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\begin{document}

\title{Successful treatment with ivabradine in a \selectlanguage{greek}β-\selectlanguage{english}blocker refractory patient
with acute decompensated HFrEF\selectlanguage{english}}



\author[1]{Tomoko Inoue}%
\author[1]{Keiji Matsunaga}%
\author[1]{Waki Kobayashi}%
\author[1]{Tetsuo Minamino}%
\affil[1]{Faculty of Medicine, Kagawa University}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Ivabradine is an established treatment for chronic heart failure with
reduced ejection fraction (HFrEF) but not for acute heart failure.
\selectlanguage{greek}β-\selectlanguage{english}blocker up-titration is often not possible because of its negative
inotropic effect (NIE). Ivabradine has no NIE; therefore, it may be
preferred over \selectlanguage{greek}β-\selectlanguage{english}blockers in patients with acute decompensated HFrEF.%
\end{abstract}%



\sloppy


\selectlanguage{greek}\textbf{Successful treatment with ivabradinein a β-blocker refractory
patient with acute decompensated HFrEF}\selectlanguage{english}

Tomoko Inoue\textsuperscript{1}, Keiji Matsunaga\textsuperscript{1},
Waki Kobayashi\textsuperscript{1}, Tetsuo Minamino\textsuperscript{1}

\textsuperscript{1}Department of Cardiorenal and Cerebrovascular
Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan

\textbf{Correspondence}

Keiji Matsunaga,

Department of Cardiorenal and Cerebrovascular Medicine, Faculty of
Medicine, Kagawa University, 1750-1 Ikenobe, Mikicho, Kita-gun, Kagawa
761-0793, Japan

Phone: +81-87-891-2150

Fax: +81-87-891-2152

E-mail: matsunaga.keiji@kagawa-u.ac.jp, inoue.tomoko@kagawa-u.ac.jp,
tomo-inoue@med. kagawa-u.ac.jp, minamino.tetsuo.gk@kagawa-u.ac.jp

\textbf{Data availability statement}

All data generated or analyzed during this study are available as part
of the article, and no additional source data are required.

\textbf{Funding Statement}

None.

\textbf{Conflict of interest disclosure}

None to declare.

\textbf{Ethics approval statement}

This manuscript was written according to the world medical association
declaration of Helsinki.

\textbf{Patient consent statement}

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy.

\textbf{Abstract}

Ivabradine is an established treatment for chronic heart failure with
reduced ejection fraction (HFrEF) but not for acute heart failure.
\selectlanguage{greek}β-\selectlanguage{english}blocker up-titration is often not possible because of its negative
inotropic effect (NIE). Ivabradine has no NIE; therefore, it may be
preferred over \selectlanguage{greek}β-\selectlanguage{english}blockers in patients with acute decompensated HFrEF.

\textbf{Key Clinical Message}

Due to the negative inotropic effect (NIE) of \selectlanguage{greek}β-\selectlanguage{english}blockers, their
up-titration is often not possible in patients with acute decompensated
HFrEF. Since ivabradine has no NIE, it may be preferred over \selectlanguage{greek}β-\selectlanguage{english}blockers
in such cases.

\textbf{Introduction}

Ivabradine is a selective I\textsubscript{f} channel inhibitor that
reduces only heart-rate and is an established treatment for chronic
heart failure with reduced ejection fraction
(HFrEF).\textsuperscript{1-3} Ivabradine has been reported to reduce
hospitalizations for heart failure and cardiovascular deaths similar to
beta-blockers, but not for its effect on acute decompensated heart
failure (ADHF).\textsuperscript{4} Inappropriate tachycardia associated
with HFrEF is a clinical symptom of ADHF, and appropriate initial
treatment is important to improve prognosis.

Considering the available evidence in chronic heart failure, \selectlanguage{greek}β-\selectlanguage{english}blockers
are often used to treat ADHF with inappropriate tachycardia. However,
patients often experience intolerance to \selectlanguage{greek}β-\selectlanguage{english}blockers because of its
negative inotropic effect (NIE), which demands alternative treatments
without NIE for ADHF with inappropriate tachycardia in clinical
practice. In this study, we have reported a case of \selectlanguage{greek}β-\selectlanguage{english}blocker refractory
patient with acute decompensated HFrEF with hypotension due to
inappropriate sinus tachycardia successfully treated with ivabradine.
Thus, we believe that ivabradine may play an important role in the acute
heart failure treatment.

