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Circulation：2010-07-06

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Abstract 1 of 7 back (Circulation. 2010;122:11-19.)
© 2010 American Heart Association, Inc.
Heart Failure
Genetic and Pharmacologic Hydrogen Sulfide Therapy Attenuates Ischemia-Induced Heart Failure in Mice
John W. Calvert, PhD; Marah Elston, BS; Chad K. Nicholson, BS; Susheel Gundewar, MD; Saurabh Jha, MD; John W. Elrod, PhD; Arun Ramachandran, MD; David J. Lefer, PhD

From the Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, Ga (J.W.C., M.E., C.K.N., D.J.L.); Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (S.G., S.J., A.R.); and Department of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio (J.W.E.).

Correspondence to David J. Lefer, PhD, Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine, 550 Peachtree St NE, Atlanta, GA 30308. E-mail dlefer@emory.edu

Received November 3, 2009; accepted May 10, 2010.

Background— Hydrogen sulfide (H2S) is an endogenous signaling molecule with potent cytoprotective effects. The present study evaluated the therapeutic potential of H2S in murine models of heart failure.

Methods and Results— Heart failure was induced by subjecting mice either to permanent ligation of the left coronary artery for 4 weeks or to 60 minutes of left coronary artery occlusion followed by reperfusion for 4 weeks. Transgenic mice with cardiac-restricted overexpression of the H2S-generating enzyme cystathione {gamma}-lyase ({alpha}MHC-CGL-Tg+) displayed a clear protection against left ventricular structural and functional impairment as assessed by echocardiography in response to ischemia-induced heart failure, as well as improved survival in response to permanent myocardial ischemia. Exogenous H2S therapy (Na2S; 100 µg/kg) administered at the time of reperfusion (intracardiac) and then daily (intravenous) for the first 7 days after myocardial ischemia also protected against the structural and functional deterioration of the left ventricle by attenuating oxidative stress and mitochondrial dysfunction. Additional experiments aimed at elucidating some of the protective mechanisms of H2S therapy found that 7 days of H2S therapy increased the phosphorylation of Akt and increased the nuclear localization of 2 transcription factors, nuclear respiratory factor 1 and nuclear factor-E2-related factor (Nrf2), that are involved in increasing the levels of endogenous antioxidants, attenuating apoptosis, and increasing mitochondrial biogenesis.

Conclusions— The results of the present study suggest that either the administration of exogenous H2S or the modulation of endogenous H2S production may be of therapeutic benefit in the treatment of ischemia-induced heart failure.

CLINICAL PERSPECTIVE

Abstract 2 of 7 back (Circulation. 2010;122:20-32.)
© 2010 American Heart Association, Inc.
Heart Failure
Long-Term Localized High-Frequency Electric Stimulation Within the Myocardial Infarct
Effects on Matrix Metalloproteinases and Regional Remodeling
Rupak Mukherjee, PhD; William T. Rivers, BS; Jean Marie Ruddy, MD; Robert G. Matthews, BS; Christine N. Koval, BS; Rebecca A. Plyler, BS; Eileen I. Chang, BS; Risha K. Patel, BS; Christine B. Kern, PhD; Robert E. Stroud, MS; Francis G. Spinale, MD, PhD

From the Division of Cardiothoracic Surgery (R.M., W.T.R., J.M.R., R.G.M., C.N.K., R.A.P., E.I.C., R.K.P., R.E.S., F.G.S.) and Department of Regenerative Medicine and Cell Biology (C.B.K.), Medical University of South Carolina, and Ralph H. Johnson VA Medical Center (F.G.S.), Charleston, SC.

Correspondence to Rupak Mukherjee, PhD, Cardiothoracic Surgery, Strom Thurmond Research Bldg, 770 MUSC Complex, Suite 625, Medical University of South Carolina, Charleston, SC 29425. E-mail mukherr@musc.edu

Received March 31, 2009; accepted May 10, 2010.

