Association of resting heart rate with cognitive decline and dementia in older adults: A population‐based cohort study

1 BACKGROUND

The global burden of dementia has increased rapidly, with 43.8 million people affected in 2016.1 The number of people living with dementia is expected to reach 131 million by 2051, with 68% residing in low- and middle-income countries.2 Dementia has a devastating impact on the quality of life of older adults, their families, and society at large. Currently, there is no cure for dementia, but growing evidence suggests that the onset of dementia could be delayed through managing modifiable risk factors.3 Evidence has also been accumulating that cardiovascular diseases (CVDs) are associated with the development of dementia, including Alzheimer's disease, possibly because of common risk factors, atherosclerotic changes of arteries, arterial stiffness, micro-embolism, and cerebral hypoperfusion.4-6

Abundant evidence has consistently shown that an elevated resting heart rate (RHR) predicts future CVD events beyond traditional CVD risk factors.7, 8 A limited number of studies also show that a high RHR is associated with cognitive decline and dementia in the general population of middle-aged adults and in patients with ischemic stroke.9, 10 However, this association has not been investigated in the general population of older adults. Besides, whether an increased RHR is independently associated with cognitive decline or the association is merely explained by the underlying CVDs has yet to be explored. This is important because an elevated RHR is associated with a higher risk of several CVDs such as ischemic heart disease (IHD), atrial fibrillation (AF), heart failure (HF), and stroke, and these CVDs are known risk factors for dementia.10-12 Therefore, a higher RHR may be linked with dementia only through an indirect pathway of these CVDs, and thus not an independent risk factor for dementia.

The aim of this population-based cohort study was to investigate the association of elevated RHR with incident dementia in a general population of older adults. We hypothesized that an elevated RHR was associated with an increased risk for dementia and global cognitive decline in older adults and that their association could be present independent of cardiovascular risk factors and CVDs. We sought to test our hypotheses by examining the associations of RHR with cognitive decline and dementia among older adults with and without prevalent and incident CVDs.

2 METHODS 2.1 Study population

Study participants were from the population-based Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), as previously described.13 Briefly, SNAC-K targeted men and women aged ≥60 years and living at home or in an institution in the Kungsholmen district of central Stockholm, Sweden. Between 2001 and 2004 (baseline), among the 5111 persons who were invited from a random sample of the population stratified by 11 age groups (60, 66, 72, 78, 81, 84, 87, 90, 93, 96, and ≥99 years), 321 were found to be ineligible and 200 died before the examination. Of the remaining 4590 eligible persons, 3363 (response rate 73%) underwent the baseline examination. Follow-up examinations were conducted every 6 years for the younger-old cohort (60, 66, and 72 years) and every 3 years for the older-old cohort (78, 81, 84, 87, 90, 93, 96, and 99 years).

Of the 3363 participants at baseline, we first excluded 814 participants who had missing information on baseline RHR or Mini-Mental State Examination (MMSE) score. These participants were older (mean age, 86.1 vs. 71.1, P < 0.001), less educated (university degree, 13.3% vs. 38.7%, P < 0.001), and more likely to be female (76.3% vs. 61.2%, P < 0.001) and live in institutions (22.4% vs. 0.4%, P < 0.001). Then, we excluded 27 participants with prevalent dementia, 11 with a baseline MMSE score < 24, 181 with non-sinus rhythm on echocardiogram (ECG), and 183 with missing covariates, leaving 2147 participants who were free of dementia at baseline and undertook at least one follow-up examination for the current analyses (Figure S1 in supporting information).

All phases of SNAC-K were approved by the Regional Ethical Review Board in Stockholm, Sweden. Written informed consents were obtained from all participants, or in the case of cognitively impaired persons, from proxies.

HIGHLIGHTS Elevated resting heart rate was associated with incident dementia in older adults. This association was independent from cardiovascular diseases. Elevated resting heart rate was also associated with accelerated cognitive decline. RESEARCH IN CONTEXT

Systematic review: We searched the literature using PubMed, Web of Science, and Embase. We identified three prospective studies that investigated the association of elevated resting heart rate (RHR) with dementia and cognitive decline in a general population of middle-aged adults, post-stroke patients, and post-menopausal women; two of them suggested an association of elevated RHR with cognitive decline.

