- Email: [email protected]
Plasma active matrix metalloproteinase 9 associated to diastolic dysfunction in patients with coronary artery disease
336
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[4] Palazzuoli A, Rizzello V, Calabro A, Gallotta M, Martini G, Quatrini I, et al. Osteoprotegerin and B-type natriuretic peptide in non-ST elevation acute coronary syndromes: relation to coronary artery narrowing and plaques number. Clin Chim Acta 2008;391:74–9. [5] Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA, Giachelli CM. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. J Biol Chem 2000;14:20959–62. [6] Bennett BJ, Scatena M, Kirk EA, Rattazzi M, Varon RM, Averill M, et al. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE−/− mice. Arterioscler Thromb Vasc Biol 2006;26:2117–24.
[7] Schnabel R, Larson MG, Dupuis J, Lunetta KL, Lipinska I, Meigs JB, et al. Relations of inflammatory biomarkers and common genetic variants with arterial stiffness and wave reflection. Hypertension 2008;51:1651–7. [8] Kim SM, Lee J, Ryu OH, Lee KW, Kim HY, Seo JA, et al. Serum osteoprotegerin levels are associated with inflammation and pulse wave velocity. Clin Endocrinol Oxf 2005;63:594–8. [9] Shewan LG, Coats AJ. Ethics in the authorship and publishing of scientific articles. Int J Cardiol 2010;144:1–2.
0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.12.094
Plasma active matrix metalloproteinase 9 associated to diastolic dysfunction in patients with coronary artery disease John W. Chu a,⁎, Gregory T. Jones b, Gregory P. Tarr b, L. Vicky Phillips b, Gerard T. Wilkins a, Andre M. van Rij b, Michael J.A. Williams a a b
Departments of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand Departments of Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
a r t i c l e
i n f o
Article history: Received 22 December 2010 Accepted 23 December 2010 Available online 28 January 2011 Keywords: Diastolic function Extracellular matrix Matrix metalloproteinase Coronary artery disease
Circulating levels of total matrix metalloproteinases (MMP) have been associated with diastolic dysfunction and heart failure [1,2]. This study aimed to investigate the relationship of the endogenous active levels of MMP-1,-2,-3 and -9 or tissue inhibitor of metalloproteinases1 (TIMP-1) and diastolic dysfunction (DD) in the setting of coronary artery disease (CAD). One hundred fifty-three patients with angiographically proven CAD were recruited retrospectively from the Dunedin Hospital Cardiology Clinical database. The patients were stable and free of heart failure symptoms at the time of recruitment. Clinical parameters recorded along with anthropometric measurements. The study protocol was approved by the Otago ethics committee. All subjects gave written informed consent before being recruited into this study. EDTA plasma samples were analysed for high-sensitivity Creactive protein (hs-CRP), creatinine, pro-MMP-9 and total TIMP-1 (GE Healthcare Life Sciences, RPN2611 and RPN2614). Endogenous plasma MMP-1, -2, -3 and -9 were measured in heparin plasma [3] samples (GE Healthcare Life Sciences, RPN2629, RPN2631, RPN2639 and RPN2634). The ratio of pro-MMP-9 to active enzyme indicated the proportion of zymogen activation. The average coefficient of variance for both activity and conventional ELISA assays was < 6%.
⁎ Corresponding author. Dunedin School of Medicine, University of Otago, Department of Cardiology, Dunedin Hospital, 201 Great King Street, Dunedin 9001, New Zealand. Tel.: + 64 3 4747007/8089; fax: +64 3 474 7655. E-mail address: [email protected] (J.W. Chu).
