pulmonaryvascular changes associated isolated mitral stenosis in india · british heartjournal,...

British HeartJournal, I975, 37, 26-36.

Pulmonary vascular changes associated withisolated mitral stenosis in India

H. D. Tandon and Jaya KasturiFrom the Department of Pathology, All-India Institute of Medical Sciences, New Delhi, India

Pulmonary vascular changes were studied in IOO cases of isolated mitral stenosis; these included go patientsin whom lung biopsies were obtained at valvotomy and io patients who came to necropsy. Medial thickness of thepulmonary arteries was measured in each case and in I2 cases was correlated with the haemodynamic data.

Most patients wereyoung, 78 being 30years ofage or less and 42 under 2oyears or less. Malespredominated2:i. All patients with mitral stenosis showed varying degrees of vascular and other associated parenchymalchanges. The most conspicuous were those observed in the muscular branches of the pulmonary artery in whichthe media was thickened in all cases, moderately in 44 and considerably in 28 cases. Dilatation lesions repre-senting grade 4 lesions of hypertensive pulmonary vascular disease (Heath and Edwards, I958), hitherto notdescribed in mitral stenosis, were observed in 4 cases. The intima wasfound to befrequently abnormal, showingoedema, fibrosis, and, more importantly, variable degrees of muscularization, often suggesting the incipientformation of a second media. Arteries and arterioles were often occluded by thrombi in various stages oforganization, and the freshly formed channels tended to acquire a muscular lining. Arterioles were muscular-ized in all cases, and in many there was a pronounced intimal proliferation. Other changes included medialhypertrophy in the veins and occasional muscularization and dilatation of the lymphatics. A notable featurewas hypertrophy of the musculature of the bronchiolo-alveolar system seen in a majority of cases. The alveolarwalls showed variable degrees of thickening and fibrosis, intimal proliferation of alveolar capillaries, and'epithelialization' of alveoli. Haemosiderosis was present in 70 cases. On the whole the more severe changeswere observed more often in the younger subjects, further supporting the observation that rheumatic mitralstenosis in India commonly affects the juvenile age groups and is characterized by association with severe

pulmonary hypertension. Medial hypertrophy was proportional to the level ofpulmonary artery pressure.

Morphological changes in the pulmonary vascula-ture and lung parenchyma in mitral stenosis are wellknown (Parker and Weiss, I936; Larrabee, Parker,and Edwards, I949; Henry, 1952; Heath andWhitaker, I955; Heath and Best, I958; Wagenvoort,I960; Walton and Heath, I960; Lendrum, I960;Roy et al., I963; Wagenvoort, Heath, and Edwards,1964; Jordan et al., I966; Bhayana et al., I969).There have been several reports on the correlationof histopathological and haemodynamic data in suchcases (Ellis et al., I95I; Graham et al., 195I; Cloweset al., I953; Denst et al., I954; Heath andWhitaker, I955; Harris and Heath, I962; Bhayanaet al., I969). Most of these studies were in adults. InIndia, mitral stenosis resulting from rheumaticheart disease commonly affects the juvenile agegroup, and is characterized by association withReceived 7 January 1974.

severe pulmonary hypertension (Mathur, I960;Padmavati, I962; Roy et al., I963).The present study is a critical analysis of the

qualitative and quantitative changes in the pulmon-ary vasculature and lung parenchyma seen in thesecases. An attempt has been made to correlate thesechanges with the available haemodynamic data.

Materials and methodsPathological material was obtained from go cases ofmitral stenosis at the time of valvotomy, and I0 cases ofthis disease which came to necropsy. In addition, Ifrandomly selected necropsy cases of comparable age,without cardiopulmonary disease, and in which the heartand lungs were grossly within normal limits, werestudied to establish baseline data in respect of the normalstructure of the lung, with special reference to pulmon-ary vasculature. Tissue for microscopical sections wasobtained from the lingula and lower lobe of the left lung

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Pulmonary vascular changes in mitral stenosis 27

FIG. I Muscular branches of the pulmonary artery showing varying grades of severity ofthickening. Medial thickness of each vessel expressed as per cent of external diameter. A) Normalvessel, 3 per cent. (VVG X 260.) B) Mild hypertrophy, 9 per cent. The internal elastic lamina isduplicated in one place. (VVG X 260.) C) Moderate hypertrophy, I4 per cent. (VVG x 260.)D) Severe hypertrophy, 20 per cent. The intima shows early muscularization. (H. and E.X I09.) E) Severe hypertrophy, 50 per cent. (Masson trichrome X 260.) F) Severe hyper-trophy, 30 per cent. There is an additional layer of longitudinal muscle in some places beneaththe external elastic lamina. (Masson trichrome x 260.)

