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New Trends in Myocardial Revascularization
Mario Mariani, MD.The coronary artery disease (CAD) is one of the most important health problem in contemporary society. The high prevalence of CAD makes recognition, management and prevention of this disease very important end-points. Fortunately, in the past three decades encouraging reductions in the consequences of CAD have been reported. Multiple causes may have contributed to this favorable trend, including: reduction of risk factors, great diffusion of intensive care units and new methods of diagnosis and treatment.
The current approaches to CAD therapy are represented by: modification of life style, reduction of risk factors, medical management and myocardial revascularization. The latter, including PTCA and coronary artery bypass grafting, is indicated in patients with refractory symptoms or ischemia despite optimal medical therapy; it should also be carried out in high-risk patients identified by current methods and in those with occupations or life styles that indicate a more aggressive approach.
Since the initial application of balloon angioplasty in humans in 1977, there has been explosive growth in the field of interventional cardioloy. While PTCA was initially restricted to relatively young patients with stable angina, normal left ventricular function and proximal, discrete, subtotal, noncalcified concentric stenosis of a single coronary artery, current indications for this procedure have expanded to include unstable angina and acute myocardial infarction, multivessel coronary artery disease and stenosis with complex morphology or coronary artery bypass grafts.
In addition to balloon angioplasty, PTCA now encompasses multiple catheter-based revascularization techniques, including the use of coronary stenting, rotational and directional coronary atherectomy, coronary laser systems, radioactive stents and balloons, associated pharmacologic therapy (i.e. glycoprotein IIb/IIIa receptor inhibitors). Experience with the currently available alternative technologies suggests that each may have a niche application that provides some advantages over the others. PTCA presents some limitations: unfavorable coronary anatomy, incessant postangioplasty restenosis or recurrent in-stent chronic total occlusion and, finally, unsuccessful procedure in a small percentage of cases.
The other current treatment strategy of CAD is coronary artery bypass grafting (CABG).. Similarly to PTCA, also CABG presents some limitations: diffuse coronary artery disease, occluded vessels without collateral recanalization, severe left ventricular dysfunction, extracardiac diseases such as severe obstructive pulmonary or cerebrovascular diseases. Many historical trials have demonstrated a more favorable outcome of patients submitted to surgical myocardial revascularization compared to medical therapy. The explosion of PTCA has recently raised the question of which method of revascularization in which patient is superior. As a result six large randomised trials (RITA, ERACI, GAB, EAST, CABRI, BARI) have compared these two kinds of intervention. These trials demonstrated that percentage of death and non-fatal MI were similar between the two treatment strategies (1-5).
Although both CABG, and PTCA have a high success rate still a high percentage of patients with CAD, often those at highest risk, are not good candidates for neither therapies due to the above mentioned limitations and to the still significant rate of post-PTCA restenosis and graft occlusion. These considerations explain the need for continuous evolving of revascularization techniques. Minimally invasive heart surgery, alternative arterial conduits, transmyocardial laser revascularization and therapeutic neoangiogenesis represent at the moment the most promising answer to this unmet medical need.
TopMinimally invasive coronary artery surgery
Minimally invasive coronary artery bypass is performed using one of two approaches: (1) a series of small holes or "ports" in the chest (referred to as PACAB, PortCAB, or port-access coronary artery bypass) or (2) a combination of ports and a small incision directly over the coronary artery to be bypassed (referred to as MIDCAB or minimally invasive coronary artery bypass). As in standard coronary artery bypass graft surgery (CABG), anesthesia is required (6).
In the PACAB method, cardiopulmonary bypass is performed using the femoral vessels. The heart is stopped and the bypasses are performed using instruments passed through the ports, with or without a small additional chest incision. The cardiac surgeon views these operations on video monitors rather than directly.
The MIDCAB procedure combines both direct and indirect techniques. In contrast to PACAB, it is performed with the intention of avoiding cardiopulmonary bypass and it is performed on a beating heart. In contrast to PACAB, the procedure was designed for bypassing only one or two coronary arteries; since suturing is done under direct vision, the coronary artery to be bypassed must lie directly beneath the incision. The coronary bypass is usually performed using the left internal mammary artery (LIMA), which lies on the inside of the chest wall very near the left anterior descending coronary artery (LAD). The LIMA is dissected from the chest wall using direct vision and/or video guidance, depending on the patient's anatomy and the surgeon's preference. Afterward the LIMA is sutured directly to the LAD. Occasionally the right internal mammary artery is used to bypass the right coronary artery.
