Pathogenesis of Senile Atrio-ventricular Valves · Pathogenesis of"Senile" Nodular Sclerosis of...

Brit. Heart J., 1966, 28, 815.

Pathogenesis of "Senile" Nodular Sclerosis ofAtrio-ventricular Valves

ARIELA POMERANCE*

From the Department of Histopathology, Central Middlesex Hospital, London N. W. 10

Nodular thickening of the atrio-ventricular valvesmay be conspicuous in the hearts of the elderly.Usually described as senile sclerosis, it is assumedto be an involutional or degenerative processassociated with advanced age. The difficulty of dis-tinguishing such changes from the results of otherpathological conditions which may have beenpresent earlier in life is well recognized (Gould,1960), and some workers attribute these changes toprocesses other than simple ageing. Robbins (1962)included senile sclerosis as a facet of arterioscleroticheart disease; Rezek and Millard (1963) consideredit was due to previous non-specific endocarditis; andAngrist (1964) thought both these processes playeda part. In the present study, necropsy material from815 patients was examined in an attempt to evaluatethe possible roles of inflammation, ageing, atheroma,hypertension, and cardiac hypertrophy in thepathogenesis ofnodular sclerosis.

SUBJECTS AND METHODSOver a period of 2j years the hearts of all patients over

10 years coming to necropsy in this hospital wereexamined in detail before fixation. Particular attentionwas paid to the site, degree and nature of valvularthickening, lipoid infiltrations, scarring, and calci-fication. Hearts with other macroscopical pathology ofthe atrio-ventricular valves were excluded from thepresent study.

Thickening of the atrio-ventricular valves was gradedas absent, slight, moderate, or marked (Fig. 1), byinspection and palpation; and lipoid deposition (athero-matosis) in the anterior cusp of the mitral valve similarlywas graded visually. All observations were made by thesame observer and the results were reproducible whilethe hearts remained unfixed. No reliable macroscopicalassessment of thickening could be made on fixed valves.

Received January 11, 1966.*In receipt of a grant from the North West Metropolitan

Regional Hospital Board.815

The hearts from all patients under 30 or over 80 yearswere fixed in formol-saline, together with representativesamples of each intermediate age-group, and materialwas selected for microscopy after 5-15 days of formalinfixation. This included at least one block through eachcusp of the atrio-ventricular valves, with adjacenttissues. Sections were stained with hematoxylin andeosin, and Weigert's elastic-van Gieson method. Heartweight, estimations of the degree of coronary and aorticatheroma, and details of pathological findings in othersystems were obtained as part of the normal necropsyroutine, and clinical data were abstracted from casenotes. All observations and information were recordedon a punch-card system.

RESULTSThere were 815 hearts which were suitable for

inclusion in this study. The age and sex distri-bution is shown in Table I.

TABLE IAGE AND SEX DISTRIBUTION OF 815 HEARTS

EXAMINED

Age-group 0-15 15-24 25-34 35-44 45-54 55-64 65-74 75-84 85-94(yr.) _____________________

Men 1 3 8 13 38 84 100 114 59Women 0 2 3 19 35 65 75 118 78

Total 1 5 11 32 73 149 175 232 137

Pathology. All adult mitral valves showed at leasta slight degree of nodular thickening of the anteriorcusp. The earliest lesion consisted of localizedplaques on the atrial surface, over the insertions ofthe chordae tendinee. With increasing severitythese plaques increased in thickness and area,eventually coalescing (Fig. 1), but remained con-fined to the zone of apposition of the cusp. Thetricuspid valve was uniformly thin and translucent(Fig. 1) in the majority of patients under 55 years,and remained so in 20 per cent of those over 85

