Clin. Cardiol. 17, 85-92 (1994)

Clinical Pathologic Correlations

This section edited bv Bruce Wiiller; M.D.

Pathology of Aortic Valve Stenosis and Pure Aortic Regurgitation A Clinical Morphologic Assessment-Part I

BRUCE WALLER, M.D.,*:$ JANE HOWARD, M.D.,t$ STEPHEN FESS, M.D.$$

“Cardiovascular Pathology Registry, St. Vincent Hospital: TNasser. Smith & Pinkerton Cardiology, Inc.; $Shumacker, Isch, Jolly Cardiovascular Surgery: $Indiana Heart Institute, Indianapolis, Indiana, USA

Summary: This two-part article examines the histologic and morphologic basis for stenotic and purely regurgitant aortic valves. Part I discusses stenotic aortic valves and Part II will dis- cuss causes of purely regurgitant aomc valves. In over 95% of stenotic aortic valves, the etiology is one of three types: congen- ital (primarily bicuspid), degenerative, or rheumatic. Other rare causes of stenotic aortic valves include active infective endo- cardi tis, homozygous type 11 hyperlipoproteinemia, and sys- temic lupus erythematosis. The causes of pure aortic regurgita- tion are multiple but can be separated into diseases affecting the valve (normal aorta) (infective endocarditis, congenital bicus- pid. rheumatic, floppy), diseases affecting the walls of aorta (nomial valve) (syphilis, Marfan’s, dissection), disease affect- ing both aorta and valve (abnormal aorta, abnormal valve) (an- kylosing spondylitis), and diseases affecting neither aorta nor valve (normal aorta, normal valve) (ventricular septa1 defect, systemic hypertension). Diseases affecting the aortic valve alone are the most common subgroup of conditions producing pure aortic valve regurgitation.

Key words: aortic valve stenosis, aortic valve regurgitation, bi- cuspid aortic valve, endocarditis, rheumatic heart disease

Introduction

Aortic valve dysfunction can result from structural alteration (congenital or acquired) of the valve or from abnormal function of a ~tructural normal valve (disease of the aorta).’, From an

Address for reprints:

Bruce Waller. M.D. 8403 Harcourt Road Suite 100 Indianapolis, IN 46260, USA

Recened: December 16, 1993 Accepted: December 17, 1993

etiologic standpoint, it is useful to divide aortic valve dysfunc- tion into either stenotic or purely regurgitant types. Most stenot- ic aortic valves are associated with clinical or laboratory evi- dence (auscultation, Doppler echocardiography, angiography) of some element of regurgitation, but by definition pure aortic regurgitation has no element of sten0sis.l. Although clinical- ly and therapeutically useful, knowledge of whether an aortic valve is both stenotic and regurgitant, or which hemodynamic lesion is “dominant,” is less helpful in establishing etiology of the aortic valve dysfunction. Stenotic aortic valves are always anatomically abnormal (fibrous thickening, commissural fusion, calcific deposits) (Fig. 1) and the causes of stenosis are limited to a few conditions. In contrast, purely regurgitant aortic valves may or may not have some anatomic abnormality and the caus- es for pure regurgitation are multiple. With the exception of con- genital causes, stenotic aortic valves usually take years to de- velop, but purely regurgitant aortic valves may develop acutely or chronica1ly.l.’

In a recent survey of operatively excised cardiac valves,3 the aortic valve was the most frequently excised native cardiac valve. Of 2,980 excised valves (2,566 patients), 1,973 (66%) were aortic (Table I). Of the 1,973 aortic valves, 1.797 (91 %) were classified as stenotic (with or without associated regurgi- tation) and 176 (9%) were purely regurgitant (Tables I, II). Ed- wards and colleague^^.^ have evaluated temporal changes in the functional classification of the aortic valve over a 20-year peri- od. There has been a rise in the frequency of operatively excised stenotic aortic valves from 32% in 1965 to 68% in 1985. During the same time period, the frequency of operatively excised pure- ly regurgitant aortic valves declined slightly from 29% in 1965 to 20% in 1985. A similar temporal analysis ofetiology of aor- tic stenosis showed declines in congenitally bicuspid (49% in 1965 to 33% in 1985) and rheumatic (33% in 1965 to 18% in 1985) valves, with a rise in degenerative valves (0 in 1965 to 46% in 1985). With regard to etiology of pure aortic regurgita- tion, declines were seen in rheumatic valves (47 to 9%), and en- docarditis ( 1 1 to 6%), with simultaneous rises in diseases caus- ing aortic root dilation ( 1 9 to 56%) and congenital bicuspid valves ( 17 to 24%) over this 20-year period:.

