J Am Soc Nephrol. 2012 Nov 30; 23(12): 1929–1939.Published online 2012 Oct 25. doi: 10.1681/ASN.2012010037
PMCID: PMC3507359
CKD and Sudden Cardiac Death: Epidemiology, Mechanisms, and TherapeuticApproachesIsaac R. Whitman, Harold I. Feldman, and Rajat Deo
Department of Medicine, andCenter for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania; andSection of Electrophysiology, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, PennsylvaniaCorresponding author.
Correspondence: Dr. Rajat Deo, Section of Electrophysiology, Division of Cardiovascular Medicine, University of Pennsylvania, 3400 SpruceStreet, 9 Founders Cardiology, Philadelphia, PA 19104. Email: [email protected]
Multiple studies demonstrate a strong independent association between CKD and cardiovascular eventsincluding death, heart failure, and myocardial infarction. This review focuses on recent clinical studies thatexpand this spectrum of adverse cardiovascular events to include ventricular arrhythmias and sudden cardiacdeath. In addition, experimental models suggest structural remodeling of the heart and electrophysiologicchanges in this population. These processes may explain the increased arrhythmic risk in kidney disease andaid in identifying patients who are at higher risk for sudden cardiac death. Finally, we review here the data tosupport the use of pharmacologic and devicebased therapies for both the primary and secondary preventionof sudden cardiac death.
CKD affects approximately 13% of adults in the United States. Its incidence continues to rise as thepopulation ages, and obesity, hypertension, and diabetes increase in prevalence. The elevated risk ofcardiovascular morbidity and mortality in this population is well established and often precedes progressionto ESRD and dialysis. Historically, the cardiovascular death associated with CKD had been attributed tothe complications of atherosclerotic disease. A substantial proportion of cardiac deaths, however, is notdirectly linked to myocardial infarction (MI), stroke, or heart failure suggesting the presence of otherprocesses contributing to cardiovascular mortality. Recently, kidney dysfunction has been evaluated asan independent risk factor for sudden cardiac death (SCD), which has been adjudicated as a distinct endpointin various cohort studies and clinical trials. This review highlights the epidemiology of kidney disease andSCD, potential mechanisms for this association, and management strategies to reduce the burden of this fatalevent.
SCD
SCD refers to an unexpected death from a cardiovascular cause with or without structural heart disease. Ingeneral, SCD events are defined as those that either are preceded by a witnessed collapse, occur within 1hour of an acute change in clinical condition, or occur not more than 24 hours since the deceased individualwas known to be in his or her usual state of health. The incidence of SCD in the United States rangesbetween 180,000 and 450,000 cases annually. Despite major advances in cardiopulmonary resuscitationand postresuscitation care, survival to hospital discharge after cardiac arrest remains poor. Survival to
hospital discharge was recently estimated to be only 7.9% among outofhospital cardiac arrests that weretreated by emergency medical services personnel. In addition, the majority of SCDs occur at home, wherethe event is often unwitnessed. The prognosis from cardiac arrests is even worse in patients with kidneydysfunction in which survival probability decreases with a declining GFR. Among patients with ESRDwho have a witnessed cardiac arrest at an outpatient dialysis facility, more than threequarters are notdischarged alive from the hospital.
Coronary heart disease (CHD) or congestive heart failure (CHF) markedly increases the risk of SCD in thepopulation. Both left ventricular dysfunction and New York Heart Association functional class areimportant risk factors for SCD and have been incorporated as diagnostic and clinical parameters that guidethe placement of implantable cardioverterdefibrillators (ICDs) for the primary prevention of SCD. Themajority of patients who suffer a cardiac arrest, however, will not have had a left ventricular ejection fraction(LVEF) <35% documented before SCD and thus would not have qualified for an ICD. In order toaddress effectively this public health dilemma, intermediate or other vulnerable subgroups of the populationneed to be identified so that preventive and management strategies can be evaluated. In addition, anunderstanding of the mechanisms underlying SCD in well defined subgroups may help to provide additionalinsight into this condition across the entire population.
