bluuebunny/crossref_metadata_2025 huggingface dataset:
Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation
Authors: Mauler Maximilian , Herr Nadine , Schoenichen Claudia , Witsch Thilo , Marchini Timoteo , Härdtner Carmen , Koentges Christoph , Kienle Korbinian , Ollivier Véronique , Schell Maximilian , Dorner Ludwig , Wippel Christopher , Stallmann Daniela , Normann Claus , Bugger Heiko , Walther Paul , Wolf Dennis , Ahrens Ingo , Lämmermann Tim , Ho-Tin-Noé Benoît , Ley Klaus , Bode Christoph , Hilgendorf Ingo , Duerschmied Daniel
Published: January 2019

Background:

Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response.

Methods:

Infarct size, heart function, and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacological depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men, and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome.

Results:

Platelet-derived serotonin induced neutrophil degranulation with release of myeloperoxidase and hydrogen peroxide (H
2
O
2
) and increased expression of membrane-bound leukocyte adhesion molecule CD11b, leading to enhanced inflammation in the infarct area and reduced myocardial salvage. In patients hospitalized with acute coronary syndrome, plasmatic serotonin levels correlated with CD11b expression on neutrophils and myeloperoxidase plasma levels. Long-term serotonin reuptake inhibition—reported to protect patients with depression from cardiovascular events—resulted in the depletion of platelet serotonin stores in mice. These mice displayed a reduction in neutrophil degranulation and preserved cardiac function. In line, patients with depression using serotonin reuptake inhibition, presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood.

Conclusions:

Taken together, we identify serotonin as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury.
LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis
Authors: Xie Yi , Ostriker Allison C. , Jin Yu , Hu Haidi , Sizer Ashley J. , Peng Gang , Morris Aaron H. , Ryu Changwan , Herzog Erica L. , Kyriakides Themis , Zhao Hongyu , Dardik Alan , Yu Jun , Hwa John , Martin Kathleen A.
Published: January 2019

Background:

Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 & Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-β1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown.

Methods:

We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle–specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis.

Results:

We demonstrate that LMO7 is induced postinjury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of
Tgfb1
mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1–dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy.

Conclusions:

LMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.
A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay
Authors: Seeger Timon , Shrestha Rajani , Lam Chi Keung , Chen Caressa , McKeithan Wesley L. , Lau Edward , Wnorowski Alexa , McMullen George , Greenhaw Matthew , Lee Jaecheol , Oikonomopoulos Angelos , Lee Soah , Yang Huaxiao , Mercola Mark , Wheeler Matthew , Ashley Euan A. , Yang Fan , Karakikes Ioannis , Wu Joseph C.
Published: January 2019

Background:

Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in myosin-binding protein C3 (
MYBPC3
) resulting in a premature termination codon (PTC). The underlying mechanisms of how PTC mutations in
MYBPC3
lead to the onset and progression of HCM are poorly understood. This study’s aim was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with
MYBPC3
PTC mutations by utilizing human isogenic induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs).

Methods:

Isogenic iPSC lines were generated from HCM patients harboring
MYBPC3
PTC mutations (p.R943x; p.R1073P_Fsx4) using genome editing. Comprehensive phenotypic and transcriptome analyses were performed in the iPSC-CMs.

Results:

We observed aberrant calcium handling properties with prolonged decay kinetics and elevated diastolic calcium levels in the absence of structural abnormalities or contracile dysfunction in HCM iPSC-CMs as compared to isogenic controls. The mRNA expression levels of
MYBPC3
were significantly reduced in mutant iPSC-CMs, but the protein levels were comparable among isogenic iPSC-CMs, suggesting that haploinsufficiency of
MYBPC3
does not contribute to the pathogenesis of HCM in vitro. Furthermore, truncated MYBPC3 peptides were not detected. At the molecular level, the nonsense-mediated decay pathway was activated, and a set of genes involved in major cardiac signaling pathways was dysregulated in HCM iPSC-CMs, indicating an HCM gene signature in vitro. Specific inhibition of the nonsense-mediated decay pathway in mutant iPSC-CMs resulted in reversal of the molecular phenotype and normalization of calcium-handling abnormalities.

Conclusions:

iPSC-CMs carrying
MYBPC3
PTC mutations displayed aberrant calcium signaling and molecular dysregulations in the absence of significant haploinsufficiency of MYBPC3 protein. Here we provided the first evidence of the direct connection between the chronically activated nonsense-mediated decay pathway and HCM disease development.
Vascular Endothelial Growth Factor Receptor 3 Regulates Endothelial Function Through β-Arrestin 1
Authors: Ma Zhiyuan , Yu Yen-Rei , Badea Cristian T. , Kovacs Jeffrey J. , Xiong Xinyu , Comhair Suzy , Piantadosi Claude A. , Rajagopal Sudarshan
Published: January 2019

Background:

Receptor signaling is central to vascular endothelial function and is dysregulated in vascular diseases such as atherosclerosis and pulmonary arterial hypertension (PAH). Signaling pathways involved in endothelial function include vascular endothelial growth factor receptors (VEGFRs) and G protein–coupled receptors, which classically activate distinct intracellular signaling pathways and responses. The mechanisms that regulate these signaling pathways have not been fully elucidated and it is unclear what nodes for cross talk exist between these diverse signaling pathways. For example, multifunctional β-arrestin (ARRB) adapter proteins are best known as regulators of G protein–coupled receptor signaling, but their role at other receptors and their physiological importance in the setting of vascular disease are unclear.

