reperfusion injury

T

R E N D S I N

CA

R D I OVA S C U L A R

ME

D I C I N E

23 (2013) 85–90

Available online at www.sciencedirect.com

www.elsevier.com/locate/tcm

Review article

Donor simvastatin treatment and cardiac allograft ischemia/reperfusion injury Antti I. Nyka¨nena,b,c,n, Raimo Tuuminena,b, and Karl B. Lemstro¨ma,b,c a

Transplantation Laboratory, Haartman Institute, P.O. Box 21 (Haartmaninkatu 3), FI-00014, University of Helsinki, Finland HUSLAB, Helsinki University Central Hospital, Helsinki, Finland c Department of Cardiothoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland b

artic le info

abstract

Article history:

Ischemia/reperfusion injury of a transplanted heart may result in serious early and late

Received 30 May 2012

adverse effects such as primary graft dysfunction, increased allograft immunogenicity,

Received in revised form

and initiation of fibroproliferative cascades that compromise the survival of the recipient.

30 June 2012

Microvascular dysfunction has a central role in ischemia/reperfusion injury through

Accepted 2 July 2012

increased vascular permeability, leukocyte adhesion and extravasation, thrombosis,

Available online 5 January 2013

vasoconstriction, and the no-reflow phenomenon. Here we review the involvement of microvascular endothelial cells and their surrounding pericytes in ischemia/reperfusion injury, and the pleiotropic, cholesterol-independent effects of statins on microvascular dysfunction. In addition, we delineate how the rapid vasculoprotective effects of statins could be used to protect cardiac allografts against ischemia/reperfusion injury by administering statins to the organ donor before graft removal and transplantation. & 2013 Elsevier Inc. All rights reserved.

Introduction Heart transplantation is often the last remaining treatment option for patients with advanced heart failure. The first human heart transplantation was performed in 1967 but it became a valid therapeutic option only after substantial advances took place in immunosuppressive medication, surgical techniques, and donor and recipient management. Today, almost 4000 adult heart transplantations are reported annually to the registry of the International Society of Heart and Lung Transplantation worldwide, and the median survival of cardiac allograft recipients is over 10 years (Stehlik et al., 2011). Despite immunosuppressive drugs that effectively target the adaptive immunity, cardiac allograft recipient survival is

n

hampered by deleterious complications such as primary graft dysfunction and development of cardiac allograft vasculopathy (CAV) (Stehlik et al., 2011). While primary graft dysfunction is detrimental to the recipient early after transplantation, CAV gradually obliterates coronary arteries in response to cumulative graft injury and is a major reason for late graft loss (Schmauss and Weis, 2008; Stehlik et al., 2011). Interestingly, very early events during cardiac allograft procurement, preservation, transplantation procedure, and restoration of circulation may result in ischemia/reperfusion injury (IRI) and compromise survival. Although IRI occurs, e.g., after surgical or percutaneous cardiac revascularization, the cytokine burst related to donor brain death and the long and global graft ischemia of the transplant make cardiac

Corresponding author at: Transplantation Laboratory, Haartman Institute, P.O. Box 21 (Haartmaninkatu 3), FI-00014, University of Helsinki, Finland. Tel.: þ358 9 1912 6590; fax: þ358 9 2411 227. E-mail address: [email protected] (A.I. Nyka¨nen). 1050-1738/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.tcm.2012.09.005

86

TR

E N D S I N

CA

R D I O VA S C U L A R

allografts especially vulnerable to IRI (Eltzschig and Eckle, 2011). Furthermore, early injury to the transplant may have far-reaching deleterious effects as IRI releases endogenous injury-related ligands that in turn activate innate immunity cells through Toll-like receptors and may ultimately aggravate the adaptive immunity response toward the allograft (Eltzschig and Eckle, 2011). Clinically available therapeutic options to prevent cardiac allograft IRI are currently limited and comprise largely of hemodynamic and hormonal optimization of the donor, the use of hypothermic cardioplegia and preservation solutions, and of logistical efforts aimed at limiting the duration of cardiac allograft ischemia time. The extension of donor criteria and the use of marginal donors to increase the number of available transplants further entail new clinically relevant organ protection strategies. Here, we review the involvement of microvascular dysfunction in cardiac allograft IRI. In addition, we delineate how the pleiotropic cholesterol-independent vasculoprotective effects of statins could be used to protect cardiac allografts against IRI and its consequences by administering statins to the organ donor before graft procurement.

