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Circulation - recientes

American Heart Association Principles on the Accessibility and Affordability of Drugs and Biologics [AHA Presidential Advisory]
11/12/2017
Elliott M. Antman, Mark A. Creager, Steven R. Houser, John J. Warner, Madeleine Konig
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Net US spending on pharmaceuticals reached $309.5 billion in 2015, an 8.5% increase from the year before, and is expected to reach between $370 and $400 billion by 2020. These current and projected levels have raised serious concerns by policy makers, providers, payers, and patient groups that they are unsustainable and threaten the affordability of and accessibility to much-needed therapies for patients. Two trends related to drugs/biologics and generic drugs/biosimilars underlie this overall increase in spending. First, the market entry prices of innovator pharmaceutical products, or brand drugs and biologics, are at levels that some assessments consider unaffordable to the healthcare system. Second, prices for some established generic drugs such as digoxin and captopril have seen sharp and rapid increases. As an evidence-based patient advocacy organization dedicated to improving the cardiovascular health of all Americans, the American Heart Association has a unique role in advocating for treatments, including medicines that are available, affordable, and accessible to patients. This advisory serves to lay out a set of principles that will guide association engagement in pursuit of this goal.

Late-Breaking Science Abstracts From the American Heart Association’s Scientific Sessions 2017 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2017 [LBS-LBRS Abstracts]
11/12/2017
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Is Instantaneous Wave-Free Ratio a New Standard of Care for Physiologic Assessment of Coronary Lesions? [On My Mind]
11/12/2017
Morton J. Kern, Arnold H. Seto
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Recent Evolution of the Treatment of Coronary Artery Disease in China [Paths to Discovery]
11/12/2017
Ya-Ling Han, John D. Rutherford
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Increase in Endovascular Therapy in Get With The Guidelines-Stroke After the Publication of Pivotal Trials [Original Research Article]
11/12/2017
Eric E. Smith, Jeffrey L. Saver, Margueritte Cox, Li Liang, Roland Matsouaka, Ying Xian, Deepak L. Bhatt, Gregg C. Fonarow, Lee H. Schwamm
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Background:Beginning in December 2014, a series of pivotal trials showed that endovascular thrombectomy (EVT) was highly effective, prompting calls to reorganize stroke systems of care. However, there are few data on how these trials influenced the frequency of EVT in clinical practice. We used data from the Get With The Guidelines-Stroke program to determine how the frequency of EVT changed in US practice.Methods:We analyzed prospectively collected data from a cohort of 2 437 975 patients with ischemic stroke admitted to 2222 participating hospitals between April 2003 and the third quarter of 2016. Weighted linear regression with 2 linear splines and a knot at January 2015 was used to compare the slope of the change in EVT use before and after the pivotal trials were published. Potentially eligible patients were defined as last known well to arrival time ≤4.5 hours and National Institutes of Health Stroke Scale score ≥6.Results:The frequency of EVT use was slowly increasing before January 2015 but then sharply accelerated thereafter. In the third quarter 2016, EVT was provided to 3.3% of all patients with ischemic stroke at all hospitals, representing 15.1% of all patients who were potentially eligible for EVT based on stroke duration and severity. At EVT-capable hospitals, 7.5% of all patients with ischemic stroke were treated in the third quarter of 2016, including 27.3% of the potentially eligible patients. From 2013 to 2016, case volumes nearly doubled at EVT-capable hospitals. Mean case volume per EVT-capable hospital was 37.6 per year in the last 4 quarters. EVT case volumes increased in nearly all US states from 2014 to the last 4 quarters, but with persistent geographic variation unexplained by differences in potential patient eligibility.Conclusions:EVT use is increasing rapidly; however, there are still opportunities to treat more patients. Reorganizing stroke systems to route patients to adequately resourced EVT-capable hospitals might increase treatment of eligible patients, improve outcomes, and reduce disparities.

Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) [Original Research Article]
11/12/2017
Michael T. Froehler, Jeffrey L. Saver, Osama O. Zaidat, Reza Jahan, Mohammad Ali Aziz-Sultan, Richard P. Klucznik, Diogo C. Haussen, Frank R. Hellinger, Jr., Dileep R. Yavagal, Tom L. Yao, David S. Liebeskind, Ashutosh P. Jadhav, Rishi Gupta, Ameer E. Hassan, Coleman O. Martin, Hormozd Bozorgchami, Ritesh Kaushal, Raul G. Nogueira, Ravi H. Gandhi, Eric C. Peterson, Shervin R. Dashti, Curtis A. Given II, Brijesh P. Mehta, Vivek Deshmukh, Sidney Starkman, Italo Linfante, Scott H. McPherson, Peter Kvamme, Thomas J. Grobelny, Muhammad S. Hussain, Ike Thacker, Nirav Vora, Peng Roc Chen, Stephen J. Monteith, Robert D. Ecker, Clemens M. Schirmer, Eric Sauvageau, Alex Abou-Chebl, Colin P. Derdeyn, Lucian Maidan, Aamir Badruddin, Adnan H. Siddiqui, Travis M. Dumont, Abdulnasser Alhajeri, M. Asif Taqi, Khaled Asi, Jeffrey Carpenter, Alan Boulos, Gaurav Jindal, Ajit S. Puri, Rohan Chitale, Eric M. Deshaies, David H. Robinson, David F. Kallmes, Blaise W. Baxter, Mouhammad A. Jumaa, Peter Sunenshine, Aniel Majjhoo, Joey D. English, Shuichi Suzuki, Richard D. Fessler, Josser E. Delgado Almandoz, Jerry C. Martin, Nils H. Mueller-Kronast
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Background:Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation.Methods:STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0–2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass.Results:A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients (P<0.001). Clinical outcomes were better in the direct group, with 60.0% (299/498) achieving functional independence compared with 52.2% (213/408) in the transfer group (odds ratio, 1.38; 95% confidence interval, 1.06–1.79; P=0.02). Likewise, excellent outcome (modified Rankin Score 0–1) was achieved in 47.4% (236/498) of direct patients versus 38.0% (155/408) of transfer patients (odds ratio, 1.47; 95% confidence interval, 1.13–1.92; P=0.005). Mortality did not differ between the 2 groups (15.1% for direct, 13.7% for transfer; P=0.55). Intravenous tissue plasminogen activator did not impact outcomes. Hypothetical bypass modeling for all transferred patients suggested that intravenous tissue plasminogen activator would be delayed by 12 minutes, but MT would be performed 91 minutes sooner if patients were routed directly to endovascular-capable centers. If bypass is limited to a 20-mile radius from onset, then intravenous tissue plasminogen activator would be delayed by 7 minutes and MT performed 94 minutes earlier.Conclusions:In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239640.

Optimizing Systems of Care for Endovascular Thrombectomy in Ischemic Stroke [Editorials]
11/12/2017
Bruce C.V. Campbell, Geoffrey A. Donnan, Stephen M. Davis
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Integrated Noninvasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients With Stable Coronary Artery Disease [Original Research Article]
11/12/2017
Ankur Gupta, Viviany R. Taqueti, Tim P. van de Hoef, Navkaranbir S. Bajaj, Paco E. Bravo, Venkatesh L. Murthy, Michael T. Osborne, Sara B. Seidelmann, Tomas Vita, Courtney F. Bibbo, Meagan Harrington, Jon Hainer, Ornella Rimoldi, Sharmila Dorbala, Deepak L. Bhatt, Ron Blankstein, Paolo G. Camici, Marcelo F. Di Carli
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Background:It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows for comprehensive evaluation of patients with known or suspected stable coronary artery disease. Because management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death.Methods:MBF and CFR were quantified in 4029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF <1.8 mL·g−1·min−1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses.Results:A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure product, type of radiotracer or stress agent used, and revascularization after scan (adjusted hazard ratio, 1.79; 95% confidence interval [CI], 1.38–2.31; P<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates; and adjusted hazard ratio, 1.03; 95% CI, 0.84–1.27; P=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI, 2.9–3.7) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI, 1.3–2.1) per year. These patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI, 0.6–1.6) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95 CI, 0.3–0.6) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the 4 concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF.Conclusions:CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.

