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Cardiovascular Research 2001 49(3):582-587; doi:10.1016/S0008-6363(00)00246-7
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Copyright © 2001, European Society of Cardiology

Transepicardial or transendocardial injury: controversies regarding angiogenic potential and mechanism of action

Shmuel Fuchs and Ran Kornowski*

The Cardiovascular Research Institute, Medlantic Research Institute, Washington Hospital Center, 110 Irving St. NW, 4B-1 Washington, DC 20010, USA

* Corresponding author. Tel.: +1-202-877-3321; fax: +1-202-877-2715 rxk3{at}mhg.edu

Received 29 June 2000; accepted 15 September 2000

KEYWORDS Angiogenesis


   1 Introduction
Top
 1 Introduction
2 Immunohistochemistry...
 3 Physiological assessment of...
 4 Perfusion changes following...
 5 Local cardiac denervation...
 6 Combined mechanical and...
 7 Conclusions
 References
 
Over the past decade, surgical and now catheter-based approaches using various mechanical devices and energy sources aimed to enhance tissue perfusion are being explored as new adjunctive therapies in patients with refractory ischemic coronary disease [1,2]. It has been suggested that the likely mechanism associated with the initiation of angiogenesis is the induction of local inflammatory processes, and that tissue changes trigger endogenous expression of variety of angiogenic cytokines acting in concert to initiate and maintain microvessel formation (i.e. angiogenesis) [3]. The improved collateral pathways may change the local ischemic milieu in a way that may culminate in a long-standing therapeutic effect in selected patients. Since angiogenesis was assumed to be a primary mechanism associated with ‘direct’ myocardial revascularization (DMR) procedures, it has been termed ‘the mechanical approach for myocardial angiogenesis’. Nevertheless, the evidence for a therapeutically significant angiogenesis following mechanical myocardial injury is inconclusive.

In the current paper we attempt to review the myocardial response to various mechanical channeling and ablative energy sources being used in practice and/or clinical investigations. Data indicative for angiogenesis in response to direct myocardial injury or to a combination of energy sources with pro-angiogenic pharmacotherapy (i.e. ‘hybrid’ approaches) are also provided and critically assessed.

1.1 Myocardial tissue responses to mechanical injury
1.1.1 Laser energy
Laser energy has specific tissue interactions that are fundamental to our ability to achieve a desirable tissue response and avoid unwarranted excessive myocardial damage. For example, unlike CO2 laser, which provides more precise ‘ablative’ characteristics with some collateral damage [4], the holmium (Ho):YAG laser (currently used in most catheter-based and several surgical DMR protocols) has profound photoacoustic effects and hence a marked thermal and photochemical impact on myocardial tissue [5,6]. Minimizing the energy being directly delivered to the myocardium may predominantly trigger natural tissue processes that may cause local myocardial reparative response rather than irreversible ablative damage [7–9].

The myocardial tissue response to a laser energy source characterized, acutely, by sharply demarcated tracks appeared as open channels surrounded by a ‘white’ rim of necrotic, heat coagulated tissue, then by a sharp ‘red’ line representing an area of ‘contracture-band’ necrosis [10]. Subsequent tissue changes include profound local inflammatory reaction predominated by cellular infiltrate of polymorphonuclear cells and monocyte macrophages, along with prominent dilated blood vessels. The affected collateral zone near the ablated tracks shows diffuse infiltration with inflammatory cells, interstitial edema, and prominent vasodilatation and extravasated red blood cells.

During the following 2–4 weeks there is regression in the size of the inflammatory infiltrate accompanied by parallel appearance of granulation tissue intersected by abundance of capillaries. At 3 weeks, the center of the channel is completely obliterated by collagen deposition. Increased Factor VIII staining, an endothelial cell specific marker, occur at 4 weeks following experimental laser DMR adjacent to the channel remnant throughout a collateral zone of normal myocardium.

If the fate of laser channels is scar formation, is it identical to scar formation following myocardial infarction? This issue was addressed in a porcine model of myocardial infarction [11]. At 4 weeks capillary and arteriolar density were significantly higher in scared channel remnants compared to myocardial infarction associated with scar. Thus, histomorphologically, laser DMR is associated with angiogenesis in granulation/scar tissue around and within the channel remnant and extends along interstitial spaces into adjacent myocardium [5]. Additional studies using laser DMR have shown increased localized bromodeoxyuridine incorporation and proliferating cell nuclear antigen positive staining in both endothelial and smooth muscle cells, findings indicative of vascular proliferation [12]. It appears that the original laser channels do not remain patent and do not form deep subendocardial perfusion-competent tracks. It should be noted, however, that the tissue response to laser energy may vary according to the type of lasers (i.e. Ho:YAG, CO2, XeCl excimer), the procedural approach (transepicardial vs. transendocardial), the energy parameters being used and the number and density of the channels being applied to the myocardium.

