Susan J. Zieman

Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness

Arterial stiffness is a growing epidemic associated with increased risk of cardiovascular events, dementia, and death. Decreased compliance of the central vasculature alters arterial pressure and flow dynamics and impacts cardiac performance and coronary perfusion. This article reviews the structural, cellular, and genetic contributors to arterial stiffness, including the roles of the scaffolding proteins, extracellular matrix, inflammatory molecules, endothelial cell function, and reactive oxidant species. Additional influences of atherosclerosis, glucose regulation, chronic renal disease, salt, and changes in neurohormonal regulation are discussed. A review of the hemodynamic impact of arterial stiffness follows. A number of lifestyle changes and therapies that reduce arterial stiffness are presented, including weight loss, exercise, salt reduction, alcohol consumption, and neuroendocrine-directed therapies, such as those targeting the renin-angiotensin aldosterone system, natriuretic peptides, insulin modulators, as well as novel therapies that target advanced glycation end products.

2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Preamble e346 1. Introduction e347 2. Overview of Acs e349 3. Initial Evaluation and Management e350 4. Early Hospital Care e359

Clinical Practice Guideline2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000134 The writing committee gratefully acknowledges the memory of Dr. Francis M. Fesmire (representative of the American College of Emergency Physicians), who died during the development of this document but contributed immensely to our understanding of non–ST-elevation acute coronary syndromes. *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply; see Appendix 1 for recusal information. †ACC/AHA Representative. ‡ACC/AHA Task Force on Practice Guidelines Liaison. §American College of Physicians Representative. ║American Academy of Family Physicians Representative. ¶Society of Thoracic Surgeons Representative. #ACC/AHA Task Force on Performance Measures Liaison. **Society for Cardiovascular Angiography and Interventions Representative. ††Former Task Force member; current member during the writing effort. This document was approved by the American Heart Association Science Advisory and Coordinating Committee and the American College of Cardiology Board of Trustees in August 2014. The online-only Comprehensive Relationships Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/ doi:10.1161/CIR.0000000000000134/-/DC1. The online-only Data Supplement files are available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/ CIR.0000000000000134/-/DC2. The American Heart Association requests that this document be cited as follows: Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ. 2014 ACC/AHA guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344–e426. This article is copublished in the Journal of the American College of Cardiology. Copies: This document is available on the World Wide Web sites of the American Heart Association (my.americanheart.org) and the American College of Cardiology (www.cardiosource.org). A copy of the document is available at http://my.americanheart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the “Policies and Development” link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/ Copyright-Permission-Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page. 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension.

Objectives Arterial stiffening and endothelial dysfunction are hallmarks of aging, and advanced glycation endproducts (AGE) may contribute to these changes. We tested the hypothesis that AGE crosslink breakers enhance endothelial flow-mediated dilation (FMD) in humans and examined the potential mechanisms for this effect. Methods Thirteen adults (nine men, aged 65 ± 2 years) with isolated systolic hypertension (systolic blood pressure > 140 mmHg, diastolic blood pressure < 90 mmHg or pulse pressure > 60 mmHg) on stable antihypertensive therapy were studied. Subjects received placebo (2 weeks) then oral alagebrium (ALT-711; 210 mg twice a day for 8 weeks). Subjects and data analyses were blinded to treatment. Arterial stiffness was assessed by carotid augmentation index (AI) and brachial artery distensibility (ArtD) using applanation tonometry and Doppler echo, and endothelial function by brachial FMD. Serum markers of collagen metabolism and vascular inflammation were assessed. Results Alagebrium reduced carotid AI by 37% (P = 0.007) and augmented pressure (16.4 ± 10 to 9.6 ± 9 mmHg; P < 0.001). Heart rate, arterial pressures, and ArtD, were unchanged. FMD increased from 4.6 ± 1.1 to 7.1 ± 1.1% with alagebrium (P < 0.05), and was unrelated to altered shear stress or regional arterial distensibility. However, FMD change was inversely related to markers of collagen synthesis, p-selectin and intracellular cell adhesion molecule (all P < 0.05). Alagebrium-associated changes in plasma nitrite plus nitrate was inversely correlated with plasma matrix metalloproteinase 9 and type I collagen (P = 0.007). Conclusions Alagebrium enhances peripheral artery endothelial function and improves overall impedance matching. Improved endothelial function correlates better with reduced vascular fibrosis and inflammation markers than with vessel distensibility. AGE-crosslink breakers may reduce cardiovascular risk in older adults by reduced central arterial stiffness and vascular remodeling.