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28 Tandon and Kasturi

in the valvotomy cases and from all lobes of both lungs inthe necropsy cases. This was fixed in I0 per cent bufferedformalin, and 5 IL thin sections were stained routinelywith haematoxylin and eosin (H. and E.), Verhoeff'sstain counterstained with Van Gieson's stain for differen-tiating between elastic and collagenous connectivetissues (WG), Masson's trichrome stain for differen-tiating between collagenous and muscular connectivetissues, Gomori's stains for reticulin (Armed ForcesInstitute of Pathology, I960), and Perl's reaction foriron. In addition, sections were stained with Mallory'sphosphotungstic acid haematoxylin for fibrin, and VonKossa's stain for calcium when necessary.

Vascular changesBlood vessels including elastic and muscular branches ofpulmonary artery, pulmonary arterioles, capillaries, andveins were examined with reference to medial thicknessand intimal proliferation. The arterial blood vessels wereclassified by Brenner's criteria (1935), the elastic branchesmeasuring iooo t± and above, muscular branches betweenI00 pt and Iooo t, and arterioles below Ioo 0 in externaldiameter.The diameters were measured by the technique of

Wagenvoort et al. (I964) using a micrometer eyepiece. Ineach section a minimum of five vessels of each categorywas measured and the mean was taken as the finalmeasurement. The medial thickness of the arteries wasmeasured from the external to the internal elasticlamina along diameters at right angles to each other, andthe average of these two measurements was expressed asa percentage of the external diameter. The upper limit ofnormal medial thickness of the muscular branches ofpulmonary artery was taken as 7 per cent.The presence of abnormal muscularized pulmonary

arterioles was sought. The criterion for this change wasthe presence of a distinct muscular media in an arterialvessel less than ioo V. in diameter.

In addition, lymphatics in the pleura, interlobularsepta, lung parenchyma, and around the pulmonaryarteries were examined for dilatation or other changes.

Pulmonary parenchymaFibrous or muscular thickening of the alveolar walls, thedegree and site of haemosiderosis if any, the presence of' epithelialization' of the alveoli, and elastic and reticulintissue changes, such as mineralization, thickening, re-duplication, and fragmentation, were sought. Theseverity of haemosiderosis was graded o to 2+ (Heathand Whitaker, I956). The severity and extent of changesin the upper and lower lobes were compared.

Haemodynamic studiesHaemodynamic data obtained at right heart catheteriza-tion, using standard techniques (Roy et al., I963), wereavailable from I2 valvotomy cases: these included pul-monary artery and wedge pressures, cardiac output,cardiac index, and pulmonary vascular resistance. Thevascular and parenchymal changes were correlated withthe haemodynamic data.

TABLE i Age and sex distribution of cases studied bybiopsy and at necropsy

Age Male Female Totalrange(yr) Biopsy Necropsy Biopsy Necropsy

O0-0 I I 2II-20 20 4 I4 2 402I-30 22 3 II 363I-40 I4 4 I I941-50 2 I 3

Total 66 34 I00

ResultsThe age and sex of the subjects are indicated inTable i. Seventy-eight patients were 30 years orless, 42 were 20 years or less.

Pathological findingsElastic arteries Moderately severe atherosclerosisin the pulmonary trunk and the extrapulmonary andintrapulmonary elastic arteries was observed in theIO cases coming to necropsy; of these 9 were be-tween the ages of i i and 30 years. Only one of thecontrol series, a subject aged 55 years, had someminimal pulmonary atherosclerosis.

