- Email: [email protected]
Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation
IJCA-18055; No of Pages 4 International Journal of Cardiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation☆ Jeonggeun Moon a,b, Hye-Jeong Lee c, Young Jin Kim c, Jong-Youn Kim d, Hui-Nam Pak d, Jong-Won Ha d, Moon-Hyoung Lee d, Boyoung Joung d,⁎ a
Cardiology Division, Department of Internal Medicine, Gachon University of Medicine and Science, Incheon, Republic of Korea Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Republic of Korea d Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 11 April 2014 Accepted 12 April 2014 Available online xxxx Keywords: Stroke Atrial fibrillation Height Diastolic function Echocardiography
a b s t r a c t Background: For decades, repeated epidemiologic observations have been made regarding the inverse relationship between stature and cardiovascular disease, including stroke. However, the concept has not been fully evaluated in patients with atrial fibrillation (AF). We investigated whether patient’s height is associated with ischemic stroke in patients with nonvalvular AF and attempted to ascertain a potential mechanism. Methods: All 558 AF patients were enrolled: 211 patients with ischemic stroke (144 men, 68 ± 10 years) and 347 no-stroke patients (275 men, 56 ± 11 years) as a control group. Clinical characteristics and echocardiographic parameters were compared between the two groups. Results: (1) Stroke patients were shorter than those in the control group (164 ± 8, vs. 169 ± 8 cm, p b 0.001). However, body mass index failed to predict ischemic stroke; (2) Short stature (OR 0.93, 95% CI 0.91–0.95, p b 0.001) along with left atrial (LA) anterior-posterior diameter and diastolic mitral inflow velocity (E) to diastolic mitral annuls velocity (E’) (E/E’) were independent predictor of stroke; (3) Height showed inverse correlation with E/E’ independently, even after adjusting for other variables, including age, sex, and body weight, and comorbidities β −0.20, p = 0.003); (4) LA size showed no correlation with stature (R = −0.06, p = 0.18), whereas left ventricular size increases according to height of patients. Conclusions: Short stature is associated with occurrence of ischemic stroke and diastolic dysfunction in patients with AF and preserved systolic function. Height is a non-modifiable risk factor of stroke and might be more important than obesity in Asian AF patients, who are relatively thinner than western populations. © 2014 Elsevier Ireland Ltd. All rights reserved.
For decades, epidemiologic observations have been made regarding the inverse relationship between stature and cardiovascular (CV) disease including stroke [1]. However, it is unclear whether height is associated with stroke occurrence in nonvalvular atrial fibrillation (AF) (NV-AF) patients. We investigated whether height is associated with occurrence of ischemic stroke in NV-AF with preserved left
☆ Funding Sources: This work was supported by research grants from the Gachon University Gil Medical Center, Republic of Korea (Grant number: 2013-10 and 2013-46, J.M.), Boryung Pharmaceutical Company (J.M.), the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (NRF-2010-0021993, NRF-2012R1A2A2A02045367, B.J.), and a grant from the Korean Healthcare Technology R&D project funded by the Ministry of Health & Welfare (HI12C1552, B.J.). ⁎ Corresponding author at: Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea 120-752. Tel.: +82 2 2228 8460; fax: +82 2 393 2041. E-mail address: [email protected] (B. Joung).
ventricular (LV) ejection fraction (EF) (≥ 50%); and whether cardiac structure and function are influenced by stature. All 558 NV-AF patients were enrolled. Ischemic stroke was defined as the presence of a focal neurologic deficit or a nonfocal encephalopathy lasting N24 h with evidence of cerebral infarction on brain magnetic resonance imaging. Echocardiography was performed and measurements were averaged for five cardiac cycles. LV EF was calculated using the modified Quinones method. Left atrial (LA) anterior–posterior (AP) diameter was measured and LA volume was calculated using the biplane area-length method. Mitral inflow velocity (E) was determined using the pulsed wave Doppler and diastolic mitral annulus velocity (E′) was measured using tissue Doppler imaging at the septal corner. E/E′ was calculated. Two-sample t-tests and chi-square tests with Fisher's exact tests were used for continuous and categorical variables, respectively. Binary logistic regression analysis was used to determine independent predictors for stroke. For inter-tertile comparison, we used the one-way ANOVA test and post hoc analyses were performed using the Bonferroni
http://dx.doi.org/10.1016/j.ijcard.2014.04.154 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Moon J, et al, Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.154
2
J. Moon et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Table 1 Baseline characteristics and intergroup comparison of study patients.
