Left ventricular systolic and diastolic function in subjects with a bicuspid aortic valve without significant valvular dysfunction

Abstract

BACKGROUND:

The bicuspid aortic valve (BAV) represents the most common cardiac congenital malformation in adults. It is frequently associated with dilation, aneurysm and dissection of the ascending aorta.

OBJECTIVE:

To evaluate left ventricular systolic and diastolic function in subjects with BAVs.

METHODS:

Thirty-five subjects with BAV (mean [± SD] age 25.9±5.7 years [range 17 to 36 years]; 18 male, 17 female) with either no valvular impairment or mild valvular impairment were recruited along with 30 control subjects (24.5±4.4 years of age [range 15 to 35 years]; 15 male, 15 female) who were matched for age, sex and body surface area. Left ventricular systolic and diastolic function were evaluated using conventional and tissue Doppler echocardiography. Left ventricular systolic and diastolic parameters were compared between the two groups.

RESULTS:

In subjects with BAVs, the ratio of mitral early diastolic velocity to late diastolic velocity was lower (0.95±0.4 versus 1.27±0.9; P=0.001), the ratio of mitral early diastolic velocity to myocardial early diastolic velocity was higher (10.1±3.2 versus 6.5±2.4; P=0.001) and the myocardial early diastolic velocity was lower (8.4±2.1 versus 15.3±3.6; P<0.001) compared with control subjects. In addition, the myocardial performance index was higher in subjects with BAVs than in control subjects (P=0.03). The left ventricular ejection fraction was also lower (53±11% versus 64±13%; P<0.001). No other statistically significant differences were observed between the two groups with regard to left ventricular systolic and diastolic parameters. In addition, the number of mitral valve prolapses and atrial septal aneurysms was higher in subjects with BAVs.

CONCLUSION:

BAVs may be associated with left ventricular systolic and diastolic dysfunction.

The bicuspid aortic valve (BAV) represents the most common cardiac congenital malformation in adults. It is frequently associated with dilation, aneurysm and dissection of the ascending aorta. The incidence of BAVs in the general population is 1.0% to 2.0% (1–3).

A congenital BAV may function normally throughout life, developing progressive calcification and stenosis, or possibly regurgitation with or without infection (2). Aortic root dilation is common in BAVs, even when the valve is hemodynamically normal; consequently, aortic dissection usually occurs in previously asymptomatic subjects (4). In most cases, BAVs remain undetected until either infection or calcification supervenes (5).

Aortic stenosis and regurgitation, infective endocarditis and aortic dissection are the most common complications of a BAV. Left coronary artery dominance is more common in subjects with BAVs (29% to 56.8%) and, in 90% of cases, the left main coronary artery is <5 mm in length (6,7). These abnormalities may contribute to an inadequate myocardial blood supply and an increased risk of myocardial infarction (8,9).

The histological characteristics of BAVs are nonspecific and have been described in several publications in subjects with Marfan syndrome (10–12). The histopathological appearance of thoracic aortic aneurysms in both Marfan syndrome and BAV is similar and includes evidence of vascular smooth muscle cell (VSMC) apoptosis and extra-cellular matrix degeneration in the absence of a significant inflammatory response (13).

Abnormalities in the ascending aorta of subjects with BAVs, specifically premature medial layer VSMC apoptosis, have been described, explaining the higher than expected prevalence of aortic dissection in these subjects (14). Recent studies have also demonstrated that there is less elastic tissue in the aortas of subjects with BAVs (15,16).

Left ventricular (LV) systolic and diastolic dysfunction has been described in subjects with Marfan syndrome, but the effect of BAVs on LV function is unknown (17,18). The literature has recently provided some information regarding the left ventricle chamber and the preserved LV function in BAV athletes both at rest and during stress tests. Galanti et al (19) reported that athletes with BAVs showed a significant progressive increase in LV dimensions and aortic diameters. However, at present, there are no additional data available regarding the general population.