Methods:

We used a combination of human samples from PAH, human microvascular endothelial cells from lung, and
Arrb
knockout mice to determine the role of ARRB1 in endothelial VEGFR3 signaling. In addition, a number of biochemical analyses were performed to determine the interaction between ARRB1 and VEGFR3, signaling mediators downstream of VEGFR3, and the internalization of VEGFR3.

Results:

Expression of ARRB1 and VEGFR3 was reduced in human PAH, and the deletion of
Arrb1
in mice exposed to hypoxia led to worse PAH with a loss of VEGFR3 signaling. Knockdown of ARRB1 inhibited VEGF-C–induced endothelial cell proliferation, migration, and tube formation, along with reduced VEGFR3, Akt, and endothelial nitric oxide synthase phosphorylation. This regulation was mediated by direct ARRB1 binding to the VEGFR3 kinase domain and resulted in decreased VEGFR3 internalization.

Conclusions:

Our results demonstrate a novel role for ARRB1 in VEGFR regulation and suggest a mechanism for cross talk between G protein–coupled receptors and VEGFRs in PAH. These findings also suggest that strategies to promote ARRB1-mediated VEGFR3 signaling could be useful in the treatment of pulmonary hypertension and other vascular disease.
Ambulance Density and Outcomes After Out-of-Hospital Cardiac Arrest
Authors: Chocron Richard , Loeb Thomas , Lamhaut Lionel , Jost Daniel , Adnet Frédéric , Lecarpentier Eric , Bougouin Wulfran , Beganton Franckie , Juvin Philippe , Marijon Eloi , Jouven Xavier , Cariou Alain , Dumas Florence ,   On behalf of Paris SDEC Investigators
Published: January 2019

Background:

In out-of-hospital cardiac arrest (OHCA), geographic disparities in outcomes may reflect baseline variations in patients’ characteristics but may also result from differences in the number of ambulances providing basic life support (BLS) and advanced life support (ALS). We aimed at assessing the association between allocated ambulance resources and outcomes in OHCA patients in a large urban community.

Methods:

From May 2011 to January 2016, we analyzed a prospectively collected Utstein database for all OHCA adults. Cases were geocoded according to 19 neighborhoods and the number of BLS (firefighters performing cardiopulmonary resuscitation and applying automated external defibrillator) and ALS ambulances (medicalized team providing advanced care such as drugs and endotracheal intubation) was collected. We assessed the respective associations of Utstein parameters, socioeconomic characteristics, and ambulance resources of these neighborhoods using a mixed-effect model with successful return of spontaneous circulation as the primary end point and survival at hospital discharge as a secondary end point.

Results:

During the study period, 8754 nontraumatic OHCA occurred in the Greater Paris area. Overall return of spontaneous circulation rate was 3675 of 8754 (41.9%) and survival rate at hospital discharge was 788 of 8754 (9%), ranging from 33% to 51.1% and from 4.4% to 14.5% respectively, according to neighborhoods (
P
<0.001). Patient and socio-demographic characteristics significantly differed between neighborhoods (
P
for trend <0.001). After adjustment, a higher density of ambulances was associated with successful return of spontaneous circulation (respectively adjusted odds-ratio [aOR], 1.31 [1.14–1.51];
P
<0.001 for ALS ambulances >1.5 per neighborhood and aOR, 1.21 [1.04–1.41];
P
=0.01 for BLS ambulances >4 per neighborhood). Regarding survival at discharge, only the number of ALS ambulances >1.5 per neighborhood was significant (aOR, 1.30 [1.06–1.59]
P
=0.01).

Conclusions:

In this large urban population-based study of out-of-hospital cardiac arrests patients, we observed that allocated resources of emergency medical service are associated with outcome, suggesting that improving healthcare organization may attenuate disparities in prognosis.
Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair
Authors: Tang Tony W.H. , Chen Hung-Chih , Chen Chen-Yun , Yen Christopher Y.T. , Lin Chen-Ju , Prajnamitra Ray P. , Chen Li-Lun , Ruan Shu-Chian , Lin Jen-Hao , Lin Po-Ju , Lu Hsueh-Han , Kuo Chiung-Wen , Chang Cindy M. , Hall Alexander D. , Vivas Eugenio I. , Shui Jr-Wen , Chen Peilin , Hacker Timothy A. , Rey Federico E. , Kamp Timothy J. , Hsieh Patrick C.H.
Published: January 2019

Background:

The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated.

