Background
A significant number of patients currently suffering from coronary artery disease (CAD) experience severe ischemia due to multi-vessel atherosclerotic obstruction, leading to heart failure and impaired myocardial function [
1]. Prophylaxis and treatment options for this population involves drug therapy, lifestyle changes, percutaneous coronary interventions (PCI) and coronary artery bypass grafting (CABG) [
1,
2]. A large portion of these individuals suffer from refractory CAD not amenable to percutaneous or conventional surgical interventions [
1‐
3]. For this patient population the extent of CAD is widespread and traditional revascularization alone is not sufficient to reinstate adequate flow through the coronary vessels. Transmyocardial revascularization (TMR) has emerged as an additional therapeutic option for these individuals. It has been reported to provide symptomatic angina relief with improved quality of life, decreased cardiac events and decreased cardiac re-hospitalizations [
4‐
6]. More importantly, TMR has been utilized to treat patients who would normally not benefit from CABG procedures alone [
4‐
6]. This surgical procedure can be performed as a stand-alone or hybrid therapy for severe patients who are not candidates for percutaneous interventions or who cannot be completely revascularized via CABG procedures [
4,
5].
Numerous mechanisms have been proposed as the source of angina relief and improved cardiac function noticed in patients receiving TMR therapy [
7]. Denervation [
1,
6], angiogenesis [
8‐
11], and redistribution of wall stress [
12] have been attributed to the postoperative improvements noted in severe angina patients [
13]. Despite the positive reverberations of laser therapy in these individuals, it still remains unclear whether TMR increases myocardial perfusion within an infarcted myocardium. Different imaging modalities have been employed to monitor patients postoperatively and to detect changes in the functional status of the heart. Reversible ischemia and regional myocardial wall motion have been assessed using stress testing with various contrast mediums via echocardiography (ECHO) [
14,
15]. In addition, magnetic resonance imaging (MRI) and computed tomography (CT) have been utilized to determine changes in cardiac pathology and define the adequacy of perfusion established in ischemic or infarcted myocardial tissue [
16]. Nuclear medicine has emerged as a minimally invasive method of objectively quantifying myocardial perfusion and viability post TMR treatment and revascularization. Nuclear stress tests such as myocardial perfusion scintigraphy (thallium 201 and technetium-99 m sestamibi (99 m-Tc)), single photon emission computed tomography (SPECT), multigated acquisition scan (MUGA), and positron emission tomography (PET) have been more commonly employed to measure the extent of ischemic burden and recovery in patients with ischemic cardiomyopathy [
17]. Nuclear imaging has a reported higher sensitivity for measuring myocardial viability and for evaluating the clinical outcomes of revascularization in contrast to echocardiography which has a greater specificity for assessing contractility [
18]. The intent of this meta- analysis was to evaluate the effect of transmyocardial laser revascularization on myocardial perfusion by analyzing results following nuclear imaging tests. Different modalities of nuclear imaging will be assessed and compared to determine if laser therapy can provide proper revascularization and adequate perfusion in patients with depressed ventricular function suffering from ischemic heart disease.
Methods
Literature search
A comprehensive search was performed using the research engines PUBMED, ScienceDirect, and MEDLINE (via EBSCOHost and OvidSP). Keywords used to identify relevant studies were: “transmyocardial revascularization imaging, TMR and TMLR perfusion, TMLR imaging, TMR, TMR and TMLR angina, TMR and TMLR refractory angina, TMLR and TMR PET scans, nuclear imaging and TMR, TMR versus medical management, nuclear imaging TMR and CABG, myocardial perfusion, and TMR versus control”. Published articles were examined from the earliest date possible to the current date, January 2016. All numerical data was extracted directly from the study text and/or tables. If percentage values were given, only then, were calculations made in order to determine the exact number of patients in an outcome group. No assumptions were made from pictorials or graphs unless a precise p-value, mean ± SD or SEM was provided.
Inclusion/exclusion criteria
For this meta-analysis, eligible studies had to be randomized or non-randomized trials that compared TMR treatment groups with control participants (TMR versus medical management, TMR versus sham, TMR/CABG versus CABG, or TMR/CABG versus TMR). Trials that examined pre versus post treatment data were excluded from the statistical analysis. Three papers (Hughes [
19‐
21]) used porcine subjects randomized to either TMR treatment or sham thoracotomy. These were included in the meta-analysis in order to provide additional data regarding PET nuclear imaging.