Microvascular endothelial and pericyte dysfunction in mediating cardiac allograft ischemia/reperfusion injury The microvascular endothelium of the transplanted heart forms a large contact interface for recipient circulating cells with donor tissues. In quiescence microvascular endothelium is inactivated: the neighboring endothelial cells (EC) are tightly interconnected by junctional proteins to form a tight barrier against plasma proteins and circulating leukocytes (Fig. 1A) (Wallez and Huber, 2008); the ECs express low levels of cell-surface adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1) to prevent leukocyte adhesion (Weis, 2008); the endothelium produces factors that control coagulation and platelet adhesion to prevent thrombosis (van Hinsbergh, 2012); and the balance of EC-derived factors regulating vascular tone such as endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) favors uninterrupted blood flow through the microcirculation (Faller, 1999). Pericytes are the second most frequent cell type in the heart after ECs, and are also essential for normal coronary microcirculation. Pericytes are supporting cells that cover coronary capillaries, precapillary arterioles, and postcapillary venules, communicate with the underlying ECs, have a common basement membrane with ECs, and actively participate in the regulation of microvascular tone and permeability (Kutcher and Herman, 2009). ECs rapidly respond to stress such as tissue trauma, ischemia, and pathogen invasion by EC cytoskeleton rearrangement, release of vasoactive substances from intracellular storage granules, increased vascular permeability, and changes in gene transcription (Nagy et al., 2012; Rondaij et al., 2006). Several hypoxic, angiogenetic, inflammatory, and thrombotic mediators such as vascular endothelial growth factor (VEGF), angiopoietin-2, RhoA GTPase, thrombin, histamine, platelet activating factor, and low cyclic

M

E D I C I N E

23 (2013) 85–90

adenosine monophosphate (cAMP) levels have been shown to increase vascular permeability (Eltzschig and Eckle, 2011; Nagy et al., 2012; Weis, 2008; Wojciak-Stothard et al., 2005). While these imprinted mechanisms are essential for tissue repair, angiogenesis, and bacterial defense, improper EC activation during IRI may be harmful (Fig. 1A). As an example, increased vascular permeability after myocardial infarction aggravates myocardial injury (Weis et al., 2004). Also, despite successful opening of an occluded coronary artery, obstruction of the microvascular bed due to endothelial swelling and disruption may result in the no-reflow phenomenon that is a strong predictor of mortality of myocardial infarct patients (Kloner, 2011). Interestingly, pericytes have also been implicated in the no-reflow phenomenon as sustained pericyte contraction results in compromised microvascular perfusion in a cerebral artery occlusion model (Yemisci et al., 2009). Remembering that the transplanted heart is confronted with donor brain death, harvesting, cold and warm ischemia, the transplantation procedure, and reperfusion, it is not surprising that microvascular quiescence is disrupted in cardiac allografts. Several experimental and clinical findings indicate that microvascular dysfunction is an important marker and a possible mediator of cardiac allograft IRI and subsequent adverse effects. Transmission electron microscope evaluation of human cardiac allografts shows that graft ischemia results in capillary endothelial edema that is present during implantation, and 30 and 60 min after reperfusion, and resolves within 1 week (Koch et al., 2001). Analysis of human endomyocardial biopsies indicates that the presence of endothelial activation in the form of ICAM-1 and histocompatibility antigen HLA-DR expression during the first 3 months after heart transplantation predicts the development of CAV (Labarrere et al., 1997). Furthermore, detection of fibrin deposits in cardiac allografts already in the first endomyocardial biopsy taken at a median of 9 days after transplantation predicts the development of CAV (Labarrere et al., 2012). This finding is particularly interesting as early cardiac fibrin deposits may be viewed as a result of IRIinduced microvascular injury, and a sign of excessive coagulation, or also as a result of increased microvascular permeability (Nagy et al., 2012). Experimental heart transplantation approaches have further delineated the role of microvascular dysfunction in IRI. Intravital fluorescence microscopy of heterotopically transplanted mouse hearts shows that reperfusion of the grafts that have been subjected to prolonged 4-h cold ischemia results in increased vascular permeability and leukocyte rolling and adhesion, and decreased capillary blood flow (Schramm et al., 2007b). Similarly, prolonged 4-h cold ischemia of rat cardiac allografts activates microvascular RhoA/ Rho-associated coiled-coil containing protein kinase (ROCK) signaling and destabilizes the endothelium already during graft cold and warm preservation, and results in profound vascular permeability and the no-reflow phenomenon immediately after cardiac allograft reperfusion (Tuuminen et al., 2011). Essentially, these studies indicate that microvascular dysfunction is present already during the graft preservation and results in compromised microvascular perfusion and

