Heart Fail Rev (2011) 16:569–573 DOI 10.1007/s10741-010-9210-6
Arrhythmic complication in cardiorenal syndrome Luigi Padeletti • Lisa Innocenti • Alessandro Paoletti Perini • Edoardo Gronda
Published online: 30 November 2010 Ó Springer Science+Business Media, LLC 2010
Abstract In this paper, two different aspects of the relationship between chronic kidney disease and sudden cardiac death (SCD) have been reviewed. In end-stage renal disease patients, SCD risk is increased, and among patients implanted with a cardioverter defibrillator (ICD), dialysed ones carry a superior relative risk compared to non-dialysed ones. Cardiorenal syndrome patients have increase in SCD risk, and when receiving ICD implantation, survival improves. Keywords Sudden cardiac death End-stage renal disease Implanted cardioverter defibrillator Cardiorenal syndrome Haemodialysis Ventricular arrhythmias Glomerular filtration rate Cardiac remodelling
Chronic kidney disease is independently associated with cardiac events, ventricular arrhythmias and sudden cardiac death (SCD). For this reason, we have focused on two different presentations of this relationship, such as the impact of sudden cardiac death among patients with endstage renal disease (ESRD) and the link between cardiorenal syndrome (CRS) and sudden cardiac death.
L. Padeletti L. Innocenti A. Paoletti Perini (&) Istituto di Clinica Medica e Cardiologia, Universita` degli Studi di Firenze, AUO Careggi, Viale Morgagni 85, 50134 Florence, Italy e-mail:
[email protected] E. Gronda FESC Gruppo Multimedica, IRCCS Sesto San Giovanni, Milan, Italy
End-stage renal disease and sudden cardiac death Patients who undergo haemodialysis have extraordinarily high risk for all-cause mortality; death rate for all US dialysed patients in 2004 was 230 events for 1000 patientsyears [1]. Similar data, showing about a 25% of relative burden of sudden cardiac death among dialysis patients, were reported in clinical trials, such as the haemodialysis and the 4D studies [2, 3]. According to the United States Renal Data System (USRDS) database, among patients undergoing haemodialysis, 64% of all cardiac deaths were due to ‘‘cardiac arrest/cause unknown’’ or arrhythmia [4]. Besides, an independent relation between renal dysfunction and ventricular tachycardia/ventricular fibrillation (VT/VF) and SCD was shown in several registers among end-stage renal disease (ESDR) or haemodialysis patients [5, 6]. In these patients, the systolic ventricular function is not necessarily reduced; on the contrary, Mangrum et al. [7] revealed, by a retrospective analysis, that up to 71% dialysis patients who died of sudden cardiac death had either normal left ventricular (LV) function or normal moderate dysfunction. Nevertheless, ESRD patients have higher incidence of SCD [1, 5] and most such events are believed to be due to ventricular arrhythmias (VT/VF). Since these events cannot be referred to the traditional risk factors of impaired LV systolic function, it appears that SCD in this peculiar population must be due to different mechanisms than those studied by the main randomized controlled trials (RCTs) on SCD. In fact, ESRD patients are subject to unique factors that can both alter the underlying substrate and trigger ventricular arrhythmic events. In haemodialysis patients, the arrhythmogenic risk is increased for several reasons.
