The eisenmenger syndrome

The Eisenmenger Syndrome By

WILLIAM SHAPIRO

E S P I T E important advances in the diagnosis and treatment of m a n y lesions characterized b y p u l m o n a r y hypertension, a n u m b e r of problems remain unsolved. Clearly, certain complex lesions leading to early death await the feasibility of cardiac or p u l m o n a r y transplantation for their cure. Especially frustrating are those patients w h o have large, potentially correctible arteriovenous communications within or just beyond the heart b u t who, in addition, have severe, fixed p u l m o n a r y hypertension which determines a lethal course ff the defect were to b e closed. A b b o t t 1 stated that D a l r y m p l e first described such a case in 1847 but E i s e n m e n g e r 2 is generally credited with the first complete description of this problem in 1897. A brief translation of his original case is presented because it was typical and complete and serves to define his syndrome. I t provides a record in English of the pertinent clinical and necropsy findings.

D

ABBREVIATED TRANSLATION OF EISENMENGER'S CASE I~EPORT2~*

A 32 year old married coachman was seen on August 1, 1894. He suffered from his illness since earliest childhood, but did not have rheumatic fever or any other illnesses. He developed normally, progressed well in school, got married when he was 20 and had a healthy child. Since early childhood, his parents noticed cyanosis which greatly increased with the slightest exertion. Every exertion brought on shortness of breath; however, he worked as a coachman quite well. In January of 1894 the patient noticed for the first time that his legs had begun to swell and his shortness of breath and palpitation worsened. The parents had always been well and the pregnancy, birth and confinement had followed a normal course. Physical Examination. The patient was tall, had heavy bones and moderately developed muscles with little panniculus adiposus. The skin and nmcous membranes were markedly cyanotic. The jugular vein was distended, especially on the right side, and it exhibited a distinct undulation. Thorax long, average width, noticeably arched, abdomen slightly bloated; there was edema of the ankles and the posterior thoracic skin. The finger tips were thickened, the nails curved, claw-like. The lungs were clear on percussion; on auscultation there were signs of a diffuse catarrh. A prominent shock was present over the precordium which spread beyond the normal

From the Pauline and Adolph Weinberger Laboratory for Cardiovascular Research, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, Texas. WXLLXA~ Sx-~Pmo, M.D.: Assistant Professor of Medicine, University of Texas Southwestern Medical School, Dallas, Texas. *Translated by Mrs. Brigitta E. Payne, Secretary to Carleton B. Chapman, M.D., Director, The Pauline and Adolph Weinberger Laboratory for Cardiovascular Research, University of Texas Southwestern Medical School, Dallas, Texas. Mrs. Payne's complete translation was edited by the author. 438 PROGRESSIN CARDIOVASCULARDISEASES,VOL, 9, NO. 5 (MARCH), 1967

THE

EISENMENGER

SYNDROME

439

limits of the heart. The apex beat was in the sixth intercostal space, 61~ cm. to the outside of the mammillary line, where cardiac dullness began and reached 4 cm. beyond the right sternal border. Over the apex of the heart a systolic murmur accompanied by a palpable thrill and a dull second sound were heard. The murmur was heard over the entire area of cardiac dullness. The maximum point was in the middle of the cardiac dullness and decreased in intensity in all directions. It could not be heard over the aorta and the pulmonary artery. In the remaining cardiac orifices, the heart sound was somewhat duller, but clearer, the second pulmonary sound not accentuated. Liver dullness extended beyond 3 flngerbreadths below the rib-cage and reached to the left mammillary line. The liver edge was plainly palpable, firmly rounded, the spleen dullness very much enlarged. Pulse rate was irregular (108), not full, artery soft. The pulse was regular between 79. and 80 after digitalis was given. Sometimes the frequency sank, to 42-46 and the numbers in between could not be observed, but at such a moment a pulse curve could be registered. "Unfortunately, it has been lost and therefore I have to limit myself to its description." On the whole, it was the curve of a pulsus bigeminus alternans. The apical beat appeared to be of longer duration than normal. On auscultation, the doubling of the heart action was sometime quite easily observed, even' if the sounds corresponding to the second pulse wave were weaker. The patient spent 4 months in the hospital and improved and worsened repeatedly. Once, for several days, the appearance of a weak diastolic murmur at the point of the systolic maximum point was observed. Towards the end, edema became generalized, the patient became very weak and suffered from headaches and repeated vomiting, the pulse became irregular, ahnost impalpable and on the 13th of November, after severe hemoptysis, the patient died. Findings of the Section (Prof. Dr. Kolisko). Clinical diagnoses: defectus septi ventriculorum; infarctus puhnonum. Anatomical diagnoses: Defectus septi ventriculorum cordis (partis posterioris septi anterioris) subsequente hypertrophia cordis praecipue ventriculi dextri. Cicatrices multiplices myocardii ventriculi sinistri e myomalacia. Degeneratio myocardii adiposa incipiens. Hyperemia mechanica universalis. In~arctus hemorrhagicus pulmonum. The heart was 5 times enlarged; the most enlarged part was the right atrium, which was larger than a man's fist. Both ventricles bulged greatly, especially the right one, both had rigid walls; the large vessels at the base of the heart appeared in normal position to each other but were dilated. The left ventricle was 8-10 ram. thick, contained at its bulging apex a globulous vegetation the size of a pigeon egg, it was centrally softened; its flesh was dark red-brown, covered with callosities, especially at the apex of its posterior wall; the endocardium was tender and showed in places the yellow tiger stripes of the inner muscle layers; the papillary muscles were thin and stretched at the apices, fibrous; the trabeculations were stretched, in some places almost membranous; its venous ostium was widened (3 fingers can pass through), the apices of the bicuspid valve were very delicate; the left atrium was moderately dilated, thin walled, in the left side of the atrial septum no abnormality was found. The right ventricle was nearly the size of a man's fist, its wall thickened to 10 ram., its trabeculations and papillary muscles were thickened and protruding; the endocardium was delicate, showing here and there the yellow tiger stripes of the inner layers of the otherwise dark red musculature. The right venous ostium was wide (4 fingerbreadths), the valves were markedly fibrous and enlarged, especially in the inner apex; so were the cords, without really a visible deformation. The conus of the pulmonary artery was normally situated with respect to the right ventricle and moderately enlarged but had in the posterior part, which corresponds to the anterior ventricular septum, a large, circular defect, which created a communication the