Clinical characteristics Age, years Male, n (%) Height, cm Body mass index (body weight [kg]/height2 [m2]), kg/m2 Paroxysmal AF, n (%) Comorbidities, n (%) CHF Hypertension Age N75 years Diabetes mellitus Dyslipidemia CHADS2 Antithrombotic medications Anti-platelet agents, n (%) Anticoagulants, n (%) Echocardiography LV EF, % LA AP diameter, mm LA volume, mL LVEDD, mm E/E′
All (n = 558)
No stroke (n = 347)
Stroke (n = 211)
p-value
60 ± 12 419 (75) 167 ± 8 25 ± 3 349 (63)
56 ± 11 275 (79) 169 ± 8 25 ± 3 242 (70)
68 ± 10 144 (68) 164 ± 8 24 ± 3 107 (51)
b0.001⁎ 0.004⁎ b0.001⁎ b0.001⁎ b0.001⁎
22 (4) 305 (55) 53 (10) 89 (16) 100 (18) 0.8 ± 0.8 127 (23) 72 (13) 81 (15)
9 (3) 153 (44) 8 (2) 35 (10) 57 (16) 0.6 ± 0.7 83 (25) 37 (11) 56 (16)
13 (6) 152 (72) 45 (21) 54 (26) 43 (20) 1.3 ± 0.8 44 (21) 35 (17) 25 (12)
0.04⁎ b0.001⁎ b0.001⁎ b0.001⁎ 0.26 b0.001⁎ 0.47 0.51 0.65
63 43 65 50 11
64 41 58 50 10
63 46 79 50 14
0.35 b0.001⁎ b0.001⁎
± ± ± ± ±
8 3 25 4 5
± ± ± ± ±
7 6 20 4 4
± ± ± ± ±
10 7 30 5 6
0.52 b0.001⁎
AF = atrial fibrillation; CHF = congestive heart failure; BMI = body mass index; LV EF = left ventricular ejection fraction; LA = left atrium/atrial; AP = anterior–posterior; LVEDD = left ventricular end-diastolic dimension; E/E′ = mitral inflow velocity/diastolic mitral annulus velocity. ⁎ Indicates p b 0.05.
procedure. Pearson's bivariate correlation was used to determine correlation between variables. Multiple linear regression analysis was performed to test the association of variables with E/E′. Baseline characteristics are shown in Table 1. Patients with stroke were older, more likely to be female, and particularly, shorter than subjects without stroke; body mass index (BMI) was smaller in the stroke group. On echocardiography, longer LA AP diameter, larger LA volume and higher E/E′ were observed in the stroke group. In a binary logistic regression analysis (Table 2), height showed an independent association with stroke, even after adjusting for age, sex, hypertension and diabetes. Meanwhile, BMI showed inverse correlation with stroke and failed to predict the adverse event independently after adjusting for demography and presence of other co-morbidities. LA AP diameter, LA volume and E/E′ also independently predicted stroke. We divided study patients into tertiles according to height (Fig. 1): LV size increases with height and it is intuitive: “the larger the body, the larger the heart” (Fig. 1-A). However, the LA volume rather showed an inverse trend, failed to reach statistical significance though (Fig. 1-B). Strikingly, E/E′ was highest in the first tertile and lowest in the third tertile (Fig. 1-C). LV size showed positive linear correlation with height (Fig. 2-A),
Table 2 Predictors of stroke in AF patients.