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FIG. 1 -Transilluminated anterior cusps of atrio-ventricular valves, to show grades of nodular thickening.( x 1 approx.). Top left-a thin translucent tricuspid cusp from a woman aged 68 with systemic hypertensionfor 10 years, and normal respiratory system. Top right-slight nodular thickening over the chordae tendinewinsertions of a mitral cusp. The more proximal opacities are areas of atheromatosis. From a woman aged 49with acromegaly and severe hypertension; the heart weighed 900 g. Bottom left-moderate nodular thickeningof mitral cusp. From a woman aged 67 without cardiac or respiratory disease. Bottom right-marked nodularthickening of mitral cusp. Although confluent, the plaques are limited to the zone of apposition with the

posterior cusp. From a man aged 53 with pulmonary fibrosis, emphysema and bronchiectasis.

years. Nodular thickening involved mainly theanterior cusp of this valve also, and developed as inthe mitral valve.

Microscopically, the plaques consisted of localizedfoci of collagenous thickening (Fig. 2) in the endo-cardium of the atrial surface (atrialis), with variablebut mainly scanty fine elastic fibrils. The normallywell-defined elastic lamina at the base of the atrialisoften showed localized fraying or fragmentationunder the collagenous plaques. Active endothelialdamage was not seen, neither was there any evi-dence of old or recent inflammatory changes. The

layers of the cusp retained their anatomical re-lations, no vessels were seen, and there was noinflammatory cell infiltration. Lipoid infiltrationwas occasionally seen but only in the oldest patients,and always on the ventricular aspect of the cusp. Nolipoid was demonstrated in the thickened plaquesof the atrial surface.

Relation of Nodular Thickening to Ageing. Thisdiffered in each sex and in mitral and tricuspidvalves, but very little progressive thickeningoccurred in the oldest groups. In men, mitral valve

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Pathogenesis of "Senile" Nodular Sclerosis of Atrio-ventricular Valves

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FIG. 2. Top-Section through an area of slight nodular thickening, showing the collagenous plaque in theatrialis and fraying of the underlying elastic lamina. (Weigert's Elastic-van Gieson. x 40). Bottom-Higher

magnification ( x 75) of elastic fragmentation underlying a plaque of nodular thickening.

thickening increased with age, but most of thisoccurred in the under 65-year groups (Fig. 3).Tricuspid valve thickening also showed a similarincrease during middle age, continuing through the65-74 year group.In women, the tricuspid valve changes with age

were similar to those in men, though women under3G

45 years had a greater incidence of moderate andmarked thickening than those between 45 and 54years. The mitral valve changes were not related toage. The highest proportions of moderate andmarked thickening were seen in the 65- to 74-yeargroup, but these differed only slightly from those inwomen under 45 or over 85 years (Fig. 4).

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Nodular thickening (Tricuspid)Females

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45-54 55-64 65-74 75-84 85-94(years)

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Nodular thickening ( Mitral )females

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Under 45 45-54 55-64Age-group (years)

65-74 75-84 85-94

FIG. 3.-Relation between age and degree of mitral andtricuspid valve thickening in men.

Normal Ageing Changes. From the above resultsit is possible to define a standard for the normalappearances of the atrio-ventricular valves in theaged. Gavey's (1949) criteria for normal heartvalves in any age-group as "the least degree ofchange observed in that group" has been applied.As 44 per cent of hearts, even in the over 85-yeargroup, had only slight mitral valve thickening, andtricuspid thickening was absent in 20 per cent, thenormal mitral valve should, therefore, show only

FIG. 4.-Relation between age and degree of mitral and tri-cuspid valve thickening in women.

slight nodular sclerosis, even in the elderly, and thenormal tricuspid valve none. These findings agree

with Gavey's, and with those of Rosenthal andFeigin (1947), who were also studying mitral valvechanges with no pre-existing standard for normalvalvular thickening.

