- Email: [email protected]
Heart rate recovery after exercise in chronic heart failure: Role of vital exhaustion and type D personality
Journal of Cardiology (2009) 53, 248—256
ORIGINAL ARTICLE
Heart rate recovery after exercise in chronic heart failure: Role of vital exhaustion and type D personality Roland von Känel (MD) a,b,∗, Jürgen Barth (PhD) c, Sonja Kohls (PhD) a, Hugo Saner (MD) a, Hansjörg Znoj (PhD) d, Gaby Saner (RN) a, Jean-Paul Schmid (MD) a a
Cardiovascular Prevention and Rehabilitation, Bern University Hospital, Inselspital, and University of Bern, Switzerland b Division of Psychosomatic Medicine, Bern University Hospital, Inselspital, and University of Bern, Switzerland c Institute of Social and Preventive Medicine, University of Bern, Switzerland d Clinical Psychology and Psychotherapy, University of Bern, Switzerland Received 30 August 2008 ; received in revised form 25 October 2008; accepted 19 November 2008 Available online 23 January 2009 KEYWORDS Chronic heart failure; Exercise; Heart rate recovery; Psychosocial factors
Summary Objective: Vital exhaustion and type D personality previously predicted mortality and cardiac events in patients with chronic heart failure (CHF). Reduced heart rate recovery (HRR) also predicts morbidity and mortality in CHF. We hypothesized that elevated levels of vital exhaustion and type D personality are both associated with decreased HRR. Methods: Fifty-one patients with CHF (mean age 58 ± 12 years, 82% men) and left ventricular ejection fraction (LVEF) ≤40% underwent standard exercise testing before receiving outpatient cardiac rehabilitation. They completed the 9-item short form of the Maastricht Vital Exhaustion Questionnaire and the 14-item type D questionnaire asking about negative affectivity and social inhibition. HRR was calculated as the difference between heart rate at the end of exercise and 1 min after abrupt cessation of exercise (HRR-1). Regression analyses were adjusted for gender, age, LVEF, and maximum exercise capacity. Results: Vital exhaustion explained 8.4% of the variance in continuous HRR-1 (p = 0.045). For each point increase on the vital exhaustion score (range 0—18) there
∗ Corresponding author at: Department of General Internal Medicine, Bern University Hospital, Freiburgstrasse 4, Inselspital, CH-3010 Bern, Switzerland. Tel.: +41 31 632 20 19; fax: +41 31 382 11 84. E-mail address: [email protected] (R. von Känel).
0914-5087/$ — see front matter © 2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jjcc.2008.11.008
Personality, exhaustion, and heart rate recovery
249
was a mean ± SEM decrease of 0.54 ± 0.26 bpm in HRR-1. Type D personality showed a trend toward statistical significance for being associated with lower levels of HRR1 explaining 6.5% of the variance (p < 0.08). The likelihood of having HRR-1 ≤18 bpm was significantly higher in patients with type D personality than in those without (odds ratio = 7.62, 95% CI 1.50—38.80). Conclusions: Elevated levels of vital exhaustion and type D personality were both independently associated with reduced HRR-1. The findings provide a hitherto not explored psychobiological explanation for poor cardiac outcome in patients with CHF. © 2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Introduction Patients with chronic heart failure (CHF) have a markedly reduced heart rate recovery (HRR) after exercise [1]. This reduction is a reliable predictor of poor clinical outcome including heart failure-related hospitalizations [2,3] and all-cause mortality [4—6]. The clinical role of decreased vagal tone in the manifestation and outcome of cardiovascular diseases is increasingly acknowledged [7,8]. HRR during the first minute after the termination of physical exercise (HRR-1) primordially reflects parasympathetic activation with sympathetic withdrawal increasingly contributing to the decline in heart rate beyond 1 min after exercise cessation [9]. While parasympathetic measures of heart rate variability such as high frequency power reflect vagal modulation confined to the heart, HRR-1 is a particularly easy-to-obtain proxy measure of overall vagal tone of the human organism [9,10]. Identifying pertinent correlates of HRR-1 might therefore advance our understanding about clinical variables potentially modulating vagal tone and associated prognosis of CHF. Behavioral cardiology research shows that psychosocial factors are associated with clinical outcome of CHF [11,12]. Specifically vital exhaustion and type D personality are now established psychosocial risk factors of cardiovascular disease [13—16]. In patients with CHF after myocardial infarction, vital exhaustion and type D personality both predicted mortality and cardiac events independent of other prognostic factors [17,18]. Vital exhaustion has been conceptualized as a state of extreme mental fatigue with a concomitant increase in irritability consequent to maladjustment to ongoing psychological stress [19]. Type D personality confers trait characteristics of experiencing negative affect which a person avoids to express in social interactions to prevent disapproval by others [20]. Psychosocial factors might exert part of their cardiac toll by virtue of an association with HRR; however, the literature to support this notion is currently scant given that to our
knowledge only two studies on this issue have been published so far. In patients with coronary artery disease elevated levels of depressed mood were associated with reduced HRR one [21] and respectively 2 [22] min after exercise cessation. However, depression, type D negative affectivity, and type D social inhibition reflect distinct constructs in patients with cardiac disease, including CHF [23]. Depression, vital exhaustion, and type D negative affectivity were also revealed as distinct psychological concepts in apparently healthy subjects [24]. These psychometric examinations merit an investigation on a relationship between HRR-1 and psychological factors above and beyond depression. We hypothesized that higher levels of vital exhaustion and type D personality would be associated with decreased HRR-1 in patients with CHF. We further predicted that these associations would be independent of previous correlates of reduced HRR, namely female gender [25], increased age [25,26], impaired left ventricular ejection fraction (LVEF) [5,27], and reduced exercise capacity [26,28]. A number of epidemiological studies suggest both a gradual and categorical relationship between reduced HRR and increased cardiovascular risk [29]. Abnormal HRR-1 is usually defined as a heart rate that declines ≤18 bpm in the first minute after abrupt cessation of exercise [30]. Applying this cut-off, we additionally explored whether psychosocial factors would relate to HRR-1 gradually and categorically assuming a threshold association in case of the latter.
Materials and methods Patients and recruitment All patients provided written informed consent to the study protocol which was approved by the ethical committee of the State of Bern, Switzerland. The study participants were 56 consecutively enrolled patients with ischemic and non-ischemic CHF. All patients underwent a 12-week compre-
250 hensive outpatient cardiac rehabilitation program tailored to the needs of patients with CHF (Cardiac Prevention and Rehabilitation Clinic, Bern University Hospital, Switzerland). All data reported here were obtained before participants entered the rehabilitation program. Inclusion criteria were a primary diagnosis of clinically stable heart failure, LVEF ≤ 40% during echocardiography, no electrocardiographic signs of atrial fibrillation or atrial flutter, and HRR-1 ≥ 1 bpm. Demographic and medical data were obtained through a history and standardized assessments. Psychological data were completely missing in five patients leaving a final sample size of 51 for the statistical analysis.
Psychological assessment Vital exhaustion We applied the German version [31] of the 9item short form of the Maastricht Vital Exhaustion Questionnaire (MVEQ) [32] to assess the symptom level of feelings of exhaustion. The questionnaire asks about undue fatigue, trouble falling asleep, waking up at night, general malaise, apathy, irritability, loss of energy, demoralization, and waking up exhausted. Each item is rated with 0 (‘‘no’’), 1 (‘‘don’t know’’), or 2 (‘‘yes’’) points giving rise to a total exhaustion score between 0 and 18. Five subjects did not complete one item of the MVEQ scale. These missing values were replaced by the mean of an individual’s completed eight items. Type D personality To assess the type D (distressed) personality we used the validated German version [33] of the original type D questionnaire (DS14) [20]. The DS14 comprises two subscales of seven items each to assess negative affectivity and social inhibition. Each item is rated on a 5-point Likert scale that rates a number of statements people often use to describe themselves (0 = ‘‘false’’, 1 = ‘‘rather false’’, 2 = ‘‘neutral’’, 3 = ‘‘rather true’’, 4 = ‘‘true’’) giving rise to a total score between 0 and 28 points for each of the subscales. Typical items are ‘‘I am often irritated’’ and ‘‘I often find myself worrying about something’’ for negative affectivity and ‘‘I find it hard to start a conversation’’ and ‘‘I often feel inhibited in social interactions’’ for social inhibition. Patients are classified as type D if both negative affectivity and social inhibition are greater than or equal to 10 points [20]. One subject missed one item and another subject missed two items of the negative affectivity subscale. The missing values were replaced by the mean of an individual’s completed items of the negative affectivity subscale.
R. von Känel et al.
Exercise testing and heart rate recovery All patients underwent symptom-limited incremental exercise testing on a computer controlled, rotational, speed independent bicycle ergometer (Ergo-metrics 800S, Ergoline® GmbH, Bitz, Germany) while kept on their medication. Exercise testing was in accordance with a standard protocol. After an initial reference phase of 3 min, during which patients cycled without a workload, the test phase began with a 10 W/min ramp protocol until volitional dyspnea or muscle fatigue forced the subjects to terminate the exertion. The protocol stipulated passive recovery from exercise by asking all patients to stop exercise abruptly and to not perform a post-exercise cool-down phase [30]. We continuously recorded a 12-lead electrocardiogram. To obtain HRR-1 we subtracted heart rate at 1 min of passive recovery from the heart rate immediately at the end of exercise. We also recorded peak heart rate during exercise and maximal exercise capacity [W].
