Collateral Formation in Patients After Percutaneous Myocardial Revascularization: A Mechanism for Improvement?

Percutaneous myocardial revascularization (PMR) has emerged as a less invasive alternative to the transmyocardial revascularization (TMR), which requires thoracotomy. Initial results of PMR are encouraging with a significant proportion of patients that experience an increase in exercise capacity, reduction in angina frequency and improvement in quality of life.1,2 Although a recent double-blinded randomized clinical trial has cast doubt on the efficacy of PMR,3 the substantial improvements seen in other clinical trials are factual. The underlying mechanism accounting for the improvement seen after PMR remains largely unknown. The initial enthusiasm on the created channels to perfuse the ischemic myocardium has been proved invalid, as most of the channels are closed soon after the procedure.4,5 Other suggested mechanisms include stimulation of angiogenesis,6 regional denervation,7,8 transformation of ischemic region into infarcted region,9 placebo or some other unknown effects. Collateral circulation confers protective effect on ischemic myocardium by improving perfusion. After myocardial infarction, patients with adequate collateral formation are more likely to have small infarction size, lower risk of aneurysm formation and reduced mortality.10,11 There is evidence that the process of collateral vessel formation, now known as arteriogenesis, closely resemble that of angiogenesis.12,13 The aim of our study is to investigate the change in the extent of collateral vessel before and after PMR and to correlate this with the improvement in angina status. Materials and Methods Procedure. Adult patients with symptomatic angina (Canadian Cardiovascular Society Class III or IV) not amendable to percutaneous coronary intervention or coronary artery bypass surgery were recruited into this study. Objective evidence of ischemia was documented by dobutamine stress echocardiogram. The demographic information including the age, sex and other cardiovascular risk factors were collected. All the patients have diagnostic coronary angiograms within 4 weeks before the procedure. Informed consent was obtained before the procedure. Three different PMR systems were used: Cardiogenesis (laser therapy; n = 10 [40%]), Biosense (laser therapy; n = 8 (32%)) and Aries (radiofrequency; n = 7 [28%]). The details of the PMR procedure have been discussed elsewhere.14 Patients were excluded if the left ventricular ejection function was less than 30%. After treatment patients were followed for six months. The trial was approved by the local Institutional Review Board. Follow-up. Coronary angiograms were performed at 6 months follow-up. The patients were divided into 2 groups according to whether angina status was improved or not. Improvement in angina status was defined as improvement of > 2 CCS class. Assessment of collateral vessel formation. The coronary angiograms before and after the procedure were analyzed with respect to the collateral circulation in the ischemic target area. The angiograms were analyzed by two independent reviewers. In case of disagreement between the two reviewers, a third blinded reviewer would made the final reading. The Rentrop scoring system was used to grade the extent of collateral circulation: 0 = no filling of distal vessel via collateral vessels; 1 = filling of side branches of the epicardial artery by collateral vessels without visualization of the epicardial artery; 2 = major side branches of the main epicardial artery filled by collateral vessels with visualization of the epicardial artery; and 3 = complete filling of the epicardial artery by collateral vessels. The collateral score was based on the injection that best opacified the collateralized vessel. The collateral score of each patient group was calculated by averaging the Rentrop score of every patient within the group. Statistic analysis. Values are expressed as mean ± SD, when appropriate, percentages were rounded. Continuous variables were compared using the two-sided student t-test for unpaired samples. Differences between proportions were compared using the Chi-square test. A value of 2 CCS classes (p = 0.003) (improvement group). The rest of the patients had either no change (n = 8; 32%) or improvement of 1 CCS class (n = 9; 36%) (no improvement group). The Rentrop scores of the improvement and no improvement groups are shown in Table 2. The Rentrop score improved in 3 patients (12%), remained unchanged in 22 patients (88%) and deteriorated in 0 patient. Overall, there was no significant change in Rentrop score at 6-month follow-up; mean difference 0.13 (SD = 0.34) (p = 0.08). There was also no correlation between the change in extent of collateral vessel formation (Rentrop score) and the improvement in angina status (CCS class) (correlation coefficient r = 0.09) at 6 months after PMR. Discussion This study shows that there is no significant increase in the extent of collateral vessels development at 6-month follow-up in patients who received PMR for treatment of refractory angina pectoris. There is also no correlation between collateral artery formation and improvement in angina status of these patients. Therefore, we conclude that the improvement