Clinical Scenario 1 Is Associated With Winter Onset of Acute Heart Failure

Abstract

Background: Several reports have evaluated the association between seasonal variation and acute heart failure (AHF) onset. Cold weather may induce AHF, but the clinical characteristics of patients susceptible to AHF during winter have not been established. Clinical Scenario (CS) is used in the early clinical management of AHF, so we investigated the relationship between CS classification and winter onset of AHF in Japan.

Methods and Results: We enrolled 582 patients hospitalized for AHF and compared the frequency of AHF among the 4 seasons in each CS group to clarify the clinical characteristics of the winter onset group. Significant increase of AHF during winter was seen in CS1 (systolic blood pressure [SBP] (>140 mmHg) (P=0.01) but not in CS2 (SBP ≥100 and ≤140 mmHg) or CS3 (SBP <100 mmHg). CS1 patients were divided into winter and other season admission groups. In multivariate analysis, only lack of loop diuretic use was associated with winter admission of CS1 patients (odds ratio 0.562, 95% confidence interval: 0.256–0.798, P=0.006).

Conclusions: Winter predominance of AHF was seen only in CS1, and lack of loop diuretic use was a risk factor for winter onset. Future studies are necessary to confirm whether loop diuretics are useful in preventing AHF with CS1 in winter. (Circ J 2015; 79: 129–135)

Seasonal variation of cardiovascular diseases such as myocardial infarction (MI), aortic dissection, pulmonary embolism and cardiac sudden death is well recognized.^1–6 As for acute heart failure (AHF) onset, several reports describe a seasonal variation with winter predominance.^7–13 Boulay et al reported that hospitalization for heart failure (HF) followed a seasonal variation and death from HF peaked during winter, both in the overall population and in subgroups defined by age (>44 years) and sex.⁷ Increasing AHF onset during winter is plausible but the mechanisms underlying the association between HF onset and seasonal variation are still unclear. Milo-Cotter et al reported that low night-time temperature was likely to play a role in this seasonal variation.¹⁴ Cold temperature causes sympathetic activation, which induces an increase in both heart rate and blood pressure (BP). Inflammation and an increase in alcohol consumption have also been proposed to explain increases in the onset of AHF in winter.^15–18

Recently, the American College of Cardiology/American Heart Association and European Society of Cardiology guidelines released a systolic BP (SBP)-guided practical recommendation (Clinical Scenario [CS]) for prehospital and early in-hospital management of AHF syndromes.¹⁹ As cold exposure during winter augments sympathetically mediated vasoconstriction, we investigated (1) the relationship between CS classification and winter onset of AHF and (2) the characteristics of patients with winter onset of AHF in Japan.

Methods

Study Population

Yonago, Tottori Prefecture, is located along the Japanese coast. According to annual statistical data from the prefectural government, the population of Yonago is 148,271 (70,133 males, 78,138 females) and the percentage of the population aged over 65 years is 23.9%.

The weather in Tottori Prefecture is often fine during summer and often snowy during winter (Figure 1). We defined spring as March 1st to May 31st, summer as June 1st to August 31st, fall as September 1st to November 30th, and winter as December 1st to February 28th.

Figure 1.

Temperature trends in Yonago, Japan (average of 2004–2010).

CS

CS is a method of prehospital and early in-hospital (first 6–12 h after presentation) management of AHF.¹⁹ AHF patients are classified by SBP at admission as follows:

CS1: HF patient with elevated SBP (>140 mmHg)

CS2: HF patient with normal SBP (≥100 and ≤140 mmHg)

CS3: HF patient with low SBP (<100 mmHg)

CS4: HF patient with acute coronary syndrome

CS5: HF patients with isolated right ventricular failure.

Inclusion and Exclusion Criteria

We retrospectively investigated 644 consecutive patients who were hospitalized for AHF from March 2004 through February 2010. AHF was defined by the Framingham criteria, and other clinical findings including B-type natriuretic peptide levels, pulmonary congestion on chest X-ray, or pulmonary hypertension evaluated by echocardiography. Patients classified as AHF with acute coronary syndrome (CS4), right ventricular failure (CS5) or with acute myocarditis were excluded from this study.

