bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.