bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex Differences in Long‐Term Outcomes With Cardiac Resynchronization Therapy in Mild Heart Failure Patients With Left Bundle Branch Block
Authors: Biton Yitschak , Zareba Wojciech , Goldenberg Ilan , Klein Helmut , McNitt Scott , Polonsky Bronislava , Moss Arthur J. , Kutyifa Valentina ,   the MADIT‐CRT Executive Committee
Published: September 2018

Background

Previous studies have shown conflicting results regarding the benefit of cardiac resynchronization therapy (
CRT
) by sex and
QRS
duration.

Methods and Results

In the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (
MADIT
‐
CRT
), we evaluated long‐term clinical outcome of heart failure (
HF
) or death, death, and
HF
alone by sex and
QRS
duration (dichotomized at 150 ms) in left bundle‐branch block patients with
CRT
with defibrillator backup (
CRT
‐D) versus implantable cardioverter‐defibrillator (
ICD
) only. There were 394 women (31%) and 887 men with left bundle‐branch block. During the median follow‐up of 5.6 years, women derived greater clinical benefit from
CRT
‐D compared with implantable cardioverter‐defibrillator only, with a significant 71% reduction in
HF
or death (hazard ratio [
HR
] 0.29,
P
<0.001) and a 77% reduction in
HF
alone (
HR
0.23,
P
<0.001) compared with men, who had a 41% reduction in
HF
or death (
HR
0.59,
P
<0.001) and a 50% reduction in
HF
alone (
HR
0.50,
P
<0.001) (all sex‐by‐treatment interaction
P
<0.05). Men and women had similar reduction in long‐term mortality with
CRT
‐D versus implantable cardioverter‐defibrillator only (men:
HR
0.70,
P
=0.03; women:
HR
0.59,
P
=0.04). The incremental benefit of
CRT
‐D in women for
HF
or death and
HF
alone was consistent with
QRS
<150 or >150 ms.

Conclusions

During long‐term follow‐up of mild
HF
patients with left ventricular dysfunction and wide
QRS
, both women and men with left bundle‐branch block derived sustained benefit from
CRT
‐D versus implantable cardioverter‐defibrillator only, with significant reduction in
HF
or death,
HF
alone, and all‐cause mortality regardless of
QRS
duration. There is an incremental benefit with
CRT
‐D in women for the end points of
HF
or death and
HF
alone.

Clinical Trial Registration

URL:
https://clinicaltrials.gov/
. Unique identifiers: NCT00180271, NCT01294449, and NCT02060110.
Effects of Exercise Training on Cardiorespiratory Fitness and Biomarkers of Cardiometabolic Health: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials
Authors: Lin Xiaochen , Zhang Xi , Guo Jianjun , Roberts Christian K. , McKenzie Steve , Wu Wen‐Chih , Liu Simin , Song Yiqing 
Published: September 2018

Background
Guidelines recommend exercise for cardiovascular health, although evidence from trials linking exercise to cardiovascular health through intermediate biomarkers remains inconsistent. We performed a meta‐analysis of randomized controlled trials to quantify the impact of exercise on cardiorespiratory fitness and a variety of conventional and novel cardiometabolic biomarkers in adults without cardiovascular disease.

Methods and Results
Two researchers selected 160 randomized controlled trials (7487 participants) based on literature searches of Medline, Embase, and Cochrane Central (January 1965 to March 2014). Data were extracted using a standardized protocol. A random‐effects meta‐analysis and systematic review was conducted to evaluate the effects of exercise interventions on cardiorespiratory fitness and circulating biomarkers. Exercise significantly raised absolute and relative cardiorespiratory fitness. Lipid profiles were improved in exercise groups, with lower levels of triglycerides and higher levels of high‐density lipoprotein cholesterol and apolipoprotein A1. Lower levels of fasting insulin, homeostatic model assessment–insulin resistance, and glycosylated hemoglobin A1c were found in exercise groups. Compared with controls, exercise groups had higher levels of interleukin‐18 and lower levels of leptin, fibrinogen, and angiotensin II. In addition, we found that the exercise effects were modified by age, sex, and health status such that people aged <50 years, men, and people with type 2 diabetes, hypertension, dyslipidemia, or metabolic syndrome appeared to benefit more.

