The spectrum of pure mitral stenosis

The American

Journal

VOLUME x

DECEMBER

Clinical The

of Cardiology NUMBER 6

1962

Studies Spectrum

Hemodynamic

of Pure

Studies in Relation

Mitral

Stenosis

to Clinical Disability*

PAUL G. HUGENHOLTZ, M.D., THOMAS J. RYAN, M.D., SAMUEL W. STEIN, M.D. and WALTER H. ABELMANN, M.D. Boston,

Massachusetts

T

HE pathophysiology of mitral stenosis has been studied mainly in patients severely disabled by their disease. Because surgery is rarely contemplated in the mildly symptomatic patient, few physiologic studies on patients in this group have been reported, and most of the information is derived indirectly from catheterization of the right side of the heart. Thus certain questions regarding the relationships between clinical symptoms and signs, physiologic variables, and severity of mitral stenosis could not he answered from the incomplete data available from biased samples. Therefore, we began four years ago to make hemodynamic observations by catheterization of the left atrium and ventricle in almost all patients with the clinical diagnosis of mitral stenosis who came to our attention in the clinics and wards of the Boston City Hospital, regardless of severity of symptoms. Analysis of the data shed new light upon the pathophysiology of mitral stenosis and the genesis of symptoms.’

signs of mitral stenosis. Presence of a diastolic, low pitched rumble at the apex and an accentuated first sound was the minimal requirement for inclusion in the study. Excluded were patients with apical systolic murmurs of grade 3 intensity or greater, and those with other evidence of mitral regurgitation at the time of cardiac catheterization’43 or with electrocardiographic and roentgenographic evidence of left ventricular enlargement. Associated Lralvular lesions were also grounds for exclusion. After a detailed history, each patient was classified according to the American Heart Association Functional Classification.4 Careful evaluation was made of the occupational setting and the ability of the patient to cope with stressful situations such as pregnancies, intercurrent infections and emotional disturbances. There were 6 patients in Class I who led an active life without symptoms. In the majority of these the diagnosis of mitral stenosis had been arrived at as the result of a routine examination. ‘Their ages ranged from 21 to 64 years; the mean was 41.6 years. Class 11 included 20 patients whose ages ranged from 28 to 62 years, the mean age being 44.2 years. They had mild, nonprogressive symptoms. All were able to continue their usual activities, which varied On unusual exertion, from housewife to truck driver. all experienced dyspnea and many complained of

MATERIAL Forty-four ambulatory patients with pure mitral stenosis were studied. The majority of patients displayed all the characteristic physical and radiologic

* From the Thorndike Memorial Laboratory and the Second and Fourth (Harvard) Medical Services, Boston City Hospital, and the Department of Medicine, Harvard Medical School. This work was supported in part by grants H442-Cl1 and HTS-5244 from the National Heart Institute, U. S. Public Health Service, and was done while Dr. Hugenholtz was a Research Fellow of the National Heart Institute (HF-8886) and Dr. Stein a Rrsearch Follow of the American Heart Association. 773

774

Hugenholtz

et al. TABLE

Hcmodynamic

Data of 44 Patients with Mitral Left

I 2 3 4 5 6

51 36 37 64 21 41

hknn

valurs

7t 8-t

9t 10 llt 12t 13t 14 15 16 17 18

19-t 20

21t 22 23 24 25 26 Mean

valuer

Mean

42

31 57 37 41 47 SO 46 41 53 SO 49 28 62 53 55 53 29 37 38 28

values

S = systolic; dilution output.

1.67

72

55 53 I .42 I .69 1 91 1.69 2 02 .91 I .58 1.38 1 27 I 44 2.08 I .52 1.60 1.37 1.63 1.41 1.45

78 99 77 70 95 144 81 84 100 53 90 70 72 93 7s 130 79 84 92 90

1 50

XR

1.64 1.54 I 57 1 .69 1.70 1.76

1.45 1.62 1.44 1.42 1 57 1.54 1.49 1.44 1.37 1.50

‘94 R6 RI 100 108 77 ‘95 76 125 94 64 100 80 54 96 54 70 78

1.55

as

I I .30

F F F F 1, F 51 F 1: F F F F 1: F 1: 1: F

1.73 1 40

42.5

D = diastolic;

1 .A8 I 51 2.05 I .45

75 67 74 75 6’1 6’)

I I

1‘ F F hi 1: M M M F M I: F 1,’ hf F LF hf F F

44.2

41 47 41 25 42 54 53 26 23 41 52 4’1 32 61 65 SO 27 40

27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

I 62 I .71

1: M hl F ?“f 1.‘

LV

=

left ventricular;

RV

F s s S s F

150. 9s

II7 92 105 70 115 U5

120‘78

14s ‘82 100 ‘55 140/x3 125 ‘7X

97

s F s S F s I S 1: s s s F 1: F s s s s s

1

120:67 121,74 96.‘58 135 ‘90 200/90 125,‘85 I30.‘75 155,‘87 91 ,‘65 127,‘7O IS3 ‘73 100,‘64 120/R?. 120,70 125,‘75 ,43;05 120,‘70 I?2 ‘72 125 j70 125i78