Changes of variable degree were observed in themuscular branches of pulmonary arteries, pulmon-ary arterioles, veins, and lymphatics, and in thealveolar walls in all cases of mitral stenosis. Changesin the arteries and arterioles were the most pro-nounced.

Muscular arteries In the normal controls, themedia of the muscular branches is thin, sand-wiched between two elastic laminae, which show noduplication or fragmentation, or focal changes only(Fig. iA). The intima is insignificant, usually com-prising a single layer of endothelial cells.

In all cases of mitral stenosis, the media of themuscular branches of the pulmonary artery wasthickened to a variable degree because of hyper-trophy of the circular muscle, with an admixture ofsmall quantities of fibrous connective tissue inadvanced lesions (Fig. iB-F).Table 2 shows the distribution of cases according

to the severity of medial thickening of the muscularpulmonary arteries. The medial thickness in themitral stenosis cases ranged from 5 to 50 per cent ofthe external diameter, as compared to 2 tO 7 per centin controls. The largest number of cases had amoderate thickening (io to I4%). It is noted that aproportionately larger number of cases in theyounger age group (20 years or below) belonged to



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TABLE 2 Distribution of cases according to severityofmedial thickening ofmuscular branches ofpulmonaryartery

Groups Cases Total Medialthickness*

Age 20 Age above (normal 2 to 7)years and 20 yearsbelow

I 9 I9 28 5 to 92 I7 27 44 IO to 143 I6 I2 28 I5 to 50

42 5g ioo

* Expressed as percentage of external diameter.

groups 2 and 3, with moderate and severe medialthickening, respectively. In a majority of cases ingroup 3, the medial thickness ranged between I5and 20 per cent; in 4 it was 2I to 30 per cent, and inI it was 50 per cent of the external diameter.In 5 cases of group 3 with severe medial thicken-

ing, there was an additional layer of longitudinalmuscle outside the circular layer and beneath theexternal elastic lamlina (Fig. IF). In association withseverer changes, the internal elastic lamina was oftenthickened, split, reduplicated, or even ruptured. Noevidence of vasculitis or fibrinoid necrosis was seenin any case.

Intimal proliferation and a variable degree offibrosis was observed in 40 cases. The earliest change

FIG. 2 Pulmonary arterial channels showing varying stages of recanalization of a thrombus.A) New channels are small and slit-like, lined by a single layer of endothelial cells. (VVGX 273.) B) The thrombus is replaced by fibrous tissue; the new channels have thicker walls, andthe largest one has acquired some muscle. (VVG x 260.) C) The lumen is occupied by two well-formed new vascular channels. One of them has a thick fibromuscular wall. The wall of theparent vessel is hypertrophic. (H. and E. x I09.)



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30 Tandon and Kastur

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FIG. 3 Dilatation lesions. A) A vein-like muscular channel is lying adjacent to a muscularpulmonary artery with a thickened media and muscularized intima. Another small independentchannel is seen within the wall of the parent vessel. (H. and E. x I09.) B) Vein-like lesion(H. and E. x I09.) C) Angiomatoid lesion. (H. and E. X 218.)



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consisted of a diffuse oedema. Later, proliferatingintimal cells embedded in a fibrillar matrix con-tributed to an eccentric or a generally concentricthickening. This was mostly fibrous connectivetissue, but in advanced lesions, there was a variabledegree of muscularization of the intima, some-times resulting in the appearance suggesting theincipient formation of a second 'media' withinthe boundaries of the internal elastic lamina (Fig.iD). In 4 cases, all in the younger groups thelumen was almost completely occluded by such alesion. Three of these 4 cases were 15 years old orless, and one was 27 years old. Two had moderate(9 to io%), and 2 had severe (IS to 20%) muscularhypertrophy.

In a few cases, the lumina of the muscularpulmonary arteries and arterioles were occluded bywhat appeared to be an organized and recanalizedthrombus (Fig. 2). The newly formed channelstended to acquire a muscular wall, later appearingas complete fibromuscular septa (Fig. 2B and C).

Characteristic dilatation lesions were seen in 4cases, all in the juvenile age group, and were of twotypes (Heath and Edwards, I958).

i) Vein-like branches of hypertrophic pulmonaryartery (Fig. 3A and 3B): a vein-like channel is seenarising from, or lying adjacent to, a hypertrophicpulmonary artery.

