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Effects of non-right-handedness on risk for sudden death associated with coronary artery disease
Effects of Non-Right-Handedness Risk for Sudden Death Associated Coronary Artery Disease
on with
Richard D. Lane, MD, Anthony C. Caruso, MD, Victoria L. Brown, BS, Beatrice Axelrod, MS, Gary E. Schwartz, PhD, Lee Sechrest, PhD, and Frank I. Marcus, MD The hypothesis that non-right-handedness is associated with sudden cardiac death was tested based on evidence that sympathetic imbalance may contribute to ventricular arrhythmogenesis and evidence that left-banders may have a shorter lifespan than right-banders. The study included 26 patients with coronary artery disease (CAD), a history of ventricular tachycar disventricular fibrillation (VT-VP), and implanted defibrillators, and 26 patients with CAD and no history of serious arrhythmias who were matched for age, sex, and New York Heart Association functional class. Patients with any history of neurologic disorders were excluded. Left-banders either wrote with the left hand or were converted from left- to right-handedness in childhood. Nonright-banders used the left hand for writing, drawing, or throwing. Handedness rates in patients with V7-VF and casecontrol subjects were compared with published norms in the general population to take expected rates into account. The rates of l&-handedness (6 of 26 or 23.1%) and non-right-handedness (9 of 26 or 34.6%) in patients with W-VF were significantly higher (p
these findings are confirmed in a prospective study, non-right-handedness should be considered a risk factor for sudden death in the context of CAD. (Am J Cardiol1994;74:74S747)
vidence from a variety of sources suggests that the central nervous system can play a significant role in ventricular arrhythmogenesis and sudden death-3 Changes in autonomic input to the heart likely mediate these brain influences. Yet, relatively little is known about how activity in different brain regions contributes to ventricular fibrillation (VF). Drawing on numerous published reports demonstrating the role of right-left sympathetic imbalance in ventricular arrhythmogenesis,4,5 Lane and Schwartz6 hypothesized that asymmetric arousal of the cerebral hemispheres could induce such an imbalance. Given evidence that left-handers may not live as long as right-handerr,? and that non-right-handers are more similar to left-handers than right-handers in patterns of cerebral lateralization,s we hypothesized that higher rates of left-handedness and non-right-handedness would be observed in victims of sudden death than in control subjects.
E
METHODS Patients:
A case-control design was used because of the relative rarity of sudden death in prospective studies. Patients with coronary artery disease (CAD) between the ages of 18 and 80 years, who were resuscitated victims of sudden death or sustained ventricular tachycardia-ventricular fibrillation (VT-VF) and had automatic implantable cardioverter-defibrillators, were compared with CAD patients with no history of serious arrhythmias. Patients were told that the purpose of the study was to examine the role of hemispheric arousal asymmetry in serious heart rhythm disturbances; handedness was not mentioned as a focus of the study, thus minimizing interest in handedness as a reason for participating. Exclusion criteria for both groups included: (1) primary valvular disease; (2) cardiomyopathy: (3) any history of neurologic disorder (e.g., stroke, seizure disorNON-RIGHT-HANDEDNESS AND SUDDEN DEATH 743
der, intracranial tumor, intracranial arteriovenous fistula, and so forth); (4) asystole lasting 210 minutes; and (5) mental retardation, dementia, or significant cognitive impairment. The diagnosis of CAD was established through chart documentation of previous myocardial infarction or the results of catheterization, stress testing, or radionuclide imaging. Absence of exclusion criteria was verified before testing through patient interview. All eligible patients with implanted cardioverter-defibrillators followed at the University Medical Center or by cardiac electrophysiologists at 3 other major medical centers in Tucson (St. Mary’s Medical Center, Tucson Medical Center, and the Veterans Affairs Medical Center) were invited to participate. Case-control patients with CAD were then identified by local cardiologists, and these patients were matched for age, sex, and New York Heart Association functional class. Matching by age was done by category: (1) ~45 years, (2) 45 to 65 years, and (3) 66 to 80 years. A chart review was completed by a research technician before each case-control patient was invited to participate. Handedness data were never available on any patient before entry into the study. Handedness Znventory9: The lo-item Edinburgh Handedness Inventory was used to assess hand preference. The subject is asked to report, for each of the following 10 activities, whether the right or left hand is preferred and whether the nonpreferred hand would ever be used if not under duress: writing, drawing, throwing, scissors, toothbrush, knife (without fork), spoon, broom (upper hand), striking match (match), and opening box (lid). In previous research on handedness and longevity, right-handedness has been defined by exclusive use of the right hand for writing, drawing, and throwing.7 People who use the left hand for any 1 of the latter 3 activities are classified as non-right-handed (i.e., not a pure right-hander). Left-handedness is defined by use of the left hand for writing, or conversion from left- to righthanded writing. Conversion was assessed by the following question from the handedness questionnaire: “Were you left-handed as a child, but taught to use your right hand instead?” All leftihanders in this study are classified as both left- and non-right-handed. Mini-Mental State Examinatiod”: This standard bedside test of cognitive function was used to detect cognitive impairment. This test assesses,orientation, registration of information, attention, calculation, short-term memory, language, and constructional abilities. It takes about 4 minutes to complete. The maximal possible score is 30. Patients were excluded if scores based on age and education level norms were below the lower quartile. Beck Depression Invento#: This self-report measure involves rating of each of 23 depressive symptoms on a 4-point ordinal scale. This measure has been used in previous research in patients at risk for sudden cardiac death. Levy Chimeric Faces Te&” Chimeric faces are composite faces created from half-faces, which are constructed and rated to demonstrate which hemisphere dominates in a particular judgment. The hemisphere that predominates in the rating in question is believed to be