440

WILLIA5s SHAPnl,0

size of a thumb, between the 2 ventricles. This defect, situated anteriorly to the inner apex of the tricuspid valve, was bordered on the lower side by the fleshy upper border, while in the back it was defined by the fibrinous, thickened and ledge-like septum membranaeeum. Upwards the defect was so situated with relation to the aorta, that its lumen fell half in the right and half in the left ventricle. The aortic valves themselves were delicate and although the right and posterior one was pulled down somewhat toward the defect, it could close. The puhnonary valves were delicate and could close also. The right auricle, enlarged the most, had a very thin wall, its endocardium was delicate. The venae cavae entering it were not markedly enlarged; the orifice of the coronary vei~ was very wide. The somewhat enlarged pulmonary artery showed on its inner surface end-arterial-like thickenings, which went all the way into the main branches of the vessels. The aorta, however, which was of normal dimensions, was thin-skinned and smooth on its inner surface. The ostia of the coronary arteries were wide, the coronary arteries had delicate walls. In place of the Ductus Botalli only the usual fibrous cord was found. The veins in the neck were somewhat dilated, the left internal jugular was obstructed by a loose blackish red thrombus, which continued as a brown, marginal and firmer attached thrombus of the left innominate by which the orifice of the jugular was displaced. The lungs emphysematous, plethoric, flooded by frothy serum, inside the left upper lobe and the left lower lobe permeated with a blackish red, hemorrhagic infarct, in which vessels obstructed by the thrombus were found. The liver was plethoric, somewhat firm. The spleen was doubled in size, plethoric, firm. W o o d a has credited Eisenmenger not only for his case presentation, but for his realization that a left-to-right shunt could potentially be abolished with the development of obstructive p u l m o n a r y hypertension and for taking pains to prove that an overriding aorta played no p a r t in the physiological disturbance of the circulation presented b y his patient. Authors subsequent to Eisenmenger, most notably Abbott 1,4,a and Taussig, 6 described "Eisenmenger's complex" as an entity combining a large ventricular septal defect and dextroposition or overriding of the aorta. The earliest available catheterization studies demonstrated that the level of pressure in the p u l m o n a r y b e d determined the direction of the shunt in these patients rather t h a n the anatomical position of the aorta. 7 Review of such data as well as previous reports allowed Seizer s and Seizer and L a q u e u r 9 to conclude that ventrieular septal defects presented a spectrum o f sizes, the size largely determining the clinical picture, and "that the most characteristic feature of Eisenmenger's complex is the presence of severe pulmonary hypertension." These conclusions h a v e b e e n frequently confinned; angioeardiograms r e p r o d u c e d in the text b y Kiellberg et a13 ~ d e m o n strated early that the direction of the shunt was unrelated to the presence of aortic overriding in ventricular septal defect. Grant, D o w n e y and M a e M a h o n 1~ found the aortic orifice in normal position with respect to the skeleton of the heart in all eases of ventrieular septal defect whose m o r p h o l o g y they carefully studied. This would indicate that overriding of the aorta is m o r e a p p a r e n t than real in ventrieular septal defect uncomplicated b y complete or incomplete transposition of the great vessels. E d w a r d s et al. 1~ have provided a new a p p r o a c h to c!assifieation and place cases of this type under "increased p u l m o n a r y arterial vasculature; cyanosis

THE EISENMENGER SYNDROME

441

present." Wood, 3 however, pleading from the point of view of the clinician has made a convincing case for retention of the term "Eisenmenger's syndrome." He pointed out that from the bedside it was usually easy enough to identify the presence of severe pulmonary hypertension but emphasized the great difficulty in differentiating the dozen or so possible lesions giving rise to the relatively homogeneous clinical group under consideration. It seemed useful, therefore, to retain the term for all shunt lesions when they resulted in severe pulmonary hypertension. His simplified definition was "pulmonary hypertension with reversed or bidirectional shunt" regardless of where the shunt happened to be located. The largest number of these cases occur in the presence of ventricular septal defects, patent ductus arteriosus and atrial septal defect. Additional lesions associated with pulmonary hypertension and reversed shunting are aorticpulmonary septal defect, truncus arteriosus, transposition of the great vessels with ventricular septal defect, corrected transposition of the great vessels with ventricular septal defect, double outlet right ventricle, single ventricle, endocardial cushion defects, single atrium, partial and total anomalous pulmonary venous drainage. Primary pulmonary hypertension, 13 pulmonary vascular obstruction, ~4 and multiple peripheral pulmonary artery stenosis ~ may also confuse the issue even in the absence of sites of reversed shunting. For the purposes of the subsequent discussion, we shall focus particularly on the problem as manifested by patients with ventricular septal defects, but it should be clear that pathogenesis and ultimate prognosis and therapy may be similar in patients with different inciting lesions. THE NATURE OF THE PULMONARY HYPERTENSION IN EISENMENGER'S SYNDROME

