circulation2010-03-16

(Circulation. 2010;121:1176-1187.)
© 2010 American Heart Association, Inc.

abstract 1 of 8
Coronary Heart Disease
Effect of Rosiglitazone on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease
The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History Trial
Hertzel C. Gerstein, MD, MSc; Robert E. Ratner, MD; Christopher P. Cannon, MD; Patrick W. Serruys, MD, PhD; Héctor M. García-García, MD, MSc; Gerrit-Anne van Es, PhD; Nikheel S. Kolatkar, MD, MPH; Barbara G. Kravitz, MS; Diane M. Miller, PhD; Chun Huang, PhD; Peter J. Fitzgerald, MD, PhD; Richard W. Nesto, MD; the APPROACH Study Group
From the McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada (H.C.G.); MedStar Research Institute, Washington, DC (R.E.R.); Brigham and Women’s Hospital, Boston, Mass (C.P.C.); Erasmus Medical Center, Rotterdam, the Netherlands (P.W.S.); Cardialysis, Rotterdam, the Netherlands (H.M.G.-G., G.v.E.); GlaxoSmithKline Research and Development, King of Prussia, Pa (N.S.K., B.G.K., D.M.M., C.H.); Stanford University Medical Center, Palo Alto, Calif (P.J.F.); and Lahey Clinic, Burlington, Mass (R.W.N.).
Correspondence to Dr H.C. Gerstein, McMaster University and Hamilton Health Sciences, Department of Medicine, Room 3V38, 1200 Main St W, Hamilton, Ontario L8N 3Z5, Canada. E-mail gerstein@mcmaster.ca
Received June 11, 2009; accepted December 7, 2009.
Background— Rosiglitazone has several properties that may affect progression of atherosclerosis. The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History (APPROACH) study was undertaken to determine the effect of the thiazolidinedione rosiglitazone on coronary atherosclerosis as assessed by intravascular ultrasound compared with the sulfonylurea glipizide.
Methods and Results— This was a randomized, double-blind, controlled 18-month study in 672 patients aged 30 to 80 years with established type 2 diabetes mellitus treated by lifestyle, 1 oral agent, or submaximal doses of 2 oral agents who had at least 1 atherosclerotic plaque with 10% to 50% luminal narrowing in a coronary artery that had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention. The primary outcome was change in percent atheroma volume in the longest and least angulated epicardial coronary artery that had not undergone intervention. Secondary outcomes included change in normalized total atheroma volume and change in total atheroma volume in the most diseased baseline 10-mm segment. Rosiglitazone did not significantly reduce the primary outcome of percent atheroma volume compared with glipizide (–0.64%; 95% confidence interval, –1.46 to 0.17; P=0.12). The secondary outcome of normalized total atheroma volume was significantly reduced by rosiglitazone compared with glipizide (–5.1 mm3; 95% confidence interval, –10.0 to –0.3; P=0.04); however, no significant difference between groups was observed for the change in total atheroma volume within the most diseased baseline 10-mm segment (–1.7 mm3; 95% confidence interval, –3.9 to 0.5; P=0.13).
Conclusions— Rosiglitazone did not significantly decrease the primary end point of progression of coronary atherosclerosis more than glipizide in patients with type 2 diabetes mellitus and coronary atherosclerosis.

Abstract 2 of 8
Coronary Heart Disease
Response to Ticagrelor in Clopidogrel Nonresponders and Responders and Effect of Switching Therapies
The RESPOND Study
Paul A. Gurbel, MD; Kevin P. Bliden, BS; Kathleen Butler, MD; Mark J. Antonino, BS; Cheryl Wei, PhD; Renli Teng, PhD; Lars Rasmussen, MD; Robert F. Storey, MD; Tonny Nielsen, MD; John W. Eikelboom, MBBS; Georges Sabe-Affaki, MD; Steen Husted, MD; Dean J. Kereiakes, MD; David Henderson, MD; Dharmendra V. Patel, MD; Udaya S. Tantry, PhD
From the Sinai Center for Thrombosis Research, Baltimore, Md (P.A.G., K.P.B., M.J.A., U.S.T.); AstraZeneca LP, Wilmington, Del (K.B., C.W., R.T.); Aalborg Sygehus Syd, Thrombosecentret Aalborg, Aalborg, Denmark (L.R.); University of Sheffield, Sheffield, United Kingdom (R.F.S.); Sydvestjysk sygehus Esbjerg, hjertemed projekt, Esbjerg, Denmark (T.N.); Hamilton General Hospital, Hamilton, Ontario, Canada (J.W.E.); Clinique Medicale Notre-Dame, Lachine, Quebec, Canada (G.S.-A.); Medicinsk kardiologisk afd. A, Århus C, Denmark (S.H.); Christ Hospital Heart and Vascular Center and Lindner Research Center, Cincinnati, Ohio (D.J.K.); Cardiology Research Associates, Ormond Beach, Fla (D.H.); and NEA Clinic, Clinical Research Center, Jonesboro, Ark (D.V.P.).
