bluuebunny/crossref_metadata_2025 huggingface dataset:
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 Visit‐to‐Visit Variation of Heart Rate and Systolic Blood Pressure on Outcomes in Chronic Systolic Heart Failure: Results From the Systolic Heart Failure Treatment With the
I
f
Inhibitor Ivabradine Trial (SHIFT) Trial
Authors: Böhm Michael , Robertson Michele , Borer Jeffrey , Ford Ian , Komajda Michel , Mahfoud Felix , Ewen Sebastian , Swedberg Karl , Tavazzi Luigi
Published: September 2018

Background

Elevated resting heart rate (
HR
) and low systolic blood pressure (
SBP
) are related to poor outcomes in heart failure (
HF
). The association between visit‐to‐visit variation in
SBP
and
HR
and risk in
HF
is unknown.

Methods and Results

In Systolic Heart Failure Treatment with the
I
f
inhibitor ivabradine Trial (
SHIFT
) patients, we evaluated relationships between mean
HR
, mean
SBP
, and visit‐to‐visit variations (coefficient of variation [
CV
]=
SD
/mean×100%) in
SBP
and
HR
(
SBP
‐
CV
and
HR
‐
CV
, respectively) and primary composite endpoint (cardiovascular mortality or
HF
hospitalization), its components, all‐cause mortality, and all‐cause hospitalization. High
HR
and low
SBP
were closely associated with risk for primary endpoint, all‐cause mortality, and
HF
hospitalization. The highest number of primary endpoint events occurred in the highest
HR
tertile (38.8% vs 16.4% lowest tertile;
P
<0.001). For
HR
‐
CV
, patients at highest risk were those in the lowest tertile. Patients in the lowest thirds of mean
SBP
and
SBP
‐
CV
had the highest risk. The combination of high
HR
and low
HR
‐
CV
had an additive deleterious effect on risk, as did that of low
SBP
and low
SBP
‐
CV
. Ivabradine reduced mean
HR
and increased
HR
‐
CV
, and increased
SBP
and
SBP
‐
CV
slightly.

Conclusions

Beyond high
HR
and low
SBP
, low
HR
‐
CV
and low
SBP
‐
CV
are predictors of cardiovascular outcomes with additive effects on risk in
HF
, but with an unknown effect size. Beyond
HR
reduction, ivabradine increases
HR
‐
CV
. Low visit‐to‐visit variation of
HR
and
SBP
might signal risk of cardiovascular outcomes in systolic
HF
.

Clinical Trial Registration

URL
:
http://www.isrctn.com/
. Unique identifier:
ISRCTN
70429960.
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.
Progression of Electrocardiographic Abnormalities in Type 1 Diabetes During 16 Years of Follow‐up: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study
Authors: Soliman Elsayed Z. , Backlund Jye‐Yu C. , Bebu Ionut , Li Yabing , Zhang Zhu‐Ming , Cleary Patricia A. , Lachin John M. ,   for the DCCT/EDIC Research Group
Published: September 2018

Background

The electrocardiogram (
ECG
) is an objective tool for cardiovascular disease (
CVD
) risk assessment.

Methods and Results

We evaluated distribution of
ECG
abnormalities and risk factors for developing new abnormalities in 1314 patients with type 1 diabetes (T1D) from the Epidemiology of Diabetes Interventions and Complications (
EDIC
) study. Annual
ECG
s were centrally read.
ECG
abnormalities were classified as major and minor according to the Minnesota
ECG
Classification. At
EDIC
year 1 (baseline), 356 (27.1%) of the participants had at least 1
ECG
abnormality (major or minor) whereas 26 (2%) had at least one major abnormality. During 16 years of follow‐up, 1016 (77.3%) participants developed at least 1 new
ECG
abnormality (major or minor), whereas 172 (13.1%) developed at least 1 new major abnormality. Independent risk factors for developing new major
ECG
abnormalities were: age, current smoking, increased systolic blood pressure, and higher glycosylated hemoglobin (hazard ratio [
HR
] [95%
CI
]: 1.04 [1.02–1.06] per 1‐year increase, 1.75 [1.22–2.53], 1.03 [1.01–1.05] per 1 mm Hg increase, and 1.16 [1.04–1.29] per 10% increase, respectively). Independent risk factors for developing any new
ECG
abnormalities (major or minor) were age and systolic blood pressure (
HR
[95%
CI
]: 1.02 [1.01–1.03] per 1‐year increase and 1.01 [1.00–1.02] per 1 mm Hg increase, respectively).

