Publications by authors named "Chau Vinh"

21 Publications

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Powerlifting score prediction using a machine learning method.

Authors:
Vinh Huy Chau

Math Biosci Eng 2021 01;18(2):1040-1050

Ho Chi Minh City University of Physical Education and Sport, Ho Chi Minh City 700000, Vietnam.

This research discusses an interesting topic, using artificial intelligence methods to predict the score of powerlifters. We collected the characteristics of powerlifters, and then used the reservoir computing extreme learning machine to build a predictive model. In order to further improve the prediction results, we propose a method to optimize the reservoir computing extreme learning machine using the whale optimization algorithm. Experimental results show that our proposed method can effectively predict the score of powerlifters with the coefficient of determination value is 0.7958 and root-mean-square error of prediction value is 16.73. This provides a reliable basis for experts to judge the results before the competition.
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http://dx.doi.org/10.3934/mbe.2021056DOI Listing
January 2021

Rapid Deterioration of Hospital-Acquired COVID-19 in a Patient on Extracorporeal Left Ventricular Assist Support.

Heart Lung 2020 Nov - Dec;49(6):808-811. Epub 2020 Sep 21.

Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Importance: As the Coronavirus disease 2019 (COVID-19) pandemic accelerates, our hospitals have become overwhelmed.

Objective: To describe detection of COVID-19 in asymptomatic hospitalized individuals awaiting advanced therapies for HF and the management of complications of COVID-19.

Design: We present a unique case report of hospital-acquired COVID-19 in a patient on temporary mechanical circulatory support.

Main Outcome: Despite intensive care and monitoring, he developed rapid progression of hypoxic respiratory failure which led to his death.

Conclusion: This case highlights various considerations for a patient with temporary MCS. It illustrates the high risk for development of COVID-19 for vulnerable hospitalized patients.
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http://dx.doi.org/10.1016/j.hrtlng.2020.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505573PMC
November 2020

Cardiogenic Shock and Hyperinflammatory Syndrome in Young Males With COVID-19.

Circ Heart Fail 2020 10 26;13(10):e007485. Epub 2020 Aug 26.

Zena and Michael A. Wiener Cardiovascular Institute (V.Q.C., G.G., K.M., E.O., E.N., N.M., S.S.M., J.P.C., L.C., G.S., A.G.P., A.L., M.G.T.,G.L., S.P.P., D.M.M.), Icahn School of Medicine at Mount Sinai, New York, NY.

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007485DOI Listing
October 2020

Predisposition or Protection?: COVID-19 in a Patient on LVAD Support With HIV/AIDS.

JACC Case Rep 2020 Jul 19;2(9):1337-1341. Epub 2020 May 19.

Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

There is a desperate search to discover effective therapies against coronavirus disease-2019 (COVID-19). Patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) comprise a unique population whose clinical course may provide insights into the effects of antiretroviral therapy on COVID-19. We describe the case of a patient with HIV/AIDS on left ventricular assist device support who was hospitalized and recovered from COVID-19. ().
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http://dx.doi.org/10.1016/j.jaccas.2020.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236747PMC
July 2020

The first 100 days of SARS-CoV-2 control in Vietnam.

Clin Infect Dis 2020 Aug 1. Epub 2020 Aug 1.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, UK.

Background: One hundred days after SARS-CoV-2 was first reported in Vietnam on January 23rd, 270 cases were confirmed, with no deaths. We describe the control measures used by the Government and their relationship with imported and domestically-acquired case numbers, with the aim of identifying the measures associated with successful SARS-CoV-2 control.

Methods: Clinical and demographic data on the first 270 SARS-CoV-2 infected cases and the timing and nature of Government control measures, including numbers of tests and quarantined individuals, were analysed. Apple and Google mobility data provided proxies for population movement. Serial intervals were calculated from 33 infector-infectee pairs and used to estimate the proportion of pre-symptomatic transmission events and time-varying reproduction numbers.