in collateral artery formation is not a mechanism for improvement in angina status after PMR. Although advance has been made in the traditional revascularization strategies in the past decade, a significant proportion of patients are precluded from either PCI or CABG. The main reason is unsuitable coronary anatomy such as diffuse coronary artery disease, small vessel caliber, total occlusion or calcified vessels. TMR has been suggested as a novel therapeutic strategy to improve myocardial perfusion and relieve angina for this group of patients. The initial belief was that the channel created by laser energy could carry arterial blood from the left ventricular cavity and perfuse the ischemic myocardium. However subsequent studies have found that the channels are closed soon after the TMR procedure.4,5 Despite the disapproval of the principle, large-scale clinical studies have shown promising results.15,16 However, surgical TMR is an invasive with reported perioperative mortality and morbidity.15,17 PMR has subsequently emerged as a less invasive percutaneous approach. Randomized trial of PMR has shown relief of angina, increase in exercise tolerance and improvement in quality of life.2 Augmentation of angiogenesis by mechanical or inflammatory stimuli in ischemic myocardium has been suggested as a mechanism for symptom relief after PMR. Histological evidence of angiogenesis has been observed in the myocardium of two patients who had PMR at 8 and 52 weeks before, with symptomatic relief but subsequently died of non-cardiac causes.18 However, the neovessels formed are structurally immature without supporting smooth muscle coat and are limited to fibrotic scar tissue. Therefore, their ability to improve perfusion is doubtful. Collateral vessels formation involves a process known as arteriogenesis, which is defined as growth and development of preexisting arteriolar connections into mature collateral vessels. Both arteriogenesis (collateral vessel development) and angiogenesis (capillary formation) are important mechanisms of vessel development in adult tissues. There are many overlaps in the mechanism of these two processes. Since arteriogenesis results in formation of structurally and functionally mature collateral vessel, it is more likely to conduct blood to the ischemic myocardium and relieve ischemia. To our knowledge, this is the first report investigating the change in extent of collateral development in patients after PMR. So far, there is no standard for assessing collateral vessels in the coronary system. The Rentrop scoring system is introduced by Rentrop et al. in 1985 as a semi-quantitative method for collateral assessment.19 This method involves visually assessing the extent of vascular filling distal to the stenotic lesion by collateral vessels after contrast injection through the guiding catheter. Quantification of the vascular filling is by using the score system from 0 to 3 (see above). The Rentrop scoring system is the most widely used method of collateral assessment nowadays because it is simple, inexpensive and readily performed during coronary angiography. Both on-line and off-line assessment can be performed. Most importantly, it does not require extra equipment into the circulatory system and therefore pose no additional risk to the patients. Although evidence of angiogenesis after TMR and PMR was observed in some of the studies, significant increase in collateral vessel development is not seen in our study. Perhaps one of the reasons is that which is important in the initiation of collateral development (there is no increase in shear stress within the preexisting arteriole after PMR). Besides, sufficient angiogenic growth factors and cytokines are necessary for collateral vessels development. Our PMR systems use only laser and radiofrequency energy to create channels but do not deliver growth factors and it is not known whether the level of growth factors would increase to a significant extent after the procedure. Moreover, using the Rentrop angiographic scoring system, only collaterals bigger than 100 mm can be visualized in the angiogram and only visible but not recruitable collaterals are assessed. There are several limitations in this study. The study was performed with three different PMR systems. However, in vitro data supports that the two Holmium-TAG laser PMR systems and the RF PMR system create similar histopathological endomyocardial lesions with almost same dimensions20 and that both different energy sources are capable of inducing an angiogenesis response in animals.21 Another limitation is that the Rentrop scoring system is a rather crude assessment, subjected to inter-observer and intra-observer variability. Also, the collateral vessels have to be larger than 100 mm to become visible angiographically. Perhaps due to these deficits, a recent study suggests that the Rentrop scoring system does not correlate with myocardial perfusion and function.22 Our study suggests that there is no significant increase in angiographically visible collateral vessel after PMR, in patients either with or without symptom relief. Therefore, it is unlikely that increase in angiographically visible collaterals accounts for symptom relief after PMR.

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