Impact of Lipid Measurements in Youth in Addition to Conventional Clinic-Based Risk Factors on Predicting Preclinical Atherosclerosis in Adulthood: The International Childhood Cardiovascular Cohort (i3C) Consortium Circulation (IF 19.309) Pub Date : 2017-11-23 Juha Koskinen, Markus Juonala, Terence Dwyer, Alison Venn, Russell Thomson, Lydia Bazzano, Gerald S. Berenson, Matthew A. Sabin, Trudy L. Burns, Jorma S. A. Viikari, Jessica G. Woo, Elaine M. Urbina, Ronald Prineas, Nina Hutri-Kähönen, Alan Sinaiko, David Jacobs, Julia Steinberger, Stephen Daniels, Olli T. Raitakari, Costan G. Magnussen
Background—Data suggest that the prediction of adult cardiovascular disease using a model comprised entirely of adult non-laboratory based risk factors is equivalent to an approach that additionally incorporates adult lipid measures. We assessed and compared the utility of a risk model based solely on non-laboratory risk factors in adolescence vs. a lipid model based on non-laboratory risk factors + lipids for predicting high-risk carotid intima-media thickness (cIMT) in adulthood.Methods—The study comprised 2,893 participants aged 12-18 years from four longitudinal cohort studies from the United States (Bogalusa Heart Study and the Insulin Study), Australia (Childhood Determinants of Adult Health Study) and Finland (The Cardiovascular Risk in Young Finns Study) and followed into adulthood when cIMT was measured (mean follow-up 23.4 years). Overweight status was defined according to the Cole classification. Hypertension was defined according to the Fourth Report on High Blood Pressure in Children and Adolescents from the National High Blood Pressure Education Program. High-risk plasma lipid levels were defined according to the National Cholesterol Education Program (NCEP) Expert Panel on Cholesterol Levels in Children. High cIMT was defined as a study-specific value ≥90th percentile. Age-and sex were included in each model.Results—In univariate models all risk factors except for borderline high-and high triglycerides in adolescence were associated with high cIMT in adulthood. In multivariable models (RR [95% CI]), male sex (2.7 [2.0-2.6]), pre-hypertension (1.4 [1.0-1.9]), hypertension (1.9 [1.3-2.9]), overweight (2.0 [1.4-2.9]), obesity (3.7 [2.0-7.0]), borderline high LDL-cholesterol (1.6 [1.2-2.2]), high LDL-cholesterol (1.6 [1.1-2.1]) and borderline low HDL-cholesterol (1.4 [1.0-1.8]) remained significant predictors of high cIMT (P always < 0.05). The addition of lipids into the non-laboratory risk model slightly, but significantly, improved discrimination in predicting high cIMT compared with non-laboratory-based risk factors only (c-statistics for laboratory-based model 0.717 [95%CI 0.685-0.748] and for non-laboratory 0.698 [95%CI 0.667-0.731], P=0.02).Conclusions—Non-laboratory-based risk factors and lipids measured in adolescence independently predicted preclinical atherosclerosis in young adulthood. The addition of lipid measurements to traditional clinic based risk factor assessment provided a statistically significant but clinically modest improvement on adolescent prediction of high cIMT in adulthood.
Surgical Enlargement of the Aortic Root Does Not Increase the Operative Risk of Aortic Valve Replacement Circulation (IF 19.309) Pub Date : 2017-11-22 Rodolfo V. Rocha, Cedric Manlhiot, Christopher M. Feindel, Terrence M. Yau, Brigitte Mueller, Tirone E. David, Maral Ouzounian
Background—Surgical aortic root enlargement (ARE) during aortic valve replacement (AVR) allows for larger prosthesis implantation and may be an important adjunct to surgical AVR in the transcatheter valve-in-valve era. The incremental operative risk of adding ARE to AVR has not been established. We sought to evaluate the early outcomes of patients undergoing AVR with or without ARE.Methods—From January 1990 to August 2014, 7039 patients underwent AVR (AVR + ARE, n=1854; AVR, n=5185) at a single institution. Patients with aortic dissection and active endocarditis were excluded. Mean age was 65±14 years and 63% were male. Logistic regression and propensity score matching were used to adjust for unbalanced variables in group comparisons.Results—Patients undergoing AVR + ARE were more likely to be female (46% vs. 34%, p<0.001) and had higher rates of previous cardiac surgery (18% vs 12%, p<0.001), COPD (5% vs. 3%, p=0.004), urgent/emergent status (6% vs 4%, p=0.01), and worse NYHA status (p<0.001). Most patients received bioprosthetic valves (AVR + ARE: 73.4% vs. AVR: 73.3%, p=0.98) and also underwent concomitant cardiac procedures (AVR+ARE: 68% vs. AVR: 67%, p=0.31). Mean prosthesis size implanted was slightly smaller in patients requiring AVR + ARE vs. AVR (23.4±2.1 vs. 24.1±2.3, p<0.001). In-hospital mortality was higher following AVR + ARE (4.3% vs. 3.0%, p=0.008), although when the cohort was restricted to patients undergoing isolated aortic valve replacement with or without root enlargement, mortality was not statistically different (AVR + ARE: 1.7% vs. AVR: 1.1%, p=0.29). Following adjustment for baseline characteristics, AVR + ARE was not associated with an increased risk of in-hospital mortality when compared with AVR (Odds Ratio 1.03, 95% CI (0.75-1.41), p=0.85). Furthermore, AVR + ARE was not associated with an increased risk of post-operative adverse events. Results were similar if propensity matching was used instead of multivariable adjustments for baseline characteristics.Conclusions—In the largest analysis to date, ARE was not associated with increased risk of mortality or adverse events. Surgical ARE is a safe adjunct to AVR in the modern era.
Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension Circulation (IF 19.309) Pub Date : 2017-11-22 Denielli da Silva Gonçalves Bos, Cathelijne E. Van Der Bruggen, Kondababu Kurakula, Xiao-Qing Sun, Karina R. Casali, Adenauer G. Casali, Nina Rol, Robert Szulcek, Cris dos Remedios, Christophe Guignabert, Ly Tu, Peter Dorfmuller, Marc Humbert, Paul J.M. Wijnker, Diederik W. D. Kuster, Jolanda van der Velden, Marie-José Goumans, Harm-Jan Bogaard, Anton Vonk-Noordegraaf, Frances S. de Man, M. Louis Handoko
Background—Beneficial effects of parasympathetic stimulation have been reported in left heart failure, however, whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in PAH-patients, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase (AchE) inhibition, in experimental pulmonary hypertension (PH).Methods—Heart rate recovery (HRR) after maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction (RVEF) was assessed in 112 PAH-patients. Expression of nicotinic (α-7nAchR) and muscarinic (m2AchR) receptors, and AchE activity were evaluated in RV (n=11) and lungs (n=7) from PAH-patients undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg/day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg; s.c.) injection followed by 4 weeks of hypoxia. In a subgroup sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomized to vehicle or treatment (both n=12). At the end-of-study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological and protein analyses.Results—PAH-patients with lower RVEF (<41%) had a significantly reduced HRR in comparison to patients with higher RVEF. In PAH RV-samples, α-7nAchR was increased and AchE activity was reduced versus controls. No difference in m2AchR expression was observed. Chronic PYR-treatment in PH-rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, as well as RV α-7nAchR and m2AchR expression. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation.Conclusions—RV dysfunction is associated with reduced systemic parasympathetic activity in PAH-patients, with an inadequate adaptive response of the cholinergic system in the right ventricle. Enhancing parasympathetic activity by PYR improved survival, RV function and pulmonary vascular remodeling in experimental-PH.
Pericardial Adipose Tissue Regulates Granulopoiesis, Fibrosis and Cardiac Function After Myocardial Infarction Circulation (IF 19.309) Pub Date : 2017-11-22 Michael Horckmans, Mariaelvy Bianchini, Donato Santovito, Remco T. A. Megens, Jean-Yves Springael, Irene Negri, Michele Vacca, Marco Di Eusanio, Antonio Moschetta, Christian Weber, Johan Duchene, Sabine Steffens
Background—The pericardial adipose tissue (AT) contains a high density of lymphoid clusters. Is unknown whether these clusters play a role in post-myocardial infarction (MI) inflammatory responses and cardiac outcome.Methods—Lymphoid clusters were examined in epicardial AT of humans with or without coronary artery disease (CAD). Murine pericardial lymphoid clusters were visualized in mice subjected to coronary artery ligation. To study the relevance of pericardial clusters during inflammatory responses after MI, we surgically removed the pericardial AT, performed B cell depletion and GM-CSF blockade. Leukocytes in murine hearts, pericardial AT, spleen, mediastinal lymph nodes, and bone marrow were quantified by flow cytometry. Cannabinoid receptor CB2 (CB2-/-) mice were used as a model for enhanced B cell responses. The effect of impaired dendritic cell (DC) trafficking on pericardial AT inflammatory responses was tested in CCR7-/- mice subjected to MI. Cardiac fibrosis and ventricular function were assessed by histology and echocardiography.Results—We identified larger B cell clusters in epicardial AT of human CAD patients compared to controls without CAD. Infarcted mice also had larger pericardial clusters and 3-fold upregulated numbers of GM-CSF-producing B cells within pericardial AT, but not spleen or lymph nodes. This was associated with higher DC and T cell counts in pericardial AT, which outnumbered DCs and T cells in lymph nodes. Analysis of DC maturation markers, tracking experiments with fluorescently labelled cells and use of CCR7-deficient mice suggested that activated DCs migrate from infarcts into pericardial AT via CCR7. B cell depletion or GM-CSF neutralization inhibited DC and T cell expansion within pericardial AT, and translated into reduced bone marrow granulopoiesis and cardiac neutrophil infiltration 3 days after MI. The relevance of the pericardial AT in mediating all these effects was confirmed by removal of pericardial AT and ex vivo coculture with pericardial AT and granulocyte progenitors. Finally, enhanced fibrosis and worsened ejection fraction in CB2-/- mice was limited by pericardial AT removal.Conclusions—Our findings unveil a new mechanism by which the pericardial AT coordinates immune cell activation, granulopoiesis and outcome after MI.
HDL Subspecies Defined by Presence of Apolipoprotein C-III and Incident Coronary Heart Disease in Four Cohorts Circulation (IF 19.309) Pub Date : 2017-11-21 Majken K. Jensen, Sarah A. Aroner, Kenneth J. Mukamal, Jeremy D. Furtado, Wendy S. Post, Michael Y. Tsai, Anne Tjønneland, Joseph F. Polak, Eric B. Rimm, Kim Overvad, Robyn L. McClelland, Frank M. Sacks
Background—The causal role of high density lipoprotein (HDL) cholesterol in cardioprotection has been questioned by genetic and randomized studies. Novel measures that relate to HDL function may contribute new information to prediction of cardiovascular risk. Apolipoprotein C-III (apoC-III) is a key regulator of lipoprotein metabolism. We investigated whether subspecies of HDL defined by apoC-III are associated with coronary heart disease (CHD).Methods—We used immuno-affinity chromatography to measure the apoA-I concentrations of HDL that contains and lacks apoC-III in two prospective studies of adults free of CHD. In the Multi-Ethnic Study of Atherosclerosis (MESA), 5,657 participants (52% women; age 52-72 y) were followed for risk of CHD from 2000-2002 through 2013. In a case-cohort study nested within the Danish Diet, Cancer and Health (DCH) study, 3,642 participants (47% women; age 51-64 y) were followed from 1994-1997 through 2010. Subsequently, we conducted a meta-analysis that combined these results with the previously published findings from two cohort studies that used similar laboratory methodology to measure lipoproteins, totaling 2,997 incident cases.Results—ApoC-III was found on 6-8% of apoA-I. The two HDL subspecies showed opposing associations with risk of CHD in each of the individual cohorts and in the meta-analysis (p-heterogeneity between the two subspecies <0.01). HDL that contains apoC-III was associated with higher risk of CHD (pooled relative risk [RR] per SD = 1.09, 95% confidence interval [95% CI] = 1.01 to 1.18), whereas HDL that lacks apoC-III was associated with lower risk (RR= 0.76; 95% CI = 0.70 to 0.83). The relative risk for HDL lacking apoC-III was even more negative than the relative risk for total HDL (RR= 0.80; 95% CI = 0.74 to 0.87).Conclusions—Our findings from four prospective studies support the hypothesis that apoC-III may mark a subfraction of HDL that is associated with higher risk of CHD. New measures reflecting HDL structure and function may provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations.