Background— Disruption of the balance between matrix metalloproteinases (MMP) and MMP inhibitors (TIMPs) within a myocardial infarct (MI) contributes to left ventricular wall thinning and changes in regional stiffness at the MI region. This study tested the hypothesis that a targeted regional approach through localized high-frequency stimulation (LHFS) using low-amplitude electric pulses instituted within a formed MI scar would alter MMP/TIMP levels and prevent MI thinning.

Methods and Results— At 3 weeks after MI, pigs were randomized for LHFS (n=7; 240 bpm, 0.8 V, 0.05-ms pulses) or were left unstimulated (UNSTIM; n=10). At 4 weeks after MI, left ventricular wall thickness (echocardiography; 0.89±0.07 versus 0.67±0.08 cm; P<0.05) and regional stiffness (piezoelectric crystals; 14.70±2.08 versus 9.11±1.24; P<0.05) were higher with LHFS than in UNSTIM. In vivo interstitial MMP activity (fluorescent substrate cleavage; 943±59 versus 1210±72 U; P<0.05) in the MI region was lower with LHFS than in UNSTIM. In the MI region, MMP-2 levels were lower and TIMP-1 and collagen levels were higher with LHFS than in UNSTIM (all P<0.05). Transforming growth factor-β receptor 1 and phosphorylated SMAD-2/3 levels within the MI region were higher with LHFS than in UNSTIM. Electric stimulation (4 Hz) of isolated fibroblasts resulted in reduced MMP-2 and MT1-MMP levels but increased TIMP-1 levels compared with unstimulated fibroblasts.

Conclusions— These unique findings demonstrate that LHFS of the MI region altered left ventricular wall thickness and material properties, likely as a result of reduced regional MMP activity. Thus, LHFS may provide a novel means to favorably modify left ventricular remodeling after MI.

CLINICAL PERSPECTIVE

Abstract 3 of 7 back (Circulation. 2010;122:33-41.)
© 2010 American Heart Association, Inc.
Imaging
Exercise Pulmonary Hypertension in Asymptomatic Degenerative Mitral Regurgitation
Julien Magne, PhD; Patrizio Lancellotti, MD, PhD, FESC; Luc A. Piérard, MD, PhD, FESC

From the Department of Cardiology, Heart Valve Disease Clinic, University Hospital Sart Tilman, University of Liège, Liège, Belgium.

Correspondence to Professor Luc Piérard and Professor Patrizio Lancellotti, Department of Cardiology, University Hospital Sart Tilman, B-4000 Liege, Belgium. E-mail lpierard@chu.ulg.ac.be and plancellotti@chu.ulg.ac.be

Received January 12, 2010; accepted May 6, 2010.

Background— Current guidelines recommend mitral valve surgery for asymptomatic patients with severe degenerative mitral regurgitation and preserved left ventricular systolic function when exercise pulmonary hypertension (PHT) is present. However, the determinants of exercise PHT have not been evaluated. The aim of this study was to identify the echocardiographic predictors of exercise PHT and the impact on symptoms.

Methods and Results— Comprehensive resting and exercise transthoracic echocardiography was performed in 78 consecutive patients (age, 61±13 years; 56% men) with at least moderate degenerative mitral regurgitation (effective regurgitant orifice area =43±20 mm2; regurgitant volume =71±27 mL). Exercise PHT was defined as a systolic pulmonary arterial pressure (SPAP) >60 mm Hg. Exercise PHT was present in 46% patients. In multivariable analysis, exercise effective regurgitant orifice was an independent determinant of exercise SPAP (P<0.0001) and exercise PHT (P=0.002). Resting PHT and exercise PHT were associated with markedly reduced 2-year symptom-free survival (36±14% versus 59±7%, P=0.04; 35±8% versus 75±7%, P<0.0001). After adjustment, although the impact of resting PHT was no longer significant, exercise PHT was identified as an independent predictor of the occurrence of symptoms (hazard ratio=3.4; P=0.002). Receiver-operating characteristics curves revealed that exercise PHT (SPAP >56 mm Hg) was more accurate than resting PHT (SPAP >36 mm Hg) in predicting the occurrence of symptoms during follow-up (P=0.032).

