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Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season
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Original article
Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season Hidehiro Kaneko (MD, PhD) ∗ , Shinya Suzuki (MD), Masato Goto (MD), Takuto Arita (MD), Yasufumi Yuzawa (MD), Naoharu Yagi (MD), Nobuhiro Murata (MD), Junji Yajima (MD), Yuji Oikawa (MD), Koichi Sagara (MD), Takayuki Otsuka (MD), Shunsuke Matsuno (MD), Hiroto Kano (MD), Tokuhisa Uejima (MD), Kazuyuki Nagashima (MD), Hajime Kirigaya (MD), Hitoshi Sawada (MD, FJCC), Tadanori Aizawa (MD, FJCC), Takeshi Yamashita (MD, FJCC) The Cardiovascular Institute, Tokyo, Japan
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Article history: Received 17 December 2013 Received in revised form 23 February 2014 Accepted 18 March 2014 Available online xxx Keywords: Heart failure Winter Japanese
a b s t r a c t Background: Seasonal variations in cardiovascular disease is well recognized. However, little is known about the presentations and outcomes of Japanese heart failure (HF) patients in the winter season. Methods and results: We used a single hospital-based cohort from the Shinken Database 2004–2012, comprising all new patients (n = 19,994) who visited the Cardiovascular Institute Hospital. A total of 375 patients who were admitted owing to acute decompensated HF were included in the analysis. Of these patients, 136 (36%) were admitted in winter. Winter was defined as the period between December and February. The HF patients admitted in winter were older, and had a higher prevalence of hypertension and diabetes mellitus than the patients admitted in other seasons. Patients with conditions categorized as clinical scenario 1 tended to be admitted more commonly in winter. HF with preserved left ventricular ejection fraction (LVEF) was more common in HF patients admitted in winter than in those admitted in other seasons. Beta-blocker use at hospital discharge was more common in the patients admitted in other seasons. Kaplan–Meier curves and log-rank test results indicated that the incidences of all-cause death, cardiovascular death, and HF admission were comparable between the patients admitted in winter and those admitted in other seasons. Conclusions: HF admission was frequently observed in the winter season and HF patients admitted in the winter season were older, and had higher prevalence of hypertension and diabetes mellitus, and preserved LVEF suggesting that we might need to pay more attention for elderly patients with hypertension, diabetes mellitus, and HF with preserved LVEF to decrease HF admissions in the winter season. © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Introduction The seasonal variation in the incidence of various cardiovascular diseases is well established [1–4]. The environmental temperature is associated with this variability, as cardiovascular events peak in winter. The physiologic consequences of a cold climate are thought to result in increased coronary risk factors and might
∗ Corresponding author at: The Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19, Nishiazabu, Minato-ku, Tokyo 106-0031, Japan. Tel.: +81 3 3408 2151; fax: +81 3 3408 2159. E-mail addresses: [email protected], [email protected] (H. Kaneko).
also cause clinical deterioration in patients with heart failure (HF). Skin cooling has been shown to increase systemic vascular resistance [5], heart rate [6], plasma norepinephrine concentration [7], circulating levels of vasoconstrictor peptides [8], and blood pressure (BP) [9]. In keeping with these changes, BP is higher in winter [10]. Cold can also induce myocardial ischemia [11]. All of these effects could clearly lead to worsening of HF. However, little is known about the clinical characteristics and outcomes of Japanese HF patients admitted in winter. In the present study, we aimed to elucidate the characteristics and clinical outcomes of patients with acute decompensated HF admitted in winter by examining data from our hospital-based cohort selected from the Shinken Database 2004–2012.
http://dx.doi.org/10.1016/j.jjcc.2014.03.004 0914-5087/© 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaneko H, et al. Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.03.004
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Methods Study patients The Shinken Database includes all patients who visited the Cardiovascular Institute in Tokyo, Japan (“Shinken” is a Japanese abbreviation for the name of the hospital), and excludes patients who are foreign travelers and those with active cancer. This hospital-based database was established to investigate the prevalence and prognosis of cardiovascular diseases in the urban areas of Japan [12,13]. The registry began in June 2004, and patients have been continually registered to the database annually. The present study analyzed data from this database collected between June 2004 and March 2013 (Shinken Database 2004–2012) and included 19,994 new visiting patients. Among them, 537 patients were admitted to our institute due to acute decompensated HF. We excluded HF patients with primary valvular heart disease (n = 138) and acute coronary syndrome (n = 24). Valvular heart disease was defined as long-standing mitral or aortic valve involvement, as documented by physical examination and echocardiography, angiography, or history of surgical repair. Finally, 375 patients were examined in the present study (Fig. 1). These patients were followed up for an average period of 857 ± 846 days. Winter was defined as the period between December and February. Ethics The ethical committee of the Cardiovascular Institute approved this study, and all the patients provided written informed consent. Data collection For each patient, after undergoing electrocardiography and chest radiography, cardiovascular status was evaluated by echocardiography, an exercise test, 24-h Holter recordings, and blood laboratory data, as prescribed by the attending physician, within 3 months after the first visit. As initial clinical parameters, collected data included gender, age, body mass index, drug information, and coexisting conditions, including hypertension, atrial fibrillation, diabetes mellitus, and dyslipidemia. In most patients, additional echocardiographic parameters included left ventricular diameter of the diastole (LVDd), LV diameter of the systole (LVDs), interventricular septum thickness (IVST), posterior wall thickness (PWT), and LV ejection fraction (LVEF) using M-mode echocardiography. Anemia was defined as a hemoglobin level of <11 g/dL. An estimated glomerular filtration rate (eGFR) was calculated using the eGFR equation for the Japanese population: eGFR = 194 × (serum
The Shinken Database 2004-2012 (n=19,994)
Acute Decompensated Heart Failure Admission (n=537) Primary Valvular Disease (n=138) Acute Coronary Syndrome (n=24) Examined in the Present Study (n=375) Fig. 1. Patient flow chart of the present study.