Correspondence to Paul A. Gurbel, MD, Sinai Center for Thrombosis Research, Cardiac Catheterization Laboratory, 2401 W Belvedere Ave, Baltimore, MD 21215. E-mail pgurbel@lifebridgehealth.org
Received October 30, 2009; accepted December 24, 2009.
Background— The antiplatelet effects of the Platelet Inhibition and Patient Outcomes (PLATO) trial dose of ticagrelor in patients nonresponsive to clopidogrel and after they switch agents are unknown.
Methods and Results— Patients with stable coronary artery disease on aspirin therapy received a 300-mg clopidogrel load; nonresponders were identified by light transmittance aggregometry. In a 2-way crossover design, nonresponders (n=41) and responders (n=57) randomly received clopidogrel (600 mg/75 mg once daily) or ticagrelor (180 mg/90 mg twice daily) for 14 days during period 1. In period 2, all nonresponders switched treatment; half of the responders continued the same treatment, whereas the others switched treatment. Inhibition of platelet aggregation was higher in nonresponders treated with ticagrelor compared with clopidogrel (P<0.05). Treatment with ticagrelor among nonresponders resulted in a >10%, >30%, and >50% decrease in platelet aggregation from baseline in 100%, 75%, and 13% of patients, respectively. Platelet aggregation fell from 59±9% to 35±11% in patients switched from clopidogrel to ticagrelor and increased from 36±14% to 56±9% in patients switched from ticagrelor to clopidogrel (P<0.0001 for both). Platelet reactivity was below the cut points previously associated with ischemic risk measured by light transmittance aggregometry, VerifyNow P2Y12 assay, and vasodilator-stimulated phosphoprotein phosphorylation in 98% to 100% of patients after ticagrelor therapy versus 44% to 76% of patients after clopidogrel therapy.
Conclusions— Ticagrelor therapy overcomes nonresponsiveness to clopidogrel, and its antiplatelet effect is the same in responders and nonresponders. Nearly all clopidogrel nonresponders and responders treated with ticagrelor will have platelet reactivity below the cut points associated with ischemic risk.

abstract 3 of 8
Epidemiology and Prevention
Dietary Intervention to Reverse Carotid Atherosclerosis
Iris Shai, RD, PhD*; J. David Spence, MD*; Dan Schwarzfuchs, MD; Yaakov Henkin, MD; Grace Parraga, PhD; Assaf Rudich, MD, PhD; Aaron Fenster, PhD; Christiane Mallett, MSc; Noah Liel-Cohen, MD; Amir Tirosh, MD, PhD; Arkady Bolotin, PhD; Joachim Thiery, MD; Georg Martin Fiedler, MD; Matthias Blüher, MD; Michael Stumvoll, MD; Meir J. Stampfer, MD, DrPH, for the DIRECT Group
From the S. Daniel Abraham Center for Health and Nutrition, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel (I.S., A.R., A.B.); Robarts Research Institute, University of Western Ontario, London, Ontario, Canada (J.D.S., G.P., A.F., C.M.); Nuclear Research Center Negev, Dimona, Israel (D.S.); Department of Cardiology, Soroka University Medical Center, Beer-Sheva, Israel (Y.H., N.L.-C.); Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel (A.T.); Institute of Laboratory Medicine (J.T., G.M.F.) and Department of Medicine (M.B., M.S.), University of Leipzig, Leipzig, Germany; and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, and Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Mass (M.J.S.).
Correspondence to Iris Shai, RD, PhD, The S. Daniel Abraham International Center for Health and Nutrition, Department of Epidemiology and Health Systems Evaluation, Ben-Gurion University of the Negev, PO Box 653, Beer-Sheva 84105, Israel. E-mail irish@bgu.ac.il
Received May 11, 2009; accepted December 28, 2009.
