Current Issues and Interrogations in Angiosome Wound Targeted Revascularization for Chronic Limb Threatening Ischemia: A Review

Despite a lack of solid evidence in applying the angiosome concept (AC) in current chronic limb threatening ischemia (CLTI) treatment, several encouraging results for improved wound healing and less for limb preservation were reported in various consistency studies. Direct revascularization (DR) following the foot angiosomes distribution (whenever feasible) may afford better clinical results compared to angiosome indifferent, or indirect revascularization (IR), however without clear benefit on survival and for major adverse limb events (MALE). Inside this interrogation, the notable influence of the remnant collaterals, the foot arches, the wound characteristics, and the type of revascularization (bypass versus endovascular) still remain ardent topics. Current evidence suggests that applying DR in daily vascular practice requires practitioners to be committed to every individual hemodynamic variable in a thorough macroand micro-vascular evaluation of the ischemic foot. It becomes clearer nowadays that not all CLTI foot ulcers hold same ischemic burden and seemingly need specific DR. In the same setting, a novel wound targeted revascularization (WTR) design was proposed assembling wider circulatory targets than genuine DR notion, as used by some authors. Beyond specific angiosomal artery reperfusion, WTR associates the available arches, the largeand medium-sized collaterals, and the arterial-arterial communicants, in an intentional “source artery” and “collateral” topographic foot revascularization. However, up to date, the notion of angiosome wound-guided revascularization (DR and WTR) detains only a reserved level of confirmation. As for DR, the WTR equally needs higher levels of evidence allowed by standardized definition, uniform indications, and pertinent results from multicenter larger prospective analysis, before large application. How to cite this paper: Alexandrescu, V.A., Sinatra, T. and Maufroy, C. (2019) Current Issues and Interrogations in Angiosome Wound Targeted Revascularization for Chronic Limb Threatening Ischemia: A Review. World Journal of Cardiovascular Diseases, 9, 168-192. https://doi.org/10.4236/wjcd.2019.93016 Received: January 3, 2019 Accepted: March 12, 2019 Published: March 15, 2019 Copyright © 2019 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/

The present review mainly focuses on current clinical issues that most vascular interventionist may encounter in his or her daily practice, since deliberately applying "angiosome-oriented" (DR), or topographically "wound-oriented" (WTR) revascularization for CLTI ulcer healing and limb salvage.

Methods of Selection
Data storage.A PubMed-Medline research focusing the AC applications in vascular surgery over the last two decades publications (1998-2018) was performed owning English language restriction.The designations "angiosome(s)"-"angiosomal" were primary analyzed, and secondary investigation was further performed World Journal of Cardiovascular Diseases via "related articles" focusing "below the knee revascularization", "ulcer healing", "diabetic foot", and "limb-salvage terms".Papers without clear clinical protocol (inclusion-exclusion criteria, revascularization techniques, and follow-up) were excluded from this study.No restrictions were expressed concerning the type of study and the type of applied statistical analysis.The majority of remarks pointed on clinical directed applications, based on original observational data [6]- [14] [16]- [30].Beyond standard clinical observations provided by the cited authors, no complementary statistical data reworking was attached at this inquiry phase.Selection process.From the initial 1655 detected as potential fitting studies, after retrieval of unconnected topics, unfitting standardized research protocols, miscellaneous reviews, non-clinical outcomes, and inappreciable data, or conclusions, forty-three group analysis (forty-one paper cohorts and two conference presentations) were selected and evaluated.

