Orthostatic Heart Rate Changes and Prognostic Outcomes in Patients With Heart Failure

Abstract

Background: Heart rate typically increases during postural changes from a supine to a standing position due to autonomic and hemodynamic factors. Changes in heart rate during orthostasis may reflect the extent of autonomic dysfunction in patients with heart failure (HF). Thus, orthostatic heart rate changes may be useful for evaluating autonomic function and may predict prognosis. This study examined the association between orthostatic heart rate changes and prognosis in patients with HF.

Methods and Results: We included 320 patients with HF in sinus rhythm (median age 70 years, 70.9% men) who were admitted to Kitasato University Hospital for HF treatment and whose heart rate was evaluated in the supine and upright positions during the stable period before discharge. We calculated heart rate changes based on supine and upright heart rate. We examined the association of orthostatic heart rate changes with patient prognosis (i.e., a composite of all-cause mortality or rehospitalization for HF). During the follow-up period (median 3.8 years; interquartile range 0.8–7.0 years), 129 events occurred. Orthostatic heart rate changes were associated with low composite event rates (log-rank P=0.015). After adjusting for potential confounders, increasing orthostatic heart rate changes were associated with decreased composite event rates (adjusted hazard ratio 0.954; 95% confidence interval 0.925–0.985; P=0.004).

Conclusions: In patients with HF, poor orthostatic heart rate changes were associated with a worse prognosis.

Heart failure (HF) is associated with high mortality and rehospitalization rates, and it is important to predict its prognosis for adequate clinical management.^1–4 Autonomic dysregulation is a characteristic pathophysiology observed in the form of elevated sympathetic activation and parasympathetic withdrawal in patients with HF.^5,6 This dysregulation is one of the most important factors leading to a poor prognosis.⁷

Autonomic function assessments include heart rate variability (HRV), heart rate recovery (HRR), baroreflex sensitivity, and muscle sympathetic activity.⁸ Reduced HRV, as determined by 24-h Holter electrocardiography, is associated with a higher risk of cardiovascular death and all-cause mortality in patients with HF.⁷ In addition, low HRR is a reported predictor of all-cause mortality.⁹ However, in patients with HF, although the validity of HRV and HRR has been demonstrated, the versatility of these measurements is limited by the requirement for 24-h Holter electrocardiography and exercise testing, respectively. Consequently, a measurement that can be adapted to more patients would facilitate heart rate evaluation in clinical practice. Unfortunately, the other currently available measurements also require intricate techniques, such as measurement of nerve activity voltage⁸ or intravenous injection of a vasoactive drug.¹⁰

One useful measure of heart rate responses is the change in heart rate that occurs as a patient transitions from a supine to a standing position.¹¹ Heart rate typically increases during postural changes from a supine to a standing position due to autonomic and hemodynamic factors, making measurements of this change clinically useful for evaluating autonomic function.¹² Notably, in patients with autonomic dysfunction, such as those with HF, this increase in heart rate from the supine to the standing position is attenuated.¹¹ Thus, the change in heart rate from the supine to the standing position may be useful as a simple test to predict prognosis in patients with HF because it reflects the extent of autonomic dysfunction. However, this has not yet been examined.

The aim of this study was to examine the association between orthostatic heart rate changes and prognosis in patients with HF.

Methods

This was a single-center retrospective observational study. We enrolled 538 consecutive patients with HF in sinus rhythm (defined as HF by the Framingham Criteria¹³) who were admitted to the Kitasato University Hospital Cardiovascular Center between March 2008 and August 2014 for HF treatment and whose heart rate was evaluated in the supine and upright positions during the stable period before discharge. However, 218 patients with arrhythmias or any pacemakers were excluded, leaving 320 patients included in the analysis (Figure 1).

Figure 1.

Flow diagram of patient selection and exclusion in this study.

The study protocol adhered to the tenets of the Declaration of Helsinki, and the study was approved by the Ethics Committee of the Kitasato University Medical Ethics Organization (B22-143). Information about the study was made available to the public, and participants were informed of their ability to opt-out of the study.

