Pathophysiology and prevalence of high output heart failure in group 1 pulmonary hypertension

Pulmonary vasodilators increase cardiac output (CO) in group 1 pulmonary hypertension (PH) and can cause high CO with unclear implications. Our objective was to describe the pathophysiology of high CO in group 1 PH.

Clinical characteristics were compared among PVDOMICS group 1 PH participants by low (cardiac index (CI) <2.2 L·min^-1·m^-2), normal or high output (CO ≥8 L·min^-1 or CI ≥4 L·min^-1·m^-2).

Of 449 group 1 PH participants, 23% (n=103) had low output, 68% (n=304) had normal CO and 9% (n=42) had high output. Increasing CO was associated with more intensive vasodilator use (triple therapy 11% versus 19% versus 33%, respectively; p=0.0008), with progressively lower pulmonary vascular resistance (p<0.0001). High output was associated with the lowest systemic vascular resistance (p<0.0001), with greater left ventricular (LV) and left atrial enlargement (p<0.001 for all). High flow resulted in an increase in LV and right ventricular (RV) work at rest, and absolute/relative RV work during exercise (p<0.0001 for all). Despite greater exercise oxygen delivery (p<0.0001), peripheral oxygen utilisation was impaired by oxygen extraction ratio (p=0.001) and arteriovenous oxygen difference (p=0.005), without incremental functional or survival benefit compared to normal output PH. After adjusting for baseline risk, high output had increased risk of death/transplantation compared to normal output (adjusted hazard ratio 2.1, 95% CI 1.2-3.7; p=0.007). In a validation cohort (n=37), 93% had normal CO at diagnosis, with the high output state developing in follow-up after vasodilator initiation.

Around one in 10 patients with group 1 PH has a high output state, which is most common in prevalent PH and related to vasodilator intensity, with adverse cardiac remodelling and myocardial workload. Further studies are needed to determine optimal vasodilator dosing with high output and therapeutic interaction with vasodilator-sparing therapies such as sotatercept.