Clinical characteristics Age Male CHADS2 score Height Body mass index Echocardiography LA AP diameter LA volume E/E′
Crude OR (95% CI)
p-value
Adjusteda OR (95% CI)⁎
p-value
1.11 (1.10–1.14) 0.56 (0.38–0.83) 32 (15–66) 0.93 (0.91–0.95) 0.87 (0.82–0.93)
b0.001⁎ 0.004⁎ b0.001⁎ b0.001⁎ b0.001⁎
– – – 0.96 (0.92–0.99) 0.94 (0.87–1.02)
– – – 0.02⁎ 0.12
1.13 (1.09–1.16) 1.04 (1.03–1.05) 1.20 (1.14–1.26)
b0.001⁎ b0.001⁎
1.10 (1.06–1.14) 1.03 (1.02–1.04) 1.10 (1.04–1.16)
b0.001⁎ b0.001⁎ b0.001⁎
b0.0018
⁎ Indicates p b 0.05. a Adjusted for age, sex, hypertension and diabetes
whereas LA volume did not (Fig. 2-B); notably E/E′ was associated with height (Fig. 2-C). In multiple linear regression analysis, height independently determined E/E′ (β = − 0.20, t = − 2.95, p = 0.003) after adjusting for age, sex, body weight, hypertension and diabetes. Main findings are as follows: 1) NV-AF patients with ischemic stroke are shorter than those without stroke; 2) LA volumes are not entirely dependent on stature, whereas LV size increases with height; and 3) stature and E/E′ showed inverse correlation. This study revealed the relationship between stature and diastolic dysfunction in NV-AF and we suggest that height is an unmodifiable risk factor; hence, more impaired diastolic function in shorter patients with NV-AF might play a pathophysiological role in stroke occurrence. Copious hypotheses have been suggested to explain the inverse relationship between short stature and stroke. Short stature is related to vessel diameter [2]. Socioeconomic status affects height and CV outcomes [3]. Inadequate nutrition during childhood results in short stature in adulthood and increases CV risk including stroke [4]. Height decreases during the aging process and short stature represents the old age of stroke patients [5]. Simultaneously, stature is influenced by prognostic factors of stroke, such as hypertension and diabetes mellitus [5]. In this study, we revealed the association between stature and diastolic dysfunction in NV-AF and this finding suggests a new hypothesis for an old observation. Height is negatively correlated with central arterial pressure augmentation because of shorter distance to sites of peripheral pulse wave reflection [6]. Greater central pressure augmentation in shorter subjects induces cardiac overloading [7] and diastolic dysfunction [8]; thus it might explain the higher prevalence of stroke in short patients. Although LV systolic dysfunction is a well-known risk factor for stroke in AF patients [9], it is still unclear whether diastolic function also plays a prognostic role regarding stroke. E/E′ reflects LV filling pressure not only in sinus rhythm but also in AF [10], and it serves as a robust prognosticator in CV diseases including AF [11]. Lee et al. [12] reported that E/E′ was a predictor of stroke in NV-AF patients. In this study, we observed an inverse association of E/E′ with stature; this novel finding can, at least partially, explain the correlation between stature and stroke.
Please cite this article as: Moon J, et al, Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.154
J. Moon et al. / International Journal of Cardiology xxx (2014) xxx–xxx
3
Fig. 1. Inter-tertile comparison of height and LVEDD (A), LA volume (B) and E/E′ (C). LVEDD increases according to the increase in height and it is intuitive: “the larger the body, the larger the heart” (A). However, the LA volume rather showed an inverse trend, although it failed to reach statistical significance (B). Notably, E/E′ was highest in the first tertile group and lowest in the third tertile group (C).
Fig. 2. Results of bivariate correlation analysis. (A) LVEDD showed weak but significant inverse linear correlation with height. (B) LA volume did not show significant correlation with stature. (C) Of note, E/E′ showed a strong association with patient's height.
Common belief is that taller individuals have larger hearts. Interestingly, in this cohort, LA volume was not necessarily larger in taller patients, whereas LV size increases with stature. This is meaningful because LA size represents the severity and chronicity of diastolic dysfunction; LA volume is a robust prognosticator in CV diseases including AF [13], and even in the general population [14]. Therefore, it can be said that shorter patients with AF suffer greater impairment of diastolic function. This concept is further supported by previous research reporting that the brain natriuretic polypeptide reflecting diastolic dysfunction was a predictor for stroke in NV-AF [15]. BMI did not show an association with stroke in our cohort; and it is contrary to previous data from western countries, which reported strong correlation between obesity and stroke and/or arrhythmia [16]. Therefore, short stature, rather than BMI, should be supposed as a non-modifiable risk factor for a stroke in non-obese populations. This study has inborn limitations of retrospective design. Particularly, demographic characteristics differed between the stroke and control group. Some patients were under the influence of antithrombotic therapy, while others were not. This study was conducted in a tertiary
referral center; therefore, our cohort might not represent all NV-AF patients.
