Triggering of Ventricular Tachycardia by Meteorologic and Emotional Stress: Protective Effect of ß-Blockers and Anxiolytics in Men and Elderly
Viktor Puli1 ,
Davor Eterovi2,
Dinko Miri1,3,
Lovel Giunio1,3,
Ajvor Lukin1 and
Damir Fabijani1
1 Division of Cardiology, Department of Medicine, University Hospital Split, Split, Croatia.
2 Department of Biophysics and Scientific Methodology, University School of Medicine, Split, Croatia.
3 University School of Medicine, Split, Croatia.
Received for publication December 8, 2003; accepted for publication June 9, 2004.
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ABSTRACT
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A circadian pattern with a morning peak and the triggering role of emotional stress have been suggested for ventricular arrhythmias. After controlling for participant baseline characteristics and medication used, the authors studied the association of emotional upset, physical activity, and meteorologic parameters with occurrence of ventricular tachycardia (VT) in 457 Croatian participants aged 1188 years consecutively assigned to undergo continuous 24-hour Holter monitoring. In 2001, multivariate analysis of possible VT precipitators was performed separately for men, women, those aged <65 years, and those aged >64 years. A U-shaped pattern of wind speed (either very weak or very strong), rising relative air moisture, falling atmospheric pressure, and emotional upset were independent predictors of VT episodes in all participant subgroups. Positive association of VT with higher atmospheric temperature or pressure was observed in women and elderly. After adjustment for external triggers, a circadian variation in VT episodes persisted in women (p = 0.01) and those aged <65 years (p < 0.0001) only. A protective effect of ß-blockers and anxiolytics was especially apparent for men and elderly, as well as an adverse effect of digitalis in women. Results suggest that meteorologic and emotional stress could be considered external triggers of VT, with age- and sex-dependent susceptibility.
anti-arrhythmia agents; atmospheric pressure; circadian rhythm; sex; stress; tachycardia; temperature
Abbreviations:
Abbreviations: ANOVA, analysis of variance; VT, ventricular tachycardia.
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INTRODUCTION
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During the last two decades, much information has been gathered on the pathophysiology of the triggering of acute cardiac events, especially acute myocardial infarction, with well-documented circadian variation and external triggers such as emotional upset and physical activity (15). Studies on the triggering factors and mechanisms for ventricular tachyarrhythmias have suggested a circadian pattern with a morning peak (68); a septadian pattern with an increased incidence on Mondays (8, 9); and a greater risk of arrhythmic episodes during very cold and very hot conditions (10), elevated levels of air pollution (11), or acute episodes of emotional stress (12, 13).
It is generally agreed that enhanced activity of the sympathetic nervous system is the most important endogenous mechanism in triggering ventricular arrhythmias, especially in the presence of structural cardiac abnormalities (6, 13, 14). However, since multiple external factors change the activity of the autonomic nervous system and could be involved in generating ventricular arrhythmias, it has been difficult to investigate all factors and to quantify their separate influence, particularly regarding meteorologic variables because of their rapid change and the interfering noise effects of other factors and mechanisms.
The aim of the present study was to delineate the effect of a number of acute triggering and chronic modifying factors on the occurrence of ventricular tachycardia (VT). We specifically addressed the question of the association of episodes of VT with short-time meteorologic fluctuations and other possible external triggers of acute coronary events after controlling for participants baseline characteristics, risk profile, and medication used.
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MATERIALS AND METHODS
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Study design
This prospective observational study was conducted from January to April 2001 in the Diagnostic Units of the Division of Cardiology, Department of Medicine, University Hospital Split, Split, Croatia. In- and outpatients consecutively assigned to undergo continuous 24-hour Holter monitoring were eligible for enrollment in the study. The study protocol was approved by the Hospital Ethics Committee, and all participants enrolled in the study gave their informed consent.
