Two cases of dilated cardiomyopathy with blood pressure-limited tolerability of cardioprotective agents improved by ivabradine

Abstract

The titration of cardioprotective agents is essential for successful treatment of heart failure (HF) patients with reduced left ventricular ejection fraction. However, hypotension is one of the limiting factors for titration. Ivabradine reduces heart rate without compromising systolic function by prolonging diastolic filling time. Herein two cases of dilated cardiomyopathy (DCM) are presented in which ivabradine improved blood pressure (BP)-limited tolerability and allowed for further titration of cardioprotective agents. In both cases, the introduction of ivabradine raised the BP, which permitted further increase of the dose of renin-angiotensin system inhibitors or beta-blockers. One major hypothesized mechanism of ivabradine-induced BP elevation has been postulated to be an increase in stroke volume due to prolonged ventricular diastolic filling time. However, ivabradine is not expected to increase BP for all HF patients. In those with small and poorly compliant ventricles with severe diastolic or restricted dysfunction, decreased heart rate and prolonged diastole may excessively suppress compensatory mechanisms, and thus may not lead to increased cardiac output and BP. In contrast, ivabradine potentially increases BP and improves BP-limited tolerability of cardioprotective agents in DCM patients with a large and compliant heart. In addition, subsequent titration of cardioprotective agents may provide additional cardiac reverse remodeling.

Learning objective: Ivabradine is usually used for heart failure patients with reduced ejection fraction when the tolerability of cardioprotective agents is maximized. This agent has no direct cardiac contractility-suppressing action. It potentially increases blood pressure and improves tolerability of cardioprotective agents in patients with a large and compliant heart such as dilated cardiomyopathy. Furthermore, subsequent titration of cardioprotective agents may provide additional cardiac reverse remodeling.

Introduction

Ivabradine, an I_f or “funny” current inhibitor, works at the sinus node to reduce heart rate (HR) without compromising systolic function by prolonging diastolic filling time [1]. Global guidelines recommend ivabradine to prevent future cardiac events for heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF) and a high sinus rate despite receiving the maximum dose of cardioprotective agents [2,3]; however, hypotension is one of the limiting factors for titration of cardioprotective agents. Presented herein are two cases of dilated cardiomyopathy (DCM) in which ivabradine improved blood pressure (BP)-limited tolerability of cardioprotective agents.

Case 1

A 39-year-old man was evaluated for shortness of breath and general malaise. Significant findings were BP 102/78 mmHg, LVEF 22%, left ventricular end-diastolic diameter (LVDd) 62 mm, and brain natriuretic peptide (BNP) concentration 566 pg/mL. Treatment for HF was started with furosemide 20 mg/day, imidapril 2.5 mg/day, and bisoprolol 1.25 mg twice daily.

Four months later, the patient was admitted for acute decompensated HF with dyspnea. His BP was 90/68 mmHg. Chest imaging confirmed pleural effusion. Secondary cardiomyopathies were ruled out by a coronary angiography and a detailed examination of the myocardium, and he was diagnosed with DCM. With intravenous furosemide and intravenous dobutamine, his symptoms of congestion resolved. However, once the dobutamine was discontinued, he developed worsening liver and renal function and symptoms related to low systemic perfusion. His bisoprolol dose was titrated to maximum tolerability (0.625 mg twice daily) under dobutamine support, and he was discharged. On discharge, his LVEF was 15% without improvement and LVDd remained at 66 mm. During the hospitalization, spironolactone 25 mg once daily was introduced, but discontinued due to hyperkalemia. However, one month later, he was hospitalized again due to worsening HF.

At subsequent outpatient examination, he presented with New York Heart Association (NYHA) class IIm symptoms; BP was 94/62 mmHg and HR was 87 bpm with sinus rhythm; and BNP concentration was 298.5 pg/mL. Echocardiography showed LVEF of 17%, LVDd of 67.0 mm, and grade I of mitral regurgitation (MR). Ivabradine 2.5 mg twice daily was started to reduce HR.

