Haemodynamic effects of acute intravenous landiolol in Takotsubo cardiomyopathy with dynamic left ventricular outflow tract obstruction

Abstract

Takotsubo cardiomyopathy (TCM) leads to serious left ventricular outflow tract (LVOT) obstruction with cardiogenic shock in 6%–20% of cases. The onset of LVOT obstruction, coupled with mitral regurgitation resulting from systolic anterior motion of mitral valve leaflets, can lead to haemodynamic instability in addition to severely impaired systolic function. We describe three patients who experienced chest discomfort following emotional stress. These patients displayed pronounced abnormalities on ECGs, insignificant obstructive coronary disease and haemodynamic instability due to LVOT obstruction. The infusion of landiolol, a short-acting beta blocker, was effective in releasing the gradient. Dynamic outflow obstruction is the major predictor of haemodynamic collapse. We suggested that an early identification of this complication in hypotensive patients with suspected TCM could be of utmost importance to optimise the therapeutic approach in the acute setting.

Background

Takotsubo cardiomyopathy (TCM) is known for its unique clinical features and pathology. The early TCM case series reported excellent short-term and long-term prognoses.^{1 2} However, recent evidence has raised concerns regarding the benign nature of TCM.^{3 4} The prognosis is generally favourable, depending on whether complications arise during the acute phase of the disease. Dynamic left ventricular outflow tract (LVOT) obstruction has been identified as the main predictor of haemodynamic collapse.⁵ β-blockers are considered effective, but they must be administered with caution if cardiogenic shock is suspected to occur.^6–8 Short-acting β-blockers, such as landiolol, can be quickly increased or decreased by adjusting the dose,⁹ and are considered to be useful drugs in cases of cardiogenic shock. In this study, we reported three cases in which landiolol treatment was successful and discussed its role in the management of TCM with LVOT obstruction.

Case presentation

Case 1

A mid-60s woman with hypertension was admitted to the emergency department with dizziness and sweating. She was feeling well until the day of admission when, while riding her bicycle to work as usual, she suddenly experienced dizziness, sweating and difficulty moving her body. Her blood pressure was 84/57 mmHg, with a heart rate of 90 beats per min (bpm), which was irregular. The respiration rate was 30 breaths per minute, and there was deoxygenation despite the patient receiving 10 L of oxygen per minute via a reservoir mask. The percutaneous oxygen saturation was measured at 100%. Her ECG showed atrial fibrillation with normal axis and ST-segment elevations in V4–V6 leads without reciprocal changes. Troponin-T level was 96 ng/L (>14 ng/L). Her transthoracic echocardiography (TTE) showed an ejection fraction of over 50%, with severe hypokinesia in the mid-apical segment of the left ventricle and hyperkinesia in the basal portion of the left ventricle and the systolic anterior motion of the mitral valve. Emergent coronary angiography (CAG) revealed normal coronary arteries. Left ventriculography (LVG) confirmed the typical apical ballooning with hyperkinesis of the left ventricular basal wall. Pull-back pressures confirmed the presence of an LVOT gradient with a peak-to-peak gradient of 51 mmHg (figure 1). Her subsequent treatment regimen comprised a short-acting beta blocker, landiolol infusion, judicious fluid resuscitation and a short course of intravenous noradrenaline. Renal blood flow could not be secured, and urine output dropped to less than 10 mL/hour (0.25 mL/kg/hour). Therefore, we inserted an intra-aortic balloon pumping device (IABP). On day 2, the echo-derived peak LVOT gradient improved from 96 mmHg to 10 mmHg (figure 2A), and the hypokinesia of the mid-apical posterior and inferior portions also improved (figure 2A), although the hyperkinesia of the basal left ventricle persisted. Her heart rate was stabilised at 80 bpm, and her systolic blood pressure improved. IABP and noradrenaline were discontinued on day 3. On day 11, TTE showed that mid-apical hypokinesia had almost disappeared, with partial hypokinesia remaining in the apical portion, and LVOT obstruction had also diminished. She was discharged on day 14 without any other complications (figure 3A).

Figure 1.

Pullback of the pigtail catheter from the apex to the basal tract of the ventricle indicates an intraventricular pressure gradient, with a peak-to-peak gradient of 51 mm Hg in the left ventricular outflow tract. LV, left ventricular.AO: Aortic pressureSpO2: Saturation of percutaneous oxygen

Figure 2.

Systolic blood pressure and left ventricular outflow gradient before and after administration of intravenous landiolol infusion.

Figure 3.

(A–C) Clinical course.NAD: Noradrenaline

Case 2

A late 80s woman was admitted to the general surgery department of our hospital with a diagnosis of left upper lobe bronchopneumonia. She also had a medical history of pancreatic cancer (cT1cN0M0, stage IA) and underwent a total pancreatectomy a year before. She had undergone postoperative chemotherapy for recurrence. Due to pneumonia, she was treated with ampicillin/sulbactam 3 g every six hours for 11 days before the heart event, and there was continuous improvement in her general condition. On day 11, however, she had chest discomfort, and ECG showed sinus rhythm with normal axis and newly appearing ST-segment elevations at V4–V6 leads. Troponin-T level was 26 ng/L. Her TTE showed severe MR and extensive akinesia in both the apical and mid-portions, as well as hyperkinesia in the basal portion of the left ventricle, with a remarkably elevated echo-derived peak LVOT gradient of 190 mmHg (peak velocity of LVOT of the 6.9 m/s) (figure 2B). After the confirmation of the absence of coronary artery disease by emergent CAG, cautious-volume administration and treatment with landiolol (initially of 3 µg/kg/min and finally of 10 µg/kg/min intravenously) were started. Subsequently, her blood pressure, urine output and clinical state improved dramatically (figure 3B). Repeated TTE revealed improvement in the LV function and resolution of the LVOT gradient to 18 mmHg (2.1 m/s of peak velocity) (figure 2B). We switched from intravenous landiolol to patch bisoprolol of 2 mg and finally to oral bisoprolol of 1.25 mg. She was discharged on day 34.

