Peripheral Arterial Disease: Pathophysiology and Therapeutics

Transcription

1 Peripheral Arterial Disease: Pathophysiology and Therapeutics

2 ii Colloquium Digital Library of Life Sciences This e-book is a copyrighted work in the Colloquium Digital Library an innovative collection of time saving references and tools for researchers and students who want to quickly get up to speed in a new area or fundamental biomedical/life sciences topic. Each PDF e-book in the collection is an in-depth overview of a fast-moving or fundamental area of research, authored by a prominent contributor to the field. We call these e-books Lectures because they are intended for a broad, diverse audience of life scientists, in the spirit of a plenary lecture delivered by a keynote speaker or visiting professor. Individual e-books are published as contributions to a particular thematic series, each covering a different subject area and managed by its own prestigious editor, who oversees topic and author selection as well as scientific review. Readers are invited to see highlights of fields other than their own, keep up with advances in various disciplines, and refresh their understanding of core concepts in cell & molecular biology. For the full list of published and forthcoming Lectures, please visit the Colloquium homepage: Access to the Colloquium Digital Library is available by institutional license. Please info@morganclaypool.com for more information. Morgan & Claypool Life Sciences is a signatory to the STM Permission Guidelines. All figures used with permission.

3 iii Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease Editors D. Neil Granger, Louisiana State University Health Sciences Center Joey P. Granger, University of Mississippi Medical Center Physiology is a scientific discipline devoted to understanding the functions of the body. It addresses function at multiple levels, including molecular, cellular, organ, and system. An appreciation of the processes that occur at each level is necessary to understand function in health and the dysfunction associated with disease. Homeostasis and integration are fundamental principles of physiology that account for the relative constancy of organ processes and bodily function even in the face of substantial environmental changes. This constancy results from integrative, cooperative interactions of chemical and electrical signaling processes within and between cells, organs and systems. This ebook series on the broad field of physiology covers the major organ systems from an integrative perspective that addresses the molecular and cellular processes that contribute to homeostasis. Material on pathophysiology is also included throughout the ebooks. The state-of the-art treatises were produced by leading experts in the field of physiology. Each ebook includes stand-alone information and is intended to be of value to students, scientists, and clinicians in the biomedical sciences. Since physiological concepts are an ever-changing work-in-progress, each contributor will have the opportunity to make periodic updates of the covered material. Published titles (for future titles please see the website,

4 Copyright 2013 by Morgan & Claypool Life Sciences All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means electronic, mechanical, photocopy, recording, or any other except for brief quotations in printed reviews, without the prior permission of the publisher. Peripheral Arterial Disease: Pathophysiology and Therapeutics Christopher Kevil ISBN: paperback ISBN: ebook DOI: /C00086ED1V01Y201307ISP040 A Publication in the Colloquium Series on INTEGRATED SYSTEMS PHYSIOLOGY: FROM MOLECULE TO FUNCTION TO DISEASE Lecture #40 Series Editors: D. Neil Granger, LSU Health Sciences Center, and Joey P. Granger, University of Mississippi Medical Center Series ISSN ISSN X ISSN print electronic

5 Peripheral Arterial Disease: Pathophysiology and Therapeutics Christopher G. Kevil and Shyamal C. Bir Department of Pathology LSU Health Sciences Center Christopher B. Pattillo Department of Molecular and Cellular Physiology LSU Health Sciences Center Nuri I. Akkus Division of Cardiology, Department of Medicine LSU Health Sciences Center COLLOQUIUM SERIES ON Integrated Systems Physiology: From Molecule to Function to Disease #40

6 vi Abstract Peripheral arterial disease (PAD) is a cardiovascular disorder of the peripheral vasculature due to progressive atherosclerotic stenosis of conduit arteries restricting blood flow to tissues. PAD is typically a disease of older individuals, and the incidence of PAD continues to rise due to an increase in cardiometabolic disease and an aging population. Importantly, all cause and cardiovascular morbidity and mortality are significantly increased in PAD patients. PAD diagnosis remains a significant challenge, as a large number of patients are asymptomatic. Moreover, PAD results in a significant financial and societal burden with underutilized diagnostics and limited effective therapies. Here we discuss PAD signs and symptoms, pathophysiological mechanisms, current management, and future disease targets and possible therapeutic treatments for PAD. Keywords peripheral vascular disease, endothelial dysfunction, atherosclerosis, diabetes, angiogenesis, arteriogenesis, stem cells, nitric oxide, pathophysiology

