Short stature is associated with incident sudden cardiac death in a large Asian cohort

Journal Pre-proof Short stature is associated with incident sudden cardiac death in a large Asian cohort Young Min Park, MD, MPH, Jeonggeun Moon, MD, PhD, In Cheol Hwang, MD, PhD, Hyunsun Lim, PhD, Bokeum Cho PII:

S1547-5271(20)30078-3

DOI:

https://doi.org/10.1016/j.hrthm.2020.01.026

Reference:

HRTHM 8262

To appear in:

Heart Rhythm

Received Date: 15 December 2019 Accepted Date: 24 January 2020

Please cite this article as: Park YM, Moon J, Hwang IC, Lim H, Cho B, Short stature is associated with incident sudden cardiac death in a large Asian cohort, Heart Rhythm (2020), doi: https://doi.org/10.1016/ j.hrthm.2020.01.026. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc. on behalf of Heart Rhythm Society.

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Type: Original clinical research paper Title: Short stature is associated with incident sudden cardiac death in a large Asian cohort Short title: Height and SCD in Asian 1

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Authors: Young Min Park, MD, MPH , Jeonggeun Moon, MD, PhD , In Cheol Hwang, MD, PhD , 1

4

Hyunsun Lim, PhD and Bokeum Cho 1

National Health Insurance Service Ilsan Hospital, Goyang, South Korea

2

Cardiology Division, Department of Internal Medicine, Gil Medical Center, Gachon University College

of Medicine, Incheon, South Korea 3

Department of Family Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon,

South Korea 4

Division of Humanities Arts and Social Sciences, Underwood International College of Yonsei

University, Seoul, South Korea Drs. Park and Moon contributed equally to this work. Corresponding author: In Cheol Hwang, Department of Family Medicine, Gil Medical Center, Gachon University College of Medicine, 1198 Guwol-dong, Namdong-gu, Incheon 405-760, South Korea. E-mail: [email protected].

Source of Funding: We received no financial support for the research, authorship and/or publication of this article. Disclosures: We declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

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Abstract Background: There is little data on the association between height and the risk of sudden cardiac death (SCD) in Asian populations. Objective: This study aimed to assess the risk of SCD as related to height in both a representative Korean population and in specific subgroups. Methods: This is a retrospective cohort study of 410,119 Koreans 20 years and older from the Korean National Health Insurance Services National Sample Cohort, who underwent a national health examination. SCD cases were adjudicated based on information within the claims database. Cox proportional hazard models were applied to estimate the hazard ratios (HR) and the 95% confidence intervals (CI) for the association between height and SCD. Potential mediators included demographic factors, health-related habits, and specific cardiovascular comorbidities. Results: During an 8.45-year follow-up period, a total of 1,341 SCDs occurred. Various factors, including short stature, were identified as risk factors for SCD. Multivariable regression analysis revealed that a 10-cm increase in height was associated with a 14% decreased risk for SCD. This relationship remained significant among the elderly, postmenopausal women, and individuals without cardiovascular disease. Conclusion: Our results indicate that short stature is a significant risk factor for SCD in a Korean population, thus supporting previously published findings correlating height to SCD risk in non-Asian populations.

Keywords: Anthropometry; Asian; height; population-based study; sudden cardiac death

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Introduction Sudden cardiac death (SCD) is an important public health issue, presenting both clinical and investigative challenges. SCD has a reported incidence of approximately 0.1% to 0.2% per year and 1

is estimated to cause 170,000 to 450,000 deaths annually, accounting for more than half of all 2

cardiovascular disease (CVD) deaths. SCD warrants attention as it is often the first manifestation of 3

CVD and is, by definition, fatal. Those considered at high risk for SCD, a definition that remains somewhat ill-defined, account for only 25–30% of SCDs. The vast majority of all SCDs occur in the 4

general population—in persons without established CVD.

Identifying factors predisposing individuals to SCD will be crucial for early intervention and prevention of SCD. Established or suspected risk factors for SCD include age, obesity, smoking, physical inactivity, dietary factors, hypertension, diabetes, dyslipidemia, high resting heart rate and 4

family history of SCD. From the preventive perspective, we must not only treat individuals known to be at high risk for SCD, we must also improve methods to identify other individuals in the larger 5,6

population who might also be predisposed to SCD. 7-9

developed to identify individuals at risk for SCD;

Several 10-year risk models have been

however these models need further refinement.