Conclusions

New
ECG
abnormalities commonly occur in the course of T1D, consistent with the recognized increasing risk for
CVD
as patients age. Advanced age, increased systolic blood pressure, smoking, and higher HbA1c are independent risk factor for developing major
ECG
abnormalities, which underscores the importance of tight glucose control in T1D in addition to management of common
CVD
risk factors.
Percutaneous Patent Ductus Arteriosus (PDA) Closure in Very Preterm Infants: Feasibility and Complications
Authors: Backes Carl H. , Cheatham Sharon L. , Deyo Grace M. , Leopold Scott , Ball Molly K. , Smith Charles V. , Garg Vidu , Holzer Ralf J. , Cheatham John P. , Berman Darren P.
Published: September 2018

Background

Percutaneous closure of patent ductus arteriosus (
PDA
) in term neonates is established, but data regarding outcomes in infants born very preterm (<32 weeks of gestation) are minimal, and no published criteria exist establishing a minimal weight of 4 kg as a suitable cutoff. We sought to analyze outcomes of percutaneous
PDA
occlusion in infants born very preterm and referred for
PDA
closure at weights <4 kg.

Methods and Results

Retrospective analysis (January 2005–January 2014) was done at a single pediatric center. Procedural successes and adverse events were recorded. Markers of respiratory status (need for mechanical ventilation) were determined, with comparisons made before and after catheterization. A total of 52 very preterm infants with a median procedural weight of 2.9 kg (range 1.2–3.9 kg) underwent attempted
PDA
closure. Twenty‐five percent (13/52) of infants were <2.5 kg. Successful device placement was achieved in 46/52 (88%) of infants. An adverse event occurred in 33% of cases, with an acute arterial injury the most common complication. We observed no association between weight at time of procedure and the risk of an adverse event. No deaths were attributable to the
PDA
closure. Compared to precatheterization trends, percutaneous
PDA
closure resulted in improved respiratory status, including less exposure to mechanical ventilation (mixed effects logistic model,
P
<0.01).

Conclusions

Among infants born very preterm, percutaneous
PDA
closure at weights <4 kg is generally safe and may improve respiratory health, but risk of arterial injury is noteworthy. Randomized clinical trials are needed to assess clinically relevant differences in outcomes following percutaneous
PDA
closure versus alternative (surgical ligation) management strategies.
Two C‐C Family Chemokines, Eotaxin and RANTES, Are Novel Independent Plasma Biomarkers for Abdominal Aortic Aneurysm
Authors: Jones Gregory T. , Phillips L. Victoria , Williams Michael J.A. , van Rij Andre M. , Kabir Tasnuva D.
Published: September 2018

Background

Inflammation of the aortic wall is recognised as a key pathogenesis of abdominal aortic aneurysm (
AAA
). This study was undertaken to determine whether inflammatory cytokines could be used as biomarkers for the presence of
AAA
.

Methods and Results

Tissue profiles of 27 inflammatory cytokine were examined in
AAA
(n=14) and nonaneurysmal (n=14) aortic tissues. Three cytokines, regulated upon activation normally T‐cell expressed and secreted (
RANTES
), eotaxin, and macrophage inflammatory protein 1 beta (
MIP‐
1b), had increased expression in
AAA
, particularly within the adventitial layer of the aortic wall. Basic fibroblast growth factor (
bFGF
) had reduced expression in all layers of the
AAA
wall. Examination of the circulating plasma profiles of
AAA
(n=442) and
AAA
‐free controls (n=970) suggested a (risk factor adjusted)
AAA
‐association with eotaxin,
RANTES
, and high sensitivity C‐reactive protein (hs
CRP
). A plasma inflammatory cytokine score, calculated using these three markers, suggested a strong risk association with
AAA
(odds ratio, 4.8; 95%
CI
, 3.5–6.7;
P
<0.0001), independent of age, sex, history of ischemic heart disease, and smoking.

