Sudden Cardiac Death May Not Be Caused By Ischemia
April 17, 2008
Sudden cardiac death (SCD) occurring in apparently healthy, asymptomatic persons, without known heart disease, continues to be a major, unsolved health problem. The actual cause of death in these patients is the sudden onset of a lethal arrhythmia, commonly ventricular fibrillation (VF) or cardiac arrest [1]. These lethal arrhythmias develop as a result of sudden injury, disruption, or arrest of the normally stable and injury-resistant conduction system (CS) [2]. Identifying the injurious agent and the basic underlying mechanism responsible for these arrhythmias is the issue if we are to prevent SCD.
Most investigators believe the fundamental cause is ischemia or ischemic injury to the CS because underlying coronary atherosclerosis is consistently present [3,4]. However, the presence of coronary atherosclerosis per se, even diffuse atherosclerosis with significant luminal stenosis, does not prove ischemia is present nor that ischemia is the cause. No chemical agents specific for ischemia or ischemic injury have been identified, and therefore, the diagnosis of ischemia is presumptive, not proven, in these SCD patients.
Reasons to Question Ischemia in SCD
First, death occurs so rapidly in these patients they often die without symptoms of chest pain or other complaints [3]. Ischemia takes time to develop even in the face of sudden and complete obstruction of blood flow in one of the major coronary arteries [5,6]. If sudden obstruction to blood flow were the cause we could expect a lethal arrhythmia to develop every time a balloon was inflated during percutaneous coronary intervention (PCI) [7]. Second, Holter monitor recordings infrequently show ischemic ST changes in the moments before the sudden collapse, certainly not massive ischemia, if that were the cause [8,9]. Holter recordings do, however, often show an increase in heart rate plus the development of complex ventricular ectopy immediately prior to the onset of the lethal arrhythmia, suggesting stimulation of the conduction system by a circulating chemical agent [8,9]. Third, SCD patients who are successfully resuscitated do not show nor necessarily proceed on to develop acute myocardial infarction (AMI), providing further evidence the lethal arrhythmia was neither a manifestation nor a precursor to an acute infarction [10].
Fourth, coronary angiograms in the majority of SCD survivors do not show a complete acute occlusion, but rather complex ulcerated plaques, with or without filling defects to suggest a thrombus [11]. These same findings are present on post-mortem angiograms of SCD patients who did not survive, providing more evidence that acute thrombotic occlusion producing severe ischemia of the CS was not the cause of the lethal arrhythmia [12]. It should be pointed out in passing that partial occlusion of a coronary artery by a complex plaque and/or mural thrombus also does not prove that ischemia is present. Such findings establish the presence of an acute lesion, but not ischemia. As long as antegrade blood flow is present one cannot state with certainty that the lesion is causing ischemia, regardless of ST changes on the electrocardiogram and/or angina-like chest pains.
Fifth, successful resuscitation of the SCD patient with rhythm stabilization indicates the triggering agent disappears quickly; otherwise the acute arrhythmia would immediately recur. This observation is evidence against a fixed coronary obstruction causing ischemia. Sixth, the CS has a rich blood supply, is relatively resistant to ischemia, and it is rare to find infarction of the CS even with large myocardial infarctions [2]. Seventh, acute interventions, such as immediate PCI, with or without stent placement, designed to relieve presumed ischemia in the SCD survivor, have been remarkably unsuccessful [11]. Based on the above evidence, we must look beyond ischemia and search for other injurious agents or mechanisms responsible for causing the lethal arrhythmias that lead to SCD [13].
The Toxic Atheroma
The contents of an atheroma are acidic [14] and the core contains many potent toxins and inflammatory compounds as a natural consequence of lipid oxidation, denaturation of proteins, cell necrosis, and a variety of intracellular reactions associated with oxidative stress [13,15-17]. Foremost among these toxins are reactive oxygen species (ROS), resulting from the production of extracellular superoxide anion by macrophages and other intimal cells, through the action of the NADPH oxidase enzyme complex [15,17,18]. Since macrophages are an important component of all atheromas, we can assume atheromas contain significant amounts of ROS. ROS have also been identified in coronary atherectomy specimens [19].
ROS are known to be extremely potent and toxic compounds [15], but at present techniques are not available to measure or assay the oxidative stress, i.e. toxicity, caused by these compounds. However, it is not unreasonable to believe the toxicity of ROS may be equivalent to absolute alcohol used to produce an AMI in patients with hypertrophic cardiomyopathy [20]. These patients often experience angina pectoris at the time of the alcohol infusion and may develop various forms of heart block and other arrhythmias [20]. The sudden discharge of ROS and other potent plaque toxins directly into the coronary circulation, at the time of plaque rupture, could be expected to stimulate cardiac nerves producing angina pectoris, injure the myocardium causing ischemic-like ST changes, and importantly, cause direct and immediate injury to the CS [13]. These clinical signs of toxic injury are indistinguishable from those of ischemic injury. Sudden severe direct injury to the CS by circulating plaque toxins could explain the sudden disruption of cardiac conduction and the precipitation of ventricular fibrillation and/or sudden cardiac arrest in the absence of ischemia in the SCD patient.
In other words, plaque toxins may have the ability, in and of themselves, to produce immediate injury to the CS before thrombosis and ischemia has time to develop [6]. This could explain the sudden collapse, the absence of occlusive thrombosis and AMI in the SCD patient [3]. The actual effect of these plaque toxins would depend upon the amount or dose discharged, the speed of discharge, their potency, the area of the heart affected, and the speed of washout by antegrade, collateral or anastomotic blood flow. Since all plaque ruptures are different we can assume the amount of toxins discharged from each plaque will vary, producing different symptoms and different acute coronary syndromes [13]. For example, a small ulceration at the shoulder of the plaque leaking small amounts of plaque toxins intermittently may produce no symptoms, whereas a large plaque in an artery supplying the CS, which “shells out,” may produce a catastrophe like SCD [13].
