Implication of heart rate optimization in patients with heart failure

Abstract

Prognostic impact of heart rate reduction therapy using ivabradine, a selective inhibitor of I_f channel that purely reduces heart rate, in patients with heart failure with reduced ejection fraction and sinus tachycardia has been demonstrated. However, ideal heart rate remains unknown. We experienced an 80-year-old woman with reduced left ventricular ejection fraction who was hospitalized due to congestive heart failure. Following the ivabradine administration that decreased her heart rate from 100 bpm down to around 60 bpm, the “overlap” between E-wave and A-wave in the trans-mitral Doppler echocardiography diminished, accompanied by an improvement in cardiac output. Heart rate optimization targeting to diminish the overlap between E-wave and A-wave might maximize cardiac output and improve the clinical course via facilitated cardiac reverse remodeling. Further studies are warranted to validate the implication of therapeutic strategy to aggressively minimize the echocardiographic “overlap” by heart rate reduction therapy in heart failure patients.

Learning objective:

Cardiac output might improve when the “overlap” length between E-wave and A-wave in the trans-mitral Doppler echocardiography minimizes during ivabradine therapy. Clinical implication of Doppler echocardiography-guided heart rate reduction therapy using ivabradine remains a future concern.

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Introduction

Ivabradine, a selective inhibitor of I_f channel that purely reduces heart rate and improves clinical outcomes in patients with heart failure with reduced ejection fraction and sinus tachycardia, is receiving attention [1, 2]. However, the clinical benefit of heart rate reduction seems to reach a plateau or become rather harmful at too reduced heart rate, and “ideal heart rate” for each individual remains unknown [3].

Our team recently proposed a formula to calculate the ideal heart rate using each patient's deceleration time, at which E-wave and A-wave adjoin each other without any overlaps in the trans-mitral Doppler echocardiographic flow, based on the hypothesis that cardiac output might be maximum and optimal reverse remodeling might be expected at the ideal heart rate [4]. However, its clinical implication in daily clinical practice remains unknown.

In this case, we performed heart rate reduction therapy using ivabradine and assessed the relationship between the overlap of both waves in the Doppler echocardiography and actually measured cardiac output. We discuss the clinical implication of Doppler echocardiography-guided heart rate optimization therapy.

Care report

On admission

An 80-year-old woman with previous history of old myocardial infarction of antero-septal wall and two-time hospitalizations due to worsening heart failure was admitted to our institute presenting nocturnal dyspnea and was hospitalized with a diagnosis of acute decompensated heart failure. She had received 2.5 mg of carvedilol and 2.5 mg of enalapril on admission. She gave written informed consent for this case report.

Blood pressure was 134/87 mmHg and heart rate was 104 bpm with sinus rhythm. Plasma B-type natriuretic peptide was 1637 pg/mL. Chest X-ray showed bilateral congestion (Fig. 1). Transthoracic echocardiography showed 47 mm of left ventricular end-diastolic diameter and 39% of left ventricular ejection fraction calculated by the modified Simpson's method with antero-septal severe hypokinesis. We initiated biphasic positive airway pressure therapy and intravenous administration of diuretics. We confirmed that she had no clinical reasons that might cause tachycardia, including infection, anemia, physical pain, and hypovolemia. Heart rate remained around 90 bpm and systolic blood pressure remained around 120 mmHg following the admission.

Fig. 1.

Chest X-ray on admission.

Calculation of ideal heart rate and initiation of heart rate reduction therapy

Transthoracic echocardiography was performed on admission, showing 201 ms of overlap length between E-wave and A-wave (Fig. 2A). Her ideal heart rate was calculated as 60 bpm, by substituting 231 ms of deceleration time in the previously proposed formula: 93 – 0.13 × [deceleration time (ms)] [4]. Cardiac index was non-invasively measured as 2.14 L/min/m², using AESCULON mini (Osypka Medical, Berlin, Germany) [5].

Fig. 2.

Trans-mitral Doppler echocardiography on admission (A) and day 5 (on ivabradine; B). On admission (A), heart rate was 104 bpm, and both E-wave and A-wave have considerable overlap with a length of 201 ms (red bar). Just before ivabradine therapy, echocardiographic parameters remained almost unchanged from those on admission (B). Following the 3-day ivabradine therapy (C), heart rate decreased to 55 bpm, and the overlap between E-wave and A-wave diminished. Deceleration time remained unchanged during the courses.

HR, heart rate; DcT, deceleration time; LVDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; SV, stroke volume.

