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] (2015) ]]]–]]]
Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Editorial Commentary
Sudden cardiac death: We are not there yet Olujimi A. Ajijola, MD, PhDn UCLA Cardiac Arrhythmia Center, Neurocardiology Research Center of Excellence, UCLA Health System. David Geffen School of Medicine, University of California-Los Angeles, Suite 660, 100 Medical Plaza, Los Angeles CA 90095-1679
Sudden cardiac death (SCD) remains the leading cause of mortality in developed nations, despite significant advances over the past half-century [1]. Major practice-changing advances have included improved identification of coronary artery disease (CAD) risk factors, aggressive prevention of CAD, improved treatment of acute coronary syndromes (ACS), recognition of some rare but high-risk genetic causes of ventricular arrhythmias (VAs), and the use of implantable cardioverter–defibrillators (ICDs). Significant impacts also have been made by the presence of automated external defibrillators in public places, and large public educational campaigns on basic and advance cardiopulmonary resuscitation. In this issue of the Journal, Mitrani and Myerburg [2] have comprehensively but concisely described recent developments in the understanding, prevention, and treatment of SCD. These developments range widely in their context, and include changes in the definition of SCD, recognition of epidemiologic trends, the evolution of SCD mechanisms, and developments in specific clinical conditions, genetic mutations, or polymorphisms. The authors also discuss the increasing recognition of the intricacies of post-cardiac arrest care, which should differ based on the duration of the arrest, i.e., time elapsed before the return of spontaneous circulation. The aim of this brief editorial is to place these developments in the overall context of where we are in the identification of risk, prevention, and treatment of SCD, and where we need to be, to make an impact on this enigmatic societal problem.
Where are we now? The study of SCD continues to be plagued by the paradox between the population of patients who receive ICDs for primary prevention of sudden death, i.e., patients with left ventricular ejection fraction (LV EF) under 35%, and the population that harbors the largest number of SCD cases, i.e., the asymptomatic general population. Further, only a fraction of those with LV EF o35% who receive ICDs receive appropriate therapies to prevent arrhythmic death. These contradictions represent profound limitations in our ability to prevent sudden death. Identifying asymptomatic patients in the general population who harbor susceptibility factors other than occult coronary artery disease (including intra-myocardial scar, genetic mutations or polymorphisms, abnormalities in autonomic function, high-risk accessory pathways, or other structural cardiac abnormalities) is daunting. The amount of resources required to develop programs worldwide to combat this issue, with the available data regarding SCD risk factors, makes such efforts non-starters [3]. It is interesting that SCD remains under-recognized for what it is, a final common pathway for death, resulting from a variety of etiologies. ACS remains the most frequently occurring etiology but many other causes exist. Genetic studies may identify polymorphisms or mutations conferring high risk of death; however, these are unlikely to account for a large fraction of SCD cases. This issue is further complicated by incomplete penetrance and heterogeneous expression of some genetic abnormalities, such that further risk stratification is required. Autonomic nervous system (ANS)
The author has indicated that there are no conflicts of interest. Dr. Ajijola is support by NIH/NHLBI HL125730 and the A.P. Giannini Foundation. n Tel.: þ1 310 206 6433; fax: þ1 310 825 2092. E-mail address: [email protected] http://dx.doi.org/10.1016/j.tcm.2015.04.009 1050-1738/& 2015 Elsevier Inc. All rights reserved.
