Adult Pulmonary Arterial Hypertension: The role of nitric oxide

The role nitric oxide plays in the regulation of pressures in the pulmonary artery is a relatively new discovery. This article will examine the history of nitric oxide as a vasodilator, the new classifications of pulmonary hypertension and the reason adult nitric oxide studies are performed in the cardiac catheterization lab. The History of Nitric Oxide as a Vasodilator Nitric oxide, as a gas, was first discovered in 1772 by Joseph Priestly, also known as nitrogen monoxide, is composed of one atom of nitrogen and one atom of oxygen. It is one of the few gaseous signaling molecules (a group of molecules that mediate communications between cells and are involved in regulation of a variety of physiological and pathological events such as control of cell growth, differentiation, and functioning), known to man. Nitric oxide is a highly reactive chemical compound with a half-life of only a few seconds. This gas binds to hemoglobin easily and diffuses freely across the cell membrane, making it an ideal signaling molecule within and between cells. Experiments with nitric oxide as early as 1867 led to its use in treating patients with angina. Nitroglycerin, in pill form, was first used in the United States during World War I, when it was discovered that factory workers who were exposed to nitroglycerin while packing shells had very low blood pressures. Nitroglycerin serves as a vasodilator because it is able to convert to nitric oxide in the body. In 1980, Furchott and Zawadski showed that when strips of blood vessels were nurtured in an organ bath and chemically stimulated, the muscles relaxed. If the endothelium was absent, the smooth muscles of the blood vessel lost their capacity to make the blood vessel expand. This showed that a previously unrecognized substance must exist that regulated the tone of the smooth muscles of blood vessels. They referred to the mystery agent as “endothelium derived relaxing factor” or EDRF.¹ Labs around the world began to try to find this mystery agent among the body’s complex biomolecules. In 1992, Murad, Furchott, and Ignarro discovered that EDRF was actually nitric oxide. This discovery showed that NO is produced from the amino acid L-arginine by the enzymatic action of nitric oxide synthase (NOS). NOS3, or eNOS, activates cyclic guanosine monophosphate, also known as cGMP, which then induces smooth muscle relaxation by multiple mechanisms.² Nitric oxide relaxes the smooth muscle in the walls of the arterioles. At each systole, the endothelial cells that line the blood vessels release a puff of NO, and this diffuses into the underlying muscle cells, causing them to relax and thus permit the surge of blood to pass through easily. One of the many causes of pulmonary hypertension is the lack of production or response to nitric oxide. The New Classifications of Pulmonary Hypertension Pulmonary hypertension is an increase in resistance and pressure in the pulmonary arteries, pulmonary veins, or pulmonary capillaries. Normal pulmonary artery pressures are 15-30mmHg systolic, 8-15mmHg diastolic and 10-17mmHg mean. Abnormal mean PA pressures are >25mmHg at rest and > 30mmHg on exertion. The sequences of events in pulmonary arterial hypertension are increased pulmonary arterial pressure, endothelial dysfunction, narrowing of the pulmonary vascular bed, right ventricular dilatation and finally, right heart failure. Originally, pulmonary hypertension was classified as either primary or secondary. The World Health Organization (WHO), in order to better treat patients with this disease, has reclassified pulmonary hypertension into the following categories:3 • Group 1 – Pulmonary arterial hypertension • Group 2 – Pulmonary hypertension associated with left heart failure • Group 3 – Pulmonary hypertension associated with lung diseases • Group 4 – Pulmonary hypertension due to chronic thrombotic and or embolic disease • Group 5 – Miscellaneous Pulmonary arterial hypertension (PAH) represents Group I within the pulmonary hypertension (PH) WHO clinical classification system: • Idiopathic pulmonary arterial hypertension (IPAH) • Familial pulmonary arterial hypertension (FPAH) • Associated with pulmonary arterial hypertension (APAH) • Collagen vascular disease • Congenital shunts • Portal hypertension • HIV infections, drugs, toxins Idiopathic pulmonary arterial hypertension has no known cause, and results in