Despite improvements in secondary prevention treatment, the incidence rates of mortality and recurrent cardiovascular events post-stroke remain high [1‐3]. This indicates that many risk factors have yet to be identified.

A slower heart rate is associated with greater longevity in many mammal species [4]. Heart rate is a vital sign which varies according to the physical needs of the body. Heart rate also reflects the balance between sympathetic and parasympathetic tone to the heart, and it has been shown to be a predictor of cardiovascular and all-cause mortality in the general population and in patients with cardiovascular disease [5‐12]. In a review article of 18 epidemiological studies, Aboyans and Criqui reported an increase in mortality rate of 30–50% for every 20-beat-per-minute (bpm) increase in resting heart rate [13]. However, the importance of heart rate is often overlooked. Although experimental studies have suggested that lowering the heart rate may protect against cerebral ischemia by reducing oxidative stress and improving endothelial function [14], whether a lower initial in-hospital heart rate is associated with a better prognosis in patients with acute ischemic stroke (AIS) has yet to be elucidated. Therefore, the objective of this study was to evaluate the relationship between mean initial in-hospital heart rate and long-term mortality in a large population of AIS patients with an extended follow-up.

We conducted this retrospective cohort study using data from the Chang Gung Research Database [15], the largest multi-institutional electronic medical records collection in Taiwan. All patients who had an AIS (International Classification of Diseases, 9th Revision, Clinical Modification codes 433.01, 433.11, 433.21, 433.31, 433.81, 433.91, 434.01, 434.11, 434.91; International Classification of Diseases, 10th Revision, Clinical Modification [ICD-10] code I63) in the first two discharge diagnoses [16, 17] between January 2010 and September 2018, and were admitted to one of the seven branch hospitals of Chang Gung Healthcare System were accrued consecutively in this study. Key demographic and clinical characteristics were collected, including stroke severity as assessed using the claims-based stroke severity index (SSI). The SSI was then converted to the National Institutes of Health Stroke Scale score using the equation: estimated National Institutes of Health Stroke Scale (eNIHSS) = 1.1722 × SSI − 0.7533 [18]. Measurements of height, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, creatinine, alanine aminotransferase (ALT), glycated hemoglobin (HbA1c), and lipid profiles were obtained from the records of the enrolled patients. Heart rate, SBP, and DBP were measured with the patients recumbent after 5 min rest and were recorded using an automated oscillometric device (DINAMAP ProCare 100, GE Medical Systems, Milwaukee, WI, USA) or a bedside patient monitor (IntelliVue MP60, Philips Medical System, Boeblingen, Germany). If the pulse was irregular, heart rates were measured by palpating the radial pulse over a period of 60 s. The mean heart rate was derived from recorded vital sign values in the first 3 days of hospitalization. Estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Disease equation as follows: eGFR (mL/min/1.73 m²) = 186 × (serum creatinine)^−1.154 × (age)^−0.203 × 0.742 (if female) [19]. Chronic kidney disease (CKD) was classified into five stages: stage 1 (eGFR ≥ 90), stage 2 (eGFR 60–89), stage 3 (eGFR 30–59), stage 4 (eGFR 15–29), and stage 5 (eGFR < 15) (all eGFR in mL/min/1.73 m²) [20].

The original cohort consisted of 41,241 patients aged ≥ 18 years. The exclusion criteria were patients: (1) hospitalized for less than 3 days; (2) admitted to a rehabilitation unit; (3) admitted through outpatient clinics; (4) with recurrent stroke during the study period; and (5) with less than one record of heart rate per day in the first 3 days of hospitalization. In addition, those without catastrophic illness cards were also excluded (beneficiaries of the National Health Insurance system in Taiwan would have been given a catastrophic illness card for 1 month because of their AIS; the National Health Insurance system in Taiwan covers more than 99.9% of the entire population) [21]. Finally, the data of 21,655 patients were used for the analysis (Fig. 1). The study was conducted in accordance with the Declaration of Helsinki and local ethical approval was obtained.

In this study of 21,655 patients with AIS, we found that the mean initial in-hospital heart rate was a predictor of all-cause mortality and cardiovascular death, independently of other known risk factors such as age and stroke severity.

The size of the study cohort allowed us to adjust for two of the strongest predictors of mortality in the multivariable model: age and stroke severity. In the subgroup analysis according to different age and stroke severity groups, the association between initial in-hospital heart rate and long-term mortality was consistent (Fig. 4). The impact of increasing heart rate on all-cause mortality seemed to be more pronounced in the patients younger than 75 years and in those with mild-to-moderate stroke (Fig. 4).