Despite the enthusiasm around these techniques, their widespread adoption cannot be endorsed until suitable data have accumulated. The role of minimally invasive coronary bypass in the treatment of patients with single-vessel coronary artery disease will be defined only by such careful comparative studies. Natural history studies of medically treated patients demonstrate a good long-term prognosis, except for the subgroup with severe proximal LAD stenosis. Conversely, observational studies suggest that angioplasty may provide a slightly better long-term survival benefit than bypass surgery for patients with single-vessel disease (7). These facts suggest that the role of minimally invasive coronary bypass in patients with single-vessel coronary disease will, for now, be limited to the few who need interventional therapy but are not suitable candidates for coronary angioplasty due to their anatomy, ie, those who have undergone one or more failed angioplasties, or those who elect surgical revascularization instead.
The most likely future application for minimally invasive surgery is in patients with extensive disease now known to have a survival benefit from the standard bypass. Recent randomized trials demonstrating equivalent 5-year survival in patients with two- and three-vessel disease who have undergone revascularization by either angioplasty or bypass surgery suggest that complete revascularization may not be as necessary as previously believed (35). Those patients with the most severe disease confined to the LAD and right coronary artery might be well served by two internal mammary artery grafts to these vessels. If this operation can be performed safely using minimally invasive techniques, efficacy comparable to standard coronary bypass might be proved in these patients.
MIDCAB is easier on the patient and is probably less expensive than traditional CABG. Nonetheless, compared with traditional CABG, exposure is limited and performance of the anastomosis more difficult. Significant ischemia leading to hemodynamic compromise of the patient may occur. Therefore, the procedure must be performed with the availability of cardiopulmonary bypass. Predictably, urgent conversion to conventional open-chest methods has occasionally been necessary.
TopAlternative arterial conduits
The superior long-term patency and survival of the internal thoracic artery (ITA) coronary artery bypass grafting compared with saphenous vein (SV) established the ITA as the conduit of choice for myocardial revascularization. Use of the ITA has expanded and the possibility of similar performance by other arteries has motivated surgeons to investigate alternative arterial conduits like the gastroepiploic artery (GEA), inferior epigastric artery (IEA) and radial artery (RA). Complete revascularization with arterial conduits is gradually becoming easier and its benefits are becoming more demonstrable. By the mid 80s accumulating data showed the clinical advantage of an 85% to 90% 10-year patency rate for the ITA compared with a 50% patency rate for the SV (8). In fact long-term patency of venous graft is poor, with consequent recurrent angina pectoris and subsequent cardiac events (9-12). The use of single as well as double ITA grafts instead of SV in CABG has been demonstrated through the years to improve survival and to reduce the recurrence of myocardial ischemia and the occurrence of late myocardial infarction without a significant increase in perioperative morbidity or mortality (13-16).
Problems related to the complex use of arterial grafts, in contrast with the SV, are that arterial conduits are more difficult to harvest, more easily damaged, more demanding to anastomose owing to fragility and small size, and more compromised by spasm or technical error, which can result in graft closure (occlusion) or myocardial hypoperfusion (patent graft but inadequate flow). However if the arterial conduits are patent immediately after surgery usually remain patent, whereas the venous grafts exhibit progressive atherosclerosis (17). In contrast, venous grafts in combination with 1 or 2 ITA grafts, are still used in majority of patients. Several reports have demonstrated that use of both ITAs as opposed to one is associated with reduced incidence of angina return and myocardial infarction (13,18).