His subsequent trajectory is shown in Fig. 1. After 4 weeks, his HR decreased by 10 bpm and systolic BP increased to 106 mmHg. Eight weeks later, his HR dropped to 73 bpm and systolic BP rose to 122 mmHg. Based on an improved BP-limited tolerability, the bisoprolol was increased to 1.25 twice daily. After 12 weeks, his HR further decreased to 65 bpm, but systolic BP was maintained at 130 mmHg. After 16 weeks, echocardiography showed LVEF was 44.8%, LVDd had improved to 56 mm, and BNP had decreased to 36.2 pg/mL. Stroke volume (SV) had increased to 69 mL from 34 mL at the time of ivabradine introduction. His MR remained at grade I.

Fig. 1.

Trajectories after ivabradine introduction in clinical findings, cardioprotective agents (A), and echocardiographic images (B) in Case 1.

NYHA, New York Heart Association; BNP, brain natriuretic peptide; LVEF, left ventricular ejection fraction; LVDd, left ventricular end-diastolic diameter; E/e’, a ratio of early-diastolic left ventricular inflow velocity (E) to e′; MR, mitral regurgitation; SV, stroke volume; BP, blood pressure; HR, heart rate; QD, quaque die (once daily); BID, bis in die (twice daily).

Case 2

A 64-year-old woman with diabetes mellitus and no previous cardiac presentations was admitted for acute HF. Significant findings were BP 92/70 mmHg, LVEF 30%, and LVDd 62 mm. Complete examination including coronary angiography and myocardial biopsy revealed a diagnosis of DCM. Furosemide 20 mg twice daily, carvedilol 10 mg twice daily, and spironolactone 25 mg once daily, were initiated. Due to hypotension, renin-angiotensin system inhibitors could not be introduced. After treatment of HF with furosemide and dobutamine, she was successfully discharged. Her pre-discharge BNP level was 950 pg/mL.

The patient was hospitalized 1 year later for worsening HF. On this second hospitalization, furosemide, and spironolactone were discontinued and azosemide 90 mg once daily was started.

Again, 1 year after her second hospitalization, she was readmitted for worsening HF. On this third hospitalization, she was treated with intravenous diuretics, dobutamine, and milrinone. Because of complete left bundle branch block, cardiac resynchronization therapy was introduced. Pacing provided a ventricular synchronized effect on the autologous pulse with A-sense V-pace, and HR was over 85 bpm. However, pre-discharge hemodynamic examination revealed a cardiac index of 1.92 L/min/m² and pulmonary artery wedge pressure of 27 mmHg. Thus, pimobendan 0.625 mg twice daily was started and carvedilol was reduced to 5 mg twice daily. Her pre-discharge BNP concentration was 595 pg/mL and LVEF had decreased to 20%.

On subsequent outpatient follow-up, her symptoms remained at NYHA class IIm, BNP concentrations remained around 200 pg/mL, and systolic BP was still around 90–100 mmHg.

At 3 months after her last outpatient follow-up, she presented with abnormal liver function from low output perfusion, and pimobendan was increased to 2.5 mg twice daily. Before long, improved blood data were obtained. However, symptoms remained NYHA class IIm with BP of 92/66 mmHg and HR of 92 bpm. Therefore, ivabradine 2.5 mg twice daily was introduced (Fig. 2). Her BNP concentration was 159.0 pg/mL.

Fig. 2.

Trajectories after ivabradine introduction in clinical findings, cardioprotective agents (A), and echocardiographic images (B) in Case 2.

NYHA, New York Heart Association; BNP, brain natriuretic peptide; LVEF, left ventricular ejection fraction; LVDd, left ventricular end-diastolic diameter; E/e’, a ratio of early-diastolic left ventricular inflow velocity (E) to e′; MR, mitral regurgitation; SV, stroke volume; BP, blood pressure; HR, heart rate; QD, quaque die (once daily); BID, bis in die (twice daily).

Four weeks later, her HR decreased to 87 bpm. Ivabradine was increased to 5 mg twice daily. Eight weeks later, her HR further decreased and systolic BP increased to 118 mmHg, and enalapril 1.25 mg once daily was started successfully. After 12 weeks, symptoms improved to NYHA class IIs and carvedilol was titrated to 10 mg twice daily by 20 weeks. At 28 weeks, echocardiography showed LVDd was slightly reduced to 54.2 mm, although LVEF was 21.6%. Her MR remained at grade I. The SV increased slightly from 28 mL to 36 mL.

