Restenosis

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The phenomenon of vessel restenosis, an immune response to damaged tissue, is known to be a common adverse event and the Achilles heel of angioplasty and stenting. Reducing restenosis is one of the highest priorities in research and the development of new endovascular technologies. Restenosis rates of drug-eluting stents appear to be significantly lower than bare-metal stents, and research is underway to determine if drug-coated balloons also improve restenosis outcomes. PTCA stent NIH.gif
The phenomenon of vessel restenosis, an immune response to damaged tissue, is known to be a common adverse event and the Achilles heel of angioplasty and stenting. Reducing restenosis is one of the highest priorities in research and the development of new endovascular technologies. Restenosis rates of drug-eluting stents appear to be significantly lower than bare-metal stents, and research is underway to determine if drug-coated balloons also improve restenosis outcomes.

Restenosis is the recurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage, and subsequently become re-narrowed. This is usually restenosis of an artery, or other blood vessel, or possibly a vessel within an organ.

Contents

Restenosis is a common adverse event of endovascular procedures. Procedures frequently used to treat vascular damage from atherosclerosis and related narrowing and re-narrowing (restenosis) of blood vessels include vascular surgery, cardiac surgery, and angioplasty. [1]

When a stent is used and restenosis occurs, this is called in-stent restenosis or ISR. [2] If it occurs following balloon angioplasty, this is called post-angioplasty restenosis or PARS. The diagnostic threshold for restenosis in both ISR and PARS is ≥50% stenosis. [3]

If restenosis occurs after a procedure, follow-up imaging is not the only way to initially detect compromised blood flow. Symptoms may also suggest or signal restenosis, but this should be confirmed by imaging. For instance, a coronary stent patient who develops restenosis may experience recurrent chest pain (angina) or have a minor or major heart attack (myocardial infarction), though they may not report it. This is why it is important that a patient comply with follow-up screenings and the clinician follows through with a thorough clinical assessment. But it is also important to note that not all cases of restenosis lead to clinical symptoms, nor are they asymptomatic. [3]

Causes

Surgery to widen or unblock a blood vessel usually has a long-lasting beneficial effect on the patient. However, in some cases, the procedure itself can cause further narrowing of the vessel, or restenosis. Angioplasty, also called percutaneous transluminal coronary angioplasty (PTCA), is commonly used to treat blockages of the coronary or peripheral arteries (such as in the limbs). The balloon inserted into the narrowing 'smashes' the cholesterol plaques (atherosclerosis) against the artery walls, thus widening the size of the lumen and increasing blood flow. However the action damages the artery walls, and they respond by using physiological mechanisms to repair the damage. (See physiology below.) [4]

A stent is a mesh, tube-like structure often used in conjunction with angioplasty to permanently hold open an artery, allowing for unrestricted blood flow, or to support a weakness in the artery wall called an aneurysm. The artery can react to the stent, perceive it as a foreign body, and respond by mounting an immune system response which leads to further narrowing near or inside the stent.[ citation needed ]

Physiology

Damage to the blood vessel wall by angioplasty triggers a physiological response that can be divided into two stages. The first stage that occurs immediately after tissue trauma, is thrombosis. A blood clot forms at the site of damage and further hinders blood flow. This is accompanied by an inflammatory immune response.[ citation needed ]

The second stage tends to occur 3–6 months after surgery and is the result of the proliferation of cells in the media, a smooth muscle wall in the vessel. This is also known as Neointimal Hyperplasia (NIHA). [5]

Diagnosis

Imaging

Vessel restenosis is typically detected by angiography, but can also be detected by duplex ultrasound and other imaging techniques. [6]

As "late loss"

Conceptual schematic illustrating effectiveness of endovascular interventions on lumen diameter to improve blood flow as represented by acute gain, late loss (restenosis), and net gain. Late Loss Restenosis.png
Conceptual schematic illustrating effectiveness of endovascular interventions on lumen diameter to improve blood flow as represented by acute gain, late loss (restenosis), and net gain.

