Pulmonary Hypertension
PKGhatak, MD
There are two separate circulatory systems - the greater and lesser circulatory systems. The greater system consists of the left atrium, left ventricle, aorta and its extensive branches to supply nutrients and oxygen to every living cell. This system is also called Systemic Circulatory System. The lesser circulatory system consists of the right atrium, right ventricle and pulmonary artery and its branches to lung alveoli. This is called the Pulmonary Circulatory system and this system delivers carbon dioxide to the lungs for elimination by ventilation and carries fully saturated oxygenated blood to the left atrium.
The circulating blood in the arterial tree exerts lateral pressure on the wall of the blood vessels and must overcome resistive wall pressure to propel forward. This wall resistance is called peripheral vascular resistance. This vascular resistance is commonly called Blood pressure - should be correctly called Systemic BP and Pulmonary BP.
Systemic blood pressure is easily measured on the arm by a BP instrument, either a mercury manometer or indirectly by a digital BP instrument which is properly calibrated. To measure the pulmonary arterial BP, a catheter must be inserted in the subclavian vein or femoral vein, then advanced to the right atrium, right ventricle to the Pulmonary artery and then record the pulmonary arterial pressure. This invasive procedure is not practical for clinical practice.
In recent years, the Doppler Echocardiography and supplemented by 12 lead ECG, have to a greater extent, made monitoring pulmonary arterial BP much simpler and practical. The normal systemic BP is 120/80mm Hg and the normal pulmonary arterial BP is 20/10 mmHg.
These two circulatory systems are interconnected. The venous return of the systemic circulation comes to the right atrium via the superior vena cava and inferior vena cava. The venous blood from pulmonary circulation returns to the left atrium by pulmonary veins. This means diseases/ conditions of one, eventually, involve the other system.
Two other numbers are important in clinical practice - Mean Arterial Pressure (MAP) and Pulmonary Capillary Wedge Pressure (PCWR). MAP is the tissue perfusion pressure. The PCWR is a good approximation of the left atrial pressure.
MAP is calculated: MAP= (systolic BP /3) + (2x diastolic BP / 3).
The pulmonary artery/capillary wedge pressure is measured by a Swan Ganz catheter. This is obtained by advancing the catheter tip to the distant pulmonary arteriole and then inflating a small balloon to prevent pulmonary artery blood flow temporarily. The normal PCWR is 8 to 10 mm Hg.
In critically ill patients, pulmonary vascular resistance (PVR) is measured several times a day. PVR guides in adjusting fluids and vasopressor therapy, adjustment of ventilator settings among other therapies. Pulmonary vascular resistance is calculated at the bedside from Swan Ganz catheter values. Pulmonary artery pressure(PAP), pulmonary artery wedge pressure (PCWP) and cardiac output (CO) are necessary to calculate the PVR.
PVR =(PAP - PCWR) / CO.
In clinical medicine, PVR is expressed by using the Wood Unit. Cardiac output is determined by thermodilution using cold saline. Woods unit is calculated using formula PVR = 80 x (PAP - PCWP) / CO. The normal PVR is 1 wood unit, a 3 Wood Unit is Pulmonary Arterial Hypertension or simply Pulmonary Hypertension. In PAH the mean pulmonary BP is over 25 mm Hg, and PCWP is over 15mm Hg.
In physics, the Hagen-Poiseuille equation is used to determine the resistance of the tube using a formula R= 8 x L. n. r>4 (>4=raise to the power 4). Where R stands for resistance, L for the length of the tube, n for the viscosity of the fluid, and r for the radius of the tube. In clinical medicine, the same equation remains valid. Variation of these parameters leads to pulmonary hypertension.
Pathological changes leading to hypertension:
Even a casual look at the Hagen-Poiseuille equation points out that a change in the lumen of the artery leads to a marked increase in BP. Regardless of different causes of PAH, there are common pathological changes in the pulmonary arterioles that produce narrowing of the arteriole lumen, increase PVR, hypertension and consequently right ventricular hypertrophy and cardiac failure and death. Pathological lesions are characterized by enhanced arteriolar smooth muscle contractility, dysfunctional arteriole due to aberrant remodeling of both endothelium and muscle layers and finally the microthrombi in capillaries.