1.1.2 Radiofrequency energy
Radiofrequency (RF) energy has been used to elicit a myocardial response with minimal tissue penetration [13,14]. Within minutes of applying RF energy, myocardial craters are formed due to heat necrosis and are filled immediately with platelets and leukocytes. Red blood cells are extravasated and trapped within a fibrinous network, surrounded by extensive intramyocardial hemorrhage and inflammatory response. The healed endocardial lesions formed at the original injury site are highly vascularized [15]. These data are supportive of the concept that shallow endomyocardial craters without deep tissue penetration may create highly vascular areas within and beyond the injury site.

1.1.3 Mechanical myocardial channeling
Mechanical myocardial channeling using a tissue-cutting device combined with vacuum extraction apparatus was proposed as a method to induce a tissue response characterized by angiogenesis and arteriogensis [16]. Acutely, a biopsy like tract is formed, characterized by intra and perichannel hemorrhage. Histopathological assessment at 2 months following the intervention in normal pig myocardium revealed obliterated channels filled with proteoglycanous matrix that contained various sized blood vessels, ranging between <25 µm and up to 400 µm. This unique tissue response, however, was not evaluated in a chronic ischemic model, precluding a comparison to other DMR approaches using either lasers or RF energy.

1.1.4 Needle insertion
Needle insertion has been proposed by several investigators to induce angiogenic responses [17,18]. Similarly to the previously described DMR modalities, the main histological findings, at 1 week were, fibrous tracts surrounding by damaged myocardium infiltrated by lymphocytes and macrophages. At 4 weeks, the inflammatory infiltrate was significantly reduced, along with reduction in capillary density and maturation of preexisting blood vessels [18].

The histological data derived from the animal DMR studies altogether are suggestive of a non-specific myocardial injury response associated with localized acute and subacute inflammation and followed by tissue regeneration characterized by increased vascularity. However, these morphological characteristics do not confirm that the observed lesions lead to nutrient flow to the ischemic myocardium.


   2 Immunohistochemistry assessment
Top
 1 Introduction
 2 Immunohistochemistry...
3 Physiological assessment of...
 4 Perfusion changes following...
 5 Local cardiac denervation...
 6 Combined mechanical and...
 7 Conclusions
 References
 
The consistent observation of increased vascularity following DMR raised the important question of the possible underlying mechanisms. Immunohistochemical staining of catheter-based DMR treated pig hearts in our laboratory showed a threefold increase in the number of cells stained positive for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and monocyte chemoattractant protein 1 (MCP-1) in laser-treated regions versus ischemic controls [19]. The staining pattern of VEGF and bFGF was regional, most intense along the channel borders, diffusing into adjacent zones and was associated with increased capillary density. In a similar chronic ischemic pig model, analysis of myocardial tissue at 6 weeks following surgical CO2 laser injury revealed a twofold increase in the VEGF messenger RNA in the ischemic zone of the laser-treated group compared with the controls [20]. Additionally, there was a threefold increase in the number of new blood vessels in the ischemic zone after DMR compared to control animals. These findings support a mechanistic paradigm in which laser myocardial injury stimulates inflammation and an angiogenic response that may subsequently cause collateral vessel sprouting within and extending from the injury site.

In another study, 4 weeks following RF ablation, immunoreactivities for bFGF and VEGF were similar to that observed after laser DMR. Intense immunoreactive staining and neovascular structures were noted within the myocardium. Similar findings were reported in a rat model of acute myocardial infarction using a 25-gauge needle to create transmural channels [17]. In this study, transforming growth factor-β (TGFβ) and bFGF but not VEGF were expressed at 1 week with a subsequent decline in the area of positive immunoreactive cells. In the pig ameroid model of chronic myocardial ischemia, VEGF expression, assessed as the myocardial area stained positive for the angiogenic factor, was similar following needle channeling and laser-DMR. It was significantly higher, however, in a group that underwent needle channeling of higher density [21].