Conclusions

Contrary to reports suggesting a distinct T helper 2–associated inflammatory profile in
AAA
, this current study suggests a more‐generalized pattern of inflammation, albeit with some potentially distinct features, including elevated plasma eotaxin and decreased plasma
RANTES
. In combination with hs
CRP
, these markers may have potential utility as
AAA
biomarkers.
Prognostic Value of Aortic Valve Area by Doppler Echocardiography in Patients With Severe Asymptomatic Aortic Stenosis
Authors: Maréchaux Sylvestre , Ringle Anne , Rusinaru Dan , Debry Nicolas , Bohbot Yoan , Tribouilloy Christophe
Published: September 2018

Background

The aim of this study was to evaluate the relationship between aortic valve area (
AVA
) obtained by Doppler echocardiography and outcome in patients with severe asymptomatic aortic stenosis and to define a specific threshold of
AVA
for identifying asymptomatic patients at very high risk based on their clinical outcome.

Methods and Results

We included 199 patients with asymptomatic severe aortic stenosis (
AVA
≤1.0 cm
2
). The risk of events (death or need for aortic valve replacement) increased linearly on the scale of log hazard with decreased
AVA
(adjusted hazard ratio 1.17; 95%
CI
1.06–1.29 per 0.1 cm
2
AVA
decrement;
P
=0.002). Event‐free survival at 12, 24, and 48 months was 63±6%, 51±6%, and 34±6%, respectively, for
AVA
0.8 to 1 cm
2
; 49±6%, 36±6%, and 26±6%, respectively, for
AVA
0.6 to 0.8 cm
2
; and 33±8%, 20±7%, and 11±5%, respectively, for
AVA
≤0.6 cm
2
(
P
trend
=0.002). Patients with
AVA
≤0.6 cm
2
had a significantly increased risk of events compared with patients with
AVA
0.8 to 1 cm
2
(adjusted hazard ratio 2.22; 95%
CI
1.41–3.52;
P
=0.001), whereas patients with
AVA
0.6 to 0.8 cm
2
had an increased risk of events compared with those with
AVA
0.8 to 1 cm
2
, but the difference was not statistically significant (adjusted hazard ratio 1.38; 95%
CI
0.93–2.05;
P
=0.11). After adjustment for covariates and aortic valve replacement as a time‐dependent variable, patients with
AVA
≤0.6 cm
2
had a significantly greater risk of all‐cause mortality than patients with
AVA
>0.6 cm
2
(hazard ratio 3.39; 95%
CI
1.80–6.40;
P
<0.0001).

Conclusions

Patients with severe asymptomatic aortic stenosis and
AVA
≤0.6 cm
2
displayed an important increase in the risk of adverse events during short‐term follow‐up. Further studies are needed to determine whether elective aortic valve replacement improves outcome in this high‐risk subgroup of patients.
Relationship of the American Heart Association's Impact Goals (Life's Simple 7) With Risk of Chronic Kidney Disease: Results From the Atherosclerosis Risk in Communities (ARIC) Cohort Study
Authors: Rebholz Casey M. , Anderson Cheryl A. M. , Grams Morgan E. , Bazzano Lydia A. , Crews Deidra C. , Chang Alex R. , Coresh Josef , Appel Lawrence J.
Published: September 2018

Background

As part of its 2020 Impact Goals, the American Heart Association developed the Life's Simple 7 metric for cardiovascular health promotion. The relationship between the Life's Simple 7 metric and incident chronic kidney disease (
CKD
) is unknown.

Methods and Results

We estimated the association between Life's Simple 7 and incident
CKD
in 14 832 Atherosclerosis Risk in Communities study participants. Ideal levels of Life's Simple 7 health factors were the following: nonsmoker or quit >1 year ago; body mass index <25 kg/m
2
; ≥150 minutes/week of physical activity; healthy dietary pattern (high in fruits and vegetables, fish, and fiber‐rich whole grains; low in sodium and sugar‐sweetened beverages); total cholesterol <200 mg/dL; blood pressure <120/80 mm Hg; and fasting blood glucose <100 mg/dL. At baseline, mean age was 54 years, 55% were women, and 26% were African American. There were 2743 incident
CKD
cases over a median follow‐up of 22 years. Smoking, body mass index, physical activity, blood pressure, and blood glucose were associated with
CKD
risk (all
P
<0.01), but diet and blood cholesterol were not.
CKD
risk was inversely related to the number of ideal health factors (
P
‐trend<0.001). A model containing the Life's Simple 7 health factors was more predictive of
CKD
risk than the base model including only age, sex, race, and estimated glomerular filtration rate (Life's Simple 7 health factors area under the
ROC
curve: 0.73, 95%
CI
: 0.72, 0.74 versus base model area under the
ROC
curve: 0.68, 95%
CI
: 0.67, 0.69;
P
<0.001).