\textbf{Case history/Examination}

A man in his 50s who had been treated for cancer therapy-related cardiac
dysfunction (CTRCD) with low left ventricular ejection fraction (LVEF)
was admitted to our hospital because of ADHF. Fourteen years ago, he
received chemotherapy consisting of rituximab (total 1500
mg/m\textsuperscript{2}), cyclophosphamide (total 5200
mg/m\textsuperscript{2}), doxorubicin (total 360
mg/m\textsuperscript{2}), vincristine, and prednisolone for malignant
lymphoma. The next year, the patient underwent consolidation therapy,
autologous transplantation, and radiotherapy (40 Gy in 27 fractions) and
has been in remission since then.

On admission to the previous hospital, he had blood pressure of 90/66 mm
Hg and heart rate of 120 bpm with regular rhythm. Subjective symptoms,
such as palpitations and shortness of breath, were equivalent to New
York Heart Association (NYHA) class IV. The patient had no infection and
trauma before the admission.

The patient was administered a \selectlanguage{greek}β-\selectlanguage{english}blocker carvedilol at a dose of 3.75
mg/day. Due to inappropriate tachycardia caused by hemodynamic
instability, the carvedilol dose was increased. However, heart-rate
reduction was not achieved because the NIE of the \selectlanguage{greek}β-\selectlanguage{english}blocker exacerbated
hypotension.

\textbf{Differential diagnosis, investigations and treatment}

On admission to our hospital, his blood pressure was 84/62 mm Hg; his
heart-rate was 120 bpm. An electrocardiogram (ECG) revealed sinus
tachycardia with a narrow QRS duration, and the heart-rate was
\textgreater{}100 bpm (Figure 1). The chest x-ray film showed a
cardiothoracic ratio of 42\%, indicating the absence of pulmonary
congestion or pleural effusion. Echocardiography showed a left
ventricular end-diastolic diameter of 55 mm and diffuse hypokinesis with
an LVEF of 24\%. The left atrial diameter was 40 mm, and the overlap of
E and A waves in transmitral flow was revealed (Figure 2).

On admission, biochemical analysis showed blood urea nitrogen,
creatinine, eGFR, and BNP levels of 55.3 mg/dL, 1.88 mg/dL, 30
mL/min/1.73 m\textsuperscript{2}, and 120 pg/mL, respectively.
Thyroid-stimulating hormone, FT4 levels were within normal ranges. The
serum creatine kinase level was 50 U/L (CK-MB \textless{} 4 ng/mL). The
Holter ECG showed only sinus tachycardia and did not detect atrial
fibrillation, non-sustained ventricular tachycardia and paroxysmal
supraventricular tachycardia.

Involvement of thyroid function as a cause of sinus tachycardia was
ruled out. Coronary angiography was performed in the previous hospital
and showed no stenosis or obstruction, ruling out the possibility of
heart failure due to ischemic heart disease. Based on the investigation,
we confirmed that inappropriate sinus tachycardia caused ADHF in the
patient with HFrEF. After admission to our hospital, inappropriate sinus
tachycardia persisted, and his brain natriuretic peptide (BNP) level
increased to 303 pg/mL.

\textbf{Outcome and follow-up}

Since the symptoms of heart failure persisted, and his heart-rate was
over 70 bpm despite the treatment with the maximum tolerated dosage of
carvedilol, the patient was administered 5 mg/day of ivabradine per os.
After 10 days, his heart-rate decreased to \textless{}100 bpm, and his
systolic blood pressure recovered to approximately 110 mm Hg. After we
increased the ivabradine dosage to 10 mg/day, his heart-rate further
decreased to 70 bpm without hypotension. His heart failure symptoms also
improved and corresponded to NYHA Class III. Echocardiography showed
that the LVEF improved to 36\% without the overlap of E and A waves
(Figure 3). After three months of ivabradine administration, his heart
failure symptoms improved to NYHA Class II with a BNP level of 12 pg/mL,
and echocardiography showed 56\% improvement in the LVEF (Figure 4).