creatinine)−1.094 × (age)−0.287 × (0.739, if the patient is female) [14]. A baseline eGFR < 60 mL min−1 1.73 m−2 was used to define chronic kidney disease (CKD) [15]. Idiopathic dilated cardiomyopathy was diagnosed by the presence of global LV dilatation with impaired systolic function occurring in the absence of known cardiac causes. Hypertrophic cardiomyopathy was diagnosed by echocardiography when hypertrophy (IVST or PWT > 12 mm) without hypertension was present. We defined HFpEF patients as HF patients with preserved LVEF (i.e. LVEF > 50%), and HFrEF patients as HF patients with reduced LVEF (i.e. LVEF ≤ 50%), as previously described [16,17]. Patients were divided into three groups by clinical scenario (CS): CS1, systolic BP (SBP) at admission >140 mmHg; CS2, ≥100 mmHg; CS3, <100 mmHg [18]. We confirmed the deaths of study patients by the medical records of our hospital or by the information obtained during follow-up. We defined cardiovascular death as death resulting from acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, or death due to other cardiovascular causes [19]. We confirmed HF events (HF requiring hospitalization or death due to HF) that were classified as per the International Classification of Diseases, 10th revision, code I50, using the medical records of our hospital or by the information obtained from follow-up. Patient follow-up The health status, incidence of cardiovascular events and mortality of patients are maintained in the database by linking these data to the medical records of the hospital and through study documents that were sent one a year to those who stopped hospital visits or who were referred to other hospitals. We excluded the follow-up data obtained after April 1, 2013 from data analysis. Therefore, the end of the follow-up period was defined as one of the following: (1) the date of death, if the date was before March 31, 2013; (2) the final hospital visit or the final response to our study documents involving prognosis with confirmation of being alive before March 31, 2013; (3) March 31, 2013, when the date of death, the final hospital visit, or the final response to our study documents involving prognosis was later than April 1, 2013. Statistical analysis Categorical and consecutive data regarding patient background are presented as numbers (%) and means ± standard deviation, respectively. The chi-square test was used for comparisons between groups, and the unpaired t-test was used for comparison of consecutive variables. Long-term, event-free survival was estimated using Kaplan–Meier curves and the log-rank test to assess the significance of differences between the two groups. Logistic regression analysis was used to identify the determinants of HF patients in the winter season. Univariate and age-adjusted Cox regression analysis were performed to clarify the association between HF admission in the winter season and long-term clinical outcomes. A probability value of <0.05 was considered to indicate a statistically significant difference. Statistical analyses were performed using SPSS (SPSS Inc., Chicago, IL, USA), version 19.0 software. Results Patient characteristics Among the 375 patients with HF, 136 (36%) were admitted in winter, and 239 patients (64%) were admitted in the other seasons. The distribution of the admission month among
Please cite this article in press as: Kaneko H, et al. Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.03.004
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60
Number of patients
50
40
30
20
10
0
Month Fig. 2. Distribution of month among the study patients.
the study patients is shown in Fig. 2. The HF patients admitted in the winter season were older than those admitted in the other seasons (70 ± 13 years vs. 67 ± 14 years, p = 0.034). Gender difference was not seen between the two groups. Patients of winter season had a higher prevalence of hypertension (65% vs. 54%, p = 0.025) and diabetes mellitus (35% vs. 24%, p = 0.023). The prevalence rates of ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, and hypertensive heart disease were comparable between the two groups. White blood cell counts (7570 ± 2925 L vs. 7857 ± 3408 L, p = 0.394) and C-reactive protein levels (1.7 ± 3.4 mg/dL vs. 1.9 ± 4.2 mg/dL, p = 0.578) at admission were comparable between the patients in winter and other seasons. B-type natriuretic peptide levels at admission were also comparable between the patients in winter and other seasons (859 ± 874 pg/mL vs. 874 ± 902 pg/mL, p = 0.877). The condition classified as CS1 tended to be more common in winter admission group (39% vs. 29%, p = 0.051) (Table 1). Ultrasound cardiography Ultrasound echocardiography revealed that LVDd (53 ± 10 mm vs. 56 ± 11 mm, p = 0.014), and LVDs (41 ± 14 mm vs. 45 ± 14 mm, p = 0.013) were smaller in HF patients in winter than those in