7 vii Contents 1. Introduction Clinical Parameters of Peripheral Arterial Disease Incidence and Burden Signs and Symptoms Clinical Diagnosis Vascular Anatomy and Physiology Vascular Anatomy Regulation of Blood Flow Hemodynamic Deficits During PAD Pathophysiology of Peripheral Arterial Disease Atherosclerosis Hypertension and Vasomotor Dysfunction Skeletal Muscle Pathology Vascular Dysfunction Responses Dyslipidemia and Vascular Dysfunction Glycemic Status and Vascular Dysfunction Thrombosis and Vascular Dysfunction Redox Stress and Vascular Dysfunction Adaptive Vascular Responses Adaptive Vascular Growth Vasculogenesis Arteriogenesis Angiogenesis Molecular Mediators of Adaptive Responses HIF

8 viii Peripheral Arterial Disease: Pathophysiology and Therapeutics NF-kB VEGF MCP bfgf NOS Current Medical Management of Peripheral Arterial Disease Supervised Exercise Therapy Pharmaceutical Therapy Pentoxifylline/Cilostazol Lipid Lowering Agents Antiplatelet Agents Emerging Targets and Therapeutic Directions Genetics and Epigenetics Stem Cell Therapy Small Molecules and Metabolic Regulators PHD Inhibitors PGC-1a Nitrite/NO Metabolism Summary References Author Biographies... 73

9 1 c h a p t e r 1 Introduction Peripheral arterial disease (PAD) is defined as a slowly progressing, occlusive vascular disease of the extremities primarily due to atherosclerosis which can involve vasculitis and thrombosis. The incidence of PAD is increasing worldwide due to an overall increase in diabetes, obesity, and other cardiovascular disorders. Importantly, the incidence of PAD will continue to increase, as the condition has historically been diagnosed in elderly populations, which are also rising worldwide. Additionally, the 2011 ACC/AHA guidelines on PAD emphasized smoking as a prime risk factor for PAD, and the prevalence of smoking continues to increase particularly in Asia. The 2005 ACC/AHA guidelines on PAD posited that 5-year outcomes on limb morbidity of PAD patients is 70 80% having stable claudication or walking pain, 10 20% having worsening claudication or resting pain, and 1 2% evolving to critical limb ischemia (CLI). Patients with resting pain and CLI have two to four times increased chance of coronary arterial disease and cerebrovascular disease with increased mortality. Increasing incidence of PAD and CLI along with diabetes and other cardiovascular disorders significantly impacts overall health care-related costs and associated loss of productivity estimated at billions of dollars. Together, PAD creates a significant burden not only on the individual patient but also on the health care system and society as a whole. With such alarming statistics of increased PAD incidence, morbidity, mortality, its socioeconomic burden, minimal effective therapeutics, and variations in medical management, it is imperative that advances in the understanding of disease pathogenesis and therapeutics be sought [1, 2].