11 15 5 10 II 17 3

I2

x0 ‘92 76 90 120 95 ‘,3 105 6X ‘J5 107 xn 90 90 XX 115 85 93 77 85

110 ‘73 115,RO lOO,‘70 no;55 ll2:RO I55/‘80 140 “X1 1 IO ‘65 87,‘50 145 ‘83 118’30 140.90 127/‘90 I lo,‘62 120,‘70 115;60 132,‘66 122 ‘75

right

fatigue. In 8 patients of this group of 20 (Cases 7, 8, 9, 11, 12, 13. 19 and 21) symptoms temporarily worsened at one time or another in their past, for example during pregnancy or intercurrent illness. At the time of study. however, all were in Class II.

ventricular:

I: =

7.9

D

25

I6 IX

I9

fibrillation

and

3 16 -2 I1 13

0

9 10 19 21 9 5 20 3 I3 15 15 15

62

I2

8 8 6

3

S =

sinus

9.3

17 5 14 19 14

13 4 4 6

26 14 20 11 17 II 30 19 I5 26 9 26 21 20 3

6.7

19 6 9 13 4 3 11 13 6

10 10 8 5 12

16.3


3 12 10 7 6 14 16 8 I0

10 14 3 11 7 5 11 6

26 25 17

83 93 88 65 96 113 305 88 08 107 105 110 1 10 75 ‘)fl 7s 80 xx

atrial

6 16

19

Heart

3 6 6 ‘, 3 13

78

24 16 14 13 14 15 IO 1X 17 6

91 .I

=

5

31 16 12 20

91 2

s F F S F F I’ s S s 1’ F 1’ F F 1’ s S

9 I2 5 3 13 5

Stenosis,

rhythm.

‘9

* Cnmputrd

‘L‘he remaining 18 patients, who had marked limitation of physical activities, fell into Class III. Their ages ranged from 23 years to 65 years and averaged 42.5 years. They experienced dyspnea after minimal exertion, and practically all had orthopTHE

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CARDlOL.OCY

I

Mitral

775

Stenosis

6 in Class I, 20 in Class II and 18 in Class III -terization

Right

/ Mitral Valve Flow (cc./diastolic sec.)

Cardiac Index (dye) (L./min./Ma.)

,.ar;r& (cm2.)

M.%IlI Pulmonary Capillary PIeSSUre (mm.

Hg)

MeaIl Pulmonary Arterial Pressure (mm.

Hg)

Heart

R. V. End Diastolic PIeSSUre (mm.

Hg)

Catheterization

Mean Right Atria1 PreSSWe (mm.

Total Pulmonary Resistance (dynes sec.

Hg)

-5)

cm.

-6)

Cxdiac Index (Fick) IL./min./MI.)

... ...

...

a

...

...

...

16 14 33

0 9 6

2 4 5

369 177 819

1391 35* 157*

21

5

4.7

455

110

14

15 19

1 5

2 4

267 290

18 89*

3.21 3.70

20

25

7

6

566

89

2.63

10 6

3

6 9

... ... .

3.60 2.60 4 38 2.30 3.08 2.22

246 135 248 110 207 87

3.2 1.2 2.4 0.8 2.8 0.5

3.03

172

1.8

3.03 2.47 3 17 3.10 2. a0 2.09 3.79 2.51 1.64 3.20 3.72 3.84 3.35 3.00 1.51 1.97 4.16 2.71 4.18 2.48

177 151 138 186 225 141 207 178 74 132 197 142 160 205 67 215 178 130 140 148

2.3 1.0 1 .o 1.6 2.1 0.9 1.3 1.5 0.5 1.1 1.5 0.9 1.5 1.6 0.5 2.5 2.5 0.9 0.9 1.4

a 26 15 12

2.93

159

1.4

15.2

2.30s 1.979 3.225 2 70 2.69 3.22 2.62 4.61 4.79 1.97 4.38 2.14 1.69 1.73 2.28 3.36 2.85 2.19

127 98 139 127 177 187 153 184 225 106 193 127 38 70 81 117 128 96

0.7 1.0 0.8 0.7 0.9 1.4 1.2 1.3 1.2 0.5 1.3 1.3 0.4 0.9 0.6 0.7 0.9 0.6

25 28 14 25

2.82

132

0.91

...

Cm.

Pulm. Artcriolar Resistance (dynes sec.

. .

... ... 1 .67 .. 2.02

II

16

.

284

17

3 a

301 265 394

96* 47 143

6

7

243

138

ir.22

4 6 9 3 9

2 5 R 5 7

169 706 272 446

147 240 77 136

2.77 2.66’ 2.93 3.23

20.3

6.2

5

350

104

i:.79

58 33 20 35

a 7 2 a

6 7 3 5

1231 739 411 812

700 262 130 232

2.30 2.32 2.48 2.04

14 15

3::4x 19 17 24

11

1;

.

28/-5 f 12 39 20 20

III

from

left atrial

pressure.

