circulation2011-03-29
发布于 2011-03-29 · 浏览 2404 · IP 山东山东
这个帖子发布于 14 年零 70 天前，其中的信息可能已发生改变或有所发展。
1.Arrhythmia/Electrophysiology
Prevention of Ventricular Fibrillation Episodes in Brugada Syndrome by Catheter Ablation Over the Anterior Right Ventricular Outflow Tract EpicardiumKoonlawee Nademanee, MD; Gumpanart Veerakul, MD; Pakorn Chandanamattha, MD; Lertlak Chaothawee, MD; Aekarach Ariyachaipanich, MD; Kriengkrai Jirasirirojanakorn, MD; Khanchit Likittanasombat, MD; Kiertijai Bhuripanyo, MD; Tachapong Ngarmukos, MD
From the Pacific Rim Electrophysiology Research Institute, Los Angeles, CA (K.N., A.A.); and the Bhumipol Adulyadej Royal Thai Air Force Hospital (G.V., K.J.), Bangkok Heart Hospital (L.C., K.B.), and Ramathibodi University Hospital (P.C., K.L., T.N.), Bangkok, Thailand.
Correspondence to Koonlawee Nademanee, MD, Pacific Rim Electrophysiology Research Institute, 1700 Cesar E. Chavez Ave, Ste 2700, Los Angeles, CA 90033. E-mail wee@pacificrimep.com
' + u + '@' + d + ''//-->
Background— The underlying electrophysiological mechanism that causes an abnormal ECG pattern and ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with the Brugada syndrome (BrS) remains unelucidated. However, several studies have indicated that the right ventricular outflow tract (RVOT) is likely to be the site of electrophysiological substrate. We hypothesized that in patients with BrS who have frequent recurrent VF episodes, the substrate site is the RVOT, either over the epicardium or endocardium; abnormal electrograms would be identified at this location, which would serve as the target site for catheter ablation.
Methods and Results— We studied 9 symptomatic patients with the BrS (all men; median age 38 years) who had recurrent VF episodes (median 4 episodes) per month, necessitating implantable cardioverter defibrillator discharge. Electroanatomic mapping of the right ventricle, both endocardially and epicardially, and epicardial mapping of the left ventricle were performed in all patients during sinus rhythm. All patients had typical type 1 Brugada ECG pattern and inducible VT/VF; they were found to have unique abnormal low voltage (0.94±0.79 mV), prolonged duration (132±48 ms), and fractionated late potentials (96±47 ms beyond QRS complex) clustering exclusively in the anterior aspect of the RVOT epicardium. Ablation at these sites rendered VT/VF noninducible (7 of 9 patients [78%]; 95% confidence interval, 0.40 to 0.97, P=0.015) and normalization of the Brugada ECG pattern in 89% (95% confidence interval, 0.52 to 0.99; P=0.008). Long-term outcomes (20±6 months) were excellent, with no recurrent VT/VF in all patients off medication (except 1 patient on amiodarone).
Conclusions— The underlying electrophysiological mechanism in patients with BrS is delayed depolarization over the anterior aspect of the RVOT epicardium. Catheter ablation over this abnormal area results in normalization of the Brugada ECG pattern and prevents VT/VF, both during electrophysiological studies as well as spontaneous recurrent VT/VF episodes in patients with BrS.
2.Epidemiology and Prevention
Association of Incident Cardiovascular Disease With Progression of Sleep-Disordered BreathingHassan A. Chami, MD, MSc; Helaine E. Resnick, PhD, MPH; Stuart F. Quan, MD; Daniel J. Gottlieb, MD, MPH
From the Department of Medicine, Boston University School of Medicine, Boston, MA (H.A.C., D.J.G.); Veterans Affairs Boston Healthcare System, West Roxbury, MA (H.A.C., D.J.G.); American Association of Homes and Services for the Aging, Washington, DC (H.E.R.); Department of Medicine, Georgetown University, Washington, DC (H.E.R.); Division of Sleep Medicine, Harvard Medical School, Boston, MA (S.F.Q.); and Arizona Respiratory Center, University of Arizona, Tucson (S.F.Q.).
Correspondence to Daniel J. Gottlieb, MD, MPH, The Pulmonary Center, Boston University School of Medicine, 72 E Concord St, R-304, Boston, MA 02118. E-mail gottlieb@bu.edu
' + u + '@' + d + ''//-->
Background— Prospective data suggest that sleep-disordered breathing enhances risk for incident and recurrent cardiovascular disease (CVD). However, a reverse causal pathway whereby incident CVD causes or worsens sleep-disordered breathing has not been studied.