These observations are in accord with the histopathological changes described in the previous section. Although no comparative study has been performed to assess possible differences in tissue reaction to the various DMR sources, it is conceivable that the common dominator of all these modalities is their ability to induce a localized and controlled injury. This injury initiates a self-limited inflammatory response, which at least in part, is responsible for the induction of angiogenesis. It is important to recognize that upregulation of angiogenic cytokines along with increased vascularity was noticed a few weeks following the injury, at a time where the inflammatory reaction is already minimal or absent. However, systematic assessment at later time points is currently unavailable.


   3 Physiological assessment of collateral perfusion
Top
 1 Introduction
 2 Immunohistochemistry...
 3 Physiological assessment of...
4 Perfusion changes following...
 5 Local cardiac denervation...
 6 Combined mechanical and...
 7 Conclusions
 References
 
Although the association between DMR and subsequent upregulation of angiogenic cytokines and increased vascularity has been established, there is limited information regarding the ultimate endpoint of any angiogenic process, which is a change in tissue perfusion. The impact of surgical DMR on myocardial blood flow (MBF) detected by microspheres technique was studies in a chronic ischemic canine model [12]. Transepicardial Ho:YAG laser channeling was applied at the time of induction of myocardial ischemia. Perfusion measurements immediately following the procedure showed no change compared to baseline. At 2 months, a ~40% increase in MBF was noted during adenosine stress (73±8 versus 53±16%, P<0.05) but not at rest in laser DMR-treated regions. Also, vascular proliferation was four times greater in laser treated regions compared to controls. It is important to recognize that in the above model DMR was performed before the induction of chronic ischemia. Thus, the observed beneficial effect of laser DMR on myocardial perfusion may not reflect the impact of similar laser application in already chronic ischemic tissue, a condition of greater clinical relevance.

In a pig model of chronic ischemic myocardium, transepicardial CO2 laser was applied and compared to a sham operation. Myocardial perfusion assessed by positron emission tomography (PET) showed no difference in 13N-ammonia uptake at 2 weeks following the procedure between laser-treated (n = 6) and sham-operated (n = 4) animals [22]. At 6 months, significant improvement in tissue perfusion compared to baseline with matched uptake of 13N-ammonia and 18F-fluorodeoxyglucosw uptake was noted in mid and basal lased segments but not in apical region of the ischemic territory, while no changes were observed in controls. Unfortunately, no further studies are currently available to confirm the encouraging results of this important but relatively small study. In addition, there is a lack of data regarding the impact of catheter-based transendocardial approach on tissue perfusion. Similarly, no physiological assessment of collateral flow following other ablative or mechanical sources is available at the time of this report.


   4 Perfusion changes following clinical direct myocardial revascularization
Top
 1 Introduction
 2 Immunohistochemistry...
 3 Physiological assessment of...
 4 Perfusion changes following...
5 Local cardiac denervation...
 6 Combined mechanical and...
 7 Conclusions
 References
 
Despite the preliminary promising clinical results of laser DMR, there seems to be a disturbing dichotomy between the favorable symptomatic response and objective measures of myocardial perfusion following the DMR procedure. This issue raises significant doubts whether any form of myocardial injury can induce a physiologically relevant angiogenic response as the main mechanism to explain the beneficial clinical results observed in some patients. Moreover, it may be that alternative mechanistic explanations are yet to be identified. Currently all available clinical data are derived from laser DMR trials.

Initial laser DMR experiences as an adjunct to bypass surgery showed improved regional wall motion and improved myocardial perfusion in DMR treated regions [4,23]. However, as the feasibility of distinguishing between the effect of DMR and the bypass surgery is marginal at most and the ability to assess the relative contribution of each of these two components is questionable.

In another small study [24,25], surgical CO2 laser DMR as ‘sole therapy’ for refractory angina was associated with improved angina class and increased exercise capacity. Transmural perfusion assessed by both 201Tl SPECT and PET were similar between lased and nonlased segments. However at 12 months, the sub-endocardial/sub-epicardial perfusion ratio increased by 20±9% in the lased segments compared to decrease of 5±2% in the nonlased segments. Interestingly, magnetic resonance imaging (MRI) perfusion assessment of collateral arterial flow has been also suggested as an alternative modality that is more sensitive than ‘conventional’ nuclear imaging. Using this technique, a preliminary study has indicated a significant improvement in myocardial perfusion and function at 1 and 6 months following catheter-based DMR in Ho:YAG laser-treated zones despite lack of apparent change in nuclear imaging studies [26]. The results from these two small studies underscore the potential of more advanced and sensitive methods to assess possible angiogenesis-related perfusion changes that may be overlooked by ‘conventional’ techniques.

