Sudden cardiac death in CKD patients

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Brookhart MA, Winkelmayer WC (2011) Trends in the use and outcomes of implantable cardioverter-defibrillators in patients undergoing dialysis in the United ...
Int Urol Nephrol DOI 10.1007/s11255-015-0994-0

NEPHROLOGY - REVIEW

Sudden cardiac death in CKD patients Beata Franczyk‑Skóra1 · Anna Gluba‑Brzózka1,4 · Jerzy Krzysztof Wranicz2 · Maciej Banach3,4 · Robert Olszewski5 · Jacek Rysz1,4 

Received: 14 January 2015 / Accepted: 20 April 2015 © Springer Science+Business Media Dordrecht 2015

Abstract  The risk of sudden cardiac death (SCD) is high in chronic kidney disease patients, and it increases with the progression of kidney function deterioration. The most common causes of SDC are the following: ventricular tachycardia, ventricular tachyarrhythmia, tachycardia torsade de pointes, sustained ventricular fibrillation and bradyarrhythmia. Dialysis influences cardiovascular system and results in hemodynamic disturbances as well as electrolyte shifts altering myocardial electrophysiology. Studies suggest that this procedure exerts both detrimental (poor volume control can exacerbate hypertension and left ventricle hypertrophy) and beneficial effects (associated with fluid removal and subsequent decrease in left ventricle stretch). Dialysis-related vulnerability to serious arrhythmias is the result of sudden shifts in fluid status and electrolytes, particularly potassium, which alter the physiological milieu. Also Ca2+ ions, in which concentration alters during dialysis, are of key importance in

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Department of Nephrology, Hypertension and Family Medicine, WAM University Hospital, Z˙ eromskiego 113, 90‑549 Lodz, Poland

the contraction of vascular smooth muscle cells and cardiac myocytes, thus exerting significant effects on hemodynamics. Due to the fact that SCD occurs with similar frequency in peritoneal dialysis and in hemodialysis patients, it seems that end-stage renal disease factors are more important than the specific ones associated with dialysis type. The results of randomized trials suggested that hemodialysis patients may not derive the same benefit of cardiovascular disease therapy including beta-blockers, calcium channel blockers and angiotensin-converting enzyme inhibitors as the general population with normal kidney function. Noninvasive tests used to stratify SCD risk in HD patients have poor positive value, and thus, combining tests including HRV, baroreceptor sensitivity and effectiveness index as well as its function indices and heart rate turbulence should be implemented. There are only few large randomized placebo-controlled trials assessing the influence of cardioprotective medications or implantable cardioverter defibrillator (ICD) implantation in dialysis patients on life quality and survival, and their results are sometimes contradictory. The decision concerning treatment and/or ICD implantation in this group of patients should be made on the basis of careful assessment of individual risk factors. Moreover, due to the high hazard of cardiovascular mortality including SCD in dialysis patients, physicians should concentrate on the early selection of high-risk patients, monitoring them and introduction of preventive measures.

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Chair of Cardiology and Cardiac Surgery, Department of Electrocardiology, WAM University Hospital, Lodz, Poland

Keywords  Sudden cardiac death · Chronic kidney disease · Risk factors · Treatment

* Anna Gluba‑Brzózka [email protected] Jacek Rysz [email protected]



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Department of Nephrology, Medical University of Lodz, Lodz, Poland

4

Healthy Aging Research Center, Medical University of Lodz, Lodz, Poland

5

Department of Cardiology and Internal Medicine, Military Medical Institute, Warsaw, Poland



Introduction The risk of sudden cardiac death (SCD) is high in chronic kidney disease patients, and it increases with the

