Summary
Background and objectives Lower heart rate variability implies increased risk of cardiovascular disease. This study aimed to evaluate the relationship between mineral metabolism and heart rate variability and longitudinal changes of heart rate variability after parathyroidectomy in stage 5 CKD patients.
Design, setting, participants, & measurements This cross-sectional study included 118 stage 5 CKD patients, 87 controls, and a prospective study in two subgroups classified as successful (n=17) and unsuccessful (n=4) parathyroidectomy follow-up enrolled from March of 2011 to December of 2012. Blood examination and 24-hour Holter for heart rate variability were measured.
Results Most heart rate variability indices were lower in stage 5 CKD patients. In multivariate stepwise regression models, serum intact parathyroid hormone was correlated with mean normal-to-normal R–R intervals, mean heart rate, and very low frequency, serum calcium was correlated with SD of 5-minute average of normal R–R intervals, and serum phosphorus was correlated with very low frequency and low frequency/high frequency. Compared with baseline, the successful parathyroidectomy subgroup had significant improvements in mean normal-to-normal R–R intervals, mean heart rate, SD of normal-to-normal R–R intervals, SD of 5-minute average of normal R–R intervals, very low frequency, high frequency, and low frequency/high frequency. There was no significant change of heart rate variability in patients after unsuccessful parathyroidectomy.
Conclusions Disorders of mineral metabolism are associated with decreased heart rate variability in stage 5 CKD. Successful parathyroidectomy may contribute to reverse this cardiovascular disease risk in severe secondary hyperparathyroidism patients.
Introduction
Cardiovascular disease (CVD) is a leading cause of mortality and accounts for 39% of overall deaths in ESRD (1). The ability to identify patients at risk for death and prescribe therapy to reduce CVD risk is of considerable significance in the care of patients with ESRD.
Secondary hyperparathyroidism (SHPT) is universal in ESRD patients and characterized by derangement of calcium/phosphate homeostasis, elevated levels of parathyroid hormone (PTH), and hyperplastic parathyroid gland (PTG) (2–4). These patients present with various bone disorders and high risk of cardiovascular morbidity and mortality (5–8). Recent studies have shown the possibility that parathyroidectomy (PTX) can reduce the risk of CVD (9–12).
In the last decade, heart rate variability (HRV) has emerged as a powerful, noninvasive clinical tool for the assessment of sympathetic and parasympathetic control of the heart using standard electrocardiographic monitoring. Lower HRV has a significant predictive value for various CVDs, such as ventricular arrhythmias and sudden death (13–16).
Previous studies have shown a marked reduction of HRV indices in ESRD patients (17–20). To our knowledge, few studies have evaluated the correlation between SHPT and HRV in ESRD patients. Thus, the present study aimed to examine the associations of mineral metabolism with HRV indices in stage 5 CKD patients and investigate longitudinal changes of HRV in two subgroups with successful and unsuccessful PTX affected by severe SHPT.
Materials and Methods
Patients
We investigated 118 stable stage 5 CKD patients ages 20–75 years. Patients had an estimated GFR<15 ml/min per 1.73 m2 while awaiting commencement of dialysis or on maintenance dialysis (either hemodialysis or peritoneal dialysis). Hemodialysis treatment was performed for 12 hours weekly using bicarbonate as dialysate. Thirty-seven severe SHPT patients who underwent total PTX with forearm autotransplantation were enrolled. PTX was performed in patients with severe hyperparathyroidism (persistent serum levels of intact PTH [iPTH]>800 pg/ml [88.0 pmol/L]) associated with hypercalcemia and/or hyperphosphatemia according to the Kidney Disease Outcomes Quality Initiative guideline (21). Patients with PTX were refractory to medical therapy, including dietary phosphate restriction, low calcium dialysis, calcium-based phosphate binders, and oral calcitriol (3.0–7.0 µg), per hemodialysis for 3–5 months (21). Because vitamin D analogs and calcimimetics were unavailable in mainland China during the study period, none of the patients took these two drugs. Successful PTX was defined as normalization of serum calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP) and maintenance of no more than two to three times serum iPTH compared with normal (ranging from 10 to 88 pg/ml). Because the PTX patients were derived from a wide geographical area, some of them dropped out after the operation because of transference to other dialysis units, inability to contact, or poor compliance. After ≥3 months after the surgery, 17 patients who underwent successful PTX were then subsequently followed up (median of 5.0 months). Four patients who underwent unsuccessful PTX were followed up for a median of 2.3 months. They were difficult to observe for a long period of time because of their strong desire for reoperation.
