Contrasting histoarchitecture of calcified leaflets from stenotic bicuspid versus stenotic tricuspid aortic valves

Preliminary findings from clinical trials of percutaneous balloon aortic valvuloplasty and intraoperative debridement of calcific deposits in patients with aortic stenosis have suggested that calcified, congenitally bicuspid aortic valves may be less amenable to these techniques than are calcified tricuspid aortic valves. Accordingly, we evaluated the histoarchitecture of calcific deposits in 30 operatively excised aortic valves. Light microscopic sections taken through the calcified aortic valve leaflets disclosed two principal types of histoarchitecture. In 11 aortic valves nodular calcific deposits were superimposed on an underlying fibrotic aortic valve leaflet (type A); in 17 valves calcific deposits were diffusely distributed throughout the body (spongiosa) of the aortic valve leaflets (type B). Two aortic valves could not be classified histologically. These histologic subtypes were not randomly distributed with regard to gross valvular morphology. All 14 bicuspid valves (100%) were type B; in contrast, 11 (69%) of 16 tricuspid aortic valves were type A, and only 3 (19%) of 16 tricuspid valves were type B (p less than 0.01). Both valves with nonclassifiable histologic features were tricuspid on the basis of gross examination. Thus, the histoarchitectural distribution of calcific deposits is different for bicuspid than for tricuspid stenotic aortic valves. The more diffuse distribution of calcium throughout the body of calcified bicuspid aortic valve leaflets may render these valves less amenable to operative and percutaneous valvuloplasty than are calcified tricuspid aortic valve leaflets on which calcific deposits are typically superimposed in nodular form.     

Echocardiographic features of combined membranous subaortic stenosis and acquired calcific aortic valvulopathy

The M-mode echocardiographic features of aortic valve structure and motion in a 45-year-old male with combined congenital subaortic diaphragm and acquired deformity of the aortic valve are described. Clinical, hemodynamic, and angiographic studies suggested calcific aortic valve disease with stenosis and insufficiency, but the additional presence of a subaortic diaphragm was not appreciated. Cardiac ultrasonography demonstrated multiple, central diastolic aortic valve cusp echoes consistent with a thickened, calcified, tricuspid aortic valve. Despite calcification of the cusps, however, enough systolic cusp excursion remained to demonstrate an early systolic, rapid movement toward closure of the right coronary cusp-a finding suggestive of fixed subvalvular obstruction. Surgery confirmed a discrete subaortic diaphragm and a tricuspid, thichened, mildly calcified aortic valve with fusion of the cusp commissures at their origins and rolling back of the cusp edges. The value of echocardiography in the evaluation of the left ventricular outflow tract and aortic valve is emphasized.     

Valve origin of the aortic incisura

The occurrence and magnitude of the incisura of the central aortic pressure were shown in 66 patients to depend on the functional state of the aortic valve. In normal subjects and children with congenital aortic stenosis (with thin flexible leaflets), the incisura ranged between 6 and 14 mm Hg. With aortic regurgitation, the incisura diminished as the severity of regurgitation increased. With calcific aortic stenosis, the incisura was smaller or absent. These observations imply a valve mechanism productive of the incisura. In vitro studies of human aortic valves confirmed these observations. Additional in vitro studies with high speed cinematography (2,000 frames/sec) of a stented normal porcine valve also showed that early diastolic stretch and recoil of the leaflets occurs. These results indicate that in the presence of a normal or diseased aortic valve the aortic incisura is produced primarily by valve distension or recoil, respectively. Distension and rebound of the aortic walls do not appear to contribute significantly in the presence of a normal or a diseased valve. Because acquired aortic valve disease affects the magnitude of the central aortic incisura, inspection of the incisura may be of ancillary value in evaluating the pathologic state of the aortic valve.     

Congenital subaortic stenosis,with deformity of the aortic valve: Report of a case with complicating subacute bacterial endocarditis and mycotic aneurysm resulting in rupture of the aorta into the pericardium

A case of congenital subaortic stenosis, with a congenitally deformed aortic valve, is described; the patient was a woman who died, at the age of 29 years, of subacute bacterial endocarditis, with a ruptured mycotic aneurysm of the aorta and cardiac tamponade. We believe that a correct diagnosis of congenital subaortic stenosis is possible in patients under the age of 20 years who show clinical evidence of aortic stenosis, with a normal or nearly normal aortic second sound.     