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progression of kidney function deterioration [1]. According to studies, cardiovascular complications are the cause of the majority of deaths of chronic kidney disease patients while cardiac arrest (CA) accounts for 61 % of overall cardiovascular mortality [2–4] in these group. According to USRDS Annual Data Report 2014 [5], the prevalence of any cardiovascular disease (defined on the basis of Medicare claims) is twice as high for those with CKD compared to those without (69.8 vs. 34.8 %). Data from USRDS Annual Data Report 2012 indicate that sudden cardiac death (SCD) is responsible for approximately 26.5 % of all-cause mortality and is linked to 64 % of all cardiac deaths [6]. The relative risk of sudden cardiac death in hemodialysis patients is estimated to be 20- to 30-fold higher than in population of people with normal renal function, and the first 9 months from the beginning of renal replacement therapy seem to be a particularly high-risk period [7, 8]. According to USRDS 2013 Annual Data Report, all-cause mortality rates adjusted (for age, race and gender) are sevenfold to eightfold greater in HD patients in comparison with general population and it is estimated that approximately 40 % of deaths in this population are related to cardiovascular causes [9, 10]. Cardiovascular causes of deaths in HD patients are attributable to the development of atherosclerosis and arteriosclerosis, left ventricular hypertrophy (LVH) and sudden cardiac death [9, 10]. According to US Renal Data System estimates, SCD is responsible for as much as 22–27 % of all deaths in hemodialysis (HD) patients [7, 11]. Another large retrospective study demonstrated that the occurrence of in-clinic cardiac arrest was 4.5 per 100,000 dialysis treatments, with a 1-year survival of only 8.4 % [12]. It has been estimated that hemodialysis patient who survived a CA have unfavorable prospects for survival since 1-year survival rates is between 8.9 and 15 % [2, 3, 12]. In the study of Pun et al. [2], 57 % of HD patients died within 24 h of cardiac arrest and only 11 % patients survived 6 months after the event. According to studies, frequent occurrence of sudden deaths in HD patients may be related not only to high prevalence of cardiac disease but also the stress of the HD procedure itself [13].

Pathogenesis of cardiac arrest The most common causes of SDC are the following: ventricular tachycardia, ventricular tachyarrhythmia, tachycardia torsade de pointes, sustained ventricular fibrillation (SVF) and bradyarrhythmia. Ventricular tachycardia are often preceded by periods of significantly accelerated sinus rhythm, increased number of ventricular excitations, R/T excitations or ischemic changes in ST segment and T-wave [14]. SCD associated with primary bradyarrhythmia is prevalent in patients with advanced heart failure.

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Acute and chronic ischemia of myocardium, reentry phenomenon and left ventricle hypertrophy are also common causes of sudden cardiac death. Mechanisms underlying acute myocardial ischemia [15, 16] contribute to a sudden and significant impairment or arrest of blood flow through coronary artery. Cardiovascular disease is the most frequent cause of acute ischemia, and it is associated with over 50 % of all SCDs. Sudden occlusion of critically narrowed coronary artery results in SCD due to myocardial infarction and further to ventricular fibrillation. Moreover, acute ischemia may be also caused by vasospasm (Prinzmetal angina), muscular bridge (MB), inflammatory state (Kawasaki disease) and congenital abnormal origin and course of coronary artery between the aorta and the pulmonary artery. Chronic myocardial ischemia usually coexists with other causative factors including post-infarct scars, autonomic disorders, electrolyte disturbances, heart failure and adverse drug effects. Reentry phenomenon is the predominant mechanisms inducing ventricular and supraventricular arrhythmia, which can be the cause of sudden cardiac death. According to guidelines, left ventricle hypertrophy (LVH) >110 g/m2 for women and 125 g/m2 for men is the independent risk factor for arrhythmia and SCD [17]. Hypertrophy is mainly the result of pressure overload and more rarely of volume overload. The structure of such ventricle is abnormal due to the increased amount of sarcomeres in thickened myocardial cells and the elevated content of connective tissue in stroma. The deposits of pathological substances appear in cardiomyocytes (e.g., glycogenosis) or in the extracellular space (e.g., amyloidosis), and in case of dilated cardiomyopathy, chaotic arrangement of fibers is observed. Heart hypertrophy is often accompanied by atypical density, structure and function of coronary microcirculation vessels which results in the decrease in coronary reserve and may be the reason for myocardial ischemia. Increased stiffness of hypertrophied left ventricle muscle is the cause of diastolic heart failure. Changes of electrophysiological features (elongation of action potential duration) and disturbed histological structure (asymmetric hypertrophy, local fibrosis) lead to the lack of the homogeneity of stimulation conduction in hypertrophied myocardium and to the increase in (triggered activity). The aforementioned phenomena may be also the cause of serious ventricular rhythm disturbances and sudden cardiac death [18–20]. Factors stimulating LVH development and LVH prevention are summarized in Table 1. Left ventricle hypertrophy increases the risk of SCD due to the prolongation of QT interval and the increase in its dispersion. However, according to Pun et al. [2], in contrast to general population, myocardial ischemia and vascular disease mechanisms seem not to play a key role in the pathogenesis of CA in hemodialysis patients. It is possible that alterations

