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.
Levosimendan Improves Hemodynamics and Submaximal Exercise Capacity in PH-HFpEF: Primary Results from the HELP-PH-HFpEFMulticenter Randomized Controlled Trial
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.
Levosimendan is a K+ATP channel activator, and via this mechanism has the potential for dilating both arterial and venous blood vessels. This experiment focused on human portal veins, and compared it to another K+ATP channel activator drug cromakalim. The in vitro preparation employed pre-treating the veins with norepinephrine to simulate the physiologic environment in heart failure syndromes.
This is a summary of an FDA sponsored meeting that included academia, regulatory and industry to address the growing problem of HFpEF that currently has no identified effective treatment. This provides insight towards how the development of novel treatment will likely proceed.
This provides a summary of the use of levosimendan as an inotropic treatment of advanced heart failure from academic experts with firsthand knowledge and experience. Discussions include the relative safety of levosimendan compared to other inotropic drugs, and the chronic use in advanced disease.
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.
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.
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.