Despite clear descriptions of pulmonary vascular lesions in conditions now known to be characterized by pulmonary hypertension (as is evident in autopsy findings in Eisenmenger's case), recognition of pulmonary hypertension as a clinical entity, with multiple causes, awaited the brilliant synthesis of Moschcowitz. 16 Prior to the availability of catheterization data, attempts to correlate pulmonary vascular lesions and cyanosis in the presence of large intracardiac 6 or extracardiac lesions 17 were severely limited. Following the suggestion by Welch and Kinney TM that greatly increased pulmonary blood flow might induce pulmonary vascular lesions a series of systematic attempts at pathophysiologic correlations was launched. Civin and Edwards 19 described marked differences between intrapulmonary arteries and arterioles found in the fetus and shortly after birth. They thought the thicker media found in the fetus contributed to the increased pulmonary vascular resistance in utero and that as the relative resistance in this Circuit dropped after birth the media thinned and became more 'appropriately adapted to the normal low pressures in the pulmonary circuit. This concept was enlarged in the classic studies of Dammann and Ferencz 2~ who plotted the

442

WILLL~

SHAPIRO

time sequence of the normal pulmonary vascular regression and then superimposed the findmgs in patients with congenital heart disease. Cases with pulmonary stenosis characterized by low pulmonary .pressures exhibited normal regression. Those lesions with large defects in which both ventricles acted with a common force upon the pulmonary and systemic beds were characterized by an apparent inhibition of the normal regression and retention of fetal pulmonary vascular architecture. This was interpreted as a protective mechanism preventing the pulmonary bed from flooding and contributing to the maintenance of systemic blood flow. These authors felt that the clinical course of such patients was governed by the state of the pulmonary vascular bed and described 3 possible phases. Phase I was characterized by thinning of the vascular media in which ease the pulmonary vascular resistance diminishes, pulmonary blood flow increases and a high output failure may occur. Phase II was characterized by retention or redevelopment of the fetal structure so that pulmonary vascular resistance was high, pulmonary blood flow and systemic blood flow balanced. Clinical signs and symptoms would be minimal. In phase III there was progressive medial hypertrophy now accompanied by intimal sclerosis, the pulmonary vascular resistance was greater than systemic vascular resistance, right-to-left shunt develops. Phases I and II were considered correctible, phase III probably beyond correction. An important observation was made in some cases of Eisenmenger's syndrome with pulmonary artery atresia in which the vessels protected from the high pressures had much more normal architecture than those exposed to high pressures. An important implication was that these phases represented a continuum through which patients might rapidly progress. These concepts found considerable support from other pathological,2227 clinical,27 and physiological studies 28~~ and did not support the hypothesis that the pulmonary vascular disease was an independent congenital or acquired lesion. 31 The implication of continuous progression of pulmonary vascular lesions led to a sense of urgency with regard to surgical repair. It was soon evident from cases in which the pulmonary vascular resistance equaled the systemic vascular resistance, and right-to-left shunting occurred, i.e., after the establishment of the Eisenmenger syndrome or reaction, surgical intervention was attended by grave risks2 2-3r Thus it was reasoned that early correction was the wisest course2s,3~ and the progressive pattern of selected patients provided support for this contention. 2s,38 Considerable, subsequently developed, physiological and pathological data did not consistently favor the hypothesis that continuous progression toward the Eisenmenger syndrome was imminent in most patients with ventricular septal defect. Quantitative studies of the pulmonary vaseulature in patients with atrial septal defectsa9 did not appear to reflect the natural history of the disease. One could well raise the question as to the accuracy with which biopsy specimens might reflect the physiological status of any given patient with a ventricular septal defect, 33 and postmortem material from infants cannot be considered typical of the spectrum present in surviving patients. An example follows:

THE

EISENMENGER

443

SYNDROME

Case 1. (PMH 116555) Twenty-six year old white male with lifelong symptoms of easy fatigability, shortness of breath on exertion. The patient worked despite these symptoms and had occasional "blackout spells" following exertion. Minimal cyanosis was noted to worsen on exertion. The patient's ability to work has gradually diminished and in recent years he has had several henmptyses. Examination. Blood pressure 140/80 mm. Hg; pulse 92. Slight white male who exhibits mild cyanosis and clubbing. Heart, Right ventricular heave, regular rhythm, very loud P2 with fixed splitting, variable soft systolic murmur at upper left sternal border. Hemoglobin: Up to 19.6 Gm. per cent kept normal by repeated phlebotomy. Roentgenograms: Cardiac size at upper limits of normal. Pulmonary artery large, right ventricle large. Lung biopsy (9/22/65): Prominent vascular congestion; no significant arterial or arteriolar changes that would suggest pulmonary arterial hypertension.

