Abstract 3758: TIMP-4 in Hypertensive Heart Disease
Hypertensive heart disease can result in left ventricular hypertrophy (LVH), abnormal extracellular matrix (ECM), and diastolic dysfunction, all of which may contribute to the development of chronic heart failure (CHF). ECM turnover is regulated in part by the balance between matrix metalloproteinases (MMPs) and the endogenous MMP inhibitors (TIMPs). Increased plasma TIMPs have been identified in hypertension (HTN) and LVH, though specificity of these measurements to the cardiovascular (CV) compartment remains unknown. We developed a plasma assay for CV specific TIMP-4 to test the hypothesis that TIMP-4 levels would be altered in LVH, and more importantly be associated with CHF. Echo-Doppler and high sensitivity ELISA for TIMP-4 were examined in 65 patients (age 32– 89, EF>60%) with HTN and 63 control subjects (age 20–90). In controls, increasing age was associated with concentric remodeling (decreased LV vol/mass ratio), abnormal relaxation (decreased TDI E’), and increased TIMP-4 (r=0.5, p < 0.01) (Fig 1⇓). Independent of the effect of age, patients with HTN and no CHF symptoms had concentric LVH (vol/mass = 0.5 ± 0.03 vs 0.7 ± 0.02 mL/g, p< 0.01), diastolic dysfunction (TDI E’ 8 ± 1 vs 11 ± 1 cm/s, p< 0.01) but no change in TIMP-4 (1.83 ± 0.14 vs 1.83 ± 0.12 ng/mL, p= 0.9). Patients with HTN and CHF symptoms had similar changes in LV structure/diastolic function but with increased TIMP-4 (2.29 ± 0.19, p<0.04) (Fig 2⇓).
Conclusion: Aging is associated with increased CV specific TIMP-4. Independent of age & HTN, patients with CHF had increased CV specific TIMP-4. These results identify a mechanistic underpinning of CHF associated with HTN and reveal a potential diagnostic/therapeutic target.