Primary pulmonary hypertension

Primary Pulmonary Hypertension

Stuart Rich

P RIMARY PULMONARY HYPERTEN- SION (PPH) is a name applied to a disease

affecting the pulmonary vascular bed that results in sustained pulmonary hypertension for which there is no apparent cause. The definition, as well as our understanding of various aspects of this disease, has changed considerably over the past several decades. This review will summarize current concepts about primary pulmonary hypertension and present data on the etiology, patho- genesis, diagnosis, and management of this disease based on published observations, data from our own institution, and data from the recent National Institutes of Health (NIH) National Registry for PPH.

THE HISTORY OF PPH

The first published description of a patient with primary pulmonary hypertension was made at autopsy by Romberg in 1891 when sclerosis of the pulmonary arteries was noted in the absence of underlying heart or lung disease’ (Table 1). Other autopsy reports followed over the next several decades but considerable confusion about the “primary” nature of the disease existed, because physicians also noted associated findings, such as mild emphysema or a history of cyanosis.2m4 Although it was becoming possible to make the diagnosis of right ventricular hypertrophy and pulmonary hypertension based on chest radiographs and the electrocardiogram, it was not until the advent of cardiac catheterization that documented evidence of increased pulmonary artery pressures allowed the description of the first series of patients with primary pulmonary hypertension.’ Because many of the clinical features of PPH overlapped with pulmonary hypertension from other recognizable causes, interest in the underlying pathophysiology increased, and the possibility that some type of vasoconstrictive factor was playing a role in these patients was popularized.6 While several questions remained about these patients, it became clear that the clinical course was typically associated with symptoms of dyspnea, limited exercise capacity, and right ventricular failure, with death often ensuing within 3 to 5 years. Attempts

to associate the pathologic vascular changes, that usually showed pulmonary arterial medial hypertrophy and intimal fibrosis, with the clinical presentation elicited more interest in pursuing a vasoconstrictive etiology.’ Early observations regarding the hemodynamic response to the administration of vasotonic compounds lent support to this theory.

A somewhat sudden increase in the number of patients seen with unexplained pulmonary hypertension in Europe in the late 196Os, eventually linked to the ingestion of the drug aminorex, further served to heighten interest in PPH.’ In light of this, the World Health Organization held a symposium in 1973, discussed the current understanding of primary pulmonary hypertension,’ and proposed a definition for the disease that has become the predominant working definition over the last two decades. Pulmonary hypertension of unknown cause, or primary pulmonary hypertension, was classified morphologically based on three histopathologic patterns, and included plexogenic pulmonary arteriopathy, pulmonary venoocclusive disease, and recurrent pulmonary thromboembolic disease.

In 1981 the National Heart, Lung, and Blood Institute (NHLBI) initiated a patient registry on primary pulmonary hypertension that sought for the first time to collect information prospectively from 32 US medical centers, using a uniform data base to characterize better the clinical features of patients with PPH.” The registry enrolled patients over 5 years and maintained follow-up for 7% years in order to clarify the natural history and survival of patients with this disease.

Epidemiology

That PPH is an uncommon disorder is unques- tionable. However, the true incidence of the

From the Deportment of Medicine, Cordiologv Section, The University of Illinois College of Medicine at Chicago.

Address reprint requests to Stuart Rich, MD, University of Illinois, Cardiology Section, PO Box 6998. Chicago, IL 60680.

0 1988 by Grune & Stratton. Inc. 0033-0620/88/3I03-0002$5.00/O

Progress in Cardiovascular Diseases, Vol XXXI, No 3 (November/December), 1988: pp 205-238 205

STUART RICH 206

Table 1. History of PPH

1891

1907

1935

1951

1959

1967

1970

1973

1981

First autopsy report of unexplained pulmonary hy-

partension by Romberg.

Monckebarg describes a case of PPH based on clin-

ical and microscopic critaria.

Brennar reports the first series of “primary pulmo-

nary arteriosclerosis” and offers clinical and his-

tologic criteria.

Drasdale publishes the first series based on cathe-

terization data and introduces the term “primary

pulmonary hypertension” (PPH).

Wood discusses the “vasconstrictive factors” in

pulmonary hypertension, and supports the con-

cept of vasodilator treatment.

The prevalence of unexplained pulmonary hyparten-

sion increases in Europe following the introduc-

tion of the drug aminorex fumarate.

Waganvoort provides an extensive review of vari-

ous pathologic types of PPH.

World Health Organization confers to standardize

the definition of PPH and suggests three distinct

subtypes.

NIH establishes a national registry on PPH in the

United States.

disease will not likely be known. In the United States it is reported in less than 1% of the cases coming to autopsy or catheterization.‘1~‘2 In the NIH Registry on PPH, approximately 200 cases from across the United States were entered, but no obvious geographic clustering was elicited.” The women-to-men prevalence was 1.7:1, less than others reported,5’7*‘3 and was similar from decade to decade. The highest prevalence occurred in the third and fourth decades for both men and women, but patients diagnosed over the age of 60 occurred in 9% of the cases. There were 12% blacks, with a female-to-male ratio of 4:l.

Differences in the prevalence of primary pulmonary hypertension appear to exist worldwide. The most notable was the increase in cases diagnosed in Europe following the introduction of aminorex fumarate, an anorexigenic drug, in 1965.* Although it is believed that these cases were drug related, the clinical manifestations of the affected patients were identical to PPH in most every aspect. There was a female-to-male predominance as well (4:1), but that may be explained by the fact that aminorex was taken primarily by women. The incidence of pulmo-

nary hypertension increased tenfold over the years 1967 to 1973, and then diminished to its original level in the years since the drug was withdrawn.

A different prevalence of PPH has been described in the tropics, where the number of patients with PPH coming to catheterization appears to be twofold higher than reported in Europe.14 In addition, there is a male-to-female predominance of 413 with a somewhat younger presentation (mean age 34 years). In all other aspects, however, the clinical manifestations of these cases appear to be similar to those in the NIH Registry, with the exception that the pulmonary artery pressures are somewhat higher. Several explanations have been proposed for these differences. It is possible that part of the higher prevalence is due to occult pulmonary infection from filariasis or schistosomiasis.” The men-to-women predominance may be real or may be influenced by local economic conditions where women of the poorer social classes may not be afforded medical attention. In addition, it is suggested that Asian Indians have relatively hyperreactive pulmonary vessels, based on the description of pulmonary hypertension at young ages occurring in patients with atria1 septal defects.“j

Several familial cases of PPH are now reported in the American population.” In the NIH Registry the incidence is 7%.” An autosomal-dominant inheritance with incomplete pene- trance is described, and often in retrospect family members who died of unexplained deaths had primary pulmonary hypertension.‘7*‘8 Patients with a positive family history share the same clinical features of the nonfamilial cases, with the exception of a shorter period from the onset of symptoms until diagnosis, likely due to a heightened awareness on the part of the patient or physician.” Histologically, the changes in the pulmonary vasculature most often described are consistent with plexogenic arteriopathy.”

THE PATHOF’HYS1OLOGY OF PRIMARY PULMONARY HYPERTENSION

Three histologic patterns are described in patients dying of unexplained pulmonary hypertension.’ They are plexogenic pulmonary arteriopathy, thrombotic pulmonary arteriopathy, and pulmonary veno-occlusive disease. Case reports

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of pathology showing sarcoidosis, emphysema- tous and intersitital lung disease, and tumor emboli, will not be considered since it is not clear if the correct diagnosis could have been made clinically in these cases. Over the past four years we have had 22 patients with PPH in whom lung pathology was available either from open-lung biopsy, autopsy, or heart-lung transplantation. In none was a disease process other than primary pulmonary hypertension found, and thus we believe the clinical diagnosis, if pursued in a thorough and organized fashion, will almost always be correct.

An important characteristic of the pulmonary arterial bed is the heterogeneity of its vasoconstrictor response to a variety of stimuli. One example is high-altitude pulmonary edema, which results from acute pulmonary hypertension due to hypoxia, that occurs only in a small portion of the normal population.20*2’ Widimsky tested the effect of another stimulus, unilateral balloon occlusion of the pulmonary arteries, in normal subjects and found a varied pulmonary pressure response ranging from a 10% to a 200% increase.22 This heterogeneity is manifested in cardiopulmonary disease states as well. Although some patients with congenital heart disease and intracardiac shunts develop severe pulmonary hypertension, others with similar-sized shunts do not.23-25 Some patients with mitral stenosis develop extreme pulmonary hypertension, whereas others with identical valve areas do not.26 Understanding the heterogeneity of pulmonary vascular responses to these stimuli, then, explains why some patients with secondary pulmonary hypertension appear to have a level of pulmonary artery pressure that is out of proportion to their underlying disease.27 It also explains why only some patients exposed to aminorex ingestion developed pulmonary hypertension.’ These patients have been referred to as “hyperreactors” with respect to pulmonary vasomotor responses, l6 It is possible that many (if not all) of the people developing PPH are hyperreactors.

Plexogenic Pulmonary Arteriopathy (PPA)

Plexogenic pulmonary arteriopathy (PPA) is the consequence of chronic severe pulmonary hypertension from a variety of etiologies.28 The sequence of lesions appears to be medial hypertrophy, intimal thickening which leads to fibrosis

(usually concentric but often eccentric in nature), with the intimal proliferation often so severe that it becomes occlusive in nature (referred to commonly as “onion-skinning”) (see Fig 1).2g The plexiform lesion appears as a multi- channeled outpouching of the pulmonary arteriolar wall, and indicates advanced disease. The exact cause of plexiform lesions is unknown. It is suggested that they represent a stage of prolifer- ative repair in an area of previous fibrinoid necrosis,30 are the result of localized jet lesions,3’ represent anastomoses between the pulmonary arteries and veins,32 or are aneurysms that develop at sites where the media are underdevel- oped or weakened.33 In any case, plexiform lesions are only found when the pulmonary hypertension originates at the precapillary level. Because of these lesions’ histologic appearance of first medial hypertrophy and then progression to intimal changes, it is presumed that pulmonary arterial vasoconstriction is the mechanism for the elevation in pulmonary artery pressure that occurs.