Participants were excluded if they had experienced episodes of acute myocardial infarction, stroke, a major surgical procedure within the past 2 months (15), malignant neoplasm, or any psychiatric diagnosis during the past 5 years (22,23) and suffered from severe congenital heart disease, atrial fibrillation or flutter, high-grade heart block, permanent pacemaker implantation, severe hepatic disease, chronic obstructive lung disease (24), or neurologic deficit (e.g., spinal cord injury or peripheral nerve trauma). We also excluded participants who were pregnant or had any infection, fever, other problems limiting their normal daily activities, or fasting blood glucose on the day of evaluation greater than 200 mg/dl, because they can decrease nerve conduction velocity and distort the results of autonomic testing (25).
Control Group
To compare HRV between stage 5 CKD patients and healthy individuals, we recruited 87 controls matched for age and sex. Exclusion criteria were the same as for the patients studied but also included any known renal disease.
Protocols
At enrollment, 5 ml venous whole blood was drawn after an overnight fast. Each participant underwent a 24-hour Holter monitoring within 1 week to allow assessment of baseline features. For hemodialysis patients, blood samples were collected before dialysis, and HRV was analyzed on a nondialysis day. For severe SHPT patients who underwent PTX, these studies were performed no more than 2 weeks before surgery. Patients were subsequently followed up after PTX, and examinations of laboratory value and HRV were repeated. Clinical characteristics, medical history, and use of medications were strictly recorded.
Between March of 2011 and December of 2012, all patients and controls gave informed consent, and the study protocols were approved by the Research Ethics Committee of The First Affiliated Hospital of Nanjing Medical University, People’s Republic of China.
Analysis of Laboratory Values
Blood routine tests were performed using an LH-750 Hematology Analyzer (Beckman Coulter, Inc., Fullerton, CA). Biochemical indices, such as serum albumin (Alb), lipid profile, Ca, P, and ALP, were measured using an Automatic Biochemical Analyzer (AU5400; Olympus Corporation, Tokyo, Japan). Serum iPTH levels were measured using a UniCel DxI800 Access Immunoassay System (Beckman Coulter, Inc., Fullerton, CA).
Analysis of HRV
Holter electrocardiogram was digitized to 12-bit data at 128 Hz with a scanner (MARS-PC; GE Company, Fairfield, CT) on which QRS complexes were collected automatically. The results were reviewed, and any errors in QRS labeling were edited manually. Computations of HRV measurements were performed using custom-made Marquetter analytical software.
Time domain variables included mean normal-to-normal R–R intervals (mean NN), SD of the normal-to-normal R–R intervals (SDNN), SD of 5-minute average of normal R–R intervals (SDANN), root mean square of differences between adjacent normal R–R intervals (rMSSD), and proportion of adjacent R–R intervals differing by >50 ms over 24 hours (pNN50%). For frequency domain analysis, the power spectrum was quantified by fast Fourier transformation for the following frequency bands: 0.0033 to <0.04 Hz (very low frequency [VLF]), 0.04 to <0.15 Hz (low frequency [LF]), and 0.15–0.4 Hz (high frequency [HF]). LF/HF was also calculated. Frequency domain measurements of HRV were transformed to natural logarithms, because their distributions were skewed (26).
