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American Cardiology Conference 2022
Helping PH-HFpEF Patients Walk Further with Levosimendan
Source: https://tenaxthera.com/wp-content/uploads/2022/04/Borlaug-ACC-2022.pdf
American Cardiology Conference 2022
Next-generation Tyrosine Kinase Inhibitors for Pulmonary Arterial Hypertension
Source: https://tenaxthera.com/wp-content/uploads/2022/04/SR-ACC-2022.pdf
Heart Failure Society of America 2021
Source: https://tenaxthera.com/wp-content/uploads/2022/04/Bourlag.-Heart-Failure-Society-of-America-2021.pdf
Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood
This landmark study used a machine learning approach to identify transcriptome associated endophenotypes of patients with heritable and idiopathic PAH. They defined five distinct clinical subgroups based on clinical presentation, severity and survival. The three largest subgroups displayed significantly different clinical characteristics, severity and survival outcomes suggesting that a molecular classification for PAH may be possible. The dysregulation of immunoglobulin genes (NOG and ALAS2), were most predictive of the subgroups with the best and worst prognosis, suggesting that these genes are key in determining patient outcome, and may therefore represent future drug targets but also a tool to identify patients responsive to current treatments. The identification of genetic signatures in PAH has been a hope for several decades and is now becoming a reality. As this field progresses one may expect that treatments will follow patient specific genetic biomarkers as is done in oncology.
Citation
Kariotis S, Jammeh E, Swietlik EM, Pickworth JA, Rhodes CJ, Otero P, Wharton J, Iremonger J, Dunning MJ, Pandya D, Mascarenhas TS, Errington N, Thompson AAR, Romanoski CE, Rischard F, Garcia JGN, Yuan JX, An TS, Desai AA, Coghlan G, Lordan J, Corris PA, Howard LS, Condliffe R, Kiely DG, Church C, Pepke-Zaba J, Toshner M, Wort S, Gräf S, Morrell NW, Wilkins MR, Lawrie A, Wang D; UK National PAH Cohort Study Consortium. Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood. Nat Commun. 2021 Dec 7;12(1):7104.Source: https://doi.org/10.1038/s41467-021-27326-0
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/ehf2.13669Source: http://doi.org/10.1002/ehf2.13669
Association Of Borderline Pulmonary Hypertension With Mortality And Hospitalization In A Large Patient Cohort: Insights From The Veterans Affairs Clinical Assessment, Reporting, And Tracking Program
This is a retrospective study of over 20,000 patients with pulmonary hypertension confirmed by cardiac catheterization, from any cause who were followed for clinical outcomes. Like other studies it confirmed the increasing mortality beginning at the mildest levels of increased pulmonary artery pressure. The case can be made for screening programs to detect early disease to initiate treatments.
Citation
Maron BA, Hess E, Maddox TM, Opotowsky AR, Tedford RJ, Lahm T, Joynt KE, Kass DJ, Stephens T, Stanislawski MA, Swenson ER, Goldstein RH, Leopold JA, Zamanian RT, Elwing JM, Plomondon ME, Grunwald GK, Barón AE, Rumsfeld JS, Choudhary G. Association of Borderline Pulmonary Hypertension With Mortality and Hospitalization in a Large Patient Cohort: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. Circulation. 2016 Mar 29;133(13):1240-8Source: https://pubmed.ncbi.nlm.nih.gov/26873944/
Treatment-related Biomarkers in Pulmonary Hypertension
This paper discusses the data for and against the use of molecular biomarkers as an enrichment strategy in future clinical trials in PAH. This is a call for the collection of prospective data to create a biomarker panel that would then be employed in future trials for PAH.
Citation
Swaminathan AC, Dusek AC, McMahon TJ. Treatment-related biomarkers in pulmonary hypertension. Am J Respir Cell Mol Biol. 2015 Jun;52(6):663-73.Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491132/
Novel Composite Clinical Endpoints and Risk Scores Used in Clinical Trials in Pulmonary Arterial Hypertension
This review is from the PVRI Innovative drug Development Initiative which includes academic, regulatory and pharmaceutical leaders in the field of PAH. They address changes in the traditional endpoints in the trials for PAH and offer newer approaches including the use of risk scores to enrich the patient pool appropriate for the type of treatment used.
Citation
Sitbon O, Nikkho S, Benza R, Cq Deng C, W Farber H, Gomberg-Maitland M, Hassoun P, Meier C, Pepke-Zaba J, Prasad K, Seeger W, Corris PA. Novel composite clinical endpoints and risk scores used in clinical trials in pulmonary arterial hypertension. Pulm Circ. 2020 Nov 18;10(4):2045894020962960Source: https://pubmed.ncbi.nlm.nih.gov/33282190/
Enrichment Benefits of Risk Algorithms for Pulmonary Arterial Hypertension Clinical Trials
This manuscript looks at 3 clinical trials in PAH that used clinical worsening events as a primary endpoint. The data from those studies were used to develop risk algorithms which could then be applied in future trials to enrich the population of PAH patients. They also show how this approach could result in a considerable cost savings through sample size reduction and increased treatment effect sizes.
Citation
Scott JV, Garnett CE, Kanwar MK, Stockbridge NL, Benza RL. Enrichment Benefits of Risk Algorithms for Pulmonary Arterial Hypertension Clinical Trials. Am J Respir Crit Care Med. 2021 Mar 15;203(6):726-736.Source: https://pubmed.ncbi.nlm.nih.gov/32937078/
Pulmonary Hypertension: From An Orphan Disease To A Global Epidemic
This review from a leader in the global aspects of pulmonary hypertension describes how what has been considered a rare disease, pulmonary hypertension, is actually quite common when one looks beyond the Western Countries and considers low-middle income countries.
