Generally, heart rate (HR) variability and fluctuation after acute and serious disorders directly reflect the severity and complexity of multiorgan dysfunction, especially in the cardiac system. Numerous previous studies have revealed that increased HR is an independent predictor of mortality in a series of cardiovascular (CV) disorders, such as acute myocardial infarction (AMI), stable coronary disease, chronic heart failure, and ischemic stroke [1, 2, 3, 4, 5]. Additionally, a series of evidence has been accumulated to identify that different patterns of HR, such as admission HR [6], discharge HR [3, 7], HR variability [8] and resting HR [9] have been associated with a higher risk of recurrent myocardial infarction (MI) and long-term mortality in patients with AMI.

Previously, the association between elevated HR on admission and CV mortality during AMI has been recognized and incorporated into different risk stratification models, such as GRACE (Global Registry of Acute Coronary Events) and TIMI (Thrombolysis in Myocardial Infarction) risk scores [7, 10]. More recent studies of patients with AMI have reported that the association between discharge HR and long-term mortality is independent and stronger than that with admission HR [1, 3]. Although the effects of admission and discharge HR on long-term outcomes after MI have been well established in recent studies, few studies have investigated the effects of post-discharge HR. Meanwhile, increased HR is believed to be an indicator of more severe conditions for patients with acute coronary syndrome (ACS) [11, 12], but there is limited research on the association with outpatient HR during the rehabilitation period. Therefore, this study aimed to explore the relationship between CV events and HR at the first post-discharge visit and the HR difference between discharge and the first outpatient visit (D-O diff).

Our findings suggest that the first post-discharge HR is indicative of the risk of MACE in patients with AMI. In addition, this association with CV mortality and morbidity in AMI was independent of and stronger than admission HR and discharge HR, both of which are independently related to mortality, as indicated by previous studies [1, 6]. To the best of our knowledge, the present study is the first to illustrate the possibility that the HR at the first post-discharge visit over a recovery period of 2–4 weeks is superior to HR at admission or discharge in predicting long-term CV outcomes in the setting of AMI.

HR is an essential, prognostic, and vital parameter that is very convenient to measure and monitor in clinical practice and may be applicable to therapeutic interventions in coronary artery disease. Several previous studies have established a link between the increased risk of mortality and different patterns of CV events and elevated resting HR [9, 14, 15, 16]. Kim et al. [4] suggested that worsening the first post-discharge HR control increases the risk of readmission due to the prevalence of CV events in patients with heart failure, including worsening heart failure, non-fatal MI, and mortality. Higher outpatient HR as a continuous parameter was related to an increased risk of mortality, with a hazard ratio of 1.037 (95% CI = 1.029–1.045). In the case of post-MI, the early double-blind Norwegian Timolol Multicenter study, Gundersen et al. [17] demonstrated that increased resting HR at 1 month after AMI was related to mortality during a 6-years follow-up regardless of timolol treatment. Although there was no definite description of the post-discharge HR, the failure of HR management in the second or fourth week after discharge was related to a poor prognosis. Our findings are consistent with these reports and suggest that the first post-discharge HR is a better predictor of long-term CV events in AMI patients compared with the two other types of HR at hospitalization, independent of the coronary severity and LVEF on admission. Hence, the present study provides important prognostic evidence for the prediction of early follow-up outpatient HR in the AMI population. Additionally, increased differences between outpatient and discharge HRs were also independent risk factors for CV events. Although causality in this observational study cannot be assessed, existing studies provide a rational explanation. In the Coronary Artery Risk Development in Young Adults (CARDIA) Study, the increment of change in HR during follow-up visits is associated with worsening diastolic function in young adults at a higher risk of incident HF and CV disease [16]. Unrevealed diastolic dysfunction is an important independent predictor of mortality after AMI, regardless of LVEF [18]. This interaction may be a confounding factor between the elevated outpatient HR and mortality. In addition, a reduction in HR potentially reduces myocardial oxygen consumption and maintains coronary perfusion due to a prolonged diastolic period and vice versa [19]. A cascade of events, including elevated left ventricular afterload and stiffness, impairments in left ventricular diastolic function, and cardiac function, are induced by an increase in HR [20].