the more activated hemisphere, as reflected by electroencephalographic measurements. If the half-face in the left visual field predominates in the judgment, it reflects dominance of the right hemisphere. The Levy Chimeric Faces Test consists of 36 pairs of chimeric face photographs presented in a booklet format. Photographs were made of each of 9 male posers with a smiling and with a neutral expression; the 2 photographs from each poser were cut in half down the midsagittal axis and recombined to make 2 different chimeras: in 1, the smile was produced by the left half of the person’s face and the neutral expression by the right half; in the other, this was reversed. Each of the 2 chimeras was paired with its mirror image, once with the normal print at the top of the page and the mirror print at the bottom, and once with the positions reversed. This yielded 4 pairs of chimeras from each poser. For any given pair, the smiling half-face in both members of the pair had been produced by 1 side of the poser’s face and the neutral expression by the other, but 1 member of the pair was a normal print and the other was its mirror image. Subjects looked at each of the 36 pairs for 4 seconds and were then given 5 seconds to indicate which chimera in the pair looked happier. Subjects were encouraged not to think too hard about their answers. The time limits were imposed in part to limit the ability to ponder responses. Subjects were allowed to give a “can’t decide” response if they felt a discrimination was impossible. The test yields a laterality score consisting of the number of left visual field (right hemisphere) choices divided by 36. CARDIOVASCULARMEASURES: New YorkHeartAssociation functional class13: To determine a patient’s New York Heart Association functional class, a research assistant asked patients which category currently fit them best: class I-patients with heart disease who have no symptoms of any kind (ordinary physical activity does not cause fatigue, palpitation, dyspnea, or angina1 pain); class II-patients who are comfortable at rest but have symptoms with ordinary physical activity; class IIIpatients who are comfortable at rest but have symptoms with less than ordinary effort; class IV-patients who have symptoms at rest. The values obtained were checked for accuracy by attending physicians. Left ventricular ejectionfraction: Chart reviews were conducted to determine ejection fraction as close to entry into the study as possible. Ejection fraction measurements by radionuclide imaging were considered most reliable, followed by cardiac catheterization and echocardiography, respectively. Only measurements from the most reliable method were included. The ejection fraction values from the chart were checked for accuracy by attending physicians. Ejection fraction was classified in 1 of 4 categories: 1 = ~20; 2 = 20 to 29; 3 = 30 to 39; and 4 = 240. Statistical analysis of handedness data: A statistical analysis was performed to see if there was a difference in the rate of left-handedness and non-righthandedness in the general population compared with CAD patients with VT-VF and with case-control patients. This was done using the normal approximation to the binomial distribution. The p value obtained is the
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Measures:
BRAIN-RELATED
MEASURES:
Edinburgh
THE AMERICAN JOURNAL OF CARDIOLOGY@ VOLUME 74
probability that a sample of 26 persons drawn from the general population would yield handedness rates equal to those observed in our sample of patients with VT-VF or the sample of case-control patients. The chi-square statistic was not used in this context. This is because of the limited number of sudden death patients available. The &i-square determines the probability that the total number of observed cases of lefthandedness or non-right-handedness would be divided between the 2 groups in a given way by chance. The chisquare statistic does not take into account expected rates of left-handedness and non-right-handedness in the population. In the absence of expected rates, the standard for meaningfulness in a clinical study of this type is a clinically important difference, which in our view consists of a twofold difference in left-handedness or non-right-handedness in the VT-VF group compared with control subjects. If the rates of left-handedness and non-right-handedness in patients with VT-VF were really twofold greater than that of control patients, the probability of obtaining a statistically significant difference with n = 26 in each group is only 3% (for the analysis of left-handedness) and 7% (for the analysis of non-right-handedness), respectively. To have an 80% chance of obtaining a statistically significant difference, assuming a twofold difference in handedness rates between the VT-VF and control groups, 474 (for the analysis of left-handedness) or 214 (for the analysis of non-right-handedness) patients would be needed in each group. This would require a multicenter study to obtain this number of patients. RESULTS The age, sex, New York Heart Association functional class, ejection fraction, number of myocardial infarctions, and handedness status of each patient are listed in Table I. Twenty-three men and 3 women formed each group. Mean ages of the patients with VT-VF and case controls were 63.4 (SD = 8.0) and 64.3 (SD = 9.7) years, respectively (p = NS), and Mini-Mental State Examination scores were 29.2 (SD = 0.97) and 29.6 (SD = 0.76), respectively (p = NS). The distribution of patients across the New York Heart Association functional classes was identical in the 2 groups. The rates of left-handedness (6 of 26 or 23.1%) and non-right-handedness (9 of 26 or 34.6%) in patients with VT-VF were significantly higher (left-handed: ZC = 2.99, p ~0.003, 2-tailed; non-right-handed: Z, = 3.79, p
TABLE Patients Age W & Sex 48 51 61 66 67 73 63 74 78 54 55 56 56 57 57 58 59 62 62 66 70 70 70 71 71 73
M M M M M M M F M M M M F M M M M M M M M M M F M M
I Patient
Characteristics
with Ventricular
Tachycardia-Ventricular
Fibrillation
NYHA Class
Number of Previous MIS
Ejection Fraction
I I I Ill I II I I I I I II II I II I Ill II I I II I I II I I
1 0 >I 1 1 0 2 0 >l 2 1 >I 1 1 1 >I 1 1 1 0 >I 2 1 0 2 3
>40 >40 240 20-29 20-29 20-29 >40 240 240 30-39 20-29 <20 >40 <20 20-29 >40 <20 30-39 >40 >40 20-29 20-29 30-39 >40 20-29 20-29
LH LH LH LH LH LH NRH NRH NRH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH
>40 30-39 >40 >40 >40 >40 >40 >40 >40 >40 >40 >40 >40 >40 <20 20-29 >40 >40 >40 >40 >40 240 >40 >40 240 140
LH LH NRH NRH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH
Handedness
Case-Controls 69 79 57 59 45 51 52 54 55 56 58 59 59 61 62 62 67 70 72 72 73 73 75 75 76 81
M M M M M M M M M F M M M M M M M M M M M M M F F M
II II I I I I I II I II I II I II Ill I I I I I I Ill I I II I
0 1 2 0 1 0 1 1 1 0 0 4 1 1 1 0 0 1 1 0 0 4-5
LH = left-handed; MI = myocardial NYHA = New York Heart Association;
3 1 1 1
infarction; NRH = non-right-handed; RH = right-handed.
