Does Pulmonary Vasoconstriction Play an Important Role in Patients with Primary Pulmonary Hypertension?

presence of pulmonary hypertension at rest, there is no morphologic study measuring the extent of vascular disease or the severity of interstitial disease in relation to pulmonary hypertension. The poor response of the patients with interstitial disease to hydralazine was comparable to the observations of another group, which had also used vasodilators in similar patients. The lack of response may indicate that vasoconstriction plays a relatively small part in the mechanism of the pulmonary hypertension. The use of bleomycin to produce an interstitial lung disease in animals may permit study of the mechanisms underlying the development of pulmonary hypertension. The question was asked, how important is pulmonary hypertension in the prognosis of patients with interstitial lung disease? While no data specifically address the role of pulmonary hypertension in patients with severe sarcoid, these patients have a high mortality and frequently develop right heart failure. Similarly, in COPD poor survival has been reported to be correlated with the presence of pulmo nary hypertension.

With regard to scleroderma, it was pointed out that there may be patchy fibrosis in both arteries and veins, medial hypertrophy, and even plexogenic lesions. There is no other disease which can give rise to such a variety of vascular abnormalities. The presence of plexogenic lesions in some patients raises the possibility of an overlap with primary pulmonary hypertension. The reactivity of the pulmonary vascular bed in some patients is illustrated by the severe pulmonary hypertensive response of the patient given iced saline solution during cardiac output measurement. That the pulmonary hypertensive response to cold also applied to environmental cold has been demonstrated in calves and included the observation of pulmonary venoconstriction. The mechanisms raised as possibly being responsible for the pulmonary hypertension included increased renin release, augmented sympathetic tone, myocardial ischemia, and pulmonary venospasm. The rise in right atrial pressure was considered to be unprecedented and unexplained.

Does Pulmonary Vasoconstriction Play an Important Role In Patients with Primary Pulmonary Hypertenslon?* A Skeptic's View of Vasodilator Therapy Milton lbcker, M.D. t

Despite isolated reports of dramatic hemodynamic and clinical improvement over the past 30 years, most patients with primary pulmonary hypertension fail to benefit from treatment with vasodiIator drugs and many develop serious adverse reactions. The failure of this approach strongly suggests that pulmonary vasoconstriction does not play an important role in the pathogenesis of this disorder.

B

ecause vasodilator drugs have proved to be a useful approach to the management of patients with systemic hypertension and left ventricular failure, 1 there has been great interest in their application in the treatment of patients with primary pulmonary hypertension. This therapeutic approach makes a number of assumptions that need to be critically evaluated: (1) pulmonary vasoconstriction plays an important role in a significant number of patients with primary pulmonary hypertension; (2) pulmonary vasoconstriction is pharmacologically responsive to drug therapy; (3) drugs can be developed that selectively antagonize this vasoconstrictor response; and (4) the benefits of drug therapy can be sustained for long periods with few adverse reactions. Most of the evidence that pulmonary vasoconstriction plays an important role in the pathogenesis of pulmonary hypertensive states is derived from the study of patients with

-From the Division of Cardiology, Department of Medicine, Mount Sinai School of Medicine of The City University of New York. tRecipient of a Research Career Development Award (K04-HL01229) from the National Heart, Lung and Blood Institute, Bethesda, Maryland. ReprInt requem: Dr: lbcker, Mount SInaI Hospital,l00th Street and

Fifth Avenue, New York CUy10029

hypoxic pulmonary hypertension and reactive pulmonary hypertension associated with mitral valve disease, in whom a dramatic reduction of pulmonary artery pressures follows specific therapeutic interventions, such as oxygen therapy and mitral valve surgeryY Unfortunately, there is little evidence that pulmonary vasoconstriction contributes to the clinical state of patients with primary pulmonary hypertension. Although the presence of medial hypertrophy in the pulmonary arterioles of affected patients4,5 and the association of primary pulmonary hypertension with disorders of known vasospastic origin4,5 suggest that pulmonary vasoconstriction is important in patients with primary pulmonary hypertension, the ultimate test of this hypothesis is the demonstration that hemodynamic and clinical improvement follows the administration of pulmonary vasodilator drugs to patients with this disorder. Unfortunately, our personal experience suggests that a successful therapeutic outcome following the use of currently available drugs is distinctly uncommon. It remains unclear, however, whether our unfavorable experience is due to the fact that the importance of pulmonary vasoconstriction has been overstated or that currently available drugs are seriously flawed in their ability to achieve this goal. EARLY EXPERIENCE WITH VASODILAn>R DRUGS