Results: A national lockdown was implemented between April 1st and 22nd. Around 200 000 people were quarantined and 266 122 RT-PCR tests conducted. Population mobility decreased progressively before lockdown. 60% (163/270) of cases were imported; 43% (89/208) of resolved infections remained asymptomatic for the duration of infection. The serial interval was 3·24 days, and 27·5% (95% confidence interval, 15·7%-40·0%) of transmissions occurred pre-symptomatically. Limited transmission amounted to a maximum reproduction number of 1·15 (95% confidence interval, 0·37-2·36). No community transmission has been detected since April 15th.

Conclusions: Vietnam has controlled SARS-CoV-2 spread through the early introduction of mass communication, meticulous contact-tracing with strict quarantine, and international travel restrictions. The value of these interventions is supported by the high proportion of asymptomatic and imported cases, and evidence for substantial pre-symptomatic transmission.
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http://dx.doi.org/10.1093/cid/ciaa1130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454342PMC
August 2020

Elevated AT1R Antibody and Morbidity in Patients Bridged to Heart Transplant Using Continuous Flow Left Ventricular Assist Devices.

J Card Fail 2020 Nov 24;26(11):959-967. Epub 2020 Jun 24.

Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, Virginia Commonwealth University Health Systems, Richmond, Virginia. Electronic address:

Background: We studied longitudinal levels of angiotensin-II type 1 receptor antibody (AT1R-Ab) and their effects on adverse events (death, treated rejection and cardiac allograft vasculopathy) in patients who were bridged to heart transplant using a continuous flow left ventricular assist device (LVAD).

Methods And Results: Sera of 77 patients bridged to heart transplant (from 2009 to 2017) were tested for AT1R-Ab and CRP before and after LVAD. Elevated AT1R-Ab was defined as >10.0 U/mL. The median follow-up after transplant was 3.6 years (interquartile range, 2.2-5.6 years). After LVAD, AT1R-Ab levels increased from baseline and remained elevated until transplant. Freedom from adverse events at 5 years was lower in those with elevated AT1R-Ab levels at time of transplant. In an adjusted, multivariable Cox analysis, an AT1R-Ab level of >10 U/mL was associated with developing the primary end point (adjusted hazard ratio 3.4, 95% confidence interval 1.2-9.2, P = .017). Although C-reactive protein levels were high before and after LVAD placement, C-reactive protein did not correlate with AT1R-Ab.

Conclusions: In LVAD patients bridged to heart transplant, an increased AT1R-Ab level at time of transplant was associated with poor outcomes after heart transplant. Post-LVAD AT1R-Ab elevations were not correlated with serum markers of systemic inflammation. Larger studies are needed to examine the pathologic role of AT1R-Ab in heart transplant.
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http://dx.doi.org/10.1016/j.cardfail.2020.06.010DOI Listing
November 2020

Hydrogen Sulfide Therapy Suppresses Cofilin-2 and Attenuates Ischemic Heart Failure in a Mouse Model of Myocardial Infarction.

J Cardiovasc Pharmacol Ther 2020 09 11;25(5):472-483. Epub 2020 May 11.

Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.

Aims: Hydrogen sulfide (HS) protects against ischemic and inflammatory injury following myocardial ischemia via induction of microRNA (miR)-21. We sought to determine whether HS attenuates ischemic heart failure with reduced ejection fraction (HFrEF) and interrogate the role of cofilin-2, a target of miR-21, in this protective process.

Methods And Results: Adult male mice underwent myocardial infarction (MI) by coronary artery ligation after baseline echocardiography. Following MI, mice were treated with NaS (100 μg/kg/day; intraperitoneal [IP]) or saline up to 28 days. End-diastolic pressure, measured by Millar catheter, was significantly increased ( < .05 vs sham) at 3 days post-MI in the saline group, which was attenuated with NaS. Left ventricular (LV) fractional shortening decreased significantly at 28 days post-MI in the saline group but was preserved with NaS and LV infarct scar size was smaller in NaS group as compared to control. Apoptotic signaling, measured by Bcl-2/Bax ratio, was significantly increased in the saline group but was mitigated with NaS. Survival rate was 2-fold higher in NaS group compared to saline control ( < .05). Proteomic analysis and Matrix-Assisted Laser Desorption/Ionization-Time of Flight (TOF)/TOF tandem mass spectrometry identified significant changes in proapoptotic cofilin-2 expression, a specific target of miR-21, between saline- and sodium sulfide -treated mice at 28 days post-MI. Western blot analysis confirmed a significant increase in cofilin-2 after MI, which was suppressed with NaS treatment. Chronic NaS treatment also attenuated inflammasome formation and activation leading to reduction of maladaptive signaling.