I’ Patients

40/0f 12 11 30 12 20

. .. 30 20.1

whose symptomr

18 14 43 22 29 70 13

1962

a 2 1 8 a 5

... 8 10

55/5$ 74 35.7

temporarily

6.8

worsened

nea. All were taking digitalis, and the majority required diuretics. Patients with overt congestive heart failure, who would be categorized in Class IV, were not included. Thus the patient material of this study falls into DECEMBER

a 6 1 10 9 5

in the past.

2.51

.

... 5 a 5.5

$R.

V.

344 206 927 467 763 2113 391

71 44 410 297 237 1328* 150*

... ...

... ...

1767

1050

848

409

pressures.

0 Fick

cardiac

2:. 87 38.76 i..29 2.62

... zm.51q :! 23

”

I!.72

output

ll Dye

two distinct groups from the point of view of disability. One group consisted of the 26 patients without significant disability in Classes I and 11. The other group included the 18 patienrs with significant disability in Class III.

Hugenholtz

776

et al.

. .:

0

01

’

05

’

’

I.0

’

1.5 MVA

2.0

’

2.5

’

0

3.0

’

05

’

’

I.0

cd

WA

. . /

I

1.5

2.0

25

I

3.0

1.5

cm2

2.0

1,j : yo.‘;: 0

0.5

IO

1.5 MVA

2.0

2.5

OM.0

3.0

0.5 MVA

cm’

2.5

3.0

L”VA cm2

1.0 WA

cm’

, : ./

1.5

2.0

2.5

3.0

cm’

Relationship of mitral valve aria (MVA) to (A) mran left atria1 pressure, (B) mitral diastolic pressure gradient, (C) left ventricular end-diastolic pressure, (D) cardiac index, (E) mean pulmonary arterial pressure. (F) pul-

FIG. 1. monary

arteriolar

resistancr.

Cloxd

circles

indicate

Class

METHODS Each patient was carefully evaluated clinically by ‘I‘he examination inat least two of the authors. cluded a standard 12-lead electrocardiogram, fluoroscopy and roentgenograms of the chest. ‘I‘he intensity of murmurs was graded from 1 to 6. as described by Levine and Harvey.” Radiologic chamber enlargcment was graded on a 1 to 4 plus scale. Cathrterization of the l~Jt sidf of thP hrart was pcrlormed in all patients by posterior transthoracic puncture of the left atrium” with the patient in the prone position under local anesthesia and mild sedation with a barbiturate. Cothetrrization c:f the right side of’ the heart by the venous route preceded left heart catheterization in 25 patients. In 5 other patients catheterization of the right side of the heart was performed by direct transthoracic puncture. Details of these methods. including the manner of obtaining pressure gradients, All pressure have been described previously.“,’ measurements were referred to a baseline 10 cm. above table top. Cardiac output was determined by the indicatordilution technic* in 41 patients using either Evans Blue (T-1824)? 4 to 5 mg. or Indocyanine Green, 3 to 4 mg. Indicator dye was always injected in the left atrium, and duplicate determinations were made in most instances. ‘I’he injrctatr was always delivered by a calibrated 1 cc. pipet, followed by a 10 cc.

I

and 11 patients,

open circles

saline flush.

Calibration

Class III patients.

into a 1000 cc. volumetric cent solution Cardio-green per

cent

water.

was done by injecting flask containing

dye

a 0.5 per

of human albumm in distilled water. dye for injection was stabilized in a 2.5

solution

of

human

Blood was obtained

albumin

in

from the brachial

distilled artery

by sampling either fractionally at constant intervals or continuously through a cuvette densitometer.Y In thr latter instance, blood was withdrawn at a constant rate of 0.7 cc. per second and was collected in a hrparinized syringe. Blood samples were centrifuged at 1500 r.p.m. and the plasma was separated. ‘I-he concentration of dye was measured in a spectrophotometer (Beckman DC). Hematocrits were determined in duplicate and multiplied by 0.96 to correct for trapped plasma.” ~I‘he output of the dcnsitomctcr was recorded on a direct writing oscillograph (Sanborn). ‘l‘he curves were calibrated by the inteIn 17 patients cardiac outgrated sample tt-chnic.‘1 put was also measured by the direct Fick method; in threr patients (Cases 27 through 30). by the Fick method only. Prr.~.rurrs were measured with strain gauge manometers (Statham P23D and G). The pressure differences and cardiac output were determined in close ‘I‘he mitral valve area succession in all patients. \vas estimated according to the formula of Gorlin and Gorlin.” by using an orifice coefficient ‘.C” of 1.0.13 1‘HE AMERIC.%NJOURNAL OF

CARDIOL.OGY

Mitral

Stenosis

777

I and II. The incidence of dilatation of the pulmonary artery in the three classes paralleled that of right ventricular enlargetnent. The cardiothoracic ratio exceeded 54 per cent in 10 of the 18 patients in Class III and in 12 of the 26 in Classes I and II. In none was cardiac enlargement considered marked. Electrocardiograms revealed atria1 fibrillation in 3 of the 26 patients in Classes I and II and in 11 of the 18 patients in Class III. P mitrale occurred in 9 of the 17 Class I and II patients with sinus rhythm and in 7 of the 9 Class III patients with similar rhythm. Unequivocal right ventricular hypertrophy was found in only 5 of 18 patients in Class III; this finding was The frontal plane mean absent in other classes. QRS axis was independent of the functional classification, but was related to the mitral valve area. Of the 17 patients whose frontal plane axis ranged from 0 to 60”, 14 (82.3%) had mitral valve areas 1.3 cm?. or larger. Of the 27 patients whose mean QRS axis exceeded +60”, 24 (88.8%) had mitral valve areas less than 1.3 cm2. in Classes

. 2.5 -

. . . .