Initial attempts to dilate the pulmonary vasculature pharmacologicallyin patients with primary pulmonary hypertension were cautiously conducted with drugs that were administered directly into the pulmonary artery and had a brief CHEST I 88 I 4 I OCTOBER. 1985I Supplement

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duration of action. These preliminary studies suggested that pulmonary vasoconstriction was important in some patients with this disorder. Isolated case reports noted short-term hemodynamic improvement following the administration of acetylcholine," tolazoline," phentolamine, g and isoproterenol;lo.u unfurtunately, the pulmonary vasculature in most patients in whom these drugs were tested proved unresponsive to these interventions.P'" The need for parenteral administration was the primary limitation of these drugs; even if hemodynamic improvement was observed, attempts to maintain any benefit with long-term oral or sublingual drug administration generally proved to be ineffective, impractical, or associated with disabling GI reactions. is-'4 The next stage in the development of vasodilator drugs fur patients with primary pulmonary hypertension was the therapeutic application of direct-acting vasodilator agents. Clinical investigators reasoned that a-adrenergic antagonists and l3-adrenergic agonists failed because the sympathetic nervous system was not involved in the pathogenesis of pulmonary vasoconstriction in most patients with this disorder; hence, a vasodilating agent that acted directly on the pulmonary circuit might exert beneficial effects not seen previously. The first direct-acting drug used successfully in patients with primary pulmonary hypertension was diazoxide. Given directly into the pulmonary artery, Wang and colleagues" first noted that the drug produced marked increases in cardiac output and decreases in pulmonary vascular resistance in three patients, followed by clinical improvement during long-term oral treatment. However, diazoxides long duration of action proved potentially dangerous. In patients in whom the magnitude of systemic vasodilation greatly exceeded that seen in the pulmonary circuit, intravenous administration of the drug resulted in prolonged and profound systemic hypotension that occasionallyled to catastrophic clinical events.":" Furthermore, even in patients in whom the initial responses to diazoxide were favorable, long-term therapy was frequently associated with diabetes, fluid retention, hirsutism, and GI distress." Because of the frequent occurrence of adverse reactions with diazoxide, other direct-acting vasodilator drugs were investigated in the hope that they might produce beneficial hemodynamic effects that were well tolerated. Rubin and Peter" showed that oral hydralazine markedly lowered pulmonary vascular resistance and increased cardiac output in four patients with primary pulmonary hypertension, without causing important changes in systemic arterial pressure. These beneficial effectswere seen at both rest and during exercise, persisted during long-term treatment with the drug, and were accompanied by symptomatic improvement. Our experience" with hydralazine in 13patients with primary and secondary pulmonary hypertension, however, contrasts dramatically with that of Rubin and Peter. Hydralazine produced only moderate pulmonary vasodilation in our patients, and the decrease in resistance in the systemic circulation exceeded that in the pulmonary circuit in all patients but one; this patient was the only one whose condition improved clinically during long-term therapy. In most of our patients, systemic arterial pressure fell and heart rate increased markedly; symptomatic hypotension was observed in four of our 13 patients, one of whom died. Our unfavorable hemodynamic and clinical experience

with hydralazine was not surprising . The drug had been used successfullyfur years in the treatment of systemic hypertension and left heart failure, and thus, was known to exert marked systemic vasodilator effects. Consequently, we might expect profound hypotension to follow drug administration if systemic vasodilation occurred without a proportional decrease in pulmonary vascular resistance; under such circumstances, the residual obstruction in the pulmonary circuit would attenuate any increase in cardiac output that would be needed to prevent a substantial fall in blood pressure." Most of the earlier intravenously (IV) administered vasodilator drugs had the same disadvantage, but symptomatic hypotension was infrequent, since their brief duration of action provided the opportunity for immediate reversibility of any deleterious circulatory reactions.U.18 With the advent of long-acting, orally effective drugs, we might expect serious hypotensive events to increase in frequency if these drugs are administered to patients whose pulmonary vascular responsiveness is unknown. Although some investigators have suggested that the ability of the pulmonary vasculature to respond to an oral vasodilator drug can be predicted accurately by prior testing with a short-acting IV agent (prostacyclln)," the response to two vasodilator interventions in the same patients may differ markedly; thus, conclusions regarding pulmonary vascular reactivity based on a single drug challenge may be inaccurate." RECENT EXPERIENCE WITH VASODILATOR DRUGS