Conclusions

The
AHA
's Life's Simple 7 metric, developed to measure and promote cardiovascular health, predicts a lower risk of
CKD
.
Ribonuclease (RNase) Prolongs Survival of Grafts in Experimental Heart Transplantation
Authors: Kleinert Eike , Langenmayer Martin C. , Reichart Bruno , Kindermann Jana , Griemert Barbara , Blutke Andreas , Troidl Kerstin , Mayr Tanja , Grantzow Tobias , Noyan Fatih , Abicht Jan‐Michael , Fischer Silvia , Preissner Klaus T. , Wanke Ruediger , Deindl Elisabeth , Guethoff Sonja
Published: September 2018

Background

Cell damage, tissue and vascular injury are associated with the exposure and release of intracellular components such as
RNA
, which promote inflammatory reactions and thrombosis. Based on the counteracting anti‐inflammatory and cardioprotective functions of ribonuclease A (
RN
ase A) in this context, its role in an experimental model of heart transplantation in rats was studied.

Methods and Results

Inbred
BN
/OrlRj rat cardiac allografts were heterotopically transplanted into inbred
LEW
/OrlRj rats. Recipients were intravenously treated every other day with saline or bovine pancreatic
RN
ase A (50 μg/kg). Toxic side effects were not found (macroscopically and histologically). Heart tissue flow cytometry and quantitative morphological analyses of explanted hearts at postoperative day 1 or postoperative day 4 showed reduced leukocyte infiltration, edema, and thrombus formation in
RN
ase A‐treated rats. In allogeneic mixed lymphocyte reactions,
RN
ase A decreased the proliferation of effector T cells.
RN
ase A treatment of rats resulted in prolonged median graft survival up to 10.5 days (interquartile range 1.8) compared to 6.5 days (interquartile range 1.0) in saline treatment (
P
=0.001). Treatment of rats with a new generated (recombinant) human pancreatic
RN
ase 1 prolonged median graft survival similarly, unlike treatment with (recombinant) inactive human
RN
ase 1 (each 50 μg/kg
IV
every other day, 11.0 days, interquartile range 0.3, versus 8.0 days, interquartile range 0.5,
P
=0.007).

Conclusions

Upon heart transplantation,
RN
ase administration appears to present a promising and safe drug to counteract ischemia/reperfusion injury and graft rejection. Furthermore,
RN
ase treatment may be considered in situations of critical reperfusion after percutaneous coronary interventions or in cardiac surgery using the heart–lung machine.
Long‐Term Outcomes of Cardiac Resynchronization Therapy Using Apical Versus Nonapical Left Ventricular Pacing
Authors: Leyva Francisco , Zegard Abbasin , Taylor Robin J. , Foley Paul W. X. , Umar Fraz , Patel Kiran , Panting Jonathan , van Dam Peter , Prinzen Frits W. , Marshall Howard , Qiu Tian
Published: September 2018

Background

Experimental evidence indicates that left ventricular (
LV
) apical pacing is hemodynamically superior to nonapical
LV
pacing. Some studies have shown that an LV apical lead position is unfavorable in cardiac resynchronization therapy. We sought to determine whether an apical
LV
lead position influences cardiac mortality after cardiac resynchronization therapy.

Methods and Results

In this retrospective observational study, the primary end point of cardiac mortality was assessed in relation to longitudinal (basal, midventricular, or apical) and circumferential (anterior, lateral, or posterior)
LV
lead positions, as well as right ventricular (apical or septal), assigned using fluoroscopy. Lead positions were assessed in 1189 patients undergoing cardiac resynchronization therapy implantation over 15 years. After a median follow‐up of 6.0 years (interquartile range: 4.4–7.7 years), an apical
LV
lead position was associated with lower cardiac mortality than a nonapical position (adjusted hazard ratio: 0.74; 95% confidence interval, 0.56–0.99) after covariate adjustment. There were no differences in total mortality or heart failure hospitalization. Death from pump failure was lower with apical than nonapical positions (adjusted hazard ratio: 0.69; 95% confidence interval, 0.51–0.94). Compared with a basal position, an apical
LV
position was also associated with lower risk of sudden cardiac death (adjusted hazard ratio: 0.34; 95% confidence interval, 0.13–0.93). No differences emerged between circumferential
LV
lead positions or right ventricular positions with respect to any end point.