\textbf{Discussion}

ADHF with inappropriate tachycardia is a clinical symptom of HFrEF. With
an elevated heart-rate, ventricular contractility increases in the
normal myocardium, whereas it decreases in the failing
myocardium.\textsuperscript{5} Consequently, inappropriate tachycardia
in heart failure induces hypotension and hemodynamic instability. In our
case, the patient's heart-rate was \textgreater{}100 bpm and the
echocardiography showed the overlap of E and A waves, which was
suspicious for inappropriate sinus tachycardia.

\selectlanguage{greek}β-\selectlanguage{english}blockers are not only a key agent in the management of chronic heart
failure, but also the most common initial therapy for inappropriate
sinus tachycardia.\textsuperscript{3,6} However, they cause temporary
symptomatic hypotension, low cardiac output states, and worsening heart
failure due to their NIE.\textsuperscript{7} \selectlanguage{greek}β-\selectlanguage{english}blockers are associated
with 41\% relative increase in the risk of hypotension, and low systolic
blood pressure (\textless{}120 mm Hg) is associated with a high risk of
in-hospital and post-discharge mortality.\textsuperscript{8,9} Because
these risks are anticipated to increase further, especially during ADHF,
the \selectlanguage{greek}β-\selectlanguage{english}blocker up-titration was not possible for inappropriate sinus
tachycardia that led to hemodynamic instability in the patient with
HFrEF.

In contrast, ivabradine is the specific heart-rate lowering agent
without NIE, while preserving ventricular contractility in chronic heart
failure.\textsuperscript{10} The absence of an NIE is an important
consideration when selecting treatment for ADHF. Ivabradine may be a
more appropriate treatment, especially for patients with HFrEF suffering
from inappropriate sinus tachycardia leading to ADHF. The CONSTATHE-DHF
study reported ivabradine as a potentially useful treatment for patients
with ADHF because it reduces heart-rate while improving left and right
ventricular functions.\textsuperscript{11} Although the current
indication for ivabradine is based on the results of the SHIFT trial,
this study did not include patients who were discharged from the
hospital for ADHF; therefore, the effects of ivabradine in these
patients were unclear. However, the ETHIC-AHF trial suggested that early
therapy with ivabradine is feasible and safe in patients with ADHF in
HFrEF.\textsuperscript{12} The SHIFT-AHF trial, which involves
ivabradine administration in patients with ADHF, is ongoing. The results
of this trial are expected, and our case suggests that ivabradine may be
preferable for patients with ADHF and HFrEF.

Another reason for selecting ivabradine for ADHF is its potential to
intervene earlier than \selectlanguage{greek}β-\selectlanguage{english}blockers in long-term prognosis. \selectlanguage{greek}β-\selectlanguage{english}blockers are
associated with survival benefits in stable chronic heart failure. While
the use of \selectlanguage{greek}β-\selectlanguage{english}blockers significantly improves LVEF, reverses left
ventricular maladaptive remodeling, and reduces all-cause mortality from
months to years,\textsuperscript{13} only a small percentage of patients
with chronic heart failure can achieve the optimal dose of \selectlanguage{greek}β-\selectlanguage{english}blockers
due to their NIE. For example, in the SHIFT trial, only 25\% patients
were on optimal \selectlanguage{greek}β-\selectlanguage{english}blocker doses.\textsuperscript{3} In addition,
although heart-rate reduction is associated with the use of \selectlanguage{greek}β-\selectlanguage{english}blockers,
no correlation with the dose of these agents has been found. In fact,
the percentage of patients who achieved an optimal heart-rate with
\selectlanguage{greek}β-\selectlanguage{english}blocker administration is small.\textsuperscript{14} For heart-rate
reduction, higher than the optimal doses of \selectlanguage{greek}β-\selectlanguage{english}blockers are mostly
required, but hemodynamic instability in patients with ADHF prevents
their administration and up-titration. However, earlier administration
of \selectlanguage{greek}β-\selectlanguage{english}blockers is desirable to improve long-term prognosis. Ivabradine
also has the effect of reducing hospitalizations for heart failure and
cardiovascular deaths. In the previous report, ivabradine showed not
only a prognostic benefit for heart-rate control, but also a prognostic
significance for the time required to achieve this
control.\textsuperscript{15} In patients with ADHF, even if hemodynamic
instability is present, administration of agents as soon as possible
after admission is essential to improve the prognosis of heart failure.
Therefore, ivabradine may be preferred over \selectlanguage{greek}β-\selectlanguage{english}blockers in these
patients.