Relation of Nodular Thickening to SystemicHypertension and Other Hyperkinetic States. Diff-erences noted between the valves of each side of theheart (Robbins, 1962; McMillan and Lev, 1964)

'LE IIRELATION OF NODULAR THICKENING OF THE ANTERIOR MITRAL CUSP AND SYSTEMIC HYPERTENSION

Degree of All cases Men Womenthickening Hypertensive Not hypertensive Hypertensive Not hypertensive Hypertensive Not hypertensive

Slight 41 (41%) 312 (47-5%,o) 21 (52%) 185 (52%) 20 (33%) 128 (42%)Moderate 38 (38%) 241 (37-50/) 11 (28%) 120 (35%) 27 (45%) 121 (40%)Marked 21 (21%) 100 (15%) 8 (20%) 47 (13%) 13 (22%) 54 (18%)

X2 = 2-75; n = 2; p > 0-2 (not significant)After standardization for age and sexx2=1 24;andp>05

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suggested that excessive thickening might be de-termined by hypertension. Comparison of mitralvalves in patients with and without systemic hyper-tension showed an increased incidence of markednodular thickening in the hypertensives, par-ticularly in men (Table II). This difference was notstatistically significant, however, confirming theimpression obtained from observations on indi-vidual patients (e.g. Fig. 1 top), that systemichypertension did not influence the degree of mitralsclerosis.As the intensity of the first heart sound is an

indication of the force with which the atrio-ventric-ular cusps appose (Wood, 1962), the degree ofmitral valve thickening in some conditions associ-ated with an increased first sound was examined.The three thyrotoxic patients showed one exampleeach of slight, moderate, and marked thickening.Anzmia, pyrexia, exertion, and emotional excite-ment had been present for too brief a time to haveaffected the valves. The altered haemodynamics ofpregnancy are maintained for long enough to meritinvestigation, but, though the only woman under 35years with marked nodular sclerosis had five chil-dren, there was no excess of women with three or

more children in the marked mitral thickeninggroup (8%, compared with 12% of those withslight and moderate thickening).

Relation of Nodular Thickening to Chronic Pul-monary Disease. Quantitative studies of pulmonaryvascular pressure were not practicable in thisseries, but comparison of the anterior tricuspid cuspchanges in patients with and without chronic pul-monary disease showed a highly significant increasein thickening in the former group. This was stillpresent after standardization for age and sex (TableIII and Fig. 5). Since almost all the 84 cases were

patients with chronic bronchitis, and right ventri-cular hypertrophy at necropsy, it seemed likely thatthe increased tricuspid thickening was related topulmonary hypertension.

'~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.

FIG. 5.-Transilluminated anterior cusp of a tricuspid valveshowing conspicuous nodular thickening, from a woman aged

56 with bronchial asthma. (x 1 approx.).

Correlation Between Nodular Thickening of Mitraland Tricuspid Valves. Comparison of the degree oftricuspid thickening present in cases with and with-out marked mitral thickening showed an almostthreefold increase in marked tricuspid thickening inthe former group (Table IV). This was no longerapparent when the cases of chronic pulmonarydisease were excluded, and it therefore appearedlikely that the degree of mitral thickening, as well astricuspid thickening, might be related to pulmonarydisease. Comparison of mitral valve changes in

TABLE IVCOMPARISON OF DEGREE OF NODULAR THICKENINGOF ANTERIOR TRICUSPID CUSP IN PATIENTS WITHAND WITHOUT MARKED MITRAL THICKENING

Degree of Marked mitral Remaining patientstricuspid thickeningthickening

None 21(21%) 268 (39%)Slight 28 (27%) 219 (32%)Moderate 25 (24%) 128 (19%)Marked 29 (28%) 70 (10%)

TABLE IIIRELATION BETWEEN NODULAR THICKENING OF THE ANTERIOR TRICUSPID CUSP AND CHRONIC PULMONARY

DISEASE

Degree of All cases Men Womenthickening

Chronic pulmonary Others Chronic pulmonary Others Chronic pulmonary Othersdisease disease disease

