Effects of graft preservation conditions on coronary endothelium and cardiac functional recovery in a rat model of donation after circulatory death.

BACKGROUND: Use of cardiac grafts obtained with donation after circulatory death (DCD) could significantly improve donor heart availability. As DCD hearts undergo potentially deleterious warm ischemia and reperfusion, clinical protocols require optimization to ensure graft quality. Thus, we investigated effects of alternative preservation conditions on endothelial and/or vascular and contractile function in comparison with the current clinical standard. METHODS: Using a rat DCD model, we compared currently used graft preservation conditions, St. Thomas n°2 (St. T) at 4°C, with potentially more suitable conditions for DCD hearts, adenosine-lidocaine preservation solution (A-L) at 4°C or 22°C. Following general anesthesia and diaphragm transection, hearts underwent either 0 or 18 min of in-situ warm ischemia, were explanted, flushed and stored for 15 min with either St. T at 4°C or A-L at 4°C or 22°C, and then reperfused under normothermic, aerobic conditions. Endothelial integrity and contractile function were determined. RESULTS: Compared to 4°C preservation, 22°C A-L significantly increased endothelial nitric oxide synthase (eNOS) dimerization and reduced oxidative tissue damage (p < 0.05 for all). Furthermore, A-L at 22°C better preserved the endothelial glycocalyx and coronary flow compared with St. T, tended to reduce tissue calcium overload, and stimulated pro-survival signaling. No significant differences were observed in cardiac function among ischemic groups. CONCLUSIONS: Twenty-two-degree Celsius A-L solution better preserves the coronary endothelium compared to 4°C St. T, which likely results from greater eNOS dimerization, reduced oxidative stress, and activation of the reperfusion injury salvage kinase (RISK) pathway. Improving heart preservation conditions immediately following warm ischemia constitutes a promising approach for the optimization of clinical protocols in DCD heart transplantation.

ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes.

Complement promotes vascular inflammation in transplant organ rejection and connective tissue diseases. Here we identify ZFYVE21 as a complement-induced Rab5 effector that induces non-canonical NF-κB in endothelial cells (EC). In response to membrane attack complexes (MAC), ZFYVE21 is post-translationally stabilized on MAC+Rab5+ endosomes in a Rab5- and PI(3)P-dependent manner. ZFYVE21 promotes SMURF2-mediated polyubiquitinylation and proteasome-dependent degradation of endosome-associated PTEN to induce vesicular enrichment of PI(3,4,5)P3 and sequential recruitment of activated Akt and NF-κB-inducing kinase (NIK). Pharmacologic alteration of cellular phosphoinositide content with miltefosine reduces ZFYVE21 induction, EC activation, and allograft vasculopathy in a humanized mouse model. ZFYVE21 induction distinctly occurs in response to MAC and is detected in human renal and synovial tissues. Our data identifies ZFYVE21 as a Rab5 effector, defines a Rab5-ZFYVE21-SMURF2-pAkt axis by which it mediates EC activation, and demonstrates a role for this pathway in complement-mediated conditions.

Comparison of Outcomes of Percutaneous Coronary Intervention on Native Coronary Arteries Versus on Saphenous Venous Aorta Coronary Conduits in Patients With Low Left Ventricular Ejection Fraction and Impella Device Implantation Achieved or Attempted (from the PROTECT II Randomized Trial and the cVAD Registry).

Patients with prior coronary artery bypass grafting (CABG) represent a high-risk cohort given associated medical conditions and worse outcome of saphenous vein graft compared with native vessel percutaneous coronary intervention (PCI). The goal of the current analysis was to compare clinical outcomes in 591 patients with and without prior CABG and multivessel coronary artery disease or unprotected left main disease and severely reduced left ventricular systolic function underwent Impella supported PCI from the PROTECT II randomized trial and the cVAD Registry. Patients with prior CABG surgery (n = 201) were compared with those without prior CABG surgery (n = 390). The primary end point of this analysis was overall mortality at 30 days. Patients with prior CABG surgery had greater Society of Thoracic Surgery mortality score compared with patients without prior CABG surgery, 7.6 ± 6.4 versus 5.1 ± 5.5, respectively, p <0.001. Saphenous vein graft PCI was performed in 17% of patients with prior CABG surgery. Number of vessels treated was lower in patients with prior CABG surgery compared with patients without prior CABG surgery, 1.66 ± 0.56 versus 1.89 ± 0.64, respectively, p <0.001. Achievement of TIMI 3 flow post PCI and overall PCI success was similar in the two groups. Overall mortality at 30 days was similar in patients with prior CABG surgery compared with patients without prior CABG surgery, 6.75% versus 6.61%, respectively, p = 1.0. In conclusion, in this high-risk cohort of patients underwent hemodynamically supported PCI, prior CABG surgery was not associated with worse outcome. The use of hemodynamic support appears to mitigate the increased risk of PCI associated with prior CABG.

