Pulmonary vasoconstriction is a physiological phenomenon and mechanism in response to alveolar hypoxia or lower oxygen levels in the smaller, higher resistant pulmonary arteries and, to some extent, the pulmonary veins. The process of vasoconstriction of the pulmonary arteries serves to redirect blood flow within the vasculature away from poorly oxygenated parts of the lungs towards better-oxygenated portions in the lungs. Ventilation and perfusion matching is the physiological balancing process between air that reaches the alveoli and perfusion. Profusion is the blood reaching the capillaries of the alveoli and is predicated on the appropriate functioning of vasoconstriction of the pulmonary vasculature in lower-oxygen states. Poor oxygen availability to tissues has profound and overarching systemic ramifications manifesting in a plethora of pathologies starting within the lungs itself. Maintaining correct and appropriate oxygen homeostasis is a critical component for systemic stability and functioning, and it begins with the pulmonary vasculature and an intact pulmonary vasoconstriction reflex. The entire details of the pulmonary vasoconstriction mechanism is not fully understood, but a large portion of the complex process involves the activity of ion channels as well as several molecular and chemical agents. An understanding of how oxygen is delivered to the tissue and its importance renders relevance to the topic of pulmonary vasoconstriction.
The mechanism of hypoxic pulmonary vasoconstriction (HPV) is reliant on the appropriate functioning and response of the pulmonary vasculature in the presence of diminished oxygen availability. Approximately 250 million alveoli are present within each lung. Each one is a functional unit that serves in allowing the delivery of inhaled oxygen from the atmosphere to the blood, and from the blood, it expels carbon dioxide back into the atmosphere. The alveolus interacts with the pulmonary capillary to allow gas exchange. The pulmonary capillaries are an extension of the pulmonary arterioles which are an extension of the pulmonary artery which exits the heart from the right atrium and bifurcates, becoming the left and right pulmonary arteries.
Theories of the Vasoconstriction Reflex
Hypoxia needs to be present for the vasoconstriction reflex to initiate. There are contrasting views as to where hypoxia is first identified in the vasculature. The classical understanding suggested that hypoxia is initially identified within the pulmonary artery, whereas a new concept submits that low oxygen levels are detected at the interaction of the capillaries and alveoli. This latter concept further suggests that from the capillary/alveoli junction, gap junctions embedded throughout the pulmonary vascular endothelium assist in transducing an electrical signal to the pulmonary arterioles, causing them to constrict.
Original Understanding of the Vasoconstriction Reflex
In comparison to this newer understanding, the original mechanism is believed to involve voltage-gated potassium and calcium channels. These channels are located in the smooth muscle cells of the pulmonary arteries and are very sensitive to hypoxia. In addition to the critical roles of potassium and calcium in hypoxic pulmonary vasoconstriction, there are indications that there could be other ion channels contributing to HPV. These ion channels are the transient receptor potential vanilloid 4 (TRPV4) and the transient receptor potential canonical 6 (TRPC).
Hypoxic pulmonary vasoconstriction is an issue with the pulmonary vasculature. However, inappropriate and chronic vasoconstriction can lead to pulmonary hypertension which has systemic ramifications. The development of pulmonary hypertension creates an impediment for the heart, specifically the right side. Excess pressure within the pulmonary artery characterizes pulmonary hypertension. The right ventricle which propels poorly oxygenated venous return into the pulmonary artery will have to work excessively harder to overcome the greater pressures in the pulmonary circuit, leading to hypertrophy and muscle damage of the heart tissue on the right side. The grim sequelae of pulmonary hypertension are heart failure manifesting with systemic cyanosis and edema, and or death.
One of the preliminary tests performed is an echocardiogram to give credence to clinical suspicion and to legitimize further testing to confirm a diagnosis. Echocardiography will relate the physiological circumstances within the four chambers of the heart, specifically the right half, to provide insight to any excess pressure build up or inappropriate hypertrophy which is what is expected in pulmonary hypertension. In addition to the size of the right atrium and ventricle, the echocardiogram evaluates right ventricular ejection fraction through the tricuspid annular plane systolic excursion (TAPSE), another important variable in assessing for the presence of hypertension in the lung's vasculature.
Right Heart Catheterization
If preliminary findings warrant further investigation, a clinician would conduct a right heart catheterization to confirm a diagnosis. A right heart catheterization will provide information regarding the mean pulmonary artery pressure, right atrial pressure, and pulmonary artery occlusion pressure. It also can provide empirical information that would be utilized to calculate a transpulmonary gradient and the pulmonary vascular resistance.
Different Variables and Calculations
In a healthy individual at rest, the mean pulmonary artery pressure (mPAP) is 14 +/- 3 mmHg while a resting (mPAP) of greater than 25 mmHg would meet the criteria for a diagnosis of pulmonary hypertension. Pulmonary artery occlusion pressure (PAOP) and mean pulmonary artery pressure (mPAP) are variables in the calculations for determining transpulmonary gradient and pulmonary vascular resistance.
One of the most sensitive findings of right heart catheterization is the pulmonary artery occlusion pressure. It has been the most susceptible and prone incorrect measurement. It is import to keep in mind that there are five criteria delineated to make sure the interpretation of PAOP is valid.
Additional testing needs to be completed to rule out other disease processes that could be contributing to the pathology. These include spiral CT scans or ventilation-perfusion lung scan in the case of renal impairment to dismiss or identify the presence of thromboembolic activity within the lung's vasculature. Pulmonary function testing to identify and categorize the presence of any intrinsic lung disease that may be contributing. Additional high-resolution CT imaging can be helpful in finding the presence of disease in the parenchyma of the lungs. Potentially likely etiologies of pulmonary hypertension are connective tissue diseases and obstructive sleep apnea. They will be investigated with serological studies and polysomnography respectively. A frequent and quick test to obtain further information is the cardiopulmonary exercise test known as the 6-minute walk test. This basic test evaluates functional capacity which, in short, represents how much physical exertion a patient can make before feeling overwhelmed.