Late loss is synonymous with restenosis and means loss of the lumen after a procedure intended to open the vessel. It measures either the percent (relative) or absolute change in minimum luminal diameter (MLD) over the months following a vascular procedure, such as the implantation of a stent graft. Late loss is one metric that is useful in determining the effectiveness of vascular interventions in clinical trials for either an individual patient or a group of patients.[ citation needed ]

However late loss is only part of the terminology in describing the outcomes of vascular interventions. For instance, the implantation of a stent graft will first provide an acute gain in lumen diameter. In other words, there is an immediate gain in lumen size because the implanted stent opens up the vessel. However, over time, the body's inflammatory immune response (described below in the "Causes" section) reacts to the stent graft via smooth muscle proliferation, etc., which pushes the stent graft back, narrowing the vessel and losing at least a percentage of what was previously gained, or late loss.[ citation needed ]

The net gain of lumen diameter is the difference between acute gain and late loss and is a measure of stent-graft effectiveness. [7]

Percent diameter restenosis

Percent diameter restenosis (or just percent diameter stenosis) is a measure observed in individual patients and is typically calculated as the difference between the minimal (or minimum) luminal diameter (MLD) from the target reference vessel diameter (RVD), divided by the RVD, and multiplied by 100 to get the percentage of stenosis. It is an important measure needed to calculate binary restenosis (see Binary Restenosis section below). The RVD is typically calculated by averaging the MLD of the healthy part of the vessel both proximal and distal to the vessel lesion. [8]

There is some controversy over the accuracy of observing the lesion MLD itself, since many atherosclerotic lesions may create uneven "hills and valleys" within the lumen, making a true MLD difficult to obtain or estimate. Some research indicates calculating "area stenosis" is also a valid measure of actual vessel stenosis compared to diameter stenosis alone, but this requires additional analysis because a tracing of the lumen border must be performed. However, there are computer programs available to automatically perform this function. It may be helpful to obtain both percent diameter and area percent stenosis, especially since the two percentages may not always correlate with each other. [9]

An occlusion, or the blocking of all blood flow through a vessel, is considered 100% percent diameter stenosis.

Binary restenosis

Binary restenosis is traditionally defined as a reduction in the percent diameter stenosis of 50% or more (≥50%). It is also known as just "binary stenosis". [10] The term "binary" means that patients are placed in 2 groups, those who have ≥50% stenosis and those who have <50% stenosis. Binary restenosis is an epidemiological method of analyzing percent diameter stenosis for observing not only an individual patient, but also performing statistical techniques on a group of patients to determine averages (descriptive measures of central tendency) or as a predictive variable.[ citation needed ]

Prevention

In the first stage of restenosis, administering anti-platelet drugs (called IIb/IIIa inhibitors) immediately after surgery greatly reduces the chance of a thrombosis occurring.[ citation needed ]

Drug-eluting stents, coated with pharmaceuticals that inhibit tissue growth and thus reduce the risk of restenosis from scar tissue and cell proliferation, are now widely used. [11] These stents reduce the occurrence of restenosis, with clinical studies showing an incidence rate of 5% or lower. [3] [12] [13]

Treatment

If restenosis occurs without a stent, it is usually treated with more angioplasty.[ citation needed ] This treatment is also used if restenosis occurs at either the proximal or distal end of the stent.[ citation needed ]

If restenosis occurs within a stent (also known as in-stent stenosis), it may be treated with repeated angioplasty and insertion of another stent inside the original, often with a drug-eluting stent. [14]

Over the past 5 years, ISR has been increasingly treated with a drug-coated balloon (DCB), which is a balloon coated with the same anti-cancer drugs that prevent restenosis, such as Paclitaxel. [15] [16] The balloon avoids the need for a double layer of metal which is used when an in-stent restenosis is treated with another stent within the original stent. Additionally, DCB treatment does not leave an implant in the body and is designed for faster drug delivery.

Alternative treatments include brachytherapy, or intracoronary radiation. The radiation kills cells and inhibits tissue growth (similar to a patient undergoing cancer therapy). [17]

Incidence

Rates of restenosis differ between devices (e.g., stent-grafts, balloon angioplasty, etc.) and location of procedure (i.e., centrally located in the heart, such as the coronary artery, or in peripheral vessels such as the popliteal artery in the leg, the pudendal artery in the pelvis, or the carotid artery in the neck).[ citation needed ]

Rates in cardiac procedures

In cardiac procedures, balloon angioplasty without stent implantation has been associated with a high incidence of restenosis, with rates ranging from 25% to 50%, and the majority of these patients need further angioplasty within 6 months. [18]

A 2010 study in India comparing coronary drug-eluting stents (DES) with coronary bare-metal stents (BMS) reported that restenosis developed in 23.1% of DES patients vs 48.8% in BMS patients, and female sex was found to be a statistically significant risk factor for developing restenosis. [19]

However, in newer-generation DES and BMS the restenosis rates are much lower. For example, the NORSTENT trial, presented in 2016, reports target-lesion revascularization rates of 5.3% and 10.3% for DES and BMS respectively. [13]

Rates in peripheral procedures

In peripheral procedures, rates are still high. A 2003 study of selective and systematic stenting for limb-threatening ischemia reported restenosis rates at 1year follow-up in 32.3% of selective stenting patients and 34.7% of systematic stenting patients. [20]