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First of all, renal failure causes both pressure and fluid overload that enhances pathological neurohormonal activation and promotes cardiac and vascular remodelling. In fact, the prevalence of left ventricular hypertrophy (LVH) is increased in early renal disease and progresses together with the decrease in renal function [8]. In uraemic patients, the atherosclerotic process is accelerated, since both traditional risk factors, such as dyslipemia, hyperhomocysteinaemia and arterial hypertension, and non-traditional ones, such as increased PTH concentrations and increased inflammation mediators and endothelial dysfunction markers, are enhanced. The consequences of the accelerated atherosclerosis are not confined to the main epicardial coronary vessels, but are extended also to intramyocardial arteries and to microvessels. It is very likely that the impaired blood supply at this level plays a major role in determining the onset of sudden ischaemic and/or arrhythmic events. Munger et al. [9] could demonstrate the occurrence of silent myocardial ischaemia in the last 30 min of a fourhour haemodialysis session. One of the main consequences of renal function impairment is the genesis of cardiac remodelling, due to pressure overload and neurohormonal activation, particularly to the hyperactivation of the Renin—Angiotensin— Aldosterone (RAA) system, which has direct and indirect effects both on the myocardicytes and on the interstitium. Consequences of this process are the reduction in left ventricular compliance, the imbalance of the systolic stress–strain relationship and the onset of local inhomogenities of electrical properties, both in the ventricles and in the atria [10]. This myocardial remodelling also affects the lusitropic phase of the diastole, as a result of slower reuptake of calcium by the sarcoplasmatic reticulum [11]. The prolongation of cytosolic calcium transient increases the duration of action potential, while it promotes the onset of delayed post-depolarization, which can trigger arrhythmic events, further favoured by conduction abnormalities linked to the fibrosis and enlargement of hypertrophied hearts [12]. As renal function decreases, the electrolytes equilibrium becomes more and more altered. Potassium balance is one of the most relevant issues in ESRD patients, as both hypokaliemia and hyperkaliemia may arise out of haemodialysis, strictly depending on dialysate solution. Serum potassium alterations are well-established proarrhythmic conditions, as they facilitate the onset of both focal and re-entry arrhythmias [13]. In a retrospective study by Karnik et al. [14], who investigated the features of dialysis unit-based cardiac arrests (CAs), it was found that patients who experienced CA were treated with low potassium bath (0–1 mEq/l) twice as much than the rest of the patients, despite similar
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pre-treatment serum potassium levels. A further impairment of serum potassium balance may be caused by an excessively fast correction of serum acidosis, which drives a fast shifting of serum potassium into the cells, so adding a further proarrhythmic effect, despite the absence of frank pre-dialysis hypokalemia. In an other series of haemodialysis ESRD patients, higher mortality was associated with hypokalemia rather than with hyperkalemia [15]. By the study of Karnik [14], it appears that also the imbalance of other serum ions concentrations, such as hypocalcemia and hypomagnesaemia, occurring during the treatment, may contribute to QT dispersion, a well-known arrhythmogenic factor [16]. In this pathological proarrhythmic background, understanding the role of implantable cardioverter defibrillators (ICDs) as means to prevent SCD is becoming an issue of increasing clinical importance. It is well established that ICD therapy reduces the risk of sudden death and all-cause mortality in patients at high risk for arrhythmic death [i.e. low ejection fraction (EF)] [17, 18], but few data are available in the set of ESRD patients. Among ICD implanted patients, dialysed ones carry a relative risk (RR) of mortality of 3.6-fold compared to nondialysed patients when the indication for ICD implantation is primary prevention (RR 2.44 when including primary and secondary prevention). Despite this, there is evidence of a survival benefit attributable to ICD in dialysed patients on secondary prevention, with 1-year survival rate of 71% for ICD patients and of 49% in non-ICD patients [19]. These data suggest that dialysis patients who have ICDs at the time of their cardiac arrest do reasonably well, favouring ICD implantation. Besides, results from the USRDS show that patients receiving dialysis, who undergo ICD implantation for secondary prevention, have similar outcomes to primary prevention patients receiving dialysis [1] (Table 1). However, the survival disadvantage is higher in dialysed patients when compared to patients with estimated glomerular filtration rate (eGFR)\60 ml/min/1.73 m2 who do not undergo dialysis [20].