Interpretation: We showed that elevated RHR was associated with high hazard for incident dementia after adjusting for vascular risk factors in a general population of older adults. Moreover, we explored the effect of cardiovascular disease (CVD) on this association, showing that the association was independent of prevalent and incident CVDs.

Future direction: This study showed evidence that RHR is a potential risk factor for dementia. While our findings merit further confirmation in different cohorts, future intervention studies to manage high RHR may result in novel preventive strategies of cognitive aging.

2.2 Data collection and assessments

At baseline, data were collected through face-to-face interviews, clinical examinations, and laboratory tests by trained staff following standard procedures. Information on age, sex, education (elementary school, high school, or university), and smoking status (never, former, or current smokers) was collected via interviews. Physical activity was assessed through a self-administered questionnaire by asking how often respondents engaged in light exercises such as walking, biking, and light aerobics (every day, several times per week, a few times per month, less frequent, or never). Body mass index (BMI) was calculated by dividing weight in kilograms by squared height in meters. A peripheral blood sample was obtained. Serum total cholesterol was measured and APOE alleles were genotyped at the university laboratory. Participans were categorized as ε4 carriers when they have at least one ε4 allele. Diagnosis of hypertension, diabetes, and CVDs (IHD, AF, HF, and cerebrovascular diseases) were made based on the comprehensive information on participants’ self-report, anamnestic data, clinical and laboratory data, medications, and registers from the Swedish National Patient Register as previously described at every study visit.14 Participants were asked to provide a list of currently used medications, and the use of medications was classified according to the Anatomical Therapeutic Chemical (ATC) classification system. The use of beta blockers, digoxin, and non-dihydropyridine calcium channel blockers (e.g., verapamil and diltiazem) was identified using ATC codes (C07, C01AA05, and C08D). Ivabradine had not been approved at baseline (2001–2004).

2.3 Assessment of ECG

RHR was obtained from a standard 12-lead ECG at baseline. ECG was recorded using MAC500 (GE Healthcare) by trained technicians based on the standard procedure. RHR was categorized into < 60, 60–69 (reference), 70–79, and ≥80 beats per minute (bpm) according to previous studies.9, 15

2.4 Cognitive assessments and diagnosis of dementia

At baseline and each follow-up visit, global cognitive function was assessed using MMSE, and dementia diagnosis was made based on Diagnostic and Statistical Manual of Mental Disorders 4th Revision (DSM-IV) criteria following a three-step procedure.16, 17 Briefly, the examining physician made a preliminary diagnosis of dementia based on interviews, clinical examination, and cognitive testing. Then, the second physician who was blind to the first diagnosis independently made a second preliminary diagnosis. Any discrepancies between the two diagnoses were resolved by a neurologist external to the data collection (LF or GG). In case the participants died before the study visit and did not have a diagnosis of dementia, the diagnosis of dementia was ascertained by physicians via thoroughly reviewing the information from the Swedish Cause of Death Register, clinical chart, and medical records.

3 STATISTICAL ANALYSIS

The baseline characteristics of participants who were included in and excluded from the analytical samples were compared using a Chi-squared test for categorical variables and a t-test for continuous variables. The association between RHR and incident dementia was assessed using a Cox proportional hazards model. Follow-up time was defined as the interval between the date of the baseline examination and the date of the following events, depending on whichever came first: the first dementia diagnosis, death, or the last study visit. RHR was used as both a categorical (60–69 bpm as the reference group) and continuous variable (per 10 bpm increment in RHR). The proportional hazards assumption was verified for categorical RHR by visual inspection of survival curves and by tests of Schoenfeld residuals. We further conducted a complementary analysis using MMSE score as an outcome to support our findings concerning dementia as the primary outcome, because MMSE is a screening tool for dementia. The association between RHR and change in MMSE score was assessed using linear mixed-effects models with random intercepts and slopes. Interaction terms between RHR and follow-up time were included in all models to estimate the effect of RHR on changes in MMSE score over time.

