Heart rate recovery (HRR) is defined as the decline in heart rate immediately following exercise. The rapid deceleration of the heart rate immediately following exercise is dependent on a complex interplay between various intrinsic, neural, and humoral factors.^1-3) The decrease in heart rate immediately after exercise is a function of the reactivation of the parasympathetic nervous system.²⁾ There are cross-sectional associations of HRR with glucose, insulin, high-density lipoprotein-cholesterol (HDL-C), triglyceride (TG), blood pressure (BP), low-density lipoprotein-cholesterol (LDL-C).^4-8) Decreased HRR is a predictor of a poor cardiovascular prognosis, independent of and in addition to other risk factors.^9-11)

Brain natruretic peptide (BNP) is a hormone that is released from the ventricles in response to an increase in left ventricular pressure and volume. Plasma BNP levels play a crucial role in the diagnosis and prognosis of heart failure (HF) patients.^{12), 13)} Increased BNP levels have been observed in patients with hypertension (HTN), atrial fibrillation, valvular heart disease, ST-segment elevation myocardial infarction and myocardial ischemia without extensive necrosis.^{14), 15)}

Higher BNP levels are consistently observed in patients with HF and coronary artery disease (CAD) with blunted HRR.^{15), 16)} Also, the correlation between BNP and cardiac autonomic function has been studied in type 2 diabetic patients.¹⁷⁾ However, there is limited data on the relationship between HRR and BNP levels in patients without HF. Also, there have been few studies of BNP levels before, after, and during exercise. The purpose of this study was to examine the association between HRR and plasma BNP levels before, after, and during exercise in patients with a normal systolic function and to determine important associated factors.

BNP is a hormone that is secreted from the cardiac ventricles in response to an increase in left ventricular pressure and volume. Moreover, elevated plasma BNP levels are highly sensitive and specific for the diagnosis and prognosis of HF, and for the prognosis of acute myocardial infarction.^{12), 13), 15)} Patients with HF have blunted HRR concurrent with the presence of higher BNP levels.¹⁶⁾ But, the BNP level is typically measured before exercise; there is little data on post-exercise BNP levels and BNP change during exercise, and few studies have considered gender differences in BNP level and HRR. We analyzed patients with normal systolic function, and found that a rapid decrease in HRR had a significant negative association with pre- and post-exercise BNP levels, but not with BNP change.

HRR is defined as the maximum heart rate during exercise, minus the heart rate after exercise, which is a measure of the actual decrease in heart rate relative to the peak heart rate during exercise. Previous studies on HRR vary in non-HF patients; the optimal prognostic cutoff values for HRR (defining normal vs. abnormal HRR) are based on specific statistical considerations or are arbitrarily selected. The most commonly used cutoff value is 12 beats per minute.¹⁴⁾ We found that patients with abnormal HRR values (?24 beats first 2 minutes of HRR) had lower HDL-C, lower peak heart rate, and higher pre- and post-exercise BNP levels than patients with normal HRR values. In addition, the patients with abnormal HRR had a significantly higher prevalence of CAD. The higher pre- and post-exercise BNP levels in the abnormal HRR group can be explained by 1) parasympathetic dysfunction, 2) diastolic dysfunction, and 3) CAD.

First, heart rate variability (HRV) is one of the best methods to detect a quantitative relationship between the cardiovascular and autonomic nervous system (ANS). The ANS-mediated response, in particular parasympathetic reactivation, is a major determinant of HRR. In healthy individuals, the parasympathetic system is dominant at rest; exercise is associated with parasympathetic withdrawal and, as the intensity of exercise is increased, with sympathetic activity.¹⁹⁾ Savin et al.¹⁹⁾ have observed significantly reduced HRR values in individuals whose parasympathetic systems were blocked with atropine after exercise, suggesting that parasympathetic reactivation, not sympathetic withdrawal, is responsible for the reduced heart rate in the recovery phase. Abnormal HRR is considered a manifestation of altered autonomic responsiveness and abnormal vagal tone, possibly leading to an increased heart rate at rest.²⁰⁾