The C-Port Distal Coronary Anastomotic Device Is Comparable With a Hand-Sewn Anastomosis: Human Histological Case Study.

Coronary artery bypass surgery is most commonly performed using a hand-sewn technique with a continuous monofilament suture. The C-Port distal anastomotic device is a miniature stapler designed to create an arteriotomy and attach the graft to the coronary artery all in one step. It is the only distal coronary anastomotic device currently approved for clinical use and can be useful in facilitating less invasive coronary surgery. This report examines the histological attributes of such an anastomosis in a patient who underwent heart transplantation approximately 1 year after robotic totally endoscopic stapled coronary bypass using the C-Port anastomotic device. There have been no previous reports of histological examination of this type of bypass graft in humans in the literature. We found that the C-Port single-shot stapled coronary anastomotic device had a similar histological appearance to a traditional hand-sewn technique using monofilament suture. The amount of inflammation around the anastomosis using the two techniques was found to be comparable in this histological case study in an explanted human heart. There was no evidence of increased neointimal hyperplasia. These findings add to the already known equivalent clinical patency rates of the C-Port device in coronary bypass procedures.

Surgical Results and Outcomes After Reimplantation for the Management of Anomalous Aortic Origin of the Right Coronary Artery.

BACKGROUND: Anomalous aortic origin of the right coronary artery (AAORCA) has been reported to cause myocardial ischemia, leading to angina, dyspnea, and decreased exercise tolerance. Reimplantation is a repair technique devised to exclude the abnormal intramural portion of the anomalous artery and avoid the known late attrition of saphenous vein grafts. Our study aims to evaluate the medium-term clinical outcomes with this technique. METHODS: A retrospective review was made of patients who underwent repair of AAORCA by reimplantation between 2002 and 2014 in two institutions in Western Australia. Follow-up computed tomography coronary angiography was used to assess the status of the reimplanted right coronary artery (RCA). Data on survival, freedom from symptoms, cardiac events, and cardiac interventions were also analyzed. RESULTS: Of the 16 patients (aged 17 to 70 years old), 14 (88%) were symptomatic before surgery, with angina (50%) and exertional dyspnea (56%) being the most common symptoms. Surgical reimplantation was successful in 15 patients (94%) without operative mortality. One patient required saphenous vein bypass grafting of the RCA intraoperatively after presumed failed repair and difficulty weaning from cardiopulmonary bypass. All patients who had successful reimplantation of AAORCA were symptom-free after surgery, and none had subsequent cardiac events attributable to the RCA or required further interventions. Ten patients (67%) had computed tomography coronary angiography after surgery; none had stenosis, kinking, or compression of the RCA by the pulmonary artery. Two further patients (including the patient who underwent saphenous vein grafting for presumed failed reimplantation) underwent conventional angiography, which demonstrated patent reimplantations. CONCLUSIONS: To the best of our knowledge, this is the largest reported series of anomalous RCA managed by surgical reimplantation. Our results suggest that this technique is safe and has excellent medium to long-term results regarding symptom-free survival.

A novel parasternal transthoracic echocardiographic window for detecting coronary ostial dilation after modified Bentall surgery.

BACKGROUND: During the modified Bentall surgery (aortic root replacement), a cuff of native aorta is implanted, together with the coronary ostium, into the aortic graft. Multi-detector computed tomography (MDCT) imaging can accurately assess the coronary ostial anastomosis site post-surgery. In this study, we assessed the feasibility of imaging the coronary ostial anastomosis site using transthoracic echocardiography (TTE). METHODS: Patients (n = 14, mean age 65 ± 12 years, 79% males) with previous Bentall surgery underwent TTE study, with MDCT (64-slice) as the reference standard. TTE used conventional and novel acoustic windows to interrogate the coronary ostia. RESULTS: All coronary ostia (n = 28) were well-visualized with MDCT. The optimum TTE acoustic window for visualizing the coronary ostia was a superiorly positioned parasternal short-axis view with the probe tilted towards the left shoulder, medially angulated for the right coronary artery ostia (RCAos) and laterally angulated for the left main coronary artery (LMAos). In this off-axis position, 10 (71%) LMAos and 13 (93%) RCAos could be visualized. In the conventional parasternal views, only 5 (36%) RCAos and no LMAos could be visualized. TTE underestimated the diameter of the LMAos (10.0 ± 2.4 mm TTE vs. 13.4 ± 2.7 mm MDCT, p = 0.007), but was similar to MDCT for the RCAos (9.8 ± 3.1 mm TTE vs. 11.1 ± 3.2 mm MDCT, p = 0.10). CONCLUSIONS: We report a novel TTE acoustic window to image the coronary ostia of post-Bentall surgery patients. Although TTE underestimates the left coronary ostium size, recognition of the ostial dilation with TTE appears feasible in most patients. Those that cannot be imaged will require alternative imaging modality such as MDCT.

