Asymptomatic Ventricular Arrhythmias in Healthy Persons: Smoke or Smoke Screen? During the past decade, considerable progress has been made in understanding the mechanisms underlying the origin of normal and ectopic beats (1-3). In addition to intrinsic sinus node automaticity, latent automatic foci exist throughout the heart, especially in the atrioventricular node and the ventricular His-Purkinje system, to provide a safety net for back-up intrinsic rhythms should the sinus node fail. These latent pacemakers may accelerate in normal hearts and may appear as ectopic beats and rhythms. The electrical conducting network within the myocardium exhibits complex spatial geometry with a potential for re-entrant conduction (4). In addition, neuroendocrine factors, mediated mostly through the autonomic nervous system, modulate the transmembrane ionic currents and the threshold for excitability. This ionic, cellular, autonomic, conductive, and neuroendocrine substrate in the normal heart provides the electrophysiologic background for understanding heart rhythm order and disorder. Ventricular ectopic beats and rhythms occur in normal hearts, but they are more prevalent in patients with organic heart disease such as coronary or hypertensive heart disease (5). The underlying mechanisms of ventricular arrhythmias may involve enhanced impulse formation (increased automaticity and triggered activity), altered impulse conduction (re-entry), disorders of repolarization (QT prolongation), or combinations of these mechanisms (6-9). Many studies have demonstrated the adverse prognostic implications of complex ventricular rhythms in patients with acute (10), subacute (11), and chronic (12) heart disease, especially among patients with established coronary heart disease. Considerable controversy exists regarding the meaning and prognostic implications of asymptomatic ventricular arrhythmias in apparently healthy persons without symptoms or signs of underlying heart disease (13-15). In brief, are ventricular arrhythmias in such persons simply innocent bystanders without prognostic meaning, or are they markers of a disordered myocardial substrate with important prognostic implications? The Framingham Heart Study has provided fundamental insight into the traditional risk factors (lipid levels, smoking, hypertension) associated with the development of premature coronary heart disease (16). The study reported in this issue of Annals by Bikkina and colleagues (17) from the Framingham group provides valuable new information on the significant and independent association between asymptomatic ventricular arrhythmias and the risk for all-cause mortality or for coronary heart disease events (death due to coronary heart disease or nonfatal myocardial infarction, whichever comes first) in men without clinically evident heart
disease. Using 1-hour ambulatory electrocardiography to record ventricular arrhythmias (frequent or complex ventricular ectopic beats), the mortality and morbidity risks associated with the ectopic beats in men were independent of the traditional coronary risk factors during an average follow-up of 5 years. The magnitude of the risk for subsequent cardiac events in men was slightly greater than twofold in those who had ventricular arrhythmias compared with those who did not have ventricular arrhythmias on the 1-hour recording after adjustment for relevant covariates. Ventricular arrhythmias were not associated with increased risk in women. What is the meaning of this arrhythmic risk in overtly healthy men? The type of analysis done by the Framingham group (Cox proportional hazards model) provides insight into possible mechanisms linking ventricular arrhythmias with adverse outcome. However, the findings are not useful for risk stratification and are not likely to be helpful to clinicians in the therapeutic decision-making process regarding management of the individual patient. One third of healthy men had one or more ventricular premature beats during the 1-hour recording, and almost 12% had frequent or complex ventricular arrhythmias. Ninety-seven percent of men without ventricular arrhythmias and 93% of men with ventricular arrhythmias were alive at 5 years. This significant difference in survival is not explainable by age or any of the usual coronary risk factors. Rather, the findings suggest, at least to me, that the ventricular arrhythmias in men may indicate abnormal myocardial substrate with enhanced automaticity. abnormal re-entrant pathways, delayed repolarization, or a combination of these phenomena. The at-risk persons might have subclinical coronary disease. Increased adrenergic activity with catecholamine excess might contribute to an abnormal myocardial substrate (18) and to enhanced thrombogenesis with an increased probability of thrombotic atherosclerotic coronary events (19). It seems unlikely that the ventricular arrhythmias themselves are responsible for the increased mortality and morbidity events because arrhythmic sudden death accounts for only a minority of the end points. Rather, it is more plausible that an unknown factor (possibly increased adrenergic activity), not recorded and not included in the covariate adjustment, contributes to the initiation of the arrhythmias as well as subclinical atherosclerotic coronary heart disease in men. Additional research along these lines should be quite productive. Why are the arrhythmia findings reported by Bikkina and colleagues (17) for men unlikely to be of use to practicing physicians at this point in time? The
