Physiology, Pulmonary Circulation

Development

Around 15 days after fertilization, blood cell vessels begin forming outside the implanted embryo, creating the initial placenta. This is vital to maintaining fetal life as it provides a mechanism that delivers oxygen and nutrients to the developing baby and discards waste products. The fetus forms red blood cell precursors and initial vasculature by day 17. Between 3 and 4 weeks after conception, the fetal heart develops all 4 chambers. It begins beating on its own distinctly representative of its vitality separate from the mother's. 

Because the developing fetus uses the placenta to maintain oxygen saturation and exchange waste for nutrients, fetal circulation is designed to transfer blood around the organs not needed while the fetus is in the womb. Therefore, since blood does not need to enter the fetal lungs or liver, three shunts maximize the efficiency of blood flow. The placenta provides the fetus with oxygen-rich blood via the umbilical vein. Once inside the fetus, blood travels through the ductus venosus, directing blood from the umbilical vein around the liver and into the inferior vena cava. A portion of the blood from the inferior vena cava empties into the right atrium and is shunted through the foramen ovale, which transfers it directly into the left atrium, thus bypassing the right ventricle and the lungs. The remaining blood in the right atrium travels through the tricuspid valve into the right ventricle.[2] Instead of diverting into the lungs, blood in the right ventricle empties into the pulmonary artery connected to the aorta by the ductus arteriosus.[3]

Once the baby is delivered and takes his first breath, the high resistance in the lungs that was present during development drops dramatically. Since the baby no longer relies on the placenta for oxygenation, the umbilical vessels are ligated: blood can enter the lungs for oxygenation. The oxygen relaxes the pulmonary vessels and causes constriction and eventual closure of the portal shunts. Once these fetal shunts are fully closed, the neonate’s blood flow is identical to an adult's.[4]

Pathophysiology

In some patients, fetal circulation shunts remain patent after delivery. Usually, patients with an open fetal shunt are asymptomatic and may only have a cardiac murmur upon auscultation. A patent foramen ovale connects the right and left atria and is usually found as an incidental finding on an echocardiogram or after a cryptogenic stroke. In patients with a patent foramen ovale, there is a possibility that a thrombus from the lower extremity may bypass the lungs. This can be accomplished when the blood enters the right atrium, flows through the foramen ovale, and empties into the left atrium.[2] The thrombus could travel from the left atrium into the systemic circulation, where it can, unfortunately, be delivered to the brain, causing a thromboembolic cerebrovascular accident (CVA).

The most worrisome complication of pulmonary circulation dysfunction is a pulmonary embolism, which usually arises as a deep venous thrombosis (DVT) of the lower extremity. Rarely do DVTs occur without satisfying at least one of the three components of Virchow’s triad: hypercoagulability, endothelial damage, and venous stasis.[5] Certain genetic disorders like factor V Leiden, protein C deficiency, and protein S deficiency, along with more common conditions like pregnancy and cancer, are related to states of hypercoagulability.[6] Endothelial damage can occur from trauma or surgery, and venous stasis is commonly associated with periods of immobility either from traveling or disability. If the deep venous thrombus is dislodged from the lower extremity, it is pushed by deoxygenated blood back into the heart and then into the lungs, where it can lodge into a small pulmonary vessel. The clot can cause hemodynamic compromise to areas proceeding it if large enough. Automatically, pulmonary vessels in the area of the thrombus vasoconstrict which causes shunting of blood to non-occluded portions of the lung.[5]

Clinical Significance

Classically, a patient with a pulmonary embolism due to a DVT presents with symptoms of crushing, pleuritic chest pain, chest pressure, or dyspnea with a history of a swollen, painful lower extremity. Upon physical exam, tachycardia is almost always present. In most cases, the chest x-ray is unremarkable, but one or both of the classic chest x-ray findings are occasionally visible. Westermark's sign is a sharp delineation between the area of perfusion and hypo-perfusion within a vessel, indicating an embolism is blocking flow, and Hampton's hump presents as a wedge-shaped, focal opacity in the periphery of the lung.[5]

When clots form in the body, they are continually being reconstructed. Clotting factor XIII is responsible for cross-linking fibrin into a mesh. Plasmin lyses the fibrin bonds upon degradation and releases the fibrin degradation products called D-dimers. In some cases of suspected pulmonary embolisms, physicians may order blood samples to test a D-dimer. An elevated D-dimer level has high sensitivity but low specificity for a pulmonary embolism. A D-dimer can be elevated in the setting of any hypercoagulable state such as pregnancy, congestive heart failure, systemic lupus erythematosus (SLE), and other chronic diseases, this test is most useful when a pulmonary embolism is suspected in a younger patient with no co-morbidities. The gold standard for diagnosing a pulmonary embolism is computed tomography (CT) angiography. The contrast is given intravenously and will indicate areas of hypoperfusion caused by a thrombus. However, when there is a contraindication to this imaging study, such as in the setting of renal failure when contrast dye cannot be given, a pulmonary ventilation/perfusion (V/Q) scan can be performed.[5]

Another potential complication of pulmonary circulation is pulmonary arterial hypertension. Pulmonary arterial hypertension is defined by a mean pulmonary artery pressure greater than twenty-five millimeters of mercury and pulmonary vascular resistance greater than three millimeters of mercury, measured via right heart catheterization. Interestingly, pulmonary arterial hypertension can be caused by various circumstances, such as obstruction of the pulmonary arteries and arterioles, increased pulmonary vascular resistance, luminal thickening, vascular remodeling, and chronic inflammation.[4]

In pulmonary arterial hypertension, there is an increase in pulmonary vascular resistance, which the destruction of the pulmonary vasculature, chronic vasoconstriction, endothelial thickening, arteriole smooth muscle hypertrophy, and endothelial wall remodeling can cause. Thromboxane and endothelin-1 are believed to have increased activity, which causes enhanced vasoconstriction, while prostacyclin and nitric oxide, which function as vasodilators, have decreased efficiency. Because of these, blood vessels are narrowed, which causes higher flow rates and, thus, pressure in the vasculature. However, these cause increased pulmonary vascular resistance, which decreases endothelial integrity. The body naturally attempts to heal endothelial damage by sending coagulation factors to the intimal surface of the vessel.[7]

Left-sided heart failure commonly causes pulmonary venous hypertension. The left side of the heart has difficulty maintaining function. Therefore, blood is forced back into the lungs, increasing pressure in the pulmonary vein. In the case of left-sided heart failure due to valve failure, decreased ejection fraction, or volume overload, blood that should be ejected into systemic circulation backs up into the left ventricle, left atrium, and finally, the pulmonary veins. Increased pulmonary venous pressure can lead to capillary remodeling and elevated capillary permeability, causing fluid leakage into the lung bases. The most common cause of this is congestive heart failure due to left heart dysfunction and volume overload.[4]