elevated pulmonary arterial pressures, which eventually lead to endothelial dysfunction and right heart failure. This disease is more common in women between the ages of 21 and 40 years. Symptoms may include shortness of breath, excessive fatigue, dizziness, weakness, ankle swelling, syncope and chest pain. Nitric Oxide Studies in the Cath Lab In order to determine whether or not there is a vasodilatory effect in the smooth muscle cells of the pulmonary arteries when nitric oxide is delivered to these cells, adult nitric oxide studies are performed in the cardiac catheterization lab. These studies are performed in order to optimize treatment based on findings as to whether or not the patient is a nitric oxide responder. Nitric oxide gas is used because of its strong effect on the pulmonary vasculature and myocytes. Patients who are thought to have idiopathic arterial pulmonary hypertension are scheduled for right heart catheterization with nitric oxide study. Pressures are measured in the right heart with a Swan-Ganz catheter. Fick and thermodilution outputs are obtained, as well as saturation runs performed, in order to exclude intracardiac shunts. Stroke volume, systemic vascular resistance, pulmonary vascular resistance and left ventricular end diastolic pressure are all calculated. Patients who have an end expiration pulmonary capillary mean wedge pressure of greater than 15mm/Hg are excluded from the study, as a high mean PCWP (which is a reflection of left atrial pressure) may indicate left ventricular dysfunction, rather than pulmonary hypertension. A respiratory therapist administers 40 parts per million of nitric oxide and oxygen for five minutes to the patient via mask. Right heart pressures and right heart functions are reanalyzed. The patient is determined to be a positive nitric oxide responder if the mean PA pressure is decreased by greater than 10mmHg, the cardiac output is increased, and the systemic blood pressure is minimally reduced or unchanged. Nitric oxide studies help to identify patients who may benefit from treatments with calcium channel blockers. These patients have been shown to have a more favorable prognosis. Previous studies have concluded that only 10-15% of patients undergoing this study are nitric oxide responders. Nitric oxide studies performed at Maine Medical Center are made possible by a strong collaboration between the cardiologist and pulmonologist, in addition to very knowledgeable cardiac catheterization lab staff, a mix of registered cardiovascular technologists, x-ray technologists, nurses and respiratory therapists. The cardiologist and pulmonologist have together developed and implemented a protocol for pulmonary hemodynamic assessment in the cardiac catheterization lab. All data is recorded and collected during the procedure, and then transferred to the pulmonologist for review and further treatment of the patient. Approximately 15 nitric oxide studies were performed at Maine Medical Center in 2008, and we have already surpassed that number for 2009. Nitric oxide studies have been performed at this hospital since 2003. Summary Idiopathic pulmonary arterial hypertension is a serious disease which predominately affects women between the ages of 21 to 40 years. The role of nitric oxide in the regulation of pulmonary artery pressures has led to performing nitric oxide studies in the cardiac catheterization lab. These studies help to determine whether or not there is a vasodilatory effect in the smooth muscles cells of the pulmonary arteries when nitric oxide is administered via mask. Data collected from the nitric oxide study leads to various medical treatments for patients who have pulmonary hypertension and who are proven to be nitric oxide responders. Donna Gagne can be contacted at dgagne1@roadrunner.com

1. Wright P. Nitric oxide: from menace to marvel of the decade. A briefing document prepared for the Royal Society and Association of British Science Writers. Available at http://www.absw.org.uk/briefings/nitric%20oxide.htm. Accessed June 25, 2009.

2. Wells W. From explosives to the gas that heals: nitric oxide in biology and medicine. Available http://www.beyonddiscovery.org/Includes/Dialogs/ExternalLink.asp?ID=&URL=http%3A//www.nobel.se/medicine/laureates/1998/index.html. Accessed June 25, 2009.

3. Simonneau G. Clinical Classification of Pulmonary Hypertension. Available at http://content.onlinejacc.org/cgi/reprint/43/12_Suppl_S/5S.pdf.