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Left Internal Mammary Artery as an Endocrine Organ: Insights Into Graft Biology and Long-term Impact Following Coronary Artery Bypass Grafting

      Abstract

      The left internal mammary artery (LIMA) is considered the criterion standard vessel for use in coronary artery bypass grafting. In recent decades, countless studies have documented its superiority over other arterial and venous coronary artery bypass grafting conduits, although the full mechanisms for this superiority remain unknown. A growing body of literature has unveiled the importance of extracellular vesicles known as exosomes in cardiovascular signaling and various pathologic states. In this review, we briefly compare the clinical longevity of the LIMA relative to other conduits, explore the effects of varying grafting techniques on clinical and angiographic outcomes, and provide physiologic insights into graft function on a cellular and molecular level. Finally, we explore exosome signaling as it pertains to atherosclerosis in support of the LIMA as an “endocrine organ.”

      Abbreviations and Acronyms:

      CABG (coronary artery bypass graft), EC (endothelial cell), f-LIMA (free grafting of the left internal mammary artery), GEA (gastroepiploic artery), is-LIMA (in situ left internal mammary artery), LAD (left anterior descending artery), LIMA (left internal mammary artery), NO (nitric oxide), PCI (percutaneous coronary intervention), RA (radial artery), RIMA (right internal mammary artery), SMC (smooth muscle cell), SVG (saphenous vein graft)
      Coronary artery bypass graft (CABG) surgery has revolutionized the treatment of patients with coronary artery disease since its initial description in the 1950s. Early experience utilized the left internal mammary artery (LIMA) implanted directly into the left ventricular myocardium (Vineberg procedure).
      • Vineberg A.
      • Miller G.
      Internal mammary coronary anastomosis in the surgical treatment of coronary artery insufficiency.
      Although there was early enthusiasm for this approach, it was never effective in relieving ischemia and subsequently became obsolete.
      • Thomas J.L.
      The Vineberg legacy: internal mammary artery implantation from inception to obsolescence.
      During this early phase, saphenous vein grafts (SVGs) became the standard of care because they were more easily obtainable and had excellent flow initially. Eventually, the LIMA made a resurgence and became widely used as a direct coronary implant, bypassing coronary occlusions upstream. Even today, combination procedures with a LIMA to the left anterior descending artery (LAD) and SVGs to other ischemic territories remain the standard of care. Irrefutable information has been gained about the longevity of LIMA arterial grafts compared with venous bypass grafts. Numerous studies have documented improved short- and long-term graft patency (97% vs 82% at 18 months and 87% to 96% vs 55% to 73.6% at 10 years) as well as clinical outcomes (mortality, myocardial infarction, reoperation, need for percutaneous intervention) when using a LIMA compared with an SVG,
      • Zeff R.H.
      • Kongtahworn C.
      • Iannone L.A.
      • et al.
      Internal mammary artery versus saphenous vein graft to the left anterior descending coronary artery: prospective randomized study with 10-year follow-up.
      • Lytle B.W.
      • Loop F.D.
      • Cosgrove D.M.
      • Ratliff N.B.
      • Easley K.
      • Taylor P.C.
      Long-term (5 to 12 years) serial studies of internal mammary artery and saphenous vein coronary bypass grafts.
      • Arima M.
      • Kanoh T.
      • Suzuki T.
      • et al.
      Serial angiographic follow-up beyond 10 years after coronary artery bypass grafting.
      • Cameron A.
      • Davis K.B.
      • Green G.
      • Schaff H.V.
      Coronary bypass surgery with internal-thoracic-artery grafts--effects on survival over a 15-year period.
      • Goldman S.
      • Zadina K.
      • Moritz T.
      • et al.
      VA Cooperative Study Group #207/297/364
      Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study.
      with generally accepted 10-year patency of 95% for the LIMA. Several landmark trials in the early 2000s, namely the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) study
      • Serruys P.W.
      • Morice M.-C.
      • Kappetein A.P.
      • et al.
      SYNTAX Investigators
      Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease [published correction appears in N Engl J Med. 2013;368(6):584].
      and the SoS (Stent or Surgery) trial,
      SoS Investigators
      Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial.
      further documented that CABG was superior to percutaneous coronary intervention (PCI) in patients with multivessel coronary artery disease in terms of the need for repeated revascularization, myocardial infarction, and all-cause mortality. By 2004, guidelines from the joint American College of Cardiology and American Heart Association indicated CABG as the preferred treatment for disease of the left main coronary artery, severe triple-vessel disease, and diffuse disease that is not amenable to treatment with PCI.
      • Eagle K.A.
      • Guyton R.A.
      • Davidoff R.
      • et al.
      American College of CardiologyAmerican Heart Association
      ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery) [published correction appears in Circulation. 2005;111(15):2014].
      Currently, LIMA remains the graft of choice owing to its excellent clinical performance, although the high prevalence of multivessel disease necessitates the use of adjunct grafts such as SVGs or other arterial conduits.
      Although the clinical superiority of the LIMA as a coronary graft is well established, the scientific reasons for this superiority remain unclear. This article focuses on the vascular biology of the LIMA, the effects of its implantation on downstream vessels, and the potential future applications for designing arterial grafts.

