Case Reports

Quadrivalvular Disease

An Autopsied Case with Massive Pulmonary Regurgitation

Tsuguya SAKAMOTO, M.D., Zen'ichiro UOZUMI, M.D., Nobuyoshi KAWAI, M.D., Yoshiyuki SAKAMOTO, M.D., Ryoko KATO, M.D., and Hideo UEDA, M.D.

SUMMARY An autopsied case of quadrivalvular heart disease was described, in which pulmonary regurgitation due to possible bicuspid valve was pre- dominant and tricuspid stenosis, mitral stenosis, and aortic stenosis with insufficiency coexisted. The patient was 47, and finally 53 years old female with long-term history of cough due to bronchial compression by the enormously dilated pulmonary . Clinical examination revealed massive pulmonary regurgitation, which was further substantiated by right heart catheterization and cineangiocardiography. The phono- cardiograms and the reference tracings suggested the co-existence of tricuspid stenosis, aortic stenosis with regurgitation and mitral stenosis. Cardiac catheterization, intracardiac phonocardiography and angio- cardiography also favored to the diagnosis of organic tricuspid stenosis. However, the ignorance of the presence of such an unusual combination misled to the precise antemortem diagnosis. Discussion was made on the rarity of quadrivalvular heart disease, and the pathogenesis of this unusual pulmonary regurgitation was analyzed based on the autopsy finding and the history as well as the clinical mani- festation. Finally, combination of the murmurs of organic and relative tricuspid stenosis was presented to explain the acoustical findings of the present case.

Additional Indexing Words: Phonocardiography Mechanocardiography Bronchial compression Right-sided Austin Flint murmur

UADRIVALVULAR heart disease was first described by Shattuck1) in 1891. However, the involvement of all four valves in a given patient is extremely rare.2) The present paper describes one of such case, in which From the Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo. Presented at the 45th Kanto-Koshinetsu-Hokuriku Regional Meeting of Japanese Circulation Society in May 27, 1967. Received for publication August 20, 1967. 303 304 SAKAMOTO, ET AL. Heart J. y, 1968 the co-existing severe pulmonary regurgitation made the other right -sided valve lesion difficult to estimate and , furthermore, almost completely masked the left-sided lesions.

CASEREPORT

The patient, working as a house-keeper over past 20 years, was first seen at age 47 years and finally at age 53. She was admitted to the Second Department of Internal Medicine, Tokyo University Hospital, with a half-year history of dry cough. Her history of heart disease was described at age 19, when she suffered from arthralgia of hip, knee and ankle joints without appreciable fever. At age 28, fever up t38 accompanied by polyarthritis persisted about 1 month and subsided by appropriate treatment (details unknown). At age 34, she occasionally complained of shortness of breath and palpitation after exertion. No history of gonococcal or syphilitic infection was found. On physical examination, excessive dry cough was observed paroxysmally, but no respiratory distress was noticed. There were slight edema on face, distinct jugular venous engorgement with dominant pulsation, and definite parasternal im- suggesting right ventricular hypertrophy. Neither anemia nor cyanosis were noticed. Pulse was regular with the rate of 54 at rest and pressure was 124/80 mm.Hg with no difference in the pulse among four limbs. Liver was palpable 2 finger breadths below the costal margin. Routine blood studies disclosed 110 per cent hemoglobin, 5.21 million red blood cells and 6,800 white blood cells with a normal differential count. Serologic test for syphilis was negative. Laboratory studies for or other infection were also negative. Palpation over the precordium revealed prominent parasternal heave maximally located in the 3rd intercostal space near the left sternal border. However, was hardly palpable. On , a grade 5 ejection systolic murmur with systolic thrill was present in the 3rd intercostal space at the left sternal border and widely transmitted over the precordium. The other main auscultatory findings were a loud and medium to high-pitched blowing diastolic murmur in the 4th inter- costal space at the left sternal border and a loud mid-diastolic rumble with diastolic thrill in the 5th intercostal space at the left parasternal region. The second heart sound was not sufficiently audible. Phonocardiogram confirmed the 2 components of the second heart sound which showed a wide splitting. The one of the diastolic murmurs was following the pulmonary component (IIP), thus the pulmonary re- gurgitation was readily diagnosed as a main valve affection. Tricuspid stenosis was suspected based on the diastolic rumble, though the positive Rivero Carvallo's sign was lacking. However, the conclusion of either organic or relative (functional) stenosis was not reached, because of the massive pulmonary regurgitation. The loud systolic murmur was thought to be caused by relative pulmonary stenosis, and the further investigation was not performed. Chest roentgenogram and fluoroscopy revealed the prominent pulmonary artery with marked pulsation, small aorta just over the pulmonary artery, and the adhesion of left pleura without exudation. Electrocardiogram revealed the right ventricular hypertrophy, and the P-wave abnormality was not so seriously analyzed as the sign of atrial overloading. All of these including physical and laboratory examination were thought to be consistent Vol. 9 No. 3 QUADRIVALVULAR HEART DISEASE 305 with the clinical diagnosis of massive pulmonary regurgitation with dilated pulmonary artery. She was on sedative and cough medicine several days and discontinued to visit the hospital. She was seen as an outpatient at age 52 for the second time, because of intract- able cough even at rest. Physical examination was essentially unchanged. The neck was pulsated as before, and showed prominent a wave, but venous pressure was only 120mm. H2O. The blood pressure was 136/82mm.Hg. Slight cyanosis was observed and edema on face and legs was also noticed slightly. Chest roent- genogram (Fig. 1) and electrocardiogram (Fig. 2) were not changed significantly,