Contemporary Landmarks
Following meticulous macro-and micro-vascular preoperative diagnostic approaches, the CLTI treatment essentially involves endovascular technology (EVT) and open surgical interventions.The superiority/inferiority of these pro-World Journal of Cardiovascular Diseases cedures in ensuring adequate limb salvage was, and still is currently debated in contemporary literature [11] [12] [24] [27].The detailed apprehension of these controversies is however beyond the purpose of this paper.Nevertheless, for both strategies, chronic total occlusions (CTO) and heavy, continuous calcifications of tibial and pedal arteries, still remain huge obstacles for all revascularization techniques, including WTR options [5] [11] [12] [25] [27].These disabilities mainly concern the technical success, associated patency, and limb salvage rates [9] [24].Contemporary limb reperfusion technology is yet subject to tremendous changes owning, or not wound topographic orientation [11] [12] [13] [14].As recently stated by Scott et al., "nothing accentuates the benefits and limitations of an endovascular or surgical procedure more than using them frequently" in CLI practice [28].Most likely, the most suitable WTR technique is the one that complements most individual anatomical and pathophysiological variables for each CLTI patient [17] [29] [30] [31] This, and any other particular technique (with, or without AC orientation) should be chosen in a flexible and balanced team deliberation, considering each method (bypass versus endovascular) as complementary and not as concurrent parts [3]
In a brief overview, the "drilling", the "subintimal", or the "parallel wire" techniques performed via ante-or retrograde accesses, can be associated to the pedal-plantar "loop", to the femoral-femoral, and the trans-tibial collaterals angioplasties with encouraging results reported in the last years [11] [12] [34] [35].

Specific Advantages of Each Method in WTR
As mentioned before, EVT is essentially reputed for minimal interventional aggression, wide accessibility, and high reproducibility since targeting one or multiple below-the-knee CTO vessels [10] [11] [26] [27].These profits seem to match in particular with WTR, by allowing specific tibial and pedal arterial trunks to be selected for reperfusion [6] [25] [26] [27].
It becomes obvious that surgical and endovascular techniques are more likely to afford complementary than competitive benefit to CLTI patients, since thoroughly selected [11] [12] [25] [26] [27] [40].Without opponent means both techniques probably need to be further pondered in interactive multidisciplinary approaches and applied in an open-minded perspective [17] [30] [41].
During the last two decades, AC with DR, and more recently WTR have been increasingly associated with targeted inferior limb revascularizations (bypass or EVT) in CLTI treatment and limb salvage interventions [6] [7] [8] [9] [10] [16] [25] [26] [27].Consequently, pressing questions in the field today are whether WTR promotes a better outcome in CLTI revascularization and whether the clinical outcomes-since WTR is being applied for tissue healing-may be better for limb preservation and for higher survival in these patients [26] [27] [30].

The Relevance of WTR in Current Vascular Practice
Current evidence suggests that applying the AC and WTR in daily clinical practice requires practitioners to be committed to ongoing learning curve [16].True clinical application of the AC primarily implies thorough evaluation of the benefit allowed by targeted macroand microvasculature reperfusion [17] [27].Effective flow mapping toward the wound zone (Figure 1) requires open-minded judgment in adapting the best techniques for best achievable direct, or collateral-enhanced distal foot flow [25] [26] [27].
Every ischemic presentation is unique with regards to its anatomical pattern, specific local pathophysiological changes, and individual distinct risk factors for tissue healing [17] [54].All concurrent pathologies must be recognized and managed in each CLTI subject, as unique combinations [16]
Younger patients or those who benefit from unaffected arterial-arterial distal limb connections may express little differences in the healing process by specifically using DR instead of indirect revascularization (IR) [16] [19] [49].These findings have previously been reported in angiosome-oriented bypass revascularization at mid-and long-term follow-up periods [3] [8] [10] [49].Concerning EVT, Spillerova et al. observed in a 161 cases retrospective series that the feasibility of targeted DR was 69% for one, 86% for two, 85% for three, and only 25% for four affected angiosomes [27].