Of the 644 patients, 582 were subdivided into CS1, CS2 or CS3 by SBP at admission (Figure 2).

Figure 2.

Flowchart of study participants. AHF, acute heart failure; CS, Clinical Scenario.

Data Sources

Demographic data such as age, sex, past history, medication, laboratory data, left ventricular ejection fraction (LVEF) and etiology of AHF were drawn from medical records. SBP and laboratory data on admission day were used. LVEF was measured by echocardiography as previously described.²⁰ Ischemic heart disease as the underlying disease was defined as follows: a history of MI, angina or prior coronary revascularization, Q wave MI on ECG, and severe stenosis (>75%) of one or more coronary arteries on coronary angiography.

Tottori University institutional review board approved this retrospective study. Because the study protocol involved a review of charts obtained as part of routine medical care only, patient consent was not required.

Statistical Analysis

Continuous variables are reported as mean±standard deviation (SD) for normally distributed variables and median (25 percentile, 75 percentile) for non-normally distributed variables. Categorical variables are reported as percentages. In the comparison of 2 groups, continuous variables were compared by t-test for normally distributed variables and Mann-Whitney U-test for non-normally distributed variables. For a comparison of 3 groups, we used analysis of variance (ANOVA) for normally distributed variables and Kruskal-Wallis test for non-normally distributed variables. The comparison of categorical variables was based on Pearson’s chi-square test. The AHF events were aggregated for each season and calculated as the incidence for each day. The comparisons of the incidence of AHF per day among each season were based on ANOVA and the post-hoc test was performed between the 2 seasonal groups that had significant difference. Demographic and clinical characteristics or medications that were significantly associated with winter onset of AHF in the univariate analysis (P<0.20) were incorporated into a multivariate logistic regression analysis. Age and sex were put into the model to adjust for their respective effects. For the patients in CS1, survival curves after hospital admission were estimated by Kaplan-Meier analysis and compared by log-rank test. A value of P<0.05 was considered significant. IBM SPSS version 20 was used for all statistical analyses.

Results

AHF onset tended to be higher during winter in the total subjects (P=0.052, ANOVA) (Figure 3). We divided them patients into 3 groups by CS classification and compared their AHF onset among the 4 seasons. Demographic data of each CS patient group are shown in Table 1. The CS1 group was older, more likely to be female or hypertensive, and their EF tended to be preserved. These patients were less likely to have atrial fibrillation. Most of their hospitalizations were first admissions and prescription rate of β-blockers and loop diuretics was relatively lower than in the other groups.

Figure 3.

Frequency of acute heart failure (AHF) onset in the 4 seasons. Data are mean±standard deviation.