Cardiac Catheterizations* 1954 Site

RA

1962

Pressure

O.~ s a t

u

72

Pressure

u

1968 02 s a t

Pressure

02 s a t

67

~

61

RV 65/38 83 100/4 67 109/7 68 PA 63/32,40 79 108/80,88 74 118/75 78 AO 90/50, 64 93 120/85, 103 88 LV 124/11 L-->R 1.75 L./min. R-->L 1.0 L./min. *Performed by Dr. C. B. Chapman, Dallas, Texas. Abbreviations: 02 sat -: per cent oxygen saturation; RA = right atrium; RV = right ventricle; PA = pulmonary artery; AO = systemic artery or aorta; LV = left ventricle; L ----->R = left-to-right shunt; R ---->L = right-to-left shunt. PMH = Parkland Memorial Hospital, Dallas, Texas. MCV --Medical College of Virginia Hospital, Richmond, Va. Cases 2 and 6 seen and studied at USNH, Portsmouth, Va.

Comment. The patient had bidirectional shunting when initially studied, but his pulmonary vascular resistance continued to progress and volume of right-toleft shunt, judged by arterial oxygen saturation, increased. Results of lung biopsy showed no evidence of vascular sclerosis which raises the possibility of reversibility. Although the clinicopathologic studies considerably improved our understanding of the problem, further refinement has been added by studies of living patients. Serial catheterization data in patients with uncomplicated ventricular septal defect have defined the clinicophysiologic spectrum this lesion presents and provide data on the likelihood of and time of development of irreversible pulmonary hypertension (Table 1). These results point to the infrequency with which such patients are observed to develop severe pulmonary hypertension. In 454 patients who have been reported to undergo serial catheterization, 52 or 11.5 per cent have had reported increases in pulmonary

444

WILLIAI~f SHAPIRO

Table 1.--Incidence of Increase in Pulmonary Arterial Pressure in Reeatheterized Patients with Ventricular Septal Defect P A Pressure Increase Reference No.

28 27 41 42 43 44 45 46 47 48 49 50 54 Totals

No. of Patients

30 3 20 32 25 6 29 90 10 53 41 40 75 454

Time Interval (yrs.)

1-8 7 1 5/12--8 1-7 1-8 1 5/12-9 2-7 4.2 8.6 1-9 1-8 1/3-3 1-7

No.

%

13 1 1 2 0 O 1 8 5 6 6 5 4 52

43 33 5 6.3 0 0 3.4 8.9 50 11.3 14.6 12.5 5.3 11.5

artery pressure. While careful data analysis a7 has cast doubt on the actual incidence of progressive increase in pressure in some of the series included in Table 1, it can undoubtedly occur. As shown especially by Mudd et al. a8 and Walker et al. 46 those ventricular septal defect patients with pressures less than 50 mm. Hg do not become problems in pulmonary hypertension. In general, the patients who progress show markedly elevated pressure and pulmonary vascular resistance at the initial catheterization, z~176 Very large shunts, usually with elevated pressures, are associated with progression 49,5~ as are elevated or relatively elevated left atrial mean pressures. 47,n~ Pulmonary pressures alone, however, may not reflect changes in pulmonary vascular resistance which ean increase without concomitant alterations in the pressure. 54 The actual incidence of progressive pulmonary vascular disease may be considerably less than indicated in the table because any significant increase in pressure (>10 mm. Hg systolic; > 8 mm. Hg mean), even when the pressure rise was within the normal range, was included. Also the patients serially catheterized were often selected for and/or permitted to undergo multiple studies because of apparent changes in their status. Clinical a,47 and physiological 5~ data indicate that the Eisenmenger reaction is typically established in early life, although patients with atrial septal defects more often develop it later and may represent a special group. 3 More infants and children with ventricular septal defects have been documented to show improvement 47,5~ or spontaneous closure 4r,5~ than progressive pulmonary hypertension. Childhood and adolescence seems, generally, to be a period of apparent stability in these patients 49 despite occasional exceptions. 49,5~ Progression in infancy has been considered more likely in patients with patent ductus arteriosus. 56 Long-term follow-up studies, however, do indicate the presence of a disproportionate number of patients with Eisenmenger's syn-

446

WILLIAM

SHAPIRO

2 cases, t h e first e x h i b i t e d d i f f e r e n t i a l c l u b b i n g a n d cyanosis a n d o b i e c t i v e e v i d e n c e of r i g h t - t o - l e f t shunt, w h i l e t h e s e c o n d case r e t a i n e d a c o n t i n u o u s murmur and had only a left-to-right shunt despite severe pulmonary hypertension.

Case 3. ( PMH 274821 ) Patent Ductus with Bidirectional Shunting Thirty-three year old male felt well despite a known heart murmur until age 15 when he experienced an episode of hemoptysis during exertion. He was again asymptomatie until age 25 when he had a massive hemoptysis while taking a shower. Data from another hospital revealed hemoglobin 18.4 Gm. per cent; electrocardiogram--right ventricular hypertrophy. Cardiac catheterization at this time (vide infra) interpreted as demonstrating severe pulmonary hypertension with bidirectional shunting probably through a ventricular septal defect. At age 31 he developed dyspnea on exertion, pedal edema, ascites and eyanosis. Clubbing and eyanosis of toes were noted to be more pronounced than that of the fingers and the correct diagnosis suggested by Dr. F. A. Bashour, Dallas, Texas. Hemoglobin 25.6 Gin. per cent. He improved after phlebotomy, digitalis, bedrest. Examination. Blood pressure 130/80; pulse 88; respirations 18. Well-developed, slightly plethoric white male. Cyanosis and clubbing of toes more marked than that of the fingers. Heart. Left border of cardiac dullness was at the midclavicular line; rhythm regular; left parasternal heave present. A rough decrescendo diastolic murmur and a short systolic murmur at third intercostal space at the left sternal border; pulrnonie second sound was loud and widely split. Liver edge 6 era. below right costal margin. Electrocardiogram: Right bundle branch block, right ventricular hypertrophy, right ventricular strain. Roentgenogram: Prominent pulmonary artery and right ventricular enlargement.