Angiography versus Hemodynamics to Predict the Natural History of Coronary Stenoses: A FAME 2-Substudy Circulation (IF 19.309) Pub Date : 2017-11-21 Giovanni Ciccarelli, Emanuele Barbato, Gabor G. Toth, Brigitta Gahl, Panagiotis Xaplanteris, Stephane Fournier, Anastasios Milkas, Jozef Bartunek, Marc Vanderheyden, Nico Pijls, Pim Tonino, William F. Fearon, Peter Jüni, Bernard De Bruyne
Background—Among patients with documented stable coronary artery disease (CAD) and in whom no revascularization was performed, we compared the respective values of angiographic diameter stenosis (DS) and of fractional flow reserve (FFR) in predicting natural history.Methods—The present analysis included the 607 patients from the Fractional flow reserve versus angiography in multivessel evaluation 2 (FAME 2) trial in whom no revascularization was performed. FFR varied from 0.20 to 1.00 (average 0.74 ± 0.16) and DS (by QCA) varied from 8% to 98% (average 53 ± 15). The primary end point, defined as VOCE (Vessel oriented clinical endpoint) at 2 years, was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent and not urgent revascularization. The stenoses were divided into 4 groups according to FFR and %DS values: Positive Concordance (PC: FFR≤0.80; DS≥50%); Negative Concordance (NC: FFR>0.80; DS<50%); Positive Mismatch (PM: FFR≤0.80; DS<50%); Negative Mismatch (NM: FFR>0.80; DS≥50%).Results—The rate of VOCE was highest in the PC group (Log Rank: X2=80.96; p=0.001), and lowest in the NC group. The rate of VOCE was higher in the PM group than in the NM group (H.R. 0.38, 95% C.I. 0.21 - 0.67; p=0.001). There was no significant difference in VOCE between the PC and the PM (both groups with FFR≤0.80, H.R. 0.77, 95% C.I. 0.57 - 1.09; p=0.149) and no significant difference in rate of VOCE between the NM and NC (both groups with FFR>0.80, H.R. 1.89, 95% C.I. 0.96 - 3.74; p=0.067).Conclusions—In patients with stable coronary disease, physiology (FFR) is a more important determinant of the natural history of coronary stenoses than anatomy (DS).Clinical Trial Registration—URL: https://clinicaltrials.gov Unique Identifier: NCT01132495.
Long Term Outcomes in Patients with Type 2 Myocardial Infarction and Myocardial Injury Circulation (IF 19.309) Pub Date : 2017-11-17 Andrew R. Chapman, Anoop S. V. Shah, Kuan Ken Lee, Atul Anand, Oliver Francis, Philip Adamson, David A. McAllister, Fiona Strachan, David E. Newby, Nicholas L. Mills
Background—Type 2 myocardial infarction and myocardial injury are common in clinical practice, but long-term consequences are uncertain. We aimed to define long-term outcomes and explore risk stratification in patients with type 2 myocardial infarction and myocardial injury.Methods—We identified consecutive patients (n=2,122) with elevated cardiac troponin I concentrations (≥0.05 μg/L) at a tertiary cardiac center. All diagnoses were adjudicated as per the Universal Definition of Myocardial Infarction. The primary outcome was all-cause death. Secondary outcomes included major adverse cardiovascular events (MACE; non-fatal myocardial infarction or cardiovascular death) and non-cardiovascular death. To explore competing risks, cause-specific hazard ratios were obtained using Cox regression models.Results—The adjudicated index diagnosis was type 1 or type 2 myocardial infarction or myocardial injury in 1,171 (55.2%), 429 (20.2%) and 522 (24.6%) patients, respectively. At five years, all-cause death rates were higher in those with type 2 myocardial infarction (62.5%) or myocardial injury (72.4%) compared with type 1 myocardial infarction (36.7%). The majority of excess deaths in those with type 2 myocardial infarction or myocardial injury were due to non-cardiovascular causes (HR 2.32, 95%CI 1.92-2.81, versus type 1 myocardial infarction). Despite this, the observed crude MACE rates were similar between groups (30.6% versus 32.6%), with differences apparent after adjustment for co-variates (HR 0.82, 95%CI 0.69-0.96). Coronary heart disease was an independent predictor of MACE in those with type 2 myocardial infarction or myocardial injury (HR 1.71, 95%CI 1.31-2.24).Conclusions—Despite an excess in non-cardiovascular death, patients with type 2 myocardial infarction or myocardial injury have a similar crude rate of major adverse cardiovascular events to those with type 1 myocardial infarction. Identifying underlying coronary heart disease in this vulnerable population may help target therapies that could modify future risk.
Cardiac Toxicity of Immune Checkpoint Inhibitors Circulation (IF 19.309) Pub Date : 2017-11-21 Gilda Varricchi, Maria Rosaria Galdiero, Carlo G. Tocchetti
Cardiotoxicity caused by chemotherapeutics such as anthracyclines is well recognized. In recent years, immunotherapy has been successfully introduced in cancer treatment. Unfortunately, cardiotoxicity seems to have emerged as an issue in recent reports.1 For decades, immunologists and oncologists have attempted to stimulate antitumor immune responses to fight cancer. Initial attempts displayed marginal success because several inhibitory pathways such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) dampen the antitumor functions of T lymphocytes. Tumors exploit these pathways to escape T cell–mediated tumor-specific immunity. Monoclonal antibodies targeting CTLA-4 (ipilimumab), PD-1 (nivolumab and pembrolizumab), and PD-L1 (atezolizumab, avelumab, durvalumab), called immune checkpoint inhibitors (ICIs), have revolutionized cancer treatments. However, dramatic responses are currently confined to few patients, presumably because of the complex network of immunosuppressive pathways in tumor microenvironments. Combined anti–CTLA-4 and anti–PD-1 blockade further enhances antitumor activity (Figure, A). ICIs are being tested in HIV-infected patients, characterized by overexpression of immune checkpoints and T-cell exhaustion. Mechanism of action of checkpoint inhibitors. A, Tumor cells escape immune surveillance by promoting checkpoint activation.Tumor cells express the immune checkpoint activator programmed cell death ligand 1 (PD-L1) and produce antigens (blue dots) that are captured by antigen-presenting cells (APCs). These cells present antigens to cytotoxic CD8+ T cells through the interaction of major histocompatibility complex (MHC) molecules and T-cell receptor (TCR). T-cell activation requires costimulatory signals mediated by the interaction between B7 and CD28. Inhibitory …
Prognostic Value of Coronary Artery Calcium in the PROMISE Study (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) Circulation (IF 19.309) Pub Date : 2017-11-21 Matthew J. Budoff, Thomas Mayrhofer, Maros Ferencik, Daniel Bittner, Kerry L. Lee, Michael T. Lu, Adrian Coles, James Jang, Mayil Krishnam, Pamela S. Douglas, Udo Hoffmann
Background: Coronary artery calcium (CAC) is an established predictor of future major adverse atherosclerotic cardiovascular events in asymptomatic individuals. However, limited data exist as to how CAC compares with functional testing (FT) in estimating prognosis in symptomatic patients. Methods: In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain (or dyspnea) and intermediate pretest probability for obstructive coronary artery disease were randomized to FT (exercise electrocardiography, nuclear stress, or stress echocardiography) or anatomic testing. We evaluated those who underwent CAC testing as part of the anatomic evaluation (n=4209) and compared that with results of FT (n=4602). We stratified CAC and FT results as normal or mildly, moderately, or severely abnormal (for CAC: 0, 1–99 Agatston score [AS], 100–400 AS, and >400 AS, respectively; for FT: normal, mild=late positive treadmill, moderate=early positive treadmill or single-vessel ischemia, and severe=large ischemic region abnormality). The primary end point was all-cause death, myocardial infarction, or unstable angina hospitalization over a median follow-up of 26.1 months. Cox regression models were used to calculate hazard ratios (HRs) and C statistics to determine predictive and discriminatory values. Results: Overall, the distribution of normal or mildly, moderately, or severely abnormal test results was significantly different between FT and CAC (FT: normal, n=3588 [78.0%]; mild, n=432 [9.4%]; moderate, n=217 [4.7%]; severe, n=365 [7.9%]; CAC: normal, n=1457 [34.6%]; mild, n=1340 [31.8%]; moderate, n=772 [18.3%]; severe, n=640 [15.2%]; P<0.0001). Moderate and severe abnormalities in both arms robustly predicted events (moderate: CAC: HR, 3.14; 95% confidence interval, 1.81–5.44; and FT: HR, 2.65; 95% confidence interval, 1.46–4.83; severe: CAC: HR, 3.56; 95% confidence interval, 1.99–6.36; and FT: HR, 3.88; 95% confidence interval, 2.58–5.85). In the CAC arm, the majority of events (n=112 of 133, 84%) occurred in patients with any positive CAC test (score >0), whereas fewer than half of events occurred in patients with mildly, moderately, or severely abnormal FT (n=57 of 132, 43%; P<0.001). In contrast, any abnormality on FT was significantly more specific for predicting events (78.6% for FT versus 35.2% for CAC; P<0.001). Overall discriminatory ability in predicting the primary end point of mortality, nonfatal myocardial infarction, and unstable angina hospitalization was similar and fair for both CAC and FT (C statistic, 0.67 versus 0.64). Coronary computed tomographic angiography provided significantly better prognostic information compared with FT and CAC testing (C index, 0.72). Conclusions: Among stable outpatients presenting with suspected coronary artery disease, most patients experiencing clinical events have measurable CAC at baseline, and fewer than half have any abnormalities on FT. However, an abnormal FT was more specific for cardiovascular events, leading to overall similarly modest discriminatory abilities of both tests. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01174550.
Computed Tomography or Functional Stress Testing for the Prediction of Risk Circulation (IF 19.309) Pub Date : 2017-11-21 David E. Newby
Article, see p 1993 The clinician now has an overwhelming array of investigations at his or her disposal for patients with suspected coronary heart disease. These tests are used to diagnose or risk-stratify patients and thereby enable the clinician to treat their symptoms and reduce their future risk. Ultimately, these investigations either assess risk factors (eg, lipid, glucose, and C-reactive protein concentrations) and proxies for disease (eg, carotid intima-media thickness and coronary artery calcium score) or are looking to provide circumstantial downstream evidence of disease (eg, markers of ischemia and infarction: Q waves on an ECG, fibrosis on magnetic resonance imaging or functional stress testing). In this issue of Circulation , Budoff and colleagues1 compare 2 of the most widely used approaches, coronary artery calcium scoring and functional stress testing, within the framework of the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain). Coronary artery calcification is considered pathognomonic of atherosclerosis and has been a marker of coronary artery disease for millennia.2 Its presence is, however, a proxy of disease because it is induced in response to atherosclerosis, and, apart from rare calcific nodules, calcification does not directly cause ischemic heart disease events. Indeed, calcification appears to be an adaptive healing response to the necrotic atheromatous plaque whereby the body attempts to limit and contain the disease, much like the calcification of a caseating granuloma from mycobacterium tuberculosis infection. However, calcification does not directly relate to the degree of luminal or functional stenosis of the coronary artery, nor does it necessarily reflect the current status of the plaque because the calcification may be inactive, ongoing, or incomplete. Indeed, large areas of inert macrocalcification are associated with plaque stability, whereas spotty calcifications or microcalcifications are associated with high-risk plaques, probably because of incomplete calcification.3– …
Modeling Major Adverse Outcomes of Pediatric and Adult Patients With Congenital Heart Disease Undergoing Cardiac Catheterization Circulation (IF 19.309) Pub Date : 2017-11-21 Natalie Jayaram, John A. Spertus, Kevin F. Kennedy, Robert Vincent, Gerard R. Martin, Jeptha P. Curtis, David Nykanen, Phillip M. Moore, Lisa Bergersen
Background: Risk standardization for adverse events after congenital cardiac catheterization is needed to equitably compare patient outcomes among different hospitals as a foundation for quality improvement. The goal of this project was to develop a risk-standardization methodology to adjust for patient characteristics when comparing major adverse outcomes in the NCDR’s (National Cardiovascular Data Registry) IMPACT Registry (Improving Pediatric and Adult Congenital Treatment). Methods: Between January 2011 and March 2014, 39 725 consecutive patients within IMPACT undergoing cardiac catheterization were identified. Given the heterogeneity of interventional procedures for congenital heart disease, new procedure-type risk categories were derived with empirical data and expert opinion, as were markers of hemodynamic vulnerability. A multivariable hierarchical logistic regression model to identify patient and procedural characteristics predictive of a major adverse event or death after cardiac catheterization was derived in 70% of the cohort and validated in the remaining 30%. Results: The rate of major adverse event or death was 7.1% and 7.2% in the derivation and validation cohorts, respectively. Six procedure-type risk categories and 6 independent indicators of hemodynamic vulnerability were identified. The final risk adjustment model included procedure-type risk category, number of hemodynamic vulnerability indicators, renal insufficiency, single-ventricle physiology, and coagulation disorder. The model had good discrimination, with a C-statistic of 0.76 and 0.75 in the derivation and validation cohorts, respectively. Model calibration in the validation cohort was excellent, with a slope of 0.97 (standard error, 0.04; P value [for difference from 1] =0.53) and an intercept of 0.007 (standard error, 0.12; P value [for difference from 0] =0.95). Conclusions: The creation of a validated risk-standardization model for adverse outcomes after congenital cardiac catheterization can support reporting of risk-adjusted outcomes in the IMPACT Registry as a foundation for quality improvement.