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11 3 c h a p t e r 2 Clinical Parameters of Peripheral Arterial Disease 2.1 INCIDENCE AND BURDEN PAD is a progressive vascular disease characterized by narrowing and occlusions in the peripheral arterial bed. It is primarily defined as an atherothrombotic syndrome with risk of involvement in other vascular beds such as cardiac and cerebral circulation with associated increased risk of death, myocardial infarction (MI), and stroke. The risk factors for developing PAD are age, male gender, diabetes, smoking, and hypercholesterolemia. Figure 1 illustrates the odds ratio of various risk factors for development of PAD. In the analysis of the National Health and Nutrition Examination Survey (NHANES), chronic renal insufficiency with estimated glomerular filtration rate less than 60 ml/min, elevated fibrinogen and C-reactive protein levels were also associated with PAD [3]. PAD is prevalent worldwide and often asymptomatic resulting in underdiagnosis and under treatment. In different studies and registries, including the presence of different risk factors (e.g., diabetes, smoking, age), the prevalence of PAD varies between 4.3% and 29% [3, 4]. For example, in the PARTNERS study [4] (PAD Awareness, Risk, and Treatment: New Resources for Survival) among 6979 patients who were 70 years or older, or who were years with a history of smoking or diabetes, 29% had PAD [4]. On the other hand, in the NHANES survey, the prevalence of PAD among adults aged 40 years and older in the United States was 4.3% in the year 2000 [3]. In the REACH (Reduction of Atherothrombosis for Continued Health) registry [5] among 67,888 patients from 44 different countries who were 45 or older with established arterial disease or three or more risk factors for atherothrombosis, the prevalence of PAD was 12.2% [4]. A diagnosis of PAD as an indicator of systemic atherosclerosis puts these patients in a category with increased risk for myocardial infarction and stroke. In the REACH registry, cardiac, cerebral, and peripheral vascular diseases were simultaneously present in 15.9% of the patients.

12 4 Peripheral Arterial Disease: Pathophysiology and Therapeutics Figure 1: Risk factor odds ratio for the development of PAD. Lau JF, Weinberg MD, Olin JW (2011), Peripheral artery disease. Part 1: clinical evaluation and noninvasive diagnosis. Nature reviews, Cardiology 8: SIGNS AND SYMPTOMS Intermittent claudication (IC) is the typical symptom of PAD. IC occurs due to inadequate blood flow to the exercising muscle resulting in subsequent ischemia and muscular pain. The calf muscle is one of the common sites of pain while walking. The calf muscles along with the quadriceps are the main muscles involved during the gait cycle, and calf blood flow rises 20-fold with exercise [6]. IC is reproducible (with similar distance/effort) cramping discomfort of the legs, hips, or buttocks depending on the location of the arterial disease. IC is produced after a predictable level of exertion per patient and not relieved until discontinuation of exertion. Patients may experience bilateral hip/buttock pain if there is aortic disease, if unilateral, this may suggest disease in the ipsilateral iliac artery. Thigh pain could be due to iliac or common femoral artery disease, whereas pain localized

13 Clinical Parameters of PAD 5 Figure 2: The Edinburgh claudication questionnaire. This established and validated questionnaire is useful in evaluating claudication symptoms for PAD diagnosis. /uploads/2012/06/edinburghclaudicationquestionnaire-toolforexaminationrooms.pdf. to the calf may be due to disease of the superficial femoral artery. Vascular disease of the arteries below the knee usually causes ankle pain. Together, these symptoms may be progressive and clearly limit mobility. The Edinburgh Claudication Questionnaire can be helpful for diagnosing IC in symptomatic patients (Figure 2) [6]. In a study using this questionnaire on 300 subjects (55-year-olds attending their general practitioner), it was found to be 91.3% (95% CI %) sensitive and 99.3% (95% CI %) specific in comparison to the diagnosis of intermittent claudication made by a physician [7]. However, a limitation is that a majority of patients have asymptomatic PAD or atypical symptoms. For example, in the PARTNERS study, only 11% of patients reported typical IC, while other patients had atypical leg pain or even pain at rest. With the progression of disease, it is possible that critical limb ischemia (CLI) can occur, and these patients will have continuous, severe, aching, rest pain located on the toes/forefoot. However, it is important to note that not all patients evolve to CLI leading to the recent hypothesis that stable PAD and unstable PAD/CLI may be two different diseases [8]. Nonetheless, critical limb ischemia may also present as gangrene and non-healing wounds which often results in amputation.