.

2.01.5 -

I.0 -

T

. .

0,5-

O-

Cl.I

Cl.B

IbJ

G’OJ

CUNICAI

. .:. : . :.: :

m

Cl. 1161

CL ASSIF/CAT/ON

FIG. 2. Distribution of mitral valve areas among 6 patients with Class I symptoms (mean = 1.8 cm*.), 20 patients with Class II symptoms (mean = 1.4 cm*.), and 18 patients with Class III symptoms (mean = 0.9 The differences between the means of Classes I cm2.). and III and of Classes II and III are significant (p < 0.01). Mitral valve areas estimated in this manner in this laboratory have shown good agreement with areas estimated by palpation at operation or postmortem Vascular resistances were calculated examination.‘s according to standard formulae used by Ellis et al.” 7 he oxygen and carbon dioxide content of expired air collected over three minutes was determined by the Blood oxygen determinamicrotechnic of Scholander. tions were made in duplicate of Neil1 and Van Slyke.

according

to the method

RESULTS CLINICAL DATA* Within

a

given

class

no

distinguishing

/[is-

or roentgenologic features permitted selection of those patients who had the more A clear distinction severe valvular obstruction. hetzoupnclasses was possible on the basis of history ; neither physical signs nor roentgenologic findings differentiated between the classes. Rotwtgtxologically, left atria1 enlargement was definite in all but 1 patient of the entire series. This chamber was enlarged 2+ or more in 16 of the 18 patients in Class III and in 16 of the 26 patients in Classes I and II. Right ventricular enlargement was present in all the patients in Class III, while it was found in 13 of the 26 torical,

physical

* Tabulations of clinical authors upon request. DECEMBER1962

data arc available

from the

HEMODYNAMIC DATA The hemodynamic data are presented in Table I. The results have been analyzed from several points of view, as shown in Figures 1 to 4. First the usual hemodynamic parameters were analyzed in relation to the mitral valve There was a strong inverse relaarea (Fig. 1). tionship between mean left atria1 pressure and mitral valve area (r = -0.618; p < 0.001). Likewise, the mean diastolic gradient was inversely related to mitral valve area (r = - 0.708 ; p < 0.001). As might be expected, these findings are also reflected in the negative correlation that was found between mean pulmonary arterial pressure and mitral valve area (r = -0.575; p < 0.01). The cardiac index decreased in direct relation to the size of the mitral orifice (r = +0.407; p < 0.01). No significant correlation existed between mitral valve area and pulmonary arteriolar resistance or left ventricular end-diastolic pressure. Secondly, these hemodynamic measurements were analyzed from the point of view of selierity When all patients were grouped acof disability. cording to their clinical classification, the distribution of the mitral valve areas was as shown in Figure 2. A near linear correlation was found between the mean mitral valve area of each class and the severity of symptoms. All patients in Class III had valve areas below 1.5 cmz. Similar

778

B . i

-$ .. Cl IeII

.

. . i -+:*

A

9’

.. .

Cl

A . 7: .:.

.. .

m

Cl III

D “=

5.0

.

.

4.0

.. ..

.. .

.

.. .

2 ‘iI :

3.0

2

2.0

1.0

I +. : Cl IelI

-

CIIU

.. . .... .. .

Yzr. . . . .

Cl IeIl

Cl%

Analysis of (A) mean left atrial pressure, (B) mitral valve gradient, (C) cardiac index, and (D) left ventricular end-diastolic pressure with respect to disability in 35 patients, all with mitral valve areas of 1.5 cm*. or less. ‘Thr diffrrrnces between the mean values in rach panel are not significant.

FIG. 3.

critical valve narrowing was found in 14 patients in Class II and in 3 patients in Class I. In order to insure that the groups to be analyzed were comparable in the degree of valve narrolving, this group of 17 patients from Classes I and II with valve areas of 1.5 cm2. or less was compared with the 18 patients in Class IIJ. Pertinent physiologic data of these selected patients arc illustrated in Figure 3. The vwuz /f/t atria1 pressure of the group cutnprising 17 Class I and II patients was 18.0 mm. Hg, S.D. 5.9. The mean left atria1 pressure of patients in Class III was 19.3 mm. Hg, S.D. 6.0. iYhile these values are elevated significantly above normal,‘” they do not differ significantly from each other (Fig. 3A). The mean diastolic gradient across the mitral valve was 10.7 mm. Hg, S.D. 3.7 in the Class I and II category, and 12.7 mm. Hg, S.D. 5.4 in no significant difference the Class III group; I)etwern tile groups (Fig. 3B) was dcmonstrated. The RZCGG c-cardiacindex was virtually identical for the two groups, being 2.81 I,. Inin.,‘M’.,