15 December 1992 • Annals of Internal Medicine • Volume 117 • Number 12 1053
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Framingham data indicate that the positive predictive accuracy of ventricular arrhythmias for identifying men with subsequent coronary events is approximately 1%—a percentage that is not encouraging for risk stratification or for selection of patients for therapeutic interventions. It should be noted, however, that the absence of frequent or complex arrhythmias in men during a 1-hour recording is associated with a high likelihood of a benign clinical course—90% specific for not experiencing a major cardiac event, with a 97% negative predictive accuracy. It is inappropriate to conclude that pharmacologic suppression of overt ventricular arrhythmias will achieve similar results because one may be treating the symptom or sign rather than the cause. Further, most available antiarrhythmic agents have potential adverse effects (20) that preclude their use in healthy persons with low event rates. Ventricular arrhythmias in men may be a "smoking gun." The arrhythmia may be a manifestation of myocardial substrate changes produced by an unknown factor that is causally related to accelerated coronary disease. A more appropriate analogy may be "where there's smoke, there's fire." Ventricular arrhythmias in healthy men may indicate a smoldering disease process that will manifest itself in the future. Ventricular arrhythmias in healthy women have no apparent adverse prognostic implications (17), and these arrhythmias may be a "smoke screen" for important risk factors. The Framingham study reported in this issue of Annals provides another example of the clinical differences that exist between the sexes. Arthur J. Moss, MD University of Rochester Medical Center Rochester, NY 14642
3.
4. 5.
6. 7.
8.
9.
10. 11.
12. 13.
14.
15.
16.
17.
18. Request for Reprints: Arthur J. Moss, MD, Heart Research Follow-up Program, Box 653, University of Rochester Medical Center, Rochester, NY 14642.
Annals of Internal Medicine. 1992;117:1053-1054.
19.
20.
References 1. Brown HF. Electrophysiology of the sinoatrial node. Physiol Rev. 1982;62:505-30. 2. Anumonwo JM, Freeman LC, Kwok WM, Kass RS. Potassium chan-
1054
15 D e c e m b e r 1992 • Annals
of Internal
Medicine
nels in the heart: Electrophysiology and pharmacologic regulation. Cardiovascular Drug Rev. 1991;9:299-316. Garan H, Fallon JT, Rosenthal S, Ruskin JN. Endocardial, intramural, and epicardial activation patterns during sustained monomorphic ventricular tachycardia in late canine myocardial infarction. Circ Res. 1987;60:879-96. Roberts DE, Hersh LT, Scher AM. Influence of cardiac fiber orientation on wavefront voltage, conduction velocity and tissue resistivity in the dog. Circ Res. 1979;44:701-12. Moss AJ. Clinical significance of ventricular arrhythmias in patients with and without coronary artery disease. Prog Cardiovas Dis. 1980;23:33-52. Noble D. The surprising heart: a review of recent progress in cardiac electrophysiology. J Physiol. 1984;353:1-50. Wit AL, Rosen MR. After depolarization and triggered activity. In: The Heart and Cardiovascular System. Fozzard HA et al., eds. New York: Raven Press; 1986:1449. Wit AL, Cranfield PF, Hoffman BF. Slow conduction and reentry in the ventricular conducting system. II. Single and sustained circus movement in networks of canine and bovine Purkinje fibers. Circ Res. 1972;30:11-22. Jackson WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. Long QT syndromes: A critical review, new clinical observations and a unified hypothesis. Prog Cardiovasc Dis. 1988;31:115-72. Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation. 1971;48:130-42. Moss AJ, Schnitzler R, Green R, DeCamilla J. Ventricular arrhythmias three weeks after acute myocardial infarction. Ann Intern Med. 1971;75:837-41. The Coronary Drug Project Research Group. Prognostic significance of premature beats following myocardial infarction. JAMA. 1973; 226:1116-24. Chiang BN, Perlman LV, Ostrander LD, Epstein RH. Relationship of premature systoles to coronary heart disease and sudden death in the Tecumseh epidemiologic study. Ann Intern Med. 1969;79:115966. Crow R, Prineas R, Blackburn H. The prognostic significance of ventricular ectopic beats among the apparently healthy. Amer Heart J. 1981;101:244-8. Rodstein M, Wolloch L, Gubner RS. Mortality study of the significance of extrasystoles in an insured population. Circulation. 1971; 44:617-24. Dawber TR, Kannel WB, Revotskie N, Kagan A. The epidemiology of coronary heart disease. The Framingham enquiry. Proc Roy Soc Med. 1962;551:265-71. Bikkina M, Larson MG, Levy D. Prognostic implications of asymptomatic ventricular arrhythmias: The Framingham Heart Study. Ann Intern Med. 1992;117:990-6. Schenk EA, Moss AJ. Cardiovascular effects of sustained norepinephrine infusions. II. Morphology. Circ Res. 1966;18:605-15. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:1514-8. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781-8.
