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BRIEF REPORTS/CLINICAL STUDIES |
From the Coronary Care Unit, Department of Cardiology, Hospital Universitario de Canarias, Tenerife, Spain.
Address for reprints: Martín J. García-González, Coronary Care Unit, Department of Cardiology, Hospital Universitario de Canarias, Ctra. La Cuesta—Taco s/n. Ofra 38320 S. Cristóbal de La Laguna, Tenerife, Spain.
Key Words: Levosimendan • ST-elevation myocardial infarction (STEMI) • myocardial stunning • cardiogenic shock
The degree of necrosis produced by ST-elevation myocardial infarction (STEMI) prior to coronary reperfusion, together with a variable amount of myocardial stunning,1 may have important prognostic repercussions. When both concur, they may give rise to a state of shock and heart failure requiring adequate treatment, classically aimed at increasing contractility (with inotropic drugs), reducing preload and postload (with vasodilating drugs), and attempting to control the cardiac remodeling process (with beta-blockers and angiotensin-converting enzyme inhibitors).2
The intravenous inotropic drugs currently available (amines and phosphodiesterase inhibitors) improve contractility by increasing intracellular concentrations of free calcium, but they may have potentially deleterious effects by increasing myocardial energy consumption and underlying ischemia and may even produce myocardial necrosis, cardiotoxicity, and arrhythmia.3
Levosimendan belongs to a new group of inotropic agents developed for cardiovascular therapy: those that enhance the sensitivity of myofilaments to calcium. This drug has positive inotropic and vasodilatory properties, as well as cardioprotective effects, which makes it particularly interesting and beneficial in this clinical context.4 This is especially so when complicated by cardiogenic shock (CS) due to severe left ventricular dysfunction.
We sought to evaluate the acute hemodynamic effects of levosimendan in patients with STEMI revascularized by primary percutaneous coronary intervention (PCI), who subsequently presented CS secondary to severe left ventricular systolic dysfunction.
PATIENTS AND METHODS
Study Patients
Between January and August 2004, we performed PCI on 5 men aged 55 to 76 years, admitted with STEMI and without previous history of cardiac failure, who fulfilled coronary revascularization criteria5 and who subsequently developed CS secondary to severe left ventricular systolic dysfunction.
Each patient was hemodynamically monitored using pulmonary artery Swan-Ganz catheter by percutaneous cannulation of the right internal jugular vein (7 Fr. Super Arrow-Flex percutaneous Sheath Introducer Set, REF product no. CP-07711). Heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), mean pulmonary arterial pressure (MPAP), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), and left ventricular ejection fraction (LVEF) were measured. The left ventricular ejection fraction was assessed by 2-dimensional echocardiography using a biplane Simpson's rule method.6 Cardiac index was calculated applying Fick's method standard formula.7 Cardiogenic shock was diagnosed according to criteria published elsewhere.8 Information was compiled by telephone contact with the patients to evaluate mortality at 30 days.
Treatment Regimens
None of the patients received previous or concomitant inotropic drugs, with the exception of digitalis. In all cases, after confirmation of hemodynamic shock and echocardiographic evaluation of ventricular function, intravenous levosimendan was administered as early as possible, with a bolus of 24 µg·kg–1 within 10 minutes, followed by a continuous 24-hour infusion of 0.2 µg·kg–1 · min–1. Additional medication (furosemide, sodium nitroprusside, nitroglycerine, digitalis) was supplied at stable doses during levosimendan administration. Hemodynamic targets were as follows: MAP 
70 mm Hg, CI 2.0 L·min–1·m–2 without signs of poor peripheral perfusion (oliguria, acidosis), and PCWP 
18 mm Hg.
Statistical Analysis
All data are presented as mean value ± SEM, unless otherwise stated. Due to the limited number of patients, no further statistical analyses were performed.
RESULTS
Five patients with STEMI and CS were admitted to the coronary care unit. In all patients, PCI procedure was performed successfully, with reestablishment of TIMI flow grade 3 in the artery responsible for the infarction, with residual stenosis of less than 30%. Baseline clinical characteristics among the patients were similar (Table I).
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Levosimendan was well tolerated. No clinically significant changes were observed in laboratory parameters. Measurements of hemodynamic and systolic function pre- and postinfusion of levosimendan are shown in Table II. All patients' hemodynamic parameters and LVEF improved, and none had serious side effects requiring early withdrawal of continuously infused levosimendan.
