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Imnatinib Mesylate as add-on Therapy for Pulmonary Arterial Hypertension: Results of the Randomized Impres Study
Report of the Phase 3 trial of imatinib for PAH. This study confirms the potential efficacy of imatinib as a treatment, the first disease modifying approach for PAH. Unfortunately, the excess of dropouts in the imatinib group attributed to side effects prevented regulatory approval.
Citation
Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galié N, Gómez-Sánchez MA, Grimminger F, Grünig E, Hassoun PM, Morrell NW, Peacock AJ, Satoh T, Simonneau G, Tapson VF, Torres F, Lawrence D, Quinn DA, Ghofrani HA. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013 Mar 12;127(10):1128-38.Source: https://pubmed.ncbi.nlm.nih.gov/23403476/
Pulmonary Vascular Disease in the Setting of Heart Failure with Preserved Ejection Fraction
Current in-depth review of the clinical features and treatment approaches. A good reference source.
Citation
Levine AR, Simon MA, Gladwin MT. Pulmonary vascular disease in the setting of heart failure with preserved ejection fraction. Trends Cardiovasc Med. 2019 May;29(4):207-217Source: https://pubmed.ncbi.nlm.nih.gov/30177249/
Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated with Heart Failure and Preserved or Reduced Ejection Fraction
Landmark paper on the extensive pulmonary vascular pathology found in all forms of left heart failure. The authors report venous and small vessel intimal thickening that was more severe than arterial intimal thickening in HF, with a pattern similar to patients with pulmonary veno-occlusive disease.
Citation
Fayyaz AU, Edwards WD, Maleszewski JJ, Konik EA, DuBrock HM, Borlaug BA, Frantz RP, Jenkins SM, Redfield MM. Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated With Heart Failure and Preserved or Reduced Ejection Fraction. Circulation. 2018 Apr 24;137(17):1796-1810.Source: https://pubmed.ncbi.nlm.nih.gov/29246894/
Therapeutic Challenges and Emerging Treatment Targets for Pulmonary Hypertension in Left Heart Disease
A very timely review of the trials to treat PH in left heart disease (LD). PH in LHD is the most common form of PH and brings a poor prognosis by increasing the morbidity and mortality risk of this patient population. Despite apparent similarities with PAH, the current guidelines do not recommend PAH-targeted drugs for PH-LHD because of the failure of previous clinical trials in proving their safety and/or efficacy in the setting of PH-LHD. The authors state that it is imperative to further improve our understanding of the pathophysiology and underlying mechanisms of PH-LHD to develop specific therapies for this disease and by doing so, establish an evidence-based approach for the management of patients with HF developing PH.
Citation
Lteif C, Ataya A, Duarte JD. Therapeutic Challenges and Emerging Treatment Targets for Pulmonary Hypertension in Left Heart Disease. J Am Heart Assoc. 2021 Jun;10(11):e020633.Source: https://pubmed.ncbi.nlm.nih.gov/34032129/
Splanchnic Nerve Block Mediated Changes in Stressed Blood Volume in Heart Failure
This important paper reviews 2 studies investigating the effects of splanchnic nerve block (SNB) on hemodynamics in patients with decompensated and ambulatory heart failure. They found that SNB reduced the estimated stressed blood volume in both studies at rest and throughout exercise. This provides strong validation of the role of stressed blood volume in PH-HFpEF.
Citation
Fudim M, Patel MR, Boortz-Marx R, Borlaug BA, DeVore AD, Ganesh A, Green CL, Lopes RD, Mentz RJ, Patel CB, Rogers JG, Felker GM, Hernandez AF, Sunagawa K, Burkhoff D. Splanchnic Nerve Block Mediated Changes in Stressed Blood Volume in Heart Failure. JACC Heart Fail. 2021 Apr;9(4):293-300.Source: https://pubmed.ncbi.nlm.nih.gov/33714749/
Potassium (K +) Channels in the Pulmonary vasculature: Implications in Pulmonary Hypertension Physiological, Pathophysiological and Pharmacological Regulation
Very high-level review of the role of K+ channels regulating the pulmonary vasculature. They explain how K+ channel conductance plays a fundamental role in pulmonary arterial function by controlling pulmonary vascular tone, regulating the population of PASMC through controlling cell apoptosis, survival, and proliferation, and by regulating the release of endothelial vasodilator factors. Given the demonstrated role of altered K+ channels in the pathophysiology of PH, drugs targeting K+ channels, could be new promising therapeutic agents in PAH.
Citation
Mondéjar-Parreño G, Cogolludo A, Perez-Vizcaino F. Potassium (K+) channels in the pulmonary vasculature: Implications in pulmonary hypertension Physiological, pathophysiological and pharmacological regulation. Pharmacol Ther. 2021 Sep;225:107835.Source: https://pubmed.ncbi.nlm.nih.gov/33744261/
Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFPEF: Results of the Randomized Placebo-Controlled Help Trial
This clinical trial using levosimendan to treat PH-HFpEF is the very first to show that any treatment can improve exercise capacity. Additionally, as a mechanistic trial, it clearly demonstrated that lowering PCWP with exercise is the target for a therapeutic benefit.
Citation
Burkhoff D, Borlaug BA, Shah SJ, Zolty R, Tedford RJ, Thenappan T, Zamanian RT, Mazurek JA, Rich JD, Simon MA, Chung ES, Raza F, Majure DT, Lewis GD, Preston IR, Rich S. Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial. JACC Heart Fail. 2021 May;9(5):360-370.Source: https://pubmed.ncbi.nlm.nih.gov/33839076/
Changes in Stressed Blood Volume with Levosimendan in Pulmonary Hypertension from Heart Failure with Preserved Ejection Fraction: Insights Regarding Mechanism of Action from the Help Trial
This brief report analyzed the data from the HELP trial and confirmed that a reduction in estimated stressed blood volume was the mechanism of action of levosimendan in these patients and that there was no evidence of any inotropic effect of levosimendan on cardiac function. The reduction in stressed blood volume was similar to what was achieved by splanchnic nerve block.
Citation
Brener MI, Hamid NB, Sunagawa K, Borlaug BA, Shah SJ, Rich S, Burkhoff D. Changes in Stressed Blood Volume with Levosimendan in Pulmonary Hypertension from Heart Failure with Preserved Ejection Fraction: Insights Regarding Mechanism of Action From the HELP Trial. J Card Fail. 2021 Jun 16:S1071-9164(21)00215-3Source: https://pubmed.ncbi.nlm.nih.gov/34144177/
Imatinib in Pulmonary Arterial Hypertension Patients with Inadequate Response to Established Therapy
This is the phase 2 randomized clinical trial of imatinib for PAH to test its efficacy and safety. There were non-significant increases in 6-minute walk, with significant reductions in pulmonary vascular resistance. The relatively small number of patients (59) makes interpretation of the results difficult. It appeared that the patients with more advanced disease responded better than those with lesser disease. This trial was used to justify pursuing a phase 3 trial for regulatory approval.
Citation
Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, Shapiro S, Golpon H, Toshner M, Grimminger F, Pascoe S. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010 Nov 1;182(9):1171-7.Source: https://pubmed.ncbi.nlm.nih.gov/20581169/
Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension
The downregulation of K+ channels has been considered a hallmark of pulmonary hypertension. This paper specifically reviews their role in PAH. The lack of any candidate drugs is largely the reason that this seems to be unrecognized in the clinical arena. K+ channels appear to regulate pulmonary vascular tome and proliferation.