We reported the main results from three models. Model 1 was adjusted for age, sex, and education. Model 2 was further adjusted for behavioral risk factors assessed at baseline (smoking, physical activity, and BMI). Model 3 was additionally adjusted for vascular risk factors at baseline (total cholesterol, hypertension, and diabetes), CVDs (IHD, AF, HF, and cerebrovascular disease at baseline), medications that reduce RHR (beta blockers, digoxin, and non-dihydropyridine calcium channel blockers), and APOE ε4 alleles. We examined the statistical interactions of RHR with age, sex, each of the CVDs, and APOE genotype on the risk of dementia.

Furthermore, to examine the contribution of underlying CVDs to the association of RHR with dementia and change in MMSE score, we repeated the analyses while excluding participants with at least one of the four CVDs (IHD, AF, HF, and cerebrovascular disease) at baseline. Next, we further excluded participants who had developed at least one CVD during follow-up to see the effect of incident CVDs on these associations. We also investigated the association of RHR with dementia and change in MMSE score among participants with at least one CVD. In addition, to explore the effect of higher and lower RHR, we examined an association of RHR with incident dementia and MMSE score changes using categorical RHR with six levels (< 50, 50–59, 60–69, 70–79, 80–89, and 90+ bpm). Finally, we conducted a sensitivity analysis using the inverse probability weighting method to evaluate the potential impact of selection bias due to dropouts on the main results.

Stata version 16.0 (StataCorp) was used for all the analyses.

4 RESULTS

The baseline characteristics of study participants according to RHR groups are presented in Table 1. The mean age of the 2147 participants was 70.6 (standard deviation [SD], 8.9) years, and 62% were women. Participants included in the analytical sample were younger and had fewer chronic diseases and a higher MMSE score than those excluded (P < 0.05, Table S1 in supporting information). The average MMSE score of all participants was 29.0 (SD, 1.2). The average RHR was 65.7 bpm (SD, 10.9). Participants without underlying CVDs at baseline had a slightly higher RHR than those with at least one CVD (66.1 ± 10.8 vs. 63.9 ± 11.2 bpm, P < 0.01; Figure S2 in supporting information). Participants in higher RHR groups were older, less educated, more likely to be current smokers and physically inactive, and to have hypertension (Table 1). The prevalence of CVDs was not significantly different among RHR groups, but those in higher RHR groups were less likely to use beta blockers. The MMSE score at baseline was similar among different RHR groups.

