2. PES Institute of Medical Sciences & Research
Abstract
• Sudden cardiac death (SCD) is responsible for approximately one
fourth of all cause mortality in dialysis patients.
• In chronic kidney disease (CKD) patients, unlike general population,
traditional coronary artery disease associated risk factors are not the
major determinants of SCD. The adverse cardiomyopathic and
vasculopathic milieu in CKD predispose these patients to arrhythmias,
conduction abnormalities, and sudden cardiac death.
3. PES Institute of Medical Sciences & Research
contd...
• In advanced kidney disease, these conditions may be further
exacerbated by electrolyte shifts, divalent ion abnormalities, sympathetic
overactivity, decreased baroreflex sensitivity, iron toxicity, and chronic
inflammation.
• The outcomes after cardiac arrest in CKD patients particularly those on
dialysis are unfavourable.
• The decision to implant a cardioverter- defibrillator depends on the
patient’s age and stage of CKD.
4. PES Institute of Medical Sciences & Research
contd..
This article will review:
• definition
• pathophysiology
• risk factors
• preventive strategies of SCD in the setting of CKD.
5. PES Institute of Medical Sciences & Research
Introduction
• Sudden cardiac death (SCD) is a sudden, unexpected death caused by cessation of
heart function. These events are defined as those deaths that are either preceded by a
witnessed collapse, or occur within 1 h of an acute change in clinical condition, or occur
within 24 h since the deceased individual was known to be in his or her usual state of
health. It is usually from an unexpected circulatory arrest, usually from a cardiac
arrhythmia.
• The 2006 American College of Cardiology/American Heart Association/Heart Rhythm
Society to establish data standards for electrophysiology defined sudden cardiac arrest
(SCA) and SCD as- SCA is the sudden cessation of cardiac activity so that the victim
becomes unresponsive, with no normal breathing and no signs of circulation.
6. PES Institute of Medical Sciences & Research
contd...
• If corrective measures are not taken rapidly, this condition progresses to
sudden death. Cardiac arrest should be used to signify an event as
described above, that is reversed, usually by Cardiopulmonary
resuscitation and/or defibrillation or cardioversion, or cardiac pacing.
• In the general population, SCD was recently estimated to be about 8% of
the out-of-hospital cardiac arrests treated by emergency medical
services personnel.
7. PES Institute of Medical Sciences & Research
Contd...
• In chronic kidney disease (CKD) patients, putting the diagnosis of SCD could
be problematic- since deaths frequently occur at home and unwitnessed.
• Other noncardiac causes of sudden death, as well as cerebrovascular event,
would also contribute to overall mortality in these patients.
• According to US Renal Data System, approximately 22% of all deaths are
caused by SCD, and the incidence increases with age: 2% per year for ages
20–44 years, 3.7% per year for ages 45–64 years, and 7% per year for ages 65
years and older.
8. PES Institute of Medical Sciences & Research
Contd...
• Nondialysis-dependent CKD patients are also at increased risk of
SCD, have a poorer prognosis postcardiac arrest compared to the
normal population
• The likelihood of survival decreases with a declining glomerular
filtration rate (GFR), Even mild reductions in kidney function,
demonstrated by higher cystatin C levels, increase the risk of SCD in
elderly patients and other susceptible population.
9. PES Institute of Medical Sciences & Research
contd...
• As per current estimate, SCD is accountable for 27% ± 2% of all-
cause mortality in dialysis patients. Compared with the average risk of
SCD, there is a 50% increased frequency of SCD on the first
hemodialysis session after the long weekend interval.
• The risk is also increased threefold in the 12 h period before the end
of the long weekend interval and increased 1.7 times in the 12 h
following commencement of the dialysis procedure after this long
interval.
10. PES Institute of Medical Sciences & Research
Pathophysiology of
sudden cardiac death
in chronic kidney
disease
11. PES Institute of Medical Sciences & Research
Pathophysiology of Sudden Cardiac
Death in Chronic Kidney Disease
• Cardiomyopathy due to left ventricular pressure and volume
overload and vasculopathy due to atherosclerosis and
arteriosclerosis predispose patients with CKD to
cardiovascular disease.
• The adverse cardiomyopathic and vasculopathic milieu
predisposes these patients to arrhythmias, conduction
abnormalities, and SCD.
12. PES Institute of Medical Sciences & Research
contd...
