bluuebunny/crossref_metadata_2025 huggingface dataset:
Cystatin C Expression is Promoted by VEGFA Blocking, With Inhibitory Effects on Endothelial Cell Angiogenic Functions Including Proliferation, Migration, and Chorioallantoic Membrane Angiogenesis
Authors: Li Zhenkun , Wang Shiyuan , Huo Xueyun , Yu Hefen , Lu Jing , Zhang Shuangyue , Li Xiaohong , Cao Qi , Li Changlong , Guo Meng , Lv Jianyi , Du Xiaoyan , Chen Zhenwen
Published: December 2018

Background

Vascular development, including vasculogenesis and angiogenesis, is involved in many diseases. Cystatin C (
CST
3) is a commonly used marker of renal dysfunction, and we have previously reported that its expression level is associated with variations in the gerbil circle of Willis. Thus, we hypothesized that
CST
3 may affect endothelial function and angiogenic capacity. In the current study, we sought to determine the influence of
CST
3 on endothelial function and explore its potential regulatory pathway.

Methods and Results

We analyzed
CST
3 and vascular endothelial growth factor A (
VEGFA)
levels in different developmental stages of gerbils using
ELISA
s and immunofluorescence (to examine the relationship between
CST
3 and
VEGFA
. We used a real‐time cell analyzer, cytotoxicity assays, and the chorioallantoic membrane assay to investigate the function of
CST
3 in endothelial cells and the chorioallantoic membrane. Additionally, we used Western blotting to explore the downstream targets of
CST
3. The expression levels of both
CST
3 and
VEGFA
were at their highest on day 10 of the embryonic stage.
CST
3 inhibited endothelial cell proliferation, migration, tube formation, and permeability, as well as vascular development in the chorioallantoic membrane. Blocking of
VEGFA
dose‐dependently increased
CST
3 expression in arterial and venous endothelial cells. Furthermore, overexpression and knockdown of
CST
3 significantly affected the protein levels of p53 and CAPN10 (calpain 10), suggesting that
CST
3 might play a role in vascular development through these proteins.

Conclusions

CST
3 may be associated with vascular development and angiogenesis, and this effect could be promoted by blocking
VEGFA
.
Relationship Between Noninvasive Assessment of Lung Fluid Volume and Invasively Measured Cardiac Hemodynamics
Authors: Uriel Nir , Sayer Gabriel , Imamura Teruhiko , Rodgers Daniel , Kim Gene , Raikhelkar Jayant , Sarswat Nitasha , Kalantari Sara , Chung Ben , Nguyen Ann , Burkhoff Daniel , Abbo Aharon
Published: December 2018

Background

Right heart catheterization is the gold standard in clinical practice for the assessment of cardiovascular hemodynamics, but it is an invasive procedure requiring expertise in both insertion and reading. Remote dielectric sensing (Re
DS
) is a noninvasive electromagnetic‐based technology intended to quantify lung fluid content.

Methods and Results

In this prospective single‐center study, Re
DS
readings were obtained in supine position just before right heart catheterization procedure in patients with heart failure. Agreement between Re
DS
and pulmonary artery wedge pressure (
PAWP
) was analyzed. Of all, 139 patients with heart failure received hemodynamic assessment and Re
DS
measurement. A good correlation was found between Re
DS
and
PAWP
measurement (
r
=0.492,
P
<0.001). Receiver operating characteristic analysis of the ability to identify a
PAWP
≥18 mm Hg resulted in a Re
DS
cutoff value of 34%, with an area under the curve of 0.848, a sensitivity of 90.7%, and a specificity of 77.1%. Overall, Re
DS
<34% carries a high negative predictive value of 94.9%.

Conclusions

Lung fluid content, as measured by Re
DS
, correlates well with
PAWP
. The high sensitivity and specificity and especially the high negative predictive value make Re
DS
a reliable noninvasive tool at the point of care, to rule out elevated
PAWP
in patients with heart failure and to help with medical management of patients with heart failure. Further studies are warranted to compare this tool with existing tests and to relate the findings to the clinical outcomes.
Reduction in Subtypes and Sizes of Myocardial Infarction With Ticagrelor in PEGASUS–TIMI 54
Authors: Bonaca Marc P. , Wiviott Stephen D. , Morrow David A. , Steg P. Gabriel , Hamm Christian , Bhatt Deepak L. , Storey Robert F. , Cohen Marc , Kuder Julia , Im KyungAh , Magnani Giulia , Budaj Andrzej , Nicolau José C. , Parkhomenko Alexander , López‐Sendón José , Dellborg Mikael , Diaz Rafael , Van de Werf Frans , Corbalán Ramón , Goudev Assen , Jensen Eva C. , Johanson Per , Braunwald Eugene , Sabatine Marc S.
Published: December 2018

Background

Ticagrelor reduced cardiovascular death, myocardial infarction (MI), or stroke in patients with prior MI in PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events [eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin). MI can occur in diverse settings and with varying severity; therefore, understanding the types and sizes of MI events prevented is of clinical importance.