Methods:

To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI.

Results:

Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate.

Conclusions:

Gut microbiota–derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.
Prospective Validation of the Emergency Heart Failure Mortality Risk Grade for Acute Heart Failure
Authors: Lee Douglas S. , Lee Jacques S. , Schull Michael J. , Borgundvaag Bjug , Edmonds Marcia L. , Ivankovic Maria , McLeod Shelley L. , Dreyer Jonathan F. , Sabbah Sam , Levy Phillip D. , O’Neill Tara , Chong Alice , Stukel Therese A. , Austin Peter C. , Tu Jack V.
Published: January 2019

Background:

Improved risk stratification of acute heart failure in the emergency department may inform physicians’ decisions regarding patient admission or early discharge disposition. We aimed to validate the previously-derived Emergency Heart failure Mortality Risk Grade for 7-day (EHMRG7) and 30-day (EHMRG30-ST) mortality.

Methods:

We conducted a multicenter, prospective validation study of patients with acute heart failure at 9 hospitals. We surveyed physicians for their estimates of 7-day mortality risk, obtained for each patient before knowledge of the model predictions, and compared these with EHMRG7 for discrimination and net reclassification improvement. We also prospectively examined discrimination of the EHMRG30-ST model, which incorporates all components of EHMRG7 as well as the presence of ST-depression on the 12-lead ECG.

Results:

We recruited 1983 patients seeking emergency department care for acute heart failure. Mortality rates at 7 days in the 5 risk groups (very low, low, intermediate, high, and very high risk) were 0%, 0%, 0.6%, 1.9%, and 3.9%, respectively. At 30 days, the corresponding mortality rates were 0%, 1.9%, 3.9%, 5.9%, and 14.3%. Compared with physician-estimated risk of 7-day mortality (PER7; c-statistic, 0.71; 95% CI, 0.64–0.78) there was improved discrimination with EHMRG7 (c-statistic, 0.81; 95% CI, 0.75–0.87;
P
=0.022 versus PER7) and with EHMRG7 combined with physicians’ estimates (c-statistic, 0.82; 95% CI, 0.76–0.88;
P
=0.003 versus PER7). Model discrimination increased nonsignificantly by 0.014 (95% CI, −0.009–0.037) when physicians’ estimates combined with EHMRG7 were compared with EHMRG7 alone (
P
=0.242). The c-statistic for EHMRG30-ST alone was 0.77 (95% CI, 0.73–0.81) and 30-day model discrimination increased nonsignificantly by addition of physician-estimated risk to 0.78 (95% CI, 0.73–0.82;
P
=0.187). Net reclassification improvement with EHMRG7 was 0.763 (95% CI, 0.465–1.062) when assessed continuously and 0.820 (0.560–1.080) using risk categories compared with PER7.

Conclusions:

A clinical model allowing simultaneous prediction of mortality at both 7 and 30 days identified acute heart failure patients with a low risk of events. Compared with physicians’ estimates, our multivariable model was better able to predict 7-day mortality and may guide clinical decisions.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02634762.
Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction
Authors: Khera Amit V. , Chaffin Mark , Zekavat Seyedeh M. , Collins Ryan L. , Roselli Carolina , Natarajan Pradeep , Lichtman Judith H. , D’Onofrio Gail , Mattera Jennifer , Dreyer Rachel , Spertus John A. , Taylor Kent D. , Psaty Bruce M. , Rich Stephen S. , Post Wendy , Gupta Namrata , Gabriel Stacey , Lander Eric , Ida Chen Yii-Der , Talkowski Michael E. , Rotter Jerome I. , Krumholz Harlan M. , Kathiresan Sekar
Published: January 2019

Background:

The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.

Methods:

We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.

Results:

The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1–6.8;
P
<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1–4.6;
P
<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants (
P
for heterogeneity=0.008).

Conclusions:

Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00597922.
Ryanodine Receptor Glycation Favors Mitochondrial Damage in the Senescent Heart
Authors: Ruiz-Meana Marisol , Minguet Marta , Bou-Teen Diana , Miro-Casas Elisabet , Castans Celia , Castellano Jose , Bonzon-Kulichenko Elena , Igual Alberto , Rodriguez-Lecoq Rafael , Vázquez Jesús , Garcia-Dorado David
Published: January 2019

Background:

Senescent cardiomyocytes exhibit a mismatch between energy demand and supply that facilitates their transition toward failing cells. Altered calcium transfer from sarcoplasmic reticulum (SR) to mitochondria has been causally linked to the pathophysiology of aging and heart failure.

Methods:

Because advanced glycation-end products accumulate throughout life, we investigated whether intracellular glycation occurs in aged cardiomyocytes and its impact on SR and mitochondria.

