Abstract
Background. Sudden death is common in end-stage renal disease (ESRD). Cardiac arrhythmia is observed frequently in patients with ESRD and is thought to be responsible for this high rate of sudden death. This study investigated the prevalence and the predictors of arrhythmia in patients on maintenance dialysis. Methods. Ninety-four patients on hemodialysis program were enrolled in the study. Routine laboratory results were noted. Arrhythmia, periods of silent ischemia, and heart-rate variability analyses were obtained from 24-hour Holter monitor recordings. Corrected QT (QTc) dispersion was calculated from 12-lead surface EKG. Echocardiographic and tissue Doppler examinations were performed on interdialytic days as well. Ventricular arrhythmia was classified according to Lown classification; classes 3 and above were accepted as complex ventricular arrhythmia (CVA). Results. The mean age was 52.5±13.2 years; 44 (46.8%) were women. Ventricular premature contractions were detected in 80 (85.1%) patients, of whom 35 (37.2%) were classified as complex ventricular arrhythmia (CVA). Coronary artery disease, hypertension, and QTc dispersion appeared as independent factors predictive of CVA development. Atrial premature contractions (APC) were detected in 53 patients (56.4%) and supraventricular arrhythmia in 15 (16%) patients; all were identified as atrial fibrillation. Duration of dialysis therapy was found as an independent predictor of APC. Conclusion. Arrhythmia is frequently observed in ESRD patients receiving hemodialysis and may be responsible for the high rate of sudden mortality. Hypertension, CAD, and QTc dispersion are independent predictors of CVA, and duration of dialysis therapy is an independent factor affecting APC development in these patients.
Cardiac arrhythmia is observed frequently in patients with end-stage renal disease (ESRD). In this study, the prevalence and predictors of arrhythmia were evaluated in patients receiving hemodialysis. Ventricular premature contractions were detected in 85.1% of patients; in 37.2%, they were classified as complex ventricular arrhythmia. Atrial premature contractions (APC) were observed in 56.4% and supraventricular arrhythmia in 16% of patients; all were identified as atrial fibrillation. Hypertension, coronary artery disease, and QTc dispersion were found as independent predictors of CVA, while duration of dialysis therapy was detected as an independent factor affecting APC development in these patients.
INTRODUCTION
Despite major advances in dialysis technology, mortality is still high in patients with end-stage renal disease (ESRD). Mortality is seen 10 to 15 times more often than it is in age- and sex-matched normal populations, and about half of the deaths are due to cardiovascular diseases.Citation[1–4] Infection and cerebrovascular disease are the other important causes of mortality.
Coronary artery disease (CAD), heart failure, and sudden death due to arrhythmia or hyperkalemia account for the majority of cardiovascular death in ESRD patients.Citation[5],Citation[6] Five-year mortality is about 80% in these patients; of these deaths, an important proportion—around 18–25%—is in the form of sudden death.Citation[7],Citation[8] It is well known that serious ventricular arrhythmia is the cause of the majority of sudden cardiac deaths, and that cardiac arrhythmia is quite common in patients on maintenance dialysis.Citation[9],Citation[10] Ventricular premature complex (VPC) reportedly occurs in 76–100% patients, while complex ventricular arrhythmia (CVA) is found in 13–36% of these patients.Citation[11–13] Supraventricular arrhythmia is also common and is observed in 20–88% of ESRD patients.Citation[14],Citation[15]
Three factors are required for lethal cardiac arrhythmia to occur: arrhythmogenic substrate, triggering factors, and changes in the activity of the autonomic nervous system. Several methods to investigate the different aspects of arrhythmogenesis have been developed. Arrhythmogenic substrate can be identified by EKG, echocardiography, coronary angiography, signal-averaged EKG (SAEKG), and nuclear/radiologic imaging modalities. Triggering factors are usually the premature ectopic beats originating from the atria or ventricles. To detect the effects of autonomic system changes on cardiovascular system, heart-rate variability (HRV) analysis is widely used.
This study sought to investigate the prevalence and the determinants of cardiac arrhythmia in patients on hemodialysis because of renal insufficiency.