Data analyses We used SPSS (version 15.0) statistical software package (Chicago, IL, USA) for data analysis. Twotailed level of significance was set at p < 0.05. All data showed a normal distribution as verified by the Kolmogorov—Smirnov test. Student’s t-test and Fisher’s exact test were applied to test for group differences in continuous and categorical variables, respectively. Pearson correlation analysis was used to estimate bivariate relationships between two variables. Multivariate linear and logistic regression analyses were employed to test whether psychological factors were significantly associated with HRR-1 independent of covariates. All independent variables were forced entry into the regression equation in one block. To prevent model overfitting, we limited the number of control variables to four [34], namely gender, age, LVEF, and maximum exercise capacity. These were selected a priori [33] based on previous literature on their possible association with HRR [5,25—28].
Results Patient characteristics Table 1 shows the demographic, medical, and psychosocial characteristics of the entire sample of patients with CHF as well as the two HRR-1 patient categories. Almost two thirds of all patients had coronary artery disease and more than half were
Personality, exhaustion, and heart rate recovery Table 1
251
Characteristics of the 51 patients with heart failure.
Variable
All patients (n = 51)
HRR-1 ≤ 18 bpm (n = 28)
HRR-1 > 18 bpm (n = 23)
Men [%] Age [years] Left ventricular ejection fraction [%] Coronary artery disease [%] Coronary artery bypass surgery [%] Number of diseased vessels [%]a Treated for hypertension [%] Systolic blood pressure [mm Hg] Diastolic blood pressure [mm Hg] Body mass index [kg/m2 ] Treated for diabetes [%] Dyslipidemia [%] Beta blocker use [%] Aspirin use [%] Angiotensin converting enzyme inhibitor use [%] Maximum exercise capacity [W] Peak heart rate during exercise [bpm] Heart rate recovery-1 [bpm] Vital exhaustion score Negative affectivity score Social inhibition score Type D personality [%]
82 57.7 ± 11.7 26.3 ± 7.3
82 59.1 ± 11.2 26.2 ± 7.1
83 55.9 ± 12.3 26.5 ± 7.7
1.000 0.336 0.899
63 24 37, 16, 10, 37 55 110.4 ± 17.6 71.4 ± 10.2 26.7 ± 5.1 16 53 94 53 71
64 25 36, 14, 11, 39 54 108.8 ± 18.5 69.8 ± 10.0 26.5 ± 4.8 21 61 93 43 71
61 22 39, 17, 9, 35 57 112.4 ± 16.7 73.5 ± 10.4 27.0 ± 5.5 9 44 96 65 70
1.000 1.000 0.971 1.000 0.468 0.198 0.701 0.269 0.267 1.000 0.160 1.000
104.8 ± 36.5 129.7 ±21.5
100.0 ± 29.6 124.1 ± 23.1
110.6 ± 43.8 136.4 ± 17.5
0.309 0.041
19.0 ± 8.8 6.2 ± 5.0 9.5 ± 5.3 9.7 ± 5.8 29
12.5 ± 4.8 7.1 ± 5.2 10.4 ± 5.4 11.1 ± 5.5 43
27.0 ± 5.3 5.0 ± 4.5 8.4 ± 5.2 7.9 ± 5.8 13
p-Value
<0.001 0.124 0.172 0.045 0.030
Values are given as means ±SD or in percentages. Statistical analysis used Student’s t-test and Fisher’s exact test. The p-value refers to differences between HRR-1 groups. HHR-1, decline in heart rate from end of exercise to 1 min recovery. a Normal coronary arteries, 1-vessel disease, 2-vessel disease, 3-vessel disease.
treated for hypertension. While the two groups categorized by HRR-1 had similar maximum exercise capacity, peak heart rate reached during exercise was expectedly higher in the high HRR-1 group relative to the low HRR-1 group. HRR-1 was not different in patients with coronary artery disease compared to those without (p = 0.55). A total of 15 patients were identified with type D personality, whereby the proportion was significantly greater in subjects with HRR-1 ≤ 18 bpm (12 of 28 patients) than in those with HRR-1 > 18 bpm (3 of 23 patients). The groups did not differ in terms of vital exhaustion scores, cardiac function, cardiovascular risk factors, and medication, with virtually all patients having beta blocker treatment. Patients with type D personality had higher scores of vital exhaustion than those without type D personality (10.2 ± 4.5 vs. 4.5 ± 4.1, p < 0.001).
Prediction of heart rate recovery Bivariate analyses There was an inverse relationship between HRR1 and exhaustion (r = −0.31, p = 0.029; Fig. 1).
In addition HRR-1 showed a trend toward statistical significance to be lower in patients with type D personality than in those without (15.7 ± 7.3 bpm vs. 20.4 ± 9.1 bpm, p < 0.09) and to negatively correlate with social inhibition (r = −0.25, p < 0.09). No significant relationships emerged between HRR-1 and gender (p = 0.59), age (p = 0.74), LVEF (p = 0.81), number of diseased vessels (p = 0.50), BMI (p = 0.35), systolic blood pressure (BP) (p = 0.15), diastolic BP (p = 0.20), beta blocker use (p = 0.59), treated diabetes (p = 0.21), and dyslipidemia (p = 0.67). In terms of exercise parameters, HRR-1 showed an expected correlation with peak heart rate during exercise (r = 0.37, p = 0.007), but not with maximum exercise capacity (p = 0.22). Controlled multivariate analyses Continuous measures of heart rate recovery. Tables 2a and 2b show the multivariate linear regression models for exhaustion scores and type D personality as predictors of continuous HRR-1 taking into account age, gender, LVEF, and maximum exercise capacity as covariates. Exhaustion
252
R. von Känel et al.
Figure 1 Bivariate relationship between exhaustion and heart rate recovery. Scatter plot with fit line (95% confidence interval) for the inverse association between the symptoms of vital exhaustion and reduced heart rate recovery in the first minute after exercise (p < 0.03).
explained a significant 8.4% of the variance in HRR1 after controlling for covariates (F1.45 = 4.26, p = 0.045). The unstandardized coefficient B indicated a reduction of 0.5 bpm in HRR-1 for each point increase on the vital exhaustion scale. Type D personality explained 6.5% of the variance in HRR1 after adjustment for covariates; however, this relationship showed only a trend toward statistical significance (F1.45 = 3.25, p < 0.08). In both models none of the covariates emerged as a significant predictor of HRR-1. Categorical measures of heart rate recovery. Tables 3a and 3b show the multivariate logistic regression models for exhaustion scores and type D personality as predictors of categorical HRR-1 (≤18 bpm vs. >18 bpm) with covariates age, gender, LVEF, and maximum exercise capacity. Whereas the level of exhaustion symptoms was not different between the two HRR-1 categories, the likelihood of having HRR-1 ≤ 18 bpm was significantly higher in patients with type D personality than in those without. None of the covariates was a significant predictor of categorical HRR-1 in either model.
Discussion Table 2a Linear exhaustion.
regression
model
Variables entered
Unstandardized coefficient B ± SEM
Constant Gender Age Left ventricular ejection fraction Maximum exercise capacity Vital exhaustion score
20.15 0.15 −0.07 0.14
± ± ± ±
for
vital
p-Value
9.44 3.66 0.14 0.21
0.038 0.967 0.636 0.519
0.02 ± 0.04
0.598
−0.54 ± 0.26
0.045
R2 of entire model = 0.115, F5,45 = 1.17, p = 0.34.
Table 2b Linear regression model for type D personality. Variables entered
Unstandardized coefficient B ± SEM
Constant Gender Age Left ventricular ejection fraction Maximum exercise capacity Type D personality
16.27 0.19 −0.07 0.18
± ± ± ±
p-Value
9.20 3.69 0.14 0.22
0.084 0.958 0.637 0.433
0.03 ± 0.04
0.427
−5.12 ± 2.84
0.078
R2 of entire model = 0.097, F5,45 = 0.97, p = 0.45.
In a sample of patients with CHF we investigated the relationship between HRR-1 and two psychosocial risk factors of cardiovascular disease-vital exhaustion and type D personality-both of which have been demonstrated to affect prognosis of CHF [17,18]. We measured the decline in heart rate into the first minute of recovery from exercise because during this interval the autonomic contribution to HRR is primordially made by the vagus nerve [9] facilitating the physiologic interpretation and potential clinical implications of findings [8]. It is an unresolved issue whether the cardiovascular risk related to HRR lies along a continuum of decreased HRR or sets off only below a threshold value of reduced HRR [29]. This uncertainty prompted us to treat HRR-1 both as a continuous and a categorical variable applying a cut-off value of HRR-1 ≤ 18 bpm to define ‘‘reduced HRR-1’’ as previously suggested for exercise protocols in which exertion was abruptly stopped [30]. We found a gradual relationship between elevated levels of vital exhaustion and decreased HRR-1. The association was observed in bivariate analysis and held significance after statistical adjustment for previous correlates of HRR. Unlike covariates gender, age, LVEF, and maximal exercise capacity, which all were not significantly associated with HRR-1, vital exhaustion explained a substantial 8.4% of the variance. However, we did not
Personality, exhaustion, and heart rate recovery Table 3a
253
Logistic regression model for vital exhaustion.
