Pulmonary arterial hypertension in rheumatic mitral stenosis: does it ...

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doi:10.1510/icvts.2009.206607

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Pulmonary arterial hypertension in rheumatic mitral stenosis: does it affect right ventricular function and outcome after mitral valve replacement?夞

Case Report

Interactive CardioVascular and Thoracic Surgery 9 (2009) 421–425

Shantanu Pandea,*, Surendra K. Agarwala, Udgeath Dhira, Amit Chaudharya, Sudeep Kumarb, Vikas Agarwalc Department of Cardiovascular and Thoracic Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India b Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India c Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

a

Institutional Report

Received 7 March 2009; received in revised form 14 May 2009; accepted 16 May 2009

Abstract

Brief Communication Nomenclature

䊚 2009 Published by European Association for Cardio-Thoracic Surgery

The Research and Ethics Committee of Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow approved the protocol and participants gave informed and written consent. Between April 2007 and April 2008, 148 isolated mitral valve replacements were performed for rheumatic heart valve disease. This study included the patients with predominant mitral stenosis with not more than moderate regurgitation. The exclusion criteria were atrial fibrillation and significant left to right shunt defined as QpyQs of 1.5 or greater. Clinical evaluation and echocardiographic assessment of patients was performed preoperatively and 6 weeks after the operation. Echocardiographic imaging was performed using a Philips Sonos 5500 and a 3.2-MHz transducer (Philips Medical Systems, Andover, MA, USA). RV function was assessed by right ventricular descent (RV descent), tricuspid annular plane systolic excursion (TAPSE), myocardial performance index (MPI) and tricuspid annular shortening (TV shortening). RV descent was assessed in apical four-chamber view. The descent of RV apex in the systole from apex to the plane

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夞 Grant support: The study was funded by the intramural grant from Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. *Corresponding author. Tel.: q91 522 2668800 ext. 2212; fax: q91 522 2668017. E-mail address: [email protected] (S. Pande).

2. Materials and methods

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The function of right ventricle (RV) has been poorly investigated in valvular heart disease, and particularly so in cases with rheumatic etiology. It has recently been established that RV function can be impaired in valvular heart disease w1x. RV function has been shown to be a major determinant of clinical outcome w2x. Since it is difficult to assess the various stages of RV dysfunction clinically or by routine echocardiography, special RV function indices need to be evaluated. RV assessment is problematic because of the crescentic shape, separate infundibulum, and prominent trabeculation of the chamber. In addition, RV function is load dependent, subject to pericardial effects, and volume and pressure overload. This clinical study was designed to assess the incidence of RV dysfunction in valvular heart disease of rheumatic etiology, particularly the effect of pulmonary arterial hypertension (PAH) and its effect on the prognosis in shortterm follow-up. N-terminal pro-brain natriuretic peptide

(pro-BNP), which has been shown to be a marker of heart failure, estimation was performed to assess its value in the cases of RV dysfunction and its value in prognosis.

Best Evidence Topic

1. Introduction

Follow-up Paper

Keywords: Valvular heart disease; Right ventricle; Brain natriuretic peptide

Negative Results

Right ventricular function affects the outcome in valvular heart disease but less is known about the relation between indices of dysfunction and outcome. Seventy patients undergoing mitral valve replacement between April 2007 and April 2008 for predominant rheumatic mitral stenosis were included in the study. Two groups were formed based on right ventricular systolic pressure (RVSP), F40 mmHg (group I, ns16) and )41 mmHg (group II, ns54). Right ventricle (RV) function indices were studied by echocardiography. RVSP reduced significantly in group II (Ps0.0001) but not in group I. Brain natriuretic peptide (BNP) was raised in all cases and reduced significantly postoperatively. Tricuspid annular plane excursion, myocardial performance index, RV descent and tricuspid valve annular shortening (TV shortening) conformed to RV dysfunction in both groups, and did not change significantly postoperatively. Regression analysis for outcome revealed TV shortening as the only significant factor (Ps0.03). Receiver operating characteristic of TV shortening and adverse outcome showed worse outcome with TV shortening of -11%. RV dysfunction was observed in all cases irrespective of RVSP. TV shortening of -11% was associated with adverse outcome. Postoperative fall in BNP levels may indicate a trend towards recovery. 䊚 2009 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.