Conclusion: NaS treatment after MI preserves LV function and improves survival through attenuation of inflammasome-mediated adverse remodeling. We propose HS donors as promising therapeutic tools for ischemic HFrEF.
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http://dx.doi.org/10.1177/1074248420923542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365756PMC
September 2020

The Imperfect Cytokine Storm: Severe COVID-19 With ARDS in a Patient on Durable LVAD Support.

JACC Case Rep 2020 Jul 8;2(9):1315-1320. Epub 2020 Apr 8.

Division of Cardiology, Department of Medicine, Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

As health systems worldwide grapple with the coronavirus disease-2019 (COVID-19) pandemic, patients with durable LVAD support represent a unique population at risk for the disease. This paper outlines the case of such a patient who developed COVID-19 complicated by a "cytokine storm" with severe acute respiratory distress syndrome and myocardial injury and describes the challenges that arose during management.
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http://dx.doi.org/10.1016/j.jaccas.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142699PMC
July 2020

Osteopontin in HFpEF: More Than Just a Remodeling-Specific Biomarker.

J Am Coll Cardiol 2019 06;73(21):2719-2721

Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.

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http://dx.doi.org/10.1016/j.jacc.2019.03.477DOI Listing
June 2019

Sacubitril/Valsartan Averts Adverse Post-Infarction Ventricular Remodeling and Preserves Systolic Function in Rabbits.

J Am Coll Cardiol 2018 11;72(19):2342-2356

Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia. Electronic address:

Background: Sacubitril/valsartan (SAC/VAL) is approved by the U.S. Food and Drug Administration for heart failure with reduced ejection fraction (HFrEF).

Objectives: This study investigated the effects of SAC/VAL on acute myocardial infarction (MI) and cardiac remodeling in a translational rabbit model of MI.

Methods: New Zealand White rabbits were sedated and underwent conscious MI (45-min ischemia) by balloon inflation (previously implanted surgically) followed by 72 h (acute protocol) or 10 weeks (chronic protocols) of reperfusion. "Infarct-sparing" protocol: SAC/VAL, VAL, or placebo were randomly allocated and administered at reperfusion. "HFrEF-treatment" protocol: rabbits were randomized, and treatment commenced after echocardiography-confirmed left ventricular ejection fraction (LVEF) ≤40%. "HFrEF-prevention" protocol: treatment started at reperfusion and continued daily throughout the study.

Results: Compared with placebo, SAC/VAL and VAL significantly reduced infarct size (TTC staining) and plasma troponin levels; however, only SAC/VAL preserved LVEF at 72 h post-MI. In the HFrEF-treatment protocol, LVEF improvement was observed with SAC/VAL compared with both placebo and VAL starting 2 weeks post-treatment, a benefit that persisted throughout study duration. In the HFrEF-prevention protocol, SAC/VAL and VAL attenuated the decline in LVEF post-MI, although SAC/VAL offered better functional protection. The functional improvement observed in both treatment protocols was paralleled by significant reduction in left ventricular (LV) scar size (Picrosirius red staining) in the SAC/VAL groups.

Conclusions: Reperfusion therapy with SAC/VAL or VAL offers robust acute infarct-sparing benefits; however, SAC/VAL treatment offered superior short-term and long-term benefits in preventing MI-induced LV dysfunction compared with VAL. SAC/VAL also significantly attenuated LV scar size following MI compared with placebo, whereas VAL did not reach statistical significance in scar reduction.
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http://dx.doi.org/10.1016/j.jacc.2018.07.102DOI Listing
November 2018

Tadalafil prevents acute heart failure with reduced ejection fraction in mice.

Cardiovasc Drugs Ther 2014 Dec;28(6):493-500

Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-020A, Richmond, VA, 23298-0204, USA,

Purpose: Phosphodiesterase-5 (PDE5) inhibitors were shown to exert powerful protection in various animal models of cardiomyopathy. Tadalafil is a long-acting and highly specific PDE5 inhibitor, which makes it the most attractive in its class for long-term management of patients with heart failure. We studied the effects of tadalafil in attenuating ischemic cardiomyopathy in mice.