Variables entered
B ± SEM
Constant Gender Age Left ventricular ejection fraction Maximum exercise capacity Vital exhaustion score
1.25 −0.36 −0.04 0.05 0.01 −0.11
± ± ± ± ± ±
2.08 0.89 0.04 0.05 0.01 0.07
OR (95% CI)
p-Value
3.49 0.70 0.96 1.06 1.00 0.90
0.548 0.688 0.240 0.320 0.699 0.117
(0.12—4.00) (0.90—1.03) (0.95—1.17) (0.98—1.02) (0.79—1.03)
Nagelkerke R2 of entire model = 0.123. Heart rate recovery ≤18 bpm was coded as ‘‘0’’ and men as ‘‘0’’.
observe a greater likelihood for higher levels of vital exhaustion in patients with HRR-1 below or equal to 18 bpm than in those above 18 bpm. This suggests a gradual relationship between vital exhaustion and HRR-1 rather than a categorical one. We further found that the proportion of patients who were classified to have type D personality was significantly greater in the patient group with HRR-1 ≤ 18 bpm relative to the group with HRR1 > 18 bpm. In the multivariate model covarying for gender, age, LVEF, and maximum exercise capacity the relatively increased likelihood for having HRR-1 ≤ 18 bpm as a type D patient maintained its significance. In addition, type D personality reached a trend toward statistical significance as a predictor of continuous HRR-1. The relationship explained 6.5% of the variance and thereby supported the findings from the categorical analysis. The amount of variance explained in HRR-1 by vital exhaustion and type D was quite similar and the proportion of type D persons in the patient group with HRR-1 defined as normal was small. Therefore, we parsimoniously interpret that our findings suggest a clinically meaningful relationship between type D personality and reduced HRR-1 in CHF. However, it would be premature to deem this association more gradual than categorical or vice versa. We found 29% of our patients to have type D personality which prevalence concurs with the 23% and 33%, respectively, observed in other samples of patients with CHF [35,36]. In addition, mean
Table 3b
exhaustion scores of our patients were only slightly lower than in a previous study investigating CHF patients [37]. To the extent that the psychological characteristics of our patients are representative for other samples of CHF patients, the potential clinical importance of the relationship between HRR-1 and vital exhaustion and type D personality is illustrated as follows. In our patients who after adjustment for covariates had an average HRR-1 of 20 bpm, an increase of 6 points on the exhaustion scale corresponded to a decline of 3.2 bpm in HRR-1. HRR-1 was on average 5.1 bpm lower in type D patients than in non-type D patients after adjustment for covariates, too. In patients referred for exercise echocardiography, HRR-1 of 25 bpm, 22 bpm, 19 bpm, and ≤16 bpm previously predicted mortality rates of 2%, 4%, 6%, and 9%, respectively, 3 years later [38]. In other words, for each 3 bpm decline in HRR-1 there was an approximate increase of 2% in the risk of dying during follow-up. Another study followed 87 postmyocardial infarction patients with LVEF≤50% of whom 31% were defined as type D for 8 years [18]. Type D patients had a relative risk of 4.7 to experience cardiac death or nonfatal myocardial infarction relative to non-type D patients. Interestingly, other psychosocial risk factors, namely anxiety, depression, and anger did not add to the predictive power of type D personality [18]. Moreover, in 2449 patients with myocardial infarction, the negative impact of late ventricular failure on
Logistic regression model for Type D personality.
Variables entered
B ± SEM
Constant Gender Age Left ventricular ejection fraction Maximum exercise capacity Type D personality
−1.29 −0.40 −0.05 0.09 0.01 2.03
± ± ± ± ± ±
2.13 0.95 0.04 0.06 0.01 0.83
OR (95% CI)
p-Value
0.28 0.67 0.95 1.09 1.01 7.62
0.546 0.674 0.152 0.139 0.606 0.014
(0.11—4.31) (0.89—1.02) (0.97—1.22) (0.99—1.03) (1.50—38.80)
Nagelkerke R2 of entire model = 0.231. Heart rate recovery ≤18 bpm was coded as ‘‘0’’, men as ‘‘0’’ and presence of type D personality as ‘‘1’’.
254 survival was greater in the presence of high versus low scores of vital exhaustion prior to the infarction and after taking into account clinical characteristics [17]. The authors concluded that the implications of a strong independent predictive value of vital exhaustion as a psychological construct should not be discounted in the clinical management of patients with CHF [17]. The recently completed Exhaustion Intervention Trial indeed demonstrated that a behavioral intervention in patients who felt exhausted after successful percutaneous coronary intervention reduces vital exhaustion scores at least in those without a history of a previous coronary event [39]. In addition, type D scores decreased in patients with coronary artery disease undergoing expanded cardiac rehabilitation with components stress management and increased physical training [40]. Whether decrease in vital exhaustion and type D personality is associated with an increase in HRR-1 has not previously been explored. If a reduction in vital exhaustion and type D characteristics through therapy lowers psychological distress, this might theoretically restore the stress-associated perturbation of the central autonomic network to improve vagus nerve function and HRR-1 in particular [8]. Exercise rehabilitation leads to an increase in HRR [41] and was also employed in the above mentioned randomized trials tailored to reduce vital exhaustion and type D characteristics [39,40]. Exercise regimens are standard in comprehensive cardiac rehabilitation programs delivered to CHF patients. Therefore, studying whether reduction in vital exhaustion and in type D characteristics due to cardiac rehabilitation potentially relate to an increase in HRR-1 merits further effort. Our study was not designed to prove causality. Therefore, intervention studies targeting either psychosocial factors (i.e. vital exhaustion and type D personality) or HRR-1 might help better understand the direction of their relationship and, moreover, whether reducing psychosocial distress is an effective means to improve HRR-1 or vice versa. It is currently unclear why abnormal HRR after exercise is associated with increased cardiovascular morbidity and mortality, although a relationship with greater active ischemia and parasympathetic insufficiency are possible physiologic underpinnings [29]. This notion concurs with experimental studies showing that HRR after the first minute of exercise cessation predominantly reflects vagal tone [9,10]. The vagus nerve exerts tonic inhibitory control over tissue macrophages thereby curtailing inflammatory activity [42]. When this cholinergic anti-inflammatory pathway is weakened the
R. von Känel et al. production of pro-inflammatory cytokines such as tumor-necrosis factor (TNF)-␣, interleukin (IL)-1, and IL-6 is upregulated [43]. The contribution of cytokine toxicity to the prognosis of CHF is abundant given that, for instance, TNF-␣ is highly expressed in the failing myocardium [44]. In patients with stable CHF, circulating levels of TNF␣ were higher in type D patients than in non-type D patients [36]. In addition, vital exhaustion directly correlated with plasma levels of C-reactive protein in healthy subjects [45]. This intriguing research should prompt further investigations about whether increased inflammatory activity is a common mechanism involved in the poor prognostic value of vital exhaustion and type D personality and decreased HRR in CHF. Our findings should be interpreted within the limitations of the study design. The sample size was rather small, thereby limiting statistical power and adjustments for additional potentially important correlates of vagal function related to life style and comorbidities [8]. If our findings are confirmed in a larger sample, this would support the robustness of an association between psychosocial risk factors of cardiovascular disease and HRR-1. Although this possibility remains to be explored, the relationships between vital exhaustion and type D personality on the one hand and reduced HRR-1 on the other might not be restricted to CHF but also to other types of heart diseases. The sample included predominantly men and virtually all patients were treated with beta blockers. However, we statistically controlled for gender and whether beta blockade influences HRR is unclear [5,46,47]. Finally, our study was cross-sectional precluding any inferences about a causal direction of the observed relationships. To conclude, the findings of the present study suggest an independent association between higher levels of vital exhaustion and type D personality on the one hand and reduced HRR-1 as a proxy measure of impaired vagal tone on the other. The findings concur with the prognostic impact of these psychological constructs as well as of decreased HRR in previous studies on patients with CHF suggesting that their relationship might be of clinical importance.