Simple anthropometric indices are very appealing as indicators for predicting SCD. A recent 10

meta-analysis indicated that the risk of SCD increases with adiposity (both general and central).

Similarly, several reports have correlated short stature with increased risk for various vascular events 11,12

that are also risk factors for SCD.

An additional prospective study of two distinct population-based 13

cohorts indicated that the corollary may also be true, taller individuals may have a lower risk of SCD.

Despite these studies, to our knowledge, there have been no studies addressing the relationship between height and SCD specifically in an Asian population. Racial difference in SCD between Asian and other groups have been reported, for example, a lower incidence and distinct risk factors, thus 14

warranting study in an Asian population.

This study aimed to assess the cumulative risk of SCD

across height in a representative Korean population, and then to examine the robustness of any found association in specific subgroups.

4

Methods Data source and study population The Korean National Health Insurance Service–National Sample Cohort (NHIS-NSC) 2002-2015 database was used for this retrospective, population-based, cohort study. The Korean NHIS is the single health insurer in Korea, and all Koreans are mandatory subscribers. All insured individuals and their dependents are required to undergo a periodic (mostly biennial) health examination. The NHISNSC contains a random sample of 1,000,000 individuals representing 2.2% of the entire Korean population, along with medical claims data including patient diagnoses, procedures, prescription 15

records, and demographic information, and is available to the public for research purposes.

Access

to the NHIS database (number: NHIS-2019-2-023) was granted and the current study was approved by the institutional review board of the National Health Insurance Service Ilsan Hospital (NHIMC 2018-01-019). Because the NHIS data are de-identified to protect private information, the need to obtain informed consent was waived. We identified 410,468 adults from the NHIS-NSC register (N = 1,000,000), who were 20 years and older and who underwent an initial baseline health examination by the NHIS between 2006 and 2009. For patients seen by the NHIS more than once during this interval, only the results of their initial screening were used. Additional information on past history (2002 to 2005) was also collected for the accuracy of the study. After excluding subjects either without height information (n = 116) or with antecedent ventricular arrhythmia (VA; n = 233), a total of 410,119 participants were eligible for the study (Fig. 1).

Outcomes and covariates SCD/VA was defined using the International Classification of Disease 10th Revision (ICD-10) codes. The clinical end points were confirmed as hospitalization or emergency department visit with the principal diagnosis of SCD (ICD-10 code, I46.9 or R99) and VAs, including ventricular tachycardia (ICD-10 code, I47.2), ventricular fibrillation (ICD-10 code, I49.01) and ventricular flutter (ICD-10 code, 16

I49.02).

Patients’ records were examined up to the time of patient death or December 31, 2015, the

5

study endopoint. Height and weight were measured using standard protocols during an NHIS health examination. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. We treated height as a continuous variable and categorized the individuals into four groups based on BMI (underweight, normal, overweight, or obese). Menopause was 17

assumed at the age of 50 years based on national Korean data.

Subjects completed a self-

administered questionnaire with categorical responses to questions on smoking status (i.e., nonsmoker, ex-smoker, current smoker), and alcohol consumption (never or light, moderate, heavy). We obtained information on comorbidities such as hypertension, type 2 diabetes, atrial fibrillation, transient ischemic attack, stroke, prior myocardial infarction, heart failure, peripheral arterial disease and thromboembolism based on patient hospitalization ICD-10 codes and prescription records (Supplementary Table 1).

Statistical analyses The data in Table 1 are presented as raw numbers and percentages for categorical variables, with age being represented as the mean ± standard deviation (SD). Competing risk regression models

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were analyzed to estimate the sub-distribution hazard ratios (HR) and the 95% confidence intervals (CI) for the association between height and cumulative SCD hazard. Death before SCD sets a competing event because patients who died during follow-up period might not have survided long enough to develop SCD. Covariates entered into the model were height (per 10 cm increment), age group, sex, BMI, smoking status, alcohol consumption, and comorbidities such as hypertension, type 2 diabetes, atrial fibrillation, transient ischemic accident, stroke, prior myocardial infarction, heart failure, peripheral arterial disease, and thromboembolism. The annual event incidence rate (IR) was calculated as the number of events per 1000 person-years. We also repeated calculations of the HRs and 95% CIs for SCD in subgroups (for each 10-cm increase in height). Two-sided P values < 0.05 were considered statistically significant. Statistical tests were conducted using SAS version 9.3 (SAS Institute, Cary, NC, USA).

