Plasma tissue inhibitor of metalloproteinase-1 levels are elevated in essential hypertension and related to left ventricular hypertrophy

BACKGROUND: Essential hypertensive patients have an increased heart and arterial collagen concentration. Increased collagen synthesis can be assessed using procollagen III N peptide (PIIINP) and reduced collagen degradation measured using tissue inhibitor of metalloproteinase-1 (TIMP-1). METHODS: Plasma TIMP-1 and PIIINP levels were measured in 31 patients with essential hypertension and in 17 normotensive control subjects. The hypertensive patients were either treatment naive (n = 18) or had been without treatment for 1 month (n = 13). Both groups of patients were screened to exclude other fibrotic diseases. RESULTS: In the hypertensive patients, TIMP-1 levels were significantly (P < .0002) elevated (median 380 ng/ mL, range 160 to 1,560 ng/mL) compared with those of the normotensive control subjects (median 178 ng/mL, range 99 to 330 ng/mL). In hypertensive subjects who had never received antihypertensive therapy there were significant correlations between TIMP-1 and left ventricular posterior wall thickness in diastole (LVPWd) (r = 0.58) (P < .02) and left ventricular mass index (r = 0.58) (P < .02). There was no difference in PIIINP levels (mean +/- 2 SD) between the hypertensive (0.56 U/mL +/- 0.3) and normotensive groups (0.52 U/mL +/- 0.2). CONCLUSIONS: The increased tissue collagen III levels found in the heart and vessels of hypertensive patients is due to a reduction in collagen degradation because of high TIMP-1 levels, rather than an increase in synthesis of collagen type III. The tissue source of this TIMP-1 is unclear.     

Tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9 levels in patients with hypertension Relationship to tissue Doppler indices of diastolic relaxation

BACKGROUND: Hypertension, hypertensive heart disease, and left ventricular (LV) hypertrophy are integral to symptomatic diastolic heart failure. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is linked to extracellular matrix fibrosis and is elevated in hypertension. We hypothesized a link between circulating TIMP-1, matrix metalloproteinase-9 (MMP-9), and resting echocardiographic LV filling parameters using tissue Doppler parameters of diastolic (dys)function. METHODS: Circulating MMP-9 and TIMP-1 levels were measured in citrated plasma by ELISA in 74 patients with hypertension (58 men, mean age 58 +/- 11 years) and 34 controls (23 men, mean age 53 +/- 13 years). All had confirmed normal short axis systolic contractility, with no significant wall motion abnormalities; the LV mass and standard resting tissue Doppler echocardiographic indices of diastolic function were also recorded. RESULTS: Both MMP-9 and TIMP-1 levels were higher in the hypertensive group (P =.0039 and P =.0054, respectively). When compared to controls, hypertensive patients had a greater LV mass (P =.0054), and differences in many of the parameters reflecting diastolic dysfunction (controls versus hypertensives: E: 0.71 +/- 0.15 v 0.81 +/- 0.15 m/sec, P =.004; A: 0.66 +/- 0.12 v 0.81 +/- 0.16 m/sec, P <.0001; e': 0.12 (0.09-0.14) v 0.09 (0.07-0.10) m/sec, P =.0017; e'/a': 1.20 (1.00-1.80) v 0.88 (0.71-1.05), P <.0001; E/e': 6.54 (4.75-7.14) v 8.89 (7.55-10.75), P <.0001, respectively). Within the hypertensive cohort, only TIMP-1 levels correlated with LV mass (r = 0.271, P =.024), LV mass index (r = 0.323, P =.007), and tissue Doppler parameters of diastolic dysfunction, including e' (r = -0.338, P =.005), a' (r = -0.350, P =.005), and E/e' (r = 0.334, P =.005). CONCLUSIONS: TIMP-1 is thought to increase tissue concentrations of collagen type I by preventing its breakdown by MMPs. Our findings therefore add weight to a hypothesis suggesting that TIMP-1 may be a key mediator of LV diastolic dysfunction through definition of ventricular matrix composition.     