All patients had trans-thoracic echocardiography and Doppler examination (GE/VingMed Vivid-3 system, USA) with analyses subsequently performed off-line. Two-dimensional, targeted M-mode echocardiography, and Doppler ultrasound measurements were obtained. All measurements were taken according to the guidelines of the American Society of Echocardiography [4,5]. All echocardiography data represent the mean of 5 measurements on different cardiac cycles. Left ventricular (LV) ejection fraction was calculated by the modified Simpson's biplane method. LV mass in grams was derived from LV linear dimensions by the following formula: LV mass = 0.8× {1.04[(LVIDd+ PWTd+ SWTd)3 (LVIDd)3]}+ 0.6 where LVIDd , PWTd and SWTd were LV internal dimension at end diastole, posterior wall thickness at end diastole and septal wall thickness at end diastole, respectively [5]. All measurements were made with archive images recorded in a blinded fashion. The pulsed Doppler measurements were obtained in the apical view with a cursor at the mitral valve inflow: maximal early (E) and late (A) transmitral velocities in diastole and E-wave deceleration time. Isovolumic relaxation time (IVRT) was measured by continuous-wave Doppler placed between the mitral inflow area and the LV outflow tract. DD was graded as mild (impaired relaxation), mild-moderate (impaired relaxation), moderate (pseudonormal pattern), and severe (restrictive filling) using the Canadian Consensus Classification [6,7]. All patients studied had preserved LV systolic function with ejection fraction ≥45%. StatView version 5.01(SAS Institute) was used to perform statistical analysis. The distribution of continuous variables (kurtosis and skewness) was assessed and analysed with either the Mann–Whitney U, Kruskal–Wallis (non-parametric trend test) or ANOVA with Fisher protected least significant difference test. Results are shown as mean ± 1SD, except variables with a non-Gaussian distribution, which are reported with medians and interquartile ranges. Odds ratios are given with 95% confidence intervals. A p-value of less than 0.05 was considered statistically significant. Multiple logistic forward stepwise regression was used to evaluate the interaction between variables and MMPs in correlation with DD. The ability of MMP markers to shift cases and controls to correct clinical categories was assessed by classification tables derived from the multiple logistic regression model, based on the work by Cook et al [8]. Non-parametric ROC curves were generated using a dedicated programme, mROC (Unité de biostatistiques, CRLC Val d'Aurelle, V1.0) [9].
Letters to the Editor
337
Table 1 Clinical characteristics according to the phases of diastolic function. Phases of diastolic dysfunction Characteristics
Normal n = 62
Mild n = 49
Mild–moderate n = 23
Moderate n = 13
Severe n = 6
Age, years Male BMI, kg/m2 WHR Hypertension (> 140/90 mmHg) Hypercholesterolemia Diabetes mellitus Coronary artery disease severity Single vessel Double vessel Triple vessel Smoking pack years GFR, ml/min hs-CRP, mg/L Medications ACEI or ARB Beta-blocker Calcium-antagonist Statin Nitrate
60.3 ± 9.3 44 (71.0) 28.5 ± 4.4 0.92 ± 0.13 26 (41.9) 32 (51.6) 14 (22.6)
66.0 ± 9.3 32 (65.3) 29.3 ± 4.5 0.94 ± 0.08 19 (38.8) 25(51.0) 10(20.4)
63.7 ± 10.5 14 (60.9) 28.5 ± 5.5 0.92 ± 0.08 13 (56.5) 14 (60.9) 3(13.0)
67.4 ± 8.9 8 (61.5) 28.9 ± 5.2 0.93 ± 0.10 7 (53.8) 6 (46.2) 3 (13.0)
66.0 ± 8. 4 (67.7) 30.2 ± 3.9 0.91 ± 0.07 3 (50.0) 3 (50.0) 1 (16.7)
0.08 0.87 0.77 0.67 0.26 0.90 0.82
28 (45.2) 18 (29.0) 16 (25.8) 7.5 (0–27.8) 85.9 ± 26.3 1.7 (1.2–3.3)
21 (42.9) 18 (36.7) 10 (20.4) 13.8 (0.5–37.5) 78.1 ± 23.6 3.2 (1.7–5.9)
7 (30.4) 8 (34.8) 8 (34.8) 7.5 (0–40.0) 78.9 ± 29.2 1.6 (1.2–2.9)
6 (46.1) 4 (30.7) 3 (23.1) 0 (0–6.8) 86.6 ± 51.1 2.7 (1.7–6.3)
4 (66.7) 0 (0.0) 2 (33.3) 3.5 (0–10.5) 68.4 ± 22.9 2.5 (2.2–6.1)
0.13
38 28 14 58 17
25 23 12 46 18
13 (56.5) 11 (47.8) 7 (30.4) 21 (91.3) 9 (29.1)
7 (53.8) 6 (46.2) 5 (38.4) 11 (84.6) 4 (30.8)
4 (66.7) 3 (50.0) 2 (33.3) 6 (100.0) 2(33.3)
(46.8) (45.2) (22.6) (93.5) (27.4)
(52.0) (46.9) (24.5) (93.9) (36.7)
P-value for trend*
0.04 0.38 <0.04 0.92 0.20 0.13 0.66 0.29
BMI = body mass index; WHR = waist hip ratio; GFR = glomerular filtration rate; and hs-CRP = high sensitivity C-reactive protein. ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker; and Statin = Hydroxmethyl glutaryl coenzyme A reductase inhibitor. Data for the characteristics are expressed as mean ± standard deviation, median (interquartile range) or n (%). *Kruskal–Wallis trend test.