TR

E N D S I N

CA

R D I OVA S C U L A R

Junctional proteins eNOS ET-1

EC Pericyte

Vasoactive peptides in storage granules

Vascular dysfunction

Hypoxia RhoA VEGF Ang2 Thrombin ROS

Permeability No-reflow Thrombosis Inflammation

EC-EC gaps eNOS ET-1

RhoA

RhoA

ICAM-1 Cell contraction

RhoA

RhoA

87

23 (2013) 85–90

E D I C I N E

IRI

Vascular quiescense Tight EC barrier Low vascular tone Anti-thrombogenic Anti-inflammatory

M

P-selectin Ang2 vWF ET-1

Cell contraction

Acetoacetyl-CoA

HMG-CoA reductase

IRI Brain death Ischemia ROS

HMG-CoA Statins Mevalonate

Donor statin treatment Vascular dysfunction Permeability No-reflow Inflammation

Farnesyl pyrophosphate

Cholesterol

Geranylgeranyl pyrophosphate

Isoprenylation and translocation to cell membrane

Inactive small GTPase

Active small GTPase Pleiotropic effects through several GTPases, e.g., statin-mediated RhoA inhibition: - Inhibition of EC contraction and vascular permeability - Decrease in exocytosis of vasoactive peptides from EC storage granules - eNOS upregulation - ET-1 downregulation

Cardiomyocyte injury Primary graft dysfunction

Innate immunity

Adaptive immunity

Fibroproliferation

Compromised long term survival Acute rejection Cardiac allograft vasculopathy

Fig. 1 – Schematic presentations of microvascular dysfunction in ischemia/reperfusion injury (A), pleiotropic mechanisms of statins (B), and donor statin treatment in cardiac allograft ischemia/reperfusion injury (C). Ang2, angiopoietin-2; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; ICAM-1, intercellular adhesion molecule-1; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor. increased vascular permeability immediately after reperfusion (Fig. 1A). Interestingly, isolated heart perfusion model results show that cardiac ECs are relatively more vulnerable

(Fedak et al., 2005), leukocyte depletion (Yamamoto et al., 2001), cyclic guanosine monophosphate signaling (Mohara et al., 2000), and cAMP (Wang et al., 2000).

to ischemia than cardiac smooth muscle cells or cardiomyocytes (Mankad et al., 1997). Furthermore, experimental studies with intervention approaches show that several signaling pathways are involved in cardiac allograft IRI as beneficial effects have been achieved by reducing oxidative stress (Hasegawa et al., 2011), adenosine-lidocaine cardioplegia (Rudd and Dobson, 2011), adenosine breakdown product inosine (Szabo et al., 2006), donor treatment with hypertonic saline (Badiwala et al., 2009), complement inactivation (Ferraresso et al., 2008), nitric oxide (Pabla et al., 1996), endothelin inhibition

Vasculoprotective effects of statins Statins – 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors – are cholesterol-lowering drugs that are widely used for primary and secondary prevention of cardiovascular disease. Statins inhibit the formation of mevalonate which is required for cholesterol biosynthesis, and the decrease in serum low-density lipoprotein level is considered to be the primary beneficial mechanism of statins in

