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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
Threshold Of Pulmonary Hypertension Associated With Increased Mortality
This screening study of more that 150,000 adults found a prevalence of pulmonary hypertension of greater than 18% ranging from mild to severe. In addition, they were able to show increasing mortality with the severity of pulmonary hypertension, beginning at the very lowest levels.
Citation
Strange G, Stewart S, Celermajer DS, Prior D, Scalia GM, Marwick TH, Gabbay E, Ilton M, Joseph M, Codde J, Playford D; NEDA Contributing Sites. Threshold of Pulmonary Hypertension Associated With Increased Mortality. J Am Coll Cardiol. 2019 Jun 4;73(21):2660-2672.Source: https://pubmed.ncbi.nlm.nih.gov/31146810/
Mild Pulmonary Hypertension and Premature Mortality Among 154 956 Men and Women Undergoing Routine Echocardiography
This large study of over 150,000 adults from the NEDA goes into deeper analysis to show how mild levels of elevation in pulmonary arterial pressure is associated with increased mortality in the general population. They conclude that notional screening strategies should be considered in as part of clinical surveillance programs.
Citation
Stewart S, Chan YK, Playford D, Strange GA; NEDA investigators. Mild pulmonary hypertension and premature mortality among 154 956 men and women undergoing routine echocardiography. Eur Respir J. 2021 May 28:2100832.Source: https://pubmed.ncbi.nlm.nih.gov/34049952/
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.
