Olprinone, phosphodiesterase III inhibitor, is useful for patients with severe acute heart failure due to takotsubo cardiomyopathy accompanied by subarachnoid hemorrhage

Introduction

A 53-year-old woman with recent severe headache was transferred to our emergency room because of sudden coma. Blood pressure (BP) was 65/40 mmHg and heart rate was 95 b.p.m. A cerebral computed tomography scan revealed subarachnoid hemorrhage (SAH) (Fig. 1). Angiogram showed a 6 mm ruptured aneurysm at the right internal carotid–posterior communicating artery (Fig. 1). Arterial blood gas analysis showed severe hypoxemia (pO₂ = 70 torr; FiO₂ = 1.0). Chest X-ray indicated normal-sized heart with severe pulmonary congestion (Fig. 2). Electrocardiogram revealed sinus tachycardia with ST elevation and inverted T wave in V₄, V₅, and V₆ (Fig. 2). Echocardiogram showed akinesis of the apex, as indicated in Figure 2. We diagnosed acute heart failure with cardiogenic shock due to takotsubo cardiomyopathy following SAH (Hunt and Kosnik grade III). Because of severe hypoxia due to severe pulmonary congestion, tracheal intubation and mechanical ventilation with 100% oxygen were needed.

In the intensive care unit, we detected the following hemodynamic and respiratory parameters: cardiac index (CI) = 1.9 L/min/m²; mean pulmonary arterial wedge pressure (mPAWP) = 22 mmHg; systemic vascular resistance index (SVRI) = 2203 dyne·s/m⁵/m²; SvO² = 60%; pO₂/FiO₂ = 70 mmHg. Pressure study revealed severe heart failure with cardiogenic shock.

Case

For cardiogenic shock, we did not choose intraaortic balloon pumping (IABP) because anticoagulant therapy should be avoided. We also did not use catecholamines, because they should not generally be used in takotsubo cardiomyopathy. Therefore, olprinone, a phosphodiesterase III (PDE III) inhibitor, was selected for the treatment of cardiogenic shock.

Olprinone was infused i.v. at the dose of 0.2 μg/kg/min. One hour after the initiation of olprinone, hemodynamics were substantially improved without any side-effects. Four hours later, olprinone dramatically improved hemodynamics and oxygenation: BP = 102/64 mmHg; heart rate = 106 b.p.m.; CI = 2.6 L/min/m²; mPAWP = 18 mmHg; SVRI = 2143 dyne·s/m⁵/m²; SvO₂ = 78%; pO₂/FiO₂ = 150 (Fig. 3).

Finally, the aneurysm was successfully clipped. Olprinone was discontinued after 3 days. Intratracheal tube was removed after 5 days. Left ventricular wall motion was normalized after 16 days. The patient was discharged after 26 days without any neurological dysfunction, and is now working as a maternity nurse.

Discussion

Takotsubo cardiomyopathy is characterized by acute left ventricular dysfunction with transient apical ballooning in absence of significant coronary artery disease.1 Typically, this condition is associated with sudden emotional or physical stress, accompanied by catecholamine surge, including SAH.2

Left ventricular abnormalities, including takotsubo cardiomyopathy, occurs in around 8% of cases of SAH in the ultra-early phase after onset.3 Some patients tend to be severe and the condition is often associated with pulmonary lung edema and hemodynamic instability, resulting in cardiogenic shock. In such cases, the management of cardiogenic shock is often very difficult. Catecholamine agents should be avoided whenever possible they have a causative role in the development of this cardiomyopathy.4 Intraaortic balloon pumping normally requires the use of anticoagulant agents, so IABP is difficult to use in patients with SAH.

Therefore, we chose olprinone, a specific PDE III inhibitor developed in Japan and extensively used in the treatment of acute heart failure. Olprinone has positive inotropic actions through the elevation of intracellular cAMP levels in cardiomyocytes.

There are many reports of heart failure due to takotsubo cardiomyopathy being treated with the calcium sensitizer levosimendan, a non-catecholamine inotrope that is not currently available in Japan, but there are few reports of treatment with a PDE III inhibitor. Padayachee reported that levosimendan was used successfully in takotsubo cardiomyopathy-related cardiogenic shock. They discussed that PDE III inhibitors may be problematic as they increase cAMP within cells, worsen myocardial stunning, and cause vasodilation resulting in hypotension.5 We are also concerned that olprinone may worsen hypotension because PDE III inhibitors have a vasodilatory effect. However, it has been reported that low-dose PDE III inhibitors exert a more potent positive inotropic effect and have a lesser effect on systemic vascular resistance than high-dose PDE III inhibitors.6 Consistent with previous report, in our case, low-dose olprinone increased cardiac output and only minimally decreased systemic vascular resistance. Therefore, worsening of hypotension did not occur after low-dose olprinone infusion. We observed hemodynamic stability, such as pulse pressure, SvO₂, and increased urine amount, accompanied with a decrease in mPAWP. However, it is necessary to carefully observe changes in CI and SVRI after treatment with low-dose PDE III inhibitor to avoid drug-induced shock.

The exact mechanism of takotsubo cardiomyopathy is still unknown, but disturbance of the calcium regulatory system has been indicated. This effect might be caused by supraphysiological levels of catecholamines, which stimulate β-adrenoreceptors and alter the expressions of calcium-regulatory protein genes. Sarcolipin regulates sarcoplasmic/endoplasmic reticulum calcium ATPase 2 by lowering its affinity for Ca²⁺, and is frequently overexpressed in stress cardiomyopathy.7 Olprinone may have some effects on this calcium regulatory system.

Conclusion

In our case, olprinone dramatically and safely improved cardiogenic shock without IABP or catecholamine agents. Low-dose olprinone can be one of the most useful therapeutic agents in patients with cardiogenic shock due to takotsubo cardiomyopathy accompanied by SAH.

Conflict of Interest

None.