Because of these unfavorable results with hydralazine, recent investigators have turned to the use of calcium channel blocking drugs fur the treatment of patients with primary pulmonary hypertension. Because calcium may play an important role in the pathogenesis of pulmonary hypertensive disorders" and because calcium channel antagonists produce favorable effects in experimentally induced pulmonary hypertension," it was logical to apply nifedipine, verapamil, and diltiazem to the treatment of primary pulmonary hypertension in man. The primary hope with the use of these agents was that selective pulmonary vasodilation could be achieved without marked systemic vasodilator effects. Early clinical experience confirmed that nifedipine lowered pulmonary vascular resistance and pulmonary artery pressures at rest and during exercise, during short- and long-term treatment, and these effects were accompanied by symptomatic improvement . zs.n Unfortunately, we were unable to confirm these favorable observations in our own patients . We" compared the hemodynamic and clinical responses to calcium channel blockade with verapamil or nifedipine to those of direct vasodilation with hydralazine in 12patients with pulmonary hypertension secondary to obliterative pulmonary vascular disorders (primary pulmonary hypertension in eight, systemic lupus erythematosus in two, thromboembolic disease in one, and progressive pulmonary hypertension after closure of a congenital ventricular septal defect in one). All three drugs produced similar decreases in pulmonary vascular resistance, but this was accompanied by a significant increase in cardiac index with hydralazine but not with nifedipine or verapamil. This was because right ventricular performance (already compromised by the disease state) deteriorated Pulmonary Vucular ReaclIvIty

during treatment with both calcium channel antagonists as a result of their negative inotropic actions, even though resistance to right ventricular ejection declined. After both nifedipine and verapamil, mean pulmonary artery pressures decreased markedly, but this amelioration of the pulmonary hypertensive state was not the result of the decrease in pulmonary vascular resistance but due to the decline in right heart output, because right heart filling pressures increased in our patients. In contrast, with hydralazine, right ventricular stroke work increased appropriately, without a change in right heart fillingpressures as pulmonary vascular resistance declined. The unfavorable hemodynamic effectsof calcium channel blockade were accompanied by severe adverse clinical events, including cardiogenic shock during acute drug administration and the exacerbation of right heart failure during long-term treatment. FUTURE ROLE OF VASODILATOR THERAPY

The clinical evidence availableat present strongly suggests that the encouraging results with vasodilator drugs that have followedtheir use in patients with systemic hypertension and left ventricular failure will not be achieved in patients with primary pulmonary hypertension. All three cardiovascular conditions are characterized by marked systemic vasoconstriction; in patients with systemic hypertension and with left ventricular failure, however, this systemic vasoconstrictor response contributes significantly to cardiovascular morbidity. In contrast, the systemic vasoconstriction that occurs in patients with primary pulmonary hypertension plays a beneficial role in supporting systemic blood pressure, as cardiac output is limited by obliterative changes in the pulmonary vasculature. The administration of vasodilator drugs to such patients neutralizes this compensatory systemic vasoconstriction without exerting notable dilatory effects on the severely diseased pulmonary vessels; hence, vasodilator therapy is likely to result in severe hypotension without producing hemodynamic benefits . In conclusion, despite numerous promising early reports of the use of vasodilator drugs in the treatment of patients with primary pulmonary hypertension, we are not enthusiastic about the present or future potential of this therapeutic approach. At present, no vasodilator drug has proved in our experience to be consistently effective in a significant number of patients . Even in patients in whom soine pulmonary vasodilator response can be achieved, selective vasodilation is an uncommon event; even were it to occur, fewofthe drugs presently advocated for these patients are well tolerated for long periods. Even if in the future a new drug proves to be consistently effective in producing sustained decreases in pulmonary vascular resistance without significant toxicity, we will still need to prove that long-term treatment improves clinical symptoms or alters prognosis in these patients . Until such evidence is available, the concept that pulmonary vasoconstriction plays an important role in the pathogenesis of primary pulmonary hypertension remains an unproved hypothesis. REFERENCES

1 Packer M. Vasodilator and inotropic therapy fOr severe chronic heart failure: passion and skepticism. 1 Am ColI Cardiol 1983;