References [1] Imai K, Sato H, Hori M, Kusuoka H, Ozaki H, Yokoyama H, Takeda H, Inoue M, Kamada T. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 1994;24:1529—35. [2] Sheppard RJ, Racine N, Roof A, Ducharme A, Blanchet M, White M. Heart rate recovery—–a potential marker of clinical
Personality, exhaustion, and heart rate recovery
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] [15]
[16]
[17]
[18]
outcomes in heart failure patients receiving beta blocker therapy. Can J Cardiol 2007;23:1135—8. Arena R, Guazzi M, Myers J, Peberdy MA. Prognostic value of heart rate recovery in patients with heart failure. Am Heart J 2006;151:851, e7—e13. Lipinski MJ, Vetrovec GW, Gorelik D, Froelicher VF. The importance of heart rate recovery in patients with heart failure or left ventricular systolic dysfunction. J Card Fail 2005;11:624—30. Nanas S, Anastasiou-Nana M, Dimopoulos S, Sakellariou D, Alexopoulos G, Kapsimalakou S, Papazoglou P, Tsolakis E, Papazachou O, Roussos C, Nanas J. Early heart rate recovery after exercise predicts mortality in patients with chronic heart failure. Int J Cardiol 2006;110:393—400. Bilsel T, Terzi S, Akbulut T, Sayar N, Hobikoglu G, Yesilcimen K. Abnormal heart rate recovery immediately after cardiopulmonary exercise testing in heart failure patients. Int Heart J 2006;47:431—40. Rosenwinkel ET, Bloomfield DM, Arwady MA, Goldsmith RL. Exercise and autonomic function in health and cardiovascular disease. Cardiol Clin 2001;19:369—87. Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol 2007;74:224—42. Buchheit M, Papelier Y, Laursen PB, Ahmaidi S. Noninvasive assessment of cardiac parasympathetic function: postexercise heart rate recovery or heart rate variability? Am J Physiol Heart Circ Physiol 2007;293:H8—10. Dewland TA, Androne AS, Lee FA, Lampert RJ, Katz SD. Effect of acetylcholinesterase inhibition with pyridostigmine on cardiac parasympathetic function in sedentary adults and trained athletes. Am J Physiol Heart Circ Physiol 2007;293:H86—92. Pelle AJ, Gidron YY, Szabó BM, Denollet J. Psychological predictors of prognosis in chronic heart failure. J Card Fail 2008;14:341—50. MacMahon KM, Lip GY. Psychological factors in heart failure: a review of the literature. Arch Intern Med 2002;162:509—16. Kop WJ, Appels AP, Mendes de Leon CF, de Swart HB, Bär FW. Vital exhaustion predicts new cardiac events after successful coronary angioplasty. Psychosom Med 1994;56:281—7. Appels A, Mulder P. Excess fatigue as a precursor of myocardial infarction. Eur Heart J 1988;9:758—64. Denollet J, Sys SU, Stroobant N, Rombouts H, Gillebert TC, Brutsaert DL. Personality as independent predictor of longterm mortality in patients with coronary heart disease. Lancet 1996;347:417—21. Pedersen SS, Lemos PA, van Vooren PR, Liu TK, Daemen J, Erdman RA, Smits PC, Serruys PW, van Domburg RT. Type D personality predicts death or myocardial infarction after bare metal stent or sirolimus eluting stent implantation: a Rapamycin Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry substudy. J Am Coll Cardiol 2004;44:997—1001. Carinci F, Nicolucci A, Ciampi A, Labbrozzi D, Bettinardi O, Zotti AM, Tognoni G. Role of interactions between psychological and clinical factors in determining 6-month mortality among patients with acute myocardial infarction. Application of recursive partitioning techniques to the GISSI-2 database. Gruppo Italiano per lo Studio della Sopravvivenza nell’ Infarto Miocardico. Eur Heart J 1997;18:835—45. Denollet J, Brutsaert DL. Personality, disease severity, and the risk of long-term cardiac events in patients with a decreased ejection fraction after myocardial infarction. Circulation 1998;97:167—73.
255 [19] Appels A. Exhaustion and coronary heart disease: the history of a scientific quest. Patient Educ Couns 2004;55:223—9. [20] Denollet J. DS14: standard assessment of negative affectivity, social inhibition, and type D personality. Psychosom Med 2005;67:89—97. [21] Hughes JW, York KM, Li Q, Freedland KE, Carney RM, Sheps DS. Depressive symptoms predict heart rate recovery after exercise treadmill testing in patients with coronary artery disease: results from the psychophysiological investigation of myocardial ischemia study. Psychosom Med 2008;70:456—60. [22] Hughes JW, Casey E, Luyster F, Doe VH, Waechter D, Rosneck J, Josephson R. Depression symptoms predict heart rate recovery after treadmill stress testing. Am Heart J 2006;151:1122, e1—e6. [23] Pelle AJ, Denollet J, Zwisler AD, Pedersen SS. Overlap and distinctiveness of psychological risk factors in patients with ischemic heart disease and chronic heart failure: are we there yet? J Affect Disord 2008;24(June) [Epub ahead of print]. [24] Kudielka BM, von Känel R, Gander ML, Fischer JE. The interrelationship of psychosocial risk factors for coronary artery disease in a working population: do we measure distinct or overlapping psychological concepts? Behav Med 2004;30:35—43. [25] Kligfield P, McCormick A, Chai A, Jacobson A, Feuerstadt P, Hao SC. Effect of age and gender on heart rate recovery after submaximal exercise during cardiac rehabilitation in patients with angina pectoris, recent acute myocardial infarction, or coronary bypass surgery. Am J Cardiol 2003;9:600—3. [26] Georgoulias P, Orfanakis A, Demakopoulos N, Xaplanteris P, Mortzos G, Vardas P, Karkavistas N. Abnormal heart rate recovery immediately after treadmill testing: correlation with clinical, exercise testing, and myocardial perfusion parameters. J Nucl Cardiol 2003;10:498—505. [27] Lima RS, De Lorenzo A, Soares AJ. Relation between postexercise abnormal heart rate recovery and myocardial damage evidenced by gated single-photon emission computed tomography. Am J Cardiol 2006;97:1452—4. [28] Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999;341:1351—7. [29] Lahiri MK, Kannankeril PJ, Goldberger JJ. Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications. J Am Coll Cardiol 2008;51:1725—33. [30] Chaitman BR. Abnormal heart rate responses to exercise predict increased long-term mortality regardless of coronary disease extent: the question is why? J Am Coll Cardiol 2003;42:839—41. [31] Schnorpfeil P, Noll A, Wirtz P, Schulze R, Ehlert U, Frey K, Fischer JE. Assessment of exhaustion and related risk factors in employees in the manufacturing industry—– a cross sectional study. Int Arch Occup Environ Health 2002;75:535—40. [32] Appels A, Höppener P, Mulder P. A questionnaire to assess premonitory symptoms of myocardial infarction. Int J Cardiol 1987;17:15—24. [33] Grande G, Jordan J, Kümmel M, Struwe C, Schubmann R, Schulze F, Unterberg C, von Känel R, Kudielka BM, Fischer J, Herrmann-Lingen C. Evaluation of the German type D scale (DS14) and prevalence of the type D personality pattern in cardiological and psychosomatic patients and healthy subjects [German]. Psychother Psychosom Med Psychol 2004;54:413—22.
256
R. von Känel et al.
[34] Babyak MA. What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models. Psychosom Med 2004;66:411—21. [35] Schiffer AA, Pedersen SS, Widdershoven JW, Denollet J. Type D personality and depressive symptoms are independent predictors of impaired health status in chronic heart failure. Eur J Heart Fail 2008;10:802—10. [36] Conraads VM, Denollet J, De Clerck LS, Stevens WJ, Bridts C, Vrints CJ. Type D personality is associated with increased levels of tumour necrosis factor (TNF)-alpha and TNFalpha receptors in chronic heart failure. Int J Cardiol 2006;113:34—8. [37] Herrmann-Lingen C, Binder L, Klinge M, Sander J, Schenker W, Beyermann B, von Lewinski D, Pieske B. High plasma levels of N-terminal pro-atrial natriuretic peptide associated with low anxiety in severe heart failure. Psychosom Med 2003;65:517—22. [38] Watanabe J, Thamilarasan M, Blackstone EH, Thomas JD, Lauer MS. Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. Circulation 2001;104:1911—6. [39] Appels A, van Elderen T, Bär F, van der Pol G, Erdman RA, Assman M, Trijsburg W, van Diest R, van Dixhoorn J, Pedersen SS. Effects of a behavioural intervention on quality of life and related variables in angioplasty patients: results of the exhaustion intervention trial. J Psychosom Res 2006;61:1—7.
[40] Karlsson MR, Edström-Plüss C, Held C, Henriksson P, Billing E, Wallén NH. Effects of expanded cardiac rehabilitation on psychosocial status in coronary artery disease with focus on type D characteristics. J Behav Med 2007;30: 253—61. [41] Dimopoulos S, Anastasiou-Nana M, Sakellariou D, Drakos S, Kapsimalakou S, Maroulidis G, Roditis P, Papazachou O, Vogiatzis I, Roussos C, Nanas S. Effects of exercise rehabilitation program on heart rate recovery in patients with chronic heart failure. Eur J Cardiovasc Prev Rehabil 2006;13:67—73. [42] Tracey KJ. The inflammatory reflex. Nature 2002;420: 853—9. [43] Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007;117:289—96. [44] El-Menyar AA. Cytokines and myocardial dysfunction: state of the art. J Card Fail 2008;14:61—74. [45] von Känel R, Frey K, Fischer J. Independent relation of vital exhaustion and inflammation to fibrinolysis in apparently healthy subjects. Scand Cardiovasc J 2004;38:28—32. [46] Desai MY, De la Pe˜ na-Almaguer E, Mannting F. Abnormal heart rate recovery after exercise as a reflection of an abnormal chronotropic response. Am J Cardiol 2001;87:1164—9. [47] Racine N, Blanchet M, Ducharme A, Marquis J, Boucher JM, Juneau M, White M. Decreased heart rate recovery after exercise in patients with congestive heart failure: effect of beta-blocker therapy. J Card Fail 2003;9:296—302.
