Instantaneous wave free ratio value impact on left internal mammary artery graft patency.

OBJECTIVES: To assess whether instantaneous wave - free ratio (iFR) value is associated with left internal mammary artery (LIMA) graft failure at 12 months follow-up post coronary artery bypass graft (CABG). BACKGROUND: Data suggests bypass to a non-significant left anterior descending artery (LAD) lesion due to visual over-estimation may lead to LIMA graft failure. Implementing iFR may result in better arterial graft patency. METHODS: In iCABG (iFR guided CABG) study patients planned to undergo an isolated CABG procedure was prospectively enrolled and iFR was performed for LAD. Coronary computed tomography angiography was performed at 2 and 12 months follow-up. The primary endpoint of this study was to determine the rate of LIMA graft occlusion or hypoperfusion at 2 and 12-months follow-up. We considered a composite secondary endpoint of Major adverse cardiovascular and cerebrovascular event (MACCE) as a secondary outcome. RESULTS: In total 69 patients were included with no differences regarding age, sex and risk factors. At 2 months, 50 of LIMAs with pre-CABG iFR median 0.855 (0.785 - 0.892) were patent. Hypoperfusion was found in 8 LIMAs (median iFR 0.88 (0.842 - 0.90)). While, 7 LIMAs (median iFR 0.91 (0.88 - 0.96)) were occluded (p = 0.04). At 12 months, when iFR of LAD was >0.85: just 12 (31.6% out of all patent LIMAS) grafts were patent and 24 (100.0% out of all hypoperfused/occluded) grafts were hypoperfused or occluded (p < 0.001). In terms of MACCE, no difference (p = 1.0) was found between all 3 groups divided according to iFR value. CONCLUSIONS: Instantaneous wave - free ratio value above 0.85 in LAD is a powerful tool predicting LIMA graft failure at 1-year follow up period.

Resilience of the Internal Mammary Artery to Atherogenesis: Shifting From Risk to Resistance to Address Unmet Needs.

Fueled by the global surge in aging, atherosclerotic cardiovascular disease reached pandemic dimensions putting affected individuals at enhanced risk of myocardial infarction, stroke, and premature death. Atherosclerosis is a systemic disease driven by a wide spectrum of factors, including cholesterol, pressure, and disturbed flow. Although all arterial beds encounter a similar atherogenic milieu, the development of atheromatous lesions occurs discontinuously across the vascular system. Indeed, the internal mammary artery possesses unique biological properties that confer protection to intimal growth and atherosclerotic plaque formation, thus making it a conduit of choice for coronary artery bypass grafting. Its endothelium abundantly expresses nitric oxide synthase and shows accentuated nitric oxide release, while its vascular smooth muscle cells exhibit reduced tissue factor expression, high tPA (tissue-type plasminogen activator) production and blunted migration and proliferation, which may collectively mitigate intimal thickening and ultimately the evolution of atheromatous plaques. We aim here to provide insights into the anatomy, physiology, cellular, and molecular aspects of the internal mammary artery thereby elucidating its remarkable resistance to atherogenesis. We propose a change in perspective from risk to resilience to decipher mechanisms of atheroresistance and eventually identification of novel therapeutic targets presently not addressed by currently available remedies.

Long-term clinical outcomes of coronary artery bypass grafting in young children with Kawasaki disease.

BACKGROUND: Although coronary artery bypass grafting is not frequently performed in children, Kawasaki disease is one of the most common indications for coronary artery bypass grafting in children. Here, we reviewed the long-term clinical outcomes including graft patency after coronary artery bypass grafting. METHODS: Between March 2004 and March 2013, six patients with Kawasaki disease underwent coronary artery bypass grafting. All patients were male. Their median age was 13.0 years (interquartile range, 7.8-17.8 years) at the timing of coronary artery bypass grafting, and the median age at the onset of Kawasaki disease was 3.3 years (interquartile range, 1.0-7.0 years). Four patients presented with multiple lesions including aneurysms. RESULTS: The median follow-up duration was 12.1 years (interquartile range, 9.5-13.1 years), and there were no operative complications or overall mortality. One patient had pre-operative symptoms such as exertional chest pain and dyspnoea on exertion, whereas one patient had ventricular tachyarrhythmia. There was an improvement in subjective symptoms after surgery in two patients. The left internal thoracic artery, right internal thoracic artery, and saphenous vein were used in five (83.3%), one (16.7%), and two (33.3%) cases, respectively. In all six patients, post-operative single-photon emission CT findings showed improved perfusion compared with pre-operative single-photon emission CT. All grafts were patent as confirmed by coronary angiography or CT angiography. CONCLUSIONS: Coronary artery bypass grafting could be a good surgical option in children with coronary lesions caused by Kawasaki disease in terms of graft patency and myocardial perfusion.