METHODS
Ninety-four patients at Başkent University Hospital in Ankara, Turkey, who were on hemodialysis for at least three months were enrolled in the study. The study protocol was approved by the local ethics committee, all patients were informed about the study protocol, and informed consent was obtained from each participant. Patients with acute infectious or inflammatory disease, malignancy, and acute coronary syndrome within the last four weeks before the study were excluded. Detailed medical histories were obtained, physical examinations were done, and routine laboratory results were noted. Twelve-lead surface EKG and SAEKGs were obtained, and echocardiographic examinations including tissue Doppler measurements were made.
Echocardiographic examinations were performed using Acuson Sequoia C256 echocardiograph (Siemens Medical Solutions USA, Inc; Malvern, Pennsylvania, USA) on interdialytic days by two cardiologists who were blinded to the study protocol. During this examination, tissue Doppler imaging of the interventricular septum and lateral wall was performed as well.
Twenty-four-hour three-channel Holter monitorization was performed. Holter recordings were analyzed both automatically and manually by a cardiologist. Atrial premature contractions (APC) were noted by number, and VPC was both expressed in number and classified according to Lown classification (see ). Classes 1 and 2 were designated simple, and classes 3 and over were accepted as CVA. Specific forms of arrhythmia were noted separately. HRV analysis was performed using the Research Tools V 2.142 for Pathfinder with a V8 Software Holter device (Delmar Reynolds Medical, Irvine, California, USA) and software. Patients who had atrial fibrillation (AF)/flutter, frequent VPC, and artifacts were excluded from the HRV analysis. Of the time-domain measures, standard deviation of all NN intervals (SDNN), standard deviation of mean NN intervals obtained from five-minutes recordings (SDANN), root mean square of successive differences (RMSSD), number of NN intervals that differed by more than 50 msec from the adjacent interval divided by the total number of all NN intervals (PNN50), and triangular index (TI) were calculated. Among the frequency measures, low-frequency (LF) and high-frequency (HF) bands and LF/HF ratio were determined.
Table 1 Lown classification of ventricular premature contractions
Silent ischemia was identified as horizontal or downsloping ST-segment depression of at least 1 mm starting from the J point and lasting ≥80 msec in the absence of ischemic symptoms. CAD was defined as the presence of typical angina, signs of ischemia on noninvasive cardiac imaging methods (e.g., exercise testing, myocardial perfusion scintigraphy), documented Q-wave myocardial infarction on EKG, or the presence of at least 50% narrowing in 1 or more of the coronary arteries.
Left ventricular hypertrophy (LVH) was accepted as the interventricular septum or posterior wall thickness ≥12 mm or left ventricular mass index on M-mode echocardiography more than 134 g/m2 in men and 110g/m2 in women.
Left ventricular systolic dysfunction was defined as global or regional wall-motion abnormality on echocardiography or ventriculography, ejection fraction (EF) less than 50%, or fractional shortening less than 25%. Diastolic dysfunction was defined as mitral E/A ratio less than 1 and isovolumetric relaxation time ≥ 110 msec or mitral E-wave deceleration time ≥ 240 msec on Doppler echocardiography.
QT interval was defined as the distance from the first deflection of the QRS complex to the end of the T wave. This value was corrected using the Bazzett formula. QT dispersion was calculated as the difference between the shortest and longest QT interval on 12-derivation surface EKG obtained at 50 mm/sec paper speed. Patients having AF, left bundle branch block, or those who were taking antiarrhythmic medications were not involved in QT analysis.
Statistical Analysis
Statistical analyses were performed using SPSS 9.0 for Windows statistical software (SPSS Inc., Chicago, Illinois, USA). Continuous variables were expressed as mean ± standard deviation. The Student t test was used to compare the continuous variables, and a chi-square test was used to compare the categorical variables between groups with and without arrhythmia. A value for p <.05 was accepted as statistically significant.
A multivariable logistic regression model was used to assess the independent predictors of factors predictive of CVA and APC development. The alternative test hypothesis was built as two-sided for each statistical analysis. Significant univariate variables with p < 0.05 were included in the multiple logistic regression analysis for odds ratios and 95% confidence intervals.
RESULTS
The mean age of the study population was 52.5 ± 13.2 years; 44 (46.8%) were women. Average time on dialysis treatment was 69.6 months (range: 3–240 months). Hypertension was the most common etiology of ESRD, followed by diabetes mellitus and glomerulonephritis.
Mean duration of the Holter recordings were 1371 ± 93 minutes. The average values of the minimum and maximum heart rates were 68.6 ± 11.9 bpm and 115.6 ± 16.1 bpm, respectively. VPC was detected in 80 (85.1%) patients, and asymptomatic non-sustained monomorphic ventricular tachycardia was noted in three patients (3.1%), two of whom had CAD. Lown classifications of the VPC are given in . In 35 (37.2%) patients, VPC was of the complex type.
