Circulation 2011-07-06

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Epidemiology and Prevention
Secondary Prevention and Mortality in Peripheral Artery Disease
National Health and Nutrition Examination Study, 1999 to 2004
Reena L. Pande, MD; Todd S. Perlstein, MD, MMSc; Joshua A. Beckman, MD, MSc; Mark A. Creager, MD
From the Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
Correspondence to Reena L. Pande, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

Background— Whether individuals with peripheral artery disease (PAD) identified by screening ankle-brachial index benefit from preventive therapies to reduce cardiovascular risk is unknown. We aimed to determine the number of US adults with PAD who are not receiving preventive therapies and whether treatment is associated with reduced mortality in PAD subjects without known cardiovascular disease.
Methods and Results— We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 with mortality follow-up through December 31, 2006. We defined PAD as an ankle-brachial index [img]/math/le.gif[/img]0.90. Of 7458 eligible participants [img]/math/ge.gif[/img]40 years, weighted PAD prevalence was 5.9±0.3% (mean±SE), corresponding to [img]/math/ap.gif[/img]7.1 million US adults with PAD. Statin use was reported in only 30.5±2.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in 24.9±1.9%, and aspirin use in 35.8±2.9%, corresponding to 5.0 million adults with PAD not taking statins, 5.4 million not taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 4.5 million not receiving aspirin. After adjustment for age, sex, and race/ethnicity, PAD was associated with all-cause mortality (hazard ratio, 2.4; 95% confidence interval, 1.9 to 2.9; P<0.0001). Even after exclusion of individuals with known cardiovascular disease, subjects with PAD had higher mortality rates (16.1±2.1%) than subjects without PAD or cardiovascular disease (4.1±0.3%), with an adjusted hazard ratio of 1.9 (95% confidence interval, 1.3 to 2.8; P=0.001). Among PAD subjects without cardiovascular disease, use of multiple preventive therapies was associated with 65% lower all-cause mortality (hazard ratio, 0.35; 95% confidence interval, 0.20 to 0.86; P=0.02).
Conclusions— Millions of US adults with PAD are not receiving secondary prevention therapies. Treatment with multiple therapies is associated with reduced all-cause mortality.

Clinical Perspective
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Heart Failure
Cardiac Dysfunction and Noncardiac Dysfunction as Precursors of Heart Failure With Reduced and Preserved Ejection Fraction in the Community
Carolyn S.P. Lam, MBBS, MRCP; Asya Lyass, PhD; Elisabeth Kraigher-Krainer, MD; Joseph M. Massaro, PhD; Douglas S. Lee, MD, PhD; Jennifer E. Ho, MD; Daniel Levy, MD; Margaret M. Redfield, MD; Burkert M. Pieske, MD, PhD; Emelia J. Benjamin, MD, ScM; Ramachandran S. Vasan, MD
From the National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA (C.S.L., A.L., J.M., D.S.L., J.E.H., D.L., E.J.B., R.S.V.); Department of Mathematics and Statistics, Boston University, Boston, MA (A.L.); Department of Cardiology, University of Graz, Graz, Austria (E.K.-K., B.P.); Department of Biostatistics, Boston University School of Public Health, Boston, MA (J.M.M.); Institute for Clinical Evaluative Sciences and Toronto General Hospital, University of Toronto, Toronto, ON, Canada (D.S.L.); Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, MD (D.L.); Mayo Clinic, Rochester, MN (M.M.R., C.S.L.); and Cardiology and Preventive Medicine and Epidemiology Sections, Department of Medicine, Boston University School of Medicine, Boston, MA (E.J.B., R.S.V.).
Correspondence to Ramachandran S. Vasan, MD, Framingham Heart Study, 73 Mt Wayte Ave, Ste 2, Framingham, MA 01702–5803. E-mail vasan@bu.edu