Acknowledgment The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
References [1] Wannamethee SG, Shaper AG, Whincup PH, Walker M. Adult height, stroke, and coronary heart disease. Am J Epidemiol 1998;148:1069–76. [2] Fisher LD, Kennedy JW, Davis KB, et al. Association of sex, physical size, and operative mortality after coronary artery bypass in the Coronary Artery Surgery Study (CASS). J Thorac Cardiovasc Surg 1982;84:334–41. [3] Allebeck P, Bergh C. Height, body mass index and mortality: do social factors explain the association? Public Health 1992;106:375–82. [4] Cook NR, Hebert PR, Satterfield S, Taylor JO, Buring JE, Hennekens CH. Height, lung function, and mortality from cardiovascular disease among the elderly. Am J Epidemiol 1994;139:1066–76.
Please cite this article as: Moon J, et al, Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.154
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J. Moon et al. / International Journal of Cardiology xxx (2014) xxx–xxx
[5] Ali LK, Saver JL, Liebeskind DS, Pineda S, Ovbiagele B. Influence of height on the clinical characteristics and prognosis of patients with ischemic stroke. Neurologist 2011;17:21–3. [6] McGrath BP, Liang YL, Kotsopoulos D, Cameron JD. Impact of physical and physiological factors on arterial function. Clin Exp Pharmacol Physiol 2001;28:1104–7. [7] Regidor E, Banegas JR, Gutierrez-Fisac JL, Dominguez V, Rodriguez-Artalejo F. Influence of childhood socioeconomic circumstances, height, and obesity on pulse pressure and systolic and diastolic blood pressure in older people. J Hum Hypertens 2006;20:73–82. [8] Smulyan H, Marchais SJ, Pannier B, Guerin AP, Safar ME, London GM. Influence of body height on pulsatile arterial hemodynamic data. J Am Coll Cardiol 1998;31:1103–9. [9] Predictors of thromboembolism in atrial fibrillation: I. Clinical features of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern Med 1992;116:1–5. [10] Sohn DW, Song JM, Zo JH, et al. Mitral annulus velocity in the evaluation of left ventricular diastolic function in atrial fibrillation. J Am Soc Echocardiogr 1999;12:927–31.
[11] Okura H, Takada Y, Kubo T, et al. Tissue Doppler-derived index of left ventricular filling pressure, E/E′, predicts survival of patients with non-valvular atrial fibrillation. Heart 2006;92:1248–52. [12] Lee SH, Choi S, Chung WJ, et al. Tissue Doppler index, E/E′, and ischemic stroke in patients with atrial fibrillation and preserved left ventricular ejection fraction. J Neurol Sci 2008;271:148–52. [13] Hoit BD. Left atrial size and function: role in prognosis. J Am Coll Cardiol 2014;63:493–505. [14] Pritchett AM, Mahoney DW, Jacobsen SJ, Rodeheffer RJ, Karon BL, Redfield MM. Diastolic dysfunction and left atrial volume: a population-based study. J Am Coll Cardiol 2005;45:87–92. [15] Shimizu H, Murakami Y, Inoue S, et al. High plasma brain natriuretic polypeptide level as a marker of risk for thromboembolism in patients with nonvalvular atrial fibrillation. Stroke 2002;33:1005–10. [16] Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2006;113:898–918.