A resonable alternative for the SV graft in conjunction with both ITAs is the right GEA. With the GEA myocardial revascularization can be achieved with the use of arterial grafts only, even in patients with three-vessels disease. The GEA is now an established conduit that is relatively easy to harvest by estending the sternotomy incision 4 to 8 cm and mobilizing the artery from the short gastric branch to the pylorus. Reports of 8- and 10-year experience with the GEA by Suma (19) and Pym and coworkers (20), respectively, have described patency of 92% to 97%. Use of the GEA for off-pump bypass has been reported with an epigastric incision and limited sternotomy or excision of the xiphoid and resection of the adjacent sternum. When used as a free graft from the aorta, patency is 80% (19-21). Harvesting complications have been only rarely reported; on the other hand, procurement of GEA in the obese is difficult and the conduit is vulnerable to twisting and technical errors. The GEA is also prone to spasm and tends to be smaller at the point of anastomosis than other arteries used for CAGB.
Experience with the IEA is much less than with the GEA. In the only reported large series Buche and Dion (22) found inferior patency compared with that of other arterial conduits. Both IEAs can be harvested through the same midline incision. Use of this artery is limited by variability in its size and the fact that it may divide and become too small or enter the rectus muscle, making dissection exceedingly difficult.
The RA was transiently used in the early seventies (23) and was reintroduced by the same group in the 1992 (24). Harvesting this conduit necessitates prior assessment of collateral circulation to the hand which can be easily performed using the Allen test. The RA is usually harvested from the nondominant arm. The artery is anostomosed proximally with the aorta if the latter is healthy; alternatively the artery can be anastomosed to the hood of an associated vein graft or to a pericardial patch placed in the aortic wall. Most surgeons using RA suggest to use perioperatively calcium channel-blocking-agents and for 3 to 12 months after intervention to prevent vasospasm. RA patency has been reported in recent studies from 84.2% to 95.7% during a mean follow-up of 3 months to 5.6 years (25, 26).
In conclusion the arterial grafts have become more technically feasible and have shown benefits; however, more follow-up data are needed to determine the long-term patency, freedom from arteriosclerosis, and efficacy of these alternative conduits.
Transmyocardial laser revascularization
Traditional interventional modalities are not always adequate for complete myocardial revascularization in advanced atherosclerotic CAD. If the lesion is distally located, a target for bypass graft anastomosis may not be identifiable. If the artery is diffusely involved with disease, graft run-off may remain suboptimal. Transmyocardial Laser Revascularization (TMLR) with or without CABG has been proposed has an alternative modality for complete revascularization. This method, also known as a form of Direct Myocardial Revascularization (DMR), works by shunting left ventricular blood directly into the ischemic myocardium, especially the subendocardial perfusion bed, via laser-mediated transmural channels. DMR can be classified according to the procedural technique (surgical or percutaneous), the route of myocardial access (epicardial or endocardial), and the form of treatment being apllied (channel-forming laser or local pharmacotherapy). Surgical DMR creates intramyocardial channels using carbon dioxide (CO2) or holmium/yttrium-aluminum-garnet (Ho:YAG) lasers using an epicardial approach. Catheter-based DMR generates endomyocardial channels from the left ventricular cavity to the subepicardial myocardium using short-pulsed lasers delivered through fiberoptic catheters. This method may provide benefits equivalent to those of surgical DMR without to need for thoracotomy, general anesthesia and, in systems that can create electromechanical maps, fluoroscopy. Both the surgical and catheter-based DMR can also be used to inject drugs directly into the ischemic myocardium.
Pathophysiology: the rationale behind TMLR involves the presupposition that the laser-created transmyocardial channels will stay patent, establish communications between the endocardium and the myocardial sinusoidal plexus, and through these communications convey oxygenated left ventricular blood to the arteriolar system, thereby reversing ischemia and relieving angina. Despite extensive investigations, the mechanism of TMLR beneficial effects is still unknown. Another suggested possible mechanism is the stimulation of angiogenesis by laser-induced myocardial injury, leading to an increased myocardial perfusion (27-30). A third proposed mechanism to explain the acute symptomatic relief observed after TMLR is damage to myocardial nerve fibers, resulting in an anesthetic effect without altered intramyocardial perfusion (31).