Table 2 Distribution of VPC according to Lown classification
A comparison of the patients with and without CVA in regard to demographic and laboratory features are given in . Patients with CVA were older and had more CAD, MI, hypertension, and a history of coronary artery bypass grafting. CRP and creatinine levels were significantly higher in patients with CVA compared with those who did not have CVA.
Table 3 Comparison of patients with and without CVA
Electrocardiographic, SAEKG, echocardiographic parameters, and tissue Doppler imaging results are given in . QTc dispersions were significantly higher in patients with CVA. The presence of late potentials (LP) and parameters of SAEKG did not differ between the groups. Of the echocardiographic findings, dimensions of both the left and right atrium were larger and EF lower in patients with CVA. The prevalence of left ventricular systolic dysfunction was higher in the CVA group. LVH, expressed as both wall thickness and mass index, did not differ between groups. Diastolic dysfunction was more prevalent in patients with CVA, but the difference between groups did not reach statistical significance. Tissue Doppler findings were similar between groups.
Table 4 ECG, signal-averaged ECG, and Doppler-echocardiographic and tissue Doppler imaging findings of the patients with and without CVA
summarizes the ambulatory EKG and HRV analysis results. Among ambulatory ECG findings, silent ischemia was significantly higher in patients with CVA (p < .001). Of the HRV analysis results, HF was higher and LF/HF ratio was lower in the group with CVA. Time domain parameters—SDNN, SDANN, RMSSD, and TI—did not differ between groups. In the multivariable analysis, CAD (OR, -0.18; 95% CI, 0.04–0.89; p = .035), hypertension (OR, -0.19; 95% CI, 0.004–0.77; p = .031) and QT dispersion (OR, 0.18; 95% CI, 1.00–1.18; p = .037) appeared as independent factors predictive of CVA development.
Table 5 Holter monitorization findings and heart rate variability analysis results in patients with and without CVA
In 53 (56.4%) patients, APC was detected. Supraventricular tachycardia was noted in 15 (16%) patients, diagnosed as AF in all of them. Patients with APC were significantly older than those without APC (56.2 ± 12.4 years vs. 44.7 ± 10.9 years, respectively; p < .001). While sex, etiology of ESRD, and prevalence of hypertension, diabetes mellitus, and dyslipidemia were similar between these two groups, duration of dialysis therapy was longer (79.2 ± 52.8 months vs. 50.4 ± 26.4 months, respectively; p =.005), and the prevalence of CAD was higher (50% vs. 16.1%; p = .002) in patients with APC. Of the laboratory values, serum potassium level was lower (4.6 ± 0.7 vs. 4.9 ± 0.7 mEq/L; p = .037) in patients with APC, while no difference was noted for the other laboratory parameters. Echocardiographic and tissue Doppler findings did not differ between groups. QT dispersions (39 ± 11 vs. 49 ± 13 msec; p = .015) and maximum QT duration (398 ± 20 vs. 408 ± 17 msec; p < .001) were significantly higher in patients with APC. Of the time domain measures of HRV, mean RR intervals, SDNN, SDANN, RMSSD, and TI were similar between the patients with and without APC. Among the frequency measures, LF was lower (56.3 ± 14.1 vs. 64.1 ± 15.1; p = .025), HF was higher (33.4 ± 15.9 vs. 22.5 ± 13.0; p = .002), and LF/HF ratio was higher (4.3 ± 3.3 vs. 2.5 ± 2.4; p = .007) in patients with APC than it was in those without APC. In the multivariable analysis, only duration of dialysis therapy (OR, 1.66; 95% CI, 1.23–2.24; p < .001) was found as an independent predictor of APC development.
DISCUSSION
Main Finding
The present study demonstrates that both ventricular and supraventricular arrhythmias are common in ESRD patients who are on hemodialysis treatment. A considerable proportion of the VPC is of the complex type. Hypertension, CAD, and QTc dispersion are independent predictors of CVA. Duration of dialysis therapy is an independent factor affecting APC development in these patients.
