Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

Abstract

P eripheral artery disease (PAD) is initiated by atherogenic mechanisms common to all major vascular territories but encompasses several distinctly important clinical sequelae.1 The global burden of PAD is large and rising, with substantial morbidity and mortality found in high-, middle-, and low-income countries. 2 The atherosclerotic occlusive disease underlying PAD is associated with an exercise limitation in the majority of patients, whereas the classic symptoms of intermittent claudication, ischemic rest pain, and ischemic ulceration are less common manifestations. 3 Patients with PAD are also at increased risk of myocardial infarction, ischemic stroke, heart failure, renovascular hypertension, and vascular death reflecting the systemic atherosclerotic burden. [4][5][6] The epidemiology of Peripheral Artery Disease Compendium© 2015 American Heart Association, Inc. The diagnosis of PAD can be ascertained by simple hemodynamic measurements, in particular, the ankle-brachial index (ABI), a test performed by measuring the systolic blood pressure in each arm and the dorsalis pedis and posterior tibial arteries of each ankle. The highest of the dorsalis pedis or posterior tibial artery pressures is the numerator of the ABI specific to each leg, whereas the highest arm pressure on either side is the denominator. A ratio of <0.90 in either leg is considered hemodynamic evidence of PAD. 16 When imaged, PAD can be characterized as one or more arterial stenoses or occlusions involving the distal aorta, iliac, femoral, popliteal, or tibial arteries. 17The underlying mechanisms responsible for the functional limitations in PAD are hemodynamic in origin, which affects the supply of oxygen and substrates to metabolically active tissue: skeletal muscle in the case of intermittent claudication and skin and subcutaneous tissues in the case of critical leg ischemia. However, additional pathophysiologic mechanisms contribute to the limb manifestations, where a reduction in blood flow alone does not fully account for the exercise limitation. Recent research into the pathophysiology of this exercise limitation has identified several important sequelae resultant from the chronic hemodynamic deficit. These changes affecting the vasculature and skeletal muscle distal to the primary hemodynamic lesions likely contribute to the mechanisms of exercise limitation in PAD. These advances are reviewed here with an additional focus on identifying possible future therapeutic strategies. Symptomatic Manifestations and Exercise Limitations in PADIn the coronary circulation, plaque rupture leading to acute ischemic events is a common clinical presentation; in PAD, progressive atherosclerosis leading to chronic stenosis and occlusion, often in series, in the arteries supplying the lower extremities dominates the symptomatic manifestations.6 Limb SymptomsPatients with PAD may present with a range of limb symptoms. Most patients are either asymptomatic or have atypical limb symptoms during exercise, whereas only a third have typical symptoms of c...

Chronology of mitochondrial and cellular events during skeletal muscle ischemia-reperfusion

“…I/R during PAD results in insuf-ficient oxygen supply secondary to reduced blood flow, mitochondriopathy leading to reduced energy supply, oxidative stress (i.e., imbalance between free radical production and elimination), and inflammation, which lead to intermittent claudication, limb pain at rest, ulcers, and, potentially, limb loss and increased morbidity/mortality (13,39,71,95,114,162) (Fig. 1).…”

Carnosine, a therapeutic potential for critical limb ischemic.

“…Recent studies suggest that up to 15% of the adult population (i.e. > 45 years) have PAD [6,23] and the incidence of age driven PAD is likely to increase [2]. Diabetes mellitus is another important risk factor for PAD.…”

“…Diabetes also affects the anatomic distribution of disease leading to a bad prognosis in these individuals [25,26]. Dyslipidemia and hypertension, though risk factors, contribute less to the pathogenesis of PAD as compared to other vascular events such as myocardial infarction and ischemic stroke [23]. Family history of PAD has also being shown to be a predisposing factor.…”

“…Imaging results from PAD patients show narrowing of lower aorta, femoral, iliac, popliteal and tibial arteries [12,16]. This narrowing causes intermittent claudication in some individual, but majority of PAD patients are usually asymptomatic [23,32]. The hemodynamic changes associated with these occlusion are diagnosed as a reduction in ankle brachial index and is dependent on the location of the occlusion and existence of blood vessels other than the occluded vessel linking the preoccluded and postoccluded sites [9].…”

“…Repeated bouts of ischemia and reperfusion results in ion pump dysregulation, mitochondrial dysfunction, ROS generation, inflammation and apoptosis. These processes if unrestricted result in damage to the muscle fibers [9,23,32]. …”