      Comparison Across Arterial Grafts

      The LIMA (or left internal thoracic artery) as a criterion standard is an in situ LIMA (is-LIMA) that requires only one anastomosis at the site of the coronary artery, although it may also be used as a sequential graft. Certain circumstances, however—proximal internal mammary artery injury/stenosis or higher length requirement—may necessitate free grafting of the LIMA (f-LIMA). However, recent trials directly comparing is-LIMA with f-LIMA documented significantly higher rates of graft failure (stenosis >75%) at 18 months in the f-LIMA group relative to the is-LIMA group (14.3% vs 0%
      • Verhelst R.
      • Etienne P.Y.
      • El Khoury G.
      • Noirhomme P.
      • Rubay J.
      • Dion R.
      Free internal mammary artery graft in myocardial revascularization.
      ; 23.3% vs 8.5%
      • Ranney D.N.
      • Williams J.B.
      • Mulder H.
      • et al.
      Comparison of outcomes and frequency of graft failure with use of free versus in situ internal mammary artery bypass conduits (from the PREVENT IV Trial).
      ). It has been postulated that severing of the vasa vasorum, which supply blood to the LIMA, as well as denervation of the artery in the process of harvesting, may limit the ability of an f-LIMA to maintain appropriate blood supply and autoregulation, contributing to its long-term failure.
      • He G.W.
      Arterial grafts for coronary artery bypass grafting: biological characteristics, functional classification, and clinical choice.
      Similar preservation of the vasa vasorum has been associated with improved patency within SVGs as well,
      • Dreifaldt M.
      • Souza D.
      • Bodin L.
      • et al.
      The vasa vasorum and associated endothelial nitric oxide synthase is more important for saphenous vein than arterial bypass grafts.
      highlighting its role in preserving graft function.
      The right internal mammary artery (RIMA)/right internal thoracic artery has a similar structure and function compared with the LIMA, although its origination from the right subclavian artery increases technical complexity and possible risk of deep sternal wound infections, thereby limiting its use in CABG. Recent studies have indicated no significant difference in the conduit patency between in situ RIMA and is-LIMA grafted onto the LAD during a mean 3-year follow-up (95.0% to 97.2% vs 96.6% to 97.4%, respectively).
      • Bonacchi M.
      • Prifti E.
      • Maiani M.
      • et al.
      Perioperative and clinical-angiographic late outcome of total arterial myocardial revascularization according to different composite original graft techniques.
      ,
      • Ji Q.
      • Xia L.
      • Shi Y.
      • et al.
      Mid-term graft patency of right versus left internal mammary artery as arterial conduit usage for left anterior descending artery revascularisation: insights from a single-centre study of propensity-matched data.
      A longer-term study documented slightly diverging results following a 17-year follow-up (85% for RIMA vs 92% for LIMA),
      • Galbut D.L.
      • Traad E.A.
      • Dorman M.J.
      • et al.
      Seventeen-year experience with bilateral internal mammary artery grafts.
      suggesting possible inherent differences between RIMA and LIMA grafts. Not surprisingly, a recent meta-analysis of 29 studies encompassing nearly 90,000 patients revealed that the use of bilateral internal mammary arteries during CABG enhances 10-year survival relative to grafting with LIMA and saphenous veins (hazard ratio, 0.78),
      • Buttar S.N.
      • Yan T.D.
      • Taggart D.P.
      • Tian D.H.
      Long-term and short-term outcomes of using bilateral internal mammary artery grafting versus left internal mammary artery grafting: a meta-analysis.
      presumably due to enhanced long-term patency of internal mammary arteries relative to saphenous veins. Although bilateral internal mammary artery grafting was associated with a mild increase in deep sternal wound infections, improvements in long-term overall and cardiovascular event-free survival outweighed this marginal risk.
      • Buttar S.N.
      • Yan T.D.
      • Taggart D.P.
      • Tian D.H.
      Long-term and short-term outcomes of using bilateral internal mammary artery grafting versus left internal mammary artery grafting: a meta-analysis.
      In the early 1970s, Carpentier et al
      • Carpentier A.
      • Guermonprez J.L.
      • Deloche A.
      • Frechette C.
      • DuBost C.
      The aorta-to-coronary radial artery bypass graft: a technique avoiding pathological changes in grafts.
      and Edwards et al
      • Edwards W.S.
      • Lewis C.E.
      • Blakeley W.R.
      • Napolitano L.
      Coronary artery bypass with internal mammary and splenic artery grafts.
      introduced the radial artery (RA) and the right gastroepiploic artery (GEA), respectively, as analogous conduits for use during CABG, with each requiring a separate minimally invasive operation for harvesting. Long-term (8- to 10-year) patency rates of GEA grafts have ranged from 70.2% to 90.2%,
      • Suma H.
      Gastroepiploic artery graft in coronary artery bypass grafting.
      • Suzuki T.
      • Asai T.
      • Nota H.
      • et al.
      Early and long-term patency of in situ skeletonized gastroepiploic artery after off-pump coronary artery bypass graft surgery.
      • Akita S.
      • Tajima K.
      • Kato W.
      • et al.
      The long-term patency of a gastroepiploic artery bypass graft deployed in a semiskeletonized fashion: predictors of patency.
      still inferior to those seen with LIMA grafts. Similarly, RA grafts have a wide range of patency rates at 9 to 10 years (79.2% to 91.6%).
      • Tinica G.
      • Chistol R.O.
      • Enache M.
      • Leon Constantin M.M.
      • Ciocoiu M.
      • Furnica C.
      Long-term graft patency after coronary artery bypass grafting: effects of morphological and pathophysiological factors.
      • Dreifaldt M.
      • Mannion J.D.
      • Geijer H.
      • Lidén M.
      • Bodin L.
      • Souza D.
      The no-touch saphenous vein is an excellent alternative conduit to the radial artery 8 years after coronary artery bypass grafting: a randomized trial.
      • Ji Q.
      • Song K.
      • Shen J.
      • et al.
      Long-term patency rate of radial artery conduits in Chinese patients undergoing off-pump coronary artery bypass grafting.
      • Achouh P.
      • Boutekadjirt R.
      • Toledano D.
      • et al.
      Long-term (5- to 20-year) patency of the radial artery for coronary bypass grafting.
      • Achouh P.
      • Isselmou K.O.
      • Boutekadjirt R.
      • et al.
      Reappraisal of a 20-year experience with the radial artery as a conduit for coronary bypass grafting.
      • Possati G.
      • Gaudino M.
      • Prati F.
      • et al.
      Long-term results of the radial artery used for myocardial revascularization.
      However, in patients presenting with acute myocardial ischemia, the RA patency rate at 5 years was reported to be considerably lower (51% to 73%).
      • Khot U.N.
      • Friedman D.T.
      • Pettersson G.
      • Smedira N.G.
      • Li J.
      • Ellis S.G.
      Radial artery bypass grafts have an increased occurrence of angiographically severe stenosis and occlusion compared with left internal mammary arteries and saphenous vein grafts.
      • Acar C.
      • Ramsheyi A.
      • Pagny J.Y.
      • et al.
      The radial artery for coronary artery bypass grafting: clinical and angiographic results at five years.
      • Possati G.
      • Gaudino M.
      • Alessandrini F.
      • et al.
      Midterm clinical and angiographic results of radial artery grafts used for myocardial revascularization.
      Importantly, the vasa vasorum of both the GEA and RA grafts are fully severed during surgical harvesting, which may partially contribute to their lower long-term patency rates, akin to the differences across f-LIMA and is-LIMA. It should be noted that morphologic parameters, including target vessel territory and diameter and the degree of stenosis, can strongly influence the long-term graft patency, with occlusion odds ratios as high as 3, depending on the prespecified cutoffs.
      • Tinica G.
      • Chistol R.O.
      • Enache M.
      • Leon Constantin M.M.
      • Ciocoiu M.
      • Furnica C.
      Long-term graft patency after coronary artery bypass grafting: effects of morphological and pathophysiological factors.
      A landmark study termed RAPCO (Radial Artery Patency and Clinical Outcomes) completed in 2015 reassessed the efficacy of RA grafting and documented clear superiority over RIMA and SVG, with 10-year patency rates of 85% to 89%.
      • Buxton B.F.
      • Hayward P.A.
      • Raman J.
      • et al.
      RAPCO Investigators
      Long-term results of the RAPCO trials.
      In part due to these results and its relative ease of harvest from the arm, the RA received class IA recommendations for use as a second conduit for CABG according to the 2018 ESC/EACTS (European Society of Cardiology/European Association for Cardio-Thoracic Surgery) guidelines.
      • Neumann F.-J.
      • Sousa-Uva M.
      • Ahlsson A.
      • et al.
      ESC Scientific Document Group
      2018 ESC/EACTS guidelines on myocardial revascularization [published correction appears in Eur Heart J. 2019;40(37):3096].
      Still, in 2021 a report by the Society of Thoracic Surgeons showed that fewer than 5% of patients with CABG received an RA as a second arterial conduit.
      • Nappi F.
      • Bellomo F.
      • Nappi P.
      • et al.
      The use of radial artery for CABG: an update.
      Two main reasons have been suggested to explain such low use. First, there are several circumstances in which the RA cannot be harvested, such as anatomic variations with high birth or termination, diffuse calcinosis/vasculitis, recent (<3 months) angiography via radial access, arteriovenous fistula involving the RA, insufficient ulnar artery compensation, or posttraumatic RA injury.
      • Nappi F.
      • Bellomo F.
      • Nappi P.
      • et al.
      The use of radial artery for CABG: an update.
      Secondly, and perhaps more profoundly, until very recently, there remained limited objective data comparing long-term effects of multiple vs single arterial grafts. Similar to the Society of Thoracic Surgeons data, a recent large Canadian study (almost 50,000 enrolled patients) found that total arterial revascularization was performed rarely (4.9% of CABG cases) but was associated with improved long-term (9-year) cardiovascular outcomes, although graft patency rates were not assessed.
      • Rocha R.V.
      • Tam D.Y.
      • Karkhanis R.
      • et al.
      Long-term outcomes associated with total arterial revascularization vs non-total arterial revascularization.
      A recently launched clinical trial (Randomization of Single vs Multiple Arterial Grafts [ROMA]) is designed to address this question and is estimated to be completed by 2030.