Given this association between handedness and patient group, and the known association between ejection fraction and risk of sudden death, the relation between handedness and ejection fraction was examined. Patients with VT-VF (mean 2.85; SD = 1.1) had lower ejection fractions than case controls (mean 3.8; SD = 0.7) (tso = 3.55, p <0.001,2-tailed). A hierarchical regression analysis was conducted examining the ability of leftNON-RIGHT-HANDEDNESS AND SUDDEN DEATH 745
FlGURE 1. Percentages of left-handed and non-righthanded patients with ventricular tachycardisventricular fibrillation (VT-VF), patients in the case-control group, and similarly aged adults in the general population.
tion fraction, suggesting that handedness is not simply a marker of ejection fraction. One possible explanation for this finding is that non-right-handedness may be a marker for some other established risk factor for sudden death.” Left-handers have higher than expected rates of a variety of medical disorders that are not linked to sudden death, including alcoholism, autoimmune disorders, breast cancer, and chromosomal abnormalities.1s Depression has been independently associated with handedness15 and sudden death,“,14 but was directly evaluated and could not be implicated as an explanation for the results of this study. Left-handers have higher than expected rates of type I diabetes and smoking,18 and a personality study revealed that left-handers, compared with right-handers, score higher on measures of dominance and lower on measures of nurturance,19 perhaps consistent with “hostility,” which has been identified as the pathogenetic core of the type A personality.20 Whereas diabetes, smoking, and hostility may predispose left-handers to develop CAD, these factors cannot explain differential mortality among those with CAD. Thus, non-right-handedness does not appear to be a marker for other established risk factors for sudden death. Left-handers also have higher than expected rates of neurologic disorders, including epilepsy, stuttering, dyslexia, and other learning disabilities.18 In a minority of cases, left-handedness is due to brain lesions in the left hemisphere,21 which could disrupt central nervous system regulation of cardiovascular function. However, all patients were screened by their physicians and excluded if any neurologic abnormality was present, and a neurologic history was also obtained from each patient by research personnel before testing. Furthermore, the high scores on the Mini-Mental State Examination are consistent with our conclusion that these patients did not have neurologic deficits. Thus, pathologic brain processes are not a likely explanation. Several studies from a variety of research paradigms suggest that the right hemisphere predominates in the control of heart rate,22 consistent with the predominantly right-sided origin of sympathetic23 and vaga124 fibers innervating the sinoatrial node. Among normal persons there is variation in the degree to which baseline hemispheric arousal is lateralized to the right hemisphere.12 Our observation that non-right-handed patients were relatively more lateralized to the left hemisphere in the performance of the Levy Chimeric Faces Test may dovetail with evidence that stimulation of left-sided sympathetics lowers VF threshold to a greater extent than does stimulation of right-sided sympathetics.1,25 Arousal asymmetries in cortical and subcortical structures may be transmitted ipsilaterally through the lateral hypothalamus, brainstem, intermediolateral cell columns of the spinal cord, and sympathetic nerves to the heart via the stellate ganglia. Asymmetries at the level of the cerebral hemispheres may also induce asymmetries in parasympathetic function27,28 that could result in a net left-right imbalance in sympathetic influences; right vagal stimulation superimposed on bilateral stellate stimulation has been shown to induce VT in the ischemic myocardium
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handedness, then non-right-handedness, to predict ejection fraction after variance in ejection fraction due to patient group was excluded. Neither left-handedness nor non-right-handedness was a significant predictor of ejection fraction. Consistent with this conclusion, 6 of 9 non-right-handed patients with VT-VF had ejection fractions 240, and 3 of 4 non-right-handed case-control patients had ejection fractions 240. Because depression has been found to increase risk of sudden death in patients with CAD,U,14 and because left-handedness has been associated with certain forms of depression, l5 the latter association was examined in a hierarchical regression analysis. Neither patient group nor handedness was a significant predictor of scores on the Beck Depression Inventory. Consistent with previous reports,16 non-right-handed patients were less right-hemisphere dominant (i.e., relatively more lateralized to the left hemisphere) than right-handed patients (t - 1.72, p ~0.05, l-tailed) on the Levy Chimeric Fat:: Test. DISCUSSION
In this exploratory case-control study, the rates of lefthandedness and non-right-handedness in a group of sudden death patients were higher than those of adults of the same age in the general population. A matched comparison group of patients with CAD with no history of serious arrhythmias had handedness rates comparable to the general population, suggesting that CAD, sex, or New York Heart Association functional class could not account for these findings. Furthermore, although patients with VT-VF had lower ejection fractions than case controls, the 2 groups were matched for New York Heart Association functional class, and no significant association was observed between handedness and ejec-
1
40 35
n VT-VF q Control 0 General
(9126) 34.6%
Population
10.2%
Left-Handed
7
Non-Right-Handed
THE AMERICAN JOURNAL OF CARDIOLOGY@’ VOLUME 74
of cats.29 Animal studies also suggest that the 2 cerebral hemispheres differ in the extent to which hemispheric activation asymmetries stimulate adrenal medullary catecholamine release.30 The hypothesized association between left-handedness and decreased longevity is controversial,31 but not without significant support. 7,32,33This general hypothesis deals with all-cause mortality, and is not specific for sudden cardiac death. The findings reported in this study are suggestive of a possible association between nonright-handedness and sudden death, and require coniirmation in a prospective study of predictors of sudden death in patients with CAD. If conlirmed by a larger, multicenter study, one possible clinical implication of such an association would be to highlight the importance of primary prevention of CAD in non-right-handed persons, given that sudden death may be the lirst clinical manifestation of CAD in 20% to 25% of patients with CAD.” Acknowledgment: We wish to thank Gordon Ewy, MD, Lionel Faitelson, MD, Kathleen Gear, RN, Mary Kay Pierce, RN, and Jerrold Winter, MD, for their substantial contributions to the recruitment of patients for this study, and Stanley Coren, PhD, for his assistance in the analysis of handedness data, including confirmation of handedness rates in the general population.