None 15 (18%) 270 (39%) 12 (19%/) 139 (42%) 3 (15%) 131 (36%)Slight 17 (20%' ) 228 (33%) 11(17%) 99 (30%) 6 (30%) 129 (35%)Moderate 25 (30%) 127 (18%) 20 (31%) 60 (18%) 5 (25%/) 67 (19%)Marked 27 (32%) 71 (10%) 21(33%) 35 (10%) 6 (30%) 36 (10%)

x2=60-60; n= 3; p= <0 001After standardization for age and sexx2=24 95; and p is still <0-001

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TABLE VRELATION BETWEEN NODULAR THICKENING OF THEANTEROIR MITRAL CUSP AND CHRONIC PULMONARY

DISEASE

Degree of mitral Chronic pulmonary Remaining patientsnodular thickening disease patients

Slight 31 (34%) 323 (50%)Moderate 40 (43%) 226 (35%)Marked 21 (23%) 99 (15%)

x2 =8-87 n=2 and p= <0-02After standardization for age and sexx2 = 7-74 and p remains < 0-02

patients with and without chronic pulmonarydisease confirmed this (Table V), and the corre-

lation remained statistically significant after stand-ardization for age and sex.

Relation of Nodular Thickening to Heart Size. Thepossibility that the severity of valvular thickeningwas merely an expression of generalized cardiachypertrophy or atrophy from any cause was ex-

amined. There was no difference in the incidence ofeach degree of nodular thickening in hearts weighingunder 300 g. (Table VI), but a considerable excess ofcases with moderate and marked mitral thickeningin those over 450 g. (Table VII). However, afterstandardization for age and sex, this correlation wasnot significant.

Relation of Nodular Thickening to Atheroma. Theblood vessels of the atrio-ventricular valves arisefrom the coronary arteries (Clarke, 1965), and ifnodular sclerosis is a manifestation of athero-

TABLE VIII

RELATION BETWEEN NODULAR THICKENING OFANTERIOR MITRAL CUSP AND MYOCARDIAL

INFARCTION

Degree of Myocardial No myocardialthickening infarction infarction

Slight 56 (46%) 298 (46 5%)Moderate 47 (38-50/,%) 236 (37%,'0)Marked 19 (15-5%) 105 (16-5%)

sclerosis, a correlation with the degree of coronaryatherosclerosis should be present. Comparison ofthe degree of nodular thickening of the mitral valvein patients with and without myocardial infarctionshowed no differences (Table VIHI), and com-parison of the degrees of coronary atherosclerosis in

TABLE IXCOMPARISON OF DEGREE OF CORONARY ATHEROMAIN PATIENTS WITH AND WITHOUT MARKED THICK-

ENING OF ANTERIOR MITRAL CUSP

Degree of Marked mitral Remaining patientscoronary atheroma thickening

None or slight 43 (44%) 218 (43%)Moderate 33 (33%) 175 (35%)Marked 23 (23%) 113 (22%)

patients with marked mitral valve thickening andthose with moderate and slight thickening (TableIX) also failed to show any relation. This is notsurprising, since the part of the valve affected bynodular sclerosis is normally avascular (Clarke,

LE VIRELATION BETWEEN NODULAR THICKENING OF ANTERIOR MITRAL CUSP AND HEART WEIGHT, IN SMALL

HEARTS

Degree of All cases Men Womenthicke ming I-__

< 300 g. Remaining < 300 g. Remaining < 300 g. Remaininghearts hearts hearts

Slight 82 (48%) 264 (47%) 27 (44%) 174 (53%) 55 (50%01) 90 (37%)Moderate 62 (36-5%) 215 (37%) 27 (440) 108 (33%) 35 (33%) 107 (43%)Marked 26 (15-5%) 94 (16%) 7 (12%) 45 (14%) 19 (17%) 49 (20%)