Indications: to be a candidate for DMR the patients must have severe angina (functional class III or IV) despite optimal medical therapy; they must have poor indications for PTCA due to high procedural risk or absence of acceptable target sites and for CABG due a prohibitive risk or absence of acceptable target vessels and/or remaining surgical conduits. In particular, there are some clinical categories who may benefits from DMR, like patients with degenerated SV grafts, diffuse coronary disease or small target vessels (e.g. diabetics), incessant post-PTCA restenosis or recurrent diffuse in-stent restenosis and chronic total occlusion with nonvisualized or poor distal vessels. Another potential use for DMR is a hibrid procedure during PTCA or CABG, an indication that may ultimately be the largest patient cohort for DMR procedures (31). At present, patients with overt heart failure or very low left ventricular ejection fraction are excluded from many study protocols.
Clinical Results: to date, clinical studies with TMLR have invariably yielded a decrease in angina, as well as improved clinical status and exercise tolerance, with mild to moderate improvement in regional cardiac perfusion (32-35). Unfortunately, except for isolated reports (36,37), no evidence of a parallel increase in overall cardiac function has been observed. On the other hand, the 1-year mortality rate of TMLR patients is the same as, if not less than, that of control patients undergoing maximal medical management (38).
Therapeutic angiogenesis, similarly to TMLR, has the potential to restore blood supply to the myocardium by providing new venues for blood flow.
Pathophysiology: angiogenesis is a complex process leading to formation of new capillaries which involves the coordinated action of several mitogens, proteases and chemotactic factors inducing endothelial cells proliferation/migration and remodeling of the extracellular matrix. However, in order to restore myocardial blood flow angiogenesis must be associated to arteriogenesis which involves the remodeling of arterioles (resistence vessels) into arteries (conductance vessels) through increases in the initial luminal diameter by a factor of 20-fold. Angiogenesis is stimulated mainly by hypoxia through the release of vascular growth factors such as the vascular endothelial growth factor (VEGF), the acidic and basic fibroblast growth factors (aFGF, bFGF) and angiopoietin (39,40,41).On the other hand, inflammation and increased fluid shear stress may lead to arteriogenesis through the activation of monocytes and the release of FGF, tumor necrosis factor alfa (TNF-alfa), insulin-like growth factor (IGF) and proteases (41,42)(Figure 1).
VEGF-induced therapeutic angiogenesis has been tested in both experimental, and clinical studies. The main characteristics of VEGF are summarized in Figure 2. VEGF is an homodimeric glycoprotein of 45.000 daltons including four isoforms: VEGF121, VEGF165, VEGF189 and VEGF206 (39). The main biological effects of VEGF are: migration/proliferation of endothelial cells, inhibition of endothelial cells apoptosis, increase in capillary permeability and release of nitric oxide (43,44). These effects are mediated by specific receptors such as the Flt-1 and the Flk-1. The system VEGF/VEGF-receptors is usually silent in the healthy adult whereas it is activated in the presence of hypoxia (45). VEGF has been administered directly as a protein, through a naked plasmid DNA encoding the VEGF165 or through a virus-mediated gene transfer.
Experimental and clinical studies: in animal models VEGF induced development of collateral circulation in myocardial and skeletal muscle (46,47) and proved to be useful in preventing myocardial dysfunction after coronary occlusion (46). Henry et al (48) showed that the intracoronary administration in patients with severe CAD of recombinant VEGF was safe and induced improvement in SPECT nuclear perfusion in 7 out of 15 patients. Similarly, intramyocardial administration of FGF in patients undergoing coronary artery bypass grafting may induce neoangiogenesis (49,50).
Although encouraging, these preliminary results in humans must be confirmed by further placebo-controlled, randomized trials aimed to evaluate the efficacy of therapeutic angiogenesis on clinical symptoms, preservation of left ventricular function and, most importantly, long-term survival of patients with severe CAD unsuitable for coronary artery bypass grafting or coronary angioplasty. Also, future trials on therapeutic angiogenesis will have to answer to the folllowing questions: which is the best angiogenic factor or combination of factors, which is the optimal dose and administration route of the factor(s), which is the clinical relevance of the potential side effects (rethinopathy, neovascularization of the atherosclerotic plaque, induction of tumor growth). Finally, a potential future application of therapeutic neoangiogenesis is its use in conjunction with TMLR through multifunctional devices able to delivery angiogenic factors into the laser-induced myocardial channels.
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