NondialysisDependent CKD and SCD
Initial studies demonstrating an increased risk of SCD among patients with kidney disease stem fromsubgroup analyses of clinical trials designed to evaluate the efficacy of ICDs. The Multicenter AutomaticDefibrillator Implantation TrialII (MADITII), which evaluated the benefit of prophylactic ICD therapy inpatients with a previous MI and a LVEF of ≤35%, investigated the risk of SCD among patients withCKD. Among participants treated with optimal medical therapy only, the risk for SCD was 17% higher forevery 10 ml/min per 1.73 m decrement in the estimated GFR (eGFR). Similarly, in the Comparison ofMedical Therapy, Pacing, and Defibrillation in Heart Failure trial, which demonstrated the benefit ofcardiac resynchronization therapy in reducing death or hospitalization in patients with advanced heart failureand conduction disease, kidney dysfunction was associated with a 67% greater risk of SCD during the 16month followup period. Similar studies in more intermediate risk populations with CHD and without heartfailure also demonstrate an independent association between kidney dysfunction and SCD (Table 1).Despite these findings, the presence of heart failure, systolic dysfunction, and/or coronary disease that wererequired for entry into these studies precluded an understanding of whether kidney dysfunction was a markerof severity of cardiac disease or an independent risk factor for SCD.
Populationbased studies have attempted to understand the risk of SCD among participants with kidneydisease by minimizing the confounding effects of prevalent cardiovascular disease. Among 4465communitybased participants from the Cardiovascular Health Study without a history of heart failure or MI,the incidence of SCD was >2.5fold higher with lower levels of kidney function (Figure 1). Furtheranalysis from this study also utilized both creatinine and cystatin C measures to identify a subgroup withpreclinical kidney disease defined as a creatininebased eGFR ≥60 ml/min per 1.73 m and cystatin C ≥1.0mg/L. After multivariate adjustment, SCD risk is twice as likely in the preclinical kidney disease groupcompared with the normal kidney function referent group (creatininebased eGFR ≥60 ml/min per 1.73 mand cystatin C <1.0 mg/L). These findings suggest that even mild reductions in kidney function increase riskof SCD, especially within susceptible populations such as the elderly.
ESRD and SCD
The majority of cardiovascularrelated deaths in ESRD are attributable to SCD events. Administrativedata suggest that arrhythmic deaths and cardiac arrests in ESRD patients, combined, represent approximately22% of all deaths. Prospective, dialysis cohorts have corroborated these findings. In the Choices for
Healthy Outcomes in Caring for ESRD trial, a total of 658 deaths occurred in 1041 dialysis participants over8 years of followup. Among these 658 deaths, 146 were due to SCD (SCD rate of 1.8% per year). Inaddition, a high incidence of SCD over a 5year longitudinal followup (SCD rate of 4.9% per year) wasobserved in a prospective cohort study of Chinese patients receiving chronic peritoneal dialysis. Despitethe slight variations in annualized rates of SCD, approximately 20%–25% of allcause mortality wasattributed to SCD. This relative risk is almost identical to that reported by the US Renal Data System(USRDS) in which 25% of allcause death among peritoneal dialysis patients and 27% of allcause deathamong hemodialysis patients in the United States were attributed to cardiac arrest.
Finally, the strong association between ESRD and SCD extends to the pediatric population as well. In aretrospective analysis of nearly 1400 deaths among ESRD patients aged 0–30 years from the USRDS,cardiac arrests and arrhythmias comprised the majority of cardiacrelated deaths, which occurred at a rate>2% per year. These findings suggest that mechanisms aside from atherosclerotic disease and CHF areresponsible for triggering fatal arrhythmias in the ESRD population.