Studies examining the effects of CO2 and/or Ho:YAG laser systems were included and papers using excimer laser treatments were excluded. All procedures were performed via a left thoracotomy or median sternotomy and none were executed via percutaneous methods.
Myocardial perfusion and ischemia were measured in subjects who had undergone nuclear rest and stress testing. For this analysis only PET, MUGA and SPECT scans were used to measure these parameters. MRI and ECHO imaging were excluded and may be considered in future analyses.
Definition of endpoints
The primary endpoint of this meta-analysis was to evaluate the effect of lasers on myocardial perfusion using different imaging modalities. Since various studies utilized different terms to describe perfusion effects in subjects with ischemic cardiomyopathy, myocardial perfusion was defined as the rate of blood flow or perfusate through the heart muscle. Under this condition, terms such as “peak filling rate, peak ejection rate, myocardial perfusion and perfusion defect” were included to denote perfusion through the heart. Likewise various studies used different terminology to describe ischemic areas or zones within the heart. In this meta-analysis studies using the terms hibernating, fibrotic, or reversible ischemia were classified together as reversible ischemia. Studies that did not specify whether a defect was reversible or irreversible were simply categorized as ischemic. All other continuous outcomes reported by imaging studies were recorded and analyzed. After assimilating terms there was a final list of five outcome measures included in this meta-analysis: LVEF, LVEDV, ischemia, reversible ischemia, and myocardial perfusion.
Nuclear imaging techniques were narrowed down to the three major types currently used for perfusion diagnostics: SPECT, MUGA and PET scans. Studies which quoted the use of MIBI, sestamibi, QGSPECT, or thallium 201 stress testing, were all categorized as SPECT imaging. In addition all types of intravenous contrast mediums and stressing agents were included in each imaging type.
The second purpose of this meta-analysis was to examine the clinical outcomes of laser therapy at short and long-term follow up. Survival, hospital re-admission and angina reduction were chosen as important clinical effects of laser treatment. In these studies hospital re-admissions were due to unstable angina and acute MI’s.
Numerical data was extracted directly from eligible papers and recorded into a master file that was analyzed by a statistician. For quantitative outcomes, values collected included means, sample sizes, standard deviations, SEMs, and/or p-values for both treatment and control groups. For categorical outcomes, values extracted were total participants present at baseline and total participants present in a category at a given time point, for both treatment and control groups. Continuous and binary outcomes were independently recorded by two individuals and cross checked, to ensure no discrepancies arose between collected data.
Data analysis
All analyses were conducted in Program R version 3.2.2 [
22]. Standardized mean difference [
23] was used as the effect size for all quantitative outcomes and log odds ratio was used as the effect size for all binary/categorical outcomes; in each case the escalc() function in the R package ‘metafor’ version 1.9.8 [
24] was used except in cases where only the
p-value was available, in which case the p_to_d2() function in the R package ‘MAd’ version 0.8.2 was used [
25]. In order for results to have consistent interpretation, values were transformed so that a positive difference in means (quantitative outcomes) or log-odds ratios (binary/categorical outcomes) between TMR treatment and control would always indicate that TMR performed better than the control and a negative difference would always indicate TMR performed worse than the control. For analyses that included multiple outcomes or time points within a study, a correlation of 0.5 was assumed among outcomes within a study and the combined effect across outcomes or time points was computed using the agg() function in the R package ‘MAd’. To evaluate the sensitivity of this assumption, analyses were run with correlations of 0, 0.5 and 0.99 among outcomes within a study. Each correlation was checked to determine whether there were differences between different correlation conclusions. Since no differences were noticed, results shown are for analyses using a correlation of 0.5. Random effects models with the Knapp and Hartung [
26] adjustment were fit using the rma() function in the R package ‘metafor’ version 1.9.8 [
24].