New Approaches for WTR
The complex cascade of tissue regeneration requires precise circumstances to occur [62].
New revascularization strategies provide modern practitioners with more efficient tools for enhancing these stages of tissue reconstruction [17].As emphasized by Elsayed et al. [63] and Chin et al. [46] key findings on hemodynamics and molecular mechanisms involved in the development of CLTI have been reported.This novel conceptualization of the ischemic threat clearly underlines the World Journal of Cardiovascular Diseases increasing role of clinical teams in preventing and applying the global limb salvage process [11] [12] [41] [63].The modern knowledge of CLTI now belongs to a much larger and "integrated" multidisciplinary medicine [41] [63] [64].based on more accurate arterial flow mapping [1] [2] [3] [25] and targeted tissue reperfusion for healing [29] [51] [55]- [60].According to this redesigned strategy, beyond current bypass and trans-catheter revascularizations [11] [12] [33] novel "hybrid" surgical and endovascular procedures [11] [12] [63] afford complementary applications for increasing limb preservation.Parallel "extreme" limb revascularization techniques such as the venous arterialization [47] [65] [66] and the cell stem treatment [11] [12] [46] were included into the rising "multidisciplinary team" practice [11] [14] [17] [41].Some of these innovative deep-veins arterialization methods propose WTR via still available "venosomes" of the threatened limb [66] although untouched by the ischemic and devastating atherosclerotic aggression [15] [66].Inasmuch current evidence upon their real benefit in limb salvage and AC application still lacks, these audacious strategies seem but to upgrade previous paradigms of CLTI surgical and endovascular treatment [12] [14] [47] [65].Over the last ten years and despite inherent controversies, an increasing number of dedicated studies have emerged (Table 1) and focus on this subject [26].While several analogous retrospective series appear to favor the DR hypothesis in endovascular analysis [6]  Macrocirculatory findings.In an initial single institutional study of 56 distal bypasses, Attinger and colleagues [69] noted that only 9.1% of healing treatments failed in wounds that were subjected to "direct" angiosome-related surgical revascularizations.These results contrast with the estimated 38.1% of treatments that lacked clinical success in wounds treated with "indirect" or non-angiosome-oriented bypasses [69].Neville and colleagues [8] in a similar retrospective surgical series of 48 patients, found that the angiosome-related surgery (DR) group exhibited a 91% healing rate and 9% amputation rate compared to the 62% healing rate and 38% amputation rate in the non-angiosome (IR) structured subgroup.Moreover, in a 64 patients prospective study, Kabra et al. [57] documented a significant difference between the tissue healing success of World Journal of Cardiovascular Diseases Abbreviations: Direct Revascularization (DR), Indirect Revascularization (IR), Toe Pressure (TP), Healing (H), Limb salvage (LS).