Catheter-based intravascular ultrasound discriminates bicuspid from tricuspid valves in adults with calcific aortic stenosis

A catheter-based intravascular ultrasound transducer was used to study aortic valve morphology in adults with calcific aortic stenosis. Examination of 14 postmortem specimens disclosed that intravascular ultrasound consistently identified the number of cusps or the presence of a calcified median raphe in the conjoined cusp, or both, and thereby distinguished a calcified bicuspid from a calcified tricuspid aortic valve. These postmortem findings were then employed to identify valvular morphology in 15 patients undergoing diagnostic cardiac catheterization or balloon aortic valvuloplasty, or both. Reproduction of criteria established in vitro allowed discrimination of congenital valvular morphology in all 15 patients, including 7 in whom assessment by intravascular ultrasound was confirmed by subsequent pathologic examination. Identification of aortic valvular morphology by intravascular ultrasound has potential therapeutic implications for patients considered to be candidates for operative or nonoperative aortic valvuloplasty.     

Demographic characteristics of patients undergoing aortic valve replacement for stenosis: relation to valve morphology.

OBJECTIVE: To determine the relative importance of the different causes of isolated aortic valve stenosis in a surgical series, and to relate these to patient characteristics including the rate of insertion of bypass grafts for coronary artery disease. DESIGN: Survey of the clinical and pathological data on patients undergoing aortic valve replacement for isolated stenosis. SETTING: Tertiary care cardiothoracic surgical unit. PATIENTS AND METHODS: 465 adult patients undergoing aortic valve replacement representing a consecutive series in one surgical unit. Retrospective review of patients records and classification of cause of aortic stenosis based on pathological examination of excised valve cusps. RESULTS: 63.7% patients had calcific bicuspid valves, 26.9% tricuspid calcific valves, and 5.4% rheumatic, 2.6% mixed pathology and 1.5% unicommissural valves. The ratio of males to females for bicuspid valves was 1.85:1 and for tricuspid calcific valves 0.76:1. The mean age of patients with bicuspid valves was 64.9 years compared with 73.4 years for those with tricuspid valves. Some 22.3% of patients with bicuspid valves and 44.8% of those with tricuspid valves had sufficient coronary artery disease to necessitate insertion of coronary bypass grafts. The differential rate of insertion of coronary bypass grafts was independent of age. CONCLUSIONS: Bicuspid calcified aortic valves are the predominant cause of isolated aortic valve stenosis followed by tricuspid calcified aortic valves. The sex and age distribution of bicuspid and tricuspid calcific aortic valve stenosis is different. The higher rate of insertion of vascular grafts in tricuspid calcific aortic valves may indicate that risk factors for atherosclerosis enhance cusp calcification in these patients.     

Electrohydraulic shock wave decalcification of stenotic aortic valves: Postmortem and intraoperative studies

Decalcification of stenotic aortic valves is limited by the difficulty in removing sufficient calcium to restore valve function without cusp perforation. The present study demonstrates that electrohydraulic shock waves generated by a hand-held lithotriptor fragmented the calcifications contained within the cusps of four necropsy specimens of stenotic aortic valves. The electrohydraulic shock waves appeared to create a cleavage plane between the valve tissue and the fragmented calcific deposits, allowing the fragmented calcined masses to be removed without cusp perforation.Five patients with severe aortic stenosis also underwent successful aortic valve decalcification augmented by electrohydraulic shock waves generated with the hand-held lithotriptor, without significant complication. The shock waves permitted removal, from the aortic valve, of calcium that had not been removed by mechanical means. These results indicate that the addition of electrohydraulic shock waves to mechanical aortic valve decalcification may facilitate successful decalcification in patients undergoing operative treatment for aortic stenosis and may allow patients to avoid the need for aortic valve replacement.     

