Resistant Hypertension: Is There a Pathophysiologic Role for the Metalloproteinase System?
Year: 2016
Type: article
Abstract: Despite significant advances in our understanding of the pathophysiology, prevention, diagnosis, and treatment of hypertension, the target organ damage associated with the hypertensive process continues to be a major public health concern. For example, the control rate of hypertension (defined as a blood pressure [BP] <140/90 mm Hg) in high income countries such as the United States and Canada is only 50% to 70%, while in low- to middle-income countries worldwide, the control rate is only 10% to 30%. Thus, hypertension is indeed a global issue affecting approximately 1 billion individuals. While there are multiple factors, individually and collectively, responsible for these dismal control rates, such as appropriate diagnosis, patient education, access to care, availability of affordable antihypertensive medications, nonadherence, and clinical inertia, resistant hypertension (RH) plays a significant role. RH, usually defined as BP >140/90 mm Hg despite at least three antihypertensive agents from different classes at optimal doses including a diuretic, increases the risk of adverse cardiovascular events. RH is increasing in frequency. In one study, almost 10% of patients remained refractory to treatment (achieving a mean BP of 168/94 mm Hg) in spite of an average of seven visits to a hypertension clinic and six antihypertensive agents. These patients had higher baseline BPs and higher rates of stroke and congestive heart failure.1 Similarly, while much is known regarding the mechanism(s) and the pathophysiology of hypertension, such as the role of sodium excess, activation of neurohumoral systems (ie, the sympathetic nervous system and renin-angiotensin-aldosterone system), cardiac and vascular dysfunction and remodeling, and inflammation, there is still a great deal that is unknown. Recently, there has been significant interest and research in the role of the family of metalloproteinases (MMPs) in the pathophysiology of cardiovascular diseases. To address both RH and MMPs, Sabbatini and colleagues from Brazil and Massachusetts, report an interesting study entitled “Increased Circulating Tissue Inhibitor of Metalloproteinase-2 Is Associated With Resistant Hypertension,” in this issue of the Journal. This cross-sectional clinical study, conducted at two separate hypertension clinics in Brazil, assessed the levels of MMP-2 and the tissue inhibitor of metalloproteinase-2 (TIMP-2) and their relationship with end-organ damage such as cardiac hypertrophy and arterial stiffness. The study included 19 patients with normotension (NT), 116 patients with nonresistant hypertension (HTN), and 119 patients with resistant hypertension (RT), aged 18 to 65 years. All patients proved adherence to treatment and had regular follow-up visits for 6 months. Researchers defined RH as a BP >140/90 mm Hg despite three or more different classes of antihypertensive agents at optimal doses or controlled BP with at least four antihypertensive agents. RH patient also underwent pill counts, ambulatory BP monitoring (ABPM), imaging, and blood studies. Some exclusion criteria included an ejection fraction <50% and cerebrovascular disease, peripheral vascular disease, nephropathy, or liver dysfunction. In addition to office BP and ABPM, researchers determined pulse wave velocity (PWV) as an index of arterial stiffness and measured microalbuminuria, MMP-2, and TIMP-2 levels. The HTN and RH patients were generally older than the NT patients (HTN 62 years, RH 60 years, NT 52 years) but there was no significant difference in sex between the three groups. There was a statistically greater percentage of black and diabetic patients in the RH compared with the HTN and NT groups. In addition, the HTN and RH patients had a higher body mass index compared with the NT patients (NT 25, HTN 27.7, RH 31.2). As expected, both the HTN and RH patients had a higher office BP than the NT patients, with the RH patients having a higher systolic BP than the HTN patients (RH 146 mm Hg compared with HTN 139 mm Hg). There was, however, no difference in ABPM between the RH and HTN groups. Both the HTN and the RH patients had a higher PWV than the NT patients, but there was no difference between the HTN and RH patients. Commensurate with the differences in BP between the HTN and RH groups compared with the NT group, both the HTN and RH patients had a greater left ventricular mass index (LVMI) than the NT patients, but, again, there was no difference between the HTN and RH patients. As anticipated, there were significant differences in biochemical parameters between the three groups. Both the HTN and RH patients had higher glycated hemoglobin and glucose levels compared with the NT patients, reflecting the greater prevalence of diabetes in these groups. Importantly, while there was no significant difference in serum creatinine between the three groups, the RH patients had significantly greater microalbuminuria, aldosterone, and aldosterone/renin ratios than either the NT or HTN groups. As expected, the RH patients required more diuretics, aldosterone antagonists, β-blockers, calcium channel blockers, and sympatholytic agents than the HTN