Second, an increase in BNP reportedly reflects an early stage of cardiac dysfunction.²¹⁾ Increased levels of plasma BNP are related to cardiac reflex parasympathetic dysfunction. The early stage of cardiac function and parasympathetic dysfunction may be associated with increased plasma BNP levels.¹⁷⁾ In our study, there was a significant correlation between delayed HRR and two BNP measurements, pre- and post-exercise. Multivariate analysis revealed that impaired HRR after exercise is significantly related with age and diastolic dysfunction.²²⁾ But in this study, the abnormal HRR group showed a significantly lower E/A ratio than the normal HRR group. The discrepancy between this study and other studies may be explained by differences in ventricular function. All subjects in this study have normal systolic function. In systolic failure, the heart overfills to compensate for the reduced pump function, which leads to chamber dilation and remodeling. However, in many older patients with HTN and ventricular hypertrophy that develop HF, dilatation does not occur.²³⁾ This results in the EF remaining in the normal range with a limited cardiac output reserve.²⁴⁾ The beneficial effects of BNP may be particularly important in hypertensive patients with decompensated HF, who demonstrated markedly reduced maximum exercise capacity compared with the reference values from healthy subjects.^{25), 26)} The E/A ratio included in this study can reflect only partially the diastolic dysfunction. This study compared the BNP levels of patients with a normal systolic function at rest and the HRR while they were exercising, and we found a difference in the E/A ratio according to HRR. Therefore, diastolic dysfunction could have substantially affected the results of this study. Although there is a significant correlation between BNP and HRR, even after correcting for confounding factors, the possibility of a difference in the HRR due to diastolic dysfunction cannot be ruled out. There are a number of potential areas in which the investigation of HRR and diastolic dysfunction could be expanded in future studies.

Third, patients with CAD had a significantly slower decrease in HRR.²⁷⁾ There was a strong correlation between the chronotropic variables (peak HR, percent peak HR and HRR after exercise) in the normal and CAD groups.¹⁸⁾ In our study, patients with CAD also had a reduced HRR. The abnormal HRR group had a significantly higher prevalence of CAD than the normal HRR group (52% vs. 28%, respectively, p=0.011), as shown in Table 1. Also, in Table 3 and 4, pre- and post-exercise BNP levels had a negative correlation with HRR. This correlation was still significant after adjusting for CAD, but the correlation values decreased more than for other parameters such as age, HTN, and DM. This result is consistent with previous findings related to the relationship between BNP and CAD.^{15), 25), 28)}

A comparative study on N-terminal pro-BNP concentrations indicated that the patients with unstable angina had higher BNP blood levels than stable patients.¹⁸⁾ Changes in serum natruretic peptide levels in patients without HF are closely correlated with the presence of exercise-induced myocardial ischemia.²⁸⁾ Revascularization can partially restore HRV during the 6 months following PTCA, suggesting that ischemia is one cause of the HRV.²⁹⁾ In this study, we performed CAG in patients with normal systolic function. CAD affected BNP and HRR, but there was a significant correlation between pre- and post-exercise BNP levels, and with HRR, even after correcting for CAD. This result suggests that the BNP level is affected more by HRR than by CAD, but further study is still needed.

This study has several limitations. First, our study was a cross-sectional survey and could not determine cause-and-effect relationships. Second, our study subjects may not be fully representative of the general adult population because they were enrolled based on the presenting complaint of chest pain. Third, our study had a relatively small sample size available for analysis. Furthermore, the study group consisted of carefully selected patients, recruited based on specific inclusion and exclusion criteria. Our findings need to be confirmed in a larger, community-based, non-selective HF cohort. Further, this study did not take into account diastolic dysfunction, which substantially affects the HRR and BNP. The E/A ratio cannot measure diastolic function fully. Lastly, this study did not investigate the smoking history of the subjects. Sidney et al.³⁰⁾ have reported that smoking is associated with a faster HRR, possibly because smoking-related beta-receptor down-regulation results in a blunted HR response to exercise.

In conclusion, HRR was independently associated with pre- and post-exercise BNP levels, but not BNP changes during exercise, even in patients with normal systolic function. The strongest association was between HRR and pre-exercise BNP levels. BNP change was less important than pre- and post-exercise BNP levels; therefore, pre-exercise BNP levels are the most powerful parameter in this study. BNP is a marker for HF, HTN, and myocardial infarction, as well as potentially for autonomic function. Prospective studies and research are still necessary for conformation.