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of tricuspid valve was calculated w3x. TAPSE was estimated using apical four-chamber view; the M mode cursor was placed through the junction of the tricuspid valve plane and RV free wall and the difference in the displacement of RV base during systole and diastole was noted. There is an excellent correlation between TAPSE and RV ejection fraction w4x. The Doppler MPI is expressed by the formula: wisovolumic contraction timeqisovolumic relaxation timey RV ejection timex. The Doppler probe was placed in the right ventricular outflow tract in short axis view to calculate the time between a and e wave (a) and ejection time (b). MPI was calculated by the formula: MPIsa–byb. It is established that MPI is unaffected by heart rate, loading conditions or the presence and severity of tricuspid regurgitation w5x. TV shortening is calculated using apical fourchamber view and assessing the tricuspid valve annulus in diastole and systole in the same cardiac cycle. The shortening is calculated by the formula: wtricuspid annular diameter in diastole – tricuspid annular diameter in systoley tricuspid annular diameter in diastolex. This has a strong correlation with tricuspid regurgitation and right ventricular systolic pressure (RVSP) w6x. Tricuspid regurgitation is graded by calculating the ratio of the tricuspid regurgitation area and the right atrial area in the same cardiac cycle. It was graded as mild (-25%), moderate (26–50%), and severe ()51%) w7x. The following cut-off values were taken as evidence of right ventricular dysfunction based on echocardiographic indices: a TAPSE value of -1.5 cm and MPI value of )0.4 was taken as indicative of RV dysfunction w8x. For RV descent and TV shortening, values of -1.25 cm and -17%, respectively, were taken as suggestive of RV dysfunction w9 x . RV function as well as Pro-BNP values may be affected by the presence of pressure overload due to raised RVSP. The patients were therefore divided into two groups, indicating none to mild PAH: group I (RVSPF40 mmHg) and moderate to severe PAH: group II (RVSP)41 mmHg). 2.1. NT-pro-B-type natriuretic peptide estimation (pro-BNP) Venous blood was collected at the time of index echocardiogram in EDTA-containing tubes 2 days before the surgery. Postoperative samples were drawn after 6 weeks. Samples were centrifuged and plasma was frozen at –80 8C for later analysis. Analysis of NT-pro-BNP was performed (standard range 0–640 fmolyml) using a commercially available sandwich enzyme immunoassay kit (Enzyme immunoassay, Biomedica, Bratislava, Slovakia). Samples from 30 healthy individuals, who were age- and sex-matched, were used to estimate the level of peptide in the normal controls. End points of the study were mortality, hospitalization for )10 days, postoperative pleural effusion, cardiac tamponade after 48 h postoperatively, re-admission (for pericardial effusion, pleural effusion, arrhythmia and congestive heart failure) and inotropic use for )24 h. These endpoints are surrogate markers of RV dysfunction and as the individual end points were expected to be small in numbers, we took a combination of the above end points.