Improved left ventricular filling accompanies reduced left ventricular mass during therapy of essential hypertension

Abnormal left ventricular diastolic performance, an early manifestation of hypertension in the heart, may precede the development of left ventricular hypertrophy. To assess effects of antihypertensive therapy on the heart, left ventricular mass (determined by echocardiography) and rapid left ventricular filling rate (determined by radionuclide ventriculography) were compared before and after 6 months of treatment of 16 patients. Nitrendipine (a dihydropyridine calcium channel blocker) was given alone or in combination with either propranolol or hydrochlorothiazide, or both, and significantly reduced blood pressure (156/103 +/- 12/7 to 137/89 +/- 10/6 mm Hg). In 6 of the 16 patients, left ventricular mass decreased by more than 10% (270 +/- 95 to 193 +/- 47 g, p less than 0.01); in the same patients, left ventricular filling rate increased (2.03 +/- 0.35 to 2.30 +/- 0.45 end-diastolic counts/s [EDC/s], p less than 0.01). In the one patient whose left ventricular mass increased (137 to 195 g), left ventricular filling rate decreased from 2.01 to 1.78 EDC/s. In the remaining nine patients who had no change in left ventricular mass, there was no significant changes in left ventricular filling. The changes in ventricular mass and filling could not be related to the extent of change in blood pressure or heart rate. These data suggest that regression of left ventricular mass during antihypertensive therapy with nitrendipine is accompanied by improved diastolic function.     

Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension.

The extracellular matrix is vital for maintaining tissue integrity, and the matrix metalloproteinases/tissue inhibitors of metalloproteinases (MMPs/TIMPs) system is involved in the regulation of extracellular matrix metabolism. Extracellular matrix turnover plays an important role in the change of large arterial mechanical properties in hypertension. However, the association of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) system and arterial stiffness is not straightforward and existing data are rather limited. Our objective is to explore the impact of the MMP-9/TIMP-1 system on large arterial stiffness in patients with essential hypertension. An automatic pulse wave velocity (PWV) measuring system was used to examine carotid-femoral PWV (CFPWV) and carotid-radial PWV (CRPWV) as the parameters reflecting central elastic large arterial and peripheral muscular medium-sized arterial elasticity, respectively; and serum MMP-9 and TIMP-1 levels, along with a number of other established biomarkers, were measured by enzyme-linked immunosorbent assay (ELISA) in 202 essential hypertensive patients and 54 age and gender-matched control subjects. Compared with the control subjects, hypertensive patients exhibited higher levels of MMP-9 (p=0.001) and TIMP-1 (p=0.002). Spearman's correlation analysis showed that serum levels of MMP-9 (p=0.014) and TIMP-1 (p=0.005) were significantly and positively correlated with CFPWV in hypertensive patients. A stepwise multiple regressive analysis demonstrated that age, systolic blood pressure, heart rate and TIMP-1 were independent predictors of CFPWV in patients with essential hypertension (adjusted r2=0.458). In conclusion, our results imply that the MMP-9/TIMP-1 system may play an important role in the determination of arterial function, and these findings may have implications for the involvement of MMP-9/TIMP-1 system in the pathophysiology of cardiovascular disease.     

Relationship between blood pressure and left ventricular mass in male patients with essential hypertension.

We performed retrospective study of the relationship between the severity and duration of hypertension and echocardiographically-detected left ventricular hypertrophy (echo-LVH) in patients with untreated essential hypertension. The subjects consisted of 92 untreated essential hypertensives who were observed for more than 5 years from the onset of diastolic hypertension (greater than or equal to 95 mmHg), and whose left ventricular (LV) mass index was measured at the end of the observation period. On the basis of the frequency of diastolic hypertension during the observation period, the population was categorized in 3 groups. In Group I (32 cases), diastolic hypertension was observed in more than 80% of blood pressures obtained throughout the entire observation period. In Group II (38 cases), diastolic hypertension was observed in 33 to 80% of the observation period. In Group III (22 cases), diastolic hypertension was observed in less than 33% of the observation period. The average diastolic blood pressure during the entire observation period in each group were 101.0, 96.0, and 90.7 mmHg in groups I, II, and III, respectively. The LV mass index was significantly higher in groups I (114.6 g/m2) and II (105.3 g/m2) than in group III (90.7 g/m2) (p less than 0.01). The prevalence of echo-LVH (more than 121 g/m2) was 34.4%, 18.4%, and 4.8% in groups I, II, and III, respectively. The average diastolic blood pressure in patients with echo-LVH (99.3 +/- 5.1 mmHg) was significantly higher than in patients without echo-LVH (95.7 +/- 4.7 mmHg). We concluded that the degree and duration of diastolic pressure elevation are closely correlated to the LV mass index.     

Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension

Arterial stiffness is an independent predictor of cardiovascular events in a hypertensive population. Serum levels of matrix metalloproteinase (MMP)-9 are associated with arterial stiffness and predict cardiovascular risk. We investigated the role of MMP-9 polymorphism -1562C>T on blood pressure (BP) and arterial stiffness in a newly diagnosed hypertensive population. Untreated hypertensive patients (n=215, mean age 46+/-13 years) were studied. Supine BP, carotid-femoral pulse wave velocity (PWV) and augmentation index were assessed. Serum biochemistry and plasma MMP-9 concentrations were measured and genotyping performed following extraction of genomic DNA. BP, aortic PWV and serum MMP-9 levels were significantly higher in T-allele carriers of the -1562C>T polymorphism with a significant gene-dose effect (P<0.0001). In a stepwise regression model adjusting for known or likely determinants, the 1562C>T polymorphism emerged as an independent predictor of systolic BP (R(2)=0.25, P<0.0001), diastolic BP (R(2)=0.16, P<0.0001) and PWV (R(2)=0.47,P<0.0001). This is the first study to show the effect of MMP-9 polymorphism on BP and aortic stiffness in a hypertensive population. These results suggest that hypertensive patients carrying the T allele may be at increased risk of cardiovascular events.     

原发性高血压患者血压变异性与左心室质量指数的相关性分析

目的探讨原发性高血压患者血压变异性(blood pressure variability,BPV)与左心室质量指数(left ventricular mass index,LVMI)的相关性。方法选择我院住院的原发性高血压患者95例,根据心电图、彩色超声心动图检查确定是否伴有左心室肥厚(left ventricular hypertrophy,LVH)分为LVH组42例及无LVH组53例,另选择血压正常且无LVH的健康体检者40例为对照组,收集3组一般临床资料,检测同型半胱氨酸(Hcy)水平,进行24 h动态血压监测,比较3组24 h、夜间、昼间平均血压、收缩压标准差和舒张压标准差及LVMI。结果3组年龄、体质量指数、吸烟、尿酸、血红蛋白、血脂、糖化血红蛋白及各时间段内平均血压比较,差异无统计学意义(P>0.05);3组性别、糖尿病比例、Hcy、肌酐、LVMI及24 h、夜间、昼间收缩压标准差和舒张压标准差比较,差异有统计学意义(P<0.05,P<0.01)。LVH组男性比例、Hcy、LVMI及24 h、夜间、昼间收缩压标准差和舒张压标准差明显高于无LVH组和对照组(P<0.05),LVH组和无LVH组糖尿病比例和肌酐水平明显高于对照组,差异有统计学意义[59.5%和56.6%vs 7.5%,(92.0±4.8)μmol/L和(81.3±15.9)μmol/L vs(65.4±13.2)μmol/L,P<0.05]。无LVH组与对照组LVMI及24 h、夜间、昼间收缩压标准差和舒张压标准差比较,差异无统计学意义(P>0.01)。LVH组非杓型高血压比例明显高于无LVH组和对照组(85.7%vs 34.0%、5.0%,P=0.000)。结论BPV与高血压患者的LVH关系密切,其可能作为靶器官损伤最新的独立预测因素。     

Blood pressure load determines left ventricular mass in essential hypertension.

