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Atherosclerosis has many manifestations. Among the most tragic is sudden cardiac death (SCD): patients succumb to fatal arrhythmias. While SCD is all-too-often the first manifestation of heart disease [1], the presence of known coronary atherosclerosis markedly increases the likelihood of sudden death [2]. Risk is sufficiently high in one subgroup, namely patients with prior myocardial infarction and left ventricular dysfunction, that prophylactic placement of implantable cardioverter-defibrillators (ICDs) produced a significant mortality benefit in the MADIT II study [3]. As a result of this and other trials, 3-4 million Americans may now be considered candidates for prophylactic ICDs. Nevertheless, widespread deployment of ICDs in large populations of patients at risk is economically impractical [4], and ignores the fact that most patients with prophylactic devices are likely never to require them [5]. The challenge is to be able to predict reliably which patients with atherosclerosis, indeed which members of the general population, are at particularly high risk for SCD. Those individuals could then receive either ICDs and/or aggressive preventative therapy tailored to the specific identified risk factor(s). From the perspectives of economics and medical ethics, identification of patients at very low risk is equally important [6]: such patients need not be exposed to the potential complications and expense of unnecessary therapy. If brought to bear on the problem in a concerted manner, potent new biological tools, phenotyping methods and population science resources will enable us to re-invent the way we identify and treat patients at risk for SCD. The Johns Hopkins Reynolds Center concept represents an ideal mechanism to implement such a concerted, biologically-based approach. The program focuses on the theme of sudden cardiac death associated with atherosclerosis. We believe that SCD is ripe for a “biological revolution”: if we can understand why specific patients have arrhythmias, we can target those patients for intensive therapy while sparing others. Moreover, treatment will become increasingly customized, based upon knowledge of the specific abnormalities underlying the arrhythmic risk in a given individual. Implicit to our approach is the premise that SCD is not a chance event but rather one with a strong deterministic basis. This premise is supported by various lines of evidence. First, sudden death “survivors”, most of whom have significant atherosclerosis, are recognized to be at especially high risk for recurrent arrhythmias [6]; something about their biological makeup is intrinsically irritable (electrically speaking) and different from that of the general coronary artery disease population. Secondly, genetic factors clearly play a role in SCD [7]. Notably, the Paris Prospective Study and an independent case-control study from Seattle have identified a family history of SCD as a powerful risk factor for SCD, independent of traditional risk factors and/or family history of myocardial infarction. In the Paris cohort, a history of SCD in one parent increased risk by 80%; a history of SCD in both parents led to a remarkable 880% increase in risk for the offspring. A number of genes have been linked to rare, heritable arrhythmias not associated with coronary disease. However, the basis of the genetic factors underlying atherosclerosis-associated SCD in the general population is unknown; their ascertainment is a major goal of our program. Third, ample evidence from animal models indicates that arrhythmias are initiated by discrete triggers and perpetuated by functional or structural abnormalities in the myocardium [7]. Taken together, the basic biology and the epidemiological studies teach us that arrhythmias are deterministic, not random, events. These considerations lend credence to the notion that SCD has a definite, but as-yet-unclear, biological basis. - SCD is woefully understudied. Until now, we and others have been nibbling at the edges of the problem rather than engaging the central questions of greatest importance. Why? Perhaps because of a lack of concerted funding, but also because the problem has simply appeared too daunting. The research program of the Johns Hopkins Reynolds Center does not pursue “more of the same” but rather seeks to engage head-on the challenge of SCD, in a comprehensive, multidisciplinary manner that we feel is most likely to break the current impasse.
- We now have powerful biological, genetic and epidemiological tools that will enable us to crack open SCD as never before. Such resources were rudimentary or nonexistent 10-20 years ago, when the emphasis in SCD began to shift from pharmacology towards the present almost-exclusive reliance on devices. Drug therapy, for all its limitations, has the laudable goal of preventing arrhythmias based on a biological understanding of how they arise; the practice of prophylactic ICDs accepts arrhythmias as a given, and focuses on terminating them rather than preventing their occurrence. Both philosophies are defensible, but we believe that the pendulum has swung too far towards devices, stifling new opportunities for biologically-based therapy (beyond traditional pharmacotherapy).
- The problem is one of enormous economic and public health importance. Unless we can effectively risk-stratify patients and populations, near-universal device placement will undermine the already-fragile health care economy in the United States [3,8].
- The theme of SCD is one which, arguably, can be more effectively addressed at Hopkins than anywhere else in the world. We have one of only three Specialized Centers of Research in Sudden Cardiac Death currently funded by the NIH; broadly-based translational research programs in arrhythmias and atherosclerosis; and an enviable track record in producing independent translational and clinical researchers. The McKusick-Nathans Institute of Genetic Medicine at Hopkins is dedicated to elucidating the genetic basis of common diseases and complex traits such as SCD. Collectively, the Hopkins leadership group represents a highly-interactive, diverse leadership team. Our focus is to make major scientific discoveries of public health impact, and to train a new generation of clinical investigators in the process.
The central aims of the Johns Hopkins Reynolds Center are to develop new means to identify individuals at high risk for SCD, and to devise novel therapies to prevent SCD in those individuals. For more information on specific projects click here. References - Schmermund A, Schwartz RS, Adamzik M, Sangiorgi G, Pfeifer EA, Rumberger JA, Burke AP, Farb A, Virmani R. Coronary atherosclerosis in unheralded sudden coronary death under age 50: histo-pathologic comparison with 'healthy' subjects dying out of hospital. Atherosclerosis 2001 Apr;155(2):499-508.
- Kannel WB, McGee DL, Schatzkin A.An epidemiological perspective of sudden death. 26-year follow-up in the Framingham Study. Drugs 1984 Oct;28 Suppl 1:1-16.
- Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML; The Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002 Mar 21;346(12):877-83.
- Weiss JP, Saynina O, McDonald KM, McClellan MB, Hlatky MA. Effectiveness and cost-effectiveness of implantable cardioverter defibrillators in the treatment of ventricular arrhythmias among medicare beneficiaries. Am J Med 2002 May;112(7):519-27.
- Pacifico A, Ferlic LL, Cedillo-Salazar FR, Nasir N Jr, Doyle TK, Henry PD. Shocks as predictors of survival in patients with implantable cardioverter-defibrillators. J Am Coll Cardiol 1999 Jul;34(1):204-10.
- Hallstrom AP, McAnulty JH, Wilkoff BL, et al.; Antiarrhythmics Versus Implantable Defibrillator (AVID) Trial Investigators. Patients at lower risk of arrhythmia recurrence: a subgroup in whom implantable defibrillators may not offer benefit. Antiarrhythmics Versus Implantable Defibrillator (AVID) Trial Investigators. J Am Coll Cardiol 2001 Mar 15;37(4):1093-9.
- Spooner PM, Albert C, Benjamin EJ, Boineau R, Elston RC, George AL Jr, Jouven X, Kuller LH, MacCluer JW, Marban E, Muller JE, Schwartz PJ, Siscovick DS, Tracy RP, Zareba W, Zipes DP.Sudden cardiac death, genes, and arrhythmogenesis : consideration of new population and mechanistic approaches from a national heart, lung, and blood institute workshop, part I. Circulation 2001 May 15;103(19):2361-4.
- Bigger JT. Expanding indications for implantable cardiac defibrillators. N Engl J Med 2002 Mar 21;346(12):931-3.
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