The present study was conducted to identify possible differences in LV systolic and diastolic functions between a group of sedentary subjects with BAVs and a group of control individuals with normal tricuspid aortic valves and a similar lifestyle. It is important to note that the effects and the impact of regular exercise in subjects with BAV is now a point of interest in athletes, whereas no data are available for possible LV dysfunction in nonathletic subjects.

METHODS

Selection of subjects

Thirty-five subjects (mean [± SD] age 25.9±5.7 years [range 17 to 36 years]; 18 male) who were referred to the cardiology outpatient clinic for various reasons and were found to have a BAV with either no valvular impairment or mild valvular impairment were included in the present study. The control group consisted of 30 successive patients (mean age 24.5±4.4 years [range 15 to 35 years]; 15 male) matched for age, sex and body surface area who were also referred to the cardiology outpatient clinic for various reasons but did not have any structural cardiac pathologies identified.

Subjects with a history of coronary artery disease, heart failure, moderate or severe valve disease, cardiomyopathy, hypertension, diabetes mellitus, chronic lung disease, hepatic and renal dysfunction, thyroid dysfunction and anemia were excluded from the study. The study groups did not include intravenous drug users or individuals who consumed alcohol. All of the subjects were in sinus rhythm. Each patient signed an informed consent form, and a local ethics committee approved the study.

Echocardiographic measurements

Two-dimensional, M-mode, pulsed and colour flow Doppler echocardiographic examinations of all subjects were performed by the same examiner (the author) using a commercially available device (Vivid 5 pro, 2 mHz to 4 mHz phased array transducer, GE, Norway). During echocardiography, a one-lead electrocardiogram was recorded continuously.

M-mode measurements were performed according to the criteria of the American Society of Echocardiography (20,21). The left atrium (LA) diameter, LV end-systolic diameter and LV end-diastolic diameter were measured. The LV ejection fraction was estimated using Simpson’s rule.

Pulsed-wave mitral flow velocities were measured from the apical four-chamber view by inserting a sample volume into the mitral leaflet tips. The mitral early diastolic velocity (E, cm/sn), late diastolic velocity (A, cm/sn), E/A ratio, E deceleration time (ms) and isovolumetric relaxation time (ms) were determined. Each representative value was calculated as the mean of three measurements. Doppler tissue imaging echocardiography was performed using transducer frequencies of 3.5 MHz to 4.0 MHz. The spectral pulsed Doppler signal filter was adjusted until a Nyquist limit of 15 cm/sn to 20 cm/sn was reached and the minimal optimal gain was used. The monitor sweep speed was set at 50 mm/s to 100 mm/s to optimize the spectral display of the myocardial velocities. The myocardial peak systolic (Sm, cm/s), early (Em, cm/s) and late (Am, cm/s) diastolic velocities, isovolumetric contraction time (ms), isovolumetric relaxation time (ms) and ejection time (ET, ms) were obtained by placing a tissue Doppler sample volume into the basal segments of the anterior, inferior, lateral and septal walls. The tricuspid annular motion was recorded at the free wall of the right ventricle. The myocardial performance index (MPI) was calculated using the following formula (22):

$$\begin{array}{c}\text{MPI}=(\text{isovolumetric}\hspace{0.17em}\text{contraction}\hspace{0.17em}\text{time}+\text{isovolumetric}\\ \text{relaxation}\hspace{0.17em}\text{time})/\text{ET}\end{array}$$

The mean LV Sm, mean Em, Am, and mean MPI values were obtained by calculating the mean of the segmental values. Therefore, the reported Doppler tissue velocities represent an average of the basal segments of the anterior, inferior, lateral and septal walls. In addition, the E/Em ratio, an important noninvasive marker of pulmonary capillary wedge pressure and LV filling pressure, was calculated.

Statistical analyses

Statistical analyses were performed using SPSS version 16.0 (IBM Corporation, USA). All values are presented as mean ± SD. Values between different groups were compared using the independent-samples t test. A χ² test was used to assess the differences between categorical variables. The relationship between parameters was determined using the Pearson coefficient of correlation; P<0.05 was considered to be statistically significant.