Statistical Analyses
Categorical variables were presented as number and proportion, and continuous variables were presented as mean ± SD or median (interquartile range). Differences between groups were compared using independent samples t or Wilcoxon rank sum test for continuous variables and chi-squared or Fisher exact test for categorical variables. Baseline serum iPTH levels were transformed to natural logarithms, because they were not normally distributed. Multiple stepwise regression models were established, and they were nonadjusted and adjusted for iPTH to identify factors affecting 24-hour HRV parameters. A paired sample t test was used to assess the differences between values recorded before and after PTX. P<0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 17.0 (SPSS Inc., Chicago, IL).
Results
Patients Characteristics
We divided all stage 5 CKD patients (n=118) into a non-PTX group (n=81) and a PTX group (n=37). The latter included a nonfollow-up group (n=16), a successful PTX follow-up group (n=17), and an unsuccessful PTX follow-up group (n=4). Clinical characteristics and laboratory results in stage 5 CKD patients and healthy controls (n=87) were shown in Table 1. Stage 5 CKD patients had lower body mass index, hemoglobin (Hb), hematocrit (Hct), HDL, total cholesterol, and Alb. Prevalent disorders in mineral metabolism, especially serum P, ALP, and iPTH abnormality, were observed in stage 5 CKD patients (Table 1).
Clinical characteristics and laboratory results
Baseline Values and Determinants of HRV
As presented in Table 2, baseline HRV analysis in stage 5 CKD patients showed lower time and frequency domains than controls, except for HF. There were no statistically significant differences in baseline HRV parameters between the successful PTX follow-up group (n=17) and the nonfollow-up group (n=16). Variables including demographics (age, sex, body mass index, dialysis vintage, systolic pressure, and diastolic pressure), laboratory values (Hb, Hct, glucose, Alb, and triglyceride), and bone metabolism panel (Ca, P, ALP, and iPTH) were selected as independent variables in the multivariable models (Table 3). Taking all HRV indices as dependent variables, we observed a powerful association between mineral metabolism and HRV indices. Serum iPTH was independently correlated with mean NN, mean HR, and VLF. Serum Ca was independently correlated with SDANN, and serum P was independently correlated with VLF and LF/HF. The results remained significant after the adjustment for iPTH (data not shown).
Baseline heart rate variability parameters of study groups
Multiple stepwise regression models predicting 24-hour heart rate variability parameters (n=118)
Baseline Information of Severe SHPT Patients with Successful PTX
PTX patients (n=37) tended to be younger, have longer dialysis vintage, and have a lower rate of diabetic mellitus than the non-PTX patients (n=81). Some PTX patients with severe anemia or hypoalbuminemia needed correction by blood transfusion or albumin infusion for preoperative preparation. Therefore, PTX patients (n=37) had higher baseline levels of serum Hb, Hct, and Alb compared with non-PTX patients (n=81). No significant differences were shown in laboratory results between the nonfollow-up group (n=16) and the successful PTX follow-up group (n=17).
Average age of successful PTX follow-up cohort (n=17) at baseline was 48.8±12.1 years. The mean duration of dialysis was 91.8 months. Thirteen patients were hypertensive, and one patient had both diabetes mellitus and coronary heart disease (Table 1).
Follow-Up Study of Laboratory Values in Successful PTX Patients
The pre- and postoperative serum indices of laboratory values are shown in Figure 1. Duration of follow-up was different in successful PTX patients, but the postoperative mineral metabolism indices were controlled at a satisfactory level, and no time trend was observed (data not shown). Serum iPTH levels were significantly lower (from 1717.8 [1350.8–3209.7] to 72.4 [42.7–242.5] pg/ml, P<0.001), and serum P levels were significantly decreased (from 6.9±1.8 to 2.9±1.5 mg/dl, P<0.001). There was also significant downregulation of serum Ca levels (10.5±0.6 versus 8.9±1.0 mg/dl, P<0.001) and serum ALP levels (527.3 [228.3–1006.8] versus 169.9 [111.0–244.8] μ/L, P<0.001). These results indicated a correction status of mineral metabolism in severe SHPT patients after total PTX with forearm transplantation. A significant increase in serum Alb levels (38.8±4.8 versus 41.9±3.7 g/L, P<0.05) was also observed in these patients.