*Cardiac index was estimated by using AESCULON mini (Osypka Medical, Berlin, Germany).

We decided to initiate 5.0 mg/day of ivabradine for >100 bpm of sinus tachycardia (Fig. 3). Beta-blocker could not be up-titrated given her persistent pulmonary congestion.

Fig. 3.

Time course following the hospitalization. Given sinus tachycardia refractory to beta-blocker therapy, ivabradine was initiated on day 3, followed by the immediate heart rate reduction.

NPPV, non-positive pressure ventilation; sBP, systolic blood pressure; BNP, B-type natriuretic peptide; HR, heart rate.

Just before ivabradine therapy, echocardiographic parameters remained almost unchanged from those on admission: overlap length was 178 ms and cardiac index was 2.17 L/min/m² (Fig. 2B).

Following heart rate reduction therapy

At 3 days following the initiation of ivabradine, the heart rate decreased to around 60 bpm. Transthoracic echocardiography showed no overlap between the two waves (Fig. 2C), accompanied by an improvement in cardiac index up to 2.31 L/min/m² as well as mitral regurgitation and left ventricular contractility. At day 10, plasma B-type natriuretic peptide level gradually decreased from 1637 pg/mL to 843 pg/mL and pulmonary congestion improved. Given the improvement in pulmonary congestion, the dose of diuretics was reduced and the dose of carvedilol was up-titrated, accompanied by further decrease in plasma B-type natriuretic peptide (down to 275 pg/mL on day 17).

She was discharged on day 25 without any symptomatic congestion with optimized heart rate. Three months following the index discharge, her left ventricular end-diastolic diameter decreased down to 44 mm and left ventricular ejection fraction increased up to 54%.

Discussion

Overlap between E-wave and A-wave and cardiac output

Our team previously hypothesized that cardiac output might be maximized when the overlap length between E-wave and A-wave at trans-mitral Doppler echocardiographic flow is “zero” [4]. Given that the overlap length had a linear association with heart rate and deceleration time, we proposed a formula to calculate ideal heart rate for each individual by substituting zero in the overlap length: [ideal heart rate (bpm)] = 93 – 0.13 × [deceleration time (ms)] [4].

In this case, we confirmed that cardiac output increased and cardiac contractility improved as the overlap length between E-wave and A-wave minimizes, although we should validate this finding in a large-scale study. Of note, during the three-day ivabradine therapy, other therapies including bilevel positive airway pressure therapy and diuretics administration remained continued and unchanged.

Acute effect of heart rate reduction therapy

The acute effect of heart rate reduction therapy remains unknown. Persistent tachycardia would deteriorate hemodynamics and impair cardiac function [6]. First-line therapy for the rate control would be beta-blocker [7]. However, we hesitated to up-titrate it given her pulmonary congestion. Heart rate reduction therapy using ivabradine with a target of 60 bpm improved cardiac output and improved pulmonary congestion without hemodynamic deterioration.

A patient who is intolerant to beta-blocker therapy due to hypotension might also be another good candidate for ivabradine therapy. Improvement in systemic blood pressure due to the increased cardiac output might give us a chance to further up-titrate beta-blocker.

Patients with acute decompensated heart failure often have tachycardia to compensate impaired cardiac function. In our theory, “overlap” of both waves would indicate unnecessary tachycardia, and such a tachycardia should be improved to minimize the overlap. On the contrary, too much heart rate reduction might rather decrease cardiac output and deteriorate hemodynamics given unnecessarily prolonged diastole phase. This is a rationale why we propose the calculation of ideal heart rate and alert too much heart rate reduction. Another note is that we should exclude any reasons that cause tachycardia and require specific managements, including infection and anemia, as we did.

Implication of ideal heart rate-guided heart rate reduction therapy

The implication of long-term ivabradine therapy in patients with heart failure under the guide of calculated ideal heart rate remains unknown. Optimized heart rate might maximize cardiac output and facilitate cardiac reverse remodeling by preserving potential energy that improves mortality and morbidity. Prospective randomized controlled trials versus conventional ivabradine therapy without any heart rate targets would be the next concern. In general, a relatively higher heart rate is preferred in patients with heart failure with preserved ejection fraction. The ideal heart rate for such cohorts also remains a future concern.

Limitation

We assessed the change in echocardiographic parameters and cardiac output during the 3-day ivabradine therapy. We waited for 3 days until ivabradine started to take effect. However, we cannot completely exclude the effects of other concomitant treatments on the outcome.

Disclosure

TI receives grant support from JSPS KAKENHI: JP20K17143. Other authors have no statements.