circulation2010-03-09
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Abstract 1 of 6 (Circulation. 2010;121:****-1077.)
© 2010 American Heart Association, Inc.
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Epidemiology and Prevention
Statins for the Primary Prevention of Cardiovascular Events in Women With Elevated High-Sensitivity C-Reactive Protein or Dyslipidemia
Results From the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and Meta-Analysis of Women From Primary Prevention Trials
Samia Mora, MD, MHS; Robert J. Glynn, ScD; Judith Hsia, MD; Jean G. MacFadyen, BA; Jacques Genest, MD; Paul M Ridker, MD, MPH
From the Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine (S.M., R.J.G., J.G.M., P.M.R.) and Cardiovascular Medicine (S.M., P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, and Department of Biostatistics, Harvard School of Public Health (R.J.G.), Boston, Mass; AstraZeneca, Philadelphia, Penn (J.H.); and McGill University Health Center, Montreal, Quebec, Canada (J.G.).
Correspondence to Samia Mora, MD, MHS, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail smora@partners.org
Received September 2, 2009; accepted December 28, 2009.
Background— Statin therapy in women without cardiovascular disease (CVD) is controversial, given the insufficient evidence of benefit. We analyzed sex-specific outcomes in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and synthesized the results with prior trials.
Methods and Results— JUPITER participants included 6801 women 60 years of age and 11 001 men 50 years of age with high-sensitivity C-reactive protein 2 mg/L and low-density lipoprotein cholesterol <130 mg/dL randomized to rosuvastatin versus placebo. Meta-analysis studies were randomized placebo-controlled statin trials with predominantly or exclusively primary prevention in women and sex-specific outcomes (20 147 women; >276 CVD events; mean age, 63 to 69 years). Absolute CVD rates (per 100 person-years) in JUPITER women for rosuvastatin and placebo (0.57 and 1.04, respectively) were lower than for men (0.88 and 1.54, respectively), with similar relative risk reduction in women (hazard ratio, 0.54; 95% confidence interval, 0.37 to 0.80; P=0.002) and men (hazard ratio, 0.58; 95% confidence interval, 0.45 to 0.73; P<0.001). In women, there was significant reduction in revascularization/unstable angina and nonsignificant reductions in other components of the primary end point. Meta-analysis of 13 154 women (240 CVD events; 216 total deaths) from exclusively primary prevention trials found a significant reduction in primary CVD events with statins by a third (relative risk, 0.63; 95% confidence interval, 0.49 to 0.82; P<0.001; P for heterogeneity=0.56) with a smaller nonsignificant effect on total mortality (relative risk, 0.78; 95% confidence interval, 0.53 to 1.15; P=0.21; P for heterogeneity=0.20). Similar results were obtained for trials that were predominantly but not exclusively primary prevention.
Conclusion— JUPITER demonstrated that in primary prevention rosuvastatin reduced CVD events in women with a relative risk reduction similar to that in men, a finding supported by meta-analysis of primary prevention statin trials.
Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.
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CLINICAL PERSPECTIVE
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Abstract 2 of 6 (Circulation. 2010;121:1078-1085.)
© 2010 American Heart Association, Inc.
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Exercise Physiology
Ethnic Differences in Physiological Cardiac Adaptation to Intense Physical Exercise in Highly Trained Female Athletes
J. Rawlins, MRCP; F. Carre, PhD; G. Kervio, PhD; M. Papadakis, MRCP; N. Chandra, MRCP; C. Edwards, MRCP; G.P. Whyte, PhD; S. Sharma, MD
From King’s College Hospital (J.R., N.C., C.E., S.S.), London, United Kingdom; French Institute of Health and Medical Research (INSERM), CIT-IT 804, University of Rennes (F.C., G.K.), Rennes, France; University Hospital Lewisham (M.P., S.S.). London, United Kingdom; and Liverpool John Moores University (G.P.W.), Liverpool, United Kingdom.
Correspondence to Professor Sanjay Sharma, Professor of Clinical Cardiology, St George’s University Hospital, London, United Kingdom. E-mail ssharma21@hotmail.com
Received October 19, 2009; accepted December 21, 2009.
Background— Ethnicity is an important determinant of cardiovascular adaptation in athletes. Studies in black male athletes reveal a higher prevalence of electric repolarization and left ventricular hypertrophy than observed in white males; these frequently overlap with those observed in cardiomyopathy and have important implications in the preparticipation cardiac screening era. There are no reports on cardiac adaptation in highly trained black females, who comprise an increasing population of elite competitors.