groups. The key findings of this study are related to the levels of MMP-2 and TIMP-2 and BP. There was no statistical difference of MMP-2 between the three groups (NT 240.1, HTN 237.0, and RH 228.9 ng/mL). However, there was a significant difference in TIMP-2 levels between the three groups. The RH patients had significantly higher levels of TIMP-2 (90.0 ng/mL) compared with either the HTN (70.1 ng/mL) or the NT (54.7 ng/mL) patients. The RH patients had a significantly lower MMP-2/TIMP-2 ratio than either the HTN or NT patients. There was no correlation between either MMP-2, TIMP-2, or MMP-2/TIMP-2 and PWV or LVMI within the HTN or RH patients; however, a positive correlation was found between TIMP-2 and LVMI when the HTN and RH patients were combined. In addition, when the HTN and RH patients were combined, a significant correlation was found between MMP-2 levels and both systolic and diastolic ABPM as well as between the MMP-2/TIMP-2 ratio and systolic ABPM. When a logistical regression for the presence of BP treatment resistance was performed in the combined HTN and RH patients and when combining the patients in all three groups, both TIMP-2 and the MMP-2/TIMP-2 ratio were independently associated with treatment resistance. The major contribution of this manuscript is the novel description of MMP-2 and TIMP-2 levels in patients with documented RH and in patients with and without HTN. MMPs are a family of calcium-dependent, zinc-containing, endopeptidases that play a central role in extracellular matrix (ECM) degradation and importantly, tissue and organ remodeling. ECM is critical for the structural support of cells and plays a role in intercellular communication, inflammation, cell migration and growth, neovascularization, apoptosis, wound healing, host immunity, angiogenesis, and organ morphogenesis. TIMPs inhibit MMPs, and dysregulation of either MMPs and/or TIMPs has been implicated in multiple pathological disorders, including cardiomyopathy, atherosclerosis, vascular disease, and hypertension.2 Researchers have identified 23 MMPs in humans and have divided them into six groups: collagenases, gelatinases, stromelysins, membrane-type MMPs, matrilysins, and other MMPs.3 They are regulated at multiple levels including gene transcription and translation, as well as at the conversion of pro-MMPs into MMPs. Intracellular interactions, inflammatory cytokines, hormones, growth factors control, and inhibitors such as α2-microglobulins and TIMPs control expression.4 There are four endogenous TIMPs (TIMP1, TIMP2, TIMP3, and TIMP4) that bind to active MMPs in a 1:1 relationship, inhibiting MMP and decreasing ECM proteolytic activity. In the normal physiological state, activities of MMPs are minimal and the balance of MMPs and TIMPs is tightly regulated. However, in pathological situations this balance can become disrupted and dysfunctional, resulting in a disturbance in proteolytic activity. Dysregulation of the balance between MMPs and TIMPs has been associated with many pathologic cardiovascular mechanisms. This imbalance may play a key role in ischemic cardiomyopathy, hypertensive heart disease, and vascular remodeling, among others. For instance, following myocardial injury, MMPs may drive the remodeling process by degrading the myocardial extracellular matrix, leading to pathologic remodeling including fibrosis and diastolic dysfunction. A decrease in cardiac TIMP-2 leading to dysregulation of MMPs has been associated with myocardial oxidative stress injury and left ventricular dilation and dysfunction.5 Interestingly, organ damage such as left ventricular hypertrophy has been associated with lower MMP-2 and higher TIMP-1 levels. This imbalance suggests a reduction in ECM degradation, which may be a compensatory protective response to ventricular remodeling and diastolic dysfunction.6 MMP-2 is also upregulated in response to high intraluminal pressure.7 These observations are critical to the interpretation of the association between the family of MMPs, together with their inhibiting enzymes, TIMPs, and the subset of patients with RH. Specifically, TIMP-2 levels are higher and the MMP-2/TIMP-2 ratio is lower in patients with RH than in those with either controlled HTN or NT. This may reflect a compensatory process to decrease ECM degradation during the development of hypertensive target organ damage such as left ventricular hypertrophy. Thus, the data reported by Sabbitini and colleagues contributes significantly to our knowledge in the area of RH. The imbalance between MMPs and TIMPs in RH could prove useful in clinical practice, although the implication remains unclear. Further studies are necessary with a larger RH population to determine the exact relationships between RH and MMPs and TIMPs. Ultimately, the understanding of MMPs, TIMPs, and ECM formation and degradation may enhance disease screening and diagnosis and ultimately lead to pharmacologic targeting of these entities. Donald J. DiPette is a Distinguished Health Sciences Professor, University of South Carolina and University of South Carolina School of Medicine, Columbia, SC.
Source: Journal of Clinical Hypertension
DOI: 10.1111/jch.12870
Institution: University of South Carolina
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2466316045