Conclusions— Exercise PHT is frequent in patients with asymptomatic degenerative mitral regurgitation. Exercise mitral regurgitation severity is a strong independent predictor of both exercise SPAP and exercise PHT. Exercise PHT is associated with markedly low 2-year symptom-free survival, emphasizing the use of exercise echocardiography. An exercise SPAP >56 mm Hg accurately predicts the occurrence of symptoms.

CLINICAL PERSPECTIVE

Abstract 4 of 7 back (Circulation. 2010;122:42-51.)
© 2010 American Heart Association, Inc.
Interventional Cardiology
Sirolimus-Eluting Stent Versus Balloon Angioplasty for Sirolimus-Eluting Stent Restenosis: Insights From the j-Cypher Registry
Mitsuru Abe, MD; Takeshi Kimura, MD; Takeshi Morimoto, MD, MPH; Takuya Taniguchi, MD; Futoshi Yamanaka, MD; Kazuhiro Nakao, MD; Nobuhito Yagi, MD; Nobuaki Kokubu, MD; Yoichiro Kasahara, MD; Yu Kataoka, MD; Yoritaka Otsuka, MD; Atsushi Kawamura, MD; Shunichi Miyazaki, MD; Koichi Nakao, MD; Kenji Horiuchi, MD; Akira Ito, MD; Hiroshi Hoshizaki, MD; Ren Kawaguchi, MD; Manabu Setoguchi, MD; Tsukasa Inada, MD; Koichi Kishi, MD; Hiroki Sakamoto, MD; Nobuyuki Morioka, MD; Masao Imai, MD; Hiroki Shiomi, MD; Hiroshi Nonogi, MD; Kazuaki Mitsudo, MD, for the j-Cypher Registry Investigators

From the Division of Cardiology (M.A., T.T., F.Y., Kazuhiro Nakao, N.Y., N.K., Y. Kasahara, Y. Kataoka, Y.O., H.N.), National Cardiovascular Center, Suita; Department of Cardiovascular Medicine (T.K., H. Shiomi), and Center for Medical Education (T.M.), Graduate School of Medicine, Kyoto University, Kyoto; Division of Internal Medicine (A.K.), Central Hospital, Fukuyama; Division of Cardiology (S.M.), Department of Internal Medicine, Kinki University School of Medicine; Division of Cardiology (A.I.), Osaka City General Hospital; Division of Cardiology (T.I.), Osaka Red Cross Hospital; Division of Cardiology (N.M.), Kishiwada Tokushukai Hospital, Osaka; Division of Cardiology (Koichi Nakao, K.H.), Saiseikai Kumamoto Hospital Cardiovascular Center, Kumamoto; Division of Cardiology (H.H., R.K.), Gunma Prefectural Cardiovascular Center, Gunma; Division of Cardiology (M.S.), National Hospital Organization Kagoshima Medical Center, Kagoshima; Division of Cardiology (K.K.), Tokushima Red Cross Hospital, Tokushima; Division of Cardiology (H. Sakamoto), Japanese Red Cross Society Wakayama Medical Center, Wakayama; Division of Cardiology (M.I., K.M.), Kurashiki Central Hospital, Kurashiki, Japan.

Correspondence to Dr Takeshi Kimura, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail taketaka@kuhp.kyoto-u.ac.jp

Received September 2, 2009; accepted April 22, 2010.

Background— Optimal treatment strategies for restenosis of sirolimus-eluting stents (SES) have not been adequately addressed yet.