Dichloroacetate prevents restenosis in preclinical animal models of vessel injury.

Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

Neoangiogenesis connecting a left internal mammary artery proximal stump to an ischemic area of the heart after bypass occlusion.

Internal mammary arteries (IMAs), via angiogenesis/arteriogenesis, have great potential for developing collaterals. This generally occurs when ischemia involves the inferior limbs or heart. Although this phenomenon may be spontaneous, it seems to be promoted by iatrogenic or voluntary occlusion of the IMAs. We present a patient who underwent triple coronary artery bypass grafting with two saphenous vein grafts and a free-graft left IMA and suffered an acute myocardial infarction 6 weeks after surgery. Emergency coronary angiography revealed occlusion of the grafts and an amazing branch arising from the proximal stump of the surgically-cut and clipped IMA, leading to the anterior wall of the heart, functionally creating an effective natural bypass, probably stimulated both by anterior wall ischemia and interrupted flow within the proximal left IMA.

The relation of left internal mammary artery atherosclerosis with urotensin-II.

BACKGROUND: The aim of our study is to investigate the effects of urotensin-II (U-II) on the left internal mammary artery (LIMA) wall and role of U-II in atherosclerotic processes affecting the long-term patency of LIMA. METHOD: Patients were divided into 2 groups, namely Group I: patients with coronary artery disease (CAD) and Group II: DM + CAD. The patients were evaluated by Gencini scoring before coronary artery bypass grafting (CABG). Routine tissue follow-up, hemotoxylin-eosin staining and immunoreactivity with U-II were observed. Then, vessel damage score, H-Score and LIMA layer thickness were calculated and evaluated statistically. RESULTS: On light microscopic examination, the LIMA total damage score in DM + CAD group was significantly higher compared to the control group. The assessment of H score revealed that U-II was more intense in tunica intima and tunica media in the DM+CAD group as compared to the control group (p < 0.05). Furthermore, tunica intima and tunica media in the DM + CAD group were thicker than in the control group (p < 0.05). CONCLUSIONS: We found that U-II is effective in atherosclerotic processes of arterial grafts. The DM + CAD group has high U-II density with high total damage score in intima and media layers of LIMA. U-II may be effective in late survival results after CABG (Tab. 3, Fig. 2, Ref. 19).

Malignant Phyllodes Tumor Recurrence in the Pleural Cavity via the Deep Inferior Epigastric Perforator Flap and Internal Mammary Vessel Bundle: A Case Report.

We report a rare case that after rapid recurrence there was pathological transition from a fibroadenoma and benign phyllodes tumor to borderline and malignant phyllodes tumor. Another rare finding included tumor dissemination in the pleural cavity via reconstructed deep inferior epigastric perforator flap edge and internal mammary vessel bundle. Hence, we eliminated the use of internal mammary vessel bundle as the recipient vessel for free-flap reconstruction to avoid recurrence in the pleural cavity. Remarkably, we achieved successful reconstruction of 2 huge defects (reconstruction of breast following mastectomy and that of chest wall following en bloc excision of recurrence) using 2 different free flaps.

Perfusion Tissue Culture Initiates Differential Remodeling of Internal Thoracic Arteries, Radial Arteries, and Saphenous Veins.

Adaptive remodeling processes are essential to the maintenance and viability of coronary artery bypass grafts where clinical outcomes depend strongly on the tissue source. In this investigation, we utilized an ex vivo perfusion bioreactor to culture porcine analogs of common human bypass grafts: the internal thoracic artery (ITA), the radial artery (RA), and the great saphenous vein (GSV), and then evaluated samples acutely (6 h) and chronically (7 days) under in situ or coronary-like perfusion conditions. Although morphologically similar, primary cells harvested from the ITA illustrated lower intimal and medial, but not adventitial, cell proliferation rates than those from the RA or GSV. Basal gene expression levels were similar in all vessels, with only COL3A1, SERPINE1, FN1, and TGFB1 being differentially expressed prior to culture; however, over half of all genes were affected nominally by the culturing process. When exposed to coronary-like conditions, RAs and GSVs experienced pathological remodeling not present in ITAs or when vessels were studied in situ. Many of the remodeling genes perturbed at 6 h were restored after 7 days (COL3A1, FN1, MMP2, and TIMP1) while others (SERPINE1, TGFB1, and VCAM1) were not. The findings elucidate the potential mechanisms of graft failure and highlight strategies to encourage healthy ex vivo pregraft conditioning.