Methods And Results: Adult male mice underwent myocardial infarction (MI) by permanent left coronary artery ligation and were treated daily with tadalafil (1 mg/kg; ip) or volume-matched 10% DMSO for 4 weeks. Twenty four hours after coronary ligation, infarct size, measured by TTC staining, was reduced from 70.1 ± 3.1% in DMSO-treated group to 49.3 ± 2.6% with tadalafil (P < 0.05). Similarly, tadalafil treatment yielded a smaller fibrotic area (8.8 ± 2.8% of LV), assessed by Masson's trichrome staining, as compared to DMSO group (21.9 ± 3.9%, P < 0.05). Apoptosis, measured by TUNEL assay, also declined with tadalafil (2.1 ± 0.2%) as compared to DMSO (6.7 ± 0.4%, P < 0.05) at 28 days post MI. Tadalafil also attenuated the increase in cardiac hypertrophy and pulmonary edema following infarction. These parameters reflect diminished left ventricular (LV) adverse remodeling and preserved fractional shortening with tadalafil at 7 and 28 days post infarction.

Conclusions: Tadalafil attenuates ischemic cardiomyopathy in mice and preserves LV function.
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http://dx.doi.org/10.1007/s10557-014-6559-0DOI Listing
December 2014

Induction of microRNA-21 with exogenous hydrogen sulfide attenuates myocardial ischemic and inflammatory injury in mice.

Circ Cardiovasc Genet 2014 Jun 13;7(3):311-20. Epub 2014 May 13.

From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.

Background: Maintaining physiological levels of hydrogen sulfide during ischemia is necessary to limit injury to the heart. Because of the anti-inflammatory effects of hydrogen sulfide, we proposed that the hydrogen sulfide donor, sodium sulfide (Na2S), would attenuate myocardial injury through upregulation of protective microRNA-21 (miR-21) and suppression of the inflammasome, a macromolecular structure that amplifies inflammation and mediates further injury.

Methods And Results: Na2S-induced miR-21 expression was measured by quantitative polymerase chain reaction in adult primary rat cardiomyocytes and in the mouse heart. We measured inflammasome formation and activity in cardiomyocytes challenged with lipopolysaccharide and ATP or simulated ischemia/reoxygenation and in the heart after regional myocardial ischemia/reperfusion, in the presence or absence of Na2S. To assess the direct anti-inflammatory effects of hydrogen sulfide in vivo, we used a peritonitis model by way of intraperitoneal injection of zymosan A. Na2S attenuated inflammasome formation and activity, measured by counting cytoplasmic aggregates of the scaffold protein apoptosis speck-like protein containing a caspase-recruitment domain (-57%) and caspase-1 activity (-50%) in isolated cardiomyocytes and in the mouse heart (all P<0.05). Na2S also inhibited apoptosis (-38%) and necrosis (-43%) in cardiomyocytes in vitro and reduced myocardial infarct size (-63%) after ischemia/reperfusion injury in vivo (all P<0.05). These protective effects were absent in cells treated with the miR-21 eraser, antagomiR-21, and in miR-21 knockout mice. Na2S also limited the severity of inflammasome-dependent inflammation in the model of peritonitis (P<0.05) in wild-type but not in miR-21 knockout mice.

Conclusions: Na2S induces cardioprotective effects through miR-21-dependent attenuation of ischemic and inflammatory injury in cardiomyocytes.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090021PMC
June 2014

Aetiologies of central nervous system infection in Viet Nam: a prospective provincial hospital-based descriptive surveillance study.

PLoS One 2012 25;7(5):e37825. Epub 2012 May 25.

Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Viet Nam.

Background: Infectious diseases of the central nervous system (CNS) remain common and life-threatening, especially in developing countries. Knowledge of the aetiological agents responsible for these infections is essential to guide empiric therapy and develop a rational public health policy. To date most data has come from patients admitted to tertiary referral hospitals in Asia and there is limited aetiological data at the provincial hospital level where most patients are seen.