Risk Adjustment Tools in Congenital Heart Disease Circulation (IF 19.309) Pub Date : 2017-11-21 James E. Lock
Article, see p 2009 The use of risk adjustment methods to assess the safety of procedures for congenital heart disease began 15 years ago.1,2 It is a good thing. Like many cardiologists and surgeons, I do not develop the tools, and I have never learned any of the arcana of methods and statistics used to develop those tools. However, I have relied on and continue to use them as an integral part of understanding the performance of an individual, program, or field. The current article by Jayaram et al3 in Circulation improves our understanding of the risks of catheterization for congenital heart disease, extending prior work4 to the many more patients and centers in the IMPACT Registry (Improving Pediatric and Adult Congenital Treatments). This article is a welcome addition to the field. Given this work, a consumer should perhaps be thinking about 3 questions. What are the probable weaknesses of all such tools? What are the weaknesses specific to this one? How …
Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension Circulation (IF 19.309) Pub Date : 2017-11-21 Charaka Hadinnapola, Marta Bleda, Matthias Haimel, Nicholas Screaton, Andrew Swift, Peter Dorfmüller, Stephen D. Preston, Mark Southwood, Jules Hernandez-Sanchez, Jennifer Martin, Carmen Treacy, Katherine Yates, Harm Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Simon Gibbs, Barbara Girerd, Simon Holden, Marc Humbert, David G. Kiely, Allan Lawrie, Rajiv Machado, Robert MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrew Peacock, Joanna Pepke-Zaba, Paula Rayner-Matthews, Olga Shamardina, Florent Soubrier, Laura Southgate, Jay Suntharalingam, Mark Toshner, Richard Trembath, Anton Vonk Noordegraaf, Martin R. Wilkins, Stephen J. Wort, John Wharton, NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH, Stefan Gräf, Nicholas W. Morrell
Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
Pulmonary Veno-Occlusive Disease Circulation (IF 19.309) Pub Date : 2017-11-21 Dave P. Miller, Harrison W. Farber
Article, see p 2022 When caring for our patients with pulmonary arterial hypertension (PAH), how many times have we wondered, could this patient really have pulmonary veno-occlusive disease/pulmonary capillary hemangiomiatosis (PVOD/PCH)? This question typically arises if there is a suggestive computed tomography scan, a low diffusing capacity of the lungs for carbon monoxide, substantial hypoxemia, or, certainly, a poor response to PAH-specific medications or development of pulmonary edema (PVOD/PCH versus unsuspected diastolic dysfunction). In fact, we recently were referred such a patient: the computed tomography scan showed septal thickening and lymphadenopathy, the diffusing capacity of the lungs for carbon monoxide was low, hypoxia requiring 8 to 10 L of supplemental oxygen was present, and marked clinical deterioration occurred after being started on PAH therapy with ambrisentan and tadalafil. Ultimately, the patient underwent lung biopsy to prove what we were certain was PVOD/PCH. To our surprise, histologically, there was no venous involvement, and she was diagnosed with idiopathic PAH (IPAH). However, based on the study by Hadinnapola and colleagues in this issue of Circulation,1 which found significant overlap in clinical, radiological, and in 1 case even histological findings, could she still have had EIF2AK4 mutations and thus PVOD/PCH genetically? In contrast to IPAH, which involves small pulmonary arteries, vascular remodeling in PVOD/PCH affects predominantly septal veins and venules, as well as capillaries.2 PVOD and PCH, previously thought to be separate conditions, are now felt to represent variable expression of the same disease.2,3 Initial clinical presentation is …
Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction Circulation (IF 19.309) Pub Date : 2017-11-21 Jae Hyung Cho, Rui Zhang, Peter J. Kilfoil, Romain Gallet, Geoffrey de Couto, Catherine Bresee, Joshua I. Goldhaber, Eduardo Marbán, Eugenio Cingolani
Background: Heart failure with preserved ejection fraction (HFpEF) represents approximately half of heart failure, and its incidence continues to increase. The leading cause of mortality in HFpEF is sudden death, but little is known about the underlying mechanisms. Methods: Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF (n=38). Rats fed a normal-salt diet (0.3% NaCl) served as controls (n=13). Echocardiograms were performed to assess systolic and diastolic function from 14 weeks of age. HFpEF-verified and control rats underwent programmed electrical stimulation. Corrected QT interval was measured by surface ECG. The mechanisms of ventricular arrhythmias (VA) were probed by optical mapping, whole-cell patch clamp to measure action potential duration and ionic currents, and quantitative polymerase chain reaction and Western blotting to investigate changes in ion channel expression. Results: After 7 weeks of a high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure and hence were diagnosed with HFpEF. Programmed electric stimulation demonstrated increased susceptibility to VA in HFpEF rats (P<0.001 versus controls). The arrhythmogenicity index was increased (P<0.001) and the corrected QT interval on ECG was prolonged (P<0.001) in HFpEF rats. Optical mapping of HFpEF hearts demonstrated prolonged action potentials (P<0.05) and multiple reentry circuits during induced VA. Single-cell recordings of cardiomyocytes isolated from HFpEF rats confirmed a delay of repolarization (P=0.001) and revealed downregulation of transient outward potassium current (Ito; P<0.05). The rapid components of the delayed rectifier potassium current (IKr) and the inward rectifier potassium current (IK1) were also downregulated (P<0.05), but the current densities were much lower than for Ito. In accordance with the reduction of Ito, both Kcnd3 transcript and Kv4.3 protein levels were decreased in HFpEF rat hearts. Conclusions: Susceptibility to VA was markedly increased in rats with HFpEF. Underlying abnormalities include QT prolongation, delayed repolarization from downregulation of potassium currents, and multiple reentry circuits during VA. Our findings are consistent with the hypothesis that potassium current downregulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death.
SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac HypertrophyUniversity of Michigan Circulation (IF 19.309) Pub Date : 2017-11-21 Xiaoqiang Tang, Xiao-Feng Chen, Nan-Yu Wang, Xiao-Man Wang, Shu-Ting Liang, Wei Zheng, Yun-Biao Lu, Xiang Zhao, De-Long Hao, Zhu-Qin Zhang, Ming-Hui Zou, De-Pei Liu, Hou-Zao Chen
Background: Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)–induced pathological cardiac hypertrophy. Methods: Male C57BL/6J wild-type and Sirt2 knockout mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/d for 4 weeks) in male C57BL/6J Sirt2 knockout mice, cardiac-specific SIRT2 transgenic (SIRT2-Tg) mice, and their respective littermates (8 to ≈12 weeks old). Metformin (200 mg/kg/d) was used to treat wild-type and Sirt2 knockout mice infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results: SIRT2 protein expression levels were downregulated in hypertrophic hearts from mice. Sirt2 knockout markedly exaggerated cardiac hypertrophy and fibrosis and decreased cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II–infused mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts against Ang II–induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II–induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function. Conclusions: SIRT2 promotes AMPK activation by deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes aging-related and Ang II–induced cardiac hypertrophy, and blunts metformin-mediated cardioprotective effects. These findings indicate that SIRT2 will be a potential target for therapeutic interventions in aging- and stress-induced cardiac hypertrophy.
Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy Circulation (IF 19.309) Pub Date : 2017-11-21 Hugh Calkins, Domenico Corrado, Frank Marcus
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and an increased risk of sudden cardiac death. Although structural abnormalities of the right ventricle predominate, it is well recognized that left ventricular involvement is common, particularly in advanced disease, and that left-dominant forms occur. The pathological characteristic of ARVC is myocyte loss with fibrofatty replacement. Since the first detailed clinical description of the disorder in 1982, significant advances have been made in understanding this disease. Once the diagnosis of ARVC is established, the single most important clinical decision is whether a particular patient’s sudden cardiac death risk is sufficient to justify placement of an implantable cardioverter-defibrillator. The importance of this decision reflects the fact that ARVC is a common cause of sudden death in young people and that sudden death may be the first manifestation of the disease. This decision is particularly important because these are often young patients who are expected to live for many years. Although an implantable cardioverter-defibrillator can save lives in individuals with this disease, it is also well recognized that implantable cardioverter-defibrillator therapy is associated with both short- and long-term complications. Decisions about the placement of an implantable cardioverter-defibrillator are based on an estimate of a patient’s risk of sudden cardiac death, as well as their preferences and values. The primary purpose of this article is to provide a review of the literature that concerns risk stratification in patients with ARVC and to place this literature in the framework of the 3 authors’ considerable lifetime experiences in caring for patients with ARVC. The most important parameters to consider when determining arrhythmic risk include electric instability, including the frequency of premature ventricular contractions and sustained ventricular arrhythmia; proband status; extent of structural disease; cardiac syncope; male sex; the presence of multiple mutations or a mutation in TMEM43; and the patient’s willingness to restrict exercise and to eliminate participation in competitive or endurance exercise.
Gene Editing Could Help Pave the Way for Pig-to-Human Transplantations Circulation (IF 19.309) Pub Date : 2017-11-21 Tracy Hampton
Although much of the promise of CRISPR-Cas9 gene editing techniques has centered around correcting disease-causing gene mutations, the advance is also showing potential in the field of xenotransplantation, for example, for making porcine organs safe for transplantation into humans. In an important step in this direction, a team led by researchers at the biotechnology company eGenesis recently edited the pig genome to deactivate a family of retroviruses. Organs from pigs, which can grow to a convenient human size, could help alleviate the growing organ shortage if scientists continue to make strides in addressing their immunological incompatibility; however, the pig genome includes remnants of ancient viral infections called porcine endogenous retroviruses (PERVs), which can be passed on to other cells when cultured together. In contrast to human endogenous retroviruses, which are mostly defective and not replication competent, PERVs that are integrated in the pig genome can be released as particles that infect human cells. As reported with other retroviruses, PERV integration could potentially lead to …
Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor–Related Cardiotoxicity Circulation (IF 19.309) Pub Date : 2017-11-21 Marion Escudier, Jennifer Cautela, Nausicaa Malissen, Yann Ancedy, Morgane Orabona, Johan Pinto, Sandrine Monestier, Jean-Jacques Grob, Ugo Scemama, Alexis Jacquier, Nathalie Lalevee, Jeremie Barraud, Michael Peyrol, Marc Laine, Laurent Bonello, Franck Paganelli, Ariel Cohen, Fabrice Barlesi, Stephane Ederhy, Franck Thuny
Immune checkpoint inhibitors (ICIs) represent a major advance in the treatment of cancer. Although clinical trials reported a low incidence of immune-related cardiovascular adverse events,1 the number of published life-threatening cases of cardiotoxicity is increasing.2 In this descriptive observational analysis, we aimed to describe the clinical manifestations, management, and outcomes of patients who developed ICI-related cardiotoxicity. The medical records of patients with a clinical suspicion of ICI-related cardiotoxicity were reviewed from the databases of 2 cardio-oncology units between March 2015 and April 2017. The patients are managed according to similar protocols. Because no specific follow-up had previously been established for patients receiving ICIs during the study period, the oncologists referred patients receiving ICIs only on the basis of their clinical suspicion of cardiovascular events. These patients had a standardized evaluation including clinical consultation, ECG, transthoracic echocardiography, and measurement of brain natriuretic peptide and troponin I serum levels. The management of cardiotoxicity was left to the physician’s discretion. The study was approved by our institutional review board, and informed consent has been obtained from the subjects. To create a pooled analysis, we also searched PubMed for English articles reporting cases of ICI-related cardiotoxicity until April 2017. We selected …
Letter by Violi et al Regarding Article, “Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure” Circulation (IF 19.309) Pub Date : 2017-11-21 Francesco Violi, Claudio Letizia, Roberto Carnevale
Nox2 is among the most important cellular producers of reactive oxidant species, which play a major role for bacteria defense by innate immune cells.1 However, Nox2 is also expressed by artery vessels, where it possesses a vasoconstrictive property.1 Thus, compared with controls, in patients with chronic granulomatous disease, a rare illness characterized prevalently by X-linked Nox2 hereditary deficiency and life-threatening infections,1 an enhanced artery dilatation was detected.2,3 This …
Response by Sag et al to Letter Regarding Article, “Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure” Circulation (IF 19.309) Pub Date : 2017-11-21 Can Martin Sag, Moritz Schnelle, Ajay M. Shah
We thank Violi and colleagues for their interest in our study.1 As noted, a growing body of evidence suggests an important involvement of Nox2 in hypertension related to a pathologically activated renin angiotensin system. This includes highly specific gene-modification studies in mouse models1,2 as well as correlative studies in humans, such as those discussed by the authors. Taken together, these results …
Letter by Li et al Regarding Article, “Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling” Circulation (IF 19.309) Pub Date : 2017-11-21 Yangxin Li, Bin Liu, Chun Liang
We read with great interest the article by Li et al,1 who demonstrated that the upregulation of ATF3, a cardiac fibroblast–enriched transcription factor, is cardioprotective against hypertensive fibrosis via suppression of Map2K3 expression and p38 MAPK signaling. Specifically, they showed that ATF3 is upregulated in cardiac fibroblasts but not in cardiomyocytes from hypertensive animals and patients with heart failure. ATF3 knockout exaggerated whereas ATF3 overexpression ameliorated ventricular remodeling in hypertensive mice. Their data strongly suggest that upregulation of ATF3 in cardiac fibroblasts is a self-compensatory protective mechanism against ventricular remodeling associated with heart failure. It is important …
Response by Du et al to Letter Regarding Article, “Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling” Circulation (IF 19.309) Pub Date : 2017-11-21 Jie Du, Xin-liang Ma, Yulin Li, Boya Chen
We thank Dr Li and colleagues for their interest in and comments on our article,1 in which we demonstrated a cell type–specific, ATF3-mediated transcriptional mechanism against hypertensive remodeling. They agreed with us that ATF3’s cardioprotective effects are cardiac fibroblast–dependent through antagonizing mitogen activated protein kinase kinase (MAP2K3)/p38-transforming growth factor-β (TGF-β) signaling. However, they raised 2 questions. First what is the importance of the cell-specific role of ATF3 in cardiac fibrosis? Second, does the ATF3-dependent mechanism have a general impact on cardiac fibrosis associated with different diseases (such as myocardium …
Cardiovascular Health in African Americans: A Scientific Statement From the American Heart Association Circulation (IF 19.309) Pub Date : 2017-11-21 Mercedes R. Carnethon, Jia Pu, George Howard, Michelle A. Albert, Cheryl A.M. Anderson, Alain G. Bertoni, Mahasin S. Mujahid, Latha Palaniappan, Herman A. Taylor, Monte Willis, Clyde W. Yancy
Background and Purpose: Population-wide reductions in cardiovascular disease incidence and mortality have not been shared equally by African Americans. The burden of cardiovascular disease in the African American community remains high and is a primary cause of disparities in life expectancy between African Americans and whites. The objectives of the present scientific statement are to describe cardiovascular health in African Americans and to highlight unique considerations for disease prevention and management. Method: The primary sources of information were identified with PubMed/Medline and online sources from the Centers for Disease Control and Prevention. Results: The higher prevalence of traditional cardiovascular risk factors (eg, hypertension, diabetes mellitus, obesity, and atherosclerotic cardiovascular risk) underlies the relatively earlier age of onset of cardiovascular diseases among African Americans. Hypertension in particular is highly prevalent among African Americans and contributes directly to the notable disparities in stroke, heart failure, and peripheral artery disease among African Americans. Despite the availability of effective pharmacotherapies and indications for some tailored pharmacotherapies for African Americans (eg, heart failure medications), disease management is less effective among African Americans, yielding higher mortality. Explanations for these persistent disparities in cardiovascular disease are multifactorial and span from the individual level to the social environment. Conclusions: The strategies needed to promote equity in the cardiovascular health of African Americans require input from a broad set of stakeholders, including clinicians and researchers from across multiple disciplines.