For each participant, three types of information were collected: data on baseline characteristics and exposure to possible external triggers of acute cardiac events obtained from the participants themselves, occurrence of cardiac arrhythmias, and values for meteorologic variables. Our findings regarding factors influencing the occurrence of cardiac arrhythmias other than VT will be reported separately.
A total of 501 participants underwent Holter monitoring during the study period, 17 of whom were unable to complete the diary. We also excluded 27 participants whose electrocardiograms were partly inaccurate or had artifacts making it impossible to analyze the record. The remaining 457 (233 men and 224 women; age range, 1188 years) participants were included in the study.
Data obtained from participants
All participants were interviewed by an attending cardiologist or specially trained nurses, who filled out the data form about demographic characteristics (age, sex, height, and weight), the presence of risk factors (current cigarette smoking; history of diabetes, hypertension, and hypercholesterolemia; previous myocardial infarction (>6 months ago); family history of heart disease; and chest pain during the previous 7 days), and medication used (aspirin, ß-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, nitrates, digitalis, diuretics, propafenone, amiodarone hydrochloride, anxiolytics, and hypolipemics). The participants also filled out a second data form, specifying the exact time of engaging in physical activities and unusual events that occurred during the monitoring. Participants were considered engaged in physical activity during a particular period if they performed any activity estimated to be greater than or equal to level 4 according to a scale from 1 to 8 metabolic equivalents, previously used for this type of study (1, 2). Exposure to emotional upset was defined as an emotional state compatible with level 3 or more according to the Onset Anger Scale, developed to assess such episodes in studies investigating the triggering of acute myocardial infarction (4). Because of their properties, sotalol hydrochloride and carvedilol were considered ß-blockers. For each participant, body mass index was calculated from body height and weight.
Holter monitoring
All participants underwent continuous 24-hour Holter monitoring with a Medilog FD4 5-channel recorder (Oxford Instruments, Abingdon, United Kingdom). The electrocardiogram was recorded continuously on a PCMCIA flash memory storage card (Oxford Instruments). The records were analyzed by using a devoted software system (Oxford Instruments Medical Systems, Medilog Cardiology, Information System V1.42, Abingdon, United Kingdom) and also manually by an experienced observer (V. P., L. G., A. L., D. F.) to detect artifacts. VT was defined as three or more ventricular extrasystoles (judged by the width of the QRS and the prematurity of QRS complexes of at least 30 percent) in succession at a rate of more than 120 beats per minute. We did not distinguish between sustained and nonsustained VT. In the analyses, the time of occurrence of each VT episode was defined as its starting moment. The time of the stored episodes was obtained from the time settings of the programmer, set to the correct local time.
Meteorologic variables
Split is the largest city in Middle Dalmatia, a region in the south of Croatia. It has a typical Mediterranean climate characterized by frequent, large, and rapid changes in atmospheric conditions. Since such changes occur most often between January and April, this period was chosen so we could analyze their influence on the occurrence of VT. Meteorologic data for the Split city area were obtained from the State Hydrometeorological Institute, Marine Meteorological Center, Split. Atmospheric temperature (in degrees Celsius), atmospheric pressure (in hectopascals), relative air moisture (in percentage of air saturation), wind speed (in meters per second), and wind direction (per 10°) were recorded every 3 hours (eight times a day: at 1 a.m., 4 a.m., 7 a.m., and 10 a.m. and at 1 p.m., 4 p.m., 7 p.m., and 10 p.m.) during the study period. We also used data on rainfall and the passage of cold or warm atmospheric fronts (coded as yes/no categorical variables).