Interestingly, contrary to the positive results from prior studies regarding the effect of discharge HR on CV mortality, our findings showed that there is a neutral association with clinical outcomes. It is worth noting that the HR at discharge was limited to approximately 70 beats/min in this population. In a recently published study [1], the findings of Alapati et al. [1] also demonstrated that discharge HR 70 bpm has a comparable risk of all-cause mortality compared with HR 60 bpm with a hazard ratio of 0.95. This is consistent with previously published data from two other large-scale studies [2, 7] concerning discharge HR. Hence, in the era of timely reperfusion, the effects of $\beta$-blockers on long-term prognosis in post-MI patients with HR 70 bpm remains debated [21]. Accordingly, our study found that an outpatient HR $>$71 bpm was associated with CV mortality in the setting of ACS. Meanwhile, our observation suggested that resting HR in the first visit after discharge rebounded following the recovery of normal physical activity. In the case of post-discharge, activation of the sympathetic nervous system increases further due to normal physical activity, and a hemodynamically unstable phase is expected compared with hospitalization. The condition, referred to as post-hospital syndrome declared by Harlan, suggests that the risks in the critical 30-day period after discharge might be derived from physiological stress and mood anxiety in different scenarios, such as decompensated heart failure and acute coronary disease [22, 23, 24]. During hospitalization, a third of patients commonly experience barren sleep, disruption of circadian rhythms, moderate/severe anxiety, and reduction of activity endurance, which can adversely affect sympathetic activity and contribute to diminished physical performance [24]. Among the 7599 patients with chronic heart failure enrolled in the CHARM (candesartan in heart failure: assessment of reduction in mortality and morbidity) research [25], the upward changes in outpatient HR in the three months preceding visit could predict readmission and cardiac death, independent of the series of HR-reducing interventions. A recent study by Ryuichi et al. [26] also indicated that an early follow-up at outpatient management within 2 weeks could improve the long-term rehospitalization rate and composite adverse endpoints, including all-cause mortality in the setting of chronic heart failure. Early follow-up care could consecutively enforce self-management during hospitalization, resulting in an improved prognosis. In the current study, the controlled HR at discharge could contribute to the small number of irresistible events, whereas it remains possible to underestimate the condition of cardiac recovery and response to medication. Hence, particular attention needs to be paid to the importance of early follow-up outpatient care, including HR lowering, which could facilitate the management and monitoring of normal daily life habits in the early recovery period.

Our observations suggest that monitoring HR at the first post-discharge visit may be beneficial in identifying AMI patients at the greatest risk of readmission and death. The mechanism beyond the association between outpatient HR and death may relate to a long-term risk of CV autonomic neuropathy in association with various pathogenic pathways, including chronic inflammatory and atherosclerosis, and infectious disease processes. Reduction of HR variability and baroreflex gain reflect intrinsic autonomic abnormalities, which are generally associated with an imbalance of the autonomic nervous system, including sympathetic hyperactivity and vagal hypoactivity. Therefore, resting tachycardia commonly manifests after AMI, and an exaggerated HR relative to the activation of the sympathetic tone is general [27, 28]. Meanwhile, a recent study by Lai et al. [29] indicated that the CV autonomic neuropathy precipitated by diabetes mellitus could contribute to sympathetic predominance and is strongly associated with subsequent major adverse CV events, independent of underlying coronary disease and other risk factors. Several other studies have also shown that autonomic dysfunction, defined as an alteration in vagal and sympathetic activities, is related to long-term CV events [30, 31]. Moreover, higher HR is also associated with cardiometabolic factors, such as increased oxidative stress, inflammation markers, glucose intolerance, and diabetes mellitus [28, 32]. In the early stage of cardiac resilience following AMI, the discrepancy regarding suboptimal lifestyle habits and CV disease burden and subsequent alterations in myocardial function are also possible contributory factors for uncontrolled resting HR in the clinic department [16, 22].

There were several limitations to this retrospective study. First, the research is observational, and as such, cannot establish a cause. Nevertheless, these findings are consistent with those of other studies [4, 17]. Second, there was a low rate of CV events in the present study. Standard guideline-directed medical therapy can contribute to a low incidence of CV deaths. Third, the status of chronic inflammatory diseases, such as pulmonary disease, was not depicted in detail in this study. In the Cox proportional hazard regression, when the level of hs-CRP was considered, outpatient HR was an independent risk factor for CV mortality and MACE. Finally, because there was no difference in discharge of $\beta$-blockers between the two subgroups, we did not discuss the influence of outpatient $\beta$-blocker treatment on the effectiveness of discharge HR for long-term CV events. We did not report the details of patients who received $\beta$-blockers in the clinic department. Further research on this relationship should be conducted.

In the case of AMI, HR monitoring at the first post-discharge visit is an important parameter associated with CV events. During the first outpatient visit, an HR above 71 beats/min was a risk factor related to the occurrence of CV mortality and other events. Hence, a thorough follow-up of HR changes in outpatients with AMI may facilitate the management of patients at a higher risk of CV events.

CL, DJF and QZ conceived the present study, participated in the design, collected and assembled all data, conducted data analysis, and drafted the manuscript. PXS commented on the manuscript drafts. LFW and XCY provided material and technical support and commented on the manuscript drafts. KBL and MLC aided the interpretation of data, commented on this study design, and provided a critical review. All authors have read and approved the manuscript.

This study was approved by the institutional review board of Beijing Chaoyang Hospital (2017-S-187) and performed in accordance with the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all the patients or their legal relatives.

We would like to express our gratitude to all those who helped us during the writing of this manuscript. We thank all the peer reviewers for their opinions and suggestions.

This research was funded by the National Key R&D Program of China, grant number 2016YFC1301102. It funded the collection of data in the outpatient department and the revision of the manuscript.

The authors declare no conflict of interest.