Expression and activity of matrix metalloproteinase-2 in calcific aortic stenosis

Calcific aortic stenosis is the main heart valve disease in the elderly, leading to massive focal calcification and thickening of the valve cusps. Matrix metalloproteinases (MMPs) are thought to contribute to this process. Therefore, the study assessed the expression of the gelatinases MMP-2 and MMP-9 and the endogenous tissue inhibitor of metalloproteinase (TIMP)-2 as well as the gelatinolytic activity in normal and stenotic valves. Human tricuspid aortic valves with and without calcific aortic stenosis were studied by immunohistochemistry for MMP-2, MMP-9 and TIMP-2. The gelatinolytic activity in native valve sections was assessed by gelatin in situ zymography with or without addition of the MMP activator p-aminophenymercuric acetate (APMA). Staining intensities for MMP-2 and TIMP-2 were elevated in stenotic valves as compared to controls. Minor staining of MMP-9 was present exclusively in stenotic valves. The morphologic distribution of gelatinolytic activity was comparable to the staining pattern of MMP-2, and since MMP-9 immunostaining demonstrated only a low number of positive cells, the observed gelatinolytic activity is likely due to MMP-2. Gelatinolytic activity was low in normal valves but significantly increased by the MMP activator APMA. In contrast, stenotic valves showed a strong basal gelatinolytic activity that could not be significantly enhanced by APMA suggesting that MMP-2 is present as a latent pro-enzyme in normal valves and activated in stenotic valves. Thus, MMP-2 might be involved in the matrix remodeling during calcific aortic stenosis.     

Congenital aortic stenosis secondary to dysplasia of congenital bicuspid aortic valves without commissural fusion

The hearts of nine children with clinical evidence of congenital valve stenosis and a congenital bicuspid aortic valve were reviewed. Aortic stenosis was diagnosed on the basis of cardiac catheterization data in four patients, operative findings in two and auscultatory findings in three. The patients were 1 month to 9 years old; six were male and three female. In each patient the two commissures of the valve were free to the aortic wall. The cusps were thickened, rolled and redundant; microscopic studies revealed that they consisted of Immature loose connective tissue consistent with a dysplastic or incompletely differentiated valve. The valve orifice was obstructed by the dysplastic cusps, and dysplastic changes rather than the commlssural fusion were responsible for the observed aortic stenosis. These valves do not appear amenable to valvotomy because obstruction Is due to the abnormal valve tissue. These findings may explain the occasional poor results of valvotomy in Infants and children with congenital aortic valve stenosis.     

The mechanism of the obstruction in calcific aortic stenosis with bicuspid valve: a reason for failure of balloon aortic valvuloplasty in the elderly

Percutaneous aortic balloon valvuloplasty failed to relieve the obstruction in 2 elderly patients with calcific aortic stenosis. Intraoperative and pathologic examination showed bicuspid aortic valve with symmetric cusps, straight and fibrotic cusp edges and fractured calcific nodules of the aortic valve. Failure of balloon valvuloplasty in these patients, in spite of successful fractures of calcific nodules, was due to inability to influence the spring-like action of the thickened edges of the valve which represents a specific additional cause of obstruction in calcific bicuspid aortic valve of the elderly.     

Impact of valvular calcification on the diagnostic accuracy of transesophageal echocardiography for the detection of congenital aortic valve malformation

BACKGROUND: Degeneration of congenital bicuspid or unicuspid aortic valves can progress more rapidly than that of tricuspid valves, and an early diagnosis significantly impacts decision making and outcome. We hypothesized that the extent of valvular calcification would negatively influence the diagnostic accuracy of multiplane transesophageal echocardiography (TEE) for the diagnosis of congenital aortic valve disease. METHODS: TEE was performed in 57 patients undergoing aortic valve replacement surgery for aortic stenosis (n = 46), pure regurgitation (n = 9), or significant regurgitation with less than severe aortic stenosis (n = 2). The degree of aortic valve calcification and the number of valve cusps were determined at surgery. RESULTS: Surgical inspection confirmed 14 bicuspid and 43 tricuspid aortic valves. Sensitivity and specificity of TEE for the diagnosis of congenital aortic valve malformation was 93% (13/14) and 91% (39/43) (P = 0.0001), respectively. In patients with no or mild aortic valve calcification (n = 13), sensitivity and specificity of TEE for the diagnosis of congenitally malformed aortic valve was 100% (5/5) and 100% (8/8) (P = 0.001), respectively. In patients with moderate or marked aortic valve calcification (n = 44), sensitivity and specificity of TEE for the diagnosis of congenitally malformed aortic valve was 89% (8/9) and 89% (31/35) (P<0.0001), respectively. In this subgroup of 44 patients, there were four false-positive and one false-negative diagnoses due to valvular calcification. CONCLUSIONS: Although TEE is highly sensitive and specific for the detection of congenital aortic valve malformations, presence of moderate or marked calcification of the aortic valve may result in false positive and false negative diagnoses.     