Comparison of laboratory values in severe SHPT patients before and after successful PTX. Serum levels of (A) iPTH, (B) P, (C) Ca, (D) ALP, (E) Alb, and (F) Hb pre- and postoperative. Data are mean ± SD (n=17). §P<0.05, *P<0.001. Alb, albumin; ALP, alkaline phosphatase; Ca, calcium; Hb, hemoglobin; iPTH, intact parathyroid hormone; P, phosphorus; PTX, parathyroidectomy; SHPT, secondary hyperparathyroidism.
Improvements of Decreased HRV in Successful PTX Patients
As presented in Table 4, we observed significant improvements in HRV parameters in severe SHPT patients after successful PTX. These parameters included mean 24-hour HR (76.8±8.1 versus 87.1±10.7 beats/min, P<0.001), mean NN (790.9±83.0 versus 699.7±91.5 ms, P<0.001), SDNN (84.2±28.6 versus 67.8±24.6 ms, P=0.003), SDANN (73.3±29.7 versus 57.9±25.4 ms, P=0.004), VLF (5.9±0.7 versus 5.4±0.9 [ln(ms2)], P=0.008), HF (1.7±2.8 versus 3.4±1.1 [ln(ms2)], P=0.02), and LF/HF (2.0±1.4 versus 1.0±0.8, P=0.008; all relative to baseline).
Heart rate variability in severe secondary hyperparathyroidism patients before and after parathyroidectomy
Changes of HRV in Unsuccessful PTX Patients
Four SHPT patients who underwent unsuccessful PTX showed no statistical significance in pre- and postoperative serum levels of iPTH (1639.9 [1491.3–2908.1] versus 1122.0 [911.2–2819.6] pg/ml, P=0.07), Ca (10.4±1.0 versus 9.8±1.8 mg/dl, P=0.50), and P (6.2±1.6 versus 5.4±1.8 mg/dl, P=0.18) in a median follow-up period of 2.3 months.
Average age of these patients at baseline was 44.5±8.9 years. The mean duration of dialysis was 106.3 months. One patient was hypertensive and had diabetes mellitus.
No statistically significant changes in HRV indices were observed in these patients before and after unsuccessful PTX (Table 4).
Discussion
In the last decade, decreased HRV has been established as a significant independent risk factor for higher mortality and cardiac death (15,16,27). It seemed to be caused by impairment of the cardiovascular autonomic control characterized by withdrawal in parasympathetic modulation and predominance in sympathetic tone (28). As in previous studies (17–20,29–33), our results showed that stage 5 CKD patients exhibited a marked reduction in HRV indices relative to age- and sex-matched controls, indicating that sympathetic hyperactivity may play an important role in increasing the risk of CVD among ESRD patients.
It has been proposed that CKD–mineral and bone disorder may be caused by disordered mineral metabolism (34,35), which is common among patients with stage 5 CKD and has been also detected in patients with stages 3 and 4 CKD (36). CVD, fractures, and mortality are its major outcomes. Increased PTH may diminish cardiac contractility, induce ventricular hypertrophy (37,38), and enhance coronary risk (39) and cardiovascular calcification (40,41). PTH also plays a role in disturbances in the autonomic nervous system—both sympathetic and parasympathetic. Wanic-Kossowska et al. (42) reported correlations between serum iPTH levels and SDNN, pNN50%, and rMSSD in 59 hemodialysis patients. Polak et al. (43) observed negative correlations between serum iPTH and both LF and HF. They also found total spectral power to be lower in patients with high serum levels of iPTH, which indicated deterioration in total autonomic activity. Here, we confirmed that disordered mineral metabolism, especially serum levels of iPTH, Ca, and P, was significantly associated with decreased HRV indices (Table 3). These results revealed that dysregulation in cardiovascular autonomic control raised by abnormal mineral metabolism could exert a cumulative effect on the risk of CVD.