Fig. 1. Chest roentgenogram. Fig. 2. Electrocardiogram. except occasional atrial premature beats. She was once hospitalized to examine the cause of persistent cough. Bronchography proved the mechanical compression of the left main bronchus and bronchoscopy pointed out the diffuse edematous swelling at the mouth of this bronchus. Conclusion was attained to the fact that the compression of bronchus by the enormously enlarged pulmonary artery is the primary cause of the persistent cough. Administration of codeine phosphoricum partly succeeded in the sedation of cough, and the edema disappeared subsequently during hospital course. Phonocardiographic examination including pulse studies was repeatedly done at 7 times during her course. The loud ejection systolic murmur was recorded in all areas (Fig. 3, A to G) and was best recorded at the upper base (Fig. 3, D and E). Though auscultation could not reveal, another type of ejection murmur of long dura- tion and slightly delayed peaked configuration was present at the upper part of the parasternal line (Fig. 3, F), which partly drowned the aortic component (IIA) of the second heart sound. The conclusion of these ejection murmurs was that the former is aortic and the latter is pulmonary. The aortic ejection sound was then identified along left sternal border (Fig. 3, B to E). The second heart sound was widely split (Fig, 3, B to D) and IIA-IIP interval was 0.06 to 0.07 sec. Neither IIA nor UP showed accentuation. No mitral or tricuspid opening snap was identified. Tracing from apex (Fig. 3, A), where the first heart sound was best audible, revealed 306 SAKAMOTO, ET AL. Heart J. , 1968

Fig. 3. Phonocardiograms. Paper speed: 100mm./sec. Time lines: 0.01 and 0.1 sec. Details: see text. Vol. 9 No. 3 QUADRIVALVULAR HEART DISEASE 307 Jap. Heart J.M 308 SAKAMOTO, ET AL. ay, 1968 the prolongation of Q-I interval (0.075 sec.) and the mid-diastolic and the faint but definite atrio-systolic murmurs, the latter of which terminated shortly before the first heart sound probably because of the upper normal limit of the P-R interval (0.19 to 0.20 sec.). Over the right ventricular area (Fig. 3, B), the mid-diastolic murmur was of large amplitude and the time course was slightly different from the apical one. The atrio-systolic murmur was of lesser amplitude, but this was of relatively large amplitude one intercostal space above (Fig. 3, C), and the time course was quite different from the apical murmur. The pulmonary regurgitant murmur was easily identified by the definite time relationship to IIP, which was clearly seen in Fig. 3D, and partly in Fig. 3C, in which both tricuspid and pulmonary diastolic murmurs were superimposed. This pulmonary regurgitant murmur con- tained both low- and high-pitched components and of decrescendo configuration.