Methods and Results

MIs were adjudicated by a blinded clinical events committee and categorized by subtype and fold elevation of peak cardiac troponin over the upper limit of normal. A total of 1042 MIs occurred in 898 of the 21 162 randomized patients over a median follow‐up of 33 months. The majority of the MIs (76%) were spontaneous (Type 1), with demand MI (Type 2) and stent thrombosis (Type 4b) accounting for 13% and 9%, respectively; sudden death (Type 3), percutaneous coronary intervention–related (Type 4a) and coronary artery bypass graft–related (Type 5) each accounted for <1%. Half of MIs (520, 50%) had a peak troponin ≥10x upper limit of normal and 21% of MIs (220) had a peak troponin ≥100× upper limit of normal. A total of 21% (224) were ST‐segment–elevation MI STEMI. Overall ticagrelor reduced MI (4.47% versus 5.25%, hazard ratio 0.83, 95% confidence interval 0.72–0.95,
P
=0.0055). The benefit was consistent among the subtypes, including a 31% reduction in MIs with a peak troponin ≥100× upper limit of normal (hazard ratio 0.69, 95% confidence interval 0.53–0.92,
P
=0.0096) and a 40% reduction in ST‐segment elevation MI (hazard ratio 0.60, 95% confidence interval 0.46–0.78,
P
=0.0002).

Conclusions

In stable outpatients with prior MI, the majority of recurrent MIs are spontaneous and associated with a high biomarker elevation. Ticagrelor reduces the MI consistently among subtypes and sizes including large MIs and ST‐segment elevation MI.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01225562.
Jeopardized Myocardium Defined by Late Gadolinium Enhancement Magnetic Resonance Imaging Predicts Survival in Patients With Ischemic Cardiomyopathy: Impact of Revascularization
Authors: Kwon Deborah H. , Obuchowski Nancy A. , Marwick Thomas H. , Menon Venu , Griffin Brian , Flamm Scott D. , Hachamovitch Rory
Published: December 2018

Background

The prognostic impact of jeopardized myocardium (
JM
) in patients with advanced ischemic cardiomyopathy (
ICM
) is unclear. We hypothesized that
JM
is an independent predictor of mortality in patients with advanced
ICM
.

Methods and Results

Patients with ICM who underwent cardiac magnetic resonance imaging between January 2002 and January 2013 were included in our study.
JM
was identified as a vascular territory with <50% myocardial scarring on cardiac magnetic resonance imaging and with >70% stenosis in a major coronary vessel that was not subsequently revascularized. A propensity score was developed for revascularization. A multivariable Cox proportional hazards model was used to evaluate the association of
JM
with all‐cause mortality. We evaluated 631 patients over a mean follow‐up of 5.1 years. Overall, 336 patients underwent subsequent revascularization during the follow‐up period, among whom 23% had remaining
JM
, while 295 patients were medically treated (57% with
JM
). There were 204 deaths (32%). On multivariable analysis,
JM
(hazard ratio, 1.88; 95% confidence interval, 1.38–2.55 [
P
<0.001]) was independently associated with all‐cause mortality after adjusting for multiple other factors. The risk associated with the presence of
JM
increased by 5% for every 10‐unit increase in left ventricular end‐systolic volume index.

Conclusions

JM
is an independent and incremental predictor of mortality in patients with advanced
ICM
. Patients undergoing revascularization with residual
JM
had similar risk of mortality compared with medically treated patients with
JM
. The risk associated with
JM
significantly increased in the presence of worsening adverse left ventricular remodeling. Cardiac magnetic resonance viability assessment may provide important risk stratification in patients with
ICM
.
Neonatal and Maternal Outcomes in Pregnant Women With Cardiac Disease
Authors: Owens Amanda , Yang Jie , Nie Lizhou , Lima Fabio , Avila Cecilia , Stergiopoulos Kathleen
Published: December 2018

Background

Pregnant women with underlying heart disease (
HD
) are at increased risk for adverse maternal, obstetric, and neonatal outcomes.

