THE MECHANISMS LEADING TO PULMONARY ARTERIAL HYPERTENSION GUIDE TREATMENT FOR THE DISEASE?
MILTON PACKER, M.D

The most common cause of pulmonary hypertension is an increase in pulmonary venous pressure, generally resulting from heart failure due to left ventricular systolic dysfunction. A variety of neurohormonal mechanisms are activated in patients with left heart failure (renin-angiotensin system, sympathetic nervous system and aldosterone), and interference with these mechanisms with the use of angiotensin converting-enzyme inhibitors, beta-blocers and aldosterone antagonists can slow the progression of heart failure and reduce the risk of death. As a result, physicians routinely treat patients with left ventricular systolic dysfunction with a broad range of neurohormonal antagonists. Therapeutic efforts are made to interfere with as many of these deleterious neurohormonal mechanisms as possible, even if the patient’s symptoms respond symptomatically to treatment with a single drug.

In contrast, some patients have pulmonary hypertension as a result of a primary pulmonary arterial disease, which may result from vasoconstriction or vascular remodeling, or both. Such patients generally have normal left ventricular function and left ventricular filling pressures, and they respond very favorably to pulmonary vasodilators, such as endothelin antagonists and prostacyclin (epoprostenol). These drugs are capable not only of antagonizing vasoconstriction, but also of modulating with neurohormonal mechanisms that can contribute to pulmonary vascular remodeling. Given these observations, should physicians pursue a strategy for patients with pulmonary arterial hypertension and right ventricular overload that is similar to the strategy currently used to manage patients with left ventricular systolic dysfunction? Should physicians treating patients with pulmonary arterial hypertension seek to modulate with as many deleterious neurohormonal mechanisms as possible, even if the patient’s symptoms respond symptomatically to treatment with a single drug?

A variety of vasoconstrictor and vasodilator mechanisms has been shown to be deranged in patients with pulmonary arterial hypertension. Among the vasoconstrictors, patients with pulmonary arterial hypertension are known to have increased uptake of serotonin, increased release of thromboxane A2, and increased expression of endothelin within the abnormal pulmonary vasculature. Circulating levels of endothelin are directly related to the level of pulmonary arterial systolic pressure. Among the vasodilators, patients with pulmonary arterial hypertension have a reduced synthesis and release of prostacyclin and diminished synthetic machinery for nitric oxide.

These observations make clear that the normal balance between serotonin, thromboxane and endothelin (on one hand) and prostacyclin and nitric oxide (on the other hand) is disrupted in patients with pulmonary hypertension, such that the vasoconstrictor systems become dominant and the vasodilator systems become dormant. The net result of these interactions is platelet activation, vasoconstriction and vascular proliferation, all of which conspire together towards the development of pulmonary hypertension.

What can physicians do to address this imbalance? Physicians can administer prostanoids (e.g., epoprostenol) to address the deficiency of prostacyclin; similarly, they can administer phosphodiesterase type 5 inhibitors (e.g., sildenafil) to boost the levels of nitric oxide. Currently, the only approved approach to antagonizing the vasoconstrictor element of pulmonary hypertension is treatment with endothelin antagonists (e.g., bosentan). Antagonism of endothelin remains critical for most patients, since endothelin can aggravate the thromboxane-prostacyclin imbalance, deplete nitric oxide and boost responsiveness to serotonin.

Should patients with pulmonary arterial hypertension receive treatment with endothelin antagonists, phosphodiesterase 5 inhibitors and prostanoids, even if their symptoms are substantially ameliorated with the use of a single drug? Clinical trials to date support the use of combined neurohormonal modulation in the treatment of pulmonary hypertension, and additional trials are in progress that are likely to support this therapeutic approach. Until these trials are completed, physicians should remember that most patients with pulmonary hypertension who respond symptomatically to a single drug continue to demonstrate dangerously elevated levels of pulmonary arterial pressure, which are known to have adverse prognostic significance.