CLI clinically presents with rest pain and tissue ulceration that are a result of insufficient peripheral perfusion [1]. This presentation is gradual and chronic, unlike the sudden manifestations of acute limb ischemia [1]. The progression rom stable arterial narrowing to outright hemodynamic compromise in the lower extremity depends on many factors. From a pathophysiologic standpoint, CLI can be difficult to distinguish from stable PAD, and they are, in fact, part of the same spectrum [1]. In certain cases, CLI may develop in the setting of conditions such as atherothrombotic or embolic disease, in situ thrombosis, inflammation, or trauma [1, 2]. These situations, however, do not account for the vast majority of CLI cases, which ultimately stem from severe peripheral atherosclerotic disease [2]. Underlying disease progression to CLI is thus generally a progression of underlying atherosclerosis [3, 4], in contrast to acute limb ischemia where a defined perfusion-limiting event is culprit [1]. Atherosclerosis in the extremities occurs in the arterial intimal layer [3], specifically in regions of turbulent blood flow [5], and some evidence points to periods of rapid progression involving plaque ulceration and hemorrhage similar to that seen in coronary artery disease [3].

What separates CLI from stable PAD is the complex chronic regulation of macro-vascular and microvascular circulation that results in an inability of innate protective mechanisms to maintain capillary bed perfusion [6]. When blood flow is restricted to the point that tissue viability is compromised, compensatory mechanisms fail, and tissue ischemia leads to pain and poor wound healing [6]. This process occurs initially with macrocirculatory reduction in arterial lumen diameter as a result of severe atherosclerotic disease, a situation which reduces blood flow. The severe multi-segment arterial disease is compounded by vasomotor paralysis and vasogenic edema [1, 7]. Microcirculatory compensatory mechanisms ultimately cannot withstand this critical level of ischemia [6]. This leads to multisystem vascular dysfunction in CLI. Endothelial cell dysfunction and dysregulation, white blood cell activation and inflammation, impaired defense mechanisms, altered microvascular flow regulation, and significant oxidative stress, among others, contribute to the final clinical picture of CLI [6].

The epidemiologic burden of CLI varies per study, but general estimates put the prevalence at between one to two million in the United States [8, 9] with an annual incidence of 220–300 per million per year [10, 11]. One large Medicare cohort, including patients only over age 65, reported an overall prevalence and annual incidence of 0.23 and 0.20 %, respectively, which is in line with prior estimates [8]. However, it was noted that with the aging population, this implies a potential increase in prevalence to 2.8–3.5 million by 2020 [8]. These numbers are significant given the high morbidity and mortality of this condition. Each decrease of ankle-brachial index (ABI) of 0.10 is associated with a 10 % increase in relative risk for a major vascular event, primarily ischemic heart disease [1, 12], and there is a 20 % mortality in the first year following presentation of CLI [1]. In fact, the 5-year mortality of CLI is estimated at 60 % [13], greater than that of acute myocardial infarction, stroke, and prostate, breast, and colorectal cancers [6].

The natural history of PAD and development of CLI, especially in an era of treatment and intervention, is difficult to define but represents a combination of both progressive decline and less linear primary presentation [1]. Contemporarily, many patients with PAD progression are treated before their symptoms reach the critical tipping point [1]. In general, more than half of patients with PAD receive some form of medical or interventional treatment, with those not receiving treatment having generally stable symptoms [1]. Claudication symptoms remain stable in approximately 75 % of patients throughout their lifetime, without evidence of progressive lower extremity deterioration [3, 14]. And when progression does occur, it is more common during the first year following diagnosis [15]. Between 6 and 9 % of patients develop symptom worsening in this first year, compared to an annual rate of 2–3 % thereafter [16]. There is evidence, however, that functional decline may not be readily recognized and may be more common than previously realized [3]. For example, in one cross-sectional study, diminished ABI was highly correlated to leg weakness and multiple functional outcomes, including reduced 6-min walk, even after adjustment for initial symptom score [16].

Longitudinal data support a progressive decline in PAD [6, 15, 17]. Of patients with claudication, approximately 15–20 % will develop rest pain or gangrene within their lifetime [1, 2]. In one cohort with claudication, more severe claudication was reported in 60 % of patients after 2.5 year follow-up, with a decline in ABI by at least 0.15 carrying a relative risk of 1.8 for severe claudication [18]. An additional longitudinal study of smokers with claudication reported an annual decrease in ABI by 21, 16, and 17 % in the first three consecutive years of follow-up, with an overall 12.5 % incidence of CLI during follow-up [19]. One 15-year outcome study of patients with claudication demonstrated gradual increase in need for major and minor amputations over time, though with a relative plateau after 2 years [17]. There remains a cohort of patients, however, who present initially with CLI without prior symptoms [6, 19–21]. This cohort represents 1–3 % of patients with CLI and is particularly common in patients who present after minor trauma and subsequent development of a nonhealing ulcer [22]. These patients are typically limited by multiple comorbidities and have impaired functional capacity, often attributing pain to other etiologies limiting detection of PAD until advanced stages [22].