      Composite and Sequential Grafts

      Several modifications to standard surgical grafting techniques have been proposed to improve long-term clinical and graft outcomes. First, a sequential grafting method can increase the number of epicardial coronary targets receiving the bypassed flow. Initial studies using sequential grafting of the LIMA (generally to the diagonal artery followed by the LAD) produced varying results, with similar overall graft patency rates relative to nonsequential LIMA grafts, albeit with some evidence of decreased flow at the distal sequential anastomosis.
      • Bakay C.
      • Onan B.
      • Korkmaz A.A.
      • Onan I.S.
      • Özkara A.
      Sequential in situ left internal thoracic artery grafting to the circumflex and right coronary artery areas.
      • Cho W.-C.
      • Kim J.B.
      • Jung S.H.
      • et al.
      Revascularization of the left anterior descending artery area using a single left internal thoracic artery: auto-Y composite grafting or sequential bypassing.
      • Ji Q.
      • Xia L.
      • Shi Y.
      • et al.
      Sequential grafting of in situ skeletonized left internal mammary artery to the left coronary system.
      • Ouzounian M.
      • Hassan A.
      • Yip A.M.
      • et al.
      The impact of sequential grafting on clinical outcomes following coronary artery bypass grafting.
      When utilizing this method for the RA, it was noted that a sequential side-to-side anastomosis maintained 100% patency at 10 years (compared to 88.7% of end-to-side anastomoses), again highlighting the potential utility of the RA in total arterial grafting.
      • Kasahara H.
      • Shin H.
      • Takahashi T.
      • Murata S.
      • Mori M.
      Comparison of patency of single and sequential radial artery grafting in coronary artery bypass.
      A second approach involves composite grafting, either via a T- or Y-graft (end-to-side anastomosis) or serial graft (end-to-end anastomosis) of free bypass grafts (RA, GEA, saphenous vein, or RIMA) to an is-LIMA prior to reaching the distal coronary targets. Early studies with LIMA-RA and LIMA-RIMA Y-composite grafts revealed excellent early (2- to 36-month) patency rates (93% to 98.1%)
      • Bonacchi M.
      • Prifti E.
      • Maiani M.
      • et al.
      Perioperative and clinical-angiographic late outcome of total arterial myocardial revascularization according to different composite original graft techniques.
      ,
      • Yilmaz A.T.
      • Ozal E.
      • Barindik N.
      • Günay C.
      • Tatar H.
      The results of radial artery Y-graft for complete arterial revascularization.
      ,
      • Calafiore A.M.
      • Di Giammarco G.
      • Teodori G.
      • et al.
      Radial artery and inferior epigastric artery in composite grafts: improved midterm angiographic results.
      with improved long-term (10-year) survival rates relative to standard LIMA-saphenous vein (noncomposite) grafts in larger studies.
      • Ben-Gal Y.
      • Gordon A.
      • Ziv-Baran T.
      • et al.
      Late outcomes of in situ versus composite bilateral internal thoracic artery revascularization.
      ,
      • Locker C.
      • Schaff H.V.
      • Dearani J.A.
      • Daly R.C.
      Improved late survival with arterial revascularization.
      In the recent SAVE-RITA (Saphenous Vein Versus Right Internal Thoracic Artery) trial, SVGs were directly compared with the RIMA for use in LIMA Y-grafts and were found to have noninferior patency rates at 1 year (97.9%)
      • Kim K.-B.
      • Hwang H.Y.
      • Hahn S.
      • Kim J.S.
      • Oh S.J.
      A randomized comparison of the Saphenous Vein Versus Right Internal Thoracic Artery as a Y-Composite Graft (SAVE RITA) trial: one-year angiographic results and mid-term clinical outcomes.
      and 10 years (94.9%),
      • Kim M.-S.
      • Kim K.-B.
      Saphenous Vein Versus Right Internal Thoracic Artery as a Y-Composite Graft: ten-year angiographic and long-term clinical results of the SAVE RITA trial.
      albeit with small sample size (100 to 200 patients). However, despite promising results with composite Y-grafts, there remains concern about the adequacy of a single bypass for multiple coronary territories and compromised blood flow to the LIMA-LAD, as well as the effects of competitive flow on graft longevity.
      • Paterson H.S.
      • Bannon P.G.
      Composite Y grafts from the left internal mammary artery: current considerations [editorial].
      Alternatively, serial grafts can be utilized when a full-length LIMA is unavailable due to severe left ventricular enlargement, difficulty/injury in LIMA harvesting, or calcification of the middle/distal LIMA causing blood flow restriction. A recent study using a LIMA + SVG anastomosed to the LAD documented no increase in major adverse cardiac events or mortality at 5 years relative to the standard LIMA-LAD approach.
      • Li D.
      • Gu S.
      • Liu Y.
      • et al.
      Outcomes of left internal mammary artery with saphenous vein composite graft to bypass the left anterior descending artery: a propensity-matched study.
      Furthermore, the LIMA + SVG exhibited 94% patency rates at 25 months, comparable to standard LIMA-LAD grafts and approximately 10% higher than matched aortocoronary SVGs, believed to be, in part, due to excess LIMA-derived nitric oxide (NO),
      • Li D.
      • Gu S.
      • Liu Y.
      • et al.
      Outcomes of left internal mammary artery with saphenous vein composite graft to bypass the left anterior descending artery: a propensity-matched study.
      although the exact mechanisms remain unknown.