In a series of 35 newly diagnosed, previously untreated patients (mean age 46 years) with mild to moderate essential hypertension, office blood pressure measurements, 24-hour ambulatory blood pressure monitoring, and determination of left ventricular mass index by echocardiography according to the formula of Devereux were performed. We aimed at correlating left ventricular mass index with systolic and diastolic office blood pressure, mean 24-hour systolic and mean 24-hour diastolic blood pressure, systolic and diastolic load. Left ventricular mass index did not correlate with office systolic and office diastolic blood pressure. On the contrary, all correlations with ambulatory blood pressure parameters and left ventricular mass index turned out to be significant (mean 24-hour systolic blood pressure: r = 0.344, P = 0.026; systolic load: r = 0.408, P = 0.020; mean 24-hour diastolic blood pressure: r = 0.490, P = 0.004; diastolic load: r = 0.504, P = 0.003). These results clearly demonstrate that ambulatory blood pressure determinants but not the office blood pressure parameters are well correlated with left ventricular mass index in mild to moderate essential hypertension. Blood pressure load is as important as mean 24-hour blood pressure in this regard.     

Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF.

The purpose of this study was to examine the role of interstitial collagenases, members of the family of matrix metalloproteinases, in the development of pulmonary fibrosis. The activity, levels and molecular forms of collagenases (matrix metalloproteinases (MMP)-1, -8 and -13), gelatinase B (MM P-9) and its main endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis patients with varying degrees of pulmonary parenchymal involvement. Collagenase activity was elevated in IPF and group 3 sarcoidosis patients. A positive correlation between BALF collagenase activity and MMP-8 levels was also observed. Western immunoblotting revealed the presence of two isoforms of MMP-8 in patient samples; an 80 kD form representing latent enzyme from polymorphonuclear neutrophils and a 55 kD form representing the fibroblast-type proform. MMP-9 levels were also elevated in both IPF and group 3 sarcoidosis patients, while TIMP-1 levels remained normal, indicating a shift in the balance between the enzyme and inhibitor, favouring MMP-9. Matrix metalloproteinase-8 is the major contributor to the bronchoalveolar lavage fluid collagenase activity in the airways of patients with idiopathic pulmonary fibrosis and sarcoidosis and may initiate collagen destruction and remodelling leading to the development of pulmonary fibrosis.     

男性瘦素水平与原发性高血压左室肥厚的相关性研究

目的 :研究瘦素 (leptin)与原发性高血压 (EH)左室肥厚 (LVH)的相关性 ,从而进一步探讨LVH的发病机制。方法 :随机选择确诊EH男性患者 4 1例 ,选正常健康男性 2 3例作为对照。晨空腹测定血清leptin水平、血清胰岛素和血糖水平 ,胰岛素与血糖乘积的倒数即胰岛素敏感性指数 (ISI)作为评价胰岛素抵抗 (IR)的指标。心脏彩超测定室间隔厚度 (IVST)、左室后壁厚度 (PWT) ,IVST与PWT之和即左室壁厚度和 (SWT)作为评价LVH的指标。采用相关分析、多元逐步回归等统计方法进行评价。结果 :EH组与对照组具有可比性 ,两者之间leptin水平有统计学意义 (P <0 .0 1)。在EH组 ,leptin水平与SWT显著相关 (r =0 .5 1,P <0 .0 1)。多元逐步回归分析显示 ,血清leptin水平和ISI与SWT相关性好。 结论 :男性血清leptin水平与EHLVH具有良好的相关性。     

原发性高血压左室质量适宜和过高对左室结构和功能的影响

目的 :利用左室质量比值 (%PLM )将左室重构分为左室质量适宜 (aLVM )、左室质量过高 (iLVM )和左室质量不足 ,观察并比较aLVM和iLVM的心脏结构和功能特点。方法 :对 187例原发性高血压 (EH)患者进行超声心动图检查 ,测量其心脏结构和功能。结果 :aLVM、iLVM和左室质量不足的分布分别占 4 8.1%、4 8.7%和 3.2 %。与aLVM相比 ,iLVM的主动脉根部内径、左房内径、左室质量和相对室壁厚度更高 (P <0 .0 5 ) ;心排血量、心搏量、左室射血分数、左室短轴缩短率和舒张早期充盈峰速度E峰 /舒张晚期充盈峰速度A峰比值更低 (P <0 .0 5 ) ;总外周血管阻力更高 (P <0 .0 5 )。结论 :与aLVM相比 ,iLVM的心脏结构和功能特点提示它是左室重构发展的进一步阶段。     

