Remodeling of the myocardium and the extracellular matrix (ECM) occurs in heart failure irrespective of its initial cause. The ECM serves as a scaffold to provide structural support as well as housing a number of cytokines and growth factors. Hence, disruption of the ECM will result in structural instability as well as activation of a number of signaling pathways that could lead to fibrosis, hypertrophy, and apoptosis. The ECM is a dynamic entity that undergoes constant turnover, and the integrity of its network structure is maintained by a balance in the function of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs). In heart disease, levels of MMPs and TIMPs are altered resulting in an imbalance between these two families of proteins. In this review, we will discuss the structure, function, and regulation of TIMPs, their MMP-independent functions, and their role in heart failure. We will review the knowledge that we have gained from clinical studies and animal models on the contribution of TIMPs in the development and progression of heart disease. We will further discuss how ECM molecules and regulatory genes can be used as biomarkers of disease in heart failure patients.

Background-Remodeling of the extracellular matrix (ECM) is a key aspect of myocardial response to biomechanical stress and heart failure. Tissue inhibitors of metalloproteinases (TIMPs) regulate the ECM turnover through negative regulation of matrix metalloproteinases (MMPs), which degrade the ECM structural proteins. Tissue inhibitor of metalloproteinases 2 is unique among TIMPs in activating pro-MMP2 in addition to inhibiting a number of MMPs. Given this dual role of TIMP2, we investigated whether TIMP2 serves a critical role in heart disease. Methods and Results-Pressure overload by transverse aortic constriction (TAC) in 8-week-old male mice resulted in greater left ventricular hypertrophy, fibrosis, dilation, and dysfunction in TIMP2-deficient (TIMP2) compared with wild-type mice at 2 weeks and 5 weeks post-TAC. Despite lack of MMP2 activation, total collagenase activity and specific membrane type MMP activity were greater in TIMP2 Ϫ/Ϫ -TAC hearts. Loss of TIMP2 resulted in a marked reduction of integrin ␤1D levels and compromised focal adhesion kinase phosphorylation, resulting in impaired adhesion of cardiomyocytes to ECM proteins, laminin, and fibronectin. Nonuniform ECM remodeling in TIMP2 Ϫ/Ϫ -TAC hearts revealed degraded network structure as well as excess fibrillar deposition. Greater fibrosis in TIMP2 Ϫ/Ϫ -TAC compared with wild-type TAC hearts was due to higher levels of SPARC (secreted protein acidic and rich in cysteine) and posttranslational stabilization of collagen fibers rather than increased collagen synthesis. Inhibition of MMPs including membrane type MMP significantly reduced left ventricular dilation and dysfunction, hypertrophy, and fibrosis in TIMP2 Key Words: tissue inhibitor of metalloproteinases Ⅲ membrane-type matrix metalloproteinases Ⅲ fibrosis Ⅲ hypertrophy I ncreased afterload leading to excess biomechanical stress is a common cause of left ventricular (LV) remodeling, which leads to cardiac dysfunction and eventual heart failure. 1,2 The extracellular matrix (ECM) is a dynamic structure, and its turnover is a physiological process that takes place in all organs. Adverse remodeling of the myocardial ECM, brought about by dysregulation in its turnover, is a key component of pressure overload-induced cardiomyopathy. This results in excess degradation and disruption of the ECM network structure or accumulation of ECM proteins and formation of fibrotic lesions. Myocardial fibrosis is also a well-known cause of diastolic dysfunction and diastolic heart failure. [3][4][5][6][7] Matrix metalloproteinases (MMPs) degrade ECM proteins, whereas their proteolytic activity is kept in check by their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the function of MMPs and TIMPs occurs in heart disease, leading to adverse ECM remodeling, and TIMPs are emerging as critical regulators of this process. 8 -13 Editorial see p 2052 Clinical Perspective on p 2105Among the 4 TIMPs, 14 TIMP2 has the unique property of activating MMP2 through formation of a tr...

Fetal growth restriction (FGR) greatly increases the risk of perinatal morbidity and mortality and is associated with increased uterine artery resistance and levels of oxidative stress. There are currently no available treatments for this condition. The hypothesis that the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (Tempol) would improve uterine artery function and rescue fetal growth was tested in a mouse model of FGR, using the endothelial nitric oxide synthase knockout mouse (Nos3(-/-)). Pregnant Nos3(-/-) and control C57BL/6J mice were treated with the superoxide dismutase-mimetic Tempol (1 mmol/L) or vehicle from Gestational Day 12.5 to 18.5. Tempol treatment significantly increased pup weight (P < 0.05) and crown-rump length (P < 0.01) in C57BL/6J and Nos3(-/-) mice. Uterine artery resistance was increased in Nos3(-/-) mice (P < 0.05); Tempol significantly increased end diastolic velocity in Nos3(-/-) mice (P < 0.05). Superoxide production in uterine arteries did not differ between C57BL/6J and Nos3(-/-) mice but was significantly increased in placentas from Nos3(-/-) mice (P < 0.05). This was not reduced by Tempol treatment. Placental System A activity was reduced in Nos3(-/-) mice (P < 0.01); this was not improved by treatment with Tempol. Treatment of Nos3(-/-) mice with Tempol, however, was associated with reduced vascular density in the placental bed (P < 0.05). This study demonstrated that treatment with the antioxidant Tempol is able to improve fetal growth in a mouse model of FGR. This was associated with an increase in uterine artery blood flow velocity but not an improvement in uterine artery function or placental System A activity.