Methods and Results— During the 3-year follow-up of 12 824 patients enrolled in the j-Cypher registry, 1456 lesions in 1298 patients underwent target-lesion revascularization (TLR). Excluding 362 lesions undergoing TLR for stent thrombosis or TLR using treatment modalities other than SES or balloon angioplasty (BA), 1094 lesions with SES-associated restenosis in 990 patients treated with either SES (537 lesions) or BA (557 lesions) constituted the study population for the analysis of recurrent TLR and stent thrombosis after the first TLR. Excluding 24 patients with both SES- and BA-treated lesions, 966 patients constituted the analysis set for the mortality outcome. Cumulative incidence of recurrent TLR in the SES-treated restenosis lesions was significantly lower than that in the BA-treated restenosis lesions (23.8% versus 37.7% at 2 years after the first TLR; P<0.0001). Among 33 baseline variables evaluated, only hemodialysis was identified to be the independent risk factor for recurrent TLR by a multivariable logistic regression analysis. After adjusting for confounders, repeated SES implantation was associated with a strong treatment effect in preventing recurrent TLR over BA (odds ratio, 0.44; 95% confidence interval, 0.32 to 0.61; P<0.0001). The 2-year mortality and stent thrombosis rates between the SES- and the BA-treated groups were 10.4% versus 10.8% (P=0.4) and 0.6% versus 0.6%, respectively.

Conclusions— Repeated implantation of SES for SES-associated restenosis is more effective in preventing recurrent TLR than treatment with BA, without evidence of safety concerns.

CLINICAL PERSPECTIVE

Abstract 5 of 7 back (Circulation. 2010;122:52-61.)
© 2010 American Heart Association, Inc.
Interventional Cardiology
Comparisons of Baseline Demographics, Clinical Presentation, and Long-Term Outcome Among Patients With Early, Late, and Very Late Stent Thrombosis of Sirolimus-Eluting Stents
Observations From the Registry of Stent Thrombosis for Review and Reevaluation (RESTART)
Takeshi Kimura, MD; Takeshi Morimoto, MD; Ken Kozuma, MD; Yasuhiro Honda, MD; Teruyoshi Kume, MD; Tadanori Aizawa, MD; Kazuaki Mitsudo, MD; Shunichi Miyazaki, MD; Tetsu Yamaguchi, MD; Emi Hiyoshi; Eizo Nishimura; Takaaki Isshiki, MD, for the RESTART Investigators

From the Department of Cardiovascular of Medicine (T. Kimura) and Center for Medical Education and Clinical Epidemiology Unit (T.M.), Graduate School of Medicine, Kyoto University, Kyoto, Japan; Division of Cardiology, Teikyo University Hospital, Teikyo, Japan (K.K., T.I.); Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford, Calif (Y.H., T. Kume); Division of Cardiology, Cardiovascular Institute Hospital, Tokyo, Japan (T.A.); Division of Cardiology, Kurashiki Central Hospital, Kurashiki, Japan (K.M.); Division of Cardiology, Department of Internal Medicine, Kinki University School of Medicine, Higashi-Osaka City, Japan (S.M.); Division of Cardiology, Cardiovascular Center, Toranomon Hospital, Tokyo, Japan (T.Y.); and Cordis Cardiology Japan, Johnson and Johnson, Tokyo, Japan (E.H., E.N.).

Correspondence to Takeshi Kimura, Department of Cardiovascular of Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507 Japan. E-mail taketaka@kuhp.kyoto-u.ac.jp

Received August 28, 2009; accepted May 11, 2010.

Background— Stent thrombosis (ST) after sirolimus-eluting stent implantation has not yet been adequately characterized, mainly because of its low incidence.