Methods and Results— Between 2004 and 2009, 240 nationally ranked black female athletes (mean age 21±4.6 years old) underwent 12-lead ECG and 2-dimensional echocardiography. The results were compared with 200 white female athletes of similar age and size participating in similar sports. Black athletes demonstrated greater left ventricular wall thickness (9.2±1.2 versus 8.6±1.2 mm, P<0.001) and left ventricular mass (187.2±42 versus 172.3±42 g, P=0.008) than white athletes. Eight black athletes (3%) exhibited a left ventricular wall thickness >11 mm (12 to 13 mm) compared with none of the white athletes. All athletes revealed normal indices of systolic and diastolic function. Black athletes exhibited a higher prevalence of T-wave inversions (14% versus 2%, P<0.001) and ST-segment elevation (11% versus 1%, P<0.001) than white athletes. Deep T-wave inversions (–0.2 mV) were observed only in black athletes and were confined to the anterior leads (V1 through V3).
Conclusions— Systematic physical exercise in black female athletes is associated with greater left ventricular hypertrophy and higher prevalence of repolarization changes than in white female athletes of similar age and size participating in identical sporting disciplines. However, a maximal left ventricular wall thickness >13 mm or deep T-wave inversions in the inferior and lateral leads are rare and warrant further investigation.
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CLINICAL PERSPECTIVE
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Abstract 3 of 6 (Circulation. 2010;121:1086-1095.)
© 2010 American Heart Association, Inc.
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Heart Failure
Physician-Directed Patient Self-Management of Left Atrial Pressure in Advanced Chronic Heart Failure
Jay Ritzema, MRCP; Richard Troughton, FRACP, PhD; Iain Melton, FRACP; Ian Crozier, FRACP, MD; Robert Doughty, FRACP, MD; Henry Krum, FRACP, PhD; Anthony Walton, FRACP; Philip Adamson, MD; Saibal Kar, MD; Prediman K. Shah, MD; Mark Richards, FRACP, DSc; Neal L. Eigler, MD; James S. Whiting, PhD; Garrie J. Haas, MD; J. Thomas Heywood, MD; Christopher M. Frampton, PhD; William T. Abraham, MD, on Behalf of the Hemodynamically Guided Home Self-Therapy in Severe Heart Failure Patients (HOMEOSTASIS) Study Group
From the University of Otago (J.R., R.T., M.R., C.M.F.), Christchurch, New Zealand; Department of Cardiology (I.M., I.C.), Christchurch Hospital, Christchurch, New Zealand; Auckland City Hospital (R.D.), Auckland, New Zealand; The Alfred Hospital (H.K., A.W.), Melbourne, Australia; Oklahoma Cardiovascular Research Group (P.A.), Oklahoma City, Okla; Cedars-Sinai Medical Center (S.K., P.K.S., N.L.E., J.S.W.), Los Angeles, Calif; Scripps Clinic (J.T.H.), La Jolla, Calif; and The Ohio State University (G.J.H., W.T.A.), Columbus, Ohio.
Correspondence to Richard Troughton, MB ChB, PhD, FRACP, University of Otago, Christchurch, PO Box 4345, Christchurch 8140, New Zealand. E-mail richard.troughton@cdhb.govt.nz
Received July 7, 2008; accepted December 18, 2009.
Background— Previous studies suggest that management of ambulatory hemodynamics may improve outcomes in chronic heart failure. We conducted a prospective, observational, first-in-human study of a physician-directed patient self-management system targeting left atrial pressure.
Methods and Results— Forty patients with reduced or preserved left ventricular ejection fraction and a history of New York Heart Association class III or IV heart failure and acute decompensation were implanted with an investigational left atrial pressure monitor, and readings were acquired twice daily. For the first 3 months, patients and clinicians were blinded as to these readings, and treatment continued per usual clinical assessment. Thereafter, left atrial pressure and individualized therapy instructions guided by these pressures were disclosed to the patient. Event-free survival was determined over a median follow-up of 25 months (range 3 to 38 months). Survival without decompensation was 61% at 3 years, and events tended to be less frequent after the first 3 months (hazard ratio 0.16 [95% confidence interval 0.04 to 0.68], P=0.012). Mean daily left atrial pressure fell from 17.6 mm Hg (95% confidence interval 15.8 to 19.4 mm Hg) in the first 3 months to 14.8 mm Hg (95% confidence interval 13.0 to 16.6 mm Hg; P=0.003) during pressure-guided therapy. The frequency of elevated readings (>25 mm Hg) was reduced by 67% (P<0.001). There were improvements in New York Heart Association class (–0.7±0.8, P<0.001) and left ventricular ejection fraction (7±10%, P<0.001). Doses of angiotensin-converting enzyme/angiotensin-receptor blockers and β-blockers were uptitrated by 37% (P<0.001) and 40% (P<0.001), respectively, whereas doses of loop diuretics fell by 27% (P=0.15).
