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Letters to the Editor
Low admission heart rate is a marker rather than a mediator of increased in-hospital mortality for patients with acute heart failure syndromes in sinus rhythm☆ Katsuya Kajimoto a,⁎, Naoki Sato b, Takehiko Keida c, Yasushi Sakata d, Kuniya Asai e, Masayuki Mizuno f, Teruo Takano e, and on behalf of the investigators of the Acute Decompensated Heart Failure Syndromes (ATTEND) registry a
Division of Cardiology, Sensoji Hospital, Tokyo, Japan Internal Medicine, Cardiology, and Intensive Care Unit, Nippon Medical School Musashi-Kosugi Hospital, Kanagawa, Japan c Department of Cardiovascular Medicine, Edogawa Hospital, Tokyo, Japan d Department of Cardiology, Osaka University Graduate School of Medicine, Osaka, Japan e Department of Internal Medicine, Nippon Medical School, Tokyo, Japan f Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan b
a r t i c l e
i n f o
Article history: Received 30 August 2013 Accepted 25 November 2013 Available online 4 December 2013 Keywords: Acute heart failure syndromes Heart rate Sinus rhythm In-hospital mortality
The product of systolic blood pressure (BP) × heart rate (HR) has been suggested to be a potential predictor of the cardiovascular prognosis [1]. It was reported that the systolic BP at admission is one of the most important prognostic indicators in patients with acute heart failure syndromes (AHFS), since a higher admission systolic BP is associated with lower mortality [2]. On the other hand, an elevated resting HR is associated with an increased risk of death in chronic heart failure patients [3]. However it is unclear whether the baseline HR influences the outcome of AHFS patients. Therefore, we investigated whether baseline HR was an in-hospital prognostic indicator for AHFS patients. The Acute Decompensated Heart Failure Syndromes (ATTEND) registry, a prospective observational multicenter cohort study, accumulates data on AHFS patients admitted to 53 hospitals throughout Japan between April 2007 and December 2011. The design and methods of this study, as well as the characteristics of the patients, have been described previously [4,5]. In this study, patients with atrial fibrillation and a permanent pacemaker at admission were excluded. Of the 4842 patients enrolled in this registry, 2728 patients who were in sinus rhythm at admission were evaluated. They were divided into baseline HR quartiles (b80, 80 to b100, 100 to b120, and ≥120 beats per minute [bpm]), and in-hospital mortality (all-cause death and cardiac death) was compared among the four groups. This study is being conducted according to the principles of the Declaration of Helsinki. Institutional review board approval was obtained at each participating medical center prior to commencing the study, and all patients provide written informed consent upon enrollment. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. Data are presented as the mean (SD), median with interquartile range, or frequency. One-way analysis of variance was employed for between-group comparison of continuous variables
☆ Funding: This work was supported by the Japan Heart Foundation. ⁎ Corresponding author at: Division of Cardiology, Sensoji Hospital, 2-30-17, Asakusa, Taito-ku, Tokyo 111-0032, Japan. Tel.: +81 3 3841 3330; fax: +81 3 3847 1452. E-mail address: [email protected] (K. Kajimoto).
with a normal distribution, while the Kruskal–Wallis H-test was used for skewed continuous variables or discrete variables and the chisquare test was used to compare nominal scale variables. Two-tailed p values of less than 0.05 were considered to indicate statistical significance. The baseline clinical characteristics of the HR quartiles are shown in Table 1. The median length of stay was 21 (14–33) days and the all-cause mortality rate during hospitalization was 6.8% (n = 185). Univariate analysis revealed a significantly higher risk of in-hospital all-cause death in patients with an HR b80 bpm or 80 to b100 bpm than in those with an HR ≥120 bpm (Table 2). The unadjusted risk of in-hospital cardiac death was significantly higher in patients with an HR of b80, 80 to b100, and 100 to b120 bpm than in those with an HR ≥120 bpm. After adjustment for multiple comorbidities and other clinical factors (Table 2), the association between HR and the risk of in-hospital all-cause mortality became weaker. However, the risk of in-hospital cardiac death for patients with an HR b80, 80 to b100, and 100 to 120 bpm was respectively increased to 2.24 times (95% confidence interval [CI], 0.99–5.06; p = 0.052), 2.34 times (95% CI, 1.06–5.51; p = 0.034), and 2.15 times (95% CI, 0.96–4.85; p = 0.064) the risk for patients with an HR ≥120 bpm. The present findings indicate that a low HR at admission may be a marker rather than a direct mediator of an increased risk of in-hospital mortality for AHFS patients in sinus rhythm at admission. In chronic heart failure patients, an elevated resting HR has been shown to be associated with an increased risk of mortality and cardiovascular disease [1,3]. On the other hand, in the urgent phase of AHFSs, tachycardia is largely a physiological and beneficial compensatory response, because structural limitations on the stroke volume mean that an increase of the HR is required to maintain a normal cardiac output [6]. Thus, the precise relation between the HR and the pathophysiology of AHFS patients is unclear [7]. Our data showed that a lower baseline HR in sinus rhythm was associated with a substantially higher in-hospital cardiac death for AHFS patients. The mechanism underlying the association of a higher admission HR with a lower in-hospital cardiac death rate for AHFS patients is not entirely clear, but some assumptions can be made. Bainbridge reported that rapid volume loading results in an increase of both BP and HR [8], and previous studies have shown that a higher baseline systolic BP is associated with a better outcome [2]. Therefore, it could be speculated that a higher risk of in-hospital cardiac death might be associated with impairment of the ability to increase HR to appropriate levels in the urgent phase of AHFS. Our study had several limitations. First, the ATTEND registry study was not a prospective randomized trial, so variables that were not investigated could have influenced the findings. Second, as we have previously reported [5], the relatively long hospital stay of our patients might be related to the Japanese healthcare system, because demographic and clinical variables were reported to be similar in Japanese AHFS patients and those from Western countries [4]. Thus,
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Table 1 Baseline characteristics of the AHFS patients and each quartile stratified by heart rate at admission.