other seasons. LVEF was greater in HF patients in the winter season (47 ± 21% vs. 39 ± 20%, p = 0.001). The prevalence of HFpEF was higher in HF patients in the winter season (46% vs. 30%, p = 0.002) (Table 2). Medication at hospital discharge The use of beta-blockers was more common in the HF patients admitted in the other seasons than in those admitted in winter (71% vs. 60%, p = 0.032). The use of other cardiovascular drugs including calcium channel blockers, rennin-angiotensin-system inhibitors, statins, loop diuretics, aldosterone antagonists, digitalis, nitrate, and amiodarone was comparable between the two groups (Table 3). Determinants of heart failure in winter Multivariate logistic regression analysis (step-wise model) including following covariates age ≥75 years, hypertension,
diabetes mellitus, and HFpEF demonstrated that diabetes mellitus [odds ratio (OR) 1.698, 95% confidence interval (CI) 1.064–2.708, p = 0.026] and HFpEF (OR 1.969, 95% CI 1.264–3.067, p = 0.003) were independent determinants of HF admission in winter (Table 4). Clinical outcomes All-cause death (in-hospital death) occurred in 9.6% (1.5%) of the HF patients admitted in winter, and in 10% (0.8%) of those admitted in the other seasons. Cardiovascular death occurred in 6.6% of the patients in winter, and 7.5% of patients in the other seasons. Readmission for HF occurred in 25% of the patients
Table 1 Characteristics of patients. Other seasons (n = 239)
Winter season (n = 136)
p-Value
Age (years) Male BMI (kg/m2 ) Hypertension Dyslipidemia Diabetes mellitus Hyperuricemia Cigarette smoking CKD Anemia ICM DCM HCM HHD AF WBC (/L) CRP (mg/dL) BNP (pg/mL)
67 ± 14 72% 24 ± 4.6 54% 28% 24% 23% 39% 13% 21% 30% 23% 2.5% 4.6% 36% 7570 ± 2925 1.7 ± 3.4 874 ± 902
70 ± 13 68% 25 ± 4.3 65% 37% 35% 24% 43% 16% 18% 28% 16% 4.4% 8.8% 40% 7857 ± 3408 1.9 ± 4.2 859 ± 874
0.034 0.412 0.295 0.025 0.079 0.023 0.909 0.397 0.460 0.390 0.655 0.099 0.315 0.101 0.474 0.394 0.578 0.877
CS I II III
29% 63% 7%
39% 55% 6%
0.051 0.111 0.705
BMI, body mass index; CKD, chronic kidney disease; ICM, ischemic cardiomyopathy; DCM, idiopathic dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HHD, hypertensive heart disease; AF, atrial fibrillation; WBC, white blood cell count; CRP, C-reactive protein level; BNP, brain natriuretic peptide; CS, clinical scenario. Data are expressed as mean ± standard deviation, or percentage.
Please cite this article in press as: Kaneko H, et al. Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.03.004
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IVST (mm) PWT (mm) LVDd (mm) LVDs (mm) LVEF (%) HFpEF HFrEF LAD (mm)
Other seasons (n = 239)
Winter season (n = 136)
p-Value
9.8 ± 4.6 9.0 ± 1.9 56 ± 11 45 ± 14 39 ± 20 30% 70% 44 ± 9.5
10.1 ± 2.7 9.2 ± 2.0 53 ± 10 41 ± 14 47 ± 21 46% 55% 44 ± 9.2
0.533 0.258 0.014 0.013 0.001 0.002 0.002 0.480
IVST, interventricular septum thickness; PWT, posterior wall thickness; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVEF, left ventricular ejection fraction; HFpEF, heart failure with preserved left ventricular ejection fraction; HFrEF, heart failure with reduced left ventricular ejection fraction; LAD, left atrial dimension. Data are expressed as mean ± standard deviation. Table 3 Medication at hospital discharge.
Beta-blockers CCBs RAS-Is Statins Loop diuretics Aldosterone antagonist Digitalis Nitrate Amiodarone
Other seasons (n = 237)
Winter season (n = 134)
p-Value
71 30 75 30 77 47 16 12 7.6
60 36 72 32 81 38 15 7 4.5
0.032 0.212 0.566 0.608 0.306 0.102 0.778 0.115 0.241
CCB, calcium-channel blocker; RAS-I, renin-angiotensin system inhibitor. Data are expressed as percentages.
Table 4 Determinants of winter heart failure.
Diabetes mellitus HFpEF
OR
95% CI
p-Value
1.698 1.969
1.064–2.708 1.264–3.067
0.026 0.003
Logistic regression analysis for heart failure admission in winter. OR, odds ratio; CI, confidence interval; HFpEF, heart failure with preserved left ventricular ejection fraction.
admitted in winter and 22% of the patients in the other seasons (Table 5). Kaplan–Meier curves and log-rank test showed that the incidences of all-cause death (Fig. 3A, log-rank p = 0.950), cardiovascular death (Fig. 3B, log-rank p = 0.826), and HF admission (Fig. 3C, log-rank p = 0.314) of the patients admitted in winter and the other seasons. Similar to Kaplan–Meier curves, unadjusted Cox regression analysis demonstrated that HF admission in winter was not significantly associated with all-cause death (HR 0.979, 95% CI 0.498–1.923, p = 0.950), cardiovascular disease death (HR 0.914, 95% CI 0.411–2.036, p = 0.826), and heart failure admission (HR 1.247, 95% CI 0.810–1.919, p = 0.315). Even after adjustment for age, HF admission in winter was not significantly associated with all-cause death (HR 0.923, 95% CI 0.470–1.815, p = 0.817), Table 5 Clinical outcomes.