2) The angiomatoid lesion (Fig. 3G): this con-sists of a cluster of dilated vascular channels ofvariable thickness, presumably arising from apulmonary artery.

Arterioles In the normal controls, the arteriolehas a single elastic lamina lined by a single layer ofendothelial cells. A thin layer of muscle, often in-complete, is rarely seen only in larger arterioles. Inpatients with mitral stenosis, arterioles were muscu-larized in all cases except three. In many cases, theyhad acquired an internal and external elastic laminasandwiching a media of circularly disposed fibres(Fig. 4). The medial thickness ranged from 4 to I7per cent of the external diameter as compared withnegligible thickness in normal controls. In themajority of cases, the thickness was 9 to I0 per cent.Intima were generally swollen. In 35 cases, there wasa pronounced intimal proliferation, often so severeas almost to obliterate the lumen.

Pulmonary veins Almost all cases showedvenous hypertrophy of mild to severe degree. Thethickening was largely the result of hypertrophy ofcircularly disposed muscle fibres, with occasionalfascicles of longitudinally disposed muscle. Intimalfibrosis of varying degree was present in 20 cases. In

some cases the thickening was so severe as almost toobliterate the lumen. In one case the lumen wascompletely occluded and was recanalized by slit-like channels resembling an organizing thrombus.In this case similar changes were observed in thearteries and arterioles.

Lymphatics Dilated lymphatics in the pleura andinterlobular septa were observed in 40 cases. Dilata-tion was pronounced in a few cases, and occasionallythe lymphatics had acquired a hypertrophiedmuscular wall (Fig. 5).

Parenchymal changes There was a variabledegree of alveolar thickening and fibrosis in mostcases. The mildest change was slight thickening ofthe alveolar septa with reduplication of reticularframework, in 25 cases. The change was moderatelysevere in 47 and severe in 28 cases. With increasingseverity the alveolar septa became thicker, encroach-ing on the lumen as a result of reduplication andcondensation of the reticulin and elastic fibres,variable degrees of collagenization, thickening of thebasement membrane of the alveolar capillaries,oedema, and 'epithelialization' of the alveoli. In 5cases the alveoli had almost a glandular appearance.In some cases with severe changes, the intimallining of the alveolar capillaries also showed con-

FIG. 4 Muscularized arteriole. The muscular mediais sandwiched between two elastic laminae. (VVGx 380.)



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FIG. 5 The oedematous interlobar septum contains a dilated lymphatic vessel, with irregularlythickened and muscular walls. (H. and E. x 8o.)

centric narrowing caused by intimal proliferation(Fig. 6).The elastic tissue of the alveolar walls was en-

crusted with deposits of iron and calcium in 4 cases.In 2 cases, there was a foreign body type of giantcell reaction around degenerated elastica.Another notable feature was the presence of

smooth-muscle hypertrophy in the bronchiolo-alveolar system. Thick strands of muscle oftenextended into the alveolar septa. This change wasobserved in 65 cases, and was particularly severe inI6; of the latter, I0 were less than 20 years of age.In some of these cases, the change extended to theinterlobular septa and the pleura (Fig. 7).

In I0 cases, the alveolar capillaries showed diffuseaneurysmal dilatation. Five of these subjects wereaged 20 years or less, and the rest were 28 to 40years old. In all these cases except one, the medialthickness of the pulmonary arteries ranged from I0tO 20 per cent of external diameter.

Haemosiderosis The occurrence, degree, andlocation of haemosiderosis varied widely. Using thegrading of Heath and Whitaker (I956), the severity

of haemosiderosis was + in 6o cases and + + in I0cases. Twelve cases had only a few scattered haemo-siderin-laden macrophages in the alveolar lumina,mostly adjacent to the interlobular septa andpleura; the remainder had none.

In 67 out of go biopsied cases, changes of equalseverity were found in the upper and lower lobesections. This finding has been further substantiatedby the observations in cases coming to necropsy,where no striking differences in severity wereobserved between different lobes.