RESULTS

There were no statistically significant differences between the BAV group and the control group with regard to age, sex, body mass index, diameters of the left atrium and the left ventricle, blood pressure, systolic pulmonary artery pressure and smoking status. Mitral valve pro-lapses (MVPs) and atrial septal aneurysms (ASAs) were more common in the BAV group than in the control group (Table 1).

TABLE 1.

Clinical and echocardiographic features of bicuspid aortic valve patients and controls

	Patients (n=35)	Controls (n=30)	P
Age, years	25.9±5.7	24.5±4.4	0.12
Male/female, n/n	18/17	15/15	0.356
Body surface area, m2	1.9±0.4	1.9±0.3	0.925
Body mass index, kg/m2	23±5	24±6	0.262
Left atrial diameter, cm	3.8±0.9	3.2±0.6	0.59
LVEDD, cm	4.8±1.9	4.4±1.5	0.53
LVESD, cm	3.6±1.2	2.5±1.0	<0.001
Systolic blood pressure, mmHg	123±13	122±12	0.39
Diastolic blood pressure, mmHg	76±9	77±9.5	0.138
SPAP, mmHg	19.3±9.5	22±8.4	0.716
Aorta diameter (sinus of Valsalva), cm	3.5±0.5	2.8±0.4	<0.001
Aorta diameter (sinotubular and tubular), cm	3.1±0.4	2.6±0.3	<0.001
Mitral valve prolapse, n	8	3	0.001
Atrial septal aneurysm, n	9	3	0.001
Smoking, n	8	10	0.679
LV systolic dysfunction (ejection fraction <50%), n (%)	6 (20)	3 (10)	0.052

Data presented as mean ± SD unless otherwise indicated. LV Left ventricular; LVEDD LV end-diastolic dimension; LVESD LV end-systolic dimension; SPAP Systolic pulmonary artery pressure

The measurements obtained using two-dimensional echocardiography showed that the BAV subjects had significantly larger aortic root dimensions than the control subjects at the sinus of Valsalva (3.5±0.5 cm versus 2.8±0.4 cm; P<0.001), at the sinotubular junction and at the tubular aorta (3.1±0.4 cm versus 2.6±0.3 cm; P<0.001) (Table 1).

LV systolic function was within the normal range in both groups; however, the LV end-systolic diameter was higher and LV ejection fraction was lower (53±11 versus 64±13; P<0.001) in the BAV group than in the control group.

In the BAV group, the E/A ratio was lower than in the control group (0.95±0.4 versus 1.27±0.9; P=0.001), whereas the E/Em ratio was higher in the BAV group than in the control group (10.1±3.2 versus 6.5±2.4; P=0.001) and the Em was lower in the BAV group than in the control group (8.4±2.1 versus 15.3±3.6; P<0.001). In addition, the MPI, which is indicative of both systolic and diastolic functions, was found to be higher in BAV subjects than in the controls (45.3±9.7 versus 38.8±7; P=0.031). There were no significant differences between the groups with respect to the Sm and Am values (P>0.05). No other statistically significant differences were found between the two groups with regard to LV systolic and diastolic parameters (Table 2).

TABLE 2.

Conventional echocardiographic and tissue Doppler echocardiographic parameters

	Patients (n= 35)	Controls (n=30)	P
Left ventricular ejection fraction, %	53±11	64±13	<0.001
E, cm/s	85.5±12	99.6±20	0.09
A, cm/s	89.5±15	78.3±18	0.58
E/A	0.95±0.4	1.27±0.9	0.001
Deceleration time, ms	179±18.7	170±13	0.747
Isovolumetric relaxation time, ms	83±13	77±15	0.264
Sm, cm/s	10.6±1.4	14.2±2.4	0.052
Am, cm/s	7.8±1.9	7.9±1.6	0.612
Em, cm/s	8.4±2.1	15.3±2.6	<0.001
E/Em	10.1±3.2	6.5±2.4	0.001
Myocardial performance index	45.3±9.7	38.8±7	0.031
Left atrial volume index, mL/m2	12.3±4.1	11.2±3.2	0.138