Mean age, years Female, n (%) Body mass index, kg/m2 Ischemic etiology, n (%) Hypertensive etiology, n (%) Valvular etiology, n (%) Idiopathic dilated etiology, n (%) Reduced LVEF (≤40%), n (%) Medical history, n (%) Prior hospitalization for heart failure Hypertension Dyslipidemia Diabetes Chronic obstructive pulmonary disease Stroke Medications prior to admission, n (%) Loop diuretic Spironolactone or Eplerenone Angiotensin-converting enzyme inhibitor Angiotensin receptor blocker Beta-blocker Calcium-channel blocker Digoxin Aspirin Statin Intravenous drugs during hospitalization, n (%) Furosemide Any vasodilator Any inotropic agent Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Heart rate, beats/min Brain natriuretic peptide, pg/ml Blood urea nitrogen, mg/dl Serum creatinine, mg/dl Serum sodium, mEq/l Hemoglobin, g/dl C-reactive protein, mg/dl Clinical features on admission, n (%) Paroxysmal nocturnal dyspnea Orthopnea Rales Jugular venous distension Peripheral edema NYHA functional class III IV
Total (n = 2728)
Heart rate quartile, bpm b80 (n = 647)
80 to b100 (n = 803)
100 to b120 (n = 737)
≥120 (n = 541)
p value
71.9 ± 14.9a 1138 (41.7) 23.2 ± 4.8a 1045 (38.3) 583 (21.4) 414 (15.2) 342 (12.5) 1552 (56.9)
76.1 ± 12.7a 313 (48.4) 23.0 ± 4.9a 240 (37.1) 118 (18.2) 91 (14.1) 56 (8.7) 258 (39.9)
73.4 ± 14.5a 331 (41.2) 22.9 ± 4.3a 329 (41.0) 153 (19.1) 144 (17.9) 97 (12.1) 428 (53.3)
69.1 ± 16.1a 290 (39.3) 23.7 ± 5.3a 273 (37.0) 156 (21.2) 126 (17.1) 114 (15.5) 471 (63.9)
68.4 ± 14.3a 204 (37.7) 23.2 ± 4.5a 203 (37.5) 156 (28.8) 53 (9.8) 75 (13.9) 395 (73.0)
b .001 b .001 0.010 0.327 b .001 b .001 0.001 b .001
799 (29.3) 1978 (72.5) 1091 (40.0) 1001 (36.7) 333 (12.2) 336 (12.3)
245 (37.9) 489 (75.6) 248 (38.3) 242 (37.4) 88 (13.6) 99 (15.3)
249 (31.0) 559 (69.6) 326 (40.6) 290 (36.1) 108 (13.4) 112 (13.9)
189 (25.6) 524 (71.1) 281 (38.1) 265 (36.0) 82 (11.1) 73 (9.9)
116 (21.4) 406 (75.0) 236 (43.6) 204 (37.7) 55 (10.2) 52 (9.6)
b .001 0.023 0.157 0.881 0.155 0.001
1076 (39.4) 409 (15.0) 375 (13.7) 904 (33.1) 802 (29.4) 808 (29.6) 164 (6.0) 911 (33.4) 668 (24.5)
318 (49.1) 124 (19.1) 107 (16.5) 260 (40.2) 267 (41.3) 248 (38.3) 52 (8.0) 266 (41.1) 184 (28.4)
367 (45.7) 142 (17.7) 109 (13.6) 286 (35.6) 248 (30.9) 251 (31.3) 50 (6.2) 293 (36.5) 216 (26.9)
256 (34.7) 91 (12.3) 99 (13.4) 228 (30.9) 185 (25.1) 197 (26.7) 38 (5.2) 204 (27.7) 158 (21.4)
135 (25.0) 52 (9.6) 60 (11.1) 130 (24.0) 102 (18.9) 112 (20.7) 24 (4.4) 148 (27.4) 110 (20.3)
b .001 b .001 0.056 b .001 b .001 b .001 0.044 b .001 b .001
2098 (76.9) 2234 (81.9) 521 (19.1) 151.8 ± 39.0a 84.8 ± 23.5a 97.1 ± 25.4a 823 [413–1478]b 26.9 ± 21.8a 1.48 ± 1.73a 139.3 ± 4.4a 11.9 ± 2.5a 0.59 [0.20–2.00]b
444 (68.6) 447 (69.1) 105 (16.2) 136.7 ± 32.0a 71.3 ± 16.5a 65.0 ± 12.1a 739 [380–1427]b 29.9 ± 18.1a 1.51 ± 1.34a 139.3 ± 5.2a 11.2 ± 2.1a 0.48 [0.15–1.67]b
605 (75.3) 645 (80.3) 138 (17.2) 145.4 ± 34.3a 80.8 ± 18.9a 88.7 ± 5.9a 858 [403–1668]b 28.8 ± 27.7a 1.55 ± 1.66a 139.4 ± 4.5a 11.6 ± 2.5a 0.63 [0.20–2.40]b
588 (79.8) 643 (87.2) 163 (22.1) 156.0 ± 37.8a 90.4 ± 23.1a 107.7 ± 5.8a 881 [463–1492]b 25.0 ± 16.9a 1.46 ± 1.60a 139.2 ± 4.0a 12.2 ± 2.7a 0.60 [0.20–1.98]b
461 (85.2) 499 (92.2) 115 (21.3) 173.6 ± 43.9a 99.4 ± 26.6a 133.2 ± 14.1a 761 [430–1306]b 23.2 ± 21.1a 1.39 ± 2.29a 139.5 ± 3.9a 12.9 ± 2.5a 0.60 [0.20–1.89]b
b .001 b .001 0.010 b .001 b .001 b .001 0.033 b .001 0.410 0.758 b .001 0.011
1502 (55.1) 1829 (67.0) 2067 (75.8) 1416 (51.9) 1737 (63.7)
271 (41.9) 314 (48.5) 402 (62.1) 314 (48.5) 457 (70.6)
435 (54.2) 498 (62.0) 583 (72.6) 400 (49.8) 529 (65.9)
456 (61.9) 544 (73.8) 585 (79.4) 392 (53.2) 466 (63.2)
340 (62.8) 473 (87.4) 497 (91.9) 310 (57.3) 285 (52.7)
b .001 b .001 b .001 0.014 b .001
934 (34.2) 1341 (49.2)
261 (40.3) 225 (34.8)
318 (39.6) 325 (40.5)
243 (33.0) 406 (55.1)
112 (20.7) 385 (71.2)
b .001 b .001
Values are shown as the no. (%). AHFS = acute heart failure syndromes; bpm = beats per minute; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association. a Mean ± SD. b Median [interquartile range].