• This is likely to be exacerbated by electrolyte shifts, divalent
ion abnormalities, diabetes, sympathetic overactivity,
inflammation and iron deposition. Impaired baroreflex
effectiveness and sensitivity, as well as obstructive sleep
apnea might also contribute to the risk of SCD.
13. PES Institute of Medical Sciences & Research
Risk Factors of Sudden
Cardiac Death in
Chronic Kidney
Disease
14. PES Institute of Medical Sciences & Research
Uremic cardiomyopathy
• In predialysis CKD patients, left ventricular hypertrophy (LVH) increases as GFR falls.
• LVH is present in almost 75% of patients starting dialysis. Hypertension, anemia,
volume overload and other risk factors can partly explain the progression of LVH.
• Even after initiation of dialysis, progressive left ventricular dilation and LVH continues
and is associated with the subsequent development of heart failure. LVH predisposes
individuals to sudden death through prolongation of corrected QT (QTc) interval or by
increasing arrhythmogenesis.
15. PES Institute of Medical Sciences & Research
contd...
• The QTc interval is longer in hemodialysis patients than in those with normal kidney
function.
• Premature ventricular complexes (PVCs) occur more during hemodialysis in patients
with LVH compared with those without it.
• In uremic patients, activation of growth factors, proto-oncogenes, plasma noradrenaline,
cytokines and angiotensin II regulate intracellular processes which accelerate cardiac
hypertrophy and myocardial fibrosis.
• Both LVH and myocardial fibrosis increase risk of sustained ventricular arrhythmias and
predisposition to SCD.
16. PES Institute of Medical Sciences & Research
Ischemic heart disease
• In dialysis dependent patients, severe coronary stenosis is associated
with the induction and lengthy persistence of ventricular arrhythmias
during and after hemodialysis.
• The number of PVCs during and after hemodialysis is higher in patients
with ischemic heart disease.
• Ischemia modified albumin (IMA), novel biomarker of acute ischemia has
high sensitivity and moderate specificity.
17. PES Institute of Medical Sciences & Research
contd...
• Cardiac mortality risk was increased sevenfold in patients with combined elevated IMA
and cardiac troponin levels. Severely impaired myocardial fatty acid metabolism
occurring as a result of recurrent myocardial ischemia, can also identify patients on
hemodialysis who are at high risk of SCD.
• Paraoxonase-1 (PON-1) is a calcium-dependent esterase which protects against
oxidative damage of various cells and lipoproteins. Low serum levels of PON-1 have
been detected in HD and non-HD dependent CKD patients. The actual association of
the roles of these cardiac biomarkers-PON-1 and IMA to SCD related to CKD is still
unknown
18. PES Institute of Medical Sciences & Research
Corrected QT interval lengthening
• QTc interval prolongation is associated with several manifestations of
uremic cardiomyopathy including LVH, left ventricular dilatation, and
reduced left ventricular ejection fraction.
• In patients with CKD, prolonged QTc interval results from inappropriate
myocardial depolarization and repolarization due to LVH and
intercardiomyocytic fibrosis.
19. PES Institute of Medical Sciences & Research
contd...
• QT dispersion that occurred for longer than 74 ms is an
independent predictor of all-cause mortality, cardiovascular
mortality, and arrhythmia-related mortality.
• QT variability index (QTvi) ≥0.1 was significantly associated
with a higher risk of arrhythmias and SCD.
QT variability index (QTvi) calculated as the logarithm of the ratio between the variances of the normalized QT and rr intervals–can provide an
estimation of the temporal variability in the myocardial repolarization process. The elevated QTvi in patients with advanced CKD is the result of both
reduced rr interval variance (secondary to reduced autonomic control of heart rate) and increased QT-interval variance.
20. PES Institute of Medical Sciences & Research
Inflammation
• Serum levels of proinflammatory cytokines increases with
declining GFR. High C-reactive protein (CRP) and cytokine
(such as interleukin [IL]-6 and platelet-activating factor) levels
are associated with ventricular arrhythmias via modulation of
ion channel function and sympathetic nervous system
hyperactivity.
21. PES Institute of Medical Sciences & Research
Contd..
• These proinflammatory cytokine (CRP and IL-6) are associated with a
doubled risk of SCD. Premature atherosclerosis and cytokines induce
plaque instability resulting in direct effect on the myocardium and the
electrical conduction system.
• Myocardial fibrosis associated with an inflammatory process causing a
delay in repolarization leading to ventricular arrhythmias and SCD.