Current Literature Review Concerning DR/WTR Strategies
DR and IR (p = 0.021).However, the difference in the limb salvage between the groups was not significant (84% versus 75%) [57] Iida et al. [6] examined 203 consecutive ischemic limbs with tissue loss undergoing endovascular reconstructions and observed an 86% limb preservation rate in the angiosome-related subgroup, which was significantly higher than the 69% in the non-specific subgroup [6].Consistent with these reports, in a similar 76 cases study of ischemic ulcers treated by both bypass and endovascular therapies, Varela et al. [10] documented significantly better results for wound healing (92% versus 73%) and limb salvage (93% versus 72%) in the angiosome-guided cohorts of patients [10] In an extended retrospective study of 744 consecutive patients, Spillerova et al. [49] observed that wound healing and limb salvage rates were both significantly improved after angiosome-targeted revascularization.In this setting, DR bypass surgery achieved significantly higher healing results than equivalent DR angioplasty [49].
In parallel studies conducted by Zheng [18] and Osawa [19] the authors similarly indicate that DR/WTR in intentional angiosome-oriented revascularization are both, technically achievable and offer superior clinical results than IR [18] [19].Both authors also emphasize the importance of the collateral network surrounding the CLI wound [18] [19] which is consistent with reports by Varela et World Journal of Cardiovascular Diseases al. [10] Attinger et al. [69] Acin et al. [55] and by our team's previous observation [7] [59] Practical information about DR in surgical applications has been equally reported by Kret et al. in a study of 106 CLTI cases [70].The authors concluded that DR may afford better clinical results than other methods, but this strategy is only applicable in 50% of common CLTI cases [70].Similarly, in a recent retrospective analysis of 161 patients by Spillerova et al., the technical success of DR seemed to depend on the number of involved and treated angiosomes [27].Technical feasibility varied from 69% to 86% for one, up to three targeted angiosomes revascularization [27].
In contrast with the abovementioned data, another contemporary endovascular analysis conducted by Blanes et al. [67] revealed that, for 32 retrospectively reviewed Rutherford category 5 also category 6 patients (owning extensive tissue necrosis), there was no significant difference between the angiosome-targeted (direct) and non-targeted (indirect) percutaneous revascularizations.Analogous publications, either by analyzing the impact of DR in the paramalleolar bypass by Deguchi et al. [71] or by following the observations of Ricco and colleagues concerning DR compared to IR peroneal bypasses [72] the patency of foot arches and both peroneal terminal branches were more important predictive factors for healing than the angiosomal orientation itself [72].Rachid and colleagues [20] reached parallel conclusions about the value of complete and permeable foot arches in angiosome-oriented infrapopliteal bypass [20].
All this complementary clinical expertise brings valuable issues in better defining and understanding real significance of DR, DR-collateral assisted, and WTR in current surgical and endovascular CLTI treatment [17] [18] [19] [26] (Table 1).It also appears more eloquent that all of these outwardly "opposing" findings instead contribute to a better understanding of collateral blood supply inside and between adjacent angiosomes touched by CLTI [17]  Microcirculatory observations.Parallel microcirculatory observations were reported by Rother et al. [22] Kawarada et al. [21] and Kagaya et al. [73] using tissue spectrometry, laser Doppler flowmetry, and tissue O 2 saturation foot mapping, respectively.Although without comparable and homogeneous design between series (inclusion-exclusion criteria), these studies however revealed few changes in angiosome-oriented (DR versus IR) tissue capillaries during the early stages of revascularization [21] [22] [73].Ostensibly, these findings about the World Journal of Cardiovascular Diseases progression of capillary reperfusion after DR/WTR appear to contradict similar research by Iida et al. [6] by Shiraki et al. [51] by Zheng et al. [74] by Kawanishi et al. [75] and by Okamoto et al. [76] using parallel methods of analysis.However, beyond undeniable worth of all mentioned works, these studies all focused on the same microcirculatory skin changes post-CLTI retrieval, but in changeable collateral environments and patients, and at different sequences in reperfusion's follow-up [17] [18] [19] [26] [77].Perhaps one of the most valuable findings of abovementioned data is that they highlight timely skin flow redistribution stages following arterial reconstruction [17] [26].They express parallel "dormant collaterals" reopening after revascularization, inflammation retrieval, and rising angio-and arteriogenetic processes around the wound at sequential time intervals [29] [30] [31] [48].Rather than being contradictory, these findings could be globally perceived as complementary pieces of a larger puzzle that merge well-timed microcirculatory events with well-timed macrocirculatory aspects of post-ischemic reperfusion [17] [26] [31].The concrete effects of CLTI revascularization afford better analysis in a sequential and time-dependent approach method.It also becomes more and more eloquent the notable role that a multidisciplinary diabetic foot team plays in the treatment and parallel follow-up after revascularization [11] [14] [41] [64] for both, DR/WTR, or IR in current practice [26].
Modern meta-analyses concerning DR/WTR.Several thorough, recent meta-analyses on this subject revealed applicable information about potential WTR usefulness and the benefit of the AC in CLTI treatment [24] [29] [78] [79].
In a systematic literature review of 1290 CLTI cases, Biancari et al. [78] found that DR may enhance superior wound healing rates, if this strategy can be technically applied [78].In the same analysis, DR limb salvage rates were, however, comparable to IR but with no statistical weight [78].Two non-randomized retrospective studies conducted by Bosanquet et al. [24] and Huang et al. [29] revealed similar end-point examinations.These authors analyzed 1868 and 779 individually published cases, respectively, and their conclusions similarly suggested that DR may improve tissue regeneration and limb preservation better than IR (or random) distal foot reperfusion [24] [29].Nevertheless, cumulative DR has not been shown to be superior to IR in terms of mortality, major adverse limb events (MALE), and reintervention rates [24].
It has also been shown that, in addition to the revascularization strategy, diabetic CLTI ulcer healing involves a multifaceted process.As described by Azuma et al. [68] the associated systemic factors, wound features, infections, wound management strategy, and revascularization technique, all additionally affect the wound healing process [68].
In a recent multicenter study of 871 limbs, Shiraki et al. [51] documented that the non-ambulatory status, decreased serum albumin, Rutherford category 6 presentations [32] local wound infection, lack of run-off foot vessels, and IR or non-application of the AC, were independent significant predictors for delayed wound healing [51].
These recent observations corroborating those of Serra et al. [80] Iida et al. [81]) Kret et al. [70] and Aydin et al. [82] indicate that, without coupled control of all concurrent risk factors for correct wound healing, and uniform diagnostic, treatment, or follow-up methods for WTR, all challenging claims "in favor" or "against" the use of the AC should be considered with caution [24] [26] [70] [80].
A new analysis and review made by Das et al. [83] in a 422 consecutive series of CLI patients, all treated by AC first-option strategy shows that beyond correct topographic foot flow reconstruction, the depths of ulcers, their duration, the albumin and the C-reactive protein levels, also the presence of local infection and gangrene represent independent factors to be carefully pondered in statistic evaluation [83].Similar findings were reported by Lo et al. [84] in another 809 patients analysis a few months ago.The renal insufficiency, Rutherford 6, TASC "C" and "D" lesions, and the liability to perform IR (inadequacy for DR) were significant factors towards tissue decay and limb loss [84].
A remarkable 3932 patient review and meta-analysis of DR in CLI treatment was recently published by Jongsma et al. [85].Over 306 screened abstracts, the Authors revealed significant improvement of healing and major amputation rates by using DR/WTR, in accordance with the AC.However, this significance tends to be lost for major amputation in bypass studies and no major difference was observed in global survival of patients [85].Congruent observations were also provided by Bunte et al., in a parallel review study focusing on AC applications in CLI [86].A recent and conspicuous review and meta-analysis made by Dilaver et al. gathered an impressive 4146 limbs analysis from 22 selected publications on AC/CLTI treatment strategy [87].The authors document global superior limb salvage and healing rates for DR versus IR however, with no effects on mortality and re-interventions in these patients [87].Specific WTR applications in diabetic patients.Several contemporary publications suggest that applying the WTR strategy and the DR, particularly in diabetic subjects with critically neuro-ischemic foot wounds and notable loss of collaterals, could be rewarding [7] [11] [14] [17] [58].
Thorough knowledge of the EAOD may help clinicians to better understand why blood flow from "a few millimeters of skin to the entire diabetic foot or leg" Thirty years after its first description, the AC [1] [2] [3] [4] continues to interest the medical community in the search for better CLTI management.
In fact, it appears that WTR and EAOD theories together may both afford useful synergies in treating collateral deprived diabetic CLTI patients [17] [26].
Prospective analyses.Contemporary literature assembles only a few available prospective series or registries concerning DR and WTR, to date (Table 1).
Beyond the above-mentioned initiatory prospective article of Kabra et al. [57] a recent 212 prospective analysis on AC-guided angioplasty in CLI conducted by Elbadawy et al. [89] was published the last year.This paper reveals better and quicker healing results for intentional endovascular DR, however with no significant difference in limb salvage and amputation free survival between groups [89].In another up-to-date 40 cases prospective analysis, Rother et al. [90] found a notable difference in "time to healing" for bypass that was superior in DR against IR.The authors observed yet no meaningful significance in immediate microcirculation changes between the studied groups [90].These two recent prospective studies seem but to confirm previous retrospective tissue healing observations about quicker median time to "tissue recovery" following DR/WTR [6] [7] [8] [9] [27] [59].These findings open the doorway towards eventual benefits upon the time for hospitalization, quality of life, social reintegration, and health costs in future research, since obtaining faster tissue recovery mediated by WTR and DR [17] [26] [85].
Recent clinical correlations.In a 2017 editorial article, Varela et al. [77] highlights the new paradigm shift for vascular practitioners that represents the introduction of AC in CLI treatment.This novel trend in current revascularization can be more specifically sustained nowadays because of the new understanding for that the major role that collaterals play in DR, and WTR [17] [18] [19] [26] [77].