Data analysis
Because the marked variability in the number of VT episodes between participants was likely to bias the relation between arrhythmic episodes and the factors we investigated, the first step was to express the occurrence of episodes in an hour as a percentage of all episodes recorded during monitoring. This method of adjusting participant episodes per hour gave each participant the same weight in the analyses, independent of the absolute number of episodes experienced during monitoring. For statistical analyses, the data were organized in two ways. In the first set of analyses, the percentages of arrhythmic episodes occurring an hour before and an hour after the point of measurement of meteorologic parameters were summed and were associated with the observed values of meteorologic and other variables. Thus, we were able to investigate the occurrence of episodes in 2-hour intervals around the different values of meteorologic parameters. We used 2-hour intervals versus 3-hour intervals to analyze the occurrence of episodes according to the presence of rainfall and the passage of a cold, warm, or no atmospheric front because of greater accuracy of classification. In the second set of analyses, we subtracted values for each successive measurement of atmospheric temperature, atmospheric pressure, and relative air moisture from the previous value. The observed differences represented the change in the level of these parameters during each single 3-hour interval, and they were associated with the sum of the percentages of arrhythmic episodes occurring in the three 1-hour intervals between measurements of meteorologic parameters. Analyses were performed for both sets of data (by 2- and 3-hour intervals).
To assess the influence of atmospheric temperature and pressure, relative air moisture, wind speed, and change in levels of meteorologic variables, we used linear regression (with calculation of the correlation coefficient and regression equation) or polynomial regression when linear models did not fit the data well. The outcome variable was frequency of VT (expressed as the percentage of a participants total episodes recorded) averaged over all observations corresponding to the particular value of the independent variable in question. For example, in the analysis of temperature versus frequency of VT, if temperatures were between 11°C and 12°C, the value of the outcome variable was obtained by averaging the percentages of VT over all participants and all times of measurement that corresponded to atmospheric temperatures between 11°C and 12°C. Thus, measurements over several participants could be included, and each participant may have contributed more than once to the value in question. The weighting factors, equal to the number of observations corresponding to the particular value of the independent variable, were used in regression analyses.
Repeated-measures analysis of variance (ANOVA) was used to assess whether the frequencies of VT differed according to time of day (eight samples per participant). To further evaluate whether the diurnal rhythm of VT depended on participant baseline characteristics (sex, age, risk factors, medication used), the generalized linear model algorithm, representing two-way ANOVA (time of day x participant characteristic), was run for each participant characteristic separately. However, the influence of meteorologic parameters and other external triggers of VT could not be analyzed within the framework of repeated-measures ANOVA algorithms because the diurnal variations in temperature, for example, varied both within participants (eight samples at different times of day) and between participants. To account for this design, we considered each measurement (not each participant) a separate entry and used multiway ANOVA.
Multiway ANOVA was used to assess whether the occurrence of episodes differed during intervals with or without physical activity, emotional upset, or rainfall; during passage of a cold, warm, or no atmospheric front; and during the blowing of winds from different directions. Mean percentages of VT episodes for wind direction per 10° were grouped according to typical winds that blow in the region; the percentages were then further combined according to the origin of the winds and the type of weather with which they were associated to enable comparable classification for analyses. To account for correlations due to repeated measurements for the same participant, the variable consisting of repeated sequences of the numbers 18 was generated and was always used as one of the independent variables in multiway ANOVA. Additionally, to adjust the diurnal and wind-direction-dependent variation in the frequency of VT for meteorologic and other triggers, multiway ANOVA was also used, and external triggering factors that have shown a significant association in final multivariate models in subgroups by sex and age were included as independent variables or covariates.
Our experiment was not a typical repeated-measures trial, in which the outcome variable is measured several times in response to controlled changes in predicting and independent variables. Except for time of day and participant baseline characteristics, all other (external) predictors of VT (meteorologic parameters, emotional upset, physical activity) were uncontrolled, quasi-random, and varied both between and within participants. Thus, repeated-measures ANOVA was possible only in part of the analyses of the diurnal rhythm of VT. For other analyses, repeated sampling enabled an increase in the sample size and partial control of confounding variables, but not the controlled-paired data. However, by suppressing the influence of subject variability, eight samples per participant carried more information than eight samples from eight different participants. In effect, use of measurements instead of participants as entries (cases) in part of the statistical analyses produced more conservative estimates of p values.