Conclusions— Physician-directed patient self-management of left atrial pressure has the potential to improve hemodynamics, symptoms, and outcomes in advanced heart failure.
Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00547729.
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CLINICAL PERSPECTIVE
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Abstract 4 of 6 (Circulation. 2010;121:1096-1103.)
© 2010 American Heart Association, Inc.
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Imaging
Mechanical Dyssynchrony After Myocardial Infarction in Patients With Left Ventricular Dysfunction, Heart Failure, or Both
Sung-Hee Shin, MD; Chung-Lieh Hung, MD; Hajime Uno, PhD; Amira H. Hassanein, MD; Anil Verma, MD; Mikhail Bourgoun, MD; Lars Køber, MD; Jalal K. Ghali, MD; Eric J. Velazquez, MD; Robert M. Califf, MD; Marc A. Pfeffer, MD, PhD; Scott D. Solomon, MD, for the Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators
From the Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass (S.H.S., C.L.H., A.H.H., A.V., M.B., M.A.F., S.D.S.); Harvard School of Public Health and Dana Farber Cancer Institute, Boston, Mass (H.U.); University of Copenhagen, Copenhagen, Denmark (L.K.); Wayne State Medical Center, Detroit, Mich (J.K.G.); and Duke University Medical Center, Durham, NC (E.J.V., R.M.C.).
Correspondence to Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail ssolomon@rics.bwh.harvard.edu
Received April 24, 2008; accepted December 15, 2009.
Background— Mechanical dyssynchrony is considered an independent predictor for adverse cardiovascular outcomes in patients with heart failure. However, its importance as a risk factor after myocardial infarction is not well defined.
Methods and Results— We examined the influence of mechanical dyssynchrony on outcome in patients with left ventricular dysfunction, heart failure, or both after myocardial infarction who were enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) echocardiography study. B-mode speckle tracking with velocity vector imaging was used to assess ventricular synchrony in 381 patients who had image quality sufficient for analysis. Time to regional peak velocity and time to strain rate were measured among 12 left ventricular segments from the apical 4- and 2- chamber views, and the SDs between all 12 segments were used as a measure of dyssynchrony. The relationships between the SD of time to regional peak velocity and strain rate and clinical outcome of death or heart failure were assessed. In a multivariate Cox model adjusted for clinical and echocardiographic variables, the SD of time to peak velocity (hazard ratio per 10 ms, 1.10; 95% confidence interval, 1.02 to 1.18; P=0.010) and the SD of time to strain rate (hazard ratio per 10 ms, 1.16; 95% confidence interval, 1.06 to 1.27; P=0.001) were independent predictors of death or heart failure.
Conclusion— Left ventricular dyssynchrony is independently associated with increased risk of death or heart failure after myocardial infarction, suggesting that contractile pattern may play a role in post–myocardial infarction prognosis.
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CLINICAL PERSPECTIVE
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Abstract 5 of 6 (Circulation. 2010;121:1104-1112.)
© 2010 American Heart Association, Inc.
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Molecular Cardiology
Notch Signaling Regulates Endothelial Progenitor Cell Activity During Recovery From Arterial Injury in Hypercholesterolemic Mice
Masaaki Ii, MD, PhD; Kyosuke Take***a, MD, PhD; Kayoko Ibusuki, MD; Corinne Luedemann, BS; Andrea Wecker, BS; Elizabeth Eaton, BS; Tina Thorne, BS; Takayuki Asahara, MD, PhD; James K. Liao, MD; Douglas W. Losordo, MD
From the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Ill (M.I., T.T., D.W.L.); Division of Cardiovascular Research, Caritas St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass (M.I., K.I., C.L., A.W., E.E., T.T., D.W.L.); Group of Vascular Regeneration Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan (M.I., T.A.); Department of Pharmacology, Osaka Medical College, Osaka, Japan (M.I.); Partners Research Facility, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, Mass (K.T., J.K.L.); and Division of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.T.).
Correspondence to Douglas W. Losordo, MD, Feinberg Cardiovascular Research Institute, Northwestern University, Tarry 14-725, 303 E Chicago Ave, Chicago, IL 60611. E-mail d-losordo@northwestern.edu
Received April 7, 2009; accepted December 15, 2009.
Background— Little is known about the role of endothelial progenitor cells (EPCs) in atherosclerosis. Accordingly, we performed a series of assessments with hypercholesterolemic (apolipoprotein E–null [ApoE–/–]) and wild-type (WT) mice to evaluate how cholesterol influences reendothelialization, atherosclerosis, and EPC function after arterial injury.