In our patient, CTRCD was the underlying cause of heart failure. A
common manifestation of radiation-induced heart disease is
pericarditis.\textsuperscript{16} Pericarditis causes diastolic
dysfunction. In patients with diastolic dysfunction, due to constrictive
pericarditis, appropriate heart-rate is associated with less
heart-failure recurrences.\textsuperscript{17} Our patient had diastolic
dysfunction combined with inappropriate sinus tachycardia, leading to
ADHF. However, it is unclear whether ivabradine has a beneficial effect
in all such patients.

\textbf{Conclusion}

\selectlanguage{greek}β-\selectlanguage{english}blockers are commonly used to treat ADHF with inappropriate
tachycardia. Due to its NIE, its up-titration is not possible in the
case of inappropriate sinus tachycardia, which leads to hemodynamic
instability in a patient with HFrEF. Therefore, administration of
ivabradine may be preferable to \selectlanguage{greek}β-\selectlanguage{english}blockers in patients with ADHF, who
have inappropriate sinus tachycardia with HFrEF, as it improves
long-term prognosis without NIE.

\textbf{Acknowledgements}

The authors thank Hiromi Nakaishi for technical assistance in performing
echocardiography in the patient.

\textbf{Author contributions}

TI: involved in analysis and interpretation of the patient's data;
conception, design, and drafting of the manuscript. KM: involved in
conception, design, critical feedback, and revision of the manuscript.
WK: involved in analysis and interpretation of the patient's data and
revision of the manuscript.

TM: involved in revision and final approval of the manuscript. All
authors discussed the case and commented on the manuscript at all
stages.

\textbf{References}

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2. Fox, K., Ford, I., Steg, P. G., Tendera, M., Ferrari, R., and
BEAUTIFUL Investigators. Ivabradine for patients with stable coronary
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6. Huizar, J. F., Ellenbogen, K. A., Tan, A. Y., and Kaszala, K.
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Am Coll Cardiol} . 2019;73(18):2328-2344.

7. McDonagh, T.A., Metra, M., et al. ESC Guidelines for the diagnosis
and treatment of acute and chronic heart failure: developed by the Task
Force for the diagnosis and treatment of acute and chronic heart failure
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8. Ko, D. T., Hebert, P. R., Coffey, C. S., et al. Adverse effects of
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overview of randomized trials. \emph{Arch Intern Med} .
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9. Nikolovska Vukadinovi\selectlanguage{polish}ć, \selectlanguage{english}A., Vukadinovi\selectlanguage{polish}ć, \selectlanguage{english}D., Borer, J., et al.
Heart-rate and its reduction in chronic heart failure and
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10. DiFrancesco, D., and Camm, J.A. Heart-rate lowering by specific and
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11. Lofrano-Alves, M. S., Issa, V. S., Biselli, B., Chizzola, P.,
Ayub-Ferreira, S. M., and Bocchi, E. A. Control of sinus tachycardia as
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12. Su, Y., Ma, T., Wang, Z, et al. Efficacy of early initiation of
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14. Maggioni, A. P., Dahlstr\selectlanguage{ngerman}öm, U., Filippatos, G, et al.
EURObservational research programme: the heart failure pilot survey
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15. Böhm, M., Borer, J., Ford, I., et al. Heart-rate at baseline
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Cardiol.} 2013;102(1):11-22.

16. Yusuf, S. W., Sami, S., \& Daher, I. N.Radiation-induced heart
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17. Imamura, T., and Kinugawa, K. Optimal heart rate modulation using
ivabradine. \emph{Int Heart J} . 2021;62(4):717-721.\selectlanguage{english}
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