We collected clinical data, including age, sex, body mass index (BMI), heart rate, blood pressure (BP), HF severity according to New York Heart Association (NYHA) functional class, and prior HF and biochemical data (hemoglobin, sodium, albumin, B-type natriuretic peptide [BNP]) at the time of discharge. Clinical details, including comorbidities and medication status, and echocardiography data, including the assessment of left ventricular ejection fraction (LVEF), were recorded during the admission period. The estimated glomerular filtration rate (eGFR) was calculated using the formula of the Japanese Society of Nephrology¹⁴ as follows:

eGFR = 194 × (serum creatinine)^1.094 × (age)^0.287 in men

eGFR = 194 × (serum creatinine)^1.094 × (age)^0.287 × 0.739 in women

Heart rate was evaluated during the period when daily changes in body weight and daily variations in heart rate and BP were stable due to improvement of HF symptoms before discharge. Patients were placed in a supine position and rested for 1 min. Subsequently, the patients sat up on their own at their usual pace. The investigator assisted the patients in rising from the bed, if necessary. The patients then stood up from the bed and maintained a standing position. Heart rate was measured throughout the test using an electrocardiogram monitor.

The heart rate in the supine position was obtained after patients had rested for at least 1 min. The highest heart rate within 30 s of standing was defined as the heart rate in the upright position. The orthostatic heart rate changes were then calculated as the difference between the heart rate in the upright and supine positions. BP was also measured in a supine position after at least 1 min of rest and at 1 min of standing.

The endpoint was a composite of all-cause mortality and rehospitalization for HF. The follow-up period was from the time of discharge to the time the patients remained alive without experiencing any events or to the time at loss to follow-up. Rehospitalization for HF was defined as hospitalization for HF treatment after discharge diagnosed by a specialist based on Framingham criteria, as confirmed by a medical chart review.

Continuous variables are expressed as the median with interquartile range (IQR) and categorical variables are presented as numbers and percentages. Subjects were divided into tertiles of orthostatic heart rate changes: lowest, change <3 beats/min; middle, change 3–7 beats/min; highest, change ≥8 beats/min. The significance of differences between groups of continuous and categorical variables was investigated using one-way analysis of variance and the Kruskal-Wallis test or the χ² test, respectively.

Missing values were handled through multiple imputation using chained equations with the “mice” package, version 3.15.0, of R software.¹⁵ Multiple imputations were repeated 50 times to generate 20 datasets with complementary missing values.

The cumulative event-free survival during follow-up was calculated according to the tertile of the orthostatic heart rate changes using Kaplan-Meier curves, and the significance of differences between groups was evaluated using log-rank tests.

We explored the association between orthostatic heart rate changes and the incidence of composite events using multivariate Cox regression analyses. In the Cox regression model, the hazard ratios (HRs) for orthostatic heart rate changes were examined by heart rate changes tertile and continuous variables. We used the restricted cubic spline method to evaluate the potential non-linear relationship between orthostatic heart rate changes and composite events. Four knots were placed at prespecified locations according to the quartile of the distribution of orthostatic heart rate changes. Multivariate Cox regression models and the restricted cubic spline method were adjusted for age, sex, BMI, LVEF, NYHA functional class, log₁₀[BNP], β-blocker use, diabetes, prior HF, changes in systolic BP (SBP; calculated as the difference between SBP in the upright and supine positions), and supine heart rate.

Statistical analyses were performed using the R Studio statistical software, version 4.2.0 (https://www.R-project.org). Statistical significance was set at P<0.05.

Results

Table 1 present baseline characteristics for all patients and the 3 groups stratified by tertiles of orthostatic heart rate changes (lowest [change <3 beats/min], middle [change 3–7 beats/min], and highest [change ≥8 beats/min]). The median age of the study participants was 70 years (IQR 58–77 years), 70.9% were male, and 78.4% were prescribed β-blockers at discharge. The median supine heart rate was 70 beats/min (IQR 62–79 beats/min), and the median orthostatic heart rate change was 5 beats/min (IQR 2–10 beats/min). Compared with the lowest heart rate change group, the highest heart rate change group had a lower supine heart rate, higher upright heart rate, lower LVEF, and a lower proportion of patients with HF with preserved ejection fraction (HFpEF).

Table 1.

