The importance of right ventricular (RV) function has been recognized only in the last few years. The RV pumps blood into the pulmonary system, which is usually a low-pressure, highly distensible, low-resistance arterial system. The RV performs approximately one-fourth of the left ventricular (LV) stroke work. The RV function plays a vital role in maintaining global cardiac performance.
Numerous clinical conditions during cardiac surgery have been shown to affect RV performance. RV dysfunction is commonly a sequela of pulmonary hypertension and is a predictor of morbidity and mortality in these patients. RV dysfunction is often overlooked as causing adverse perioperative outcomes. Acute RV failure after cardiac surgery is a significant morbidity and mortality cause. RV failure induced by pulmonary hypertension has a mortality rate of up to 48%. Due to its unique pathophysiology, RV failure may not respond to routine therapeutic measures such as volume resuscitation and may need inotropic support.
In this issue, Bharathi KS et al. present a randomized clinical trial of the use of levosimendan to manage patients with RV dysfunction after mitral valve surgery. They report a significant reduction in RV dysfunction in patients administered levosimendan 0.1 mcg/kg/min. RV dysfunction in the setting of chronic congestive heart failure, as in mitral valve disease, results from pulmonary hypertension, chronically increased RV afterload, and altered RV geometry and function due to LV dysfunction (ventricular interdependence). The benefits of levosimendan in RV dysfunction associated with valvular heart disease have been demonstrated earlier too.
An increase in cardiac output during exercise is associated with a significant increase in blood pressure in systemic circulation. However, pulmonary circulation remains a low-pressure system during exercise. During exertion, a fourfold rise in systemic cardiac output is associated with a minimal increase in pulmonary pressures and a fall in PVR. The difference between the two circulations is based on the ability of the lung to recruit partially collapsed or non-recruited vessels as cardiac output increases and the relatively low degree of vascular motor tone in the proximal pulmonary vascular bed. The more compliant RV can accommodate a higher right-sided venous return but can’t tolerate acute increases in afterload and tends to dilate, limiting its ability to increase contractility.
The pulmonary system is an essential determinant of RV afterload. A decrease in pulmonary vascular resistance (PVR) helps support the failing RV by reducing its afterload. Traditionally, management of RV failure is directed at optimizing right-sided filling pressures, avoidance of hypoxia/hypercarbia, and reducing afterload. The management of RV dysfunction has centered on reduction in afterload with the use of pulmonary vasodilators and, in recent times, nitric oxide. Use of inotropy to enhance RV output has been limited. More longer-term outcome data on inotropes in RV dysfunction is needed, and using their lowest possible dose is recommended to sustain systemic perfusion.
There is no gold standard therapeutic agent to support the RV. Dobutamine, levosimendan, and phosphodiesterase III inhibitors are preferred in patients with RV dysfunction in patients with pulmonary hypertension caused by left heart disease. They favor ventricular-arterial coupling by combining RV inotropy and pulmonary vasodilation. Dobutamine may reduce blood pressure; thus, integrating it with a vasopressor, such as noradrenaline, is recommended. Mishra et al. reported that milrinone was clinically better than levosimendan for managing patients with pulmonary hypertension and LV dysfunction, as it increased the rate and decreased systemic vascular resistance (SVR). A recent meta-analysis has shown levosimendan to be more effective and safe for treating acute RV dysfunction.
Phosphodiesterase III inhibitors exert a positive inotrope effect on the RV, but phosphodiesterase III receptors are absent in the pulmonary vasculature. Since they reduce SVR, they need to be combined with a vasopressor. RV pressure overload is associated with supraventricular arrhythmias, such as atrial fibrillation, atrial flutter, or atrial tachycardia, negatively affecting RV filling and thereby aggravating RV failure. The use of vasopressors and inotropes can potentially promote arrhythmia in such situations.