Background— Heart failure (HF) is a clinical syndrome characterized by signs and symptoms involving multiple organ systems. Longitudinal data demonstrating that asymptomatic cardiac dysfunction precedes overt HF are scarce, and the contribution of noncardiac dysfunction to HF progression is unclear. We hypothesized that subclinical cardiac and noncardiac organ dysfunction would accelerate the manifestation of HF.
Methods and Results— We studied 1038 participants of the Framingham Heart Study original cohort (mean age, 76±5 years; 39% men) with routine assessment of left ventricular systolic and diastolic function. Major noncardiac organ systems were assessed with the use of serum creatinine (renal), serum albumin (hepatic), ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1:FVC ratio; pulmonary), hemoglobin concentration (hematologic/oxygen-carrying capacity), and white blood cell count (systemic inflammation). On follow-up (mean, 11 years), there were 248 incident HF events (146 in women). After adjustment for established HF risk factors, antecedent left ventricular systolic dysfunction (hazard ratio, 2.33; 95% confidence interval, 1.43 to 3.78) and diastolic dysfunction (hazard ratio, 1.32; 95% confidence interval, 1.01 to 1.71) were associated with increased HF risk. After adjustment for cardiac dysfunction, higher serum creatinine, lower FEV1:FVC ratios, and lower hemoglobin concentrations were associated with increased HF risk (all P<0.05); serum albumin and white blood cell count were not. Subclinical dysfunction in each noncardiac organ system was associated with a 30% increased risk of HF (P=0.013).
Conclusions— Antecedent cardiac dysfunction and noncardiac organ dysfunction are associated with increased incidence of HF, supporting the notion that HF is a progressive syndrome and underscoring the importance of noncardiac factors in its occurrence.

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Heart Failure
Puma Deletion Delays Cardiac Dysfunction in Murine Heart Failure Models Through Attenuation of Apoptosis
Adel Mandl, MD; Ly Huong Pham, BS; Kalman Toth, MD, DSc, FESC; Gerald Zambetti, PhD; Peter Erhardt, MD, PhD
From the Boston Biomedical Research Institute, Watertown, MA (A.M., L.H.P., P.E.); First Department of Medicine, Division of Cardiology, University of Pecs Medical School, Pecs, Hungary (A.M., K.T.); and Cancer Center, St. Jude Children's Research Hospital, Memphis, TX (G.Z.).
Correspondence to Peter Erhardt, MD, PhD, Boston Biomedical Research Institute, 64 Grove St, Watertown, MA 02472. E-mail erhardt@bbri.org

Background— Puma (p53-upregulated modulator of apoptosis) is a proapoptotic Bcl-2 family protein that serves as a general sensor in response to pathological apoptotic stimuli. In previous work, we demonstrated that puma ablation protects the heart from reperfusion injury in a Langendorff setting. Consistent with this, downregulation of Puma in isolated cardiac myocytes prevented apoptosis induced by different proapoptotic agents. Here, we extended our research to investigate the role of Puma, a downstream mediator of p53, in the development of heart failure using Puma–/– mice.
Methods and Results— Mice underwent transverse aortic constriction, and the characteristics of cardiac remodeling were analyzed by echocardiography, histology, and gene expression at multiple time points after surgery. Four weeks after the operation, puma deletion attenuated pressure overload–induced apoptosis and fibrosis; however, it did not affect hypertrophy and angiogenesis and maintained functional performance (fractional shortening, 39% versus 25.2% in Puma–/– versus WT mice, respectively). Even at 12 weeks after transverse aortic constriction, Puma–/– mice displayed only slightly reduced contractility. In addition, transverse aortic constriction induced puma expression in a partially p53-dependent manner. To corroborate these findings, we studied another heart failure model in which heart-specific mdm4 deletion leads to p53 activation and dilated cardiomyopathy. In these mice, Puma was upregulated and its deletion rescued the cardiomyopathy phenotype.
Conclusions— Our data indicate that Puma might be a critical component of the apoptotic signaling pathways that contribute to ventricular remodeling and heart failure. Therefore, Puma inactivation may serve as a preferential target to prevent heart failure induced by cellular stress.