Hemodynamic characterization of calcified stenotic human aortic valves before and after treatment with a novel aortic valve repair system

BACKGROUND AND AIM OF THE STUDY: The repair of calcified stenotic aortic valves may be a viable alternative to current valve treatments for early-stage aortic valve disease. To date, evaluation of valve repair feasibility on the benchtop has not been performed. A pulsatile flow system for testing intact human aortic valves was developed to perform quantitative hemodynamic and mechanical assessment of a new aortic valve repair approach. METHODS: Intact calcified human aortic valves were divided into two groups with effective orifice area (EOA) > or =2.0 cm2 (group I, n = 6) or <2.0 cm2 (group II, n = 6). All valves were chemically debrided in stages for up to 60 min. A subset of valves in each group was also surgically debrided. At each stage, pre- and post-treatment hemodynamic assessment and video motion analysis were performed in the pulsatile flow system at multiple levels of physiological loading. Mineral removed was quantified using atomic absorption spectroscopy. RESULTS: Progressive removal of mineral with both mechanical and chemical debridement was associated with improved hemodynamic function of calcified human aortic valves. Improvements in EOA of up to 40% and decreases in transvalvular pressure gradient (deltaP) of up to 46% were seen. No clinically relevant increases in regurgitation were observed. CONCLUSION: Repair of stenotic calcified aortic valves using surgical and chemical debridement showed that removal of calcific deposits was directly associated with improvements in valve hemodynamic function. The level of improvement was proportional to the degree of aortic valve stenosis, to the use of surgical debridement, and to the duration of chemical debridement treatment. The study results suggested that aortic valve repair warrants further investigation as an alternative to current valve treatments in patients with early to mid-stage calcific aortic valve disease.     

Congenitally bicuspid aortic valve causing severe,pure aortic regurgitation without superimposed infective endocarditis: Analysis of 13 patients requiring aortic valve replacement

Although stenosis and infective endocarditis are commonly appreciated complications of the congenitally bicuspid aortic valve, pure severe aortic regurgitation complicating this congenital malformation, unassociated with either stenosis or infection, is not well recognized. Among 189 patients who had aortic valve replacement at the National Heart, Lung, and Blood institute because of isolated pure aortic regurgitation, the congenitally bicuspid aortic valve, never the site of infective endocarditis, was responsible for the aortic regurgitation in 13 (7 percent). This report describes certain clinical and morphologic findings in 13 men, aged 26 to 65 years (mean 43), who required aortic valve replacement because of severe aortic regurgitation secondary to a noninfected, nonstenotic congenitally bicuspid aortic valve. Although not generally recognized, the noninfected congenitally bicuspid aortic valve is an important cause of pure aortic regurgitation severe enough to warrant aortic valve replacement.     