Available online at www.sciencedirect.com
ORIGINAL ARTICLE
Heart rate recovery after exercise in chronic heart failure: Role of vital exhaustion and type D personality Roland von Känel (MD) a,b,∗, Jürgen Barth (PhD) c, Sonja Kohls (PhD) a, Hugo Saner (MD) a, Hansjörg Znoj (PhD) d, Gaby Saner (RN) a, Jean-Paul Schmid (MD) a a
Cardiovascular Prevention and Rehabilitation, Bern University Hospital, Inselspital, and University of Bern, Switzerland b Division of Psychosomatic Medicine, Bern University Hospital, Inselspital, and University of Bern, Switzerland c Institute of Social and Preventive Medicine, University of Bern, Switzerland d Clinical Psychology and Psychotherapy, University of Bern, Switzerland Received 30 August 2008 ; received in revised form 25 October 2008; accepted 19 November 2008 Available online 23 January 2009 KEYWORDS Chronic heart failure; Exercise; Heart rate recovery; Psychosocial factors
Summary Objective: Vital exhaustion and type D personality previously predicted mortality and cardiac events in patients with chronic heart failure (CHF). Reduced heart rate recovery (HRR) also predicts morbidity and mortality in CHF. We hypothesized that elevated levels of vital exhaustion and type D personality are both associated with decreased HRR. Methods: Fifty-one patients with CHF (mean age 58 ± 12 years, 82% men) and left ventricular ejection fraction (LVEF) ≤40% underwent standard exercise testing before receiving outpatient cardiac rehabilitation. They completed the 9-item short form of the Maastricht Vital Exhaustion Questionnaire and the 14-item type D questionnaire asking about negative affectivity and social inhibition. HRR was calculated as the difference between heart rate at the end of exercise and 1 min after abrupt cessation of exercise (HRR-1). Regression analyses were adjusted for gender, age, LVEF, and maximum exercise capacity. Results: Vital exhaustion explained 8.4% of the variance in continuous HRR-1 (p = 0.045). For each point increase on the vital exhaustion score (range 0—18) there
∗ Corresponding author at: Department of General Internal Medicine, Bern University Hospital, Freiburgstrasse 4, Inselspital, CH-3010 Bern, Switzerland. Tel.: +41 31 632 20 19; fax: +41 31 382 11 84. E-mail address: [email protected] (R. von Känel).
0914-5087/$ — see front matter © 2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jjcc.2008.11.008
Personality, exhaustion, and heart rate recovery
249
was a mean ± SEM decrease of 0.54 ± 0.26 bpm in HRR-1. Type D personality showed a trend toward statistical significance for being associated with lower levels of HRR1 explaining 6.5% of the variance (p < 0.08). The likelihood of having HRR-1 ≤18 bpm was significantly higher in patients with type D personality than in those without (odds ratio = 7.62, 95% CI 1.50—38.80). Conclusions: Elevated levels of vital exhaustion and type D personality were both independently associated with reduced HRR-1. The findings provide a hitherto not explored psychobiological explanation for poor cardiac outcome in patients with CHF. © 2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Introduction Patients with chronic heart failure (CHF) have a markedly reduced heart rate recovery (HRR) after exercise [1]. This reduction is a reliable predictor of poor clinical outcome including heart failure-related hospitalizations [2,3] and all-cause mortality [4—6]. The clinical role of decreased vagal tone in the manifestation and outcome of cardiovascular diseases is increasingly acknowledged [7,8]. HRR during the first minute after the termination of physical exercise (HRR-1) primordially reflects parasympathetic activation with sympathetic withdrawal increasingly contributing to the decline in heart rate beyond 1 min after exercise cessation [9]. While parasympathetic measures of heart rate variability such as high frequency power reflect vagal modulation confined to the heart, HRR-1 is a particularly easy-to-obtain proxy measure of overall vagal tone of the human organism [9,10]. Identifying pertinent correlates of HRR-1 might therefore advance our understanding about clinical variables potentially modulating vagal tone and associated prognosis of CHF. Behavioral cardiology research shows that psychosocial factors are associated with clinical outcome of CHF [11,12]. Specifically vital exhaustion and type D personality are now established psychosocial risk factors of cardiovascular disease [13—16]. In patients with CHF after myocardial infarction, vital exhaustion and type D personality both predicted mortality and cardiac events independent of other prognostic factors [17,18]. Vital exhaustion has been conceptualized as a state of extreme mental fatigue with a concomitant increase in irritability consequent to maladjustment to ongoing psychological stress [19]. Type D personality confers trait characteristics of experiencing negative affect which a person avoids to express in social interactions to prevent disapproval by others [20]. Psychosocial factors might exert part of their cardiac toll by virtue of an association with HRR; however, the literature to support this notion is currently scant given that to our
knowledge only two studies on this issue have been published so far. In patients with coronary artery disease elevated levels of depressed mood were associated with reduced HRR one [21] and respectively 2 [22] min after exercise cessation. However, depression, type D negative affectivity, and type D social inhibition reflect distinct constructs in patients with cardiac disease, including CHF [23]. Depression, vital exhaustion, and type D negative affectivity were also revealed as distinct psychological concepts in apparently healthy subjects [24]. These psychometric examinations merit an investigation on a relationship between HRR-1 and psychological factors above and beyond depression. We hypothesized that higher levels of vital exhaustion and type D personality would be associated with decreased HRR-1 in patients with CHF. We further predicted that these associations would be independent of previous correlates of reduced HRR, namely female gender [25], increased age [25,26], impaired left ventricular ejection fraction (LVEF) [5,27], and reduced exercise capacity [26,28]. A number of epidemiological studies suggest both a gradual and categorical relationship between reduced HRR and increased cardiovascular risk [29]. Abnormal HRR-1 is usually defined as a heart rate that declines ≤18 bpm in the first minute after abrupt cessation of exercise [30]. Applying this cut-off, we additionally explored whether psychosocial factors would relate to HRR-1 gradually and categorically assuming a threshold association in case of the latter.
Materials and methods Patients and recruitment All patients provided written informed consent to the study protocol which was approved by the ethical committee of the State of Bern, Switzerland. The study participants were 56 consecutively enrolled patients with ischemic and non-ischemic CHF. All patients underwent a 12-week compre-
250 hensive outpatient cardiac rehabilitation program tailored to the needs of patients with CHF (Cardiac Prevention and Rehabilitation Clinic, Bern University Hospital, Switzerland). All data reported here were obtained before participants entered the rehabilitation program. Inclusion criteria were a primary diagnosis of clinically stable heart failure, LVEF ≤ 40% during echocardiography, no electrocardiographic signs of atrial fibrillation or atrial flutter, and HRR-1 ≥ 1 bpm. Demographic and medical data were obtained through a history and standardized assessments. Psychological data were completely missing in five patients leaving a final sample size of 51 for the statistical analysis.
Psychological assessment Vital exhaustion We applied the German version [31] of the 9item short form of the Maastricht Vital Exhaustion Questionnaire (MVEQ) [32] to assess the symptom level of feelings of exhaustion. The questionnaire asks about undue fatigue, trouble falling asleep, waking up at night, general malaise, apathy, irritability, loss of energy, demoralization, and waking up exhausted. Each item is rated with 0 (‘‘no’’), 1 (‘‘don’t know’’), or 2 (‘‘yes’’) points giving rise to a total exhaustion score between 0 and 18. Five subjects did not complete one item of the MVEQ scale. These missing values were replaced by the mean of an individual’s completed eight items. Type D personality To assess the type D (distressed) personality we used the validated German version [33] of the original type D questionnaire (DS14) [20]. The DS14 comprises two subscales of seven items each to assess negative affectivity and social inhibition. Each item is rated on a 5-point Likert scale that rates a number of statements people often use to describe themselves (0 = ‘‘false’’, 1 = ‘‘rather false’’, 2 = ‘‘neutral’’, 3 = ‘‘rather true’’, 4 = ‘‘true’’) giving rise to a total score between 0 and 28 points for each of the subscales. Typical items are ‘‘I am often irritated’’ and ‘‘I often find myself worrying about something’’ for negative affectivity and ‘‘I find it hard to start a conversation’’ and ‘‘I often feel inhibited in social interactions’’ for social inhibition. Patients are classified as type D if both negative affectivity and social inhibition are greater than or equal to 10 points [20]. One subject missed one item and another subject missed two items of the negative affectivity subscale. The missing values were replaced by the mean of an individual’s completed items of the negative affectivity subscale.
R. von Känel et al.
Exercise testing and heart rate recovery All patients underwent symptom-limited incremental exercise testing on a computer controlled, rotational, speed independent bicycle ergometer (Ergo-metrics 800S, Ergoline® GmbH, Bitz, Germany) while kept on their medication. Exercise testing was in accordance with a standard protocol. After an initial reference phase of 3 min, during which patients cycled without a workload, the test phase began with a 10 W/min ramp protocol until volitional dyspnea or muscle fatigue forced the subjects to terminate the exertion. The protocol stipulated passive recovery from exercise by asking all patients to stop exercise abruptly and to not perform a post-exercise cool-down phase [30]. We continuously recorded a 12-lead electrocardiogram. To obtain HRR-1 we subtracted heart rate at 1 min of passive recovery from the heart rate immediately at the end of exercise. We also recorded peak heart rate during exercise and maximal exercise capacity [W].
