Novel Approaches to Treat Peripheral Artery Disease

Introduction

Peripheral artery disease (PAD) affects more than 200 million adults globally, and the incidence is high as approximately 20 percent of people over the age of 70 years are affected by this condition. As most patients with PAD do not exhibit typical symptoms, it is often underdiagnosed in a primary care setting. Some of the risk factors for developing peripheral artery disease include smoking, hypertension (high blood pressure), diabetes (high blood sugar), hyperlipidemia (high levels of fats), and certain races and ethnicities. PAD management strategies mainly aim to reduce cardiovascular risk and improve walking ability. Therefore, healthcare professionals emphasize lifestyle modifications such as incorporating a healthy diet, physical exercises, and regular medications to lower the rate of PAD progression and improve the quality of life.

What Is Peripheral Artery Disease?

Peripheral artery disease is a condition that occurs due to narrowing or blockage of the vessels that carry blood away from the heart to the lower extremities (legs and feet). It is more common in the legs than the arms and is caused by atherosclerosis (the accumulation of plaque or fatty deposits in the arteries). It can equally affect males and females and is seen in more than eight million people over 40 years in the United States. The restriction of blood flow is the hallmark of PAD, and its characteristic symptoms include severe pain or heaviness in the legs during physical activity but relieved by rest, muscle atrophy (weakness), leg cramps, numbness, smooth and shiny skin, which is pale, or discolored, difficulty walking, and climbing stairs, unhealing sores or ulcers in the feet.

How Is Peripheral Artery Disease Diagnosed?

Peripheral artery disease is diagnosed based on the patient’s symptoms, risk factors, medical and family history, and a thorough physical examination. The patient’s walking ability is also assessed. Still, some patients do not exhibit claudication symptoms (pain, discomfort, or numbness) or may walk very little due to physical ailments or other limitations. Physical examination of patients may show diminished or lower extremity pulses. It is confirmed by a noninvasive test called ankle-brachial index (ABI). It measures the blood pressure in the lower extremities (ankles) and is compared with the blood pressure in the arms at rest and after exercise. Doppler studies are also conducted to evaluate blood flow occlusion and velocities. In some cases, computed tomography (CT) or magnetic resonance angiography (MRA) may also be recommended.

What Are the Novel Approaches to Treat Peripheral Artery Disease?

Some treatment strategies for peripheral artery disease include smoking cessation, lifestyle modifications, exercises, pharmacotherapy, which provides antiplatelet therapy, endovascular repair, peripheral vasodilators, drugs to reduce blood pressure, cholesterol, etc, and surgery. However, recently, gene therapy, nano-therapy, cell therapy, targeted therapy, and combination drug therapies have been highlighted. The novel approaches for treating peripheral artery disease include:

• Antiplatelet Therapy: Antiplatelet drugs such as Aspirin, Ticagrelor, Clopidogrel, and Vorapaxar are mostly indicated in PAD. The effectiveness of Aspirin is well established, but the impact of optimum doses of the drug on PAD still needs to be completely understood. It may be determined in further clinical trials. Studies have demonstrated that dual antiplatelet therapy (DAPT) can be beneficial in PAD, but its impact is still unclear. However, a significant reduction has been observed in the major adverse cardiovascular events (MACE) in patients who received DAPT compared to Aspirin monotherapy. Recently, a few clinical trials also focused on optimizing the duration of DAPT following revascularization to compare the benefits of different treatment modalities. In addition to medications, supportive therapies and traditional medicines to relieve pain are also being evaluated. Rivaroxaban, a relatively new drug, is a direct oral anticoagulant commonly recommended for venous thromboembolism and stroke prevention. Studies have shown that Rivaroxaban plus Aspirin is an important breakthrough in treating PAD, as it has better cardiovascular outcomes than Aspirin alone.

• Anti-hypertensive Drugs: The administration of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) is known to be associated with reducing major adverse cardiovascular events and critical limb ischemia. Along with these medications, paying more attention to preventing the condition can substantially improve long-term outcomes.

• Statin Therapy: Statins are suitable for treating PAD as they cause notable changes in atherosclerotic plaque composition and reduce necrotic core (dead tissues) and overall atheroma (fatty material) volume. The initiation of statin therapy after revascularization has proven effective and safe in various clinical studies.

• Monoclonal Antibodies: Drugs such as Evolocumab lower low-density lipoprotein (LDL) levels by inhibiting the enzyme proprotein convertase subtilisin-Kexin type 9 (PCSK9). Research also reported that combining statins with Evolocumab reduced cardiovascular events and prevented major adverse limb disorders.

• Gene Therapy: Medications may not be suitable for many individuals due to aging and other medical conditions such as diabetes. Targeted and gene therapy are promising treatment options for such patients and have future potential in managing peripheral artery disease. It is based on genetic material encoding, which uses angiogenesis factors to induce blood vessel formation, initiating tissue recovery. The treatment is more efficient if administered directly into the ischemic muscle tissues via intramuscular or intra-arterial routes. Various analyses have been conducted to identify novel therapeutic targets for this therapy to recognize the molecular basis of peripheral artery disease. However, many patients experienced moderate or severe edema (swelling) during clinical gene therapy trials, indicating that long-term and slow release is more effective. The development of immunological responses, stimulation of the innate immune system, and accelerated blood clearance are a few limitations of gene therapy, which can cause various unwanted or severe symptoms.

• Regenerative Medicine: Cell therapy or regenerative medicine is considered one of the emerging fields in medicine and is known to be beneficial in conditions such as diabetes, ischemic stroke, vascular complications, and trauma. It is not only limited to the injection of cells into the vascular network but can also activate regenerative pathways via neo-vessel formation, which helps in recovering limb activity. Many clinical studies have reported that cell transplantation is highly effective in patients with critical limb ischemia. However, identifying ideal endothelial cells for therapeutic application requires further investigations. Mesenchymal stem cells (MSCs) derived from various potential sources are promising options for treating peripheral arterial diseases. Intramuscular and intravenous routes were commonly employed in preclinical and clinical studies. Bone-marrow-derived mononuclear cells have been used successfully by the intra-arterial route. Some limitations of cell therapy include obtaining, differentiating, and transferring the ideal cells to the intended sites.

• Nano therapy: Nanotechnology is a new disease treatment route that helps deliver drug agents to specific sites. Proteins are encapsulated within nanoparticles (NPs) to prevent them from enzyme degradation and ensure their regulated release into the cells for achieving high therapeutic efficiency. These techniques target and adhere to the affected areas and help improve drug reaction and effectiveness. Cyclic arginyl glycyl aspartic acid (RGD) is developed to interact with integrin and P-selectin receptors. Angiogenic peptide-loaded nanoliposomes also help improve vascular density.

Conclusion

Peripheral artery disease is a complication of systemic atherosclerosis and affects millions of people worldwide. It differs from coronary artery disease and other cerebrovascular diseases due to its risk factors for disease pathogenesis. Novel treatment approaches are safe, highly productive, and associated with minimal side effects. These modalities may halt the progression of atherosclerosis or may even successfully treat peripheral artery disease. However, healthy eating patterns, quitting smoking, effectively managing stress, and being physically active can help prevent peripheral artery disease.