      Effect of Revascularization on Native Atherosclerosis

      Although the differences in graft patency and clinical outcomes based on graft type are well documented, considerably less is known regarding the effect of revascularization on native vessel atherosclerosis. A recent study found that arterial grafts (LIMA, RAs) protect native coronary vessels from atherosclerotic disease progression by as much as 5-fold over 10 years relative to SVGs.
      • Dimitrova K.R.
      • Hoffman D.M.
      • Geller C.M.
      • Dincheva G.
      • Ko W.
      • Tranbaugh R.F.
      Arterial grafts protect the native coronary vessels from atherosclerotic disease progression.
      Post-hoc analysis of the MASS (Medicine, Angioplasty, or Surgery Study) II trial indicated a significant decrease in disease progression in the LAD when a LIMA graft is used compared with an SVG.
      • Borges J.C.
      • Lopes N.
      • Soares P.R.
      • et al.
      Five-year follow-up of angiographic disease progression after medicine, angioplasty, or surgery.
      In comparison with PCI to the LAD, revascularization with a LIMA carries a significantly lower risk of not only conduit disease progression (hazard ratio, 0.18 to 0.27) but also downstream coronary disease progression (hazard ratio, 0.34 to 0.39), with no significant benefit noted in the latter between bare metal stents and drug-eluting stents.
      • Zhang M.
      • Guddeti R.R.
      • Matsuzawa Y.
      • et al.
      Left internal mammary artery versus coronary stents: impact on downstream coronary stenoses and conduit patency.
      These studies further suggest that the improved patient outcomes with LIMA grafting likely stem from a combination of improved graft patency as well as decreased atherosclerosis progression, preventing future adverse events. Corroborating this apparent “endocrine function,” numerous case reports have revealed coronary plaque regression following a LIMA graft to the LAD, with occasional near-complete resolution of visible plaque.
      • Valooran G.J.
      • Nair S.K.
      • Chandrasekharan K.
      Rare case of proximal coronary plaque regression after distal arterial grafting.
      • Shiga Y.
      • Miura S.-I.
      • Nishikawa H.
      • et al.
      Regression of coronary plaque after coronary artery bypass graft.
      • Dodic S.
      • Kovacevic D.
      • Bjelobrk M.
      • et al.
      Spontaneous regression of proximal LAD subocclusive stenosis after left internal mammary artery bypass grafting.
      In contrast, no similar reports have been documented for SVGs, and only modest decreases in atherosclerotic plaque volume and total atheroma volume (1% to 10%) have been observed with intense lipid-lowering therapy (achieved low-density lipoprotein cholesterol level of 60 to 70 mg/dL [to convert value to mmol/L, multiply by 0.0259]).
      • Tsujita K.
      • Sugiyama S.
      • Sumida H.
      • et al.
      PRECISE–IVUS Investigators
      Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial.
      • Nicholls S.J.
      • Ballantyne C.M.
      • Barter P.J.
      • et al.
      Effect of two intensive statin regimens on progression of coronary disease.
      • Nissen S.E.
      • Nicholls S.J.
      • Sipahi I.
      • et al.
      ASTEROID Investigators
      Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.
      As such, LIMA grafting appears to achieve antiatherosclerotic effects beyond those achieved by optimized medical management. Deconvolution of the molecular cues the LIMA graft provides to the coronary artery would provide new insights into novel and potentially curative technologies to reverse coronary artery disease.

      Physiologic Insights Into Graft Function

      It is well established that the LIMA and saphenous veins, although sharing several functional and structural properties, exhibit crucial anatomic and physiologic differences.
      • Motwani J.G.
      • Topol E.J.
      Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention.
      ,
      • Otsuka F.
      • Yahagi K.
      • Sakakura K.
      • Virmani R.
      Why is the mammary artery so special and what protects it from atherosclerosis?.
      Both the internal mammary arteries and saphenous veins consist of a tunica intima, media, and adventitia, with smooth muscle cells (SMCs) within the tunica media and a layer of endothelial cells (ECs) lining the lumen of the vessel. The endothelium of the LIMA contains significantly less fenestrations compared with that of saphenous veins, which may prevent the extravasation of lipoproteins and subsequent atherogenesis. Unsurprisingly, SVGs become exposed to substantially higher levels of shear stress following a CABG. In this process of “arterialization,” it is believed that endothelial injury leads to rapid neointimal growth from infiltration of SMCs, proteoglycan, and type I/III collagen, triggering the higher proclivity toward luminal stenosis.
      • Otsuka F.
      • Yahagi K.
      • Sakakura K.
      • Virmani R.
      Why is the mammary artery so special and what protects it from atherosclerosis?.
      Such atherosclerotic changes have been observed as early as 13 months after CABG, with the development of a necrotic core and foam cell accumulation between 1 and 3 years.
      • Otsuka F.
      • Yahagi K.
      • Sakakura K.
      • Virmani R.
      Why is the mammary artery so special and what protects it from atherosclerosis?.
      Ex vivo perfusion cultures from SVGs revealed higher intimal and medial cell proliferation relative to those obtained from the LIMA.
      • Prim D.A.
      • Menon V.
      • Hasanian S.
      • et al.
      Perfusion tissue culture initiates differential remodeling of internal thoracic arteries, radial arteries, and saphenous veins.
      In addition to the higher levels of shear stress, SVGs are exposed to higher transluminal pressures relative to their native state. Interestingly, high-pressure distention during preparation of SVGs has been shown to induce a pressure-dependent up-regulation of several biomarkers, including platelet EC adhesion molecule and vascular cell adhesion molecule, both of which are central in recruitment of inflammatory cells and progression to atherosclerosis.
      • Khaleel M.S.
      • Dorheim T.A.
      • Duryee M.J.
      • et al.
      High-pressure distention of the saphenous vein during preparation results in increased markers of inflammation: a potential mechanism for graft failure.
      Because SVGs are subjected to high pressures both during the preparation and after grafting, such findings offer an additional explanation for increased atherogenesis in SVGs.
      Across arterial grafts, the RA contains a higher proportion of SMCs and less elasticity relative to the LIMA, with increased endogenous expression of RhoA/Rho kinase pathway proteins that are responsible for its propensity toward vasospasm.
      • Kun X.
      • Lefeng W.
      • Rongjing D.
      • Xincun Y.
      RhoA/ROK pathway related to the mechanism of higher susceptibility to spasm in RA than in IMA.
      Additionally, comparative histopathology has documented that intimal hyperplasia, arteriosclerosis, and medial calcification are more likely to develop in the RA than in the LIMA.
      • Ruengsakulrach P.
      • Sinclair R.
      • Komeda M.
      • Raman J.
      • Gordon I.
      • Buxton B.
      Comparative histopathology of radial artery versus internal thoracic artery and risk factors for development of intimal hyperplasia and atherosclerosis.
      Appropriately, the RA has a more robust increase in tension with application of vasoconstrictive agents (norepinephrine, potassium chloride, phenylephrine, and endothelin-1)
      • Chamiot-Clerc P.
      • Copie X.
      • Renaud J.F.
      • Safar M.
      • Girerd X.
      Comparative reactivity and mechanical properties of human isolated internal mammary and radial arteries.
      ,
      • Mangoush O.
      • Athanasiou T.
      • Nakamura K.
      • et al.
      Antioxidant properties of the internal thoracic artery and the radial artery.
      as well as the absence of histamine-induced relaxation
      • Stähli B.E.
      • Greutert H.
      • Mei S.
      • et al.
      Absence of histamine-induced nitric oxide release in the human radial artery: implications for vasospasm of coronary artery bypass vessels.
      during in vitro testing, which although appropriate for its native anatomic location, could lead to reduced blood flow during states of systemic stress. Similarly, the GEA has been noted to have increased contractility relative to the LIMA in response to norepinephrine and angiotensin II, highlighting its propensity toward vasospasm like the RA,
      • Cracowski J.L.
      • Stanke Labesque F.
      • Chavanon O.
      • Blin D.
      • Bessard G.
      • Devillier P.
      Reactivity of the human internal mammary artery and the gastroepiploic artery to constrictor substances.
      although histamine-induced relaxation has been noted to be similar.
      • Ochiai M.
      • Ohno M.
      • Taguchi J.
      • et al.
      Responses of human gastroepiploic arteries to vasoactive substances: comparison with responses of internal mammary arteries and saphenous veins.
      To our knowledge, no ex vivo studies have been performed analyzing the functional differences between innate LIMA and RIMA.

