Pulmonary Hypertension in Mitral Valve Disease -- Rheumatic Mitral Stenosis Versus Organic Mitral Regurgitation: The Doppler-Echocardiographic Study Revisited

Purpose: The aims of the study were to determine the factors associated with PH among patients with mitral valve disease, and the similarities and differences in the subgroups of mitral stenosis (MS) and mitral regurgitation (MR). Methods: Patients with isolated moderate to severe organic mitral valve disease were prospectively enrolled. Pulmonary hypertension (PH) was dened echocardiographically as pulmonary artery systolic pressure > 50 mmHg. Patients with MS who had mitral valve area > 1.5 cm 2 and patients with MR who had effective regurgitant orice area < 20 mm 2 were excluded. Results: There were 318 patients (mean age 54.3 ± 15.5 years, 57.6% female, 66.7% MR). PH was present in 119 (37.4%) patients (48.1% and 31.8% in MS and MR, respectively). Severe mitral valve disease was reported in 245 (77.0%) patients. Left atrial (LA) diameter and pulmonary artery pressure were signicantly higher in patients with MS. Dyspnea, LA volume index, signicant tricuspid and pulmonary regurgitation, severe mitral valve disease and the presence of MS were independently associated with PH. Among patients with MS, LA volume index and severe disease were independently associated with PH. Signicant tricuspid and pulmonary regurgitation, LA volume index and severe disease were independently associated with PH in patients with MR. Conclusions: PH is common in patients with mitral valve disease. LA volume index and severe disease were, in common, independently associated with PH in patients with mitral valve disease and in the subgroups of MS and MR. leading to PH [5]. LA remodeling, atrial brillation and PH share in common the ultimate pathophysiological consequences and are of prognostic signicance in patients with MS and MR. The presence of PH, dened as pulmonary artery systolic pressure > 50 mmHg at rest, is a valuable sign in determining the need for valvular intervention in patients with mitral valve disease [6, 7]. Several previous studies have veried the factors associated with PH (eg. age, LA enlargement, MR severity) in patients with isolated organic MR [1–3]. However, this issue remains under-recognized in patients with MS. The objectives of the present study were to determine the factors associated with PH in patients with mitral valve disease and, specically, in the subgroups of patients with MS and MR. The study also evaluated the similarities and differences regarding the echocardiographic ndings in patients with MS versus MR. Whitney test were used to compare continuous variables, whereas Chi square and Fisher’s exact test were performed for categorical variables. Univariate and multivariate factors associated with PH were evaluated using logistic regression analysis (forward stepwise method for multivariate analysis) and presented as an odds ratio (95% condence interval). For all tests performed, a two-tailed p-value < 0.05 was considered to be statistically signicant. PASW Statistic (SPSS) 18.0 (SPSS, Inc., Chicago, IL, USA) was used to perform all statistical analyses. pulmonary artery pressure, PASP pulmonary artery systolic pressure, PH pulmonary hypertension, PR pulmonary regurgitation, PVR pulmonary vascular resistance, S’ TV peak systolic myocardial velocity of lateral tricuspid annulus, TAPSE tricuspid annular plane systolic excursion, TR tricuspid regurgitation valve area, PAEDP pulmonary artery end-diastolic PAP pulmonary artery PASP pulmonary artery systolic pressure, PH pulmonary hypertension, PR pulmonary regurgitation, PVR pulmonary vascular RAP right S’ TV peak systolic myocardial velocity of lateral systolic


Introduction
Mitral valve disease is common and can be classi ed according to the anatomical and pathophysiological abnormalities into mitral stenosis (MS) and mitral regurgitation (MR). Pulmonary hypertension (PH) is a common consequence of mitral valve disease and has been reported to occur in 23-33% of patients [1][2][3][4]. Chronic pressure and volume overload of the left atrium (LA) in patients with mitral valve disease lead to an increased LA pressure, LA enlargement, and subsequently, a passive backward transmission of pressure to the pulmonary vascular bed, which triggers pulmonary vasoconstriction, leading to PH [5]. LA remodeling, atrial brillation and PH share in common the ultimate pathophysiological consequences and are of prognostic signi cance in patients with MS and MR. The presence of PH, de ned as pulmonary artery systolic pressure > 50 mmHg at rest, is a valuable sign in determining the need for valvular intervention in patients with mitral valve disease [6,7]. Several previous studies have veri ed the factors associated with PH (eg. age, LA enlargement, MR severity) in patients with isolated organic MR [1][2][3]. However, this issue remains under-recognized in patients with MS. The objectives of the present study were to determine the factors associated with PH in patients with mitral valve disease and, speci cally, in the subgroups of patients with MS and MR. The study also evaluated the similarities and differences regarding the echocardiographic ndings in patients with MS versus MR.