1. Lown B, Varier R, Rabiiowitz S. Neural and psychologic mechanisms and the problem of sudden cardiac death. Am J Cardiol 1977;39:89&902. 2. Skinner JE, Reed JC. Blockade of frontocortical-brain stem pathway prevents ventricular fibrillation of ischemic heart. Am J Physiol 1981;249:H156-H163. 3. Kamack T, Jennings JR. Biobehavioral factors in sudden cardiac death. Psychol Bull 1991;109:42-75. 4. Schwartz PJ, Priori SG. Sympathetic nervous system and cardiac arrhythmias. In: Zipes DP, Jalife J, eds. Cardiac Elecb-ophysiology. Philadelphia: WB Saunders, 1990:330-343. 5. Abildskov JA. The sympathetic imbalance hypothesis of QT interval prolongation. .I Cardiovasc Eiectrophysiol 1991;23:55-59. 6. Lane RD, Schwartz G. Induction of lateral&d sympathetic input to the heart by the CNS during emotional arousal: a possible newophysiologic bigger of sudden cardiac death. Psychosom Med 198x49:274-284. 7. Coren S, H&pan DF. Left-handedness: a marker for decreased survival fitness. Psycho1 Bull 1991;109:9&106. 6. Mesulam M-Marsel. principles of Behavioral Neurology. Philadelphia: FA Davis, 1985. 9. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inven-
tory. Neuropsychologia 1971;9:97-113. 10. Cmm RM, Anthony JC, Bassett SS, F&t& MF. Population-based norms for the Mini-Mental State Examination by age and educational level. JAMA 1993;269: 23862391. 11. Ahem DK, Go&in L, Anderson JL, Tiemey C, Hallstrom A, Ewart C, Capone RJ, S&on E, Komfield D, Herd JA, Richardson DW, Follick MJ. Biobehavioral variables and mortality or cardiac arrest in the cardiac arrhythmia pilot study (CAPS). Am J Cardiol 1990;66:5962. 12. Levy J, Heller W, Banich MT, Burton LA. Asymmetry of perception in free viewing of chimeric faces. Brain Cogn 1983;2:404-419. 13. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 6th ed. Boston: Little, Brown, 1964114. 14. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on 6.month survival. JAMA 1993;270:1819-1825. 15. Davidson RJ, Schaffer CE. Affect and disorders of affect: behavioral and electrophysiological studies. In: Flor-Henry P, Gmzelier J, eds. Later&y and Psychopathology. New York: Elsevier, 1983:24%268. 16. Heller MW, Levy J. Perception and expression of emotion in right-handers and left-handers. Neuropsychologia 1981;19:263-272. 17. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: epidemiology, transient risk, and intervention assessment. Ann Intern Med 1993;119:1187-1197. 16. London WP. Left-handedness and life expectancy. Percept Mot Skills 1989; 68:104&1042. 19. Coren S. Personality differences between left- and right-handers: an overlooked minority group? J Res Pm 1994;28:214-229. 20. Siegler IC, Peterson BL, Barefoot JC, Williams RB. Hostility during late adolescencepredicts coronary risk factors at mid-l&Am JEpidemioll991; 136:14&154. 21. Orsini DL, Satz P. A syndrome of pathological left-handedness correlates of early left hemisphere injury. Arch New01 1986;43:333-337. 22. Swartz CM, Abram R, Lane RD, DuBois MA, Sxinivasaraghavan J. Heart rate differences between right unilateral and left unilateral electmconvulsive therapy. J New01 Neurosurg Psychiatry 1994;57:97-99. 23. Levy MN, Ng ML, Zieske H. Functional distribution of the peripheral cardiac sympathetic pathways. Circ Res 1966;14:65&661. 24. Hamlin RL, Smith CR. Effects of vagal stimulation on S-A and A-V nodes. Am J Physiol 1968;215:56&568. 25. Varier R, Thompson P, Lawn B. Ventricular vulnerability during sympathetic stiiulation: role of heart rate and blood pressure. Cardiovasc Res 1974;8:602610. 26. Fang HS, Wang SC. Cardioaccderator and cardioaugmentor points in hypothalamus of the dog. Am J Physiol 1962;203:147-150. 27. Lane RD, Wallace JD, Petrosky PP, Schwartz GE, Gradman AH. Supraventicular tachycaxiia in patients with right hemisphere strokes. Stroke 1992;23:362-366. 26. Barron SA, Rogovski Z, Hemli Y. Autonomic consequences of cerebral hemisphere infarction. Stroke 1994,25:113-l 16. 29. Bergamaschi M. Role of the sympathetic and parasympathetic innenration in the genesis of ventricular arrhythmias during experimental myocardial ischemia. In: Schwartz PJ, Brown AM, Malliani A, Zanchetti A, eds. Neural Mechanisms in Cardiac Arrhythmias. New York: Raven Press, 1978:139-154. 30. Hachinski VC, Oppenheimer SM, Wilson JX, Guiraudon C, Cechetto DF. Asymmetty of sympathetic consequences of experimental stroke. Arch New01 1992; 49:697-702. 31. Harris LJ. Do left-handers die sooner than right-handers? Commentary on Coren and Halpem’s (1991) “Left-handedness: a marker for decreased survival fitness.” Psycho1 Bull 1993;114:203-234. 32. Aggleton JP, Kentridge RW, Nave NJ. Evidence for longevity differences between left handed and right handed men: an archival study of cricketers. J Epidemiol Community Health 1993;47:20&209. 33. Hugdahl K, Satz P, Mitmshiia M, Miller EN. Left-handedness and old age: do left-handers die earlier? Neuropsychologia 1993;3 1:325-333.