86 Clin. Cardiol. Vol. 17, February 1994

Rc. 1 calcitic deposits (white material).

Radiographs of operatively excised stenotic aortic valves (congenitally bicuspid, left; degenerative three-cuspid, right) showing heavy

Aortic Stenosis

In patients ages 15 years and older, obstruction of tlie native aortic valve is caused by at least seven etiologies (Tables I-III) (Figs. 2-5): I . Congenital

A. Unicuspid (Figs. 2,6) B. Bicuspid (Figs. I , 2,7) C. Tricuspid D. Quadricuspid

2. Rheumatic (Figs. 2,8)

3. Degenerative (old age, senile, wear and tear, atherosclero- sis) (Figs. 3 ,9) 4. Active infective endocarditis6 (Figs. 3, 10) 5. Homozygous type II hyperlipoproteine~nia~ (Fig. 3) 6. Inborn errors of metabolism

Fabry’s disease8 Ochronosis (alkapton~ria)~

7 . Systemic lupus erythematosisLO Of these etiologies, congenital, rheumatic, and degenerative conditions account for 90% of patients with aortic stenosis (Tables I-IIQS. 11-14

Congenital Aortic Valve Stenosis

Of 1,797 operatively excised stenotic valves (Table II) (Figs. I , 2,7) , 557 ( 3 1 %) were congenitally malformed (unicuspid, TABLE I Functional and morphologic classification of 2,980 opera-

tively excised cardiac valves from 2,566 patients aged >I5 years be- tween December 1962 and December 1992

Lesion Number (%) aortic valves

Stenosis Isolated aortic stenosis (AS) Combined lesions

AS + mitral stenosis (MS)

1036 (58) 761 (42) 758

AS + MS + tricuqpid ytenosis AS + MS + tricuspid regurgitation

2 1

Subtotal 1797(91) Pure regurgitation

lsolated pure aortic regurgitation (AR) 128 (73) Combined lesions 48 (27)

AR + MS 34 AR + mitral regurgitation 14

Subtotal 176 (9) Total 1973 (100)

TABLE I1 Etiology of operatively excised stenotic aortic valves

Etiology Number (8) valves

Isolated aortic stenosis Congenital

Unicuspid Bicuspid Tricuspid Quadricuspid

Degenerative Uncertain

Combined lesions Rheumatic

Total

1036 (58 ) 557 (54)

17 (3) 535 (96)

4(< 1) 1 (< 1 )

472 (46)

761 (42) 761 (100)

1797 ( 100)

7~

B. Waller e/ (11.: Aortic valve stenosis and regurgitation 87

TAHI.I: 111 Etiology of operatively excised stenotic aortic valves

Davies" Subramanianl? Subrammian' ' Petersoni4 Pawk' Wdler' ( 1980) ( 1984) (1985) ( 1985) (1987) ( 1993) Totah (%)

Rheumatic Congenital

( hicuspid) Degenerative Infective endocarditis M i x c d etiology Indeterminate Totals

31 113

(104) 22 0

14 7

I87

130 I92

(171) 38 0 0

14 374

148 57

(40) 0 5 0 3

213

25 54

(53) 30 0 0 0

I09

153 266

216 0 0

1 1 646

(248)

76 I 1248 (38) 557 I239 (37)

(535) ( I15 I ) (93) 472 778 (23) 0 5 (0.2) 0 14 (0.5) 7 42 ( 1.3 )