2.2. Statistics The data are expressed as mean and S.D. for the whole cohort and median and range for individual groups. Nonparametric tests were utilized to obtain significance while comparing variables in both groups. The Wilcoxon signedrank test was used to compare two values of a variable in same group, while the Mann–Whitney U-test was utilized to calculate significance between two values of a variable in two different groups. Logistic regression analysis was performed to determine the effect of single variable and combination of variables in predicting outcome. Pearson’s correlation was used to correlate two variables. x2 with Fischer’s exact tests were used as appropriate for comparison of proportions. Receiver operating characteristic (ROC) of each echocardiographic parameter to predict RV function was estimated using a parametric binormal approach. All analysis was performed with SPSS 10 version for Windows (SPSS, Inc. Chicago, IL, USA). 3. Results A total of 70 patients (mean age 35.96"14.7 years, 32 men) were included in the study. Sixteen had RVSP F40 mmHg (group I) and 54 had RVSP 41 mmHg (group II). There were two deaths in the study, one patient died before surgery after enrollment into the study, due to congestive heart failure, while the other died 3 months post-operation due to pneumonitis and septicemia. Both cases were in group II. There was no operative mortality. Table 1 compares the preoperative echocardiographic variables of both groups. Operative parameters and additional surgical procedures are compared in Table 2. Postoperative variables are given in Table 3. Change in the values of echocardiographic parameters of left ventricular (LV) function and RV indices after mitral valve replacement are provided in Table 4. RVSP significantly reduced in group Table 1 Preoperative clinical and echocardiographic parameters Variable

Group I ns16 median (range)

Group II ns54 median (range)

P-value

NYHA class LVEDD (mm) LVESD (mm) LVEF (%) LA (mm) RVSP (mmHg) MVA (cm2) TR jet areayRAA TAPSE (cm) RV descent (cm) TV shortening (%) MPI NT-pro-BNP (fmolyml)

3 (2–3) 54 (43–73) 37 (26–60) 55 (40–71) 52 (31–97) 32.5 (22–39) 0.95 (0.60–2.0) 0.24 (0.07–0.63) 1.30 (0.68–1.97) 0.85 (0.10–1.95) 17 (4–34) 1.96 (1.17–6.17) 69 (11–610)

3 (2–3) 47.5 (28–69) 31 (16–45) 60 (40–76) 53 (37–120) 60 (41–115) 0.80 (0.40–2.10) 0.22 (0–0.61) 1.23 (0.34–2.71) 0.91 (0.04–2.29) 16.5 (2–36) 2.05 (0.72–6.04) 65 (9–640)

0.09 0.01 0.02 0.1 0.1 0.0001 0.1 0.9 0.8 0.6 0.8 0.8 0.9

NYHA, New York Heart Association; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter; LVEF, left ventricular ejection fraction, LA, left atrium; RVSP, right ventricular systolic pressure; MVA, mitral valve area; TR jet areayRAA, tricuspid valve regurgitation areay right atrial area; TAPSE, tricuspid annular plane systolic excursion; RV descent, right ventricular descent; TV shortening, tricuspid valve annular shortening; MPI, myocardial performance index; NT-pro-BNP, N-terminal-proB-type natreuretic peptide.

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Table 2 Additional surgical procedures Group II ns54 median (range)

P-value

CPB (min) ACC (min) De Vega’s annuloplasty (n) TV commissurotomy (n) LA reduction (n)

54.5 (40–120) 29.5 (19–80) 1 0 0

56 (32–170) 27 (20–71) 5 5 4

0.4 0.9 0.7 0.7 0.6

CPB, cardiopulmonary bypass; ACC, aortic cross-clamp; De Vega’s annuloplasty, De Vega’s tricuspid valve annuloplasty; TV commissurotomy, tricuspid valve commissurotomy; LA reduction, left atrial reduction. Table 3 Postoperative echocardiographic parameters P-value

NYHA class LVEDD (mm) LVESD (mm) LVEF (%) LA (mm) RVSP (mmHg) TR jet areayRAA TAPSE (cm) RV descent (cm) TV shortening (%) MPI NT-pro-BNP (fmolyml)

1 (1–2) 48 (41–69) 35 (20–62) 55 (15–67) 45 (29–66) 32.5 (30–59) 0.13 (0–0.37) 0.91 (0.12–1.53) 0.82 (0.33–2.20) 19.5 (8–22) 1.74 (0.92–2.31) 24 (7–120)