Cardiac Catheterizations Age 33t Site

Age 25* Pressure

SVC RA RV PA AO

--160/20 -140/80

PVR L~ B

43 It 0.69 L./min.

R --->L

0.77 L./min.

Pressure

O.~ sat

--14 58 134/14 58 -Ascending aorta -92 Descending aorta 121/76, 98 77 Dye: R ~ L Cineangiocardiogram: PDA with L ~ B, ?R ---~ L

*Courtesy Dr. A. S. Nadas, Boston, Mass. ~Performed by Dr. M. C. McNalley, Dallas, Texas.

Case 4. (PMH 254189) Patent Ductus, Severe Pulmonary Hypertension, No R --~ L Shunt Twenty-three year old white female with known murmur since age 3 months. She had episodes pneumonia as child, and has never been able to keep up with contemporaries having gradually worsening dyspnea on exertion. She can now walk one block without dyspnea, and has occasionally had paroxysmal nocturnal dyspnea, palpitations and spells of weakness and dizziness.

THE

447

EISEN~V~ENGER S Y N D R O M E

Examination. Blood pressure 100/70; pulse 92; respirations 9,0; temperature 98. Thin, small white female. No cyanosis, but clubbing of fingers and toes noted. Heart. Enlarged to anterior axillary line with active apex impulse, P2 louder than A2, Grade IV/VI systolic murmur over precordium with radiation to neck and axilla. Laterally in second to third intercostal space a diastolic component continuous with systolic murmur was heard. A grade II/VI decrescendo diastolic murmur heard down left sternal border. Hemoglobin 22 Gin. per cent; hematocrit 65; white blood count 8,000. Electrocardiogram: Left ventricular hypertrophy, left ventricular strain. Roentgenogram: Left ventricular enlargement, prominent pulmonary artery and puhnonary plethora. Cardiac Catheterization* Site

Pressure

RA RV PA Wedge

5 98/6 ~110/61 1~

Aorta

116/64

O~ s a t

Arch

74 74 79 -98

Descending

95

SBF PBF PVR SVR~

3.0 L,/min. 3.9 16 rt 25 .tt

*Performed by Dr. M. C. McNalley, Dallas, Texas. ~No change while breathing 100 per cent 02. ~SVR = systemic vascular resistance (Wood units).

Dye: No evidence R ---->L; cineangiocardiogram: L --> R through patent ductus arteriosus; minimal aortic stenosis and aortic insufficiency. R i g h t - t o - l e f t shunts, h o w e v e r , n e e d n o t a l w a y s b e a r e s u l t of p r o g r e s s i v e p u l m o n a r y v a s c u l a r d i s e a s e b u t m a y d e v e l o p as a c o n s e q u e n c e of r i g h t v e n t r i c u l a r failure, e s p e c i a l l y in p a t i e n t s w i t h a t r i a l s e p t a l d e f e c t s . S y s t e m i c v a s c u l a r c o l l a p s e ~ a n d exercise 56 m a y a c u t e l y r e v e r s e p r e d o m i n a n t l e f t - t o - r i g h t s h u n t s or i n c r e a s e t h e v o l u m e of r i g h t - t o - l e f t shunts.

Case 5 (MCV 5-04-34-24) Atrial Septal Defect, Pulmonary Hypertension; Presence of R --> L Shunt Associated with Development of Congestive Failure Thirty-four year old white male had been well until 5 years ago when he developed progressively severe shortness of breath until at present walking across a room results in severe dyspnea. Ten and 2 months prior to being seen he had hemoptysis--on one occasion he brought up a cupful of bright red blood. No cyanosis, edema but has had pain in the midchest after exertion. Thirteen years ago, the patient was able to walk up a steep mountain at an ambient temperature of 40 ~ below zero without complaint. Examination. Blood pressure 170/100 ram. Hg; pulse 90 and regular. Well developed white male in no distress. Heart. Left border of cardiac dullness 11 cm. lateral to the midsternal line; rhythm regular; right parasternal heave. P2 widely split and somewhat loud. No murmurs. Hemoglobin 15.6 Gin. per cent. Roentgenograms and fluoroscopy: Dilatation proximal pulmonary arteries with decreased peripheral puhnonary vasculature, right ventricular enlargement. Electrocardiogram: Right ventricular hypertrophy, right ventricular strain.

448

WILLIAM SHAPIRO

Cardiac Catheterizations (Dyspnea worsened between caths.) 8/20/63 Site

svc co, Rv PA \Vedge LA LV BA PBF ( L./min. ) SBF (L./nfin.) PBF: SBF PVR (~t) Dye

Pressure

~ ~ 100/0

9/12/63 O: sat

Pressure

02 s a t

77 -85

1~ 19 104/2-21

51 ---

112/45, 65 108/49, 6-7

63 --

90/40, 70 7

86 --

-5 125/0 120/70, 90

95 95 95

PAp 100% 09 PAp ex

12 6.7 1.8:1 5.3 Small L ----->R; no R ---->L

131/54, 8-1 ---152/98, 118 89 10.2 6.8 1.5:1 6 L ~ R and R --> L

Necropsy findings (sudden death occurred at age 38): (Examination limited to heart and lungs.) Moderately enlarged heart with right ventricular dilatation and hypertrophy (wall thickness of 1 cm.). There was a 3 cm. interatrial defect. Left ventricular dilatation was present and the wall thickness was i cm. Pulmonary congestion and induration were noted.