PCSK9 Variants, LDL-Cholesterol, and Neurocognitive Impairment: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study Circulation (IF 19.309) Pub Date : 2017-11-16 Matthew T. Mefford, Robert S. Rosenson, Mary Cushman, Michael E. Farkouh, Leslie A. McClure, Virginia G. Wadley, Marguerite R. Irvin, Vera A. Bittner, Monika M. Safford, Ransi Somaratne, Keri L. Monda, Paul Muntner, Emily B. Levitan
Background—Despite concerns about adverse neurocognitive events raised by prior trials, pharmacologic PCSK9 inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in life-long exposure to low LDL-C can provide information on the potential long-term effects of low LDL-C on neurocognitive impairment and decline.Methods—We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among African-American REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants with (n=241) and without (n=10,454) C697X or Y142X LOF variants. Neurocognitive tests included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery (Word List Learning, Delayed Recall, Animal Fluency) and Six Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score ≥ 1.5 standard deviations (SD) below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments, or, separately, a score <5 on any SIS assessment at baseline or during follow-up. Neurocognitive decline was assessed using standardized continuous scores on individual neurocognitive tests.Results—The mean sample age was 64 years (SD 9), 62% were women, and the prevalence of neurocognitive impairment at any assessment was 6.3% by CERAD and 15.4% by SIS definitions. Adjusted odds ratios (ORs) for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% CI 0.58, 2.13) using the CERAD battery and 0.89 (95% CI 0.61, 1.30) using the SIS assessment. Standardized average differences in individual neurocognitive assessment scores over the 5.6 year (range 0.1, 9.1) study period ranged between 0.07 (95% CI -0.06, 0.20) and -0.07 (95% CI -0.18, 0.05) among participants with versus without PCSK9 LOF variants. Patterns of neurocognitive decline were similar between participants with and without PCSK9 LOF variants (all p > 0.10). ORs for neurocognitive impairment per 20 mg/dL LDL-C decrements were 1.02 (95% CI 0.96, 1.08) and 0.99 (95% CI 0.95, 1.02) for the CERAD and SIS definitions of impairment, respectively.Conclusions—These results suggest life-long exposure to low PCSK9 levels and cumulative exposure to lower LDL-C are not associated with neurocognitive effects in African Americans.
Magnitude of Soluble ST2 as a Novel Biomarker for Acute Aortic Dissection Circulation (IF 19.309) Pub Date : 2017-11-16 Yuan Wang, Xin Tan, Hai Gao, Hui Yuan, Rong Hu, Lixin Jia, Junming Zhu, Lizhong Sun, Hongjia Zhang, Lianjun Huang, Dong Zhao, Pei Gao, Jie Du
Background—Misdiagnosis of acute aortic dissection (AAD) can lead to significant morbidity and death. Soluble ST2 (sST2) is a cardiovascular injury-related biomarker. The extent to which sST2 is elevated in AAD and whether sST2 can discriminate AAD from other causes of sudden-onset severe chest pain is unknown.Methods—We measured plasma concentrations of sST2 (R&D systems assay) in 1360 patients, including 1027 participants in the retrospective discovery set and 333 patients with initial suspicion of AAD enrolled in the prospective validation cohort. Measures of discrimination for differentiating AAD from other causes of chest pain were calculated.Results—In the acute phase, sST2 levels were higher in patients with AAD than those with either acute myocardial infarction (AMI) in the first case-control discovery set within 24h symptom onset or pulmonary embolism (PE) patients in the second discovery set (medians of 129.2 ng/mL vs. 14.7 with p<0.001 for AAD vs. AMI and 88.6 vs. 9.3 with p<0.001 for AAD vs. PE). In the prospective validation set, sST2 was most elevated in AAD patients (median [25, 75 percentile]: 76.4 [49.6, 130.3]) and modestly elevated in AMI (25.0 [15.5, 37.2]), PE (14.9 [10.2, 30.1]) and angina patients (21.5 [13.1, 27.6], all p<0.001 vs. AAD). The area under ROC curve for AAD patients versus all control patients within 24h presenting in emergency department were 0.97 (0.95, 0.98) for sST2, 0.91 (0.88, 0.94) for D-dimer, 0.50 (0.44, 0.56) for cTnI respectively. At a cutoff level of 34.6 ng/mL, sST2 had the sensitivity of 99.1%, specificity of 84.9%, positive predictive value of 68.7%, negative predictive value of 99.7%, positive likelihood ratio of 6.6 and negative likelihood ratio of 0.01.Conclusions—Among patients with suspected aortic dissection in the emergency department, sST2 showed superior overall diagnostic performance than D-dimer or cTnI. Additional study is needed to determine if sST2 might be a useful "rule-out" marker for AAD in the emergency room.
A Transcatheter InterAtrial Shunt Device for the Treatment of Heart Failure with Preserved Ejection Fraction (REDUCE LAP-HF I): A Phase 2, Randomized, Sham-Controlled Trial Circulation (IF 19.309) Pub Date : 2017-11-15 Ted Feldman, Laura Mauri, Rami Kahwash, Sheldon Litwin, Mark J. Ricciardi, Pim van der Harst, Martin Penicka, Peter S. Fail, David M. Kaye, Mark C. Petrie, Anupam Basuray, Scott L. Hummel, Rhondalyn Forde-McLean, Christopher D. Nielsen, Scott Lilly, Joseph M. Massaro, Daniel Burkhoff, Sanjiv J. Shah
Background—In non-randomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), less symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and mid-range or preserved ejection fraction (EF ≥ 40%). We conducted the first randomized, sham-controlled trial to evaluate the IASD in HF with EF ≥ 40%.Methods—REDUCE LAP-HF I was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association (NYHA) class III or ambulatory class IV HF, EF ≥ 40%, exercise PCWP ≥ 25 mmHg, and PCWP-right atrial pressure gradient ≥ 5 mmHg. Participants were randomized (1:1) to the IASD vs. a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness endpoint was exercise PCWP at 1 month. The primary safety endpoint was major adverse cardiac, cerebrovascular, and renal events (MACCRE) at 1 month. PCWP during exercise was compared between treatment groups using a mixed effects repeated measures model analysis of covariance that included data from all available stages of exercise.Results—A total of 94 patients were enrolled, of which n=44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared to sham-control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mmHg in the treatment group vs. 0.5±5.0 mmHg in the control group (P=0.14). There were no peri-procedural or 1-month MACCRE in the IASD group and 1 event (worsening renal function) in the control group (P=1.0).Conclusions—In patients with HF and EF ≥ 40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation.Clinical Trial Registration—URL: http://clinicaltrials.gov. Unique identifier: NCT02600234
Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools: The CENTRAL MRI Randomized Controlled Trial Circulation (IF 19.309) Pub Date : 2017-11-15 Yftach Gepner, Ilan Shelef, Dan Schwarzfuchs, Hila Zelicha, Lilac Tene, Anat Yaskolka Meir, Gal Tsaban, Noa Cohen, Nitzan Bril, Michal Rein, Dana Serfaty, Shira Kenigsbuch, Oded Komy, Arik Wolak, Yoash Chassidim, Rachel Golan, Hilla Avni-Hassid, Avital Bilitzky, Benjamin Sarusi, Eyal Goshen, Elad Shemesh, Yaakov Henkin, Michael Stumvoll, Matthias Blüher, Joachim Thiery, Uta Ceglarek, Assaf Rudich, Meir J. Stampfer, Iris Shai
Background—We aimed to assess whether distinct lifestyle strategies can differentially affect specific body adipose depots.Methods—We performed an eighteen-month randomized controlled trial among 278 sedentary adults with abdominal obesity (75%) or dyslipidemia in an isolated workplace with a monitored provided lunch. Participants were randomized to iso-caloric low-fat (LF) or Mediterranean/low-carbohydrate (MED/LC) diet+28g walnuts/day with/without added moderate physical activity (PA;80% aerobic; supervised/free gym membership). Overall primary outcome was body fat re-distribution, and the main specific endpoint was visceral adipose tissue (VAT). We further followed the dynamics of different fat depots [deep/superficial subcutaneous (D/SSAT), liver, pericardial, muscle, pancreas and renal-sinus] by magnetic-resonance-imaging.Results—Of 278 participants (age=48y; 89%men, body-mass-index=30.8kg/m2), 86% completed the trial, with good adherence. The LF group preferentially decreased reported fat intake (-21.0% vs. -11.5% for the MED/LC; P<0.001), and the MED/LC group decreased reported carbohydrates intake (-39.5%vs. -21.3% for the LF;P<0.001). The PA+ groups significantly increased the metabolic-equivalents (METs)/week vs. the PA- groups (19.0 vs. 2.1;P=0.009). Whereas final moderate weight loss was indifferent, exercise attenuated the waist circumference rebound with the greatest effect in MED/LCPA+ group (P<0.05). VAT (-22%), intra-hepatic (-29%), and Intra-pericardial (-11%) fats declines were higher than pancreatic and femur intermuscular fats (1-2%) loss. Independent of weight loss, PA+ with either diet had a significantly greater effect on decreasing VAT [mean-of-difference=-6.67cm2;95%CI:(-14.8 to -0.45) compared with PA-]. The MED/LC diet was superior to LF in decreasing intra-hepatic, intra-pericardial and pancreatic fats (P<0.05 for all). In contrast, renal-sinus and femoral-intermuscular fats were not differentially altered by lifestyle interventions, but by weight loss per-se. In multivariate models, further adjusted for weight loss, losing VAT or intra-hepatic fat were independently associated with improved lipid profile, losing deep-SAT with improved insulin sensitivity and losing superficial-SAT remained neutral except of association with decreased leptin.Conclusions—Moderate weight loss alone inadequately reflects the significant lifestyle effects on atherogenic and diabetogenic fat depots. The MED/LC diet mobilizes specific ectopic fat depots, and exercise has an independent contribution to VAT loss. Fat depots exhibit diverse responsiveness and are differentially related to cardiometabolic markers. Distinct lifestyle protocols may uniquely induce fat mobilization from specific anatomical sites.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01530724.