Data presented as mean ± SD unless otherwise indicated. A Mitral late diastolic velocity; Am Myocardial late diastolic velocity; E Mitral early diastolic velocity; Em Myocardial early diastolic velocity; Sm Mean left ventricular systolic myocardial velocity

DISCUSSION

Fibrillin, fibronectin and tenascin abnormalities occur in subjects with BAV. In addition, Bonderman et al (23) suggested that VSMC apoptosis plays a primary role in the development of aneurysms in these subjects.

The FBN1 gene encodes fibrillin-1, a large glycoprotein that is secreted from cells and deposited in the extracellular matrix in structures known as microfibrils. Microfibrils are found at the periphery of elastic fibres, including the elastic fibres in the medial layer of the ascending aorta and in tissues that are not associated with elastic fibres (24). Fedak et al (25) reported that fibrilin-1 content was reduced in subjects with BAVs.

The histopathological appearance of thoracic aortic aneurysm in Marfan syndrome and in BAVs is similar, and includes evidence of VSMC apoptosis and extracellular matrix degeneration in the absence of a significant inflammatory response (19).

Abnormalities in the ascending aorta of subjects with BAV, specifically premature medial layer VSMC apoptosis, have been described, explaining the higher than expected prevalence of aortic dissections in these subjects (14,16).

Previous studies have provided evidence for LV systolic and diastolic dysfunction in adults with Marfan syndrome, but the effects of a BAV on LV function are unknown (17–19). Recently, Kiotsekoglou et al (13) demonstrated significant biventricular diastolic and biatrial systolic and diastolic dysfunction in subjects with Marfan syndrome. They also suggest that these findings indicate that Marfan syndrome independently affects diastolic function. Diastolic abnormalities could be attributed to a fibrillin-1 deficiency and the dysregulation of transforming growth factor-beta activity in the cardiac extracellular matrix (13). In addition, Santarpia et al (26) demonstrated that the LV longitudinal (P=0.01), circumferential (P=0.01) and radial (P<0.001) strain (%) were lower in subjects with BAV. Stefani et al (27) suggested that young trained athletes who have BAVs have a normal LV performance but that these athletes also tend to have a lower strain in the LV basal segments than healthy subjects. Recently, Bilen et al (28) suggested that left atrial volume and E/e’ ratio is increased in BAV patients.

In our study, similar to Marfan syndrome, we observed impaired LV systolic and diastolic function. In addition, the MVP and ASA were higher in subjects with BAV than in subjects in the control group.

In our initial study, we determined that LV systolic and diastolic function are impaired in subjects with BAVs.

The most significant limitation to our study was an insufficient number of subjects. Other limitations include the fact that the present study was not prospective and that the same examiner performed all of the echocardiograms. Although it was stated that functional abnormalities could not be attributed to the presence of ischemic heart disease, its presence cannot be ruled out as a factor due to the fact that none of the subjects underwent angiography because there was no indication that warranted the procedure. Similarly, although none of the study subjects had a history or symptoms of diabetes, chronic obstructive pulmonary disease or atherosclerosis, laboratory tests for these conditions were not performed and, hence, these cannot be completely ruled out as other underlying factors potentially affecting myocardial function. In addition, the pulmonary venous Doppler inflow patterns, LV strain and speckle tracking parameters were not measured.

CONCLUSION

BAVs appear to be associated with impaired LV systolic function, although the mechanisms behind this association are not completely understood. Our study revealed significant LV diastolic dysfunction in subjects with a BAV in the absence of significant valvular disease. In addition, there are relationships between BAV and MVP and ASA.

With regard to the underlying pathogenetic mechanisms, further investigation is needed to determine whether the observed abnormalities are caused by a fibrillin-1 deficiency and transforming growth factor-beta dysregulation. Our current findings are hypothesis generating and verification using prospective studies is needed.