Possible Mechanisms
The pathophysiology of SCD is complex and is believed to require the interaction between a transient eventand underlying substrate. This process induces electrical instability and ventricular arrhythmias followed byhemodynamic collapse. An understanding of the mechanisms inciting these events may help clarify when theinteraction between a triggering event and the underlying substrate proves harmful. Structural andelectrophysiologic remodeling of the heart, vascular calcification and fibrosis, autonomic dysregulation, andvolume and electrolyte shifts are some of the underlying processes thought to explain the increasedpredisposition for SCD in people with CKD (Figure 2). Finally, although some of the studies supporting theproposed mechanisms discussed below have been conducted in people with CKD who are not on renalreplacement therapy, the majority of data come from the ESRD population.
Kidney disease induces adverse cardiac remodeling that includes left ventricular hypertrophy (LVH) andcardiac fibrosis. Several clinical studies, including ones that have enrolled participants with mild to moderatereductions in eGFR, demonstrate an independent association between CKD and LVH. Specifically,there is a progressive increase in the prevalence of LVH and left ventricular mass as eGFR declines. Inaddition, among participants with more advanced kidney disease on dialysis, contrastenhanced magneticresonance imaging demonstrates a diffuse pattern of gadolinium uptake suggestive of fibrosis and anonischemic cardiomyopathy. The pathogenesis of these conditions is considered to be multifactorial, andthe presence of commonly associated comorbidities such as hypertension, diabetes, and anemia explain onlypart of the left ventricular remodeling. The molecular basis for these changes includes activation ofgrowth factors, protooncogenes, plasma noradrenalin, cytokines, and angiotensin II. These factors regulateintracellular processes that accelerate cardiac hypertrophy, myocardial fibrosis, and apoptosis. BothLVH and cardiac fibrosis have been implicated in increasing the risk for sustained ventricular arrhythmiasand the predisposition to SCD.
Kidney disease is also associated with vascular disease including calcification and stiffening of the bloodvessels. Declines in eGFR and endothelial dysfunction are interrelated processes that diminish vascularelasticity and subsequently increase ischemic events. Human studies demonstrate that an impairedendotheliumdependent vasodilatory response is associated with mild kidney dysfunction. If untreated,these interdependent conditions progress and establish a cyclical relationship that results in further kidneyand vascular damage. Subsequent remodeling and sclerosis of the vessels can compromise the perfusionreserve and increase the risk for ischemic events, which are a common trigger for the initiation ofarrhythmias. In the setting of ESRD, vascular remodeling is even more pronounced because calciumphosphate deposition may further exacerbate vascular integrity. Elevated phosphate concentrations andan increase in the calciumphosphate product contribute to myocardial and vessel calcification as well as
plaque instability, and increase SCD risk by 20%–30%.
Structural changes can alter the electrophysiologic properties of the myocardium. Fibrosis disrupts the normalmyocardial architecture and results in a slowing of conduction velocity across the diseased tissue. Thispathology can form heterogeneous zones of conduction and repolarization that can sustain a reentrantarrhythmia such as ventricular tachycardia. These structural changes impair cardiac conduction, delayventricular activation, and create late potentials in the terminal portion of the QRS complex. Furthermore,these low amplitude signals, which can be detected using a specialized signalaveraged electrocardiographicrecording, have been identified in approximately 25% of dialysis patients. Several studies have alsoevaluated QT dispersion, which reflects nonhomogeneous recovery of ventricular excitability and iscalculated as the difference between the longest and shortest QT interval in a standard 12leadelectrocardiogram. The QT dispersion is maximally elevated in the postdialysis period and reflects agreater susceptibility to arrhythmias.
In addition to scarbased reentrant arrhythmias that require heterogeneous zones of conduction, kidneydysfunction also increases the risk of automatic or triggerbased arrhythmias. These rhythms are sensitiveto adrenergic activity. Human studies demonstrate that ESRD increases the rate of sympathetic nervedischarge, which is mediated by an afferent signal arising in diseased kidneys. This enhanced autonomictone in the setting of electrophysiologic remodeling explains the basis for an increased frequency ofpremature ventricular complexes that occur in >75% of ESRD patients during and shortly after dialysissessions. Sympathetic activity in these patients likely reflects a more serious pathophysiologic state becauseit correlates with an overall increased risk of death and cardiovascular events.