Discussion

This report describes two cases of DCM with improved BP-limited tolerability of cardioprotective agents after initiation of ivabradine. These findings suggest that improved BP-limited tolerability may allow subsequent titration of cardioprotective agents and contribute to an improved prognosis in DCM.

Western guidelines recommend ivabradine to reduce cardiac events for stable patients with HF with reduced LVEF under guideline-directed medical therapy with a maximum tolerated dose of beta-blockers for a patient in sinus rhythm with a resting HR of >70 bpm [2,3]. In contrast, in Japan, ivabradine is indicated for patients with a resting HR of >75 bpm. The successful treatment of HF with reduced LVEF requires increasing cardioprotective agents to the maximum tolerated dose. However, hypotension is one of the limiting factors for titration of cardioprotective agents. Actually, in the SHIFT and J-SHIFT trials, 50%–66% of patients had hypotension as the reason for failure to reach the target dose of beta-blockers at the initiation of ivabradine [1,4]. In other words, most HF patients with reduced LVEF are unable to increase the dose of cardioprotective agents because of hypotension. If their BP-limited tolerability is improved, then they could be expected to receive higher doses of cardioprotective agents. In these two DCM cases, the introduction of ivabradine raised the BP, which permitted increasing doses of renin-angiotensin system inhibitors or beta-blockers.

Consistent with these cases, several studies have reported that ivabradine raises BP. In a study by Rimoldi et al., HR reduction by ivabradine was correlated with increased SV and central arterial pressure in patients with coronary artery disease [5]. Finsterer et al. reported the beneficial effect of ivabradine on BP elevation in a patient with cardiomyopathy associated with Becker muscular dystrophy [6]. Furthermore, even in patients with low cardiac output, ivabradine added after dobutamine administration additionally increased the systolic BP [7]. A recent systemic review and meta-analysis showed that ivabradine tends to slightly increase BP (+3.4 mmHg, p = 0.09), although not significantly [8].

Some hypothesized mechanisms have been postulated for ivabradine-induced BP elevation [9]. One major mechanism is an increase of SV. Reduction of HR, especially using ivabradine, prolongs diastolic filling time in the ventricle, thereby increasing SV. Elevated central BP is potentially associated with increased SV pumped into the aorta and may be pronounced, especially in patients with impaired Windkessel function. In our cases, SV was elevated early after ivabradine initiation. The increase in SV was also linked to an increase in pulse pressure. Furthermore, ivabradine has been reported to have a positive inotropic effect due to enhanced sarcoplasmic/endoplasmic reticulum calcium ATPase 2a activity, which may be mediated by increased phosphorylation of phospholamban [10].

Not all HF patients are expected to have an increased BP with ivabradine. Even if LVEF is preserved, in patients with small SV, a compensatory mechanism of HR elevation without an incomplete relaxation is required to maintain cardiac output. In such patients with small and poorly compliant ventricles and severe diastolic or restricted dysfunction, decreased HR and prolonged diastole may excessively suppress compensatory mechanisms, and, as a result, may not lead to increased cardiac output and BP. Thus, from the perspective of personalized medicine, it is necessary to clarify what type of patients can expect a beneficial BP effect.

In conclusion, ivabradine potentially increases BP and improves BP-limited tolerability of cardioprotective agents in DCM patients with a large and compliant heart. Subsequent titration of cardioprotective agents may provide additional cardiac reverse remodeling.

Declaration of Competing Interest

T.O. received lecture fees from Ono Yakuhin, Medtronics, Novartis, and Otsuka, and received research grants from Ono Yakuhin, Bayer, Daiichi-Sankyo, and Amgen Astellas. T.M. received lecture fees and unrestricted research grants from the Department of Cardiology at Nagoya University Graduate School of Medicine, Bayer, Daiichi-Sankyo, Dainippon Sumitomo, Kowa, MSD, Mitsubishi Tanabe, Boehringer Ingelheim, Novartis, Pfizer, Sanofi-Aventis, Takeda, Astellas, Otsuka, and Teijin. The other authors declare that they have no conflicts of interest.