caution must be exercised when generalizing our current results to different cohorts of patients. In conclusion, our findings suggest that the baseline HR of AHFS patients who were in sinus rhythm may be a marker rather than a
mediator of in-hospital cardiac mortality. In contrast to patients with chronic heart failure, a lower baseline HR seems to be associated with a substantially higher in-hospital cardiac death rate for AHFS patients. It was recently proposed that cardiac death, which is a
Table 2 Adjusted and unadjusted risk of in-hospital mortality stratified by the baseline heart rate. Endpoint
HR quartile
Quartile
Unadjusted odds ratio
(95% CI)
p value
Adjusteda odds ratio
(95% CI)
p value
All-cause mortality
b80 bpm 80 to b100 bpm 100 to b 120 bpm ≥120 bpm b80 bpm 80 to b100 bpm 100 to b 120 bpm ≥120 bpm
1st 2nd 3rd 4th 1st 2nd 3rd 4th
2.06 2.25 1.39 1.00 2.90 2.56 1.81 1.00
(1.24–3.44) (1.38–3.68) (0.82–2.36)
0.006 0.001 0.224
1.40 1.78 1.27
(0.75–2.61) (0.99–3.19) (0.69–2.34)
0.288 0.082 0.447
(1.51–5.59) (1.34–4.88) (0.91–3.57)
0.001 0.005 0.009
2.24 2.34 2.15
(0.99–5.06) (1.06–5.15) (0.96–4.85)
0.052 0.034 0.064
Cardiac death
a Odds ratios were adjusted by age, gender, body mass index, etiology of heart failure, prior hospitalization for heart failure, systolic blood pressure, left ventricular ejection fraction, New York Heart Association functional class, blood urea nitrogen, C-reactive protein, use of beta blockers, and use of digoxin at admission. HR = heart rate; CI = confidence interval; bpm = beats per minute.
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disease-specific end-point, might be a superior choice for studies of AHFSs compared with all-cause mortality [9]. Accordingly, our findings may have clinical implications for the early identification of high-risk AHFS patients and raise the possibility of initiating early countermeasures to prevent in-hospital cardiac death. However, taking geographical differences of AHFS into consideration, further investigation is needed to examine the association between admission HR and the in-hospital outcome of AHFS patients in sinus rhythm. We thank the study investigators for their contributions, and the Japan Heart Foundation for funding this study. We also express our appreciation to Katsunori Shimada, PhD (Statz Institute, Inc., Tokyo, Japan) for his expert assistance with the statistical analysis. Appendix A. Study investigators (53 hospitals) Nippon Medical School: Naoki Sato, Kuniya Asai, Ryo Munakata, Toshiyuki Aokage, and Asuka Yoshida; Tokyo Women's Medical University: Yuichiro Minami, Dai Yumino, Masayuki Mizuno, Erisa Kawada, Kentaro Yoshida, Yuri Ozaki, Tomohito Kogure, and Shintaro Haruki; Saitamaken Saiseikai Kurihashi Hospital: Masayuki Mizuno; Aoyama Hospital, Tokyo Women's Medical University: Katsuya Kajimoto; Saiseikai Kumamoto Hospital: Koichi Nakao, Tadashi Sawamura, and Toshiaki Nuki; Toyota Memorial Hospital: Ryoji Ishiki and Shigeki Yokota; Tokushima Prefectural Central Hospital: Hiroyuki Fujinaga, Takashi Yamamoto, Kenji Harada, Akihiro Saito, Norihito Kageyama, and Takanobu Okumura; Chiba Hokusoh Hospital, Nippon Medical School: Noritake Hata, Koji Murai, and Ayaka Nozaki; Shizuoka Medical Center: Hidekazu Kawanaka and Jun Tanabe; Hyogo Prefectural Amagasaki Hospital: Yukihito Sato; Oji General Hospital: Katsuhisa Ishii, Hitoshi Oiwa, Tomoaki Matsumoto, Daisuke Yoshida, and Nobuo Kato; Showa University Fujigaoka Hospital: Hiroshi Suzuki and Nobuyuki Shimizu; Edogawa Hospital: Takehiko Keida, Masaki Fujita, Kentaro Nakamura, Toshiya Chinen, Kentaro Meguro, Tatsuro Kikuchi, Toshiyuki Nishikido, Marohito Nakata, Tatsuya Yamashita, and Masaya Nakata; Kurashiki Central Hospital: Akitoshi Hirono, Kazuaki Mitsudo, Kazushige Kadota, Noriko Makita, and Nagisa Watanabe; Hyogo College of Medicine: Masaaki Kawabata and Kenichi Fujii; Yamaguchi University: Shinichi Okuda and Shigeki Kobayashi; Fukui Cardiovascular Center: Ikuo Moriuchi, Kiyo-o Mizuno, Kazuo Osato, Tatsuaki Murakami, Yoshifumi Shimada, Katsushi Misawa, Hiromasa Kokado, Takashi Fujita, Yoshitomo Fukuoka, and Syu Takabatake; Tokyo Medical University Hospital: Yoshifumi Takata, Manabu Miyagi, Nobuhiro Tanaka, and Akira Yamashina; Yatsu Hoken Hospital: Shinji Sudo; Shonan Dai-ichi Hospital: Koichi Shimamura and Michitaka Nagashima; Komatsu Municipal Hospital: Tomoya Kaneda, Kosei Ueda, Hiromasa