The 2006 SIROCCO trial compared the sirolimus drug-eluting stent with a bare nitinol stent for atherosclerotic lesions of the subsartorial artery, reporting restenosis at 2 year follow-up was 22.9% and 21.1%, respectively. [21]

A 2009 study compared bare nitinol stents with percutaneous transluminal angioplasty (PTA) in subsartorial artery disease. At 1 year follow-up, restenosis was reported in 34.4% of stented patients versus 61.1% of PTA patients. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Angioplasty</span> Procedure to widen narrow arteries or veins

Angioplasty, also known as balloon angioplasty and percutaneous transluminal angioplasty (PTA), is a minimally invasive endovascular procedure used to widen narrowed or obstructed arteries or veins, typically to treat arterial atherosclerosis.

<span class="mw-page-title-main">Coronary artery bypass surgery</span> Surgical procedure to restore normal blood flow to an obstructed coronary artery

Coronary artery bypass surgery, also known as coronary artery bypass graft, is a surgical procedure to treat coronary artery disease (CAD), the buildup of plaques in the arteries of the heart. It can relieve chest pain caused by CAD, slow the progression of CAD, and increase life expectancy. It aims to bypass narrowings in heart arteries by using arteries or veins harvested from other parts of the body, thus restoring adequate blood supply to the previously ischemic heart.

<span class="mw-page-title-main">Stent</span> Type of medical device

In medicine, a stent is a tube usually constructed of a metallic alloy or a polymer. It is inserted into the lumen of an anatomic vessel or duct to keep the passageway open. Stenting refers to the placement of a stent. The word "stent" is also used as a verb to describe the placement of such a device, particularly when a disease such as atherosclerosis has pathologically narrowed a structure such as an artery.

<span class="mw-page-title-main">Angiography</span> Medical imaging technique

Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins, and the heart chambers. Modern angiography is performed by injecting a radio-opaque contrast agent into the blood vessel and imaging using X-ray based techniques such as fluoroscopy.

<span class="mw-page-title-main">Coronary catheterization</span> Radiography of heart and blood vessels

A coronary catheterization is a minimally invasive procedure to access the coronary circulation and blood filled chambers of the heart using a catheter. It is performed for both diagnostic and interventional (treatment) purposes.

<span class="mw-page-title-main">Stenosis</span> Abnormal narrowing of a blood vessel or other tubular organ or structure

Stenosis is the abnormal narrowing of a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture.

Intravascular ultrasound (IVUS) or intravascular echocardiography is a medical imaging methodology using a specially designed catheter with a miniaturized ultrasound probe attached to the distal end of the catheter. The proximal end of the catheter is attached to computerized ultrasound equipment. It allows the application of ultrasound technology, such as piezoelectric transducer or CMUT, to see from inside blood vessels out through the surrounding blood column, visualizing the endothelium of blood vessels.

<span class="mw-page-title-main">Cardiac catheterization</span> Insertion of a catheter into a chamber or vessel of the heart

Cardiac catheterization is the insertion of a catheter into a chamber or vessel of the heart. This is done both for diagnostic and interventional purposes.

<span class="mw-page-title-main">Percutaneous coronary intervention</span> Medical techniques used to manage coronary occlusion

Percutaneous coronary intervention (PCI) is a minimally invasive non-surgical procedure used to treat narrowing of the coronary arteries of the heart found in coronary artery disease. The procedure is used to place and deploy coronary stents, a permanent wire-meshed tube, to open narrowed coronary arteries. PCI is considered 'non-surgical' as it uses a small hole in a peripheral artery (leg/arm) to gain access to the arterial system, an equivalent surgical procedure would involve the opening of the chest wall to gain access to the heart area. The term 'coronary angioplasty with stent' is synonymous with PCI. The procedure visualises the blood vessels via fluoroscopic imaging and contrast dyes. PCI is performed by an interventional cardiologists in a catheterization laboratory setting.

<span class="mw-page-title-main">Drug-eluting stent</span> Medical implant

A drug-eluting stent (DES) is a tube made of a mesh-like material used to treat narrowed arteries in medical procedures both mechanically and pharmacologically. A DES is inserted into a narrowed artery using a delivery catheter usually inserted through a larger artery in the groin or wrist. The stent assembly has the DES mechanism attached towards the front of the stent, and usually is composed of the collapsed stent over a collapsed polymeric balloon mechanism, the balloon mechanism is inflated and used to expand the meshed stent once in position. The stent expands, embedding into the occluded artery wall, keeping the artery open, thereby improving blood flow. The mesh design allows for stent expansion and also for new healthy vessel endothelial cells to grow through and around it, securing it in place.