Sphingosine-1-phosphate receptor 1 regulates neointimal growth in a humanized model for restenosis.

OBJECTIVE: The main objective of this study was to define a role of sphingosine-1-phosphate receptor 1 (S1PR1) in the arterial injury response of a human artery. The hypotheses were tested that injury induces an expansion of S1PR1-positive cells and that these cells accumulate toward the lumen because they follow the sphingosine-1-phosphate gradient from arterial wall tissue (low) to plasma (high). METHODS: A humanized rat model was used in which denuded human internal mammary artery (IMA) was implanted into the position of the abdominal aorta of immunosuppressed Rowett nude rats. This injury model is characterized by medial as well as intimal hyperplasia, whereby intimal cells are of human origin. At 7, 14, and 28 days after implantation, grafts were harvested and processed for fluorescent immunostaining for S1PR1 and smooth muscle α-actin. Nuclei were stained with 4',6-diamidine-2'-phenylindole dihydrochloride. Using digitally reconstructed, complete cross sections of grafts, intimal and medial areas were measured, whereby the medial area had virtually been divided into an outer (toward adventitia) and inner (toward lumen) layer. The fraction of S1PR1-positive cells was determined in each layer by counting S1PR1-positive and S1PR1-negative cells. RESULTS: The fraction of S1PR1-postive cells in naive IMA is 58.9% ± 6.0% (mean ± standard deviation). At day 28 after implantation, 81.6% ± 4.4% of medial cells were scored S1PR1 positive (P < .01). At day 14, the ratio between S1PR1-positive and S1PR1-negative cells was significantly higher in the lumen-oriented inner layer (9.3 ± 2.1 vs 6.0 ± 1.0; P < .01). Cells appearing in the intima at day 7 and day 14 were almost all S1PR1 positive. At day 28, however, about one-third of intimal cells were scored S1PR1 negative. CONCLUSIONS: From these data, we conclude that denudation of IMA specifically induces the expansion of S1PR1-positive cells. Based on the nonrandom distribution of S1PR1-positive cells, we consider the possibility that much like lymphocytes, S1PR1-positive smooth muscle cells also use S1PR1 to recognize the sphingosine-1-phosphate gradient from tissue (low) to plasma (high) and so migrate out of the media toward the intima of the injured IMA.

Robotic lymphadenectomy of an internal mammary lymph node metastasis.

A 58-year-old woman was diagnosed with a left-sided lone internal mammary swollen lymph node on a routine follow-up computer tomography, 42 months after a left mastectomy in the context of a ductal carcinoma grade III. The suspected metastasis was successfully removed in toto using a 3-port-da Vinci robotic procedure and the patient was discharged home without any complication on the third postoperative day. Robotically assisted oncological lymph node removal is safe, easily performed and economically affordable.

Adipo/cytokines in atherosclerotic secretomes: increased visfatin levels in unstable carotid plaque.

BACKGROUND: Novel pro-inflammatory and anti-inflammatory derivatives from adipose tissue, known as adipokines, act as metabolic factors. The aim of this study was to analyse the secreted expression of different adipo/cytokines in secretomes of unstable carotid atherosclerotic plaque versus non-atherosclerotic mammary artery. METHODS: We evaluated the secretion levels of adiponectin, visfatin, lipocalin-2, resistin, IL-6 and TNFR2 by ELISA in human secretomes from cultured unstable carotid atherosclerotic plaque (n = 18) and non-atherosclerotic mammary artery (n = 13). We also measured visfatin serum levels in patients suffering from atherosclerosis and in a serum cohort of healthy subjects (n = 16). RESULTS: We found that visfatin levels were significantly increased in unstable carotid atherosclerotic plaque secretome than in non-atherosclerotic mammary artery secretome. No differences were found with regard the other adipo/cytokines studied. Regarding visfatin circulating levels, there were no differences between unstable carotid atherosclerotic plaque and non-atherosclerotic mammary artery group. However, these visfatin levels were increased in comparison to serum cohort of healthy subjects. CONCLUSIONS: Of all the adipo/cytokines analysed, only visfatin showed increased levels in secretomes of unstable carotid atherosclerotic plaque. Additional human studies are needed to clarify the possible role of visfatin as prognostic factor of unstable carotid atherosclerotic plaque.