Conclusions
This meta‐analysis showed that exercise significantly improved cardiorespiratory fitness and some cardiometabolic biomarkers. The effects of exercise were modified by age, sex, and health status. Findings from this study have significant implications for future design of targeted lifestyle interventions.
Clinical Utility of Ventricular Repolarization Dispersion for Real‐Time Detection of Non‐ST Elevation Myocardial Infarction in Emergency Departments
Authors: Al‐Zaiti Salah S. , Callaway Clifton W. , Kozik Teri M. , Carey Mary G. , Pelter Michele M. 
Published: September 2018

Background

A specific electrocardiographic (
ECG
) marker of ischemia would greatly improve the speed and accuracy of detecting and treating non‐
ST
elevation myocardial infarction (
NSTEMI
). We hypothesize that ischemia induces ventricular repolarization dispersion (
VRD
), altering the T‐wave before any
ST
segment deviation. We sought to evaluate the clinical utility of
VRD
to (1) detect
NSTEMI
cases in the emergency department (
ED
) and (2) identify
NSTEMI
cases at high risk for in‐hospital major adverse cardiac events (
MACEs
).

Methods and Results

We continuously recorded 12‐lead Holter
ECG
s from chest pain patients upon their arrival to the
ED
.
VRD
was quantified using principal component analysis of the 12‐lead
ECG
to compute a T‐wave complexity ratio (ie, ratio of second to first eigenvectors of repolarization). Clinical outcomes were obtained from hospital records
.
The sample was composed mainly of older males (n=369; ages 63±12 years; 63% males), and 92 (25%) had
NSTEMI
and 26 (7%) had
MACEs
. Baseline T‐wave complexity ratio modestly correlated with peak troponin levels (
r
=0.41;
P
<0.001) and was a good classifier of
NSTEMI
events (area under the curve=0.70). An increased T‐wave complexity ratio on the presenting
ECG
was strongly associated with
NSTEMI
(odds ratio [
OR]
=3.8 [2.1 to 5.8]) and in‐hospital
MACE
(
OR
=8.2 [3.1 to 21.5]).

Conclusions

A simple measure of global
VRD
on the presenting 12‐lead
ECG
correlates with ischemic myocardial injury and can discriminate
NSTEMI
cases very early during evaluation. Prospective studies should validate these findings and test whether
VRD
can guide therapy.
Toward Personalized Medicine: Using Cardiomyocytes Differentiated From Urine‐Derived Pluripotent Stem Cells to Recapitulate Electrophysiological Characteristics of Type 2 Long QT Syndrome
Authors: Jouni Mariam , Si‐Tayeb Karim , Es‐Salah‐Lamoureux Zeineb , Latypova Xenia , Champon Benoite , Caillaud Amandine , Rungoat Anais , Charpentier Flavien , Loussouarn Gildas , Baró Isabelle , Zibara Kazem , Lemarchand Patricia , Gaborit Nathalie 
Published: September 2018

Background

Human genetically inherited cardiac diseases have been studied mainly in heterologous systems or animal models, independent of patients' genetic backgrounds. Because sources of human cardiomyocytes (
CM
s) are extremely limited, the use of urine samples to generate induced pluripotent stem cell–derived
CM
s would be a noninvasive method to identify cardiac dysfunctions that lead to pathologies within patients' specific genetic backgrounds. The objective was to validate the use of CMs differentiated from urine‐derived human induced pluripotent stem (UhiPS) cells as a new cellular model for studying patients' specific arrhythmia mechanisms.