Reimplantation of anomalous single coronary artery from pulmonary artery: diagnosis and surgical management.

A newborn presented in cardiogenic shock with the diagnosis of anomalous single coronary artery from pulmonary artery and was successfully revived with prostaglandin (PGE1) infusion. She underwent surgical implantation of her coronary arteries while receiving PGE1 infusion to maintain high oxygen tension for the coronaries during cardiopulmonary bypass. She was discharged in 2 weeks with good biventricular function and moderate mitral regurgitation. At 2 months follow-up, she was gaining weight with preserved ventricular function and moderate mitral regurgitation.

Neutralizing IL-6 reduces human arterial allograft rejection by allowing emergence of CD161+ CD4+ regulatory T cells.

Perioperative injuries to an allograft exacerbate graft rejection, which in humans is primarily mediated by effector memory T cells. IL-6 transcripts in human coronary artery segments rapidly increase posttransplantation into immunodeficient mouse hosts compared with those of pretransplant specimens and fall dramatically by 30 d. Adoptive transfer of human PBMCs allogeneic to the artery 2 d postoperatively results in T cell infiltrates and intimal expansion 4 wk later. Ab neutralization of human IL-6 reduces the magnitude of intimal expansion and total T cell infiltration but increases the relative expression of CD161 while decreasing other Th17 markers. Coculture of MHC class II-expressing human endothelial cells (ECs) with allogeneic CD4(+) memory T cells results in T cell activation and EC secretion of IL-6. Neutralizing IL-6 in primary allogeneic T cell-EC cocultures results in enhanced T cell proliferation of CD161(+) CD4(+) T cells, reduces total T cell proliferation upon restimulation in secondary cultures (an effect dependent on CD161(+) T cells), increases expression of FOXP3 in CD161(+) T cells, and generates T cells that suppress proliferation of freshly isolated T cells. These data suggest that IL-6 released from injured allograft vessels enhances allogeneic T cell infiltration and intimal expansion in a model of human allograft rejection by inhibiting an increase in CD161(+) regulatory T cells.

IFN-gamma primes intact human coronary arteries and cultured coronary smooth muscle cells to double-stranded RNA- and self-RNA-induced inflammatory responses by upregulating TLR3 and melanoma differentiation-associated gene 5.

Atherosclerosis of native coronary arteries and graft arteriosclerosis in transplanted hearts are characterized by activation of innate and adaptive immune responses. Nucleic acids generated by infections or cell death have been detected within arteriosclerotic lesions, and it is known that microbial and synthetic nucleic acids evoke inflammatory responses in cultured vascular cells. In this study, we report that model RNA, but not DNA, instigated robust cytokine and chemokine production from intact human coronary arteries containing both intrinsic vascular cells and resident/infiltrating leukocytes. An ssRNA analog induced TNF-alpha and IFN-gamma-induced protein of 10 kDa secretion by isolated human PBMCs, but not vascular cells. Conversely, synthetic dsRNA induced these inflammatory mediators by vascular cells, but not PBMCs. IFN-gamma, a cytokine linked to atherosclerosis and graft arteriosclerosis, potentiated the inflammatory responses of intact arteries and cultured vascular smooth muscle cells (VSMCs) to polyinosinic:polycytidylic acid [poly(I:C)] and was necessary for inflammatory responses of VSMC to self-RNA derived from autologous cells. IFN-gamma also induced the expression of TLR3, melanoma differentiation-associated gene 5, and retinoic acid-inducible gene I dsRNA receptors. Small interfering RNA knockdown revealed that TLR3 mediated VSMC activation by poly(I:C), whereas melanoma differentiation-associated gene 5 was more important for VSMC stimulation by self-RNA. IFN-gamma-mediated induction of dsRNA receptors and priming for inflammatory responses to poly(I:C) was confirmed in vivo using immunodeficient mice bearing human coronary artery grafts. These findings suggest that IFN-gamma, and by inference adaptive immunity, sensitizes the vasculature to innate immune activators, such as RNA, and activation of IFN-gamma-primed vascular cells by exogenous or endogenous sources of RNA may contribute to the inflammatory milieu of arteriosclerosis.