Ventricular arrhythmias and SCD in ESRD patients may be related to the timing of dialysis. An inability tomaintain homeostasis predisposes these patients to adverse events especially after a long interdialytic interval.Cardiac arrhythmias and SCD are more common on Mondays and Tuesdays after hemodialysisfreeweekends, and during the 12 hours after initiation of an hemodialysis session. These findings suggestthat major shifts in BP, electrolytes, and volume may induce triggers that result in arrhythmias.
Therapeutic Strategies to Prevent SCD
Few clinical trials have been designed specifically to evaluate the efficacy of therapeutics and interventionsfor SCD prevention in the CKD population. The approach to reducing SCD risk in this group relies on dataobtained from other highrisk populations and subgroup analyses of clinical trials.
Pharmacologic Agents
Pharmacologic agents used to treat comorbid conditions such as hypertension, diabetes, hyperlipidemia, andcoronary disease are known to reduce the risk of severe cardiovascular complications including death.Because the pathways linking kidney disease to arrhythmic events and SCD are complex and likely involvehigh BP, dyslipidemia, and glucose intolerance, aggressive treatment of these common conditions mayprotect partially these patients from SCD.
β Adrenergic Antagonists (βBlockers)
βblockers are antiarrhythmic and antiischemic agents that not only reduce the risk of hospitalizations anddeath but also the risk of SCD. Randomized controlled trials providing this evidence have generallyexcluded individuals with CKD. In a recent metaanalysis that evaluated the efficacy of βblockers inCKD patients with heart failure, there was a 34% relative reduction in cardiovascular mortality in treatedpatients compared with placebo. Although SCD was not a separate adjudicated outcome in these analyses,the effect on cardiovascular death likely was a result of an effect on both sudden and nonsuddencardiovascular events. Limited data also exist on the effect of βblocker therapy in CKD patients without
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heart failure and in patients receiving dialysis. In dialysis the hypotensive side effects of βblockers may beexacerbated by marked fluctuations in extracellular fluid volume. Adequately powered prospectiverandomized control trials assessing the effects of βblockers in a broader population of individuals withadvanced CKD are necessary.
Statins
Statins lower cholesterol and have antioxidant properties that help attenuate endothelial dysfunction, preventplaque rupture in vessel walls, and inhibit platelet aggregation and thrombus formation. Statin therapyassociates with significant reductions in allcause mortality in a series of clinical trials. These benefitswere paralleled by a reduction in SCD incidence; however, limited data exist on the reduction of this specificoutcome. This class of medications appears to be effective and safe for the secondary prevention ofcardiovascular events in individuals with mild kidney disease. Retrospective analysis from the Cholesteroland Recurrent Events study, which was a randomized trial of pravastatin versus placebo in individuals withprevious MI, identified 1711 participants (approximately 41% of the study population) with mild kidneydisease. Pravastatin resulted in a 28% reduction in the primary endpoint of cardiovascular death or MI.Similar findings were documented in a metaanalysis that included 25,017 participants with CKD notrequiring dialysis from 26 randomized controlled trials: statins decreased both the risk of allcause mortalityand cardiovascular events by nearly 20% each. Although SCD was not a separate, adjudicated outcome inthese studies, their benefit in reducing cardiovascular mortality among higher risk participants with CHD iswell established and likely reflects prevention of both sudden and nonsudden cardiac death.
Several clinical trials have evaluated the role of statins in the dialysis population. Most recently, The Study ofHeart and Renal Protection (SHARP) randomized 9270 patients with CKD to ezetimibe plus simvastatin orplacebo. At the time of randomization, approximately onethird of the participants were receivingmaintenance dialysis. After a median followup of 4.9 years, patients randomized to an ezetimibe/simvastatin combination experienced a 17% reduction in major atherosclerotic events compared with theplacebo group. Further subgroup analysis did not demonstrate a difference in the reduction of atheroscleroticevents between study participants receiving chronic dialysis and those who were not. These findings suggestthat statins and a subsequent lowering of the LDL may be beneficial in a wide range of patients with CKDincluding those on dialysis. These results differ from two other placebocontrolled statin trials in dialysispopulations that did not demonstrate a reduction in cardiovascular death, MI and stroke, althoughsecondary analyses from the AURORA study suggest some benefit from rosuvastatin treatment in dialysispatients with diabetes. This failure to achieve statistical significance in primary trials may have derivedfrom the smaller number of participants enrolled in these trials. The SHARP study also noted that statintherapy was safe in patients with kidney disease. There was no excess elevation of hepatic transaminases,hepatitis, gallstones, or pancreatitis.