Haemodynamic and clinical dataResting pulmonary arterial pressure was raised inall cases. Pulmonary hypertension was mild (20 to29 mmHg mean pressure) in 5, moderate (30 to 49mmHg) in 6, and severe (58 mmHg) in i case.Pulmonary artery wedge pressure was also raised inall; in all cases except 2, the pressure was between 20and 28 mmHg. The pulmonary vascular resistancewas normal in 8 cases, and increased in 2 cases. Thecorrelation between medial hypertrophy of thepulmonary arteries and the pulmonary artery pres-sure (Fig. 8) was significant (P < o-oi).



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FIG. 6 The alveolar septa are severely thickened and oedematous. Multiple channels derivedfrom alveolar capillaries are seen, showing concentric narrowing caused by intimal proliferation.The alveolar spaces are 'epithelialized'. (H. and E. x i6o.)

DiscussionIn India, isolated mitral stenosis following acuterheumatism commonly affects subjects below 20years of age. In the series of Vaishnava, Webb, andCherian (I960) from South India, 26 per cent of thepatients were below the age of I3 years. In a seriesof 754 cases of rheumatic heart disease (Roy et al.,I963), I7I subjects were 20 years of age or younger:of these io8 had pure or predominant mitralstenosis, i.e. I4 per cent of the whole series. Ouranalysis deals only with cases who were operatedupon (go cases) or came to necropsy. In this group,the proportion of juvenile cases is still higher, 42 percent being 20 years of age or less and 78 per cent 30years of age or less. This confirms the increasedprevalence of mitral stenosis in younger age groupsin India: a large number of cases needing operationwere in these groups.

Morphological changesQualitative changes in the pulmonary vasculatureand parenchyma were seen consistently in almost

every case; these changes appeared to be moresevere in the juvenile age group. Using the preciseand measurable parameter of medial thickening ofpulmonary arteries, a larger proportion of youngsubjects was affected as the lesion became moresevere. In group 3 with the severest thickening, i6out of 28 subjects were 20 years of age or less(Table 2). Furthermore, in 5 cases of group 3 therewas an additional layer of longitudinally disposedmuscle just inside the external elastic lamiina. Theseverest degree of other changes, e.g. intimal pro-liferation in the arteries, veins, and arterioles,smooth muscle hypertrophy in the bronchiolo-alveolar system, aneurysmal dilatation of the alveolarcapillaries, was observed more often in the youngage group.

Dilatation lesions were observed in 4 patients, allof whom were less than 20 years of age. This is asignificant finding. Bhayana et al. (1969) from Indiahave reported these in 5 of their series of 25 cases,but their photomicrographs do not convincinglyshow the lesion described by Heath and Edwards(1958). This lesion is believed to be indicative of



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FIG. 7 Muscular hypertrophy of the bronchiolo-alveolar system. (H. and E. x i6o.)

severe pulmonary hypertension (grade 4 of Heathand Edwards, I958) and is reported to occur only inidiopathic pulmonary hypertension, congenitalheart disease (Wagenvoort, I959), or schistosomiasis(Brewer, 1955; Naeye, Ig6Ia). Progression of

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2

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FIG. 8 Scattergram showing the correlation ofpulmonary artery pressures and medial thickness of thepulmonary arteries.

vascular changes to this degree has not beenreported in isolated mitral stenosis (Heath andEdwards, I958; Wagenvoort, I959), though Heathand Edwards (i958) have reported the developmentof fibrinoid necrosis of the arteries in a very fewcases. The latter change has not been observed inour series or in other Indian series (Roy et al., I963;Bhayana et al., I969).These observations seem to indicate that pulmon-

ary hypertension is a dominant feature in Indiancases, particularly in the younger age groups. Otherworkers (Denst et al., I954; Parker and Weiss, I936)have also observed that the pulmonary vascularchanges observed in the older age groups are lesssevere compared with those seen in younger sub-jects. It is possible, therefore, that the higher levelsof pulmonary hypertension in the young patientsmerely reflect an age-related response.Roy et al. (I963) have postulated that the high

prevalence of severe pulmonary hypertensionassociated with the severe vascular changes seen insuch cases may indicate a hypersensitive reaction ofthe pulmonary vasculature to a fulminating rheu-matic process, or a tissue response to multiple overtattacks of rheumatic fever, caused by lack ofchemoprophylaxis in Indian patients, or continuinglow grade rheumatic activity. Denst et al. (I954)