Methods: We conducted a prospective Provincial Hospital-based descriptive surveillance study in adults and children at thirteen hospitals in central and southern Viet Nam between August 2007-April 2010. The pathogens of CNS infection were confirmed in CSF and blood samples by using classical microbiology, molecular diagnostics and serology.

Results: We recruited 1241 patients with clinically suspected infection of the CNS. An aetiological agent was identified in 640/1241 (52%) of the patients. The most common pathogens were Streptococcus suis serotype 2 in patients older than 14 years of age (147/617, 24%) and Japanese encephalitis virus in patients less than 14 years old (142/624, 23%). Mycobacterium tuberculosis was confirmed in 34/617 (6%) adult patients and 11/624 (2%) paediatric patients. The acute case fatality rate (CFR) during hospital admission was 73/617 (12%) in adults and to 42/624 (7%) in children.

Conclusions: Zoonotic bacterial and viral pathogens are the most common causes of CNS infection in adults and children in Viet Nam.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037825PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360608PMC
December 2012

Cinaciguat, a novel activator of soluble guanylate cyclase, protects against ischemia/reperfusion injury: role of hydrogen sulfide.

Am J Physiol Heart Circ Physiol 2012 Mar 20;302(6):H1347-54. Epub 2012 Jan 20.

Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, USA.

Cinaciguat (BAY 58-2667) is a novel nitric oxide (NO)-independent activator of soluble guanylate cyclase (sGC), which induces cGMP-generation and vasodilation in diseased vessels. We tested the hypothesis that cinaciguat might trigger protection against ischemia/reperfusion (I/R) in the heart and adult cardiomyocytes through cGMP/protein kinase G (PKG)-dependent generation of hydrogen sulfide (H(2)S). Adult New Zealand White rabbits were pretreated with 1 or 10 μg/kg cinaciguat (iv) or 10% DMSO (vehicle) 15 min before I/R or with 10 μg/kg cinaciguat (iv) at reperfusion. Additionally, adult male ICR mice were treated with either cinaciguat (10 μg/kg ip) or vehicle 30 min before I/R or at the onset of reperfusion (10 μg/kg iv). The PKG inhibitor KT5283 (KT; 1 mg/kg ip) or dl-propargylglycine (PAG; 50 mg/kg ip) the inhibitor of the H(2)S-producing enzyme cystathionine-γ-lyase (CSE) were given 10 and 30 min before cinaciguat. Cardiac function and infarct size were assessed by echocardiography and tetrazolium staining, respectively. Primary adult mouse cardiomyocytes were isolated and treated with cinaciguat before simulated ischemia/reoxygenation. Cinaciguat caused 63 and 41% reduction of infarct size when given before I/R and at reperfusion in rabbits, respectively. In mice, cinaciguat pretreatment caused a more robust 80% reduction in infarct size vs. 63% reduction when given at reperfusion and preserved cardiac function following I/R, which were blocked by KT and PAG. Cinaciguat also caused an increase in myocardial PKG activity and CSE expression. In cardiomyocytes, cinaciguat (50 nM) reduced necrosis and apoptosis and increased H(2)S levels, which was abrogated by KT. Cinaciguat is a novel molecule to induce H(2)S generation and a powerful protection against I/R injury in heart.
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http://dx.doi.org/10.1152/ajpheart.00544.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311478PMC
March 2012

Outcomes in patients with chronicity of left bundle-branch block with possible acute myocardial infarction.

Am Heart J 2011 Apr;161(4):698-704

Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, USA.

Introduction: Guidelines derived from patients in clinical trials indicate that emergency department patients with likely myocardial infarction (MI) who have new left bundle-branch block (LBBB) should undergo rapid reperfusion therapy. Whether this pertains to lower risk emergency department patients with LBBB is unclear.

Methods: A total of 401 consecutive patients with LBBB undergoing an MI rule-out protocol were included. Left bundle-branch blocks were classified as chronic; new; or, if no prior electrocardiogram (ECG) was available, as presumably new. Left bundle-branch blocks were considered concordant if there was ≥1 mm concordant ST elevation or depression. Rates of MI, peak MB values in MI patients, and 30-day mortality were compared across groups.