TABLE 1. Baseline characteristics of study participants by resting heart rate Characteristics Total sample (n = 2147) RHR < 60 bpm (n = 674) RHR 60–69 bpm (n = 776) RHR 70–79 bpm (n = 467) RHR ≥80 bpm (n = 230) P-values Age (years), mean (SD) 70.6 (8.9) 69.5 (8.8) 70.7 (8.9) 71.6 (9.0) 71.7 (9.1) 0.0003 Female sex, n (%) 1333 (62.1) 363 (53.9) 523 (67.4) 304 (65.1) 143 (62.2) <0.001 Education, n (%) Elementary 265 (12.3) 65 (9.6) 100 (12.9) 64 (13.7) 36 (15.7) 0.006 High school 1033 (48.1) 311 (46.1) 377 (48.6) 221 (47.3) 124 (53.9) University 849 (39.5) 298 (44.2) 299 (38.5) 182 (39.0) 70 (30.4) Smoking status, n (%) Never 954 (44.4) 289 (42.9) 341 (43.9) 225 (48.2) 99 (43.0) 0.048 Former smoker 860 (40.1) 299 (44.4) 304 (39.2) 165 (35.3) 92 (40.0) Current smoker 333 (15.5) 86 (12.8) 131 (16.9) 77 (16.5) 39 (17.0) Light physical activity, n (%) Every day 811 (37.8) 249 (36.9) 309 (39.8) 165 (35.3) 88 (38.3) 0.03 Several times/week 858 (40.0) 293 (43.5) 309 (39.8) 176 (37.7) 80 (34.8) 2–3 times/month 252 (11.7) 75 (11.1) 88 (11.3) 57 (12.2) 32 (13.9) Less frequent 129 (6.0) 34 (5.0) 41 (5.3) 36 (7.7) 18 (7.8) Never 97 (4.5) 23 (3.4) 29 (3.7) 33 (7.1) 12 (5.2) BMI (kg/m2), mean (SD) 26.0 (3.9) 25.9 (3.6) 26.0 (4.0) 26.2 (4.1) 26.0 (4.2) 0.76 SBP (mmHg), mean (SD) 144.5 (19.5) 142.1 (19.7) 145.7 (19.9) 144.0 (18.5) 148.1 (18.6) 0.0001 DBP (mmHg), mean (SD) 82.8 (10.3) 81.2 (9.9) 83.0 (10.2) 83.1 (9.8) 85.9 (11.7) <0.0001 TC (mmol/l), mean (SD) 6.1 (1.1) 5.9 (1.0) 6.1 (1.1) 6.1 (1.2) 6.1 (1.1) 0.003 Medical history, n (%) Diabetes 158 (7.4) 49 (7.3) 46 (5.9) 39 (8.4) 24 (10.4) 0.10 Hypertension 1508 (70.2) 436 (64.7) 567 (73.1) 328 (70.2) 177 (77.0) <0.001 Heart failure 86 (4.0) 32 (4.8) 28 (3.6) 15 (3.2) 11 (4.8) 0.49 Atrial fibrillation 68 (3.2) 31 (4.6) 20 (2.6) 9 (1.9) 8 (3.5) 0.05 Ischemic heart disease 234 (10.9) 97 (14.4) 78 (10.1) 32 (6.9) 27 (11.7) 0.001 Cerebrovascular disease 86 (4.0) 25 (3.7) 38 (4.9) 14 (3.0) 9 (3.9) 0.39 Use of beta blockers, n (%) 400 (18.6) 185 (27.5) 138 (17.8) 56 (12.0) 21 (9.1) <0.001 Use of calcium blockers*, n (%) 32 (1.5) 5 (0.7) 17 (2.2) 6 (1.3) 4 (1.7) 0.14 Use of digoxin, n (%) 15 (0.7) 6 (0.9) 2 (0.3) 6 (1.3) 1 (0.4) 0.17 MMSE score, mean (SD) 29.0 (1.2) 29.1 (1.1) 29.0 (1.2) 29.1 (1.1) 28.8 (1.3) 0.08 APOE ɛ4 allele carrier, n (%) 628 (29.3) 204 (30.3) 216 (27.8) 139 (29.8) 69 (30.0) 0.75 Abbreviations: APOE, apolipoprotein E; BMI, body mass index; bpm, beats per minute; DBP, diastolic blood pressure; MMSE, Mini-Mental State Examination; RHR, resting heart rate; SBP, systolic blood pressure; SD, standard deviation; TC, total cholesterol. *Use of non-dihydropyridine calcium channel blockers.

During a total of 19,344 person-years of follow-up (median per person, 11.4 years), 289 participants were diagnosed with dementia (incidence 14.9 per 1000 person-years). Participants with RHR ≥80 bpm, compared to those with RHR 60–69 bpm, had an average 55% increased risk for developing dementia in the fully adjusted model (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.06, 2.26; Table 2, Model 3). There was no evidence of interactions of RHR with age, sex, HF, AF, IHD, cerebrovascular disease, or APOE genotype (P for all interactions > 0.10). The association of high RHR with dementia remained significant after excluding participants with at least one of the four CVDs at baseline (HF, AF, IHD, or cerebrovascular disease). Further exclusion of participants who developed any of the four CVDs during follow-up did not change the results materially (Table 2). We repeated our analyses among participants with CVDs at baseline, and no significant association between RHR and dementia was found in this group (Table S2 in supporting information).