Conclusions

In recipients of cardiac resynchronization therapy, an apical
LV
lead position was associated with better long‐term cardiac survival than a nonapical position. This effect was due to a lower risk of pump failure and sudden cardiac death.
Stroke Risk and Treatment in Patients with Atrial Fibrillation and Low CHA
2
DS
2
‐VASc Scores: Findings From the ORBIT‐AF I and II Registries
Authors: Jackson Larry R. , Kim Sunghee , Fonarow Gregg C. , Freeman James V. , Gersh Bernard J. , Go Alan S. , Hylek Elaine M. , Kowey Peter R. , Mahaffey Kenneth W. , Singer Daniel , Thomas Laine , Blanco Rosalia , Peterson Eric D. , Piccini Jonathan P. ,   the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Patients and Investigators
Published: September 2018

Background

Current American College of Cardiology/American Heart Association guidelines suggest that for patients with atrial fibrillation who are at low risk for stroke (CHA
2
DS
2
VASc=1) (or women with CHA
2
DS
2
VASc=2) a variety of treatment strategies may be considered. However, in clinical practice, patterns of treatment in these “low‐risk” patients are not well described. The objective of this analysis is to define thromboembolic event rates and to describe treatment patterns in patients with low‐risk CHA
2
DS
2
VASc scores.

Methods and Results

We compared characteristics, treatment strategies, and outcomes among patients with a CHA
2
DS
2
VASc=0, CHA
2
DS
2
VASc=1, females with a CHA
2
DS
2
VASc=2, and CHA
2
DS
2
VASc ≥2 in ORBIT‐AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) I & II. Compared with CHA
2
DS
2
VASc ≥2 patients (84.2%), those with a CHA
2
DS
2
VASc=0 (60.3%), 1 (69.9%), and females with a CHA
2
DS
2
VASc score=2 (72.4%) were significantly less often treated with oral anticoagulation (
P
<0.0001). Stroke rates were low overall and ranged from 0 per 100 patient‐years in those with CHA
2
DS
2
VASc=0, 0.8 (95% confidence interval [CI] [0.5–1.2]) in those with CHA
2
DS
2
VASc=1, 0.8 (95% CI [0.4–1.6]) in females with a CHA
2
DS
2
VASc score=2, and 1.7 (95% CI [1.6–1.9]) in CHA
2
DS
2
VASc ≥2. All‐cause mortality (per 100 patient‐years) was highest in females with a CHA
2
DS
2
VASc score=2 (1.4) (95% CI [0.8–2.3]), compared with patients with a CHA
2
DS
2
VASc=0 (0.2) (95% CI [0.1–1.0]), and CHA
2
DS
2
VASc=1 (1.0) (95% CI [0.7–1.4]), but lower than patients with a CHA
2
DS
2
VASc ≥2 (5.7) (95% CI [5.4–6.0]).

Conclusion

The majority of CHA
2
DS
2
VASc=0‐1 patients are treated with oral anticoagulation. In addition, the absolute risks of death and stroke/transient ischemic attack were low among both male and females CHA
2
DS
2
VASc=0‐1 as well as among females with a CHA
2
DS
2
VASc score=2.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01701817.
Activin Receptor‐Like Kinase 4 Haplodeficiency Mitigates Arrhythmogenic Atrial Remodeling and Vulnerability to Atrial Fibrillation in Cardiac Pathological Hypertrophy
Authors: Wang Qian , Chen Yihe , Zhang Daoliang , Li Changyi , Chen Xiaoqing , Hou Jianwen , Fei Yudong , Wang Yuepeng , Li Yigang
Published: September 2018

Background

Activin receptor‐like kinase 4 (
ALK
4) is highly expressed in mammal heart. Atrial fibrillation (
AF
) is closely related to ventricular pressure overload. Because pressure overload increases atrial pressure and leads to atrial remodeling, it would be informative to know whether
ALK
4 exerts potential effects on atrial remodeling and
AF
vulnerability in a pressure‐overload model.

