Keywords
floppy mitral valve - mitral valve prolapse - aorta - distensibility
Introduction
Floppy mitral valve/mitral valve prolapse (FMV/MVP) is considered to be a heritable
disorder of connective tissue and has a prevalence of 2 to 3% in the general population.[1]
[2]
[3] FMV/MVP is most commonly transmitted by an autosomal dominant inheritance with a
variable degree of penetration.[1]
[4]
[5]
[6] The term FMV comes from surgical and pathologic studies, and refers to the expansion
of the area of the mitral valve leaflets with elongated chordae tendineae and frequently
dilated mitral annulus. MVP is a nonspecific finding and can be produced by several
mechanisms such as papillary muscle rupture or dysfunction, left ventricular (LV)
wall motion abnormalities, small LV size, hyperdynamic LV function, and others. Thus,
FMV is the central issue in primary MVP and for these reasons it should be used in
all cases of primary MVP.[7] Patients with FMV/MVP over the years may develop severe mitral regurgitation (MR)
requiring surgery or other interventional therapy. FMV/MVP is the most common cause
for mitral valve surgery in developed countries.[1]
[2]
[3]
[6]
The clinical phenotype of FMV/MVP is widely heterogeneous, ranging from a benign clinical
course with a normal life expectancy to adverse outcomes with significant morbidity
and mortality, mostly related to MR and its complications. As a connective tissue
disorder, FMV/MVP may be associated with structural abnormalities of other organs.[1]
[2]
[8]
[9] Glesby and Pyeritz emphasized some of these findings using the acronym MASS, indicating
involvement of the mitral valve, aorta, skeleton and skin.[9] Occasionally, FMV/MVP may be part of a well-defined syndrome of a heritable connective
tissue disorder such as the Marfan syndrome, Ehlers–Danlos syndrome, polycystic kidney
disease, and others.[9]
[10]
[11] Although involvement of the aorta has been suggested in FMV/MVP patients, and a
stiff aorta may increase the severity of MR, there is a lack of information related
to function of the aorta in patients with FMV/MVP.[9]
[10]
[11]
[12] The present study was undertaken to evaluate aortic function in patients with FMV/MVP
and significant MR.
Methods
Study Population
Seventeen patients (11 men, 6 women) with isolated FMV/MVP and significant MR requiring
surgery were studied. The severity of MR was determined by left ventriculogram and
by two-dimensional transthoracic echocardiogram using several methods including area
of regurgitant jet compromising the left atrium, vena contracta, effective regurgitant
orifice, regurgitant volume, regurgitant fraction, and/or pulmonary vein systolic
flow reversal. All patients had chronic symptomatic MR requiring surgical intervention
in which the cardiologist, interventional cardiologist, and cardiothoracic surgeon
were in agreement. The diagnosis of FMV/MVP was established preoperatively by echocardiography
and by direct inspection of the mitral valve during surgery. FMV was also established
with histopathologic examination in 15 of the patients. All patients had isolated
FMV/MVP and those with a known heritable connective tissue disorder were excluded
prior to entry into the study. Heritable connective tissue disorders were excluded
by taking a detailed personal and family history. Twenty individuals (9 men, 11 women)
matched for age and gender without FMV/MVP or MR were used as control.
All studied subjects (patients and controls) underwent selective coronary arteriography
and left ventriculography. Coronary arteriography and left ventriculography were performed
as part of a preoperative evaluation in patients with FMV/MVP and to define coronary
anatomy in the control group as part of their clinical evaluation. None of the studied
individuals had significant coronary artery disease (defined as > 40% stenosis in
any of the coronary arteries). The protocol of the study was approved by the Institutional
Review Board (IRB); individual consent was waived due to the retrospective nature
of the study.