The physiological mechanisms which determine the pulmonary vascular resistance after birth 65 and the precise factors responsible for the early or late development of irreversible pulmonary hypertension in the presence of intracardiac shunts are still under active investigation. Animal experiments in which high flow left-to-right shunts were created have not consistently led to the development of pulmonary vascular lesions although concomitant exposure of the pulmonary circulation to systemic pressures appeared to increase the incidence. 6G'6s In addition to the roles of oxygenation65 and fetal pulmonary and right ventrieular architecture 19,69-7~ in determining postnatal changes in pulmonary vascular resistance, Danilowicz, Rudolph and Hoffman 72 have recently described an additional determinant. They found pressure gradients between the main and peripheral pulmonary arteries in 25 infants under 4 months. Five of these who had patent ductus arteriosus or ventricular septal defect were recatheterized 5-20 months later and the gradients were no longer detectable. Cineangiograms had shown the peripheral pulmonary arteries to arise at abnormally acute angles and were smaller in caliber than expected but discrete stenoses were not visualized. With growth the angles became less acute, the disparity in size diminished, and the pressure gradients disappeared. The gradual disappearance of this "physiological" bilateral peripheral pulmonary arterial stenosis must be included as an additional mechanism determining pulmonary resistance in early infancy and aid in explaining disparities between previous physiological and pathological observations. The most nearly prospective studies of circulatory dynamics in ventricular

T H E EISEN1VfENGER S Y N D R O M E

449

septal defect are those of Hoffman and Rudolph 5~ who have studied 62 infants, most initially under 3 months; 40 were recatheterized. Upon restudy 25 per cent exhibited spontaneous closure; 27 per cent had smaller defects; 33 per cent were relatively unchanged and were doing well--i.e., 85 per cent cured, improving or well. Fifteen per cent were and had been in serious condition. The largest shunts were associated with elevations in the left atrial mean pressure. In 5 the pulmonary vascular resistances rose between studies; all these patients had high resistances to begin with and all had elevated left atrial mean pressures. These observations on the association between large shmats, high pulmonary vascular resistance and high left atrial pressures have been noted by others as wellY ,55 Hoffman and Rudolph interpreted their data to show that all patients with ventricular septal defect underwent an initial decrease in pulmonary vascular resistance before developing a secondary rise. The drop could occur variably within the first year of life and the secondary rise sometime within the subsequent 21/2 years. This does not conflict with other evidence of progressive changes occurring later in life, but indicates that simple retention of fetal vascular architecture probably does not occur at sea level. This could be a factor at high altitude where the effects of hypoxemia are superimposed, however. 7z,7~ Elevations of left atrial pressure, possibly occurring as a manifestation of left ventricular inadequacy during the period of decreased pulmonary resistance and large volume left-to-right shunting, may be an important determinant in the development of the Eisenmenger syndrome.47,5~ Indeed, pulmonary hypertension can be induced in dogs by pulmonary venous obstruction 68 and recently West, Dollery and Heard r~ demonstrated in an isolated dog lung preparation a mechanism by which increased pulmonary venous pressure can result in an increase in the pulmonary vascular resistance. They showed perivaseular edema to occur following induced rises in pulmonary venous pressure. They developed evidence indicating that this edema was responsible for the resultant increased pulmonary vascular resistance because of the general correlation with interstitial edema, the regional distribution of the effect, the sensitivity to the arteriovenous pressure difference, the effect of hypertonic urea infusions and the demonstration of edema around the small arteries and veins in rapidly frozen sections. They reasoned that edema interfered with the tethering effect of the lung parenehyma which normally held the vessels open. These data suggest that, in addition to high pressure and flow, other factors influence pulmonary vascular resistance and may be important in the development of irreversible anatomical changes. Furthermore, elevated pulsatile pressures increase impulse activi[y in pulmonary arterial baroreceptor fibers; 76 the latter may mediate variations in vascular resistance prior to development of severe anatomical changes. Hypoxemia, a result of any right-to-left shunting, would be expected to produce or aggravate elevations of pulmonary artery pressures. 74,77-79 Pulmonary parenchymal damage due to repeated pulmonary infections as well as certain probable tissue effects of grossly elevated pulmonary flow may also promote progress of pulmonary vascular disease in patients with hyperkinetic pulmonary hypertension, s~

450

WILLIAM SHAPIRO

Final solution of the pathogenesis of pulmonary hypertension in Eisenmenger's syndrome awaits suflqcient prospective clinical, physiological, pathological and animal investigations to settle the questions raised by the data already available. THERAPY