cGMP-Elevating Compounds and Ischemic Conditioning Provide Cardioprotection Against Ischemia and Reperfusion Injury via Cardiomyocyte-Specific BK Channels [Original Research Article]
11/12/2017
Sandra Frankenreiter, Piotr Bednarczyk, Angelina Kniess, Nadja I. Bork, Julia Straubinger, Piotr Koprowski, Antoni Wrzosek, Eva Mohr, Angela Logan, Michael P. Murphy, Meinrad Gawaz, Thomas Krieg, Adam Szewczyk, Viacheslav O. Nikolaev, Peter Ruth, Robert Lukowski
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Background:The nitric oxide–sensitive guanylyl cyclase/cGMP-dependent protein kinase type I signaling pathway can afford protection against the ischemia/reperfusion injury that occurs during myocardial infarction. Reportedly, voltage and Ca2+-activated K+ channels of the BK type are stimulated by cGMP/cGMP-dependent protein kinase type I, and recent ex vivo studies implicated that increased BK activity favors the survival of the myocardium at ischemia/reperfusion. It remains unclear, however, whether the molecular events downstream of cGMP involve BK channels present in cardiomyocytes or in other cardiac cell types.Methods:Gene-targeted mice with a cardiomyocyte- or smooth muscle cell–specific deletion of the BK (CMBK or SMBK knockouts) were subjected to the open-chest model of myocardial infarction. Infarct sizes of the conditional mutants were compared with litter-matched controls, global BK knockout, and wild-type mice. Cardiac damage was assessed after mechanical conditioning or pharmacological stimulation of the cGMP pathway and by using direct modulators of BK. Long-term outcome was studied with respect to heart functions and cardiac fibrosis in a chronic myocardial infarction model.Results:Global BK knockouts and CMBK knockouts, in contrast with SMBK knockouts, exhibited significantly larger infarct sizes compared with their respective controls. Ablation of CMBK resulted in higher serum levels of cardiac troponin I and elevated amounts of reactive oxygen species, lower phosphorylated extracellular receptor kinase and phosphorylated AKT levels and an increase in myocardial apoptosis. Moreover, CMBK was required to allow beneficial effects of both nitric oxide–sensitive guanylyl cyclase activation and inhibition of the cGMP-degrading phosphodiesterase-5, ischemic preconditioning, and postconditioning regimens. To this end, after 4 weeks of reperfusion, fibrotic tissue increased and myocardial strain echocardiography was significantly compromised in CMBK-deficient mice.Conclusions:Lack of CMBK channels renders the heart more susceptible to ischemia/reperfusion injury, whereas the pathological events elicited by ischemia/reperfusion do not involve BK in vascular smooth muscle cells. BK seems to permit the protective effects triggered by cinaciguat, riociguat, and different phosphodiesterase-5 inhibitors and beneficial actions of ischemic preconditioning and ischemic postconditioning by a mechanism stemming primarily from cardiomyocytes. This study establishes mitochondrial CMBK channels as a promising target for limiting acute cardiac damage and adverse long-term events that occur after myocardial infarction.