Assessment of Aortic Function
Aortic distensibility was determined from changes in the aortic diameter (systolic
minus diastolic) and aortic pressure (systolic minus diastolic), as described previously.[13]
[14]
[15]
[16] In the cardiac catheterization laboratory, aortic pressures were measured directly
using fluid-filled catheters prior to the injection of contrast medium. Left ventriculogram
was performed in the right anterior oblique projection using the General Electric
Innova system (General Electric Healthcare); frame-by-frame analysis was then performed
to define LV end-systolic and end-diastolic frames. Aortic diameters were then measured
at end-systole and end-diastole 2 cm and 4 cm above the aortic valve ([Fig. 1]); measuring aortic distensibility at two different levels of the aorta was performed
to further strengthen the results, as described previously.[16] LV end-diastolic and end-systolic volumes were also measured, as well as ejection
fraction was determined.
Fig. 1 Left ventriculogram in the right anterior oblique projection. Aortic diameters were
measured at end-systole and end-diastole 2 cm and 4 cm above the aortic valve (dotted
line).
Aortic distensibility was measured using the formula[16]:
Statistical Analysis
Descriptive data are shown as mean ± 1 standard deviation. To determine statistical
significance between the two groups Fisher's exact test, chi-square or the Student's
t-test were used where appropriate. A p-value < 0.05 was considered as statistically significant.
Results
Baseline demographic and clinical parameters are shown in [Table 1]. As compared with control, patients with FMV/MVP had greater LV end-systolic (88 ± 72
mL versus 35 ± 15 mL; p = 0.002) and end-diastolic (165 ± 89 mL versus 100 ± 41 mL; p = 0.005) volumes, and lower LV ejection fraction compared with control (50 ± 12%
versus 57 ± 6%; p = 0.034). Aortic pressures (systolic, diastolic, mean) and pulse pressure (systolic
minus diastolic) were not statistically significant between the two groups.
Table 1
Baseline characteristics and clinical parameters in patients with FMV/MVP and control
|
FMV/MVP (n = 17)
|
Control (n = 20)
|
p Value
|
|
Age (years)
|
55 ± 14
|
54 ± 18
|
0.887
|
|
Gender
|
|
|
0.385
|
|
Male, n (%)
|
11 (65)
|
9 (45)
|
|
|
Female, n (%)
|
6 (35)
|
11 (55)
|
|
|
Heart rate (bpm)
|
77 ± 13
|
81 ± 15
|
0.404
|
|
Systolic blood pressure (mm Hg)
|
132 ± 28
|
118 ± 24
|
0.103
|
|
Diastolic blood pressure (mm Hg)
|
78 ± 16
|
70 ± 10
|
0.064
|
|
Mean blood pressure (mm Hg)
|
99 ± 20
|
92 ± 16
|
0.240
|
|
Pulse pressure (mm Hg)
|
54 ± 15
|
48 ± 23
|
0.378
|
|
LVEDP (mm Hg)
|
18 ± 9
|
14 ± 5
|
0.077
|
|
LVESV (mL)
|
88 ± 72
|
35 ± 15
|
0.002
|
|
LVEDV (mL)
|
165 ± 89
|
100 ± 41
|
0.005
|
|
LVEF (%)
|
50 ± 12
|
57 ± 6
|
0.034
|
|
Severe mitral regurgitation, n (%)
|
14 (82)
|
0 (0)
|
< 0.0001
|
Abbreviations: FMV/MVP, floppy mitral valve/mitral valve prolapse; LVEDP, left ventricular
end-diastolic pressure; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular
ejection fraction; LVESV, left ventricular end systolic volume.
[Table 2] shows aortic diameters in systole and diastole, and aortic distensibility in FMV/MVP
and control groups. Systolic and diastolic diameters at both levels of the aorta (2
cm and 4 cm above the aortic valve) were not statistically different between the two
groups. Change of the aortic diameter from diastole to systole was significantly less
in patients with FMV/MVP compared with control group at 2 cm above the aortic valve
(0.06 ± 0.04 versus 0.16 ± 0.08 cm, respectively; p < 0.0005) and 4 cm above the aortic valve (0.06 ± 0.03 versus 0.15 ± 0.07 cm, respectively;
p < 0.0001). Aortic distensibility was also significantly lower in patients with FMV/MVP
compared with control group at 2 cm above the aortic valve (1.00 ± 0.19 versus 3.78 ± 1.10
10−3 mm Hg−1, respectively; p = 0.027; [Fig. 2A]) and 4 cm above the aortic valve (0.89 ± 0.16 versus 3.22 ± 0.19 10−3 mm Hg−1, respectively; p = 0.007; [Fig. 2B]).