金属蛋白酶-9及其抑制物-1在实验性心动过速性心肌病中的变化

目的观察心动过速性心肌病（TIC）时金属蛋白酶（MMP）-9及其抑制剂（TIMP）-1的变化。方法对11只犬采用快速右房起搏建立TIC模型组，6只犬作假手术组（对照组）。应用超声心动图和心导管检查测量在窦性心律下的血流动力学数据。应用电子显微镜观察左室组织的超微结构改变。MMP-9及TIMP-一1的相对变化通过免疫印迹法获得。结果8周后，与对照组相比，TIC组犬左室舒张末期容积及收缩末期容积均显著增加（P〈0．05）；左室射血分数在起搏1周后显著减小（P〈0．05）。左室压力最大上升速率显著下降，最大下降速率绝对值显著下降（P〈0．05和0．001），左室舒张末期压显著增大，左室松弛时间常数明显延长（P〈0．05），二尖瓣血流频谱A波峰值流速和E波峰值流速均显著减小。心肌细胞超微结构发生变化，同时MMP-9增加，TIMP-1减少。结论快速右房起搏可制造TIC模型，TIC时MMP-9增加，TIMP-1减少。     

血清胰岛素样生长因子-1与原发性高血压患者左心室肥厚和蛋白尿的关系

目的探讨血清胰岛素样生长因子-1(IGF-1)与原发性高血压(EH)患者心脏和肾脏损害的关系。方法选择51例EH患者和30例正常受试者,根据是否合并左心室肥厚(LVH)将EH病患者分为EH组和EH+LVH组,同时按不同血压等级分为3个组。用酶联免疫分析方法测定血清IGF-1水平,用散射比浊法测定尿白蛋白排泄率(UAER)。根据心脏超声各参数计算左心室质量指数(LVMI)。结果不同血压水平各组中,随着动脉血压水平的升高,血清IGF-1、LVMI、UAER均升高,组间差异有统计学意义;EH组血清IGF-1高于正常对照组(P<0.05),EH+LVH组血清IGF-1高于EH组(P<0.05),并显著高于正常对照组(P<0.01);EH组UAER显著高于正常对照组(P<0.01),EH+LVH组UAER显著高于正常对照组和EH组(P<0.01,P<0.01);血清IGF-1与LVMI、UAER均存在正相关性(r=0.41,P<0.05;r=0.53,P<0.05)。结论(1)循环血IGF-1水平与LVMI、UAER均密切相关,表明IGF-1参与了EH病的发生发展,并且很可能在EH心脏、肾脏损害的病理生理过程中起到了至关重要的作用。(2)EH病患者心脏、肾脏受损程度基本平行。     

Continuous relation between left ventricular mass and cardiovascular risk in essential hypertension

The detection of left ventricular (LV) hypertrophy on echocardiography is a powerful risk indicator in essential hypertension. However, the prognostic impact of LV mass values within the "normal" range and the shape of the relation between LV mass and prognosis remain unclear. Thus, 1925 white subjects with uncomplicated essential hypertension underwent off-therapy 24-hour blood pressure monitoring and M-mode echocardiography. During 4. 0+/-2 years of follow-up, there were 181 major cardiovascular events (2.4/100 patient-years) and 49 deaths from all causes. In the 5 gender-specific quintiles of LV mass distribution (partition values: 92, 105, 120, and 138 g/m(2) in men and 79, 91, 102, and 116 g/m(2) in women), cardiovascular event rates were 0.8, 1.7, 2.2, 2.9, and 4. 3 per 100 patient-years. After adjustment for several risk factors, including 24-hour ambulatory blood pressure, the relative risk (RR) of developing a cardiovascular event increased progressively from the first quintile (RR 1) to the second (RR 1.6, 95% CI 0.8 to 3.1), third (RR 1.9, 95% CI 1.01 to 4.0), fourth (RR 3.0, 95% CI 1.5 to 5. 8), and fifth (RR 3.5, 95% CI 1.8 to 6.8) quintile. For all-cause death, the RR in the fifth quintile compared with the first quintile was 4.3 (95% CI 1.2 to 13.4). In conclusion, the powerful relation between LV mass and risk of cardiovascular disease in subjects with uncomplicated essential hypertension is continuous over a wide range of LV mass values, even below the current "upper normal" limits. The relation remains significant after control for traditional risk factors, including ambulatory blood pressure.