ReninAngiotensinAldosterone System Blockers
Dysregulation of the reninangiotensinaldosterone system (RAAS) comprises a fundamental abnormality incardiorenal disorders. Experimental evidence suggests that hyperaldosteronism may both result from andcontribute to kidney injury. Animal models with kidney damage demonstrate a 10fold increase in plasmaaldosterone concentrations that precede the onset of hypertension, proteinuria, and glomerulosclerosis. Morerecently, epidemiologic studies demonstrate that elevated aldosterone concentrations are an independent riskfactor for SCD in patients with coronary atherosclerosis and reduced eGFR. These findings provideadditional justification for the use of RAAS inhibitors in patients with kidney disease.
Medications that inhibit activation of RAAS are known to provide survival benefits in patients with CHF orMI. The benefits of angiotensinconverting enzyme inhibitors extend to patients with mild kidneydysfunction. In the Heart Outcomes and Prevention Evaluation study, treatment with ramipril reducedcardiovascular events, including cardiovascular mortality, to a similar extent as patients with normal kidney
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function. Mineralocorticoid receptor blockers such as spironolactone and eplerenone are also known toreduce SCD by 20%–30% in clinical trials enrolling patients with heart failure. These benefits extend tothe subgroup with mild renal insufficiency; however, no trials have evaluated whether mineralocorticoidreceptor blockers reduce SCD risk in patients with kidney disease alone and without heart failure.
ICDs
The American Heart Association’s recommendations for ICD implantation have evolved from identifyingpatients who have survived a cardiac arrest to highrisk populations for the primary prevention of SCD.For this later group, large clinical trials demonstrate that ICDs reduce mortality when implanted in those withclinical heart failure and a LVEF ≤35%. These clinical trials excluded participants with advancedkidney disease and ESRD; as a result, only registrybased and singlecenter data are available to inform ICDimplantation in these patients.
ICDs appear to reduce mortality risk in heart failure patients with CKD who are not on hemodialysis. Aretrospective analysis from MADITII identified nearly 500 study participants (approximately 40% of thestudy population) with CKD. In participants with an eGFR ≥35 ml/min per 1.73 m , the risks of allcausemortality and SCD were significantly lower in the ICD group than in the conventional therapy group after 2years of followup (Figure 3). No significant difference was found in either mortality or SCD risk betweenthe two treatment groups for an eGFR <35 ml/min per 1.73 m . The similar risk of SCD in the ICD andconventionally treated groups at an eGFR <35 ml/min per 1.73 m suggests reduced ICD responsiveness inthis population with more advanced kidney disease.
ICDs appear efficacious in dialysis patients who have survived an episode of sudden cardiac arrest.ESRD patients, identified from the Medicare database, who underwent ICD implantation within 30 days ofthe sudden cardiac arrest episode had a 42% reduction in death over a 5year period than a matched sampleof patients who did not undergo ICD implantation after experiencing cardiac arrest (Figure 4). Uncertainty,however, remains in defining the optimal use of ICD placement for primary prevention in these patients.ESRD patients have a high mortality risk even after ICD implantation, averaging 45 deaths per 100patientyears of followup. According to a recent analysis from the USRDS that evaluated outcomes innearly 10,000 dialysis patients undergoing ICD implantation over a 12year period, the majority ofcardiovascular deaths were arrhythmic. This group of ESRD patients was also more likely to receiveappropriate therapies for ventricular fibrillation or ventricular tachycardia compared with their nonESRDcounterparts. This discordance between appropriate ICD shocks and increased arrhythmic mortalitysuggests that patients with severe kidney dysfunction may be intermittently refractory to ICD therapiesbecause of the unique metabolic derangements imparted by renal failure and dialytic treatment.Defibrillation thresholds have also been reported to be higher in this group and may increase the risk ofICD nonresponsiveness. In addition, the high risk of allcause mortality in ICD patients on dialysis may beexplained by competing risks from other lifethreatening disease process that the ICD would not be expectedto effect. Finally, ESRD patients have a high risk of periprocedural complications; approximately 5% ofdevices became infected during each year of followup. This complication can result in sepsis that isrefractory to antibiotic therapy, infective endocarditis, and often requires extraction of the entire ICD system.