0.76 in the Class I and II group, and 2.82 I,. ‘Inin.,‘M”., S.D. 0.93 in the Class III group. The cardiac index of normal subjects measured with the indicator-dilution method in this lal)orator), is 3.60 L.,‘min. /M2., S.D. 0.60.‘n Thus the cardiac index of both groups was significant11 lIelow normal (p < 0.01) (Fig. 3C). This held equally for the cardiac output measured by the Fick method during catherization of the right side of the heart. Although le]i ventricular end-diustol~(.lressitre W;IS elevated in isolated instances, the mean value fell in the normal rangel for both groups, tleing 7.2 mm. Hg, S.D. 4.0 in the Class I and II group and 6.2 mm. Hg, S.D. 4.8 in the Class III group (Fig. 3D). The mean pulmonary arterial pressure (Fig. 4A) was normal for the Class I and II patients, having a mean value of 21.5 mm. Hg, S.D. 6.8. In contrast, the mean value for pulmonar! artrrial pressure in the Class III group of palients was significantly higher at a value of 35.7 mm. Hg, S.D. 21.3 (p < 0.05). The mran \,alues for pulmonary arteriolar rt’S.D.

THE: AMERIC.AN

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OF (:ARI~lOI.OC:Y

Mitral

Stenosis

779

B

l

CLI&ll

CLIU

CLI8Il

CLJII

FIG. 4. Analysis of (A) mean pulmonary arterial pressure, and (B) pulmonary arteriolar resistance with respect to degree of disability in 27 patients with mitral valve areas of 1.8 cm*. or less. The diffcwnces between the mean values of both groups are significant (see text).

sis&c~ (Fig. 4B) likewise reflected a significant difference (p < 0.02) between the two categories, although there was considerable overlap. The Class I and II group of patients had a mean value of 105 dynes sec. cm.?, S.D. 59.3, whereas this value for the Class III patients was 425 dynes sec. cm.?, S.D. 404. DISCUSSION GENERAL.GONSIDERATIONS In general, patients with the more severe symptoms had the more significant degree of mitral blockade (Fig. 2). In fact, all patients with significant disability had severe mitral stenosis. On the other hand, 3 of the totally asymptomatic patients and 14 of the mildly symptomatic group had similar small valve areas. Therefore, symptoms alone may not give a true indication of the actual mitral valve size. The recognition of this fact was made possilIle by the design of the present study, DECEb4RER

1962

which aimed at a broad sample of patients with mitral stenosis including those who were asymptomatic. The majority of clinical physiologic studies of mitral stenosis either failed to include patients with mild symptoms or did not disIn most tinguish them as a separate group. reports, hemodynamic data are given only in isolated cases of mitral stenosis with few or no symptoms.17-‘” No specific hemodynamic pattern distinguishes these patients from the normal, nor were any of the mildly symptomatic patients found to have a severely narrowed mitral valve. SiInilarly, the present patients in Classes I and II, considered as a group, presented measurements bordering on normal during right heart catheterization. Only the British and Swedish group of workersZfi--‘?*have given detailed information on patients in Classes I and II and have compared them with individuals in Classes III and IV. Wade’6 and Eliasch, 27 both using a clinical classification comparable to ours, concluded

Hugenholtz

780

that their patients in (3asscs 1 anti II, unlike those in (Iasses III and IV, differed hemod\,AnalyG5 namicall>, little, if any, from normal. of their data reveals individual cases with low cardiac index and slightly ele\ratcd pulmonar!. capillary pressures. Holmgren,2h although using a different clinical classification and giving no estimation of valve size, also considered his mildly symptomatic patients hemod~~lanlicall~~ normal at rest. None of these bvorkcrs rmplo~-ccl catheterization of the left side of the heart, and hence the mitral valve areas of these patients remain unknown. HEhlODYNAMl(:

(:ONSIDEKAlTONS

()j

Corrrlation &mptoms und Pulmoncq I~usculo~ The striking finding of the present RPsistamr: study was that 10 patients with few symptoms had se\‘ere stenosis as evidenced t)y mitral valve The fact that 17 areas of 1 .O cm?. or less.* patients of the same mildly symptomatic group could t)e matched, in terms of val1.e size (1.5 cm’. or less), with the 18 patients b\-ith C:lass III symptoms permitted A valid coinparison t)etween them. It was lloped that such an analysis might answer the question: Do patients with comparat)le ~211.e areas t)ut \aryiny disat)ility differ clinicall!. or lle~nod~na~~~icall~~’ These two groups did not cliffcr in IIIC’~ lrft atria1 prcysurc. mean mitral diastolic pressure cardiac index nor left \,cntricular gradient. Likelvisc, heart rate, end-diastolic pressure.. rhythm and lnitral lra1i.e flow showed no differences. Division of these patients t)), clinical criteria into (Jassrs I and II on the one hand, and C:lass III on the other, did, however. ha\~ its hemodynamic parallel. The mean \,alucs ful pulmonaty arterial pressure, pulmonar)~ arteriolar resistance and total pulmonary. resistance ~vcre sie;nificantly hi,yher in Class III than in the CIass I and II patients (Fig. 4). Thus, while there was no difference I)ct\veen the two groups in the degree of ot)struction at the mitral valve, the primar) t)lock, the>differed in the degree of ot)struction at the pulmonary- vascular level. This relationship suggests that it is this st~cont10r~~ block that is associated with tile disatjling symptoms of mitral stenosis. Furthermore, it sheds some light rIpon the rclationship t,ct\veen mitral val\rc area and pulmonary vascular resistance, w1Gch has remained controversial. \,t’hilc C~:forlin’7~2!’ founct a loqa-

ct al. rithmic relationship, C:arman and associates:“) and Arau,jo and Lukas?” disclaimed any ut)ligatory relationship. The latter group actual11 challenged the concept of an increased pulmonar) vascular resistance performing an active protective function in mitral stenosis. The present data indicate that if any relationship between mitral valve area and pulmonar) \,ascular resistance exists, it may be biased t)b the relative proportion of symptomatic (Class III) to as)mptomatic (Classes I and II) patients present in any given series. This series confirms the findings of others”,“’ that symptoms may relate in a direct fashion to the degree of mitral stenosis, provided increased pulmonary vascular resistance is present. However, the present data also suggest that rherr must be many patients with severe mitral stenosis without such secondary t Jock and, therefore, bith few if any s)-mptoms. Huno, appearing only during exertion or other stres<. Thus, when the physiolo+c data fail to diffcrc.ntiate t)etwcen patients \vith cquat valve areas t jut with symptoms diRering in severity, the question presents itself: \Yould hemodynamic 0t)scrvations during csercise allow this cliffert7itiation:’ .\ few reports deal with this question.‘“,“,“” Irl these the accent has tIeen placed on the tlcmodynamic findings rather than on the correlation of these findings with the clinical symptoms. \Vade and co-workerP found that, although r-csponse to exercise is normal in Class 1 patients, cardiac index and stroke volume may not rise in the Class II patient as much as in a normal individual. Eliasch?’ has shown that duringL rxcrcisc pulmonary capillary pressure and pulmonar). arterial pressure indemay alter pendently, and consequently the pulmonar) artcriolar resistance may actually decrease. Adequate exercise studies could not be pcrformed in the present series in which the transdorsal technic was used. It appeared of interest to analyze 8 of the 26 patients in Classes I and II who had shown increased disat)i!ity during a past period of increased hemodynamic stress experienced during infection, metabolic disorders or anemia. As a group, these 8 patients differed from thei] counterparts in Classes I and II: They had a s~nallcr mitral valve arca (1 .?I 215. 1.6 cm?.), ‘I’IIh

AMERICt\N

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Mitral higher mean values for left atria1 pressure (18 US. 14 mm. Hg) and mitral valve gradient (10 ~1s. 8 mm. Hg) and a lower cardiac index (2.77 US. 2.98 L. ;min./M2.). Most remarkable was the high incidence of atria1 fibrillation (627’). These data were practically identical to those obtained in the 17 patients in Classes I and II, Here whose valve areas were 1.5 cm2. or less. the incidence of atria1 fibrillation, however, was lower (35Oj,). On the other hand, when compared to the Class III patients (mean mitral valve area 0.9 cm2., mean left atria1 pressure 19 mm. Hg, and mean mitral diastolic pressure gradient 13 mm. Hg), they proved not to have as extreme values. Only the frequency of atria1 fibrillation was identical and cardiac index was equally low. Thus, the history of temporary worsening with definite change toward Class III symptoms could indicate the presence of significant narrowing of the valve, and therefore would seem helpful in predicting the severity of mitral stenosis. On the other hand, these criteria were not infallible, since no such history could he obtained from 8 of the 17 patients in Classes I and II with a mitral valve area of less than 1.5 cm?. Thus the clinical response to hemodynamic stress, although physiologically perhaps the most ideal exercise test, appears not as informative as was hoped. Further studies are needed on the hemodynamic response to exercise in the patient with mitral stenosis and mild symptoms. In this regard, it is of interest that the electrocardiographic axis bore a relationship to the degree of mitral valve obstruction. Rightward displacement of the mean frontal plane QRS axis, reported by others21,23 as occurring in mitral stenosis associated with increased pulmonary vascular resistance, in this series was found even in the absence of such elevated secondar)- block. Thus the electrocardiogram may he a more sensitive indicator of chronic right ventricular overload than hemodynamic studies at rest. ADAPTIVE

MECHANISMS

Role of Decreased Cardiac Output: Mitral stenosis is usually thought to be accompanied by a decreased cardiac output.31 This has been well substantiated in severely symptomatic patients.18 J6 tz7 On the other (Class III, Iv) hand, the mildly symptomatic patients (Class I and II) were found to be hemodynamically near normal.2x However, the present data indicate that low cardiac output remains the DECEMBER