Stepwise multiple regression models were used to analyze the independent predictive significance of a large number of meteorologic and other triggering and modifying (independent) variables on the occurrence of VT (dependent variable). Because of the great number of variables, we performed two previous selection models to evaluate confounding by participants characteristics and medication used. Variables that showed an association of p
0.1 in these models, together with sex and age, meteorologic parameters, and other external triggers (physical activity and emotional upset), were included in the final models as independent variables. The three final models separately analyzed the occurrence of VT according to 1) basic meteorologic parameters, 2) passage of atmospheric fronts, and 3) change in the level of meteorologic parameters. We estimated the influence of levels of basic meteorologic parameters separately from passage of atmospheric fronts since the latter represent complex meteorologic phenomena associated with significant fluctuations in the former. Passage of an atmospheric front was included as a "dummy" variable. For wind speed, both observed values and quadratic function obtained from univariate regression analysis were tested in multivariate models, and a better-fitting variable was considered in the final models. Since sex differences in the pathophysiology of the autonomic nervous system and occurrence of cardiac events including arrhythmias have been suggested (1517), we performed multivariate analyses for men and women separately. We also separately analyzed data for participants younger than and older than 64 years of age. Independent predictive values of the variables were expressed by using a standardized partial regression coefficient ß and the corresponding p value.
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RESULTS
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Participant characteristics
Mean age was 59 (standard deviation, 14) years, 49 percent of the participants were women, and mean body mass index was 26 (standard deviation, 4) kg/m2. Regarding medical history, 58 percent of the participants were hypertensive, 53 percent had experienced chest pain in the previous 7 days, 35 percent were hypercholesterolemic, 34 percent had a family history of heart disease, and 16 percent were diabetic, were smokers, or had had a previous myocardial infarction. Thirty-four percent used aspirin, 31 percent a diuretic, 30 percent ß-blockers or angiotensin-converting enzyme inhibitors, 17 percent anxiolytics, 15 percent hypolipemics, 13 percent nitrates or calcium channel blockers, 8 percent digitalis, 6 percent propafenone, and 2 percent amiodarone.
Meteorologic variables
Plotting the mean percentage of VT according to wind speed suggested a U-shaped relation well described by a quadratic polynomial function (figure 1). The lowest rate of events corresponded to 39 m/second. Regarding wind direction, a greater frequency of arrhythmic episodes was observed for southerly and southeasterly wind components (figure 2 and table 1). A positive linear relation was observed for the occurrence of VT versus atmospheric temperature (figure 3). In addition, the mean percentage of VT episodes was greater during periods with rainfall in comparison to periods without rainfall (2.1 and 3.6 percent, respectively; p = 0.02). The distribution of mean percentages of episodes was not uniform during passage of a cold, warm, or no atmospheric front (4.3, 2.1, and 3.7 percent, respectively; p = 0.001). Plotting the mean percentage of VT episodes versus an increase in atmospheric pressure by 3-hour intervals suggested a negative linear correlation, whereas a positive linear correlation was suggested for an increase in relative air moisture (figure 4). No significant association was found between arrhythmic episodes and atmospheric pressure (r = 0.18, p = 0.29), relative air moisture (r = 0.09, p = 0.45), or change in atmospheric temperature (r = 0.16, p = 0.53).

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FIGURE 1. Mean percentage of ventricular tachycardia (VT) episodes according to wind speed (in meters/second) for study participants in Split, Middle Dalmatia, Croatia, JanuaryApril 2001. The p and r values were obtained from the polynomial (quadratic) regression analysis; quadratic regression equation: y = 4.83 0.59X + 0.042X 2.
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FIGURE 2. Mean percentage of ventricular tachycardia (VT) episodes according to wind direction (in degrees) for study participants in Split, Middle Dalmatia, Croatia, JanuaryApril 2001. The p value was obtained from analysis of variance.