Please cite this article as: Moon J, et al, Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.154
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation☆ Jeonggeun Moon a,b, Hye-Jeong Lee c, Young Jin Kim c, Jong-Youn Kim d, Hui-Nam Pak d, Jong-Won Ha d, Moon-Hyoung Lee d, Boyoung Joung d,⁎ a
Cardiology Division, Department of Internal Medicine, Gachon University of Medicine and Science, Incheon, Republic of Korea Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Republic of Korea d Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 11 April 2014 Accepted 12 April 2014 Available online xxxx Keywords: Stroke Atrial fibrillation Height Diastolic function Echocardiography
a b s t r a c t Background: For decades, repeated epidemiologic observations have been made regarding the inverse relationship between stature and cardiovascular disease, including stroke. However, the concept has not been fully evaluated in patients with atrial fibrillation (AF). We investigated whether patient’s height is associated with ischemic stroke in patients with nonvalvular AF and attempted to ascertain a potential mechanism. Methods: All 558 AF patients were enrolled: 211 patients with ischemic stroke (144 men, 68 ± 10 years) and 347 no-stroke patients (275 men, 56 ± 11 years) as a control group. Clinical characteristics and echocardiographic parameters were compared between the two groups. Results: (1) Stroke patients were shorter than those in the control group (164 ± 8, vs. 169 ± 8 cm, p b 0.001). However, body mass index failed to predict ischemic stroke; (2) Short stature (OR 0.93, 95% CI 0.91–0.95, p b 0.001) along with left atrial (LA) anterior-posterior diameter and diastolic mitral inflow velocity (E) to diastolic mitral annuls velocity (E’) (E/E’) were independent predictor of stroke; (3) Height showed inverse correlation with E/E’ independently, even after adjusting for other variables, including age, sex, and body weight, and comorbidities β −0.20, p = 0.003); (4) LA size showed no correlation with stature (R = −0.06, p = 0.18), whereas left ventricular size increases according to height of patients. Conclusions: Short stature is associated with occurrence of ischemic stroke and diastolic dysfunction in patients with AF and preserved systolic function. Height is a non-modifiable risk factor of stroke and might be more important than obesity in Asian AF patients, who are relatively thinner than western populations. © 2014 Elsevier Ireland Ltd. All rights reserved.
For decades, epidemiologic observations have been made regarding the inverse relationship between stature and cardiovascular (CV) disease including stroke [1]. However, it is unclear whether height is associated with stroke occurrence in nonvalvular atrial fibrillation (AF) (NV-AF) patients. We investigated whether height is associated with occurrence of ischemic stroke in NV-AF with preserved left
☆ Funding Sources: This work was supported by research grants from the Gachon University Gil Medical Center, Republic of Korea (Grant number: 2013-10 and 2013-46, J.M.), Boryung Pharmaceutical Company (J.M.), the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (NRF-2010-0021993, NRF-2012R1A2A2A02045367, B.J.), and a grant from the Korean Healthcare Technology R&D project funded by the Ministry of Health & Welfare (HI12C1552, B.J.). ⁎ Corresponding author at: Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea 120-752. Tel.: +82 2 2228 8460; fax: +82 2 393 2041. E-mail address: [email protected] (B. Joung).
ventricular (LV) ejection fraction (EF) (≥ 50%); and whether cardiac structure and function are influenced by stature. All 558 NV-AF patients were enrolled. Ischemic stroke was defined as the presence of a focal neurologic deficit or a nonfocal encephalopathy lasting N24 h with evidence of cerebral infarction on brain magnetic resonance imaging. Echocardiography was performed and measurements were averaged for five cardiac cycles. LV EF was calculated using the modified Quinones method. Left atrial (LA) anterior–posterior (AP) diameter was measured and LA volume was calculated using the biplane area-length method. Mitral inflow velocity (E) was determined using the pulsed wave Doppler and diastolic mitral annulus velocity (E′) was measured using tissue Doppler imaging at the septal corner. E/E′ was calculated. Two-sample t-tests and chi-square tests with Fisher's exact tests were used for continuous and categorical variables, respectively. Binary logistic regression analysis was used to determine independent predictors for stroke. For inter-tertile comparison, we used the one-way ANOVA test and post hoc analyses were performed using the Bonferroni
http://dx.doi.org/10.1016/j.ijcard.2014.04.154 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Moon J, et al, Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.154
2
J. Moon et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Table 1 Baseline characteristics and intergroup comparison of study patients.