I797 3326 ( lo())

bicuspid. tricuspid, and quadricuspid) (Table II). Ofthe 557 con- genitally malformed valves, 96 were bicuspid, 3% unicuspid and < 1 % tricuspid or quadricuspid (Table 11). In five previous studies of operatively excised stenotic congenital aortic valves, bicuspid aortic valves accounted for underlying congenital aor- tic valve lesions (in patients aged > I5 years) ranging from

Degenerative

Active infective endocarditis (massive obstructing vegetation)

Congenitally bicuspid c=zz===L-

Congentially unicuspid / r==> ~ A 7

("Exclamation point") (One lateral attachment)

Rheumatic' Severe

1 thickened mitral

FIG. 2 Diagram showing three causes of aortic valve stenosis (see Figs. 3.4).

Homozygous type II hyperlipoproteinemia

Thickened cusps

r

Chronic renal failure (with or without chronic hemodialvsisl Metastatic

calcific deposits

?

FIG. 3 Diagram showing four additional causes of aortic valve steno- sis (see Figs. 2,4).

88 Clin. Cardiol. Vol. 17, February 1994

Rheumatoid arthritis

Discrete subaortic stenosis

FIG. 4 Diagram showing three additional causes of aortic valve stenosis (see Figs. 2 3 ) .

70%13 to 98%14 (average 93%) (Table 111). Of patien& with iso- lated aortic valve stenosis, the configuration of the aortic valve usually can be predicted by age. In patients aged 15 to 65 years, nearly 75% are unicuspid or bicuspid aortic valves iind only 25%) are tricuspid valves.I5 In patients olderthan 65 years, 90% of the stenotic aortic valves are tricuspid.

- Pure re ur itation (Y%Y

:ombin (27%) Pure aortic

re urgitation fn = 176)

Etiology: isolated aortic stenosis

FIG. 5 Diagrnm showing the frequency and etiology of operatively excised aortic valves: aortic valve stenosis.

Etiology: other lesions t aortic stenosis (n = 761)

(n = 1036)

FIG. 6 Operatively excised unicuspid (unicommissural) stenotic aor- tic valves.

Unicuspid Aortic Valve

Two types of congenital unicuspid aortic valves have been described: the dome-shaped orifice (“acommissural” valve) and the eccentrically shaped orifice (“uniconunissud’ valve) (Figs. 2,6, 11). The acommissural or dome-shaped unicuspid valve resembles the type of valve seen in congenital pulmonic steno- sis-a “volcano-like’’ structure with a centrally located oiifice. The unicommissural unicuspid aortic valve has an orificc re- sembling an “exclamation point.” The congenital unicomniis- sural aortic valve occurs in 0.075% of the general population and affects men 9 to 10 times more frequently than wornen?

Unicommissural aortic valves, in contrast to bicuspid aortic valves, are inherently stenotic at birth. Secondary calcification develops between the second and fourth decades which wors- ens the degree of stenosis. Of 1,529 operatively excised stenot- ic aortic valves, only 45 (3%) were uniconimissural (Table 1). Figure 12 illustrates acquired changes in bicuspid and tricuspid aortic valves which make the echocardiographic recognition of congenital unicuspid aortic valves difficult if not impossible.

Bicuspid Aortic Valve

The congenital bicuspid aortic valve is the most frequent in& formation of the aortic valve and the second most common con- genital cardia anomaly in the general population (Figs. I , 2.7). The incidence of bicuspid aortic valve ranges from 0.9 to 2.5%. Of 1,797 operatively excised stenotic valves, S35 (30%) were congenitally bicuspid, and of the 557 excised stenotic valves with congenital etiology, 96% were bicuspid. The bicuspid aor- tic valve exists in two major forms: a right-left and an anterior- posterior orientation of the two cusps. The frequency of each form is about 50%.15 A ruphe or false commissure is recognized in one of the two cusps in about 50% of the valves.I5. l 6 When present, the raphe is always found in the right cusp ofthe right- left variety and in the anterior cusp of the anterior-posterior type. Minor rotations of the commissures of the two basic forms of bicuspid aortic valves account in part for the variable sensitivi- ty and specificity of M-mode and two-dimensional echocardio- graphic detection of congenital bicuspid aortic valves (Fig. 13).