Table 1 shows the clinical characteristics of the study population. The number of smoking pack years was higher in the mild DD group. There were no differences in age, cardiovascular risk factors, renal function and pharmacotherapy. The level of hs-CRP was higher in the mild and moderate DD groups, however, it is worth noting that all groups had median levels below < 5 mg/L. Patients with more advanced phases of DD had higher E/A ratio, shorter deceleration time, IVRT and a larger left atrium, as anticipated. They had thicker inter-ventricular septum and posterior wall. In the mild-moderate DD group, the ejection fraction was higher. Because of the small number of patients with severe DD in the cohort, we combined this group with the moderate DD group for analysis in relation to MMP levels. There were no significant differences in plasma MMP-1, -2, -3, and proMMP-9 levels. Plasma active MMP-9 increased significantly with
more severe phases of DD, in particular from mild to mild-moderate phases (Table 2). These results were unchanged when the analysis was repeated without combining the moderate and severe DD groups. Adjusted for age, smoking pack years, CAD severity, hypertension and hs-CRP, elevated active MMP-9 (> 2 ng/mL) had an odds ratios of 6.1 (95% confidence interval [CI]: 1.7–21.2, and p = 0.005) and 9.1 (95% CI: 2.2–37.2, and p = 0.003) for association with mild–moderate DD and moderate or severe DD respectively. The cut-off of 2 ng/mL gave the best trade-off in terms of sensitivity and specificity between normal controls and moderate/severe DD, with values of 0.645 and 0.655, respectively. The addition of active MMP-9 and TIMP-1 to the regression model resulted in an increase of subjects being placed in their correct diastolic function category from 47.1% to 59.1%, with improved classification across all categories. This was associated
Table 2 Comparison of echocardiographic and biochemical data according to the phases of diastolic function. Phases of diastolic dysfunction Echocardiographic data
Normal n = 62
Mild n = 49
Mild–moderate n = 23
Moderate or severe n = 19
P-value for trend*
Ejection fraction, % Peak E, cm/s Peak A, cm/s E/A † DT, ms IVRT, ms LVM,g/m2 LVDD, mm IVS, mm PW, mm LA, mm Metalloproteinase data‡ Active MMP-1, ng/mL Active MMP-2, ng/mL Active MMP-3, ng/mL Pro-total MMP-9, ng/mL Active MMP-9, ng/mL TIMP-1, ng/mL
57 ± 8 84 ± 15 66 ± 14 1.3 ± 0.2 217 ± 32 88 ± 21 97 ± 30 48 ± 5 11 ± 2 10 ± 2 38 ± 5
57 ± 8 66 ± 15 85 ± 18 0.8 ± 0.1 264 ± 50 115 ± 20 102 ± 35 48 ± 6 11 ± 2 11 ± 2 41 ± 4
63 ± 9 62 ± 13 80 ± 15 0.8 ± 0.2 236 ± 47 90 ± 15 106 ± 20 46 ± 6 12 ± 2 11 ± 1 40 ± 4
59 ± 8 88 ± 25 56 ± 22 1.7 ± 1.0 167 ± 128 86 ± 26 110 ± 64 47 ± 6 13 ± 3 12 ± 2 42 ± 6
<0.04 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.46 0.30 <0.02 <0.05 <0.008
2.8 (1.1–5.0) 15.7 (11.3–18.4) 2.9 (1.3–5.0) 25.1 (15.9–37.1) 1.4 (1.0–2.1) 212 (186–246)
2.2 (1.0–3.7) 13.9 (9.2–18.4) 3.8 (2.1–7.0) 24.0 (17.3–43.6) 1.5 (0.9–2.0) 242 (212–279)
2.8 (1.0–6.8) 18.4 (14.0–22.3) 2.2 (1.7–3.2) 20.4 (14.3–26.2) 2.1 (1.5–3.0) 220 (187–277)
3.1 (1.2–4.4) 14.6 (8.8–16.3) 3.2 (1.7–4.5) 29.2 (18.2–38.8) 2.4 (1.6–3.0) 224 (208–274)
0.68 0.20 0.37 0.53 <0.003 0.07
DT = E-wave deceleration time; IVRT = isovolumic relaxation time; and LVDD = left ventricular diastolic dimension. IVS = interventricular septum thickness; PW = posterior wall thickness; LA = left atrial dimension; MMP = matrix metalloproteinase; and TIMP = tissue inhibitor of matrix metalloproteinase. Echocardioraphic data are expressed as mean ± standard deviation. *Kruskal–Wallis trend test. † E/A could not be calculated for 4 patients with atrial fibrillation. ‡ Results are expressed as medians and interquartile range.