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TABLE 1. Mean percentage of episodes of ventricular tachycardia associated with four typical wind directions among all study participants and in subgroups by sex and age, Split, Middle Dalmatia, Croatia, JanuaryApril 2001
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FIGURE 3. Mean percentage of ventricular tachycardia (VT) episodes according to atmospheric temperature (in °C) for study participants in Split, Middle Dalmatia, Croatia, JanuaryApril 2001. The p and r values were obtained from linear regression analysis; linear regression equation: y = 0.742 + 0.245X.
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Possible external triggers
Significantly more VT episodes occurred during the 2-hour intervals with emotional stress than during those without (7.8 and 3.6 percent, respectively; p < 0.0001). We found no difference in the occurrence of VT with respect to engaging in physical activity (mean percentages for intervals with and without such activity: 3.9 and 3.7 percent, respectively; p = 0.73).
Circadian pattern
There was a circadian variation in the mean percentage of VT episodes according to 2-hour intervals for the whole group of participants, with the lowest occurrence between 3 a.m. and 5 a.m. and the highest between 9 a.m. and 11 a.m. (table 2). Analysis of the influence of participants baseline characteristics and medication used on circadian rhythm is shown in table 3. Significant differences are depicted in figures 5 and 6. Anxiolytics and ß-blockers reduced the frequencies and slightly eliminated the morning peak of VT (figure 5). Compared with men, women had a lower frequency of VT during late night (35 a.m.) and a higher frequency during the subsequent early morning period (68 a.m.) (figure 6). Participants who used digitalis had a greater occurrence of VT from 9 a.m. to 8 p.m. (figure 6).
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TABLE 2. Mean percentage of episodes of ventricular tachycardia during 2-hour daily intervals among all study participants and in subgroups by sex and age, Split, Middle Dalmatia, Croatia, JanuaryApril 2001
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TABLE 3. Influence of participant characteristics and medication used on circadian distribution of ventricular tachycardia, Split, Middle Dalmatia, Croatia, JanuaryApril 2001*
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FIGURE 5. Mean percentage of ventricular tachycardia (VT) episodes by 2-hour periods according to use (yes) or nonuse (no) of ß-blockers and anxiolytics for study participants in Split, Middle Dalmatia, Croatia, JanuaryApril 2001. The p values were obtained from general linear model analysis (repeated-measures analysis of variance). Both ß-blockers (p = 0.001) and anxiolytics (p = 0.003) reduced the VT frequency and slightly eliminated the late morning peak, but the basic circadian pattern remained present.
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FIGURE 6. Mean percentage of ventricular tachycardia (VT) episodes by 2-hour periods according to sex and use (yes) or nonuse (no) of digitalis for study participants in Split, Middle Dalmatia, Croatia, JanuaryApril 2001. The p values were obtained from general linear model analysis (repeated-measures analysis of variance). There were no significant sex differences in daily frequencies of VT, but the circadian pattern of occurrence was different (interaction existed, p = 0.02). Regarding use of digitalis, both greater frequencies (p = 0.002) and a different circadian pattern with an excess of occurrence during daylight (p = 0.02) were observed.
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Multiple adjustments
The independent predictive significance of participant baseline characteristics, risk factors, and medication used regarding the occurrence of VT in selection models, according to sex and age subgroups, is given in table 4.
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TABLE 4. Previous selection multivariate analysis models of factors modifying the occurrence of ventricular tachycardia in participants according to sex and age, Split, Middle Dalmatia, Croatia, JanuaryApril 2001*,
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Sex
A U-shaped pattern of wind speed, rising relative air moisture, falling atmospheric pressure, and emotional upset were external triggers that independently increased the likelihood of VT in both sexes. Passage of a cold front or engaging in physical activity increased, whereas passage of a warm front reduced, that likelihood in men; higher atmospheric temperature and pressure increased the likelihood in women. Considering the modifying factors in men, using a ß-blocker, anxiolytic, or diuretic had a protective effect, but using aspirin, having a family history of heart disease, or having had a previous myocardial infarction were predictors of VT episodes (table 5). Of possible modifiers in women, previous myocardial infarction was negatively associated and using digitalis was positively associated, whereas the effect of using a diuretic depended on the type of meteorologic variable studied (table 5). After adjustment for meteorologic and other external triggers, both circadian variation in VT frequency and dependence on wind direction were eliminated for men but not women (tables 1 and 2).