Total PTX with forearm autograft transplantation remains the primary therapeutic means of addressing medication-refractory SHPT. A more recent investigation conducted by Sharma et al. (44) observed significantly reduced rates of all-cause and cardiovascular mortality in 150 dialysis patients who underwent near-total parathyroidectomy relative to 1044 non-PTX control patients. Accumulating evidence showed that successful PTX in severe SHPT patients led to substantial cardiovascular benefits, including improvement in BP (11,45), amelioration of uremic tumoral calcinosis (46,47), decrease in thickness of coronary artery intima media (10), and reduction in left ventricular mass index (48). However, whether successful PTX can affect cardiac autonomic outflow in severe SHPT remains unclear.
We then subjected 17 successful PTX patients to another 5.0 months of follow-up and observed a substantial correction of serum iPTH, Ca, P, and ALP and a significant increase in serum Alb (Figure 1). Improvements in HRV indices (mean HR, mean NN, SDNN, SDANN, VLF, HF, and LF/HF) (Table 4) indicated a decrease in sympathetic activity and an increase in parasympathetic activity. No significant changes of HRV were shown in patients after unsuccessful PTX (Table 4); however, the possibility of statistical error because of the small sample size and the short duration of follow-up demanded vigilance. The mechanisms by which successful PTX conferred benefits on HRV were not certain. The correction of mineral markers and serum Alb level may partially but crucially represent the impact of SHPT on HRV. Whether other factors contributed to the reversal of decreased HRV in these patients remained unknown. We also cannot exclude the possibility that PTX can improve HRV in cases of less severe SHPT. Sharma et al. (44) suggested that significantly corrected laboratory values, such as serum Alb, Hct, iPTH, Ca, and P, may have remarkable beneficial effects on cardiovascular outcomes. In our study, we speculate that the improvement of HRV may represent an important pathway linking PTX to better patient survival.
This study showed that successful PTX in severe SHPT patients could lead to amelioration of abnormal mineral metabolism and a relative physiologic sympathovagal balance. Patient selection during the follow-up study may have introduced some selection bias. However, there were no statistically significant differences between the successful PTX follow-up group and the nonfollow-up group. The lack of matched non-PTX controls was one limitation of the present study. Generally, severe SHPT patients can be scheduled for surgery shortly after they are confirmed refractory to medical therapy. Using untreated severe SHPT patients as controls during follow-up studies was not considered acceptable by medical ethicists. In the future, the longitudinal changes of HRV indices should be investigated in studies with larger sample sizes and longer observation periods.
Our data have shown a significant reduction in baseline HRV parameters in stage 5 CKD patients relative to age- and sex-matched controls. This result may reflect dysfunction of the cardiac autonomic nervous system as sympathetic hyperactivity. Disorders of mineral metabolism were correlated with decreased HRV in stage 5 CKD. Successful PTX in severe SHPT patients may contribute to reverse this high CVD risk by blunting sympathetic hyperactivity and enhancing parasympathetic activity as indicated by HRV parameters. Our research provides a novel insight into the mechanism linking PTX to CVD risk and the potential therapeutic avenue in severe SHPT patients.
Disclosures
None.
Acknowledgments
The authors thank Chengjing Yan and Qiaodi Zhang for assistance with the measurement of laboratory indices, Yun Xia, Zhihui Song, and Jing Tu for assistance with the analysis of heart rate variability, Feng Chen and Min Cai for assistance with statistical analyses, and Cuiping Liu for the management of blood samples.
This study was funded by National Natural Science Foundation of China (81270408), ZX07 200908, RC201162, 2010(IB10), and LJ201125, PAPD.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
- Received October 9, 2012.
- Accepted March 29, 2013.
- Copyright © 2013 by the American Society of Nephrology
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