88

TR

E N D S I N

CA

R D I O VA S C U L A R

cardiovascular disease. In addition to limiting cholesterol biosynthesis, statins have pleiotropic cholesterolindependent effects that are largely derived from inhibition of the formation of mevalonate pathway intermediates farnesyl pyrophosphate and geranylgeranyl pyrophosphate (Fig. 1B). These isoprenoids are attached to a variety of cell signaling proteins through isoprenylation, and these lipophilic attachments translocate the signaling proteins to the cell membrane which in most cases regulates their activity. The most important isoprenylated proteins affected by statins belong to small GTPase proteins that include the Rac and Rho families. They regulate a wide range of cell functions such as growth, morphogenesis, cytokinesis, and different signaling pathways (Jacobson, 2008; Wang et al., 2008). Rho is particularly important for statin-mediated vasculoprotection as statin-mediated RhoA inhibition increases vasculoprotective eNOS (Hernandez-Perera et al., 1998) and heme oxygenase-1 (HO-1) (Lee et al., 2004), and decreases vasoconstrictor ET-1 (Hernandez-Perera et al., 1998). RhoA downstream mediator ROCK links statins to the EC cytoskeleton changes, as ROCKmediated myosin light chain phosphorylation drives actin cytoskeleton contraction and formation of intracellular stress fibers that results in EC contraction, opening of interendothelial gaps, and loss of endothelial integrity (Jacobson, 2008; Wang et al., 2008; Wojciak-Stothard et al., 2005). Importantly, at least part of the pleiotropic antiinflammatory effects of statins is considered to be derived from HMG-CoA reductase-independent regulation of leukocyte function antigen-1 (LFA-1) on leukocytes. The inactive form of certain statins binds to this integrin, resulting in inhibition of LFA-1/ICAM-1 interaction and adhesion of leukocytes to ECs (Schramm et al., 2007a). Similarly LFA-1/ICAM1-mediated mechanisms also modify co-stimulatory signaling between antigen presenting cells and T-cells that is important for the initiation of adaptive immune responses (Weitz-Schmidt et al., 2001). The pleiotropic effects of statins are difficult to differentiate from their cholesterol-lowering effects in the clinical setting, but some evidence of cholesterol-independent effects have been derived from studies comparing statins and cholesterol absorption inhibitor ezemibe. Despite achieving similar serum cholesterol levels, statins reduce RhoA/ ROCK activation and result in better endothelial function (Jacobson, 2008; Wang et al., 2008). In addition, myocardial protection with statins is rapid as acute coronary syndrome patients undergoing percutaneous cardiac revascularization benefit from atorvastatin pretreatment that is administered at 12 h and immediately before the balloon angioplasty (Patti et al., 2007). Several experimental studies show that statins inhibit myocardial IRI (Bulhak et al., 2007; Di Napoli et al., 2001; Efthymiou et al., 2005). These beneficial effects are rapid as they are achieved by giving statins even at reperfusion (Efthymiou et al., 2005). Endothelial layer permeability assays indicate that statins inhibit vascular permeability caused by several IRI-related factors such as VEGF (Zeng et al., 2005), thrombin (Jacobson, 2008), and hypoxia-reoxygenation (Wojciak-Stothard et al., 2005). Furthermore, downregulation of the activity of inflammatory transcription factors NF-kB,

M

E D I C I N E

23 (2013) 85–90

AP-1, and hypoxia-inducible factor-1 (HIF-1) in vascular cells may also contribute to the anti-inflammatory effects of statins (Dichtl et al., 2003).

Heart transplant recipient statin treatment Statins are routinely administered to heart transplant recipients as two important randomized studies indicate that pravastatin (Kobashigawa et al., 2005) and simvastatin (Wenke et al., 2003) initiated early after transplantation have beneficial effects on long-term survival and the development of CAV. Although lowered cholesterol levels may explain the beneficial effects of heart transplant recipient statin treatment, experimental studies indicate that statins may inhibit CAV also through its cholesterol-independent anti-inflammatory effects (Shimizu et al., 2003).