Methods and Results

Cells obtained from urine samples of a patient with long
QT
syndrome who harbored the
HERG
A561P gene mutation and his asymptomatic noncarrier mother were reprogrammed using the episomal‐based method. Uhi
PS
cells were then differentiated into
CM
s using the matrix sandwich method.

Uhi
PS
‐
CM
s showed proper expression of atrial and ventricular myofilament proteins and ion channels. They were electrically functional, with nodal‐, atrial‐ and ventricular‐like action potentials recorded using high‐throughput optical and patch‐clamp techniques. Comparison of HERG expression from the patient's Uhi
PS
‐
CM
s to the mother's Uhi
PS
‐
CM
s showed that the mutation led to a trafficking defect that resulted in reduced delayed rectifier K
+
current (I
Kr
). This phenotype gave rise to
action potential
prolongation and arrhythmias.

Conclusions
UhiPS cells from patients carrying ion channel mutations can be used as novel tools to differentiate functional CMs that recapitulate cardiac arrhythmia phenotypes.
Effect of PCSK9 Inhibition by Alirocumab on Lipoprotein Particle Concentrations Determined by Nuclear Magnetic Resonance Spectroscopy
Authors: Koren Michael J. , Kereiakes Dean , Pourfarzib Ray , Winegar Deborah , Banerjee Poulabi , Hamon Sara , Hanotin Corinne , McKenney James M. 
Published: September 2018

Background

In patients with discordance between low‐density lipoprotein (
LDL
) cholesterol and
LDL
particle (
LDL
‐P) concentrations, cardiovascular risk more closely correlates with
LDL
−P.

Methods and Results

We investigated the effect of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, on lipoprotein particle concentration and size in hypercholesterolemic patients, using nuclear magnetic resonance spectroscopy. Plasma samples were collected from patients receiving alirocumab 150 mg every 2 weeks (n=26) or placebo (n=31) during a phase
II
, double‐blind, placebo‐controlled trial in patients (
LDL
cholesterol ≥100 mg/
dL
) on a stable atorvastatin dose. In this post hoc analysis, percentage change in concentrations of
LDL
−P, very‐low‐density lipoprotein particles, and high‐density lipoprotein particles from baseline to week 12 was determined by nuclear magnetic resonance. Alirocumab significantly reduced mean concentrations of total
LDL
‐P (−63.3% versus −1.0% with placebo) and large (−71.3% versus −21.8%) and small (−54.0% versus +17.8%)
LDL
‐P subfractions and total very‐low‐density lipoprotein particle concentrations (−36.4% versus +33.4%; all
P
<0.01). Total high‐density lipoprotein particles increased with alirocumab (+11.2% versus +1.4% with placebo;
P
<0.01). There were greater increases in large (44.6%) versus medium (17.7%) or small high‐density lipoprotein particles (2.8%) with alirocumab.
LDL
‐P size remained relatively unchanged in both groups; however, very‐low‐density and high‐density lipoprotein particle sizes increased to a significantly greater extent with alirocumab.

Conclusions

Alirocumab significantly reduced
LDL
‐C and
LDL
‐P concentrations in hypercholesterolemic patients receiving stable atorvastatin therapy. These findings may be of particular relevance to patients with discordant
LDL
‐C and
LDL
‐P concentrations.

Clinical Trial Registration

URL
:
https://clinicaltrials.gov
. Unique identifier: NCT01288443.
Hemodynamic Correlates of Abnormal Aortic Root Dimension in an Adult Population: The Strong Heart Study
Authors: de Simone Giovanni , Roman Mary J. , De Marco Marina , Bella Jonathan N. , Izzo Raffaele , Lee Elisa T. , Devereux Richard B. 
Published: September 2018

Background
We evaluated the relationship of aortic root dimension (ARD) with flow output and both peripheral and central blood pressure, using multivariable equations predicting ideal sex‐specific ARD at a given age and body height.