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with improved model fit, as indicated by a decrease of 10 points using the Bayesian Information Criteria. The addition of active MMP9 and TIMP-1 to these same variables resulted in an increase of area under the curve of 9% and 6%, respectively, for the discrimination between controls and mild/moderate DD (from 0.73 (95% CI 0.60– 0.83) to 0.82 (95% CI 0.70–0.89)), and between controls and moderate/severe DD (from 0.76 (95% CI 0.62–0.86) to 0.82 (95% CI 0.70–0.90)). In conclusion, this study indicates that elevated level of the active form of MMP-9 is associated with DD, and the level of elevation correlates with the phases of DD in patients with CAD. This finding may reflect abnormal extracellular matrix metabolism in myocardial ischemia and the prognostic value of this marker needs to be further evaluated. Future prospective longitudinal studies will be required to explore the role of this enzyme on this important and common clinical problem. Heart Foundation of New Zealand, Auckland, New Zealand. Southland Medical Foundation, Invercargill, New Zealand. Special thanks to Mrs. Maree McCormack for her assistance with participant recruitment. This study was made possible through the funding support of the Heart Foundation of New Zealand. Dr John W. Chu was supported in part by the Southland Medical Foundation, Invercargill, New Zealand, as a W & G S Dick Research Fellow. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [10].
References [1] Saglam M, Karakaya O, Esen AM, et al. Contribution of plasma matrix metalloproteinases to development of left ventricular hypertrophy and diastolic dysfunction in hypertensive subjects. Tohoku J Exp Med 2006;208:117–22. [2] Ahmed SH, Clark LL, Pennington WR, et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: Relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 2006;113:2089–96. [3] Castellazzi M, Tamborino C, Fainardi E, et al. Effects of anticoagulants on the activity of gelatinases. Clin Biochem 2007;40:1272–6. [4] Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: A report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167–84. [5] Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: A report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63. [6] Rakowski H, Appleton C, Chan KL, et al. Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography: From the Investigators of Consensus on Diastolic Dysfunction by Echocardiography. J Am Soc Echocardiogr 1996;9:736–60. [7] Yamada H, Goh PP, Sun JP, et al. Prevalence of left ventricular diastolic dysfunction by Doppler echocardiography: Clinical application of the Canadian Consensus Guidelines. J Am Soc Echocardiogr 2002;15:1238–44. [8] Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med 2006;145:21–9. [9] Kramar A, Faraggi D, Fortune A, Reiser B. mROC: A computer program for combining tumour markers in predicting disease states. Comput Meth Programs Biomed 2001;66:199–207. [10] Shewan LG and Coats AJ. Ethics in the authorship and publishing of scientific articles. Int J Cardiol 2010;144:1–2.
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.12.093
Comparison of different body habitus between patients with mitral valve prolapse and normal populations in young Taiwanese females Mao-Jen Lin a, Ting-Hsiang Lin b, Hau-De Lin a, Chung-Sheng Lin c,⁎ a b c
The Division of Cardiology, Department of Medicine, Buddhist Tzu-Chi General Hospital, Taichung branch, Taiwan Department of Statistics, National Taipei University, Taipei, Taiwan Department of Internal Medicine, Chung-Shan Medical University Hospital and School of Medicine, Chung-Shan Medical University, Taichung, Taiwan
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Article history: Received 20 December 2010 Accepted 23 December 2010 Available online 20 January 2011 Keywords: Body habitus Mitral valve prolapse Taiwan
The mitral valve prolapse (MVP) syndrome is one of the most prevalent cardiac valvular abnormalities and may affect as much as 5–15% of the population [1]. The weight of patients with MVP is often ⁎ Corresponding author. Department of Internal Medicine, Chung Shan Medical University Hospital, 110, Section 1, Chien Kuo North Road, Taichung, Taiwan 402. Tel.: +886 4 24739595 #34711; fax: +886 4 24739220. E-mail address: [email protected] (C.-S. Lin).
lower, and the habitus may be asthenic. Blood pressure (BP) is also normal or lower, and orthostatic hypotension may present. It has never been studied in association with body habitus in Taiwanese MVP patients. Thus we attempt to answer whether the descriptions regarding body habitus parameters in Western literature also apply to Taiwanese female patients. The study protocol was approved by the institution review board and ethics committee of Tzu Chi General Hospital, and informed consent was obtained from all participants. We consecutively recruited female patients aged between 20 and 30 years old. MVP patients without other organic heart disease were selected. Normal, age-matched volunteers without MVP and body habitus that cohered to normal population study reports in Taiwan (e.g., height range from 149 to 169 cm; weight range from 36 to 69 kg,) were recruited. Each patient completed a survey of symptoms of chest tightness, palpitation or breathless sensation. The diagnosis of MVP based on demonstration of thick, redundant leaflets and chordae with systolic displacement of the leaflets into the left atrium in two-dimensional echocardiogrpahy [2]. The measurement of body parameters included height, weight, body mass index
Letters to the Editor
[4] Palazzuoli A, Rizzello V, Calabro A, Gallotta M, Martini G, Quatrini I, et al. Osteoprotegerin and B-type natriuretic peptide in non-ST elevation acute coronary syndromes: relation to coronary artery narrowing and plaques number. Clin Chim Acta 2008;391:74–9. [5] Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA, Giachelli CM. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. J Biol Chem 2000;14:20959–62. [6] Bennett BJ, Scatena M, Kirk EA, Rattazzi M, Varon RM, Averill M, et al. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE−/− mice. Arterioscler Thromb Vasc Biol 2006;26:2117–24.