© 1992 American College of Physicians
• Volume 117 • Number 12
Downloaded From: https://annals.org/ by a University of Kentucky User on 08/23/2018
disease. Using 1-hour ambulatory electrocardiography to record ventricular arrhythmias (frequent or complex ventricular ectopic beats), the mortality and morbidity risks associated with the ectopic beats in men were independent of the traditional coronary risk factors during an average follow-up of 5 years. The magnitude of the risk for subsequent cardiac events in men was slightly greater than twofold in those who had ventricular arrhythmias compared with those who did not have ventricular arrhythmias on the 1-hour recording after adjustment for relevant covariates. Ventricular arrhythmias were not associated with increased risk in women. What is the meaning of this arrhythmic risk in overtly healthy men? The type of analysis done by the Framingham group (Cox proportional hazards model) provides insight into possible mechanisms linking ventricular arrhythmias with adverse outcome. However, the findings are not useful for risk stratification and are not likely to be helpful to clinicians in the therapeutic decision-making process regarding management of the individual patient. One third of healthy men had one or more ventricular premature beats during the 1-hour recording, and almost 12% had frequent or complex ventricular arrhythmias. Ninety-seven percent of men without ventricular arrhythmias and 93% of men with ventricular arrhythmias were alive at 5 years. This significant difference in survival is not explainable by age or any of the usual coronary risk factors. Rather, the findings suggest, at least to me, that the ventricular arrhythmias in men may indicate abnormal myocardial substrate with enhanced automaticity. abnormal re-entrant pathways, delayed repolarization, or a combination of these phenomena. The at-risk persons might have subclinical coronary disease. Increased adrenergic activity with catecholamine excess might contribute to an abnormal myocardial substrate (18) and to enhanced thrombogenesis with an increased probability of thrombotic atherosclerotic coronary events (19). It seems unlikely that the ventricular arrhythmias themselves are responsible for the increased mortality and morbidity events because arrhythmic sudden death accounts for only a minority of the end points. Rather, it is more plausible that an unknown factor (possibly increased adrenergic activity), not recorded and not included in the covariate adjustment, contributes to the initiation of the arrhythmias as well as subclinical atherosclerotic coronary heart disease in men. Additional research along these lines should be quite productive. Why are the arrhythmia findings reported by Bikkina and colleagues (17) for men unlikely to be of use to practicing physicians at this point in time? The
15 December 1992 • Annals of Internal Medicine • Volume 117 • Number 12 1053
Downloaded From: https://annals.org/ by a University of Kentucky User on 08/23/2018
Framingham data indicate that the positive predictive accuracy of ventricular arrhythmias for identifying men with subsequent coronary events is approximately 1%—a percentage that is not encouraging for risk stratification or for selection of patients for therapeutic interventions. It should be noted, however, that the absence of frequent or complex arrhythmias in men during a 1-hour recording is associated with a high likelihood of a benign clinical course—90% specific for not experiencing a major cardiac event, with a 97% negative predictive accuracy. It is inappropriate to conclude that pharmacologic suppression of overt ventricular arrhythmias will achieve similar results because one may be treating the symptom or sign rather than the cause. Further, most available antiarrhythmic agents have potential adverse effects (20) that preclude their use in healthy persons with low event rates. Ventricular arrhythmias in men may be a "smoking gun." The arrhythmia may be a manifestation of myocardial substrate changes produced by an unknown factor that is causally related to accelerated coronary disease. A more appropriate analogy may be "where there's smoke, there's fire." Ventricular arrhythmias in healthy men may indicate a smoldering disease process that will manifest itself in the future. Ventricular arrhythmias in healthy women have no apparent adverse prognostic implications (17), and these arrhythmias may be a "smoke screen" for important risk factors. The Framingham study reported in this issue of Annals provides another example of the clinical differences that exist between the sexes. Arthur J. Moss, MD University of Rochester Medical Center Rochester, NY 14642
3.