2:841-52 2 Abraham AS, Cole RB, Bishop 1. Effects of prolonged oxygen administration on the pulmonary hypertension of patients with chronic bronchitis. Cire Res 1968; 23:147-57 3 Dalen IE, MatIofflM, Evans G, et al. Early reduction of pulmonary vascular resistance after mitral valve replacement. N Eng) 1 Med 1967; 277:387-94 4 Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension. A pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42:1163-84 5 Reeves]'I; Noonan ]A. Microarteriographic studies of primary pulmonary hypertension. Arch Patholl973; 95:50-55 6 Walcott G, Burchell HB, Brown AL. Primary pulmonary hypertension. Am 1 Moo 1970; 49:70-79 7 Wood P. Pulmonary hypertension with special reference to the vasoconstrictor factor. Br Heart 11958; 20:557-70 8 Dresdale D'( Michtom RJ, Schultz M. Recentstudies in primary pulmonary hypertension including pharmacodynamic observations on pulmonary vascular resistance. Bull NYAcad Med 1954; 30:195-207 9 Ruskin IN, Hutter AM lr. Primary pulmonary hypertension treated with oral phentolamine. Ann Intern Med 1979; 90:772-74 10 Shettigar UR, Hultgren HN, Specter M, Martin R, Davies DH . Primary pulmonary hypertension: favorable effect of isoproterenol. N Eng) 1 Med 1976; 295:1414-15 11 Lee TO lr, Roveti GC, Ross RS. The hemodynamic effects of isoproterenol on pulmonary hypertension in man. Am Heart 1 1963; 65:361-67 12 Daoud FS, Reeves ]'I; Kelly DB. Isoproterenol as a potential pulmonary vasodilator in primary pulmonary hypertension. Am 1 Cardioll978; 42:817-22 13 Lupi-Herrera E, Bialostozsky 0, Sobrino A. The role of is0proterenol in pulmonary artery hypertension of unknown etiology. Chest 1981; 79:292-96 14 Cha SD, Kirschbaum M, Maranhao V. Paine E, Gooch AS. Phentolamine for primary pulmonary hypertension. Ann Intern Med 1979; 91:927-28 15 Wang SWS, Pohl lEF, Rowlands 01, Wade EG . Diazoxide in treatment of primary pulmonary hypertension. Br Heart 1 1978; 40:572-74 16 Rubino 1M, Schroeder IS. Diazoxide in treatment of primary pulmonary hypertension. Dr Heart 1 1979; 42:362-63 17 Buch J, Wennevold A. Hazards of diazoxide in pulmonary hypertension. Br Heart 1 1981; 46:401-03 18 Honey M, Cotter L, Davies N, Denison D. Clinical and haemodynamic effectsof diazoxide in primary pulmonary hypertension. Thorax 1980; 35:269-76 19 Rubin LJ, Peter RH . Oral hydralazine therapy fOr primary pulmonary hypertension. N Eng) 1 Moo 1980; 302:69-73 20 Packer M, Greenberg B, Massie B, Dash H. Deleterious effects of hydralazine in patients with pulmonary hypertension. N Eng) 1 Med 1982; 306:1326-31 21 Rozkovec A, Stradling J, Minty K, Shepard G, Oakley CM . Hydralazine in pulmonary hypertension. N Eng) 1 Med 1982; 307:1214-15 22 Rich S, Martinez J, Lam W, Levy PS, Rosen KM. Reassessment of the effects of vasodilator drugs in primary pulmonary hypertension: guidelines fOr determining a pulmonary vasodilator response. Am Heart 1 1983; 105:119-27 23 Lloyd TO . Responses to hypoxia of pulmonary arterial strips in nonaqueous baths. 1 Appl Physioll970; 28:566-69 24 McMurthy IF, Davidson AB, Reeves]'I; Grover RF. Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs. Cire Res 1976; 38:99-104 25 Camerinl F, Alberti E, Klugmann S, Silvi A. Primary pulmonary hypertension: effects of nifedipine. Br Heart 1 1980; 44:352-56 26 Rubin LJ, Nicod P, Hillis LD, Firth BG. Ueatment of primary CHEST I 88 I 4 I OCTOBER. 1985 I Supplement

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pulmonary hypertension with nUedipine : a hemodynamic and scintigraphic evaluation. Ann Intern Med 1983; 99:433-38 27 Olivari MT, Cohn IN, Carlyle P, Levine TB. Beneficial hemodynamic and exercise response to nifedipine in primary pulmonary hypertension [Abstract] . J Am Coil Cardioll983; 1:735 28 Packer M, Medina N, Yushak M. Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to obliterative pulmonary vascular disease. J Am Coil Cardioll984; 4:890-901 DISCUSSION