At times echocardiographic visualization of a bicuspid aor- tic valve is difficult to distinguish between the congenital and the acquired forms (Fig. 14). In a bicuspid aortic valve with min-

B. Waller c’t c i l . : Aortic valve stenosis and regurgitation 89

FIG. 7 Several variations of operatively excised congenitally bicuspid aoilic valves.

FIG. X Operatively excised stenotic aoi-tic (upper) and niitral (low- er) viilves from a patient with rheumatic heart disease.

imal or moderate amounts of calcific deposits, distinguishing congenital from acquired bicuspid aortic valves usually can be made from simple cuspal measurements (Fig. 14). The circum- ferential distances between each commissure are about equal in normal tricuspid aortic valves and in congenitally bicuspid valves. With the fusion of one of three commissures (ucquired bicuspid aortic valve), the cusp containing the fused commis- sure is at least twice as long as the remaining commissitral length. In the congenital bicuspid aortic valve, the cusp con- taining the false commissure (raphe) (conjoined cusp) is of sim- ilar length to that of the other cusp. In severely calcified aortic valves, the echocardiographic and anatomic distinction between congenital and acquired forms may not be possible.

Information ofthe natural history of a congenitally bicuspid aortic valve is limited. Based on a series of 85 necropsy patients aged 15-79 years, RobertsiS provided some data on this sub- ject. Of the 85 patients, 61 (72%) had aortic stenosis with or without aortic regurgitation, I I ( 13%) had pure aortic regurgi- tation, 13 (15%) had functionally normal bicuspid valves (Fig. 15). Ofthe 1 I patients with pure aortic regurgitation, 8 (9%) had infective endocarditis as the basis ofthe regurgitation and 3 (4%) had pure regurgitation as an intrinsic complication of the bicus- pid valve. Stenotic bicuspid aortic valves generally contain heavy calcitic deposits at an earlier age (fourth and tilth decades) com- paed with stenotic tricuspid valves (sixth and seventh decades).

90 Clin. Cardiol. Vol. 17. February 1994

FIG. 9 Thrcc operatively excised stenotic aortic valves "degerative i n ctiology.

FIG. 10 Top and bottom views of an operatively excised stenotic :lor- tic valve with active infective endocarditia.

Rheumatic Aortic Valve Stenosis Congenital Acquired variants

Rhcuinatic aortic valve stenosis in this study is defined by the associated presence of an anatomically abnormal mitlal valve (diffuse leaflet or margin of closure fibrosis, usually stenotic) and an aortic valve characterized by commissural fusion of at least one and generally two or three commissures (Figs. 2,8). The clilssic stenotic aortic valve of rheumatic etiology has se-

Unicommissural 8 unicuspid

Congenital

Conaenital a@ bicusmd

4 t h acquired' commissural

fusion

Tricuspid valve with acquired fusion of two

of three commissures

Acquired variant

Congenital Tricuspid valve with bicuspid acquired fusion of one

("Volcano," no ("Exclamation point," of three comrnissures ' I I

Dome Unicommissural

lateral attachments) one lateral attachment) FIG. 12 Diagram showing comparison of congenital unicuspid and bicuspid aortic valves with acquired variants showing difficulties in echocardiographic distinction.

FIG. 1 1 aortic valvcs. From Ref. 1 with permission.

Dingrani showing the two types ofcongenitally unicuspid

B. Waller et ~ 1 . : Aortic valve stenosis and regurgitation 91

Right-left cusps

Fused comrniss

R Anterior

Anterior-posterior cusps

FIG. I3 Diagram showing rotational variations of the two types of congenitally bicuspid aortic valves: right-left cusps; anterior-posteri- or cusps. The “false-commissure” of raphe is indicated by an ‘mow. From Ref. I with pemiission.

vere fusion of all three commissures producing a central trian- gular-shaped orifice.

