34	<0.01
RMSSD (ms^2)	−0.20	0.08
Very low frequency (ms^2) (S)	−0.28	0.01
Low frequency (ms^2) (S)	−0.32	<0.01
High frequency (ms^2)	−0.19	0.10
Total power (ms^2)	−0.29	0.01
LF/HF (ms^2)	−0.16	0.17
HRV – patients not on β-blockers
Mean RR (ms)	−0.20	0.15
Mean HR (1/min)	0.20	0.17
STD HR (1/min)	−0.36	<0.01
SDNN (ms^2)	−0.42	<0.01
RMSSD (ms^2)	−0.25	0.07
Very low frequency (ms^2) (S)	−0.28	0.04
Low frequency (ms^2) (S)	−0.35	0.01
High frequency (ms^2)	−0.26	0.06
Total power (ms^2)	−0.33	0.02
LF/HF (ms^2)	−0.14	0.32

(S) = Spearman's test; RR = r–r interval; HR = heart rate; STD HR = standard deviation of heart rate; SDNN = Standard deviation of all NN intervals; RMSSD = Square root of the mean of the squares of successive R–R interval differences; LF/HF = ratio of low frequency to high frequency.

Table 5 Bivariate and multivariate associations with SDNN

Variable	SDNN (ms^2)
	r value	P value	β	P value
Age (years) (S)	−0.21	0.08
Sex (S)	−0.37	<0.01	−0.26	0.01
Body mass index (kg/m^2)	0.04	0.71
Diabetes status (S)	−0.34	<0.01	−0.23	0.06
eGFR (ml/min/1.73m^2)	0.13	0.26
Blood biochemistry
Glutathione peroxidase (U/l)	0.05	0.67
Total antioxidant capacity (mmol/l)	0.11	0.33
F2-isoprostanes (pg/ml)	−0.34	<0.01	−0.27	0.01
Albumin (g/l)(S)	0.17	0.15
Phosphate (mmol/l)	0.15	0.21
HOMA-IR (S)	0.23	0.05
HaemoglobinA1c (%) (S)	−0.42	<0.001	−0.15	0.24
C-reactive protein (mg/l)	0.10	0.37
Medications
β-Blockers (%) (S)	0.07	0.53
ACE-I (%)(S)	−0.03	0.82
Statins (%)(S)	0.20	0.08

R² = 28.7%, P<0.01; (S) = Spearman's Test; SDNN = Standard deviation of all NN intervals; eGFR = estimated glomerular filtration rate; HOMA-IR = homeostatic model of assessment-insulin resistance; ACE-I = angiotensin converting enzyme inhibitor.

Figure 1 Relationship between SDNN and plasma F2-isoprostanes in patients with CKD (r = 0.34, P < 0.01).

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