New Interrogations in Angiosome-Oriented Revascularization
In light of increasing clinical information, several new questions confront researchers and clinicians regarding the applicability of the AC in CLTI.These interrogations, and at this level of CLTI understanding and treatment can be summarized [93] as: 1) What specifically defines today the term "direct revascularization" (DR), wound-directed, or "angiosome-guided" revascularization?Beyond targeting the principal angiosomal arteries (Figure 1), should the main regional collaterals, the arterial-arterial communicants and the foot arches also be included in a broader WTR strategy?2) What is the best diagnostic method for accurately applying WTR? [17] [25] [26] It becomes obvious that single macro, or micro-vascular evaluation can only poorly define the whole regional hemodynamic changes of DR/WTR versus IR in the CLTI context [18] [26].
Concerning the first question, while a majority of authors define DR as suc-World Journal of Cardiovascular Diseases cessful reperfusion of main foot angiosomal branches (the "source arteries" alone) [6] [69] or Direct "collateral-mediated" revascularization via the foot arches and the metatarsal communicants [16] [30] While some authors analyze pedal arches patency and DR as separate (and competitor) hemodynamic entities in CLTI [20] [94] others assemble both notions in a broader regional perfusion vision as to intentionally target topographic revascularization towards the wound zone [16]  Thereafter, a precise and widely accepted definition of DR is still pending [26] It is probably not conceivable to judge any further DR/IR analysis without preliminary solid ground consensus about truly definition of DR [85] [93] [95].
Regarding the second question, it has recently become more apparent that only the combination of microand macrocirculatory diagnostic methods can improve regional foot flow assessment regardless of the CLTI collateral pattern of distribution [17] [18] [19] [21] [26].Future investigations are certainly needed to prove this perspective [25].
Future prospective databases and analyses may bring new clarification on topographic revascularization subject.
For the last interrogation the answer remains more complex.Performing WTR implies supervision of precise diagnostic and therapeutic stages, each gathering specific challenges and individual defiance factors.From a pragmatic perspective the high frequency of severe atherosclerotic disease, long occlusions and dense calcifications currently encountered in specific angiosomal "source arteries" to treat [26] [27] still represents a daily challenge for every committed interventionist.