Clinical Perspective
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Imaging
Mitral Valve Abnormalities Identified by Cardiovascular Magnetic Resonance Represent a Primary Phenotypic Expression of Hypertrophic Cardiomyopathy
Martin S. Maron, MD; Iacopo Olivotto, MD; Caitlin Harrigan, BA; Evan Appelbaum, MD; C. Michael Gibson, MD; John R. Lesser, MD; Tammy S. Haas, RN; James E. Udelson, MD; Warren J. Manning, MD; Barry J. Maron, MD
From the Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, MA (M.S.M., C.H., J.E.U.); Referral Center for Myocardial Diseases, Azienda Ospedaliera Universitaria Careggi, Florence, Italy (I.O.); PERFUSE Core Laboratory and Data Coordinating Center, Harvard Medical School, Boston, MA (E.A., C.M.G., W.J.M.); Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.A., C.M.G., W.J.M.); and Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (J.R.L., T.S.H., B.J.M.).
Correspondence to Martin S. Maron, MD, Tufts Medical Center, No. 70, 800 Washington St, Boston, MA 02111. E-mail mmaron@tuftsmedialcenter.org

Background— Whether morphological abnormalities of the mitral valve represent part of the hypertrophic cardiomyopathy (HCM) disease process is unresolved. Therefore, we applied cardiovascular magnetic resonance to characterize mitral valve morphology in a large HCM cohort.
Methods and Results— Cine cardiac magnetic resonance images were obtained in 172 HCM patients (age, 42±18 years; 62% men) and 172 control subjects. In addition, 15 HCM gene-positive/phenotype-negative relatives were studied. Anterior mitral leaflet (AML) and posterior mitral leaflet lengths were greater in HCM patients than in control subjects (26±5 versus 19±5 mm, P<0.001; and 14±4 versus 10±3 mm, P<0.001, respectively), including 59 patients (34%) in whom AML length alone, posterior mitral leaflet length alone, or both were particularly substantial (>2 SDs above controls). Leaflet length was increased compared with controls in virtually all HCM age groups, including young patients 15 to 20 years of age (AML, 26±5 versus 21±4 mm; P=0.0002) and those [img]/math/ge.gif[/img]60 years of age (AML, 26±4 versus 19±2 mm; P<0.001). No relation was evident between mitral leaflet length and LV thickness or mass index (P=0.09 and P=0.16, respectively). A ratio of AML length to LV outflow tract diameter of >2.0 was associated with subaortic obstruction (P=0.001). In addition, AML length in 15 genotype-positive relatives without LV hypertrophy exceeded that of matched control subjects (21±3 versus 18±3 mm; P<0.01).
Conclusions— In HCM, mitral valve leaflets are elongated independently of other disease variables, likely constituting a primary phenotypic expression of this heterogeneous disease, and are an important morphological abnormality responsible for LV outflow obstruction in combination with small outflow tract dimension. These findings suggest a novel role for cardiac magnetic resonance in the assessment of HCM.

Clinical Perspective
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Molecular Cardiology
Nonmuscle Myosin Light-Chain Kinase Deficiency Attenuates Atherosclerosis in Apolipoprotein E–Deficient Mice via Reduced Endothelial Barrier Dysfunction and Monocyte Migration
Chongxiu Sun, PhD; Mack H. Wu, MD; Sarah Y. Yuan, MD, PhD
From the Division of Research, Department of Surgery, University of California Davis School of Medicine, Sacramento, CA.
Correspondence to Sarah Yuan, MD, PhD, Professor and Director of Research, Department of Surgery, University of California Davis School of Medicine, 4625 2nd Ave, Room 3005, Sacramento, CA 95817. E-mail sarahyuan@ucdavis.edu