Medial hypertrophy of the muscular pulmonary arteries and arterioles without intimal lesions also is described in cases of severe primary pulmonary hypertension.34 Referred to as “pulmonary medial hypertrophy,” it is unclear whether the absence of intimal changes suggests this is a distinct pathologic entity or a variant of plexogenic pulmonary arteriopathy. Generally, the thickness of the media of the muscular pulmonary arteries is proportional to the level of the pulmonary arterial pressure.35936 It is suggested that in children more advanced changes occur when the medial hypertrophy is inadequate for the level of pulmonary hypertension.36

The histologic finding of plexiform lesions in primary pulmonary hypertension is reported between 28% to 71% of the patients.7934*37 It is more common in women than in men, and in a somewhat younger age group than patients with PPH in generaL3* PPA is also seen in patients with pulmonary hypertension associated with congenital heart disease, cirrhosis, and aminorex ingestion.’ Congenital heart disease causes plexogenic pulmonary arteriopathy when there is a left-to-right shunt at the post tricuspid level, eg, ventricular septal defect (VSD), patient ductus arteriosus (PDA). In this setting, the increase in pulmonary blood flow is associated with systemic

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Fig 1. (A) An illustration of the pathophysiology of plexogenic pulmonary arteriopathy is shown. In the early stages (left) medial hypertrophy from vasoconstriction is the only abnormality, and probably is not uniform la to cl. This progresses with secondary changes of medial hypertrophy associated with eccentric (d) and concentric Isminer intimal fibrosis (ef, and plexiform lesions (f). (6) Thrombotic pulmonary arteriopathy is illustrated. In this condition, the initial abnormality invohres the pulmonary endothelium, which results in eccentric intimal fibrosis (b) and thrombosis in situ with recanalized channels (c)

that tend to reduce the area of the pulmonary vascular bed. Eventually, the initial fibrosis becomes progressive fd) and occasionally even occlusive fe). with secondary medial hypertrophy paralleling the increase in pulmonary artery pressure (d, e, f). (C) Pulmonary veno-occlusive disease is illustrated. The disease arises from fibrosis of the pulmonary venous (b, c) with a normal arteriolar bed (a). Over time, the fibrosis becomes severe fe), which predisposes to thrombosis in situ (f) and secondary hypertrophy of the arterioles fd) as the pulmonary venous pressure rises. (D) Pulmonary collagen-vascular disease

is illustrated. Cellular infiltration involving the media lb) or intima (c) from circulating antibodies would produce the initial vascular changes. The subsequent chronic changes would be similar to plexogenic arteriopathy Id, e. f) from any cause. Since no lung tissue has been studied from these patients in the initial stages, the pathophysiology shown remains speculative.

arterial blood pressures that promote these vas- monary vascular changes to accommodate the cular changes.30 Increased pulmonary blood flow increased pulmonary blood flow and elevated alone, eg, with atria1 septal defect (ASD) or pressure.32 If corrected early enough, these anomalous pulmonary venous drainage, does not changes are reversible.*’ cause this as a rule. 25 The high-pressure shunt The association of PPA with cirrhosis is also results in pulmonary vasoconstriction and pul- well established.39 It is speculated to be related to

PRIMARY PULMONARY HYPERTENSION

the effects of passage of nonmetabolized vasoactive compounds through the liver into the lungs.40r4’ Exposure to these compounds would cause pulmonary vasoconstriction and, subsequently, pulmonary hypertension. Which compounds are responsible is still completely unknown. It is interesting to note that prostaglandin F-2-alpha is one substance that has vasoconstrictor effects on both the pulmonary and portal vascular beds.42

Aminorex is the amphetamine-like compound that was associated with severe unexplained pulmonary hypertension in Europe.8 It has been postulated that, when aminorex is administered to susceptible individuals, sustained pulmonary hypertension will develop. In Europe, only about 1 out of 1,000 people exposed to the drug developed pulmonary hypertension. Again, the mechanism for this process would be pulmonary vasoconstriction with subsequent pulmonary hypertension. The median survival of patients with pulmonary hypertension associated with aminorex was almost three times longer than patients with PPH diagnosed over the same time period. However, while some patients improved when the aminorex was discontinued, others had a progressive downhill course even though the causative agent had been withdrawn.

There are other less well-established observations that link pulmonary vasoconstriction to primary pulmonary hypertension. The association with Raynaud’s phenomenon, which occurs in a small percentage of patients with PPH, may suggest a generalized abnormality in vascular tone.43,44 The presence of a gradient of thromboxane metabolites across the pulmonary vascular bed in patients with PPH at least implicates vasoconstrictive compounds in these patients, although it does not resolve whether thromboxane production is a cause or a result of the underlying condition.4s The lessons learned from patients with intracardiac shunts, cirrhosis, and aminorex ingestion provides an understanding for the pathophysiology of PPA as a distinct subset of primary pulmonary hypertension. Exposure to a specific agent or stimulus produces progressive and severe pulmonary vasoconstriction in susceptible patients, even if the agent is withdrawn. In the clinical spectrum of the disease, our experience suggests that these patients

are most likely to be women, and relatively young. 38 Extrapolating from the literature on congenital heart disease and aminorex ingestion, there is every reason to believe that the disease is reversible if detected and treated at the early stages.

Thrombotic Pulmonary Arteriopathy (TPA)

Thrombotic pulmonary arteriopathy (TPA) describes another subset of pulmonary vascular changes that has been attributed to patients with PPH.’ Upon examination of the pulmonary vascular bed in these patients, one sees predominantly eccentric intimal fibrosis, along with medial hypertrophy with fibroelastic intimal pads in the arteries and arterioles (but without onion-skinning or plexiform lesions).7*34 Scat- tered evidence of old recanalized thrombus (the colander lesion) is also found, usually appearing as fibrous webs in the small vascular channels (see Fig 1). Although the literature refers to this pattern as microthromboemboli, it is more likely that these lesions represent thrombosis in situ and not repeated embolization. Consistently, no source for the emboli is found in these patients.

Recent research suggests that exposure of subendothelial cell structures may provide the substrate for vascular thrombosis.46 Elevated intravascular pressure disrupts the normal vascular endothelial layer. and alterations of the physiologic function of endothelial cells can create a procoagulant environment!’ In thrombotic pulmonary arteriopathy it is probable that some unknown stimulus results in a perturbation of the endothelium at the microvascular level, thus altering the character of the pulmonary vascular bed from anticoagulant to procoagulant. A generalized disorder of the pulmonary arteriolar bed would result in diffuse intimal proliferation and thrombosis with the development of pulmonary hypertension paralleling the severity of the occlusions, and progressing over time.

To date, detectable abnormalities in clotting or lytic mechanisms have not been consistently uncovered in patients with primary pulmonary hypertension. We evaluated coagulation profiles including prothrombin time, partial thrombo- plastin time, thrombin time, bleeding time, fibrinogen levels, fibrin split products, and anti- thrombin III levels, as well as studies of pulmo-

210 STUART RICH

nary and systemic platelet size, number, and aggregation, and generally found normal values.49 A prolongation in euglobulin lysis time is noted in patients with PPH, but the mechanism remains unexplained.49*50 We explored the possibility that alterations in plasma fibrinolytic com- ponents may occur in these patients, and measured plasminogen antigen, functional plasminogen concentration, and alpha II antiplasmin levels in several patients with primary pulmonary hypertension; again no obvious abnormalities were uncovered.5’ Consequently, we were unable to link thrombotic pulmonary arteriopathy to an abnormality in circulating plasma proteins. Most recently, we used an assay of fibrinopeptide A and the in vivo response to heparin to assess thrombin activity in 12 patients with PPH.s2 Eleven of the 12 had elevated fibrinopeptide A levels, and there was a prompt decrease following intravenous (IV) heparin in nine. These data suggest that thrombin activity is increased in patients with PPH, with perhaps endothelial injury serving as the substrate for this phenomenon.

Often, the distinction between thrombotic and plexogenic arteriopathy is difficult, because some patients can have histologic features of both. Generally, a distinction can be made because one would tend to call PPA the presence of concentric laminar intimal fibrosis, medial hypertrophy, and an occasional thrombotic lesion, even without plexiform lesions; one would call TPA the pattern of eccentric intimal fibrosis, even with extensive intimal proliferation, associated with thrombotic lesions but without concentric laminar intimal fibrosis.34

Thrombotic pulmonary arteriopathy is reported to account for 20% to 56% of the cases of PPH .7,34,37 As distinguished from PPA, it appears to be evenly divided between men and women, and is found in a somewhat older population.38 Specific agents causing thrombotic pulmonary arteriopathy are not identified. The association of pulmonary hypertension occurring during pregnancy, when a systemic procoagulant state occurs, aroused curiosity,53*54 and TPA is described in patients with congenital heart disease from ostium secundum atria1 septal defects.25 The reports of improved survival in patients with PPH who have been treated with chronic anticoagulation further supports the

notion that thrombosis is a factor in some of these patients.55

Pulmonary Veno-occlusive Disease (PVODJ

Pulmonary veno-occlusive disease (PVOD) represents another distinct class of histologic patterns described in PPH.9 Widespread intimal proliferation and fibrosis of the intrapulmonary veins and venules is the hallmark of this pattern, with the lesion frequently resulting in complete obliteration of the venous channels (see Fig 1).56 Recanalized thrombi are also frequently found. Medial hypertrophy is commonly seen at the arteriolar level, believed to be a consequence of the secondary increase in pulmonary artery pressure from the venous obstruction. The pulmonary venous obstruction explains the increased pulmonary capillary wedge pressure described in patients in the late stages of the disease5’T5’ and the increase in basilar bronchovascular markings described on the chest radiograph.59@ Recently, cases with intimal changes involving the arteriolar as well as the venous bed are described, and referred to as pulmonary vascular occlusive disease.61

There are several reasons to believe that pulmonary veno-occlusive disease is a distinct subset of primary pulmonary hypertension. Pathophys- iologically, PVOD appears to represent a syndrome of fibrosis of the pulmonary venous bed with changes in the venous intima, predisposing to thrombosis in situ and promoting or adding to the vascular occlusions6’ Several cases are described of mediastinal fibrosis involving virtually every level of the pulmonary venous bed extending from the small venules to the large pulmonary veins as they enter into the left atrium.62-64 Descriptions of pulmonary veno- occlusive disease occurring after viral illnesses,65 the administration of chemotherapy,66 and toxin exposure’j7 suggest that there may be several etiologic agents.

The number of published cases of PVOD is less than 100, and account for less than 7% of the cases with PPH.7*34 There appears to be a slight men-to-women predominance, with the ages ranging from infancy to >60 years. Perhaps more than other pulmonary vascular diseases, PVOD causes symptoms of dyspnea and orthopnea and can mimic frank left-ventricular failure in its later stages. The diagnosis, once only made

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Arterial l Venous I

Fig 2. A graphic illustration of the determination of the pulmonary capillary wedge pressure in PVOD is shown. In

actuality, the pressure that is measured comes from several capillary channels. As long as some remain patent. the wedge pressure will reflect left atrial pressure (as shown). If a segment is sampled in which none of the capillary

channds is patent (eg. the bottom vessel shown). the wedge pressure will be elevated.

at the time of autopsy, can be made antemortum. Frequently, the chest radiograph will show increased bronchovascular markings and Kerley B lines that reflect chronically increased pulmonary capillary pressures.S9*60 In addition, the lung scan will show diffuse patchy nonsegmental abnormalities.38 Upon catheterization, the pulmonary capillary wedge pressures might be normal or elevated depending on the severity of the disease (see Fig 2). In PVOD one may find a difference in the pulmonary capillary wedge pressures obtained at several sites within the same lung. 68.69 As with plexogenic pulmonary arteriopathy, cases of familial PVOD are reported in siblings, suggesting that some type of inheritable tendency towards the development of this disorder is possible.“,”

Pulmonary Collagen Vascular Disease (PCVD)

Pulmonary collagen vascular disease (PCVD) is probably an additional subset of PPH. Over the years, many patients with collagen-vascular diseases and severe pulmonary hypertension were described. “*” Much of the time there is coexistent interstitial lung disease, with the subsequent pulmonary hypertension considered to be a result of a multitude of factors (hypoxemia, interstitial fibrosis, and acute vasculitis). Some patients develop severe pulmonary hypertension

without any evidence for pulmonary parenchy- ma1 disease, the most notable being patients with CREST syndrome.79 Curiously, the histopathologic findings in the lungs of these patients show severe pulmonary vascular changes similar to plexogenic pulmonary arteriopathy, indistin- guishable from PPH (see Fig 1).73~75~79 Although it is possible that evidence of acute vasculitis would have been found if lung specimens were obtained earlier in the disease, this remains unproven.