Background— It is currently unknown whether dietary weight loss interventions can induce regression of carotid atherosclerosis.
Methods and Results— In a 2-year Dietary Intervention Randomized Controlled Trial–Carotid (DIRECT-Carotid) study, participants were randomized to low-fat, Mediterranean, or low-carbohydrate diets and were followed for changes in carotid artery intima-media thickness, measured with standard B-mode ultrasound, and carotid vessel wall volume (VWV), measured with carotid 3D ultrasound. Of 140 complete images of participants (aged 51 years; body mass index, 30 kg/m2; 88% men), higher baseline carotid VWV was associated with increased intima-media thickness, age, male sex, baseline weight, blood pressure, and insulin levels (P<0.05 for all). After 2 years of dietary intervention, we observed a significant 5% regression in mean carotid VWV (–58.1 mm3; 95% confidence interval, –81.0 to –35.1 mm3; P<0.001), with no differences in the low-fat, Mediterranean, or low-carbohydrate groups (–60.69 mm3, –37.69 mm3, –84.33 mm3, respectively; P=0.28). Mean change in intima-media thickness was –1.1% (P=0.18). A reduction in the ratio of apolipoprotein B100 to apolipoprotein A1 was observed in the low-carbohydrate compared with the low-fat group (P=0.001). Participants who exhibited carotid VWV regression (mean decrease, –128.0 mm3; 95% confidence interval, –148.1 to –107.9 mm3) compared with participants who exhibited progression (mean increase, +89.6 mm3; 95% confidence interval, +66.6 to +112.6 mm3) had achieved greater weight loss (–5.3 versus –3.2 kg; P=0.03), greater decreases in systolic blood pressure (–6.8 versus –1.1 mm Hg; P=0.009) and total homocysteine (–0.06 versus +1.44 µmol/L; P=0.04), and a higher increase of apolipoprotein A1 (+0.05 versus –0.00 g/L; P=0.06). In multivariate regression models, only the decrease in systolic blood pressure remained a significant independent modifiable predictor of subsequent greater regression in both carotid VWV (β=0.23; P=0.01) and intima-media thickness (β=0.28; P=0.008) levels.
Conclusions— Two-year weight loss diets can induce a significant regression of measurable carotid VWV. The effect is similar in low-fat, Mediterranean, or low-carbohydrate strategies and appears to be mediated mainly by the weight loss–induced decline in blood pressure.

abstract 4 of 8
Heart Failure
Relationship Between Coronary Microvascular Dysfunction and Cardiac Energetics Impairment in Type 1 Diabetes Mellitus
G. Nallur Shivu, MRCP; T.T. Phan, MRCP; K. Abozguia, MRCP; I. Ahmed, MRCP; A. Wagenmakers, PhD; A. Henning, PhD; P. Narendran, MRCP, PhD; M. Stevens, MD; M. Frenneaux, MD, FRCP
From the Department of Cardiovascular Medicine (G.N.S., T.T.P., K.A., I.A., A.W., P.N., M.S.), University of Birmingham, Birmingham, United Kingdom, University of Aberdeen, School of Medicine, Foresterhill, Aberdeen, United Kingdom (M.F.), and the Institute for Biomedical Engineering, Swiss Federal Institute of Technology (ETH Zurich) and University of Zurich (A.H.), Zurich, Switzerland.
Correspondence to Dr Ganesh Nallur Shivu, Department of Cardiovascular Medicine, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom. E-mail drgani23@gmail.com
Received April 23, 2009; accepted January 7, 2010.
Background— Asymptomatic subjects with diabetes mellitus have an impaired cardiac energetics status that may play a significant role in the development of heart failure. In the present study, we assessed the role of microvascular dysfunction in the development of impaired cardiac energetics in subjects with type 1 diabetes mellitus.