Results:

Quantitative proteomics, Western blot and immunofluorescence demonstrated a significant increase in advanced glycation-end product–modified proteins in the myocardium of old mice (≥20months) compared with young ones (4-6months). Glyoxalase-1 activity (responsible for detoxification of dicarbonyl intermediates) and its cofactor glutathione were decreased in aged hearts. Immunolabeling and proximity ligation assay identified the ryanodine receptor (RyR2) in the SR as prominent target of glycation in aged mice, and the sites of glycation were characterized by quantitative mass spectrometry. RyR2 glycation was associated with more pronounced calcium leak, determined by confocal microscopy in cardiomyocytes and SR vesicles. Interfibrillar mitochondria—directly exposed to SR calcium release—from aged mice had increased calcium content compared with those from young ones. Higher levels of advanced glycation-end products and reduced glyoxalase-1 activity and glutathione were also present in atrial appendages from surgical patients ≥75 years as compared with the younger ones. Elderly patients also exhibited RyR2 hyperglycation and increased mitochondrial calcium content that was associated with reduced myocardial aerobic capacity (mitochondrial O
2
consumption/g) attributable to less respiring mitochondria. In contracting HL-1 cardiomyocytes, pharmacological glyoxalase-1 inhibition recapitulated RyR2 glycation and defective SR-mitochondria calcium exchange of aging.

Conclusions:

Mitochondria from aging hearts develop calcium overload secondary to SR calcium leak. Glycative damage of RyR2, favored by deficient dicarbonyl detoxification capacity, contributes to calcium leak and mitochondrial damage in the senescent myocardium.
Glycemic Control, Cardiac Autoimmunity, and Long-Term Risk of Cardiovascular Disease in Type 1 Diabetes Mellitus
Authors: Sousa Giovane R. , Pober David , Galderisi Alfonso , Lv HuiJuan , Yu Liping , Pereira Alexandre C. , Doria Alessandro , Kosiborod Mikhail , Lipes Myra A.
Published: January 2019

Background:

Poor glycemic control is associated with increased risk of cardiovascular disease (CVD) in type 1 diabetes mellitus (T1DM); however, little is known about mechanisms specific to T1DM. In T1DM, myocardial injury can induce persistent cardiac autoimmunity. Chronic hyperglycemia causes myocardial injury, raising the possibility that hyperglycemia-induced cardiac autoimmunity could contribute to long-term CVD complications in T1DM.

Methods:

We measured the prevalence and profiles of cardiac autoantibodies (AAbs) in longitudinal samples from the DCCT (Diabetes Control and Complications Trial) in participants with mean hemoglobin A
1c
(HbA
1c
) ≥9.0% (n=83) and ≤7.0% (n=83) during DCCT. We assessed subsequent coronary artery calcification (measured once during years 7–9 in the post-DCCT EDIC [Epidemiology of Diabetes Interventions and Complications] observational study), high-sensitivity C-reactive protein (measured during EDIC years 4–6), and CVD events (defined as nonfatal myocardial infarction, stroke, death resulting from CVD, heart failure, or coronary artery bypass graft) over a 26-year median follow-up. Cardiac AAbs were also measured in matched patients with type 2 diabetes mellitus with HbA
1c
≥9.0% (n=70) and ≤7.0% (n=140) and, as a control for cardiac autoimmunity, patients with Chagas cardiomyopathy (n=51).

Results:

Apart from HbA
1c
levels, the DCCT groups shared similar CVD risk factors at the beginning and end of DCCT. The DCCT HbA
1c
≥9.0% group showed markedly higher cardiac AAb levels than the HbA
1c
≤7.0% group during DCCT, with a progressive increase and decrease in AAb levels over time in the 2 groups, respectively (
P
<0.001). In the HbA
1c
≥9.0% group, 46%, 22%, and 11% tested positive for ≥1, ≥2, and ≥3 different cardiac AAb types, respectively, similar to patients with Chagas cardiomyopathy, compared with 2%, 1%, and 0% in the HbA
1c
≤7.0% group. Glycemic control was not associated with AAb prevalence in type 2 diabetes mellitus. Positivity for ≥2 AAbs during DCCT was associated with increased risk of CVD events (4 of 6; hazard ratio, 16.1; 95% CI, 3.0–88.2) and, in multivariable analyses, with detectable coronary artery calcification (13 of 31; odds ratio, 60.1; 95% CI, 8.4–410.0). Patients with ≥2 AAbs subsequently also showed elevated high-sensitivity C-reactive protein levels (6.0 mg/L versus 1.4 mg/L in patients with ≤1 AAbs;
P
=0.003).