VEGF blockade inhibits lymphocyte recruitment and ameliorates immune-mediated vascular remodeling.

RATIONALE: There are conflicting data on the effects of vascular endothelial growth factor (VEGF) in vascular remodeling. Furthermore, there are species-specific differences in leukocyte and vascular cell biology and little is known about the role of VEGF in remodeling of human arteries. OBJECTIVE: We sought to address the role of VEGF blockade on remodeling of human arteries in vivo. METHODS AND RESULTS: We used an anti-VEGF antibody, bevacizumab, to study the effect of VEGF blockade on remodeling of human coronary artery transplants in severe combined immunodeficient mice. Bevacizumab ameliorated peripheral blood mononuclear cell-induced but not interferon-gamma-induced neointimal formation. This inhibitory effect was associated with a reduction in graft T-cell accumulation without affecting T-cell activation. VEGF enhanced T-cell capture by activated endothelium under flow conditions. The VEGF effect could be recapitulated when a combination of recombinant intercellular adhesion molecule 1 and vascular cell adhesion molecule-1 rather than endothelial cells was used to capture T cells. A subpopulation of CD3+ T cells expressed VEGF receptor (VEGFR)-1 by immunostaining and FACS analysis. VEGFR-1 mRNA was also detectable in purified CD4+ T cells and Jurkat and HSB-2 T-cell lines. Stimulation of HSB-2 and T cells with VEGF triggered downstream ERK phosphorylation, demonstrating the functionality of VEGFR-1 in human T cells. CONCLUSIONS: VEGF contributes to vascular remodeling in human arteries through a direct effect on human T cells that enhances their recruitment to the vessel. These findings raise the possibility of novel therapeutic approaches to vascular remodeling based on inhibition of VEGF signaling.

Stent-graft repair of coronary vein graft aneurysm.

The authors describe treating a 6-cm right coronary artery bypass graft aneurysm that was causing recurrent angina. With use of the combined skills of interventional radiologists and cardiologists, the aneurysm was successfully occluded by using a stent-graft typically used to treat aneurysms in the peripheral circulation. One month after the procedure, the aneurysm had sealed at follow-up computed tomographic angiography.

Interferon-gamma induces human vascular smooth muscle cell proliferation and intimal expansion by phosphatidylinositol 3-kinase dependent mammalian target of rapamycin raptor complex 1 activation.

Interferon (IFN)-gamma, a cytokine characteristically expressed in arteriosclerotic diseases, acts directly on vascular smooth muscle cells to induce cellular proliferation and intimal expansion. Signaling by the mammalian target of rapamycin raptor complex, known as mTORC1, is associated with cell growth and is active within arteriosclerotic lesions but is not known to be triggered by proinflammatory factors in vascular smooth muscle cells. We investigated the mechanisms for the proarteriosclerotic effects of IFN-gamma in the absence of leukocytes by exploiting the species specificity of this cytokine in a chimeric model of immunodeficient mouse recipients bearing human coronary artery grafts and intravenously inoculated with adenovirus encoding a human IFN-gamma transgene. We found that IFN-gamma-mediated vascular smooth muscle cell proliferation and intimal expansion were associated with phosphorylation of the mTORC1 effector ribosomal protein S6 kinase 1, that the graft morphological changes and S6 kinase 1 activation were inhibited by the mTORC1 inhibitor rapamycin in vivo, and that IFN-gamma-induced mTORC1 signaling was dependent on phosphatidylinositol 3-kinase activity under serum-free conditions in vitro. Our work establishes an immunologic stimulus for mTORC1 signaling in vascular smooth muscle cells, emphasizes that mTORC1 activation is critical in immune-mediated vascular remodeling, and provides further mechanistic insight into the successful clinical application of rapamycin therapy for atherosclerosis and graft arteriosclerosis.

Arterial grafting for myocardial revascularization: how better is it?

PURPOSE OF REVIEW: Arterial conduits are becoming popular in cardiac surgery. Clinical studies and long-term follow-ups have proven that this technique provides satisfactory long-lasting results. The purpose of this review is to give an overview of the main articles from recent literature and compare the latest results. RECENT FINDINGS: Arterial conduits are currently used in cardiac surgery and clinical follow-ups are confirming some advantages in performing multiple arterial revascularization compared to the saphenous vein and the mammary artery. Mid-term follow-ups are encouraging the use of the radial artery as the second conduit of choice after the internal mammary artery. Moreover, off-pump cardiac surgery is an alternative to perform extensive myocardial revascularization in selected patients. Use of in-situ mammary arteries and off-pump surgery has already been described as the ideal solution to guarantee the 'no touch aorta technique'. Recent results lead us to use the radial artery and the gastroepiploic artery as complement composite grafts to perform total arterial myocardial revascularization during off-pump coronary surgery. SUMMARY: Arterial grafting provides satisfactory results. The second graft of choice after the mammary artery is the radial artery, but long-term results are still not available. To reduce the risk of major neurological complications, selected patients benefit from off-pump arterial revascularization.