Data analyses We used SPSS (version 15.0) statistical software package (Chicago, IL, USA) for data analysis. Twotailed level of significance was set at p < 0.05. All data showed a normal distribution as verified by the Kolmogorov—Smirnov test. Student’s t-test and Fisher’s exact test were applied to test for group differences in continuous and categorical variables, respectively. Pearson correlation analysis was used to estimate bivariate relationships between two variables. Multivariate linear and logistic regression analyses were employed to test whether psychological factors were significantly associated with HRR-1 independent of covariates. All independent variables were forced entry into the regression equation in one block. To prevent model overfitting, we limited the number of control variables to four [34], namely gender, age, LVEF, and maximum exercise capacity. These were selected a priori [33] based on previous literature on their possible association with HRR [5,25—28].
Results Patient characteristics Table 1 shows the demographic, medical, and psychosocial characteristics of the entire sample of patients with CHF as well as the two HRR-1 patient categories. Almost two thirds of all patients had coronary artery disease and more than half were
Personality, exhaustion, and heart rate recovery Table 1
251
Characteristics of the 51 patients with heart failure.
Variable
All patients (n = 51)
HRR-1 ≤ 18 bpm (n = 28)
HRR-1 > 18 bpm (n = 23)
Men [%] Age [years] Left ventricular ejection fraction [%] Coronary artery disease [%] Coronary artery bypass surgery [%] Number of diseased vessels [%]a Treated for hypertension [%] Systolic blood pressure [mm Hg] Diastolic blood pressure [mm Hg] Body mass index [kg/m2 ] Treated for diabetes [%] Dyslipidemia [%] Beta blocker use [%] Aspirin use [%] Angiotensin converting enzyme inhibitor use [%] Maximum exercise capacity [W] Peak heart rate during exercise [bpm] Heart rate recovery-1 [bpm] Vital exhaustion score Negative affectivity score Social inhibition score Type D personality [%]
82 57.7 ± 11.7 26.3 ± 7.3
82 59.1 ± 11.2 26.2 ± 7.1
83 55.9 ± 12.3 26.5 ± 7.7
1.000 0.336 0.899
63 24 37, 16, 10, 37 55 110.4 ± 17.6 71.4 ± 10.2 26.7 ± 5.1 16 53 94 53 71
64 25 36, 14, 11, 39 54 108.8 ± 18.5 69.8 ± 10.0 26.5 ± 4.8 21 61 93 43 71
61 22 39, 17, 9, 35 57 112.4 ± 16.7 73.5 ± 10.4 27.0 ± 5.5 9 44 96 65 70
1.000 1.000 0.971 1.000 0.468 0.198 0.701 0.269 0.267 1.000 0.160 1.000
104.8 ± 36.5 129.7 ±21.5
100.0 ± 29.6 124.1 ± 23.1
110.6 ± 43.8 136.4 ± 17.5
0.309 0.041
19.0 ± 8.8 6.2 ± 5.0 9.5 ± 5.3 9.7 ± 5.8 29
12.5 ± 4.8 7.1 ± 5.2 10.4 ± 5.4 11.1 ± 5.5 43
27.0 ± 5.3 5.0 ± 4.5 8.4 ± 5.2 7.9 ± 5.8 13
p-Value
<0.001 0.124 0.172 0.045 0.030
Values are given as means ±SD or in percentages. Statistical analysis used Student’s t-test and Fisher’s exact test. The p-value refers to differences between HRR-1 groups. HHR-1, decline in heart rate from end of exercise to 1 min recovery. a Normal coronary arteries, 1-vessel disease, 2-vessel disease, 3-vessel disease.
treated for hypertension. While the two groups categorized by HRR-1 had similar maximum exercise capacity, peak heart rate reached during exercise was expectedly higher in the high HRR-1 group relative to the low HRR-1 group. HRR-1 was not different in patients with coronary artery disease compared to those without (p = 0.55). A total of 15 patients were identified with type D personality, whereby the proportion was significantly greater in subjects with HRR-1 ≤ 18 bpm (12 of 28 patients) than in those with HRR-1 > 18 bpm (3 of 23 patients). The groups did not differ in terms of vital exhaustion scores, cardiac function, cardiovascular risk factors, and medication, with virtually all patients having beta blocker treatment. Patients with type D personality had higher scores of vital exhaustion than those without type D personality (10.2 ± 4.5 vs. 4.5 ± 4.1, p < 0.001).
Prediction of heart rate recovery Bivariate analyses There was an inverse relationship between HRR1 and exhaustion (r = −0.31, p = 0.029; Fig. 1).
In addition HRR-1 showed a trend toward statistical significance to be lower in patients with type D personality than in those without (15.7 ± 7.3 bpm vs. 20.4 ± 9.1 bpm, p < 0.09) and to negatively correlate with social inhibition (r = −0.25, p < 0.09). No significant relationships emerged between HRR-1 and gender (p = 0.59), age (p = 0.74), LVEF (p = 0.81), number of diseased vessels (p = 0.50), BMI (p = 0.35), systolic blood pressure (BP) (p = 0.15), diastolic BP (p = 0.20), beta blocker use (p = 0.59), treated diabetes (p = 0.21), and dyslipidemia (p = 0.67). In terms of exercise parameters, HRR-1 showed an expected correlation with peak heart rate during exercise (r = 0.37, p = 0.007), but not with maximum exercise capacity (p = 0.22). Controlled multivariate analyses Continuous measures of heart rate recovery. Tables 2a and 2b show the multivariate linear regression models for exhaustion scores and type D personality as predictors of continuous HRR-1 taking into account age, gender, LVEF, and maximum exercise capacity as covariates. Exhaustion
252
R. von Känel et al.
Figure 1 Bivariate relationship between exhaustion and heart rate recovery. Scatter plot with fit line (95% confidence interval) for the inverse association between the symptoms of vital exhaustion and reduced heart rate recovery in the first minute after exercise (p < 0.03).
explained a significant 8.4% of the variance in HRR1 after controlling for covariates (F1.45 = 4.26, p = 0.045). The unstandardized coefficient B indicated a reduction of 0.5 bpm in HRR-1 for each point increase on the vital exhaustion scale. Type D personality explained 6.5% of the variance in HRR1 after adjustment for covariates; however, this relationship showed only a trend toward statistical significance (F1.45 = 3.25, p < 0.08). In both models none of the covariates emerged as a significant predictor of HRR-1. Categorical measures of heart rate recovery. Tables 3a and 3b show the multivariate logistic regression models for exhaustion scores and type D personality as predictors of categorical HRR-1 (≤18 bpm vs. >18 bpm) with covariates age, gender, LVEF, and maximum exercise capacity. Whereas the level of exhaustion symptoms was not different between the two HRR-1 categories, the likelihood of having HRR-1 ≤ 18 bpm was significantly higher in patients with type D personality than in those without. None of the covariates was a significant predictor of categorical HRR-1 in either model.
Discussion Table 2a Linear exhaustion.
regression
model
Variables entered
Unstandardized coefficient B ± SEM
Constant Gender Age Left ventricular ejection fraction Maximum exercise capacity Vital exhaustion score
20.15 0.15 −0.07 0.14
± ± ± ±
for
vital
p-Value
9.44 3.66 0.14 0.21
0.038 0.967 0.636 0.519
0.02 ± 0.04
0.598
−0.54 ± 0.26
0.045
R2 of entire model = 0.115, F5,45 = 1.17, p = 0.34.
Table 2b Linear regression model for type D personality. Variables entered
Unstandardized coefficient B ± SEM
Constant Gender Age Left ventricular ejection fraction Maximum exercise capacity Type D personality
16.27 0.19 −0.07 0.18
± ± ± ±
p-Value
9.20 3.69 0.14 0.22
0.084 0.958 0.637 0.433
0.03 ± 0.04
0.427
−5.12 ± 2.84
0.078
R2 of entire model = 0.097, F5,45 = 0.97, p = 0.45.
In a sample of patients with CHF we investigated the relationship between HRR-1 and two psychosocial risk factors of cardiovascular disease-vital exhaustion and type D personality-both of which have been demonstrated to affect prognosis of CHF [17,18]. We measured the decline in heart rate into the first minute of recovery from exercise because during this interval the autonomic contribution to HRR is primordially made by the vagus nerve [9] facilitating the physiologic interpretation and potential clinical implications of findings [8]. It is an unresolved issue whether the cardiovascular risk related to HRR lies along a continuum of decreased HRR or sets off only below a threshold value of reduced HRR [29]. This uncertainty prompted us to treat HRR-1 both as a continuous and a categorical variable applying a cut-off value of HRR-1 ≤ 18 bpm to define ‘‘reduced HRR-1’’ as previously suggested for exercise protocols in which exertion was abruptly stopped [30]. We found a gradual relationship between elevated levels of vital exhaustion and decreased HRR-1. The association was observed in bivariate analysis and held significance after statistical adjustment for previous correlates of HRR. Unlike covariates gender, age, LVEF, and maximal exercise capacity, which all were not significantly associated with HRR-1, vital exhaustion explained a substantial 8.4% of the variance. However, we did not
Personality, exhaustion, and heart rate recovery Table 3a
253
Logistic regression model for vital exhaustion.