1 (1–3) 46 (39–60) 32 (22–50) 55 (20–60) 42 (30–80) 38 (26–76) 0.18 (0–0.42) 0.98 (0.05–2.32) 0.75 (0.15–2.70) 13 (2–33) 1.66 (0.88–3.23) 21 (6–120)

0.1 0.4 0.4 0.8 0.6 0.1 0.3 0.7 0.8 0.2 0.4 0.3

This study evaluates patients of rheumatic valvular heart disease and evidence of RV dysfunction wdefined by MPI (0.40) and TAPSE (-1.5 cm)x w8x. Though group I patients had no or mild pulmonary hypertension, they still exhibited RV dysfunction. There are several factors other than pulmonary artery pressure that may contribute to RV dysfunction in valvular heart disease, for example, ventricular interdependence and RV ischemia w10x. It was observed that RVSP had no effect on the outcome. Previous studies

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Table 4 Comparison of pre and postoperative variables Group 2 ns54 median (range) P-value

Preoperative

Postoperative

P-value

1 (1–2) 48 (41–69) 35 (20–62) 55 (15–67) 45 (29–66) 32.5 (30–59) 0.13 (0–0.37) 0.91 (0.12–1.53) 0.82 (0.33–2.20) 19.5 (8–22) 1.74 (0.92–2.31) 24 (7–260)

0.04 0.06 0.6 0.2 0.06 1.0 1.0 1.0 0.8 0.8 1.0 0.002

3 (2–3) 47.5 (28–69) 31 (16–45) 60 (40–76) 53 (37–120) 60 (41–115) 0.22 (0–0.61) 1.23 (0.34–2.71) 0.91 (0.04–2.29) 16.5 (2–36) 2.05 (0.72–6.04) 65 (9–640)

1 (1–3) 46 (39–60) 32 (22–50) 55 (20–60) 42 (20–80) 38 (26–76) 0.18 (0–0.42) 0.98 (0.05–2.32) 0.75 (0.15–2.70) 13 (2–33) 1.66 (0.88–3.23) 21 (6–120)

0.02 0.3 0.1 0.005 0.001 0.001 0.9 0.1 0.9 0.3 0.5 0.001

NYHA, New York Heart Association; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter; LVEF, left ventricular ejection fraction; LA, left atrium; RVSP, right ventricular systolic pressure; MVA, mitral valve area; TR jet areayRAA, tricuspid valve regurgitation areayright atrial area; TAPSE, tricuspid annular plane systolic excursion; RV descent, right ventricular descent; TV shortening, tricuspid valve annular shortening; MPI, myocardial performance index; NT-pro-BNP, N-terminal-pro-B-type natreuretic peptide.

Nomenclature

Postoperative

3 (2–3) 54 (43–73) 37 (26–60) 55 (40–71) 52 (31–97) 32.5 (22–39) 0.24 (0.07–0.63) 1.3 (0.68–1.97) 0.85 (0.10–1.95) 17 (4–34) 1.96 (1.17–6.17) 69 (11–610)

Brief Communication

Preoperative

State-of-the-art


NYHA class LVEDD (mm) LVESD (mm) LVEF (%) LA (mm) RVSP (mmHg) TR jet areayRAA TAPSE (cm) RV descent (cm) TV shortening (%) MPI NT-pro-BNP (fmolyml)

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II while it remained similar to preoperative values in group I (Table 4). Correlation between different RV indices was

4. Discussion

Best Evidence Topic

NYHA, New York Heart Association; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter; LVEF, left ventricular ejection fraction; LA, left atrium; RVSP, right ventricular systolic pressure; MVA, mitral valve area; TR jet areayRAA, tricuspid valve regurgitation areay right atrial area; TAPSE, tricuspid annular plane systolic excursion; RV descent, right ventricular descent; TV shortening, tricuspid valve annular shortening; MPI, myocardial performance index; NT-pro-BNP, N-terminal-proB-type natreuretic peptide.