Methods and Results

We measured echocardiographic diastolic ARD at the sinuses of Valsalva in 3160 adults (aged 42±16 years, 61% women) from the fourth examination of the Strong Heart Study who were free of prevalent coronary heart disease, and we compared measured data with the theoretical predicted value to calculate a
z
score. Central blood pressure was estimated by applanation tonometry of the radial artery in 2319 participants. ARD
z
scores were divided into tertiles representing small, normal, and large ARD. Participants with large ARD exhibited greater prevalence of central obesity and higher levels of inflammatory markers and lipids (0.05<
P
<0.0001). Stroke volume, heart rate, and both cuff and central diastolic blood pressure were progressively greater from small to large ARD (all
P
<0.0001). Pulse pressure was higher in small ARD (
P
<0.0001). In multivariable analysis, ARD
z
score was related positively to stroke volume, either cuff or central diastolic blood pressure, and negatively to pulse pressure. Large ARD was also independently correlated to higher waist circumference and percentages of neutrophils and plasminogen activator inhibitor‐1 (all
P
<0.01).

Conclusions
Aortic root dilatation is associated with high diastolic blood pressure, high stroke volume, central fat distribution, and inflammatory status. In contrast, at a given diastolic blood pressure and stroke volume, aortic root dilatation is associated with lower pulse pressure and systolic blood pressure.
Rescue of Pressure Overload‐Induced Heart Failure by Estrogen Therapy
Authors: Iorga Andrea , Li Jingyuan , Sharma Salil , Umar Soban , Bopassa Jean C. , Nadadur Rangarajan D. , Centala Alexander , Ren Shuxun , Saito Tomoaki , Toro Ligia , Wang Yibin , Stefani Enrico , Eghbali Mansoureh 
Published: September 2018

Background

Estrogen pretreatment has been shown to attenuate the development of heart hypertrophy, but it is not known whether estrogen could also
rescue
heart failure (
HF
). Furthermore, the heart has all the machinery to locally biosynthesize estrogen via aromatase, but the role of local cardiac estrogen synthesis in
HF
has not yet been studied. Here we hypothesized that cardiac estrogen is reduced in
HF
and examined whether exogenous estrogen therapy can rescue
HF
.

Methods and Results

HF
was induced by transaortic constriction in mice, and once mice reached an ejection fraction (
EF
) of ≈35%, they were treated with estrogen for 10 days. Cardiac structure and function, angiogenesis, and fibrosis were assessed, and estrogen was measured in plasma and in heart. Cardiac estrogen concentrations (6.18±1.12 pg/160 mg heart in
HF
versus 17.79±1.28 pg/mL in control) and aromatase transcripts (0.19±0.04, normalized to control,
P
<0.05) were significantly reduced in
HF
. Estrogen therapy increased cardiac estrogen 3‐fold and restored aromatase transcripts. Estrogen also rescued
HF
by restoring ejection fraction to 53.1±1.3% (
P
<0.001) and improving cardiac hemodynamics both in male and female mice. Estrogen therapy stimulated angiogenesis as capillary density increased from 0.66±0.07 in
HF
to 2.83±0.14 (
P
<0.001, normalized to control) and reversed the fibrotic scarring observed in
HF
(45.5±2.8% in
HF
versus 5.3±1.0%,
P
<0.001). Stimulation of angiogenesis by estrogen seems to be one of the key mechanisms, since in the presence of an angiogenesis inhibitor estrogen failed to rescue
HF
(ejection fraction=29.3±2.1%,
P
<0.001 versus E2).

Conclusions

Estrogen rescues pre‐existing
HF
by restoring cardiac estrogen and aromatase, stimulating angiogenesis, and suppressing fibrosis.
Subcutaneous Implantable Cardioverter Defibrillator in Patients With Hypertrophic Cardiomyopathy: An Initial Experience
Authors: Weinstock Jonathan , Bader Yousef H. , Maron Martin S. , Rowin Ethan J. , Link Mark S. 
Published: September 2018

Background

The subcutaneous implantable cardioverter defibrillator (S‐
ICD
) has been developed to avert risks associated with transvenous defibrillator leads. The technology is attractive for younger patients, such as those with hypertrophic cardiomyopathy (HCM). However, there are limited data on S‐
ICD
use in
HCM
.