Value of Progression of Coronary Artery Calcification for Risk Prediction of Coronary and Cardiovascular Events: Result of the Heinz Nixdorf Recall (HNR) Study Circulation (IF 19.309) Pub Date : 2017-11-15 Nils Lehmann, Raimund A. Erbel, Amir A. Mahabadi, Michael Rauwolf, Stefan Möhlenkamp, Susanne Moebus, Hagen Kälsch, Thomas Budde, Axel Schmermund, Andreas Stang, Dagmar Führer-Sakel, Christian Weimar, Ulla Roggenbuck, Nico Dragano, Karl-Heinz Jöckel
Background—Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular (CV) events.Methods—In 3281 participants (45-74 years), free from CV disease until the 2nd visit, risk factors and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events as well as total CV events including revascularization were recorded during a follow-up time of 7.8±2.2 years after the 2nd CT. The added predictive value of ten CAC progression algorithms on top of risk factors including baseline CAC was evaluated using survival analysis, C-statistics, net reclassification improvement (NRI), and integrated discrimination index (IDI). A subgroup analysis of risk in CAC categories was performed.Results—We observed 85 (2.6%) hard coronary, 161 (4.9%) hard CV and 241 (7.3%) total CV events. Absolute CAC progression was higher with vs. without subsequent coronary events [median 115 (Q1-Q3 23-360) vs. 8 (0-83), p<0.0001; similar for hard/total CV events]. Some progression algorithms added to predictive value of baseline CT and risk assessment in terms of C-statistic or IDI, especially for total CV events. However, CAC progression did not improve models including CAC5y and 5-year risk factors. An excellent prognosis was found for 921 participants with double zero CACb=CAC5y=0 [10-year coronary and hard/total CV risk: 1.4%, 2.0% and 2.8%], which was for participants with incident CAC 1.8%, 3.8% and 6.6%, respectively. When CACb progressed from 1-399 to CAC5y≥400, coronary and total CV risk were nearly twofold compared to subjects, who remained below CAC5y=400. Participants with CACb≥400 had high rates of hard coronary and hard/total CV events [10-year risk: 12.0%, 13.5% and 30.9%, respectively].Conclusions—CAC progression is associated with coronary and CV event rates, but adds only weakly to risk prediction. What counts is the most recent CAC value and risk factor assessment. Therefore, a repeat scan more than five years apart may be of additional value, except when a double zero CT scan is present or when the subjects are already at high risk.
ICare-ACS (Improving Care Processes for Patients With Suspected Acute Coronary Syndrome): A Study of Cross-System Implementation of a National Clinical Pathway Circulation (IF 19.309) Pub Date : 2017-11-14 Martin P. Than, John W. Pickering, Jeremy M. Dryden, Sally J. Lord, S. Andrew Aitken, Sally J. Aldous, Kate E. Allan, Michael W. Ardagh, John W.N. Bonning, Rosie Callender, Laura R.E. Chapman, Jonathan P. Christiansen, Andre P.J. Cromhout, Louise Cullen, Joanne M. Deely, Gerard P. Devlin, Katherine A. Ferrier, Christopher M. Florkowski, Christopher M.A. Frampton, Peter M. George, Gregory J. Hamilton, Allan S. Jaffe, Andrew J. Kerr, G. Luke Larkin, Richard M. Makower, Timothy J.E. Matthews, William A. Parsonage, W. Frank Peacock, Bradley F. Peckler, Nicholaas C. van Pelt, Louise Poynton, A. Mark Richards, Anthony G. Scott, Mark B. Simmonds, David Smyth, Oliver P. Thomas, Andrew C.Y. To, Stephen A. Du Toit, Richard W. Troughton, Kim M. Yates
BACKGROUND: Efforts to safely reduce length of stay for emergency department patients with symptoms suggestive of acute coronary syndrome (ACS) have had mixed success. Few system-wide efforts affecting multiple hospital emergency departments have ever been evaluated. We evaluated the effectiveness of a nationwide implementation of clinical pathways for potential ACS in disparate hospitals.METHODS: This was a multicenter pragmatic stepped-wedge before-and-after trial in 7 New Zealand acute care hospitals with 31 332 patients investigated for suspected ACS with serial troponin measurements. The implementation was a clinical pathway for the assessment of patients with suspected ACS that included a clinical pathway document in paper or electronic format, structured risk stratification, specified time points for electrocardiographic and serial troponin testing within 3 hours of arrival, and directions for combining risk stratification and electrocardiographic and troponin testing in an accelerated diagnostic protocol. Implementation was monitored for >4 months and compared with usual care over the preceding 6 months. The main outcome measure was the odds of discharge within 6 hours of presentation.RESULTS: There were 11 529 participants in the preimplementation phase (range, 284-3465) and 19 803 in the postimplementation phase (range, 395-5039). Overall, the mean 6-hour discharge rate increased from 8.3% (range, 2.7%-37.7%) to 18.4% (6.8%-43.8%). The odds of being discharged within 6 hours increased after clinical pathway implementation. The odds ratio was 2.4 (95% confidence interval, 2.3-2.6). In patients without ACS, the median length of hospital stays decreased by 2.9 hours (95% confidence interval, 2.4-3.4). For patients discharged within 6 hours, there was no change in 30-day major adverse cardiac event rates (0.52% versus 0.44%; P=0.96). In these patients, no adverse event occurred when clinical pathways were correctly followed.CONCLUSIONS: Implementation of clinical pathways for suspected ACS reduced the length of stay and increased the proportions of patients safely discharged within 6 hours.CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au/ (Australian and New Zealand Clinical Trials Registry). Unique identifier: ACTRN12617000381381.
Impact of Regionalization of ST Elevation Myocardial Infarction Care on Treatment Times and Outcomes for Emergency Medical Services Transported Patients Presenting to Hospitals with Percutaneous Coronary Intervention: Mission: Lifeline Accelerator-2 Circulation (IF 19.309) Pub Date : 2017-11-14 James G. Jollis, Hussein R. Al-Khalidi, Mayme L. Roettig, Peter B. Berger, Claire C. Corbett, Shannon Doerfler, Christopher B. Fordyce, Timothy D. Henry, Lori Hollowell, Zainab Magdon-Ismail, Ajar Kochar, James J. McCarthy, Lisa Monk, Peter K. O'Brien, Thomas D. Rea, Jay Shavadia, Jacqueline Tamis-Holland, B. Hadley Wilson, Khaled M. Ziada, Christopher B. Granger
Background: Regional variations in reperfusion times and mortality in patients with ST-segment elevation myocardial infarction (STEMI) are influenced by differences in coordinating care between emergency medical services (EMS) and hospitals. Building on the Accelerator-1 Project, we hypothesized that time to reperfusion could be further reduced with enhanced regional efforts.Methods: Between April 2015 and March 2017, we worked with 12 metropolitan regions across the United States with 132 PCI-capable hospitals and 946 EMS agencies. Data were collected in the ACTION-Get With The Guidelines Registry for quarterly Mission: Lifeline reports. The primary endpoint was the change in the proportion of EMS transported patients with first medical contact to device (FMC2D) time ≤90 minutes from baseline to final quarter. We also compared treatment times and mortality to patients treated in hospitals not participating in the project during the corresponding time period.Results: During the study period, 10,730 patients were transported to PCI-capable hospitals, including 974 in the baseline quarter and 972 in the final quarter who met inclusion criteria. Median age was 61 years; 27% were female, 6% had cardiac arrest and 6% had shock on admission; 10% were black, 12% Latino, and 10% were uninsured. By the end of the intervention, all process measures reflecting coordination between EMS and hospitals had improved, including the proportion of patients with a FMC2D time of ≤90 minutes (67% to 74%; P<0.002), a FMC to catheterization laboratory activation of <20 minutes (38% to 56%; P<0.0001), and emergency department dwell time of <20 minutes (33% to 43%; P<0.0001). Of the 12 regions, 9 reduced FMC2D time, and 8 met or exceeded the national goal of 75% of patients treated <90 minutes. Improvements in treatment times corresponded with a significant reduction in mortality (in-hospital death 4.4% to 2.3%; P=0.001) that was not apparent in hospitals not participating in the project during the same time-period.Conclusions: Organization of care among EMS and hospitals in 12 regions was associated with significant reductions in time to reperfusion in patients with STEMI, and in-hospital mortality. These findings support a more intensive regional approach to emergency care for patients with STEMI.
Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study) Circulation (IF 19.309) Pub Date : 2017-11-13 Kenneth W. Mahaffey, Bruce Neal, Vlado Perkovic, Dick de Zeeuw, Greg Fulcher, Ngozi Erondu, Wayne Shaw, Elisa Fabbrini, Tao Sun, Qiang Li, Mehul Desai, David R. Matthews
BACKGROUND: Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation.METHODS: The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo. The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death).RESULTS: Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%). The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P<0.001). In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.97; P<0.001 for noninferiority, P=0.02 for superiority) with no statistical evidence of heterogeneity (interaction P value=0.18) between the primary (HR, 0.98; 95% CI, 0.74-1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72-0.95) cohorts. Renal outcomes (HR, 0.59; 95% CI, 0.44-0.79 versus HR, 0.63; 95% CI, 0.39-1.02; interaction P value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51-0.90 versus HR, 0.64; 95% CI, 0.35-1.15; interaction P value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively. Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43-3.00 versus HR, 1.52; 95% CI, 0.70-3.29; interaction P value=0.63).CONCLUSIONS: Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients. Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups. Additional studies will provide further insights into the effects of canagliflozin in these patient populations.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.
Canagliflozin: Cui Bono? Circulation (IF 19.309) Pub Date : 2017-11-13 Matthew A. Cavender, Mikhail Kosiborod
Cardiovascular disease accounts for the majority of excess deaths seen in patients with Type 2 diabetes (T2D).1 Thus, in order to improve outcomes in this population, clinicians should focus on therapies that decrease the risk of subsequent cardiovascular events. Over the last two years, randomized controlled clinical trials have identified several agents that decrease cardiovascular events in patients with T2D with or at high risk for cardiovascular disease (CVD) - effects likely unrelated to glucose-lowering, the indication for which they were originally developed.2-5 One of these therapies (empagliflozin), a sodium glucose co-transporter-2 inhibitor (SGLT-2i), was found to reduce the risks of major adverse cardiovascular events (MACE), CV death, hospitalization for heart failure, and progression of nephropathy in patients with CVD.2 However, it is unknown whether SGLT-2i can also reduce cardiovascular events in the lower risk population of patients with T2D but without established CVD.
Cardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: A Subanalysis of EMPA-REG OUTCOME Circulation (IF 19.309) Pub Date : 2017-11-13 Subodh Verma, C. David Mazer, Mohammed Al-Omran, Silvio E. Inzucchi, David Fitchett, Uwe Hehnke, Jyothis T. George, Bernard Zinman
Peripheral artery disease (PAD) is one of the most common cardiovascular complications in patients with type 2 diabetes mellitus (T2DM)1 and is a predictor of cardiovascular death.2 Interventions that reduce cardiovascular complications in this patient population are urgently required. In the EMPA-REG OUTCOME trial, the sodium glucose cotransporter 2 inhibitor empagliflozin reduced the risk of cardiovascular death by 38% (hazard ratio [HR], 0.62; 95% confidence interval [CI] 0.49-0.77]) and hospitalization for heart failure (HHF) by 35% (HR, 0.65; 95% CI, 0.50-0.85) versus placebo when given in addition to standard of care.3 We report analyses of the effects of empagliflozin on cardiovascular outcomes, mortality, and renal outcomes in patients with and without PAD at baseline in the EMPA-REG OUTCOME trial.
Availability and Use of Shared Data From Cardiometabolic Clinical Trials Circulation (IF 19.309) Pub Date : 2017-11-13 Muthiah Vaduganathan, Amulya Nagarur, Arman Qamar, Ravi B. Patel, Ann Marie Navar, Eric D. Peterson, Deepak L. Bhatt, Gregg C. Fonarow, Clyde W. Yancy, Javed Butler
BACKGROUND: Sharing of patient-level clinical trial data has been widely endorsed. Little is known about how extensively these data have been used for cardiometabolic diseases. We sought to evaluate the availability and use of shared data from cardiometabolic clinical trials.METHODS: We extracted data from ClinicalStudyDataRequest.com, a large, multisponsor data-sharing platform hosting individual patient-level data from completed studies sponsored by 13 pharmaceutical companies.RESULTS: From January 2013 to May 2017, the platform had data from 3374 clinical trials, of which 537 (16%) evaluated cardiometabolic therapeutics (phase 1, 36%; phase 2, 17%; phase 2/3, 1%; phase 3, 42%; phase 4, 4%). They covered 74 therapies and 398 925 patients. Diabetes mellitus (60%) and hypertension (15%) were the most common study topics. Median time from study completion to data availability was 79 months. As of May 2017, ClinicalStudyDataRequest.com had received 318 submitted proposals, of which 163 had signed data-sharing agreements. Thirty of these proposals were related to cardiometabolic therapies and requested data from 79 unique studies (15% of all trials, 29% of phase 3/4 trials). Most (96%) data requesters of cardiometabolic clinical trial data were from academic centers in North America and Western Europe, and half the proposals were unfunded. Most proposals were for secondary hypothesis-generating questions, with only 1 proposed reanalysis of the original study primary hypothesis. To date, 3 peer-reviewed articles have been published after a median of 19 months (9-32 months) from the data-sharing agreement.CONCLUSIONS: Despite availability of data from >500 cardiometabolic trials in a multisponsor data-sharing platform, only 15% of these trials and 29% of phase 3/4 trials have been accessed by investigators thus far, and a negligible minority of analyses have reached publication.