Table 1. Characteristics of Patients in Each CS

	Total (n=582)	CS1 (n=223)	CS2 (n=295)	CS3 (n=64)	P value
Age	78 (72, 83)	79 (72, 84)	79 (73, 84)	75 (58, 81)	<0.01
Male	331 (56.9%)	113 (50.7%)	175 (59.3%)	43 (67.2%)	0.03
EF ≥40%	355 (61.0%)	149 (66.8%)	175 (59.3%)	31 (48.4%)	0.02
Ischemic heart disease	163 (28.0%)	61 (27.4%)	88 (29.8%)	14 (21.9%)	0.42
Prior HF hospitalization	263 (45.2%)	70 (31.4%)	157 (53.2%)	36 (56.3%)	<0.01
In-hospital mortality	56 (9.6%)	10 (4.5%)	29 (9.8%)	17 (26.6%)	<0.01
SBP (mmHg)	130 (111, 155)	163 (151, 179)	121 (110, 130)	91 (82, 95)	<0.01
Na (mEq/L)	139 (136, 142)	140 (137, 142)	139 (136, 141)	136 (133, 139)	<0.01
Hb (g/dl)	11.4±2.4	11.7±2.4	11.1±2.4	11.4±2.2	0.02
Cr (mg/dl)	1.2 (0.8, 1.8)	1.1 (0.8, 1.8)	1.2 (0.8, 1.7)	1.3 (0.9, 1.8)	0.31
Alb (g/dl)	3.5 (3.1, 3.8)	3.5 (3.1, 3.8)	3.5 (3.1, 3.8)	3.4 (2.8, 3.9)	0.44
CRP (mg/dl)	0.6 (0.2, 1.7)	0.5 (0.2, 1.4)	0.6 (0.2, 1.7)	0.9 (0.3, 3.5)	0.07
T-bil (mg/dl)	0.8 (0.6, 1.2)	0.7 (0.5, 1.0)	0.8 (0.6, 1.2)	1.0 (0.7, 1.6)	<0.01
History
Hypertension	282 (48.5%)	142 (63.7%)	120 (40.7%)	20 (31.3%)	<0.01
Diabetes	204 (35.1%)	87 (39.0%)	100 (33.9%)	17 (26.6%)	0.15
COPD	60 (10.3%)	36 (16.1%)	22 (7.5%)	2 (3.1%)	<0.01
Atrial fibrillation	266 (45.4%)	80 (35.9%)	150 (50.8%)	34 (53.1%)	<0.01
Drugs on admission
ACEI/ARB	363 (62.4%)	130 (58.3%)	190 (64.4%)	43 (67.2%)	0.255
β-blocker	201 (34.5%)	58 (26.0%)	119 (40.3%)	24 (37.5%)	<0.01
Loop diuretic	383 (65.8%)	113 (50.7%)	222 (75.3%)	48 (75.0%)	<0.01

Data are mean±standard deviation or median (25 percentile, 75 percentile).

ACEI, angiotensin-converting enzyme inhibitor; Alb, albumin; ARB, angiotensin-receptor blocker; Cr, creatinine; CRP, C-reactive protein; COPD, chronic obstructive pulmonary disease; CS, Clinical Scenario; EF, ejection fraction; Hb, hemoglobin; HF, heart failure; SBP, systolic blood pressure; T-bil, total bilirubin.

Winter predominance of AHF onset was seen only in the CS1 group (P=0.01, ANOVA) (Figure 4). In order to detect risk factors for winter onset of AHF in this group, we compared the clinical characteristics of patients with winter admission with those of patients admitted in other seasons (Table 2). C-reactive protein (CRP) (P=0.043) was significantly higher, and bilirubin (P=0.016) and the prescription rate of loop diuretics (P=0.005) were significantly lower in the subjects with winter admission compared with the other subjects. In multivariate analysis, only the lack of loop diuretic use (odds ratio 0.562, 95% confidence interval: 0.256–0.798, P=0.006) was significantly associated with winter onset of AHF among CS1 patients (Table 3). Among the patients in the CS1 group, there was no significant difference in the cumulative survival rate between those with winter admission and other seasons’ admissions (Figure 5).

Figure 4.

Seasonal variation of the event ratio of acute heart failure (AHF) onset (Upper) and the number of patients in each Clinical Scenario (CS) (Lower). Data are mean±standard deviation (Upper). *P<0.01, **P<0.05.

Table 2. Clinical Characteristics of HF Patients in the CS1 Group With Winter Admission and Those With Admission in Another Season