Conclusions:

Poor glycemic control is associated with cardiac autoimmunity in T1DM. Furthermore, cardiac AAb positivity is associated with an increased risk of CVD decades later, suggesting a role for autoimmune mechanisms in the development of CVD in T1DM, possibly through inflammatory pathways.
Impella Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock
Authors: Schrage Benedikt , Ibrahim Karim , Loehn Tobias , Werner Nikos , Sinning Jan-Malte , Pappalardo Federico , Pieri Marina , Skurk Carsten , Lauten Alexander , Landmesser Ulf , Westenfeld Ralf , Horn Patrick , Pauschinger Matthias , Eckner Dennis , Twerenbold Raphael , Nordbeck Peter , Salinger Tim , Abel Peter , Empen Klaus , Busch Mathias C. , Felix Stephan B. , Sieweke Jan-Thorben , Møller Jacob Eifer , Pareek Nilesh , Hill Jonathan , MacCarthy Philip , Bergmann Martin W. , Henriques José P.S. , Möbius-Winkler Sven , Schulze P. Christian , Ouarrak Taoufik , Zeymer Uwe , Schneider Steffen , Blankenberg Stefan , Thiele Holger , Schäfer Andreas , Westermann Dirk
Published: January 2019

Background:

Percutaneous mechanical circulatory support devices are increasingly used in acute myocardial infarction complicated by cardiogenic shock (AMI-CS), despite limited evidence for their effectiveness. The aim of this study was to evaluate outcomes associated with use of the Impella device compared with intra-aortic balloon pump (IABP) and medical treatment in patients with AMI-CS.

Methods:

Data of patients with AMI-CS treated with the Impella device at European tertiary care hospitals were collected retrospectively. All patients underwent early revascularization and received optimal medical treatment. Using IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial inclusion and exclusion criteria, 372 patients were identified and included in this analysis. These patients were matched to 600 patients from the IABP-SHOCK II trial. The following baseline criteria were used as matching parameters: age, sex, mechanical ventilation, ejection fraction, prior cardiopulmonary resuscitation, and lactate. Primary end point was 30-day all-cause mortality.

Results:

In total, 237 patients treated with an Impella could be matched to 237 patients from the IABP-SHOCK II trial. Baseline parameters were similarly distributed after matching. There was no significant difference in 30-day all-cause mortality (48.5% versus 46.4%,
P
=0.64). Severe or life-threatening bleeding (8.5% versus 3.0%,
P
<0.01) and peripheral vascular complications (9.8% versus 3.8%,
P
=0.01) occurred significantly more often in the Impella group. Limiting the analysis to IABP-treated patients as a control group did not change the results.

Conclusions:

In this retrospective analysis of patients with AMI-CS, the use of an Impella device was not associated with lower 30-day mortality compared with matched patients from the IABP-SHOCK II trial treated with an IABP or medical therapy. To further evaluate this, a large randomized trial is warranted to determine the effect of the Impella device on outcome in patients with AMI-CS.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT03313687.
Twenty Year Trends and Sex Differences in Young Adults Hospitalized With Acute Myocardial Infarction
Authors: Arora Sameer , Stouffer George A. , Kucharska-Newton Anna M. , Qamar Arman , Vaduganathan Muthiah , Pandey Ambarish , Porterfield Deborah , Blankstein Ron , Rosamond Wayne D. , Bhatt Deepak L. , Caughey Melissa C.
Published: January 2019

Background:

Sex differences are known to exist in the management of older patients presenting with acute myocardial infarction (AMI). Few studies have examined the incidence and risk factors of AMI among young patients, or whether clinical management differs by sex.

Methods:

The Atherosclerosis Risk in Communities (ARIC) Surveillance study conducts hospital surveillance of AMI in 4 US communities (MD, MN, MS, and NC). AMI was classified by physician review, using a validated algorithm. Medications and procedures were abstracted from the medical record. Our study population was limited to young patients aged 35 to 54 years.

Results:

From 1995 to 2014, 28 732 weighted hospitalizations for AMI were sampled among patients aged 35 to 74 years. Of these, 8737 (30%) were young. The annual incidence of AMI hospitalizations increased for young women but decreased for young men. The overall proportion of AMI admissions attributable to young patients steadily increased, from 27% in 1995 to 1999 to 32% in 2010 to 2014 (
P
for trend=0.002), with the largest increase observed in young women. History of hypertension (59% to 73%,
P
for trend<0.0001) and diabetes mellitus (25% to 35%,
P
for trend<0.0001) also increased among young AMI patients. Compared to young men, young women presenting with AMI were more often black and had a greater comorbidity burden. In adjusted analyses, young women had a lower probability of receiving lipid-lowering therapies (relative risk [RR]=0.87; 95% confidence interval [CI], 0.80–0.94), nonaspirin antiplatelets (RR=0.83; 95% CI, 0.75–0.91), beta blockers (RR=0.96; 95% CI, 0.91–0.99), coronary angiography (RR=0.93; 95% CI, 0.86–0.99) and coronary revascularization (RR = 0.79; 95% CI, 0.71–0.87). However, 1-year all-cause mortality was comparable for women versus men (HR=1.10; 95% CI, 0.83–1.45).