Kato, and Toshinori Higashikata; Sendai Cardiovascular Center: Kanichi Fujimori, Hiroshi Kobayashi, Shinya Fujii, Masahiro Yagi, Yuri Ozaki, and Jyunko Takaki; Gunma Prefectural Cardiovascular Center: Eiji Yamashita and Takuji Toyama; Seirei Hamamatsu General Hospital: Tetsuo Hirata, Kazuho Kamisihima, and Toshiaki Oka; Osaka City General Hospital: Ryushi Komatsu, Akira Itoh, Takahiko Naruko, Yukio Abe, Eiichirou Nakagawa, Atsuko Furukawa, Naoto Kinou, Shoko Uematsu, and Isao Tabuchi; Suwa Central Hospital: Taku Imai; Kyushu University Hospital: Takafumi Sakamoto and Koji Todaka; Nagasaki University Hospital of Medicine and Dentistry: Yuji Koide and Koji Maemura;
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.087
Tokai University School of Medicine: Koichiro Yoshioka; Fukushima Medical University: Akiomi Yoshihisa, Takamasa Sato, and Yasuchika Takeishi; Yokohama City University Medical Center: Toshiaki Ebina, Kazuo Kimura, and Masaaki Konishi; Tottori University Hospital: Masahiko Kato, Yoshiharu Kinugasa, Katsunori Ishida, Shinobu Sugihara, and Kiyotaka Yanagihara; Asahikawa Medical College: Toshiharu Takeuchi, Motoi Okada, and Naoyuki Hasebe; Showa University School of Medicine: Tetsuo Sakai, Taku Asano, Yoshino Minoura, Tsutomu Toshida, Takatoshi Sato, Yuya Yokota, and Seita Kondo; Osaka University Hospital: Yasushi Sakata, Issei Komuro, Kinya Otsu, Shizuya Yamashita, and Yoshihiro Asano; Kitamurayama Hospital: Asuka Yoshida; Sensoji Hospital: Katsuya Kajimoto; Osaka Police Hospital: Kazunori Kashiwase and Yasunori Ueda; Komaki City Hospital: Taizo Kondo, Katsuhiro Kawaguchi, and Akinori Sawamura; Fukuoka Wajiro Hospital: Taro Saito, Toru Higa, Hiroo Noguchi, Yoko Yanagita, Keita Nakamura, and Tomo Komaki; Saitama Medical University International Medical Center: Toshihiro Muramatsu, Tomomi Koizumi, Yoshie Nakajima, Toshihiko Kikutani, Yoshifimi Ikeda, Toru Tamaki, Shuhei Funada, and Harumi Ogawa; Saiseikai Nagasaki Hospital: Koichiro Sakuragawa; Keio University School of Medicine: Shun Kohsaka; Saiseikai Futsukaichi Hospital: Shin-ichi Ando, Toshiaki Kadokami, Eiko Ishida, and Katsumi Ide; Sakurabashi Watanabe Hospital: Yohei Sotomi, Yoshiharu Higuchi, and Motoko Uehara; Nagoya City University Graduate School of Medical Sciences: Toshihiko Goto and Nobuyuki Ohte; Tohoku University Hospital: Masanobu Miura, Nobuyuki Shiba, Kotaro Nochioka, and Hiroaki Shimokawa; Nippon Steel Yawata Memorial Hospital: Shiro Ishihara, Tokushi Koga, Shinichiro Fujishima, Shigeru Kaseda, and Yoshie Haga; St. Marianna University School of Medicine Hospital: Keisuke Kida; Tokyo Women's Medical University Yachiyo Medical Center: Kazuho Kamisihima; Okinawa Prefectural Nannbu Medical Center & Children's Medical Center: Makiko Nakamura, Osahiko Sunagawa, Takafumi Miyara, Youji Taba, Takashi Touma, and Osamu Shinjo; Jichi Medical University: Yoshioki Nishimura, Kazuomi Kario, and Hayato Shimizu; Nippon Medical School Musashi Kosugi Hospital: Takahiro Uchida, Ken-ichi Amitani, and Naoki Sato.
References [1] Palatini P, Julius S. Heart rate and the cardiovascular risk. J Hypertens 1997;15:3–17. [2] Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53:557–73. [3] Fox K, Borer JS, Camm J, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50:823–30. [4] Sato N, Kajimoto K, Asai K, et al. Acute decompensated heart failure syndromes (ATTEND) registry prospective observational multicenter cohort study: rationale, design, and preliminary data. Am Heart J 2010;159:949–55. [5] Kajimoto K, Sato N, Keida T, et al. Association between length of stay, frequency of in-hospital death, and causes of death in Japanese patients with acute heart failure syndromes. Int J Cardiol Feb 21 2013;168(1):554–6. [6] Francis GS, Goldsmith SR, Ziesche S, et al. Relative attenuation of sympathetic drive during exercise in patients with congestive heart failure. J Am Coll Cardiol 1985;5:832–9. [7] Peterson PN, Rumsfeld JS, Liang L, et al. A validated risk score for in-hospital mortality in patients with heart failure from the American Heart Association get with the guidelines program. Circ Cardiovasc Qual Outcomes 2010;3:25–32. [8] Bainbridge FA. The influence of venous filling upon the rate of the heart. J Physiol 1915;50:65–84. [9] Allen LA, Hernandez AF, O'Connor CM, et al. End points for clinical trials in acute heart failure syndromes. J Am Coll Cardiol 2009;53:2248–58.