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have also postulated a direct role of rheumatic feverin the induction of vascular lesions, since changescaused by age or raised pulmonary arterial pressuredo not fully explain their pathogenesis.The most consistent finding was the musculariza-

tion of arterioles seen in all but three cases. In themost advanced lesions, the arterioles resembledsmall arteries with an internal and external elasticlamina, except for their small size. Apart frommuscular hypertrophy, the lumen was furthernarrowed because of intimal proliferation in 35cases. In the series of Heath and Whitaker (1955)this was observed only in cases with severe pulmon-ary hypertension (more than 70 mmHg) and wasabsent in all cases of mild (less than 40 mmHg) andsome of moderate (4I to 50 mmHg) hypertension.Such a correlation with the level of pulmonaryartery pressure was not evident in our series, since itwas observed with varying severity in all the I2cases whose haemodynamic data were available andwhose pulmonary artery pressures ranged from 23tO 58 mmHg.The figures for medial thickness of the pulmonary

arteries are variable in the western studies. In theseries of Jordan et al. (I966) comprising 20 patientsall ofwhom were 30 tO 55 years of age, the maximummedial thickness reported was I7 per cent of theexternal diameter and was seen in only one case.

Heath and Whitaker (I955) on the other handreported medial thicknesses of I5 per cent or morein 20 of their 3I cases, with ages ranging from 23 to55 years. These contrast with our figure of 28 out ofI00 cases in which the medial thickness was I5 percent or more. Criteria for measuring the severity ofvascular changes used by other western workers are

less precise (Denst et al., 1954).Our observations suggest that medial thickening

is probably the result of medial hypertrophy(Wagenvoort, I960; Naeye, Ig6Ib) though vaso-

constriction may be a contributory factor (O'Neal,Thomas, and Hartroft, I955; Short, I957). Hyper-plastic changes in the muscle constituting the arterialmedia, muscularization of the arterial intima and ofarterioles, and the presence of additional fasciculi oflongitudinal muscle in the arterial media reinforcesuch a theory (Wade and Ball, I957; Heath andBest, 1958; Wagenvoort, I960; Walton and Heath,I960; Heath, I963). These mechanisms probablyresult in increased mechanical rigidity of the vesselwall, as postulated by Burton (I954).Our observations seem to support a speculation

by Wagenvoort et al. (I964) that at least one of themodes of evolution of the dilatation lesions is byrecanalization of the pulmonary arteries. It seemsthat the recanalized channels acquire a muscularwall of their own, out of a haemodynamic necessity,

in response to the high pressure. These may dilate,resulting in a plexus of independent vessels withinthe adventitial boundary of a large one.The smooth muscle hyperplasia in the bronchiolo-

alveolar system was a conspicuous feature in ourcases. It was particularly pronounced in the youngsubjects. In severity it was related to the changesin the alveolar walls rather than to the medialhypertrophy of the pulmonary arteries. It has beenreported by Rodbard (1950) and Liebow, Loring,and Felton (I953) in a variety of pulmonary dis-orders, and by Roy et al. (I963) in cases of juvenilemitral stenosis. The significance of the change is notunderstood. In some way perhaps it is related to aquick rise in pulmonary vascular pressures in ayoung person, as postulated by Roy et al. (I963).

Correlation of haemodynamic and morpho-logical changesOur analysis is handicapped by the fact that thenumber of cases in this series on whom haemo-dynamic data were available is small, but there wasa significant correlation between medial hyper-trophy of the pulmonary arteries and the pulmonaryartery pressure. Roy et al. (I963), from this insti-tute, have published data on 62 cases, and theirstudies indicate the frequent occurrence of severepulmonary hypertension particularly in youngpatients.

Haemodynamic data were obtained from the records ofthe Department of Cardiology. Assistance provided byMr. P. Ganguli of the Medical Illustration Unit isgratefully acknowledged.

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pulmonaryvascular changes associated isolated mitral stenosis in india · british heartjournal,...

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