      Differences in Genomic and Proteomic Profiles of CABG Conduits

      A number of studies have previously assessed the gene expression and proteomic differences across the SMCs and ECs comprising typical CABG conduits (Table
      • Antoniades C.
      • Shirodaria C.
      • Van Assche T.
      • et al.
      GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function.
      • Tadjkarimi S.
      • O'Neil G.S.
      • Luu T.N.
      • et al.
      Comparison of cyclic GMP in human internal mammary artery and saphenous vein: implications for coronary artery bypass graft patency.
      • He G.-W.
      • Fan L.
      • Grove K.L.
      • Furnary A.
      • Yang Q.
      Expression and function of endothelial nitric oxide synthase messenger RNA and protein are higher in internal mammary than in radial arteries.
      • Gaudino M.
      • Toesca A.
      • Maggiano N.
      • Pragliola C.
      • Possati G.
      Localization of nitric oxide synthase type III in the internal thoracic and radial arteries and the great saphenous vein: a comparative immunohistochemical study.
      • Wackenfors A.
      • Ingemansson R.
      • Malmsjö M.
      Endothelin receptors in endothelium-denuded human coronary artery bypass grafts and coronary arteries.
      • Subramanian V.A.
      • Hernandez Y.
      • Tack-Goldman K.
      • Grabowski E.F.
      • Weksler B.B.
      Prostacyclin production by internal mammary artery as a factor in coronary artery bypass grafts.
      • Schmalfuss C.M.
      • Chen L.Y.
      • Bott J.N.
      • Staples E.D.
      • Mehta J.L.
      Superoxide anion generation, superoxide dismutase activity, and nitric oxide release in human internal mammary artery and saphenous vein segments.
      • Yang Z.
      • Oemar B.S.
      • Carrel T.
      • Kipfer B.
      • Julmy F.
      • Lüscher T.F.
      Different proliferative properties of smooth muscle cells of human arterial and venous bypass vessels: role of PDGF receptors, mitogen-activated protein kinase, and cyclin-dependent kinase inhibitors.
      • Turner N.A.
      • Ho S.
      • Warburton P.
      • O'Regan D.J.
      • Porter K.E.
      Smooth muscle cells cultured from human saphenous vein exhibit increased proliferation, invasion, and mitogen-activated protein kinase activation in vitro compared with paired internal mammary artery cells.
      • Del Rizzo D.F.
      • Yurkova N.
      • Moon M.C.
      • Litchie B.
      • Zahradka P.
      Platelet-derived growth factor-induced expression of c-fos in human vascular smooth muscle cells: implications for long-term graft patency.
      • Friedl R.
      • Li J.
      • Schumacher B.
      • et al.
      Intimal hyperplasia and expression of transforming growth factor-β1 in saphenous veins and internal mammary arteries before coronary artery surgery.
      • Zhu T.
      • Lan B.
      • Meng L.
      • et al.
      ECM-related gene expression profile in vascular smooth muscle cells from human saphenous vein and internal thoracic artery.
      • Mitra A.K.
      • Jia G.
      • Gangahar D.M.
      • Agrawal D.K.
      Temporal PTEN inactivation causes proliferation of saphenous vein smooth muscle cells of human CABG conduits.
      • Sur S.
      • Sugimoto J.T.
      • Agrawal D.K.
      Coronary artery bypass graft: why is the saphenous vein prone to intimal hyperplasia?.
      • Hata J.A.
      • Petrofski J.A.
      • Schroder J.N.
      • et al.
      Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts.
      • Alattar M.
      • Jiang C.
      • Luan Z.
      • Pan T.
      • Liu L.
      • Li J.
      Neuropilin 1 expression in human aortas, coronaries and the main bypass grafts.
      • Jia G.
      • Mitra A.K.
      • Cheng G.
      • Gangahar D.M.
      • Agrawal D.K.
      Angiotensin II and IGF-1 regulate connexin43 expression via ERK and p38 signaling pathways in vascular smooth muscle cells of coronary artery bypass conduits.
      • Payeli S.K.
      • Latini R.
      • Gebhard C.
      • et al.
      Prothrombotic gene expression profile in vascular smooth muscle cells of human saphenous vein, but not internal mammary artery.
      • Arishiro K.
      • Hoshiga M.
      • Ishihara T.
      • Kondo K.
      • Hanafusa T.
      Connexin 43 expression is associated with vascular activation in human radial artery.
      • Li D.Y.
      • Chen H.J.
      • Staples E.D.
      • et al.
      Oxidized low-density lipoprotein receptor LOX-1 and apoptosis in human atherosclerotic lesions.
      • Ferrari G.
      • Quackenbush J.
      • Strobeck J.
      • et al.
      Comparative genome-wide transcriptional analysis of human left and right internal mammary arteries.
      ). Key differences in the expression of genes related to vasoreactivity, oxidative stress, cell migration and proliferation, inflammation, and atherosclerosis have been described across the various grafts.
      TableGene Expression and Proteomic Differences Across CABG Conduits
      Reference, yearPathwayProtein (gene)CABG conduits comparedResultsSignificanceReference
      Antoniades et al,
      • Antoniades C.
      • Shirodaria C.
      • Van Assche T.
      • et al.
      GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function.
      2008
      VasoreactivityGTP-cyclohydrolase 1 (GCH1)LIMA and SVLIMA expresses higher levels of GCH1GCH1 regulates a cofactor for eNOS synthesis, leading to higher NO levels in LIMAAntoniades et al
      • Antoniades C.
      • Shirodaria C.
      • Van Assche T.
      • et al.
      GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function.
      Tadjkarimi et al,
      • Tadjkarimi S.
      • O'Neil G.S.
      • Luu T.N.
      • et al.
      Comparison of cyclic GMP in human internal mammary artery and saphenous vein: implications for coronary artery bypass graft patency.
      1992
      cGMPLIMA and SVLIMA has increased levels of cGMP at baseline and if stimulatedHigher cGMP levels in LIMA lead to improved vasodilationTadjkarimi et al
      • Tadjkarimi S.
      • O'Neil G.S.
      • Luu T.N.
      • et al.
      Comparison of cyclic GMP in human internal mammary artery and saphenous vein: implications for coronary artery bypass graft patency.
      He et al,
      • He G.-W.
      • Fan L.
      • Grove K.L.
      • Furnary A.
      • Yang Q.
      Expression and function of endothelial nitric oxide synthase messenger RNA and protein are higher in internal mammary than in radial arteries.
      2011

      Gaudino et al,
      • Gaudino M.
      • Toesca A.
      • Maggiano N.
      • Pragliola C.
      • Possati G.
      Localization of nitric oxide synthase type III in the internal thoracic and radial arteries and the great saphenous vein: a comparative immunohistochemical study.
      2003
      eNOS (NOS3)LIMA, SV, and RALIMA expresses higher levels of eNOSLIMA has higher levels of NOHe et al
      • He G.-W.
      • Fan L.
      • Grove K.L.
      • Furnary A.
      • Yang Q.
      Expression and function of endothelial nitric oxide synthase messenger RNA and protein are higher in internal mammary than in radial arteries.


      Gaudino et al
      • Gaudino M.
      • Toesca A.
      • Maggiano N.
      • Pragliola C.
      • Possati G.
      Localization of nitric oxide synthase type III in the internal thoracic and radial arteries and the great saphenous vein: a comparative immunohistochemical study.
      Wackenfors et al,
      • Wackenfors A.
      • Ingemansson R.
      • Malmsjö M.
      Endothelin receptors in endothelium-denuded human coronary artery bypass grafts and coronary arteries.
      2003
      Endothelin receptor type A and B (EDNRA, EDNRB)LIMA, SV, and coronary arteriesEndothelin receptors more highly expressed in SVLIMA is relatively protected from endothelin-induced vasoconstrictionWackenfors et al
      • Wackenfors A.
      • Ingemansson R.
      • Malmsjö M.
      Endothelin receptors in endothelium-denuded human coronary artery bypass grafts and coronary arteries.
      Subramanian et al,
      • Subramanian V.A.
      • Hernandez Y.
      • Tack-Goldman K.
      • Grabowski E.F.
      • Weksler B.B.
      Prostacyclin production by internal mammary artery as a factor in coronary artery bypass grafts.
      1986
      ProstacyclinLIMA and SVLIMA produces higher levels of prostacyclin at baseline and if stimulatedHigher prostacyclin levels in LIMA reduce vasoconstriction and platelet aggregationSubramanian et al
      • Subramanian V.A.
      • Hernandez Y.
      • Tack-Goldman K.
      • Grabowski E.F.
      • Weksler B.B.
      Prostacyclin production by internal mammary artery as a factor in coronary artery bypass grafts.
      Mangoush et al,
      • Mangoush O.
      • Athanasiou T.
      • Nakamura K.
      • et al.
      Antioxidant properties of the internal thoracic artery and the radial artery.
      2008