Methods and Results— A total of 2721 Sleep Heart Health Study participants (mean age 62, standard deviation=10 years; 57% women; 23% minority) without CVD at baseline underwent 2 polysomnograms 5 years apart. Incident CVD events, including myocardial infarction, congestive heart failure, and stroke, were ascertained and adjudicated. The relation of incident CVD to change in apnea-hypopnea index between the 2 polysomnograms was tested with general linear models, with adjustment for age, sex, race, study center, history of diabetes mellitus, change in body mass index, change in neck circumference, percent sleep time spent in supine sleep, and time between the 2 polysomnograms. Incident CVD occurred in 95 participants between the first and second polysomnograms. Compared with participants without incident CVD, those with incident CVD experienced larger increases in apnea-hypopnea index between polysomnograms. The difference in adjusted mean apnea-hypopnea index change between subjects with and without incident CVD was 2.75 events per hour (95% confidence interval, 0.26 to 5.24; P=0.032). This association persisted after subjects with central sleep apnea were excluded. Compared with participants without incident CVD, participants with incident CVD had greater increases in both mean obstructive and central apnea indices, by 1.75 events per hour (95% confidence interval, 0.10 to 1.75; P=0.04) and by 1.07 events per hour (95% confidence interval, 0.40 to 1.74; P=0.001), respectively.
Conclusions— In a diverse, community-based sample of middle-aged and older adults, incident CVD was associated with worsening sleep-disordered breathing over 5 years.
3.Heart Failure
Human Cardiac Stem Cell Differentiation Is Regulated by a Mircrine MechanismToru Hosoda, MD, PhD; Hanqiao Zheng, MD; Mauricio Cabral-da-Silva, PhD; Fumihiro Sanada, MD; Noriko Ide-Iwata, MD; Barbara Ogórek, PhD; Jo?o Ferreira-Martins, PhD; Christian Arranto, MD; Domenico D'Amario, MD; Federica del Monte, MD; Konrad Urbanek, MD; David A. D'Alessandro, MD; Robert E. Michler, MD; Piero Anversa, MD; Marcello Rota, PhD; Jan Kajstura, PhD; Annarosa Leri, MD
From the Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.H., H.Z., M.C.-d.-S., F.S., N.I.-I., B.O., J.F.-M., C.A., D.D., K.U., P.A., M.R., J.K., A.L.); Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.d.M.); and Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY (D.A.D., R.E.M.).
Correspondence to Toru Hosoda, MD, PhD, or Annarosa Leri, MD, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail thosoda@partners.org
'//-->
or aleri@partners.org[/url]
' + u + '@' + d + ''//-->
Background— Cardiac stem cells (CSCs) delivered to the infarcted heart generate a large number of small fetal-neonatal cardiomyocytes that fail to acquire the differentiated phenotype. However, the interaction of CSCs with postmitotic myocytes results in the formation of cells with adult characteristics.
Methods and Results— On the basis of results of in vitro and in vivo assays, we report that the commitment of human CSCs (hCSCs) to the myocyte lineage and the generation of mature working cardiomyocytes are influenced by microRNA-499 (miR-499), which is barely detectable in hCSCs but is highly expressed in postmitotic human cardiomyocytes. miR-499 traverses gap junction channels and translocates to structurally coupled hCSCs favoring their differentiation into functionally competent cells. Expression of miR-499 in hCSCs represses the miR-499 target genes Sox6 and Rod1, enhancing cardiomyogenesis in vitro and after infarction in vivo. Although cardiac repair was detected in all cell-treated infarcted hearts, the aggregate volume of the regenerated myocyte mass and myocyte cell volume were greater in animals injected with hCSCs overexpressing miR-499. Treatment with hCSCs resulted in an improvement in ventricular function, consisting of a better preservation of developed pressure and positive and negative dP/dt after infarction. An additional positive effect on cardiac performance occurred with miR-499, pointing to enhanced myocyte differentiation/hypertrophy as the mechanism by which miR-499 potentiated the restoration of myocardial mass and function in the infarcted heart.
Conclusions— The recognition that miR-499 promotes the differentiation of hCSCs into mechanically integrated cardiomyocytes has important clinical implications for the treatment of human heart failure.