Variables entered
B ± SEM
Constant Gender Age Left ventricular ejection fraction Maximum exercise capacity Vital exhaustion score
1.25 −0.36 −0.04 0.05 0.01 −0.11
± ± ± ± ± ±
2.08 0.89 0.04 0.05 0.01 0.07
OR (95% CI)
p-Value
3.49 0.70 0.96 1.06 1.00 0.90
0.548 0.688 0.240 0.320 0.699 0.117
(0.12—4.00) (0.90—1.03) (0.95—1.17) (0.98—1.02) (0.79—1.03)
Nagelkerke R2 of entire model = 0.123. Heart rate recovery ≤18 bpm was coded as ‘‘0’’ and men as ‘‘0’’.
observe a greater likelihood for higher levels of vital exhaustion in patients with HRR-1 below or equal to 18 bpm than in those above 18 bpm. This suggests a gradual relationship between vital exhaustion and HRR-1 rather than a categorical one. We further found that the proportion of patients who were classified to have type D personality was significantly greater in the patient group with HRR-1 ≤ 18 bpm relative to the group with HRR1 > 18 bpm. In the multivariate model covarying for gender, age, LVEF, and maximum exercise capacity the relatively increased likelihood for having HRR-1 ≤ 18 bpm as a type D patient maintained its significance. In addition, type D personality reached a trend toward statistical significance as a predictor of continuous HRR-1. The relationship explained 6.5% of the variance and thereby supported the findings from the categorical analysis. The amount of variance explained in HRR-1 by vital exhaustion and type D was quite similar and the proportion of type D persons in the patient group with HRR-1 defined as normal was small. Therefore, we parsimoniously interpret that our findings suggest a clinically meaningful relationship between type D personality and reduced HRR-1 in CHF. However, it would be premature to deem this association more gradual than categorical or vice versa. We found 29% of our patients to have type D personality which prevalence concurs with the 23% and 33%, respectively, observed in other samples of patients with CHF [35,36]. In addition, mean
Table 3b
exhaustion scores of our patients were only slightly lower than in a previous study investigating CHF patients [37]. To the extent that the psychological characteristics of our patients are representative for other samples of CHF patients, the potential clinical importance of the relationship between HRR-1 and vital exhaustion and type D personality is illustrated as follows. In our patients who after adjustment for covariates had an average HRR-1 of 20 bpm, an increase of 6 points on the exhaustion scale corresponded to a decline of 3.2 bpm in HRR-1. HRR-1 was on average 5.1 bpm lower in type D patients than in non-type D patients after adjustment for covariates, too. In patients referred for exercise echocardiography, HRR-1 of 25 bpm, 22 bpm, 19 bpm, and ≤16 bpm previously predicted mortality rates of 2%, 4%, 6%, and 9%, respectively, 3 years later [38]. In other words, for each 3 bpm decline in HRR-1 there was an approximate increase of 2% in the risk of dying during follow-up. Another study followed 87 postmyocardial infarction patients with LVEF≤50% of whom 31% were defined as type D for 8 years [18]. Type D patients had a relative risk of 4.7 to experience cardiac death or nonfatal myocardial infarction relative to non-type D patients. Interestingly, other psychosocial risk factors, namely anxiety, depression, and anger did not add to the predictive power of type D personality [18]. Moreover, in 2449 patients with myocardial infarction, the negative impact of late ventricular failure on
Logistic regression model for Type D personality.
Variables entered
B ± SEM
Constant Gender Age Left ventricular ejection fraction Maximum exercise capacity Type D personality
−1.29 −0.40 −0.05 0.09 0.01 2.03
± ± ± ± ± ±
2.13 0.95 0.04 0.06 0.01 0.83
OR (95% CI)
p-Value
0.28 0.67 0.95 1.09 1.01 7.62
0.546 0.674 0.152 0.139 0.606 0.014
(0.11—4.31) (0.89—1.02) (0.97—1.22) (0.99—1.03) (1.50—38.80)
Nagelkerke R2 of entire model = 0.231. Heart rate recovery ≤18 bpm was coded as ‘‘0’’, men as ‘‘0’’ and presence of type D personality as ‘‘1’’.
254 survival was greater in the presence of high versus low scores of vital exhaustion prior to the infarction and after taking into account clinical characteristics [17]. The authors concluded that the implications of a strong independent predictive value of vital exhaustion as a psychological construct should not be discounted in the clinical management of patients with CHF [17]. The recently completed Exhaustion Intervention Trial indeed demonstrated that a behavioral intervention in patients who felt exhausted after successful percutaneous coronary intervention reduces vital exhaustion scores at least in those without a history of a previous coronary event [39]. In addition, type D scores decreased in patients with coronary artery disease undergoing expanded cardiac rehabilitation with components stress management and increased physical training [40]. Whether decrease in vital exhaustion and type D personality is associated with an increase in HRR-1 has not previously been explored. If a reduction in vital exhaustion and type D characteristics through therapy lowers psychological distress, this might theoretically restore the stress-associated perturbation of the central autonomic network to improve vagus nerve function and HRR-1 in particular [8]. Exercise rehabilitation leads to an increase in HRR [41] and was also employed in the above mentioned randomized trials tailored to reduce vital exhaustion and type D characteristics [39,40]. Exercise regimens are standard in comprehensive cardiac rehabilitation programs delivered to CHF patients. Therefore, studying whether reduction in vital exhaustion and in type D characteristics due to cardiac rehabilitation potentially relate to an increase in HRR-1 merits further effort. Our study was not designed to prove causality. Therefore, intervention studies targeting either psychosocial factors (i.e. vital exhaustion and type D personality) or HRR-1 might help better understand the direction of their relationship and, moreover, whether reducing psychosocial distress is an effective means to improve HRR-1 or vice versa. It is currently unclear why abnormal HRR after exercise is associated with increased cardiovascular morbidity and mortality, although a relationship with greater active ischemia and parasympathetic insufficiency are possible physiologic underpinnings [29]. This notion concurs with experimental studies showing that HRR after the first minute of exercise cessation predominantly reflects vagal tone [9,10]. The vagus nerve exerts tonic inhibitory control over tissue macrophages thereby curtailing inflammatory activity [42]. When this cholinergic anti-inflammatory pathway is weakened the
R. von Känel et al. production of pro-inflammatory cytokines such as tumor-necrosis factor (TNF)-␣, interleukin (IL)-1, and IL-6 is upregulated [43]. The contribution of cytokine toxicity to the prognosis of CHF is abundant given that, for instance, TNF-␣ is highly expressed in the failing myocardium [44]. In patients with stable CHF, circulating levels of TNF␣ were higher in type D patients than in non-type D patients [36]. In addition, vital exhaustion directly correlated with plasma levels of C-reactive protein in healthy subjects [45]. This intriguing research should prompt further investigations about whether increased inflammatory activity is a common mechanism involved in the poor prognostic value of vital exhaustion and type D personality and decreased HRR in CHF. Our findings should be interpreted within the limitations of the study design. The sample size was rather small, thereby limiting statistical power and adjustments for additional potentially important correlates of vagal function related to life style and comorbidities [8]. If our findings are confirmed in a larger sample, this would support the robustness of an association between psychosocial risk factors of cardiovascular disease and HRR-1. Although this possibility remains to be explored, the relationships between vital exhaustion and type D personality on the one hand and reduced HRR-1 on the other might not be restricted to CHF but also to other types of heart diseases. The sample included predominantly men and virtually all patients were treated with beta blockers. However, we statistically controlled for gender and whether beta blockade influences HRR is unclear [5,46,47]. Finally, our study was cross-sectional precluding any inferences about a causal direction of the observed relationships. To conclude, the findings of the present study suggest an independent association between higher levels of vital exhaustion and type D personality on the one hand and reduced HRR-1 as a proxy measure of impaired vagal tone on the other. The findings concur with the prognostic impact of these psychological constructs as well as of decreased HRR in previous studies on patients with CHF suggesting that their relationship might be of clinical importance.