The history of invasive and interventional cardiology is complex, with multiple groups working independently on similar technologies. Invasive and interventional cardiology is currently closely associated with cardiologists, though the development and most of its early research and procedures were performed by diagnostic and interventional radiologists.

Fractional flow reserve (FFR) is a diagnostic technique used in coronary catheterization. FFR measures pressure differences across a coronary artery stenosis to determine the likelihood that the stenosis impedes oxygen delivery to the heart muscle.

<span class="mw-page-title-main">Coronary stent</span> Medical stent implanted into coronary arteries

A coronary stent is a tube-shaped device placed in the coronary arteries that supply blood to the heart, to keep the arteries open in patients suffering from coronary heart disease. The vast majority of stents used in modern interventional cardiology are drug-eluting stents (DES). They are used in a medical procedure called percutaneous coronary intervention (PCI). Coronary stents are divided into two broad types: drug-eluting and bare metal stents. As of 2023, drug-eluting stents were used in more than 90% of all PCI procedures. Stents reduce angina and have been shown to improve survival and decrease adverse events after a patient has suffered a heart attack—medically termed an acute myocardial infarction.

<span class="mw-page-title-main">Zotarolimus</span> Chemical compound

Zotarolimus is an immunosuppressant. It is a semi-synthetic derivative of sirolimus (rapamycin). It was designed for use in stents with phosphorylcholine as a carrier. Zotarolimus, or ABT-578, was originally used on Abbott's coronary stent platforms to reduce early inflammation and restenosis; however, Zotarolimus failed Abbott's primary endpoint to bring their stent/drug delivery system to market. The drug was sold/distributed to Medtronic for use on their stent platforms, which is the same drug they use today. Coronary stents reduce early complications and improve late clinical outcomes in patients needing interventional cardiology. The first human coronary stent implantation was first performed in 1986 by Puel et al. However, there are complications associated with stent use, development of thrombosis which impedes the efficiency of coronary stents, haemorrhagic and restenosis complications are problems associated with stents.

<span class="mw-page-title-main">Pulmonary artery stenosis</span> Medical condition

Pulmonary artery stenosis (PAS) is a narrowing of the pulmonary artery. The pulmonary artery is a blood vessel moving blood from the right side of the heart to the lungs. This narrowing can be due to many causes, including infection during pregnancy, a congenital heart defect, a problem with blood clotting in childhood or early adulthood, or a genetic change.

Julio Palmaz is a doctor of vascular radiology at University of Texas Health Science Center at San Antonio. He studied at the National University of La Plata in Argentina, earning his medical degree in 1971. He then practiced vascular radiology at the San Martin University Hospital in La Plata before moving to the University of Texas Health and Science Center at San Antonio. He is known for inventing the balloon-expandable stent, for which he received a patent filed in 1985. It was recognized in Intellectual Property International Magazine as one of "Ten Patents that Changed the World" in the last century. His early stent research artifacts are now part of the medical collection of the Smithsonian Institution in Washington, DC. He continues to innovate on his initial designs, developing new endovascular devices.

<span class="mw-page-title-main">Bioresorbable stent</span> Medical stent that dissolves or is absorbed by the body

A bioresorbable stent is a tube-like device (stent) that is used to open and widen clogged heart arteries and then dissolves or is absorbed by the body. It is made from a material that can release a drug to prevent scar tissue growth. It can also restore normal vessel function and avoid long-term complications of metal stents.

Neointimal hyperplasia refers to proliferation and migration of vascular smooth muscle cells primarily in the tunica intima, resulting in the thickening of arterial walls and decreased arterial lumen space. Neointimal hyperplasia is the major cause of restenosis after percutaneous coronary interventions such as stenting or angioplasty. The term neointima is used because the cells in the hyperplastic regions of the vascular wall have histological characteristics of both intima and normal artery cells.

A dual therapy stent is a coronary artery stent that combines the technology of an antibody-coated stent and a drug-eluting stent. Currently, second-generation drug-eluting stents require long-term use of dual-antiplatelet therapy, which increases the risk of major bleeding occurrences in patients. Compared to drug-eluting stents, dual therapy stents have improved vessel regeneration and cell proliferation capabilities. As a result, dual therapy stents were developed to reduce the long-term need for dual-antiplatelet therapy.

Alfredo E. Rodríguez is an Argentine interventional cardiologist, clinical researcher, and author. He is the Chief of Interventional Cardiology Service at Otamendi Hospital and Director and Founder of the Cardiovascular Research Center (CECI) a non -profit Research Organization in Buenos Aires Argentina.

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