Methods and Results— The Registry of Stent Thrombosis for Review and Reevaluation (RESTART) is a Japanese nationwide registry of sirolimus-eluting stent–associated ST comprising 611 patients with definite ST (early [within 30 days; EST], 322 patients; late [between 31 and 365 days; LST], 105 patients; and very late [>1 year; VLST], 184 patients). Baseline demographics, clinical presentation, and long-term outcome of sirolimus-eluting stent–associated ST were compared among patients with EST, LST, and VLST. Baseline demographics were significantly different according to the timing of ST. Characteristic demographic factors for LST/VLST versus EST identified by multivariable model were hemodialysis, end-stage renal disease not on hemodialysis, absence of circumflex target, target of chronic total occlusion, prior percutaneous coronary intervention, and age <65 years. For LST versus VLST, they were hemodialysis, heart failure, insulin-dependent diabetes mellitus, and low body mass index. Patients with LST had a significantly higher rate of Thrombolysis in Myocardial Infarction grade 2/3 flow (36%) at the time of ST than those with EST (13%) (P<0.0001) and VLST (17%; P<0.0001). Mortality rate at 1 year after ST was significantly lower in patients with VLST (10.5%) compared with those with EST (22.4%; P=0.003) or LST (23.5%; P=0.009).

Conclusion— ST timing–dependent differences in baseline demographic features, Thrombolysis in Myocardial Infarction flow grade, and mortality rate suggest possible differences in the predominant pathophysiological mechanisms of ST according to timing after sirolimus-eluting stent implantation.

CLINICAL PERSPECTIVE

Abstract 6 of 7 back (Circulation. 2010;122:62-69.)
© 2010 American Heart Association, Inc.
Valvular Heart Disease
Thirty-Day Results of the SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) Registry
A European Registry of Transcatheter Aortic Valve Implantation Using the Edwards SAPIEN Valve
Martyn Thomas, MD; Gerhard Schymik, MD; Thomas Walther, MD; Dominique Himbert, MD; Thierry Lefèvre, MD; Hendrik Treede, MD; Holger Eggebrecht, MD; Paolo Rubino, MD; Iassen Michev, MD; Rüdiger Lange, MD; William N. Anderson, PhD; Olaf Wendler, MD

From St Thomas’ Hospital, London, UK (M.T.); Städisches Klinikum und Herzklinik, Karlsruhe, Germany (G.S.); Herzzentrum, Leipzig, Germany (T.W.); Hôpital Bichat, Paris, France (D.H.); Jacques Cartier, Massy, France (T.L.); University Heart Center, Hamburg, Germany (H.T.); Uniklinik, Essen, Germany (H.E.); Clinica Montevergine, Mercogliano, Italy (P.R.); Hospital San Raffaele, Milan, Italy (I.M.); Deutsches Herzzentrum, Munich, Germany; Lake Forest, Calif (W.N.A.); and King’s College Hospital, London, UK (O.W.).

Correspondence to Martyn Thomas, MD, Director of Cardiac Services, Cardiology Department, 6th Floor E Wing, St Thomas’ Hospital, Lambeth Palace Rd, London SE1 7EH, UK. E-mail mttwins@aol.com

Received September 5, 2009; accepted April 19, 2010.

Background— Transcatheter aortic valve implantation was developed to mitigate the mortality and morbidity associated with high-risk traditional aortic valve replacement. The Edwards SAPIEN valve was approved for transcatheter aortic valve implantation transfemoral delivery in the European Union in November 2007 and for transapical delivery in January 2008.

Methods and Results— The SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) Registry was designed to assess the initial clinical results of the Edwards SAPIEN valve in consecutive patients in Europe after commercialization. Cohort 1 consists of 1038 patients enrolled at 32 centers. Patients who were treated with the transapical approach (n=575) suffered more comorbidities than the transfemoral patients (n=463), resulting in a significantly higher logistic EuroSCORE (29.1% versus 25.7%; P<0.001). Therefore, these groups are considered different, and outcomes cannot be compared. Overall short-term procedural success was observed in 93.8%. The incidence of valve embolization was 0.3% (n=3), and coronary obstruction was reported for 0.6% (n=6 cases). Incidence of stroke was 2.5% and similar for both procedural approaches. Thirty-day mortality was 6.3% in transfemoral patients and 10.3% in transapical patients. The occurrence of vascular complications was not a predictor of <30-day mortality in the transfemoral population.