NON-RIGHT-HANDEDNESS AND SUDDEN DEATH 747
on with
Richard D. Lane, MD, Anthony C. Caruso, MD, Victoria L. Brown, BS, Beatrice Axelrod, MS, Gary E. Schwartz, PhD, Lee Sechrest, PhD, and Frank I. Marcus, MD The hypothesis that non-right-handedness is associated with sudden cardiac death was tested based on evidence that sympathetic imbalance may contribute to ventricular arrhythmogenesis and evidence that left-banders may have a shorter lifespan than right-banders. The study included 26 patients with coronary artery disease (CAD), a history of ventricular tachycar disventricular fibrillation (VT-VP), and implanted defibrillators, and 26 patients with CAD and no history of serious arrhythmias who were matched for age, sex, and New York Heart Association functional class. Patients with any history of neurologic disorders were excluded. Left-banders either wrote with the left hand or were converted from left- to right-handedness in childhood. Nonright-banders used the left hand for writing, drawing, or throwing. Handedness rates in patients with V7-VF and casecontrol subjects were compared with published norms in the general population to take expected rates into account. The rates of l&-handedness (6 of 26 or 23.1%) and non-right-handedness (9 of 26 or 34.6%) in patients with W-VF were significantly higher (p
these findings are confirmed in a prospective study, non-right-handedness should be considered a risk factor for sudden death in the context of CAD. (Am J Cardiol1994;74:74S747)
vidence from a variety of sources suggests that the central nervous system can play a significant role in ventricular arrhythmogenesis and sudden death-3 Changes in autonomic input to the heart likely mediate these brain influences. Yet, relatively little is known about how activity in different brain regions contributes to ventricular fibrillation (VF). Drawing on numerous published reports demonstrating the role of right-left sympathetic imbalance in ventricular arrhythmogenesis,4,5 Lane and Schwartz6 hypothesized that asymmetric arousal of the cerebral hemispheres could induce such an imbalance. Given evidence that left-handers may not live as long as right-handerr,? and that non-right-handers are more similar to left-handers than right-handers in patterns of cerebral lateralization,s we hypothesized that higher rates of left-handedness and non-right-handedness would be observed in victims of sudden death than in control subjects.
E
METHODS Patients:
A case-control design was used because of the relative rarity of sudden death in prospective studies. Patients with coronary artery disease (CAD) between the ages of 18 and 80 years, who were resuscitated victims of sudden death or sustained ventricular tachycardia-ventricular fibrillation (VT-VF) and had automatic implantable cardioverter-defibrillators, were compared with CAD patients with no history of serious arrhythmias. Patients were told that the purpose of the study was to examine the role of hemispheric arousal asymmetry in serious heart rhythm disturbances; handedness was not mentioned as a focus of the study, thus minimizing interest in handedness as a reason for participating. Exclusion criteria for both groups included: (1) primary valvular disease; (2) cardiomyopathy: (3) any history of neurologic disorder (e.g., stroke, seizure disorNON-RIGHT-HANDEDNESS AND SUDDEN DEATH 743
der, intracranial tumor, intracranial arteriovenous fistula, and so forth); (4) asystole lasting 210 minutes; and (5) mental retardation, dementia, or significant cognitive impairment. The diagnosis of CAD was established through chart documentation of previous myocardial infarction or the results of catheterization, stress testing, or radionuclide imaging. Absence of exclusion criteria was verified before testing through patient interview. All eligible patients with implanted cardioverter-defibrillators followed at the University Medical Center or by cardiac electrophysiologists at 3 other major medical centers in Tucson (St. Mary’s Medical Center, Tucson Medical Center, and the Veterans Affairs Medical Center) were invited to participate. Case-control patients with CAD were then identified by local cardiologists, and these patients were matched for age, sex, and New York Heart Association functional class. Matching by age was done by category: (1) ~45 years, (2) 45 to 65 years, and (3) 66 to 80 years. A chart review was completed by a research technician before each case-control patient was invited to participate. Handedness data were never available on any patient before entry into the study. Handedness Znventory9: The lo-item Edinburgh Handedness Inventory was used to assess hand preference. The subject is asked to report, for each of the following 10 activities, whether the right or left hand is preferred and whether the nonpreferred hand would ever be used if not under duress: writing, drawing, throwing, scissors, toothbrush, knife (without fork), spoon, broom (upper hand), striking match (match), and opening box (lid). In previous research on handedness and longevity, right-handedness has been defined by exclusive use of the right hand for writing, drawing, and throwing.7 People who use the left hand for any 1 of the latter 3 activities are classified as non-right-handed (i.e., not a pure right-hander). Left-handedness is defined by use of the left hand for writing, or conversion from left- to righthanded writing. Conversion was assessed by the following question from the handedness questionnaire: “Were you left-handed as a child, but taught to use your right hand instead?” All leftihanders in this study are classified as both left- and non-right-handed. Mini-Mental State Examinatiod”: This standard bedside test of cognitive function was used to detect cognitive impairment. This test assesses,orientation, registration of information, attention, calculation, short-term memory, language, and constructional abilities. It takes about 4 minutes to complete. The maximal possible score is 30. Patients were excluded if scores based on age and education level norms were below the lower quartile. Beck Depression Invento#: This self-report measure involves rating of each of 23 depressive symptoms on a 4-point ordinal scale. This measure has been used in previous research in patients at risk for sudden cardiac death. Levy Chimeric Faces Te&” Chimeric faces are composite faces created from half-faces, which are constructed and rated to demonstrate which hemisphere dominates in a particular judgment. The hemisphere that predominates in the rating in question is believed to be