Methods and Results— Unexpectedly, reendothelialization (assessed by resistance to Evans blue staining) and circulating EPC counts (EPC culture assay) were greater in ApoE–/– mice than in WT mice, and transplantation of ApoE–/– bone marrow in WT mice accelerated endothelial recovery and increased recruitment of bone marrow–derived EPCs to the neoendothelium. Cholesterol concentration-dependently promoted the proliferation (MTS assay) of both ApoE–/– and WT EPCs, and the concentration dependence of EPC adhesion (to vitronectin-, collagen type I–, fibronectin-, and laminin-coated plates), migration (modified Boyden chamber assay), and antiapoptotic (terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling stain) activity was biphasic. Cholesterol enhanced the messenger RNA expression (quantitative, real-time reverse-transcription polymerase chain reaction) of vascular endothelial growth factor and inhibited Notch1 messenger RNA expression in both ApoE–/– and WT EPCs, whereas endothelial nitric oxide synthase messenger RNA expression increased in ApoE–/– EPCs and declined in WT EPCs after cholesterol exposure. EPC activity was greater in Notch1+/– EPCs than in WT EPCs, and transplantation of Notch1+/– bone marrow accelerated endothelial recovery after arterial injury in WT mice.
Conclusion— The results presented here provide novel insights into the role of EPCs during atherosclerosis and suggest that cholesterol and Notch1 may be involved in the regulation of EPC activity.
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CLINICAL PERSPECTIVE
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Abstract 6 of 6 (Circulation. 2010;121:1113-1123.)
© 2010 American Heart Association, Inc.
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Molecular Cardiology
Functional Mesenchymal Stem Cells Derived From Human Induced Pluripotent Stem Cells Attenuate Limb Ischemia in Mice
Qizhou Lian, MD, PhD; Yuelin Zhang, MPhil; Jinqiu Zhang, MD, PhD; Hua Kun Zhang, MPhil; Xingang Wu, MD; Yang Zhang, MPhil; Francis Fu-Yuen Lam, PhD; Sarang Kang, BSc; Jian Chuan Xia, PhD; Wing-Hong Lai, MPhil; Ka-Wing Au, PhD; Yen Yen Chow, MSc; Chung-Wah Siu, MBBS; Chuen-Neng Lee, MD; Hung-Fat Tse, MD, PhD
From the Cardiology Division, Department of Medicine (Q.L., Y.Z., X.W., Y.Z., S.K., W.-H.L., K.-W.A., Y.Y.S., C.-W.S., H.-F.T.) and Research Centre of Heart, Brain, Hormone, and Healthy Aging (Q.L., C.-W.S., H.-F.T.), University of Hong Kong, Hong Kong, China; Institute of Medical Biology, Singapore (J.Z.); School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China (F.F.-Y.L.); Central Laboratory of Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, China (H.K.Z.); State Key Laboratory of Oncology in Southern China, Guangzhou, China (J.C.X.); and Department of Surgery, National University Hospital, National University of Singapore, Singapore (C.-N.L.).
Correspondence to Qizhou Lian, MD, PhD, or Hung-Fat Tse, MD, PhD, Cardiology Division, Department of Medicine, University of Hong Kong, Hong Kong, China. E-mail qzlian@hkucc.hku.hk or hftse@hkucc.hku.hk
Received August 2, 2009; accepted January 5, 2010.
Background— Aging and aging-related disorders impair the survival and differentiation potential of bone marrow mesenchymal stem cells (MSCs) and limit their therapeutic efficacy. Induced pluripotent stem cells (iPSCs) may provide an alternative source of functional MSCs for tissue repair. This study aimed to generate and characterize human iPSC-derived MSCs and to investigate their biological function for the treatment of limb ischemia.
Methods and Results— Human iPSCs were induced to MSC differentiation with a clinically compliant protocol. Three monoclonal, karyotypically stable, and functional MSC-like cultures were successfully isolated using a combination of CD24– and CD105+ sorting. They did not express pluripotent-associated markers but displayed MSC surface antigens and differentiated into adipocytes, osteocytes, and chondrocytes. Transplanting iPSC-MSCs into mice significantly attenuated severe hind-limb ischemia and promoted vascular and muscle regeneration. The benefits of iPSC-MSCs on limb ischemia were superior to those of adult bone marrow MSCs. The greater potential of iPSC-MSCs may be attributable to their superior survival and engraftment after transplantation to induce vascular and muscle regeneration via direct de novo differentiation and paracrine mechanisms.
Conclusions— Functional MSCs can be clonally generated, beginning at a single-cell level, from human iPSCs. Patient-specific iPSC-MSCs can be prepared as an "off-the-shelf" format for the treatment of tissue ischemia.