Prognostic Importance of Cardiac Arrhythmias in ESRD
The presence of CVA has been shown to be associated with increased mortality in certain patient groups.Citation[16] The association of CVA with mortality in patients who have ESRD has also been analyzed. Sforzini and colleaguesCitation[17] revealed that 44.4% of ESRD patients die from cardiovascular causes; 25% of these deaths occur in the form of sudden death. Arrhythmia documented by Holter monitorization was found to be an independent prognostic factor for four years' survival in that study. D'Elia and colleaguesCitation[18] reported that complex arrhythmia (Lown class 3 and above) occurs in 26% of uremic patients and was associated with increased five-year mortality. These findings show the seriousness of arrhythmia in this population.
Factors Causing Arrhythmia in ESRD
Many factors have been identified as a cause of increased prevalence of arrhythmia in patients with ESRD, among them the presence of CAD, heart failure, electrolyte abnormalities, LVH, left ventricular systolic and diastolic dysfunction, hypertension, diabetes mellitus, LP on SAEKG, increased QT dispersion, duration of renal replacement therapy, increased volume load, uremic toxins, and silent ischemia.Citation[19] Several studies have evaluated the effects of these factors on arrhythmia. However, few of these factors were analyzed in these individual studies, and the relative importance of these factors in the genesis of arrhythmia is not known. We tried to evaluate all factors that may be important for the development of arrhythmia, and this may be the first comprehensive study involving all of these parameters simultaneously in this specific patient population.
With respect to prevalence of arrhythmia, these results are usually in accordance with those reported in the literature. For example, CVA is reported in 13–36% of ESRD patients.Citation[11–13],Citation[20] CVA was found in 37.2% of the patients, which is somewhat higher. The prevalence of supraventricular arrhythmia in the present study is in accordance with those reported in literature (16–69%).Citation[20–22]
Many factors, such as autonomic neuropathy, altered ventricular structure and function, increased ventricular wall tension, myocyte hypertrophy, and myocardial calcification and fibrosis may lead to QT-interval prolongation and increased dispersion in ESRD patients.Citation[23],Citation[24] Studies have revealed that QT dispersion is more prolonged in uremic subjects than it is in normal controls and is related to the development of life-threatening arrhythmia.Citation[24],Citation[25] The present results are in accordance with these findings. Increased QT dispersion is an independent predictor for the development of CVA.
Left ventricular hypertrophy is very common in ESRD patients and is an important determinant of arrhythmia development.Citation[26] Myocardial fibrotic bands are thought to prevent the propagation of the impulse leading to re-entrant ventricular arrhythmia. No association was found between the presence LVH and CVA development. This might be due to the fact that the prevalence of LVH was very high (92.6%) in this study population.
Hypertension is another cause of arrhythmia in uremic patients. DeLima and colleaguesCitation[27] found that hypertension and CAD are the most important determinants of CVA in ESRD patients. Hypertension was thought to induce arrhythmia by causing mechanical stress and provoking ischemia, especially in the presence of LVH or myocardial fibrosis. Another study reported that hypertension together with diabetes mellitus and advanced age are the predictors of arrhythmia in uremic patients.Citation[25] This study demonstrated that hypertension is an independent predictor of CVA.
Silent ischemia is a relatively common finding in patients receiving renal replacement therapy. Data regarding its effect on the development of arrhythmia are limited. Aronow and colleaguesCitation[28] found that silent ischemia was present in 27% and CVA in 69% of uremic patients older than 65 years. In another trial, silent ischemia was noted in 15.5% of patients undergoing 48-hour Holter monitorization.Citation[29] Silent ischemia was detected in 10.6% of the study population, and on univariate analysis it was associated with CVA development.
In patients with ESRD, the prevalence of CAD is 5 to 20 times of that seen in the age-matched normal population.Citation[30] In addition to an aggregation of atherosclerotic risk factors, vascular remodeling due to increased volume load is also thought to be a cause of ischemic heart disease in patients receiving renal replacement therapy.Citation[31] In one study, CAD was found to be the most important determinant of arrhythmia development.Citation[32] Narula and coworkersCitation[33] found that CAD and silent ischemia are the most powerful predictors of ventricular arrhythmia. In another study, older age and left ventricular systolic dysfunction were identified as independent determinants of arrhythmia development in patients who were on renal replacement therapy.Citation[21] Analysis of Holter recordings by Tamura and colleagues revealed that Lown class 4A- and B-type ventricular arrhythmia was noted in 17% of the uremic patients in whom left ventricular systolic dysfunction, age, and male sex were associated with development of arrhythmia.Citation[34] These results are in accordance with these results. Left ventricular systolic dysfunction was found to be a predictor of CVA. On the other hand, the prevalence of diastolic dysfunction did not affect the development of arrhythmia in the patient population.
