Document Type : Review
1 Department of Cardiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2 Student Research Committee, Department of Modern Sciences & Technologies, Mashhad University of Medical Sciences, Mashhad, Iran
Atherosclerosis is a chronic slow-developing condition affecting medium-size and large blood vessels. It is the principal underlying pathology of coronary heart disease and stroke. In some countries, coronary artery disease (CAD) is the cause of nearly half (48%) of the deaths and, loss of productivity life. Peripheral arterial disease (PAD) is defined as atherosclerosis in peripheral arteries instead of coronary arteries. CAD and PAD have same risk factors and underlying pathophysiological processes. Therefore, patient with CAD should be considered for PAD. Ankle brachial index (ABI), duplex sonography, and some other non-invasive techniques are recommended for PAD diagnosis in patients with the history of CAD. Pharmacotherapy, endovascular interventions, and surgical management could be chosen according to the patient’s situation. Cardiologists and general practitioners should consider PAD in a patient with CAD or DM as a strong correlated disease.
Atherosclerosis and coronary artery disease (CAD)
The term arteriosclerosis was first introduced by Johnan Lobstein in 1833 explaining the clinical-pathologic relationship between infarction and atherosclerosis (1,2).
Atherosclerosis is a chronic slow-developing condition affecting medium-size and large blood vessels. It is the principal underlying pathology of coronary heart disease and stroke. It is initially an inflammatory response to various forms of endothelial injury associated with vascular smooth muscle cell proliferation (3).
Atherosclerosis major risk factors
Age, male sex, heredity, high blood pressure, high blood cholesterol levels, diabetes mellitus, smokings, socioeconomic conditions, and being overweight are well-established risk factors for atherosclerosis (4,5). Scientists concluded that increased atherosclerosis will lead to increase in serum total cholesterol (TC) which might cause the increase in CAD in the Asian countries (6).
A reduction in levels of plasma HDL-C is associated with elevated risk of atherosclerotic disease. Moreover, most of the patients with CAD possess low HDL-C levels. On the other hand, LDL-C has several major risk factors including age, low HDL-C (140/90 mm Hg), diabetes, family history of premature CAD (7). Delavar et al. have comprehensively studied the status of dyslipidemia in Iran. Their report stated that the TC≥240 mg/dl was in 11.4%, and triglyceride ≥150 mg/dl in 41.5%, HDL-C60 mg/dl in 24.7%, and 130High blood pressure (HBP) is another risk factor for CAD. According to WHO, about 600 million people suffer from HBP are at risk of heart attack, stroke, and cardiac failure. It is estimated that 7.1 million deaths globally are due to HBP that is about 13 percent of the global fatality. Researches indicated that about 62 percent of strokes and 49 percent of heart attacks were caused by HBP (9).
CAD causes more than half of (60%) all mortality in individuals with diabetes. In people with type 1 or type 2 diabetes, the risk of cardiovascular events increases 2-3 times and is higher in women (10).
Smoking is another risk factor for CAD, American Heart Association (AHA) estimates that the number of smokers are 1.3 billion and it will rise to 1.7 billion by 2025 worldwide if the global prevalence of tobacco use remains unchanged (11). AHA reports that use of tobacco kills 5.4 million people each year worldwide. It predicts that tobacco-related deaths will significantly increase to more than 8 million deaths a year by 2030. Some 80% of those deaths will occur in the developing countries (12).
Pathophysiology of atherosclerosis
Atherosclerosis is characterized by the accumulation of fat and cholesterol, lipoprotein oxidation, inflammation, cellular rubbish outcomes calcium, wound tissue, and other substances developed within the inner lining of arteries (13). It is also related to infiltration of mononuclear cells and smooth muscle generation (14). Complicated pathological process in blood vessels walls progresses over many years. Cholesterol and fatty materials remain inside the lumen of arteries and form plaques. These plaques or deposits make the inner surface of the blood vessels to be irregular and lead to narrow the lumen, thus blood flows through them with difficulty. Therefore, blood vessels become less flexible and the plaque can rupture and lead to the formation of a blood clot. The blood clot can develop in a coronary artery; in this case, it can result in a heart attack. In addition, the blood clot can form in the brain, which can lead to a stroke (15).
Atherosclerosis and inflammation
Atherosclerosis is also associated with innate and acquired immune responses that start in the early years of life and it becomes clinically apparent in later life (16-19). The role of inflammation in atherosclerosis has been known over three decades ago. Several studies confirmed that inflammatory mechanisms performed an important part in atherosclerosis and the initial stages accompanied by inflammation (20,21).
