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Technology and Heart Failure Therapeutics (THT) 2024

“PH-HFpEF: Levosimendan”

Dr Sanjiv Shah

March 6, 2024

Westin Boston Seaport, Boston

Source: https://tenaxthera.com/wp-content/uploads/2024/03/Shah_Levo_THT-.pdf

PVDOMICS Study Group. Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease

This is the first report from the PVDOMICs study, an NIH funded multicenter project designed to better understand the clinical, biological and genetic features and differences between all forms of pulmonary hypertension. This initial paper describes the clinical features of over 1000 subjects in Groups 1-5 pulmonary hypertension. The notable findings include 1) there is often a mixture of etiologies in each of the groups; 2) DLCO is depressed in Groups 1-3; 3) Right atrial volume is enlarged in Groups 1-4 even when the right ventricle is not; 4) Group 1 patients frequently have ground glass findings on Chest CT scan and nocturnal desaturation; 5) Survival is poorest in Group 3.

The finding that there is right atrial enlargement before it is right ventricular enlargement is particularly relevant to the numerous reports that increased right atrial pressure is a powerful predictor of survival in PH, and that the mechanism appears to be associated with increased stressed blood volume. These data provide support for the potential of levosimendan as a fundamental treatment of pulmonary hypertension.

Citation

Hemnes AR, Leopold JA, Radeva MK, Beck GJ, Abidov A, Aldred MA, Barnard J, Rosenzweig EB, Borlaug BA, Chung WK, Comhair SAA, Desai AA, Dubrock HM, Erzurum SC, Finet JE, Frantz RP, Garcia JGN, Geraci MW, Gray MP, Grunig G, Hassoun PM, Highland KB, Hill NS, Hu B, Kwon DH, Jacob MS, Jellis CL, Larive AB, Lempel JK, Maron BA, Mathai SC, McCarthy K, Mehra R, Nawabit R, Newman JH, Olman MA, Park MM, Ramos JA, Renapurkar RD, Rischard FP, Sherer SG, Tang WHW, Thomas JD, Vanderpool RR, Waxman AB, Wilcox JD, Yuan JX, Horn EM; PVDOMICS Study Group. Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease. J Am Coll Cardiol. 2022 Aug 16;80(7):697-718.

Source: https://pubmed.ncbi.nlm.nih.gov/35953136/

Elucidating the Clinical Implications and Pathophysiology of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Call to Action: A Science Advisory From the American Heart Association

This is a comprehensive review of the published clinical studies related to pulmonary hypertension in heart failure with preserved ejection fraction (PH-HFpEF). It includes clinical and hemodynamic definitions of the disease, epidemiology, pathophysiology, animal models and treatment approaches, and clinical trials. They importantly stress the urgent unmet need to make progress in this disease so as to reduce the high burden of the disease. This is a wonderful source document for finding the latest research and publications.

Citation

Brittain EL, Thenappan T, Huston JH, Agrawal V, Lai YC, Dixon D, Ryan JJ, Lewis EF, Redfield MM, Shah SJ, Maron BA; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; and Stroke Council. Elucidating the Clinical Implications and Pathophysiology of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Call to Action: A Science Advisory From the American Heart Association. Circulation. 2022 Jul 11:101161CIR0000000000001079

Source: https://pubmed.ncbi.nlm.nih.gov/35862198/

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/

Understanding the Pathobiology of Pulmonary Hypertension Due to Left Heart Disease

This is an in depth authoritative review of the field of pulmonary hypertension due to left heart disease. Written by one of the most renown thought leaders, it covers all facets of basic and clinical science, with insights into potential effective therapies. A must read for anyone who is involved with translational of clinical investigations in this area.

Citation

Huston JH, Shah SJ. Understanding the Pathobiology of Pulmonary Hypertension Due to Left Heart Disease. Circ Res. 2022 Apr 29;130(9):1382-1403.

Source: https://pubmed.ncbi.nlm.nih.gov/35482841/

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.