Much additional information can be extrapolated from data on symptom development in PAD prior to reaching CLI. The vast majority of patients develop claudication subtly [3]. Using clinical and imaging data, several characteristics of this transition have been identified. In the landmark Edinburgh Artery Study, a large-scale cohort of 1592 subjects aged 55–74 years, the overall PAD incidence, as defined by development of claudication, was reported in 179 cases (11.2 %) during 12-year follow-up [23]. Conversion to claudication is often a bilateral phenomenon, demonstrated in a small series assessing subjective symptom progression [3]. This was confirmed via angiographic data that demonstrated more rapid progression of arterial disease in superficial femoral arteries with concomitant contralateral superficial femoral artery occlusion [24]. Atherosclerotic disease may progress without significant change in symptoms in legs with higher ABIs [3]. In these patients, symptom development may lag behind imaging-based progression. In one small cohort with known PAD, claudication symptoms progressed in two extremities over a 5-year period, while angiographic disease progressed in 14 of the 19 assessed extremities (73 %) [25]. In an additional cohort, those with known PAD developed new or progressive lesions in 17 of 48 extremities (35 %), which correlated with development of claudication and functional impairment as a result of decreased 6-min walk distance [3]. These results indicate that PAD progression, while ultimately leading to increased symptoms , may often proceed unnoticed despite radiographic evidence of disease progression. Patients may subtly decrease their activity levels to compensate for increasing disease burden [26, 27], giving both patients and caregivers a false sense of security. Over time, as disease severity increases and tissue perfusion is compromised, CLI may emerge. And unfortunately, in many cases, patients die secondary to cardiovascular events before stable PAD progresses to CLI.

Many of the same risk factors that give rise to PAD initially are also suspected in the development of CLI (Table 13.1 and Fig. 13.1). Early recognition and aggressive risk factor modification in PAD is thought to decrease symptom severity and reduce incidence of CLI [28], but data in this area is limited. Given the difficulty in identifying the transition between stable PAD and CLI, much of the recommendations for management and prevention of CLI are extrapolated from stable PAD and claudication data and management recommendations [28]. Additionally, since CLI is rarely studied in isolation, it is important to extract information from surgical and amputation-based studies where CLI, resulting in significant ischemia and gangrene, may prompt treatment necessity.

Non-modifiable risk factors, namely, age, race, and gender, all have associations with PAD and development of CLI. PAD develops in a longitudinal pattern with prevalence increasing linearly with age [1]. Both the seminal Framingham Study [29] and National Health and Nutrition Examination Survey (NHANES) report [30] document this increased prevalence. A large series of Medicare data in patients with CLI demonstrated that this longitudinal progression is also true of CLI. A progressive rise in prevalence and incidence was noted in patients between 65 and 85 years [8]. Though patients who first present at younger ages represent a small portion of the overall PAD cohort, they have overall poorer long-term outcomes [31]. This includes higher late amputation rate (17 versus 3.9 %) [32] and increased rate of failed bypasses (92 versus 65 %) [33]. Additionally, in a comparative series of contrasting patients younger than 49 years of age (mean age 43 years) and those between 60 and 75 years of age (mean age 67 years) who had PAD requiring amputation, though there was no overall difference in 5-year survival between the groups (62 versus 47 %), the mean age of death in the younger cohort was greater than 20 years earlier than the older group (mean age of death 48 versus 69 years) [33].

Racial predispositions identified for PAD appear to be similar in CLI. In the aforementioned Medicare cohort, overall prevalence and incidence of CLI was highest in black patients (0.49 and 0.41 %, respectively), while lowest in Asian patients (0.12 and 0.10 %, respectively) [8]. Black patients, after risk factor adjustment, had a 2.3 times higher risk of CLI development than white patients [8]. This difference has important clinical applications, as black patients are also at 2–4 times higher risk of lower limb loss than white patients. Additionally, in the year following CLI diagnosis , black patients demonstrated the highest incidence of amputation and lowest rates of revascularization (27.8 %, HR 0.87, respectively) in stark contrast to white patients who demonstrated the highest incidence of revascularization with lower rates of amputation (32.8 %, HR 1.3, respectively) [8].

Gender differences may also have significant clinical impact in the progression of CLI. Women tend to have lower overall prevalence of symptomatic PAD, but are more likely to present with CLI [34]. This initial PAD prevalence gap narrows significantly with advancing age [34]. Sex-related differences have been reported in several vascular diseases, and a multitude of prior studies have demonstrated essentially equivocal rates of amputation and overall survival in PAD between men and women [34]. However, one recent study investigating gender differences in the era of intervention reports that women were on average 3.5 years older at the time of intervention and were more likely to present with CLI (OR 1.21) [34]. This study noted that women were more likely to present with more advanced disease, resulting in higher mortality in both intermittent claudication and CLI [34]. This was attributed, potentially, to relative underutilization of preventative care in women [35], with less consistent achievement of target outcomes (e.g., blood pressure, low-density lipoprotein, and hemoglobin A1c) [36], which may have resulted in increased perioperative cardiovascular events and death in this intervention-based study [34].