TABLE 2. The association of baseline resting heart rate with incident dementia in SNAC-K (n = 2029) No. of participants No. of dementia cases Incidence (1000 person-years)(95%CI) Hazard ratio (95% CI) RHR Model 1* Model 2* Model 3* Total sample (n = 2029) RHR per 10 bpm increment 2029 289 1.08 (0.98, 1.20) 1.09 (0.98, 1.21) 1.13 (1.02, 1.26) Categorical RHR RHR < 60 bpm 633 79 12.6 (10.1, 15.7) 1.01 (0.75, 1.37) 1.04 (0.77, 1.40) 0.94 (0.69, 1.27) RHR 60–69 bpm 736 98 13.8 (11.3, 16.8) 1.00 [Reference] 1.00 [Reference] 1.00 [Reference] RHR 70–79 bpm 440 73 18.4 (14.6, 23.1) 1.26 (0.93, 1.70) 1.28 (0.94, 1.74) 1.27 (0.93, 1.74) RHR > 80 bpm 220 39 20.0 (14.6, 27.4) 1.45 (1.00, 2.11) 1.51 (1.04, 2.20) 1.55 (1.06, 2.26) Participants without prevalent CVD (n = 1667) RHR per 10 bpm increment 1667 203 1.14 (1.01, 1.29) 1.13 (1.00, 1.28) 1.16 (1.02, 1.31) Categorical RHR RHR < 60 bpm 493 43 8.5 (6.3, 11.5) 0.96 (0.66, 1.41) 1.02 (0.69, 1.50) 0.98 (0.66, 1.45) RHR 60-69 bpm 610 71 11.7 (9.3, 14.8) 1.00 [Reference] 1.00 [Reference] 1.00 [Reference] RHR 70-79 bpm 385 59 16.7 (12.9, 21.5) 1.44 (1.02, 2.03) 1.46 (1.03, 2.07) 1.46 (1.03, 2.09) RHR > 80 bpm 179 30 18.1 (12.7, 25.9) 1.54 (1.00, 2.36) 1.60 (1.04, 2.47) 1.73 (1.11, 2.69) Participants without prevalent and incident CVD (n = 1199) RHR per 10 bpm increment 1199 109 1.20 (1.01, 1.42) 1.21 (1.01, 1.44) 1.27 (1.06, 1.52) Categorical RHR RHR < 60 bpm 362 24 6.6 (4.4, 9.8) 0.99 (0.59, 1.67) 1.02 (0.60, 1.73) 1.07 (0.62, 1.83) RHR 60–69 bpm 425 37 8.9 (6.5, 12.3) 1.00 [Reference] 1.00 [Reference] 1.00 [Reference] RHR 70–79 bpm 284 30 11.8 (8.2, 16.8) 1.35 (0.83, 2.19) 1.34 (0.82, 2.19) 1.52 (0.91, 2.52) RHR > 80 bpm 128 18 16.1 (10.2, 25.6) 1.73 (0.98, 3.05) 1.80 (1.01, 3.22) 2.13 (1.17, 3.88) Abbreviations: bpm, beats per minute; CI, confidence interval; CVD, cardiovascular disease; RHR, resting heart rate. *Model 1 was adjusted for age, sex, and education; Model 2 was further adjusted for smoking, physical activity, and body mass index; in Model 3, total cholesterol, hypertension, diabetes, use of beta blockers, non-dihydropyridine calcium channel blocker, and digoxin, APOE genotype, and whenever applicable (total sample), prevalent CVDs (heart failure, ischemic heart disease, atrial fibrillation, cerebral vascular disease) were added to Model 2.

Regarding cognitive function, the MMSE score declined over time during the follow-up period in all RHR groups (Table 3). However, participants with RHR 70–79 and +80 bpm had a greater decline compared to those with RHR 60–69 bpm (Table 3). The associations remained significant even after excluding prevalent CVDs at baseline and incident CVDs developed during the follow-up period (Table 3). Participants with CVDs showed steeper cognitive decline than the total population and CVD-free participants (Table S3 in supporting information).

TABLE 3. Average annual changes in the Mini-Mental State Examination score by resting heart rate in SNAC-K β-coefficient (95% confidence interval), MMSE score RHR Model 1* Model 2* Model 3* Total sample (n = 2147) RHR per 10 bpm increment –0.03 (–0.06,- -0.01) –0.04 (–0.06, –0.01) –0.04 (–0.06, –0.01) Categorical RHR RHR < 60 bpm 0.00 (–0.05, 0.06) 0.00 (–0.05, 0.06) 0.01 (–0.05, 0.06) RHR 60–69 bpm 0.00 (reference) 0.00 (reference) 0.00 (reference) RHR 70–79 bpm –0.10 (–0.17, –0.04) –0.10 (–0.17, –0.04) –0.10 (–0.17, –0.04) RHR > 80 bpm –0.13 (–0.21, –0.04) –0.13 (–0.21, –0.04) –0.13 (–0.21, –0.04) Participants without prevalent CVD (n = 1771) RHR per 10 bpm increment

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