Absence of histamine-induced nitric oxide release in the human radial artery: implications for vasospasm of coronary artery bypass vessels.

Radial artery (RA) bypass grafts can develop severe vasospasm. As histamine is known to induce vasospasm, its effect on RA was assessed compared with the classic bypass vessels internal mammary artery (MA) and saphenous vein (SV). The vessels were examined in organ chambers for isometric tension recording. Histamine induced contractions on baseline; the sensitivity was higher in RA and SV than MA. After precontraction with norepinephrine, histamine did not evoke relaxations of RA but induced relaxations of MA and less of SV at lower concentrations; it induced contractions at higher concentrations, reaching similar levels in all three vessels. Indomethacin did not affect the response of MA and RA but potentiated relaxations and reduced contractions of SV. Endothelium removal, N(omega)-nitro-L-arginine methyl ester (L-NAME), or the H2-receptor blocker cimetidine did not affect the response of RA, but inhibited relaxations and enhanced contractions in MA and inhibited relaxations in SV; in the latter, only L-NAME enhanced contractions. Real-time PCR detected much lower expression of endothelial H2-receptor in RA than MA or SV. Western blots revealed similar endothelial nitric oxide (NO) synthase expression in all three vessels. Relaxations to acetylcholine were identical in RA and MA. Thus histamine releases NO by activating the endothelial H2-receptor, the expression of which is much lower in RA than MA or SV. H2-receptor activation also releases prostaglandins in SV, partially antagonizing NO. The lack of histamine-induced NO production represents a possible mechanism of RA vasospasm.

Using the bilateral internal mammary artery in the left or right coronary artery system: 5-year comparison of operation techniques and angiographic results.

OBJECTIVE: Using the bilateral internal mammary artery (IMA) in coronary artery bypass grafting (CABG) surgery has prolonged survival, improved functional capacity, and reduced the rate of reintervention without increasing postoperative early morbidity and mortality. METHODS: Between January 1996 and December 1997, 94 CABG operations were performed using the bilateral IMA. In Group A (n = 45), the right IMA was anastomosed to the left coronary artery system; in Group B (n = 49), the right IMA was anastomosed to the right coronary artery system. The left IMA was always anastomosed to the left coronary artery system in both groups. RESULTS: There was 1 death (Group A) (1.06%), and 1 late death (Group B) (1.07%). One patient in Group A underwent balloon angioplasty, and 1 patient in Group B underwent reoperation after the follow-up. Pre- and postoperative data were similar between both groups, except for off-pump CABG, which was higher in Group B (2.2% versus 36.7%; P <.001). Twenty-three randomized patients in each group underwent control angiography until May 2002. Angiographic results showed that the patency of the right IMA to the right or left coronary artery system was similar (78.26% versus 82.6%; P = .7). But the left IMA had a better patency rate than the right IMA (95.65% versus 80.43%; P = .02). The patency rates of the left and right IMA anastomosis on the beating heart in Group B were not significantly different (92.3% versus 76.9%; P = .27). The patency of right IMA anastomosis with or without off-pump technique in Group B was similar (76.9% versus 80%; P = .84). CONCLUSIONS: Bilateral IMA can be used with low morbidity and mortality. The angiographic and clinical results of off-pump CABG show that bilateral IMA can also be used in off-pump surgery with similar results.

Early left ventricular function recovery after trap-door coronary transfer repair of ALCAPA in an adult patient.

Anomalous origin of the left coronary from the pulmonary artery (ALCAPA) is a rare congenital malformation, which may result in myocardial infarction, congestive heart failure, and sudden death if left untreated. Despite frequently advanced pathologic changes, there seems to be significant potential for the recovery of myocardial function in individuals with left ventricular dysfunction after the establishment of physiologic coronary circulation, particularly in the pediatric population. Reports of ALCAPA repair in adulthood are scarce and little information exists regarding the response of the left ventricle to revascularization in this age group. In this report, repair of ALCAPA in a significantly symptomatic adult patient with ventricular dysfunction is described, leading to an early recovery of left ventricular function.