4.Hypertension
Long-Term Cardiac pro-B-Type Natriuretic Peptide Gene Delivery Prevents the Development of Hypertensive Heart Disease in Spontaneously Hypertensive RatsAlessandro Cataliotti, MD, PhD*; Jason M. Tonne*; Diego Bellavia, MD, PhD; Fernando L. Martin, MD; Elise A. Oehler; Gerald E. Harders; Jarryd M. Campbell; Kaw-Whye Peng, PhD; Stephen J. Russell, MD, PhD; Lorenzo S. Malatino, MD; John C. Burnett, Jr, MD; Yasuhiro Ikeda, DVM, PhD
From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (A.C., D.B., F.L.M., E.A.O., G.E.H., J.C.B.) and Department of Molecular Medicine (J.M.T., J.M.C., K.P., S.J.R., Y.I.), Mayo Clinic, College of Medicine, Rochester, MN; and Section of Hypertension and Cardio-Renal Diseases, Department of Medicine, University of Catania, Catania, Italy (L.S.M.).
Correspondence to Yasuhiro Ikeda, Molecular Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail ikeda.yasuhiro@mayo.edu
' + u + '@' + d + ''//-->
Background— Diastolic dysfunction associated with high blood pressure (BP) leads to cardiac remodeling and fibrosis and progression to congestive heart failure. B-type natriuretic peptide (BNP) has BP-lowering, antifibrotic, and antihypertrophic properties, which makes BNP an attractive agent for attenuating the adverse cardiac remodeling associated with hypertension. In the current study, we tested the effects of sustained cardiac proBNP gene delivery on BP, cardiac function, and remodeling in spontaneously hypertensive rats (SHR).
Methods and Results— We used the myocardium-tropic adeno-associated virus serotype 9 (AAV9) vector to achieve continuously enhanced cardiac rat proBNP expression. In SHR, a single systemic administration of AAV9 vector allowed long-term cardiac BNP overexpression, resulting in reductions in systolic and diastolic BP for 9 months after injection. Left ventricular (LV) thickness, LV end-systolic dimensions, and LV mass were reduced, whereas ejection fraction was significantly increased, in BNP-treated compared with untreated SHR. Circumferential systolic strain and strain rate of the early phase of diastole were improved in BNP-treated compared with untreated SHR. Noncardiac overexpression of BNP via AAV2 vector was not associated with changes in BP and plasma BNP in SHR. Furthermore, normal Wistar rats injected with AAV9 proBNP vector showed significantly reduced heart weights 4 weeks after injection without BP reduction.
Conclusions— AAV9 vector facilitates sustained cardiac proBNP overexpression and improves LV function in hypertensive heart disease. Long-term proBNP delivery improved both systolic and diastolic function. The effects on cardiac structure and function occurred independently of BP-lowering effects in normal Wistar rats.
5. Molecular Cardiology
Protease-Resistant Stromal Cell–Derived Factor-1 for the Treatment of Experimental Peripheral Artery DiseaseVincent F.M. Segers, MD, PhD; Vyacheslav Revin, MD; Weitao Wu, MD; Helen Qiu, BS; Zheng Yan, MS; Richard T. Lee, MD; Anthony Sandrasagra, PhD
From Provasculon Inc., Cambridge, MA (V.F.M.S., V.R., W.W., H.Q., Z.Y., A.S.); and Harvard Stem Cell Institute and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (R.T.L.).
Correspondence to Vincent F.M. Segers, MD, PhD, Provasculon Inc, 14 Cambridge Center Building 1, Cambridge, MA 02142. E-mail vincent.segers@provasculon.com
' + u + '@' + d + ''//-->
Background— Peripheral artery disease is a potentially incapacitating disease for which pharmacological options are limited. Stromal cell–derived factor-1 (SDF-1) is a chemokine that attracts endothelial progenitor cells and promotes angiogenesis. Therapeutic use of SDF-1 in hindlimb ischemia may be challenged by proteolytic degradation. We hypothesized that protease-resistant variants of SDF-1 can increase blood flow in an experimental model of hindlimb ischemia.
Methods and Results— We screened a peptide library for mutations in SDF-1 that provide resistance to matrix metalloproteinase cleavage. Recombinant SDF-1 proteins carrying the mutations were designed, expressed, and purified, and activity of mutant proteins was tested with receptor activation assays and in vivo Matrigel plug assays. SSDF-1(S4V), which is resistant to both dipeptidylpeptidase IV/CD26 and matrix metalloproteinase-2 cleavage, was active in vitro and induced angiogenesis in vivo. We then designed and purified fusion proteins of SSDF-1 and SSDF-1(S4V) with the sequence of self-assembling peptide nanofibers for incorporation into nanofibers. In a blinded and randomized hindlimb ischemia mouse study, SSDF-1(S4V) delivery by nanofibers improved blood flow as measured by laser Doppler from 23.1±1.9% (untreated control) to 55.1±5.7% 6 weeks after surgery (P
or edit.nagy@karolinska.se[/url]
' + u + '@' + d + ''//-->
Background— The development of aortic valve stenosis is not only associated with calcification and extracellular matrix remodeling, but also with inflammation. The aim of this study was to determine the role of proinflammatory signaling through the leukotriene (LT) pathway in aortic stenosis.