Methods and Results

HCM
patients identified at risk for sudden death were considered for S‐
ICD
implantation. Patients were screened for potential oversensing by surface electrocardiography (ECG). At implant, defibrillation threshold (
DFT
) testing was performed at 65, 50, and 35 joules (J). Twenty‐seven patients were considered for S‐
ICD
implantation, and after screening, 23 (85%) remained eligible. The presence of a bundle branch block was associated with screening failure, whereas elevated body mass index (BMI) showed a trend toward association. One patient passed screening at rest, but failed with an
ECG
obtained after exercise. At implant, the S‐
ICD
terminated ventricular fibrillation (
VF
) with a 65J shock in all 15 implanted patients and a 50J shock was successful in 12 of 15. A 35J shock terminated
VF
in 10 of 12 patients.
DFT
failure at 50 J was associated with a higher
BMI
. There were no appropriate shocks after a median follow‐up of 17.5 (3–35) months, and 1 patient received an inappropriate shock attributable to a temporary reduction in
QRS
amplitude while bending forward, resulting in oversensing, despite successful screening.

Conclusions

In a high‐risk
HCM
cohort without a pacing indication referred for consideration of an
ICD
, the majority were eligible for S‐
ICD
. The S‐
ICD
is effective at recognizing and terminating
VF
at implant with a wide safety margin.
Impact of Nitrate Use on Survival in Acute Heart Failure: A Propensity‐Matched Analysis
Authors: Ho Edwin C. , Parker John D. , Austin Peter C. , Tu Jack V. , Wang Xuesong , Lee Douglas S. 
Published: September 2018

Background
There is limited evidence that the use of nitrates in acute decompensated heart failure early after presentation to a hospital can improve clinical outcomes. We aimed to determine whether early nitrate exposure is associated with improved survival in a large retrospective cohort study.

Methods and Results

We examined 11 078 acute decompensated heart failure patients who presented to emergency departments in Ontario, Canada, between 2004 and 2007, in the Enhanced Feedback For Effective Cardiac Treatment and the Emergency Heart failure Mortality Risk Grade studies. In propensity‐matched analyses, we examined the effect of nitrate administration in the acute emergency department setting for its impact on death at 7, 30, and 365 days. In propensity‐matched analyses, we found no difference in survival between those who received nitrates in the emergency department and the non‐nitrate comparator group. Hazard ratios for mortality were 0.76 (95%
CI
; 0.51, 1.12) over 7 days, 0.97 (95%
CI
; 0.77, 1.21) over 30 days, and 0.91 (95%
CI
; 0.82, 1.02) over 1 year of follow‐up. There was no significant difference in survival or hospital length of stay between nitrate and non‐nitrate controls in extended follow‐up. There was also no significant effect of nitrates in subgroups stratified by presence of chest pain, troponin elevation, chronic nitrate use, and known coronary artery disease.

Conclusions
In acute decompensated heart failure, use of nitrates acutely in the emergency department setting was not associated with improvement in short‐term or near‐term survival. Our study does not support generalized use of nitrates when the primary goal of therapy is to reduce mortality.
Synergistic Utility of Brain Natriuretic Peptide and Left Ventricular Strain in Patients With Significant Aortic Stenosis
Authors: Goodman Andrew , Kusunose Kenya , Popovic Zoran B. , Parikh Roosha , Barr Tyler , Sabik Joseph F. , Rodriguez L. Leonardo , Svensson Lars G. , Griffin Brian P. , Desai Milind Y. 
Published: September 2018

Background

In aortic stenosis (
AS
), symptoms and left ventricular (
LV
) dysfunction represent a later disease state, and objective parameters that identify incipient
LV
dysfunction are needed. We sought to determine prognostic utility of brain natriuretic peptide (
BNP
) and left ventricular global longitudinal strain (
LV
‐
GLS
) in patients with aortic valve area <1.3 cm
2
.