The elevated risk for both sudden and nonsudden deaths in ESRD patients and concerns for proceduralbased complications related to ICD implantation emphasize the need for prospective clinical trials. TheImplantable Cardioverter Defibrillators in Dialysis Patients trial has been approved in the Netherlands andaims to evaluate whether ICD therapy in dialysis patients aged 55–80 years will reduce the risk of SCDcompared with patients with no ICDs. Until more definitive data are available, ICD implantation indialysis patients requires a thorough review of the individual’s history for sudden cardiac arrest, presence ofheart failure, left ventricular dysfunction, functional status, and a consideration of other medicalcomorbidities.
This review has clarified that CKD patients are at an increased risk of sudden cardiac arrest, an outcome thatis often fatal and carries a poor prognosis. Structural and electrophysiologic remodeling of the heart, vasculardisease, and autonomic dysregulation are some of the underlying processes identified to explain the increasedpredisposition for SCD in people with CKD. Translational studies provide some insights into potentialtargets for identifying CKD patients who may be at higher risk for SCD events. Future studies will need toidentify novel approaches toward arrhythmic risk stratification in CKD patients and evaluate whethertreatment with medical and interventional therapies is effective and safe.
Disclosures
None.
Acknowledgments
R.D. is supported by National Institutes of Health Grant K23DK089118.
FootnotesPublished online ahead of print. Publication date available at www.jasn.org.
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Figures and Tables
Table 1.
Studies evaluating an association between kidney disease and SCD
Successive tertiles of decliningeGFR are associated with 0.1%,0.25%, and 0.32% yearly risk ofSCD, respectively
Low
Cystatin C tertile 2:eGFR 69–85,n=1582;
Cystatin C tertile 3:eGFR ≤68, n=1304
MADITII, Multicenter Automated Defibrillator Implantation Trial II; NYHA, New York Heart Association;UPMC, University of Pittsburgh Medical Center; COMPANION, Comparison of Medical Therapy, Pacingand Defibrillation in Heart Failure; HERS, Heart and Estrogen/Progestin Replacement Study; DDCD, DukeDatabank for Cardiovascular Disease; CHS, Cardiovascular Health Study.
Cr, creatinine (mg/dl), or eGFR, estimated GFR (ml/min per 1.73 m ).Defined as history of MI, coronary artery bypass graft surgery, percutaneous coronary intervention, or CHDon angiography.Defined as significant CHD on angiography.Defined as history of MI or CHF.
Figure 1.
32
c
33
d
a 2
b
c
d
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Mortality rates according to kidney function and ICD status. In this subgroup analysis from the MADITII study, mortalityrates increased across eGFR categories in both the ICD and conventional treatment groups. In addition, mortality wassignificantly lower in the ICD group compared with the conventional therapy group in patients with an eGFR >35 ml/min
2 28
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Mortality rates in ESRD patients who had a history of cardiac arrest. “Number at risk” reflects the number of patients whosurvived to each time interval (i.e., 12, 24, 36, and 48 months). The 1, 2, 3, 4, and 5year survival in the ICD group was71%, 53%, 36%, 25%, and 22%, respectively; in the noICD group, it was 49%, 33%, 23%, 16%, and 12% (P<0.001),respectively.
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