Patients with PPH frequently have positive antinuclear antibody tests.*’ We reevaluated this by measuring serum antinuclear antibody titers in 39 patients with primary pulmonary hypertension without any evidence of collagen vascular disease, 16 patients with pulmonary hypertension secondary to congenital and acquired heart and lung disease, and 20 control subjects using KB cell antigen (a common antigen substrate; Electra-Nucleonics Inc, Columbia, MD).8’ In our laboratory we obtained a positive test (titer 1:80 or greater) in 40% of the patients with PPH, with the titers ranging from 1:80 to 1:1280. Among the patients with secondary pulmonary hypertension, only one had a positive titer (1:160). None of our control subjects had titers above 1:40. Our data support that positive antinuclear antibodies occur in up to 40% of the patients with primary pulmonary hypertension, and that it is not a nonspecific finding related to the presence of elevated pulmonary artery pressures. For these reasons, we believe that, in some patients, etiologically PPH is a collagen-vascular disease that is confined to the lungs.

THE DIAGNOSIS OF PPH

As a rule, the clinical diagnosis of PPH can be made with a high level of accuracy (Fig 3). The NIH Registry used specific exclusion criteria, underscoring the fact that PPH is diagnosed only when no secondary causes for pulmonary hypertension coexist (see Table 2).” When following these guidelines, we never had a patient for whom the diagnosis of PPH was made clinically and another cause for the pulmonary hypertension was found histologically.

The most common symptom of primary pulmonary hypertension is dyspnea.‘“*13,82 Studies on the mechanism of dyspnea suggest that, although lung function is intrinsically normal, patients

STUART RICH

Fig 3. An algorithm for the workup of a patient with unexplained pulmonary hypertension is provided. The distinction of primary from secondary pulmonary hypertension is crucial, because the treatment of the secondary forms

can vary widely.

with pulmonary hypertension hyperventilate to compensate for arterial hypoxemia resulting from the combination of reduced cardiac output and ventilation perfusion inequalities in the lung.83 Initially, the hyperventilation is most notable with exercise, but as the disease progresses it occurs at rest. Minute ventilation was reduced in patients with PPH at all levels of activity,” and the sensation of hyperventilation is inter- preted as dyspnea by the patient.

Table 2. Secondary Causes of Pulmonary Hypertension*

Persistent fetal circulation

Congenital heart disease

Valvular heart disease

Primary myocardial disease

Pulmonary thromboembolic disease

Obstructive lung disease

Interstitial lung disease

Arterial hypoxemia associated with hypercapnea

Collagen vascular disease

Parasitic disease involving the lung

Sickle cell anemia

History of IV drug use

Granulomatous lung disease

Chronic liver disease

Pulmonary valve or artery stenosis

Pulmonary various hypertension

*Adapted from Rich et al.‘c

Syncope may also be an early symptom of pp~~l’WU2 In most cases it is effort related, believed due to a limited ability to increase cardiac output with activity. Some patients may present with syncope at rest. In these cases an arrhythmic cause for the syncope should be considered. Given their limited cardiac output, a relatively benign tachyarrhythmia could produce marked systemic hypotension.

Angina, which can be very typical in character, is also a common symptom in patients with PPH.” It most often is precipitated by stress, suggesting that it may represent right ventricular ischemia. Indeed, biochemical evidence of right ventricular ischemia was demonstrated in the presence of increased right ventricular afterload in animal studies.84

Most of the other symptoms noted in PPH relate to right ventricular dysfunction, most no- tably fatigue, edema, and peripheral cyanosis.” Recurrent laryngeal nerve compression from an enlarged pulmonary artery producing hoarseness (Ortner’s syndrome) is also described, but this is uncommon.85-87

The physical examination of a patient with PPH is similar to that of a patient with pulmonary hypertension of a variety of causes.5,‘o*12-‘4~82 Right-sided third and fourth heart sounds are common, and pulmonary ejection and regurgitant murmurs may also be heard. Tricuspid regurgitation is extremely common and often is the most notable auscultatory finding. Associa- tions have been made between the severity of the physical findings and the hemodynamics, including the presence of a third heart sound and tricuspid regurgitation associated with increased right atria1 pressure and reduced cardiac output.” Clubbing is not a feature of primary pulmonary hypertension and should suggest to the clinician that chronic lung disease or a missed congenital heart defect is present.

The chest radiographic findings of patients with PPH include enlargement of the main and hilar pulmonary arteries with pruning of the peripheral vasculature often noted.‘“” As a rule the lung fields are clear, although increased bronchovascular markings at the bases have been described in pulmonary veno-occlusive disease.s6-6’ A good-quality, upright, posterior-ante- rior and lateral chest radiograph is an important initial screening test in pulmonary hypertension

213

to help exclude lung disease as the underlying cause. It should be kept in mind, though, that clear lung fields on a chest radiograph do not exclude interstitial lung disease as a possible etiology.89

The electrocardiogram usually reflects changes of right ventricular hypertrophy.“,” Right-axis deviation, and T wave abnormalities referred to as a strain pattern are also common, but do not necessarily parallel the severity of the underlying pulmonary hypertension.” Sinus rhythm seems to be the rule, since no patient with chronic atria1 fibrillation and primary pulmonary hypertension has yet been reported. In fact, there is a notable disparity regarding the absence of atria1 arrhythmias in patients with PPH when compared with patients with car pulmonale from lung disease, in whom atria1 arrhythmias are very common.9’ The latter group, however, usually does not have as severe pulmonary artery hypertension and restricted cardiac outputs as seen in the patients with PPH. This suggests the possibility of extreme dependency upon atria1 systole in patients with PPH, and perhaps that atria1 fibrillation is incompatible with survival. We recently evaluated this while studying two patients with PPH and syncope associated with palpitations. During electrophysiologic testing the patients underwent a ventricular pacing study. It was noted that during simple ventricular pacing (and thus the absence of atria1 systole), the systemic blood pressure declined pre- cipitously, requiring that the ventricular pacing be terminated promptly.

Pulmonary function tests are necessary in the work-up of a patient with pulmonary hypertension to rule out underlying obstructive airways disease. Although chronic asthma or mild obstructive airways disease may appear to be inconsistent with elevated pulmonary artery pressures, the acknowledgment of “hyperreactors” whose pulmonary artery pressures appears out of proportion to the disease state was previously discussed. It is our policy not to diagnose primary pulmonary hypertension in the patient whose pulmonary function tests reveal unequivo- cal abnormalities in airways function, A mild restrictive pattern on pulmonary function tests, however, is commonly seen in patients with pulmonary hypertension, and believed due, in part, to increased stiffness of the lung that occurs from

the elevated pulmonary artery pressures.” The NIH Registry on PPH notes that, on average, patients had a 20% reduction in predicted lung volumes without any other evidence of parenchy- ma1 lung disease. Marked restrictive patterns in patients with PPH is described, but it is not clear whether this was actually due to the pulmonary hypertension itself.92 Hypoxemia is a ubiquitous finding, and is attributed to both ventilation/ perfusion inequalities within the lung, and a reduced cardiac output, that result in a reduced mixed venous oxygen content.10”3 A wide spectrum of a reduction in diffusing capacity is also extremely common, and is attributed to the pulmonary vascular disease.‘0*92-94 However, there has been no association made between any of the abnormalities in pulmonary function tests, including diffusing capacity, and any other index of severity of the underlying PPH.”

A perfusion lung scan is an essential compo- nent in making the diagnosis of primary pulmonary hypertension. Two patterns of pulmonary perfusion are described in patients with primary pulmonary hypertension.38,95 One is a normal perfusion pattern, and the other shows diffuse patchy perfusion abnormalities (see Fig 4). While studying the basis for these patterns we observed that a normal perfusion pattern represents underlying plexogenic pulmonary arteriopathy, whereas patchy distribution of the tracer suggests either thrombotic pulmonary arteriopathy or pulmonary veno-occlusive disease.” The latter can be distinguished by a chest radiograph showing increased bronchovascular markings. Patients with patchy perfusion abnormalities on lung scan were also found to have the highest levels of fibrinopeptide A, consistent with an underlying thrombotic process.52 The severity of the abnormality in perfusion in the lung scans does not seem to parallel the hemodynamics, because we performed serial lung scans in our patients with PPH and did not see progressive changes over time consistent with the patients’ worsening clinical state.

Perhaps the strongest argument for performing a lung scan is to distinguish patients with PPH from those who have pulmonary hypertension secondary to chronic pulmonary thromboembolism.96 Absence of a clinical history of pulmonary emboli does not exclude their occur- rence. The differentiation of these two entities

STUART RICH

may be made with a high degree of certainty using the lung scan alone.97 The distinction is extremely important, however, because pulmonary hypertension from chronic pulmonary thromboemboli is a completely different disorder that may be amenable to surgical thromboendarterectomy, often times with very gratifying results.98 The risks associated with lung scans in these patients have been grossly overstated. There are three case reports in the early literature of patients with pulmonary hypertension who died following lung scans, but it is not certain that the deaths were clearly associated. 99-1o1 In the NIH Registry on PPH there has not been one morbid clinical event associated with the performance of a lung scan in any of the patients with pulmonary hypertension.”

In the patient in whom pulmonary thromboembolism is suspected, a pulmonary angiogram is essential to confirm the diagnosis. Since the perfusion lung scan will reliably distinguish patients with primary pulmonary hypertension from those with pulmonary thromboembolic disease, we always perform a lung scan first.97 If it reveals single or multiple segmental or subsegmental defects, we will perform a pulmonary angiogram to determine if the patient has pulmonary hypertension from chronic thromboembolic disease. We prefer to do selective left and right pulmonary arterial injections, with the selection of the vessel based on the location of the perfusion abnormalities on lung scan. Patients with chronic pulmonary thromboemboli will generally have large proximal vascular cut-offs with markedly abnormal-looking patent vessels reflecting

THROMBOTIC

“ENO-c&L”SI”E

Fig 4. Perfusion lung scans from two patients with PPH are shown. The scan on the left shows a normal distribution of tracer. Histologic evalustion

showed that the patient had plexogenic pulmonary arteriopathy. The scan on the right

shows diffuse patchy distribution of tracer without clear segmental or subsegmental de- facts. Histologically, this pa-

tient had thrombotic pulmonary arteriopathy.

the secondary changes of pulmonary hypertension as well.51”6 Patients with primary pulmonary hypertension usually have dilatation of the proximal and hilar pulmonary vessels, which then taper relatively rapidly, with marked pruning of the distal vessels noted.88 The morphology of the pulmonary vessels and the rate of taper reflect the level of pulmonary arterial pressure. By performing pulmonary wedge angiograms under magnification, we were able to estimate the pulmonary artery pressure from the appearance of the vessel using a computerized nomogram.“’ However, we were unable to distinguish the histologic pattern of plexogenic pulmonary arteriopathy from thrombotic pulmonary arteriopathy by the gross appearance of the pulmonary wedge angiogram. On the other hand, pulmonary wedge angiography was quite helpful in evaluating pulmonary vascular disease in children with congenital heart defects.‘03v104 By qualitative and quantitive analysis, the severity of the vascular changes was estimated and correlated closely with lung pathology. In our experience with PPH, however, the hemodynamic and pathologic alterations are so extensive that all of our patients usually fall in the most advanced classi- fication of changes by wedge angiography.

