Pathophysiology

Peripheral arterial insufficiency is caused by hemodynami-cally significant narrowing of the arterial circulation, usually from atherosclerosis, which clinically reduces blood flow to the affected limb. Longitudinal epidemiologic studies such as the Framingham Heart Study (Murabito et al., 1997), and INTERHEART study (Yusuf et al., 2004) have defined the risk factors for PVD.

Traditional Risk Factors

The prevalence of PVD increases with age. The incidence of IC in five large population-based studies is four times higher and prevalence eight times higher comparing the 35-39 to the 70-74 age group (Dormandy and Rutherford, 2000).

Smoking

Smoking is a very strong independent cause of atherosclerotic PVD. The severity of PVD increases with the number of cigarettes smoked (Cronenwett et al., 1984; Powell et al., 1997) and the amount of exposure to second-hand smoke (Barnoya and Glantz, 2005). In a series of epidemiologic studies, the incidence of developing IC among smokers is twofold to threefold higher than in nonsmokers (Dormandy and Rutherford, 2000). Smokers develop IC approximately a decade before nonsmokers (Kannel and Shurtleff, 1973), and the association between smoking and PVD may be stronger than the association between smoking and CAD (Fowkes et al., 1992; Kannel, 1994). Moreover, smokers are much more likely to progress to CLI than nonsmokers. Smokers with IC have an 11-fold greater amputation rate than nonsmokers (Dormandy et al., 1999a).

Smoking cessation slows the progression of disease, improves the symptoms of IC, decreases the likelihood of amputation, improves the patency of revascularization procedures (Krupski, 1991), and improves overall longevity (Taylor et al., 2002). Finally, all-cause mortality is significantly reduced by smoking cessation, but not by smoking reduction (Godtfredsen et al., 2002). It is imperative that patients entirely cease smoking and not just reduce their consumption of tobacco products.

Diabetes Mellitus

Diabetes/glucose intolerance is one of the most powerful independent modifiable risk factors that contributes to the development of PVD, IC, and CLI (Murabito et al., 1997; Fowkes et al., 1992; Kannel and McGee, 1979). The incidence of IC in diabetic patients is approximately two times higher than in nondiabetic patients (Dormandy and Rutherford, 2000). Diabetes not only has a significant effect on the larger-vessel arterial circulation, but also directly causes microangiopathy as well. Therefore, in conjunction with diabetic peripheral neuropathy, these patients are particularly vulnerable to amputation.

Approximately 60% of all nontraumatic amputations performed in the United States each year are in diabetic patients (ADA Fact Sheet, 2005). The diabetic patient with PVD has approximately a 10-fold higher amputation rate than a nondiabetic patient (Da Silva et al., 1979). There does not appear to be any significant difference in micro-vascular or macrovascular comorbidity between type 1 and type 2 diabetics (Zander et al., 2002). However, there is a dose-response relationship between the HbA1c level and the risk of amputation (Lehto et al., 1996). Therefore, patients with diabetes should be aggressively treated to normalize glycemic control. In addition, diabetic patients should be instructed on good foot hygiene, such as proper-fitting shoes and foot hygiene, to avoid skin breakdown and ulcer formation.

Hyperlipidemia

As in CAD, low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels are directly related, while high-density lipoprotein cholesterol (HDL-C) levels are indirectly related, to the progression of PVD, and the observed risk seems to demonstrate a linear relationship (Fowkes et al., 1992; Murabito et al., 2002). Most data on lipid-lowering therapy are from patients with CAD. However, several studies specifically demonstrate an improvement in the relative risk of an abnormal ABI, walking distance on a treadmill, frequency and severity of claudication, and limb loss (Blan-kenhorn et al., 1991; Buchwald et al., 1996; Mohler et al., 2003; Pedersen et al., 1998), suggesting that all patients with PVD should be treated with lipid-lowering therapy regardless of baseline LDL-C.

Hypertension

Hypertension is a major risk factor for PVD and carries a 2.5-fold age-adjusted risk for men and a 3.9-fold age-adjusted risk for women (Kannel and McGee, 1985; Murab-ito et al., 1997). There have been concerns, based on early case reports, that beta-blockade therapy may worsen the symptoms of IC. A meta-analysis on this subject and critical review of these studies concluded that beta blockers are safe and do not worsen IC (Radack and Deck, 1991). ACE inhibitors (ACEIs) may offer significant benefits for the prevention of atherosclerotic vascular disease beyond that expected from a reduction in blood pressure alone However, there remains considerable debate as to whether or not the data from the HOPE (Heart Outcomes, 2000) and EUROPA (Fox et al., 2003) studies can be generalized to all ACEIs.

Gender

The initial data from Framingham suggested that men develop IC approximately 10 years before women (Kannel et al., 1970). More recent data do not support this observation (Hirsch et al., 2001; Murabito et al., 2003; Reunanen et al., 1982). In light of these data, patients should be screened for PVD regardless of gender.