Patient selection
The study population consisted of consecutive patients over 18 years of age who had clinical indications that warranted echocardiography. Patients with a diagnosis of isolated moderate to severe organic mitral valve disease were prospectively enrolled in the study. Patients with mild MS, de ned as a mitral valve area > 1.5 cm 2 and patients with mild MR, de ned as an effective regurgitant ori ce area < 20 mm 2 , were excluded. Other exclusion criteria were patients with combined signi cant MS and MR, functional MR, previous percutaneous balloon mitral valvotomy, co-existing moderate to severe aortic valve disease, a prosthetic valve, previous cardiac surgery, left ventricular systolic dysfunction (left ventricular ejection fraction < 50%), congenital or pericardial disease, renal dysfunction, pulmonary or hepatic disease and those who had a limited or poor-quality echocardiographic study.
Vital signs and an electrocardiogram were obtained in all patients on the day of echocardiography. Dyspnea was de ned using the New York Heart Association function classes II -IV. The study protocol was approved by the institutional review board of Siriraj Hospital, Mahidol University (Bangkok, Thailand). Informed consent was obtained from all patients.

Echocardiography
All patients underwent a comprehensive transthoracic echocardiographic examination, including 2-dimensional and 3-dimensional, Mmode, Doppler echocardiography, and tissue Doppler imaging. The average of 3-5 consecutive cardiac cycles was used for the analysis of echocardiographic measurements. The severity of MR was quantitatively assessed using proximal isovelocity surface area method and grading according to standard recommendations [8]. The severity of MS was graded using mitral valve area [9]. The mitral valve anatomy in MS was assessed using Wilkins score [10]. Patients with MS who were found to have a mitral valve area < 1.0 cm 2 , and patients with MR who were found to have an effective regurgitant ori ce area ≥ 40 mm 2 and regurgitant volume ≥ 60 ml were considered to have severe disease (Fig. 1). Continuous-wave and pulse-wave Doppler spectra of pulmonic regurgitation and tricuspid regurgitation were obtained for the determination of pulmonary artery pressure, including mean pulmonary artery pressure, pulmonary artery end-diastolic pressure, pulmonary vascular resistance and pulmonary artery systolic pressure (Fig. 1) [11]. PH was de ned as pulmonary artery systolic pressure > 50 mmHg [6.7]. The severity of pulmonic regurgitation and tricuspid regurgitation were determined using the combination of multiple parameters [8]. Moderate or greater degree of pulmonic regurgitation and tricuspid regurgitation were considered signi cant regurgitation. LA diameter and volume, left ventricular dimensions, volume, mass and systolic function were evaluated as previously recommended [12] and indexed for body surface area. The assessment of right ventricular systolic function was performed using the tricuspid annular plane systolic excursion and the peak systolic myocardial velocity of lateral tricuspid annulus [12].

Statistical Analysis
Subject characteristics were reported using descriptive statistics, including frequencies and percentage for categorical variables.
Continuous variables were reported as mean ± standard deviation for normally distributed variables and median (25th − 75th percentile) for non-normally distributed continuous variables. Normality of distribution of variables was examined by Kolmogorov-Smirnov test.
The Student t-test and Mann Whitney test were used to compare continuous variables, whereas Chi square and Fisher's exact test were performed for categorical variables. Univariate and multivariate factors associated with PH were evaluated using logistic regression analysis (forward stepwise method for multivariate analysis) and presented as an odds ratio (95% con dence interval). For all tests performed, a two-tailed p-value < 0.05 was considered to be statistically signi cant. PASW Statistic (SPSS) 18.0 (SPSS, Inc., Chicago, IL, USA) was used to perform all statistical analyses.