1962

Stenosis hallmark of significant mitral stenosis regardless of the severity of symptoms and degree of disability (Fig. 3C). Specifically, the 17 patients in Classes I and II with mitral valve areas of 1.5 cm’. or less showed a mean cardiac index of 2.81 L. min.,‘M2., a value significantly lower than the nortnal (3.6 L.,/min./M2., p < 0.01). In fact, the cardiac output of this group was identical to that of patients in Class III with comparable valve areas (Fig. 3C, Table I). This observation, made during left heart catheterization I))- the indicator-dilution method, applied equally well to the outputs obtained by the Fick method during right heart catheterization. Sel.eral mechanisms have been postulated to explain the decreased cardiac output of patients with mitral stenosis.3nB3’ An inverse relationship between pulmonary vascular resistance and cardiac index was described by Lewis,lR while Araujo2” and Semler and co-workers”? found that, during rest and exercise, variable responses in cardiac output and pulmonary vascular resistance occurred. The present data indicate that pulmonary vascular resistance is not the prime factor effecting a decrease in cardiac output. Two populations, clearly separable by virtue of normal (Class I and II) and elevated (Class III) pulmonary vascular resistance (Fig. 4B), have virtually identical cardiac outputs (Fig. 3C). Harvey and co-workers33 have attributed the decreased cardiac output in some patients with mitral stenosis to myocardial failure. Fleming and Wood”” postulated a myocardial factor as the reason for a decreased cardiac output in 24 of their 750 cases with mitral stenosis. In none of these 24 patients was pulmonary vascular resistance or pulmonary wedge pressure elevated significantly. However, none of these investigators reported left ventricular end-diastolic pressures, since nearly all of their data were based on studies made on the right side of the heart. The present report indicates that such a decreased cardiac output may occur in the absence of an elevated ventricular end-diastolic pressure. Atria1 fibrillation has been postulated to affect cardiac output adverscly.35s36 Although there was a tendency for atria1 fibrillation to be associated with the lower cardiac outputs (Table I), its occurrence among subjects with higher outputs, and the presence of low flows in the absence of fibrillation indicate that this arrhythmia is not the major determinant of decreased cardiac output.

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It appears, then, that the fall in cardiac output is primarily dependent upon obstruction at the mitral valve, as shown l)y the correlation in Figure 1D. -Any relation to the parameter3 Itlcntioned al)o\,e, such as rate, rhythm, m>ocardiai factors and clcvatrd pulmonary vascular rcsiytante, appears to exist primaril>to the exWnt that these parameters arc related (0 ttics size of the mitral orificr. (barman and Lange”’ most rcccntl\rcpurtctl 4 patients \vith significant mitral stenosis, lob cardiac output and normal pulmonary arterial and wedge pressures. Their data also permit attril)utiun of lhc low cardiac output to tllc ol)structioti at the mitral valve itself. Carrliac~ Oul)ut

and

Regulatory

Roll

“1

bft

,4trium:

The search for the exact mcchanisnl that lowers cardiac output continues. It is possible that the control of cardiac output is the result of a complex function of the factors mentioned”‘j or of other influences such as the prexsure or wall tension in the left atrium ur pulmonary veins.“” \Yolumr receptors ha\:e ~CWI demonstrated in the left atria1 wall.“Y l’ In acute experiments, an incrcasc itt urinary- ilo\\ and, presumat)ly a dccrcase in circulatory vulume, has been observed when the Irft atria1 \vall In this was distended 1)~ a variety of maneuvers. study no significant correlation t)et\\-ten cardiac was c\.idcnt. index and left atria1 prcssurc This would t)e the expected result, howrvcr, if left atria1 pressure was successfully controlling cardiac output.J’ On the other hand. Donald and associates&” found that the dvcrcased cardiac output in severe mitral stenosis did not return successful \.alvotom\.. normal following to The present evidence neither confirms t& rejects the possibility of a regulatory role of l)aro- or stretch-receptors in the left atrium. The decrease in cardiac output was olwrvcd in our patients early in the discasc, ljcfore the advent of serious symptoms: thus, it ma>’ well 1~ an early adaptive response to anatomic narrow:Such a rcsponsc is ing of the mitral \,alvc. protective inasmuch as it pre\YnLs left atria1 pressure frown rising to critical levels wlicre pulThe cxtcnt to monary edema might ensue. which a given patient responds with? and adapts to, a decreased cardiac output ma) well 1~ a major determinant of the severity of symptoms and the extent of disability. SUMMARY The pathophysiology reassessed, with special