All-cause death In-hospital death Cardiovascular death Heart failure admission
Other seasons (n = 239)
Winter season (n = 136)
p-Value
10 0.8 7.5 22
9.6 1.5 6.6 25
0.880 0.566 0.742 0.533
Data are expressed as percentages.
cardiovascular death (HR 0.860, 95% CI 0.386–1.916, p = 0.712), and HF admission (HR 1.216, 95% CI 0.790–1.871, p = 0.375) (Supplementary Table 1). Discussion The present study reports the data from an observational cohort of HF patients that was analyzed to determine the characteristics and outcomes of acute decompensated HF patients who were admitted in winter. The major findings of the present study were as follows: (1) Admission for HF occurred frequently in winter (136/375, 36%). (2) The HF patients admitted in the winter season were older than those admitted in the other seasons. The prevalence of hypertension and diabetes mellitus was greater in the patients in the winter season. The CS1 classification tended to be more common and LVEF was higher in the patients admitted in winter than in those admitted in other seasons. (3) Kaplan–Meier curves and log-rank test results showed the incidences of all-cause death (log-rank p = 0.950), cardiovascular death (log-rank p = 0.826), and hospital admission for HF (logrank p = 0.314) in the patients admitted in winter and other seasons. In the present study, HF admission was commonly observed in winter (36%) when compared with the other seasons, which was in agreement with a previous study [20]. HF patients admitted in the winter season were older than those admitted in the other seasons. Furthermore, patients in the winter season more frequently had hypertension and diabetes mellitus compared with those admitted in the other seasons. Interestingly, HF patients in winter had a higher prevalence of HFpEF than HF patients in the other seasons. As older age, hypertension, and diabetes mellitus are well-known clinical features of HF with preserved LVEF [17], our results suggest that HFpEF is an important clinical presentation of HF patients in the winter season. Despite these differences in patient characteristics, clinical outcomes including in-hospital mortality, long-term mortality, long-term cardiovascular mortality, and occurrences of readmission for HF were comparable between the HF patients admitted in winter and the other seasons. Since HF patients in winter were older than those admitted in the other seasons, we performed an age-adjusted Cox regression analysis. Even after adjustment for age, HF admission in winter was not significantly associated with long-term outcomes. Because the HF patients admitted in winter had diabetes mellitus more frequently, we might expect these patients to have worse clinical outcomes than those admitted in the other seasons. On the other hand, the patients admitted in winter were more likely to have a CS1 condition, which was thought to be associated with clinical outcomes more favorable than other CS categories. The results of the present study are in keeping with the seasonal variation observed in other cardiovascular diseases such as acute coronary syndrome and sudden death [1,4]. Consequently, these cardiovascular diseases might share common mechanisms that exacerbate the amplitude of the seasonal variation of other cardiovascular syndromes. For example, the hemodynamic stresses and neurohumoral activation that accompany lower temperatures might exacerbate HF, induce myocardial ischemia, and precipitate arrhythmias [6–11]. Furthermore, both ischemia and arrhythmias could worsen HF. Other mechanisms could also underlie the seasonal variation in HF. For example, respiratory infection, especially those related to influenza, are more frequent in winter and could precipitate HF [21]. Although there were no significant
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Fig. 3. Kaplan–Meier curves for all-cause death rate (A), cardiovascular death rate (B), and heart failure admission rate (C).
differences in the white blood cell counts and serum C-reactive protein levels on hospital admission between patients in winter and other seasons, we need to pay attention to infections including respiratory infection and influenza virus infection as important worsening factors of HF in the winter season. In addition, alcohol
consumption increases in December [22]. Considering that alcohol induces atrial fibrillation and depresses myocardial contractility, increased consumption of alcohol might aggravate HF in winter [22,23]. Depression, which also worsens in the winter season, might contribute to acute HF [24].
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Clinical implications The results of the present study have clinical significance and might affect HF management. Considering that almost 40% of the HF admissions in this study occurred in winter, increased vigilance in winter is warranted in clinical practice. Moreover based on the higher prevalence of older age, hypertension, and CS1 in the HF patients seen in winter, BP control should be closely monitored in such patients, especially among the elderly. Study limitations The present study had several limitations. Our hospital is a single-department cardiovascular facility; therefore, the results of this study cannot be generalized to all medical centers. Furthermore, the sample size of the present study was limited, and thus, the statistical power might not be strong enough for any negative data to be conclusive. As described above, the inflammatory markers on admission were comparable between HF patients in the winter season and in the other seasons. However, further studies are needed to clarify the association between infection and HF admission in the winter season. Conclusions HF admission was frequently observed in the winter season and HF patients admitted in the winter season were older, had higher prevalence of hypertension and diabetes mellitus, and preserved LVEF. Therefore, we might need to pay more attention to elderly patients with hypertension, diabetes mellitus, and HF with preserved LVEF to decrease HF admissions in the winter season. Acknowledgments We thank Shiro Ueda and Nobuko Ueda of Medical Edge Co Ltd, for assembling the database by Clinical Study Supporting System (CliSSS), and Ineko Hayakawa, Hiroaki Arai, and Hiroshi Aoki for data management and system administration. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jjcc.2014.03.004. References [1] Marchant B, Ranjadayalan K, Stevenson R, Wilkinson P, Timmis AD. Circadian and seasonal factors in the pathogenesis of acute myocardial infarction: the influence of environmental temperature. Br Heart J 1993;69:385–7. [2] Ornato JP, Peberdy MA, Chandra NC, Bush DE. Seasonal pattern of acute myocardial infarction in the National Registry of Myocardial Infarction. J Am Coll Cardiol 1996;28:1684–8. [3] Spencer FA, Goldberg RJ, Becker RC, Gore JM. Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction. J Am Coll Cardiol 1998;31:1226–33. [4] Arntz HR, Willich SN, Schreiber C, Bruggemann T, Stern R, Schultheiss HP. Diurnal, weekly and seasonal variation of sudden death. Population-based analysis of 24,061 consecutive cases. Eur Heart J 2000;21:315–20.