Of 1,797 operatively excised stenotic aortic valves, rheumat- ic etiology accounted for 76 1 (42%) (Tables I, III). In other stud- ies, rheumatic etiology varied from 17%” to 69%113 (average 38%) (Table 111). Differences in frequency primarily are relat- ed to various definitions of rheumatic aortic disease (history of rheumatic fever only, commissural fusion only, required pres- ence of m i d stenosis, isolated aortic stenosis).

Degenerative Aortic Valve Stenosis

Degenerative aortic valve stenosis is defined by the follow- ing clinical and anatomic features: (1) the patient is over 65 years of age, ( 2 ) the aortic valve is tricuspid, ( 3 ) absent commissural fusion, and (4) mounds of calcific deposits in the sinuses of Valsalva (Figs. 1,3,9). This etiology of aortic stenosis has been known by different names: “wear and tear,” “senile,” “old age,”

*

Sinotu bular

False cornrnissure Fused commissure

+ Diffusely fibrotic

+ Calcific deposits + Cusp containing false or fused + cornrnissureequal 0 to margin of (*X longer

x t y >>Z) closure of remaining cusp

Cusp containing

+ commissure equal (Larger) to remaining cusp

False or fused 0 cornrnissure

cusp) of sinotubular

+ cusps

false or fused 0

(Lower in located at level + junction

FIG. 14 tinctions of the congenital and acquired bicuspid aortic valves.

Diagram indicating morphologic and morphornetric dis-

“atherosclerotic.”’~’y The presence of other age-related changes in the same hearts (calcified mitral annulus, calcified coronary arteries) provides additional evidence for establishing this etio-

As”

Functionally normal ) )-\ , Infective endocarditis (1 5%) 1 (9%)

Purely regurgitant without infection

(4%)

Stenosis (72%)

FIG. IS Diagram showing “natural history” of congenitally bicuspid aortic valves. A = anterior, P = posterior. From Ref. I with permission.

92 Clin. Cardiol. Vol. 17, February 1994

logic diagnosis. Of 1,797 excised stenotic aortic valves, 472 (26%) were classified as degenerative (Tables I, 111). Of isolat- ed stenotic aortic valves excised, degenerative etiology account- ed for 46% of valves (Table 11).

Rare Etiologies of Aortic Valve Stenosis

Unusual or rare forms of aortic valve stenosis constitute far less than 1 % of operatively excised aortic valves (Table 111). These etiologies include: homozygous type I1 (Fig. 3), hyper- lipoproteineinia (Fig. 3): active infective endocarditis (Figs. 3, 10): metabolic or enzymatic abnormalities in which metabol- ic products accumulate in the aortic cusps (Fabry’s disease, ochronosis),*S ‘j and systematic lupus erythematosis.“’

Some patients with aortic stenosis have recurrent gastroin- testinal bleeding commonly localized to the cecum and wend- ing colon.’0 Resected lesions have disclosed dilated mucosal and submucosal vessels and The exact relationship or mechanism of this colonic angiodysplasia and aortic valve stenosis is unknown. No correlation has been noted belween eti- ology of the aortic stenosis and “Heyde’s Syndrome.”21-23 Re- cent reports 23. 24 have indicated that aortic valve replacement, rather than bowel resection, offers the best relief of recurrent bleeding.

Etiology of Aortic Stenosis, Catheter Balloon Valvuloplasty, and the Role of the Two-Dimensional Echocardiogram

Recent attempts at a nonsurgical treatment of aortic valve stenosis with the use of catheter balloon dilation (valvuloplas- ty) has met with variable success in short- and long-term out- come. “Restenosis” has been a major problem. Waller and col- league~’~ suggested early on that early success or failure and early and late restenosis are related to etiology of the aortic stenosis.2s, Nonrheumatic etiologies (congenital bicuspid, de- generative) of stenosis are dilated by aortic wall stretching at nonfused commissures, and early restenosis is likely related to elastic recoil. Stenotic rheumatic aortic stenosis is dilated by commissural splitting and late restenosis is usually due to refu- sion by fibrous tissue?s. 26 The two-dimensional echocardio- gram can be extremely valuable in providing prevalvuloplasty infonnation on the etiology of the aortic stenosis and suggest- ing the likelihood of limited success andor early restenosis.

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