the more activated hemisphere, as reflected by electroencephalographic measurements. If the half-face in the left visual field predominates in the judgment, it reflects dominance of the right hemisphere. The Levy Chimeric Faces Test consists of 36 pairs of chimeric face photographs presented in a booklet format. Photographs were made of each of 9 male posers with a smiling and with a neutral expression; the 2 photographs from each poser were cut in half down the midsagittal axis and recombined to make 2 different chimeras: in 1, the smile was produced by the left half of the person’s face and the neutral expression by the right half; in the other, this was reversed. Each of the 2 chimeras was paired with its mirror image, once with the normal print at the top of the page and the mirror print at the bottom, and once with the positions reversed. This yielded 4 pairs of chimeras from each poser. For any given pair, the smiling half-face in both members of the pair had been produced by 1 side of the poser’s face and the neutral expression by the other, but 1 member of the pair was a normal print and the other was its mirror image. Subjects looked at each of the 36 pairs for 4 seconds and were then given 5 seconds to indicate which chimera in the pair looked happier. Subjects were encouraged not to think too hard about their answers. The time limits were imposed in part to limit the ability to ponder responses. Subjects were allowed to give a “can’t decide” response if they felt a discrimination was impossible. The test yields a laterality score consisting of the number of left visual field (right hemisphere) choices divided by 36. CARDIOVASCULARMEASURES: New YorkHeartAssociation functional class13: To determine a patient’s New York Heart Association functional class, a research assistant asked patients which category currently fit them best: class I-patients with heart disease who have no symptoms of any kind (ordinary physical activity does not cause fatigue, palpitation, dyspnea, or angina1 pain); class II-patients who are comfortable at rest but have symptoms with ordinary physical activity; class IIIpatients who are comfortable at rest but have symptoms with less than ordinary effort; class IV-patients who have symptoms at rest. The values obtained were checked for accuracy by attending physicians. Left ventricular ejectionfraction: Chart reviews were conducted to determine ejection fraction as close to entry into the study as possible. Ejection fraction measurements by radionuclide imaging were considered most reliable, followed by cardiac catheterization and echocardiography, respectively. Only measurements from the most reliable method were included. The ejection fraction values from the chart were checked for accuracy by attending physicians. Ejection fraction was classified in 1 of 4 categories: 1 = ~20; 2 = 20 to 29; 3 = 30 to 39; and 4 = 240. Statistical analysis of handedness data: A statistical analysis was performed to see if there was a difference in the rate of left-handedness and non-righthandedness in the general population compared with CAD patients with VT-VF and with case-control patients. This was done using the normal approximation to the binomial distribution. The p value obtained is the
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Measures:
BRAIN-RELATED
MEASURES:
Edinburgh
THE AMERICAN JOURNAL OF CARDIOLOGY@ VOLUME 74
probability that a sample of 26 persons drawn from the general population would yield handedness rates equal to those observed in our sample of patients with VT-VF or the sample of case-control patients. The chi-square statistic was not used in this context. This is because of the limited number of sudden death patients available. The &i-square determines the probability that the total number of observed cases of lefthandedness or non-right-handedness would be divided between the 2 groups in a given way by chance. The chisquare statistic does not take into account expected rates of left-handedness and non-right-handedness in the population. In the absence of expected rates, the standard for meaningfulness in a clinical study of this type is a clinically important difference, which in our view consists of a twofold difference in left-handedness or non-right-handedness in the VT-VF group compared with control subjects. If the rates of left-handedness and non-right-handedness in patients with VT-VF were really twofold greater than that of control patients, the probability of obtaining a statistically significant difference with n = 26 in each group is only 3% (for the analysis of left-handedness) and 7% (for the analysis of non-right-handedness), respectively. To have an 80% chance of obtaining a statistically significant difference, assuming a twofold difference in handedness rates between the VT-VF and control groups, 474 (for the analysis of left-handedness) or 214 (for the analysis of non-right-handedness) patients would be needed in each group. This would require a multicenter study to obtain this number of patients. RESULTS The age, sex, New York Heart Association functional class, ejection fraction, number of myocardial infarctions, and handedness status of each patient are listed in Table I. Twenty-three men and 3 women formed each group. Mean ages of the patients with VT-VF and case controls were 63.4 (SD = 8.0) and 64.3 (SD = 9.7) years, respectively (p = NS), and Mini-Mental State Examination scores were 29.2 (SD = 0.97) and 29.6 (SD = 0.76), respectively (p = NS). The distribution of patients across the New York Heart Association functional classes was identical in the 2 groups. The rates of left-handedness (6 of 26 or 23.1%) and non-right-handedness (9 of 26 or 34.6%) in patients with VT-VF were significantly higher (left-handed: ZC = 2.99, p ~0.003, 2-tailed; non-right-handed: Z, = 3.79, p
TABLE Patients Age W & Sex 48 51 61 66 67 73 63 74 78 54 55 56 56 57 57 58 59 62 62 66 70 70 70 71 71 73
M M M M M M M F M M M M F M M M M M M M M M M F M M
I Patient
Characteristics
with Ventricular
Tachycardia-Ventricular
Fibrillation
NYHA Class
Number of Previous MIS
Ejection Fraction
I I I Ill I II I I I I I II II I II I Ill II I I II I I II I I
1 0 >I 1 1 0 2 0 >l 2 1 >I 1 1 1 >I 1 1 1 0 >I 2 1 0 2 3
>40 >40 240 20-29 20-29 20-29 >40 240 240 30-39 20-29 <20 >40 <20 20-29 >40 <20 30-39 >40 >40 20-29 20-29 30-39 >40 20-29 20-29
LH LH LH LH LH LH NRH NRH NRH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH
>40 30-39 >40 >40 >40 >40 >40 >40 >40 >40 >40 >40 >40 >40 <20 20-29 >40 >40 >40 >40 >40 240 >40 >40 240 140
LH LH NRH NRH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH RH
Handedness
Case-Controls 69 79 57 59 45 51 52 54 55 56 58 59 59 61 62 62 67 70 72 72 73 73 75 75 76 81
M M M M M M M M M F M M M M M M M M M M M M M F F M
II II I I I I I II I II I II I II Ill I I I I I I Ill I I II I
0 1 2 0 1 0 1 1 1 0 0 4 1 1 1 0 0 1 1 0 0 4-5
LH = left-handed; MI = myocardial NYHA = New York Heart Association;
3 1 1 1
infarction; NRH = non-right-handed; RH = right-handed.