Methods and Results— After macroscopic dissection of surgically removed human aortic valves, RNA was extracted from 311 preparations derived from 68 patients to differentiate normal, thickened, and calcified areas from each cusp. Subsequently, quantitative polymerase chain reaction analysis was used to correlate gene expression patterns with preoperative echocardiographic parameters. The messenger RNA levels of the LT-forming enzyme 5-lipoxygenase increased 1.6- and 2.2-fold in thickened and calcified tissue, respectively, compared with normal areas of the same valves. In thickened tissues, messenger RNA levels for 5-lipoxygenase (r=–0.35; P=0.03), its activating protein (5-lipoxygenase activating protein; r=–0.39; P=0.02), and LTA4 hydrolase (r=–0.48; P=0.01) correlated inversely with the velocity–time integral ratio. In addition, leukotriene A4 hydrolase transcripts correlated inversely with aortic valve area, indexed for body surface area (r=–0.52; P=0.007). Immunohistochemical stainings revealed LT receptor expression on valvular myofibroblasts. In primary cultures of human myofibroblasts derived from stenotic aortic valves, Leukotriene C4 (LTC4) increased intracellular calcium, enhanced reactive oxygen species production, reduced the mitochondrial membrane potential, and led to morphological cell cytoplasm changes and calcification.
Conclusions— The upregulation of the LT pathway in human aortic valve stenosis and its correlation with clinical stenosis severity, taken together with the potentially detrimental LT-induced effects on valvular myofibroblasts, suggests one possible role of inflammation in the development of aortic stenosis.
7.
Vascular Medicine
Platelet Protease Nexin-1, a Serpin That Strongly Influences Fibrinolysis and ThrombolysisYacine Boulaftali, PhD; Benoit Ho-Tin-Noe, PhD; Ana Pena, PhD; Stéphane Loyau, BScTech; Laurence Venisse, BScTech; Déborah Fran?ois, MSc; Benjamin Richard, PhD; Véronique Arocas, PhD; Jean-Philippe Collet, MD, PhD; Martine Jandrot-Perrus, MD, PhD; Marie-Christine Bouton, PhD
From INSERM U698, CHU Xavier Bichat, Université Paris 7 (Y.B., B.H.-T.-N., S.L., L.V., D.F., B.R., V.A., M.-J.P., M.-C.B.); and INSERM U937, Institut de Cardiologie, H?pital de la Pitié-Salpêtrière (A.P., J.C.), Paris, France.
Correspondence to Marie-Christine Bouton, Unité INSERM U698, CHU Xavier Bichat, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. E-mail marie-christine.bouton@inserm.fr
' + u + '@' + d + ''//-->
Background— Protease nexin-1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma, but we have shown recently that PN-1 is present within the α-granules of platelets.
Methods and Results— In this study, the role of platelet PN-1 in fibrinolysis was investigated with the use of human platelets incubated with a blocking antibody and platelets from PN-1–deficient mice. We showed by using fibrin-agar zymography and fibrin matrix that platelet PN-1 inhibited both the generation of plasmin by fibrin-bound tissue plasminogen activator and the activity of fibrin-bound plasmin itself. Rotational thromboelastometry and laser scanning confocal microscopy were used to demonstrate that PN-1 blockade or deficiency resulted in increased clot lysis and in an acceleration of the lysis front. Protease nexin-1 is thus a major determinant of the lysis resistance of platelet-rich clots. Moreover, in an original murine model in which thrombolysis induced by tissue plasminogen activator can be measured directly in situ, we observed that vascular recanalization was significantly increased in PN-1–deficient mice. Surprisingly, general physical health, after tissue plasminogen activator–induced thrombolysis, was much better in PN-1–deficient than in wild-type mice.
Conclusions— Our results reveal that platelet PN-1 can be considered as a new important regulator of thrombolysis in vivo. Inhibition of PN-1 is thus predicted to promote endogenous and exogenous tissue plasminogen activator–mediated fibrinolysis and may enhance the therapeutic efficacy of thrombolytic agents.