Conclusions:

The proportion of AMI hospitalizations attributable to young patients increased from 1995 to 2014 and was especially pronounced among women. History of hypertension and diabetes among young patients admitted with AMI increased over time as well. Compared with young men, young women presenting with AMI had a lower likelihood of receiving guideline-based AMI therapies. A better understanding of factors underlying these changes is needed to improve care of young patients with AMI.
Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk
Authors: O’Donoghue Michelle L. , Fazio Sergio , Giugliano Robert P. , Stroes Erik S.G. , Kanevsky Estella , Gouni-Berthold Ioanna , Im KyungAh , Lira Pineda Armando , Wasserman Scott M. , Češka Richard , Ezhov Marat V. , Jukema J. Wouter , Jensen Henrik K. , Tokgözoğlu S. Lale , Mach François , Huber Kurt , Sever Peter S. , Keech Anthony C. , Pedersen Terje R. , Sabatine Marc S.
Published: January 2019

Background:

Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined.

Methods:

Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration.

Results:

The median (interquartile range) baseline Lp(a) concentration was 37 (13–165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01–1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%–46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated (
r
=0.37; 95% CI, 0.36–0.39;
P
<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67–0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80–1.08;
P
interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively.

Conclusions:

Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01764633.
Accuracy of Fractional Flow Reserve Derived From Coronary Angiography
Authors: Fearon William F. , Achenbach Stephan , Engstrom Thomas , Assali Abid , Shlofmitz Richard , Jeremias Allen , Fournier Stephane , Kirtane Ajay J. , Kornowski Ran , Greenberg Gabriel , Jubeh Rami , Kolansky Daniel M. , McAndrew Thomas , Dressler Ovidiu , Maehara Akiko , Matsumura Mitsuaki , Leon Martin B. , De Bruyne Bernard ,   For the FAST-FFR Study Investigators
Published: January 2019

Background:

Measuring fractional flow reserve (FFR) with a pressure wire remains underutilized because of the invasiveness of guide wire placement or the need for a hyperemic stimulus. FFR derived from routine coronary angiography (FFR
angio
) eliminates both of these requirements and displays FFR values of the entire coronary tree. The FFR
angio
Accuracy versus Standard FFR (FAST-FFR) study is a prospective, multicenter, international trial with the primary goal of determining the accuracy of FFR
angio
.

Methods:

Coronary angiography was performed in a routine fashion in patients with suspected coronary artery disease. FFR was measured in vessels with coronary lesions of varying severity using a coronary pressure wire and hyperemic stimulus. Based on angiograms of the respective arteries acquired in ≥2 different projections, on-site operators blinded to FFR then calculated FFR
angio
using proprietary software. Coprimary end points were the sensitivity and specificity of the dichotomously scored FFR
angio
for predicting pressure wire–derived FFR using a cutoff value of 0.80. The study was powered to meet prespecified performance goals for sensitivity and specificity.

Results:

Ten centers in the United States, Europe, and Israel enrolled a total of 301 subjects and 319 vessels meeting inclusion/exclusion criteria which were included in the final analysis. The mean FFR was 0.81 and 43% of vessels had an FFR≤0.80. The per-vessel sensitivity and specificity were 94% (95% CI, 88% to 97%) and 91% (86% to 95%), respectively, both of which exceeded the prespecified performance goals. The diagnostic accuracy of FFR
angio
was 92% overall and remained high when only considering FFR values between 0.75 to 0.85 (87%). FFR
angio
values correlated well with FFR measurements (
r
=0.80,
P
<0.001) and the Bland–Altman 95% confidence limits were between −0.14 and 0.12. The device success rate for FFR
angio
was 99%.

Conclusions:

FFR
angio
measured from the coronary angiogram alone has a high sensitivity, specificity, and accuracy compared with pressure wire–derived FFR. FFR
angio
has the promise to substantially increase physiological coronary lesion assessment in the catheterization laboratory, thereby potentially leading to improved patient outcomes.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique Identifier: NCT03226262.
Endovascular Thrombus Removal for Acute Iliofemoral Deep Vein Thrombosis
Authors: Comerota Anthony J. , Kearon Clive , Gu Chu-Shu , Julian Jim A. , Goldhaber Samuel Z. , Kahn Susan R. , Jaff Michael R. , Razavi Mahmood K. , Kindzelski Andrei L. , Bashir Riyaz , Patel Parag , Sharafuddin Mel , Sichlau Michael J. , Saad Wael E. , Assi Zakaria , Hofmann Lawrence V. , Kennedy Margaret , Vedantham Suresh ,   For the ATTRACT Trial Investigators
Published: January 2019

Background:

The ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) previously reported that pharmacomechanical catheter–directed thrombolysis (PCDT) did not prevent postthrombotic syndrome (PTS) in patients with acute proximal deep vein thrombosis. In the current analysis, we examine the effect of PCDT in ATTRACT patients with iliofemoral deep vein thrombosis.