Methods and Results

Wild‐type littermates and
ALK
4
+/−
mice were subjected to abdominal aortic constriction or a sham operation. After 4 or 8 weeks, echocardiographic and hemodynamic measurements were performed, and inducibility of
AF
was tested. The hearts were divided into atria and ventricles and then were fixed in formalin for staining, or they were weighted and snap‐frozen for quantitative real‐time polymerase chain reaction and Western blot analysis. Compared with wild‐type littermates,
ALK
4
+/−
mice demonstrated a similar extent of atrial hypertrophy but significantly suppressed atrial fibrosis at 8 weeks post–abdominal aortic constriction.
ALK
4 haplodeficiency partially blocked abdominal aortic constriction–induced upregulation of monocyte chemotactic protein 1 and interleukin‐6, and the increased chemotaxin of macrophages.
ALK
4 haplodeficiency also blunted a reduction of connexin 40 and redistribution of connexin 43 from the intercalated disk to the lateral membranes, thereby improving localized conduction abnormalities. Meanwhile,
ALK
4 haplodeficiency inhibited abdominal aortic constriction–induced decreased

I
N

a
,

I
C

a‐L
and

I
K

1
densities as well as the accompanying action potential duration shortening. Mechanistically,
ALK
4 haploinsufficiency resulted in the suppression of Smad2/3 activity in this model.

Conclusions

Our results demonstrate that
ALK
4 haplodeficiency ameliorates atrial remodeling and vulnerability to
AF
in a pressure‐overload model through inactivation of the Smad2/3 pathway, suggesting that
ALK
4 might be a potential therapeutic target in combating pressure overload–induced
AF
.
Efficacy and Safety of Edoxaban in Patients With Active Malignancy and Atrial Fibrillation: Analysis of the ENGAGE AF‐TIMI 48 Trial
Authors: Fanola Christina L. , Ruff Christian T. , Murphy Sabina A. , Jin James , Duggal Anil , Babilonia Noe A. , Sritara Piyamitr , Mercuri Michele F. , Kamphuisen Pieter W. , Antman Elliott M. , Braunwald Eugene , Giugliano Robert P.
Published: September 2018

Background

Anticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse.

Methods and Results

The
ENGAGE AF
‐
TIMI
48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230–771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78–3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07–2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83–1.42). Relative outcomes with higher‐dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism (
HR
, 0.60 [95% CI, 0.31–1.15] for malignancy versus
HR
, 0.89 [95% CI, 0.76–1.05] for no malignancy; interaction
P
=0.25) and major bleeding (
HR
, 0.98 [95% CI, 0.69–1.40] for malignancy versus
HR
, 0.79 [95% CI, 0.69–1.05] for no malignancy; interaction
P
=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher‐dose edoxaban versus warfarin in patients with malignancy (
HR
, 0.54; 95% CI, 0.31–0.93) compared with no malignancy (
HR
, 1.02; 95% CI, 0.88–1.18; interaction
P
=0.026).

Conclusions

In patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.
Osteoprotegerin and Cardiovascular Events in High‐Risk Populations: Meta‐Analysis of 19 Prospective Studies Involving 27 450 Participants
Authors: Tschiderer Lena , Klingenschmid Gerhard , Nagrani Rajini , Willeit Johann , Laukkanen Jari A. , Schett Georg , Kiechl Stefan , Willeit Peter
Published: September 2018

Background

Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease (
CVD
) in the general population, its relevance as a biomarker among populations at high
CVD
risk is less clear.

Methods and Results

Three independent reviewers systematically searched PubMed,
EMBASE
, and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high
CVD
risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow‐up of 4.2 years, 4066
CVD
events were recorded. In a random‐effects meta‐analysis, the pooled risk ratio for
CVD
events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12–1.50;
P
<0.001; I
2
=68.3%). There was evidence for presence of publication bias (
P
value from Egger's test=0.013). Correction for publication bias using the trim‐and‐fill method reduced the risk ratio to 1.21 (95% confidence interval, 1.03–1.42;
P
<0.001). The risk ratios did not vary significantly by population type, geographical region, statistical adjustment, sample or assay type, age, sex, or length of follow‐up.