4. 5.
6. 7.
8.
9.
10. 11.
12. 13.
14.
15.
16.
17.
18. Request for Reprints: Arthur J. Moss, MD, Heart Research Follow-up Program, Box 653, University of Rochester Medical Center, Rochester, NY 14642.
Annals of Internal Medicine. 1992;117:1053-1054.
19.
20.
References 1. Brown HF. Electrophysiology of the sinoatrial node. Physiol Rev. 1982;62:505-30. 2. Anumonwo JM, Freeman LC, Kwok WM, Kass RS. Potassium chan-
1054
15 D e c e m b e r 1992 • Annals
of Internal
Medicine
nels in the heart: Electrophysiology and pharmacologic regulation. Cardiovascular Drug Rev. 1991;9:299-316. Garan H, Fallon JT, Rosenthal S, Ruskin JN. Endocardial, intramural, and epicardial activation patterns during sustained monomorphic ventricular tachycardia in late canine myocardial infarction. Circ Res. 1987;60:879-96. Roberts DE, Hersh LT, Scher AM. Influence of cardiac fiber orientation on wavefront voltage, conduction velocity and tissue resistivity in the dog. Circ Res. 1979;44:701-12. Moss AJ. Clinical significance of ventricular arrhythmias in patients with and without coronary artery disease. Prog Cardiovas Dis. 1980;23:33-52. Noble D. The surprising heart: a review of recent progress in cardiac electrophysiology. J Physiol. 1984;353:1-50. Wit AL, Rosen MR. After depolarization and triggered activity. In: The Heart and Cardiovascular System. Fozzard HA et al., eds. New York: Raven Press; 1986:1449. Wit AL, Cranfield PF, Hoffman BF. Slow conduction and reentry in the ventricular conducting system. II. Single and sustained circus movement in networks of canine and bovine Purkinje fibers. Circ Res. 1972;30:11-22. Jackson WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. Long QT syndromes: A critical review, new clinical observations and a unified hypothesis. Prog Cardiovasc Dis. 1988;31:115-72. Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation. 1971;48:130-42. Moss AJ, Schnitzler R, Green R, DeCamilla J. Ventricular arrhythmias three weeks after acute myocardial infarction. Ann Intern Med. 1971;75:837-41. The Coronary Drug Project Research Group. Prognostic significance of premature beats following myocardial infarction. JAMA. 1973; 226:1116-24. Chiang BN, Perlman LV, Ostrander LD, Epstein RH. Relationship of premature systoles to coronary heart disease and sudden death in the Tecumseh epidemiologic study. Ann Intern Med. 1969;79:115966. Crow R, Prineas R, Blackburn H. The prognostic significance of ventricular ectopic beats among the apparently healthy. Amer Heart J. 1981;101:244-8. Rodstein M, Wolloch L, Gubner RS. Mortality study of the significance of extrasystoles in an insured population. Circulation. 1971; 44:617-24. Dawber TR, Kannel WB, Revotskie N, Kagan A. The epidemiology of coronary heart disease. The Framingham enquiry. Proc Roy Soc Med. 1962;551:265-71. Bikkina M, Larson MG, Levy D. Prognostic implications of asymptomatic ventricular arrhythmias: The Framingham Heart Study. Ann Intern Med. 1992;117:990-6. Schenk EA, Moss AJ. Cardiovascular effects of sustained norepinephrine infusions. II. Morphology. Circ Res. 1966;18:605-15. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:1514-8. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781-8.
© 1992 American College of Physicians
• Volume 117 • Number 12
Downloaded From: https://annals.org/ by a University of Kentucky User on 08/23/2018