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Results Baseline characteristics of the 410,119 study participants are shown in Table 1. Mean height was 169.8 ± 6.5 cm for men and 156.4 ± 6.2 cm for women. In both sexes, taller adults tended to be younger, current smokers, with fewer comorbidities than shorter adults. An inverse association between height and BMI was noted as significant in women, but not in men. Factors associated with SCD were identified in the current cohort (Table 2). In the multivariable regression model, SCD risk was significantly higher in those 65 and older compared to those 20–29 (HR, 6.22; 95% CI, 4.87–7.93), men compared to women (HR, 1.87; 95% CI, 1.54–2.26), current smokers compared to never smokers (HR, 1.68; 95% CI, 1.44–1.97), and patients with one or more comorbidities relative to those with no known comorbidities such as hypertension, type 2 diabetes, atrial fibrillation, stroke, myocardial infarction, and heart failure (all p<0.01). Both a higher BMI and greater height correlated with a lower risk of SCD. A 10-cm increase in height lowered the risk of SCD by 14% (HR, 0.86; 95% CI, 0.78–0.95). From the time of their initial health exam, patients were followed for an average of 8.45 years. During this time, a total of 1,341 SCDs occurred. The overall IR of SCD was 0.4 per 1000 personyears. Risk of SCD per 10-cm increment among various groups is presented in Table 3. The association was significant and/or remarkable in individuals without comorbidities. In addition, an inverse association between height and the risk of SCD remained significant in postmenopausal women (HR, 0.71; 95% CI, 0.59–0.85) and the elderly (HR, 0.81; 95% CI, 0.71–0.93) in whom agerelated loss of height is accelerated.

Discussion Accurate risk assessment for SCD remains challenging, therefore it is imperative that additional risk indicators be identified to aid risk stratification and targeted prevention. Very few studies have

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assessed adult height as an independent predictor of SCD at the population level. The Emerging Risk Factors Collaboration conducted a meta-analysis for cause-specific mortality, but height did not reach 19

statistical significance as a factor predicting sudden death.

However, this study analyzed

heterogenous populations (from 121 prospective studies) with Caucasians being the predominant group (85% of participants). A separate population-based, prospective study, assessing two distinct 13

cohorts of different ages, indicated that taller individuals have a lower risk of SCD.

However, this

study was limited in power due to sample size, thus precluding the careful subgroup analyse we performed. The low frequency of SCD in relatively healthy populations required us to access the NHIS-NCS database to obtain a sufficient number of subjects to provide adequate power for this analysis. This large cohort study indicated that taller Koreans may be at lower risk for SCD, reflecting the same correlation identified in other studies of non-Asian populations. It is notable that SCD rates have dropped with the advent of advanced medical technology and the global increase in population 20

height.

SCD results from a complex interplay of factors (i.e., broadly categorized as structural, 4

functional, and electrogenic) that can lead to ventricular tachyarrhythmias. Myocardial ischemia is a major cause of ventricular fibrillation, and short stature is a well-described risk factor for coronary 21,22

heart disease (CHD),

3,23

which in turn is a strong risk factor for SCD.

This might hint at an

important mechanistic link relating height to SCD risk, that is, the lower risk of SCD among taller individuals may be due to a lower risk of CHD. The novel finding in this study results from our stratified subgroup analyses. Positive associations in groups at lower risk for SCD (e.g., individuals without metabolic or vascular disease) are expected, because height’s relative contribution to SCD risk may be larger in the less-risk group. It might hold true for sex. Several studies suggest that pre-existing coronary disease is less predictive for SCD in women, and other etiologies are more likely.

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In a prior study, the association between 13

greater height and lower SCD risk was statistically significant only in men,

which was explained by a

male preponderance in the risk of SCD. We, however, cannot agree with their elucidaton as focus is not the SCD itself but its association with height. The robustness of the association between height and SCD risk in the elderly likely parallels the association between height and SCD in postmenopausal women. Age-related loss of height is

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more severe in women than men.

A Japanese prospective study reported that marked height loss is

independently associated with an increased risk of both all-cause mortality and coronary heart disease.

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More studies from different populations are needed to confirm the stratified findings

demonstrated in this study.

Study limitations This study has some limitations that warrant consideration. First is the identification of bona fide SCD cases in our data set. Recognizing SCD can be difficult and typically requires corroboration by trained 27

physicians.