Conclusion— Technical proficiency can be learned and adapted readily as demonstrated by the short-term procedural success rate and low 30-day mortality rates reported in the SOURCE Registry. Specific complication management and refinement of patient selection are needed to further improve outcomes.

CLINICAL PERSPECTIVE

Abstract 7 of 7 back (Circulation. 2010;122:70-79.)
© 2010 American Heart Association, Inc.
Vascular Medicine
Comprehensive Peroxidase-Based Hematologic Profiling for the Prediction of 1-Year Myocardial Infarction and Death
Marie-Luise Brennan, MD, PhD; Anupama Reddy, PhD; W. H. Wilson Tang, MD; Yuping Wu, PhD; Danielle M. Brennan, MS; Amy Hsu, MS; Shirley A. Mann, BS; Peter L. Hammer, PhD{dagger}; Stanley L. Hazen, MD, PhD

From the Department of Cell Biology (M.-L.B., S.A.M., S.L.H.), Center for Cardiovascular Diagnostics and Prevention (M.-L.B., A.R., W.H.W.T., S.A.M., S.L.H.), and Department of Cardiovascular Medicine (W.H.W.T., D.M.B., A.H., S.L.H.), Cleveland Clinic, Cleveland, Ohio; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio (M.-L.B., W.H.W.T., S.L.H.); Rutgers Center for Operations Research, Rutgers University, Piscataway, NJ (A.R., P.L.H.); and Department of Mathematics, Cleveland State University, Cleveland, Ohio (Y.W.). Dr ML Brennan is currently at the Department of Medicine, Stanford University, Palo Alto, Calif.

Correspondence to Stanley L. Hazen, MD, PhD, Cleveland Clinic, Center for Cardiovascular Diagnostics and Prevention, 9500 Euclid Ave, NE10, Cleveland, OH 44195. E-mail hazens@ccf.org

Received May 22, 2009; accepted April 30, 2010.

Background— Recognition of biological patterns holds promise for improved identification of patients at risk for myocardial infarction (MI) and death. We hypothesized that identifying high- and low-risk patterns from a broad spectrum of hematologic phenotypic data related to leukocyte peroxidase-, erythrocyte- and platelet-related parameters may better predict future cardiovascular risk in stable cardiac patients than traditional risk factors alone.

Methods and Results— Stable patients (n=7369) undergoing elective cardiac evaluation at a tertiary care center were enrolled. A model (PEROX) that predicts incident 1-year death and MI was derived from standard clinical data combined with information captured by a high-throughput peroxidase-based hematology analyzer during performance of a complete blood count with differential. The PEROX model was developed using a random sampling of subjects in a derivation cohort (n=5895) and then independently validated in a nonoverlapping validation cohort (n=1474). Twenty-three high-risk (observed in ≥10% of subjects with events) and 24 low-risk (observed in ≥10% of subjects without events) patterns were identified in the derivation cohort. Erythrocyte- and leukocyte (peroxidase)-derived parameters dominated the variables predicting risk of death, whereas variables in MI risk patterns included traditional cardiac risk factors and elements from all blood cell lineages. Within the validation cohort, the PEROX model demonstrated superior prognostic accuracy (78%) for 1-year risk of death or MI compared with traditional risk factors alone (67%). Furthermore, the PEROX model reclassified 23.5% (P<0.001) of patients to different risk categories for death/MI when added to traditional risk factors.

Conclusion— Comprehensive pattern recognition of high- and low-risk clusters of clinical, biochemical, and hematologic parameters provided incremental prognostic value in stable patients having elective diagnostic cardiac catheterization for 1-year risks of death and MI.