	Winter admission (n=88)	Other seasons’ admission (n=135)	P value
Age (years)	79 (73, 84)	79 (70, 84)	0.743
Male (%)	45 (51.1%)	68 (50.4%)	0.911
EF ≥40% (%)	64 (72.7%)	85 (63.0%)	0.130
Ischemic heart disease (%)	27 (30.7%)	34 (25.2%)	0.368
Prior HF hospitalization (%)	27 (30.7%)	43 (31.9%)	0.854
SBP (mmHg)	163 (152, 177)	163 (150, 180)	0.869
Na (mEq/L)	139 (137, 142)	140 (137, 142)	0.375
Hb (g/dl)	11.7±2.4	11.7±2.4	0.883
Cr (mg/dl)	1.0 (0.7, 1.9)	1.2 (0.8, 1.8)	0.436
Alb (g/dl)	3.6 (3.0, 3.9)	3.4 (3.2, 3.8)	0.616
CRP (mg/dl)	0.5 (0.3, 2.5)	0.4 (0.1, 1.2)	0.043
T-bil (mg/dl)	0.7 (0.4, 1.0)	0.8 (0.6, 1.1)	0.016
History
Hypertension (%)	55 (62.5%)	87 (64.4%)	0.768
Diabetes (%)	37 (42.0%)	50 (37.0%)	0.454
Atrial fibrillation (%)	31 (35.2%)	49 (36.3%)	0.871
COPD (%)	16 (18.2%)	20 (14.8%)	0.504
Drugs on admission
ACEI/ARB (%)	54 (61.4%)	76 (56.3%)	0.453
β-blocker (%)	25 (28.4%)	33 (24.4%)	0.509
Loop diuretic (%)	38 (43.2%)	84 (62.2%)	0.005

Data are mean±standard deviation or median (25 percentile, 75 percentile). P value is significant <0.05. Abbreviations as in Table 1.

Table 3. Clinical Characteristics of HF Patients With Winter Admission and Those With Other Seasons’ Admissions (CS1, Multivariate Analysis)

Variable	Multivariate analysis OR (95% CI)	P value
Age	1.006 (0.980–1.033)	0.660
Male	1.084 (0.613–1.918)	0.782
EF ≥40%	1.560 (0.840–2.895)	0.159
T-bil	0.644 (0.350–1.183)	0.156
CRP	1.080 (0.987–1.181)	0.095
Loop diuretics	0.562 (0.256–0.798)	0.006

CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Figure 5.

Kaplan-Meier curve for all-cause mortality vs. admission season (winter or other seasons) in Clinical Scenario 1.

Discussion

Our findings are follows. First, winter predominance of AHF onset was seen in CS1 patients but not in CS2 and CS3 patients. Second, the lack of loop diuretic use was an independent risk factor for winter onset of AHF in CS1 patients.

Seasonal Variation of AHF Onset in CS1

Boulay et al reported that deaths and hospitalizations peaked during winter in patients with HF,⁷ and other previous studies in both the Northern Hemisphere^8–11 and Southern Hemisphere^12,13 also report the same seasonal variation of HF deaths and hospitalizations. The present study has expanded on these previous studies by demonstrating that seasonal variation is observed in CS1 but not CS2 and CS3 in Japan.

Several mechanisms have been suggested to explain the winter predominance of AHF onset. Izzo et al¹⁵ reported that systemic vascular resistance and plasma norepinephrine increase in winter compared with summer in patients with borderline hypertension and in normotensive subjects. The peripheral vasoconstriction caused by cold exposure raises BP. Gheorghiade et al²¹ and Kawaguchi et al²² characterized CS1 patients as having an acute elevation of filling pressures that parallels the increase in BP. Its underlying pathophysiology is mostly related to vascular causes associated with limited left ventricular compliance or a rapidly changing pressure-volume relationship. The peripheral vasoconstriction caused by cold stimulation may partly explain why seasonal variation was observed only in CS1 in the present study. Tu et al reported that the distribution of BP shifted higher in winter in a large cohort study.²³ The seasonal variation in BP, per se, might be another potential mechanism of the winter predominance of AHF onset in CS1, which raises the possibility of a discrepancy between CS classification and the principal pathophysiology of HF.

Clinical Characteristics of CS1 Patients With Winter Onset of AHF

To clarify the susceptibility to winter onset of AHF, we compared the clinical characteristics of CS1 patients with winter admission to those with admission during other seasons (Table 2). The CS1 patients hospitalized during winter were likely to have higher CRP. Respiratory infections, especially influenza-related diseases, increase during winter, leading to worsening of HF.^16,17 Thus, infection is likely to contribute to the winter onset of AHF in CS1.

