Table 3.
MMPs, MMP inducers, and MMP inhibitor roles in ECM metabolism in patients with HTN.
| Study | Study Design | Sample Size (men) | Treatment (duration) | MMP-9 ng/mL (before Rx) | TIMP-1 ng/mL (before Rx) | Other MMPs and Inflammatory Markers | Laboratory Method | Results Summary |
|---|---|---|---|---|---|---|---|---|
| Laviades et al110 | Case-controlled | 60 (41): control patients = 23; HTN = 37 | Lisinopril (1 y) | N/A | ↑ | MMP-1 ↓ | ELISA | • Patients with HTN and LVH had more depressed extracellular degradation of type I collagen |
| • Treatment resulted in increased MMP-1 and decreased TIMP-1 | ||||||||
| Li-Saw-Hee et al64 | Case-controlled | 56 (16): control patients = 24; HTN = 32 | Enalapril or losartan (8 wks) | ↓ | ↓ | None | ELISA | • Treatment did not impact MMP-9 or TIMP-1 levels |
| • No relationships between MMP-9 or TIMP-1 and LV mass or diastolic dysfunction | ||||||||
| Zervoudaki et al,65 | Case-controlled | 67 (29): control patients = 25; HTN = 42 | Amlodipine (6 mo) | ↓ | Not tested | MMP-2 ↓ | ELISA | • Patients with HTN and higher SVR (> 1,440 dynes/s/cm-5) showed further lower MMP-9 and MMP-2 levels |
| • Treatment with amlodipine increased MMP-9 levels only | ||||||||
| Zervoudaki et al,66 | Randomized controlled trial (randomized to diltiazem and felodipine) | 117 (68): control patients = 45; HTN = 72 | Diltiazem and felodipine (6 mo) | ↓ | Not tested | MMP-2 ↓ | ELISA | • Treatment with felodipine increased MMP-2 levels only |
| • Treatment with diltiazem did not affect MMP-2 or MMP-9 | ||||||||
| • Intensity of alteration of MMP-2 levels independent of felodipine, suggesting a pressure-independent mechanism | ||||||||
| Tayebjee et al,63 recruited participants from the ASCOT trial | Case-controlled | 141 (108): control patients = 45; HTN = 96 (untreated = 12, treated = 84) | N/A (3 y) | ↑ | ↑ | None | ELISA | • MMP-9 levels decreased and TIMP-1 levels increased in treated group vs untreated group (change not statistically significant) |
| Yasmin et al58 | Case-controlled | 240 (117): Isolated systolic hypertension (ISH) = 116, Control = 114 | N/A | ↑ | N/A | MMP-2: ↑; TIMP-2: no Δ; SEA: ↑ | ELISA | • Trial used ISH to study arterial wall stiffness |
| • MMP-9, MMP-2, and SEA increased in patients with ISH | ||||||||
| • MMP-9, MMP-2, and SEA correlated with aortic PWV (MMP-9 was strongest) | ||||||||
| • CRP independently correlated with PWV | ||||||||
| • Positive association between MMP-9 and CRP in healthy group | ||||||||
| Saglam et al61 | Case-controlled | 50 (34): all HTN (LVH = 27, no LVH = 23) | N/A | ↑ with LVH | N/A | MMP-3 ↑ with LVH | EIA | • MMP-9 and MMP-3 levels increased in patients with HTN and LVH |
| • MMP-9 and MMP-3 levels correlated with LV diastolic dysfunction | ||||||||
| Tayebjee et al60 | Case-controlled | 108 (81): control patients = 34; HTN = 74 (untreated = 27, treated = 47) | N/A (only noted patients who were antihypertensive) | ↑ | ↑ | None | ELISA | • MMP-9 and TIMP-1 levels increased in patients with HTN (treated or untreated) |
| • TIMP-1 only correlated with LV mass and diastolic dysfunction but not MMP-9 | ||||||||
| Ahmed et al57 | Case-controlled | 102 (64): control patients = 53 (HTN = 14, no HTN = 39); LVH = 49 (CHF = 26, no CHF = 23) | Different agents by PCP: diuretics, ACE inhibitors, ARB, aldosterone blockers, vasodilators, α blockers, β blockers | ELISA | • Patients with HTN and normal LV structure and function had normal MMP/TIMP profile | |||
| • Patients with HTN and LVH without CHF had decreased MMP-2, MMP-13, and MMP-9 | ||||||||
| • Elevated TIMP-1 strongly associated and a strong predictor for LVH and CHF (especially levels ≥ 1,200 ng/mL) | ||||||||
| Derosa et al,111 | Case-controlled | 192 (97): control patients = 96; HTN = 96 | N/A | ↑ | ↑ | MMP-2 ↑ | ELISA | • Levels and activities of MMP-2, MMP-9, and TIMP-1 increased in patients with HTN |
| Onal et al62 | Case-controlled | 49 (18): control patients = 16; HTN = 33 | Lisinopril or candesartan (3 mo); patients on previous antihypertensive medications stopped for 1 wk before enrollment | ↑ not statistically significant | ↓not statistically significant | N/A | ELISA | • MMP-9 decreased, TIMP-1 increased after treatment |
| • 24 h urinary albumin excretion did not significantly change | ||||||||
| • No Δ between lisinopril and candesartan groups | ||||||||
| • Changes in MMP-9 and TIMP-1 not correlated with changes in BP measurements or 24 h urinary albumin excretion | ||||||||