Prevention of Ventricular Fibrillation Episodes in Brugada Syndrome by Catheter Ablation Over the Anterior Right Ventricular Outflow Tract EpicardiumKoonlawee Nademanee, MD; Gumpanart Veerakul, MD; Pakorn Chandanamattha, MD; Lertlak Chaothawee, MD; Aekarach Ariyachaipanich, MD; Kriengkrai Jirasirirojanakorn, MD; Khanchit Likittanasombat, MD; Kiertijai Bhuripanyo, MD; Tachapong Ngarmukos, MD
From the Pacific Rim Electrophysiology Research Institute, Los Angeles, CA (K.N., A.A.); and the Bhumipol Adulyadej Royal Thai Air Force Hospital (G.V., K.J.), Bangkok Heart Hospital (L.C., K.B.), and Ramathibodi University Hospital (P.C., K.L., T.N.), Bangkok, Thailand.
Correspondence to Koonlawee Nademanee, MD, Pacific Rim Electrophysiology Research Institute, 1700 Cesar E. Chavez Ave, Ste 2700, Los Angeles, CA 90033. E-mail wee@pacificrimep.com
' + u + '@' + d + ''//-->
Background— The underlying electrophysiological mechanism that causes an abnormal ECG pattern and ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with the Brugada syndrome (BrS) remains unelucidated. However, several studies have indicated that the right ventricular outflow tract (RVOT) is likely to be the site of electrophysiological substrate. We hypothesized that in patients with BrS who have frequent recurrent VF episodes, the substrate site is the RVOT, either over the epicardium or endocardium; abnormal electrograms would be identified at this location, which would serve as the target site for catheter ablation.
Methods and Results— We studied 9 symptomatic patients with the BrS (all men; median age 38 years) who had recurrent VF episodes (median 4 episodes) per month, necessitating implantable cardioverter defibrillator discharge. Electroanatomic mapping of the right ventricle, both endocardially and epicardially, and epicardial mapping of the left ventricle were performed in all patients during sinus rhythm. All patients had typical type 1 Brugada ECG pattern and inducible VT/VF; they were found to have unique abnormal low voltage (0.94±0.79 mV), prolonged duration (132±48 ms), and fractionated late potentials (96±47 ms beyond QRS complex) clustering exclusively in the anterior aspect of the RVOT epicardium. Ablation at these sites rendered VT/VF noninducible (7 of 9 patients [78%]; 95% confidence interval, 0.40 to 0.97, P=0.015) and normalization of the Brugada ECG pattern in 89% (95% confidence interval, 0.52 to 0.99; P=0.008). Long-term outcomes (20±6 months) were excellent, with no recurrent VT/VF in all patients off medication (except 1 patient on amiodarone).
Conclusions— The underlying electrophysiological mechanism in patients with BrS is delayed depolarization over the anterior aspect of the RVOT epicardium. Catheter ablation over this abnormal area results in normalization of the Brugada ECG pattern and prevents VT/VF, both during electrophysiological studies as well as spontaneous recurrent VT/VF episodes in patients with BrS.
2.Epidemiology and Prevention
Association of Incident Cardiovascular Disease With Progression of Sleep-Disordered BreathingHassan A. Chami, MD, MSc; Helaine E. Resnick, PhD, MPH; Stuart F. Quan, MD; Daniel J. Gottlieb, MD, MPH
From the Department of Medicine, Boston University School of Medicine, Boston, MA (H.A.C., D.J.G.); Veterans Affairs Boston Healthcare System, West Roxbury, MA (H.A.C., D.J.G.); American Association of Homes and Services for the Aging, Washington, DC (H.E.R.); Department of Medicine, Georgetown University, Washington, DC (H.E.R.); Division of Sleep Medicine, Harvard Medical School, Boston, MA (S.F.Q.); and Arizona Respiratory Center, University of Arizona, Tucson (S.F.Q.).
Correspondence to Daniel J. Gottlieb, MD, MPH, The Pulmonary Center, Boston University School of Medicine, 72 E Concord St, R-304, Boston, MA 02118. E-mail gottlieb@bu.edu
' + u + '@' + d + ''//-->
Background— Prospective data suggest that sleep-disordered breathing enhances risk for incident and recurrent cardiovascular disease (CVD). However, a reverse causal pathway whereby incident CVD causes or worsens sleep-disordered breathing has not been studied.