Fig. 4. Reference tracings. Details: see text. Vol. 9 No. 3 QUADRIVALVULAR HEART DISEASE 309

Fig. 5. Pressure curves from PA, RV and RA.

Though this configuration is commonly observed in case with , the quality was much more similar to the murmur of organic pulmonary insufficiency. In the upper part of the left parasternal line (Fig. 3, F), another type of regurgitant murmur started from IIA was recorded, and this was mainly high-pitched, sug- gesting the presence of aortic regurgitation. Again, one intercostal space below, both regurgitant diastolic murmurs were superimposed (Fig. 3, E). In the upper sternal border of both left and right sides the atrial sound was recorded with significant amplitude (Fig. 3, G) and this was distinctly audible in the neck (Fig. 3, H). The ejection systolic murmur was also present in both sides of the neck with lesser in- tensity. The jugular phlebogram (Fig. 4, A) taken the other day disclosed pro- minent a wave, decreased x and v and almost absent y with little or no subsequent ascent. This a wave was also demonstrated over the enlarged liver (Fig. 4, B). Thus the presence of significant tricuspid stenosis without tricuspid regurgitation was strongly suspected based on both phonocardiograms and jugular phlebogram. The carotid arterial pulse tracing (Fig. 4, C) taken several weeks later demonstrated slow rise of anacrotic wave, but without prolongation of corrected t-time. However, upstroke time was prolonged (0.22 sec.). Total ejection time (ET) was within a normal limit when corrected by heart rate (RR=0.09, ET=0.33 sec., respectively). Though the fine vibrations on the ascending limb were clearly demonstrated, the other morphological as well as all measures were not significant to estimate the presence as well as the degree of the co-existing aortic stenosis. Functional phono- cardiography utilizing amyl nitrite inhalation resulted in the tremendous intensifica- tion of systolic murmurs and the diastolic murmur of pulmonary regurgitation. No separate observation as to the behavior of either mitral or tricuspid diastolic murmur was possible. The same results were observed by the same procedure several months later. Intravenous serotonin administration caused extreme augmentation of the pulmonary regurgitant murmur, however, it was resulted in severe suffocation with tremendous tricuspid regurgitant murmur, which persisted about 2 min. No con- clusion was obtained as to aortic and involvements by these tests. Right heart catheterization (Table I) disclosed the moderately elevated right ventricular pressure, the presence of pressure gradient of 35mm.Hg between right and pulmonary artery, and decreased diastolic pressure level in the pulmo- nary artery with occasionally observed incisura. Right atrial a wave was of significant 310 SAKAMOTO, ET AL. Heart J. y, 1968

Table I. Cardiac Catheterization Data

Fig. 6. Intracardiac phonocardiograms. External ones are inscribed simultaneously.

height and x and v waves were not present, and y descent was not observed (Fig. 5). These were consistent with those of the jugular phlebogram. Despite the prominent a wave in the , no appreciable counterpart in the right ventricle was recorded, Vol. 9 No. 3 QUADRIVALVULAR HEART DISEASE 311 thus, there was distinct presystolic pressure gradient between these 2 chambers . The mid-diastolic gradient was thought to be minimum . Left heart catheterization was not performed, partly because of the patient's precarious condition and partly the ignorance of the left-sided valve lesions. Intracardiac phonocardiography was done subsequently to the right heart catheterization and it was repeated again during the procedure of angiocardiography . The intense ejection systolic murmur and also pulmonary regurgitant murmur were recorded in the pulmonary valve area (Fig. 6, A). The latter was following small but distinct IIP, though this is partly covered by the murmur. The simultaneously recorded external phonocardiogram taken from the 4th intercostal space parasternally showed the different diastolic murmur, which showed mixed diastolic murmurs of both tricuspid and pulmonary. At the inflow tract (Fig. 6, B), the systolic murmur was greatly attenuated and pulmonary diastolic murmur was absent . On the other hand, low-pitched mid-diastolic murmur was clearly demonstrated and was definitely audible by monitor system. The atrial sound was present from the pulmonary artery to the right atrium, but it was loudest at the inflow tract of the right ventricle (Fig. 6, B). In the right atrium, there was no systolic murmurs, either regurgitant or ejection type. Angiocardiography injecting Angio-Conray(R)into the right atrium disclosed the enormously enlarged pulmonary artery (Fig. 7). Furthermore, the crescent

