Altered systemic shear stress has been shown to have a detrimental effect on cardiovascular health. As an initial step in elucidating whether similar biomechanical forces adversely affect pulmonary vascular health, we quantified the mean WSS in patients with PAH as compared to age- and sex-matched controls. We found significantly lower wall shear stress in the pulmonary arteries of five subjects with moderate or severe PAH compared to control subjects using combined magnetic resonance imaging and computational fluid dynamics to visualize and quantify subject-specific, three-dimensional hemodynamic conditions. This study also provides novel insight into the time-varying blood flow features that exist in the pulmonary vasculature in health and disease and suggests a mechanism by which conditions of low shear stress may result in disease progression.
Numerous secondary observations can be made about alterations in velocity and flow in the pulmonary vasculature of PAH. The swirling, high-wall-velocity flow noted in normal subjects at rest did not occur in PAH patients, thus leading to significantly lower wall shear stresses. The most notable difference in flow features between a PAH patient and a normal subject, as shown in Figures and , are the higher, swirling velocities along the wall in the normal subject. In comparison, flow is basically stagnant for more than half of the cardiac cycle in the PAH patient, with higher flow velocities along the wall only occurring at peak systole. These higher flow velocities along the walls of the proximal vessels in normal subjects led to an overall six times higher wall shear stress than in PAH patients when compared across all subjects. Interestingly, this difference in wall shear stress was diminished in the distal vasculature, likely due to pruning of the distal arteries, thus leading to similar distributions of flow.
It has been extensively demonstrated in the systemic circulation that wall shear stress modulates endothelial function. Specifically, systemic increases in WSS result in elevated expression of eNOS.[3
] Nitric oxide is also a primary modulator of pulmonary vasodilation and target of PAH drug therapies, such as sildenafil.[29
] In addition, WSS alters pulmonary expression of Hsp90, an activator of eNOS, NAD(P)H dehydrogenase quinone 1, an antioxidant, monocyte-chemotactic protein 1, and platelet endothelial cell adhesion molecule 1.[28
] Reduction in angiotensin-converting enzyme has also been shown with increases in pulmonary vasculature shear stress.[37
] Therefore, one could conclude that dramatic changes in the WSS of the pulmonary vasculature, as we demonstrated in PAH, would have significant effects on pulmonary endothelial health and remodeling.
Our findings may elucidate one of the mechanisms by which epoprostenol improves patient outcomes, results in long-term reductions of pulmonary vascular resistance, and partially reverses disease progression.[38
] Epoprostenol has been shown to significantly affect cardiac output and pulmonary vascular resistance and to cause long-term vasodilation despite lack of response to acute vasodilator testing. This may suggest a unique mechanism of action when given chronically.[38
] We propose epoprostenol may alter wall shear stress in the pulmonary arteries by increasing cardiac output resulting in a positive remodeling response and long-term vasodilation. However, our current therapies at best stabilize but do not reverse the process. Perhaps this frustration is because we are combating two entities: the disease itself and the resulting abnormal biomechanical effects on the endothelium and gene expression. If shear stress is found to be a major determinant of and contributor to PAH, a target of future therapies may be alteration of the biomechanical environment as a means of reversing disease progression. Great interest now exists in using more aggressive therapy, e.g., epoprostenol, earlier in the disease treatment algorithm to get the most effect possible early on. This study may lend additional support to this proposed approach.
Clinically, assessment of wall shear stress by magnetic resonance, an imaging modality with increased utilization in clinical practice for the evaluation of right ventricular function, may serve to stratify disease severity and monitor the efficacy of existing and emerging therapies. Currently, symptomatology and PVR are the primary methods of assessing disease severity and response to therapy. However, measurement of WSS may prove to be a more comprehensive, non-invasive metric for tailoring therapy and determining prognosis.
The primary limitations of this study are the small number of patients and the severity of their disease. While there was an order of magnitude difference in WSS for each patient compared to control, this represents a small study of only five severe PAH patients. Of note, the broad age range of patients (16 to 50) was purposely chosen to increase the heterogeneity of the patient population and, therefore, improve possible applicability of findings. While this pilot study found a significant difference in WSS in PAH patients, and may lead to further advances in the basic science of this disease, future work must investigate the use of these non-invasive imaging and CFD techniques in a greater number of patients including a “healthier” PAH population to determine the sensitivity and specificity of these methods and clinical applicability.
This study represents the first time that three-dimensional hemodynamic conditions have been quantified in patient-specific models of pulmonary arterial hypertension and is an important step toward elucidating the role of shear stress in regulating pulmonary artery endothelial cell dysfunction. Our results point to a biomechanical mechanism as a component of pulmonary endothelial cell dysfunction and further progression of the disease. As distal resistance increases, flow is decreased in the enlarged proximal vessels, leading to decreased wall shear stress, which is known to negatively impact endothelial cell health. This shear-mediated endothelial dysfunction can lead to further remodeling of the proximal vessels, as well as downstream remodeling via endocrine signaling, resulting in worsening of the disease and further decreases in wall shear stress. All of these changes suggest a contribution of the unhealthy disease state to disease progression, that is, PH begets PH.