There has been considerable reluctance to perform pulmonary angiograms in patients with pulmonary hypertension. The literature reveals that the fatalities that were reported largely occurred in patients in clinical right ventricular failure with elevated right ventricular end diastolic pressures.‘05-‘08 By injecting selectively or subselectively with smaller amounts of contrast,

PRIMARY PULMONARY HYPERTENSION 215

one can minimize the risks of the procedure. Because we observed that one mechanism for a cardiac arrest in this setting can be hypotension and bradycardia (presumably vagal in origin), we pretreat patients whose right ventricular end diastolic pressure is elevated, or whose cardiac output is markedly reduced, with 1 mg of intravenous (IV) atropine before performing the angiogram, and eliminated adverse reactions. Hypotension from pulsatile distention of the pulmonary arteries with pressures up to 60 mm Hg has been demonstrated in the dog and had been attributed to vagally mediated mechanorecep- tors in the pulmonary arteries.“” It has also been suggested that the use of low osmolar or nonionic contrast agents may be safer in pulmonary hypertension.lW In the NIH Registry on PPH there were no deaths or sustained morbidity reported among 50 patients who received pulmonary angiograms during the course of their clinical evaluations.” Consequently, we emphasize that although caution should be exercised in studying these patients, the potential benefits clearly outweigh the risks; thus pulmonary angiography should not be withheld if thromboembolic disease is suspected.

Echocardiographic imaging and Doppler studies can be particularly helpful in assessing patients who present with unexplained pulmonary hypertension. A careful study should exclude congenital heart disease, valvular heart disease, or abnormalities in left ventricular function, the presence of which would exclude the diagnosis of primary pulmonary hypertension. In addition, one can characterize the severity of the pulmonary vascular disease and its impact on cardiac function with ultrasound.

The typical appearance of an echocardiogram in a patient with severe pulmonary hypertension shows right ventricular and right atria1 enlargement with a normal to reduced left ventricular cavity.“’ Midsystolic closure of the pulmonic valve is commonly seen and is demonstrated by Doppler studies to be caused by a reflected pressure wave that is produced by the high pulmonary vascular resistance which results in transient retrograde blood flo~.“‘~“~ Pulmonic and tricuspid insufficiency is also easily detected with Doppler interrogation. Reversal of the normal septal curvature, associated with right ventricular pressure overload states, is also easily

seen with two-dimensional echocardiography.” Attention is focused on the transseptal pressure gradient as an important hemodynamic deter- minant of this abnormal septal configuration”4 with the degree of septal distortion paralleling the severity of the pulmonary hypertension.“’

In the NIH Registry on PPH it was noted that the left ventricular internal diastolic dimension as measured on M-mode echocardiography was normal or reduced in all of the patients with primary pulmonary hypertension.” Hemody- namic correlations between the pulmonary vascular resistance and echocardiographic findings revealed an inverse relationship between left ventricular internal dimension and pulmonary vascular resistance, suggesting that underfilling of the left ventricle was a reflection of the severity of the pulmonary vascular disease. There was no association between the right ventricular internal dimension and the level of the pulmonary vascular resistance. Using echocardiographic and Doppler techniques, we showed a marked redistribution of left ventricular filling from early to late diastole in patients with primary pulmonary hypertension.“6 This alteration in diastolic filling coincided with the ventricular septal distortion that is present before the onset of transmitral inflow and persists throughout the early diastolic filling period. The dependence on late diastolic filling to achieve adequate left ventricular preload would be of particular significance in patients who develop arrhythmias that result in the loss of the late diastolic booster effect of atria1 systole. This provides a hemodynamic explanation for why we have not observed atria1 fibrillation in patients with primary pulmonary hypertension, consistent with a marked dependence upon the effect of atria1 systole for left ventricular filling. The implications of these findings may also apply to the therapy of primary pulmonary hypertension. Often, vasodilator drugs produce an increase in cardiac output without a concommitant reduction in pulmonary artery pressure.“’ In this setting, one might predict that the increased volume loading of the left ventricle, at a time when early filling dynamics are impaired because of distortion of the ventricular septum, may result in an increased pulmonary capillary wedge pressure and a worsening in symptoms of orthopnea and dyspnea. Indeed, this was reported as an adverse

216 STUART RICH

effect of vasodilator drugs in some patients with PPH.“’

Several strategies were developed using Doppler ultrasound to noninvasively determine the pulmonary artery pressure. These focused on the changes in the systolic flow velocity profile across the pulmonic va1ve,119-121 the magnitude of tricuspid regurgitant flow velocity,‘** and characteristics of pulmonic regurgitant flow veloci- ties.123 Although one can reliably detect marked elevations in pulmonary artery pressure using these techniques, the precision with which one can measure the level of pulmonary artery pressure is less certain.‘24 Changes within a given patient seem to accurately reflect hemodynamic changes, and the use of serial Doppler studies has been reported to follow drug therapy which resulted in a lowering of the pulmonary artery pressure.‘25 The real challenge, however, is the accurate and cost-effective application of noninvasive testing to detect mild elevations in pulmonary artery pressure in patients with PPH before advanced changes occur in the pulmonary vascular bed.

Cardiac catheterization is an absolute require- ment for establishing the diagnosis of primary pulmonary hypertension.” Besides allowing the exclusion of other cardiac causes, it also establishes the severity of the disease and allows assessment of prognosis. Because congenital heart disease can often be missed (particularly in patients with ostium secundum atria1 septal defects) as an underlying cause of pulmonary hypertension, it is our preference to exclude the presence of an intracardiac shunt by performing a hydrogen curve at the time of catheterization, even if our index of suspicion is low. In patients with a predominant right-to-left shunt, an early detectable hydrogen curve deflection will still be apparent, as some left-to-right shunting always coexists. Other mechanisms to exclude the presence of a shunt, including coximetry determinations and green-dye methodology are acceptable, but less sensitive.

By definition, patients with primary pulmonary hypertension should have a low or normal pulmonary capillary wedge pressure.” Although it has been often stated that one may be unable to obtain an accurate wedge pressure in these patients, this has not been our experience. When persistent in pursuing a wedge pressure, we and

others noted that in cases when the wedge pressure was higher than anticipated, it was a true reflection of left ventricular filling dynamics.‘26 As previously stated, left ventricular diastolic compliance becomes significantly impaired in primary pulmonary hypertension and parallels the severity of the disease; thus, pulmonary capillary wedge pressures tend to rise in the late stages in patients with PPH.‘*’ However, we did not observe wedge pressures exceeding 15 to 16 mm Hg even in people with severe PPH, with the exception of one patient with veno-occlusive disease. The presence of a substantially elevated wedge pressure should be collaborated with left ventricular catheterization to see if it reflects an abnormal left ventricular end-diastolic pressure, mitral valve stenosis, or impairment of left atria1 filling by stenosis of the pulmonary venous system.

When measuring the hemodynamics, one should pay particular attention to right atria1 and right ventricular end-diastolic pressures. We found that right ventricular function closely parallels the prognosis of patients with PPH and, consequently, right ventricular stroke volume and right atria1 pressure have prognostic implications.128*l*9 The measurements of all right-sided pressures are properly made at end-expiration (and not an average of the inspiratory and expi- ratory cycles), to avoid incorporating negative intrathoracic pressures. Typically, one will find mean pulmonary artery pressures at the level of 50 to 60 mm Hg, with increases in right atria1 pressures very common.10~128~129 Although physicians tend to discount elevations in right atria1 pressure as being inaccurate in the presence of tricuspid regurgitation, we observed detectable tricuspid regurgitation (by Doppler techniques) in virtually all of our patients with primary pulmonary hypertension, and yet found an entire constellation of right atria1 pressures that corre- late closely with the right ventricular end- diastolic pressure. The right atrium should be an extremely compliant chamber (as there are no venous valves present), because regurgitant blood through the tricuspid valve can be trans- mitted to the entire systemic venous system. Thus, we believe that the right atria1 pressure reflects the diastolic compliance of the right ventricle.

The Fick method for determining cardiac out-


put is most accurate in patients with low cardiac output states, although we found determinations of cardiac output using thermodilution techniques satisfactory in the management of our patients. Since a thermodilution cardiac output is the cardiac output across the right ventricular outflow tract, this can be influenced by swings in the respiratory cycle. Thus, if one is looking for precision, it is advisable to time the injections of the iced saline to the respiratory cycle.

It can be extremely difficult to pass a catheter to the pulmonary artery in patients with primary pulmonary hypertension due to tricuspid regurgitation, a dilated right atrium and ventricle, and low cardiac output. In addition, often when the catheter is finally placed into the pulmonary artery for chronic monitoring purposes, it will dip backwards into the right ventricle or right atrium. This is compounded by the lack of stiffness of the flow-directed balloon catheters. For these reasons, the Swan-Ganz Guidewire TD Catheter was developed specifically for patients with pulmonary hypertension (American Ed- wards Laboratories, Irvine, CA). It has an extra port for the placement of a 0.32 guidewire, to provide better stiffness to the catheter.13’ In our experience, this dramatically facilitates not only the placement of the catheter to the pulmonary artery, but virtually eliminates instances of the catheter flipping back retrograde during chronic- monitoring studies.

Other diagnostic modalities have been used in the diagnosis of pulmonary hypertension. Because right ventricular ejection fraction is inversely proportional to the pulmonary artery pressure,‘3’ the determination of pulmonary hypertension from radionuclide ventriculography is a popular technique at some centers. This technique also allows the determination of hemodynamics during exercise (of possible use in evaluating patients with predominantly exercise related symptoms) and the effects of drug on exercise performance.‘32 The major problem with applying radionuclide ventriculography to the right ventricle is that it lacks sensitivity and specificity in estimating the pulmonary artery pressure.‘33*‘34 Overlap of the right atrium with the right ventricle is one reason that this technique has not gained wide acceptance.

Computed tomography (CT) has also been used as an aid in the diagnosis of pulmonary

hypertension.‘35 It was shown that the dimen- sions of the proximal pulmonary arteries corre- late well with the pulmonary artery pressure,‘36 but their clinical measurement, which has been made primarily from chest radiography, is often inaccurate.13’ CT allows a precise, noninvasive measurement of the diameter of the pulmonary arteries, from which estimates of the mean pulmonary artery pressure can be made.‘35 CT has also been reported to be useful in distinguishing pulmonary veno-occlusive disease in a patient with pulmonary hypertension.13*

Pulmonary artery diameter can also be pre- cisely measured from magnetic resonance imaging (MRI). 139 In addition, MRI can evaluate the severity of pulmonary hypertension by providing direct measurements of right ventricular wall thickness, which also correlates with the mean pulmonary artery pressure.‘39 Somewhat more exciting, however, is the application of gated magnetic resonance imaging in estimating pulmonary vascular resistance by also providing information about pulmonary blood flo~.‘~ In the future, it may also be possible to provide pathophysiologic information about patients with PPH using MRI to measure lung tissue perfusion.