Recently, researchers demonstrated that characterization of low-grade systemic inflammation can be carried out by an increase (usually two- to threefold) in systemic plasma concentration of cytokines including interlokine-6 (IL-6), tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) (7). This low-grade inflammatory status has been found in CAD and PAD patients (15).
Evidence has shown that low-grade inflammation has highly been accepted as the basic condition in many diseases. For instance, low-grade inflammation is responsible for obesity and many obesity-related diseases such as type 2 diabetes, atherosclerosis, and metabolic syndrome. Furthermore, slight increase in level of CRP is associated with many none-inflammatory medical conditions (22). Most of these chronic diseases are associated with CAD and PAD. Therefore, underlying CAD and PAD risk factors could trigger endothelial dysfunction and inflammation.
A strong relationship between inflammation and atherothrombosis is demonstrated in CAD by the presence of macrophages, T-lymphocytes, and mast cells in unstable atherosclerotic plaques connected with the elevated expression of different inflammatory markers in plasma such as pro-inflammatory cytokines, amyloid A, adhesion molecules, and CRP (23).
Peripheral arterial disease (PAD)
PAD is defined as an arterial occlusive disease especially in lower limbs (24). PAD is another clinical manifestation of CAD with the same underlying pathophysiological process (25). Indentifying sensitive markers for CAD diagnosis is the greatest goal of any cardiologist. PAD could be a sensitive marker for CAD and cerebrovascular disease (26).
Overall, 12–20% of general population aged between 55-65 years are affected by PAD (25). It is reported that 12 million people have atherosclerosis-associated conditions in United States (27,28). Moreover, about 27 million people suffer from PAD in Europe and USA (25,29).
According to the Table 1, Rutherford stage classification in PAD covers a wide range of symptoms and signs (30). Intermittent claudication also can induce pain or weakness and serious ischemia can induce ulcer, gangrene, or rest pain (24).
Same as CAD, smoking, hypertension, dyslipidemia, and diabetes mellitus (DM) are major risk factors of plaque progression in PAD (31). DM could increase the risk of PAD by two to four fold (32). In a study among German population, PAD had higher prevalence in DM patients versus non-diabetics (26.3%vs.15.3%) (33). In the USA, among 50 to 70 years old subjects, 22% of diabetic population had PAD, whereas PAD was diagnosed for around 21.1% of diabetic population in an Italian study on 30 years and older diabetic patients (34,35). Some novel biomarkers could increase in PAD such as C-reactive protein and homocysteine (36-38).
Most of the time superficial femoral, popliteal, abdominal aorta and iliac arteries are involved in peripheral atherosclerosis (24).
Some novel gene polymorphisms have been found in PAD such as SLC2A10, PAOD1, LSq-1, and CHRNA3 (rs1051730) (38). In 2010, SLC2A10 was found as an independent polymorphism gene that could lead diabetic patients to PAD (39). In recent studies, significant roles of genetic polymorphisms have been reported. Therefore, PAD is a genetics and environmental interaction disease with same risk factors of CAD.
Prevalence of peripheral arterial stenosis
In a study in USA, authors showed that around 5.8% of general population aged 40 years or more had peripheral arterial stenosis according to the ABI diagnostic test (40).
Weitz JI et al. reported that more than 27 million people suffered from PAD in Europe and north America (41). Diehm C. showed that PAD prevalence was around 15-20% of general population (42). Some scientists believe that CAD and PAD occur synchronized and more than 50% of the CAD positive patients could have active progressive plaque in peripheral arteries (43).
Diagnosis of PAD
1-Noninvasive method of ankle brachial index (ABI) is widely used for PAD detection, normal range between 09-1.2, the result that is less than 0.9 has 95% sensitivity and 99% specificity in disease diagnosis compared to PAD angiographic studies (44). According to Criqui MH et al, ABI more than 1.4 may be associated with cardiovascular events, thus both high and low ABI are unfavorable (45).
Some other diagnostic methods:
2-Computed Tomographic Angiography
3-Magnetic Resonance Angiography
5-Pulse Volume Recording (31,41,46)
Treatment of Peripheral arterial stenosis
PAD treatments are divided into pharmacotherapy, Endovascular interventions, and surgical management (47). The most beneficial treatment of PAD is lifestyle changes and physical rehabilitation programmes (48).
Angiotensin-converting enzyme (ACE) inhibitors, statins, aspirin, pentoxifylline, cilostazol, naftidrofuryl, and ticlopidine are effective for medical management of PAD (47,49).