TABLE VIIRELATION BETWEEN NODULAR THICKENING OF ANTERIOR MITRAL CUSP AND HEART WEIGHT, IN LARGE

HEARTS

Degree of All cases Men Womenthickening

> 450 g. Remaining hearts > 450 g. Remaining hearts > 450 g. Remaining hearts

Slight 59 (40%) 285 (49%) 49 (49%) 155 (55-5%') 18 (28-5%) 134 (43%)Moderate 57 (38%/o) 211 (36%,') 37 (37%) 89 (32-5%) 20 (41%) 128 (40%O)Marked 34 (22%) 86 (15%) 19 (19%) 35 (12%) 16 (30 5%) 54 (17%)

x2 =952; n=2;p= < 0-01; but afterstandardization for age and sexx =494;andp=>005

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1965). Although there was no correlation betweennodular thickening and coronary disease, thereappeared to be an association with the degree oflipoid infiltration (atheromatosis) of the proximalpart of the ventricular surface of the cusp (Table X).Patients with marked mitral nodular sclerosis alsohad an increased incidence of marked mitral athero-matosis, and this was statistically significant afterstandardization for age and sex.

TABLE XCOMPARISON OF DEGREE OF MITRAL

ATHEROMATOSIS IN PATIENTS WITH AND WITHOUTMARKED THICKENING OF ANTERIOR MITRAL CUSP

Degree Marked mitral thickening Remainingof mitral patients

atheromatosis

None or alight 22 (21 %,h) 264 (42%)Moderate 60 (58%) 302 (49%)Marked 22 (21%) 59 (9%)

x2= 190; n=2; p= <0-001After standardization for ageAnd sex x2= 13-95; and p re-mains < 0-001

DISCUSSIONThe findings in the present study do not support

views that "senile" sclerosis of atrio-ventricularvalves is due to previous inflammation, athero-sclerosis, or involutionary changes; they confirmthe suggestion by McMillan and Lev (1964) thatnormal valve movement is responsible for thenodular thickenings.Although post-inflammatory deformities are

more common on the left side (Lepeschkin, 1952),like nodular sclerosis, and the localization of endo-carditis on the line of valve closure is also de-termined by heemodynamic factors (Rodbard,1963; Lepeschkin, 1952), there was no histologicalevidence of previous endocarditis in the plaques ofnodular sclerosis. These appeared to be a pro-liferative thickening localized to the atrialis, theanatomical layers remained distinct, and there wasno associated vascularization or inflammatory cellinfiltration. They did not contain lipoid or showcalcification, as would be expected in athero-sclerotic lesions, and were not related to coronaryatherosclerosis. Since the impact on closing issufficiently forceful to be audible as the first heartsound (Dock, 1945), the histological demonstrationof localized damage to elastica (Fig. 2) at sites ofgreatest tension (i.e. over the chordx tendineseinsertions) is not surprising. McMillan and Lev(1964) thought that the plaques were due to tensingof the chordse resulting in elastic proliferationopposite their insertions, but elastic proliferation

was not a striking finding in the present series. Theauthor considers that these plaques are a responseto repeated trauma, analogous to cutaneous callusformation.The observations on changes in nodular sclerosis

with age indicate that "senile sclerosis" is a mis-leading term since the abnormal degree of thicken-ing generally implied by this description is aslikely to be found in a middle-aged patient as in asenile one, and the slight degree of nodularity whichis normal in the aged was also present in all patientsover 20 years. If involutionary changes are re-sponsible for excessive nodular thickening, thiscondition should continue to develop in the elderlyat least at the same rate as in middle age, and thefinding that very little progressive increase inseverity occurred in the older groups thereforeindicates that senility is not responsible for " senile"valvular sclerosis.The pathogenesis of excessive nodular thickening

is not clear. It is possible that the increase through-out middle age is the result of cumulativemechanical stress, and the lack of further develop-ment in old age is due to the chemical changes invalve collagen which occur in the elderly (Verzarand Thoenen 1960; Angrist, 1964). However, thewide range in degrees of thickening between peopleof the same age-group indicates that individuallyvariable factors must be concerned. A similar un-explained variability has been noted in monkeys(Lapin and Yakovleva, 1963). The importance ofgenetic factors in determining life span and cardio-vascular disease is well known, and the reactivity ofthe valve endocardium may also be geneticallydetermined. It was not possible to test this hypo-thesis in the present investigation.The changes in degree of nodular thickening with