      Schmalfuss et al,
      • Schmalfuss C.M.
      • Chen L.Y.
      • Bott J.N.
      • Staples E.D.
      • Mehta J.L.
      Superoxide anion generation, superoxide dismutase activity, and nitric oxide release in human internal mammary artery and saphenous vein segments.
      1999
      Oxidative stressSOD1 (SOD1)LIMA and RALIMA demonstrates increased SOD activityLIMA exhibits increased protection against oxidative stressMangoush et al
      • Mangoush O.
      • Athanasiou T.
      • Nakamura K.
      • et al.
      Antioxidant properties of the internal thoracic artery and the radial artery.


      Schmalfuss et al
      • Schmalfuss C.M.
      • Chen L.Y.
      • Bott J.N.
      • Staples E.D.
      • Mehta J.L.
      Superoxide anion generation, superoxide dismutase activity, and nitric oxide release in human internal mammary artery and saphenous vein segments.
      Yang et al,
      • Yang Z.
      • Oemar B.S.
      • Carrel T.
      • Kipfer B.
      • Julmy F.
      • Lüscher T.F.
      Different proliferative properties of smooth muscle cells of human arterial and venous bypass vessels: role of PDGF receptors, mitogen-activated protein kinase, and cyclin-dependent kinase inhibitors.
      1998

      Turner et al,
      • Turner N.A.
      • Ho S.
      • Warburton P.
      • O'Regan D.J.
      • Porter K.E.
      Smooth muscle cells cultured from human saphenous vein exhibit increased proliferation, invasion, and mitogen-activated protein kinase activation in vitro compared with paired internal mammary artery cells.
      2007
      Cell proliferation and migrationp42 MAPK1 (MAPK1)LIMA and SVSV shows increased sensitivity to PDGF with increased p42 MAPK1 protein levelsp42 MAPK1 activation via PDGF leads to increased cell proliferation in SVs relative to LIMAYang et al
      • Yang Z.
      • Oemar B.S.
      • Carrel T.
      • Kipfer B.
      • Julmy F.
      • Lüscher T.F.
      Different proliferative properties of smooth muscle cells of human arterial and venous bypass vessels: role of PDGF receptors, mitogen-activated protein kinase, and cyclin-dependent kinase inhibitors.


      Turner et al
      • Turner N.A.
      • Ho S.
      • Warburton P.
      • O'Regan D.J.
      • Porter K.E.
      Smooth muscle cells cultured from human saphenous vein exhibit increased proliferation, invasion, and mitogen-activated protein kinase activation in vitro compared with paired internal mammary artery cells.
      Del Rizzo et al,
      • Del Rizzo D.F.
      • Yurkova N.
      • Moon M.C.
      • Litchie B.
      • Zahradka P.
      Platelet-derived growth factor-induced expression of c-fos in human vascular smooth muscle cells: implications for long-term graft patency.
      2002
      c-Fos (FOS)LIMA, SV, and RAPDGF-induced expression of c-Fos is greatest in SV SMCsArterial conduits are more resistant to mitogenic effects of PDGF due to lower c-Fos expressionDel Rizzo et al
      • Del Rizzo D.F.
      • Yurkova N.
      • Moon M.C.
      • Litchie B.
      • Zahradka P.
      Platelet-derived growth factor-induced expression of c-fos in human vascular smooth muscle cells: implications for long-term graft patency.
      Friedl et al,
      • Friedl R.
      • Li J.
      • Schumacher B.
      • et al.
      Intimal hyperplasia and expression of transforming growth factor-β1 in saphenous veins and internal mammary arteries before coronary artery surgery.
      2004
      TGF-β1 (TGFB1)LIMA and SVSV exhibits higher TGF-β1 expressionIncreased TGF-β1 activity in SVs induces intimal hyperplasiaFriedl et al
      • Friedl R.
      • Li J.
      • Schumacher B.
      • et al.
      Intimal hyperplasia and expression of transforming growth factor-β1 in saphenous veins and internal mammary arteries before coronary artery surgery.
      Zhu et al,
      • Zhu T.
      • Lan B.
      • Meng L.
      • et al.
      ECM-related gene expression profile in vascular smooth muscle cells from human saphenous vein and internal thoracic artery.
      2013
      ECM-related genes (COL4A4, COL11A1, FN1, TNC, THBS1, FBLN1, MMP3, MMP9, TIMP3, WNT5A, SGCD)LIMA and SVSV SMCs have higher expression of ECM-related genesSV SMCs have more migrating capacityZhu et al
      • Zhu T.
      • Lan B.
      • Meng L.
      • et al.
      ECM-related gene expression profile in vascular smooth muscle cells from human saphenous vein and internal thoracic artery.
      Mitra et al,
      • Mitra A.K.
      • Jia G.
      • Gangahar D.M.
      • Agrawal D.K.
      Temporal PTEN inactivation causes proliferation of saphenous vein smooth muscle cells of human CABG conduits.
      2009

      Sur et al,
      • Sur S.
      • Sugimoto J.T.
      • Agrawal D.K.
      Coronary artery bypass graft: why is the saphenous vein prone to intimal hyperplasia?.
      2014

      Hata et al,
      • Hata J.A.
      • Petrofski J.A.
      • Schroder J.N.
      • et al.
      Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts.
      2005
      Phosphatase and tensin homologue deleted on chromosome 10 (PTEN)LIMA and SVPTEN activity is higher in LIMA SMCsAbsence of high PTEN levels in SV SMCs increases their proliferative capacityMitra et al
      • Mitra A.K.
      • Jia G.
      • Gangahar D.M.
      • Agrawal D.K.
      Temporal PTEN inactivation causes proliferation of saphenous vein smooth muscle cells of human CABG conduits.


      Sur et al
      • Sur S.
      • Sugimoto J.T.
      • Agrawal D.K.
      Coronary artery bypass graft: why is the saphenous vein prone to intimal hyperplasia?.