[7] Schnabel R, Larson MG, Dupuis J, Lunetta KL, Lipinska I, Meigs JB, et al. Relations of inflammatory biomarkers and common genetic variants with arterial stiffness and wave reflection. Hypertension 2008;51:1651–7. [8] Kim SM, Lee J, Ryu OH, Lee KW, Kim HY, Seo JA, et al. Serum osteoprotegerin levels are associated with inflammation and pulse wave velocity. Clin Endocrinol Oxf 2005;63:594–8. [9] Shewan LG, Coats AJ. Ethics in the authorship and publishing of scientific articles. Int J Cardiol 2010;144:1–2.
0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.12.094
Plasma active matrix metalloproteinase 9 associated to diastolic dysfunction in patients with coronary artery disease John W. Chu a,⁎, Gregory T. Jones b, Gregory P. Tarr b, L. Vicky Phillips b, Gerard T. Wilkins a, Andre M. van Rij b, Michael J.A. Williams a a b
Departments of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand Departments of Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
a r t i c l e
i n f o
Article history: Received 22 December 2010 Accepted 23 December 2010 Available online 28 January 2011 Keywords: Diastolic function Extracellular matrix Matrix metalloproteinase Coronary artery disease
Circulating levels of total matrix metalloproteinases (MMP) have been associated with diastolic dysfunction and heart failure [1,2]. This study aimed to investigate the relationship of the endogenous active levels of MMP-1,-2,-3 and -9 or tissue inhibitor of metalloproteinases1 (TIMP-1) and diastolic dysfunction (DD) in the setting of coronary artery disease (CAD). One hundred fifty-three patients with angiographically proven CAD were recruited retrospectively from the Dunedin Hospital Cardiology Clinical database. The patients were stable and free of heart failure symptoms at the time of recruitment. Clinical parameters recorded along with anthropometric measurements. The study protocol was approved by the Otago ethics committee. All subjects gave written informed consent before being recruited into this study. EDTA plasma samples were analysed for high-sensitivity Creactive protein (hs-CRP), creatinine, pro-MMP-9 and total TIMP-1 (GE Healthcare Life Sciences, RPN2611 and RPN2614). Endogenous plasma MMP-1, -2, -3 and -9 were measured in heparin plasma [3] samples (GE Healthcare Life Sciences, RPN2629, RPN2631, RPN2639 and RPN2634). The ratio of pro-MMP-9 to active enzyme indicated the proportion of zymogen activation. The average coefficient of variance for both activity and conventional ELISA assays was < 6%.
⁎ Corresponding author. Dunedin School of Medicine, University of Otago, Department of Cardiology, Dunedin Hospital, 201 Great King Street, Dunedin 9001, New Zealand. Tel.: + 64 3 4747007/8089; fax: +64 3 474 7655. E-mail address: [email protected] (J.W. Chu).