Methods and Results— A total of 2721 Sleep Heart Health Study participants (mean age 62, standard deviation=10 years; 57% women; 23% minority) without CVD at baseline underwent 2 polysomnograms 5 years apart. Incident CVD events, including myocardial infarction, congestive heart failure, and stroke, were ascertained and adjudicated. The relation of incident CVD to change in apnea-hypopnea index between the 2 polysomnograms was tested with general linear models, with adjustment for age, sex, race, study center, history of diabetes mellitus, change in body mass index, change in neck circumference, percent sleep time spent in supine sleep, and time between the 2 polysomnograms. Incident CVD occurred in 95 participants between the first and second polysomnograms. Compared with participants without incident CVD, those with incident CVD experienced larger increases in apnea-hypopnea index between polysomnograms. The difference in adjusted mean apnea-hypopnea index change between subjects with and without incident CVD was 2.75 events per hour (95% confidence interval, 0.26 to 5.24; P=0.032). This association persisted after subjects with central sleep apnea were excluded. Compared with participants without incident CVD, participants with incident CVD had greater increases in both mean obstructive and central apnea indices, by 1.75 events per hour (95% confidence interval, 0.10 to 1.75; P=0.04) and by 1.07 events per hour (95% confidence interval, 0.40 to 1.74; P=0.001), respectively.
Conclusions— In a diverse, community-based sample of middle-aged and older adults, incident CVD was associated with worsening sleep-disordered breathing over 5 years.
3.Heart Failure
Human Cardiac Stem Cell Differentiation Is Regulated by a Mircrine MechanismToru Hosoda, MD, PhD; Hanqiao Zheng, MD; Mauricio Cabral-da-Silva, PhD; Fumihiro Sanada, MD; Noriko Ide-Iwata, MD; Barbara Ogórek, PhD; Jo?o Ferreira-Martins, PhD; Christian Arranto, MD; Domenico D'Amario, MD; Federica del Monte, MD; Konrad Urbanek, MD; David A. D'Alessandro, MD; Robert E. Michler, MD; Piero Anversa, MD; Marcello Rota, PhD; Jan Kajstura, PhD; Annarosa Leri, MD
From the Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.H., H.Z., M.C.-d.-S., F.S., N.I.-I., B.O., J.F.-M., C.A., D.D., K.U., P.A., M.R., J.K., A.L.); Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (F.d.M.); and Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY (D.A.D., R.E.M.).
Correspondence to Toru Hosoda, MD, PhD, or Annarosa Leri, MD, Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail thosoda@partners.org
'//-->
or aleri@partners.org[/url]
' + u + '@' + d + ''//-->
Background— Cardiac stem cells (CSCs) delivered to the infarcted heart generate a large number of small fetal-neonatal cardiomyocytes that fail to acquire the differentiated phenotype. However, the interaction of CSCs with postmitotic myocytes results in the formation of cells with adult characteristics.
Methods and Results— On the basis of results of in vitro and in vivo assays, we report that the commitment of human CSCs (hCSCs) to the myocyte lineage and the generation of mature working cardiomyocytes are influenced by microRNA-499 (miR-499), which is barely detectable in hCSCs but is highly expressed in postmitotic human cardiomyocytes. miR-499 traverses gap junction channels and translocates to structurally coupled hCSCs favoring their differentiation into functionally competent cells. Expression of miR-499 in hCSCs represses the miR-499 target genes Sox6 and Rod1, enhancing cardiomyogenesis in vitro and after infarction in vivo. Although cardiac repair was detected in all cell-treated infarcted hearts, the aggregate volume of the regenerated myocyte mass and myocyte cell volume were greater in animals injected with hCSCs overexpressing miR-499. Treatment with hCSCs resulted in an improvement in ventricular function, consisting of a better preservation of developed pressure and positive and negative dP/dt after infarction. An additional positive effect on cardiac performance occurred with miR-499, pointing to enhanced myocyte differentiation/hypertrophy as the mechanism by which miR-499 potentiated the restoration of myocardial mass and function in the infarcted heart.
Conclusions— The recognition that miR-499 promotes the differentiation of hCSCs into mechanically integrated cardiomyocytes has important clinical implications for the treatment of human heart failure.