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TABLE 5. Final multivariate analysis models* of factors influencing the incidence of ventricular tachycardia according to meteorologic variables by sex, Split, Middle Dalmatia, Croatia, JanuaryApril 2001
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Age
In both age groups, a U-shaped pattern of wind speed, higher atmospheric temperature, rising relative air moisture, falling atmospheric pressure, and emotional upset were associated with a higher occurrence of VT. Rising occurrence of episodes associated with increasing atmospheric pressure and lower occurrence during passage of a warm front were observed among the participants older than age 64 years only. In this group, using digitalis, using aspirin, or having a family history of heart disease increased the likelihood of VT, whereas using a ß-blocker or anxiolytic lowered it. In the age group less than 65 years, using an anxiolytic reduced the likelihood of VT when accounting for the level of meteorologic parameters; using a ß-blocker or anxiolytic lowered and engaging in physical activity increased the likelihood when we accounted for alteration of meteorologic parameters (table 6). Meteorologic and other external triggers did not alter a nonuniform distribution of VT according to wind direction for both age groups, but it changed the circadian pattern in the older group (tables 1 and 2).
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TABLE 6. Final multivariate analysis models* of factors influencing the incidence of ventricular tachycardia according to meteorologic variables by age, Split, Middle Dalmatia, Croatia, JanuaryApril 2001
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DISCUSSION
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The present study suggests that a number of acute triggering and chronic modifying factors have considerable influence on precipitating VT, variously in different population subgroups. To our knowledge, our findings are the first to show that the influence of several meteorologic variables on the occurrence of arrhythmic episodes is independent of modifying factors and is also independent of other external triggering events such as physical activity and emotional stress.
The U-shaped pattern of association between wind speed and VT, with the lowest occurrence between 3 m per second and 9 m per second, is suggestive of a beneficial effect of modest wind-mediated stimuli in comparison to their absence or exaggeration. It remains unclear why southerly and southeasterly wind components are independently linked to a greater occurrence of VT and why this difference persisted in only women after adjustment for other triggers. While we did not record lower temperatures, our results for the temperature range above 0°C agree with a U-shaped relation between frequency of ventricular tachyarrhythmias and mean "felt temperature" reported by Fries et al. (10), with the highest frequency of episodes during very cold and very hot conditions. A greater number of arrhythmic episodes during higher levels of atmospheric pressure throughout the day or during periods of decreasing atmospheric pressure may be due to enhanced sympathetic activity. Animal models suggest that exposure to elevated ambient pressure increases arterial pressure, cardiac contractility, and oxygen consumption (18, 19) while coronary flow may remain unchanged (19), whereas lowering pressure within the range of natural change (20 mmHg) seems to aggravate both stimulus-evoked and spontaneous pain, increase blood pressure, and increase heart rate (20). Periods of increasing relative air moisture may impair sweat evaporation and thermal regulation or burden other adaptive physiologic mechanisms.
Women were more sensitive to daily fluctuations in atmospheric temperature and pressure, whereas a response to complex atmospheric phenomena represented by passage of a front was apparent in only men. Furthermore, circadian variation in VT episodes was eliminated by external triggers in men. More common parasympathetic activation during myocardial ischemia seems to protect women against ventricular arrhythmias (15, 16), which may preserve endogenous circadian rhythm regardless of exposure to external triggers and may explain why we observed a protective effect of ß-blockers and anxiolytics in men but not in women. Lower occurrence of VT in women during the late night hours may be due to an enhanced protective effect of parasympathetic activity associated with sleeping. On the other hand, a significantly higher frequency of VT in the next 2-hour period in women may have resulted from a substantial change in autonomic balance due to sympathetic arousal after awakening, which reverts the previous parasympathetic predomination.