Methods and Results

Five‐hundred and thirty‐one patients between January 2007 and December 2008 with aortic valve area <1.3 cm
2
(86% with aortic valve area ≤1.1 cm
2
) and left ventricular ejection fraction ≥50% who had
BNP
drawn ≤90 days from initial echo were included. Society of Thoracic Surgeons (
STS
) score and mortality were recorded. Mean
STS
score, glomerular filtration rate, and median
BNP
were 11±5, 73±35 mL/min per 1.73 m , and 141 (60–313) pg/mL, respectively; 78% were in New York Heart Association class ≥II. Mean
LV
‐stroke volume index (
LV
‐
SVI
) and
LV
‐
GLS
were 39±10 mL/m
2
and −13.9±3%. At 4.7±2 years, 405 patients (76%) underwent aortic valve replacement; 161 died (30%). On multivariable survival analysis, age (hazard ratio [
HR
] 1.46), New York Heart Association class (
HR
1.27), coronary artery disease (
HR
1.72), decreasing glomerular filtration rate (
HR
1.15), increasing
BNP
(
HR
1.16), worsening
LV
‐
GLS
(
HR
1.13) and aortic valve replacement (time dependent) (
HR
0.34) predicted survival (all
P
<0.01). For mortality, the c‐statistic incrementally increased as follows (all
P
<0.01):
STS
score (0.60 [0.58–0.64]),
STS
score+
BNP
(0.67 [0.62–0.70]), and
STS
score+
BNP
+
LV
‐
GLS
(0.74 [0.68–0.78]).

Conclusions

In normal
LVEF
patients with significant aortic stenosis,
BNP
and
LV
‐
GLS
provide incremental (additive not duplicative) prognostic information over established predictors, suggesting that both play a synergistic role in defining outcomes.
Potential Role of Regulator of G‐Protein Signaling 5 in the Protection of Vagal‐Related Bradycardia and Atrial Tachyarrhythmia
Authors: Qin Mu , Liu Xu , Liu Tao , Wang Teng , Huang Congxin 
Published: September 2018

Background

The regulator of G‐protein signaling 5 (Rgs5), which functions as the regulator of G‐protein‐coupled receptor (
GPCR
) including muscarinic receptors, has a potential effect on atrial muscarinic receptor‐activated

I
KA

ch
current.

Methods and Results

In the present study, hearts of Rgs5 knockout (
KO
) mice had decreased low‐frequency/high‐frequency ratio in spectral measures of heart rate variability. Loss of Rgs5 provoked dramatically exaggerated bradycardia and significantly (
P
<0.05) prolonged sinus nodal recovery time in response to carbachol (0.1 mg/kg, intraperitoneally). Compared to those from wild‐type (
WT
) mice, Langendorff perfused hearts from Rgs5
KO
mice had significantly (
P
<0.01) abbreviated atrial effective refractory periods and increased dominant frequency after administration of acetylcholine (
AC
h; 1 μmol/L). In addition, whole patch clamp analyses of single atrial myocytes revealed that the
AC
h‐regulated potassium current (

I
KA

ch
) was significant increased in the time course of activation and deactivation (
P
<0.01) in Rgs5
KO
, compared to those in
WT
, mice. To further determine the effect of Rgs5, transgenic mice with cardiac‐specific overexpression of human Rgs5 were found to be resistant to
AC
h‐related effects in bradycardia, atrial electrophysiology, and atrial tachyarrhythmia (
AT
).

Conclusion

The results of this study indicate that, as a critical regulator of parasympathetic activation in the heart, Rgs5 prevents vagal‐related bradycardia and
AT
through negatively regulating the

I
KA

ch
current.