In our multivariate analysis, only a lack of loop diuretic use was a contributing factor for winter onset of AHF in CS1 patients (Table 3). Loop diuretics can reduce body fluid retention, which is induced by increased caloric and sodium intake from food or alcohol consumption and by a decrease in water loss by transpiration and perspiration during winter. Walma et al reported that withdrawal of long-term diuretics led to symptoms of HF or increase in BP in most cases.²⁴ The therapeutic strategy for CS1, which is related to vascular failure, is usually vasodilators. In the present study, we suggest that prescription of loop diuretics may be a useful therapeutic strategy for patients susceptible to AHF, especially during winter. According to the report of Masuyama et al, long-acting rather than short-acting loop diuretics may be favorable.²⁵ Sustained natriuretic action of long-acting loop diuretics may contribute to minimizing neurohumoral activation and rebound sodium retention.²⁶ The subjects of this study were admitted from 2004 through 2010 before the report of Masuyama et al. Thus the prescription rate of long-acting loop diuretics was quite low in the present study. Further studies are required to investigate the preventive effect of long-acting loop diuretics for winter onset of AHF.

Clinical factors related to winter onset of AHF are still controversial. Gallerani et al⁶ and Milo-Cotter et al¹⁴ reported that winter onset of AHF was independent of sex, age, major cardiovascular risk factors, and outcome. However, other previous studies^7,8,10,13 suggest that patients aged over 75 were most at risk of seasonal variations in HF hospitalizations and deaths. Martínez-Sellés et al found a higher rate of hospitalization of males aged <80 years and females aged ≥80 years.¹⁰ Kaneko et al²⁷ reported that patients with preserved EF, older age, hypertension, and CS1 were susceptible to winter admission of AHF. They emphasized the importance of BP control during winter, especially in the elderly patients. In the present study, neither age nor sex was significantly associated with winter onset of AHF (Table 3). These discrepancies may be partly explained by us extracting a contributing factor for winter onset using only data from CS1 patients.

Clinical Outcomes of CS1 Patients With Winter Onset of AHF

Kanako et al reported no significant difference seen in long-term mortality and HF admissions between winter admissions and other seasons’ admissions.²⁷ In the present study, we compared 6 months’ mortality between winter admissions and other seasons’ admissions only for CS1. There was no significant difference between the 2 groups. However, 6 months’ mortality tended to be low among patients admitted in winter as compared with those admitted in other seasons (P=0.053, data not shown) if data for CS1, CS2 and CS3 were combined. The relationship between winter onset and long-term prognosis may be different among CS1, CS2 and CS3, and further studies with a large number of patients are necessary to address this issue.

Study Limitations

First, it was conducted at a single center and the sample size was relatively small. Thus, winter onset of AHF tended to be high but did not reach the statistical significance reported by previous studies. Second, the ratio of ischemic heart disease was lower in the present study than in other Japanese ADHF registries.^28,29 The older age of the study subjects (average 78 years old) may at least partly explain the lower ratio of ischemic heart disease (28%) in this study. Third, we could not assess the effects of other weather parameters such as humidity and atmospheric pressure. Finally, the distribution of BP usually shifts higher in winter. Some AHF patients who were basically categorized as CS2 in other seasons might be shifted into CS1 in winter by this seasonal variation of BP. Thus physicians might need to consider that the classification of CS ought to be revised to account for seasonal variation.

In conclusion, winter predominance of AHF onset was seen only for CS1 patients. Lack of loop diuretic use was a risk factor for winter onset of AHF in these patients. To reduce the onset of AHF with CS1 in winter, further studies are required to investigate the preventive effects of loop diuretics and/or to ascertain which HF patients will benefit from loop diuretic therapy.

Disclosures

Name of Grant: None.

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