Most of the weather-related trigger conditions and emotional upset increased the likelihood of VT in both age groups. However, a reduced likelihood at lower levels of atmospheric pressure or during the passage of a warm front, as well as elimination of a circadian pattern, was observed in only the elderly. Poor tolerance and reduced physiologic responses to external events might more easily facilitate autonomic nervous system imbalance in older people, making them more vulnerable to trigger-related arrhythmic episodes irrespective of the time of day and more susceptible to protective effects of ß-blockers and anxiolytics. In addition, these two drugs eliminated the circadian rhythm and in particular a late morning peak by reducing the overall occurrence of VT. Both emotional upset and anxiety have been recognized as impairing the balance of the autonomic nervous system via excessive sympathetic activation, which plays a leading role in cardiac arrhythmogenesis (13, 21). Our findings support that concept, imply that some meteorologic circumstances may provoke similar endogenous effects, and suggest an interfering and protective role of ß-blockers and anxiolytics, particularly in men.
It is likely that a serum digoxin concentration of 0.50.8 ng/ml constitutes the optimal therapeutic range, whereas concentrations of 1.2 ng/ml or higher increase myocardial oxygen consumption, arrhythmogenesis, and the risk of mortality (22, 23). However, greater risk of VT associated with digitalis for our female participants supports the recently raised concerns about the appropriate role of digitalis therapy in women. A proarrhythmic effect may be involved in an increased risk of death for women, but not men, whose heart failure is treated with digitalis (24). Furthermore, according to the generalized linear model analysis in the present study, it seems that the adverse effect of digitalis is most pronounced during the wake time (9 a.m.8 p.m.), when other external stressors probably contribute to ischemic events and/or autonomic imbalance.
We were unable to define the presence of coronary heart disease because a number of participants were undergoing a diagnostic procedure to address this question. A positive association of aspirin with episodes of VT, particularly apparent in elderly and men, may be an indicator of diagnosed and treated progressive atherosclerosis, which precipitated episodes of myocardial ischemia and VT.
In drawing conclusions about the factors associated with the occurrence of VT, it is important to recognize that there may be further uncontrolled factors and that our observations require additional corroboration. The second important question relates to the differences in outdoor and indoor exposure to meteorologic factors. Since atmospheric pressure perturbations created by wind-induced turbulence appear to penetrate buildings (25), and cardiac and other morbidity and mortality are related to environmental influences such as meteorologic factors or air pollution (9, 10, 2629), a close relation between indoor and outdoor ambient conditions seems likely, with no substantial difference in the effects on humans. There may have been a misclassification bias regarding the passage of atmospheric fronts because it is difficult to determine the exact starting and ending moment of such a phenomenon. Because morbidity and mortality patterns with respect to weather condition differ between regions and climates (28, 30), the extent to which our findings apply to other climatic environments, and even perhaps to the study area in other seasons, can be questioned.
Our observational findings cannot prove that external triggers cause episodes of VT. Furthermore, the influence of some incompletely controlled or unrecognized confounders cannot be disregarded. However, this prospective study provides evidence for a clear association of mental stress and several meteorologic conditions with a greater likelihood of episodes of VT. In addition, the present study lends further indirect support for the current concept that an imbalance in the autonomic nervous system, with sympathetic predomination, is the leading cause of increased risk of VT. Regarding clinical implications, it seems that both personal (e.g., avoiding exposure to meteorologic and other external triggers, receiving adequate medicamentous treatment, and staying in air-conditioning indoors) and public (e.g., windproofing of bus shelters) measures may be useful in lowering the risk of tachyarrhythmic events.
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NOTES
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Correspondence to Dr. Viktor Puli, Division of Cardiology, Department of Medicine, University Hospital Split, oltanska 1, 21000 Split, Croatia (e-mail: viktor.culic{at}st.htnet.hr). 
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