age in men parallels the changes in blood pressureobserved by Master, Lasser, and Jaffe (1958), andthe differences between the valves of each side of theheart, also observed by previous workers (Robbins,1962; McMillan and Lev, 1964), suggested thatblood pressure might influence the degree ofthickening. The increased incidence of tricuspidthickening in patients dying with chronic chestdisease indicated that this was likely to be so in thepulmonary circulation, and similar tricuspid changesnoted by Dmitrieva (1961) in patients with rheu-matic mitral stenosis or pulmonary fibrosis andemphysema, are confirmatory findings.There was, however, no correlation between

systemic hypertension and the degree of mitral thick-ening, and increased closing force of the mitral valvealso appeared unrelated to increased thickening,though there were too few examples of diseases

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associated with accentuated first heart sounds forreliable assessment. Anamia and pyrexia werecommon but their duration was insufficient to pro-duce valve sclerosis. Cumulative effects from thealtered heemodynamics of pregnancy might haveaccounted for the lack of correlation between ageand degree of thickening found only in mitralvalves in women, but multiparity was not associatedwith increased thickening. The possibility that in-creased valvular sclerosis was a facet of generalizedcardiac hypertrophy was also considered, but noassociation with heart size was found. Most of thehearts over 450 g. were from hypertensive orischtemic heart disease cases, and this finding was,therefore, additional evidence against hypertensionand arteriosclerosis as factors responsible for ex-cessive nodular thickening.As well as the absence of any quantitative or

histological evidence for Robbins' (1962) view, anatherosclerotic pathogenesis for sclerosis of atrio-ventricular valves seems unlikely on anatomicalgrounds, as the relevant part of the valve is avascular(Clarke, 1965). Lipoid deposition does occur in theanterior cusp of the mitral valve but proximally(Fig. 1) and on the ventricular surface. Althoughthere was a significant correlation between theseverity of this condition and mitral valve thicken-ing, it is difficult to envisage a causative relation.Since normal degrees of both conditions appear tobe due to the same hmmodynamic factors (Pom-erance, 1966, 1967), it is more probable that anyfactor increasing their severity acts at both sites.The correlation between mitral and tricuspid

nodular thickening and pulmonary disease suggeststhat this factor may be hypoxia. Severe pulmonarydisease increases the work of both ventricles(Altschule, 1962) and changes in the left side of theheart are, therefore, not as unexpected as might atfirst appear. This increased work is determined byhypoxia (Mack and Snider, 1956), and while geneticvariation in endothelial reactivity cannot be excluded,hypoxia affecting collagen formation is a more pro-bable mechanism. There is experimental support forthis hypothesis in the nodular thickenings inducedin rat heart valves by anoxia (Dalton et al., 1945;Highman and Altland, 1949). These lesions occurredin the distal part of the valve, were most conspic-uous in the mitral valves, and resembled those ofhuman nodular sclerosis, and it is therefore likelythat the pathogenesis is also the same in both species.

SUMMARYThe pathology and pathogenesis of nodular

"senile" sclerosis of the atrio-ventricular valves hasbeen studied.

At least a slight nodularity was found at the line ofclosure of all adult mitral valves. The degree ofthickening increased throughout middle age in bothatrio-ventricular valves, but showed little furtherprogression in the elderly. It differed widely be-tween people of the same age-group, and thenormal appearances, even over 85 years, consistedof slight nodular thickening of the mitral valveonly. The location and histology of the thickenedfoci indicated that they were a response to repeatedimpact, analogous to cutaneous callus formation.There was no associated endocarditis or athero-sclerosis.