Letters to the Editor
Low admission heart rate is a marker rather than a mediator of increased in-hospital mortality for patients with acute heart failure syndromes in sinus rhythm☆ Katsuya Kajimoto a,⁎, Naoki Sato b, Takehiko Keida c, Yasushi Sakata d, Kuniya Asai e, Masayuki Mizuno f, Teruo Takano e, and on behalf of the investigators of the Acute Decompensated Heart Failure Syndromes (ATTEND) registry a
Division of Cardiology, Sensoji Hospital, Tokyo, Japan Internal Medicine, Cardiology, and Intensive Care Unit, Nippon Medical School Musashi-Kosugi Hospital, Kanagawa, Japan c Department of Cardiovascular Medicine, Edogawa Hospital, Tokyo, Japan d Department of Cardiology, Osaka University Graduate School of Medicine, Osaka, Japan e Department of Internal Medicine, Nippon Medical School, Tokyo, Japan f Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan b
a r t i c l e
i n f o
Article history: Received 30 August 2013 Accepted 25 November 2013 Available online 4 December 2013 Keywords: Acute heart failure syndromes Heart rate Sinus rhythm In-hospital mortality
The product of systolic blood pressure (BP) × heart rate (HR) has been suggested to be a potential predictor of the cardiovascular prognosis [1]. It was reported that the systolic BP at admission is one of the most important prognostic indicators in patients with acute heart failure syndromes (AHFS), since a higher admission systolic BP is associated with lower mortality [2]. On the other hand, an elevated resting HR is associated with an increased risk of death in chronic heart failure patients [3]. However it is unclear whether the baseline HR influences the outcome of AHFS patients. Therefore, we investigated whether baseline HR was an in-hospital prognostic indicator for AHFS patients. The Acute Decompensated Heart Failure Syndromes (ATTEND) registry, a prospective observational multicenter cohort study, accumulates data on AHFS patients admitted to 53 hospitals throughout Japan between April 2007 and December 2011. The design and methods of this study, as well as the characteristics of the patients, have been described previously [4,5]. In this study, patients with atrial fibrillation and a permanent pacemaker at admission were excluded. Of the 4842 patients enrolled in this registry, 2728 patients who were in sinus rhythm at admission were evaluated. They were divided into baseline HR quartiles (b80, 80 to b100, 100 to b120, and ≥120 beats per minute [bpm]), and in-hospital mortality (all-cause death and cardiac death) was compared among the four groups. This study is being conducted according to the principles of the Declaration of Helsinki. Institutional review board approval was obtained at each participating medical center prior to commencing the study, and all patients provide written informed consent upon enrollment. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. Data are presented as the mean (SD), median with interquartile range, or frequency. One-way analysis of variance was employed for between-group comparison of continuous variables
☆ Funding: This work was supported by the Japan Heart Foundation. ⁎ Corresponding author at: Division of Cardiology, Sensoji Hospital, 2-30-17, Asakusa, Taito-ku, Tokyo 111-0032, Japan. Tel.: +81 3 3841 3330; fax: +81 3 3847 1452. E-mail address: [email protected] (K. Kajimoto).
with a normal distribution, while the Kruskal–Wallis H-test was used for skewed continuous variables or discrete variables and the chisquare test was used to compare nominal scale variables. Two-tailed p values of less than 0.05 were considered to indicate statistical significance. The baseline clinical characteristics of the HR quartiles are shown in Table 1. The median length of stay was 21 (14–33) days and the all-cause mortality rate during hospitalization was 6.8% (n = 185). Univariate analysis revealed a significantly higher risk of in-hospital all-cause death in patients with an HR b80 bpm or 80 to b100 bpm than in those with an HR ≥120 bpm (Table 2). The unadjusted risk of in-hospital cardiac death was significantly higher in patients with an HR of b80, 80 to b100, and 100 to b120 bpm than in those with an HR ≥120 bpm. After adjustment for multiple comorbidities and other clinical factors (Table 2), the association between HR and the risk of in-hospital all-cause mortality became weaker. However, the risk of in-hospital cardiac death for patients with an HR b80, 80 to b100, and 100 to 120 bpm was respectively increased to 2.24 times (95% confidence interval [CI], 0.99–5.06; p = 0.052), 2.34 times (95% CI, 1.06–5.51; p = 0.034), and 2.15 times (95% CI, 0.96–4.85; p = 0.064) the risk for patients with an HR ≥120 bpm. The present findings indicate that a low HR at admission may be a marker rather than a direct mediator of an increased risk of in-hospital mortality for AHFS patients in sinus rhythm at admission. In chronic heart failure patients, an elevated resting HR has been shown to be associated with an increased risk of mortality and cardiovascular disease [1,3]. On the other hand, in the urgent phase of AHFSs, tachycardia is largely a physiological and beneficial compensatory response, because structural limitations on the stroke volume mean that an increase of the HR is required to maintain a normal cardiac output [6]. Thus, the precise relation between the HR and the pathophysiology of AHFS patients is unclear [7]. Our data showed that a lower baseline HR in sinus rhythm was associated with a substantially higher in-hospital cardiac death for AHFS patients. The mechanism underlying the association of a higher admission HR with a lower in-hospital cardiac death rate for AHFS patients is not entirely clear, but some assumptions can be made. Bainbridge reported that rapid volume loading results in an increase of both BP and HR [8], and previous studies have shown that a higher baseline systolic BP is associated with a better outcome [2]. Therefore, it could be speculated that a higher risk of in-hospital cardiac death might be associated with impairment of the ability to increase HR to appropriate levels in the urgent phase of AHFS. Our study had several limitations. First, the ATTEND registry study was not a prospective randomized trial, so variables that were not investigated could have influenced the findings. Second, as we have previously reported [5], the relatively long hospital stay of our patients might be related to the Japanese healthcare system, because demographic and clinical variables were reported to be similar in Japanese AHFS patients and those from Western countries [4]. Thus,
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Table 1 Baseline characteristics of the AHFS patients and each quartile stratified by heart rate at admission.