Judkins in 1964 performed the first endovascular intervention for treating PAD (46). endovascular intervention could be balloon angioplasty or stenting (46). In a study after 4 years follow-up, no significant difference found between surgical bypass and endovascular intervention (50).
Surgical management is seldom indicated in patients with PAD, as the patient at the risk of amputation (46).
In conclusion, cardiologists and general practitioners should consider PAD in a patient with CAD or DM as a strong correlated disease.
ABI, duplex sonography and some other non-invasive techniques are recommended for PAD diagnosis in the patients with the history of atherosclerosis. In addition, lifestyle changes in the PAD patients and pharmacotherapy should be considered.
We would like to thank Clinical Research Development Center of Ghaem Hospital for their assistant in this manuscript. This study was supported by a grant from the Vice Chancellor for Research of the Mashhad University of Medical Sciences for the research project as a medical student thesis with approval number of 910893.
Conflict of Interest
The authors declare no conflict of interest.
- Lindquist S, Craig EA. The Heat-Shock Proteins. Annu Rev Genet. 1988;22:631-677.
- Leibowitz JO. The history of coronary heart disease. Berkeley, Los Angeles: University of California Press; 1970.
- Ross R, Glomset J, Harker L. Response to injury and atherogenesis. Am J Pathol. 1977;86:675.
- Yousefzadeh G, Mahdavi-Jafari F, Shokoohi M, et al. Modulation of coronary artery disease risk factors by menopausal status: A population based study among Iranian women (KERCADRStudy). ARYA Atheroscler. 2013;9:332-336.
- Nazeminezhad R, Tajfard M, Latiff LA, et al. Dietary intake of patients with angiographically defined coronary artery disease and that of healthy controls in Iran. Eur J Clin Nutr. 2014;68:109-113.
- Ueshima H, Sekikawa A, Miura K, et al. Cardiovascular disease and risk factors in Asia: a selected review. Circulation. 2008;118:2702-2709.
- Calle MC. Inflammatory Markers are Modulated by Diet in Latinos with Type 2 Diabetes and by Resistance Exercise in a Healthy Population: University of Connecticut; 2011.
- Delavar MA, Lye M, Khor GL, et al. Prevalence of metabolic syndrome among middle aged women in babol, Iran. Southeast Asian J Trop Med Public Health. 2009;40:612-628.
- Sheet-Populations SF. International cardiovascular disease statistics. American Heart Association. 2004.
- Mendis S, Puska P, Norrving B. Global atlas on cardiovascular disease prevention and control: World Health Organization; 2011.
- Sheet-Populations SF. International Cardiovascular Disease Statistics. American Heart Association. 2008.
- Sheet-Populations SF. International Cardiovascular Disease Statistics. American Heart Association. 2009.
- Chan SH, Wang LL, Chang KF, et al. Altered temporal profile of heat shock factor 1 phosphorylation and heat shock protein 70 expression induced by heat shock in nucleus tractus solitarii of spontaneously hypertensive rats. Circulation. 2003;107:339-345.
- Businaro R, Profumo E, Tagliani A, et al. Heat-shock protein 90: A novel autoantigen in human carotid atherosclerosis. Atherosclerosis. 2009;207:74-83.
- Brevetti G, Piscione F, Silvestro A, et al. Increased inflammatory status and higher prevalence of three-vessel coronary artery disease in patients with concomitant coronary and peripheral atherosclerosis. Thromb Haemost. 2003;89:1058-1063.
- Liao D-F, Jin Z-G, Baas AS, et al. Purification and Identification of Secreted Oxidative Stress-induced Factors from Vascular Smooth Muscle Cells. J Biol Chem. 2000;275:189-196.
- Chung S-W, Lee J-H, Choi K-H, et al. Extracellular heat shock protein 90 induces interleukin-8 in vascular smooth muscle cells. Biochemical and biophysical research communications. 2009;378:444-449.
- Xu Q. Role of Heat Shock Proteins in Atherosclerosis. Arterioscler Thromb Vasc Biol. 2002;22:1547-1559.
- Luikart SD, Panoskaltsis-Mortari A, Hinkel T, et al. Mactinin, a fragment of cytoskeletal alpha-actinin, is a novel inducer of heat shock protein (Hsp)-90 mediated monocyte activation. BMC Cell Biol. 2009;10:60.
- Elkind MS. Impact of innate inflammation in population studies. Ann N Y Acad Sci. 2010;1207:97-106.
- Wick G, Knoflach M, Xu Q. Autoimmune and inflammatory mechanisms in atherosclerosis. Annu Rev Immunol. 2004;22:361-403.