Cardiorenal syndrome and sudden cardiac death Cardiorenal syndrome is a clinical condition that includes a variety of acute and chronic dysfunctions where the primary failing organ could be either the heart or the kidney [21]. Any primary impairment in one of the two organs promotes and perpetuates a complex combination of feedback mechanisms which further decreases the function of both of them. There are several pathways through which the kidney and the heart cross-talk to each other: the main ones are
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Table 1 Studies that have investigated the relationship between implantable cardioverter defibrillators (ICDs), haemodialysis and survival Study
Groups of interest
Results
Herzog et al. 2005 [19]
Dialysed ICD patients versus dialysed non-ICD patients
ICD patients get higher survival rate (71%) than non-ICD patients (49%)
Sakhuja et al. 2009 [20]
ICD dialysed patients versus ICD non-dialysed patients
ICD dialysed patients have a lower survival rate than ICD non-dialysed ones
haemodynamic imbalance and neurohormonal and paracrine signalling activation. On one side, pressure fluid overload and sodium retention, altered electrolytes levels and acidemia due to renal failure may contribute to enhance ventricular dysfunction, accelerating cardiac remodelling and so increasing the risk of arrhythmias; on the other, myocardial dysfunction promotes the worsening of kidney function, so that a vicious circle is triggered; hypervolemia, RAA system activation, inflammatory cytokines, nitric oxide dysregulation, oxidative and mechanical stress and increase in myocardial oxygen consumption are all factors that lead to myocytes injury and death [22] (Fig. 1). This situation justifies the fact that the incidence of cardiovascular events (such as myocardial ischaemia, heart failure occurrence and arrhythmias) in renal dysfunction patients increases as eGFR gets lower. In fact, it was observed that patients with eGFR \30 ml/min/1.73 m2 have higher incidence of coronary heart disease, stroke or transient ischemic attack, peripheral arterial disease and chronic heart failure [23]. Furthermore, impairment in renal function carries higher incidence of atrial fibrillation, as both overall prevalence of AF and new onset AF are inversely related to eGFR, even after adjustment for the presence of hypertension and diabetes [24, 25]. Several studies have shown that renal dysfunction is associated with increased rates of sudden cardiac death Fig. 1 Potential causal factors for sudden cardiac death
(SCD). (Table 2) In the second national health nutrition examination survey, eGFR values lower than 70 ml/min/ 1.73 m2 were associated with 68% increase in the risk of death from any cause and 51% increase in the risk of death from cardiovascular causes, when compared with a eGFR of at least 90 ml/min/1.73 m2 [27]. Data from the MADIT-II study show that, in patients with ischemic LV dysfunction, for each 10-U reduction in eGFR, the risk of SCD increases by 17% [27]. In the COMPANION study, which enrolled patients with ischemic LV dysfunction and LV dyssynchrony, the presence of renal dysfunction is associated with increased risk for SCD (HR 1.69; CI 1.06–2.69) [28]. This relationship is confirmed even in a sole-women coronary disease population [29], where the risk of SCD results 1.7% in patients with eGFR \40 ml/min/1.73 m2 versus 0.6% in patients with eGFR between 40 and 60 ml/ min/1.73 m2 (P \ 0.001). Moreover, in the same study, eGFR \ 40 ml/min/1.73 m2 appears to be an independent predictor of SCD, even when adjusted for several variables (HR 3.2; CI 1.9–5.3). Adjustment for congestive heart failure (CHF) and myocardial infarction (MI) during follow-up diminished this association (HR 2.3; CI 1.3–3.9), suggesting that CHF and MI mediated only part of the association between kidney dysfunction and SCD. Also in this subset of patients, investigating the role of ICD therapy is of great interest. Patients with reduced
Inflammation/ Oxydative Stress/ Endothelial dysfunction
Electrolytes imbalance Great vessels atherosclerosis
SCD
Chronic fluid overload
ischemia
Microvascular atherosclerosis
LVH Chronic pressure overload
Neurohormonal activation
Systolic & Diastolic Dysfunction
Vascular Fibrosis
Cardiac Fibrosis
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Table 2 Studies who have investigated the relationship between sudden cardiac death (SCD) and impaired renal function Study
Groups of interest
Results
Goldenberg et al. 2006 [27]
eGFR \ 35 ml/min/1.73 m2 versus eGFR [ 35 ml/min/1.73 m2
In ischemic LV dysfunction patients risk of SCD increases by 17%
Saxon et al. 2006 [28]
Renal dysfunction versus normal renal function