Int Urol Nephrol Table 1  Factors stimulating LVH development and LVH prevention

Factors stimulating LVH development in CKD patients Hypervolemia Hypertension Anemia Diabetes mellitus Malnutrition Hyperparathyroidism Vitamin D deficiency Hypoalbuminemia Increased activity of sympathetic system

Prevention of LVH development in CKD patients

Volemia control Hypertension control Anemia treatment Glycemic control Kidney transplantation Parathyroid removal

Aortic valve calcification LVH left ventricle hypertension, CKD chronic kidney disease

in ventricular structure and disturbances in myocyte intracellular signaling due to ‘uremic milieu’ may enhance the susceptibility of dialysis patients to CA and translate into poor outcomes of this group [2, 21–23]. Chronic uremia contributes to endothelial dysfunction which along with left ventricle hypertrophy increases patients’ susceptibility to arrhythmias [24]. In HD patients, myocardial fibrosis associated with prolonged uremia is more diffuse even in the absence of serious coronary artery occlusive disease [25, 26] perhaps due to repetitive hemodialysisinduced cardiac injury [27], capillary/myocyte mismatch [28] as well as disorders of mineral metabolism and secondary hyperparathyroidism [29]. Myocardial fibrosis in these patients is also associated with prolonged high sympathetic output [30]. Moreover, uremia-related cardiomyopathy could cause conduction slowdown and abnormal repolarization dispersion both being proarrhythmic [31]. According to Sherif et al. [32] study, the progression of CKD is associated with a significant impairment of cardiac repolarization CKD in the absence of significant structural heart disease or drugs known to affect QT interval. In their study, about two-thirds of patients with CKD had QTc interval prolongation, while 20 % had QTc interval >500 ms which further significantly prolonged with the progression of chronic kidney disease. The prolongation of QTc interval which is independent of underlying structural heart diseases, electrolytes imbalance and druginduced delayed repolarization may increase both the risk of sudden cardiac death and the susceptibility of druginduced arrhythmia [32]. It has been demonstrated that LVH and systolic dysfunction stimulate cardiac ion channels remodeling resulting in the development of channelopathies due to continuous decrease in the amount of naturally redundant K+ channels accompanied by the increase in the sensitivity to inhibition of the remaining ones [33], which finally lead to the aggravation of repolarization and an elevated risk of lethal arrhythmias [34].

Dialysis-related vulnerability to serious arrhythmias is the result of sudden shifts in fluid status and electrolytes, particularly potassium [24], which alter the physiological milieu. Also Ca2+ ions, in which concentration alters during dialysis, are of key importance in the contraction of vascular smooth muscle cells and cardiac myocytes, thus exerting significant effects on hemodynamics [35, 36]. Serum concentration of ionized Ca increases during sessions with dialysate Ca of 1.5 and 1.75 mmol/l and declines to the lower limits of normal following HD with 1.25 mmol/l. Moreover, according to studies, the use of dialysate with lower Ca concentration is associated with significantly larger decline in blood pressure compared to dialysate with higher Ca level in patients with normal cardiac function [37] and those with impaired cardiac function [38], perhaps due to decreased left ventricular contractility [35]. Dialysis influences cardiovascular system and results in hemodynamic disturbances as well as electrolyte shifts altering myocardial electrophysiology. Studies suggest that this procedure exerts both detrimental (poor volume control can exacerbate hypertension and LVH) and beneficial effects (associated with fluid removal and subsequent decrease in left ventricle stretch) [24, 39]. The thesis of adverse influence of dialysis on the occurrence of SCD may be supported by the fact that SCD is most frequent on hemodialysis days, especially on the first HD day after the long dialysis free, i.e., on Mondays for Monday, Wednesday and Friday HD patients and Tuesdays for Tuesday, Thursday and Saturday HD patients [7, 13, 40]. Moreover, according to Bleyer et al. [13] study, most SCD occurred in the first 12-h period beginning from the start of dialysis (nearly the half of them during the dialysis), especially in the 12-h period before HD at the end of the weekend interval. The stress-related sudden cardiac death during first 12 h of dialysis is associated with the quick elimination of toxins and fluids which have accumulated for over 44 or 68 h. In normal condition, healthy kidneys provide