Background— Endothelial dysfunction and monocyte migration are key events in the pathogenesis of atherosclerosis. Nonmuscle myosin light-chain kinase (nmMLCK), the predominant MLCK isoform in endothelial cells, has been shown to contribute to vascular inflammation by altering endothelial barrier function. However, its impact on atherogenesis remains unknown.
Methods and Results— We investigated the role of nmMLCK in the development of atherosclerotic lesions in apolipoprotein E–deficient (apoE–/–) mice fed an atherogenic diet for 12 weeks. Histopathological examination demonstrated that nmMLCK deficiency (apoE–/–nmmlck–/–) reduced the size of aortic lesions by 53%, lipid contents by 44%, and macrophage deposition by 40%. Western blotting and reverse-transcription polymerase chain reaction revealed the expression of nmMLCK in aortic endothelial cells and peripheral blood monocytes. Measurements of transendothelial electric resistance indicated that nmMLCK deficiency attenuated endothelial barrier dysfunction caused by thrombin, oxidized low-density lipoprotein, and tumor necrosis factor α. In monocytes, nmMLCK deficiency reduced their migration in response to the chemokine monocyte chemoattractant protein-1. Further mechanistic studies showed that nmMLCK acted through both myosin light chain phosphorylation-coupled and -uncoupled pathways; the latter involved Rous sacracoma virus homolog genes-encoded tyrosine kinases (Src) signaling. Moreover, depletion of Src via gene silencing, site-specific mutagenesis, or pharmacological inhibition of Src greatly attenuated nmMLCK-dependent endothelial barrier dysfunction and monocyte migration.
Conclusions— Nonmuscle myosin light-chain kinase contributes to atherosclerosis by regulating endothelial barrier function and monocyte migration via mechanisms involving not only kinase-mediated MLC phosphorylation but also Src activation.

Clinical Perspective
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Resuscitation Science
Perishock Pause
An Independent Predictor of Survival From Out-of-Hospital Shockable Cardiac Arrest
Sheldon Cheskes, MD; Robert H. Schmicker, MS; Jim Christenson, MD; David D. Salcido, MPH; Tom Rea, MD; Judy Powell, RN; Dana P. Edelson, MD; Rebecca Sell, MD; Susanne May, PhD; James J. Menegazzi, PhD; Lois Van Ottingham, RN, BSN; Michele Olsufka, BSN; Sarah Pennington, RN; Jacob Simonini, ACP; Robert A. Berg, MD; Ian Stiell, MD, MSc; Ahamed Idris, MD; Blair Bigham, MSc; Laurie Morrison, MD, MSc, on behalf of the Resuscitation Outcomes Consortium (ROC) Investigators
From the University of Toronto, Toronto, ON, Canada (S.C., B.B., L.M.); University of Washington, Seattle (R.H.S., T.R., J.P., S.M., L.V.O., M.O.); University of British Columbia, Vancouver, BC, Canada (J.C.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.J.M., D.D.S.); St. Paul's Hospital, Vancouver, BC, Canada (S.P.); Region of Peel, Emergency Medical Services, Brampton, ON, Canada (J.S.); University of Chicago Medical Center, Chicago, IL (D.E.); University of Ottawa, Ottawa, ON, Canada (I.S.); Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia (R.A.B.); University of Texas Southwestern Medical Center, Dallas (A.I.); and University of California/San Diego, San Diego (R.S.).
Correspondence to Sheldon Cheskes, MD, Sunnybrook-Osler Centre for Pre-Hospital Care, Brown's Line, Ste 100, Toronto, ON, Canada M8W 3S2. E-mail scheskes@socpc.ca

