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ETA Selective vs Dual ETA/ETB Blockade Feature ETA Selective (e.g., zibotentan, ambrisentan) Dual ETA/ETB (e.g., macitentan, bosentan) Pulmonary vasodilation Strong Strong Antifibrotic effect Preserved Preserved ET1 clearance via ETB Preserved Blocked Nitric oxide signaling Preserved Reduced Fluid retention risk Lower Higher HFpEF tolerability Better Worse PHLHD trial outcomes Neutral Negative / harmful Clinical Trial Signals (HighLevel) * Dual ERAs in PH due to left heart disease showed no benefit and more edema * ETA selective agents demonstrated: * Better hemodynamic tolerability * Less sodium and water retention * More favorable pulmonary vascular resistance effects without excessive PCWP rise No ERA has shown outcome benefit in HFpEF, but harm signals are stronger with dual blockade

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Garritson, J