THE NATURAL HISTORY OF PRIMARY PULMONARY HYPERTENSION

The natural history of PPH is described in several small series, with a typical mean survival of 2 to 3 years for patients from the time of their diagnosis~55~12'~'28~141 It should be emphasized, however, that there are patients with PPH for whom survival exceeding 10 years is well documented.‘42,‘43 This is an important consideration when evaluating the effects of medical treatment and the urgency for seeking aggressive treatment options such as heart-lung transplant.‘U

From the data in the NIH Registry on PPH, two important features regarding the natural history of the disease became apparent. The first was that the hemodynamic derangements occurring with PPH follow a typical pattern. Patients who present very early in the course of the disease have marked elevations in pulmonary artery pressure but relatively normal cardiac function. Patients diagnosed later in the disease manifested lower cardiac outputs and higher right atria1 pressures, but similar pulmonary

218

TIME I I L I ,

Fig 5. The clinical course of PPH is diagrammed. Initially. with increasing pulmonary artery pressure. the patient will likely be symptom free, or symptomatic with marked activity only /Stage I). Eventually, the entire constellation of symptoms will be manifest, and can remain stable (Stage II). Ultimately, as right ventricular failure ensues and cardiac output declines symptoms will progress

and lead to death (Stage Ill). It appears from the studies of PPH that each of these stages can have a highly variable

time course.

artery pressures (see Fig 5). Over time, the stroke volume becomes progressively reduced, rather than the pulmonary artery pressure becoming progressively increased. It is unclear why the pulmonary arterial pressure does not continue to increase later in the course of the disease. It is interesting to note, however, that pulmonary hypertension results in an increase in the fiber length of the pulmonary vascular smooth muscle to one that is closer to the optimal length for active vasoconstriction.‘45*‘46 It is possible that the pulmonary arteries maintain this fiber length and keep the pulmonary transmural pressure constant as a protective measure. Even- tually, as the right ventricle begins to fail, the right atria1 pressure and right ventricular end- diastolic pressures increase in an attempt to compensate for the severe elevation in pulmonary vascular resistance.‘*‘-iz9

In the early stages of the disease, when an elevated pulmonary artery pressure is the only hemodynamic abnormality, the patient is usually minimally symptomatic, and the sensation of dyspnea may be apparent only with exercise. As the cardiac output diminishes, however, hypoxemia and dyspnea increase and frank fatigue and syncope become apparent. When the right ventricle fails, venous congestion with edema mani- fests.

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The other important feature of PPH, which was confirmed by the NIH Registry, is the highly variable clinical course.‘*’ Some patients may present with minimal symptoms with early hemodynamic changes of pulmonary hypertension, and then progress through an entire spectrum of changes and die within a 6-month period,14’ whereas others follow a similar course, but over a 6-year period. Even spontaneous regression of PPH is reported, although this is dis- tinctly uncommon.‘48V*49 This suggests that the progression of the disease in the pulmonary vasculature can occur at different rates, which can- not be determined by the clinical evaluation of a given patient at a single point in time. The natural history is also influenced by other factors, such as the functional status of the heart and lungs at the time of the disease. Once right ventricular failure becomes manifest, survival beyond 2 years is unlikely.‘27~‘29

Patients with PPH usually die of either right ventricular failure or sudden death. As right ventricular failure progresses, the patients become more dyspneic, fatigued, and edematous. Syncopal episodes may become more frequent. Symptoms suggesting coexistent left ventricular failure, such as tachypnea or orthopnea, are also seen. This does not mean that left ventricular systolic failure is occurring. Severe right ventricular hypertension can affect the diastolic mechanical and compliance characteristics of the left ventricle, increasing left ventricular end- diastolic pressure and decreasing left ventricular filling. Consequently, the symptoms from elevated left atria1 pressure and decreased cardiac output do not reflect left heart failure, but rather altered left ventricular mechanics secondary to right ventricular dysfunction.84*‘50

There are likely several mechanisms for the sudden death seen in PPH. Any tachyarrhythmia, especially one that results in the loss of effective atria1 systole, can produce severe hypotension and may be the most common mechanism. However, sudden death as the first manifestation of PPH is reported, without an obvious cause.“’ Additional scenarios, such as an acute pulmonary embolus, or sudden right ventricular ischemia or infarction from coronary insufficiency are also possible and probably occur in a number of cases.15* As a rule, however, sudden death is a very late manifestation of the disease.


When we compared the clinical and hemodynamic features of patients in the NIH Registry on PPH who died of sudden death to those who died with progressive right ventricular failure, they were found to be similar in every aspect.

MANAGEMENT OF PATIENTS WITH PPH

It is our practice, before making specific rec- ommendations regarding the management of patients with PPH, to characterize their disease based on the chest radiograph, lung scan, echocardiogram, and hemodynamics. Although prospective studies have not been done, we believe that some patients with plexogenic pulmonary arteriopathy have a more rapidly progressive course than those with thrombotic pulmonary arteriopathy. Patients with pulmonary veno- occlusive disease seem to have a highly variable but generally ominous clinical course, but again, the number of patients that have been studied is small.

Lifestyle Changes

Although some feel that the diagnosis of primary pulmonary hypertension implies total dis- ability for the patient, this is not necessarily true. However, when performing exercise studies in patients with PPH under hemodynamic monitoring, it becomes very apparent that marked hemodynamic changes occur early with the onset of increased physical exercise.‘s3 There is a rapid increase in pulmonary artery systolic pressure that is associated with marked tachycardia, but only modest increases in cardiac output. It is obvious, then, that right ventricular wall stress becomes extremely high in the face of physical activity. Given the hazards that a sudden and severe increase in ventricular wall stress can have on ventricular performance, it would be advisable to suggest a change in lifestyle for patients with PPH towards activities where strenuous physical activity and sudden isometric workloads can be avoided.

We observed that one of the most common clinical features of PPH is an extraordinarily variable sense of well-being from day to day. Virtually all of the patients evaluated with PPH report to us that on any given day their sense of well-being and effort tolerance may improve to the point that they begin to wonder if their disease has regressed, whereas on another day

the symptoms of fatigue and dyspnea become markedly worse with an occasional sense of impending death. No study has analyzed the basis of these wide swings in symptomatology, and it is our practice to advise patients to follow their symptoms and limit activity on days when they feel more symptomatic and maximize their activities on days when their symptoms are at a reduced level. The diagnosis of PPH is not inconsistent with a productive life, as many of our patients return to an active career with modest modifications in their work demands.

The subject of pregnancy should be discussed with all women of child-bearing potential. Although women with pulmonary hypertension may survive pregnancy, the physiologic changes that occur in pregnancy can potentially aggra- vate the disease and result in death of the mother or child.ls4 Besides the increase in circulating blood volume and oxygen consumption that will increase right ventricular work, circulating procoagulant factors and the risks of pulmonary embolism from deep venous thrombosis and amniotic fluid are major concerns. In addition, the stress of delivery could provoke syncope or cardiac arrest, and a syndrome of postpartum circulatory collapse has also been described.‘54x’5s At this time, we feel that surgical sterilization should be given consideration by women with PPH or their husbands.

Digoxin

Digoxin is a positive inotropic agent that is of clinical value in patients with left ventricular systolic failure. As controversies have arisen regarding the effectiveness of long-term digoxin in the treatment of patients with left ventricular dysfunction, it is obvious that it will be difficult, if not impossible, to prove that the use of digoxin in any way influences the overall outcome of patients with right ventricular systolic dysfunction and pulmonary hypertension. On the other hand, there is nothing unique about the sarco- meres of the right ventricle to suggest that they would be unresponsive to the inotropic properties of digoxin. Animal studies performed on the utility of digoxin in right ventricular systolic overload showed that the prior administration of digoxin helped prevent the reduction in contractility of the right ventricle.‘56.‘57 Consequently, we advocate the administration of digoxin to our

220 STUART RICH

patients with primary pulmonary hypertension as prophylaxis, even in the absence of right ventricular failure, unless there is a coexistent problem that would reduce the safety of taking this medication.

Diuretic Therapy

Considerable controversy also exists about the role of diuretics in the treatment of patients with primary pulmonary hypertension. Diuretics do not possess pulmonary vasodilator properties, and thus would not be expected to lower pulmonary artery pressure or pulmonary vascular resistance. Their role in the treatment of patients with pulmonary hypertension has been traditionally limited to patients manifesting right ventricular failure and systemic venous congestion. We found, however, that diuretics are much more effective in providing symptomatic relief than one might anticipate

As discussed earlier, pulmonary capillary congestion and increased left ventricular filling pressures may contribute to the sensation of dyspnea and orthopnea in patients with pulmonary hypertension due to left ventricular diastolic dysfunction. Others describe increased extravascular lung water in patients with right heart failure from car pulmonale.‘58 A modest reduction in the capillary wedge pressure from diuretics may afford relief from these symptoms. More impor- tantly, however, diuretics work to reduce right ventricular wall stress in the right ventricle that is volume overloaded. We have had no problems with systemic hypotension or reduced cardiac output after using diuretic therapy in patients with elevated right atria1 pressures, and we initiated diuretic therapy in patients with symptoms of dyspnea and elevated jugular venous pressures. As for other conditions, dosage is determined by the patients’ symptoms.

Principles of Vasodilator Drug Administration

In the last decade, the main focus of the therapy used for patients with pulmonary hypertension was on vasodilator drugs. We believe that these drugs should not be administered without measuring pulmonary hemodynamics, of which the clinician should have a thorough understanding.

The most commonly followed hemodynamic

parameter is the pulmonary vascular resistance (PVR). The technology does not exist to measure directly the actual resistance in the pulmonary vascular bed. Consequently, through an adapta- tion of Ohm’s law, a hydraulic equivalent equa- tion has been derived to calculate the pulmonary vascular resistance. Is9 In reality, the derived value is a ratio of the pulmonary artery pressure to the pulmonary blood flow. Although the calcu- lation of pulmonary vascular resistance helps to characterize the severity of many cardiovascular diseases, the changes that occur in pulmonary vascular resistance from interventions can be misinterpreted for several reasons. First is the assumption that the pulmonary capillary wedge pressure that is measured to determine the downstream pressure within the pulmonary arterial bed is the true closing pressure for the arterial system. Although this appears to hold true for normal subjects,‘60 it does not necessarily hold true for patients with cardio-pulmonary diseases during which the pulmonary capillary wedge pressure may underestimate the downstream pressure. This has been demonstrated in chronic obstructive lung disease, and left heart disease, and may also occur in primary pulmonary hypertension.‘6’,‘62 Plotting the slope of the pressure- flow relationship by measuring the pulmonary artery pressure at several different cardiac outputs may be a more physiologic way to characterize the pulmonary vascular resistance.163 However, one never knows whether a fall in resistance should be attributed to vasodilation or recruitment of vascular channels, since the pulmonary vasculature does not represent a closed system. In addition, the calculated pulmonary vascular resistance is most often reduced with vasodilators in patients with PPH by increasing the cardiac output while leaving the pulmonary artery pressure unchanged.“’ This is often inter- preted as representing a reduction in right ventricular afterload, while in reality it represents an increase in right ventricular work and wall stress by increasing right ventricular volume in the face of a markedly elevated systolic pressure. Conse- quently, we do not rely solely on the numerical value for pulmonary vascular resistance, or change in resistance, as a measure of the effects of drug therapy. Rather, we focus on the hemodynamic parameters that appear to reflect best


the state of the disease, namely, the pulmonary artery pressure, right atria1 pressure, and stroke volume.

The establishment of baseline hemodynamic values should be done with the patient at rest, in as relaxed a stable state as possible. Even when this is achieved, it is noted that substantial hemodynamic variability exists in the pulmonary vascular bed that will produce periodic changes in cardiac output and pulmonary artery pressure.‘64 This is another potential source of misin- formation regarding the clinical course of PPH and the influence of drugs. We evaluated the phenomenon of variability in the pulmonary vascular bed in 12 patients with primary pulmonary hypertension in whom systemic and venous catheters were placed. Hourly measurements of cardiac output and systemic and pulmonary pressures were taken during six consecutive hours of bed rest.lG Marked swings that were not necessarily in the same direction, occurred in pressure and flow in every patient, suggesting constant changes in vaso-motor tone within the pulmonary vascular bed. The higher the level of the pulmonary hypertension, the greater the swings. The phenomenon of variability, however, is not unique to primary pulmonary hypertension. Variability exists within most diseases and is generally proportional to the severity of the disease state. Consequently, variations in the frequency of ectopy in patients with heart disease, changes in arterial oxygen in patients with chronic lung disease, and changes in blood pressure in patients with systemic hypertension have all been demonstrated and appear to represent a facet of the disease process during which auto- regulation becomes impaired.‘6s”67 In this regard, trends in the hourly changes of the hemodynamics in patients with pulmonary hypertension probably give more reliable information than any measurement made at a single point in time.