Epidemiological studies have consistently shown that resting heart rate is a predictor of all-cause and cardiovascular mortality in the general population and in patients with cardiovascular disease [22‐24]. However, the previous studies have reported inconsistent results about the relationship between heart rate and the clinical outcomes of patients with AIS. The Prevention Regimen for Effectively Avoiding Second Strokes study reported that heart rate was a risk factor for mortality in stroke patients, and, importantly, that a low heart rate was associated with better functional outcomes and lower rates of cognitive impairment after an AIS [25]. In addition, the Gutenberg Health Study reported that both a higher and lower heart rate were associated with a higher risk of mortality [26]. However, Ritter et al. reported that significant tachycardia or bradycardia in AIS did not independently predict the clinical course or outcomes [27]. A higher resting heart rate at admission has also been reported to be independently associated with in-hospital mortality in AIS patients without AF [28]. In addition, Lee et al. reported that in patients with AF hospitalized for AIS, the mean heart rate during the acute period was not associated with stroke recurrence, but was associated with mortality (nonlinear, J-shaped association) [29]. In the present study, mean initial in-hospital heart rate was associated with long-term all-cause and cardiovascular mortality in the overall cohort (Fig. 2), and in the patients with and without AF (Fig. 4). However, the effect of heart rate on long-term mortality seemed to be more pronounced in the patients without AF than in those with AF (Fig. 4). We also found that the long-term survival progressively declined as the level of mean initial in-hospital heart rate increased; however, there was no clear evidence of a J-curve relationship between the mean initial in-hospital heart rate and long-term mortality (Fig. 3).

In the multivariable Cox regression analysis, history of dyslipidemia, higher total cholesterol levels, and higher BMI are associated with improved long-term survival after AIS (Table 2). Although dyslipidemia and high BMI are well-known risk factors for cardiovascular disease, this has not been the case for post-stroke mortality. From several large cohorts, blood lipid levels and BMI have generally been inversely associated with post-stroke mortality [30‐32]. There may be unknown protective factors associated with dyslipidemia and high BMI.

Although heart rate is traditionally considered to be a risk factor for cardiovascular disease [33], we found that high initial in-hospital heart rate was a risk factor for both cardiovascular death and all-cause mortality after AIS in the current study. In the long-term follow-up of this study, cardiovascular death and cancer were the leading and secondary causes of death (40.7% and 17.1% of total mortality), respectively. Benetos et al. reported that heart rate was a predictive factor for non-cardiovascular mortality in both men and women in a French population [34]. Another prospective population study also reported that an increased mortality risk associated with a high heart rate was related mainly to diseases of non-cardiovascular or non-malignant origin [35]. However, many studies have demonstrated an association between an elevated heart rate and increased risks of cancer recurrence and mortality [36‐38]. For example, a previous meta-analysis found that a higher resting heart rate was associated with increased risks of coronary heart disease, sudden cardiac death, heart failure, AF, stroke, cardiovascular disease, total cancer, and all-cause mortality [39].

Heart rate has been associated with plaque vulnerability, sympathetic hyperactivity, and atherosclerosis [40‐42], and therefore, the role of arterial stress related to heart rate in the underlying mechanisms of the progression and clinical manifestations of cardiovascular diseases has gained increasing attention. In this study, the patients with a higher resting heart rate had more cardiovascular risk factors than those in the lowest group (Table 1). Some investigators have also indicated that many cardiovascular risk factors are also related to sympathetic hyperactivity [43‐45]. Reduction of heart rate has been shown to delay the progression of coronary atherosclerosis in monkeys [46, 47], and reduce the rate of increase in carotid intima-media thickness in asymptomatic patients [48]. In a model of dyslipidemic mice, chronic heart rate reduction via ivabradine maintained cerebral endothelial function and prevented cerebral artery remodeling [49]. However, whether beta-blockers, calcium-channel blockers, or I(f) channel inhibitor are associated with survival benefit in patients with coronary artery disease is still inconclusive [50‐52]. In addition to the above agents, cholinesterase inhibitors can also slow the heart rate via increasing cholinergic effect and show some potential in improving the lifespan [53‐55]; however, further studies are needed to investigate whether they can improve survival after AIS. We hope that using appropriate medications to reduce heart rate may play a role in improving the long-term survival after AIS in the future.

Heart rate is a simple measurement with important prognostic implications in patients with AIS, and it should no longer be neglected in risk flowcharts.