Mean age, years Female, n (%) Body mass index, kg/m2 Ischemic etiology, n (%) Hypertensive etiology, n (%) Valvular etiology, n (%) Idiopathic dilated etiology, n (%) Reduced LVEF (≤40%), n (%) Medical history, n (%) Prior hospitalization for heart failure Hypertension Dyslipidemia Diabetes Chronic obstructive pulmonary disease Stroke Medications prior to admission, n (%) Loop diuretic Spironolactone or Eplerenone Angiotensin-converting enzyme inhibitor Angiotensin receptor blocker Beta-blocker Calcium-channel blocker Digoxin Aspirin Statin Intravenous drugs during hospitalization, n (%) Furosemide Any vasodilator Any inotropic agent Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Heart rate, beats/min Brain natriuretic peptide, pg/ml Blood urea nitrogen, mg/dl Serum creatinine, mg/dl Serum sodium, mEq/l Hemoglobin, g/dl C-reactive protein, mg/dl Clinical features on admission, n (%) Paroxysmal nocturnal dyspnea Orthopnea Rales Jugular venous distension Peripheral edema NYHA functional class III IV
Total (n = 2728)
Heart rate quartile, bpm b80 (n = 647)
80 to b100 (n = 803)
100 to b120 (n = 737)
≥120 (n = 541)
p value
71.9 ± 14.9a 1138 (41.7) 23.2 ± 4.8a 1045 (38.3) 583 (21.4) 414 (15.2) 342 (12.5) 1552 (56.9)
76.1 ± 12.7a 313 (48.4) 23.0 ± 4.9a 240 (37.1) 118 (18.2) 91 (14.1) 56 (8.7) 258 (39.9)
73.4 ± 14.5a 331 (41.2) 22.9 ± 4.3a 329 (41.0) 153 (19.1) 144 (17.9) 97 (12.1) 428 (53.3)
69.1 ± 16.1a 290 (39.3) 23.7 ± 5.3a 273 (37.0) 156 (21.2) 126 (17.1) 114 (15.5) 471 (63.9)
68.4 ± 14.3a 204 (37.7) 23.2 ± 4.5a 203 (37.5) 156 (28.8) 53 (9.8) 75 (13.9) 395 (73.0)
b .001 b .001 0.010 0.327 b .001 b .001 0.001 b .001
799 (29.3) 1978 (72.5) 1091 (40.0) 1001 (36.7) 333 (12.2) 336 (12.3)
245 (37.9) 489 (75.6) 248 (38.3) 242 (37.4) 88 (13.6) 99 (15.3)
249 (31.0) 559 (69.6) 326 (40.6) 290 (36.1) 108 (13.4) 112 (13.9)
189 (25.6) 524 (71.1) 281 (38.1) 265 (36.0) 82 (11.1) 73 (9.9)
116 (21.4) 406 (75.0) 236 (43.6) 204 (37.7) 55 (10.2) 52 (9.6)
b .001 0.023 0.157 0.881 0.155 0.001
1076 (39.4) 409 (15.0) 375 (13.7) 904 (33.1) 802 (29.4) 808 (29.6) 164 (6.0) 911 (33.4) 668 (24.5)
318 (49.1) 124 (19.1) 107 (16.5) 260 (40.2) 267 (41.3) 248 (38.3) 52 (8.0) 266 (41.1) 184 (28.4)
367 (45.7) 142 (17.7) 109 (13.6) 286 (35.6) 248 (30.9) 251 (31.3) 50 (6.2) 293 (36.5) 216 (26.9)
256 (34.7) 91 (12.3) 99 (13.4) 228 (30.9) 185 (25.1) 197 (26.7) 38 (5.2) 204 (27.7) 158 (21.4)
135 (25.0) 52 (9.6) 60 (11.1) 130 (24.0) 102 (18.9) 112 (20.7) 24 (4.4) 148 (27.4) 110 (20.3)
b .001 b .001 0.056 b .001 b .001 b .001 0.044 b .001 b .001
2098 (76.9) 2234 (81.9) 521 (19.1) 151.8 ± 39.0a 84.8 ± 23.5a 97.1 ± 25.4a 823 [413–1478]b 26.9 ± 21.8a 1.48 ± 1.73a 139.3 ± 4.4a 11.9 ± 2.5a 0.59 [0.20–2.00]b
444 (68.6) 447 (69.1) 105 (16.2) 136.7 ± 32.0a 71.3 ± 16.5a 65.0 ± 12.1a 739 [380–1427]b 29.9 ± 18.1a 1.51 ± 1.34a 139.3 ± 5.2a 11.2 ± 2.1a 0.48 [0.15–1.67]b
605 (75.3) 645 (80.3) 138 (17.2) 145.4 ± 34.3a 80.8 ± 18.9a 88.7 ± 5.9a 858 [403–1668]b 28.8 ± 27.7a 1.55 ± 1.66a 139.4 ± 4.5a 11.6 ± 2.5a 0.63 [0.20–2.40]b
588 (79.8) 643 (87.2) 163 (22.1) 156.0 ± 37.8a 90.4 ± 23.1a 107.7 ± 5.8a 881 [463–1492]b 25.0 ± 16.9a 1.46 ± 1.60a 139.2 ± 4.0a 12.2 ± 2.7a 0.60 [0.20–1.98]b
461 (85.2) 499 (92.2) 115 (21.3) 173.6 ± 43.9a 99.4 ± 26.6a 133.2 ± 14.1a 761 [430–1306]b 23.2 ± 21.1a 1.39 ± 2.29a 139.5 ± 3.9a 12.9 ± 2.5a 0.60 [0.20–1.89]b
b .001 b .001 0.010 b .001 b .001 b .001 0.033 b .001 0.410 0.758 b .001 0.011
1502 (55.1) 1829 (67.0) 2067 (75.8) 1416 (51.9) 1737 (63.7)
271 (41.9) 314 (48.5) 402 (62.1) 314 (48.5) 457 (70.6)
435 (54.2) 498 (62.0) 583 (72.6) 400 (49.8) 529 (65.9)
456 (61.9) 544 (73.8) 585 (79.4) 392 (53.2) 466 (63.2)
340 (62.8) 473 (87.4) 497 (91.9) 310 (57.3) 285 (52.7)
b .001 b .001 b .001 0.014 b .001
934 (34.2) 1341 (49.2)
261 (40.3) 225 (34.8)
318 (39.6) 325 (40.5)
243 (33.0) 406 (55.1)
112 (20.7) 385 (71.2)