References [1] Imai K, Sato H, Hori M, Kusuoka H, Ozaki H, Yokoyama H, Takeda H, Inoue M, Kamada T. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 1994;24:1529—35. [2] Sheppard RJ, Racine N, Roof A, Ducharme A, Blanchet M, White M. Heart rate recovery—–a potential marker of clinical
Personality, exhaustion, and heart rate recovery
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] [15]
[16]
[17]
[18]
outcomes in heart failure patients receiving beta blocker therapy. Can J Cardiol 2007;23:1135—8. Arena R, Guazzi M, Myers J, Peberdy MA. Prognostic value of heart rate recovery in patients with heart failure. Am Heart J 2006;151:851, e7—e13. Lipinski MJ, Vetrovec GW, Gorelik D, Froelicher VF. The importance of heart rate recovery in patients with heart failure or left ventricular systolic dysfunction. J Card Fail 2005;11:624—30. Nanas S, Anastasiou-Nana M, Dimopoulos S, Sakellariou D, Alexopoulos G, Kapsimalakou S, Papazoglou P, Tsolakis E, Papazachou O, Roussos C, Nanas J. Early heart rate recovery after exercise predicts mortality in patients with chronic heart failure. Int J Cardiol 2006;110:393—400. Bilsel T, Terzi S, Akbulut T, Sayar N, Hobikoglu G, Yesilcimen K. Abnormal heart rate recovery immediately after cardiopulmonary exercise testing in heart failure patients. Int Heart J 2006;47:431—40. Rosenwinkel ET, Bloomfield DM, Arwady MA, Goldsmith RL. Exercise and autonomic function in health and cardiovascular disease. Cardiol Clin 2001;19:369—87. Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol 2007;74:224—42. Buchheit M, Papelier Y, Laursen PB, Ahmaidi S. Noninvasive assessment of cardiac parasympathetic function: postexercise heart rate recovery or heart rate variability? Am J Physiol Heart Circ Physiol 2007;293:H8—10. Dewland TA, Androne AS, Lee FA, Lampert RJ, Katz SD. Effect of acetylcholinesterase inhibition with pyridostigmine on cardiac parasympathetic function in sedentary adults and trained athletes. Am J Physiol Heart Circ Physiol 2007;293:H86—92. Pelle AJ, Gidron YY, Szabó BM, Denollet J. Psychological predictors of prognosis in chronic heart failure. J Card Fail 2008;14:341—50. MacMahon KM, Lip GY. Psychological factors in heart failure: a review of the literature. Arch Intern Med 2002;162:509—16. Kop WJ, Appels AP, Mendes de Leon CF, de Swart HB, Bär FW. Vital exhaustion predicts new cardiac events after successful coronary angioplasty. Psychosom Med 1994;56:281—7. Appels A, Mulder P. Excess fatigue as a precursor of myocardial infarction. Eur Heart J 1988;9:758—64. Denollet J, Sys SU, Stroobant N, Rombouts H, Gillebert TC, Brutsaert DL. Personality as independent predictor of longterm mortality in patients with coronary heart disease. Lancet 1996;347:417—21. Pedersen SS, Lemos PA, van Vooren PR, Liu TK, Daemen J, Erdman RA, Smits PC, Serruys PW, van Domburg RT. Type D personality predicts death or myocardial infarction after bare metal stent or sirolimus eluting stent implantation: a Rapamycin Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry substudy. J Am Coll Cardiol 2004;44:997—1001. Carinci F, Nicolucci A, Ciampi A, Labbrozzi D, Bettinardi O, Zotti AM, Tognoni G. Role of interactions between psychological and clinical factors in determining 6-month mortality among patients with acute myocardial infarction. Application of recursive partitioning techniques to the GISSI-2 database. Gruppo Italiano per lo Studio della Sopravvivenza nell’ Infarto Miocardico. Eur Heart J 1997;18:835—45. Denollet J, Brutsaert DL. Personality, disease severity, and the risk of long-term cardiac events in patients with a decreased ejection fraction after myocardial infarction. Circulation 1998;97:167—73.
255 [19] Appels A. Exhaustion and coronary heart disease: the history of a scientific quest. Patient Educ Couns 2004;55:223—9. [20] Denollet J. DS14: standard assessment of negative affectivity, social inhibition, and type D personality. Psychosom Med 2005;67:89—97. [21] Hughes JW, York KM, Li Q, Freedland KE, Carney RM, Sheps DS. Depressive symptoms predict heart rate recovery after exercise treadmill testing in patients with coronary artery disease: results from the psychophysiological investigation of myocardial ischemia study. Psychosom Med 2008;70:456—60. [22] Hughes JW, Casey E, Luyster F, Doe VH, Waechter D, Rosneck J, Josephson R. Depression symptoms predict heart rate recovery after treadmill stress testing. Am Heart J 2006;151:1122, e1—e6. [23] Pelle AJ, Denollet J, Zwisler AD, Pedersen SS. Overlap and distinctiveness of psychological risk factors in patients with ischemic heart disease and chronic heart failure: are we there yet? J Affect Disord 2008;24(June) [Epub ahead of print]. [24] Kudielka BM, von Känel R, Gander ML, Fischer JE. The interrelationship of psychosocial risk factors for coronary artery disease in a working population: do we measure distinct or overlapping psychological concepts? Behav Med 2004;30:35—43. [25] Kligfield P, McCormick A, Chai A, Jacobson A, Feuerstadt P, Hao SC. Effect of age and gender on heart rate recovery after submaximal exercise during cardiac rehabilitation in patients with angina pectoris, recent acute myocardial infarction, or coronary bypass surgery. Am J Cardiol 2003;9:600—3. [26] Georgoulias P, Orfanakis A, Demakopoulos N, Xaplanteris P, Mortzos G, Vardas P, Karkavistas N. Abnormal heart rate recovery immediately after treadmill testing: correlation with clinical, exercise testing, and myocardial perfusion parameters. J Nucl Cardiol 2003;10:498—505. [27] Lima RS, De Lorenzo A, Soares AJ. Relation between postexercise abnormal heart rate recovery and myocardial damage evidenced by gated single-photon emission computed tomography. Am J Cardiol 2006;97:1452—4. [28] Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999;341:1351—7. [29] Lahiri MK, Kannankeril PJ, Goldberger JJ. Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications. J Am Coll Cardiol 2008;51:1725—33. [30] Chaitman BR. Abnormal heart rate responses to exercise predict increased long-term mortality regardless of coronary disease extent: the question is why? J Am Coll Cardiol 2003;42:839—41. [31] Schnorpfeil P, Noll A, Wirtz P, Schulze R, Ehlert U, Frey K, Fischer JE. Assessment of exhaustion and related risk factors in employees in the manufacturing industry—– a cross sectional study. Int Arch Occup Environ Health 2002;75:535—40. [32] Appels A, Höppener P, Mulder P. A questionnaire to assess premonitory symptoms of myocardial infarction. Int J Cardiol 1987;17:15—24. [33] Grande G, Jordan J, Kümmel M, Struwe C, Schubmann R, Schulze F, Unterberg C, von Känel R, Kudielka BM, Fischer J, Herrmann-Lingen C. Evaluation of the German type D scale (DS14) and prevalence of the type D personality pattern in cardiological and psychosomatic patients and healthy subjects [German]. Psychother Psychosom Med Psychol 2004;54:413—22.
256
R. von Känel et al.
[34] Babyak MA. What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models. Psychosom Med 2004;66:411—21. [35] Schiffer AA, Pedersen SS, Widdershoven JW, Denollet J. Type D personality and depressive symptoms are independent predictors of impaired health status in chronic heart failure. Eur J Heart Fail 2008;10:802—10. [36] Conraads VM, Denollet J, De Clerck LS, Stevens WJ, Bridts C, Vrints CJ. Type D personality is associated with increased levels of tumour necrosis factor (TNF)-alpha and TNFalpha receptors in chronic heart failure. Int J Cardiol 2006;113:34—8. [37] Herrmann-Lingen C, Binder L, Klinge M, Sander J, Schenker W, Beyermann B, von Lewinski D, Pieske B. High plasma levels of N-terminal pro-atrial natriuretic peptide associated with low anxiety in severe heart failure. Psychosom Med 2003;65:517—22. [38] Watanabe J, Thamilarasan M, Blackstone EH, Thomas JD, Lauer MS. Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. Circulation 2001;104:1911—6. [39] Appels A, van Elderen T, Bär F, van der Pol G, Erdman RA, Assman M, Trijsburg W, van Diest R, van Dixhoorn J, Pedersen SS. Effects of a behavioural intervention on quality of life and related variables in angioplasty patients: results of the exhaustion intervention trial. J Psychosom Res 2006;61:1—7.
[40] Karlsson MR, Edström-Plüss C, Held C, Henriksson P, Billing E, Wallén NH. Effects of expanded cardiac rehabilitation on psychosocial status in coronary artery disease with focus on type D characteristics. J Behav Med 2007;30: 253—61. [41] Dimopoulos S, Anastasiou-Nana M, Sakellariou D, Drakos S, Kapsimalakou S, Maroulidis G, Roditis P, Papazachou O, Vogiatzis I, Roussos C, Nanas S. Effects of exercise rehabilitation program on heart rate recovery in patients with chronic heart failure. Eur J Cardiovasc Prev Rehabil 2006;13:67—73. [42] Tracey KJ. The inflammatory reflex. Nature 2002;420: 853—9. [43] Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007;117:289—96. [44] El-Menyar AA. Cytokines and myocardial dysfunction: state of the art. J Card Fail 2008;14:61—74. [45] von Känel R, Frey K, Fischer J. Independent relation of vital exhaustion and inflammation to fibrinolysis in apparently healthy subjects. Scand Cardiovasc J 2004;38:28—32. [46] Desai MY, De la Pe˜ na-Almaguer E, Mannting F. Abnormal heart rate recovery after exercise as a reflection of an abnormal chronotropic response. Am J Cardiol 2001;87:1164—9. [47] Racine N, Blanchet M, Ducharme A, Marquis J, Boucher JM, Juneau M, White M. Decreased heart rate recovery after exercise in patients with congestive heart failure: effect of beta-blocker therapy. J Card Fail 2003;9:296—302.
Available online at www.sciencedirect.com