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Education Posts

Group PH-LD

Article Type: Treatments

Venous Tone and Stressed Blood Volume in Heart Failure

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.

Citation
Fudim M, Kaye DM, Borlaug BA, Shah SJ, Rich S, Kapur NK, Costanzo MR, Brener MI, Sunagawa K, Burkhoff D. Venous Tone and Stressed Blood Volume in Heart Failure: JACC Review Topic of the Week. J Am Coll Cardiol. 2022 May 10;79(18):1858-1869.
Source: https://pubmed.ncbi.nlm.nih.gov/35512865/

Targeting ATP-Sensitive K+ Channels to Treat Pulmonary Hypertension

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.

Citation
Breen E, Yuan JX. Targeting ATP-Sensitive K+ Channels to Treat Pulmonary Hypertension. Am J Respir Cell Mol Biol. 2022 May;66(5):476-478.
Source: https://pubmed.ncbi.nlm.nih.gov/35238728/

Heart Failure Society of America 2021

Levosimendan Improves Hemodynamics and Submaximal Exercise Capacity in PH-HFpEF: Primary Results from the HELP-PH-HFpEFMulticenter Randomized Controlled Trial

Source: https://tenaxthera.com/wp-content/uploads/2022/04/Bourlag.-Heart-Failure-Society-of-America-2021.pdf

Levosimendan-Induced Venodilation is Mediated by Opening of Potassium Channels

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.

Citation
Burkhoff D, Rich S, Pollesello P, Papp Z. Levosimendan-induced venodilation is mediated by opening of potassium channels. ESC Heart Failure (2021) DOI: 10.1002/ehf2.13669
Source: http://doi.org/10.1002/ehf2.13669

Levosimendan Beyond Inotropy and Acute Heart Failure: Evidence of Pleiotropic Effects on the Heart and Other Organs: An Expert Panel Position Paper

Levosimendan has been used in Europe for the past 20 years as an intravenous inotropic treatment of acute decompensated heart failure. This expert panel with firsthand experience in its clinical efficacy summarizes this experience and the many unexplored potential uses in various conditions. Levosimendan is a pleotropic drug with multiple mechanisms of action.

Citation
Farmakis D, Alvarez J, Gal TB, Brito D, Fedele F, Fonseca C, Gordon AC, Gotsman I, Grossini E, Guarracino F, Harjola VP, Hellman Y, Heunks L, Ivancan V, Karavidas A, Kivikko M, Lomivorotov V, Longrois D, Masip J, Metra M, Morelli A, Nikolaou M, Papp Z, Parkhomenko A, Poelzl G, Pollesello P, Ravn HB, Rex S, Riha H, Ricksten SE, Schwinger RHG, Vrtovec B, Yilmaz MB, Zielinska M, Parissis J. Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper. Int J Cardiol. 2016 Nov 1;222:303-312.
Source: https://pubmed.ncbi.nlm.nih.gov/27498374/

Comparison of The Vasorelaxing Effect of Cromakalim and the New Inodilator, Levosimendan, In Human Isolated Portal Vein

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.

Citation
Pataricza J, Hõhn J, Petri A, Balogh A, Papp JG. Comparison of the vasorelaxing effect of cromakalim and the new inodilator, levosimendan, in human isolated portal vein. J Pharm Pharmacol. 2000 Feb;52(2):213-7
Source: https://pubmed.ncbi.nlm.nih.gov/10714952/

Developing Therapies for Heart Failure with Preserved Ejection Fraction: Current State and Future Directions

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.

Citation
Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, Shah SJ, Ahmed A, Bonow RO, Cleland JG, Cody RJ, Chioncel O, Collins SP, Dunnmon P, Filippatos G, Lefkowitz MP, Marti CN, McMurray JJ, Misselwitz F, Nodari S, O'Connor C, Pfeffer MA, Pieske B, Pitt B, Rosano G, Sabbah HN, Senni M, Solomon SD, Stockbridge N, Teerlink JR, Georgiopoulou VV, Gheorghiade M. Developing therapies for heart failure with preserved ejection fraction: current state and future directions. JACC Heart Fail. 2014 Apr;2(2):97-112.
Source: https://pubmed.ncbi.nlm.nih.gov/24720916/

Levosimendan in Acute and Advanced Heart Failure: an Appraisal of the Clinical Database and Evaluation of its Therapeutic Applications

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.

Citation
Altenberger J, Gustafsson F, Harjola VP, Karason K, Kindgen-Milles D, Kivikko M, Malfatto G, Papp Z, Parissis J, Pollesello P, Pölzl G, Tschöpe C. Levosimendan in Acute and Advanced Heart Failure: An Appraisal of the Clinical Database and Evaluation of Its Therapeutic Applications. J Cardiovasc Pharmacol. 2018 Mar;71(3):129-136.
Source: https://pubmed.ncbi.nlm.nih.gov/28817484/

Levosimendan Efficacy and Safety: 20 Years Of Simdax in Clinical Use

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.

Citation
Papp Z, Agostoni P, Alvarez J, Bettex D, Bouchez S, Brito D, Černý V, Comin-Colet J, Crespo-Leiro MG, Delgado JF, Édes I, Eremenko AA, Farmakis D, Fedele F, Fonseca C, Fruhwald S, Girardis M, Guarracino F, Harjola VP, Heringlake M, Herpain A, Heunks LMA, Husebye T, Ivancan V, Karason K, Kaul S, Kivikko M, Kubica J, Masip J, Matskeplishvili S, Mebazaa A, Nieminen MS, Oliva F, Papp JG, Parissis J, Parkhomenko A, Põder P, Pölzl G, Reinecke A, Ricksten SE, Riha H, Rudiger A, Sarapohja T, Schwinger RHG, Toller W, Tritapepe L, Tschöpe C, Wikström G, Lewinski DV, Vrtovec B, Pollesello P. Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use. J Cardiovasc Pharmacol. 2020 Jul;76(1):4-22.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374352/

Oral Levosimendan in Patients with Severe Chronic Heart Failure --the Persist Study

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.

Citation
Nieminen MS, Cleland JG, Eha J, Belenkov Y, Kivikko M, Põder P, Sarapohja T. Oral levosimendan in patients with severe chronic heart failure --the PERSIST study. Eur J Heart Fail. 2008 Dec;10(12):1246-54.
Source: https://pubmed.ncbi.nlm.nih.gov/18945637/
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