The testing of vasoactive compounds in patients with primary pulmonary hypertension has been reported since Dresdale’s initial series in 1951.5 In a sense, there is nothing unique about the acute testing of drugs in patients with primary pulmonary hypertension from any other cardiopulmonary disease. However, over the years lessons have been learned in the observa-

tion of acute drug testing in general, that need to be reemphasized in the patient with PPH.

Many of the reports on the effects of drugs in patients with PPH provide a baseline value and a “peak” effect of the drug. The problem with this practice is that it incorporates observer bias. Because of the variability that occurs in the resting hemodynamics of patients with PPH, the physician may choose a high recording as the baseline value, and then a favorable change as the peak drug effect, when no true drug influence has occurred. This became apparent to us when evaluating captopril in patients with PPH.16’ When we recorded the dose-response relationship between drug administration and pulmonary hemodynamics, we found no effect over a 4%hour period. However, had we chosen “peak” drug effect, we would have been able to claim substantial hemodynamic improvements in all of the patients, because of the marked hemodynamic variability. This problem can be addressed in one of two ways. One can measure serial pressures over time prior to drug treatment, using the mean value as the control, and then several more periodic recordings after drug administration, using the mean value as the drug effect. Obviously, when one is trying to evaluate the acute effect of a drug over a short period of time, this becomes problematic. A preferred approach is to use a consistent timed effect of the drug. That is, select the time interval during which the drug appears to exert its greatest hemodynamic influence, make measurements of control values, and then record the values that occur at a specified time interval irrespective of the variability that may occur. We observed that a change in the pulmonary artery pressure of 22%, and in pulmonary resistance of 36%, is necessary for an investigator to be certain that the drug had a true effect in a single patient with PPH.‘64 When evaluating a drug in a series of patients, the likelihood of a measurement being influenced by variability causing a falsely low reading will be offset by the equal likelihood of it creating a falsely high reading in other patients. Thus, by applying standard parametric statisti- cal tests, if a significant change is observed, even if it is small, one can attribute it to the drug and not to variability.

Many investigators used the strategy of testing

222 STUART RICH

several drugs to see if a patient responds to one class of agent when he or she fails to respond to another. This always raises the possibility of overlapping drug effects, since it is difficult to know the actual washout of the drug in PPH. Simply waiting for hemodynamic variables to return to control levels may not be adequate. From the pharmacokinetic standpoint, several half-lives of the drug need to pass in order for one to evaluate the pure influence of a new agent.

Controversy also surrounds the definition of a beneficial drug effect. Some investigators empirically chose a reduction in pulmonary vascular resistance of 20% or greater as a measure of a beneficial drug effect**; others suggest a reduction of 30% which, although an equally arbitrary value, may be more reliable.‘69 In either case, it is very possible to have a response during which the pulmonary artery pressure is increased with drug administration while the calculated pulmonary vascular resistance is reduced.‘r7 It would be inappropriate, and actually contradictory, to place a patient on a drug whose effect is to increase the pulmonary artery pressure in the face of pulmonary hypertension. This is another reason we choose to focus less on the calculated pulmonary vascular resistance, and more on the directly measured variables of pulmonary artery pressure, right atria1 pressure, and cardiac output.

Aside from the standard measurements of systemic and pulmonary pressures and cardiac output, several other hemodynamic parameters should be monitored in testing and treating patients with PPH. Since no drug is specific for the pulmonary vascular bed, vasodilator influences usually occur in both the systemic and pulmonary arteries. Traditionally, we looked for drugs that exert more preferential effects on the pulmonary bed, since excessive systemic vasodilation can cause hypotension, syncope, and even myocardial ischemia. We advocated comparing the relative change that occurs in pulmonary vascular resistance against the change in systemic vascular resistance to identify drugs that appear to have a more preferential pulmonary vasodilator effect.‘17 Although this does not guarantee that the drug will be beneficial to the patient over the long term, in our experience it

does identify those patients in whom the pulmonary artery pressure is reduced along with an increase in cardiac output.

We also prefer to monitor the change in stroke volume over that in cardiac output, as a reflection of the change in ventricular performance and pulmonary blood flow. Patients with PPH and reduced cardiac outputs frequently have increased resting heart rates.” A modest increase in cardiac output may represent a better improvement in ventricular function if it is associated with a reduction in resting heart rate.

Another important physiologic variable that is frequently overlooked is the systemic arterial oxygen content. As mentioned earlier, systemic arterial hypoxemia is virtually ubiquitous in patients with PPH, and is attributed to a low cardiac output and ventilation/perfusion inequalities in the lung. Effective vasodilator drugs may result in vasodilation of blood vessels supplying poorly ventilated areas of the lung, and worsen the systemic hypoxemia.‘70 This is particularly noticeable in the patients with underlying chronic lung disease.17’ It is less of a problem in patients with primary pulmonary hypertension, but should not be overlooked, especially in the patient who presents with substantial hypoxemia at baseline.‘18*‘72 It is our practice to monitor systemic arterial oxygen content before and after drug administration to screen for this potential adverse drug effect. In the patient with advanced PPH and low cardiac output, tissue delivery of oxygen may be severely compromised and lead to acidosis. In these patients, an increase in cardiac output, without a reduction in arterial oxygen saturation, can result in improved oxygen tissue delivery that may be beneficial to the patient.‘73 It remains unknown, however, if this type of improvement can be translated into long-term benefits to the patient.

VASODILATOR DRUGS USED IN THE THERAPY OF PRIMARY PULMONARY HYPERTENSION

The published literature on the effects of vasodilator drugs in patients with PPH has been controversial at the very least. For every paper published that describes beneficial effects another describes its adverse side effects. The


major drugs that have been tested in the past will be reviewed briefly.

Tolazoline

Tolazoline is an agent that received early attention as a possible treatment for PPH.‘74 Although classified as a histamine agonist and alpha-adrenergic antagonist, it also possesses strong chronotropic properties. Tolazoline gained popularity as an agent to acutely test the responsiveness of the pulmonary vascular bed in patients with pulmonary hypertension from several etiologies.‘75-‘77 Although tolazoline may acutely lower pulmonary artery pressure and PVR, it has never been documented to be an effective chronic oral therapy. The high incidence of side effects with oral usage, as well as the short half-life requiring dosing every 3 to 4 hours limits its potential as an oral drug. Cur- rently, the role of tolazoline as a pulmonary vasodilator, if any, will probably be limited to short-term use in patients with congenital heart disease undergoing surgical correction.‘78

Acetylcholine

Acetylcholine was also reported in the 1950s as an agent used to test the vasomotor responsiveness of the pulmonary vascular bed in patients with primary pulmonary hypertension. In fact, it was the hemodynamic response to acetylcholine that led Wood to believe that vasoconstriction is a physiologic mechanism in PPH.6 Acetylcholine is rapidly inactivated by the lung, which may explain why the IV administration seems to produce selective pulmonary effects. There are published case reports of dramatic acute reductions of pulmonary artery pressure, but because no oral form of acetylcholine exists, chronic therapy with this drug is not feasible.6~‘75*‘7g-‘*’ The early experience with acetylcholine also demonstrated a patient with PPH who, on initial testing, had a reduction in pulmonary artery pressure but failed to respond to a rechallenge with the drug 3 years later.“” This suggests that the progression of PPH may be associated with a loss of vasoreactivity. No drug was formally tested in this regard, and whether the demonstration of the loss of a vasodilator effect from a

single drug has predictive value in terms of patient survival remains unknown.

Isoproterenol

Isoproterenol is a potent beta-adrenergic drug that affects both systemic and pulmonary vascular beds, and increases cardiac output by chronotropic and inotropic mechanisms.‘83 The enthusiasm of using isoproterenol in patients with PPH resulted because of a case report of a favorable response to chronic sublingual treatment.‘842’85 A critical look at the published literature, however, shows that, perhaps more than any other agent, isoproterenol results in an increase in pulmonary artery pressure in the face of a calculated reduction in pulmonary vascular resistance.“7*‘86S’87 This is likely due to the fact that the increase in pulmonary blood flow offsets whatever vasodilation is occurring. Terbutaline has been advocated as an oral analogue of isoproterenol for chronic therapy, but there are no convincing reports that it produces any sustained beneficial effects either.lE8

Alpha-Adrenergic Blockers

The demonstration of alpha-adrenergic vasoconstrictive influences on the pulmonary vascular bed in laboratory animals,‘*g and data suggesting similar effects in man,‘90S’g’ have provided the basis for attempting to use alpha- adrenergic blockers as therapy in patients with PPH. The literature on the clinical use of phentolamine and phenoxybenzamine is very limited, however.‘g2-‘g4 We noted that some patients who were placed on chronic long-term phentolamine therapy had a subjective impression of clinical improvement although we were unable to docu- ment hemodynamic changes in pulmonary artery pressure or pulmonary vascular resistance.“7 This could be related to the peripheral shunting of systemic blood to the muscles and skin. The alpha-blocking agents, however, have many intolerable side effects. Prazosin possesses direct smooth muscle-relaxing properties as well as being an alpha blocker, and is much better tolerated. Clinical studies have failed to show a consistent beneficial response to oral prazosin, even in patients who experience a reduction in pulmonary resistance from intravenous phen-

224 STUART RICH

tolamine.‘95 Thus, although alpha-adrenergic receptors regulate pulmonary vascular tone in the normal state, it is unlikely that they play a significant role in PPH.

Diazoxide

Diazoxide is a thiazide derivative with potent vasodilator properties but devoid of diuretic effects. It has been widely used intravenously in the treatment of hypertensive crises, and reports have appeared of its acute effects in patients with primary pulmonary hypertension. Early reports of substantial reductions of pulmonary artery pressure’96-‘98 are not noted in subsequent observations.“7~‘99 It also has a particularly hazardous property of causing a marked reduction in systemic blood pressure, and the deaths that have been reported from diazoxide administration 2w204 are very worrisome. For these reasons, we no longer test and advise against challenging patients who have PPH with diazoxide.

It is curious, however, that the only documentation of a drug causing a sustained reduction in pulmonary artery pressure and improvement in lifestyle for greater than 5 years was a case report of a patient with PPH treated with chronic oral diazoxide therapy. 205 Whether this patient would have responded similarly to other vasodilating agents remains unknown, but it serves as an illustration that the chronic administration of a drug that results in the reduction of pulmonary artery pressure may be associated with long-term benefit to the patient.

Nitroprusside

Sodium nitroprusside is a potent vasodilator that acts on the arterial and venous beds. It gained popularity, like diazoxide, because it rapidly lowers systemic blood pressure in patients with hypertensive crises. The short half-life of the drug is an additional advantage, because the effects rapidly dissipate when the infusion of the drug is stopped. Acute challenges of nitroprusside have been reported in patients with secondary pulmonary hypertensionm but there are no published studies on its influence in patients with primary pulmonary hypertension. Nitroglycerin, another nitrate compound with vasodilating properties, was tested in both IV and sublingual forms in patients with primary pulmonary hyper-

tension.203*207 Its influence on pulmonary pressures seems to be modest at best, and its influence on cardiac output minimal. Some investigators even report a decline in cardiac output from isosorbide dinitrate.203 There are no long-term reports of beneficial effects using the nitroglycerine preparations in patients with PPH.