Transit-time flow measurement as a predictor of coronary bypass graft failure at one year angiographic follow-up.

BACKGROUND: Transit-time flow measurement (TTFM) is a commonly used intraoperative method for evaluation of coronary artery bypass graft (CABG) anastomoses. This study was undertaken to determine whether TTFM can also be used to predict graft patency at one year postsurgery. METHODS: Three hundred forty-five CABG patients with intraoperative graft flow measurements and one year angiographic follow-up were analyzed. Graft failure was defined as more than 50% stenosis including the "string sign." Logistic regression analysis was used to analyze the risk of graft failure after one year based on graft vessel type, anastomatic configuration, and coronary artery size. RESULTS: Nine hundred eighty-two coronary anastomoses were performed of which 12% had signs of graft failure at one year angiographic follow-up. In internal mammary arteries (IMAs), analysis showed a 4% decrease in graft failure odds for every 1 mL/min increase in TTFM (OR = 0.96, CI = [0.93; 0.99], p = 0.005). ROC analysis showed good discriminative ability for TTFM alone AUC = 69.5% in IMA grafts. For single-vein grafts the decrease in graft failure odds was 2% for every 1 mL/min increase in TTFM (OR = 0.98; CI = [0.97; 1.00], p = 0.059) and AUC of 59.9%. There were no significant relationships between TTFM and graft failure in other graft types or graft configurations. CONCLUSION: The TTFM method has good discriminative ability for assessing the risk of graft failure in certain graft types within the first year after CABG surgery and is a valuable instrument for intraoperative quality assessment of bypass grafts.

Spontaneous spiral dissection of left internal thoracic artery graft.

The left internal thoracic artery (LITA) is considered the most reliable coronary artery bypass grafting conduit due to its high rate of long-term patency. LITA grafts are extremely durable and associated complications are infrequent. We present a case with spontaneous spiral dissection of a LITA graft to the left anterior descending artery, which was assessed by optical coherence tomography (OCT) and intravascular ultrasound (IVUS). OCT was superior in visualizing the disrupted flap, false lumen, and intramural hematoma, but it did not visualize the full extent of the vessel wall. In contrast, IVUS allowed more complete and deeper vessel visualization, and thus better appreciation of the extent of intramural hematoma. Combined use of these two modalities provides complementary details on imaging of a LITA dissection.

Aortocoronary Saphenous Vein Graft Aneurysm with Fistula to the Right Atrium: Percutaneous Management of Surgical Complication.

Aneurysmal dilatation of aortocoronary saphenous vein grafts (SVG) is a rare but known complication after coronary artery bypass grafting (CABG). They are most commonly found incidentally, although some may present with unstable angina or myocardial infarction (MI). Rarely, these aneurysms can develop into fistulas to the neighboring cardiac chambers. We report the case of a 66-year old woman with a history of CABG in 1996 with a left internal mammary artery (LIMA) graft to the left anterior descending and a SVG to distal right coronary artery presenting with non-ST segment elevation myocardial infarction (NSTEMI) complicated with congestive heart failure. Selective Coronary and Graft angiography showed an aneurysm in the mid SVG with a fistula into the right atrium (RA) resulting in a significant left to right shunt. The significant left to right shunt diverted blood flow from right coronary artery territory resulting in recurrent ischemia and angina and introduced a significant volume overload on the right ventricle resulting in over heart failure. Secondary to the course of LIMA graft along the sternum, surgery was not an option. Secondary to continued symptoms percutaneous intervention was performed with placement of two 6.0 x 50 mm Viabahn self-expanding covered stent with aggressive post-dilation resulting in successful closure with no residual flow. Percutaneous intervention is shown to be an effective approach to manage both aortocoronary fistula and grafts ruptures and is associated with better outcomes than surgical and conservative options. To the best of our knowledge, this is the first reported case of a successful closure of fistulous communication of a SVG aneurysm to the RA utilizing multiple peripheral covered stents.

Chemoembolization via the left internal mammary artery supplying hepatocellular carcinoma.