Methods:

Within a large multicenter randomized trial, 391 patients with acute deep vein thrombosis involving the iliac or common femoral veins were randomized to PCDT with anticoagulation versus anticoagulation alone (No-PCDT) and were followed for 24 months to compare short-term and long-term outcomes.

Results:

Between 6 and 24 months, there was no difference in the occurrence of PTS (Villalta scale ≥5 or ulcer: 49% PCDT versus 51% No-PCDT; risk ratio, 0.95; 95% CI, 0.78–1.15;
P
=0.59). PCDT led to reduced PTS severity as shown by lower mean Villalta and Venous Clinical Severity Scores (
P
<0.01 for comparisons at 6, 12, 18, and 24 months), and fewer patients with moderate-or-severe PTS (Villalta scale ≥10 or ulcer: 18% versus 28%; risk ratio, 0.65; 95% CI, 0.45–0.94;
P
=0.021) or severe PTS (Villalta scale ≥15 or ulcer: 8.7% versus 15%; risk ratio, 0.57; 95% CI, 0.32–1.01;
P
=0.048; and Venous Clinical Severity Score ≥8: 6.6% versus 14%; risk ratio, 0.46; 95% CI, 0.24–0.87;
P
=0.013). From baseline, PCDT led to greater reduction in leg pain and swelling (
P
<0.01 for comparisons at 10 and 30 days) and greater improvement in venous disease–specific quality of life (Venous Insufficiency Epidemiological and Economic Study Quality of Life unit difference 5.6 through 24 months,
P
=0.029), but no difference in generic quality of life (
P
>0.2 for comparisons of SF-36 mental and physical component summary scores through 24 months). In patients having PCDT versus No-PCDT, major bleeding within 10 days occurred in 1.5% versus 0.5% (
P
=0.32), and recurrent venous thromboembolism over 24 months was observed in 13% versus 9.2% (
P
=0.21).

Conclusions:

In patients with acute iliofemoral deep vein thrombosis, PCDT did not influence the occurrence of PTS or recurrent venous thromboembolism. However, PCDT significantly reduced early leg symptoms and, over 24 months, reduced PTS severity scores, reduced the proportion of patients who developed moderate-or-severe PTS, and resulted in greater improvement in venous disease–specific quality of life.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00790335.
A Three-Arm Randomized Trial of Different Renal Denervation Devices and Techniques in Patients With Resistant Hypertension (RADIOSOUND-HTN)
Authors: Fengler Karl , Rommel Karl-Philipp , Blazek Stephan , Besler Christian , Hartung Philipp , von Roeder Maximilian , Petzold Martin , Winkler Sindy , Höllriegel Robert , Desch Steffen , Thiele Holger , Lurz Philipp
Published: January 2019

Background:

Both radiofrequency and ultrasound endovascular renal sympathetic denervation (RDN) have proven clinical efficacy for the treatment of hypertension. We performed a head-to-head comparison of these technologies.

Methods:

Patients with resistant hypertension were randomly assigned in a 1:1:1 manner to receive either treatment with (1) radiofrequency RDN of the main renal arteries; (2) radiofrequency RDN of the main renal arteries, side branches, and accessories; or (3) an endovascular ultrasound–based RDN of the main renal artery. The primary end point was change in systolic daytime ambulatory blood pressure at 3 months.

Results:

Between June 2015 and June 2018, 120 patients were enrolled (mean age, 64±9 years±SD; mean daytime blood pressure, 153/86±12/13 mm Hg). Of these, 39 were randomly assigned to radiofrequency main renal artery ablation, 39 to combined radiofrequency ablation of the main artery and branches, and 42 to ultrasound-based treatment. Baseline daytime blood pressure, clinical characteristics, and treatment were well balanced between the groups. At 3 months, systolic daytime ambulatory blood pressure decreased by 9.5±12.3 mm Hg (
P
<0.001) in the whole cohort. Although blood pressure was significantly more reduced in the ultrasound ablation group than in the radiofrequency ablation group of the main renal artery (–13.2±13.7 versus –6.5±10.3 mm Hg; mean difference, –6.7 mm Hg; global
P
=0.038 by ANOVA, adjusted
P
=0.043), no significant difference was found between the radiofrequency ablation groups (–8.3±11.7 mm Hg for additional side branch ablation; mean difference, –1.8 mm Hg; adjusted
P
>0.99). Similarly, the blood pressure reduction was not found to be significantly different between the ultrasound and the side branch ablation groups. Frequencies of blood pressure response ≥5 mm Hg were not significantly different (global
P
=0.77).