Hydralazine

Rubin and Peter were the first to report the use of hydralazine in patients with PPH, showing that it reduced the pulmonary vascular resistance in four patients, acutely and chronically.208 Lupi-Herrera et al observe that hydralazine was most effective in those patients whose PPH was least severe.‘09 Others, including ourselves, are unable to demonstrate sustained beneficial effects from hydralazine in PPH.20332’o~211 More recently, there are reports indicating that hydralazine may increase pulmonary artery pressure and right atria1 pressure in these patients.“8,2’2 Our experience is that hydralazine, more than the other vasodilators, can cause a deterioration in the patient’s clinical condition, and worsen the symptoms of dyspnea and right heart failure when administered chronically.“’ In these cases, it appears that hydralazine increases cardiac output by reducing systemic resistance and leaves the pulmonary circulation unable to accommodate the increased pulmonary blood flow. The increased venous return to the right ventricle results in increased right ventricular wall stress, and subsequently leads to right ventricular failure. Increased venous return to the left ventricle might also be associated with higher left atria1 pressures from the reduced left ventricular compliance, and thus worsen the symptoms of dyspnea.212 For these reasons, we no longer use hydralazine as a drug to test for vasodilator effects in patients with primary pulmonary hypertension.

Calcium Channel-Blocking Drugs

The availability of calcium channel-blocking drugs adds a new physiologic approach towards vasodilation of the pulmonary vascular bed. The calcium blockers relax vascular smooth muscle by diminishing the intracellular movement of calcium during contraction,2’3 rather than by a


direct effect as is seen with hydralazine and minoxidil. In laboratory animals, calcium blockers appear to diminish the pulmonary vasoconstrictor response to hypoxia and PGF-2- alpha.2’“2’6 The most widely tested drug in patients with PPH has been nifedipine. When compared to the other classes of vasodilator drugs, nifedipine seems to result more consistently in a reduction in pulmonary artery pressure and pulmonary vascular resistance.210~217~225 It is reported to exert favorable changes at rest and with exercise223 and to improve right ventricular ejection fraction.‘** Some reports suggest that the acute effects are sustained over the long term. 2’7~218~220 However, adverse effects of nifedipine are also frequently reported, and include systemic hypotension,226 pulmonary edema,**’ hypoxemia,228 right ventriuclar failure,*72~229 cardiogenic shock,“* sinus-node arrest,226 and death.230 The point has also frequently been made that the response to nifedipine varies widely from patient to patient,2’0*23’ which may reflect the level of underlying right ventricular function. The experience with nifedipine serves to underscore the need for hemodynamic monitoring when initiating vasodilator therapy in PPH. Reports on the use of diltiazem and verapamil are more limited, but seem to parallel the favorable232-236 and unfavorable”* experiences with nifedipine. It should also be kept in mind that diltiazem and verapamil can have adverse effects on heart rate and conduction.

Angiotension-Converting Enzyme Inhibitors

Since angiotensin possesses pulmonary vasoconstrictive properties the rationale of treating patients with PPH with angiotensin-converting enzyme inhibitors appears to be sound.237‘239 Cap- topril, the most widely available inhibitor, has been reported in several studies in patients with PPH. As with other drugs, studies suggesting both beneficial and adverse effects have been forthcoming.‘68.240-245 Again, as with other agents, the early enthusiasm has not been borne out by the documentation of long-term beneficial effects. Upon review of the use of captopril in pulmonary hypertension, it appears that it may be helpful in improving cardiac output in patients with pulmonary hypertension secondary to left ventricular dysfunction.245*246 Although it

usually leaves the pulmonary artery pressure unchanged, the increase in cardiac output may ameliorate some of the patient’s symptoms. Cap- tropril’s effects in left heart failure are related to secondary activation of the renin-angiotensin system, that acts to sustain systemic vascular resistance at the expense of left ventricular contractility. 247 Such activation likely occurs in PPH when the cardiac output is markedly reduced. In this setting, the angiotensin-converting enzyme inhibitors could possibly be useful as an adjunc- tive therapy, provided they do not reduce the systemic blood pressure excessively.

Given the common practice to empirically administer vasodilator drugs to patients with primary pulmonary hypertension, there is a sur- prising paucity of information to suggest that any of these agents influence their clinical course or survival. For this reason, we evaluted the chronic treatment of 23 patients with PPH who acutely were tested with hydralazine and nifedipine. 248 We observed that the five patients who were unable to exhibit an acute decrease in pulmonary vascular resistance of 20% or greater had a poor short-term outcome. The remaining 18 patients who were able to elicit an acute reduction in pulmonary resistance were then observed over the next 2 years with respect to their clinical outcome. The nine patients who were treated with a vasodilator, however, had the same clinical response and mortality as those who were left untreated. Presently, it remains to be proven that any vasodilator drug administered chronically for PPH can alter the natural history of the disease.

Although the experience with congenital heart disease and aminorex-induced pulmonary hypertension suggests that PPH may be reversible early in the course of the disease, there undoubt- edly is a stage during which drug therapy offers no hope of improvement, and only exposes the patient to hazardous side effects. How to identify the transition from responsive to unresponsive remains a challenge. In our experience, the effect of vasodilators on patients whose right atria1 pressure exceeds 15 mm Hg or whose stroke volume index is below 20 ml/beat/M’ is uni- formly dismal, and we currently use these parameters as a basis to exclude patients from vasodilator testing.

226 STUART RICH

OTHER MEDlCAL THERAPIES OF PPH

Anticoagulant Therapy for Primary Pulmonary Hypertension

The histological observation that diffuse microvascular thrombosis exists in patients with primary pulmonary hypertension led physicians to the empiric use of anticoagulant therapy.7”4 The best evidence to support the use of anticoagulants in patients with PPH comes from the work of Fuster et al, who reviewed the experience of the Mayo Clinic over a 15year period in patients with primary pulmonary hypertension.” Al- though retrospective in nature, their study did suggest a therapeutic benefit with respect to survival in the patients who were treated with anticoagulant therapy. In addition, they subsequently reported regression of pulmonary hypertension in one patient who was treated with anticoagulant therapy, suggesting that, at least in that patient, an active thrombotic process was effectively arrested by the anticoagulant therapy?

Many physicians feel uncomfortable adminis- tering anticoagulants to patients with PPH who may have hepatic congestion and an enhanced risk for bleeding episodes. On the other hand, once patients with PPH go into right heart failure with venous congestion, they run the risk of developing deep vein thrombosis and subsequent pulmonary embolism, which would almost certainly be catastrophic. As we reach a better understanding of the role of thrombosis in patients with chronic pulmonary hypertension, it should become clearer which patients are most likely to benefit from anticoagulation. At the present time, we give strong consideration to initiating anticoagulant therapy to all of the patients with PPH. The ultimate decision rests on our perception of the risk/benefit ratio in each patient as determined individually.

Oxygen

Although hypoxia can produce acute and chronic pulmonary hypertension in animalsZSO and man,2517252 it does not appear to be an etiologic factor in PPH. lo On the other hand, because hypoxemia is extremely common in patients with PPH, there is an impetus to try oxygen administration as a therapy. None of the published

reports on the effects of oxygen in PPH suggest that it does more than improve the patients sense of well-being. 187,188.203,253,254 lts use has been cau-

tioned, however, from the observation that it tends to increase systemic vascular resistance, which could ultimately be detrimental.242 Since mild to moderate hypoxemia only slightly affects pulmonary vascular resistance, oxygen is unlikely to be of value in the average patient with PPH. Decreases in Pa02 below 50 mm Hg increase pulmonary vascular resistance dramatically. 25s*256 Chronic oxygen administration may be an approximate consideration in this subset.

Amrinone

Amrinone is a nonglycosidic, nonadrenergic inotropic agent that has been developed for treating congestive heart failure. Its attractiveness towards treating pulmonary hypertension is enhanced by its peripheral vasodilating properties. We compared the short-term effects of amrinone to hydralazine and nifedipine in patients with PPH, but found little effect in the doses used.2’0 Others found a similar lack of inotropic response in patients with right heart failure.“’ It is possible that the inotropic response to amrinone is dependent upon concom- itant vasodilation, which is difficult to achieve in PPH. Since patients with PPH die of right ventricular failure, one is tempted to try other inotropic drugs as therapy. The recent observation that inotropic therapy may accelerate ventricular dysfunction in left heart failure,258 however, should serve to temper enthusiasm for using inotropic drugs as chronic therapy for PPH.

Miscellaneous

Several preliminary tests of a variety of agents have been used in patients with PPH and include prostaglandin inhibition with indomethacin,‘“*“3 antihistamines,18’ aspirin,i8’ alone and with di- pyridamole,2°3 steroids,18’ and azathioprine.18’ Although the investigators tended to conclude that these drugs were largely ineilective, the few number of patients and lack of scientific design really leaves the question unanswered as to whether they could be helpful. Because the rationale for their use was based on hypotheses regarding the etiology of PPH, we may return to some of these agents as our understanding of the


basic pathophysiologic mechanisms of PPH improves.

PPH AND CARDIOGENIC SHOCK

In the late stages of the disease, patients with PPH may present in florid right heart failure and cardiogenic shock. No effective therapeutic regimen was established in these patients, because the physician is usually faced with the difficult task of trying to lower a severely elevated pulmonary vascular resistance in a patient with systemic hypotension. The immediate goal of therapy in this setting should be an increase in cardiac output and the maintenance of systemic blood pressure to prevent right ventricular ischemia?’ Dopamine, in vasoconstricting doses, may be of value since it will improve contractility and increase blood pressure while leaving the pulmonary vasculature unaffected.260 The combination of dopamine with nitroprusside is useful in the management of postoperative pulmonary hypertension in children, following repair of congenital heart disease. 261 Once the patient is stabi- iized, it is advisable to maintain the inotropic support for a time to allow right ventricular end-diastolic pressure and volume to decrease.262 If successful, the patient may be weaned grad- ually.

NEWER PHARMACOLOGIC APPROACHES TO THE TREATMENT OF PPH

High Dose Calcium Channel-Blocking Therapy

The published studies regarding the effectiveness of vasotonic agents in patients with primary pulmonary hypertension generally used conventional doses of drugs. It is understandable to expect that the dose of a drug that works effectively for one condition might work for another condition. However, for the very reason that no drug has been shown to be specific for the pulmonary vascular bed, it should not be surpris- ing that there might be different dose responsiveness for pulmonary vascular diseases. In that perspective, we recently evaluated a novel regimen using high doses of calcium channel-blocking drugs as therapy for primary pulmonary hypertension.263 On the premise that conventional doses of these agents may not be an adequate challenge to patients with PPH, we

developed a drug protocol that initially challenges patients with conventional doses of nifedipine or diltiazem, and then gives consecutive hourly doses until a 50% fall in pulmonary vascular resistance and a 33% fall in pulmonary artery pressure is achieved, or until untoward side effects are manifested. We observed that the initial drug challenges produced only marginal reductions in pulmonary artery pressure and pulmonary vascular resistance, similar to previous published experiences. However, of the 13 patients tested, 8 responded to continued hourly doses with a mean reduction in pulmonary pressure of 48% and of pulmonary vascular resistance of 60% (see Fig. 6). These patients were discharged on the high doses of nifedipine (up to 240 mg per day), or diltiazem (up to 900 mg per day) as chronic therapy and followed as outpa- tients. At the present time, six patients returned for restudy after 1 year. In five of the six the reduction in pulmonary artery pressure and pulmonary vascular resistance was sustained over the year and was associated with regression of right ventricular hypertrophy, as evidenced by changes on the electrocardiogram and echocardiogram, and verified hemodynamically at catheterization. The pulmonary artery pressure and vascular resistance of one patient who reduced her medication back to a conventional dose returned to its initial level. The five patients who failed to respond to the high-dose drug challenge

I Q I I b

HOURS

Fig 6. The response to high-dose nifediiine therapy in one of our patients with PPH is shown. Twenty mg of nifedipine was given orelly every hour (arrows) until a fall in

pulmonary artery pressure and rise in cardiac output occurred. In this patient seven consecutive doses were

required. The patient then received 120 rng of nifedipine (asterisk) every 6 hours with sustained effects of the

treatment.