Fig. 7. Angiocardiogram showing RA, RV and PA. Each chamber is shown in the diagram on the right. moon-shaped filling defect of the tricuspid valve was very suggestive of the presence of organic tricuspid stenosis. Cineangiography injecting the dye into pulmonary artery demonstrated the massive pulmonary regurgitation and the markedly delayed clearance of the dye from the right ventricle. No detailed observation of the valve itself was possible. As the final conclusion of the diagnosis after repeated discussion, pulmonary artery dilatation, pulmonary regurgitation, and pulmonary stenosis were established. The primary significance was directed to the unusually dilated pulmonary artery, and both regurgitation and stenosis of the valve were interpreted as functional in . Heart J. 312 SAKAMOTO, ET AL. y, 1968 origin by most of the cardiologists concerned. Co-existing tricuspid stenosis, aortic stenosis, aortic regurgitation and mitral stenosis were all ignored as of insignificant degree. The patient was discharged and on the cough medicine including codeine and was seen as an outpatient regularly once a month. She was well until she complained of easy fatiguability and jaundice 11 months after discharge. She was hospitalized again as having infectious hepatitis and treated with prednisolone and diuretics. Unfortunately, however, marked edema with electrolyte imbalance developed, and she died suddenly under serious arrhythmias. Postmortemexamination: The heart weighed 420Gm. and the right ventricle showed marked hypertrophy and slight dilatation. The myocardium measured 8mm. in thickness. There was no significant left ventricular hypertrophy and the myocardial thickness was 9mm. Both atria were moderately dilated. All four cardiac valves had organic involvement. The severest was in the pulmonary valve,

Fig. 8. Close-up view of each valves (A•`E), and photomicrograph of the liver (F). Vol. 9 No. 3 QUADRIVALVULAR HEART DISEASE 313 which essentially consisted of 2 cusps and the anterior cusp was absent. The anterior one third of the left cusp was entirely rudimentary and attached to the valve ring as a small crest (Fig. 8, A). The right cusp was also underdeveloped and was almost absent. Thus the pulmonary valve was strikingly incompetent. The valve ring measured 5.5cm. in circumference. On the other hand, the pulmonary artery was enormously dilated from the origin to both right and left branches and the wall was moderately thin with slight sclerosis (Fig. 8, B). The circumference of the main pulmonary artery measured 17cm. Over the wall at the outflow tract of the right ventricle, fibroplastic endocardial jet lesions were observed extensively. The tricuspid valve ring measured 8cm. in circumference. Its commissure showed fibrous thickening and moderate fusion, and the chordae tendineae also showed adhesion, thickening and shortening. Thus, the moderate degree of tricuspid stenosis with possible insufficiency was established (Fig. 8, C). The mitral valve leaflets also revealed similar changes, giving moderate stenosis (Fig. 8, D). The mitral ring was 5cm. The aortic ring was 4.5cm. in circumference and fibrous thickening with adhesion was present between right and posterior cusps. The orifice was also significantly incompetent. Thus, the predominant aortic stenosis with moderate insufficiency was confirmed (Fig. 8, E). Aorta had no arteriosclerotic changes and the coronary were patent. With all fibroplastic changes of mitral, tricuspid and aortic valves, there was no congenital anomaly of these valves. The other outstanding findings were the pulmonary edema with congestion and deposition of hemosiderin of both lungs, general jaundice and edema, congestive cirrhosis of the liver (780Gm.) of mild degree (Fig. 8, F), and the left pleural ad- hesion.