• High levels of inflammatory mediators in CKD induce production of
reactive oxygen species resulting in an accelerated vascular
atherosclerosis and arterial calcification.
22. PES Institute of Medical Sciences & Research
Contd...
• High homocysteine levels are common in CKD patients and
are associated with atherothrombolic events and incidents of
cardiovascular mortality.
• The accumulation of asymmetric dimethylarginine in CKD
inhibits nitric oxide synthesis in endothelial cells inducing
endothelial dysfunction, vasoconstriction, and atherosclerosis.
23. PES Institute of Medical Sciences & Research
Electrolyte shifts
• The rapid change in the extracellular concentration of electrolytes
during a dialysis session effect cellular membrane polarization and
stability.
• Dialysis with a potassium dialyzate concentration of 0 mmol/l or 1
mmol/l was considered a significant risk factor for cardiac arrest.
• Hypocalcemia after hemodialysis is associated with prolonged
corrected QTc interval and SCD.
24. PES Institute of Medical Sciences & Research
Divalent ion abnormalities
• Hyperphosphatemia is associated with hyperparathyroidism, smooth
muscle proliferation, vascular calcification, and coronary
atherosclerosis. All these could alter microcirculatory hemodynamics,
raise extravascular resistance and impair myocardial perfusion.
• Hyperphosphatemia and elevated Ca++ x PO4 product were
correlated with an increase in the risk of death related to coronary
artery disease (CAD) and SCD.
25. PES Institute of Medical Sciences & Research
Rapid ultrafiltrate removal during
hemodialysis
• Ultrafiltrate removal may contribute to an acute reduction of
circulating volume, hypotension, tissue ischemia, maladaptive
cardiac structural changes, arrhythmias and SCD.
• There is a small increase in all-cause mortality without an
increase in cardiac mortality in patients undergoing a UF rate
higher than 10 ml/h/kg.
26. PES Institute of Medical Sciences & Research
Contd...
• Higher UF rates are associated with greater CV mortality
• Intradialytic recurrent myocardial stunning due to hypotension
secondary to rapid ultrafiltrate removal may over time lead to
irreversible fibrotic changes and CHF, arrhythmias and SCD.
27. PES Institute of Medical Sciences & Research
Iron overload
• Iron overload can promote reactive oxygen species and free
radical production resulting in intercardiomyocytic fibrosis
leading to conduction abnormalities and prologed QTc
dispersion.
• Also, it has been associated with elevated rates of
hospitalization and mortality in patients with ESRD.
28. PES Institute of Medical Sciences & Research
Sympathetic overactivity
• Augmented sympathetic activity is seen during hemodialysis
sessions. This could aggravate hypertension, ventricular
hypertrophy, and heart failure and result in increased risk of
SCD.
• There is also reduced amount of renalase (which metabolizes
catecholamines) secretion by injured kidneys in CKD resulting
in augmented sympathetic drive.
29. PES Institute of Medical Sciences & Research
Baroreflex effectiveness and sensitivity
• Impaired arterial baroreflex function in CKD is associated with an
increased risk of ventricular arrhythmia and SCD.
• Patients with CKD and diabetes had a greater reduction in both
baroreflex sensitivity and effectiveness than patients with CKD who
did not have diabetes.
• Reduced baroreceptor effective index is an independent predictor of
all-cause mortality, while reduced baroreflex sensitivity is an
independent predictor of SCD.
30. PES Institute of Medical Sciences & Research
Obstructive sleep apnea
• Episodes of nocturnal arterial oxygen desaturation,
has been reported to affect 21%–47% of patients
undergoing dialysis compared with 2%–4% of the
general population.
31. PES Institute of Medical Sciences & Research
Strategies to prevent
sudden cardiac
death
RAAS: Renin Angiotensin Aldosterone System, PCI: Percutaneous coronary intervention, CABG:
Coronary artery bypass graft, ICD: Implantable cardioverter defibrillator
32. PES Institute of Medical Sciences & Research
β-Blockers
• Use of the β-blocker carvedilol reduces morbidity, and all-
cause and cardiovascular mortality in patients with ESRD and
dilated cardiomyopathy who are undergoing dialysis.
• In a retrospective study, HD patients using beta-blockers had
a lower rate of SCD.
33. PES Institute of Medical Sciences & Research
Calcium channel blockers
• Calcium channel blocker (CCB) may have potential
cardioprotective effects by preventing coronary artery spasm,
normalizing intracellular Ca++ concentration, limiting injury
after cardiac arrest and preventing fatal arrhythmias.