Follow-up Paper


Negative Results



Variable

Protocol


studied. There was a strong positive correlation between TAPSE and MPI preoperatively (rs0.712, Ps0.003) and a positive correlation between tricuspid valve annular diameter in diastole (TVADD) and TR jet areayRAA (rs0.325, Ps0.01). A weak negative correlation was observed between mitral valve area and RVSP preoperatively (rs –0.349, Ps0.005). Outcome in the two groups is given in Table 5. There was no significant difference in RV function indices in cases with preoperative tricuspid valve involvement requiring surgery (ns11) when compared to those not requiring tricuspid valve intervention (ns59). Similarly, there was no significant change in RV function indices after surgery in patients with tricuspid intervention (ns11) and without it (ns59). There was a significant reduction in pro-BNP in both groups after operation (Table 4) as compared to preoperative values but they did not become normal. pro-BNP levels in healthy controls were 3.89" 3.73 fmolyml. Forward logistic regression analysis was performed to predict the possibility of LV and RV function indices and NT-pro-BNP estimation, affecting the combined end points. TV annular shortening could predict composite end point with 41.7% accuracy, Ps0.03 wOR 0.92 (95% CI 0.86–0.99)x. ROC of TV annular shortening (Fig. 1) indicated the cut-off point at 11%. Patients with TV annular shortening of -11% had a higher rate of adverse events (area under the curves0.743, Ps0.003).

Case Report

Variable

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Table 5 Outcome variables Variables



P-value

Hospital stay (n) Cardiac tamponade (n) Pleural effusion (n) Inotrope requirement for )24 h Hospital stay of )10 days Re-admission Death (n) Combined numbers of patients with adverse outcome (combined end point) (n)

9 (6–20) 0 0 7 2 0 0 9

9 (5–20) 2 1 22 8 1 2 25

0.8 0.9 0.3 0.2 0.5 0.9 0.4 0.1

have also shown that RV dysfunction is a better predictor of outcome than pulmonary hypertension w11x. TAPSE predicted the survival in patients with pulmonary hypertension in a study by Forfia et al. w12x. Since RV dysfunction was present preoperatively in all cases in the present study, it did not predict the outcome when both groups were analyzed. Interestingly, TV annular shortening (a measure of circular fiber shortening of RV) predicted adverse outcome. ROC indicated a value of TV shortening of 11% as cut-off for predicting adverse outcome. In normal subjects TV annular shortening is 22% w9x. Though the predictive power for this variable with sensitivity and specificity of -80% and accuracy of -50% is poor, this cut-off value provides a clue for future studies. RV has predominantly longitudinal muscle fibers subendocardially, and their dysfunction is measured by MPI and TAPSE, which assess the contraction of longitudinal plane from RV apex to tricuspid valve w13x. Circumferential fibers of RV are parallel to atrioventricular

groove and encircle pulmonary infundibulum, subepicardially. When dysfunction of these fibers as measured by TV annular shortening is added to the longitudinal fiber dysfunction, it predicts the adverse outcome in these patients, as was evident in the present study. The change in indices of RV function postoperatively was mixed in both groups and was not statistically significant, though MPI has shown some recovery. Laichbury et al. w14x showed that pro-BNP was not raised in patients with raised pulmonary artery pressures in the absence of right heart failure. Thus, pro-BNP may be a better marker for RV dysfunction. The present study has also shown that the values were raised in all patients irrespective of their RVSP. Also, the echocardiographic indices were suggestive of presence of RV dysfunction in all patients, which may explain the increase in their proBNP values. NT-pro-BNP estimation could not predict outcome in these cases as reported in some sparse studies w15x. The reason could be the presence of RV dysfunction in all the cases as evidenced by manifold increase from the value in healthy individuals. There was a significant decrease of peptide levels in both groups, which may have occurred due to a decrease in pulmonary artery pressure and reduction in the distension of RV indicating an early trend in the improvement of RV function after operation. Although the echocardiographic indices did not change significantly after the operation, a long-term echocardiographic follow-up may show a change in these parameters of RV function as well. 5. Conclusion RV dysfunction of longitudinal muscle fiber is present in all patients presenting with predominant mitral stenosis. pro-BNP estimation shows a significant decrease post-operation indicating an early trend of recovery. TV annular shortening of -11% predicts adverse outcome. 5.1. Limitations of the study The small number of patients and the short-term followup (6 weeks) is a major limitation of this study. References