- Eklund CM. Proinflammatory cytokines in CRP baseline regulation. Advances in clinical chemistry. 2009;48:111-136.
- Rajappa M, Sen S, Sharma A. Role of pro-/anti-inflammatory cytokines and their correlation with established risk factors in South Indians with coronary artery disease. Angiology. 2009;60:419-426.
- Aronow WS. Peripheral arterial disease of the lower extremities. Arch Med Sci. 2012;8:375-388.
- Schiattarella GG, Perrino C, Magliulo F, et al. Physical activity in the prevention of peripheral artery disease in the elderly. Front Physiol. 2014;5:12.
- Criqui MH, Denenberg JO. The generalized nature of atherosclerosis: how peripheral arterial disease may predict adverse events from coronary artery disease. Vasc Med. 1998;3:241-245.
- Kleindienst R, Schett G, Amberger A, et al. Atherosclerosis as an autoimmune condition. Isr J Med Sci. 1995;31:596-599.
- Sun J, Liao JK. Induction of angiogenesis by heat shock protein 90 mediated by protein kinase Akt and endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol. 2004;24:2238-2244.
- Brevetti G, Chiariello M. Peripheral arterial disease: the magnitude of the problem and its socioeconomic impact. Curr Drug Targets Cardiovasc Haematol Disord. 2004;4:199-208.
- Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg. 2000;31:S1-S296.
- Aronow WS. Peripheral arterial disease. Geriatrics. 2007;62:19-25.
- Criqui MH, Denenberg JO, Langer RD, et al. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med. 1997;2:221-226.
- Lange S, Diehm C, Darius H, et al. High prevalence of peripheral arterial disease and low treatment rates in elderly primary care patients with diabetes. Exp Clin Endocrinol Diabetes. 2004;112:566-573.
- Beach KW, Bedford GR, Bergelin RO, et al. Progression of lower-extremity arterial occlusive disease in type II diabetes mellitus. Diabetes Care. 1988;11:464-472.
- Faglia E, Caravaggi C, Marchetti R, et al. Screening for peripheral arterial disease by means of the ankle-brachial index in newly diagnosed Type 2 diabetic patients. Diabet Med. 2005;22:1310-1314.
- Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997;277:1775-1781.
- Darius H, Pittrow D, Haberl R, et al. Are elevated homocysteine plasma levels related to peripheral arterial disease? Results from a cross-sectional study of 6880 primary care patients. Eur J Clin Invest. 2003;33:751-757.
- Katwal AB, Dokun AO. Peripheral arterial disease in diabetes: is there a role for genetics? Curr Diab Rep. 2011;11:218-225.
- Jiang YD, Chang YC, Chiu YF, et al. SLC2A10 genetic polymorphism predicts development of peripheral arterial disease in patients with type 2 diabetes. SLC2A10 and PAD in type 2 diabetes. BMC Med Genet. 2010;11:126.
- Allison MA, Ho E, Denenberg JO, et al. Ethnic-specific prevalence of peripheral arterial disease in the United States. Am J Prev Med. 2007;32:328-333.
- Weitz JI, Byrne J, Clagett GP, et al. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation. 1996;94:3026-3049.
- Diehm C, Schuster A, Allenberg JR, et al. High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study. Atherosclerosis. 2004;172:95-105.
- Sabeti S, Schlager O, Exner M, et al. Progression of carotid stenosis detected by duplex ultrasonography predicts adverse outcomes in cardiovascular high-risk patients. Stroke. 2007;38:2887-2894.
- McDermott MM, Greenland P, Liu K, et al. The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study. Ann Intern Med. 2002;136:873-883.
- Criqui MH, McClelland RL, McDermott MM, et al. The ankle-brachial index and incident cardiovascular events in the MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2010;56:1506-1512.
- Ouriel K. Peripheral arterial disease. Lancet. 2001;358:1257-1264.
- Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608-1621.
- Tierney S, Fennessy F, Hayes DB. ABC of arterial and vascular disease. Secondary prevention of peripheral vascular disease. BMJ. 2000;320:1262-1265.
- Rice TW, Lumsden AB. Optimal medical management of peripheral arterial disease. Vasc Endovascular Surg. 2006;40:312-327.
- Wolf GL, Wilson SE, Cross AP, et al. Surgery or balloon angioplasty for peripheral vascular disease: a randomized clinical trial. Principal investigators and their Associates of Veterans Administration Cooperative Study Number 199. J Vasc Interv Radiol. 1993;4:639-648.