Heart transplant donor simvastatin treatment and ischemia/reperfusion injury The rationale for treating heart transplant donors with statins before graft harvesting relates to the critical role of vascular dysfunction in IRI, the rapid vasculoprotective effects of statins, and the vulnerability of cardiac allografts to IRI-initiated harmful long-term effects (Fig. 1C). Importantly, the prerequisite for such a strategy is that the timeframe would fit to the window of organ donor treatment in clinical transplantation. We have evaluated the effect of donor simvastatin treatment on rat cardiac allograft IRI and its long-term consequences by treating donor rats with a single peroral dose of simvastatin administered 2 h before graft harvesting—a protocol relevant for the time-frame in clinical organ donation (Tuuminen et al., 2011). Donor simvastatin treatment decreased cardiac allograft IRI and resulted also in beneficial long-term effects in CAV models. Rapid microvascular protection was identified as a central mediator of donor simvastatin treatment since it inhibited microvascular EC and pericyte RhoA/ROCK activation and EC–EC gap formation induced by graft cold and warm preservation, increased graft expression of vasculoprotective HO-1, and decreased iNOS, HIF-1a, and ET-1. Donor simvastatin treatment abolished the profound vascular permeability and the no-reflow phenomenon that occurred immediately after cardiac allograft reperfusion, and resulted in diminished cardiomyocyte injury and macrophage and neutrophil infiltration. Interestingly, similar protection against IRI was not achieved by recipient simvastatin treatment indicating that the protective effect of donor simvastatin treatment is carried in the transplanted heart. An additional vasculoprotective mechanism behind donor simvastatin treatment may be the flow-dependent transcription factor Kruppel-like factor 2 (KLF2) as the loss of pulsatile flow results in KLF2 downregulation and EC dysfunction, both that are rescued by simvastatin (Gracia-Sancho et al., 2010). The effects of statins against IRI may not be restricted only to the heart as kidney donor atorvastatin pretreatment for 3 days inhibits kidney graft IRI (Gottmann et al., 2007), addition

TR

E N D S I N

CA

R D I OVA S C U L A R

of simvastatin to liver storage solution prevents EC dysfunction and improves microcirculation after reperfusion (Russo et al., 2012), intraperitoneal simvastatin inhibits liver IRI (Lai et al., 2008), and simvastatin ameliorates lung IRI (Naidu et al., 2003). This is important considering multi-organ donation and donor simvastatin treatment, as its possible beneficial and harmful effects to all transplantable organs have to be taken into consideration.

Clinical and future perspectives Although it is difficult to differentiate the cholesterol- and noncholesterol-mediated effects of statins in the clinical setting, accumulating evidence indicates that statins have pleiotropic vasculoprotective effects. As these protective effects appear to be rapid, the pleiotropic effects should be taken into consideration for example, when considering the continuation or discontinuation of statin treatment during elective surgery or coronary interventions (Merla et al., 2007). The beneficial safety profile, long clinical experience, and low cost of statins make donor statin treatment an attractive therapeutic strategy to protect solid organ transplants. However, randomized trials are needed to evaluate whether donor simvastatin treatment has protective effects in the clinical setting where multiple factors are present that cannot be taken into account in experimental studies. As we have found that simvastatin 80 mg given to brain dead human organ donors via nasogastric tube is absorbed and metabolized into its active metabolite in hours (Tuuminen et al., 2011), we have initiated a randomized clinical trial at the Helsinki University Central Hospital that will hopefully reveal whether donor simvastatin treatment provides clinical benefit.

ref ere nces

Badiwala MV, Ramzy D, Tumiati LC, Tepperman ED, Sheshgiri R, Prodger JL, et al. Donor pretreatment with hypertonic saline attenuates primary allograft dysfunction: a pilot study in a porcine model. Circulation 2009;120:S206–14. Bulhak A, Roy J, Hedin U, Sjoquist PO, Pernow J. Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation. American Journal of Physiology—Heart and Circulatory Physiology 2007;292:H3158–63. Di Napoli P, Antonio Taccardi A, Grilli A, Spina R, Felaco M, Barsotti A, et al. Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: an ex vivo study in isolated working rat hearts. Cardiovascular Research 2001;51:283–93. Dichtl W, Dulak J, Frick M, Alber HF, Schwarzacher SP, Ares MP, et al. HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology 2003;23:58–63. Efthymiou CA, Mocanu MM, Yellon DM. Atorvastatin and myocardial reperfusion injury: new pleiotropic effect implicating multiple prosurvival signaling. Journal of Cardiovascular Pharmacology 2005;45:247–52. Eltzschig HK, Eckle T. Ischemia and reperfusion—from mechanism to translation. Nature Medicine 2011;17:1391–401.