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continuous and gentle clearance [13]. Bleyer et al. [13] suggested that the stress associated with dialysis contributed to the occurrence of SCD mainly in those patients with underlying cardiac disease. Also Yetkin et al. [41] demonstrated that considerable sudden shifts in electrolytes and fluid volume during dialysis session might provoke the occurrence of life-threatening arrhythmias in susceptible patients. Such suggestion is supported by the fact that the incidence of diabetes mellitus (57.5 %), hypertension (92.5 %), cardiomyopathy (mean left ventricular ejection fraction 45.7 ± 16.7 %), chronic heart failure (CHF) (55.7 %) and cardiovascular disease (55.7 %) was high in patients who suffered SCD and in those who had CA within 12 h from the beginning of dialysis was even higher [13].

Studies also revealed the presence of enhanced regional and transmural dispersion of repolarization in end-stage renal disease (ESRD) patients [31], which can be analyzed using microvolt T-wave alternans (MTWA) being computer amplified ‘beat-to-beat variation in the morphology, amplitude, or timing of the T-waves in ECG sinus rhythm’ [24]. According to a small study of Friedman et al. [42], alternans behavior before and after dialysis may differ which suggest that dialysis could influence cardiac repolarization and induce arrhythmias [24]. The changes occurring in cardiovascular system of patients with chronic kidney disease including those on dialysis are shown in Fig. 1.

Risk factors for SCD in HD patients

CKD

HA

LVH

CHF

CAD

Arrhythmia

SCD Fig. 1  Changes occurring in cardiovascular system in patients with CKD including HD patients. CKD chronic kidney disease, HA arterial hypertension, LVH left ventricle hypertrophy, CHF chronic heart failure, CAD cardiovascular disease, SCD sudden cardiac death

Table 2  Types of examinations and disorders associated with sudden cardiac death in hemodialysis patients [67]

According to Poulikakos et al. study [108], the arrhythmic risk at the time of dialysis initiations comparable to the arrhythmic risk observed in post-infarction patients with compromised left ventricular function. Factors related to dialysis including the length of renal replacement therapy period, time from last dialysis and occurrence of blood pressure drops during hemodialysis are concerned to correlate with the risk of cardiovascular death. Due to the fact that SCD occurs with similar frequency in peritoneal dialysis and in hemodialysis patients, it seems that ESRD factors are more important than the specific ones associated with dialysis type [16, 43]. Risk factors for SCD in hemodialysis patients are summarized in Table 2. According to studies, the use of low potassium (1–2 mmol/l) and calcium (1–1.25 mmol/l) dialysate [44, 45] as well as fast ultrafiltration rate [46, 47] are associated with increased risk of cardiovascular mortality and SCD [7]. Also in Karnik et al. [45] study, the utilization of 0 mEq/l potassium dialysate resulted

Type of examination

Disorder

Resting electrocardiography test

Intraventricular conductivity disorders Atrioventricular block (or AV block) Left ventricle hypertrophy Prolonged QRS and QT interval Tachycardia Preexcitation Episodes of non-sustained ventricular tachycardia

Holter electrocardiography or implanted device control

Coronarography Exercise tolerance testing

Ventricular stimulation R/T Alterations of ST segment Decreased heart rate variability The risk aggravates with the increased number of occluded coronary vessels Alterations of ST segment Occurrence of exercise-induced arrhythmia