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Original article
Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season Hidehiro Kaneko (MD, PhD) ∗ , Shinya Suzuki (MD), Masato Goto (MD), Takuto Arita (MD), Yasufumi Yuzawa (MD), Naoharu Yagi (MD), Nobuhiro Murata (MD), Junji Yajima (MD), Yuji Oikawa (MD), Koichi Sagara (MD), Takayuki Otsuka (MD), Shunsuke Matsuno (MD), Hiroto Kano (MD), Tokuhisa Uejima (MD), Kazuyuki Nagashima (MD), Hajime Kirigaya (MD), Hitoshi Sawada (MD, FJCC), Tadanori Aizawa (MD, FJCC), Takeshi Yamashita (MD, FJCC) The Cardiovascular Institute, Tokyo, Japan
a r t i c l e
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Article history: Received 17 December 2013 Received in revised form 23 February 2014 Accepted 18 March 2014 Available online xxx Keywords: Heart failure Winter Japanese
a b s t r a c t Background: Seasonal variations in cardiovascular disease is well recognized. However, little is known about the presentations and outcomes of Japanese heart failure (HF) patients in the winter season. Methods and results: We used a single hospital-based cohort from the Shinken Database 2004–2012, comprising all new patients (n = 19,994) who visited the Cardiovascular Institute Hospital. A total of 375 patients who were admitted owing to acute decompensated HF were included in the analysis. Of these patients, 136 (36%) were admitted in winter. Winter was defined as the period between December and February. The HF patients admitted in winter were older, and had a higher prevalence of hypertension and diabetes mellitus than the patients admitted in other seasons. Patients with conditions categorized as clinical scenario 1 tended to be admitted more commonly in winter. HF with preserved left ventricular ejection fraction (LVEF) was more common in HF patients admitted in winter than in those admitted in other seasons. Beta-blocker use at hospital discharge was more common in the patients admitted in other seasons. Kaplan–Meier curves and log-rank test results indicated that the incidences of all-cause death, cardiovascular death, and HF admission were comparable between the patients admitted in winter and those admitted in other seasons. Conclusions: HF admission was frequently observed in the winter season and HF patients admitted in the winter season were older, and had higher prevalence of hypertension and diabetes mellitus, and preserved LVEF suggesting that we might need to pay more attention for elderly patients with hypertension, diabetes mellitus, and HF with preserved LVEF to decrease HF admissions in the winter season. © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Introduction The seasonal variation in the incidence of various cardiovascular diseases is well established [1–4]. The environmental temperature is associated with this variability, as cardiovascular events peak in winter. The physiologic consequences of a cold climate are thought to result in increased coronary risk factors and might
∗ Corresponding author at: The Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19, Nishiazabu, Minato-ku, Tokyo 106-0031, Japan. Tel.: +81 3 3408 2151; fax: +81 3 3408 2159. E-mail addresses: [email protected], [email protected] (H. Kaneko).
also cause clinical deterioration in patients with heart failure (HF). Skin cooling has been shown to increase systemic vascular resistance [5], heart rate [6], plasma norepinephrine concentration [7], circulating levels of vasoconstrictor peptides [8], and blood pressure (BP) [9]. In keeping with these changes, BP is higher in winter [10]. Cold can also induce myocardial ischemia [11]. All of these effects could clearly lead to worsening of HF. However, little is known about the clinical characteristics and outcomes of Japanese HF patients admitted in winter. In the present study, we aimed to elucidate the characteristics and clinical outcomes of patients with acute decompensated HF admitted in winter by examining data from our hospital-based cohort selected from the Shinken Database 2004–2012.
http://dx.doi.org/10.1016/j.jjcc.2014.03.004 0914-5087/© 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaneko H, et al. Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.03.004
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Methods Study patients The Shinken Database includes all patients who visited the Cardiovascular Institute in Tokyo, Japan (“Shinken” is a Japanese abbreviation for the name of the hospital), and excludes patients who are foreign travelers and those with active cancer. This hospital-based database was established to investigate the prevalence and prognosis of cardiovascular diseases in the urban areas of Japan [12,13]. The registry began in June 2004, and patients have been continually registered to the database annually. The present study analyzed data from this database collected between June 2004 and March 2013 (Shinken Database 2004–2012) and included 19,994 new visiting patients. Among them, 537 patients were admitted to our institute due to acute decompensated HF. We excluded HF patients with primary valvular heart disease (n = 138) and acute coronary syndrome (n = 24). Valvular heart disease was defined as long-standing mitral or aortic valve involvement, as documented by physical examination and echocardiography, angiography, or history of surgical repair. Finally, 375 patients were examined in the present study (Fig. 1). These patients were followed up for an average period of 857 ± 846 days. Winter was defined as the period between December and February. Ethics The ethical committee of the Cardiovascular Institute approved this study, and all the patients provided written informed consent. Data collection For each patient, after undergoing electrocardiography and chest radiography, cardiovascular status was evaluated by echocardiography, an exercise test, 24-h Holter recordings, and blood laboratory data, as prescribed by the attending physician, within 3 months after the first visit. As initial clinical parameters, collected data included gender, age, body mass index, drug information, and coexisting conditions, including hypertension, atrial fibrillation, diabetes mellitus, and dyslipidemia. In most patients, additional echocardiographic parameters included left ventricular diameter of the diastole (LVDd), LV diameter of the systole (LVDs), interventricular septum thickness (IVST), posterior wall thickness (PWT), and LV ejection fraction (LVEF) using M-mode echocardiography. Anemia was defined as a hemoglobin level of <11 g/dL. An estimated glomerular filtration rate (eGFR) was calculated using the eGFR equation for the Japanese population: eGFR = 194 × (serum
The Shinken Database 2004-2012 (n=19,994)
Acute Decompensated Heart Failure Admission (n=537) Primary Valvular Disease (n=138) Acute Coronary Syndrome (n=24) Examined in the Present Study (n=375) Fig. 1. Patient flow chart of the present study.