Cardioprotection Is Alive But Remains Enigmatic [Editorials]
11/12/2017
Gerd Heusch
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Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit+ Cells [Original Research Article]
11/12/2017
Zhongming Chen, Wuqiang Zhu, Ingrid Bender, Wuming Gong, Il-Youp Kwak, Amritha Yellamilli, Thomas J. Hodges, Natsumi Nemoto, Jianyi Zhang, Daniel J. Garry, Jop H. van Berlo
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Background:Although cardiac c-kit+ cells are being tested in clinical trials, the circumstances that determine lineage differentiation of c-kit+ cells in vivo are unknown. Recent findings suggest that endogenous cardiac c-kit+ cells rarely contribute cardiomyocytes to the adult heart. We assessed whether various pathological stimuli differentially affect the eventual cell fates of c-kit+ cells.Methods:We used single-cell sequencing and genetic lineage tracing of c-kit+ cells to determine whether various pathological stimuli would result in different fates of c-kit+ cells.Results:Single-cell sequencing of cardiac CD45-c-kit+ cells showed innate heterogeneity, indicative of the existence of vascular and mesenchymal c-kit+ cells in normal hearts. Cardiac pressure overload resulted in a modest increase in c-kit-derived cardiomyocytes, with significant increases in the numbers of endothelial cells and fibroblasts. Doxorubicin-induced acute cardiotoxicity did not increase c-kit-derived endothelial cell fates but instead induced cardiomyocyte differentiation. Mechanistically, doxorubicin-induced DNA damage in c-kit+ cells resulted in expression of p53. Inhibition of p53 blocked cardiomyocyte differentiation in response to doxorubicin, whereas stabilization of p53 was sufficient to increase c-kit-derived cardiomyocyte differentiation.Conclusions:These results demonstrate that different pathological stimuli induce different cell fates of c-kit+ cells in vivo. Although the overall rate of cardiomyocyte formation from c-kit+ cells is still below clinically relevant levels, we show that p53 is central to the ability of c-kit+ cells to adopt cardiomyocyte fates, which could lead to the development of strategies to preferentially generate cardiomyocytes from c-kit+ cells.

Stem Cell Therapy for Congenital Heart Disease [Systematic Review]
11/12/2017
Diamantis I. Tsilimigras, Evangelos K. Oikonomou, Demetrios Moris, Dimitrios Schizas, Konstantinos P. Economopoulos, Konstantinos S. Mylonas
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Background:Congenital heart disease (CHD) constitutes the most prevalent and heterogeneous group of congenital anomalies. Although surgery remains the gold standard treatment modality, stem cell therapy has been gaining ground as a complimentary or alternative treatment option in certain types of CHD. The aim of this study was to present the existing published evidence and ongoing research efforts on the implementation of stem cell-based therapeutic strategies in CHD.Methods:A systematic review was conducted by searching Medline, ClinicalTrials.gov, and the Cochrane library, along with reference lists of the included studies through April 23, 2017.Results:Nineteen studies were included in this review (8 preclinical, 6 clinical, and 5 ongoing trials). Various routes of cardiac stem cell delivery have been reported, including intracoronary, intramyocardial, intravenous, and epicardial. Depending on their origin and level of differentiation at which they are harvested, stem cells may exhibit different properties. Preclinical studies have mostly focused on modeling right ventricle dysfunction or failure and pulmonary artery hypertension by using pressure or volume overload in vitro or in vivo. Only a limited number of clinical trials on patients with CHD exist, and these primarily focus on hypoplastic left heart syndrome. Cell-based tissue engineering has recently been introduced, and research currently is focusing on developing cell-seeded grafts and patches that could potentially grow in parallel with whole body growth once implanted in the heart.Conclusions:It seems that stem cell delivery to the diseased heart as an adjunct to surgical palliation may provide some benefits over surgery alone in terms of cardiac function, somatic growth, and quality of life. Despite encouraging preliminary results, stem cell therapies for patients with CHD should only be considered in the setting of well-designed clinical trials. More wet laboratory research experience is needed, and translation of promising findings to large clinical studies is warranted to clearly define the efficacy and safety profile of this alternative and potentially groundbreaking therapeutic approach.