Clinical characteristics Age, years Male, n (%) Height, cm Body mass index (body weight [kg]/height2 [m2]), kg/m2 Paroxysmal AF, n (%) Comorbidities, n (%) CHF Hypertension Age N75 years Diabetes mellitus Dyslipidemia CHADS2 Antithrombotic medications Anti-platelet agents, n (%) Anticoagulants, n (%) Echocardiography LV EF, % LA AP diameter, mm LA volume, mL LVEDD, mm E/E′
All (n = 558)
No stroke (n = 347)
Stroke (n = 211)
p-value
60 ± 12 419 (75) 167 ± 8 25 ± 3 349 (63)
56 ± 11 275 (79) 169 ± 8 25 ± 3 242 (70)
68 ± 10 144 (68) 164 ± 8 24 ± 3 107 (51)
b0.001⁎ 0.004⁎ b0.001⁎ b0.001⁎ b0.001⁎
22 (4) 305 (55) 53 (10) 89 (16) 100 (18) 0.8 ± 0.8 127 (23) 72 (13) 81 (15)
9 (3) 153 (44) 8 (2) 35 (10) 57 (16) 0.6 ± 0.7 83 (25) 37 (11) 56 (16)
13 (6) 152 (72) 45 (21) 54 (26) 43 (20) 1.3 ± 0.8 44 (21) 35 (17) 25 (12)
0.04⁎ b0.001⁎ b0.001⁎ b0.001⁎ 0.26 b0.001⁎ 0.47 0.51 0.65
63 43 65 50 11
64 41 58 50 10
63 46 79 50 14
0.35 b0.001⁎ b0.001⁎
± ± ± ± ±
8 3 25 4 5
± ± ± ± ±
7 6 20 4 4
± ± ± ± ±
10 7 30 5 6
0.52 b0.001⁎
AF = atrial fibrillation; CHF = congestive heart failure; BMI = body mass index; LV EF = left ventricular ejection fraction; LA = left atrium/atrial; AP = anterior–posterior; LVEDD = left ventricular end-diastolic dimension; E/E′ = mitral inflow velocity/diastolic mitral annulus velocity. ⁎ Indicates p b 0.05.
procedure. Pearson's bivariate correlation was used to determine correlation between variables. Multiple linear regression analysis was performed to test the association of variables with E/E′. Baseline characteristics are shown in Table 1. Patients with stroke were older, more likely to be female, and particularly, shorter than subjects without stroke; body mass index (BMI) was smaller in the stroke group. On echocardiography, longer LA AP diameter, larger LA volume and higher E/E′ were observed in the stroke group. In a binary logistic regression analysis (Table 2), height showed an independent association with stroke, even after adjusting for age, sex, hypertension and diabetes. Meanwhile, BMI showed inverse correlation with stroke and failed to predict the adverse event independently after adjusting for demography and presence of other co-morbidities. LA AP diameter, LA volume and E/E′ also independently predicted stroke. We divided study patients into tertiles according to height (Fig. 1): LV size increases with height and it is intuitive: “the larger the body, the larger the heart” (Fig. 1-A). However, the LA volume rather showed an inverse trend, failed to reach statistical significance though (Fig. 1-B). Strikingly, E/E′ was highest in the first tertile and lowest in the third tertile (Fig. 1-C). LV size showed positive linear correlation with height (Fig. 2-A),
Table 2 Predictors of stroke in AF patients.