2
T
R E N D S I N
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(dys)function is tightly linked to ventricular electrophysiology, and therefore arrhythmogenesis. Dynamics of heart rate and the QT interval have been used to develop metrics related to autonomic activity, and consequently, to the risk of SCD in the general asymptomatic population, and in patients with ischemic and non-ischemic cardiomyopathy. The oscillatory nature of cardiac ANS function on short (respiratory cycle), intermediate (circadian cycle), and longtime scales limits how readily applicable autonomic tests are. Provocative tests are therefore required, typically requiring a significant amount of resources, and impractical on a largescale basis. Perhaps, the most striking and alarming trend in SCD is the gradual evolution of the most common mechanisms of sudden death from VT/VF to asystole and pulseless electrical activity (PEA)[4]. This specifically refers to PEA/asystole not due to reversible or non-cardiac (for example, tension pneumothorax, pulmonary embolism, hypovolemia, and trauma) causes that would not be strictly classified as SCD. Contrary to VAs, where correction of the electrical disturbance, and prevention of its recurrence by ischemia and other causes is the primary strategy, PEA/asystole requires the rapid assessment of a variety of potential etiologies (the H's and T's described by the American Heart Association and European Resuscitation Council [5]), and as a result, an efficacious intervention, akin to cardioversion or defibrillation, does not exist. Further, the time scale for correction of PEA/asystole is typically longer than for VT/VF. It has been proposed that the incidence of PEA/asystole as causes of SCD has risen with widespread use of beta-blockers [6] and anti-arrhythmic medications. This raises the possibility that VT/VF and PEA/ asystole are merely common final pathways for SCD, and the use of therapies that modulate myocyte electrophysiology simply shifts the manifest rhythm to PEA/asystole. Cardiac pacing may theoretically alleviate asystole; however, studies on pacing for asystolic arrest have not demonstrated a benefit [7,8]. PEA as a cause of SCD remains a major challenge from multiple standpoints, including definition, mechanisms, appropriate models, and treatment [4]. Outcomes following PEA/asystole as the mechanism of SCD are also worse, compared to VT/VF [9]. These considerations highlight the importance of improving our understanding of PEA/asystole in the fight against SCD.
Where do we go from here? Arguably, the two most important areas to prioritize our future investigations to impact SCD are (1) the identification of individuals at risk for whom ICD implantation would be of high yield and (2) elucidating the mechanistic underpinnings of PEA/asystole, such that more effective treatment strategies may be developed. SCD is a manifestation of a variety of etiologies; hence, it is unlikely that a single marker applied to the population would capture all individuals at risk for SCD. As a result, accurate
ME
D I C I N E
] (2015) ]]]–]]]
prediction of risk is likely to come from models that capture a variety of risk factors demonstrated reliably in populationbased studies. Such risk prediction models are yet to be developed, validated, and applied prospectively. In the era of big data, bioinformatics approaches will most likely be required to comb vast amounts of data needed to produce accurate risk stratification models. Such models would require iterative prospective validation in the population to be useful. The challenge posed by the increasing incidence of PEA/ asystole deserves particular attention. Mechanistic understanding of PEA/asystole is needed to continue to impact SCD. The development of appropriate laboratory models for PEA is critical to enable dissection of the basic cellular mechanisms of PEA. Also important are broad systematic prospective randomized trials of pharmacologic therapies, and the development of rapidly deployable mechanical support in the field to temporarily restore perfusion. In conclusion, while the review article by Mitrani and Myerburg describes recent developments in the field of SCD, it highlights significant knowledge and therapeutic gaps, and the vast opportunities for life-saving interventions in the identification, treatment, and prevention of SCD.
re fe r en ces
[1]
[2] [3]
[4]
[5]
[6]
[7]
[8]
[9]
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 2015;131:e29–322. Mitrani RA, Myerburg RJ. Ten advances defining sudden cardiac death. Trends Cardiovasc Med 2015. Goldberger JJ, Basu A, Boineau R, Buxton AE, Cain ME, Canty JM Jr, et al. Risk stratification for sudden cardiac death: a plan for the future. Circulation 2014;129:516–26. Myerburg RJ, Halperin H, Egan DA, Boineau R, Chugh SS, Gillis AM, et al. Pulseless electric activity: definition, causes, mechanisms, management, and research priorities for the next decade: report from a National Heart, Lung, and Blood Institute workshop. Circulation 2013;128: 2532–41. Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S729–67. Youngquist ST, Kaji AH, Niemann JT. Beta-blocker use and the changing epidemiology of out-of-hospital cardiac arrest rhythms. Resuscitation 2008;76:376–80. Cummins RO, Graves JR, Larsen MP, Hallstrom AP, Hearne TR, Ciliberti J, et al. Out-of-hospital transcutaneous pacing by emergency medical technicians in patients with asystolic cardiac arrest. N Engl J Med 1993;328:1377–82. Hedges JR, Syverud SA, Dalsey WC, Feero S, Easter R, Shultz B. Prehospital trial of emergency transcutaneous cardiac pacing. Circulation 1987;76:1337–43. Mader TJ, Nathanson BH, Millay S, Coute RA, Clapp M, McNally B. Out-of-hospital cardiac arrest outcomes stratified by rhythm analysis. Resuscitation 2012;83:1358–62.