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in increased risk of death. Bleyer et al. [13] demonstrated that also predialysis serum potassium level below 4 mEq/l was more frequent in HD patients who experienced SCD. Due to the fact that low potassium level is a risk factor for SCD, the adjustment of dialysis baths in patients, it seems reasonable. In HD patients with K+ concentrations below 4 mEq/l, the use of dialysate with increased potassium level should be considered. Higher concentration of this ion in dialysate could lower the risk of ventricular ectopy and increase patient’s baseline serum potassium, thus leading to the decrease in QT interval and QT dispersion during HD and reduction in SCD risk [13]. However, according to Pun et al. [44], high levels of serum potassium concentration were associated with increased risk of SCD. It seems that both hyper- and hypokalemia enhance the risk of sudden cardiac death [48]. There are no guidelines or recommendations concerning K+, Ca2+ and Mg2+ concentrations in dialysate which could prevent sudden cardiac death. Volume overload, hypertension and hyperkalemia also in the studies of Zehender et al. [49] and Johnston et al. [50] have been associated with a higher incidence of sudden cardiac death. Moreover, the fluctuations in potassium serum concentration frequently results in ventricular ectopy [51], as well as increased both QT interval and QT dispersion during the HD interval [52, 53]. Among other risk factors for ventricular arrhythmia and SCD, there are alterations in acid–base balance (blood pH and bicarbonate levels), anemia, loss of vagal tone due to uremia, diffuse myocardial fibrosis influencing conduction and repolarization as well as hypoxia related to sleep apnea [24]. Serum albumin 125 g/m2 in dialysis patients was shown to increase the risk of overall mortality by 30 % [76]. In general population, severe left ventricular systolic dysfunction (LVSD) is used as a marker of increased risk of SCD [77]. However, it seems that risk factors for SCD in HD patients are slightly different from that seen in general population, since according to studies in dialysis patients who experienced sudden death, LVSD was not significantly increased [78, 79]. It appears that in HD patients, diastolic dysfunction rather than left ventricular systolic dysfunction plays causative role in the SCD [7]. Among independent risk factors for cardiac death and ventricular tachyarrhythmia, there are also psychological factors such as depression, anxiety and chronic emotional stress [80]. Also mutations in genes coding ion channels resulting, for example, in long QT syndrome or in NOS1AP gene increase the risk of SCD [81]. In HD patients, the use of antiarrhythmic drugs, i.e., biosotal, propafenone and antifungal agents, administered to treat and prevent mycoses may increase the risk of sudden cardiac death due to the elongation of QT interval, despite

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Int Urol Nephrol Table 3  Factors increasing the risk of sudden cardiac death Category

Disease

Cardiovascular diseases

Hypertension Left ventricle hypertrophy History of myocardial infarction Ischemic heart disease Diabetes mellitus Hyperlipidemia Anemia Metabolic acidosis Positive history

Other diseases

History

Psychological factors

Smoking Lack of physical activity Depression Anxiety Emotional stress

Genetic factors

Mutations in genes coding ion channels

the reduction in doses and the extending of time between doses application. Factors increasing the risk of SCD are summarized in Table 3.

Factors affecting survival Pun et al. [2] found that dialysis characteristics including the presence of an indwelling catheter and dialyzer, Kt/V as well as dialysate characteristics did not relate to outcome. The comparison of demographic data of Pun et al. [2] study, including ethnicity, comorbidities (hypertension, diabetes and cardiovascular disease) and kidney disease, causes between non-survivors and survivors revealed no significant differences; however, non-survivors were more likely to have indwelling catheters at the time of the event (39.6 vs. 18.3 %; OR 2.87; p = 0.001). Moreover, according to this study, patients who did not survive 6 months were more likely to be older (67.8 vs. 63.2 years; OR 1.02 per decade; p = 0.005), to be male (54 vs. 39 %; OR 1.89; p = 0.008) and to spend less time on dialysis (median vintage 2.3 vs. 4.1 years; p