Burden of Catastrophic Health Expenditures for Acute Myocardial Infarction and Stroke Among Uninsured in the United States Circulation (IF 19.309) Pub Date : 2017-11-13 Rohan Khera, Jonathan C. Hong, Anshul Saxena, Alejandro Arrieta, Salim S. Virani, Ron Blankstein, James A. de Lemos, Harlan M. Krumholz, Khurram Nasir
Acute myocardial infarction (AMI) and stroke are unanticipated major healthcare events that require emergent and expensive care. Given the potential financial implications of AMI and stroke among uninsured patients, we sought to evaluate rates of catastrophic healthcare expenditures (CHEs), defined as expenses beyond financial means, in a period before the implementation of insurance expansion and protections in the Affordable Care Act.1
Potential U.S. Population Impact of the 2017 American College of Cardiology/American Heart Association High Blood Pressure Guideline Circulation (IF 19.309) Pub Date : 2017-11-13 Paul Muntner, Robert M. Carey, Samuel Gidding, Daniel W. Jones, Sandra J. Taler, Jackson T. Wright, Paul K. Whelton
Background—The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults provides recommendations for the definition of hypertension, systolic and diastolic blood pressure (BP) thresholds for initiation of antihypertensive medication and BP target goals. The objective of this study was to determine the prevalence of hypertension, implications of recommendations for antihypertensive medication and prevalence of BP above the treatment goal among US adults using criteria from the 2017 ACC/AHA and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC7) guidelines.Methods—We analyzed data from the 2011-2014 National Health and Nutrition Examination Survey (N=9,623). NHANES (National Health and Nutrition Examination Survey) participants completed study interviews and an examination. For each participant, blood pressure was measured three times following a standardized protocol and averaged. Results were weighted to produce US population estimates.Results—According to the 2017 ACC/AHA and JNC7 guidelines, the overall crude prevalence of hypertension among US adults was 45.6% (95% confidence interval [CI] 43.6%,47.6%) and 31.9% (95%CI 30.1%, 33.7%), respectively, and antihypertensive medication was recommended for 36.2% (95%CI 34.2%, 38.2%) and 34.3% (32.5%, 36.2%) of US adults, respectively. Compared to US adults recommended antihypertensive medication by JNC7, those recommended treatment by the 2017 ACC/AHA guideline but not JNC7 had higher cardiovascular disease (CVD) risk. Non-pharmacological intervention is advised for the 9.4% of US adults with hypertension according to the 2017 ACC/AHA guideline who are not recommended antihypertensive medication. Among US adults taking antihypertensive medication, 53.4% (95%CI 49.9%, 56.8%) and 39.0% (95%CI 36.4%, 41.6%) had BP above the treatment goal according to the 2017 ACC/AHA and JNC7 guidelines, respectively. Overall, 103.3 (95%CI 92.7, 114.0) million US adults had hypertension according to the 2017 ACC/AHA guideline of whom 81.9 (95%CI 73.8, 90.1) million were recommended antihypertensive medication.Conclusions—Compared with the JNC 7 guideline, the 2017 ACC/AHA guideline results in a substantial increase in the prevalence of hypertension but a small increase in the percentage of U.S. adults recommended antihypertensive medication. A substantial proportion of US adults taking antihypertensive medication is recommended more intensive BP lowering under the 2017 ACC/AHA guideline.
Effects of Bariatric Surgery in Obese Patients With Hypertension: The GATEWAY Randomized Trial (Gastric Bypass to Treat Obese Patients With Steady Hypertension) Circulation (IF 19.309) Pub Date : 2017-11-13 Carlos Aurelio Schiavon, Angela Cristine Bersch-Ferreira, Eliana Vieira Santucci, Juliana Dantas Oliveira, Camila Ragne Torreglosa, Priscila Torres Bueno, Julia Caldas Frayha, Renato Nakagawa Santos, Lucas Petri Damian, Patricia Malvina Noujaim, Helio Halpern, Frederico L.J. Monteiro, Ricardo Vitor Cohen, Carlos H. Uchoa, Marcio Gonçalves de Souza, Celso Amodeo, Luiz Bortolotto, Dimas Ikeoka, Luciano F. Drager, Alexandre Biasi Cavalcanti, Otavio Berwanger
BACKGROUND: Recent research efforts on bariatric surgery have focused on metabolic and diabetes mellitus resolution. Randomized trials designed to assess the impact of bariatric surgery in patients with obesity and hypertension are needed.METHODS: In this randomized, single-center, nonblinded trial, we included patients with hypertension (using ≥2 medications at maximum doses or >2 at moderate doses) and a body mass index between 30.0 and 39.9 kg/m2. Patients were randomized to Roux-en-Y gastric bypass plus medical therapy or medical therapy alone. The primary end point was reduction of ≥30% of the total number of antihypertensive medications while maintaining systolic and diastolic blood pressure <140 mm Hg and 90 mm Hg, respectively, at 12 months.RESULTS: We included 100 patients (70% female, mean age 43.8±9.2 years, mean body mass index 36.9±2.7 kg/m2), and 96% completed follow-up. Reduction of ≥30% of the total number of antihypertensive medications while maintaining controlled blood pressure occurred in 41 of 49 patients from the gastric bypass group (83.7%) compared with 6 of 47 patients (12.8%) from the control group with a rate ratio of 6.6 (95% confidence interval, 3.1-14.0; P<0.001). Remission of hypertension was present in 25 of 49 (51%) and 22 of 48 (45.8%) patients randomized to gastric bypass, considering office and 24-hour ambulatory blood pressure monitoring, respectively, whereas no patient submitted to medical therapy was free of antihypertensive drugs at 12 months. A post hoc analysis for the primary end point considering the SPRINT (Systolic Blood Pressure Intervention Trial) target reached consistent results, with a rate ratio of 3.8 (95% confidence interval, 1.4-10.6; P=0.005). Eleven patients (22.4%) from the gastric bypass group and none in the control group were able to achieve SPRINT levels without antihypertensives. Waist circumference, body mass index, fasting plasma glucose, glycohemoglobin, low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and 10-year Framingham risk score were lower in the gastric bypass than in the control group.CONCLUSIONS: Bariatric surgery represents an effective strategy for blood pressure control in a broad population of patients with obesity and hypertension.CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT01784848.
Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) Circulation (IF 19.309) Pub Date : 2017-11-13 Marc P. Bonaca, Patrice Nault, Robert P. Giugliano, Anthony C. Keech, Armando Lira Pineda, Estella Kanevsky, Julia Kuder, Sabina A. Murphy, J. Wouter Jukema, Basil S. Lewis, Lale Tokgozoglu, Ransi Somaratne, Peter S. Sever, Terje R. Pedersen, Marc S. Sabatine
BACKGROUND: The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events.METHODS: FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85 or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia.RESULTS: Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.0098 and without PAD (HR 0.86; 95% CI, 0.80-0.93; P=0.0003; Pinteraction=0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91; P=0.0040) for those with PAD and 0.81 (0.73-0.90; P<0.0001) for those without PAD (Pinteraction=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38-0.88; P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL.CONCLUSIONS: Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.
Inflammation and Atherosclerosis Circulation (IF 19.309) Pub Date : 2017-11-14 Göran K. Hansson
Does inflammation matter in coronary artery disease? Is it a driving force in atherosclerosis or merely an epiphenomenon? Is there space for novel therapies besides those targeting cholesterol? The CANTOS trial (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), which was presented at the European Society of Cardiology meeting in Barcelona a few weeks ago, provides answers to these important questions. Indeed, the results of this trial open up a new avenue for cardiovascular prevention. Atherosclerosis, the underlying pathology in most cases of myocardial infarction, ischemic stroke, and ischemic gangrene, is a disease of complex genesis that has remained controversial for decades. Clinical and experimental studies have provided unequivocal evidence for an etiologic role of cholesterol and also offered strong support for a pathogenic role of inflammation.1 By targeting cholesterol, blood pressure, and cigarette smoking, cardiovascular prevention has become one of the great success stories in medicine. We have witnessed a reduction in the incidence of myocardial infarction by ≈40% in large parts of the world during the past 2 decades, and a substantial part of this decrease can be ascribed to preventive medicine.1 Cholesterol-lowering statin therapy reduces the incidence of major adverse cardiovascular events by 25% to 50% in individuals with elevated low-density lipoprotein cholesterol and has become standard therapy for …
Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevations of Low-Density Lipoprotein Cholesterol Levels of 190 mg/dL or Above Circulation (IF 19.309) Pub Date : 2017-11-14 Antonio J. Vallejo-Vaz, Michele Robertson, Alberico L. Catapano, Gerald F. Watts, John J. Kastelein, Chris J. Packard, Ian Ford, Kausik K. Ray
Background: Patients with primary elevations of low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL are at a higher risk of atherosclerotic cardiovascular disease as a result of long-term exposure to markedly elevated LDL-C levels. Therefore, initiation of statin therapy is recommended for these individuals. However, there is a lack of randomized trial evidence supporting these recommendations in primary prevention. In the present analysis, we provide hitherto unpublished data on the cardiovascular effects of LDL-C lowering among a primary prevention population with LDL-C ≥190 mg/dL.Methods: We aimed to assess the benefits of LDL-C lowering on cardiovascular outcomes among individuals with primary elevations of LDL-C ≥190 mg/dL without preexisting vascular disease at baseline. We performed post hoc analyses from the WOSCOPS (West of Scotland Coronary Prevention Study) randomized, placebo-controlled trial, and observational posttrial long-term follow-up, after excluding individuals with evidence of vascular disease at baseline. WOSCOPS enrolled 6595 men aged 45 to 64 years, who were randomly assigned to pravastatin 40 mg/d or placebo. In the present analyses, 5529 participants without evidence of vascular disease were included, stratified by LDL-C levels into those with LDL-C <190 mg/dL (n=2969; mean LDL-C 178±6 mg/dL) and those with LDL-C ≥190 mg/dL (n=2560; mean LDL-C 206±12 mg/dL). The effect of pravastatin versus placebo on coronary heart disease and major adverse cardiovascular events were assessed over the 4.9-year randomized controlled trial phase and on mortality outcomes over a total of 20 years of follow-up.Results: Among 5529 individuals without vascular disease, pravastatin reduced the risk of coronary heart disease by 27% (P=0.002) and major adverse cardiovascular events by 25% (P=0.004) consistently among those with and without LDL-C ≥190 mg/dL (P-interaction >0.9). Among individuals with LDL-C ≥190 mg/dL, pravastatin reduced the risk of coronary heart disease by 27% (P=0.033) and major adverse cardiovascular events by 25% (P=0.037) during the initial trial phase and the risk of coronary heart disease death, cardiovascular death, and all-cause mortality by 28% (P=0.020), 25% (P=0.009), and 18% (P=0.004), respectively, over a total of 20 years of follow-up.Conclusions: The present analyses provide robust novel evidence for the short- and long-term benefits of lowering LDL-C for the primary prevention of cardiovascular disease among individuals with primary elevations of LDL-C ≥190 mg/dL.
Closing the Remaining Evidence Gap Circulation (IF 19.309) Pub Date : 2017-11-14 Karol E. Watson, Gregg C. Fonarow
Article, see p 1878 Abundant observational evidence has shown the association between elevated low-density lipoprotein cholesterol (LDL-C) levels and adverse cardiovascular outcomes and premature cardiovascular death.1,2 Extensive and highly consistent clinical trial evidence has also shown the benefits of lowering LDL-C with statin therapy in reducing cardiovascular risk.3–8 For these reasons, the 2013 American College of Cardiology/American Heart Association cholesterol guidelines recommended statin therapy in these 4 statin benefit groups8: Clinical atherosclerotic cardiovascular disease (ASCVD) LDL-C ≥190 mg/dL, ≥21 years of age Primary prevention—diabetes mellitus: 40–75 years of age, LDL-C 70–189 mg/dL Primary prevention—no diabetes mellitus (7.5%), 10-year ASCVD risk, 40–75 years of age, LDL-C 70–189 mg/dL Although overwhelming clinical trial evidence supports statin benefit groups 1,3–5 3,7,8 and 4,6,8 until now there has not been direct randomized clinical trial evidence for improved outcomes in statin benefit group 2. The 2013 American College of Cardiology/American Heart Association cholesterol guidelines writing committee recognized that individuals ≥21 years of age with primary, severe elevations of LDL-C (≥190 mg/dL) have a high lifetime risk for ASCVD events. Therefore, the committee recommended statin treatment irrespective of calculated 10-year ASCVD risk in this high-risk cohort. Despite the evidence …
Timing of Angiography and Outcomes in High-Risk Patients With Non–ST-Segment–Elevation Myocardial Infarction Managed Invasively Circulation (IF 19.309) Pub Date : 2017-11-14 Pierre Deharo, Gregory Ducrocq, Christoph Bode, Marc Cohen, Thomas Cuisset, Shamir R. Mehta, Charles Pollack, Stephen D. Wiviott, Yedid Elbez, Marc S. Sabatine, Philippe Gabriel Steg
Background: In patients with non–ST-segment–elevation myocardial infarction (NSTEMI) and GRACE (Global Registry of Acute Coronary Events) score >140, coronary angiography (CAG) is recommended by European and American guidelines within 24 hours. We sought to study the association of very early (ie, ≤12 hours), early (12–24 hours), and delayed (>24 hours) CAG in patients with NSTEMI with GRACE score >140 with ischemic outcomes.Methods: The TAO trial (Treatment of Acute Coronary Syndrome With Otamixaban) randomized patients with NSTEMI and CAG scheduled within 72 hours to heparin plus eptifibatide versus otamixaban. In this post hoc analysis, patients with a GRACE score >140 were categorized into 3 groups according to timing of CAG from admission (<12, ≥12–<24, and ≥24 hours). The primary ischemic outcome was the composite of all-cause death and myocardial infarction within 180 days of randomization.Results: CAG was performed in 4071 patients (<12 hours, n=1648 [40.5%]; 12–24 hours, n=1420 [34.9%]; ≥24 hours, n=1003 [24.6%]). With CAG ≥24 hours as a reference, CAG from 12 to 24 hours was not associated with a lower risk of primary ischemic outcome at 180 days (odds ratio, 0.96; 95% confidence interval, 0.75–1.23), whereas CAG <12 hours was associated with a lower risk of death and myocardial infarction (odds ratio, 0.71; 95% confidence interval, 0.55–0.91). Performing CAG <12 hours was also associated with a lower risk of death and myocardial infarction (odds ratio, 0.76; 95% confidence interval, 0.61–0.94; P=0.01) compared with CAG performed at 12 to 24 hours. No difference was observed in bleeding complications.Conclusions: In patients with high-risk NSTEMI, undergoing CAG within the initial 12 hours after admission (as opposed to later, either 12–24 or ≥24 hours) was associated with lower risk of ischemic outcomes at 180 days.