PURPOSE: To present radiologic findings that show favorable tumor response after chemoembolization via the left internal mammary artery (LIMA). MATERIALS AND METHODS: Between October 2002 and April 2013, 57 patients with hepatocellular carcinoma (HCC) underwent 69 sessions of chemoembolization via the LIMA. Imaging findings including tumor size, location, and visibility of tumor-feeding artery on cross-sectional images were retrospectively reviewed in consensus by two radiologists. Tumor response after chemoembolization via the LIMA was assessed by the modified Response Evaluation Criteria in Solid Tumors on follow-up multidetector computed tomography in consensus. RESULTS: The mean tumor size supplied by the LIMA was 6.8 cm (range, 1.0-21.0 cm). HCCs supplied by the LIMA tended to be located in the subcapsular area including exophytic features (57 of 57; 100%) and were more likely to be located in the left lobe of the liver (56 of 57; 98%). HCCs supplied by the LIMA were more likely to be multiple or infiltrative (52 of 57; 91%) and marginally recurred (43 of 57; 75%). Feeding arteries of the LIMA were identified in a high percentage of cases (49 of 66; 74%) on cross-sectional images obtained before embolization. Regarding tumor response, tumors that were newly developed or exclusively supplied by the LIMA showed better target tumor response (P = .011 and P < .0001, respectively). On multivariate analysis, tumors exclusively supplied by the LIMA showed significantly better target tumor response with odds ratio of 16.32. CONCLUSIONS: Chemoembolization via the LIMA has a favorable target tumor response when HCCs are exclusively supplied by the LIMA.

Wnt signaling cascade in restenosis: a potential therapeutic target of public health relevance in a North American cohort of Nebraska State.

Cardiovascular disease is a leading cause of morbidity and mortality in United States, including Nebraska. Neointimal hyperplasia leading to restenosis is a major public health problem. Identification of key signaling molecules in biochemical pathways is an attractive strategy for development of predictive biomarkers in occlusive vascular diseases (OVD). Our pilot study aimed to identify the role of Wnt-frizzled signaling in restenosis in a North American cohort. North American patients (n = 9) undergoing coronary artery bypass graft surgery at Nebraska Heart Institute, Lincoln, were enrolled. Human saphenous veins (SV) (n = 9) and left internal mammary arteries (LIMA) (n = 9) received post-surgery at Creighton University, Omaha, were harvested using Collagenase-IV digestion method. Isolated primary VSMCs were cultured for 3-4 weeks, and passages P3-P7, were used for molecular biology experiments. The study was approved by the Institutional Review Board. RNA was extracted using trizol method and mRNA transcripts were identified using reverse transcriptase-polymerase chain reaction followed by 2% agarose gel electrophoresis. Mean age of surgery patients (n = 9) was 60.3 years (SD ± 6.5 years). Wnt2 and Wnt5a mRNA transcripts were expressed in human VSMCs; however, Wnt1, Wnt4 and Wnt11 mRNA were not expressed; beta-actin was used as an internal control. Receptor studies demonstrated the expression of Fzd1, Fzd2 and Fzd5 mRNA in hVSMCs. Our preliminary data implicates the public health significance of Wnt signaling in bypass graft patients in Nebraska. Future molecular biology approach-based community health studies targeting Wnt pathway may aid in the development of cost-effective predictive biomarkers for OVD susceptible populations.

Coronary artery bypass graft: why is the saphenous vein prone to intimal hyperplasia?

Proliferation and migration of smooth muscle cells and the resultant intimal hyperplasia cause coronary artery bypass graft failure. Both internal mammary artery and saphenous vein are the most commonly used bypass conduits. Although an internal mammary artery graft is immune to restenosis, a saphenous vein graft is prone to develop restenosis. We found significantly higher activity of phosphatase and tensin homolog (PTEN) in the smooth muscle cells of the internal mammary artery than in the saphenous vein. In this article, we critically review the pathophysiology of vein-graft failure with detailed discussion of the involvement of various factors, including PTEN, matrix metalloproteinases, and tissue inhibitor of metalloproteinases, in uncontrolled proliferation and migration of smooth muscle cells towards the lumen, and invasion of the graft conduit. We identified potential target sites that could be useful in preventing and (or) reversing unwanted consequences following coronary artery bypass graft using saphenous vein.

Comparison of thermal damage of the internal thoracic artery using ultra high radiofrequency and monopolar diathermy.

