The heart, lungs, and blood vessels represent an integrally coupled system. Sickle cell disease (SCD) is characterized by a diffuse, progressive vascular disease that not only directly damages cardiac microvasculature but also places abnormal mechanical stressors on the heart by increasing preload (anemia) and afterload (peripheral and pulmonary vascular damage). The heart may also be damaged by the sequelae of treatments for SCD, such as chronic transfusions. In this section, we focus on how the primary vascular physiology described in earlier sections impacts the integrated cardiovascular system.
Pathophysiology of Cardiovascular Disease
Cardiac output and pulmonary blood flow are increased in 30% to 60% of SCD patients to compensate for the anemia,1 comparable to pulmonary blood flow in a moderate atrial septal defect.2 Although acute increases in systemic and pulmonary blood flow increase wall shear stress, resulting in vasodilation, chronically elevated blood flow produces eccentric arterial remodeling and cardiac dilation.3 By Laplace’s law, arterial and cardiac chamber dilation increases tensile stress, leading to eccentric vascular remodeling and compensatory wall thickening.4,5 In advanced pulmonary hypertension, arterial dilation ultimately results in decreased wall shear stress, which may impair further shear-mediated nitric oxide signaling.6 Arterial dilation also causes decreased vascular compliance, increasing the afterload on the right and left ventricles.2
Chemical insults to vascular endothelia result from systemic hypoxia, ischemia-reperfusion injury, vascular inflammation, and products of red cell fragmentation and frank intravascular hemolysis; mechanisms of these processes have been described in previous chapters. Increased erythropoiesis also reinforces these processes, because proerythroblasts release potent chemokines including vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF).7 In addition, sickle erythrocytes generate a significant amount of reactive oxygen species,8 which can further potentiate vascular and cardiac toxicity. Free heme may further augment PlGF release through induction of erythroid Krüppel-like factor (EKLF)9 and Nrf2-mediated antioxidant response.10 Although VEGF polymorphisms offer some prognostic value with respect to vaso-occlusive risk,11 a central role for VEGF in chronic vasculopathy has not been defined. In contrast, PlGF overexpression promotes pulmonary hypertension in normal mice by stimulating endothelin release12,13 and contributes to pulmonary emphysema.14 PlGF increases airway hyperresponsiveness by stimulating interleukin-13 and leukotriene release.15 PlGF also promotes vascular leak, edema, and inflammation via endothelial cells and monocytes16,17 and promotes a procoagulant state by increasing tissue factor and PAI-1 expression.18 PlGF also modulates adverse vascular remodeling through VEGF release and via prostaglandin mediated pathways.19-21 The hyperactive erythropoiesis, erythropoietin, free heme, and hypoxia seen in SCD contribute to increased production of PlGF.9,10,15,22-24
Thus, sickle hemoglobin (HbS) triggers progressive microvascular damage and vascular dysfunction through multiple interconnected mechanisms. The systemic and pulmonary microvasculature suffers mechanical insults from poorly deformable, adhesive, and sickled erythrocytes, manifesting as microinfarcts in the heart, kidney, spleen, liver, ...