Balloon dilatation of calcific aortic stenosis in elderly patients: postmortem, intraoperative, and percutaneous valvuloplasty studies

To assess the safety and efficacy of percutaneous balloon valvuloplasty in calcific aortic stenosis, balloon dilatation of critically stenosed, calcified aortic valves was performed in five postmortem hearts, in five patients intraoperatively before aortic valve replacement, and in two elderly patients percutaneously at the time of diagnostic catheterization. The etiology of aortic stenosis in the 12 cases was rheumatic in two, congenital bicuspid calcific stenosis in one, and senile calcific degenerative stenosis in the remaining nine. Prevalvuloplasty examination in the 10 postmortem and intraoperative cases revealed rigid valve leaflets with commissural fusion in three valves and extensive nodular calcification in seven. Subsequent balloon dilatation with 15 to 18 mm valvuloplasty balloons resulted in decreased cusp rigidity and increased mobility of valve leaflets in all cases, without evidence of tearing of valve leaflets, disruption of the valvular ring, or liberation of calcific or valvular debris. In the three valve specimens with commissural fusion, balloon dilatation resulted in partial or complete separation of leaflets along fused commissures. In two cases with extensive nodular calcification, balloon dilatation resulted in a fracture of a calcified leaflet that was evident on both gross and radiologic examination. After postmortem and intraoperative studies, percutaneous catheter valvuloplasty was performed at the time of diagnostic catheterization in two elderly patients (93- and 85-year-old women) with long-standing calcific aortic stenosis. Balloon dilatation with 12 to 18 mm balloons resulted in significant decreases in aortic gradients and significant increases in cardiac index and aortic valve area in both patients. Percutaneous valvuloplasty in both patients resulted in a mild increase in aortic insufficiency and no evidence of embolic phenomena.     

Role of M mode echocardiography in congenital aortic stenosis

M mode ultrasonic recognition of a bicuspid aortic valve or congenttally stenotic aortic valve rests on detection of the following criteria: eccentricity index, increased leaflet thickness, multiple diastolic cusp lines and presence of a central systolic line. In this investigation, M mode ultrasonic tracings from 118 children were interpreted by evaluators who did not know the diagnosis. Twenty-eight records from children with aortic valve stenosis (25 with a bicuspid valve and 3 with a tricuspid valve), were intermixed with records of 90 children with a catheterization-proved normal aortic valve to determine how many criteria were present in each tracing. Additionally, tracings were reviewed for overall visual appearance of the criteria, without measurement, to attempt to identtty those with an abnormal aortic valve. Finally, all echoes were viewed simultaneously and ranked from the most normal in appearance to the most abnormal aortic valve image. Rankings were then compared with measured pressure gradients across the aortic valve.

An eccentricity index value greater than 1.5, thought to be indicative of a bicuspid aortic valve, was found in 29 percent of patients with aortic stenosis and 20 percent of normal children. Mean eccentricity index values for the two groups were statistically similar. Increased leaflet thickness was not detected in any tracing. Multiple diastolic cusp lines were present in 64 percent of patients with aortic stenosis and 60 percent of normal children. None of these criteria were sensitive or selective for dlagnosing aortic stenosis from an M mode tracing of a given patiënt. On the basis of subjective visual appearance, 39 percent of tracings of patients with aortic stenosis were identified correctly. No useful correlation existed between the ranking an M mode tracing received for degree of valve normality or abnormality and the aortic pressure gradient. This investigation shows that M mode echocardiography of the aortic valve, despite prior recommendations to the contrary, has limited usefulness in diagnosing congenital aortic stenosis.     

Calcific aortic insufficiency—a review of 26 patients

Twenty-six patients, 8.3 per cent of all patients with aortic valve disease, and 10.7 per cent of all patients with any degree of aortic insufficiency detected in our catheterization laboratory, had pure calcific aortic insufficiency (no associated stenosis). Nineteen (73 per cent) males and seven (27 per cent) females ranged in age from 25 to 75 years of age (mean 51). Twenty-three per cent were younger than 40. Sixteen (62 per cent) had rheumatic heart disease, one had luetic aortic valve disease, one had congenital bicuspid valve, and eight (31 per cent) had aortic insufficiency of undetermined etiology. Twenty-three patients (89 per cent) had an aortic systolic ejection murmur, and seven (28 per cent) had an aortic ejection click. Aortic valve calcification was detected by plain chest films in only four patients (16 per cent), and by routine image intensification fluoroscopy (before catheterization) in fifteen patients (68 per cent). The remaining 32 per cent had the calcification of the aortic valve detected during catheterization.Aortic valve calcification was severe in nine patients (35 per cent), moderate in eleven patients (42 per cent), and minimal in six patients (22 per cent). Aortic insufficiency was severe in twenty patients (77 per cent), moderate in five patients (19 per cent), and minimal in one patient (4 per cent). Nineteen patients (77 per cent) had reduced left ventricular contractility. Sixteen patients (67 per cent) had low cardiac index. Eighteen patients had normal coronary arteries and three patients had obstructive coronary artery disease. Aortic stenosis was misdiagnosed as the predominant lesion in fourteen patients (54 per cent)—prior to catheterization. This series demonstrates that all patients with calcified aortic valve disease and with ejection murmurs do not necessarily have aortic stenosis. Pure calcific aortic insufficiency is a distinct entity, more common than previously suspected.     