      Hata et al
      • Hata J.A.
      • Petrofski J.A.
      • Schroder J.N.
      • et al.
      Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts.
      Alattar et al,
      • Alattar M.
      • Jiang C.
      • Luan Z.
      • Pan T.
      • Liu L.
      • Li J.
      Neuropilin 1 expression in human aortas, coronaries and the main bypass grafts.
      2014
      Neuropilin 1 (NRP1)LIMA and SVSVs have higher NRP1 expression within adventitiaHigher levels of NRP1, a co-receptor for VEGF, within SV walls increases susceptibility to intimal hyperplasia developmentAlattar et al
      • Alattar M.
      • Jiang C.
      • Luan Z.
      • Pan T.
      • Liu L.
      • Li J.
      Neuropilin 1 expression in human aortas, coronaries and the main bypass grafts.
      Jia et al,
      • Jia G.
      • Mitra A.K.
      • Cheng G.
      • Gangahar D.M.
      • Agrawal D.K.
      Angiotensin II and IGF-1 regulate connexin43 expression via ERK and p38 signaling pathways in vascular smooth muscle cells of coronary artery bypass conduits.
      2007
      Cx43 (GJA1)LIMA and SVAngiotensin II and IGF-1 stimulates Cx43, which leads to higher SMC proliferation in SVs than LIMAGrowth factor–induced Cx43 expression leads to higher proliferation in SV SMCsJia et al
      • Jia G.
      • Mitra A.K.
      • Cheng G.
      • Gangahar D.M.
      • Agrawal D.K.
      Angiotensin II and IGF-1 regulate connexin43 expression via ERK and p38 signaling pathways in vascular smooth muscle cells of coronary artery bypass conduits.
      Payeli et al,
      • Payeli S.K.
      • Latini R.
      • Gebhard C.
      • et al.
      Prothrombotic gene expression profile in vascular smooth muscle cells of human saphenous vein, but not internal mammary artery.
      2008
      ThrombosisTF, tPA (TFPLAT)LIMA and SVLIMA exhibits lower TF but higher tPA levelsDifferential TF/tPA expression leads to longer clotting times and slower SMC migration in LIMAPayeli et al
      • Payeli S.K.
      • Latini R.
      • Gebhard C.
      • et al.
      Prothrombotic gene expression profile in vascular smooth muscle cells of human saphenous vein, but not internal mammary artery.
      Arishiro et al,
      • Arishiro K.
      • Hoshiga M.
      • Ishihara T.
      • Kondo K.
      • Hanafusa T.
      Connexin 43 expression is associated with vascular activation in human radial artery.
      2010
      InflammationCx43 (GJA1)LIMA and RACx43 correlates with NF-κβ in RA SMCs but not in LIMA SMCsLIMA SMCs show decreased inflammatory responseArishiro et al
      • Arishiro K.
      • Hoshiga M.
      • Ishihara T.
      • Kondo K.
      • Hanafusa T.
      Connexin 43 expression is associated with vascular activation in human radial artery.
      Li et al,
      • Li D.Y.
      • Chen H.J.
      • Staples E.D.
      • et al.
      Oxidized low-density lipoprotein receptor LOX-1 and apoptosis in human atherosclerotic lesions.
      2002
      AtherosclerosisoxLDL receptor-1 (OLR1)LIMA, SV, and carotid arteriesoxLDL receptor-1 expression is increased in SV, carotid arteries, and atherosclerotic plaquesLIMA exhibits fewer oxLDL receptors, possibly protecting from atherosclerosisLi et al
      • Li D.Y.
      • Chen H.J.
      • Staples E.D.
      • et al.
      Oxidized low-density lipoprotein receptor LOX-1 and apoptosis in human atherosclerotic lesions.
      CABG, coronary artery bypass graft; cGMP, cyclic guanosine monophosphate; Cx43, connexin 43; EMC, extracellular matrix; eNOS, endothelial nitric oxide synthase; IGF-1, insulin-like growth factor 1; LIMA, left internal mammary artery; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; NO, nitric oxide; oxLDL, oxidized low-density lipoprotein; PDGF, platelet-derived growth factor; RA, radial artery; SMC, smooth muscle cells; SOD1, superoxide dismutase 1; SV, saphenous vein; TF, tissue factor; TGF-β1, transforming growth factor β1; tPS, tissue plasminogen activator; VEGF, vascular endothelial growth factor. For expansion of gene symbols, use search tool at www.genenames.org.
      Importantly, the LIMA and other vascular grafts differ in the activity of a key regulator of vessel wall homeostasis, NO. Nitric oxide is a gas that is continuously synthesized from the amino acid L-arginine by the constitutive calmodulin-dependent enzyme NO synthase within the ECs lining the vessel lumen. Stimulation of NO production is mediated predominantly via nonreceptor pathways (by shear stress from blood flow) with additional autocrine/paracrine signaling (from bradykinin stimulating endothelial B2 kinin receptors). Subsequently, NO stimulates cyclic guanosine monophosphate production within nearby SMCs, causing vasorelaxation. Early studies indicated that relative to saphenous veins, the LIMA exhibits increased NO release,
      • Yang Z.H.
      • von Segesser L.
      • Bauer E.
      • Stulz P.
      • Turina M.
      • Lüscher T.F.
      Different activation of the endothelial L-arginine and cyclooxygenase pathway in the human internal mammary artery and saphenous vein.
      ,
      • Liu Z.G.
      • Ge Z.D.
      • He G.W.
      Difference in endothelium-derived hyperpolarizing factor-mediated hyperpolarization and nitric oxide release between human internal mammary artery and saphenous vein.
      NO-mediated protection from serotonin-induced constriction,
      • Yang Z.H.
      • Diederich D.
      • Schneider K.
      • et al.
      Endothelium-derived relaxing factor and protection against contractions induced by histamine and serotonin in the human internal mammary artery and in the saphenous vein.
      and uniquely NO-mediated vasodilation from exogenous L-arginine.
      • Thorin-Trescases N.
      • Hamilton C.A.
      • Reid J.L.
      • et al.
      Inducible L-arginine/nitric oxide pathway in human internal mammary artery and saphenous vein.
      Collectively, other studies have indicated that the LIMA exhibits increased NO bioactivity and decreased propensity toward vasoconstriction due to differential protein expression (Table). NO is also instrumental in scavenging reactive oxygen species produced by oxidative stress, quenching superoxide ion O2- to form the less oxidizing OONO- (Figure) and thereby reducing O2--mediated DNA damage, lipid and protein oxidation, and mitochondrial dysfunction. To deal with oxidative stress, cells utilize the enzyme superoxide dismutase, which converts O2- into the less reactive H2O2, proceeding down the free radical scavenger cascade (Figure). Comparison studies have similarly documented increased activity of superoxide dismutase and related enzymes in LIMA explants relative to SVGs, conferring the LIMA with increased protection from oxidative stress and subsequent cellular damage (Table).
      Figure thumbnail gr1
      FigureProposed “endocrine” differences contributing to variable graft function among left internal mammary artery (LIMA) grafts and saphenous vein grafts (SVGs). The LIMA and SVGs are believed to secrete different types of exosomes containing microRNA, proteins, and other small molecules. Relative to those from SVGs, exosomes from the LIMA are thought to be rich in substances that induce nitric oxide (NO) production, scavenge free radicals via induction of super oxide dismutase (SOD), and reduce the proliferative effects of vascular smooth muscle cells. These combined actions lead to vasodilatory and anti-inflammatory effects that likely contribute to the enhanced longevity of LIMA grafts. L-arg, L-arginine.
      Among the other cardiovascular pathways, evidence has revealed extensive differences in the expression of mRNA and proteins involved in cellular migration and proliferation across CABG conduits. Typical mitogens such as platelet-derived growth factor B, angiotensin II, and insulin-like growth factor 1 result in higher activity and expression of key proliferative proteins such as p42 mitogen-activated protein kinase, c-Fos, neuropilin 1, transforming growth factor-β1, and certain matrix metalloproteinases in the SMCs of SVGs and RAs, increasing their propensity toward accelerated intimal hyperplasia (Table). Conversely, these pathways are markedly reduced within the SMCs of LIMA explants, leading to cellular quiescence and low levels of inflammation. Similarly, proteins involved in thrombosis (tissue factor) and the development of atherosclerotic plaques (oxidized low-density lipoprotein receptors) exhibit reduced expression in LIMA SMCs, decreasing the risk of eventual graft failure (Table) through plaque rupture or luminal stenosis.