creatinine)−1.094 × (age)−0.287 × (0.739, if the patient is female) [14]. A baseline eGFR < 60 mL min−1 1.73 m−2 was used to define chronic kidney disease (CKD) [15]. Idiopathic dilated cardiomyopathy was diagnosed by the presence of global LV dilatation with impaired systolic function occurring in the absence of known cardiac causes. Hypertrophic cardiomyopathy was diagnosed by echocardiography when hypertrophy (IVST or PWT > 12 mm) without hypertension was present. We defined HFpEF patients as HF patients with preserved LVEF (i.e. LVEF > 50%), and HFrEF patients as HF patients with reduced LVEF (i.e. LVEF ≤ 50%), as previously described [16,17]. Patients were divided into three groups by clinical scenario (CS): CS1, systolic BP (SBP) at admission >140 mmHg; CS2, ≥100 mmHg; CS3, <100 mmHg [18]. We confirmed the deaths of study patients by the medical records of our hospital or by the information obtained during follow-up. We defined cardiovascular death as death resulting from acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, or death due to other cardiovascular causes [19]. We confirmed HF events (HF requiring hospitalization or death due to HF) that were classified as per the International Classification of Diseases, 10th revision, code I50, using the medical records of our hospital or by the information obtained from follow-up. Patient follow-up The health status, incidence of cardiovascular events and mortality of patients are maintained in the database by linking these data to the medical records of the hospital and through study documents that were sent one a year to those who stopped hospital visits or who were referred to other hospitals. We excluded the follow-up data obtained after April 1, 2013 from data analysis. Therefore, the end of the follow-up period was defined as one of the following: (1) the date of death, if the date was before March 31, 2013; (2) the final hospital visit or the final response to our study documents involving prognosis with confirmation of being alive before March 31, 2013; (3) March 31, 2013, when the date of death, the final hospital visit, or the final response to our study documents involving prognosis was later than April 1, 2013. Statistical analysis Categorical and consecutive data regarding patient background are presented as numbers (%) and means ± standard deviation, respectively. The chi-square test was used for comparisons between groups, and the unpaired t-test was used for comparison of consecutive variables. Long-term, event-free survival was estimated using Kaplan–Meier curves and the log-rank test to assess the significance of differences between the two groups. Logistic regression analysis was used to identify the determinants of HF patients in the winter season. Univariate and age-adjusted Cox regression analysis were performed to clarify the association between HF admission in the winter season and long-term clinical outcomes. A probability value of <0.05 was considered to indicate a statistically significant difference. Statistical analyses were performed using SPSS (SPSS Inc., Chicago, IL, USA), version 19.0 software. Results Patient characteristics Among the 375 patients with HF, 136 (36%) were admitted in winter, and 239 patients (64%) were admitted in the other seasons. The distribution of the admission month among
Please cite this article in press as: Kaneko H, et al. Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.03.004
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60
Number of patients
50
40
30
20
10
0
Month Fig. 2. Distribution of month among the study patients.
the study patients is shown in Fig. 2. The HF patients admitted in the winter season were older than those admitted in the other seasons (70 ± 13 years vs. 67 ± 14 years, p = 0.034). Gender difference was not seen between the two groups. Patients of winter season had a higher prevalence of hypertension (65% vs. 54%, p = 0.025) and diabetes mellitus (35% vs. 24%, p = 0.023). The prevalence rates of ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, and hypertensive heart disease were comparable between the two groups. White blood cell counts (7570 ± 2925 L vs. 7857 ± 3408 L, p = 0.394) and C-reactive protein levels (1.7 ± 3.4 mg/dL vs. 1.9 ± 4.2 mg/dL, p = 0.578) at admission were comparable between the patients in winter and other seasons. B-type natriuretic peptide levels at admission were also comparable between the patients in winter and other seasons (859 ± 874 pg/mL vs. 874 ± 902 pg/mL, p = 0.877). The condition classified as CS1 tended to be more common in winter admission group (39% vs. 29%, p = 0.051) (Table 1). Ultrasound cardiography Ultrasound echocardiography revealed that LVDd (53 ± 10 mm vs. 56 ± 11 mm, p = 0.014), and LVDs (41 ± 14 mm vs. 45 ± 14 mm, p = 