Clinical Implications

Abstract

HomeHypertensionVol. 67, No. 5Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 May 2016https://doi.org/10.1161/HYPERTENSIONAHA.116.07596Hypertension. 2016;67:801Protein Aggregation in Aged and Hypertensive Heart (p 1006)Download figureDownload PowerPointDegenerative diseases are largely defined by protein aggregates in affected tissues. We analyzed cardiac aggregates for changes during normal aging and after sustained angiotensin II–induced hypertension. Detergent-insoluble aggregates were isolated from mouse hearts, and constituent proteins were characterized. Gel quantitation indicated pronounced shifts with aging and hypertension, and mass spectrometry identified proteins that altered significantly. Because both aged and hypertensive hearts undergo fibrosis, we examined aggregates from cardiac myofibroblasts. During in vitro senescence, myofibroblasts accrued aggregates containing many proteins that accumulated during normal aging or induced hypertension. There was significant overlap of identified proteins that altered in abundance within cardiac aggregates as mice aged naturally or were made hypertensive by angiotensin II infusion or as cardiac myofibroblasts underwent replicative aging. Thus, aggregates that arise from disparate causes (aging, hypertension, and replicative senescence) may have common underlying mechanisms of accrual. Many of these proteins relate to inflammation, stress response, and protein homeostasis and have been previously associated with age-progressive neurodegenerative diseases. Cardiac senescence-associated pathology may be considered Alzheimer disease of the heart based on overlap in risk factors (such as ApoE alleles) and protective drugs (eg, aspirin), and the overlap in aggregation components may implicate a common underlying molecular mechanism. Clinicians should be mindful that, as we develop new mechanistic insights and novel therapies for either disease, they might also be applicable to the other.Vascular Function and Cardiovascular Outcomes (p 1045)Nitroglycerine-induced vasodilation may be not only a control test for flow-mediated vasodilation (FMD) measurement but also a useful marker of the grade of atherosclerosis. Although it is well known that FMD is an independent predictor of future cardiovascular events, it has been also shown that FMD is not associated with future cardiovascular events in cases of a relatively low grade of atherosclerosis and in cases of a severe stage of atherosclerosis, after adjusting for various confounders. There is no previous study investigating the association between FMD combined with nitroglycerine-induced vasodilation and cardiovascular events. We evaluate the prognostic value of FMD combined with nitroglycerine-induced vasodilation for future cardiovascular events in 402 subjects, including healthy subjects and patients with cardiovascular disease. There were significant differences between the Kaplan–Meier curves for first major cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, and revascularization) in subgroups of subjects categorized as being above or below the cutoff values for FMD and nitroglycerine-induced vasodilation (Figure). After adjustment for age, sex, body mass index, and cardiovascular risk factors, below cutoff nitroglycerine-induced vasodilation, especially in combination with below cutoff FMD, remained a strong independent indicator of cardiovascular events. FMD combined with nitroglycerine-induced vasodilation may be useful as a surrogate marker of future cardiovascular events.Download figureDownload PowerPointMaladaptive Adventitial Remodeling in Hypertension (p 890)Download figureDownload PowerPointThe primary function of large arteries is to store elastic energy during systole and to use this energy to augment blood flow during diastole. In this way, healthy central arteries decrease the workload on the heart and promote perfusion of critical organs such as the kidney, brain, and heart during diastole. The aorta stiffens in diverse conditions—including aging, hypertension, diabetes mellitus, obesity, and cigarette smoking—which reduces its capacitance, or Windkessel function. Such stiffening is often indicated clinically by an increase in pulse wave velocity and is a harbinger of renal failure, stroke, dementia, and heart failure. Using a mouse model of hypertension, we found that an early, exuberant deposition of collagen thickens the adventitia well beyond that needed to normalize the increased biaxial wall stresses that result from high blood pressure (note striking deposition of collagen in the adventitia in hypertension in the Figure). Moreover, this maladaptive response appears to be driven in large part by inflammation in the adventitia. The most striking consequence of the maladaptive remodeling is a profound loss of energy storage capability, that is, a reduced Windkessel function. This loss occurs because the thickened adventitial collagen limits cyclic outward expansion of the media and thus deformation of the energy storing elastic fibers. These results highlight the need to therapeutically address mechanisms of adventitial inflammation and fibrosis to prevent the untoward long-term effects of central artery stiffening. 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