14 6 Peripheral Arterial Disease: Pathophysiology and Therapeutics 2.3 CLINICAL DIAGNOSIS The physical examination is very helpful and important in the evaluation of PAD. In the PARTNERS study, if only a history was used to diagnose PAD, 85% of PAD patients would be missed. A systematic approach of palpation of pulses, auscultation of arteries, and inspection of skin conditions provide important clues about the presence of PAD. As an example, greater than a 20 mm Hg blood pressure difference between arms is suggestive of narrowing of arteries supplying the upper extremities. Lack of palpable pulses, weakening of pulse with loss of symmetry in either extremity, pulses in brachial, radial, ulnar, femoral, popliteal, dorsalis pedis, and posterior tibial arteries are indicative of significant PAD. Auscultation for bruits using a stethoscope in the abdomen, flank, and groin can suggest abdominal aortic disease, renal artery, and iliac/femoral artery diseases, respectively. With inspection of the extremities, skin color changes with cyanosis or pallor are often apparent. Additionally, cold temperature of skin, lack of hair with the presence of trophic skin or muscle changes, and ulcerations suggest significant PAD. Eventually, with continued ischemia, some patients may develop leg ulcerations. Development of skin pallor with elevation of the lower extremity at degrees (Buerger s angle) and loss of capillary refill in the toes are also useful PAD indications. Nevertheless, PAD may still be underdiagnosed by physical exam. In a 2010 Canadian Study of 1236 patients, with a complete physical exam (all dorsalis pedis and posterior tibial pulses palpated with auscultation for a femoral bruit) diagnostic sensitivity for PAD by physical exam was only 58% although with a much better specificity of 98% [9]. The ankle brachial index (ABI) is the most commonly used and well-accepted test for diagnosis of PAD. ABI is the ratio of systolic blood pressure measured at the ankle to that measured at the brachial artery. Normally, due to reflected waves and changes in lower extremity vessel thickness (with increased hydrostatic pressure with walking) and consequent stiffness, systolic blood pressure is higher in the ankles than the arms [10]. ABI is a non-invasive, simple, and inexpensive test that takes about 10 minutes to perform, is reproducible, is well studied and has prognostic implications. It has a sensitivity of 79 95% and specificity of % for diagnosis of PAD [11]. Figure 3 illustrates how the ABI is measured. Diagnosis of PAD is made by ABI < 0.9, and severity of PAD can be defined as severe if <0.4, moderate ( ), or mild ( ). Individuals with an ABI 0.9 or ³ 1.4 should be considered at increased risk for cardiovascular events and mortality. The lower the ABI ( 0.4), the higher mortality risk these individuals will carry with them. Subjects with ABI between 0.91 and 1 are considered borderline for cardiovascular risk and may need further evaluation [10]. In individuals with an abnormal ABI, PAD diagnosis is confirmed; however ABI does not identify the location of occlusion. Another limitation of ABI is that not all patients have compressible vessels, such as patients with heavily calcified arteries (diabetics, elderly, renal insufficiency,

15 Clinical Parameters of PAD 7 Figure 3: Measurement of the ankle-brachial index (ABI) using a hand-held Doppler device. Calculation of ABI is the ratio of the highest SBP in the dorsalis pedis or posterior tibial arteries of each leg to the highest SBP in the brachial artery of each arm. Lau JF, Weinberg MD, Olin JW (2011), Peripheral artery disease. Part 1: clinical evaluation and noninvasive diagnosis. Nature reviews, Cardiology 8: rheumatoid arthritis). In these patients with non-compressible vessels, measurement may not be obtainable or may be above the interpretable range of 1.4. The rate of coexisting peripheral arterial occlusive disease ranges from 60% to 80% in patients within this high ABI range [10]. Moreover, in patients with extensive collateral arterial formation ABI at rest may be falsely elevated, especially in aortoiliac and ileofemoral occlusions. In these cases of suspected PAD with normal ABI at rest (³0.9), exercise testing is useful. An ABI that decreases by 20% following exercise indicates PAD, while a normal ABI following exercise suggests another cause for the patient s symptoms. Plantar flexion may serve as an alternative to treadmill testing in evaluating muscle pain in patients with intermittent claudication [12]. During active plantar flexion, the patient repeatedly stands up on the toes up to 50 times, and the ABI is measured before and after. In patients with non-compressible vessels, since digital arteries are usually not affected by calcinosis, measurement of the toe systolic pressure and calculation of the toe brachial index is often