Regular Tachycardia With Abnormal QRS Axis [ECG Challenges]
11/12/2017
Raȷin Choudhury, Mattias Duytschaever, Sebastien Knecht, Yves Vandekerckhove, Rene Tavernier
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Meta-Analysis of Death and Myocardial Infarction in the DEFINE-FLAIR and iFR-SWEDEHEART Trials [Research Letter]
11/12/2017
Colin Berry, John D. McClure, Keith G. Oldroyd
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Letter by Jin-Shan and Xue-Bin Regarding Article, “Fractional Flow Reserve and Cardiac Events in Coronary Artery Disease: Data From a Prospective IRIS-FFR Registry (Interventional Cardiology Research Incooperation Society Fractional Flow Reserve)” [Correspondence]
11/12/2017
He Jin-Shan, Li Xue-Bin
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Response by Ahn and Park to Letter Regarding Article, “Fractional Flow Reserve and Cardiac Events in Coronary Artery Disease: Data From a Prospective IRIS-FFR Registry (Interventional Cardiology Research Incooperation Society Fractional Flow Reserve)” [Correspondence]
11/12/2017
Jung-Min Ahn, Seung-Jung Park
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Letter by Triantafyllou and Straub Regarding Article, “Thresholds for Ambulatory Blood Pressure Among African Americans in the Jackson Heart Study” [Correspondence]
11/12/2017
Georgios A. Triantafyllou, Adam C. Straub
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Letter by Chi and Marszalek Regarding Article, “Composite End Points in Clinical Research: A Time for Reappraisal” [Correspondence]
11/12/2017
Gerald Chi, Jolanta Marszalek
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2017 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary [ILCOR Summary Statement]
4/12/2017
Theresa M. Olasveengen, Allan R. de Caen, Mary E. Mancini, Ian K. Maconochie, Richard Aickin, Dianne L. Atkins, Robert A. Berg, Robert M. Bingham, Steven C. Brooks, Maaret Castren, Sung Phil Chung, Julie Considine, Thomaz Bittencourt Couto, Raffo Escalante, Raul J. Gazmuri, Anne–Marie Guerguerian, Tetsuo Hatanaka, Rudolph W. Koster, Peter J. Kudenchuk, Eddy Lang, Swee Han Lim, Bo Lofgren, Peter A. Meaney, William H. Montgomery, Peter T. Morley, Laurie J. Morrison, Kevin J. Nation, Kee–Chong Ng, Vinay M. Nadkarni, Chika Nishiyama, Gabrielle Nuthall, Gene Yong–Kwang Ong, Gavin D. Perkins, Amelia G. Reis, Giuseppe Ristagno, Tetsuya Sakamoto, Michael R. Sayre, Stephen M. Schexnayder, Alfredo F. Sierra, Eunice M. Singletary, Naoki Shimizu, Michael A. Smyth, David Stanton, Janice A. Tiȷssen, Andrew Travers, Christian Vaillancourt, Patrick Van de Voorde, Mary Fran Hazinski, Jerry P. Nolan
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The International Liaison Committee on Resuscitation has initiated a near-continuous review of cardiopulmonary resuscitation science that replaces the previous 5-year cyclic batch-and-queue approach process. This is the first of an annual series of International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations summary articles that will include the cardiopulmonary resuscitation science reviewed by the International Liaison Committee on Resuscitation in the previous year. The review this year includes 5 basic life support and 1 pediatric Consensuses on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Each of these includes a summary of the science and its quality based on Grading of Recommendations, Assessment, Development, and Evaluation criteria and treatment recommendations. Insights into the deliberations of the International Liaison Committee on Resuscitation task force members are provided in Values and Preferences sections. Finally, the task force members have prioritized and listed the top 3 knowledge gaps for each population, intervention, comparator, and outcome question.

Learning From Major Clinical Trials [Perspective]
4/12/2017
Marc A. Pfeffer
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