Discussion
Multiple clinical trials have reported the benefits of laser therapy on patients with severe and diffuse coronary artery disease. Significant improvements in clinical symptoms have been demonstrated by many randomized clinical trials and evidence supporting reduced angina, inotropic support, ICU admissions, hospital LOS, and arrhythmias, as well, increased QOL and exercise tolerance have been demonstrated [
28,
29,
34‐
36]. However many studies have argued that there is a lack of evidence supporting more objective measures of cardiac function such as myocardial perfusion, ischemia and LVEF [
17,
32,
37]. Therefore this meta-analysis aimed to examine current literature to determine the effect of laser therapy on these outcomes. Almeda et al. [
17] and Tasse et al. [
37] both reviewed four multicentre clinical trials [
34,
36,
38,
39] and their findings on myocardial perfusion and LVEF [
17,
37]. They reported that although Frazier et al. [
34] demonstrated a 20% increase in myocardial perfusion, Allen et al. [
38] showed no significant change when compared to medical management. Furthermore two other papers showed increases in perfusion with thallium scans [
40,
41] while three others reported no change [
34], [
42,
43]. Together, these findings contribute conflicting evidence and inconsistency towards efforts to determine whether or not TMR promotes angiogenesis and/or increased myocardial perfusion. Early results from Frazier et al. showed interesting findings from 31 patients receiving laser therapy [
44]. All patients were subject to PET, dobutamine echocardiography,
201TI- SPECT and MUGA scans at 3 and 6 months post treatment. Three-month follow-up via SPECT displayed no change in perfusion in lased and non-lased segments, however on PET scans the ratio of subendocardial to subepicardial (SEn/SEp) perfusion increased by 14% (
p < 0.001). Furthermore, at 6 months SPECT scans showed no change in perfusion while PET scans demonstrated improvements in 36% of lased segments. Similar results were reported by Cooley et al. whereby PET results indicated significant SEn/SEp perfusion changes in lased patients (
p < 0.0001) but SPECT scans did not (
p > 0.05) [
40]. Furthermore they reported an accuracy of 82% and sensitivity of 89% with PET imaging analysis.
Measuring subendocardial and subepicardial perfusion is considerably important in evaluating laser effects on perfusion. Since it has been understood that TMR channels occlude via thrombosis, it is the initial blood flow from the left ventricle to the myocardial vascular plexus that alleviates ischemia in a viable area of myocardium [
46]. In the past it has been hypothesized that camerosinuisoidal connections formed with the ventricle can develop into arteriolar channels or vessels, supporting the theory of increased subendocardial perfusion [
44]. In addition it has been thought that blood flow can redistribute from areas of adequate perfusion (epicardium) to areas of inadequate perfusion (endocardium) [
36]. The current consensus is that mechanical, thermal and oxidative stress in the surrounding myocardial tissue can elicit responses such as VEGF upregulation [
47] and angiogenesis [
45]. In either case, it may be that PET scans have the sensitivity necessary to detect these changes in perfusion while SPECT and MUGA scans do not. Results from this meta-analysis determined that there were no significant differences in myocardial perfusion between control and treatment groups at 3 or 12 months using SPECT, PET or MUGA scans. However 6-month follow up did show a significant improvement in myocardial perfusion using PET imaging. This result highlights a number of important points. (1) Imaging modalities need to have the capability of measuring subendocardial perfusion in TMR patients in order to detect increased collateral blood flow in the radial direction as opposed to the transmural (2) due to the cost of PET scans there are limited clinical trials performed on lased patients (3) the 6 month PET results from this analysis were based on three porcine models and therefore must be taken with light consideration. Despite this fact, they do coincide with other reports in human trials [
44] and porcine models [
4,
45] showcasing that in order to validate PET as a standard for follow up in TMR patients, there needs to be more data published on its efficacy to warrant the cost-benefit of using this imaging modality and lastly (5) more clinical trials are necessary to prove whether the increase in subendocardial perfusion is temporary or has a lasting effect in patients.