Background— Perishock pauses are pauses in chest compressions before and after defibrillatory shock. We examined the relationship between perishock pauses and survival to hospital discharge.
Methods and Results— We included out-of-hospital cardiac arrest patients in the Resuscitation Outcomes Consortium Epistry–Cardiac Arrest who suffered arrest between December 2005 and June 2007, presented with a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia), and had cardiopulmonary resuscitation process data for at least 1 shock (n=815). We used multivariable logistic regression to determine the association between survival and perishock pauses. In an analysis adjusted for Utstein predictors of survival, the odds of survival were significantly lower for patients with preshock pause [img]/math/ge.gif[/img]20 seconds (odds ratio, 0.47; 95% confidence interval, 0.27 to 0.82) and perishock pause [img]/math/ge.gif[/img]40 seconds (odds ratio, 0.54; 95% confidence interval, 0.31 to 0.97) compared with patients with preshock pause <10 seconds and perishock pause <20 seconds. Postshock pause was not independently associated with a significant change in the odds of survival. Log-linear modeling depicted a decrease in survival to hospital discharge of 18% and 14% for every 5-second increase in both preshock and perishock pause interval (up to 40 and 50 seconds, respectively), with no significant association noted with changes in the postshock pause interval.
Conclusions— In patients with cardiac arrest presenting in a shockable rhythm, longer perishock and preshock pauses were independently associated with a decrease in survival to hospital discharge. The impact of preshock pause on survival suggests that refinement of automatic defibrillator software and paramedic education to minimize preshock pause delays may have a significant impact on survival.

Clinical Perspective
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Vascular Medicine
Increased Adipose Tissue Oxygen Tension in Obese Compared With Lean Men Is Accompanied by Insulin Resistance, Impaired Adipose Tissue Capillarization, and Inflammation
Gijs H. Goossens, PhD; Alessandro Bizzarri, MSc; Nicolas Venteclef, PhD; Yvonne Essers, BSc; Jack P. Cleutjens, PhD; Ellen Konings, MSc; Johan W.E. Jocken, PhD; Merima [img]/math/Ccaron.gif[/img]ajlakovi[img]/math/cacute.gif[/img], PhD; Volker Ribitsch, PhD; Karine Clément, MD, PhD; Ellen E. Blaak, PhD
From the Department of Human Biology, NUTRIM School for Nutrition, Toxicology, and Metabolism (G.H.G., Y.E., E.K., J.W.E.J., E.E.B.), and Department of Pathology (J.P.C.), Maastricht University Medical Centre, Maastricht, Netherlands; Joanneum Research Forschungsgesellschaft mbH, MATERIALS (Institute of Surface Technologies and Photonics), Sensorsystems, Graz, Austria (A.B., M.[img]/math/Ccaron.gif[/img]., V.R.); and INSERM Nutriomique U872 (Eq 7), University Pierre et Marie Curie Paris 6, Cordelier Research Centre, Paris, France (N.V., K.C.).
Correspondence to Dr G.H. Goossens, Department of Human Biology, NUTRIM School for Nutrition, Toxicology, and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht, Netherlands. E-mail G.Goossens@maastrichtuniversity.nl

Background— Adipose tissue (AT) dysfunction in obesity contributes to chronic, low-grade inflammation that predisposes to type 2 diabetes mellitus and cardiovascular disease. Recent in vitro studies suggest that AT hypoxia may induce inflammation. We hypothesized that adipose tissue blood flow (ATBF) regulates AT oxygen partial pressure (AT PO2), thereby affecting AT inflammation and insulin sensitivity.
Methods and Results— We developed an optochemical measurement system for continuous monitoring of AT PO2 using microdialysis. The effect of alterations in ATBF on AT PO2 was investigated in lean and obese subjects with both pharmacological and physiological approaches to manipulate ATBF. Local administration of angiotensin II (vasoconstrictor) in abdominal subcutaneous AT decreased ATBF and AT PO2, whereas infusion of isoprenaline (vasodilator) evoked opposite effects. Ingestion of a glucose drink increased ATBF and AT PO2 in lean subjects, but these responses were blunted in obese individuals. However, AT PO2 was higher (hyperoxia) in obese subjects despite lower ATBF, which appears to be explained by lower AT oxygen consumption. This was accompanied by insulin resistance, lower AT capillarization, lower AT expression of genes encoding proteins involved in mitochondrial biogenesis and function, and higher AT gene expression of macrophage infiltration and inflammatory markers.
Conclusions— Our findings establish ATBF as an important regulator of AT PO2. Nevertheless, obese individuals exhibit AT hyperoxia despite lower ATBF, which seems to be explained by lower AT oxygen consumption. This is accompanied by insulin resistance, impaired AT capillarization, and higher AT gene expression of inflammatory cell markers.
Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: ***2451.