Participant Characteristics

Factor	All patients (n=320)	Heart rate change tertile			P value
		Lowest (n=103)	Middle (n=106)	Highest (n=111)
Age (years)	70 (58, 77)	70 (62, 77)	70 (59, 77)	67 (54, 76)	0.119
Male sex	227 (70.9)	79 (76.7)	66 (62.3)	82 (73.9)	0.050
BMI (kg/m2)	22.0 [20.0, 25.1]	21.6 [20.0, 25.7]	22.2 [20.0, 24.6]	22.4 [20.0, 25.1]	0.975
Heart rate (beats/min)
In supine position	70 [62, 79]	74 [66, 82]	68 [61, 76]	69 [60, 78]	<0.001
In upright position	75 [68, 86]	73 [67, 81]	73 [65, 82]	83 [73, 92]	<0.001
Change in heart rate (beats/min)	5 [2, 10]	0 [−2, 2]	5 [4, 6]	12 [9, 16]	<0.001
SBP (mmHg)
In supine position	110 [100, 123]	111 [100, 127]	109 [101, 120]	108 [99, 122]	0.580
In upright position	105 [93, 114]	107 [92, 118]	107 [95, 116]	104 [91, 113]	0.378
Change in SBP (mmHg)	−6 [−16, 2]	−7 [−18, 1]	−6 [−12, 2]	−6 [−18, 3]	0.667
DBP (mmHg)
In supine position	62 [56, 69]	60 [56, 69]	62 [57, 69]	62 [55, 69]	0.536
In upright position	61 [54, 70]	60 [52, 69]	61 [55, 70]	62 [56, 70]	0.147
Change in DBP (mmHg)	0 [−7, 6]	−2 [−8, 3]	0 [−7, 7]	0 [−6, 8]	0.180
MAP (mmHg)
In supine position	79 [71, 85]	77 [70, 88]	79 [74, 85]	79 [71, 85]	0.901
In upright position	76 [68, 84]	74 [68, 84]	77 [70, 85]	76 [69, 85]	0.549
Change in MAP (mmHg)	−2 [−8, 3]	−3 [−9, 2]	−2 [−8, 4]	−2 [−8, 5]	0.476
Ischemic etiology	147 (45.9)	48 (46.6)	47 (44.3)	52 (46.8)	0.921
LVEF (%)	46 [34, 59]	52 [36, 63]	45 [35, 59]	43 [32, 53]	0.011
LVEF ≥50%	127 (40.7)	52 (51.0)	41 (39.8)	34 (31.8)	0.018
NYHA functional class
II	253 (82.1)	85 (85.0)	76 (76.8)	92 (84.4)	0.236
III	53 (17.2)	15 (15.0)	21 (21.2)	17 (15.6)	0.437
IV	2 (0.6)	0 (0.0)	2 (2.0)	0 (0.0)	0.119
Prior HF	150 (46.9)	54 (52.4)	46 (43.4)	50 (45.0)	0.379
Comorbidities
Hypertension	258 (80.6)	84 (81.6)	87 (82.1)	87 (78.4)	0.756
Diabetes	192 (60.0)	66 (64.1)	66 (62.3)	60 (54.1)	0.276
Dyslipidemia	176 (55.0)	58 (56.3)	54 (50.9)	64 (57.7)	0.579
Current smoker	71 (22.5)	25 (24.5)	23 (22.1)	23 (21.1)	0.832
Medications
ACEi/ARB	272 (85.0)	86 (83.5)	91 (85.8)	95 (85.6)	0.873
β-blocker	251 (78.4)	73 (70.9)	84 (79.2)	94 (84.7)	0.048
Aldosterone blocker	135 (42.2)	44 (42.7)	40 (37.7)	51 (45.9)	0.469
Diuretic	227 (70.9)	73 (70.9)	78 (73.6)	76 (68.5)	0.709
Laboratory data
Hemoglobin (g/dL)	12.0 [10.6, 13.7]	11.7 [10.3, 13.3]	12.2 [10.7, 13.8]	12.3 [10.8, 13.7]	0.192
Sodium (mEq/L)	138 [137, 140]	138 [137, 140]	138 [137, 140]	139 [137, 140]	0.720
Albumin (g/dL)	3.7 [3.4, 4.0]	3.7 [3.4, 4.0]	3.7 [3.2, 4.0]	3.8 [3.5, 4.1]	0.178
BNP (pg/mL)	272.2 [131.9, 741.8]	278.5 [167.3, 759.8]	272.7 [130.1, 902.5]	235.2 [97.9, 562.6]	0.192
eGFR (mL/min/1.73 m2)	55.3 [35.0, 69.7]	52.8 [33.2, 68.8]	54.3 [31.3, 71.1]	58.8 [42.0, 71.9]	0.151

Unless indicated otherwise, data are expressed as the median [interquartile range] or n (%). Patients were divided into 3 groups according to tertiles of orthostatic heart rate changes (lowest, change <3 beats/min; middle, change 3–7 beats/min; highest, change ≥8 beats/min). ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; BNP, B-type natriuretic peptide; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; MAP, mean arterial pressure; NYHA, New York Heart Association; SBP, systolic blood pressure.