© 2010 American Heart Association, Inc.
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Epidemiology and Prevention
Statins for the Primary Prevention of Cardiovascular Events in Women With Elevated High-Sensitivity C-Reactive Protein or Dyslipidemia
Results From the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and Meta-Analysis of Women From Primary Prevention Trials
Samia Mora, MD, MHS; Robert J. Glynn, ScD; Judith Hsia, MD; Jean G. MacFadyen, BA; Jacques Genest, MD; Paul M Ridker, MD, MPH
From the Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine (S.M., R.J.G., J.G.M., P.M.R.) and Cardiovascular Medicine (S.M., P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, and Department of Biostatistics, Harvard School of Public Health (R.J.G.), Boston, Mass; AstraZeneca, Philadelphia, Penn (J.H.); and McGill University Health Center, Montreal, Quebec, Canada (J.G.).
Correspondence to Samia Mora, MD, MHS, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail smora@partners.org
Received September 2, 2009; accepted December 28, 2009.
Background— Statin therapy in women without cardiovascular disease (CVD) is controversial, given the insufficient evidence of benefit. We analyzed sex-specific outcomes in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and synthesized the results with prior trials.
Methods and Results— JUPITER participants included 6801 women 60 years of age and 11 001 men 50 years of age with high-sensitivity C-reactive protein 2 mg/L and low-density lipoprotein cholesterol <130 mg/dL randomized to rosuvastatin versus placebo. Meta-analysis studies were randomized placebo-controlled statin trials with predominantly or exclusively primary prevention in women and sex-specific outcomes (20 147 women; >276 CVD events; mean age, 63 to 69 years). Absolute CVD rates (per 100 person-years) in JUPITER women for rosuvastatin and placebo (0.57 and 1.04, respectively) were lower than for men (0.88 and 1.54, respectively), with similar relative risk reduction in women (hazard ratio, 0.54; 95% confidence interval, 0.37 to 0.80; P=0.002) and men (hazard ratio, 0.58; 95% confidence interval, 0.45 to 0.73; P<0.001). In women, there was significant reduction in revascularization/unstable angina and nonsignificant reductions in other components of the primary end point. Meta-analysis of 13 154 women (240 CVD events; 216 total deaths) from exclusively primary prevention trials found a significant reduction in primary CVD events with statins by a third (relative risk, 0.63; 95% confidence interval, 0.49 to 0.82; P<0.001; P for heterogeneity=0.56) with a smaller nonsignificant effect on total mortality (relative risk, 0.78; 95% confidence interval, 0.53 to 1.15; P=0.21; P for heterogeneity=0.20). Similar results were obtained for trials that were predominantly but not exclusively primary prevention.
Conclusion— JUPITER demonstrated that in primary prevention rosuvastatin reduced CVD events in women with a relative risk reduction similar to that in men, a finding supported by meta-analysis of primary prevention statin trials.
Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.
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CLINICAL PERSPECTIVE
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Abstract 2 of 6 (Circulation. 2010;121:1078-1085.)
© 2010 American Heart Association, Inc.
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Exercise Physiology
Ethnic Differences in Physiological Cardiac Adaptation to Intense Physical Exercise in Highly Trained Female Athletes
J. Rawlins, MRCP; F. Carre, PhD; G. Kervio, PhD; M. Papadakis, MRCP; N. Chandra, MRCP; C. Edwards, MRCP; G.P. Whyte, PhD; S. Sharma, MD
From King’s College Hospital (J.R., N.C., C.E., S.S.), London, United Kingdom; French Institute of Health and Medical Research (INSERM), CIT-IT 804, University of Rennes (F.C., G.K.), Rennes, France; University Hospital Lewisham (M.P., S.S.). London, United Kingdom; and Liverpool John Moores University (G.P.W.), Liverpool, United Kingdom.
Correspondence to Professor Sanjay Sharma, Professor of Clinical Cardiology, St George’s University Hospital, London, United Kingdom. E-mail ssharma21@hotmail.com
Received October 19, 2009; accepted December 21, 2009.
Background— Ethnicity is an important determinant of cardiovascular adaptation in athletes. Studies in black male athletes reveal a higher prevalence of electric repolarization and left ventricular hypertrophy than observed in white males; these frequently overlap with those observed in cardiomyopathy and have important implications in the preparticipation cardiac screening era. There are no reports on cardiac adaptation in highly trained black females, who comprise an increasing population of elite competitors.