E N D S I N
C
A R D I O V A S C U L A R
M
E D I C I N E
] (2015) ]]]–]]]
Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Editorial Commentary
Sudden cardiac death: We are not there yet Olujimi A. Ajijola, MD, PhDn UCLA Cardiac Arrhythmia Center, Neurocardiology Research Center of Excellence, UCLA Health System. David Geffen School of Medicine, University of California-Los Angeles, Suite 660, 100 Medical Plaza, Los Angeles CA 90095-1679
Sudden cardiac death (SCD) remains the leading cause of mortality in developed nations, despite significant advances over the past half-century [1]. Major practice-changing advances have included improved identification of coronary artery disease (CAD) risk factors, aggressive prevention of CAD, improved treatment of acute coronary syndromes (ACS), recognition of some rare but high-risk genetic causes of ventricular arrhythmias (VAs), and the use of implantable cardioverter–defibrillators (ICDs). Significant impacts also have been made by the presence of automated external defibrillators in public places, and large public educational campaigns on basic and advance cardiopulmonary resuscitation. In this issue of the Journal, Mitrani and Myerburg [2] have comprehensively but concisely described recent developments in the understanding, prevention, and treatment of SCD. These developments range widely in their context, and include changes in the definition of SCD, recognition of epidemiologic trends, the evolution of SCD mechanisms, and developments in specific clinical conditions, genetic mutations, or polymorphisms. The authors also discuss the increasing recognition of the intricacies of post-cardiac arrest care, which should differ based on the duration of the arrest, i.e., time elapsed before the return of spontaneous circulation. The aim of this brief editorial is to place these developments in the overall context of where we are in the identification of risk, prevention, and treatment of SCD, and where we need to be, to make an impact on this enigmatic societal problem.
Where are we now? The study of SCD continues to be plagued by the paradox between the population of patients who receive ICDs for primary prevention of sudden death, i.e., patients with left ventricular ejection fraction (LV EF) under 35%, and the population that harbors the largest number of SCD cases, i.e., the asymptomatic general population. Further, only a fraction of those with LV EF o35% who receive ICDs receive appropriate therapies to prevent arrhythmic death. These contradictions represent profound limitations in our ability to prevent sudden death. Identifying asymptomatic patients in the general population who harbor susceptibility factors other than occult coronary artery disease (including intra-myocardial scar, genetic mutations or polymorphisms, abnormalities in autonomic function, high-risk accessory pathways, or other structural cardiac abnormalities) is daunting. The amount of resources required to develop programs worldwide to combat this issue, with the available data regarding SCD risk factors, makes such efforts non-starters [3]. It is interesting that SCD remains under-recognized for what it is, a final common pathway for death, resulting from a variety of etiologies. ACS remains the most frequently occurring etiology but many other causes exist. Genetic studies may identify polymorphisms or mutations conferring high risk of death; however, these are unlikely to account for a large fraction of SCD cases. This issue is further complicated by incomplete penetrance and heterogeneous expression of some genetic abnormalities, such that further risk stratification is required. Autonomic nervous system (ANS)
The author has indicated that there are no conflicts of interest. Dr. Ajijola is support by NIH/NHLBI HL125730 and the A.P. Giannini Foundation. n Tel.: þ1 310 206 6433; fax: þ1 310 825 2092. E-mail address: [email protected] http://dx.doi.org/10.1016/j.tcm.2015.04.009 1050-1738/& 2015 Elsevier Inc. All rights reserved.