b .001 b .001
Values are shown as the no. (%). AHFS = acute heart failure syndromes; bpm = beats per minute; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association. a Mean ± SD. b Median [interquartile range].
caution must be exercised when generalizing our current results to different cohorts of patients. In conclusion, our findings suggest that the baseline HR of AHFS patients who were in sinus rhythm may be a marker rather than a
mediator of in-hospital cardiac mortality. In contrast to patients with chronic heart failure, a lower baseline HR seems to be associated with a substantially higher in-hospital cardiac death rate for AHFS patients. It was recently proposed that cardiac death, which is a
Table 2 Adjusted and unadjusted risk of in-hospital mortality stratified by the baseline heart rate. Endpoint
HR quartile
Quartile
Unadjusted odds ratio
(95% CI)
p value
Adjusteda odds ratio
(95% CI)
p value
All-cause mortality
b80 bpm 80 to b100 bpm 100 to b 120 bpm ≥120 bpm b80 bpm 80 to b100 bpm 100 to b 120 bpm ≥120 bpm
1st 2nd 3rd 4th 1st 2nd 3rd 4th
2.06 2.25 1.39 1.00 2.90 2.56 1.81 1.00
(1.24–3.44) (1.38–3.68) (0.82–2.36)
0.006 0.001 0.224
1.40 1.78 1.27
(0.75–2.61) (0.99–3.19) (0.69–2.34)
0.288 0.082 0.447
(1.51–5.59) (1.34–4.88) (0.91–3.57)
0.001 0.005 0.009
2.24 2.34 2.15
(0.99–5.06) (1.06–5.15) (0.96–4.85)
0.052 0.034 0.064
Cardiac death
a Odds ratios were adjusted by age, gender, body mass index, etiology of heart failure, prior hospitalization for heart failure, systolic blood pressure, left ventricular ejection fraction, New York Heart Association functional class, blood urea nitrogen, C-reactive protein, use of beta blockers, and use of digoxin at admission. HR = heart rate; CI = confidence interval; bpm = beats per minute.
100
Letters to the Editor
disease-specific end-point, might be a superior choice for studies of AHFSs compared with all-cause mortality [9]. Accordingly, our findings may have clinical implications for the early identification of high-risk AHFS patients and raise the possibility of initiating early countermeasures to prevent in-hospital cardiac death. However, taking geographical differences of AHFS into consideration, further investigation is needed to examine the association between admission HR and the in-hospital outcome of AHFS patients in sinus rhythm. We thank the study investigators for their contributions, and the Japan Heart Foundation for funding this study. We also express our appreciation to Katsunori Shimada, PhD (Statz Institute, Inc., Tokyo, Japan) for his expert assistance with the statistical analysis. Appendix A. Study investigators (53 hospitals) Nippon Medical School: Naoki Sato, Kuniya Asai, Ryo Munakata, Toshiyuki Aokage, and Asuka Yoshida; Tokyo Women's Medical University: Yuichiro Minami, Dai Yumino, Masayuki Mizuno, Erisa Kawada, Kentaro Yoshida, Yuri Ozaki, Tomohito Kogure, and Shintaro Haruki; Saitamaken Saiseikai Kurihashi Hospital: Masayuki Mizuno; Aoyama Hospital, Tokyo Women's Medical University: Katsuya Kajimoto; Saiseikai Kumamoto Hospital: Koichi Nakao, Tadashi Sawamura, and Toshiaki Nuki; Toyota Memorial Hospital: Ryoji Ishiki and Shigeki Yokota; Tokushima Prefectural Central Hospital: Hiroyuki Fujinaga, Takashi Yamamoto, Kenji Harada, Akihiro Saito, Norihito Kageyama, and Takanobu Okumura; Chiba Hokusoh Hospital, Nippon Medical School: Noritake Hata, Koji Murai, and Ayaka Nozaki; Shizuoka Medical Center: Hidekazu Kawanaka and Jun Tanabe; Hyogo Prefectural Amagasaki Hospital: Yukihito Sato; Oji General Hospital: Katsuhisa Ishii, Hitoshi Oiwa, Tomoaki Matsumoto, Daisuke Yoshida, and Nobuo Kato; Showa University Fujigaoka Hospital: Hiroshi Suzuki and Nobuyuki Shimizu; Edogawa Hospital: Takehiko Keida, Masaki Fujita, Kentaro Nakamura, Toshiya Chinen, Kentaro Meguro, Tatsuro Kikuchi, Toshiyuki Nishikido, Marohito