Results: A majority of patients (64%) had new (37%) or presumably new LBBB (27%). A total of 116 patients (29%) had MI, with no significant difference in prevalence or size of MI among the 3 ECG groups. Myocardial infarction was diagnosed in 86% of patients with concordant ECG changes versus 27% of patients without concordant ECG changes (P < .01). Peak MB was >5× normal in 50% who had concordant ST changes compared to none of those who did not. Concordant ST changes were the most important predictor of MI (odds ratio 17, 95% CI 3.4-81, P < .001) and an independent predictor of mortality (odds ratio 4.3, 95% CI 1.3-15, P < .001); new or presumably new LBBB was neither.

Conclusions: Most patients with possible MI with new or presumably new LBBB do not have MI. Concordant ECG changes were an important predictor of MI and death. Current guidelines regarding early reperfusion therapy for patients with LBBB should be reconsidered.
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http://dx.doi.org/10.1016/j.ahj.2011.01.008DOI Listing
April 2011

Mitigation of the progression of heart failure with sildenafil involves inhibition of RhoA/Rho-kinase pathway.

Am J Physiol Heart Circ Physiol 2011 Jun 11;300(6):H2272-9. Epub 2011 Mar 11.

Div. of Cardiology, Box 980204, Virginia Commonwealth Univ., 1101 E. Marshall St., Rm. 7-020A, Richmond, VA 23298, USA.

Chronic inhibition of phosphodiesterase-5 with sildenafil immediately after permanent occlusion of the left anterior descending coronary artery was shown to limit ischemic heart failure (HF) in mice. To mimic a more clinical scenario, we postulated that treatment with sildenafil beginning at 3 days post-myocardial infarction (MI) would also reduce HF progression through the inhibition of the RhoA/Rho-kinase pathway. Adult male ICR mice with fractional shortening < 25% at day 3 following permanent left anterior descending coronary artery ligation were continuously treated with either saline (volume matched, ip, 2 times/day) or sildenafil (21 mg/kg, ip, 2 times/day) for 25 days. Echocardiography showed fractional shortening preservation and less left ventricular end-diastolic dilatation with sildenafil treatment compared with saline treatment at 7 and 28 days post-MI (P < 0.05). Both fibrosis and apoptosis, determined by Masson's trichrome and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), respectively, were attenuated in the sildenafil-treated mice (P < 0.05 vs. saline). Western blot analysis showed enchanced Bcl-2-to-Bax ratio with sildenafil treatment (P < 0.05 vs. saline). Activity assay showed sildenafil-mediated PKG activation 1 day after treatment (P < 0.05 vs. sham and saline). PKG activation was associated with sildenafil-mediated inhibition of Rho kinase (P < 0.05) compared with saline treatment, whereas PKG inhibition with KT-5823 abolished this inhibitory effect of sildenafil. In conclusion, for the first time, our findings show that chronic sildenafil treatment, initiated at 3 days post-MI, attenuates left ventricular dysfunction independent of its infarct-sparing effect, and this cardioprotection involves the inhibition of the RhoA/Rho-kinase pathway. Sildenafil may be a promising therapeutic tool for advanced HF in patients.
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http://dx.doi.org/10.1152/ajpheart.00654.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119085PMC
June 2011

Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats.

Am J Respir Crit Care Med 2010 Sep 27;182(5):652-60. Epub 2010 May 27.

Director of the Victoria Johnson Center for Obstructive Lung Disease Research, Virginia Commonwealth University, 1220 East Broad Street, Richmond, VA 23298, USA.

Rationale: Most patients with pulmonary arterial hypertension (PAH) die from right heart failure. Beta-adrenergic receptor blockade reduces mortality by about 30% in patients with left-sided systolic heart failure, but is not used in PAH.

Objectives: To assess the effect of the adrenergic receptor blocker carvedilol on the pulmonary circulation and right heart in experimental pulmonary hypertension in rats.

Methods: Angioproliferative pulmonary hypertension was induced in rats by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia. Carvedilol treatment was started after establishment of pulmonary hypertension and right heart dysfunction.