The angiographic features of bicuspid and unicommissural aortic stenosis

Stenosis of a congenitally bicuspid aortic valve results in a characteristic angiographic appearance: In systole the valve leaflets are domed, and there is a central jet that corresponds to the orifice of the stenotic valve. In diastole the sinuses of Valsalva reflect the morphologic features of the 2 aortic cusps.     

Treatment of calcific aortic stenosis by balloon valvuloplasty

Recent reports have established the feasibility of using balloon valvuloplasty to reduce left ventricular outflow tract obstruction due to a calcified aortic valve. The present study summarizes experiences with this technique in 9 patients (7 women, 2 men, mean age 78 years) in whom balloon valvuloplasty was used to treat calcific aortic stenosis. Peak aortic valve gradient (mm Hg) decreased from 68 +/- 8 (mean +/- standard error of the mean) before valvuloplasty to 35 +/- 5 after valvuloplasty (p = 0.003). Mean aortic valve gradient decreased from 57 +/- 7 before valvuloplasty to 30 +/- 5 after valvuloplasty (p = 0.006). Calculated aortic valve area increased from 0.42 +/- 0.04 to 0.81 +/- 0.06 cm2 (p = 0.005). Balloon valvuloplasty failed to diminish aortic valve obstruction in only 1 patient who, at subsequent surgery, had a congenitally bicuspid aortic valve. Significant aortic regurgitation was not observed in any of the 9 patients after valvuloplasty. One patient did have a highly focal, presumably embolic, brain stem infarct during the procedure. Femoral arterial blood loss, related to wire-guided exchange of balloon catheters too large for a 12Fr introducer sheath, was minimized by direct arterial exposure in 8 of the 9 patients. Thus, these findings confirm the efficacy of balloon valvuloplasty for the treatment of calcific aortic stenosis. The procedure, however, is not without hazard.     

Retinal embolization of bicuspid aortic valve calcification

We report the case of a 36-year-old man with calcified bicuspid aorta. Aortic disease was diagnosed after retinal embolism, which caused loss of vision affecting the left eye. Doppler examination did not identify carotid stenosis. Transthoracic echocardiography showed thickness and calcification of two leaflets, moderate aortic regurgitation, high normal left ventricular diastolic dimensions, and high normal interventricular septum thickness. Parasternal long-axis view in the systolic frame showed dilated left ventricular outflow tract, dilated ascending aorta, and calcification and thickening of aortic leaflets, causing an echo-lucent area, in the diastolic frame. It also showed the eccentric position of the closed valve leaflets, short axis in the diastolic frame, and the absence of the typical "Y" letter sign, tracked by the three leaflets (septal, right coronary, and left coronary) in the normal tricuspid aortic valve. On long-axis parasternal acquisition, we note high normal interventricular septum thickness and high normal diastolic diameter. Color Doppler analysis from the apical five-chamber view showed aortic regurgitation; regurgitant jet area was about 44% of the outflow tract, so aortic regurgitation was classified as moderate. Pulsed Doppler showed a high normal value of peak aortic velocity. Transesophageal echocardiography was performed, but no further findings were identified. We think that the likely retinal embolism sources were the aortic calcified leaflets, even if the aortic valve was not stenotic and with no signs of endocarditis. However, because we cannot exclude other potential causes, we put the patient on anticoagulant therapy. Furthermore, aortic valve replacement was not advised.