Fig. 1. ROC curve of TV annular shortening in predicting adverse outcome.

w1x Nagel E, Stuber M, Hess OM. Importance of the right ventricle in valvular heart disease. Eur Heart J 1996;17:829–836.

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w10x

w12x

w13x

w15x


w14x

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w11x

tricuspid annular motion and myocardial performance. J Am Soc Echocardiogr 2004;17:443–447. Lambertz H, Sechtem U, Soeding S, Kemmer HP, Krebs W. Pathophysiology of tricuspid insufficiency: analysis of the motion of the tricuspid valve annulus using 2-dimensional echocardiography. Z Cardiol 1985;74:662–669. Borer JS, Hochreiter C, Rosen S. Right ventricular function in severe non-ischaemic mitral insufficiency. Eur Heart J 1999;12(Suppl B):22– 25. Yeo TC, Dujardin KS, Tei C, Mahoney DW, McGoon MD, Seward JB. Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol 1998;81:1157–1161. Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, Chamera E, Corretti MC, Champion HC, Abraham TP, Girgis RE and Haussoun PM. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med 2006;174:1034–1041. Rushmer RF, Crystal DK, Wagner C. The functional anatomy of ventricular contraction. Circ Res 1953;1:162–170. Laichbury JG, Campbell E, Frampton CM, Yandle TG, Nicholls MG, Richards AM. Brain natriruetic peptide and N-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath. J Am Coll Cardiol 2003;42:728–735. Weber M, Hamm C. Role of B-type natriuretic peptide and NT-Pro BNP in clinical routine. Heart 2006;92:843–849.

Case Report

w2x de Groote P, Millaire A, Foucher-Hossien C, Nugue O, Marchandise X, Ducloux G, Lablanche JM. Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 1998;32:948–954. w3x Shah AR, Grodman R, Salazar MF, Rehman NU, Coppola J, Braff R. Assessment of acute right ventricular dysfunction induced by right coronary artery occlusion using echocardiographic atrioventricular plane displacement. Echocardiography 2000;17:513–519. w4x Kaul S, Tei C, Hopkins JM, Shah PM. Assessment of right ventricular function using two-dimensional echocardiography. Am Heart J 1984;107:526–531. w5x Tei C, Dujardin KS, Hodge DO, Bailey KR, McGoon MD, Tajik AJ, Seward SB. Doppler echocardiographic index for assessment of global ventricular function. J Am Soc Echocardiogr 1996;9:838–847. w6x Pande S, Agarwal SK, Majumdar G, Kapoor A, Kale N, Kundu A. Valvuloplasty in rheumatic tricuspid disease. Asian Cardiovasc Thorac Ann 2008;16:107–111. w7x Tager R, Skudicky D, Mueller U, Essop R, Hammond G, Sareli P. Longterm follow-up of rheumatic patients undergoing left sided valve replacement with tricuspid annuloplasty – validity of preoperative echocardiographic criteria in the decision to perform tricuspid annuloplasty. Am J Cardiol 1998;81:1013–1016. w8x Miller D, Farah MG, Liner A, Fox K, Schluchter M, Hoit BD. The relation between quantitative right ventricular ejection fraction and indices of

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Negative Results Follow-up Paper Best Evidence Topic Proposal for Bailout Procedure Work in Progress Report State-of-the-art Brief Communication Nomenclature