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In-hospital evolutionary complications of the patients included paroxystic atrial fibrillation without hemodynamic repercussions (patients 1 and 4), transitory nonspecific intraventricular conduction delay (patient 1), and pericarditis (patient 4). One patient required circulatory assistance with an intra-aortic balloon pump and mechanical ventilation due to respiratory failure prior to infusion of levosimendan (patient 3). None of the patients developed multiple-organ failure. All patients were discharged from the hospital in good condition within 6 and 15 days postadmission. No cardiac events or mortality were recorded at 30 days.
DISCUSSION
Myocardial stunning is characterized by reversible myocardial dysfunction, which recovers after some delay.1,9 In a clinical setting, it can give rise to a state of cardiac failure—and even CS—with prognostic repercussions on morbidity and mortality. It may appear in diverse clinical circumstances such as, within others, early reperfusion with thrombolysis or PCI. The biomolecular mechanisms responsible for its pathogenesis are cytosolic calcium overload in myocardiocytes, formation of oxygen-derived free radicals during reperfusion (which contribute to calcium overload, deactivate enzymes, reduce contractility, and stimulate apoptosis), loss of myofilaments, and reduction of their sensitivity to calcium.10
Levosimendan is derived from pyridazinone dinitrile, which acts in 2 basic ways: first, it boosts contractility by enhancing the sensitivity of myofilaments to calcium by binding to cardiac C troponin, in a calcium-dependent way, without affecting myocardial relaxation time11,12; second, it exerts a coronary and systemic vasodilatory effect by opening adenosine triphosphate–dependent potassium (KATP) channels and blocking the liberation of endothelin-1.13
These actions have a series of hemodynamic effects, such as an increase in contractility, systolic volume, and CI; reduction of MPAP, PCWP, and CVP; and a slight positive effect on the increase of end-diastolic distensibility, without causing the increased myocardial energy consumption underlying ischemia and arrhythmia associated with other inotropic drugs.14 In the setting of coronary ischemia, this mechanism sets levosimendan apart from other positive inotropic drugs and might be of major importance.
Cardiogenic shock is the leading cause of death in patients who are hospitalized for acute myocardial infarction.15 In patients with acute ischemia requiring inotropic support, only very limited pharmacological approaches are available. All currently positive inotropic drugs increased intracellular concentrations of cyclic adenosine monophosphate (AMP) and calcium ions.16 The favorable effects of levosimendan on myocardial oxygen consumption were confirmed in patients with CS undergoing surgical revascularization.17
In our study, intravenously administered levosimendan, after a PCI procedure in patients with STEMI and CS, was safe, effective, and significantly improved LVEF. Levosimendan dosage varied depending on each patient's individual hemodynamic response, until a maximum continuous infusion dose of 0.2 µg·kg–1 · min–1 was reached in every patient. Levosimendan causes dose-related decreases in PCWP and MPAP; in addition, it increases CI. These hemodynamic effects appeared to be accompanied by an improvement of symptoms and were not associated with a significant increase in the number of adverse events.18 Furthermore, the doses of levosimendan used in the present study have previously proved effective19 and well tolerated.20,21 Similar to the findings in other studies,18,19,22,23 this drug produced notable improvements in our patients not only regarding LVEF, CI, MAP, and other hemodynamic parameters but also in their clinical condition. They all reached the hemodynamic objectives intended before enrollment. This may have positively influenced the prognosis of these patients. Although there is not a comparative group of patients, and the study was not designed to assess the safety of the drug, complications detected in study patients cannot be ascribed to the use of levosimendan but can be attributed to the pathologic condition itself because their onset was previous to the use of the drug. Moreover, continuously infused levosimendan withdrawal was not required in any of the cases.
In addition, this study evaluates the effects of intravenous levosimendan in patients with CS, which had been excluded in larger levosimendan trials.18,22,23 The data available on the effects of this drug in this population are scarce. Therefore, our data contribute to this knowledge.
The study does have some limitations. The trial was nonrandomized and open-label, so any comparison regarding efficacy and especially safety to currently available inotropic therapy for this condition is not allowed. Another limitation is that these favorable preliminary data are from a small case series.
In conclusion, this study looks at a new group of patients not previously reported on, and its results demonstrate that levosimendan may have exerted positive inotropic and cardioprotective effects in patients with STEMI and CS. However, further investigation is warranted, and levosimendan cannot be generally recommended in these patients unless these preliminary data are confirmed by a controlled, randomized, double-blind study in a larger series of patients.
REFERENCES
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