Tobacco use, specifically smoking, is the greatest modifiable contributor to PAD and is a well-defined driver of CLI development. Smoking increases the risk of PAD, with greater risk evident in heavy smokers (RR3.94) [23]. A direct correlation has been noted with number of cigarettes smoked [37, 38]. In fact, the association between smoking and PAD is almost twice that of smoking and coronary artery disease [39]. Smoking also directly correlates with PAD progression [40, 41]. Smoking accelerates claudication onset by nearly 10 years compared to nonsmoking patients, and these patients are more than twice as likely to develop CLI [23, 31]. This has many important clinical implications, as smokers with PAD have greater disease severity, poorer survival rates, increased amputation risk, and reduced arterial bypass graft patency [31, 42]. In patients with claudication, continued smoking increases amputation risk [43, 44]. Smoking cessation , not surprisingly, leads to clinical benefit. Smoking cessation, even within just a few years, reduces risk of progression from PAD to CLI [1, 12], with improved ankle pressure and exercise tolerance and decreased risk of fatal vascular complications [37]. Smoking cessation also improves 10-year survival compared to continued smoking (82 versus 46 %, respectively) [40]. Additionally, alternative vascular pathology associated with smoking, including thromboangiitis obliterans (Buerger’s disease), increases risk of ulcer formation by limiting protective sensory mechanisms and increasing inflammation [1].

Diabetes mellitus (DM) similarly has a strong link to PAD and is a substantial contributor to CLI development, though minimal data is available to assess the effect of DM control in prevention of CLI. There is a high coincidence of these two diseases, with as many as 20–30 % of patients with PAD having concomitant DM [40]. Annual CLI prevalence and incidence are remarkably higher in those with DM (1.03 and 0.86 %, respectively) than in the general population [8]. Both the degree and duration of DM are linked to PAD development, and there are independent associations between PAD progression to CLI and diabetes [40, 45, 46]. Patients with diabetes are at least five times as likely as nondiabetics to develop CLI and have an overall mortality two times that of nondiabetics [45]. There are also increased rates of complications. In patients who have developed CLI, progression to gangrene is much greater in those with diabetes (40 versus 9 %) [47]. In fact, greater than 50 % of gangrenous lesions causing amputation occur in the diabetic population [48]. DM patients have lower limb salvage rates [49], with an overall 15–28 times greater likelihood of requiring amputation [8, 50]. This situation is compounded by increased interventional complication rates, including postoperative myocardial infarction, wound infection and need for additional surgical debridement, and increased hospital and long-term mortality [37, 51–53]. The etiology of this increased morbidity is unclear but likely multifactorial. Pathophysiologically, PAD in DM is similar to non-DM though with a greater predilection for the infrapopliteal vessels [40]. The altered metabolic milieu of DM is pro-inflammatory and pro-atherogenic, with increased vascular bed dysfunction [40]. Additionally, DM presents a host of increased clinical complications. These include peripheral neuropathy masking symptoms and delaying PAD diagnosis as well as the additional effect of diabetes and hyperglycemia in impairment of wound healing [40]. And among those with DM , risk of CLI development may be predicted by less traditional PAD risk factors, highlighting the large effect that DM plays on CLI development [54]. As demonstrated in a small survey of PAD and CLI patients, these less traditional risk factors include ABI less than 0.5 in the prior 1–3 years (OR 3.39), microvascular complications such as retinopathy (OR 12.98), heart failure (OR 1.91), and previous prostanoid treatment (OR 15.92) [54]. Overall, DM presents great risk for both the development and management of CLI, a situation of increasing concern as rates of DM continue to increase in the US population at large.

Hypertension is an independent risk factor for PAD but has unclear direct association to CLI. The NHANES and PAD Awareness, Risk and Treatment: New Resources for Survival (PARTNERS) reports both demonstrated a high prevalence of hypertension in patients with PAD (74 and 92 %, respectively), and patients in the Framingham Heart study demonstrated a 2.5–4 times rate of claudication in those with elevated blood pressure [4, 29]. In patients with DM and PAD, blood pressure lowering leads to reduced cardiovascular events [40, 55]. However, tight blood pressure control in the United Kingdom Prospective Diabetes Study (UKPDS), also assessing DM and PAD, did not have any effect on PAD development as assessed by amputation risk [56]. Traditional recommendations have followed general guidelines, with target blood pressure less than 140/90 mmHg in the absence of other comorbidities [1]. However, acute blood pressure reduction carries a potential risk of decreased limb perfusion [49]. Of note, initial concern that blood pressure control with nonselective beta-blockade (e.g., propranolol) may be detrimental through reduction of cardiac output and decreased skeletal muscle vasodilatation was not confirmed in two meta-analyses of mild-moderate lower limb ischemia, and beta-blockers are generally safe to use in this population [49]. In CLI, lower extremity perfusion is paramount and blood pressure control becomes a less clear goal. In one center, target blood pressure for CLI is recommended to be set above traditional guidelines until ulcer healing has occurred, though this approach has not been scientifically investigated [37, 57]. Interestingly, in one longitudinal study of claudication, systolic blood pressure in the middle tertile (153–170 mmHg) was the only variable which led to a reduced risk of ABI deterioration [19].