DISCUSSION The clinical and pathologic findings of quadrivalvular heart disease were most concisely reviewed by Ayres et al.2) They collected 5 cases from the literature and added another case with marked stenosis of all four valves proved by cardiac catheterization and confirmed by autopsy. In our series of autopsy, no case had the involvement of four valves. Even trivalvular disease was only 9 instances, of which the pulmonary valve affection was only one and it was not predominant lesion. The true pathogenesis of the pulmonary regurgitation in the present case remains a matter of speculation. However, the specimen strongly suggests the presence of bicuspid pulmonary valve3)-5) prior to the destruction, though it is extremely rare as a sole congenital anomaly.6) This valve might be destroy- ed by subsequent bacterial endocarditis7),8) or rheumatic involvement.7),9) Pathologic examination demonstrated that the other possibility ofmassive regur- gitation reviewed by Laneve et al.10)is not the cause in our case. Unusual dila- tation of pulmonary artery without dilated pulmonary valve ring suggests the pulmonary regurgitation is the earliest involvement, because the other stenotic valve lesions may deprive of the forward blood flow to develop the aneurysmal 314 SAKAMOTO, ET AL. Jap. Heart J. May, 1968 dilatation. Bicuspid pulmonary valve , if present as a congenital anomaly, favors to the dilatation of this artery by the presence of mild pulmonary stenosis . It is likely that the already dilated pulmonary artery was further intensified to give aneurysmal dilatation by the massive regurgitation. The history of bronchial compression by this pulmonary artery favors to this consideration . The aortic, mitral and tricuspid valve involvements are most likely rheumatic in origin, because the stenotic lesion is predominant . However, the possibility of the acquired pulmonary stenosis by rheumatic infection ,1),2) which is later on destroyed by the recurrent , is not denied by confidence. The clinical diagnosis of quadrivalvular heart disease is difficult , unless one considers the possibility of such a valvular involvement. This is mainly due to the presence of similar murmurs which locate closely each other. In our past experience, a mild organic pulmonary regurgitation was missed by the co-existence of aortic regurgitation of moderate degree in the case afore- mentioned. In the present case, the aortic regurgitation was initially missed by all physicians. Also both tricuspid and mitral diastolic murmurs were not separately appreciated by all. Only the phonocardiograms, though repeatedly taken, disclosed the presence of the 2 diastolic regurgitant murmurs, the difference of the 2 diastolic rumbles and the prolongation of Q-1 interval which favors to the presence of mitral stenosis. Tricuspid stenosis was initially re- cognized by clinical ground, but the overwhelming pulmonary regurgitation made the correct antemortem diagnosis difficult. In the presence of sinus rhythm, the murmur of tricuspid stenosis is said mainly atrio-systolic in timing,11) but the tricuspid diastolic murmur in the present case was predominantly mid-diastolic. The absence of mid-diastolic pressure gradient between right atrium and right ventricle, therefore, is not consistent with the timing of the murmur. Moreover, distinct atrio-systolic pressure gradient is manifested by the less prominent atrio-systolic murmur and loud atrial sound. All dis- crepancies between phonocardiographic and hemodynamic data may suggest the presence of the right-sided Austin Flint murmur,12),14) which is the counter- part of that of aortic regurgitation. Massive pulmonary regurgitation may give such a murmur. Reubi et al.15) experienced "presystolic" murmur due to relative tricuspid stenosis in a case of massive regurgitation due to the pulmonary artery dilatation caused by panarteritis. In this case, the presystole may be superimposed with the rapid-filling phase, because of (heart rate was 90) with 1st degree A-V block (Fig. 215)). Therefore, the murmur under their discussion is most likely mid-diastolic in time. Sloman and Wee16) also experienced such a murmur which was localized at the inflow tract of the right ventricle by intracardiac phonocardiography. In our case, the same finding was observed, and this may imply that the mid-diastolic Vol. 9 No. 3 QUADRIVALVULAR HEART DISEASE 315 murmur is predominantly the one of the right-sided Austin Flint murmur and atypical atrio-systolic murmur is due to the organic tricuspid stenosis. The co-existence of organic mitral and the Austin Flint murmur in combined mitral and aortic valvular disease was already confirmed by us.17) In such a case, both amyl nitrite and methoxamine intensify or provoke the 2 types of diastolic rumble, the former does the murmur of mitral stenosis and the latter the Austin Flint murmur. As almost all case reports described, the exact anatomical diagnosis based on the clinical findings is more or less retrospective in quadrivalvular heart disease. Though the repeated phonocardiography was of real diagnostic help, the misdiagnosis undoubtedly originates in the ignorance of this unusual combination of valvular disease.

REFERENCES

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