M

E D I C I N E

23 (2013) 85–90

89

Faller DV. Endothelial cell responses to hypoxic stress. Clinical and Experimental Pharmacology and Physiology 1999;26: 74–84. Fedak PW, Rao V, Verma S, Ramzy D, Tumiati L, Miriuka S, et al. Combined endothelial and myocardial protection by endothelin antagonism enhances transplant allograft preservation. Journal of Thoracic and Cardiovascular Surgery 2005;129: 407–15. Ferraresso M, Macor P, Valente M, Della Barbera M, D’Amelio F, Borghi O, et al. Posttransplant ischemia–reperfusion injury in transplanted heart is prevented by a minibody to the fifth component of complement. Transplantation 2008;86:1445–51. Gottmann U, Brinkkoetter PT, Hoeger S, Gutermann K, Coutinho ZM, Ruf T, et al. Atorvastatin donor pretreatment prevents ischemia/reperfusion injury in renal transplantation in rats: possible role for aldose-reductase inhibition. Transplantation 2007;84:755–62. Gracia-Sancho J, Villarreal Jr. G, Zhang Y, Yu JX, Liu Y, Tullius SG, et al. Flow cessation triggers endothelial dysfunction during organ cold storage conditions: strategies for pharmacologic intervention. Transplantation 2010;90:142–9. Hasegawa T, Okada K, Okita Y, Pinsky DJ. Antioxidant properties of pioglitazone limit nicotinamide adenine dinucleotide phosphate hydrogen oxidase and augment superoxide dismutase activity in cardiac allotransplantation. Journal of Heart and Lung Transplantation 2011;30:1186–96. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, SanchezPascuala R, Hernandez G, Diaz C, et al. Effects of the 3hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. Journal of Clinical Investigation 1998;101:2711–9. Jacobson J. Statins in endothelial signaling and activation. Antioxidants & Redox Signaling 2008;11:811–21. Kloner RA. No-reflow phenomenon: maintaining vascular integrity. Journal of Cardiovascular Pharmacology and Therapeutics 2011;16:244–50. Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA, et al. Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. Journal of Heart and Lung Transplantation 2005;24:1736–40. Koch A, Bingold TM, Oberlander J, Sack FU, Otto HF, Hagl S, et al. Capillary endothelia and cardiomyocytes differ in vulnerability to ischemia/reperfusion during clinical heart transplantation. European Journal of Cardio-Thoracic Surgery 2001;20: 996–1001. Kutcher ME, Herman IM. The pericyte: cellular regulator of microvascular blood flow. Microvascular Research 2009;77: 235–46. Labarrere CA, Nelson DR, Faulk WP. Endothelial activation and development of coronary artery disease in transplanted human hearts. JAMA: The Journal of American Medical Association 1997;278:1169–75. Labarrere CA, Woods JR, Hardin JW, Campana GL, Ortiz MA, Jaeger BR, et al. Value of the first post-transplant biopsy for predicting long-term cardiac allograft vasculopathy (cav) and graft failure in heart transplant patients. PLoS One 2012;7:e36100. Lai IR, Chang KJ, Tsai HW, Chen CF. Pharmacological preconditioning with simvastatin protects liver from ischemia– reperfusion injury by heme oxygenase-1 induction. Transplantation 2008;85:732–8. Lee TS, Chang CC, Zhu Y, Shyy JY. Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation 2004;110:1296–302. Mankad PS, Amrani M, Rothery S, Severs NJ, Yacoub MH. Relative susceptibility of endothelium and myocardial cells to ischaemia–reperfusion injury. Acta Physiologica Scandinavica 1997;161:103–12.

