April 18, 2024
This soon-to-be classic review offers a very understandable explanation about the importance of venous return in normal physiology and heart failure. While preload is an old concept, it has never been appreciated to have a major impact in managing heart failure patients until now. The studies referenced in this paper predict novel treatments of heart failure based on the concepts of stressed and unstressed blood volume. Levosimendan is the first drug to ever result in clinical improvement based on these concepts.
This editorial offers an explanation of the recent science that implicates downregulation of K+ATP channels in various forms of pulmonary hypertension. Given the clinical safety of levosimendan as a K+ATP channel activator, it may hold great promise for many forms of pulmonary hypertension.
This is the first publication that explains the remarkable discovery of levosimendan working clinically on the splanchnic venous circulation. Considered an inotrope due to its action as a calcium sensitizer, it has been known that it also has vasodilatory properties due to ATP-sensitive K+ (K(ATP)) channel activation. Levosimendan has demonstrated to be effective in lowering PCWP in a broad spectrum of acute HF trials. The classical teaching was that the fall in PCWP was attributed to its inotropic effect which would, theoretically, increase LV ejection and thereby result in greater ‘emptying’ of the pulmonary venous system. However, the hemodynamic studies of levosimendan in HF patients show a rapid and marked reduction in PCWP before meaningful increases in cardiac output occur, which raised questions about a different mechanism of action. An analysis of the data from the recent HELP trial inpatients with pulmonary hypertension associated with HFpEF supports that the mechanism of action to be a reduction in stressed blood volume, with no evidence for an inotropic effect. This is consistent with the vasodilator effects of levosimendan as a K(ATP) channel activator on the splanchnic bed. There are also considerable data that support the downregulation of K+ channels as one of the fundamental processes that underlies the development of pulmonary hypertensive vascular disease. Whether a long-term reduction in pulmonary arterial pressure due to the K(ATP) channel activation from levosimendan is also possible in these patients is unknown, but needs to be studied. Levosimendan is the first drug to ever show a clinically meaningful effect in this patient group of pulmonary hypertension associated with left heart disease.
This is a report of a randomized clinical trial of oral levosimendan as a chronic treatment for HFrEF. 300 patients were included in the trial which lasted 6 months. The primary endpoint, which was not achieved, was a novel composite that included symptoms and mortality. The secondary endpoints of NT-proBNP and patient questionnaire were achieved. Serious adverse events were not encountered.
A review of the known vascular effects of levosimendan via K+ ATP channel activation. The author discusses how levosimendan may be effective in heart failure outside of direct inotropic actions.
This is a review of the role of K+ATP channels in the cardiovascular system, and the potential of K+ channel opener drugs. Included in the review is the finding that myocardial ischemia may be prevented from K+ATP channel activators, including levosimendan, via effects on cardiac mitochondria.
This was a small randomized clinical trial of oral levosimendan for HFrEF as an add-on medication for a 6-month period. The primary assessment was determined by echocardiography which included estimates of PCWP and tissue Doppler velocities. Both parameters improved in the levosimendan treated group compared to control.
An extensive review of the 20 year experience of levosimendan in Europe, covering the indicated application for use in ADHF and the experience in a multitude of other clinical situations. This is a great reference paper that covers the broad scope of preclinical and clinical features of levosimendan.
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