Results
There were 318 patients enrolled in the study (mean age 54.3 ± 15.5 years) of whom 183 (57.6%) were female. PH was reported in 119 (37.4%) patients. Table 1 shows the baseline characteristics and echocardiographic data in all patients and in patients with and without PH. Dyspnea, history of heart failure, atrial brillation, the use of diuretics and anticoagulants, and severe mitral valve disease were signi cantly more common in patients with PH.  Table 2. Dyspnea, history of stroke and atrial brillation were more common in patients with MS than those with MR. Table 3 shows the comparisons of baseline characteristics and echocardiographic data in patients with and without PH as well as the subgroups of patients with MS and MR.  Data are expressed as number (%), mean ± standard deviation and median (25th − 75th percentile).

Factors Associated With Pulmonary Hypertension
In univariate analysis, dyspnea, atrial brillation, left ventricular ejection fraction, LA volume index, signi cant tricuspid regurgitation, signi cant pulmonic regurgitation, tricuspid annular plane systolic excursion, and clinically more severe disease were signi cantly associated with PH in patients with mitral valve disease. This was also true for patients with MS than patients with MR. Table 4 shows independent factors associated with PH in patients with mitral valve disease and in the subgroups of MS and MR.

Signi cance Of Pulmonary Hypertension In Mitral Valve Disease
The presence of PH in patients with mitral valve disease adversely affects the clinical symptoms and it is a predictor of poor long-term outcome, including event-free survival, even after successful corrective interventions [13,14]. Patients with mitral valve disease and PH are vulnerable to right heart failure and/or pulmonary edema, which greatly contribute to the morbidity and mortality. The current guidelines on treatments of valvular heart disease recommend valvular intervention for asymptomatic patients with mitral valve disease and pulmonary artery systolic pressure > 50 mmHg [6,7].

Pathophysiological Consequences of Mitral Valve Disease in Association with Pulmonary Hypertension
The initial insult leading to PH in chronic mitral valve disease differs between MS and MR. MS leads to LA pressure overload imposed by the stenotic mitral valve, while MR leads to volume overload from signi cant regurgitation. Despite these different pathophysiological mechanisms, the common anatomical and physiologic changes include an increased LA pressure, LA enlargement, a passive backward transmission of pressure to the pulmonary vessels, pulmonary vasoconstriction, irreversible vascular remodeling of pulmonary arterial wall, an increased pulmonary vascular resistance, and eventually PH [5,[15][16][17]. Among patients with mitral valve disease in the present study, dyspnea, LA volume index, signi cant regurgitation of right-sided heart valves, severe disease and stenotic lesion were independent determinants of PH. These ndings emphasize the importance of the pathophysiological alterations of mitral valve disease, such as the severity of clinical disease, LA remodeling and stenotic lesion, leading to PH. The relationship between New York Heart Association functional class and PH in patients with mitral valve disease has previously been reported [2,18]. The more severe the mitral valve disease, the greater is the expected LA dilatation and the higher pulmonary pressure. The present study showed that MS was a more signi cant determinant of PH than MR, regardless of clinical symptoms, cardiac rhythm, and the severity of mitral valve disease. As previously recognized, LA volume index and the severity of MR were identi ed as the independent determinants of PH and had prognostic implications in patients with MR [1,2,19]. However, less has been reported with regard to patients with MS. The present study showed that LA volume index and severe disease were important determinants of PH both in patients with MS and those with MR. Our ndings con rm the importance of LA remodeling to the development of PH in patients with mitral valve disease, and supported the fundamental relationship in term of pathophysiological mechanisms.

Study Limitations
The present study has some limitations. Similar to several previous studies, the majority of patients in the present study had a severe disease and the results may not be applicable to patients with milder disease. The present study focused on the determinants of PH in patients with mitral valve disease and the outcome data are not available. The assessment of pulmonary artery pressure in the present study was achieved solely by Doppler echocardiography, not by right heart catheterization. However, the echocardiographic estimation of pulmonary artery pressure has been well-validated and reinforced by the current guideline for the routine clinical practice [11].

Conclusions
PH is a common clinical and pathophysiological consequence of mitral valve disease with a prevalence of 37.4% in the present study.
Echocardiography can be a valuable way to assess LA function and the likelihood of PH both in patients with MS and those with MR.

Competing interests
The authors declare that they have no completing interests. Figure 1