A discussion ensued on the negative inotropic effects of the various calcium channel blockers. In patients with preserved ventricular function, nifedipine and diltiazem probably exert less negative inotropic effects than verapamil. In contrast, in patients with compromised right or left ventricular function, all of the three available calcium channel blockers can exert important negative inotropic effects, although preliminary evidence suggests that diltiazem may be the least cardiodepressant. This may explain why adverse hemodynamic and clinical reactions have been reported following the administration of nifedipine and verapamil to patients with primary pulmonary hypertension, whereas similar unfavorable events have not yet been observed with diltiazem. Should patients who show no acute pulmonary vasodilator

response to vasodilators receive long-term treatment? Many

of those present felt that patients who failed to respond to IV prostacyclin were unlikely to respond favorably to other vasodilator drugs, given either acutely or chronically; similar findings have not been established, however, for other agents (ie, nitroglycerin, nitroprusside, or nifedipine). Estimates of the proportion of patients who might show long-term hemodynamic and symptomatic improvement with vasodilator therapy varied from 10 to 35 percent; this range probably reflects differences in the criteria used to select patients for treatment. The discussants pointed out that these patients must be characterized both clinically and pathologically. From a clinical point of view, they all have unexplained pulmonary hypertension, but from a pathologic standpoint, it is not known how many have plexifurm lesions , and , thus, would not be expected to respond favorably to vasodilator therapy. One reason for the differing perceptions of the efficacy of vasodilators is that each investigator sees relatively few patients. Consequently, it is important that the experience of various centers be combined and analyzed, using a mechanism such as the NIH primary pulmonary hypertension registry.

Vasoconstriction and Remodeling In Pulmonary Hypertenslon* Barbara Meyrlck, Ph.D.; and Kenneth L. Brigham, M.D .

In one group of sheep, Eacherichia coli endotoxin ~given intravenously three times per week for ten weeks, "llnd in another group the cyclooxygenase inhibitor indomethacin was given subcutaneously two times per day for three weeks. Both groups developed the structural and functional changes of modest but sustained pulmonary hypertension and showed granulocyte sequestration in the peripheral lung. Indomethacin enhanced pulmonary vasoreactivity, but endotoxin depressed reactivity transiently. Prolonged inJIammation of the lung may be associated with alterations in vasoreactivity and the development ofchronic pulmonary hypertension. pulmonary hypertension develops in several Chronic human diseases when chronic or repeated inJIammation of the lung is seen, eg, cystic fibrosis' and chronic bronchitis and emphysema. I In addition, patients who die after a prolonged, acute course of the adult respiratory distress syndrome often have persistent pulmonary hypertension .v' The purpose of the present study was to establish in awake sheep (1) whether repeated lung inJIammation caused by *From the Departments of Pathology and Medicine, Pulmonary Circulation Center, B-1308, Medical Center North, Vanderbilt University School of Medicine, Nashville . t Associate Professor of Pathology and Medicine. *Professor of Medicine. Supported by Grant No. HL 19153(SCOR in Pulmonary Vascular Diseases) from the National Heart, Lung and Blood Institute, and a grant from the Kroc Foundation. Reprint f"fIquutB: Dr. Meyrlck, B-l308, MedJcal Center North, Vanderbilt University SchOol of Medicine, NtJlhmlle 37232 288S

E coli endotoxemia leads to the functional and structural changes of chronic pulmonary hypertension, and (2)whether chronic inhibition of the cyclooxygenase pathway leads to maintained vasoconstriction, resulting in the structural changes of chronic pulmonary hypertension. MATERIALS AND METHODS

Chronically catheterized sheep were prepared as previously described and measurements made twice weekly of baseline pulmonary and systemic artery pressure, left atrial pressure, cardiac output, arterial blood gases, pH , and number of circulating white blood cells." Pulmonary vasoreactivity in response to breathing 12 percent oxygen and to a l-ml bolus injection (O.I....glml) of an analog ofPGHI (PGHI-A; Upjohn Co, Kalamazoo, MI) wasalso tested twice weekly throughout the experiments. In some sheep the caudal mediastinal lymph node wascannulated. In these sheep, measurements were made of the levels of the stable metabolites of prostacyclin and thromboxane A. in lung lymph and blood plasma. I Structural Studies Baseline biopsy tissue was taken from each animal at the time of catheter insertion and at various times throughout the experiments. The biopsy technique bas been previously described. 7 Sections from the biopsy tissue were stained with hematoxylin and eosin and used to assess number of peripheral lung granulocytes." At the end of the experiments the sheep were killed by an overdose of pentobarbital and the lungs and heart removed intact. The pulmonary arterial circulation was distended with a barium sulfate gelatin mixture prior to fixation by means of airway distention with 10 percent of formolsaline solution, and quantitative techniques were applied to assess the structural changes of chronic pulmonary hypertension. 1-4