Conclusions

In populations at high
CVD
risk, elevated circulating osteoprotegerin levels are associated with a higher risk for future
CVD
events. The magnitude of association appears weaker than in the general population.
Estimated Life Expectancy Without Recurrent Cardiovascular Events in Patients With Vascular Disease: The SMART‐REACH Model
Authors: Kaasenbrood Lotte , Bhatt Deepak L. , Dorresteijn Jannick A.N. , Wilson Peter W.F. , D'Agostino Ralph B. , Massaro Joseph M. , van der Graaf Yolanda , Cramer Maarten J.M. , Kappelle L. Jaap , de Borst Gert J. , Steg Ph. Gabriel , Visseren Frank L. J.
Published: September 2018

Background

In patients with vascular disease, risk models may support decision making on novel risk reducing interventions, such as proprotein convertase subtilisin/kexin type 9 inhibitors or anti‐inflammatory agents. We developed and validated an innovative model to estimate life expectancy without recurrent cardiovascular events for individuals with coronary, cerebrovascular, and/or peripheral artery disease that enables estimation of preventive treatment effect in lifetime gained.

Methods and Results

Study participants originated from prospective cohort studies: the
SMART (Secondary Manifestations of Arterial Disease)
cohort and
REACH (Reduction of Atherothrombosis for Continued Health)
cohorts of 14 259 (
REACH
Western Europe), 19 170 (
REACH
North America) and 6959 (
SMART
, The Netherlands) patients with cardiovascular disease. The SMART‐REACH model to estimate life expectancy without recurrent events was developed in
REACH
Western Europe as a Fine and Gray competing risk model incorporating cardiovascular risk factors. Validation was performed in
REACH
North America and
SMART
. Outcomes were (1) cardiovascular events (myocardial infarction, stroke, cardiovascular death) and (2) noncardiovascular death. Predictors were sex, smoking, diabetes mellitus, systolic blood pressure, total cholesterol, creatinine, number of cardiovascular disease locations, atrial fibrillation, and heart failure. Calibration plots showed high agreement between estimated and observed prognosis in
SMART
and
REACH
North America. C‐statistics were 0.68 (95%
confidence interval,
0.67–0.70) in
SMART
and 0.67 (95%
confidence interval,
0.66–0.68) in
REACH
North America. Performance of the SMART‐REACH model was better compared with existing risk scores and adds the possibility of estimating lifetime gained by novel therapies.

Conclusions

The externally validated SMART‐REACH model could be used for estimation of anticipated improvements in life expectancy without recurrent cardiovascular events in individual patients with cardiovascular disease in Western Europe and North America.
Acute Pericarditis and Cancer Risk: A Matched Cohort Study Using Linked UK Primary and Secondary Care Data
Authors: Søgaard Kirstine Kobberøe , Sørensen Henrik Toft , Smeeth Liam , Bhaskaran Krishnan
Published: September 2018

Background

We aimed to examine whether acute pericarditis is an indicator of undetected cancer and identify patient‐level factors associated with high cancer risk among patients presenting with pericarditis.

Methods and Results

A population‐based matched cohort study was conducted using primary care data from the
UK
Clinical Practice Research Datalink linked to Hospital Episode Statistics. Patients with acute pericarditis (n=6530) were matched to a comparison cohort (n=26 111) on age, sex, calendar time, and general practice. We estimated cumulative cancer incidences, and calculated hazard ratios using Cox regression. Effect modification by patients' characteristics and lifestyle factors was examined, and we fitted a parsimonious model to evaluate absolute excess risk of later cancer among pericarditis patients by key patient‐level factors. We identified 728 and 1379 incidents of cancer among pericarditis patients and the comparison cohort (median follow‐up, 2.8 and 3.5 years). Pericarditis was associated with an elevated subsequent risk of any cancer (hazard ratio=3.03; 95% confidence interval, 2.74–3.36). The association was particularly pronounced 0 to 3 months after pericarditis (hazard ratio=23.56; 95% confidence interval, 18.00–30.83), but a more‐modest association remained thereafter (hazard ratio=1.95; 95% confidence interval, 1.48–2.57 after 3–12 months, and hazard ratio=1.40; 95% confidence interval, 1.21–1.62 after >12 month). Older individuals hospitalized with pericarditis and with combinations of obesity and smoking were at the highest excess risk of having a cancer diagnosis 3 to 12 months later, reaching 4.8%.

Conclusions

Occult cancers may be going undiagnosed during the acute episode of pericarditis. Patients presenting with pericarditis and combinations of older age, obesity, smoking, and a need for hospitalization might warrant targeted investigations for cancer.