28

Nonetheless, the overall IR in our study was similar to other Asian studies,

indicating

adequate case validation. Second, our analysis does not include potential confounders, such as echocardiographic findings,

29,30

31

depressive mood,

or genetic background. Genome-wide association

studies have reported that a minor allele of Glypican 5 is associated with both a lower risk of SCD and height.

33

32

Prospective studies to investigate gene-environment interactions and thus to determine 34

the causal relationships are further needed.

Finally, the variables analyzed in our study were

assessed at only one time point, which warrants a future sequential study.

Conclusion Despite these limitations, this large Korean cohort study provides evidence that shorter stature may serve as a risk factor for SCD among the elderly, postmenopausal women, and individuals without metabolic or vascular diseases. From a clinical perspective, if our findings are reproducible, then height might be evaluated as part of future strategies aimed at SCD prevention for the highest risk subgroups in the community. Further studies are needed to understand the underlying mechanisms by which height relates to SCD as well as to determine whether targeted clinical practice that takes height into account can provide a better approach for SCD risk stratification.

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Table 1. Baseline characteristics of participants distributed by height Men ≤164 cm 42,990 54.63 ± 13.14 6,004 (13.97) 20,538 (47.77) 16,448 (38.26)

165–169 cm 57,269 47.24 ± 13.15 17,442 (30.46) 28,788 (50.27) 11,039 (19.28)

170–173 cm 51,994 42.02 ± 12.32 24,116 (12.32) 22,686 (46.38) 5,192 (9.99)

Number Age group, years 20–39 40–59 ≥60 Body mass index, kg/m2 <18.5 1,272 (2.96) 1,304 (2.28) 1,106 (2.13) 18.5–22.9 14,828 (34.49) 19,151 (33.44) 17,364 (33.40) 23.0–24.9 12,244 (28.48) 15,337 (26.78) 13,854 (26.65) ≥25 14,646 (34.07) 21,477 (37.50) 19,670 (37.83) Current smoker 14,997 (36.73) 22,923 (42.06) 22,724 (45.79) Heavy drinker 2,577(6.35) 3,203(5.89) 2,425 (4.90) Comorbidities Hypertension 14,921 (34.71) 14,382 (25.11) 9,488 (18.25) Type 2 diabetes 5,375 (12.50) 5,529 (9.65) 3,601 (6.93) Atrial fibrillation 541 (1.26) 548 (0.96) 373 (0.72) TIA 773 (1.80) 704 (1.23) 427 (0.82) Stroke 2,463 (5.73) 1,767 (3.09) 1,003 (1.93) Myocardial infarction 535 (1.24) 476 (0.83) 301 (0.58) Heart failure 739 (1.72) 507 (0.89) 289 (0.56) PAD 4,640 (10.79) 4,123 (7.20) 2,540 (4.89) Thromboembolism 309 (0.72) 293 (0.51) 169 (0.33) TIA, transient ischemic attack; PAD, peripheral arterial disease. Data are presented as mean ± standard deviation or raw number (%).

>173 cm 59,019 36.70 ± 10.85 38,764 (65.68) 17,890 (30.31) 2,365 (4.01)

Women ≤151 cm 41,914 58.78±12.80 3,179 (7.58) 17,255 (41.17) 21,480 (51.25)

152–155 cm 44,934 50.21±12.84 8,898 (19.80) 24,879 (55.37) 11,157 (24.83)

156–160 cm 62,204 44.32±12.64 21,702 (34.89) 32,858 (52.82) 7,644 (12.29)

>160 cm 49,795 37.24±11.66 29,287 (58.82) 18,508 (37.17) 2,000 (4.02)

1,362 (2.31) 20,182 (34.20) 15,492 (26.25) 21,983 (37.25) 27,999 (49.57) 2,574 (4.58)

1,300 (3.10) 14,053 (33.53) 10,640 (25.39) 15,921 (37.98) 1,070 (2.74) 132 (0.34)

1,506 (3.35) 18,666 (41.54) 10,361 (23.06) 14,401 (32.05) 2.74 (2.89) 197 (0.47)

3,373 (5.42) 30,212 (48.57) 13,439 (21.60) 15,180 (24.40) 1,206 (3.47) 329 (0.57)

4,941(9.92) 27,996 (56.22) 8,391 (16.85) 8,467 (17.00) 2.89 (4.44) 426 (0.92)