Results of a multicenter registry with CO2 laser as ‘sole therapy’ for end-stage coronary artery disease in 200 patients showed a significant decrease in the number of segments with reversible perfusion defects without a change or increase in the number of segments with fixed defects in DMR-treated regions [27]. In a substudy, using stress echocardiography in 12 patients treated with surgical CO2 laser DMR, a significant improvement in regional contractility in DMR-treated segments was found, which may reflect enhanced perfusion in laser-treated regions [28]. However, no control patients were included in this registry or its substudy and the findings could have been due to the natural course of collateral development.

In phase I studies of catheter-based laser DMR procedures in patients not amenable to conventional revascularization techniques symptomatic benefit was found despite lack of improvement of reversible perfusion defects in nuclear imaging studies [29–31]. Recently, three randomized studies comparing surgical laser DMR to medical therapy alone showed symptomatic benefit and improved exercise tolerance but no significant changes between and within groups in myocardial perfusion assessed by nuclear scanning [32–34]. A fourth randomized study showed angina relief in 72% of the surgical laser-treated patients versus 13% in the control arm [35]. Contrary to the other three clinical trials, this study showed improvement in myocardial perfusion characterized by a 20% reduction in the number of segments with reversible perfusion defects at 12 months versus 27% increase in the medical group compared to baseline (P = 0.002). However, these nuclear scanning did not show any difference in the number of fixed defects per patient between the groups.

Currently, all published DMR clinical trials are either registries or randomized ‘open-label’ studies. One of the primary endpoint in these studies is patients’ reports of symptom relief. Using this data it may be impossible to rule out the possibility that such improvement may arise from a placebo effect. A multicenter US DIRECT study, due to be reported the fall of 2000, should evaluate the role of placebo effect in symptomatic improvement of DMR patients. Preliminary results from this trial showed no benefit from laser OMR compared to placebo alone when patients were kept "blinded" to treatment.

The dichotomy between consistent symptomatic relief and lack of improvement in perfusion may be explained by (1) a true lack of DMR effect on myocardial perfusion as assessed by objective measures and hence, an alternative underlying mechanism such as laser-induced denervation, (2) insufficient sensitivity of conventional nuclear imaging methods to assess subtle, albeit clinically relevant, changes in myocardial perfusion (e.g. subendocardial vs. subepicardial) and (3) a powerful placebo effect. Whether subtle changes in myocardial perfusion detected only by more sophisticated methods such as MRI perfusion or PET will correlate with clinical improvement should be further evaluated in a larger series of patients.


   5 Local cardiac denervation mechanism
Top
 1 Introduction
 2 Immunohistochemistry...
 3 Physiological assessment of...
 4 Perfusion changes following...
 5 Local cardiac denervation...
6 Combined mechanical and...
 7 Conclusions
 References
 
The contrast between clinical improvement and lack of changes in myocardial perfusion raises the possibility that other mechanisms may be involved in laser DMR-induced angina relief. Furthermore, if the time dependent effect of laser DMR, observed in animal studies, on the growth of collateral applies to the human response, the rapid reduction of angina following DMR cannot be related to early increased organ perfusion. Therefore, localized cardiac denervation may contribute to the rapidly observed symptomatic response. Compelling physiologic and biochemical evidence of denervation has been provided by Kwong and co-workers [36,37]. Cardiac afferent nerve function was assessed in dogs following Ho:YAG laser transmural channeling by the epicardial application of bradykinin and was found blunted at 2 weeks in treated regions versus controls. In addition, immunoblot analysis of tissue samples taken from laser-treated regions demonstrated a substantial reduction in tyrosine hydroxylase, an indirect measure of postganglionic sympathetic nerve density [36]. However, using the same animal model, only partial denervation was observed following endocardial non-transmural laser channeling [37]. Using direct in situ neuronal recording, Hirsch et al. observed no acute affect of surgical Ho:YAG laser DMR on afferent or efferent axonal function [38].

PET imaging of resting and stress myocardial perfusion with [13N]-ammonia and of sympathetic innervation using [11C]-hydroxyephedrine (HED) was recently used in eight patients before, and 2 months after, surgical DMR [39]. There were no changes in the extent of myocardial perfusion defects while myocardial HED uptake decrease by an average of 27% compared to baseline. These data suggest that an improvement in angina in surgical DMR-treated patients may be at least in part due to sympathetic denervation and not due to improved myocardial perfusion.