| Collier et al,112 | Cross-sectional; observational | HTN with HFpEF = 181; HTN asymptomatic = 94 (LAVI ≥ 34 mL/m2 = 30, LAVI < 34 mL/m2 = 64) | N/A | ↑ in HFpEF | ↓ in HFpEF | MMP-2; CITP; PIIINP; PINP; PICP; MCP-1; IL-6; IL-8; TNF-α (for levels, see Results Summary) | ELISA, EIA, ECIA | • Patients who were AH and with LAVI ≥ 34 mL/m2 had higher levels of MMP-2 and lower levels of TIMP-1 than those with LAVI < 34 mL/m2 |
| • MMP-9, MMP-2, BNP, PIIINP, and CITP levels significantly correlated with LAVI | ||||||||
| • Patients with HTN and HFpEF had higher MMP-9, MMP-2, BNP, PIIINP, CITP, IL-6, IL-8, and MCP-1 | ||||||||
| • No significant Δ in TNF-α between HFpEF and AH | ||||||||
| • MMP-9/TIMP-1 significantly identified patients with AH with risk of LVDD compared with BNP | ||||||||
| Tan et al54 | Cross-sectional | 256 (197): control patients = 54; HTN = 202 (never treated = 67, treated = 135) | Antihypertensive medications not specified (median 5 y) | ↑ | ↑ | IL-6: no Δ; sCD40L: no Δ | ELISA | • MMP-9 and TIMP-1 levels increased in HTN |
| • MMP-9 and TIMP-1 levels positively correlated with large arterial stiffness measures | ||||||||
| • MMP-9/TIMP-1 ratio not different between patients with HTN and control patients and not correlated with arterial stiffness | ||||||||
| • IL-6 and sCD40L not correlated with large arterial stiffness | ||||||||
| Ergul et al67 2004 | Case-controlled | 32 (24): control patients = 13; HTN = 19 | CCB, ACEI, β blockers, diuretics, ARB | ↓ | N/A | MMP-2 ↓; EMMRIN ↓; MT-1-MMP ↓; FGF-2 ↑ | Zymography | • In addition to reduction in MMPs, their inducers and activators were also downregulated |
| • Increased deposition of ECM proteins (FGF-2) | ||||||||
| Ritter et al113 | Cross-sectional | 122 (40): all TRH (patients who were obese = 67, patients who were not obese = 55) | Three anti-hypertensive agents at optimal doses, the exact medications used are not available | ↑ | No Δ | MMP-2: no Δ; TIMP-1: no Δ; TIMP-2: no Δ | ELISA | • MMP-9 and MMP-9/TIMP-1 increased in patients who were obese with TRH compared with patients who were not obese with TRH |
| • MMP-9 and MMP-9/TIMP-1 associated with LVH in patients who were obese with TRH | ||||||||
| • CRP increased in patients who were obese with TRH | ||||||||
| • Positive correlation between MMP-9 and fat mass | ||||||||
| Friese et al,114 | Cross-sectional | 68 (52): control patients = 18; HTN = 20; HTN and ESRD = 30 | ACEI, α antagonists, ARB, diuretics, β blockers, CCB | ↑ | N/A | MMP-1; MMP-2; MMP-3; MMP-10 (for levels, see Results Summary) | ELISA, ECIA | • MMP-9 increased in patients with HTN compared with control patients |
| • No Δ in MMP-9 between ESRD and HTN | ||||||||
| • MMP-2 and MMP-10 higher in patients with HTN-ESRD compared with patients with HTN and control patients | ||||||||
| • No Δ in MMP-2 and MMP-10 between patients with HTN and control patients | ||||||||
| • Positive correlation between MMP-2 and MMP-10 | ||||||||
| • Positive correlation between MMP-9 and systolic BP | ||||||||
| • Negative correlation between MMP-2 and BMI |
ACEI = angiotensin-converting enzyme inhibitors, AH = asymptomatic with HTN, ARB = angiotensin receptor blockers, BMI = body mass index, BNP = brain natriuretic peptide, BP = blood pressure, CCB = calcium channel blockers, CHF = congestive heart failure, CITP = carboxy-terminal telopeptide of collagen-I, CRP = C-reactive protein, ECIA = electrochemiluminescence immunoassay, ECM = extracellular matrix, EIA = enzyme immunoassay, ELISA = enzyme-linked immunosorbent assay, ESRD = end-stage renal disease, FGF-2 = fibroblast growth factor-2, HFpEF = heart failure with preserved ejection fraction, HTN = hypertension, IL = interleukin, ISH = isolated systolic hypertension, LAVI = left atrium volume index, LV = left ventricular, LVDD = left ventricular diastolic dysfunction, LVH = left ventricular hypertrophy, MCP-1 = monocyte chemoattractant protein-1, MMP = matrix metalloproteinase, MT-1-MMP = Membrane type 1-matrix metalloproteinase, PICP = carboxy-terminal propeptide of collagen type I, PIIINP = amino-terminal propeptide of procollagen type III, PINP = procollagen type I N propeptide, PWV = pulse wave velocity, Rx = prescription, sCD40L = soluble CD40L, SEA = serum elastase activity, SVR = systemic vascular resistance, TIMP = tissue inhibitor of matrix metalloproteinase, TNF = tumor necrosis factor, TRH = treatment-resistant hypertension.