6,953 (11.78) 2,520 (4.27) 308 (0.52) 336 (0.57) 590 (1.00) 205 (0.35) 194 (0.33) 1,745 (2.96) 109 (0.18)

18,143 (43.29) 5,354 (12.77) 480 (1.15) 1,104 (2.63) 2,882 (6.88) 370 (0.88) 1,372 (3.27) 6,916 (16.50) 333 (0.79)

13,002 (28.94) 3,941 (8.77) 367 (0.82) 745 (1.66) 1,635 (3.64) 197 (0.44) 653 (1.45) 4,912 (10.93) 245 (0.55)

12,001 (19.29) 3,599 (5.79) 287 (0.46) 692 (1.11) 1,269 (2.04) 182 (0.29) 502 (0.81) 4,877 (7.84) 230 (0.37)

4,978 (10.00) 1,454 (2.92) 169 (0.34) 265 (0.53) 451 (0.91) 86 (0.17) 212 (0.43) 2,266 (4.55) 89 (0.18)

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Table 2. Factors associated with sudden cardiac death in the cohort

Height, per 10cm increment

Hazard ratioa

95% confidence interval

P value

0.86

0.78–0.95

0.004

Age group, years 20–39

1

40–59

2.28

1.82–2.84

<0.001

≥60

6.22

4.87–7.93

<0.001

1.87

1.54–2.26

<0.001

<18.5

1.27

0.96–1.70

0.100

18.5–22.9

1

23.0–24.9

0.78

0.67–0.91

0.001

≥25

0.86

0.75–0.98

0.022

Male sex 2

Body mass index, kg/m

Smoking status Never

1

Ex-

1.36

1.11–1.67

0.003

Current

1.68

1.44–1.97

<0.001

Drinking habit Never or light

1

Moderate

0.78

0.68–0.90

<0.001

Heavy

0.96

0.78–1.20

0.745

Hypertension

1.78

1.55–2.06

<0.001

Type 2 diabetes

1.34

1.15–1.56

<0.001

Atrial fibrillation

3.07

2.39–3.95

<0.001

Transient ischemic attack

1.02

0.73–1.42

0.917

Stroke

1.51

1.26–1.82

<0.001

Myocardial infarction

1.95

1.42–2.69

<0.001

Heart failure

2.05

1.60–2.61

<0.001

Peripheral arterial disease

0.98

0.83–1.15

0.802

Thromboembolism

1.17

0.72–1.91

0.519

Comorbidity

a

From stepwise multivariable regression analysis.

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Table 3. Risk for sudden cardiac death per 10-cm increase in height among various groups No. SCD

PYs

IR / 103 PYs

HR

95% CI

1,341

3,364,550

0.40

0.86

0.78–0.96

20–39

141

1,228,014

0.11

1.08

0.81–1.50

40–59

433

1,522,734

0.28

0.95

0.79–1.15

≥60

767

613,802

1.25

0.81

0.71–0.93

Male

829

1,743,680

0.48

0.95

0.84–1.08

Premenopausal

108

940,377

0.11

0.92

0.62–1.37

Postmenopausal

404

680,493

0.59

0.71

0.59–0.85

Yes

744

759,939

0.98

0.88

0.76–1.01

No

597

2,604,611

0.23

0.86

0.74–1.00

Yes

268

250,404

1.07

0.83

0.66–1.06

No

1,073

3,114,146

0.34

0.88

0.78–0.98

Yes

95

23,470

4.05

1.17

0.81–1.70

No

1,246

3,341,080

0.37

0.85

0.76–0.94

Yes

168

92,841

1.81

0.75

0.56–1.01

No

1,173

3,271,709

0.36

0.89

0.79–0.99

Yes

49

17,822

2.75

1.30

0.81–2.09

No

1,292

3,346,728

0.39

0.85

0.77–0.95

Yes

110

33,308

3.30

0.90

0.64–1.27

No

1,231

3,331,242

0.37

0.86

0.77–0.96

Overall Age group, years

Sex

Hypertension

Type 2 diabetes

Atrial fibrillation

Stroke

Myocardial infarction

Heart failure

SCD, sudden cardiac death; PY, person-year; IR, incidence rate; HR, hazard ratio; CI, confidence interval. P<0.05 in bold.

15

Figure Legend Figure 1. Schematic diagram outlining the study design and study population obtained from the data of National Health Insurance Service-National Sample Cohort

Event follow-up began on the day of the first medical check-up. SCD, sudden cardiac death.