Acute Myocardial Infarction Circulation (IF 19.309) Pub Date : 2017-11-14 Etienne Puymirat, Tabassome Simon, Guillaume Cayla, Yves Cottin, Meyer Elbaz, Pierre Coste, Gilles Lemesle, Pascal Motreff, Batric Popovic, Khalife Khalife, Jean-Noel Labèque, Thibaut Perret, Christophe Le Ray, Laurent Orion, Bernard Jouve, Didier Blanchard, Patrick Peycher, Johanne Silvain, Philippe Gabriel Steg, Patrick Goldstein, Pascal Guéret, Loic Belle, Nadia Aissaoui, Jean Ferrières, François Schiele, Nicolas Danchin
Background: ST-segment–elevation myocardial infarction (STEMI) and non–ST-segment–elevation myocardial infarction (NSTEMI) management has evolved considerably over the past 2 decades. Little information on mortality trends in the most recent years is available. We assessed trends in characteristics, treatments, and outcomes for acute myocardial infarction in France between 1995 and 2015.Methods: We used data from 5 one-month registries, conducted 5 years apart, from 1995 to 2015, including 14 423 patients with acute myocardial infarction (59% STEMI) admitted to cardiac intensive care units in metropolitan France.Results: From 1995 to 2015, mean age decreased from 66±14 to 63±14 years in patients with STEMI; it remained stable (68±14 years) in patients with NSTEMI, whereas diabetes mellitus, obesity, and hypertension increased. At the acute stage, intended primary percutaneous coronary intervention increased from 12% (1995) to 76% (2015) in patients with STEMI. In patients with NSTEMI, percutaneous coronary intervention ≤72 hours from admission increased from 9% (1995) to 60% (2015). Six-month mortality consistently decreased in patients with STEMI from 17.2% in 1995 to 6.9% in 2010 and 5.3% in 2015; it decreased from 17.2% to 6.9% in 2010 and 6.3% in 2015 in patients with NSTEMI. Mortality still decreased after 2010 in patients with STEMI without reperfusion therapy, whereas no further mortality gain was found in patients with STEMI with reperfusion therapy or in patients with NSTEMI, whether or not they were treated with percutaneous coronary intervention.Conclusions: Over the past 20 years, 6-month mortality after acute myocardial infarction has decreased considerably for patients with STEMI and NSTEMI. Mortality figures continued to decline in patients with STEMI until 2015, whereas mortality in patients with NSTEMI appears stable since 2010.
Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension Circulation (IF 19.309) Pub Date : 2017-11-14 Toshie Saito, Kazuya Miyagawa, Shih-Yu Chen, Rasa Tamosiuniene, Lingli Wang, Orr Sharpe, Erik Samayoa, Daisuke Harada, Jan-Renier A.J. Moonen, Aiqin Cao, Pin-I Chen, Jan K. Hennigs, Mingxia Gu, Caiyun G. Li, Ryan D. Leib, Dan Li, Christopher M. Adams, Patricia A. del Rosario, Matthew Bill, Francois Haddad, Jose G. Montoya, William H. Robinson, Wendy J. Fantl, Garry P. Nolan, Roham T. Zamanian, Mark R. Nicolls, Charles Y. Chiu, Maria E. Ariza, Marlene Rabinovitch
Background: Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic, or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue, and elevated cytokines have been related to PAH pathogenesis but without a clear understanding of how these abnormalities are initiated, perpetuated, and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies.Methods: Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry, confirmed by enzyme-linked immunosorbent assay, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next-generation sequencing, functional studies in cultured monocytes and endothelial cells, and hemodynamic and lung studies in a rat.Results: SAM domain and HD domain-containing protein 1 (SAMHD1), an innate immune factor that suppresses HIV replication, was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH versus 12 control lungs. Elevated SAMHD1 was localized to endothelial cells, perivascular dendritic cells, and macrophages, and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH versus control lungs (n=4). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase mRNAs were elevated in PAH versus control lungs (n=10), and proteins were localized to macrophages. HERV-K deoxyuridine triphosphate nucleotidohydrolase induced SAMHD1 and proinflammatory cytokines (eg, interleukin 6, interleukin 1β, and tumor necrosis factor α) in circulating monocytes, pulmonary arterial endothelial cells, and also activated B cells. Vulnerability of pulmonary arterial endothelial cells (PAEC) to apoptosis was increased by HERV-K deoxyuridine triphosphate nucleotidohydrolase in an interleukin 6-independent manner. Furthermore, 3 weekly injections of HERV-K deoxyuridine triphosphate nucleotidohydrolase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8) and elevated interleukin 6.Conclusions: Our study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.
Human Endogenous Retrovirus K and Pulmonary Arterial Hypertension Circulation (IF 19.309) Pub Date : 2017-11-14 Miranda K. Culley, Stephen Y. Chan
Article, see p 1920 Pulmonary arterial hypertension (PAH) is a deleterious disease of the lung vasculature characterized by endothelial dysfunction, medial hypertrophy and proliferation, and eventual occlusion of the pulmonary arterioles. Although a number of genetic and environmental triggers have been described as causative, the specific molecular origins of this vascular disease are still unknown. Multiple lines of evidence now converge to connect immune dysregulation to PAH in humans and animal models. Previous reports suggest that altered inflammatory dynamics, such as hematopoietic and myeloid expansion, B- and T-cell dysfunction, increased cytokine production, circulating autoantibodies, and tertiary lymphoid tissue neogenesis, may initiate or drive PAH.1 Clinically, a well-established causative link exists between autoimmune connective tissue disorders and PAH. Furthermore, infectious agents, such as Schistosoma mansoni and human immunodeficiency virus (HIV), are known to alter the immune cell repertoire and predispose to the development of PAH. However, a mechanistic understanding of the exogenous or endogenous factors that drive immune dysfunction remains largely undefined. Prior studies have aimed to characterize the role of exogenous viruses in PAH. For example, HIV-associated PAH has been attributed to decreased CD4+ T-cell function, indicating a role for T-cell–mediated immune dysregulation.2 Separately, HIV-encoded proteins such …
Enhanced Therapeutic and Long-Term Dynamic Vascularization Effects of Human Pluripotent Stem Cell–Derived Endothelial Cells Encapsulated in a Nanomatrix Gel Circulation (IF 19.309) Pub Date : 2017-11-14 Shin-Jeong Lee, Young-Doug Sohn, Adinarayana Andukuri, Sangsung Kim, Jaemin Byun, Ji Woong Han, In-Hyun Park, Ho-Wook Jun, Young-sup Yoon
Background: Human pluripotent stem cell (hPSC)–derived endothelial cells (ECs) have limited clinical utility because of undefined components in the differentiation system and poor cell survival in vivo. Here, we aimed to develop a fully defined and clinically compatible system to differentiate hPSCs into ECs. Furthermore, we aimed to enhance cell survival, vessel formation, and therapeutic potential by encapsulating hPSC-ECs with a peptide amphiphile (PA) nanomatrix gel.Methods: We induced differentiation of hPSCs into the mesodermal lineage by culturing on collagen-coated plates with a glycogen synthase kinase 3β inhibitor. Next, vascular endothelial growth factor, endothelial growth factor, and basic fibroblast growth factor were added for endothelial lineage differentiation, followed by sorting for CDH5 (VE-cadherin). We constructed an extracellular matrix–mimicking PA nanomatrix gel (PA-RGDS) by incorporating the cell adhesive ligand Arg-Gly-Asp-Ser (RGDS) and a matrix metalloproteinase-2–degradable sequence. We then evaluated whether the encapsulation of hPSC-CDH5+ cells in PA-RGDS could enhance long-term cell survival and vascular regenerative effects in a hind-limb ischemia model with laser Doppler perfusion imaging, bioluminescence imaging, real-time reverse transcription–polymerase chain reaction, and histological analysis.Results: The resultant hPSC-derived CDH5+ cells (hPSC-ECs) showed highly enriched and genuine EC characteristics and proangiogenic activities. When injected into ischemic hind limbs, hPSC-ECs showed better perfusion recovery and higher vessel-forming capacity compared with media-, PA-RGDS–, or human umbilical vein EC–injected groups. However, the group receiving the PA-RGDS–encapsulated hPSC-ECs showed better perfusion recovery, more robust and longer cell survival (> 10 months), and higher and prolonged angiogenic and vascular incorporation capabilities than the bare hPSC-EC–injected group. Surprisingly, the engrafted hPSC-ECs demonstrated previously unknown sustained and dynamic vessel-forming behavior: initial perivascular concentration, a guiding role for new vessel formation, and progressive incorporation into the vessels over 10 months.Conclusions: We generated highly enriched hPSC-ECs via a clinically compatible system. Furthermore, this study demonstrated that a biocompatible PA-RGDS nanomatrix gel substantially improved long-term survival of hPSC-ECs in an ischemic environment and improved neovascularization effects of hPSC-ECs via prolonged and unique angiogenic and vessel-forming properties. This PA-RGDS–mediated transplantation of hPSC-ECs can serve as a novel platform for cell-based therapy and investigation of long-term behavior of hPSC-ECs.
International Expert Consensus on Switching Platelet P2Y12 Receptor–Inhibiting Therapies Circulation (IF 19.309) Pub Date : 2017-11-14 Dominick J. Angiolillo, Fabiana Rollini, Robert F. Storey, Deepak L. Bhatt, Stefan James, David J. Schneider, Dirk Sibbing, Derek Y.F. So, Dietmar Trenk, Dimitrios Alexopoulos, Paul A. Gurbel, Willibald Hochholzer, Leonardo De Luca, Laurent Bonello, Daniel Aradi, Thomas Cuisset, Udaya S. Tantry, Tracy Y. Wang, Marco Valgimigli, Ron Waksman, Roxana Mehran, Gilles Montalescot, Francesco Franchi, Matthew J. Price
Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is the treatment of choice for the prevention of atherothrombotic events in patients with acute coronary syndromes and for those undergoing percutaneous coronary interventions. The availability of different oral P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor) has enabled physicians to contemplate switching among therapies because of specific clinical scenarios. The recent introduction of an intravenous P2Y12 inhibitor (cangrelor) further adds to the multitude of modalities and settings in which switching therapies may occur. In clinical practice, it is not uncommon to switch P2Y12 inhibitor, and switching may be attributed to a variety of factors. However, concerns about the safety of switching between these agents have emerged. Practice guidelines have not fully elaborated on how to switch therapies, leaving clinicians with limited guidance on when and how to switch therapies when needed. This prompted the development of this expert consensus document by key leaders from North America and Europe with expertise in basic, translational, and clinical sciences in the field of antiplatelet therapy. This expert consensus provides an overview of the pharmacology of P2Y12 inhibitors, different modalities and definitions of switching, and available literature and recommendations for switching between P2Y12 inhibitors.