Methods and Results— Between 2004 and 2009, 240 nationally ranked black female athletes (mean age 21±4.6 years old) underwent 12-lead ECG and 2-dimensional echocardiography. The results were compared with 200 white female athletes of similar age and size participating in similar sports. Black athletes demonstrated greater left ventricular wall thickness (9.2±1.2 versus 8.6±1.2 mm, P<0.001) and left ventricular mass (187.2±42 versus 172.3±42 g, P=0.008) than white athletes. Eight black athletes (3%) exhibited a left ventricular wall thickness >11 mm (12 to 13 mm) compared with none of the white athletes. All athletes revealed normal indices of systolic and diastolic function. Black athletes exhibited a higher prevalence of T-wave inversions (14% versus 2%, P<0.001) and ST-segment elevation (11% versus 1%, P<0.001) than white athletes. Deep T-wave inversions (–0.2 mV) were observed only in black athletes and were confined to the anterior leads (V1 through V3).
Conclusions— Systematic physical exercise in black female athletes is associated with greater left ventricular hypertrophy and higher prevalence of repolarization changes than in white female athletes of similar age and size participating in identical sporting disciplines. However, a maximal left ventricular wall thickness >13 mm or deep T-wave inversions in the inferior and lateral leads are rare and warrant further investigation.
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CLINICAL PERSPECTIVE
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Abstract 3 of 6 (Circulation. 2010;121:1086-1095.)
© 2010 American Heart Association, Inc.
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Heart Failure
Physician-Directed Patient Self-Management of Left Atrial Pressure in Advanced Chronic Heart Failure
Jay Ritzema, MRCP; Richard Troughton, FRACP, PhD; Iain Melton, FRACP; Ian Crozier, FRACP, MD; Robert Doughty, FRACP, MD; Henry Krum, FRACP, PhD; Anthony Walton, FRACP; Philip Adamson, MD; Saibal Kar, MD; Prediman K. Shah, MD; Mark Richards, FRACP, DSc; Neal L. Eigler, MD; James S. Whiting, PhD; Garrie J. Haas, MD; J. Thomas Heywood, MD; Christopher M. Frampton, PhD; William T. Abraham, MD, on Behalf of the Hemodynamically Guided Home Self-Therapy in Severe Heart Failure Patients (HOMEOSTASIS) Study Group
From the University of Otago (J.R., R.T., M.R., C.M.F.), Christchurch, New Zealand; Department of Cardiology (I.M., I.C.), Christchurch Hospital, Christchurch, New Zealand; Auckland City Hospital (R.D.), Auckland, New Zealand; The Alfred Hospital (H.K., A.W.), Melbourne, Australia; Oklahoma Cardiovascular Research Group (P.A.), Oklahoma City, Okla; Cedars-Sinai Medical Center (S.K., P.K.S., N.L.E., J.S.W.), Los Angeles, Calif; Scripps Clinic (J.T.H.), La Jolla, Calif; and The Ohio State University (G.J.H., W.T.A.), Columbus, Ohio.
Correspondence to Richard Troughton, MB ChB, PhD, FRACP, University of Otago, Christchurch, PO Box 4345, Christchurch 8140, New Zealand. E-mail richard.troughton@cdhb.govt.nz
Received July 7, 2008; accepted December 18, 2009.
Background— Previous studies suggest that management of ambulatory hemodynamics may improve outcomes in chronic heart failure. We conducted a prospective, observational, first-in-human study of a physician-directed patient self-management system targeting left atrial pressure.
Methods and Results— Forty patients with reduced or preserved left ventricular ejection fraction and a history of New York Heart Association class III or IV heart failure and acute decompensation were implanted with an investigational left atrial pressure monitor, and readings were acquired twice daily. For the first 3 months, patients and clinicians were blinded as to these readings, and treatment continued per usual clinical assessment. Thereafter, left atrial pressure and individualized therapy instructions guided by these pressures were disclosed to the patient. Event-free survival was determined over a median follow-up of 25 months (range 3 to 38 months). Survival without decompensation was 61% at 3 years, and events tended to be less frequent after the first 3 months (hazard ratio 0.16 [95% confidence interval 0.04 to 0.68], P=0.012). Mean daily left atrial pressure fell from 17.6 mm Hg (95% confidence interval 15.8 to 19.4 mm Hg) in the first 3 months to 14.8 mm Hg (95% confidence interval 13.0 to 16.6 mm Hg; P=0.003) during pressure-guided therapy. The frequency of elevated readings (>25 mm Hg) was reduced by 67% (P<0.001). There were improvements in New York Heart Association class (–0.7±0.8, P<0.001) and left ventricular ejection fraction (7±10%, P<0.001). Doses of angiotensin-converting enzyme/angiotensin-receptor blockers and β-blockers were uptitrated by 37% (P<0.001) and 40% (P<0.001), respectively, whereas doses of loop diuretics fell by 27% (P=0.15).