0.013) were smaller in HF patients in winter than those in other seasons. LVEF was greater in HF patients in the winter season (47 ± 21% vs. 39 ± 20%, p = 0.001). The prevalence of HFpEF was higher in HF patients in the winter season (46% vs. 30%, p = 0.002) (Table 2). Medication at hospital discharge The use of beta-blockers was more common in the HF patients admitted in the other seasons than in those admitted in winter (71% vs. 60%, p = 0.032). The use of other cardiovascular drugs including calcium channel blockers, rennin-angiotensin-system inhibitors, statins, loop diuretics, aldosterone antagonists, digitalis, nitrate, and amiodarone was comparable between the two groups (Table 3). Determinants of heart failure in winter Multivariate logistic regression analysis (step-wise model) including following covariates age ≥75 years, hypertension,
diabetes mellitus, and HFpEF demonstrated that diabetes mellitus [odds ratio (OR) 1.698, 95% confidence interval (CI) 1.064–2.708, p = 0.026] and HFpEF (OR 1.969, 95% CI 1.264–3.067, p = 0.003) were independent determinants of HF admission in winter (Table 4). Clinical outcomes All-cause death (in-hospital death) occurred in 9.6% (1.5%) of the HF patients admitted in winter, and in 10% (0.8%) of those admitted in the other seasons. Cardiovascular death occurred in 6.6% of the patients in winter, and 7.5% of patients in the other seasons. Readmission for HF occurred in 25% of the patients
Table 1 Characteristics of patients. Other seasons (n = 239)
Winter season (n = 136)
p-Value
Age (years) Male BMI (kg/m2 ) Hypertension Dyslipidemia Diabetes mellitus Hyperuricemia Cigarette smoking CKD Anemia ICM DCM HCM HHD AF WBC (/L) CRP (mg/dL) BNP (pg/mL)
67 ± 14 72% 24 ± 4.6 54% 28% 24% 23% 39% 13% 21% 30% 23% 2.5% 4.6% 36% 7570 ± 2925 1.7 ± 3.4 874 ± 902
70 ± 13 68% 25 ± 4.3 65% 37% 35% 24% 43% 16% 18% 28% 16% 4.4% 8.8% 40% 7857 ± 3408 1.9 ± 4.2 859 ± 874
0.034 0.412 0.295 0.025 0.079 0.023 0.909 0.397 0.460 0.390 0.655 0.099 0.315 0.101 0.474 0.394 0.578 0.877
CS I II III
29% 63% 7%
39% 55% 6%
0.051 0.111 0.705
BMI, body mass index; CKD, chronic kidney disease; ICM, ischemic cardiomyopathy; DCM, idiopathic dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HHD, hypertensive heart disease; AF, atrial fibrillation; WBC, white blood cell count; CRP, C-reactive protein level; BNP, brain natriuretic peptide; CS, clinical scenario. Data are expressed as mean ± standard deviation, or percentage.
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IVST (mm) PWT (mm) LVDd (mm) LVDs (mm) LVEF (%) HFpEF HFrEF LAD (mm)
Other seasons (n = 239)
Winter season (n = 136)
p-Value
9.8 ± 4.6 9.0 ± 1.9 56 ± 11 45 ± 14 39 ± 20 30% 70% 44 ± 9.5
10.1 ± 2.7 9.2 ± 2.0 53 ± 10 41 ± 14 47 ± 21 46% 55% 44 ± 9.2
0.533 0.258 0.014 0.013 0.001 0.002 0.002 0.480
IVST, interventricular septum thickness; PWT, posterior wall thickness; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVEF, left ventricular ejection fraction; HFpEF, heart failure with preserved left ventricular ejection fraction; HFrEF, heart failure with reduced left ventricular ejection fraction; LAD, left atrial dimension. Data are expressed as mean ± standard deviation. Table 3 Medication at hospital discharge.
Beta-blockers CCBs RAS-Is Statins Loop diuretics Aldosterone antagonist Digitalis Nitrate Amiodarone
Other seasons (n = 237)
Winter season (n = 134)
p-Value
71 30 75 30 77 47 16 12 7.6
60 36 72 32 81 38 15 7 4.5
0.032 0.212 0.566 0.608 0.306 0.102 0.778 0.115 0.241
CCB, calcium-channel blocker; RAS-I, renin-angiotensin system inhibitor. Data are expressed as percentages.
Table 4 Determinants of winter heart failure.
Diabetes mellitus HFpEF
OR
95% CI
p-Value
1.698 1.969
1.064–2.708 1.264–3.067
0.026 0.003
Logistic regression analysis for heart failure admission in winter. OR, odds ratio; CI, confidence interval; HFpEF, heart failure with preserved left ventricular ejection fraction.
admitted in winter and 22% of the patients in the other seasons (Table 5). Kaplan–Meier curves and log-rank test showed that the incidences of all-cause death (Fig. 3A, log-rank p = 0.950), cardiovascular death (Fig. 3B, log-rank p = 0.826), and HF admission (Fig. 3C, log-rank p = 0.314) of the patients admitted in winter and the other seasons. Similar to Kaplan–Meier curves, unadjusted Cox regression analysis demonstrated that HF admission in winter was not significantly associated with all-cause death (HR 0.979, 95% CI 0.498–1.923, p = 0.950), cardiovascular disease death (HR 0.914, 95% CI 0.411–2.036, p = 0.826), and heart failure admission (HR 1.247, 95% CI 0.810–1.919, p = 0.315). Even after adjustment for age, HF admission in winter was not significantly associated with all-cause death (HR 0.923, 95% CI 0.470–1.815, p = 0.817), Table 5 Clinical outcomes.