228 STUART RICH

did not appear to differ from those who did by their age, duration of symptoms, or level of pulmonary hypertension. Although our experience is still limited, it appears that the severity of the disease as reflected by the stroke volume index and right atria1 pressure will likely be the best predictor of response. Surprisingly, while adverse side effects of these drugs in high doses were anticipated, no patient who was placed on chronic therapy had the drug discontinued because of systemic hypotension or other intolerable side effects.

The reason for the apparent selective pulmonary effects of the high doses of calcium blockers we observed is not known. However, it appears that, rather than being selective for a specific arterial bed, calcium channel blockers work preferentially on vascular smooth muscle that has heightened tone and is vasoconstricted, leaving the other vascular beds largely unaffected.263 The large doses of calcium channel blockers required in patients with PPH suggest that there is a different sensitivity of vascular beds or disease states to the effects of calcium channel blockade.

One patient who responded acutely to the high-dose calcium channel-blocking regimen subsequently died when her therapy was sud- denly discontinued six months later during an episode of gastroenteritis. Before her death, a repeat catheterization showed her pulmonary pressures to be suprasystemic off treatment. The rebound pulmonary hypertension that occurred in this patient supports the notion that active pulmonary vasoconstriction occurred, and serves to caution physicians against the sudden with- drawal of vasodilator therapy in a patient with primary pulmonary hypertension in whom a substantial vasodilator response is achieved.

Several questions regarding the efficacy of high doses of calcium channel-blocking drugs in PPH remain to be resolved. What proportion of patients with PPH will respond? Does it prolong survival? Are the beneficial effects of the high dose of calcium channel-blocking agents sustained indefinitely, and are there long-term toxic effects associated with such high doses? These questions have not yet been answered and need to be addressed in the future. In any case, the lesson learned from the observation that high doses of

calcium channel-blocking drugs can be effective in patients with PPH where conventional doses have failed, requires reexamination of notions regarding all vasodilator drugs in the treatment of this disease. Since conventional doses were used in the past, it may be unfair to characterize other classes of vasodilators as also being ineffec- tive. Future studies to evaluate the effectiveness of vasotonic agents in patients with PPH would do well to limit the dose of drug administered to a physiologic response, rather than a fixed dose determined from its effects in other diseases.

Prostaglandin Manipulation in PPH

Prostaglandins appear to play an important role in modulating pulmonary vascular tone in normal physiologic conditions264*265 and in some forms of pulmonary hypertension.266 Prostaglan- din E, (PGE,) received early attention in patients with mitral stenosis,267 which led to its subsequent use in treating PPH.268 Although modest reductions of pulmonary artery pressure and pulmonary vascular resistance were noted, adverse reactions precluded its administration at higher doses.267*268 Prostacyclin (PG12) has largely replaced PGE, because of its greater potency. Like PGE,, it requires IV administration. It was acutely evaluated in patients with PPH and was shown to have a substantial effect in reducing pulmonary vascular resistance.269 In addition, reductions in pulmonary artery pressure also occurred, but the upper limit of drug that can be administered is generally limited by the coexistence of induced systemic hypotension. The current experience suggests, however, that the acute response to a challenge with IV prostacyclin may be a safe way to determine the vasodilator responsiveness of the pulmonary vascular bed in patients with PPH.236*274272 If this is the case, it may be preferable to characterize patients based on their response to prostacyclin prior to evaluating other therapeutic modalities.

Jones et al have used an infusion of prostacyclin administered through an implantable IV infusion pump as chronic therapy for patients who acutely responded to the drug.273 Although substantial reductions in pulmonary artery pressure were not achieved with regimen, it was observed that there was symptomatic improvement in the patients receiving the drug, and


patients who were considered to be extremely ill were sustained until heart-lung transplantation. The experience with the use of chronic IV PGI, is quite limited, and more experience regarding its long-term effectiveness is required.

We recently evaluated the effects of a thromboxane synthetase inhibitor in ten patients with PPH.45 On the premise that thromboxane, a vasoconstrictor, may be liberated in patients with PPH, we sought to test the acute and chronic effectiveness of the investigational agent CGSI 3080, which has potent thromboxane synthetase inhibitor properties. In addition, these drugs also promote an increase in the endothelial production of PG12, by shunting through internal pathways.274 Although we were able to demonstrate any acute hemodynamic effects of the thromboxane synthetase inhibitor, after 3 months of therapy the drug did produce a significant fall in pulmonary vascular resistance, which was further reduced by the administration of nifedipine. The lessons learned from this study are twofold. First, combination drug therapy for patients with PPH may be worthwhile. The use of drugs with different pharmacological actions that may induce a favorable environment in the pulmonary vascular bed needs to be pursued. In addition, it also demonstrated that one may not need to show acute effectiveness of an agent in order to prove long-term benefit. Advanced vascular changes in PPH have been associated with a poor response to vasodilator challenge.*” By altering the physiologic environment in the pulmonary bed, perhaps with thromboxane synthetase inhibitors or similar drugs, one might be able to promote local “healing” to render it more responsive to vasodilator drug administration, and perhaps arrest or delay the progression of the disease.

Type-Speci’c Therapy of PPH

Recently, we reported our ability to distinguish the histologic subtypes of patients with primary pulmonary hypertension based on their chest radiographs and perfusion lung scans.38 One approach to the pharmacologic therapy of patients with PPH might be to develop different treatment modalities based on the histologic patterns. In this regard, the administration of vasodilator drugs would be most appropriate for

patients who appear to have the plexogenic arter- iopathic form of PPH. In these patients, chronic persistent vasoconstriction is believed to be the underlying disease process, and chronic vasodilator therapy may be indicated even in the absence of acute hemodynamic responsiveness. Patients who appear to have pulmonary thrombotic arteriopathy should probably all be treated with chronic anticoagulant therapy. Although it is not likely that anticoagulation will cause regression or reversal of the disease, it might arrest the disease and allow enhanced survival in these patients. The patient in whom veno-occlusive disease is suspected presents as a true therapeutic dilemma. We have previously cautioned against the use of vasodilator drugs in these patients, since we have seen it associated with pulmonary edema and death.3* Anticoagulant therapy would appear to be a more rational approach, although if the disease process is one of chronic fibrosis rather than thrombosis it may not afford any substantial clinical benefit.

NONPHARMACOLOGIC THERAPIES IN PRIMARY

PULMONARY HYPERTENSION

Atria1 Septostomy

It has been established that patients with congenital heart disease and left-to-right shunts can develop severe pulmonary hypertension (Ei- senmenger’s reaction) and present with a similar constellation of clinical symptoms as patients with PPH. It appears, however, that patients who have this disease seem to have a more prolonged clinical course than those with PPH, which has been attributed to the existence of the anatomic shunt that allows shunt reversal with blood flow going right to left.*“j This would tend to reduce preload in the right ventricle, and reduce right ventricular wall stress, although it creates systemic cyanosis and frequent syncope as a consequence. Animal data shows that dogs with atria1 septal defects and right ventricular pressure overload from pulmonary artery banding tolerate exercise better and have better right ventricular function than those subjected to a sham operation.277*278 In addition, patients with primary pulmonary hypertension who have an underlying patent foramen ovale may live longer,“’ and perhaps the creation of a small atria1 septal

230 STUART RICH

defect might afford clinical benefit to the severely ill patient with PPH. On this premise we performed an atria1 septostomy percutaneously on a patient with PPH who we had been following chronically, who presented with severe pulmonary hypertension and critically low cardiac oUtpUt.279 Although we were successful in creating right-to-left shunting acutely with an increased cardiac output, the patient died 36 hours later from pulmonary edema. The studies we performed subsequently on the diastolic properties of the left ventricle in PPH suggest to us that any potential increase in blood flow from creating a right-to-left shunt in the face of severe pulmonary hypertension might be offset by a restriction in left ventricular filling, since the diastolic compliance of the left ventricle is severely compromised and appears to be related to the level of the pulmonary artery pressure.“6 Thus, by increasing left ventricular preload without reducing pulmonary artery pressure, one might not be able to shunt blood adequately into the left ventricle, and thus pulmonary edema could ensue. Perhaps a small shunt may afford just enough reduction in right ventricular wall stress to keep a patient alive for a potential heart-lung transplant without causing severe increases in left ventricular preload. More data regarding the applicability of this strategy need to be forthcoming.

Heart Lung Transplantation

With advances in organ transplantation, it is possible to transplant en bloc the entire heart and lungs of a prospective donor to a recipient who has underlying severe cardiopulmonary disease.*” Since the first operation was performed in 1980, there have been more than 100 successful heart-lung transplantations performed worldwide. Early mortality from heart-lung transplantation is generally due to hemorrhage and infection in the perioperative period, with the perioperative mortality typically reaching 25% to 30%~~~’ In patients who survive, however, a dramatically improved lifestyle, with patients often returning to functional Class I, can be expected. The subsequent mortality of these patients appears related to chronic rejection and infection that occurs with all other organ transplantation, and graft atherosclerosis seen in heart transplant patients. Somewhat unique to this transplant,

however, is the observation that chronic rejection may occur in the lung in the absence of any evidence of rejection in the heart. This can lead to a state of chronic obliterative bronchiolitis, which can cause considerable impairment in pulmonary function and even necessitate a second heart-lung transplant.**’ In addition, physicians need to be selective when considering a patient with PPH for heart-lung transplantation. A recent review by Glanville et al shows that the survival of patients with PPH may not be worse than heart-lung transplant recipients in the near term.‘” It has always been our policy that heart-lung transplantation be reserved for those patients with PPH with a demonstrable decline in their clinical course and whose hemodynamic variables suggest little likelihood for long-term survival. In any event, heart-lung transplantation offers, for the first time, an opportunity for patients with end-stage primary pulmonary hypertension to undergo a procedure that can afford a dramatic improvement in the quality of life indefinitely.

CONCLUSION

Primary pulmonary hypertension remains an uncommon disease with several subsets that arise from different etiologies. Although its predilec- tion for younger age groups and females is confirmed, it appears that the natural history can be quite variable, and thus not all patients will necessarily have a progressive downhill course. The diagnosis can be made sasfely and reliably, in experienced hands.

The treatment of PPH remains our major challenge. While there is a good rationale to use anticoagulation, the role of conventional vasodilators remains uncertain. There appears to be considerable promise in newer therapies that use IV prostacyclin and high-dose calcium channel- blocking drugs. In any case, the development of strategies that allow an earlier diagnosis will likely result in better responses to all treatments. Finally, in the patient with advanced disease, heart-lung transplantation now offers another therapeutic option.

ACKNOWLEDGMENT

I wish to thank Bruce H. Brundage, MD for his guidance and support of this work, and Lisa Kaufmann, RN, for the invaluable help she provided me in the care of these patients.


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Primary pulmonary hypertension