The mechanism for most of the life-threatening ventricular arrhythmia is re-entry. Inhomogeneous and slow conduction are required for a re-entrant circuit to develop. LP is thought to originate from the abnormal areas of ventricular myocardium with delayed activation and show the substrate for re-entry. CAD, left ventricular systolic dysfunction, LVH, increased myocardial fibrosis, and calcium-phosphate precipitates are among the factors causing abnormal conduction and LP formation in ESRD patients.Citation[35],Citation[36] The prevalence of LP on SAEKG has been reported to occur in 14–25% of uremic patients, and CAD, systolic dysfunction, and hypertension were the determinants of LP formation in these analyses.Citation[36–38] Researchers hypothesized that this condition would be a predictor of re-entry and sudden death. LP was detected in 13.8% of the study population, but LP was not found to affect the development of CVA.
Cardiac autonomic neuropathy is a common finding in uremic patients. Compared with healthy individuals of similar age and sex, HRV parameters were found to be decreased in ESRD patients.Citation[39],Citation[40] It has been shown that decreased HRV is associated with increased risk of ventricular arrhythmia and sudden death in certain populations, such as post-MI and heart failure patients.Citation[41] Fukuta and colleaguesCitation[42] compared HRV parameters of ESRD patients with those of the healthy controls and found that HRV parameters are decreased in these patients, and that this finding is related to long-term mortality. Another investigation revealed that HRV parameters compared with predialysis values were increased after the dialysis session, which was thought to be due to the removal of the metabolites that decrease heart rate.Citation[43] In a report by Thomson and colleagues,Citation[14] cardiac parasympathetic tonus abnormalities have been noted in 76% of uremic patients. In another study, increased sympathetic tonus was found as the predominant autonomic abnormality in patients receiving renal replacement therapy.Citation[44] Of the time domain measures, SDNN, SDANN, RMSSD, and TI were similar between the groups with and without CVA. On the other hand, of the frequency measures, HF was higher and LF/HF ratio lower in patients with CVA. These findings are in contrast with those reported in the literature. Analysis of the data shows that the power in the HF band, which reflects the activity of the parasympathetic nervous system, is higher in patients with CVA. We cannot explain this finding, and it may only be a coincidence.
The duration of the renal replacement therapy is another factor for the development of cardiac arrhythmia. Erem and colleaguesCitation[22] reported that dialysis duration is one predictor of ventricular arrhythmia. In this study, although the duration was longer in patients with CVA, the difference between groups did not reach statistical significance.
On logistic regression analysis, hypertension and CAD were determined to be the most important determinants of CVA. Considering hypertension, which is one of the most common etiology of ESRD or very commonly seen in the course of it, and CAD, which is again much more common in these patients than it is in the normal population, early diagnosis and treatment of these two conditions deserve particular attention in preventing both long-term morbidity and mortality in this population.
The prevalence of supraventricular arrhythmia in the present study in general is similar to that reported in literature. Atrial fibrillation is the most common supraventricular arrhythmia in these patients. On univariate analysis, advanced age, silent ischemia, CAD, and duration of dialysis therapy were associated with supraventricular arrhythmia. In multivariable analysis, of these factors, only duration of dialysis therapy was found as an independent predictor of supraventricular arrhythmia.
CONCLUSION
Both ventricular and supraventricular arrhythmia are very common in ESRD patients receiving hemodialysis therapy. CAD, hypertension, and QTc dispersion appeared as independent factors predictive of CVA development. Duration of dialysis therapy is an independent factor affecting development of supraventricular arrhythmia. The increased rate of CVA may be responsible for the high sudden mortality and death rate seen in ESRD patients receiving hemodialysis.
ACKNOWLEDGMENT
The authors would like to thank to our sonographer, Vahide Simsek, and the physicians, nurses, and technicians working in the hemodialysis unit for their generous help.
Notes
*This work was presented in part at the XVI Annual Meeting of the Mediterranean Association of Cardiology and Cardiac Surgery, September 26–29, 2004, Bodrum, Turkey.
The authors report that there was no financial support from any organization for this study. The authors report no conflict of interest.
Related Research Data
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