What Is Still Needed?
Similar to other developing theories of interdisciplinary interest, the limited current evidence has fueled an expected debate concerning the advantages and downsides of the AC oriented DR/WTR in CLTI [16] [30].
The implementation of the AC in current CLTI therapy represents a rational hypothesis but still remains theoretical and without practical validation at the present time.Although currently successfully employed in specific myocardial revascularization [52] neurosurgery [53] and plastic reconstructive skin flap prospective analysis (level "A" of evidence) [64] are mandatory to fulfill the present understanding of the WTR applications in CLTI (available level "C" of evidence) [64] as to provide concrete proofs and algorithms for its clinical utility Limitations.The majority of current notifications in this review are based on clinical observational data.Therefore, the level of evidence is low because of the lack of available randomized, prospective, and multicentric variable analysis.
Due to relative scarcity of consistent standardized series, no complementary study quality scoring at the inclusion of documents, and no statistical data reworking were attached in this discussion.
Further stratification of information in accordance to Cochrane recommendations, in a meta-analysis profile is scheduled in a near stage of this work.

Conclusion
The notion of angiosome wound-guided revascularization (via DR or WTR) detains only a reserved level of confirmation at the present time.As for DR, the WTR equally needs higher levels of evidence allowed by standardized definition, uniform indications, and pertinent multicenter and prospective results, before larger applications.

Table 1 .
Clinical and demographical features of main observational studies analyzing the benefit of angiosome-guided revascularization.
V. A.Alexandrescu et al.