In ischemic LV dysfunction and dyssynchrony patients risk of SCD increases (HR 1.69; C. I. 1.06–2.69)
Deo et al. 2008 [29]
eGFR \ 40 ml/min/1.73 m2 versus eGFR [ 40 ml/min/1.73 m2
In women with coronary disease risk of SCD results 1.7% versus 0.6%
eGFR who received an ICD have a significant better survival compared to patients with reduced eGFR who did not receive an ICD [30]. Several authors could demonstrate that renal dysfunction was independently related to significant increase in overall burden of appropriate ICD therapy both in all-cause cardiomyopathy [31] and in non-ischemic patients [32]. In fact, it has been established that in these patients, as the renal function decreases, the time to first appropriate ICD therapy is significantly shorter in terms of both time to first appropriate shock and time to first appropriate therapy. Hreybe et al. [31] studied a population of 230 consecutive patients who underwent ICD implantation according to up-to-date guidelines; patients were stratified for serum creatinine levels (\1 mg/dl, between 1 and 1.4 mg/dl and [1.4 mg/dl); subjects in the first group experienced a 3.8% of ICD shocks in the first year of follow-up, whereas subjects in the third group had a 22.7% rate of shock events during the same time. In this cohort of patients, renal function was proved to be an independent predictor of the time to first appropriate ICD shock. Despite the established efficacy of ICD in preventing mortality in chronic renal failure (CRF) patients, SCD rates remain still very high [20, 23, 26] and increase as renal function worsens [33]. It has been observed that the efficacy of ICD therapy may be attenuated as renal function decreases both in RCTs [27, 28] and in clinical real world studies [29]. A retrospective analysis from MADIT-II population, while confirming that renal function was the most powerful predictor of mortality risk, showed that there was no benefit in survival among patients with eGFR \35 ml/min/1.73 m2 [27]. Possible explanations for this finding are two. First of all, a progressive increase in defibrillation threshold with worsening renal failure has been documented. Wase A et al. [34] found that there is a clear trend for higher defibrillation thresholds (DFTs) and increasing rates of individuals with high DFTs ([20 joules) as eGFR declines (from [60 ml/min/1.73 m2 to ESRD). An other important reason of the attenuation of device benefit among patients with severe renal failure is that, considering SCD as death within a certain interval from the onset of symptoms or unwitnessed in the absence of known symptoms, it is
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possible that not all mortal events defined as SCD were related to a primary rhythm disturbance. This factor may play an important role, especially in patients with advanced renal disease in whom co-morbidities are common. Thus, it appears that the choice of adequate therapeutic strategy in preventing mortality in CRF patients must be tailored on each patient’s features. In this perspective, Amin et al. [35] developed an actual algorithm to identify which CRF patients may really benefit by primary prevention ICD implantation, according to age and residual renal function. For eGFR between 30 and 59 ml/min/ 1.73 m2, ICD implantation seems to be sensible for patients aged less than 80 years; for eGFR between 15 and 29 ml/ min/1.73 m2, it seems to be indicated in patients aged less than 75 years; for ESRD patients, it seems to be sensible in patients aged less than 65 years.
Conclusions ESRD patients have an increased risk of arrhythmias and SCD, as they usually have enhanced cardiac and vascular remodelling and, consequently, altered electrophysiological mechanisms. For this reason, ICD implantation is often indicated in these patients. CRS is related to increased incidence of SCD as well, and ICD implantation has been proved to be efficacious in this condition too. Nevertheless, it has been shown that SCD rate increases as renal function worsens, despite the presence of ICDs. The potential reasons why this phenomenon happens are the following: first, the progressive increase in defibrillation threshold with decreasing renal function; second, the possibility that not every case of so-called SCD matches an arrhythmic event. This is the reason why, when dealing with CRF, therapeutic decisions must be taken according to each patient’s characteristics. References 1. USRDS (2007) Annual data report Bethesda, Maryland: National institute of diabetes and digestive and kidney disease, 2007 2. Cheung AK, Sarnak MJ, Yan G et al (2004) Cardiac diseases in maintenance haemodialysis patients: results of the HEMO study. Kidney Int 65:2380–2389
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