Obesity

Obesity, as measured by an increased body mass index (BMI) greater than 30, has long been recognized as a risk factor for atherosclerotic disease. It is now recognized that adipocytes, particularly visceral adipocytes, contribute to a proinflam-matory state by generating a variety of cytokines (e.g., IL-6, TNF-a, CRP), which play a direct role in the development of atherosclerosis (Hansson, 2005). As further support, liposuc-tion does not seem to lower risk for CAD, because it reduces subcutaneous fat mass but has no effect on lowering visceral fat mass (Klein et al., 2004).

Nontraditional Risk Factors

High-Sensitivity C-Reactive Protein

Atherosclerosis is a disease of chronic low-grade inflammation. High-sensitivity CRP is a nonspecific marker of inflammation emerging as a simple but powerful marker of atherosclerotic risk. Prospective data from the Physicians' Health Study demonstrate that baseline levels of hsCRP independently predict future risk of developing symptomatic PVD (Ridker et al., 1998).

Lipoprotein(a)

Lipoprotein(a) [Lp(a)] is an atherogenic subspecies of LDL that is covalently linked to apoprotein(a). Apo(a) is homologous to plasminogen. Lp(a) may exacerbate risk for ACS by inhibiting endogenous fibrinolysis (Hajjar et al., 1989). Furthermore, Lp(a) may augment the release of endothelial plasminogen activator inhibitor-1 (PAI-1), which further impairs fibrinolysis (Etingin et al., 1991). The net result is that Lp(a) contributes to atherogenesis and a prothrombotic or hypercoagulable state.

Lipoprotein(a) has been implicated as an independent predictor of PVD (Cheng et al., 1997; Prior et al., 1995). However, many of these studies are cross-sectional or retrospective and cannot establish causal relationships between risk factors and disease. Prospective data from the Physicians' Health Study did not show a significant relationship in baseline Lp(a) levels and the future development of PVD (Ridker et al., 2001). Widespread screening of Lp(a) levels in the general population is not recommended. However, this should be considered in patients who present with premature vascular disease and few traditional risk factors. Niacin can modestly reduce Lp(a) levels. There is no clinical trial evidence to prove that reducing serum levels of Lp(a) reduces risk for the development or progression of PVD.

Fibrinogen

Fibrinogen has been implicated in atherogenesis by early epidemiologic studies (Kannel et al., 1987). However, fibrinogen is an acute-phase reactant, with considerable intrapatient variability in its expression over time. Other markers of inflammation, such as hsCRP, have a more powerful association in predicting PVD. Furthermore, fibrinogen levels are directly related to age, obesity, cigarette smoking, diabetes, and LDL-C, and inversely related to HDL-C, physical activity, alcohol use, and estrogen levels. Controversy surrounds the independent predictive value of hyperfibrinogenemia. Therefore, routine fibrinogen level screening is not recommended, unless there is suspicion of a hypercoagulable state.

Natural History

Atherosclerosis is an age-dependent disease that begins in childhood and progresses throughout adulthood, particularly if the risk factors are left unchecked. However, early studies suggested that PVD led a contrary, benign course

symptoms in more than one vascular bed. (Modified from Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc 1999;47:1255-1258.)

symptoms in more than one vascular bed. (Modified from Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc 1999;47:1255-1258.)

that was not progressive (Imparato et al., 1975; McAllister, 1976). However, in most of these studies, IC was used as an end point, not ABI or even a patient functional assessment. Intermittent claudication is a relatively insensitive marker of PVD presence. Those studies typically reported a stabilization or improvement in IC over time, which does not necessarily indicate stabilization or improvement in the disease process, ability to ambulate, or functional status. Early authors suggested that relief of IC over time was a sign of improved collateral flow, but to experience IC, a patient must be physically active. Stabilization or improvement of IC was strongly related to functional decline (i.e., patients walked at a slower pace and for shorter distances to avoid experiencing IC) (McDermott et al., 2004). Thus, PVD is a progressive disorder that leads to a significant decline in quality of life.

Coexisting Vascular Disease

The most important fact regarding the diagnosis and management of PVD is that PVD is a powerful, independent predictor of mortality (Criqui et al., 1992). Intermittent claudication and/or CLI can have a significant impact on quality of life. Many patients may accept their physical limitations as a consequence of aging and tolerate this morbidity. Less than 5% of patients with IC will ever progress to amputation. Much more significant, however, is that PVD is a systemic disorder, and it has considerable overlap with CAD and cerebrovascular disease, ultimately leading to an increase in mortality. Approximately 40% of patients with atherosclerotic vascular disease manifest symptoms in more than one vascular bed (Fig. 27-23) (Ness and Aronow, 1999). Compared to people without PVD, patients with PVD are about four times more likely to have an MI (Criqui et al., 1992) and two to three times more likely to have a stroke (Wilterdink and Easton, 1992). The all-cause mortality rate in patients with PVD is about equal between men and women and is elevated even in asymptomatic patients (Hiatt, 2001). The lower the ABI, the greater is the risk for cardiovascular events. Patients with CLI, who typically have the lowest ABI, have an annual mortality rate of 25% (Dormandy et al., 1999b; McKenna et al., 1991; Vogt et al., 1993b).

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