Several of the following pathways are known to alter and result in pulmonary hypertension:
Nitrous oxide (NO) + soluble Guanylate cyclase pathway. The endothelial cells produce NO which binds with guanylate cyclase that produces guanosine triphosphate then transforms to guanosine monophosphate which is a potent vasodilator. It also prevents platelet aggregation and microthrombi.
Prostacyclin + Thromboxane A2 pathway. Prostacyclin is produced by the endothelial cells of arterioles. Prostacyclin binds with surface receptors of the smooth muscle cells, then activates ATP (adenosine triphosphate), and finally becomes cyclic AMP (adenosine monophosphate). AMP is anti-inflammatory and prevents platelet microthrombi.
Endothelin pathway. Endothelin is a peptide, produced by the cell membrane of endothelial cells. It is a potent vasoconstrictor. Also produce smooth muscle hypertrophy, cell migration and fibrosis.
The reversible Hypoxic pathway. The sympathetic nerve fibers abundantly supply even the smallest branches of pulmonary arterioles. The system is activated by chemoreceptors located in the carotid and aortic bodies. These receptors monitor PaO2 (partial pressure of oxygen); hypoxia causes reflex vasoconstriction and in prolonged hypoxemia migration of cells in and around arterioles produces fibrosis.
Clinical Classification of PAH:
PAH is categorized into 1. idiopathic, 2. familial, 3. secondary to other diseases, of which the most often are scleroderma and other collagen vascular diseases, HIV infection, portal hypertension, congestive heart failure. 4. Drug induced and toxins.
Familial cases are due to the mutation of genes, the important gene mutations are: BMPR II, AIK I, ENG, SMAD 9, CAV 1, KCNK 3.
Drugs responsible for PAH are - Aminorex, Fenfluramine, Dexfenfluramine, Rapeseed oil, Benfluorex, several Serotonin reuptake inhibitors (SSRIs). Toxins - Tobacco smoke, chemical solvents.
Therapeutics:
There are no cures for pulmonary hypertension. Medications used for the treatment of systemic BP are ineffective in pulmonary hypertension. Treatment of pulmonary hypertension produces only slowing down the progression of the disease.
The following groups of drugs are used in pulmonary hypertension-
Phosphodiesterase inhibitors. - Sildenafil and Tadalafil. Adenosine monophosphate and Guanosine monophosphates are converted to cyclic forms (c-AMP & c-GMP) by the action of adenylyl-cyclase and guanylyl-cyclase respectively. Cyclic AMP and cyclic GMP have a multitude of cellular functions including cell proliferation and growth. c-AMP and c-GMP are broken down by Phosphodiesterase. Sildenafil and Tadalafil inhibit the action of diesterase.
Soluble Guanylate cyclase stimulators. - Riociguat. It increases intracellular cGMP.
Prostacyclin analogs. - Epoprostenol, Treprostinil, Iloprost. Prostacyclin produces smooth muscle relaxation, lowers pulmonary blood pressure, acts as an anti-inflammatory, inhibits platelet microthrombi.
Prostacyclin receptor agonist. - Selexipag. It is a vasodilator and prevents platelet adhesion.
Endothelial receptor antagonist. - Bosentan, Ambrisentan, Macitentan. Endothelin is a vasoconstrictor and increases pulmonary BP. These drugs prevent binding Endothelin to its receptors and blunt endothelin actions.
Additional agents used in the treatment of pulmonary hypertension are Oxygen, diuretics, nutrition and pulmonary rehabilitation.
Pulmonary hypertension detection by doppler echocardiogram is very useful for the diagnosis of new cases and monitoring the effects of therapy. More research is needed in pulmonary hypertension and in finding effective and less toxic drugs.
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