34. PES Institute of Medical Sciences & Research
Digoxin
• In digoxin therapy, there is risk of narrow therapeutic
window, long half-life, and the potential risk for lethal
arrhythmias in presence of hypokalemia. Hemodialysis
involves large potassium fluxes, so digoxin is not a good
choice in these patients
35. PES Institute of Medical Sciences & Research
Renin-angiostensin-aldosterone system
blockers
• High aldosterone levels are reported to be an independent risk
factor for SCD in non-CKD patients. In the “Fosinopril in
Dialysis Trial” there was no reduction in cardiovascular events
in the treated patients group.
• The use of ACE inhibitors and ARBs was associated with a
significantly reduced risk of SCD after 6 months of treatment
in survivors of a cardiac arrest.
36. PES Institute of Medical Sciences & Research
Statin
• Benefit in reducing all cardiac events was observed, but no
effect on CV deaths or all-cause mortality was reported.
37. PES Institute of Medical Sciences & Research
Dialysate
• K + dialyzate concentration from 0 mmol/l to 1 mmol/l is
associated with increased risk of cardiac arrest.
• K + dialysate of <2 mmol/l (or <3 mmol/l if pre-HD serum K +
is <5 mmol/l) confers an increased risk of SCD.
• Serum and dialysate Ca++, and serum-dialysate Ca++
gradients should be monitored in determining the optimal
dialysate Ca prescription.
38. PES Institute of Medical Sciences & Research
Ultrafiltration
• Daily dialysis or nocturnal hemodialysis therapies can prevent
prolonged myocardial damage by removing excessive fluid in
a longer session.
• In a randomized controlled study, patients treated 2.5 h for six
times a week, showed more favorable survival and decreased
left ventricular mass index compared with those treated 3.5 h
three times a week.
39. PES Institute of Medical Sciences & Research
contd...
• Similarly, in another study, patients undergoing nocturnal HD
showed better survival rates compared with other patients.
• Higher dialysis dose may control volume overload, improve
the uremic milieu, diminish levels of inflammatory markers and
reduce LVH and left ventricular dilation, thereby reducing the
risk of SCD
40. PES Institute of Medical Sciences & Research
Coronary revascularisation
• Risk of long-term repeated revascularization, myocardial
infarction, and SCD is more in patients with CKD than in those
with normal kidney function.
• A significant reduction in repeat revascularization and a trend
toward reduced mortality was observed in drug eluting stent
compared with bare metal stent treated dialysis patients.
41. PES Institute of Medical Sciences & Research
Implantable cardioverter defibrillator
• There is a significant reduction in the risk of all-cause mortality
and SCD risk in CKD patients with estimated glomerular
filtration rate (eGFR) ≥35 ml/min per 1.73 m2 treated with ICD
compared with those in the no ICD therapy.
42. PES Institute of Medical Sciences & Research
Conclusion
• About one fourth of hemodialysis patients will die from SCD.
• Among CKD patient, CAD risk factors play very small role as compared
to the general population.
• Cardiomyopathy and ischemic heart disease predispose to conduction
abnormalities and arrythmogenesis, which can be exacerbated by
electrolyte shifts, excess ultrafiltrate removal, iron overload, divalent ion
abnormalities, sympathetic overactivity, and baroreflex abnormalities.
43. PES Institute of Medical Sciences & Research
Contd...
• Beta-blockers, CCB and Renin angiotensin aldosterone system blockers have been
associated with a survival benefit after an arrhythmic cardiac arrest.
• Both low potassium dialysate and extremes of serum potassium levels, as well as low
calcium dialysate and large serum to dialysate calcium gradients, have been shown to
increase risk of SCD.
• It is also important to avoid excessive rates of fluid removal per HD session, as high UF
volumes have been associated with SCD. Short daily-HD or nocturnal-HD may be
considered, especially for patients with several comorbidities or those with
hemodynamic instability.
44. PES Institute of Medical Sciences & Research
contd...
• Recommendation regarding revascularisation should be individualised,
and other supportive therapies may be needed to prevent SCD in CAD
patients.
• The survival following cardiac arrest is very poor in the setting of CKD.
The decision to implant a cardioverter-defibrillator should be influenced
by age and CKD stage. In a recent ICD2 trial, prophylactic ICD therapy
did not reduce the rate of SCD or all cause mortality