Levosimendan is a positive inotropic agent generally used for acute LV dysfunction. It increases the calcium sensitivity of cardiac troponin C and thus exerts a positive inotropic effect. It does not increase intracellular calcium concentrations and therefore does not increase the metabolic demand on the heart. The drug offers a unique combination of pulmonary vasodilatation and positive inotropy. Although its role in systolic left heart failure management is well established, limited data are available on its use in RV failure. Levosimendan, with its inotropic, pulmonary vasodilatory, and cardioprotective properties, has the potential to become the agent of choice in RV dysfunction caused by pulmonary hypertension. When used in RV dysfunction, levosimendan was found to decrease RV end-systolic volume, increase RV ejection fraction, and improve mixed venous oxygen saturation (from 63 ± 8 to 70 ± 8%).
Levosimendan does not affect diastolic function as the calcium-sensitizing effect is related to intracellular calcium levels. Intracellular calcium decreases in diastole to maintain diastolic function. Levosimendan opens adenosine triphosphate (ATP)-dependent K+ channels in vascular smooth muscle cells to vasodilate vessels. It vasodilates arterial and venous smooth muscle cells, reducing both RV preload and afterload. Opening the mitochondrial ATP-dependent K+ channels in the myocytes provides the myocardium protection against ischemia-reperfusion injury, apoptosis, and oxidative stress. Dilatation of coronary arteries also improves oxygen supply protecting the myocardium against ischemia. It has been postulated that the improvement in RV function with levosimendan may partly be attributed to the improved LV function.
Levosimendan has been reported to attenuate pulmonary arterial occlusive lesions and reduce RV remodeling in pulmonary vasculopathy. Its use is associated with increased capillary density, myocyte size reduction, and reduction in atrial natriuretic peptide and B-type natriuretic peptide levels. In a rat model study mimicking pulmonary hypertension, long-term levosimendan improved RV function without increasing RV myocardial oxygen consumption, leading to improved external efficiency. Inhibition of pulmonary arterial smooth muscle cell proliferation, pulmonary vascular medial wall thickness, and RV hypertrophy has also been demonstrated after long-term use of levosimendan.
The elimination half-life of Levosimendan is just about an hour. About 5% of levosimendan is converted to a metabolite OR-1855 in the intestine, which is converted to OR-1896 in the liver by acetylation. OR-1896 has hemodynamic effects similar to those of levosimendan. It has an elimination half-life of 70–80 h, so the hemodynamic impact of Levosimendan persists for 7–9 days after a 24 h infusion of levosimendan. A decrease in pulmonary capillary wedge pressure may be seen for 7–9 days and a rise in cardiac output for 12–13 days after a 24 hours infusion.
RV dysfunction is an underdiagnosed common cause of perioperative hemodynamic instability. In the words of Wanner and Filipovic “one can only prevent and treat what one has considered—you may forget the RV, but the RV will not forget you.” The current literature favors levosimendan for RV dysfunction caused by pulmonary hypertension. Large, well-designed, and adequately powered randomized clinical trials should be conducted to evaluate its efficacy, safety, and clinical outcomes in patients with RV dysfunction.
1. Campo A, Mathai SC, Le Pavec J, Zaiman AL, Hummers LK, Boyce D, et al Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension Eur Respir J. 2011;38:359–67
2. Wanner PM, Filipovic M. The right ventricle-you may forget it, but it will not forget you J Clin Med. 2020;9:432
3. Bharathi KS, Pruthi G, Dhananjaya M, Prasanna Simha P. The effect of levosimendan on the right ventricular function in patients with right ventricular dysfunction undergoing mitral valve surgery Ann Card Anaesth. 2023;26:51–7
4. Rosenkranz S, Gibbs JS, Wachter R, De Marco T, Vonk-Noordegraaf A, Vachiéry JL. Left ventricular heart failure and pulmonary hypertension Eur Heart J. 2016;37:942–54