Given this association between handedness and patient group, and the known association between ejection fraction and risk of sudden death, the relation between handedness and ejection fraction was examined. Patients with VT-VF (mean 2.85; SD = 1.1) had lower ejection fractions than case controls (mean 3.8; SD = 0.7) (tso = 3.55, p <0.001,2-tailed). A hierarchical regression analysis was conducted examining the ability of leftNON-RIGHT-HANDEDNESS AND SUDDEN DEATH 745
FlGURE 1. Percentages of left-handed and non-righthanded patients with ventricular tachycardisventricular fibrillation (VT-VF), patients in the case-control group, and similarly aged adults in the general population.
tion fraction, suggesting that handedness is not simply a marker of ejection fraction. One possible explanation for this finding is that non-right-handedness may be a marker for some other established risk factor for sudden death.” Left-handers have higher than expected rates of a variety of medical disorders that are not linked to sudden death, including alcoholism, autoimmune disorders, breast cancer, and chromosomal abnormalities.1s Depression has been independently associated with handedness15 and sudden death,“,14 but was directly evaluated and could not be implicated as an explanation for the results of this study. Left-handers have higher than expected rates of type I diabetes and smoking,18 and a personality study revealed that left-handers, compared with right-handers, score higher on measures of dominance and lower on measures of nurturance,19 perhaps consistent with “hostility,” which has been identified as the pathogenetic core of the type A personality.20 Whereas diabetes, smoking, and hostility may predispose left-handers to develop CAD, these factors cannot explain differential mortality among those with CAD. Thus, non-right-handedness does not appear to be a marker for other established risk factors for sudden death. Left-handers also have higher than expected rates of neurologic disorders, including epilepsy, stuttering, dyslexia, and other learning disabilities.18 In a minority of cases, left-handedness is due to brain lesions in the left hemisphere,21 which could disrupt central nervous system regulation of cardiovascular function. However, all patients were screened by their physicians and excluded if any neurologic abnormality was present, and a neurologic history was also obtained from each patient by research personnel before testing. Furthermore, the high scores on the Mini-Mental State Examination are consistent with our conclusion that these patients did not have neurologic deficits. Thus, pathologic brain processes are not a likely explanation. Several studies from a variety of research paradigms suggest that the right hemisphere predominates in the control of heart rate,22 consistent with the predominantly right-sided origin of sympathetic23 and vaga124 fibers innervating the sinoatrial node. Among normal persons there is variation in the degree to which baseline hemispheric arousal is lateralized to the right hemisphere.12 Our observation that non-right-handed patients were relatively more lateralized to the left hemisphere in the performance of the Levy Chimeric Faces Test may dovetail with evidence that stimulation of left-sided sympathetics lowers VF threshold to a greater extent than does stimulation of right-sided sympathetics.1,25 Arousal asymmetries in cortical and subcortical structures may be transmitted ipsilaterally through the lateral hypothalamus, brainstem, intermediolateral cell columns of the spinal cord, and sympathetic nerves to the heart via the stellate ganglia. Asymmetries at the level of the cerebral hemispheres may also induce asymmetries in parasympathetic function27,28 that could result in a net left-right imbalance in sympathetic influences; right vagal stimulation superimposed on bilateral stellate stimulation has been shown to induce VT in the ischemic myocardium
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handedness, then non-right-handedness, to predict ejection fraction after variance in ejection fraction due to patient group was excluded. Neither left-handedness nor non-right-handedness was a significant predictor of ejection fraction. Consistent with this conclusion, 6 of 9 non-right-handed patients with VT-VF had ejection fractions 240, and 3 of 4 non-right-handed case-control patients had ejection fractions 240. Because depression has been found to increase risk of sudden death in patients with CAD,U,14 and because left-handedness has been associated with certain forms of depression, l5 the latter association was examined in a hierarchical regression analysis. Neither patient group nor handedness was a significant predictor of scores on the Beck Depression Inventory. Consistent with previous reports,16 non-right-handed patients were less right-hemisphere dominant (i.e., relatively more lateralized to the left hemisphere) than right-handed patients (t - 1.72, p ~0.05, l-tailed) on the Levy Chimeric Fat:: Test. DISCUSSION
In this exploratory case-control study, the rates of lefthandedness and non-right-handedness in a group of sudden death patients were higher than those of adults of the same age in the general population. A matched comparison group of patients with CAD with no history of serious arrhythmias had handedness rates comparable to the general population, suggesting that CAD, sex, or New York Heart Association functional class could not account for these findings. Furthermore, although patients with VT-VF had lower ejection fractions than case controls, the 2 groups were matched for New York Heart Association functional class, and no significant association was observed between handedness and ejec-
1
40 35
n VT-VF q Control 0 General
(9126) 34.6%
Population
10.2%
Left-Handed
7
Non-Right-Handed
THE AMERICAN JOURNAL OF CARDIOLOGY@’ VOLUME 74
of cats.29 Animal studies also suggest that the 2 cerebral hemispheres differ in the extent to which hemispheric activation asymmetries stimulate adrenal medullary catecholamine release.30 The hypothesized association between left-handedness and decreased longevity is controversial,31 but not without significant support. 7,32,33This general hypothesis deals with all-cause mortality, and is not specific for sudden cardiac death. The findings reported in this study are suggestive of a possible association between nonright-handedness and sudden death, and require coniirmation in a prospective study of predictors of sudden death in patients with CAD. If conlirmed by a larger, multicenter study, one possible clinical implication of such an association would be to highlight the importance of primary prevention of CAD in non-right-handed persons, given that sudden death may be the lirst clinical manifestation of CAD in 20% to 25% of patients with CAD.” Acknowledgment: We wish to thank Gordon Ewy, MD, Lionel Faitelson, MD, Kathleen Gear, RN, Mary Kay Pierce, RN, and Jerrold Winter, MD, for their substantial contributions to the recruitment of patients for this study, and Stanley Coren, PhD, for his assistance in the analysis of handedness data, including confirmation of handedness rates in the general population.