Unusual ST-Segment Elevation in the Anterolateral Precordial Leads Circulation (IF 19.309) Pub Date : 2017-11-14 Andrés Ricardo Pérez-Riera, Raimundo Barbosa-Barros, Rodrigo Daminello-Raimundo, Luiz Carlos de Abreu, Adrian Baranchuk
The patient is a 65-year-old white male with history of type 2 diabetes mellitus, hypertension, chronic smoking, and prior stroke with residual left hemiparesis and aphasia. His medication included losartan, furosemide, simvastatin, and metformin.He was admitted to the emergency room in cardiac arrest and was quickly resuscitated with cardiopulmonary resuscitation and external electric cardioversion maneuvers. Immediately after return of spontaneous circulation, a 12-lead ECG was performed (Figure 1).Figure 1. ECG performed immediately after cardiopulmonary arrest reversion. Based on the ECG, what is the most likely etiology of his cardiac arrest?Please turn the page to read the diagnosis.The firstECG shows accelerated junctional rhythm and a heart rate of 94 bpm, with J point and anterior …
Early Outcomes of Repair of Left Ventricular Apical Aneurysms in Patients With Hypertrophic Cardiomyopathy Circulation (IF 19.309) Pub Date : 2017-11-14 Anita Nguyen, Hartzell V. Schaff, Rick A. Nishimura, Joseph A. Dearani, Steve R. Ommen
Apical aneurysms are outpouchings at the apex of the left ventricle, described as discrete, thin-walled dyskinetic or akinetic segments of the most distal portion of the ventricular chamber (Figure). Apical aneurysms are relatively rare in hypertrophic cardiomyopathy (HCM) with subaortic obstruction, but have been reported in 15% to 30% of patients with apical HCM (ApHCM) or midventricular obstruction (MVO). Aneurysms are associated with a wide spectrum of adverse outcomes including sudden cardiac death, ventricular arrhythmias, heart failure, and mortality.1,2 In a cohort of 93 patients with HCM and apical aneurysms, Rowin and colleagues1 reported a combined adverse event rate (cardiac-related mortality, heart failure, malignant arrhythmias requiring intervention, and thromboembolic events) of 6.4% per year. Furthermore, in a recent review, Jan et al2 reported overall mortality in patients with apical aneurysms of 9% to 10.5% over a mean/median follow-up of 2 to 6.5 years. Apical aneurysms in hypertrophic cardiomyopathy. A, Apical aneurysm of the left ventricle and midventricular obstruction. B, Dashed lines depict site of aneurysm resection and myectomy. C, Enlarged ventricular cavity, and resolution of midventricular obstruction and aneurysm following surgery. D, Preoperative transthoracic …
Letter by Natale et al Regarding Article, “Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study)” Circulation (IF 19.309) Pub Date : 2017-11-14 Francesco Natale, Marco Di Maio, Paolo Calabrò
We appreciated the article titled “Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study),” recently published in Circulation by Pérez de Isla et al.1 As the authors state, patients with familial hypercholesterolemia (FH) have a 3- to 13-fold greater risk of premature atherosclerotic cardiovascular disease than individuals without FH. Therefore, patients with FH had a much higher …
Response by Pérez de Isla et al to Letter Regarding Article, “Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study)” Circulation (IF 19.309) Pub Date : 2017-11-14 Leopoldo Pérez de Isla, Adriana Saltijeral Cerezo, Pedro Mata
We thank Natale and colleagues for their interesting comments about our article.1 Their comments provide important information, and we would like to discuss several of these points. We agree with the authors that familial hypercholesterolemia (FH) is frequent, underdiagnosed, and undertreated and that the …
Letter by Jin-shan and Xue-bin Regarding Article, “Impact of the Clinical Frailty Scale on Outcomes After Transcatheter Aortic Valve Replacement” Circulation (IF 19.309) Pub Date : 2017-11-14 He Jin-shan, Li Xue-bin
We read with great interest the article by Shimura et al1 about the prognostic impact of the Clinical Frailty Scale (CFS) on outcomes after transcatheter aortic valve replacement, which indicates that in addition to reflecting the degree of frailty and showing significant correlation with body mass index, albumin, gait speed, and grip strength, the CFS is a useful marker for predicting late mortality in an elderly transcatheter aortic valve replacement cohort. Attracted by the simple and useful characteristic of this tool, …
Response by Yamamoto et al to Letter Regarding Article, “Impact of the Clinical Frailty Scale on Outcomes After Transcatheter Aortic Valve Replacement” Circulation (IF 19.309) Pub Date : 2017-11-14 Masanori Yamamoto, Tetsuro Shimura, Kentaro Hayashida
We would like to thank Jin-shan and Xue-bin for their kind interest in our recent publication in Circulation.1 Their letter highlights the importance of Clinical Frailty Scale (CFS) assessment before invasive catheter and surgical therapy. Before invasive therapy, regardless of catheter-based or surgical approaches, all patients must undergo preassessment screening to evaluate the safety of the procedure in light of patients’ comorbidities and other clinical variables. The results of the OCEAN-TAVI study (Optimized Catheter Valvular Intervention) suggest that CFS should form part of the preoperative assessment as a means to improve patient outcomes after transcatheter aortic valve replacement (TAVR). As we previously …
Diagnosis and Management of Noncardiac Complications in Adults With Congenital Heart Disease: A Scientific Statement From the American Heart Association Circulation (IF 19.309) Pub Date : 2017-11-14 George K. Lui, Arwa Saidi, Ami B. Bhatt, Luke J. Burchill, Jason F. Deen, Michael G. Earing, Michael Gewitz, Jonathan Ginns, Joseph D. Kay, Yuli Y. Kim, Adrienne H. Kovacs, Eric V. Krieger, Fred M. Wu, Shi-Joon Yoo
Life expectancy and quality of life for those born with congenital heart disease (CHD) have greatly improved over the past 3 decades. While representing a great advance for these patients, who have been able to move from childhood to successful adult lives in increasing numbers, this development has resulted in an epidemiological shift and a generation of patients who are at risk of developing chronic multisystem disease in adulthood. Noncardiac complications significantly contribute to the morbidity and mortality of adults with CHD. Reduced survival has been documented in patients with CHD with renal dysfunction, restrictive lung disease, anemia, and cirrhosis. Furthermore, as this population ages, atherosclerotic cardiovascular disease and its risk factors are becoming increasingly prevalent. Disorders of psychosocial and cognitive development are key factors affecting the quality of life of these individuals. It is incumbent on physicians who care for patients with CHD to be mindful of the effects that disease of organs other than the heart may have on the well-being of adults with CHD. Further research is needed to understand how these noncardiac complications may affect the long-term outcome in these patients and what modifiable factors can be targeted for preventive intervention.
Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Co-Transporter 2 Inhibitor: Results From the EASEL Population-Based Cohort Study Circulation (IF 19.309) Pub Date : 2017-11-13 Jacob A. Udell, Zhong Yuan, Toni Rush, Nicholas M. Sicignano, Michael Galitz, Norman Rosenthal
Background: Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose co-transporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual endpoints or safety concerns.Methods: We performed a population-based cohort study among type 2 diabetes patients with established cardiovascular disease newly initiated on antihyperglycemic agents (AHAs) within the US Department of Defense Military Health System between 4/1/2013 and 12/31/2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite endpoint of all-cause mortality (ACM) and hospitalization for heart failure (HHF) event, major adverse cardiovascular events (MACE; defined as ACM, nonfatal myocardial infarction, and nonfatal stroke), and individual endpoints were evaluated using conditional Cox models comparing new SGLT2i users with other AHAs. Exploratory safety endpoint was below-knee lower extremity amputation (BKA). Intent-to-treat and on-treatment analyses were performed.Results: After propensity matching, 25,258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of ACM and HHF (1.73 vs. 3.01 events per 100 person-years; HR 0.57; 95% CI: 0.50-0.65) and MACE (2.31 vs. 3.45 events per 100 person-years; HR 0.67, 95% CI: 0.60-0.75). SGLT2i initiation was also associated with a ≈two-fold higher risk of BKA (0.17 vs. 0.09 events per 100 person-years; HR 1.99, 95% CI: 1.12-3.51). Due to the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis.Conclusions: In this high-risk cohort, initiation of SGLT2i was associated with lower ACM, HHF, and MACE and higher BKA risk. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the BKA risk extends across the class of medication as the study was not powered to make comparisons among individual treatments.
Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation Circulation (IF 19.309) Pub Date : 2017-11-12 Lu-Chen Weng, Sarah R. Preis, Olivia L. Hulme, Martin G. Larson, Seung Hoan Choi, Biqi Wang, Ludovic Trinquart, David D. McManus, Laila Staerk, Honghuang Lin, Kathryn L. Lunetta, Patrick T. Ellinor, Emelia J. Benjamin, Steven A. Lubitz
Background—The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown.Methods—We estimated lifetime risk of AF in individuals from the community-based Framingham Heart Study. Polygenic risk for AF was derived using a score of approximately 1,000 AF-associated single nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk.Results—Among 4,606 participants without AF at age 55 years, 580 developed incident AF (median follow-up, 9.4 years; 25th-75th percentile, 4.4-14.3 years). The lifetime risk of AF after age 55 years was 37.1%, and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at age 55 years, those in low polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval [CI], 15.4%-29.1%), whereas those in high risk tertiles had a risk of 48.2% (95% CI, 41.3%-55.1%). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition (P value <0.001).Conclusions—In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible, and together with clinical risk factor burden explains a substantial gradient in long-term AF risk.
Persistent Long-Term Structural, Functional, and Metabolic Changes After Stress-Induced (Takotsubo) Cardiomyopathy Circulation (IF 19.309) Pub Date : 2017-11-11 Caroline Scally, Amelia Rudd, Alice Mezincescu, Heather Wilson, Janaki Srinivasan, Graham Horgan, Paul Broadhurst, David E. Newby, Anke Henning, Dana K. Dawson
BACKGROUND: Takotsubo cardiomyopathy is an increasingly recognized acute heart failure syndrome precipitated by intense emotional stress. Although there is an apparent rapid and spontaneous recovery of left ventricular ejection fraction, the long-term clinical and functional consequences of takotsubo cardiomyopathy are ill-defined.METHODS: In an observational case-control study, we recruited 37 patients with prior (>12-month) takotsubo cardiomyopathy, and 37 age-, sex-, and comorbidity-matched control subjects. Patients completed the Minnesota Living with Heart Failure Questionnaire. All participants underwent detailed clinical phenotypic characterization, including serum biomarker analysis, cardiopulmonary exercise testing, echocardiography, and cardiac magnetic resonance including cardiac 31P-spectroscopy.RESULTS: Participants were predominantly middle-age (64±11 years) women (97%). Although takotsubo cardiomyopathy occurred 20 (range 13-39) months before the study, the majority (88%) of patients had persisting symptoms compatible with heart failure (median of 13 [range 0-76] in the Minnesota Living with Heart Failure Questionnaire) and cardiac limitation on exercise testing (reduced peak oxygen consumption, 24±1.3 versus 31±1.3 mL/kg/min, P<0.001; increased VE/VCO2 slope, 31±1 versus 26±1, P=0.002). Despite normal left ventricular ejection fraction and serum biomarkers, patients with prior takotsubo cardiomyopathy had impaired cardiac deformation indices (reduced apical circumferential strain, ‒16±1.0 versus ‒23±1.5%, P<0.001; global longitudinal strain, ‒17±1 versus ‒20±1%, P=0.006), increased native T1 mapping values (1264±10 versus 1184±10 ms, P<0.001), and impaired cardiac energetic status (phosphocreatine/γ-adenosine triphosphate ratio, 1.3±0.1 versus 1.9±0.1, P<0.001).CONCLUSIONS: In contrast to previous perceptions, takotsubo cardiomyopathy has long-lasting clinical consequences, including demonstrable symptomatic and functional impairment associated with persistent subclinical cardiac dysfunction. Taken together our findings demonstrate that after takotsubo cardiomyopathy, patients develop a persistent, long-term heart failure phenotype.CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02989454.
American Heart Association Principles on the Accessibility and Affordability of Drugs and Biologics: A Presidential Advisory From the American Heart Association Circulation (IF 19.309) Pub Date : 2017-01-01 Elliott M. Antman, Mark A. Creager, Steven R. Houser, John J. Warner, Madeleine Konig, On behalf of the American Heart Association
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.
The Value of Preoperative Assessment Before Noncardiac Surgery in the Era of Value-Based Care Circulation (IF 19.309) Pub Date : 2017-11-07 Lee A. Fleisher
Over the past several decades, the field of preoperative cardiac evaluation before noncardiac surgery has evolved substantially. Initially, the focus was on identifying high-risk patients who might benefit from additional interventions, but the value of those interventions, such as coronary revascularization, was unknown. Beginning around the time of the publication of the first American College of Cardiology/American Heart Association (ACC/AHA) Guidelines in 1996, the focus has evolved from identification of risk to targeted evaluation and treatment for those in whom it would impact outcome, ie, those in whom there is clearly value. There are currently 3 major Society Guidelines, the 2014 ACC/AHA Guidelines,1 the 2014 European Society of Cardiology/European Society of Anesthesiology,2 and the 2017 Canadian Cardiovascular Society (CCS),3 that address preoperative assessment. There are clear differences between the first 2 guidelines and the more recent CCS Guidelines, which may, in part, reflect the evolution of new evidence since the publication of earlier guidelines. However, a notable philosophical difference in data interpretation is clear as well. Until recently, the ACC/AHA Guidelines, and most medical consultations, included the assumption that surgery was not only indicated but would occur. As health care moves from volume to value, shared decision making around the risks and benefits of surgery …
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