Conclusions— Physician-directed patient self-management of left atrial pressure has the potential to improve hemodynamics, symptoms, and outcomes in advanced heart failure.
Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00547729.
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CLINICAL PERSPECTIVE
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Abstract 4 of 6 (Circulation. 2010;121:1096-1103.)
© 2010 American Heart Association, Inc.
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Imaging
Mechanical Dyssynchrony After Myocardial Infarction in Patients With Left Ventricular Dysfunction, Heart Failure, or Both
Sung-Hee Shin, MD; Chung-Lieh Hung, MD; Hajime Uno, PhD; Amira H. Hassanein, MD; Anil Verma, MD; Mikhail Bourgoun, MD; Lars Køber, MD; Jalal K. Ghali, MD; Eric J. Velazquez, MD; Robert M. Califf, MD; Marc A. Pfeffer, MD, PhD; Scott D. Solomon, MD, for the Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators
From the Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass (S.H.S., C.L.H., A.H.H., A.V., M.B., M.A.F., S.D.S.); Harvard School of Public Health and Dana Farber Cancer Institute, Boston, Mass (H.U.); University of Copenhagen, Copenhagen, Denmark (L.K.); Wayne State Medical Center, Detroit, Mich (J.K.G.); and Duke University Medical Center, Durham, NC (E.J.V., R.M.C.).
Correspondence to Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail ssolomon@rics.bwh.harvard.edu
Received April 24, 2008; accepted December 15, 2009.
Background— Mechanical dyssynchrony is considered an independent predictor for adverse cardiovascular outcomes in patients with heart failure. However, its importance as a risk factor after myocardial infarction is not well defined.
Methods and Results— We examined the influence of mechanical dyssynchrony on outcome in patients with left ventricular dysfunction, heart failure, or both after myocardial infarction who were enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) echocardiography study. B-mode speckle tracking with velocity vector imaging was used to assess ventricular synchrony in 381 patients who had image quality sufficient for analysis. Time to regional peak velocity and time to strain rate were measured among 12 left ventricular segments from the apical 4- and 2- chamber views, and the SDs between all 12 segments were used as a measure of dyssynchrony. The relationships between the SD of time to regional peak velocity and strain rate and clinical outcome of death or heart failure were assessed. In a multivariate Cox model adjusted for clinical and echocardiographic variables, the SD of time to peak velocity (hazard ratio per 10 ms, 1.10; 95% confidence interval, 1.02 to 1.18; P=0.010) and the SD of time to strain rate (hazard ratio per 10 ms, 1.16; 95% confidence interval, 1.06 to 1.27; P=0.001) were independent predictors of death or heart failure.
Conclusion— Left ventricular dyssynchrony is independently associated with increased risk of death or heart failure after myocardial infarction, suggesting that contractile pattern may play a role in post–myocardial infarction prognosis.
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CLINICAL PERSPECTIVE
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Abstract 5 of 6 (Circulation. 2010;121:1104-1112.)
© 2010 American Heart Association, Inc.
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Molecular Cardiology
Notch Signaling Regulates Endothelial Progenitor Cell Activity During Recovery From Arterial Injury in Hypercholesterolemic Mice
Masaaki Ii, MD, PhD; Kyosuke Take***a, MD, PhD; Kayoko Ibusuki, MD; Corinne Luedemann, BS; Andrea Wecker, BS; Elizabeth Eaton, BS; Tina Thorne, BS; Takayuki Asahara, MD, PhD; James K. Liao, MD; Douglas W. Losordo, MD
From the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Ill (M.I., T.T., D.W.L.); Division of Cardiovascular Research, Caritas St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass (M.I., K.I., C.L., A.W., E.E., T.T., D.W.L.); Group of Vascular Regeneration Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan (M.I., T.A.); Department of Pharmacology, Osaka Medical College, Osaka, Japan (M.I.); Partners Research Facility, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, Mass (K.T., J.K.L.); and Division of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.T.).
Correspondence to Douglas W. Losordo, MD, Feinberg Cardiovascular Research Institute, Northwestern University, Tarry 14-725, 303 E Chicago Ave, Chicago, IL 60611. E-mail d-losordo@northwestern.edu
Received April 7, 2009; accepted December 15, 2009.
Background— Little is known about the role of endothelial progenitor cells (EPCs) in atherosclerosis. Accordingly, we performed a series of assessments with hypercholesterolemic (apolipoprotein E–null [ApoE–/–]) and wild-type (WT) mice to evaluate how cholesterol influences reendothelialization, atherosclerosis, and EPC function after arterial injury.