Excessive nodular thickening was not related tosenility, systemic hypertension, cardiac hyper-trophy, or multiparity, but chronic pulmonarydisease was associated with a significantly increaseddegree of thickening in both atrio-ventricularvalves.Abnormal degrees of nodular thickening appear

to result from an abnormal response of valvularendothelium. Although genetic factors cannot beexcluded, it is suggested that in man, as in rats,hypoxia is important in the pathogenesis of nodularsclerosis of the atrio-ventricular valves.

I am grateful to Dr. Richard Doll for advice on thestatistical aspects of this investigation, and to Dr.R. A. B. Drury for his continued support and provisionof laboratory facilities. Thanks are also due to the staffof the Histopathology Department for the extra technicalwork involved, to Mr. A. Booker and Miss D. Haglundfor the photography, and to Dr. D. Trevan for thephotomicrography.

REFERENCESAltschule, M. D. (1962). Cor pulmonale: A disease of the

whole heart. Dis. Chest, 41, 398.Angrist, A. (1964). Ageing heart valves and a unitary patho-

logical hypothesis for sclerosis. J. Geront., 19, 135.Clarke, J. A. (1965). An X-ray microscopic study of the blood

supply to the valves of the human heart. Brit. Heart J.,27, 420.

Dalton, A. J., Jones, B. F., Peters, V. B., and Mitchell, E. R.(1945). Organ changes in rats exposed repeatedly tolowered oxygen tension with reduced barometricpressure.J. nat. Cancer Inst., 6, 161.

Dmitrieva, V. S. (1961). Compensatory sclerosis of the cardiacvalves in certain diseases. Tr. Kursk. Med. Inst., 15,369. [Abstracted in Excerpta med. (Amst.), Sect. XVIII,1962,6,727-728.]

Dock, W. (1945). Further evidence for the purely valvularorigin of the first and third heart sounds. Amer. HeartJ'.,30, 332.

Gavey, C. J. (1949). The cardiology of old age. Lancet, 2, 725.Gould, S. E. (1960). Pathology of the Heart, 2nd ed., p. 554.

C. C. Thomas, Springfield, Illinois.Highman, B., and Altland, P. D. (1949). Acclimatization

response and pathologic changes in rats at an altitude of25,000 feet. Arch. Path., 48, 503.

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Lapin, B. A., and Yakovleva, L. A. (1963). Comparative - (1967). Ageing changes in human heart valves. Brit.Pathology in Monkeys, p. 167. C. C. Thomas, Spring- HeartJ'. In the press.field, Illinois. Rezek, P. R., and Millard, M. (1963). Autopsy Pathology,

Lepeschkin, E. (1952). On the relation between the site of p. 260. C. C. Thomas, Springfield, Illinois.valvular involvement in endocarditis and the blood Robbins, S. L. (1962). Textbook of Pathology with Clinicalpressure on resting on the valve. Amer. J. med. Sci., Application, 2nd ed., p. 397. W. B. Saunders, Phil-224, 318. adelphia and London.

Mack, I., and Snider, G. L. (1956). Respiratory insufficiency Rodbard, S. (1963). Blood velocity and endocarditis. Circu-and chronic cor pulmonale. Circulation, 13, 419. lation, 27, 18.

McMillan, J. B., and Lev, M. (1964). The aging heart: II, Rosenthal, J., and Feigin, I. (1947). Pathology of the mitralThe valves. . Geront., 19, 1. valve in the older age groups. Amer. Heart J., 33, 346.

Master, A. M., Lasser, R. P., and Jaffe, H. L. (1958). Blood Verzar, F., and Thoenen, H. (1960). Die Wirkung von Elek-pressure in white people over 65 years of age. Ann. trolyten auf die thermische Kontraktion von Collagen-intern. Med., 48, 284. faden. Gerontologia (Basel), 4, 112.

Pomerance, A. (1966). Atheroma of the mitral valve. J. Wood, P. (1962). Diseases of the Heart and Circulation, 2nd ed.,Atheroscler. Res. In the press. p. 63. Eyre and Spottiswoode, London.



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