All patients had trans-thoracic echocardiography and Doppler examination (GE/VingMed Vivid-3 system, USA) with analyses subsequently performed off-line. Two-dimensional, targeted M-mode echocardiography, and Doppler ultrasound measurements were obtained. All measurements were taken according to the guidelines of the American Society of Echocardiography [4,5]. All echocardiography data represent the mean of 5 measurements on different cardiac cycles. Left ventricular (LV) ejection fraction was calculated by the modified Simpson's biplane method. LV mass in grams was derived from LV linear dimensions by the following formula: LV mass = 0.8× {1.04[(LVIDd+ PWTd+ SWTd)3 (LVIDd)3]}+ 0.6 where LVIDd , PWTd and SWTd were LV internal dimension at end diastole, posterior wall thickness at end diastole and septal wall thickness at end diastole, respectively [5]. All measurements were made with archive images recorded in a blinded fashion. The pulsed Doppler measurements were obtained in the apical view with a cursor at the mitral valve inflow: maximal early (E) and late (A) transmitral velocities in diastole and E-wave deceleration time. Isovolumic relaxation time (IVRT) was measured by continuous-wave Doppler placed between the mitral inflow area and the LV outflow tract. DD was graded as mild (impaired relaxation), mild-moderate (impaired relaxation), moderate (pseudonormal pattern), and severe (restrictive filling) using the Canadian Consensus Classification [6,7]. All patients studied had preserved LV systolic function with ejection fraction ≥45%. StatView version 5.01(SAS Institute) was used to perform statistical analysis. The distribution of continuous variables (kurtosis and skewness) was assessed and analysed with either the Mann–Whitney U, Kruskal–Wallis (non-parametric trend test) or ANOVA with Fisher protected least significant difference test. Results are shown as mean ± 1SD, except variables with a non-Gaussian distribution, which are reported with medians and interquartile ranges. Odds ratios are given with 95% confidence intervals. A p-value of less than 0.05 was considered statistically significant. Multiple logistic forward stepwise regression was used to evaluate the interaction between variables and MMPs in correlation with DD. The ability of MMP markers to shift cases and controls to correct clinical categories was assessed by classification tables derived from the multiple logistic regression model, based on the work by Cook et al [8]. Non-parametric ROC curves were generated using a dedicated programme, mROC (Unité de biostatistiques, CRLC Val d'Aurelle, V1.0) [9].
Letters to the Editor
337
Table 1 Clinical characteristics according to the phases of diastolic function. Phases of diastolic dysfunction Characteristics
Normal n = 62
Mild n = 49
Mild–moderate n = 23
Moderate n = 13
Severe n = 6
Age, years Male BMI, kg/m2 WHR Hypertension (> 140/90 mmHg) Hypercholesterolemia Diabetes mellitus Coronary artery disease severity Single vessel Double vessel Triple vessel Smoking pack years GFR, ml/min hs-CRP, mg/L Medications ACEI or ARB Beta-blocker Calcium-antagonist Statin Nitrate
60.3 ± 9.3 44 (71.0) 28.5 ± 4.4 0.92 ± 0.13 26 (41.9) 32 (51.6) 14 (22.6)
66.0 ± 9.3 32 (65.3) 29.3 ± 4.5 0.94 ± 0.08 19 (38.8) 25(51.0) 10(20.4)
63.7 ± 10.5 14 (60.9) 28.5 ± 5.5 0.92 ± 0.08 13 (56.5) 14 (60.9) 3(13.0)
67.4 ± 8.9 8 (61.5) 28.9 ± 5.2 0.93 ± 0.10 7 (53.8) 6 (46.2) 3 (13.0)
66.0 ± 8. 4 (67.7) 30.2 ± 3.9 0.91 ± 0.07 3 (50.0) 3 (50.0) 1 (16.7)
0.08 0.87 0.77 0.67 0.26 0.90 0.82
28 (45.2) 18 (29.0) 16 (25.8) 7.5 (0–27.8) 85.9 ± 26.3 1.7 (1.2–3.3)
21 (42.9) 18 (36.7) 10 (20.4) 13.8 (0.5–37.5) 78.1 ± 23.6 3.2 (1.7–5.9)
7 (30.4) 8 (34.8) 8 (34.8) 7.5 (0–40.0) 78.9 ± 29.2 1.6 (1.2–2.9)
6 (46.1) 4 (30.7) 3 (23.1) 0 (0–6.8) 86.6 ± 51.1 2.7 (1.7–6.3)
4 (66.7) 0 (0.0) 2 (33.3) 3.5 (0–10.5) 68.4 ± 22.9 2.5 (2.2–6.1)
0.13
38 28 14 58 17
25 23 12 46 18
13 (56.5) 11 (47.8) 7 (30.4) 21 (91.3) 9 (29.1)
7 (53.8) 6 (46.2) 5 (38.4) 11 (84.6) 4 (30.8)
4 (66.7) 3 (50.0) 2 (33.3) 6 (100.0) 2(33.3)
(46.8) (45.2) (22.6) (93.5) (27.4)
(52.0) (46.9) (24.5) (93.9) (36.7)
P-value for trend*
0.04 0.38 <0.04 0.92 0.20 0.13 0.66 0.29
BMI = body mass index; WHR = waist hip ratio; GFR = glomerular filtration rate; and hs-CRP = high sensitivity C-reactive protein. ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker; and Statin = Hydroxmethyl glutaryl coenzyme A reductase inhibitor. Data for the characteristics are expressed as mean ± standard deviation, median (interquartile range) or n (%). *Kruskal–Wallis trend test.