Fig. 2 Aortic distensibility at 2 cm (A) and 4 cm (B) above the aortic valve are shown in patients with floppy mitral valve (FMV)/mitral
valve prolapse (MVP) and in the control group.
Table 2
Aortic diameters and distensibility in patients with FMV/MVP and control
|
FMV/MVP (n = 17)
|
Control (n = 20)
|
p Value
|
|
2 cm above aortic valve
|
|
|
|
|
Aortic systolic diameter (cm)
|
2.72 ± 0.40
|
2.97 ± 0.61
|
0.163
|
|
Aortic diastolic diameter (cm)
|
2.66 ± 0.40
|
2.81 ± 0.60
|
0.376
|
|
Change in aortic diameter (cm)
|
0.06 ± 0.04
|
0.16 ± 0.08
|
< 0.0005
|
|
Aortic distensibility[a]
|
1.00 ± 0.19
|
3.78 ± 1.10
|
0.027
|
|
4 cm above aortic valve
|
|
|
|
|
Aortic systolic diameter (cm)
|
2.78 ± 0.42
|
3.00 ± 0.61
|
0.227
|
|
Aortic diastolic diameter (cm)
|
2.72 ± 0.42
|
2.85 ± 0.63
|
0.482
|
|
Change in aortic diameter (cm)
|
0.06 ± 0.03
|
0.15 ± 0.07
|
< 0.0001
|
|
Aortic distensibility[a]
|
0.89 ± 0.16
|
3.22 ± 0.19
|
0.007
|
Abbreviation: FMV/MVP, floppy mitral valve/mitral valve prolapse.
Note: All data shown represents mean ± standard deviation except for aortic distensibility
that is shown as mean ± standard error of the mean.
a Units for aortic distensibility are 10−3 mm Hg−1.
Discussion
FMV/MVP can result in significant MR and if not treated can lead to heart failure.
In symptomatic patients with FMV/MVP and severe MR, mitral valve surgery is the treatment
of choice. FMV/MVP is the most common cause for mitral valve surgery in developed
countries today.[1]
[2]
[3]
[6]
FMV/MVP is considered to be a heritable disorder of connective tissue.[1]
[4]
[5]
[6] Histopathologic characteristics in the leaflets of the mitral valve in patients
with FMV/MVP include collagen dissolution and disruption in the pars fibrosa, and
replacement of the dense collagenous fibrosa by loose myxomatous connective tissue;
similar histologic changes are found in the chordae tendineae.[7]
[17]
[18]
[19]
The present study demonstrated that aortic distensibility in the ascending aorta is
decreased in patients with FMV/MVP and significant MR. Although aortic dysfunction
may precipitate the progression of MR, up to this point there has been no information
related to aortic function in patients with FMV/MVP.[1]
[2] It is possible that subtle histologic changes of the aortic wall may be present
contributing to aortic dysfunction in these patients.[1]
[2]
[8]
[9]
[10]
[11]
[12] Preliminary studies from our laboratory have shown that patients with FMV/MVP and
severe MR requiring surgery have polymorphisms of matrix metalloproteinases that alter
collagen synthesis and degradation. Whether these findings are related to structural
abnormalities and/or functional changes of the aortic wall remains to be defined.
The patients with FMV/MVP in this study had significant symptomatic MR. It is known
that MR is associated with increased sympathetic activity and decrease in forward
stroke volume, which both may decrease vasa-vasorum blood flow to the outer aortic
wall of the ascending aorta.[20]
[21]
[22] Previous studies at The Ohio State University and other investigations have shown
that a decrease in vasa-vasorum flow is associated with decreased aortic distensibility.[23]
[24] Further, it is known that patients with FMV/MVP even without MR may have high adrenergic
activity and hyper-response to adrenergic stimulation.[25]
[26] Previous studies from our laboratory have shown that patients with FMV/MVP have
β1-adrenergic receptor polymorphisms that enhance adrenergic activity.[27] High adrenergic activity may alter vasa-vasorum flow that in turn influences aortic
function in patients with FMV/MVP with or without MR.