   6 Combined mechanical and angiogenic therapy
Top
 1 Introduction
 2 Immunohistochemistry...
 3 Physiological assessment of...
 4 Perfusion changes following...
 5 Local cardiac denervation...
 6 Combined mechanical and...
7 Conclusions
 References
 
Combining intramyocardial injection of transgenes encoding for angiogenic factors in the setting of DMR has been tested with the hypothesis that this strategy could enhance the revascularization achieved by either DMR or local angiogenic drug delivery alone. Using this strategy in a pig model of chronic ischemia, it was found that transfection efficiency was improved and wall motion abnormalities were completely reversed within 6 weeks of DMR combined with the direct injection of an expression plasmid encoding VEGF [40]. In a chronic ischemia model in dogs, Yamamoto et al., observed an increase in vascularity including twofold increase in density of vessels larger than 50 µm in animals treated with surgical laser combined with bFGF injected into the channel [41]. This was accompanied by twofold increase in blood flow to the ischemic territory.

Another ‘hybrid’ approach to enhance the expression and uptake of angiogenic cytokines has been the local use of continuous-wave Doppler ultrasound energy source and contrast agents to enhance the myocardial uptake of intravenously injected VEGF into the myocardium. An eightfold increase in VEGF uptake was found in the heart treated by ultrasound alone and a thirteenfold increase with the addition of an ultrasonic contrast agent [42]. Finally, a recent interesting experimental study has demonstrated a novel method whereby VEGF production and angiogenic response could be stimulated using low intensity (subcontractile threshold) electrical stimulation of skeletal muscles [43]. This method was associated with VEGF production and increased capillary density in a rat model of hindlimb ischemia. It remains to be determined whether such an approach could be applied to the myocardium and whether it would result in a biologically relevant angiogenic response.


   7 Conclusions
Top
 1 Introduction
 2 Immunohistochemistry...
 3 Physiological assessment of...
 4 Perfusion changes following...
 5 Local cardiac denervation...
 6 Combined mechanical and...
 7 Conclusions
References
 
The use of localized, controlled mechanical injury to improve ischemic symptoms may represent an alternative approach to the treatment of cardiovascular disease. Most of current available data derives from surgical (transepicardial) and catheter-based (transendocardial) laser DMR studies. The effect of laser DMR on myocardial tissue, expression of angiogenic cytokines, and collateral function has been studied in various experimental models. In addition, growing clinical experiences derived from DMR procedures indicate symptomatic benefit despite inconsistent or lack of improvement in myocardial perfusion.

Despite the growing experience, several fundamental questions remain to be answered. If angiogenesis is the main mechanism to explain the improved angina symptoms in patients, how can the paucity of data regarding improved myocardial perfusion be explained? What is the appropriate method to assess subtle regional changes in collateral flow? Using conventional nuclear imaging techniques, the majority of clinical trials showed no improvement in myocardial perfusion, while only few animal studies have addressed this most relevant endpoint. Nonetheless, it is possible that the effect of DMR on collateral vessel function may be small in magnitude, detectable only by sophisticated and sensitive methods. Such improvement may be, however, sufficient to reset anginal pain thresholds and cause sustained symptomatic relief in patients. Alternatively, placebo effect rather than angiogenesis, may be the logical explanation for patients response.

A second important question is whether additional mechanisms, such as denervation, may solely or partially contribute to the relatively impressive clinical effect. It is frequently stated that the legitimacy of using mechanical approaches for ‘direct’ myocardial revascularization would wane if denervation would turn out to be the dominant mechanism of benefit. Denervation would be of main concern if associated with increased incidence of myocardial infarction, silent ischemia episodes, and more importantly, sudden death; however, according to currently available data, this does not seem to be the case.

From a mechanistic perspective, it is unknown whether the use of various DMR methods will have different tissue responses that would impact on symptomatic response and tissue perfusion. Preliminary experimental studies are underway to test various alternative energy sources for laser DMR, such as RF ablation. Combining intramyocardial injection of proangiogenic pharmacotherapy in the setting of DMR is another attractive approach that needs to be tested and validated but potentially could further enhance the effect achieved by mechanical injury alone. Altogether, the ‘direct’ myocardial revascularization approach, if proven to be effective in appropriately designed clinical trials, may constitute an exciting new therapeutic strategy for patients with wide variety of refractory coronary ischemic syndromes. Achieving this goal and reducing potential side effects, however, will necessitate further investigational efforts to address several, as yet unanswered, questions.

Time for primary review 20 days.


   References
Top
 1 Introduction
 2 Immunohistochemistry...
 3 Physiological assessment of...
 4 Perfusion changes following...
 5 Local cardiac denervation...
 6 Combined mechanical and...
 7 Conclusions
 References
 

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