The surgical literature demonstrates the prohibitive risk of attempted direct closure of the responsible defect in patients with Eisenmenger's syndromeY2,34 To be sure startling exceptions to this general experience are occasionally presented 6e but most of these patients had dominant left-to-right shunting, s2 Few, if any, surgeons are deliberately attempting corrective surgery in this group. Despite conflicting data on the pulmonary vascular effects of various agents, rg,Sa-s~ there is no drug available that can reliably affect the course of this syndrome. Alternative surgical approaches have been attempted in small groups of patients with mixed results. The Dammann-Muller operation s6 or pulmonary artery banding has been carried out in a number of cases. This technic involves the creation of pulmonary artery stenosis with the expectation that a decrease in the mean and pulse pressure to which the vessels are subjected will stimulate or allow regression of the pulmonary vascular pathology. There are a number of isolated experiments of nature as well as surgical maneuvers such as banding of one pulmonary artery in truneus which have provided anatomical evidence that this is a reasonable hypothesis. In 1961 Dammann et al. 8~ reported short-term results in 8 patients with Eisenmenger's syndrome (including case 6, vide infra). They had had no follow-up biopsies in this group and the operative mortality rate was 25 per cent. It was suggested that other patients with high pressure ventricular septal defects (patients who had not yet developed right-to-left shunts and now considered correetible) were prevented from developing irreversible pulmonary vascular disease, but that those with established Eisenmenger's at the time of the banding procedure might require 5--6 years for regression of their lesions. In a current report 8r they have added a number of cases of Eisenmenger's syndrome but still cannot say with confidence whether or not this procedure has been beneficial. This operation, in fact, has found its most popular application in left-to-right shunts beyond the A-V valves associated with refractory congestive failure in early infancy.88 The promising results in this situation allow the conclusion that this form of palliation may carry potentially curable infants into the age and weight range in which complete correction is more feasible than it is in early infancy.

Case 6. Eisenmenger's Syndrome with a 51~-Year Follow-Up Alter Pulmonary Artery Banding Twelve year old male with a long history of poor exercise tolerance and mikt cyanosis aggravated by exertion. On examination the patient was slender but well developed. There was a left parasternal lift, very loud Pc; no murmurs or gallops were heard. Electrocardiogram revealed right axis deviation, right ventricular hypertrophy, right ventricular strain. Roentgenograms revealed a nearly normal heart size, prominent pulmonary artery and right

THE

EISENR~ENGER

451

SYNDROME

ventricle and diminished peripheral pulmonary vascularity. No progression of x-ray or electrocardiographic findings was noted between ages 7 and 12. He was referred to Dr. F. Dammann, Jr., Charlottesville, Virginia, for consideration of a banding procedure (R. S. in reference 86).

Cardiac Catheterizations A g e 8* Site

RA Rv

PA "Wedge AO SBF ( L./min. ) PBF ( L./min. ) R ~ L as %SBF PVR (~)

A g e 12

Pressure

03 s a t

g 90/5 120/78, 98 -120/80, 98 3.2 1.7 47 >28

61 61 --74

Pressure

108/0-6 --106/60, 76 5.04 2.1 58

02 s a t

63 63

78

*Performed by Dr. R. Gorlin at USNH, Portsmouth, Va.

Addendum Follow-up "2/21/66 at age 19 (courtesy of Martha Carpenter, M.D., Department of Surgery, University of Virginia Hospital, Charlottesville): In August 1960 cardiac catheterization at this hospital (performed about 1 year after catheterization age 12) showed equal pressures on both sides of the heart and peripheral arterial desaturation to 65 per cent. It was felt that pulmonary artery banding was indicated. This was carried out in August 1960, but the pulmonary artery could not be narrowed as much as was felt optimal because of cardiac slowing. However, the pulmonary artery was narrowed approximately 30 per cent and there was a thrill distal to the band, Since his operation he has improved and is now able to work a full day and walks any distance he wants to without stopping, but he continues to be quite cyanotic. Examination. He is a small, thin boy; he is markedly cyanotic at rest, and there is moderate clubbing. There is a right ventricular impulse maximal at the lower left sternal border. No thrills are palpable. First heart sound is normal and maximal at the upper left sternal border with a markedly accentuated pulmonary closure sound. There is a grade II very short systolic ejection murmur maximal at the upper left sternal border and a peculiar twanging diastolic sound. Roentgenogram: Normal cardiac size with a rounded globular configuration and dilated main pulmonary artery segment. Pulmonary vascularity is decreased peripherally. Comparison with the preoperative (1960) chest film shows that the heart now has a much more globular configuration; but, otherwise, not too much change. Electrocardiogram: QRS axis +110~ right ventrieular hypertrophy. In addition there are pretty good ventrieular potentials on the left. Hematoerit 64 per cent; hemoglobin 21.7 Gin. per cent. A s e c o n d a p p r o a c h has b e e n to insert p e r f o r a t e d p a t c h e s into the d e f e c t s 89-91 in t h e h o p e t h a t t h e d i m i n i s h e d p u l m o n a r y flow will p e r m i t d e c r e a s e s in p u l m o n a r y p r e s s u r e b u t will a l l o w a n e s c a p e v a l v e if r i g h t - s i d e d p r e s s u r e s r e m a i n e l e v a t e d or increase. D i r e c t o b s e r v a t i o n d u r i n g a n d f o l l o w i n g conv e n t i o n a l s u r g i c a l closure t e c h n i c s has i n d i c a t e d t h a t r i g h t v e n t r i c u l a r f a i l u r e d u e to v e n t r i e u l o t o m y a n d e l i m i n a t i o n of t h e e s c a p e v a l v e effect a f f o r d e d b y t h e d e f e c t h a v e b e e n t h e p r i n c i p a l causes of d e a t h f o l l o w i n g c o m p l e t e re-