It is well appreciated today that aortic function changes with age; however, age cannot
be a factor in this study since patients with FMV/MVP were matched for age and gender
with the control group.[28]
[29]
[30] Coronary artery disease also may affect aortic function.[16] For this reason, only patients with minimal coronary artery disease were included
in this study. Moreover, the degree of coronary artery disease, though minimal, was
similar between groups.
Clinical Implications: Aorta—The Forgotten Dynamic Organ in MR
Beyond serving as conduit for blood flow, the aorta is important in maintaining LV
performance, myocardial perfusion, and arterial function throughout the cardiovascular
system. When blood is ejected from the LV during systole into the aorta, a pulse wave
is generated. The speed at which the pulse wave travels in the aorta is defined as
the pulse wave velocity (PWV) and is directly related to the elastic properties of
the aortic wall. Under normal conditions, when the pulse wave reaches the peripheral
circulation, the waves return to the ascending aorta as reflected waves. When the
elastic properties of the aorta are normal, reflected waves arrive at the root of
the aorta early in diastole and form the diastolic wave that facilitates coronary
blood flow. When the aorta is stiff, there is an increase in the PWV and reflected
wave velocity. Thus, reflected waves arrive earlier in the root of the aorta, during
systole, fusing with the systolic portion of the pulse pressure wave. This results
in an increase in systolic pressure, LV work and mass, and in the disappearance of
the diastolic wave. Increase in the systolic pressure may increase the severity of
MR, while the disappearance of the diastolic wave may compromise coronary flow. Thus,
a decrease in aortic distensibility (i.e., stiffening of the aorta) results in an
increase in LV afterload, which may result in LV dysfunction, and in turn, increase
in the severity of MR. Left atrial dilatation and dysfunction also ensue ([Fig. 3]). In addition, a stiff aorta may result in impaired LV relaxation and decreased
early diastolic filling, resulting in an increase in left atrial work to maintain
LV stroke volume.[13]
[29]
[31]
[32]
[33]
[34]
[35]
[36]
Fig. 3 (A) When blood is ejected from the left ventricle (LV) into the aorta during systole,
a pulse wave is generated. The speed at which the pulse wave travels in the aorta
is defined as the pulse wave velocity (PWV; white arrows) and is directly related
to the elastic properties of the aortic wall (dotted line represents the expansion
of a normal aorta). When the pulse wave reaches the periphery, it returns to the ascending
aorta as reflected waves. Normally, the reflected waves reach the ascending aorta
early in diastole, resulting in the formation of the diastolic wave that facilitates
coronary blood flow. (B) In a stiff aorta, there is an increase in the PWV and reflected wave velocity; the
reflected waves return early to the aortic root and fuse with the systolic portion
of the pulse pressure, resulting in an increase in systolic aortic pressure and the
disappearance of the diastolic wave. Increased systolic aortic pressure will increase
the severity of mitral regurgitation (MR) (slightly modified from Boudoulas et al.[36]).
Conclusion
The aorta becomes stiffer with age. It follows that aortic PWV increases progressively
with age. In fact, aortic PWV doubles between the second and eighth decade of life.
However, the rate of increase in the PWV is greater after the fifth decade. It should
be mentioned that significant MR in patients with FMV/MVP usually occurs after the
age of 50 at which the aorta becomes stiff.[28]
[29]
[30]
[33] Thus, abnormal aortic function, which also deteriorates with age, may play an important
role in the progression of MR in patients with FMV/MVP. It follows that aortic function
should be evaluated routinely in patients with FMV/MVP, especially if MR is present,
in the same way that LV and left atrial structure and function are measured today.
