Left heart disease (LHD) is the most prevalent cause of pulmonary hypertension (PH) and can be due to systolic or diastolic dysfunction or valvular heart disease. Regardless of the cause, the common mechanism of PH associated with LHD is elevated left atrial pressure that leads to a passive increase in pulmonary pressure. In some patients, additional components such as endothelial dysfunction (due to a decrease in nitric oxide and increase in endothelin-1) and vasoconstriction result in vascular remodeling, leading to further increases in pulmonary artery pressure (PAP) and right ventricular failure. When present, PH is associated with a worse prognosis in patients with LHD.1
Significant advances have been achieved in the treatment of pulmonary arterial hypertension (PAH), including 14 different therapies that target 4 different pathways. While these treatments have improved the quality of life and survival for patients with PAH, there are currently no approved therapies for those with PH due to LHD (PH-LHD). Several drugs have undergone clinical trials targeting heart failure patients with or without PH, all with disappointing results. One explanation is believed to be the inherent difficulty in defining the right population. This highlights one of the major challenges in PH-LHD: that is, how to appropriately classify patients hemodynamically to best reflect the changes occurring in the pulmonary vasculature. Pulmonary hypertension is defined as a mean PAP (mPAP) 25 mm Hg, with PAH including pulmonary artery wedge pressure (PAWP) < 15 mm Hg and pulmonary vascular resistance (PVR) 3 Wood units. For PH-LHD, a PAWP 15 mm Hg is required along with an mPAP 25 mm Hg. The challenge, however, is with patients who have a mixture of both pre- and post-capillary PH due to the progression of pulmonary vascular remodeling. This group has been commonly referred to as mixed PH or out-of-proportion PH, and the common hemodynamic markers used to define this group are transpulmonary gradient (TPG: mPAP - PAWP) 12 mm Hg and/or PVR 3 Wood units.2
During the Fifth World Symposium on Pulmonary Hypertension, the two following recommendations were instituted. First, in order to form a cohesive terminology, the term combined postcapillary and precapillary PH (Cpc-PH) should be used in place of out-of-proportion PH.1 Second, it was recommended that diastolic pulmonary gradient (DPG: diastolic PAP - PAWP) be used in lieu of TPG as the hemodynamic marker for PH-LHD since the diastolic PAP is less influenced by the PAWP and stroke volume compared to TPG. This recommendation was based on a study by Gerges et al. demonstrating that a TPG 12 mm Hg and a DPG 7 mm Hg was predictive of outcome in patients with postcapillary PH.3 The discussion points also focused on the importance of performing a skilled right heart catheterization with attention paid to obtaining the PAWP at the physiologically optimal point.
In subsequent studies, the DPG failed to serve as a predictive marker in the heart failure population. Furthermore, a low DPG also appears to correlate with outcome, thus a U-shaped relationship seems to apply in evaluating DPG and PH-LHD.4 Based on the collective data, the European Society of Cardiology/European Respiratory Society established a guideline recommending that patients with Cpc-PH adhere to the criteria of DPG 7 mm Hg and/or PVR > 3 Wood units (Table 1).5