Clinical Perspective
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Vascular Medicine
Rhesus Macaques Develop Metabolic Syndrome With Reversible Vascular Dysfunction Responsive to Pioglitazone
Xiuqin Zhang, MD, PhD*; Rongli Zhang, MD, PhD*; Susanne Raab, PhD; Wen Zheng, MS; Jue Wang, MD, PhD; Na Liu, MS; Tiangang Zhu, MD; Lifang Xue, MD; Zhentao Song, BSc; Jiaming Mao, BSc; Kaitao Li, MS; Huiliang Zhang, MS; Yan Zhang, MD, PhD; Chao Han, BSc; Yi Ding, BSc; Hui Wang, BSc; Ning Hou, BSc; Yuli Liu, BSc; Shujiang Shang, MS; Chuanyun Li, PhD; Elena Sebokova, PhD; Heping Cheng, PhD; Paul L. Huang, MD, PhD
From the Institute of Molecular Medicine, Peking University, Beijing, China (X.Z., R.Z., W.Z., J.W., N.L., Z.S., J.M., K.L., H.Z., Y.Z., C.H., Y.D., H.W., N.H., Y.L., S.S., C.L., H.C.); PRDM, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.R., E.S.); Department of Medical Ultrasonics, Peking University People's Hospital, Beijing, China (T.Z., L.X.); Cardiology Division and Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA (P.L.H.).
Correspondence to Heping Cheng, PhD, Institute of Molecular Medicine, Peking University, No.5 Yiheyuan Rd, Haidian District, Beijing 100871, China. E-mail chengp@pku.edu.cn

Background— The metabolic syndrome (MetS) is a constellation of clinical features that include central obesity, hypertension, atherogenic dyslipidemia, and insulin resistance. However, the concept remains controversial; it has been debated whether MetS represents nothing more than simultaneous co-occurrence of individual risk factors or whether there are common shared pathophysiological mechanisms that link the individual components.
Methods and Results— To investigate the emergence of metabolic and cardiovascular components during the development of MetS, we identified MetS-predisposed animals (n=35) in a large population of rhesus macaques (Macaca mulatta, 12.7±2.9 years old, n=408), acclimated them to standardized conditions, and monitored the progression of individual component features over 18 months. In 18 MetS animals with recently developed fasting hyperinsulinemia, central obesity, hypertension, and atherogenic dyslipidemia, we found that individual metabolic and cardiovascular components track together during the transition from pre-MetS to onset of MetS; MetS was associated with a 60% impairment of flow-mediated dilation, establishing the mechanistic link with vascular dysfunction. Pioglitazone treatment (3 mg/kg body weight/d for 6 weeks), a peroxisome proliferator–activated receptor [img]/math/gamma.gif[/img] agonist, reversibly improved atherogenic dyslipidemia and insulin resistance and fully restored flow-mediated dilation with persistent benefits.
Conclusions— Coemergence of metabolic and cardiovascular components during MetS progression and complete normalization of vascular dysfunction with peroxisome proliferator-activated receptor [img]/math/gamma.gif[/img] agonists suggest shared underlying mechanisms rather than separate processes, arguing for the benefit of early intervention of MetS components. Predictive nonhuman primate (NHP) models of MetS should be highly valuable in mechanistic and translational studies on the pathogenesis of MetS in relation to cardiovascular disease and diabetes mellitus.

Clinical Perspective
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Circulation Topic Review
Circulation's Editors' Picks: Most Important Articles Published Each Week
The Editors
Correspondence to The Editors, Circulation Editorial Office, 560 Harrison Avenue, suite 502, Boston, MA 02118. E-mail circ@circulationjournal.org

The following articles are being highlighted as part of Circulation's Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in Circulation and the Circulation subspecialty journals. The studies included in this article represent the Editors' Picks for each Circulation issue published in 2009. Parts II and III, including the Editors' Picks for 2010 and 2011, will follow in forthcoming issues.

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