Methods and Results— Twenty-five asymptomatic subjects with type 1 diabetes mellitus (mean age ±1 SD 33±8 years) and 26 age-, sex-, and body mass index–matched healthy control subjects (32±8 years old) were recruited into the study. The type 1 diabetes mellitus subjects were divided into 2 age-matched groups (newly diagnosed [<5 years] and longer-duration [>10 years] diabetes) to assess the impact of microvascular disease. All subjects had an echocardiogram and an exercise ECG performed, followed by magnetic resonance spectroscopy and stress magnetic resonance imaging. Compared with healthy control subjects, the phosphocreatine/ -ATP ratio was reduced significantly both in subjects with longer-term (2.1±0.5 versus 1.5±0.4, P<0.000) and newly diagnosed (2.1±0.5 versus 1.6±0.2, P<0.000) diabetes. The phosphocreatine/ -ATP ratio was similar in newly diagnosed diabetes subjects and those with longer-term disease (1.6±0.2 versus 1.5±0.4, P=0.32). The mean myocardial perfusion reserve index in the longer-term type 1 diabetes mellitus subjects was significantly lower than in healthy control subjects (1.7±0.6 versus 2.3±0.4, P=0.005). On univariate analysis, there was no significant correlation of phosphocreatine/ -ATP ratio with myocardial perfusion reserve index (r=0.21, P=0.26).
Conclusions— We demonstrate that young subjects with uncomplicated type 1 diabetes mellitus have impaired myocardial energetics irrespective of the duration of diabetes and that the impaired cardiac energetics status is independent of coronary microvascular function. We postulate that impairment of cardiac energetics in these subjects primarily results from metabolic dysfunction rather than microvascular impairment.

abstract 5 of 8
Heart Failure
Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy
Davide Gianni, MS*; Airong Li, MD, PhD*; Giuseppina Tesco, MD, PhD; Kenneth M. McKay; John Moore; Kunal Raygor; Marcello Rota, PhD; Judith K. Gwathmey, VMD; G. William Dec, MD; Thomas Aretz, MD; Annarosa Leri, MD; Marc J. Semigran, MD; Piero Anversa, MD; Thomas E. Macgillivray, MD; Rudolph E. Tanzi, PhD; Federica del Monte, MD, PhD
From the Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, Mass (D.G., J.K.G., F.d.M.); Genetics and Aging Research Unit (A.L., G.T., K.M.M., J.M., K.R., R.E.T.), Department of Pathology (T.A.), Cardiac Unit (G.W.D., M.J.S.), and Cardiac Surgical Division (T.E.M.), Massachusetts General Hospital, Boston; and Departments of Anesthesia and Medicine, Brigham and Women’s Hospital, Boston, Mass (M.R., A.L., P.A.).
Correspondence to Federica del Monte, MD, PhD, Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA 02125. E-mail fdelmont@bidmc.harvard.edu ; or Rudolph E. Tanzi, PhD, Genetics and Aging Research Unit, Massachusetts General Hospital, Boston, MA 02129. E-mail tanzi@helix.harvard.edu
Received May 11, 2009; accepted December 30, 2009.
Background— Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of β-amyloid impair cell function and lead to cell death.
Methods and Results— We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca2+ homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a.
Conclusions— On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca2+ handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function.

abstract 6 of 8
Imaging
High-Sensitivity Troponin T Concentrations in Acute Chest Pain Patients Evaluated With Cardiac Computed Tomography
James L. Januzzi, Jr, MD; Fabian Bamberg, MD, MPH; Hang Lee, PhD; Quynh A. Truong, MD, MPH; John H. Nichols, BA; Mahir Karakas, MD; Asim A. Mohammed, MD; Christopher L. Schlett, BS; John T. Nagurney, MD; Udo Hoffmann, MD, MPH*; Wolfgang Koenig, MD, PhD*
From the Division of Cardiology (J.L.J., Q.A.T., A.A.M.), the Cardiac MR PET CT Program, Department of Radiology (F.B., Q.A.T., J.H.N., C.L.S., U.H.), the Biostatistics Center (H.L.), and Department of Emergency Medicine (J.T.N.), Massachusetts General Hospital, Boston, Mass; and the Department of Internal Medicine II and Cardiology (M.K., W.K.), University of Ulm Medical Center, Ulm, Germany.
Correspondence to Udo Hoffmann, MD, MPH, Cardiac MR PET CT Program, Massachusetts General Hospital, 165 Charles River Plaza, Suite 400, Boston, MA 02114. E-mail uhoffmann@partners.org
Received July 12, 2009; accepted December 17, 2009.
Background— For evaluation of patients with chest pain and suspected acute coronary syndrome (ACS), consensus guidelines recommend use of a cardiac troponin cut point that corresponds to the 99th percentile of a healthy population. Most conventional troponin methods lack sufficient precision at this low level.
