CLI: disease burden

Critical limb ischemia (CLI) is at the end of the peripheral artery disease (PAD) spectrum and is associated with high amputation and mortality rates and poor quality of life. Macrovascular lesions induce a reduction of distal perfusion and nutrient blood flow to the tissues and microcirculation exchange are severely affected. CLI is an eminent condition in the general population with a strong social impact.

The prevalence of CLI in the population aged 60–90 years is estimated as 1% (0.5–1.2%) with male to female ratio around 3:1 and 5–10% of patients with asymptomatic peripheral arterial obstructive disease or claudication will progress to CLI within 5 years from the first diagnosis.
Several studies have shown that over 50% of CLI patients do not have any PAD symptoms 6 months prior to the onset of CLI. The major risk factors for PAD include smoking, hyperlipidaemia, hypertension and, particularly for development of CLI, diabetes. Diabetic patients are, at least, fivefold more likely to develop CLI than non-diabetic patients.

Recent evidences showed that other factors than limb blood flow contribute to pathophysiology of CLI. For a long-time research in this field focused mainly on vasculopathy and the resulting ischemia/reperfusion injury. Recent data, however, support the important role of a link between vasculopathy and myopathy in CLI. Indeed, several data suggest the skeletal muscle as a determinant of morbidity and mortality outcomes in CLI.

The international consensus on the definition of CLI is the following: any patient with chronic ischemic rest pain, ulcers, or gangrene attributable to an objectively proven arterial occlusive disease. CLI is not to be confused with acute occlusion of the distal arterial tree, but rather a disease process that occurs in a chronic setting of months to years and, if left untreated, ultimately leads to limb loss secondary to lack of adequate blood flow and oxygenation through the distal extremities. Given that CLI is a severe manifestation of PAD, these patients are classified in the more severe ends of the Fontaine classification (stage III-IV) or the Rutherford classification (grades 4-6; Table I). CLI does not always progress though the various stages of this classification system.


Table I. Classification scheme of peripheral arterial disease


The diagnosis of CLI is straightforward because of the vascular examination, the ankle-brachial index (ABI), and a number of imaging modalities, but the understanding of the complex pathophysiology is still limited and cannot be seen as simple vascular disease. Moreover, the choice of optimal care for patients with CLI, is not straightforward yet.


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