Measurements And Main Results: Compared with vehicle-treated animals, treatment with carvedilol resulted in increased exercise endurance; improved right ventricular (RV) function (increased tricuspid annular plane systolic excursion and decreased RV dilatation); and an increased cardiac output. The morphology of the pulmonary vessels and the RV afterload were not affected by carvedilol. Carvedilol treatment was associated with enhancement of RV fetal gene reactivation, increased protein kinase G (PKG) activity, and a reduction in capillary rarefaction and fibrosis. Metoprolol had similar but less pronounced effects in the SU5416 and hypoxia model. Cardioprotective effects were noted of both carvedilol and metoprolol in the monocrotaline model. In the case of carvedilol, but not metoprolol, part of these effects resulted from a prevention of monocrotaline-induced lung remodeling.

Conclusions: Adrenergic receptor blockade reverses RV remodeling and improves RV function in experimental pulmonary hypertension. Beta-adrenergic receptor blockers are not recommended in humans with PAH before their safety and efficacy are assessed in well-designed clinical trials.
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http://dx.doi.org/10.1164/rccm.201003-0335OCDOI Listing
September 2010

Pharmacologic inhibition of myeloid differentiation factor 88 (MyD88) prevents left ventricular dilation and hypertrophy after experimental acute myocardial infarction in the mouse.

J Cardiovasc Pharmacol 2010 Apr;55(4):385-90

School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.

Background: Myeloid differentiation factor 88 (MyD88) is an endogenous adaptor protein that coordinates the inflammatory response to agonists of the Toll-like receptor and interleukin-1 receptor families. This particular response is activated following myocardial ischemia and infarction and may represent a viable target for pharmacologic inhibition. The current study tested MyD88 inhibitors in a murine model of nonreperfused acute myocardial infarction (AMI).

Methods: AMI was induced by permanent ligation of the left coronary artery. Adult, male, Imprinting Control Region mice were randomized to daily injections with 1 of 2 MyD88 pharmacologic inhibitors (ST2825 25 mg/kg or IMG2005 1 mg/kg), saline, or pretreatment with MyD88-targeted silencing small interfering RNA (siRNA) or scrambled nontargeted siRNA (n = 6 for each group). Echocardiography was performed at baseline and 7 days after surgery to evaluate pathologic cardiac enlargement.

Results: Pharmacologic inhibition of MyD88 with ST2825 or IMG2005) and MyD88-targeted siRNA protected against left ventricular (LV) dilatation (reduced LV end-systolic and LV end-diastolic diameter) and hypertrophy. This protection occurred despite no measurable reduction in infarct size.

Conclusions: Pharmacologic MyD88 inhibition protects against pathologic LV remodeling without altering infarct scar formation. MyD88 may be a viable target for pharmacologic inhibition in AMI.
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http://dx.doi.org/10.1097/FJC.0b013e3181d3da24DOI Listing
April 2010

Interleukin-1 trap attenuates cardiac remodeling after experimental acute myocardial infarction in mice.

J Cardiovasc Pharmacol 2010 Feb;55(2):117-22

Pauley Heart Center, Virginia Commonwealth University, Richmond, 23298-0281, USA.

Background: Interleukin-1 (IL-1) is an inflammatory cytokine that responds as an acute phase reactant during acute myocardial infarction. Conflicting data describe the role of anti-IL-1 interventions to reduce cardiac remodeling after AMI. IL-1 Trap is a modified recombinant fusion protein that binds circulating IL-1. Our study evaluated the effects of murine IL-1 Trap on cardiac remodeling after AMI resulting from permanent surgical coronary artery ligation.

Methods: Mice received treatment with intraperitoneal injection of murine IL-1 Trap (1 mg/kg [n = 5], 5 mg/kg [n = 5], or 30 mg/kg [n = 5]) or NaCl 0.9% (saline; n = 10) every 48 hours after surgery. Transthoracic echocardiography was performed at baseline and 7 days after surgery. Inhibition of IL-1 signaling was determined by measurement of IL-6 plasma levels (enzyme-linked immunosorbent assay) after IL-1b injection. Apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) was measured in murine heart samples and in a primary culture of murine cardiomyocytes.

Results: Mice treated with 5 mg/kg or 30 mg/kg IL-1 Trap had more favorable cardiac remodeling and echocardiographic assessment of infarct size at 7 days compared with saline (P < 0.05 for each comparison). Treatment with IL-1 Trap also reduced apoptosis and IL-6 levels compared with saline treatment.