of mitral stenosis is emphasis upon relation

et al. of physiologic variables to severity of symptoms and degree of disability. Data from 44 patients with pure mitral stenosis are presented. CJathctcrization of the left side of the heart was peri’ormed in all and catheterization of the riallt side of the heart in 25 patients. Twenty-six patients were in (:lass I or t t (:\merican Heart Association Functional C:lassification) with mild symptoms or none at all, while 18 patients were in Class III with sevrrt ~;!lllptorlls;. As expected, inverse relationships existed i,ctwcen left atria1 pressure and mitral valve area ir = - 0.618), pulmonary arlerial prrssurc and mitral valve area (r = -0.575), and l)et\\‘een mean mitral diastolic pressure gradient and tnitral valve area (r = -0.708). There relationship between cardiac \%.a< a positive index and mitral valve area (r = +0.407). :I11 correlation coefficients were significant to tlI( 1 per cent level. Seventeen of the 26 patients in C:lasses I and II had mitral valve areas of 1.5 cm?. or less. ‘lXis indicates that severe mitral stenosis can I)e found in a nearly asymptomatic state. ALL of the 18 1:lass III patients had val\-e areas uf less These two groups of patients than 1 .5 cm’. with similar degree of valve narrowing were compared. C:ardiac output was significantl) (p < 0.01) reduced in tjoth categories (2.81 1,. min. M’. for CXasses I and II. and 2.82 I,. min. MS. for class III patientsj. Left atria1 pressure in the two groups, 18 and 19 mm. Hg, respectively, and tnean diastolic pressure gracticnt, 11 and 13 mm. Hg, respectively, did not show si@icant differences. Ho\yever, pullnonar! arterial pressure, 22 mm. Hg in <:lasses I and II and 36 mm. Hg in Glass III, as well as pulmonaq arteriolar resistance, 105 compared to 425 dynes sec. cm. -$, did allow a hemodynamic distinction t,etwet’n the two clinically different group”. These data suggest that the degre-ee of pulmonary \,ascular disease is an important d~*tcrtninant of the symptoms of mitral stenosib. 1‘‘01 Class t and II patkents, history, physical examination and radiographic studies did not allow an accurate prediction of the mitral valve size. It is suggested that one of the earliest adaptive mechanisms to mitral blockade is a decrease in cardiac output and that this is not mediated, initially, through an elevated pulmonary vascular resistance, myocardial failure or atria1 fibrillation. It is one of the means 1,); which a

THE AMERICANJOURNALOF CARDIOLOG’,

Mitral patient with severe stenosis of the mitral valve may remain asymptomatic for prolonged periods of time. kRNOWLEDGMENT \Vr gratefully

acknowledge the assistance of Drs. G. Katznclson, R. M. Jreissaty and W. B. Lrbowitz with some of thr studies and are indebted to Dr. 1.. B. Ellis for rrviewing the manuscript. Mary Collins, R. N.. the Misses Fclicitas Honegger and Margaret Hale, and Mrs. Fayr Alpert gave valuable technical assistance.

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&IL. .I. L).. KOPELMAN, H. and \vl,rtt.~n~. .\. C:. Circulatory chanqs in mitral stenosis at rest and on cxcrcisc. Rrit. Hart .I.. 14: 363, 1952. SEMLER, H. .I.. SHEPIIERU. .I. T. and \Voou. I;. H. The role of the vcssvl tone in maintaining pulmonary vascular resistance in patients with mitral stenosis. C.‘ircuintim. 19: 386. 1959. HARVEY. Ii. N. ct al. Mrchanical and m)ocardial factors in rheumatic hrart disrasr with mitral stc.nosis. C’midutim. 11 : 531. 1955. FI INNO. H. A. and \Z’OOIL P. ‘l’hr myocat-dial f,ictar in mitral \.al\r disrast,. Ijtir. Hml,t .I.. 31: 117. 1959. SEr ZER. .I. Wrcts of atria1 fibrillation upon thv circrtlation in patients with mitral strnosis. :I II,. lhr/ ./.. 59: 518. 1960.

?t

al.

dynamic patterns in mitral stmosis. Circulation. 24: 712, 1961. 38. PAIWI..AI., .4. S. A study of right and lrft atria1 rr./. Phyml., 120: 596, 1953. rcptors. 3’). \Yi:Lr. I,. G. Volumr wcrptors. 1 n : Symposium on salt and watc‘r mctaholism. Circ/rlrIlzorr. 2 1 : 1 OIJ2. 1960. 40. HPNRY. .I. P.. GAUER, 0. H. and KIXVI..S. .I. I,. tCvidrnct, of the atria1 location of receptors inHucncing urine Hwv. C’ircdrttwnRPS., 4: 85, 1956. 41. HE&R>., .I. P. and PP:.~R(:~. .I. \V. Possiblr rolr of cardiac atrial stretch rt‘ccptors in induction of changrs in urine flow. .I. Phwiol., 131 : 572. 1956. 42. H.wn\., F. .I.. r~/ N/. Cardiac function in exprrimental mitral stc.nosis. (.‘itcduI~or~ Ri.\.. 1 : 21 9, 1953. 43. l)m~\m, K. \\‘.. HISHOP. .I. M., \~ADE. 0. I>. and \\~oRM&I.o. f’. N. Cardiorrspiratory function 2 vrars after mitral \alrutomy. ~.‘/;,I. .\i.. 16: 325. 1’157.

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