Nakata, Tatsuya Yamashita, and Masaya Nakata; Kurashiki Central Hospital: Akitoshi Hirono, Kazuaki Mitsudo, Kazushige Kadota, Noriko Makita, and Nagisa Watanabe; Hyogo College of Medicine: Masaaki Kawabata and Kenichi Fujii; Yamaguchi University: Shinichi Okuda and Shigeki Kobayashi; Fukui Cardiovascular Center: Ikuo Moriuchi, Kiyo-o Mizuno, Kazuo Osato, Tatsuaki Murakami, Yoshifumi Shimada, Katsushi Misawa, Hiromasa Kokado, Takashi Fujita, Yoshitomo Fukuoka, and Syu Takabatake; Tokyo Medical University Hospital: Yoshifumi Takata, Manabu Miyagi, Nobuhiro Tanaka, and Akira Yamashina; Yatsu Hoken Hospital: Shinji Sudo; Shonan Dai-ichi Hospital: Koichi Shimamura and Michitaka Nagashima; Komatsu Municipal Hospital: Tomoya Kaneda, Kosei Ueda, Hiromasa Kato, and Toshinori Higashikata; Sendai Cardiovascular Center: Kanichi Fujimori, Hiroshi Kobayashi, Shinya Fujii, Masahiro Yagi, Yuri Ozaki, and Jyunko Takaki; Gunma Prefectural Cardiovascular Center: Eiji Yamashita and Takuji Toyama; Seirei Hamamatsu General Hospital: Tetsuo Hirata, Kazuho Kamisihima, and Toshiaki Oka; Osaka City General Hospital: Ryushi Komatsu, Akira Itoh, Takahiko Naruko, Yukio Abe, Eiichirou Nakagawa, Atsuko Furukawa, Naoto Kinou, Shoko Uematsu, and Isao Tabuchi; Suwa Central Hospital: Taku Imai; Kyushu University Hospital: Takafumi Sakamoto and Koji Todaka; Nagasaki University Hospital of Medicine and Dentistry: Yuji Koide and Koji Maemura;
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.087
Tokai University School of Medicine: Koichiro Yoshioka; Fukushima Medical University: Akiomi Yoshihisa, Takamasa Sato, and Yasuchika Takeishi; Yokohama City University Medical Center: Toshiaki Ebina, Kazuo Kimura, and Masaaki Konishi; Tottori University Hospital: Masahiko Kato, Yoshiharu Kinugasa, Katsunori Ishida, Shinobu Sugihara, and Kiyotaka Yanagihara; Asahikawa Medical College: Toshiharu Takeuchi, Motoi Okada, and Naoyuki Hasebe; Showa University School of Medicine: Tetsuo Sakai, Taku Asano, Yoshino Minoura, Tsutomu Toshida, Takatoshi Sato, Yuya Yokota, and Seita Kondo; Osaka University Hospital: Yasushi Sakata, Issei Komuro, Kinya Otsu, Shizuya Yamashita, and Yoshihiro Asano; Kitamurayama Hospital: Asuka Yoshida; Sensoji Hospital: Katsuya Kajimoto; Osaka Police Hospital: Kazunori Kashiwase and Yasunori Ueda; Komaki City Hospital: Taizo Kondo, Katsuhiro Kawaguchi, and Akinori Sawamura; Fukuoka Wajiro Hospital: Taro Saito, Toru Higa, Hiroo Noguchi, Yoko Yanagita, Keita Nakamura, and Tomo Komaki; Saitama Medical University International Medical Center: Toshihiro Muramatsu, Tomomi Koizumi, Yoshie Nakajima, Toshihiko Kikutani, Yoshifimi Ikeda, Toru Tamaki, Shuhei Funada, and Harumi Ogawa; Saiseikai Nagasaki Hospital: Koichiro Sakuragawa; Keio University School of Medicine: Shun Kohsaka; Saiseikai Futsukaichi Hospital: Shin-ichi Ando, Toshiaki Kadokami, Eiko Ishida, and Katsumi Ide; Sakurabashi Watanabe Hospital: Yohei Sotomi, Yoshiharu Higuchi, and Motoko Uehara; Nagoya City University Graduate School of Medical Sciences: Toshihiko Goto and Nobuyuki Ohte; Tohoku University Hospital: Masanobu Miura, Nobuyuki Shiba, Kotaro Nochioka, and Hiroaki Shimokawa; Nippon Steel Yawata Memorial Hospital: Shiro Ishihara, Tokushi Koga, Shinichiro Fujishima, Shigeru Kaseda, and Yoshie Haga; St. Marianna University School of Medicine Hospital: Keisuke Kida; Tokyo Women's Medical University Yachiyo Medical Center: Kazuho Kamisihima; Okinawa Prefectural Nannbu Medical Center & Children's Medical Center: Makiko Nakamura, Osahiko Sunagawa, Takafumi Miyara, Youji Taba, Takashi Touma, and Osamu Shinjo; Jichi Medical University: Yoshioki Nishimura, Kazuomi Kario, and Hayato Shimizu; Nippon Medical School Musashi Kosugi Hospital: Takahiro Uchida, Ken-ichi Amitani, and Naoki Sato.
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