When CO
2 and Ho:YAG lasers were analyzed individually, no statistically significant differences were found between CO
2 and Ho:YAG lasers in any of the analyzed metrics (ischemia and myocardial perfusion) except for LVEF. The CO
2 laser system did not demonstrate an improvement in the LVEF of lased patients as compared to the MM group. This may be due to conflicting reports on the contractility and wall motion noticed in TMR patients via MRI and echocardiography [
13,
48‐
50]. More importantly, both CO
2 and Ho:YAG lasers demonstrated an improvement in myocardial perfusion, however this increase was not considered significant. This could be the result of the fact that many studies in this category included SPECT and MUGA imaging as opposed to the more sensitive PET scan, which has demonstrated superiority in measuring subendocardial perfusion. When both lasers were compared against each other to determine whether the type of laser had an effect on myocardial perfusion and ischemia, up to a 12 month follow up, no statistically significant difference was noted. Despite the difference in thermal damage [
51], thermoacoustics [
52], thermal dispersion [
53], and fibrosis [
48] described between CO
2 and Ho:YAG lasers, it has been difficult to prove superiority of one laser type over the other. Studies which report increased vascular density [
20] with the Ho:YAG laser also report increased fibrosis [
48] which may conflict with myocardial contractility. Therefore it is the balance of fibrosis and angiogenesis that is important in determining perfusion measures in lased hearts.
In an effort to answer whether TMR therapy has an effect on objective cardiac measures this meta-analysis examined short and long term survival rates and hospital re-admissions. There were no statistically significant differences between control and treatment groups in either 30-day or 12 month survival rates. However the estimated survival rate was higher for those receiving laser therapy as compared to control patients at both 30-days and 12 months. From the studies included in these subsections, 30 day mortality was attributed to unstable angina [
34], sole CABG therapy [
35], acute MI [
39], LV dysfunction, ventricular fibrillation, respiratory insufficiency, multisystem organ failure [
38] as well as higher preoperative patient risk scores from renal disease, IABP support, previous CABG, PTCA, HF, angina class and previous MI [
54]. Long term mortality was associated with low LVEF, acute MI [
34], sudden cardiac death of unknown etiology [
30], cancer, intracerebral hemorrhage [
13] as well as preoperative risk factors of age, EF, DM and dialysis [
55]. It is possible that the statistically non-significant differences in survival rates associated with laser therapy could be a result of the significantly higher proportion of individuals with unstable angina reported at baseline in our analysis. In addition, many authors also argue that patients with severe symptoms are categorized into the treatment group in nonrandomized clinical trials. Studies that report higher than average survival rates claim that it is due to their stringent study selection criteria.
Survival and hospital re-admission rates were reportedly better for TMR patients than control, however this result was not significant. This is encouraging since many patients are re-admitted due to unstable angina and our preliminary baseline characteristics demonstrated a higher proportion of unstable angina in treatment patients. Angina reduction was also analyzed at 3, 6 and 12 months for both laser types collectively. All reported data included a reduction of at least two or more angina classifications. Patients in the treatment group experienced a statistically significant reduction in angina compared to control patients at all three time points. This is consistent with published literature demonstrating the known effect of TMR on angina relief, which can persist 5 years following laser therapy [
56].
Limitations
There were many challenges in putting together a comprehensive analysis on myocardial perfusion and imaging techniques. The primary difficulty arose in being able to standardize outcome measures from all studies. Due to the variability in endpoints and terminology used by each imaging modality, certain outcomes were combined in order to create categories for analysis. This paper only included 16 studies, which specifically looked at cardiac function via 3 imaging modalities, therefore the effect of MRI and ECHO was not taken into consideration. Furthermore, only data from control versus treatment groups were included and 3 out of 16 studies used a porcine model, due to low search results from PET imaging. Some analyses were confounded by time and laser type as multiple time points or laser types were included. All of these factors could have an influence on the results of this paper. In the future, pre versus post treatment imaging data, would need to be analyzed and combined with the current data to determine the overall effect of TMR. In addition MRI and ECHO studies could be included to provide further insight since MRI has been reported to show regional myocardial function with advanced spatial resolution [
57].
Acknowledgements
This meta-analysis was supported by the members of the Khalpey Laboratory. We would like to thank Destiny Dicken and Katie Stavoe Marsh for helping with data collection as well as the Bio5 Statistics Consulting Group for providing guidance on statistical analyses. Additionally we thank, Meghna Jayaraman, Nowroz Sohrab and Priyanshi Shah from the Khalpey lab for assisting with independent data review.