2
T
R E N D S I N
C
A R D I O V A S C U L A R
(dys)function is tightly linked to ventricular electrophysiology, and therefore arrhythmogenesis. Dynamics of heart rate and the QT interval have been used to develop metrics related to autonomic activity, and consequently, to the risk of SCD in the general asymptomatic population, and in patients with ischemic and non-ischemic cardiomyopathy. The oscillatory nature of cardiac ANS function on short (respiratory cycle), intermediate (circadian cycle), and longtime scales limits how readily applicable autonomic tests are. Provocative tests are therefore required, typically requiring a significant amount of resources, and impractical on a largescale basis. Perhaps, the most striking and alarming trend in SCD is the gradual evolution of the most common mechanisms of sudden death from VT/VF to asystole and pulseless electrical activity (PEA)[4]. This specifically refers to PEA/asystole not due to reversible or non-cardiac (for example, tension pneumothorax, pulmonary embolism, hypovolemia, and trauma) causes that would not be strictly classified as SCD. Contrary to VAs, where correction of the electrical disturbance, and prevention of its recurrence by ischemia and other causes is the primary strategy, PEA/asystole requires the rapid assessment of a variety of potential etiologies (the H's and T's described by the American Heart Association and European Resuscitation Council [5]), and as a result, an efficacious intervention, akin to cardioversion or defibrillation, does not exist. Further, the time scale for correction of PEA/asystole is typically longer than for VT/VF. It has been proposed that the incidence of PEA/asystole as causes of SCD has risen with widespread use of beta-blockers [6] and anti-arrhythmic medications. This raises the possibility that VT/VF and PEA/ asystole are merely common final pathways for SCD, and the use of therapies that modulate myocyte electrophysiology simply shifts the manifest rhythm to PEA/asystole. Cardiac pacing may theoretically alleviate asystole; however, studies on pacing for asystolic arrest have not demonstrated a benefit [7,8]. PEA as a cause of SCD remains a major challenge from multiple standpoints, including definition, mechanisms, appropriate models, and treatment [4]. Outcomes following PEA/asystole as the mechanism of SCD are also worse, compared to VT/VF [9]. These considerations highlight the importance of improving our understanding of PEA/asystole in the fight against SCD.
Where do we go from here? Arguably, the two most important areas to prioritize our future investigations to impact SCD are (1) the identification of individuals at risk for whom ICD implantation would be of high yield and (2) elucidating the mechanistic underpinnings of PEA/asystole, such that more effective treatment strategies may be developed. SCD is a manifestation of a variety of etiologies; hence, it is unlikely that a single marker applied to the population would capture all individuals at risk for SCD. As a result, accurate
ME
D I C I N E
] (2015) ]]]–]]]
prediction of risk is likely to come from models that capture a variety of risk factors demonstrated reliably in populationbased studies. Such risk prediction models are yet to be developed, validated, and applied prospectively. In the era of big data, bioinformatics approaches will most likely be required to comb vast amounts of data needed to produce accurate risk stratification models. Such models would require iterative prospective validation in the population to be useful. The challenge posed by the increasing incidence of PEA/ asystole deserves particular attention. Mechanistic understanding of PEA/asystole is needed to continue to impact SCD. The development of appropriate laboratory models for PEA is critical to enable dissection of the basic cellular mechanisms of PEA. Also important are broad systematic prospective randomized trials of pharmacologic therapies, and the development of rapidly deployable mechanical support in the field to temporarily restore perfusion. In conclusion, while the review article by Mitrani and Myerburg describes recent developments in the field of SCD, it highlights significant knowledge and therapeutic gaps, and the vast opportunities for life-saving interventions in the identification, treatment, and prevention of SCD.
re fe r en ces
[1]
[2] [3]
[4]
[5]
[6]
[7]
[8]
[9]
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 2015;131:e29–322. Mitrani RA, Myerburg RJ. Ten advances defining sudden cardiac death. Trends Cardiovasc Med 2015. Goldberger JJ, Basu A, Boineau R, Buxton AE, Cain ME, Canty JM Jr, et al. Risk stratification for sudden cardiac death: a plan for the future. Circulation 2014;129:516–26. Myerburg RJ, Halperin H, Egan DA, Boineau R, Chugh SS, Gillis AM, et al. Pulseless electric activity: definition, causes, mechanisms, management, and research priorities for the next decade: report from a National Heart, Lung, and Blood Institute workshop. Circulation 2013;128: 2532–41. Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S729–67. Youngquist ST, Kaji AH, Niemann JT. Beta-blocker use and the changing epidemiology of out-of-hospital cardiac arrest rhythms. Resuscitation 2008;76:376–80. Cummins RO, Graves JR, Larsen MP, Hallstrom AP, Hearne TR, Ciliberti J, et al. Out-of-hospital transcutaneous pacing by emergency medical technicians in patients with asystolic cardiac arrest. N Engl J Med 1993;328:1377–82. Hedges JR, Syverud SA, Dalsey WC, Feero S, Easter R, Shultz B. Prehospital trial of emergency transcutaneous cardiac pacing. Circulation 1987;76:1337–43. Mader TJ, Nathanson BH, Millay S, Coute RA, Clapp M, McNally B. Out-of-hospital cardiac arrest outcomes stratified by rhythm analysis. Resuscitation 2012;83:1358–62.