Methods and Results— In a cross-sectional study, 377 patients (mean age 53.7 years, 64.2% male) with chest pain and low to intermediate likelihood for ACS were enrolled in the emergency department. Blood was tested with a precommercial high-sensitivity troponin T assay (hsTnT) and compared with a conventional cardiac troponin T method. Patients underwent a 64-slice coronary computed tomography coronary angiogram at the time of phlebotomy, on average 4 hours from initial presentation. Among patients with acute chest pain, 37 (9.8%) had an ACS. Using the 99th percentile cut point for a healthy population (13 pg/mL), hsTnT had 62% sensitivity, 89% specificity, 38% positive predictive value, and 96% negative predictive value for ACS. Compared with the cardiac troponin T method, hsTnT detected 27% more ACS cases (P=.001), and an hsTnT above the 99th percentile strongly predicted ACS (odds ratio 9.0, 95% confidence interval 3.9 to 20.9, P<0.001). Independent of ACS diagnosis, computed tomography angiography demonstrated that concentrations of hsTnT were determined by numerous factors, including the presence and severity of coronary artery disease, left ventricular mass, left ventricular ejection fraction, and regional left ventricular dysfunction.
Conclusions— Among low- to intermediate-risk patients with chest pain, hsTnT provides good sensitivity and specificity for ACS. Elevation of hsTnT identifies patients with myocardial injury and significant structural heart disease, irrespective of the diagnosis of ACS.

abstract 7 of 8
Interventional Cardiology
Randomized Trial of Simple Versus Complex Drug-Eluting Stenting for Bifurcation Lesions
The British Bifurcation Coronary Study: Old, New, and Evolving Strategies
David Hildick-Smith, MD, FRCP; Adam J. de Belder, MD, FRCP; Nina Cooter, MSc; Nicholas P. Curzen, PhD, FRCP; Tim C. Clayton, MSc; Keith G. Oldroyd, MD, FRCP; Lorraine Bennett, MSc; Steve Holmberg, MD, FRCP; James M. Cotton, MD, FRCP; Peter E. Glennon, PhD, FRCP; Martyn R. Thomas, MD, FRCP; Philip A. MacCarthy, PhD, FRCP; Andreas Baumbach, MD, FRCP; Niall T. Mulvihill, MD; Robert A. Henderson, DM, FRCP; Simon R. Redwood, MD; Ian R. Starkey, BSc, FRCP; Rodney H. Stables, DM, FRCP
From the Sussex Cardiac Centre (D.H.-S., A.J.d.B., N.C., L.B., S.H.), Brighton and Sussex University Hospitals, Brighton, United Kingdom; Southampton University Hospitals (N.P.C.), Southampton, United Kingdom; London School of Hygiene & Tropical Medicine (T.C.C.), London, United Kingdom; Golden Jubilee National Hospital (K.G.O.), Glasgow, United Kingdom; Heart and Lung Centre (J.M.C.), Wolverhampton, United Kingdom; Walsgrave Hospital (P.E.G.), Coventry, United Kingdom; King’s College Hospital (M.R.T., P.A.M.), London, United Kingdom; Bristol Heart Institute (A.B.), Bristol, United Kingdom; St James Hospital (N.T.M.), Dublin, Ireland; Nottingham University Hospitals (R.A.H.), Nottingham, United Kingdom; St Thomas Hospital (S.R.R.), London, United Kingdom; Edinburgh Royal Infirmary (I.R.S.), Edinburgh, United Kingdom; and Liverpool Heart and Chest Hospital (R.H.S.), Liverpool, United Kingdom. Coordinating center: Sussex Cardiac Centre, Brighton and Sussex University Hospitals, Brighton, United Kingdom.
Correspondence to David Hildick-Smith, Sussex Cardiac Centre, Royal Sussex County Hospital, Eastern Rd, Brighton, BN8 5QH, United Kingdom. Email david.hildick-smith@bsuh.nhs.uk
Received June 23, 2009; accepted December 14, 2009.
Background— The optimal strategy for treating coronary bifurcation lesions remains a subject of debate. With bare-metal stents, single-stent approaches appear to be superior to systematic 2-stent strategies. Drug-eluting stents, however, have low rates of restenosis and might offer improved outcomes with complex stenting techniques.