BACKGROUND: The internal thoracic artery (ITA) has been accepted worldwide as a first choice conduit for myocardial revascularisation. It still remains questionable what is the best method for ITA harvesting in a skeletonized fashion according to structural integrity of artery, as a risk factor of early and late graft failure. The purpose of this study was to determine the impact of the ultra-high radiofrequency energy used for ITA harvesting on arterial structural integrity, in particular on the endothelial layer. METHODS: Seventy-four ITA specimens were divided into two groups depending on device used for harvesting (radiofrequency-knife (RF) or electrocauter (EC)). Thermal damage on arterial structural integrity was measured using light microscope, morphometric imaging analysis and immunohistochemical methods. RESULTS: Thermal damage of endothelium was 2.8 times higher in EC than in RF group (p = 0.041) and 5 times higher in patients older than 66 years of age (p = 0.002). Extent of endothelial damage (graded from 0 to 3) was significantly higher in EC group (p = 0.03). Also, in EC group, in patients older than 66 years of age higher proportion of extent of endothelial damage was found (p = 0.027). CONCLUSIONS: The endothelial damage was more often in EC than in RF group as in the patients older than 66 years of age. Demonstrated results suggest that the radiosurgery in comparison to conventional electrocautery is safe and effective method, and significantly reduces thermal damage to endothelial layer of artery.

Level of Perivascular Inflammation Is Significantly Lower Around the Left Internal Mammary Artery Than Around Native Coronary Arteries.

BACKGROUND: The left internal mammary artery (LIMA) is protected from developing atherosclerosis. Perivascular inflammation, which is closely associated with atherosclerosis, can be measured by perivascular adipose tissue attenuation on computed tomography angiography. Whether the absence of atherosclerosis in LIMA is related to the lower level of perivascular inflammation is unknown. This study was performed to compare the level of perivascular inflammation between LIMA in situ and native coronary arteries in patients with coronary artery disease. METHODS AND RESULTS: A total of 573 patients who underwent both computed tomography angiography and optical coherence tomography imaging were included. The level of perivascular adipose tissue attenuation between LIMA in situ and coronary arteries was compared. Perivascular adipose tissue attenuation around LIMA in situ was significantly lower around the 3 coronary arteries (-82.9 [-87.3 to -78.0] versus -70.8 [-75.9 to -65.9]; P<0.001), irrespective of the level of pericoronary inflammation or the number of vulnerable features on optical coherence tomography. When patients were divided into high and low pericoronary inflammation groups, those in the high inflammation group had more target vessel failure (hazard ratio, 2.97 [95% CI, 1.16-7.59]; P=0.017). CONCLUSIONS: The current study demonstrated that perivascular adipose tissue attenuation was significantly lower around LIMA in situ than around native coronary arteries. The lower level of perivascular inflammation may be related to the low prevalence of atherosclerosis in LIMA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04523194.

SERCA2a gene transfer prevents intimal proliferation in an organ culture of human internal mammary artery.

Coronary restenosis, a major complication of percutaneous balloon angioplasty, results from neointimal proliferation of vascular smooth muscle cells (VSMCs). The sarco/endoplasmic reticulum calcium ATPase 2a isoform (SERCA2a), specific to contractile VSMCs, has been reported previously to be involved in the control of the Ca(2+)-signaling pathways governing proliferation and migration. Moreover, SERCA2a gene transfer was reported to inhibit in vitro VSMC proliferation and to prevent neointimal thickening in a rat carotid injury model. The aim of this study was to evaluate the potential therapeutic interest of SERCA2a gene transfer for prevention of in-stent restenosis using a ex vivo model of human left internal mammary artery (hIMA) intimal thickening. Left hIMAs, obtained at the time of aorto-coronary bypass surgeries, were subjected to balloon dilatation followed by infection for 30 min with adenoviruses encoding either human SERCA2 and green fluorescence protein (GFP) or control gene (ß-galactosidase, ß-gal) and GFP. Proliferation of subendothelial VSMCs and neointimal thickening were observed in balloon-injured hIMA maintained 14 days in organ culture under constant pressure and perfusion. SERCA2a gene transfer prevented vascular remodeling and significantly (P<0.01, n=5) reduced neointimal thickening in injured arteries (intima/media ratio was 0.07±0.01 vs 0.40±0.03 in ß-gal-infected arteries). These findings could have potential implications for treatment of pathological in-stent restenosis.