Methods and Results— Unexpectedly, reendothelialization (assessed by resistance to Evans blue staining) and circulating EPC counts (EPC culture assay) were greater in ApoE–/– mice than in WT mice, and transplantation of ApoE–/– bone marrow in WT mice accelerated endothelial recovery and increased recruitment of bone marrow–derived EPCs to the neoendothelium. Cholesterol concentration-dependently promoted the proliferation (MTS assay) of both ApoE–/– and WT EPCs, and the concentration dependence of EPC adhesion (to vitronectin-, collagen type I–, fibronectin-, and laminin-coated plates), migration (modified Boyden chamber assay), and antiapoptotic (terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling stain) activity was biphasic. Cholesterol enhanced the messenger RNA expression (quantitative, real-time reverse-transcription polymerase chain reaction) of vascular endothelial growth factor and inhibited Notch1 messenger RNA expression in both ApoE–/– and WT EPCs, whereas endothelial nitric oxide synthase messenger RNA expression increased in ApoE–/– EPCs and declined in WT EPCs after cholesterol exposure. EPC activity was greater in Notch1+/– EPCs than in WT EPCs, and transplantation of Notch1+/– bone marrow accelerated endothelial recovery after arterial injury in WT mice.
Conclusion— The results presented here provide novel insights into the role of EPCs during atherosclerosis and suggest that cholesterol and Notch1 may be involved in the regulation of EPC activity.
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CLINICAL PERSPECTIVE
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Abstract 6 of 6 (Circulation. 2010;121:1113-1123.)
© 2010 American Heart Association, Inc.
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Molecular Cardiology
Functional Mesenchymal Stem Cells Derived From Human Induced Pluripotent Stem Cells Attenuate Limb Ischemia in Mice
Qizhou Lian, MD, PhD; Yuelin Zhang, MPhil; Jinqiu Zhang, MD, PhD; Hua Kun Zhang, MPhil; Xingang Wu, MD; Yang Zhang, MPhil; Francis Fu-Yuen Lam, PhD; Sarang Kang, BSc; Jian Chuan Xia, PhD; Wing-Hong Lai, MPhil; Ka-Wing Au, PhD; Yen Yen Chow, MSc; Chung-Wah Siu, MBBS; Chuen-Neng Lee, MD; Hung-Fat Tse, MD, PhD
From the Cardiology Division, Department of Medicine (Q.L., Y.Z., X.W., Y.Z., S.K., W.-H.L., K.-W.A., Y.Y.S., C.-W.S., H.-F.T.) and Research Centre of Heart, Brain, Hormone, and Healthy Aging (Q.L., C.-W.S., H.-F.T.), University of Hong Kong, Hong Kong, China; Institute of Medical Biology, Singapore (J.Z.); School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China (F.F.-Y.L.); Central Laboratory of Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, China (H.K.Z.); State Key Laboratory of Oncology in Southern China, Guangzhou, China (J.C.X.); and Department of Surgery, National University Hospital, National University of Singapore, Singapore (C.-N.L.).
Correspondence to Qizhou Lian, MD, PhD, or Hung-Fat Tse, MD, PhD, Cardiology Division, Department of Medicine, University of Hong Kong, Hong Kong, China. E-mail qzlian@hkucc.hku.hk or hftse@hkucc.hku.hk
Received August 2, 2009; accepted January 5, 2010.
Background— Aging and aging-related disorders impair the survival and differentiation potential of bone marrow mesenchymal stem cells (MSCs) and limit their therapeutic efficacy. Induced pluripotent stem cells (iPSCs) may provide an alternative source of functional MSCs for tissue repair. This study aimed to generate and characterize human iPSC-derived MSCs and to investigate their biological function for the treatment of limb ischemia.
Methods and Results— Human iPSCs were induced to MSC differentiation with a clinically compliant protocol. Three monoclonal, karyotypically stable, and functional MSC-like cultures were successfully isolated using a combination of CD24– and CD105+ sorting. They did not express pluripotent-associated markers but displayed MSC surface antigens and differentiated into adipocytes, osteocytes, and chondrocytes. Transplanting iPSC-MSCs into mice significantly attenuated severe hind-limb ischemia and promoted vascular and muscle regeneration. The benefits of iPSC-MSCs on limb ischemia were superior to those of adult bone marrow MSCs. The greater potential of iPSC-MSCs may be attributable to their superior survival and engraftment after transplantation to induce vascular and muscle regeneration via direct de novo differentiation and paracrine mechanisms.
Conclusions— Functional MSCs can be clonally generated, beginning at a single-cell level, from human iPSCs. Patient-specific iPSC-MSCs can be prepared as an "off-the-shelf" format for the treatment of tissue ischemia.
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