Conclusions: IL-1 Trap ameliorates cardiac remodeling and reduces cardiomyocyte apoptosis after experimental acute myocardial infarction in the mouse.
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http://dx.doi.org/10.1097/FJC.0b013e3181c87e53DOI Listing
February 2010

Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through protein-kinase g-dependent generation of hydrogen sulfide.

Circulation 2009 Sep;120(11 Suppl):S31-6

Department of Internal Medicine, Virginia Commonwealth University, Richmond, 23298, USA.

Background: Tadalafil is a novel long-acting inhibitor of phosphodiesterase-5. Because cGMP-dependent protein kinase (PKG) signaling plays a key role in cardioprotection, we hypothesized that PKG activation with tadalafil would limit myocardial ischemia/reperfusion (I/R) injury and dysfunction. Additionally, we contemplated that cardioprotection with tadalafil is mediated by hydrogen sulfide (H(2)S) signaling in a PKG-dependent fashion.

Methods And Results: After baseline transthoracic echocardiography (TTE), adult ICR mice were injected i.p. with vehicle (10% DMSO) or tadalafil (1 mg/kg) with or without KT5823 (KT, PKG blocker, 1 mg/kg) or dl-propargylglycine (PAG, Cystathionine-gamma-lyase [CSE, H(2)S-producing enzyme] blocker; 50 mg/kg) 1 hour before coronary artery ligation for 30 minutes and reperfusion for 24 hours, whereas C57BL wild-type and CSE-knockout mice were treated with either vehicle or tadalafil. After reperfusion, TTE was performed and hearts were collected for infarct size (IS) measurement using TTC staining. Survival was increased with tadalafil (95%) compared with control (65%, P<0.05). Infarct size was reduced with tadalafil (13.2+/-1.7%) compared to vehicle (40.6+/-2.5%; P<0.05). KT and PAG abolished tadalafil-induced protection (IS: 39.2+/-1% and 51.2+/-2.4%, respectively) similar to genetic deletion of CSE (47.2+/-5.1%). Moreover, tadalafil preserved fractional shortening (FS: 31+/-1.5%) compared to control (FS: 22+/-4.8%, P<0.05). Baseline FS was 44+/-1.7%. KT and PAG abrogated the preservation of LV function with tadalafil by decline in FS to 17+/-1% and 23+/-3%, respectively. Compared to vehicle, myocardial H(2)S production was significantly increased with tadalafil and was abolished with KT.

Conclusions: PKG activation with tadalafil limits myocardial infarction and preserves LV function through H(2)S signaling.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.108.843979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230451PMC
September 2009

Anakinra in experimental acute myocardial infarction--does dosage or duration of treatment matter?

Cardiovasc Drugs Ther 2009 Apr 13;23(2):129-35. Epub 2008 Nov 13.

VCU Pauley Heart Center, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA 23298-0281, USA.

Purpose: Interleukin-1 (IL-1) receptor antagonist (Ra) is a naturally occurring IL-1 blocker with a cardioprotective effect during acute myocardial infarction (AMI). Anakinra, recombinant-human IL-1Ra, has been used to prevent heart failure in a mouse model of AMI. The aim of this study was to determine the optimal therapeutic regimen for anakinra in AMI.

Methods: We performed dose-response experiments comparing anakinra 1 mg/kg with 100 mg/kg doses, and duration-response experiments comparing 1-week to 2-week treatment. Echocardiography was used to assess cardiac remodeling and systolic function. Histopathology was used to detect apoptotic cardiomyocytes.

Results: A higher dose of anakinra was not associated with additional improvement in cardiac remodeling or function. The 2-week anakinra treatment had sustained and more favorable remodeling and systolic function compared to 1-week treatment with significantly smaller left ventricular end-systolic diameter and greater fractional shortening 4 weeks after AMI.

Conclusion: Anakinra inhibits apoptosis and ameliorates cardiac remodeling up to 4 weeks after infarction. A 2-week regimen is superior to a 1-week regimen, whereas a higher dose did not provide any further benefit over standard doses.
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http://dx.doi.org/10.1007/s10557-008-6154-3DOI Listing
April 2009