Clinical characteristics Age Male CHADS2 score Height Body mass index Echocardiography LA AP diameter LA volume E/E′
Crude OR (95% CI)
p-value
Adjusteda OR (95% CI)⁎
p-value
1.11 (1.10–1.14) 0.56 (0.38–0.83) 32 (15–66) 0.93 (0.91–0.95) 0.87 (0.82–0.93)
b0.001⁎ 0.004⁎ b0.001⁎ b0.001⁎ b0.001⁎
– – – 0.96 (0.92–0.99) 0.94 (0.87–1.02)
– – – 0.02⁎ 0.12
1.13 (1.09–1.16) 1.04 (1.03–1.05) 1.20 (1.14–1.26)
b0.001⁎ b0.001⁎
1.10 (1.06–1.14) 1.03 (1.02–1.04) 1.10 (1.04–1.16)
b0.001⁎ b0.001⁎ b0.001⁎
b0.0018
⁎ Indicates p b 0.05. a Adjusted for age, sex, hypertension and diabetes
whereas LA volume did not (Fig. 2-B); notably E/E′ was associated with height (Fig. 2-C). In multiple linear regression analysis, height independently determined E/E′ (β = − 0.20, t = − 2.95, p = 0.003) after adjusting for age, sex, body weight, hypertension and diabetes. Main findings are as follows: 1) NV-AF patients with ischemic stroke are shorter than those without stroke; 2) LA volumes are not entirely dependent on stature, whereas LV size increases with height; and 3) stature and E/E′ showed inverse correlation. This study revealed the relationship between stature and diastolic dysfunction in NV-AF and we suggest that height is an unmodifiable risk factor; hence, more impaired diastolic function in shorter patients with NV-AF might play a pathophysiological role in stroke occurrence. Copious hypotheses have been suggested to explain the inverse relationship between short stature and stroke. Short stature is related to vessel diameter [2]. Socioeconomic status affects height and CV outcomes [3]. Inadequate nutrition during childhood results in short stature in adulthood and increases CV risk including stroke [4]. Height decreases during the aging process and short stature represents the old age of stroke patients [5]. Simultaneously, stature is influenced by prognostic factors of stroke, such as hypertension and diabetes mellitus [5]. In this study, we revealed the association between stature and diastolic dysfunction in NV-AF and this finding suggests a new hypothesis for an old observation. Height is negatively correlated with central arterial pressure augmentation because of shorter distance to sites of peripheral pulse wave reflection [6]. Greater central pressure augmentation in shorter subjects induces cardiac overloading [7] and diastolic dysfunction [8]; thus it might explain the higher prevalence of stroke in short patients. Although LV systolic dysfunction is a well-known risk factor for stroke in AF patients [9], it is still unclear whether diastolic function also plays a prognostic role regarding stroke. E/E′ reflects LV filling pressure not only in sinus rhythm but also in AF [10], and it serves as a robust prognosticator in CV diseases including AF [11]. Lee et al. [12] reported that E/E′ was a predictor of stroke in NV-AF patients. In this study, we observed an inverse association of E/E′ with stature; this novel finding can, at least partially, explain the correlation between stature and stroke.
Please cite this article as: Moon J, et al, Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.154
J. Moon et al. / International Journal of Cardiology xxx (2014) xxx–xxx
3
Fig. 1. Inter-tertile comparison of height and LVEDD (A), LA volume (B) and E/E′ (C). LVEDD increases according to the increase in height and it is intuitive: “the larger the body, the larger the heart” (A). However, the LA volume rather showed an inverse trend, although it failed to reach statistical significance (B). Notably, E/E′ was highest in the first tertile group and lowest in the third tertile group (C).
Fig. 2. Results of bivariate correlation analysis. (A) LVEDD showed weak but significant inverse linear correlation with height. (B) LA volume did not show significant correlation with stature. (C) Of note, E/E′ showed a strong association with patient's height.
Common belief is that taller individuals have larger hearts. Interestingly, in this cohort, LA volume was not necessarily larger in taller patients, whereas LV size increases with stature. This is meaningful because LA size represents the severity and chronicity of diastolic dysfunction; LA volume is a robust prognosticator in CV diseases including AF [13], and even in the general population [14]. Therefore, it can be said that shorter patients with AF suffer greater impairment of diastolic function. This concept is further supported by previous research reporting that the brain natriuretic polypeptide reflecting diastolic dysfunction was a predictor for stroke in NV-AF [15]. BMI did not show an association with stroke in our cohort; and it is contrary to previous data from western countries, which reported strong correlation between obesity and stroke and/or arrhythmia [16]. Therefore, short stature, rather than BMI, should be supposed as a non-modifiable risk factor for a stroke in non-obese populations. This study has inborn limitations of retrospective design. Particularly, demographic characteristics differed between the stroke and control group. Some patients were under the influence of antithrombotic therapy, while others were not. This study was conducted in a tertiary
referral center; therefore, our cohort might not represent all NV-AF patients.
Acknowledgment The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
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Please cite this article as: Moon J, et al, Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.154