5. Guerrero-Orriach JL, Ariza-Villanueva D, Florez-Vela A, Garrido-Sánchez L, Moreno-Cortés MI, Galán-Ortega M, et al Cardiac, renal, and neurological benefits of preoperative levosimendan administration in patients with right ventricular dysfunction and pulmonary hypertension undergoing cardiac surgery: Evaluation with two biomarkers neutrophil gelatinase-associated lipocalin and neuronal enolase Ther Clin Risk Manag. 2016;12:623–30
6. Ishihara S, Gayat E, Sato N, Arrigo M, Laribi S, Legrand M, et al Similar hemodynamic decongestion with vasodilators and inotropes: Systematic review, meta-analysis, and meta-regression of 35 studies on acute heart failure Clin Res Cardiol. 2016;105:971–80
7. Arrigo M, Mebazaa A. Understanding the differences among inotropes Intensive Care Med. 2015;41:912–5
8. Mishra A, Kumar B, Dutta V, Arya VK, Mishra AK. Comparative effect of levosimendan and milrinone in cardiac surgery patients with pulmonary hypertension and left ventricular dysfunction J Cardiothorac Vasc Anesth. 2016;30:639–46
9. Qiu J, Jia L, Hao Y, Huang S, Ma Y, Li X, et al Efficacy and safety of levosimendan in patients with acute right heart failure: A meta-analysis Life Sci. 2017;184:30–6
10. Green EM, Givertz MM. Management of acute right ventricular failure in the intensive care unit Curr Heart Fail Rep. 2012;9:228–35
11. Arrigo M, Huber LC, Winnik S, Mikulicic F, Guidetti F, Frank M, et al Right ventricular failure: Pathophysiology, diagnosis and treatment Card Fail Rev. 2019;5:140–6
12. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola VP, et al EuroHeart Failure Survey II (EHFS II): A survey on hospitalized acute heart failure patients: Description of population Eur Heart J. 2006;27:2725–36
13. Hansen MS, Andersen A, Nielsen-Kudsk JE. Levosimendan in pulmonary hypertension and right heart failure Pulm Circ. 2018;8:2045894018790905 doi: 10.1177/2045894018790905
14. Morelli A, Teboul JL, Maggiore SM, Vieillard-Baron A, Rocco M, Conti G, et al Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: A pilot study Crit Care Med. 2006;34:2287–93
15. Haikala H, Nissinen E, Etemadzadeh E, Levijoki J, Lindén IB. Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation J Cardiovasc Pharmacol. 1995;25:794–801
16. Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. Levosimendan, a novel Ca2+sensitizer, activates the glibenclamide-sensitive K+channel in rat arterial myocytes Eur J Pharmacol. 1997;333:249–59
17. Parissis JT, Rafouli-Stergiou P, Paraskevaidis I, Mebazaa A. Levosimendan: From basic science to clinical practice Heart Fail Rev. 2009;14:265–75
18. Kaheinen P, Pollesello P, Levijoki J, Haikala H. Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels J Cardiovasc Pharmacol. 2001;37:367–74
19. Wang YB, Hao GZ, Jiang YF, Fu XH, Fan WZ, Miao Q, et al Effects of levosimendan on right ventricular function in patients with acute decompensated heart failure Acta Cardiol Sin. 2019;35:585–91
20. Hansen MS, Andersen A, Holmboe S, Schultz JG, Ringgaard S, Simonsen U, et al Levosimendan prevents and reverts right ventricular failure in experimental pulmonary arterial hypertension J Cardiovasc Pharmacol. 2017;70:232–8
21. Hansen MS, Andersen A, Tolbod LP, Hansson NH, Nielsen R, Vonk-Noordegraaf A, et al Levosimendan improves cardiac function and myocardial efficiency in rats with right ventricular failure Pulm Circ. 2018;8:2045893217743122 doi: 10.1177/2045893217743122
22. Mieth A, Andersen A, Tolbod LP, Hansson NH, Nielsen R, Vonk-Noordegraaf A, et al Levosimendan attenuates pulmonary vascular remodeling Intensive Care Med. 2011;37:1368–77
23. Hillgaard TK, Andersen A, Andersen S, Vildbrad MD, Ringgaard S, Nielsen JM, et al Levosimendan prevents pressure-overload-induced right ventricular failure J Cardiovasc Pharmacol. 2016;67:275–82
24. Revermann M, Schloss M, Mieth A, Babelova A, Schröder K, Neofitidou S, et al Levosimendan attenuates pulmonary vascular remodeling Intensive Care Med. 2011;37:1368–77
25. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikäinen PJ. Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure Int J Clin Pharmacol Ther. 2002;40:465–71
26. Lilleberg J, Laine M, Palkama T, Kivikko M, Pohjanjousi P, Kupari M. Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure Eur J Heart Fail. 2007;9:75–82