452

W I L L I A M SHAPIRO

pairY ,92 Other observations have shown little, if any, postoperative decline in pulmonary vascular resistance in ventricular septal defect with severe pulmonary hypertension and persistent elevation for at least a year or more has been reported; s2,ga this has also been reported in cases of high resistance atrial septal defects, patent ductus arteriosus and aortic-septal defects 7~,86-ss although further progression usually seems to have been halted. Dammann's estimate 86 that 5 or 6 years may be necessary for regression after reduction of pressure has yet to be systematically tested, Mere closure of a defect need not be expected to result in a decrease in pressure if pulmonary blood flow is not significantly greater than systemic flow in the presence of high pulmonary artery pressures. The patches that have been devised have been observed to close in a variable period by ingrowth of fibrin and fibrous tissue21 Braunwald and Morrow 9~ reported on the placement of sueh patches in 4 patients with atrial septal defects and the Eisenmenger syndrome in 1963. In 2, the holes were open 5-8 months postoperatively---they had 10 mm. holes. In 2 with 6 ram. holes closure occurred in 3 weeks. All 4 survived with benefit, but pulmonary arterial pressures did not decrease rapidly in 3 of the 4. Although this technic has been tried in 3 dogs and 18 calves with artificially created ventrieular septal defects, 91 results of this procedure in human beings with ventricular septal defects have not been reported. A 2-stage procedure 96 involving creation of a ductus, in order to provide an escape valve, at the time of direct repair of the ventricular defect followed in 3--6 months by closure of the ductus has been reported in a limited series. It was not found suitable for patients with Eisenmenger's syndrome and appears unnecessary today for others with uncomplicated ventricular defectsY Since pulnaonary hypertension is established most often in early childhood and the Eisenmenger syndrome frequently develops during this period, it might be pertinent to inquire into the feasibility of definitive correction in infancy. Bloomfield4z has recently weighed the estimated risk of operative mortality at age 1 against the hypothetical chance of developing irreversible changes by age 7. In the opinion of this author the figures he chose for these possibilities were very reasonable. Those calculations not only showed no advantage but rather a disadvantage to early operation in the present state of the surgical art. Thus, the admonition of Nadas, Rudolph and Gross 56 given in 1960 appears to remain valid, i.e., fear of progression of pulmonary vascular disease should not be a deciding factor in timing surgery in children with ventricular septal defect. In the interval, however, a major advance has been the demonstration of the safety in routine performance of catheterization and angiography in large numbers of neonates and ill children under 6 months of age by Mauck, ~s Rudolph and colleagues, 5~ and Lambert et al. 1~176 These procedures allow identification of those children who, shortly after birth, have elevated pulmonary vascular resistances and elevated left atrial pressures. Reeatheterization within the first year, irrespective of the clinical picture, will detect further rises in pulmonary resistance and provide valid indication to subject susceptible patients to surgical correction5~ in the hope of the probable prevention of the development of the Eisenmenger syndrome.

THE EISEN5IENGER SYNDROME

453 CONCLUSIONS

C u r e of the E i s e n m e n g e r s y n d r o m e at present rests on its prevention. T w o maior factors seem required: (1) a c c u r a t e appraisal in i n f a n c y of those destined to b e c o m e irreversible (early serial catheterizations w i t h careful attention to the left atrial m e a n pressure in addition to the usual measurem e n t s ) ; (2) sharply decreasing the risk of total correction of serious lesions in infants u n d e r 1-2 years of age. ACKNOWLEDGMENT

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defects with perforated prostheses. Surg., Gynec. Obst. 116:579, 1963. Reis, R. L., and Braunwald, N. S.: Gradual closure of ventrieular septal defects: an experimental study. Surgery 56:820, 1964. Kay, J. H., Anderson, R. M., Tolentino, P., Dykstra, P., Shapiro, M. J., Meihaus, J. E., and Magidson, O.: The surgical repair of high pressure ventricular septal defect through the right atrium. Surgery 48:65, 1960. Burchell, H. B.: Regression of pulmonary vascular hypertension after cure of intracardiac defects. In W . R. Adams and I. Veith (Eds.): Pulmonary Circulation. New York, Grune and Stratton, 1958, p. 245. Reeve, R., Seizer, A., Popper, R. W., Leeds, R., and Gerbode, F. L.: Reversibility of pulmonary hypertension following cardiac surgery. Circulation 32:II-177, 1965. Anabtawi, I. N., Ellison, R. G., and Ellison, L. T.: Natural history of pulmonary hypertension in surgically treated patent ductus arteriosus. Circulation 31:I-61, 1965. Sirak, H. D., and Hosier, D. M.: Creation of a temporary artificial ductus for the surgical correction of ventricular septal defects associated with severe puhnonary hypertension. A two-stage operation. J. Thor. Cardiovas. Surg. 37:1, 1959. Cooley, D. A., Hollman, G. L., and Hamman, A. S.: Congenital cardiovascular anomalies in adults: results of surgical treatment in 167 patients over age 35. Amer. J. Cardiol. 17: 303, 1966. Mauck, H. P., Jr.: Personal communication. Hoffman, J. I. E., Danilowicz, D., and Rudolph, A. M.: Hemodynamics, clinical features, and course of atrial shunts in infancy. Circulation 32:I1113, 1965. Lambert, E. C,. Kelsch, J. V., and Vlad, P.: Differential diagnosis of ventricular septal defect in infancy: a common problem. Amer.. J. Cardiol. 11:447, 1963.