Pulmonary blood flow and pulmonary hypertension: Is the pulmonary circulation flowophobic or flowophilic?

Abstract

Increased pulmonary blood flow (PBF) is widely thought to provoke pulmonary vascular obstructive disease (PVO), but the impact of wall shear stress in the lung is actually poorly defined. We examined information from patients having cardiac lesions which impact the pulmonary circulation in distinct ways, as well as experimental studies, asking how altered hemodynamics impact the risk of developing PVO. Our results are as follows: (1) with atrial septal defect (ASD; increased PBF but low PAP), shear stress may be increased but there is little tendency to develop PVO; (2) with normal PBF but increased pulmonary vascular resistance (PVR; mitral valve disease) shear stress may also be increased but risk of PVO still low; (3) with high PVR and PBF (e.g., large ventricular septal defect), wall shear stress is markedly increased and the likelihood of developing PVO is much higher than with high PBF or PAP only; and (4) with ASD, experimental and clinical observations suggest that increased PBF plus another stimulus (e.g., endothelial inflammation) may be required for PVO. We conclude that modestly increased wall shear stress (e.g., ASD) infrequently provokes PVO, and likely requires other factors to be harmful. Likewise, increased PAP seldom causes PVO. Markedly increased wall shear stress may greatly increase the likelihood of PVO, but we cannot discriminate its effect from the combined effects of increased PAP and PBF. Finally, the age of onset of increased PAP may critically impact the risk of PVO. Some implications of these observations for future investigations are discussed.

Keywords: pulmonary blood flow; pulmonary hypertension; shear stress.

Figure 1

Mean PAP vs. the pulmonary to systemic flow ratio (Qp:Qs) in normal adults[54] and people with an ASD. With relatively few exceptions, PAP remains normal or only mildly elevated despite markedly increased PBF. Siltanen[156] (n = 129): patients > 15 years old (mean = 31 years) who had ASD repair; Swan[101] (n = 24): 27 years old (mean) apparently unselected patients; Tworetsky[157] (n = 19): 12 years old (mean) patients who had ASD closure; Dexter[36] (n = 60): 3–57 years old apparently unselected patients. Colored symbols (small triangles and filled circles) depict individual patients (n = 84) from Weidman,[160] Nielsen,[159] and Kirklin.[158] Standard deviation bars are given when available.

Figure 2

Systolic PAP (sPAP) before and after surgical closure of ASD in 65 patients with PH. Most patients had considerable reduction in PAP after repair, indicating that a large component of the pre-operative PH was not due to PVO. (Note that this figure overestimates the fall in PVR with ASD closure since most patients had increased PBF prior to operation.) Systolic PAP was used as mean PAP and PVR was not available in all studies. Data are from seven studies and include only patients with systolic PAP > 50 mmHg. Patients were all adults except in Cohn[163] and Walker,[164] which included an indeterminate number of children. Time from surgery to the post-operative cath was 2 months to 10 years, except in one patient (2 weeks). Data do not reflect intra- and postoperative deaths, and underestimates the incidence of progressive PH since in some patients PAP increases with time after ASD closure.[–168]

Figure 3

Change in PVR after mitral valve intervention (MVI) to effect relief of mitral stenosis/regurgitation (circles, n = 61 patients) or closure of VSD (dots, n = 110 patients). Nearly all mitral valve patients patients had a large fall in PVR after relief of left atrial hypertension, while many patients with VSD had unchanged or increased PVR after repair. For mitral valve replacement/valvuloplasty: data are from six studies where PVR (usually not indexed) and left atrial pressure were included for individual patients before and after mitral valve repair, replacement, or balloon valvuloplasty. Patients had mitral stenosis, regurgitation, or both. In all studies, the patients were mostly adults in the third to seventh decade, but at least nine were in their teens. Post-procedure hemodynamics were obtained at least once, and usually several months after intervention. Only patients with pre-intervention PVR > 3 Wood units, and post-intervention LAP < 15 mmHg are included.[–66] For VSD repair, data are from seven reports and limited to patients with surgical VSD closure, who had pre- and post-operative cardiac catheterization, and the age of repair could be linked to hemodynamics. In some cases, data were estimated from figures. All patients were 2-18 years old, save for 3 older patients; 75 patients were 2-10 years old at operation. Some patients also had ASD and/or patent ductus arteriosus closure. Time from surgery to the post-operative cath was 4 months to 13 years, usually > 1 year. Unindexed PVR was converted to indexed PVR by assuming the body surface area for a male of average weight and height at the age of operation. Data do not reflect intra- and postoperative deaths, and underestimates the incidence of progressive PH since in some patients PAP increases with time after VSD closure.[–105107108161162]