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J Clin Hypertens (Greenwich). 2012;14:808–809. ©2012 Wiley Periodicals, Inc.
New developments in cardiovascular translational sciences have significantly advanced our understanding of the endovascular biology of blood pressure. Reductions in vascular elasticity and vessel compliance of conduit arteries are key components of both ISH and SDH. Vascular changes from the matrix metalloproteinase family of enzymes are involved in arterial wall remodeling and vascular stiffness. This new translational information helps further our understanding of both ISH and SDH.
Hypertension is a significant risk factor for cardiovascular morbidity and mortality, and the risk for hypertension dramatically increases with age. Lowering blood pressure (BP) to within the normal range improves long-term outcomes.1 Due to a progressive increase in systolic BP and a decrease in diastolic BP with age, most elderly persons develop isolated systolic hypertension (ISH), accompanied by increased pulse pressure.2 Combined systolic/diastolic hypertension (SDH) predominantly occurs in patients younger than 45 years. In this issue of The Journal of Clinical Hypertension, Ghiadoni and colleagues used transthoracic Doppler echocardiography to evaluate coronary flow reserve (CFR) in ISH vs SDH in an elderly cohort. They found that while ISH patients had lower CFR than SDH, CFR was above the normal threshold for both groups. Multivariate regression analysis revealed that ISH and dyslipidemia were independent predictors of CFR. Therefore, this study suggested that worse coronary microvascular endothelial dysfunction occurred with ISH.
An increase in systolic BP, which is present in both ISH and SDH, often develops as a result of reduced elasticity and compliance of central conduit arteries. Initiating factors include age-associated arterial stiffening, atherosclerosis-associated accumulation of arterial calcium and collagen, and the degradation of arterial elastin.3 An increase in diastolic BP during SDH results from an increased systemic vascular resistance coupled with inappropriate cardiac output.4 Increased vascular resistance at the arteriole level is due to increased neurohormonal activity and autoregulatory reaction of smooth muscle to expanded plasma volume.5 The latter develops due to impaired kidney sodium secretion.
Endothelial dysfunction is a critical component in the development of arterial hypertension.6 The study by Ghiadoni and colleagues measured CFR, which is a common method to evaluate endothelial function in hypertensive patients.7 The novelty of this study is that endothelial function in ISH has not previously been compared with SDH. Interestingly, they demonstrated that CFR was impaired in patients with ISH. Future studies that assess peripheral circulation would add to these findings.
The findings provide a strong foundation for future examination of endothelial function in patients with arterial hypertension. This study serves as a good example of translational research, to bridge to basic science in vitro and in vivo experiments with clinical diagnostics.8 One contributor to endothelial function is the matrix metalloproteinase (MMP) family of enzymes, which facilitate the development of high BP by stimulating arterial wall remodeling to induce vessel stiffening (Figure).9 Systolic BP positively correlates with circulating MMP-9 levels in humans,10 and applying high intra-luminal pressure within the mouse vasculature increases MMP-9 levels.11 Inhibiting MMP-2 improves endothelial function and prevents the development of hypertension in insulin-resistant animal models.12 In vitro, MMP-2 degrades endothelial nitric oxide synthase and its cofactor heat shock protein 90, both of which inhibit vasodilation.12 In addition, MMP-2 degrades big endothelin-1 to produce a vasoconstrictor and cleaves the extracellular domain of β2-adrenergic receptors to suppress β-agonist–induced vasodilation,13,14 both of which lead to increased vascular resistance and high BP (Figure). Thus, maintaining nitric oxide bioavailability through mechanisms that inhibit MMPs could be a therapeutic approach to managing patients with arterial hypertension.
Figure FIGURE. Matrix metalloproteinase (MMP)-2 and MMP-9 increase arterial stiffness and induce endothelial dysfunction, which results in impaired vascular elasticity and compliance and subsequent arterial hypertension. MMP-2 also inhibits vasodilation by affecting vasodilators.
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Lipid levels are another factor that contributes to endothelial function. By excluding patients with diabetes mellitus, Ghiadoni and colleagues were able to assess atherosclerosis-associated changes in the intima and media of arteries that was independent of glucose and insulin. Intima-medial thickening and plaque are among the most frequently observed variables in elderly patients with ISH.15 MMPs have a strong link with atherosclerosis progression and plaque destabilization, both of which contribute to arterial stiffening and the progression of endothelial dysfunction.16,17 Targeting MMPs, therefore, also has therapeutic application in the management of patients with dyslipidemia and ISH or SDH.
The extracellular matrix accumulation of calcium in the arterial wall is known as vascular calcification. Vascular calcification is stimulated by smooth muscle cell apoptosis, microvesicle release, the abnormal expression of mineralization inhibitors, or the deposition of minerals.18 Medial calcification reduces arterial wall elasticity to stiffen the wall and accelerates pulse wave velocity. Both of these events widen the pulse pressure to result in ISH.19 A recent large clinical trial confirmed that pulse pressure and ISH were significantly associated with arterial calcification, with the magnitude of the association being higher for ISH than SDH.20 These findings indicate that differential vascular calcification may explain the CFR differences observed between ISH and SDH.
The findings of this study are novel and interesting, and several aspects need to be considered when interpreting and translating these results. First, age-matched healthy controls are lacking. Including a control group of patients of the same age with no arterial hypertension would help to place these findings in a broader context. Second, the sample size in this study is relatively small. Large-scale multicenter clinical trials are warranted to confirm these findings. Third, additional variables beyond CFR are needed to provide additional details on the coronary microvascular function. Because the development of SDH involves dysfunction in resistance arteries, comparing endothelial function in this vessel type may elucidate differential pathogenesis mechanisms between ISH and SDH.