90

TR

E N D S I N

CA

R D I O VA S C U L A R

Merla R, Daher IN, Ye Y, Uretsky BF, Birnbaum Y. Pretreatment with statins may reduce cardiovascular morbidity and mortality after elective surgery and percutaneous coronary intervention: clinical evidence and possible underlying mechanisms. American Heart Journal 2007;154:391–402. Mohara J, Oshima K, Tsutsumi H, Takeyoshi I, Matsumoto K, Morishita Y. FK409 ameliorates ischemia–reperfusion injury in heart transplantation following 12-hour cold preservation. Journal of Heart and Lung Transplantation 2000;19:694–700. Nagy JA, Dvorak AM, Dvorak HF. Vascular hyperpermeability, angiogenesis, and stroma generation. Cold Spring Harbor Perspectives in Medicine 2012;2:a006544. Naidu BV, Woolley SM, Farivar AS, Thomas R, Fraga C, Mulligan MS. Simvastatin ameliorates injury in an experimental model of lung ischemia–reperfusion. Journal of Thoracic and Cardiovascular Surgery 2003;126:482–9. Pabla R, Buda AJ, Flynn DM, Blesse SA, Shin AM, Curtis MJ, et al. Nitric oxide attenuates neutrophil-mediated myocardial contractile dysfunction after ischemia and reperfusion. Circulation Research 1996;78:65–72. Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G, et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDAACS randomized trial. Journal of the American College of Cardiology 2007;49:1272–8. Rondaij MG, Bierings R, Kragt A, van Mourik JA, Voorberg J. Dynamics and plasticity of Weibel–Palade bodies in endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology 2006;26:1002–7. Rudd DM, Dobson GP. Early reperfusion with warm, polarizing adenosine-lidocaine cardioplegia improves functional recovery after 6 hours of cold static storage. Journal of Thoracic and Cardiovascular Surgery 2011;141:1044–55. Russo L, Gracia-Sancho J, Garcia-Caldero H, Marrone G, GarciaPagan JC, Garcia-Cardena G, et al. Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers. Hepatology 2012;55:921–30. Schmauss D, Weis M. Cardiac allograft vasculopathy: recent developments. Circulation 2008;117:2131–41. Schramm R, Menger MD, Harder Y, Schmits R, Adam O, WeitzSchmidt G, et al. Statins inhibit lymphocyte homing to peripheral lymph nodes. Immunology 2007a;120:315–24. Schramm R, Menger MD, Kirsch S, et al. The subepicardial microcirculation in heterotopically transplanted mouse hearts: an intravital multifluorescence microscopy study. Journal of Thoracic and Cardiovascular Surgery 2007b;134 210-7, 217 e1.. Shimizu K, Aikawa M, Takayama K, Libby P, Mitchell RN. Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins. Circulation 2003;108:2113–20. Stehlik J, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dobbels F, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-eighth adult heart

M

E D I C I N E

23 (2013) 85–90

transplant report-2011. Journal of Heart and Lung Transplantation 2011;30:1078–94. Szabo G, Stumpf N, Radovits T, Sonnenberg K, Gero D, Hagl S, et al. Effects of inosine on reperfusion injury after heart transplantation. European Journal of Cardio-Thoracic Surgery 2006;30:96–102. Tuuminen R, Syrjala S, Krebs R, Keranen MA, Koli K, AboRamadan U, et al. Donor simvastatin treatment abolishes rat cardiac allograft ischemia/reperfusion injury and chronic rejection through microvascular protection. Circulation 2011;124:1138–50. Wallez Y, Huber P. Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis. Biochimica et Biophysica Acta 2008;1778:794–809. van Hinsbergh VW. Endothelium-role in regulation of coagulation and inflammation. Seminars in Immunopathology 2012;34: 93–106. Wang CY, Aronson I, Takuma S, Homma S, Naka Y, Alshafie T, et al. cAMP pulse during preservation inhibits the late development of cardiac isograft and allograft vasculopathy. Circulation Research 2000;86:982–8. Wang CY, Liu PY, Liao JK. Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends in Molecular Medicine 2008;14:37–44. Weis S, Shintani S, Weber A, Kirchmair R, Wood M, Cravens A, et al. Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. Journal of Clinical Investigation 2004;113:885–94. Weis SM. Vascular permeability in cardiovascular disease and cancer. Current Opinion in Hematology 2008;15:243–9. Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nature medicine 2001;7:687–92. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K, et al. Simvastatin initiated early after heart transplantation: 8-year prospective experience. Circulation 2003;107:93–7. Wojciak-Stothard B, Tsang LY, Haworth SG. Rac and Rho play opposing roles in the regulation of hypoxia/reoxygenationinduced permeability changes in pulmonary artery endothelial cells. American Journal of Physiology—Lung Cellular and Molecular Physiology 2005;288:L749–60. Yamamoto H, Moriyama Y, Hisatomi K, Yotsumoto G, Taira A, Sakata R. A leukocyte depleting filter reduces endothelial cell dysfunction and improves transplanted canine heart function. Journal of Heart and Lung Transplantation 2001;20:670–8. Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nature Medicine 2009;15:1031–7. Zeng L, Xu H, Chew TL, Eng E, Sadeghi MM, Adler S, et al. HMG CoA reductase inhibition modulates VEGF-induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation. FASEB Journal 2005;19:1845–7.