What Evidence Supports This View?
A number of studies show the majority of SCD patients have multiple ruptured plaques, without associated thrombosis, located throughout the coronary tree [12,13,21]. Therefore the SCD patient has several plaque ruptures that could serve as sources of plaque toxins. Further evidence suggests plaque rupture is a sudden, spontaneous event, occurring, without warning, at any time of the day or night [13] discharging potent toxins without prior symptoms. Pathologic studies may show contraction bands or myocytolysis in the purkinje fibers downstream of these plaque ruptures in the SCD patient, providing objective evidence of acute CS injury [2,13,22]. Baroldi showed different types of myocardial necrosis in patients with acute coronary disease suggesting there is more than one pathogenetic mechanism of injury responsible for producing acute coronary disease [22].
We postulate the sudden release of plaque toxins, primarily ROS, at the time of spontaneous plaque rupture, is the triggering agent and the fundamental cause of the lethal arrhythmia responsible for SCD in the otherwise asymptomatic patient with latent atherosclerosis.
Clinical Implications
If this view of the pathogenesis of SCD is correct it means we must begin to approach the management of the SCD survivor differently. We must begin to think in terms of two different mechanisms, toxic injury and ischemic injury, and devise the means to deal with each. Specifically we must be prepared to administer antioxidant drugs such as superoxide desmustase that have the ability to neutralize ROS and other plaque toxins [23]. Success in preventing and/or managing SCD, our most common cardiac problem, will lead to improved methods of managing all acute coronary syndromes.
References
1. Kim C, Fahrenbruch CE, Cobb LA, Eisenberg MS. Out-of-hospital cardiac arrest in men and women. Circulation 2001;104:2699-2703.
2. Rossi L. Pathologic changes in the cardiac conduction and nervous system in sudden coronary death. Ann NY Acad Sci 1982;382:50-68.
3. Friedman M, Manwaring JH, Rosenman RH, Donlon G, Ortega P, Grube SM. Instantaneous and sudden deaths: clinical and pathological differentiation in coronary artery disease. JAMA 1973;225:1319-28.
4. Warners C, Robert S. Sudden coronary death: relation of amount and distribution of coronary narrowing at necropsy to previous symptoms of myocardial ischemia, left ventricular scarring, and heart weight. Am J Cardiol 1984;54:65-73.
5. Meissner MD, Akhtar M, Lehmann MH. Nonischemic sudden tachyarrhythmic death in atherosclerotic heart disease. Circulation 1991;84:905-12.
6. Ojio S, Takatsu H, Tanaka T, et al. Considerable time from the onset of plaque rupture and/or thrombi until the onset of acute myocardial infarction in humans: coronary angiographic findings within 1 week before onset of infarction. Circulation. 2000;102:2063-69.
7. Zipes DP, Wellens HJJ. Sudden cardiac death. Circulation 1998;98:2334-51.
8. Kempf FC Jr, Josephson ME. Cardiac arrest recorded on ambulatory electrocardiograms. Am J Cardiol 1984;53:1577-82.
9. Olshausen KV, Witt T, Pop T, Treese N, Bethge K-P, Meyer J. Sudden cardiac death while wearing a holter monitor. Am J Cardiol 1991;67:381-86.
10. Hurwitz JL, Josephson ME. Sudden cardiac death in patients with chronic coronary heart disease. Circulation 1992;85[suppl I]:I43-I49.
11. Spaulding CM, Joly L-M, Rosenberg A, et al. Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med 1997;336:1629-33.
12. Frink RJ. Chronic ulcerated plaques: new insights into the pathogenesis of acute coronary disease. J Invas Cardiol 1994;6:173-85.
13. Frink RJ. Inflammatory atherosclerosis: characteristics of the injurious agent. First edition. The Heart Research Foundation of Sacramento: Sacramento, California, 2002.
14. Naghavi M, John R, Naguib S, et al. pH Heterogeneity of human and rabbit atherosclerotic plaques; a new insight into detection of vulnerable plaque. Atherosclerosis 2002;164:27-35.
15. Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: part I: basic mechanisms and in vivo monitoring of ROS. Circulation 2003;108:1912-16.
16. Chisolm GM, Ma G, Irwin KC, et al. 7B-Hydroperoxycholest-5-en-3B-ol, a component of human atherosclerotic lesions, is the primary cytotoxin of oxidized human low density lipoprotein. Proc Natl Acad Sci U S A 1994;91:11452-56.
17. Roberts MJD, Young IS, Trouton TG, et al. Transient release of lipid peroxides after coronary artery balloon angioplasty. Lancet 1990;336:143-45.
18. Cathcart MK. Regulation of superoxide anion production by NADPH oxidase in monocytes/macrophages: contributions to atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:23-28.
19. Azumi H, Inoue N, Ohashi Y, et al. Superoxide generation in directional coronary atherectomy specimens of patients with angina pectoris: important role of NAD(P)H oxidase. Arterioscler Thromb Vasc Biol 2002;22:1838-44.
20. Lakkis NM, Nagueh SF, Kleiman NS, et al. Echocardiography-guided ethanol septal reduction for hypertrophic obstructive cardiomyopathy. Circulation 1998;98:1750-55.
21. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O’Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000;343:915-22.
22. Baroldi G. Different types of myocardial necrosis in coronary heart disease: a pathophysiologic review of their functional significance. Am Heart J 1975;89:742-52.
23. Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: part II: animal and human studies. Circulation 2003;108:2034-40.
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