Table 1 shows the clinical characteristics of the study population. The number of smoking pack years was higher in the mild DD group. There were no differences in age, cardiovascular risk factors, renal function and pharmacotherapy. The level of hs-CRP was higher in the mild and moderate DD groups, however, it is worth noting that all groups had median levels below < 5 mg/L. Patients with more advanced phases of DD had higher E/A ratio, shorter deceleration time, IVRT and a larger left atrium, as anticipated. They had thicker inter-ventricular septum and posterior wall. In the mild-moderate DD group, the ejection fraction was higher. Because of the small number of patients with severe DD in the cohort, we combined this group with the moderate DD group for analysis in relation to MMP levels. There were no significant differences in plasma MMP-1, -2, -3, and proMMP-9 levels. Plasma active MMP-9 increased significantly with
more severe phases of DD, in particular from mild to mild-moderate phases (Table 2). These results were unchanged when the analysis was repeated without combining the moderate and severe DD groups. Adjusted for age, smoking pack years, CAD severity, hypertension and hs-CRP, elevated active MMP-9 (> 2 ng/mL) had an odds ratios of 6.1 (95% confidence interval [CI]: 1.7–21.2, and p = 0.005) and 9.1 (95% CI: 2.2–37.2, and p = 0.003) for association with mild–moderate DD and moderate or severe DD respectively. The cut-off of 2 ng/mL gave the best trade-off in terms of sensitivity and specificity between normal controls and moderate/severe DD, with values of 0.645 and 0.655, respectively. The addition of active MMP-9 and TIMP-1 to the regression model resulted in an increase of subjects being placed in their correct diastolic function category from 47.1% to 59.1%, with improved classification across all categories. This was associated
Table 2 Comparison of echocardiographic and biochemical data according to the phases of diastolic function. Phases of diastolic dysfunction Echocardiographic data
Normal n = 62
Mild n = 49
Mild–moderate n = 23
Moderate or severe n = 19
P-value for trend*
Ejection fraction, % Peak E, cm/s Peak A, cm/s E/A † DT, ms IVRT, ms LVM,g/m2 LVDD, mm IVS, mm PW, mm LA, mm Metalloproteinase data‡ Active MMP-1, ng/mL Active MMP-2, ng/mL Active MMP-3, ng/mL Pro-total MMP-9, ng/mL Active MMP-9, ng/mL TIMP-1, ng/mL
57 ± 8 84 ± 15 66 ± 14 1.3 ± 0.2 217 ± 32 88 ± 21 97 ± 30 48 ± 5 11 ± 2 10 ± 2 38 ± 5
57 ± 8 66 ± 15 85 ± 18 0.8 ± 0.1 264 ± 50 115 ± 20 102 ± 35 48 ± 6 11 ± 2 11 ± 2 41 ± 4
63 ± 9 62 ± 13 80 ± 15 0.8 ± 0.2 236 ± 47 90 ± 15 106 ± 20 46 ± 6 12 ± 2 11 ± 1 40 ± 4
59 ± 8 88 ± 25 56 ± 22 1.7 ± 1.0 167 ± 128 86 ± 26 110 ± 64 47 ± 6 13 ± 3 12 ± 2 42 ± 6
<0.04 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.46 0.30 <0.02 <0.05 <0.008
2.8 (1.1–5.0) 15.7 (11.3–18.4) 2.9 (1.3–5.0) 25.1 (15.9–37.1) 1.4 (1.0–2.1) 212 (186–246)
2.2 (1.0–3.7) 13.9 (9.2–18.4) 3.8 (2.1–7.0) 24.0 (17.3–43.6) 1.5 (0.9–2.0) 242 (212–279)
2.8 (1.0–6.8) 18.4 (14.0–22.3) 2.2 (1.7–3.2) 20.4 (14.3–26.2) 2.1 (1.5–3.0) 220 (187–277)
3.1 (1.2–4.4) 14.6 (8.8–16.3) 3.2 (1.7–4.5) 29.2 (18.2–38.8) 2.4 (1.6–3.0) 224 (208–274)
0.68 0.20 0.37 0.53 <0.003 0.07
DT = E-wave deceleration time; IVRT = isovolumic relaxation time; and LVDD = left ventricular diastolic dimension. IVS = interventricular septum thickness; PW = posterior wall thickness; LA = left atrial dimension; MMP = matrix metalloproteinase; and TIMP = tissue inhibitor of matrix metalloproteinase. Echocardioraphic data are expressed as mean ± standard deviation. *Kruskal–Wallis trend test. † E/A could not be calculated for 4 patients with atrial fibrillation. ‡ Results are expressed as medians and interquartile range.