The median follow-up period was 3.8 years (IQR 0.8–7.0 years). During the follow-up period, all-cause mortality or rehospitalization for HF occurred in 129 patients (n=42 and n=87, respectively).

Kaplan-Meier analysis with log-rank tests showed that high orthostatic heart rate changes were associated with low composite event rates (Figure 2). Table 2 presents results of univariate and multivariate Cox regression analyses of composite events. After adjustment for the Cox regression models in the multivariate analysis, increasing orthostatic heart rate changes were associated with a decreased risk of composite events (adjusted HR per 1-beat/min increase 0.954; 95% confidence interval [CI]: 0.925–0.985; P=0.004). A graded reduction in the risk of composite event rates was observed in the middle heart rate change group (adjusted HR 0.632; 95% CI 0.404–0.989; P=0.045) and highest heart rate change group (adjusted HR 0.482; 95% CI 0.301–0.773; P=0.003) compared with the lowest heart rate change group. Like the Cox regression models, the adjusted restricted cubic spline of the orthostatic heart rate changes indicated that the risk of composite event rates decreased with increasing orthostatic heart rate changes (Figure 3).

Figure 2.

Survival curves of the association between orthostatic heart rate changes and all-cause death or rehospitalization for heart failure.

Table 2.

Cox Regression Analysis for All-Cause Mortality or Rehospitalization for HF

	Unadjusted			AdjustedB
	HR	95% CI	P value	HR	95% CI	P value
Change in heart rate (per 1-beat/min)	0.961	0.936–0.986	0.003	0.954	0.925–0.985	0.004
Change in heart rate categoryA
Lowest	1.000	Reference	–	1.000	Reference	–
Middle	0.743	0.491–1.123	0.158	0.632	0.404–0.989	0.045
Highest	0.538	0.352–0.822	0.004	0.482	0.301–0.773	0.003

^APatients were divided into 3 groups according to tertiles of orthostatic heart rate changes (lowest, change <3 beats/min; middle, change 3–7 beats/min; highest, change ≥8 beats/min). ^BAdjusted for age, sex, body mass index, left ventricular ejection fraction, New York Heart Association functional class, log₁₀[B-type natriuretic peptide], β-blocker use, diabetes, prior HF, change in systolic blood pressure, and supine heart rate. CI, confidence interval; HF, heart failure; HR, hazard ratio.

Figure 3.

Restricted cubic spline of associations of changes in heart rate and all-cause mortality or rehospitalization for heart failure. The gray shaded area represents the 95% confidence interval. Data were adjusted for age, sex, body mass index, left ventricular ejection fraction, New York Heart Association functional class, log₁₀[B-type natriuretic peptide], β-blocker use, diabetes, prior heart failure, changes in systolic blood pressure, and supine heart rate. CI, confidence interval; HR, hazard ratio.

Discussion

This study demonstrated that an increase in orthostatic heart rate changes was an independent prognostic predictor for composite events, even after adjusting for pre-existing HF prognostic factors, β-blocker use, and supine heart rate in patients with HF. These results suggest that orthostatic heart rate changes, which can be determined rapidly, easily, and non-invasively, are useful for the stratification of the clinical event risk in patients with HF.

Previous studies have reported that reduced HRV is an independent predictor of death,¹⁶ and indices of autonomic function determined by HRV have been shown to have independent predictive value for long-term outcomes in patients with chronic HF.^7,16 In addition, previous studies have suggested that early HRR after exercise is an independent predictor of mortality and that HRR after the 6-min walk test is a powerful prognostic factor that performs better than distance ambulated in patients with chronic HF.^9,17 The validity of HRV and HRR has been demonstrated; however, these previous studies required the generation of 24-h Holter electrocardiograms and exercise testing while also requiring specialized software to analyze HRV and HRR. These requirements limit the versatility of HRV and HRR methods; therefore, a measurement that can be adapted to more patients is needed in clinical practice. Orthostatic heart rate changes can be measured in patients who do not have a 24-h Holter electrocardiogram or who are unable to perform exercise testing, and the findings of our study imply that orthostatic heart rate changes may have potential for risk stratification in clinical practice, although further studies are needed to confirm the reproducibility and applicability of orthostatic heart rate changes in routine clinical settings for chronic HF patients.

