There is a paucity of data describing the invasive assessment of afterload and influence on cardiac output in patients supported on left ventricular assist device (LVAD) therapy. From 2015 to 2018, patients on LVAD therapy were evaluated with simultaneous left/right heart catheterization ramp study for speed optimization. Hemodynamic parameters from 31 patients without significant aortic insufficiency were analyzed. Mean central aortic pressure (MAP) was elevated at 87 ± 13 mm Hg at baseline. No direct association between MAP and cardiac index (CI) was found (r = 0.11, p = 0.20). However, variable MAP provided vastly different patterns of cardiac output response to speed increments (positive correlation, p = 0.047 for MAP <80 mm Hg; negative trend, p = 0.25 for MAP > 100 mm Hg). Patients noted to be hypertensive (MAP > 90, n = 8) received nitrate therapy and experienced both improvement in biventricular filling pressures and a mean increase in CI from 2.4 to 2.9 L/min/m2 (+22%, p = 0.04) at a fixed revolutions per minute. High afterload is common in patients on LVAD therapy, is associated with poor response to ramp, and is ameliorated by nitrates. These findings serve as a foundation to evaluate the dynamic effects of high afterload and chronic vasodilator therapy in patients with durable LVADs.