4.Hypertension
Long-Term Cardiac pro-B-Type Natriuretic Peptide Gene Delivery Prevents the Development of Hypertensive Heart Disease in Spontaneously Hypertensive RatsAlessandro Cataliotti, MD, PhD*; Jason M. Tonne*; Diego Bellavia, MD, PhD; Fernando L. Martin, MD; Elise A. Oehler; Gerald E. Harders; Jarryd M. Campbell; Kaw-Whye Peng, PhD; Stephen J. Russell, MD, PhD; Lorenzo S. Malatino, MD; John C. Burnett, Jr, MD; Yasuhiro Ikeda, DVM, PhD
From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology (A.C., D.B., F.L.M., E.A.O., G.E.H., J.C.B.) and Department of Molecular Medicine (J.M.T., J.M.C., K.P., S.J.R., Y.I.), Mayo Clinic, College of Medicine, Rochester, MN; and Section of Hypertension and Cardio-Renal Diseases, Department of Medicine, University of Catania, Catania, Italy (L.S.M.).
Correspondence to Yasuhiro Ikeda, Molecular Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail ikeda.yasuhiro@mayo.edu
' + u + '@' + d + ''//-->
Background— Diastolic dysfunction associated with high blood pressure (BP) leads to cardiac remodeling and fibrosis and progression to congestive heart failure. B-type natriuretic peptide (BNP) has BP-lowering, antifibrotic, and antihypertrophic properties, which makes BNP an attractive agent for attenuating the adverse cardiac remodeling associated with hypertension. In the current study, we tested the effects of sustained cardiac proBNP gene delivery on BP, cardiac function, and remodeling in spontaneously hypertensive rats (SHR).
Methods and Results— We used the myocardium-tropic adeno-associated virus serotype 9 (AAV9) vector to achieve continuously enhanced cardiac rat proBNP expression. In SHR, a single systemic administration of AAV9 vector allowed long-term cardiac BNP overexpression, resulting in reductions in systolic and diastolic BP for 9 months after injection. Left ventricular (LV) thickness, LV end-systolic dimensions, and LV mass were reduced, whereas ejection fraction was significantly increased, in BNP-treated compared with untreated SHR. Circumferential systolic strain and strain rate of the early phase of diastole were improved in BNP-treated compared with untreated SHR. Noncardiac overexpression of BNP via AAV2 vector was not associated with changes in BP and plasma BNP in SHR. Furthermore, normal Wistar rats injected with AAV9 proBNP vector showed significantly reduced heart weights 4 weeks after injection without BP reduction.
Conclusions— AAV9 vector facilitates sustained cardiac proBNP overexpression and improves LV function in hypertensive heart disease. Long-term proBNP delivery improved both systolic and diastolic function. The effects on cardiac structure and function occurred independently of BP-lowering effects in normal Wistar rats.
5. Molecular Cardiology
Protease-Resistant Stromal Cell–Derived Factor-1 for the Treatment of Experimental Peripheral Artery DiseaseVincent F.M. Segers, MD, PhD; Vyacheslav Revin, MD; Weitao Wu, MD; Helen Qiu, BS; Zheng Yan, MS; Richard T. Lee, MD; Anthony Sandrasagra, PhD
From Provasculon Inc., Cambridge, MA (V.F.M.S., V.R., W.W., H.Q., Z.Y., A.S.); and Harvard Stem Cell Institute and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (R.T.L.).
Correspondence to Vincent F.M. Segers, MD, PhD, Provasculon Inc, 14 Cambridge Center Building 1, Cambridge, MA 02142. E-mail vincent.segers@provasculon.com
' + u + '@' + d + ''//-->
Background— Peripheral artery disease is a potentially incapacitating disease for which pharmacological options are limited. Stromal cell–derived factor-1 (SDF-1) is a chemokine that attracts endothelial progenitor cells and promotes angiogenesis. Therapeutic use of SDF-1 in hindlimb ischemia may be challenged by proteolytic degradation. We hypothesized that protease-resistant variants of SDF-1 can increase blood flow in an experimental model of hindlimb ischemia.
Methods and Results— We screened a peptide library for mutations in SDF-1 that provide resistance to matrix metalloproteinase cleavage. Recombinant SDF-1 proteins carrying the mutations were designed, expressed, and purified, and activity of mutant proteins was tested with receptor activation assays and in vivo Matrigel plug assays. SSDF-1(S4V), which is resistant to both dipeptidylpeptidase IV/CD26 and matrix metalloproteinase-2 cleavage, was active in vitro and induced angiogenesis in vivo. We then designed and purified fusion proteins of SSDF-1 and SSDF-1(S4V) with the sequence of self-assembling peptide nanofibers for incorporation into nanofibers. In a blinded and randomized hindlimb ischemia mouse study, SSDF-1(S4V) delivery by nanofibers improved blood flow as measured by laser Doppler from 23.1±1.9% (untreated control) to 55.1±5.7% 6 weeks after surgery (P
or edit.nagy@karolinska.se[/url]
' + u + '@' + d + ''//-->
Background— The development of aortic valve stenosis is not only associated with calcification and extracellular matrix remodeling, but also with inflammation. The aim of this study was to determine the role of proinflammatory signaling through the leukotriene (LT) pathway in aortic stenosis.