The mechanism underlying the association between orthostatic heart rate changes and prognosis remains to be elucidated and requires further study. One possible mechanism may involve chronotropic incompetence, which is defined as the inability of the heart rate to increase adequately during physical exertion to match cardiac output to metabolic demand.^18,19 In patients with HF, chronotropic incompetence has been associated with reduced exercise capacity and poor prognosis.^20–24 One reported mechanism underlying chronotropic incompetence is autonomic dysfunction,^25,26 and the heart rate typically increases during postural changes from supine to standing due to both autonomic and hemodynamic factors. Heart rate typically increases during orthostasis,¹² but the increase in heart rate may be smaller in patients with HF due to autonomic dysfunction. Therefore, in the present study, patients in the group with the lowest changes in orthostatic heart rate may have a higher severity of autonomic neuropathy and a worse prognosis than patients in the groups with higher changes in orthostatic heart rate.

The baroreflex is defined as the main short-term compensatory mechanism that buffers blood pressure changes to maintain circulatory homeostasis. Typically, the baroreflex was evaluated by the infusion of vasoactive drugs to impose transient hypotension or hypertension. In this study, BP responses to orthostasis were not different and remained within the normal range across all 3 groups, consistent with findings in healthy individuals.²⁷ In the present study, the highest heart rate was obtained within 30 s of standing, and the BP was measured at 1 min of standing. Because BP was not measured by the beat-by-beat method immediately after standing, our study was unable to accurately capture the actual extent of orthostatic hypotension. It seems difficult to accurately verify the contribution of the baroreceptor reflex in our clinical study. However, the lowest heart rate change group showed only slight changes in heart rate. Patients who lost their orthostatic heart rate response may potentially be attempting to maintain BP within the normal range through vasoconstriction. In addition, the lowest heart rate change group had a higher proportion of HFpEF patients, many of whom exhibited chronotropic incompetence. Chronotropic incompetence is observed in 30–50% of HFpEF patients^28,29 and is associated with poor prognosis. One of the mechanisms underlying the blunted baroreflex sensitivity in HFpEF is a decreased β-adrenoceptor responsiveness in the sinus node,³⁰ which may explain the differences in heart rate response observed among the groups in this study. In addition, the highest heart rate change group had a higher proportion of patients with heart failure with reduced ejection fraction (HFrEF). It is possible that in patients with HFrEF, cardiac output and BP are reduced immediately after orthostasis, and that reactive sympathetic activation leads to an increase in heart rate. However, because we did not measure these transient drops in BP or cardiac output after standing in the present study, further investigations are needed to clarify the mechanisms behind the observed results.

Our study has several limitations. First, it was a single-center retrospective study, and it exclusively enrolled Asian patients with HF. Further research is necessary to establish whether our results are generalizable to other populations. Second, there was limited information on the extent of β-blocker use, orthostatic hypotension, and the cause of death, which made it impossible to perform a detailed analysis of these factors. Third, the standing test was conducted only once before discharge, and thus the reproducibility and potential variability of the heart rate response over time were not sufficiently evaluated. Repeated measurements and further validation across multiple centers are needed to confirm the robustness of heart rate responses as a clinical tool. Finally, we were unable to compare the prognostic predictive ability of orthostatic heart rate changes with other autonomic measures, such as HRV and HRR. However, orthostatic heart rate changes may be a more measurable and versatile indicator than HRV and HRR, especially for patients who have not undergone assessment by 24-h Holter electrocardiography or who are unable to perform exercise testing.

Conclusions

Poor orthostatic heart rate changes were associated with a poor prognosis in patients with HF. Although heart rate measurement is simple and has potential for risk stratification in clinical practice, further studies are needed to confirm its reproducibility and applicability in routine clinical settings.

Acknowledgments

We would like to thank all the collaborators from our teams at Kitasato University Hospital for their clinical work.

Sources of Funding

This work was supported, in part, by JSPS KAKENHI (Grant no. 21H03309).

Disclosures

K.K. has received funding outside of the submitted work from Eiken Chemical Co. Ltd. and SoftBank Corporation. J.A. is a member of Circulation Journal’s Editorial Team.

IRB Information

This study was approved by the Ethics Committee of the Kitasato University Medical Ethics Organization (B22-143).

Data Availability

The deidentified participant data will not be shared.

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