Advanced glycation endproduct crosslinking in the cardiovascular system: Potential therapeutic target for cardiovascular disease

Advanced glycation endproducts (AGEs) are formed by a reaction between reducing sugars and biological amines. Because of their marked stability, glycated proteins accumulate slowly over a person’s lifespan, and can contribute to age-associated structural and physiological changes in the cardiovascular system such as increased vascular and myocardial stiffness, endothelial dysfunction, altered vascular injury responses and atherosclerotic plaque formation. The mechanisms by which AGEs affect the cardiovascular system include collagen crosslinking, alteration of low-density lipoprotein molecules and impairment of cellular nitric oxide signalling through their interaction with AGE receptors (RAGEs). Thus, the accumulation of AGEs may help to explain the increased cardiac risk associated with aging as well as diabetes mellitus and hypertension, two conditions that accelerate and enhance AGE formation.A variety of new pharmacological approaches are being developed to reduce the pathophysiological impact of AGEs. These agents can prevent AGE and AGE crosslink formation, break pre-existing AGE crosslinks, and block the interaction between AGEs and RAGEs. Such agents have been shown to reduce vascular and myocardial stiffness, inhibit atherosclerotic plaque formation and improve endothelial function in animal models. Improvement in vascular compliance has also been demonstrated with AGE crosslink breakers in clinical trials. These studies offer promise to reduce the cardiac risk associated with isolated systolic hyperten-sion, diastolic dysfunction and diabetes.

Cardiac Care for Older Adults Time for a New Paradigm

Recent decades have witnessed striking growth in the number of older adults both in the United States and throughout much of the world, largely due to improved public health, nutrition, and medical care. Between 2000 and 2030, the proportion of the worlds population age 65 years and older is

Secondary prevention of atherosclerotic cardiovascular disease in older adults: A scientific statement from the American heart association

Since the initial scientific statement on Secondary Prevention of Coronary Heart Disease (CHD) in the Elderly was published in 2002,1 several trends have continued that make an update highly appropriate. First, the graying of the US population and those of other industrialized countries has progressed unabated because more adults are surviving into their senior years. The number of Americans aged ≥75 years was estimated at 18.6 million in 2010, representing ≈6% of the population,2 and it is expected to double by 2050. The population aged ≥85 years is growing the most rapidly, with numbers expected to reach 19.5 million by 2040. In 2008, 67% of the 811 940 cardiovascular deaths in the United States occurred in people aged ≥75 years.3 In parallel to this increase in the older adult demographic, the number of Americans with CHD has increased to an estimated 16.3 million, more than half of whom are >65 years of age.3 Similarly, 7 million have had a stroke, the incidence of which approximately doubles with successive age decades after 45 to 54 years.3 Peripheral artery disease (PAD) affects 8 to 10 million Americans, the majority of whom are >65 years of age. Between 2015 and 2030, annual US costs related to atherosclerotic cardiovascular disease (ASCVD) are projected to increase from

Diabetes and cardiovascular disease in older adults: Current status and future directions

84.8 billion to

Associations of Total and High-Molecular-Weight Adiponectin With All-Cause and Cardiovascular Mortality in Older Persons The Cardiovascular Health Study

202 billion.3 Moreover, given that ASCVD often undermines functional capacity and independence and increases reliance on long-term care, indirect expenses related to ASCVD are also expected to increase. Thus, the need for effective secondary prevention measures in the older adult population with known ASCVD has never been greater. Notably, the 2011 American Heart Association (AHA)/American College of Cardiology Foundation (ACCF) updated guidelines for secondary prevention of CHD broadened …

Association of Fetuin-A With Incident Diabetes Mellitus in Community-Living Older Adults The Cardiovascular Health Study

The prevalence of diabetes increases with age, driven in part by an absolute increase in incidence among adults aged 65 years and older. Individuals with diabetes are at higher risk for cardiovascular disease, and age strongly predicts cardiovascular complications. Inflammation and oxidative stress appear to play some role in the mechanisms underlying aging, diabetes, cardiovascular disease, and other complications of diabetes. However, the mechanisms underlying the age-associated increase in risk for diabetes and diabetes-related cardiovascular disease remain poorly understood. Moreover, because of the heterogeneity of the older population, a lack of understanding of the biology of aging, and inadequate study of the effects of treatments on traditional complications and geriatric conditions associated with diabetes, no consensus exists on the optimal interventions for older diabetic adults. The Association of Specialty Professors, along with the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and the American Diabetes Association, held a workshop, summarized in this Perspective, to discuss current knowledge regarding diabetes and cardiovascular disease in older adults, identify gaps, and propose questions to guide future research.