Differential impact of heart rate and blood pressure on outcome in patients with heart failure with reduced versus preserved left ventricular ejection fraction

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Abstract

Background

In contrast to patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF; HFREF) the prognostic role of heart rate (HR) and blood pressure (BP) in patients with HF and preserved LVEF (HFPEF) is not well known. The aim of this study was to characterize the relationship between HR and BP and outcomes in HFPEF and to compare it to HFREF.

Methods

The association between HR and BP and outcomes (median follow-up: 38 months) was analyzed in patients with HFREF (LVEF  45%; n = 6792) and HFPEF (LVEF > 45%; n = 988) from the Digitalis Investigator Group trial.

Results

Mortality (35% vs. 23%) and HF hospitalization rates (31% vs. 20%; p < 0.001 for both) were higher in HFREF compared to HFPEF. In HFREF, higher HR and lower systolic and diastolic BP quartiles were associated with higher mortality and HF hospitalization rates. By contrast, there was no significant association between HR and BP respectively and mortality in HFPEF, and there was no significant association between systolic BP and hospitalization risk in HFPEF either. However, HF hospitalization rates were significantly related to increasing HR and decreasing diastolic BP quartile respectively (4.9, 6.8, 6.8, and 10.5 and 5.5, 8.1, 6.0, and 10.1 respectively events per 1000 person-years) in HFPEF. In HFPEF, there was also evidence of a significant J-shaped relationship between pulse pressure and mortality.

Conclusions

The prognostic value of HR and BP differed substantially between HFREF and HFPEF. These data may provide a foundation for the design of novel interventions in HFPEF patients.

Introduction

Several well validated prognostic models [1], [2] have been developed for the estimation of risk in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF; HFREF). Among the contributory parameters, simple hemodynamic indices, including lower systolic blood pressure (BP) [2] and a higher resting heart rate (HR) [3], have been shown to be associated with an increased mortality in these patients. Pathophysiologically, these two measures are reflective of reduced cardiac output and elevated cardiac adrenergic drive [4], which also correlate with survival in patients with HFREF [5]. In this context, renin–angiotensin system inhibition has been shown to improve cardiac output and β-antagonists to reduce HR in patients with HFREF, and both classes of agents are well known to improve prognosis in these patients [4].

By contrast, it remains uncertain whether a similar relationship exists between HR or BP and outcome in patients with HF and preserved LVEF (HFPEF). Similar to that for HFREF, the clarification of the nature and extent of an association between HR or BP and prognosis in these patients holds substantial importance, particularly given ongoing controversy about the pathophysiology of HFPEF and the relative failure of therapies with proven efficacy in HFREF [6], [7], [8], [9].

Accordingly, the aim of the present study was to compare the relationship between HR and BP with outcome in a large cohort of HFREF and HFPEF patients that contributed to the Digitalis Investigations Group (DIG) trial.

Section snippets

Participants

The present study is a post hoc analysis of the randomized DIG trial [10] performed using the study database obtained from the National Heart, Lung, and Blood Institute (NHLBI; website https://biolincc.nhlbi.nih.gov/studies/dig/). Patients with a clinical diagnosis of HF and LVEF  45% or > 45% and “probable diastolic HF” [11] recruited between January 1991 and August 1993 in the United States and Canada were included in the main or an ancillary trial parallel to the main trial. We labeled this

Clinical characteristics of patients with HFREF and HFPEF

Patients with HFREF and HFPEF differed substantially at baseline, as shown in Table 1. Besides other differences, patients with HFREF had higher HR, lower systolic and diastolic BP, and lower PP.

Outcome in HFREF and HFPEF

Patients with HFREF had higher all-cause mortality and a higher HF hospitalization risk than HFPEF patients, and cardiac and cardiovascular mortality was also higher in HFREF patients (p < 0.001 for all comparisons using log rank tests or χ2 tests, as shown in Table 1), while non-cardiovascular mortality

Discussion

The present study demonstrated substantial differences in the prognostic value of simple clinical parameters such as HR and BP in a large cohort of HF patients with either reduced or preserved LVEF. In HFREF, higher HR and lower systolic and diastolic BP and PP correlated with all-cause mortality. By contrast, however, these variables did not correlate in a similar way with mortality in HFPEF patients; rather, PP appeared to be related to outcome in a J-shaped manner in these patients.

Acknowledgement

We thank Dr. Christopher M. Reid for technical support. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [35].

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    The randomized DIG trial was conducted and supported by the NHLBI in collaboration with the Department of Veterans Affairs Cooperative Studies Program. Dr. Maeder was supported by the Swiss National Science Foundation (Grant PBZHB-121007). Dr. Kaye is supported by a program grant from the National Health and Medical Research Council of Australia.

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