Book of Abstracts - New Frontiers 2022

Abstracts of oral presentations

POTASSIUM CHANNELS AS POTENTIAL TARGETS IN PULMONARY HYPERTENSION COMPLICATING HEART FAILURE WITH PRESERVED EJECTION FRACTION (PH-HFpEF)

Z. Papp 1 , F. Sárkány 1 , P. Polesello 2

1 Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; 2 Orion Pharma, Orion Corporation, Espoo, Finland

Vascular remodeling in pulmonary hypertension (PH) includes the proliferation and migration of pulmonary artery smooth muscle cells, alterations in endothelial cell function and the activation of inflammatory cells. Endothelial and vascular K + channels are dysregulated in PH: certain K + channel types are downregulated, others are upregulated consistent with a more fetal phenotype in the remodeled pulmonary vasculature. Accordingly, K + channel dysregulation has been targeted by different pharmacological strategies in PH with the aim of restoring normal K + channel activities and vascular function. Nevertheless, to date, these efforts have not brought the expected clinical benefits. The hurdles of K + channel targeting can be illustrated through an example of ATP-sensitive K + (K(ATP)) channels, as recent data revealed that both LoF and GoF mutations in genes encoding subunits of K(ATP) channels can result in PH. Collectively, the widespread involvement of K + channels in cardiovascular and other organ functions makes it difficult to deliver selective therapies for the pulmonary circulation via K + channel activators. Levosimendan is a Ca 2+ -sensitizer inodilator evoking prominent reductions in pulmonary capillary wedge pressure. K(ATP) channel activation is involved in the vasodilator effects of Levosimendan, nevertheless, complimentary contributions of additional K + channels (e.g. BKCa and Kv), endothelial NO-dependent and cAMP-related mechanisms have been also implicated. In short, Levosimendan is a potent vasodilator augmenting tissue perfusions in most organs and vascular beds, although Levosimendan sensitivities are not uniformwithin the cardiovascular system. Results of the HELP phase 2B study (where low dose, repeated Levosimendan administrations were employed in PH-HFpEF patients) included improvements in exercise capacity and reductions in systemic venous pressure as well as pulmonary venous resistance in the absence of changes in arterial resistances (both in the systemic circulation and in the pulmonary system). Hemodynamic data of the HELP study are in line with Levosimendan-induced selective venodilation and partial redistribution of the circulating blood volume from the arterial side to the venous side within the circulatory system. Taken together, currently available preclinical and clinical data are consistent with the proposal that restoration of dysregulated K + channel function is a potential strategy in treating PH. Nevertheless, the widespread involvement of K + channels in biological processes complicate selective K + channel targeting in the vasculature of the lungs. The apparent benefit of drug induced modulation of circulating blood volume distribution requires further investigations in PH-HFpEF patients.

Keywords: pulmonary hypertension, heart failure with preservedn ejection fraction, K+ channels, levosimendan, treatment

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