Methods and Results— After macroscopic dissection of surgically removed human aortic valves, RNA was extracted from 311 preparations derived from 68 patients to differentiate normal, thickened, and calcified areas from each cusp. Subsequently, quantitative polymerase chain reaction analysis was used to correlate gene expression patterns with preoperative echocardiographic parameters. The messenger RNA levels of the LT-forming enzyme 5-lipoxygenase increased 1.6- and 2.2-fold in thickened and calcified tissue, respectively, compared with normal areas of the same valves. In thickened tissues, messenger RNA levels for 5-lipoxygenase (r=–0.35; P=0.03), its activating protein (5-lipoxygenase activating protein; r=–0.39; P=0.02), and LTA4 hydrolase (r=–0.48; P=0.01) correlated inversely with the velocity–time integral ratio. In addition, leukotriene A4 hydrolase transcripts correlated inversely with aortic valve area, indexed for body surface area (r=–0.52; P=0.007). Immunohistochemical stainings revealed LT receptor expression on valvular myofibroblasts. In primary cultures of human myofibroblasts derived from stenotic aortic valves, Leukotriene C4 (LTC4) increased intracellular calcium, enhanced reactive oxygen species production, reduced the mitochondrial membrane potential, and led to morphological cell cytoplasm changes and calcification.
Conclusions— The upregulation of the LT pathway in human aortic valve stenosis and its correlation with clinical stenosis severity, taken together with the potentially detrimental LT-induced effects on valvular myofibroblasts, suggests one possible role of inflammation in the development of aortic stenosis.
7.
Vascular Medicine
Platelet Protease Nexin-1, a Serpin That Strongly Influences Fibrinolysis and ThrombolysisYacine Boulaftali, PhD; Benoit Ho-Tin-Noe, PhD; Ana Pena, PhD; Stéphane Loyau, BScTech; Laurence Venisse, BScTech; Déborah Fran?ois, MSc; Benjamin Richard, PhD; Véronique Arocas, PhD; Jean-Philippe Collet, MD, PhD; Martine Jandrot-Perrus, MD, PhD; Marie-Christine Bouton, PhD
From INSERM U698, CHU Xavier Bichat, Université Paris 7 (Y.B., B.H.-T.-N., S.L., L.V., D.F., B.R., V.A., M.-J.P., M.-C.B.); and INSERM U937, Institut de Cardiologie, H?pital de la Pitié-Salpêtrière (A.P., J.C.), Paris, France.
Correspondence to Marie-Christine Bouton, Unité INSERM U698, CHU Xavier Bichat, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. E-mail marie-christine.bouton@inserm.fr
' + u + '@' + d + ''//-->
Background— Protease nexin-1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma, but we have shown recently that PN-1 is present within the α-granules of platelets.
Methods and Results— In this study, the role of platelet PN-1 in fibrinolysis was investigated with the use of human platelets incubated with a blocking antibody and platelets from PN-1–deficient mice. We showed by using fibrin-agar zymography and fibrin matrix that platelet PN-1 inhibited both the generation of plasmin by fibrin-bound tissue plasminogen activator and the activity of fibrin-bound plasmin itself. Rotational thromboelastometry and laser scanning confocal microscopy were used to demonstrate that PN-1 blockade or deficiency resulted in increased clot lysis and in an acceleration of the lysis front. Protease nexin-1 is thus a major determinant of the lysis resistance of platelet-rich clots. Moreover, in an original murine model in which thrombolysis induced by tissue plasminogen activator can be measured directly in situ, we observed that vascular recanalization was significantly increased in PN-1–deficient mice. Surprisingly, general physical health, after tissue plasminogen activator–induced thrombolysis, was much better in PN-1–deficient than in wild-type mice.
Conclusions— Our results reveal that platelet PN-1 can be considered as a new important regulator of thrombolysis in vivo. Inhibition of PN-1 is thus predicted to promote endogenous and exogenous tissue plasminogen activator–mediated fibrinolysis and may enhance the therapeutic efficacy of thrombolytic agents.
最后编辑于 2022-10-09 · 浏览 2404
15 3 4