Key pointsr At rest, dopamine induces recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) and increases venous admixture (i.e.Q s /Q t ).r Dopamine increases during exercise, and may be partly responsible for exercise-induced IPAVA recruitment.r In this study, we antagonized dopamine receptors with metoclopramide, and observed improved pulmonary gas exchange but no difference in IPAVA recruitment during exercise.r Dopamine blockade decreased cardiac output at peak exercise, resulting in decreased exercise performance.r Increasing endogenous dopamine is important for the normal healthy response to exercise. Abstract Pulmonary gas exchange, as evaluated by the alveolar-arterial oxygen difference (A-aD O 2 ), is impaired during intense exercise, and has been correlated with recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) as measured by agitated saline contrast echocardiography. Previous work has shown that dopamine (DA) recruits IPAVA and increases venous admixture (Q s /Q t ) at rest. As circulating DA increases during exercise, we hypothesized that A-aD O 2 and IPAVA recruitment would be decreased with DA receptor blockade. Twelve healthy males (age: 25 ± 6 years,V O 2 max : 58.6 ± 6.5 ml kg −1 min −1 ) performed two incremental staged cycling exercise sessions after ingestion of either placebo or a DA receptor blocker (metoclopramide 20 mg). Arterial blood gas, cardiorespiratory and IPAVA recruitment (evaluated by agitated saline contrast echocardiography) data were obtained at rest and during exercise up to 85% ofV O 2 max . On different days, participants also completed incremental exercise tests and exercise tolerance (time-to-exhaustion (TTE) at 85% ofV O 2 max ) with or without dopamine blockade. Compared to placebo, DA blockade did not change O 2 consumption, CO 2 production, or respiratory exchange ratio at any intensity. At 85%V O 2 max , DA blockade decreased A-aD O 2 , increased arterial O 2 saturation and minute ventilation, but did not reduce IPAVA recruitment, suggesting that positive saline contrast is unrelated to A-aD O 2 . Compared to placebo, DA blockade decreased maximal cardiac output,V O 2 max and TTE. Despite improving pulmonary gas exchange, blocking dopamine receptors appears to be detrimental to exercise performance. These findings suggest that endogenous dopamine is important to the normal cardiopulmonary response to exercise and is necessary for optimal high-intensity exercise performance.

Aims To examine the relative association between fasting plasma glucose vs post‐load (1‐h and 2‐h) glucose levels based on the oral glucose tolerance test in pregnancy and large‐for‐gestational‐age and hypertensive disorders of pregnancy outcomes. Methods All live singleton births between October 2008 and December 2014 in Alberta, Canada were included. Gestational diabetes mellitus was diagnosed using Diabetes Canada criteria. Logistic regression models were used to examine the association between fasting plasma glucose vs post‐load values and large‐for‐gestational‐age infants and hypertensive disorders of pregnancy after adjusting for maternal characteristics and pharmaceutical intervention in gestational diabetes pregnancies. Results Among 257 547 pregnancies, 208 344 (80.9%) had negative 50‐g glucose challenge tests, 36 261 (14.1%) had negative 75‐g oral glucose tolerance tests, and 12 942 (5.0%) had gestational diabetes based on either elevated fasting plasma glucose (n=4130, 1.6%) or elevated 1‐h and/or 2‐h oral glucose tolerance test values (n=8812, 3.4%). Large‐for‐gestational‐age and hypertensive disorders of pregnancy rates were 8.1% and 5.1% in negative glucose challenge test pregnancies, 11.0% and 7.0% in negative oral glucose tolerance test pregnancies, 22.4% and 11.9% in gestational diabetes pregnancies with elevated fasting plasma glucose, and 9.1% and 8% in gestational diabetes pregnancies with elevated post‐load levels, respectively. Among gestational diabetes pregnancies, those with elevated fasting plasma glucose were at higher risk of large‐for‐gestational age (adjusted odds ratio 2.66, 95% CI 2.39–2.96) and hypertensive disorders of pregnancy (adjusted odds ratio 1.51, 95% CI 1.33–1.72) outcomes relative to pregnancies with post‐load glucose elevations only. Fasting plasma glucose remained significantly associated with adverse outcomes in gestational diabetes pregnancies with and without pharmacological intervention. Conclusions Elevated fasting plasma glucose in women with gestational diabetes is a stronger predictor of large‐for‐gestational‐age and hypertensive disorders of pregnancy outcomes than elevated post‐load glucose.