Case 3

A late 50s woman who had a panic attack was transferred to the ear, nose and throat department at our hospital because of nasal bleeding. She lost consciousness and experienced generalised seizures within 20 min of arrival. Her blood pressure was 50/30 mmHg, and her heart rate was 59 bpm. Her ECG showed sinus rhythm with a normal axis and newly appearing ST-segment elevations in her left precordial leads. Her TTE showed severe hypokinesia of the mid-apical segment of the left ventricle. Normal CAG, but LVG showed the presence of severe apical dyskinesis with basal hyperkinesis. The echo-derived peak LVOT gradient was 102 mm Hg (figure 4), which disappeared dramatically after the intravenous administration of 3 µg/kg/min of landiolol (figure 2C).

Figure 4.

Continuous wave Doppler represents intraventricular peak gradient of 102 mmHg (see arrow). LVOT, left ventricular outflow tract.

At discharge, her TTE revealed normal LV function (figure 3C). At 1-months follow-up, the LV function and wall motion had completely normalised.

Outcome and follow-up

Case 1 and case 3: After continued oral bisoprolol treatment, the patient was followed up 6 months after hospital discharge at a cardiology outpatient clinic.

But in case 2, she died 2 months later from the underlying disease (pancreatic cancer).

Discussion

We were able to save the lives of three patients who experienced cardiogenic shock due to TCM with LVOT obstruction using landiolol infusion. Due to its ultra-short action, landiolol can be administered while closely monitoring vital signs and adjusting dosage as necessary, providing both safety and efficacy.

The prevalence of LVOT obstruction in a large cohort of TCM patients was reported to range between 7% and 25%.^{4 10–13} According to a previous report, around 10% of patients showed CS, and the presence of LVOT as a predictor was reported to be OR 4.62 (1.456–14.62).⁴ Positive inotropes should be avoided, and rather than volume depletion, careful fluid administration under haemodynamic monitoring should be considered.^{10 14} β-blockers are effective in cases of cardiogenic shock with LVOT gradient, but caution must be exercised during their use because they are often associated with heart failure in clinical practice. In addition, animal experiments have reported that the pressor effect of norepinephrine may be abolished. Therefore, a cardio selective beta-1-blocker with a short half-life could represent an important agent for the acute management of TCM.¹⁵ Selective beta-1-blockade has been shown to effectively reduce the intraventricular gradient, LV basal hyperkinesis and subsequent systolic anterior motion of the mitral valve.¹⁶

Currently, esmolol and landiolol are the only two ultra-short-acting selective β1-blockers available in clinical practice. Short-acting beta-blockers that can be injected intravenously include esmolol and landiolol. Their blood half-life is 9 and 4 min, and their β1 selectivity is 20 and 277, respectively.⁹ Such short-acting beta-blockers have several advantages. First, their effects disappear quickly once stopped. Second, adjusting the dose to reach the target heart rate is easier, and third, the drug follows a one-compartment model for distribution, thus facilitating the estimation of blood concentration during continuous dosage. A report comparing esmolol and landiolol found that landiolol did not significantly reduce mean blood pressure, while esmolol caused a reduction of approximately 40% at single doses that equally reduced heart rate.¹⁷ In animal experiments, high-dose landiolol did not increase left ventricular end diastolic pressure (LVEDP) with decreased left ventricular contractile force; however, esmolol significantly decreased left ventricular contractile force and increased LVEDP.¹⁸ Compared with esmolol, landiolol has weaker inotropic action, and its main effect is chronotropic, with an earlier onset of chronotropic action compared with inotropic action. Therefore, landiolol is considered a drug that can be used safely when a decrease in blood pressure is to be avoided as much as possible. It is important to carefully determine the appropriate dose while closely monitoring fluctuations in vital signs and providing sufficient fluid resuscitation.

Migliore et al showed in a single case report that intravenous metoprolol (a beta-1-cardio-selective blocker with 4–6 hours half-life) administered to a mid-60s woman with TCM and LVOT obstruction significantly reduced the intraventricular gradient from 40 to 20 mmHg.¹⁹ Furthermore, in a multicentre Japanese study by Yoshioka et al,²⁰ propranolol (a non-selective beta blocker with 4–5 hours half-life) was administered to 13 patients with TTC. Out of these, eight patients presented with TTC and mid-ventricular obstruction; and intravenous infusion reduced the intraventricular gradient from 90±42 to 22±9 mmHg in them. Previous reports have suggested that low doses of esmolol may be useful in this challenging scenario.⁸ Accordingly, the dose of landiolol hydrochloride can be increased to 10 µg/kg/min.²¹

Learning points.

• Our three female patients showed Takotsubo cardiomyopathy (TCM) with haemodynamic instability due to left ventricular outflow tract (LVOT) obstruction.

• We suggested that early identification of this complication in hypotensive patients with suspected TCM could be of utmost importance to optimise the therapeutic approach in the acute setting.

• Suppression of ventricular contractility with short-acting beta-blocker infusion led to the resolution of the LVOT gradient and subsequent clinical improvement.

Ethics statements

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