Classifications of Pulmonary Hypertension
The complete pathophysiology of pulmonary hypertension is not entirely understood. The current etiologies of pulmonary hypertension are stratified into five groups.
Idiopathic Pulmonary Hypertension
Of these groups, idiopathic PH has the least defined mechanisms and is the group that is still is being understood. There are two prevailing concepts to the origin and progression of idiopathic PH. The most prevalent understanding of what precipitates pulmonary hypertension was commonly believed to be derangement in the production and underproduction of local vasoconstrictors and dilators simply denoted as the vasoconstriction theory. The vasodilators include prostacyclin and nitric oxide, and the vasoconstrictors include thromboxane and endothelin.
Roles of Chemical and Molecular Agents in Idiopathic Pulmonary Hypertension
In the vasoconstriction theory, nitric oxide plays a critical role in maintaining appropriate vascular tone produced and regulated by two enzymes, nitric oxide synthase II and III. Patients with idiopathic pulmonary hypertension are found to have diminished levels of NO. Prostacyclin is a product of arachidonic metabolism, is an effective vasodilator systemically, and exerts effects on platelets as well. In patients with remodeling in the lungs vasculature, there are decreased levels of prostacyclin and the enzyme prostacyclin synthase, giving more validity to the correlation between the role of pulmonary arterial vasodilators and pulmonary hypertension. On the contrary, endothelin 1 is a systemic vasoconstrictor which is found in abnormally high quantities in idiopathic PH.
Newer Understanding of Idiopathic Pulmonary Hypertension
The new understanding that is becoming more accepted is more centered on the concept of endothelial and smooth muscle cell activity in the context of arterial remodeling. The issue in remodeling the vessels is specifically involving the extracellular matrix that creates the architecture in the vessel that contributes to increased vascular resistance. The bone morphogenetic receptor type 2 (BMR2) is involved with cell growth, proliferation, and osteogenesis. It is believed that a mutation in BMR2 is directly involved in idiopathic PH. Another process that can contribute to the pulmonary vasoconstriction is an inappropriately high sensitivity to depolarization in the smooth muscle cells within the vessels. This alteration in the resting potential set point is possibly altered due to potassium channel irregularities that cause increase availability of calcium.
Sleep Apnea and Pulmonary Hypertension
A distinct relationship exists between obstructive sleep apnea (OSA) and the existence of pulmonary hypertension (PH). The link of causation has not been established to define OSA as the direct singular cause of PH, however, an association is there. It is thought to believe that OSA contributes to PH by inducing hypoxia during sleep which creates a cycle of oxygen desaturation that leads to decreased nitric oxide synthase, endothelin derangements, and an increase of sympathetic tone.
Diagnosing Pulmonary Hypertension
Hypoxic pulmonary vasoconstriction manifests clinically as pulmonary hypertension. In order to fully properly diagnose pulmonary hypertension, tests must establish whether the clinical criteria has been met, what part of the vasculature is pathologic, the degree of pulmonary hypertension, and a potential cause. Diligent and appropriate investigations need to be conducted due to the ambiguous nature and usual lack of suspicion for pulmonary hypertension. Early detection is paramount to long-term morbidity and mortality. The initial process of diagnosis begins with detecting pulmonary hypertension in the clinical setting. A routine or situational ECG is one way that suspicion can be formed outside of a history and physical. Right hearted issues such as hypertrophy should be expected, regardless of whether the right atrium or the right ventricle are involved, overcompensating against the excess pressure of the pulmonary circuit.
For clinicians, in the context of pulmonary hypertension secondary to excessive and inappropriate pulmonary vasoconstriction, the roles are two-fold and extremely crucial. The physician has to have enough clinical acumen to extrapolate a suspicion for pulmonary vasoconstriction from a routine history and physical. The second layer to the clinician’s role is to make sure a thorough investigation is followed through, and if a diagnosis is obtained, swift and appropriate therapy is initiated to stave off the disease progression, limit morbidity, and prolong mortality.
Nonsurgical Treatment Options
Therapy will be catered to the patient's individual pathological profile. All pharmaceutical regimens are not always indicated for patients; however, if there are no contraindications, anticoagulation is recommended for all diagnoses of idiopathic pulmonary hypertension. If pharmacological therapy is indicated, agents such as phosphodiesterase-5 inhibitors, calcium channel blockers, and endothelin receptor antagonists can be utilized. If pulmonary vasoconstriction is refractory to pharmacological therapy or if the severity of disease is extreme, surgery can be an option. Patients with obstructive sleep apnea should be screened for pulmonary hypertension, and likewise, pulmonary hypertensive patients should be evaluated for sleep apnea because there could be an association. If a patient has sleep apnea, a continuous positive airway pressure (CPAP) mask is prescribed for the patient to wear during sleep.
Surgical options entail creating an anatomical environment that is conducive to relieving pressures on the right side of the heart with a procedure called an atrial septostomy producing a right-left shunt at the level of the atria. Once the disease reaches a state where correction is unattainable, lung transplantation options can be explored. In this scenario, both lungs are usually transplanted to lessen the potential for postoperative complications.
In conclusion, pulmonary vasoconstriction is an insidious process that is ambiguous in nature, allowing it to go undetected. When it is finally recognized, the destruction of associated systems and structures are often forgone. It is paramount to keep it in the differential and to address the possibility to prevent the devastating sequela that can ultimately lead to a patient’s demise.