      Role of Exosomes in Cardiovascular Signaling

      Outside the aforementioned differences on a genomic/proteomic level, relatively little is known about other secretory substances that differ across ECs and SMCs comprising the LIMA and saphenous veins. Recently, it has been discovered that nano-sized lipid vesicles known as exosomes are secreted by a variety of cell types and have been implicated in intercellular communication, angiogenesis, and numerous other cellular functions,
      • Théry C.
      • Zitvogel L.
      • Amigorena S.
      Exosomes: composition, biogenesis and function.
      as well as protection in pathologic states such as ischemic reperfusion injury
      • Yellon D.M.
      • Davidson S.M.
      Exosomes: nanoparticles involved in cardioprotection?.
      and atherosclerosis.
      • Huber H.J.
      • Holvoet P.
      Exosomes: emerging roles in communication between blood cells and vascular tissues during atherosclerosis.
      Intriguingly, exosomes enriched in certain shear stress–induced microRNAs (miR-143/145) secreted by ECs have been reported to be protective against atherosclerosis.
      • Hergenreider E.
      • Heydt S.
      • Tréguer K.
      • et al.
      Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs.
      Conversely, atherosclerotic conditions promote packaging of endothelial miRNA-92a-3p into exosomes, which are subsequently transferred to neighboring ECs and promote intimal proliferation and cellular migration.
      • Liu Y.
      • Li Q.
      • Hosen M.R.
      • et al.
      Atherosclerotic conditions promote the packaging of functional microRNA-92a-3p into endothelial microvesicles.
      Studies have documented up-regulation (miR-21, miR-34a, miR-146a, miR-146b-5p, miR-210, miR-1273)
      • Raitoharju E.
      • Lyytikäinen L.-P.
      • Levula M.
      • et al.
      miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study.
      ,
      • Wang R.
      • Dong L.-D.
      • Meng X.-B.
      • Shi Q.
      • Sun W.-Y.
      Unique MicroRNA signatures associated with early coronary atherosclerotic plaques.
      and down-regulation (miR-125a-5p, miR-155, miR-199a/b-3p, miR-221, miR-100)
      • Wang R.
      • Dong L.-D.
      • Meng X.-B.
      • Shi Q.
      • Sun W.-Y.
      Unique MicroRNA signatures associated with early coronary atherosclerotic plaques.
      • Hao L.
      • Wang X.-G.
      • Cheng J.-D.
      • et al.
      The up-regulation of endothelin-1 and down-regulation of miRNA-125a-5p, -155, and -199a/b-3p in human atherosclerotic coronary artery.
      • Wang J.
      • Wu Q.
      • Yu J.
      • Cao X.
      • Xu Z.
      miR-125a-5p inhibits the expression of NLRP3 by targeting CCL4 in human vascular smooth muscle cells treated with ox-LDL.
      of particular microRNAs within atheromatous plaques relative to the atheroma-free internal mammary arteries. A number of other microRNAs have been expressed differentially depending on the cell types associated with atheromatous plaques (leukocytes, vascular SMCs, ECs).
      • Raitoharju E.
      • Oksala N.
      • Lehtimäki T.
      MicroRNAs in the atherosclerotic plaque.
      Of particular interest is miR-126, the most abundant microRNA in ECs, which is also highly expressed within exosomes. Studies have found that exosome-mediated transfer of miR-126 promotes EC repair in an electric denudation model of endothelium
      • Jansen F.
      • Yang X.
      • Hoelscher M.
      • et al.
      Endothelial microparticle-mediated transfer of MicroRNA-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles.
      and appropriately attenuates intimal hyperplasia in a rat model of vein graft disease.
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      miRNA-126-3p Carried by human umbilical cord mesenchymal stem cell enhances endothelial function through exosome-mediated mechanisms in vitro and attenuates vein graft neointimal formation in vivo.
      A recent review compiled data on exosome-derived microRNAs from 92 studies, highlighting unique exosomal profiles based on cell lineages.
      • Cui M.
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      A narrative review of the research status of exosomes in cardiovascular disease.
      Interestingly, ischemic cardiomyocytes were noted to release exosomes containing miR-222/143, which subsequently promote angiogenesis.
      • Ribeiro-Rodrigues T.M.
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      • et al.
      Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis.
      Similarly, miR-217 from cardiac exosomes was found to promote pathologic cardiac hypertrophy and fibrosis by regulating phosphatase and tensin homologue deleted on chromosome 10,
      • Nie X.
      • Fan J.
      • Li H.
      • et al.
      miR-217 Promotes cardiac hypertrophy and dysfunction by targeting PTEN.
      a molecule previously noted to have higher activity in the LIMA relative to SVGs (Table). Other microRNAs such as miR-92a-3p from EC-derived exosomes, miR-342-5p from circulating exosomes, and miR-31 from adipose stem cell–derived exosomes have all been reported to protect the heart from ischemia, while EC exosome–derived MST1 and VCAM1 inhibit cell autophagy and regulate local inflammatory responses.
      • Cui M.
      • Han Y.
      • Yang J.
      • Li G.
      • Yang C.
      A narrative review of the research status of exosomes in cardiovascular disease.
      ,
      • Zhu D.
      • Wang Y.
      • Thomas M.
      • et al.
      Exosomes from adipose-derived stem cells alleviate myocardial infarction via microRNA-31/FIH1/HIF-1α pathway.
      As such, it is likely that the increased longevity of LIMA grafts is secondary to specialized exosomes that deliver a crucial combination of vasodilatory and anti-inflammatory compounds such as NO, antioxidant, and antiatherogenic microRNAs and other antiproliferative proteins (Figure), which may also provide downstream atherosclerotic protection during composite grafting. However, the full exosomal or “endocrine” profile of vascular cells comprising the various CABG conduits (arterial vs venous) is currently unknown. Understanding of exosomal output from these different grafts will allow better characterization of their endocrine influence and potentially either allow, in the long-term, molecular editing of harvested grafts to ensure optimal performance following implant.

      Conclusion and Future Directions

      Since the introduction of the LIMA in CABG, an overwhelming amount of evidence has documented its superiority over SVGs with respect to longevity and patency rates. Although other arterial grafts have been utilized with high success rates and have shown efficacy in halting progression of atherosclerosis, only the LIMA has thus far been associated with spontaneous regression of downstream atheromatous plaques. Numerous molecular pathways related to inflammation, cell proliferation and migration, thrombosis, and vasodilation have been implicated in the success of LIMA grafting. The collective proteome and microRNA content within this unique tissue likely provides inherent and downstream perfusion benefit through antiproliferative, anti-inflammatory, antioxidant, and vasodilatory cues. Understanding of the protective secretory profile germane to the vascular cells comprising the LIMA in relation to other surgical conduits serves to unlock new opportunities in the development of platforms to reverse coronary artery disease. With the emergence of 3D printing, genetic engineering, and other nanotechnologies, it may be possible to synthetically mimic the endocrine function of the LIMA, thereby creating an “off-the-shelf” conduit (and potentially modified drug-eluting stents) that provides maximal beneficial properties to the diseased coronary vessels.

      Potential Competing Interests

      Dr Behfar has been a member of the board and received grants and royalties from Rion LLC, has patents from Cardio3 Biosciences and Rion LLC, and has stock in Rion LLC, Deverra Therapeutics, and Sorrento Therapeutics, Inc. The other authors report no competing interests.

      Acknowledgments

      The authors would like to thank Margaret Alice McKinney from Mayo Media Services for her excellent artistic skills in preparing the central figure.

      Supplemental Online Material

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