Conclusions:

In patients with resistant hypertension, endovascular ultrasound–based RDN was found to be superior to radiofrequency ablation of the main renal arteries only, whereas a combined approach of radiofrequency ablation of the main arteries, accessories, and side branches was not.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02920034.
Cardiac Biomarkers and Left Ventricular Hypertrophy in Relation to Outcomes in Patients With Atrial Fibrillation: Experiences From the RE‐LY Trial
Authors: Hijazi Ziad , Verdecchia Paolo , Oldgren Jonas , Andersson Ulrika , Reboldi Gianpaolo , Di Pasquale Giuseppe , Mazzotta Giovanni , Angeli Fabio , Eikelboom John W. , Ezekowitz Michael D. , Connolly Stuart J. , Yusuf Salim , Wallentin Lars
Published: January 2019

Background

Cardiac biomarkers and left ventricular hypertrophy (
LVH
) are related to the risk of stroke and death in patients with atrial fibrillation. We investigated the interrelationship between
LVH
and cardiac biomarkers and their independent associations with outcomes.

Methods and Results

Plasma samples were obtained at baseline in 5275 patients with atrial fibrillation in the
RE
‐
LY
(Randomized Evaluation of Long‐Term Anticoagulation Therapy) trial.
NT
‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), cardiac troponin I and T, and growth differentiation factor‐15 were determined using high‐sensitivity (hs) assays.
LVH
was defined by
ECG
. Cox models were adjusted for baseline characteristics,
LVH
, and biomarkers.
LVH
was present in 1257 patients. During a median follow‐up of 2.0 years, 165 patients developed a stroke and 370 died.
LVH
was significantly (
P
<0.0001) associated with higher levels of all biomarkers in linear regression analyses adjusting for baseline characteristics. Geometric mean ratios (95% CIs) were as follows:
NT
‐pro
BNP
, 1.32 (1.25–1.38); hs cardiac troponin I, 1.67 (1.57–1.78); hs troponin T, 1.38 (1.32–1.44); and growth differentiation factor‐15, 1.09 (1.05–1.12). For stroke, the hazard ratios (95% CIs) per 50% increase were as follows:
NT
‐pro
BNP,
1.09 (1.00–1.19); hs cardiac troponin I, 1.09 (1.03–1.15); hs troponin T, 1.14 (1.06–1.24); and growth differentiation factor‐15, 1.22 (1.08–1.38) (all
P
<0.05). For death, hazard ratios (95% CIs) were as follows:
NT
‐pro
BNP
, 1.24 (1.17–1.31); hs cardiac troponin I, 1.13 (1.10–1.17); hs troponin T, 1.28 (1.23–1.34); and growth differentiation factor‐15, 1.31 (1.22–1.42) (all
P
<0.0001).
LVH
was not significantly associated with stroke or death after adjustment for biomarkers.

Conclusions

Cardiac biomarkers are significantly associated with
LVH
. The prognostic value of biomarkers for stroke and death is not affected by
LVH
. The prognostic information of
LVH
is attenuated in the presence of cardiac biomarkers.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
00262600.
Exercise Training Adds Cardiometabolic Benefits of a Paleolithic Diet in Type 2 Diabetes Mellitus
Authors: Otten Julia , Andersson Jonas , Ståhl Jens , Stomby Andreas , Saleh Ahmed , Waling Maria , Ryberg Mats , Hauksson Jon , Svensson Michael , Johansson Bengt , Olsson Tommy
Published: January 2019

Background

The accumulation of myocardial triglycerides and remodeling of the left ventricle are common features in type 2 diabetes mellitus and represent potential risk factors for the development of diastolic and systolic dysfunction. A few studies have investigated the separate effects of diet and exercise training on cardiac function, but none have investigated myocardial changes in response to a combined diet and exercise intervention. This 12‐week randomized study assessed the effects of a Paleolithic diet, with and without additional supervised exercise training, on cardiac fat, structure, and function.

Methods and Results

Twenty‐two overweight and obese subjects with type 2 diabetes mellitus were randomized to either a Paleolithic diet and standard‐care exercise recommendations (
PD
) or to a Paleolithic diet plus supervised exercise training 3 hours per week (
PD
‐
EX
). This study includes secondary end points related to cardiac structure and function, ie, myocardial triglycerides levels, cardiac morphology, and strain were measured using cardiovascular magnetic resonance, including proton spectroscopy, at baseline and after 12 weeks. Both groups showed major favorable metabolic changes. The
PD
‐
EX
group showed significant decreases in myocardial triglycerides levels (−45%,
P
=0.038) and left ventricle mass to end‐diastolic volume ratio (−13%,
P
=0.008) while the left ventricle end‐diastolic volume and stroke volume increased significantly (+14%,
P
=0.004 and +17%,
P
=0.008, respectively). These variables were unchanged in the
PD
group.

Conclusions

Exercise training plus a Paleolithic diet reduced myocardial triglycerides levels and improved left ventricle remodeling in overweight/obese subjects with type 2 diabetes mellitus.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
01513798.