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with improved model fit, as indicated by a decrease of 10 points using the Bayesian Information Criteria. The addition of active MMP9 and TIMP-1 to these same variables resulted in an increase of area under the curve of 9% and 6%, respectively, for the discrimination between controls and mild/moderate DD (from 0.73 (95% CI 0.60– 0.83) to 0.82 (95% CI 0.70–0.89)), and between controls and moderate/severe DD (from 0.76 (95% CI 0.62–0.86) to 0.82 (95% CI 0.70–0.90)). In conclusion, this study indicates that elevated level of the active form of MMP-9 is associated with DD, and the level of elevation correlates with the phases of DD in patients with CAD. This finding may reflect abnormal extracellular matrix metabolism in myocardial ischemia and the prognostic value of this marker needs to be further evaluated. Future prospective longitudinal studies will be required to explore the role of this enzyme on this important and common clinical problem. Heart Foundation of New Zealand, Auckland, New Zealand. Southland Medical Foundation, Invercargill, New Zealand. Special thanks to Mrs. Maree McCormack for her assistance with participant recruitment. This study was made possible through the funding support of the Heart Foundation of New Zealand. Dr John W. Chu was supported in part by the Southland Medical Foundation, Invercargill, New Zealand, as a W & G S Dick Research Fellow. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [10].
References [1] Saglam M, Karakaya O, Esen AM, et al. Contribution of plasma matrix metalloproteinases to development of left ventricular hypertrophy and diastolic dysfunction in hypertensive subjects. Tohoku J Exp Med 2006;208:117–22. [2] Ahmed SH, Clark LL, Pennington WR, et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: Relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 2006;113:2089–96. [3] Castellazzi M, Tamborino C, Fainardi E, et al. Effects of anticoagulants on the activity of gelatinases. Clin Biochem 2007;40:1272–6. [4] Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: A report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167–84. [5] Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: A report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63. [6] Rakowski H, Appleton C, Chan KL, et al. Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography: From the Investigators of Consensus on Diastolic Dysfunction by Echocardiography. J Am Soc Echocardiogr 1996;9:736–60. [7] Yamada H, Goh PP, Sun JP, et al. Prevalence of left ventricular diastolic dysfunction by Doppler echocardiography: Clinical application of the Canadian Consensus Guidelines. J Am Soc Echocardiogr 2002;15:1238–44. [8] Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med 2006;145:21–9. [9] Kramar A, Faraggi D, Fortune A, Reiser B. mROC: A computer program for combining tumour markers in predicting disease states. Comput Meth Programs Biomed 2001;66:199–207. [10] Shewan LG and Coats AJ. Ethics in the authorship and publishing of scientific articles. Int J Cardiol 2010;144:1–2.
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.12.093
Comparison of different body habitus between patients with mitral valve prolapse and normal populations in young Taiwanese females Mao-Jen Lin a, Ting-Hsiang Lin b, Hau-De Lin a, Chung-Sheng Lin c,⁎ a b c
The Division of Cardiology, Department of Medicine, Buddhist Tzu-Chi General Hospital, Taichung branch, Taiwan Department of Statistics, National Taipei University, Taipei, Taiwan Department of Internal Medicine, Chung-Shan Medical University Hospital and School of Medicine, Chung-Shan Medical University, Taichung, Taiwan
a r t i c l e
i n f o
Article history: Received 20 December 2010 Accepted 23 December 2010 Available online 20 January 2011 Keywords: Body habitus Mitral valve prolapse Taiwan
The mitral valve prolapse (MVP) syndrome is one of the most prevalent cardiac valvular abnormalities and may affect as much as 5–15% of the population [1]. The weight of patients with MVP is often ⁎ Corresponding author. Department of Internal Medicine, Chung Shan Medical University Hospital, 110, Section 1, Chien Kuo North Road, Taichung, Taiwan 402. Tel.: +886 4 24739595 #34711; fax: +886 4 24739220. E-mail address: [email protected] (C.-S. Lin).
lower, and the habitus may be asthenic. Blood pressure (BP) is also normal or lower, and orthostatic hypotension may present. It has never been studied in association with body habitus in Taiwanese MVP patients. Thus we attempt to answer whether the descriptions regarding body habitus parameters in Western literature also apply to Taiwanese female patients. The study protocol was approved by the institution review board and ethics committee of Tzu Chi General Hospital, and informed consent was obtained from all participants. We consecutively recruited female patients aged between 20 and 30 years old. MVP patients without other organic heart disease were selected. Normal, age-matched volunteers without MVP and body habitus that cohered to normal population study reports in Taiwan (e.g., height range from 149 to 169 cm; weight range from 36 to 69 kg,) were recruited. Each patient completed a survey of symptoms of chest tightness, palpitation or breathless sensation. The diagnosis of MVP based on demonstration of thick, redundant leaflets and chordae with systolic displacement of the leaflets into the left atrium in two-dimensional echocardiogrpahy [2]. The measurement of body parameters included height, weight, body mass index