1. Lown B, Varier R, Rabiiowitz S. Neural and psychologic mechanisms and the problem of sudden cardiac death. Am J Cardiol 1977;39:89&902. 2. Skinner JE, Reed JC. Blockade of frontocortical-brain stem pathway prevents ventricular fibrillation of ischemic heart. Am J Physiol 1981;249:H156-H163. 3. Kamack T, Jennings JR. Biobehavioral factors in sudden cardiac death. Psychol Bull 1991;109:42-75. 4. Schwartz PJ, Priori SG. Sympathetic nervous system and cardiac arrhythmias. In: Zipes DP, Jalife J, eds. Cardiac Elecb-ophysiology. Philadelphia: WB Saunders, 1990:330-343. 5. Abildskov JA. The sympathetic imbalance hypothesis of QT interval prolongation. .I Cardiovasc Eiectrophysiol 1991;23:55-59. 6. Lane RD, Schwartz G. Induction of lateral&d sympathetic input to the heart by the CNS during emotional arousal: a possible newophysiologic bigger of sudden cardiac death. Psychosom Med 198x49:274-284. 7. Coren S, H&pan DF. Left-handedness: a marker for decreased survival fitness. Psycho1 Bull 1991;109:9&106. 6. Mesulam M-Marsel. principles of Behavioral Neurology. Philadelphia: FA Davis, 1985. 9. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inven-
tory. Neuropsychologia 1971;9:97-113. 10. Cmm RM, Anthony JC, Bassett SS, F&t& MF. Population-based norms for the Mini-Mental State Examination by age and educational level. JAMA 1993;269: 23862391. 11. Ahem DK, Go&in L, Anderson JL, Tiemey C, Hallstrom A, Ewart C, Capone RJ, S&on E, Komfield D, Herd JA, Richardson DW, Follick MJ. Biobehavioral variables and mortality or cardiac arrest in the cardiac arrhythmia pilot study (CAPS). Am J Cardiol 1990;66:5962. 12. Levy J, Heller W, Banich MT, Burton LA. Asymmetry of perception in free viewing of chimeric faces. Brain Cogn 1983;2:404-419. 13. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 6th ed. Boston: Little, Brown, 1964114. 14. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on 6.month survival. JAMA 1993;270:1819-1825. 15. Davidson RJ, Schaffer CE. Affect and disorders of affect: behavioral and electrophysiological studies. In: Flor-Henry P, Gmzelier J, eds. Later&y and Psychopathology. New York: Elsevier, 1983:24%268. 16. Heller MW, Levy J. Perception and expression of emotion in right-handers and left-handers. Neuropsychologia 1981;19:263-272. 17. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: epidemiology, transient risk, and intervention assessment. Ann Intern Med 1993;119:1187-1197. 16. London WP. Left-handedness and life expectancy. Percept Mot Skills 1989; 68:104&1042. 19. Coren S. Personality differences between left- and right-handers: an overlooked minority group? J Res Pm 1994;28:214-229. 20. Siegler IC, Peterson BL, Barefoot JC, Williams RB. Hostility during late adolescencepredicts coronary risk factors at mid-l&Am JEpidemioll991; 136:14&154. 21. Orsini DL, Satz P. A syndrome of pathological left-handedness correlates of early left hemisphere injury. Arch New01 1986;43:333-337. 22. Swartz CM, Abram R, Lane RD, DuBois MA, Sxinivasaraghavan J. Heart rate differences between right unilateral and left unilateral electmconvulsive therapy. J New01 Neurosurg Psychiatry 1994;57:97-99. 23. Levy MN, Ng ML, Zieske H. Functional distribution of the peripheral cardiac sympathetic pathways. Circ Res 1966;14:65&661. 24. Hamlin RL, Smith CR. Effects of vagal stimulation on S-A and A-V nodes. Am J Physiol 1968;215:56&568. 25. Varier R, Thompson P, Lawn B. Ventricular vulnerability during sympathetic stiiulation: role of heart rate and blood pressure. Cardiovasc Res 1974;8:602610. 26. Fang HS, Wang SC. Cardioaccderator and cardioaugmentor points in hypothalamus of the dog. Am J Physiol 1962;203:147-150. 27. Lane RD, Wallace JD, Petrosky PP, Schwartz GE, Gradman AH. Supraventicular tachycaxiia in patients with right hemisphere strokes. Stroke 1992;23:362-366. 26. Barron SA, Rogovski Z, Hemli Y. Autonomic consequences of cerebral hemisphere infarction. Stroke 1994,25:113-l 16. 29. Bergamaschi M. Role of the sympathetic and parasympathetic innenration in the genesis of ventricular arrhythmias during experimental myocardial ischemia. In: Schwartz PJ, Brown AM, Malliani A, Zanchetti A, eds. Neural Mechanisms in Cardiac Arrhythmias. New York: Raven Press, 1978:139-154. 30. Hachinski VC, Oppenheimer SM, Wilson JX, Guiraudon C, Cechetto DF. Asymmetty of sympathetic consequences of experimental stroke. Arch New01 1992; 49:697-702. 31. Harris LJ. Do left-handers die sooner than right-handers? Commentary on Coren and Halpem’s (1991) “Left-handedness: a marker for decreased survival fitness.” Psycho1 Bull 1993;114:203-234. 32. Aggleton JP, Kentridge RW, Nave NJ. Evidence for longevity differences between left handed and right handed men: an archival study of cricketers. J Epidemiol Community Health 1993;47:20&209. 33. Hugdahl K, Satz P, Mitmshiia M, Miller EN. Left-handedness and old age: do left-handers die earlier? Neuropsychologia 1993;3 1:325-333.
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