All-cause death In-hospital death Cardiovascular death Heart failure admission
Other seasons (n = 239)
Winter season (n = 136)
p-Value
10 0.8 7.5 22
9.6 1.5 6.6 25
0.880 0.566 0.742 0.533
Data are expressed as percentages.
cardiovascular death (HR 0.860, 95% CI 0.386–1.916, p = 0.712), and HF admission (HR 1.216, 95% CI 0.790–1.871, p = 0.375) (Supplementary Table 1). Discussion The present study reports the data from an observational cohort of HF patients that was analyzed to determine the characteristics and outcomes of acute decompensated HF patients who were admitted in winter. The major findings of the present study were as follows: (1) Admission for HF occurred frequently in winter (136/375, 36%). (2) The HF patients admitted in the winter season were older than those admitted in the other seasons. The prevalence of hypertension and diabetes mellitus was greater in the patients in the winter season. The CS1 classification tended to be more common and LVEF was higher in the patients admitted in winter than in those admitted in other seasons. (3) Kaplan–Meier curves and log-rank test results showed the incidences of all-cause death (log-rank p = 0.950), cardiovascular death (log-rank p = 0.826), and hospital admission for HF (logrank p = 0.314) in the patients admitted in winter and other seasons. In the present study, HF admission was commonly observed in winter (36%) when compared with the other seasons, which was in agreement with a previous study [20]. HF patients admitted in the winter season were older than those admitted in the other seasons. Furthermore, patients in the winter season more frequently had hypertension and diabetes mellitus compared with those admitted in the other seasons. Interestingly, HF patients in winter had a higher prevalence of HFpEF than HF patients in the other seasons. As older age, hypertension, and diabetes mellitus are well-known clinical features of HF with preserved LVEF [17], our results suggest that HFpEF is an important clinical presentation of HF patients in the winter season. Despite these differences in patient characteristics, clinical outcomes including in-hospital mortality, long-term mortality, long-term cardiovascular mortality, and occurrences of readmission for HF were comparable between the HF patients admitted in winter and the other seasons. Since HF patients in winter were older than those admitted in the other seasons, we performed an age-adjusted Cox regression analysis. Even after adjustment for age, HF admission in winter was not significantly associated with long-term outcomes. Because the HF patients admitted in winter had diabetes mellitus more frequently, we might expect these patients to have worse clinical outcomes than those admitted in the other seasons. On the other hand, the patients admitted in winter were more likely to have a CS1 condition, which was thought to be associated with clinical outcomes more favorable than other CS categories. The results of the present study are in keeping with the seasonal variation observed in other cardiovascular diseases such as acute coronary syndrome and sudden death [1,4]. Consequently, these cardiovascular diseases might share common mechanisms that exacerbate the amplitude of the seasonal variation of other cardiovascular syndromes. For example, the hemodynamic stresses and neurohumoral activation that accompany lower temperatures might exacerbate HF, induce myocardial ischemia, and precipitate arrhythmias [6–11]. Furthermore, both ischemia and arrhythmias could worsen HF. Other mechanisms could also underlie the seasonal variation in HF. For example, respiratory infection, especially those related to influenza, are more frequent in winter and could precipitate HF [21]. Although there were no significant
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Fig. 3. Kaplan–Meier curves for all-cause death rate (A), cardiovascular death rate (B), and heart failure admission rate (C).
differences in the white blood cell counts and serum C-reactive protein levels on hospital admission between patients in winter and other seasons, we need to pay attention to infections including respiratory infection and influenza virus infection as important worsening factors of HF in the winter season. In addition, alcohol
consumption increases in December [22]. Considering that alcohol induces atrial fibrillation and depresses myocardial contractility, increased consumption of alcohol might aggravate HF in winter [22,23]. Depression, which also worsens in the winter season, might contribute to acute HF [24].
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Clinical implications The results of the present study have clinical significance and might affect HF management. Considering that almost 40% of the HF admissions in this study occurred in winter, increased vigilance in winter is warranted in clinical practice. Moreover based on the higher prevalence of older age, hypertension, and CS1 in the HF patients seen in winter, BP control should be closely monitored in such patients, especially among the elderly. Study limitations The present study had several limitations. Our hospital is a single-department cardiovascular facility; therefore, the results of this study cannot be generalized to all medical centers. Furthermore, the sample size of the present study was limited, and thus, the statistical power might not be strong enough for any negative data to be conclusive. As described above, the inflammatory markers on admission were comparable between HF patients in the winter season and in the other seasons. However, further studies are needed to clarify the association between infection and HF admission in the winter season. Conclusions HF admission was frequently observed in the winter season and HF patients admitted in the winter season were older, had higher prevalence of hypertension and diabetes mellitus, and preserved LVEF. Therefore, we might need to pay more attention to elderly patients with hypertension, diabetes mellitus, and HF with preserved LVEF to decrease HF admissions in the winter season. Acknowledgments We thank Shiro Ueda and Nobuko Ueda of Medical Edge Co Ltd, for assembling the database by Clinical Study Supporting System (CliSSS), and Ineko Hayakawa, Hiroaki Arai, and Hiroshi Aoki for data management and system administration. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jjcc.2014.03.004. References [1] Marchant B, Ranjadayalan K, Stevenson R, Wilkinson P, Timmis AD. Circadian and seasonal factors in the pathogenesis of acute myocardial infarction: the influence of environmental temperature. Br Heart J 1993;69:385–7. [2] Ornato JP, Peberdy MA, Chandra NC, Bush DE. Seasonal pattern of acute myocardial infarction in the National Registry of Myocardial Infarction. J Am Coll Cardiol 1996;28:1684–8. [3] Spencer FA, Goldberg RJ, Becker RC, Gore JM. Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction. J Am Coll Cardiol 1998;31:1226–33. [4] Arntz HR, Willich SN, Schreiber C, Bruggemann T, Stern R, Schultheiss HP. Diurnal, weekly and seasonal variation of sudden death. Population-based analysis of 24,061 consecutive cases. Eur Heart J 2000;21:315–20.
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Please cite this article in press as: Kaneko H, et al. Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.03.004