Methods and Results— Patients with significant coronary bifurcation lesions were randomized to either a simple or complex stenting strategy with drug-eluting stents. In the simple strategy, the main vessel was stented, followed by optional kissing balloon dilatation/T-stent. In the complex strategy, both vessels were systematically stented (culotte or crush techniques) with mandatory kissing balloon dilatation. Five hundred patients 64±10 years old were randomized; 77% were male. Eighty-two percent of lesions were true bifurcations (>50% narrowing in both vessels). In the simple group (n=250), 66 patients (26%) had kissing balloons in addition to main-vessel stenting, and 7 (3%) had T stenting. In the complex group (n=250), 89% of culotte (n=75) and 72% of crush (n=169) cases were completed successfully with final kissing balloon inflations. The primary end point (a composite at 9 months of death, myocardial infarction, and target-vessel failure) occurred in 8.0% of the simple group versus 15.2% of the complex group (hazard ratio 2.02, 95% confidence interval 1.17 to 3.47, P=0.009). Myocardial infarction occurred in 3.6% versus 11.2%, respectively (P=0.001), and in-hospital major adverse cardiovascular events occurred in 2.0% versus 8.0% (P=0.002), respectively. Procedure duration and x-ray dose favored the simple approach.
Conclusions— When coronary bifurcation lesions are treated, a systematic 2-stent technique results in higher rates of in-hospital and 9-month major adverse cardiovascular events. This difference is largely driven by periprocedural myocardial infarction. Procedure duration is longer, and x-ray dose is higher. The provisional technique should remain the preferred strategy in the majority of cases.

abstract 8 of 8
Molecular Cardiology
Thioredoxin-1 Gene Therapy Enhances Angiogenic Signaling and Reduces Ventricular Remodeling in Infarcted Myocardium of Diabetic Rats
Samson Mathews Samuel, MPhil; Mahesh Thirunavukkarasu, PhD; Suresh Varma Penumathsa, PhD; Srikanth Koneru, MD; Lijun Zhan, BS; Gautam Maulik, PhD; Perumana R. Sudhakaran, PhD; Nilanjana Maulik, PhD
From the Molecular Cardiology and Angiogenesis Laboratory (S.M.S., M.T., S.V.P., S.K., L.Z., N.M.), Department of Surgery, UCONN Health Center, Farmington, Conn; Department of Biochemistry (S.M.S., P.R.S.), University of Kerala, Trivandrum, Kerala, India; and Department of Cancer Biology (G.M.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Mass.
Correspondence to Nilanjana Maulik, PhD, FAHA, FACN, FICA, Professor, Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030-1110. E-mail nmaulik@neuron.uchc.edu
Received April 22, 2009; accepted December 30, 2009.
Background— The present study evaluated the reversal of diabetes-mediated impairment of angiogenesis in a myocardial infarction model of type 1 diabetic rats by intramyocardial administration of an adenoviral vector encoding thioredoxin-1 (Ad.Trx1). Various studies have linked diabetes-mediated impairment of angiogenesis to dysfunctional antioxidant systems in which thioredoxin-1 plays a central role.
Methods and Results— Ad.Trx1 was administered intramyocardially in nondiabetic and diabetic rats immediately after myocardial infarction. Ad.LacZ was similarly administered to the respective control groups. The hearts were excised for molecular and immunohistochemical analysis at predetermined time points. Myocardial function was measured by echocardiography 30 days after the intervention. The Ad.Trx1-administered group exhibited reduced fibrosis, oxidative stress, and cardiomyocyte and endothelial cell apoptosis compared with the diabetic myocardial infarction group, along with increased capillary and arteriolar density. Western blot and immunohistochemical analysis demonstrated myocardial overexpression of thioredoxin-1, heme oxygenase-1, vascular endothelial growth factor, and p38 mitogen-activated protein kinase-β, as well as decreased phosphorylated JNK and p38 mitogen-activated protein kinase- , in the Ad.Trx1-treated diabetic group. Conversely, we observed a significant reduction in the expression of vascular endothelial growth factor in nondiabetic and diabetic animals treated with tin protoporphyrin (SnPP, a heme oxygenase-1 enzyme inhibitor), even after Ad.Trx1 therapy. Echocardiographic analysis after 4 weeks of myocardial infarction revealed significant improvement in myocardial functional parameters such as ejection fraction, fractional shortening, and E/A ratio in the Ad.Trx1-administered group compared with the diabetic myocardial infarction group.
Conclusions— This study demonstrates for the first time that impairment of angiogenesis and myocardial dysfunction can be regulated by Ad.Trx1 gene therapy in streptozotocin-induced diabetic rats subjected to infarction.