Methods and Results

Inpatient maternal delivery admissions and linked neonatal stays for women with cardiomyopathy, adult congenital HD, pulmonary hypertension (
PH
), and valvular HD were explored utilizing the Statewide Planning and Research Cooperative System (New York), January 1, 2000, through December 31, 2014, with the
International Classification of Diseases, Ninth Revision
,
Clinical Modification (ICD‐9‐CM)
. Maternal major adverse cardiac events, neonatal adverse clinical events (
NACE
), and obstetric complications were recorded. Outcomes were compared using multiple logistic regression modeling. Among 2 284 044 delivery admissions, 3871 women had
HD
; 676 (17%) had cardiomyopathy, 1528 (40%) had valvular HD, 1367 (35%) had adult congenital HD, and 300 (8%) had
PH
. Major adverse cardiac events occurred in 16.1% of women with
HD
, with most in the cardiomyopathy (45.9%) and
PH
(25%) groups.
NACE
was more common in offspring of women with
HD
(18.4% versus 7.1%), with most in the cardiomyopathy (30.0%) and
PH
(25.0%) groups. Increased risk of
NACE
was noted for women with
HD
(odds ratio [
OR
]: 2.8; 95% confidence interval [
CI
], 2.5–3.0), with the highest risk for those with cardiomyopathy (
OR
: 5.9; 95%
CI
, 5.0–7.0) and
PH
(
OR
: 4.5; 95%
CI
, 3.4–5.9). Preeclampsia (
OR
: 5.1; 95%
CI
, 3.0–8.6), major adverse cardiac events (
OR
: 2.3; 95%
CI
, 1.8–2.9), preexisting diabetes mellitus (
OR
: 4.3; 95%
CI
, 1.5–12.3), and obstetric complications (
OR
: 2.9; 95%
CI
, 1.7–5.2) were independently associated with higher
NACE
risk.

Conclusions

Neonatal complications were higher in offspring of pregnant women with
HD
, particularly cardiomyopathy and
PH
. Preeclampsia, major adverse cardiac events, obstetric complications, and preexisting diabetes mellitus were independently associated with a higher risk of
NACE
.
Machine Learning Outperforms ACC/AHA CVD Risk Calculator in MESA
Authors: Kakadiaris Ioannis A. , Vrigkas Michalis , Yen Albert A. , Kuznetsova Tatiana , Budoff Matthew , Naghavi Morteza
Published: December 2018

Background

Studies have demonstrated that the current US guidelines based on American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equations Risk Calculator may underestimate risk of atherosclerotic cardiovascular disease (
CVD
) in certain high‐risk individuals, therefore missing opportunities for intensive therapy and preventing
CVD
events. Similarly, the guidelines may overestimate risk in low risk populations resulting in unnecessary statin therapy. We used Machine Learning (
ML
) to tackle this problem.

Methods and Results

We developed a
ML
Risk Calculator based on Support Vector Machines (
SVM
s) using a 13‐year follow up data set from
MESA
(the Multi‐Ethnic Study of Atherosclerosis) of 6459 participants who were atherosclerotic CVD‐free at baseline. We provided identical input to both risk calculators and compared their performance. We then used the FLEMENGHO study (the Flemish Study of Environment, Genes and Health Outcomes) to validate the model in an external cohort.
ACC
/
AHA
Risk Calculator, based on 7.5% 10‐year risk threshold, recommended statin to 46.0%. Despite this high proportion, 23.8% of the 480 “Hard
CVD
” events occurred in those not recommended statin, resulting in sensitivity 0.76, specificity 0.56, and
AUC
0.71. In contrast,
ML
Risk Calculator recommended only 11.4% to take statin, and only 14.4% of “Hard
CVD
” events occurred in those not recommended statin, resulting in sensitivity 0.86, specificity 0.95, and
AUC
0.92. Similar results were found for prediction of “All
CVD
” events.

Conclusions

The
ML
Risk Calculator outperformed the ACC/AHA Risk Calculator by recommending less drug therapy, yet missing fewer events. Additional studies are underway to validate the
ML
model in other cohorts and to explore its ability in short‐term
CVD
risk prediction.
Digoxin and Platelet Activation in Patients With Atrial Fibrillation: In Vivo and In Vitro Study
Authors: Pastori Daniele , Carnevale Roberto , Nocella Cristina , Bartimoccia Simona , Novo Marta , Cammisotto Vittoria , Piconese Silvia , Santulli Maria , Vasaturo Fortunata , Violi Francesco , Pignatelli Pasquale ,   Atherosclerosis in Atrial Fibrillation (ATHERO‐AF) Study Group
Published: December 2018

Background

Digoxin use was shown to be associated with an increased risk of cardiovascular events in atrial fibrillation (
AF
). We hypothesized that digoxin may affect cardiovascular risk by increasing platelet activation.

Methods and Results

Post hoc analysis of a prospective study of anticoagulated
patients with AF
. Patients were divided into 2 groups balanced for age, sex, and cardiovascular risk factors: digoxin users (n=132) and nonusers (n=388). Urinary excretion of 11‐dehydro‐thromboxane B
2
(TxB
2
), a marker of platelet activation, and serum digoxin concentration (
SDC
) were measured. In vitro experiments were performed on platelets from healthy subjects and AF patients, which were incubated with scalar doses of digoxin (0.6–2.4 ng/mL) with or without prestimulation with a sub‐threshold of collagen. Median 11‐dehydro‐TxB
2
was 105.0 (
interquartile range,
60.0–190.0) ng/mg creatinine, and median
SDC
was 0.65 (
interquartile range,
0.40–1.00) ng/mL. Urinary 11‐dehydro‐TxB
2
and
SDC
were correlated (
r
s
=0.350,
P
<0.001). Patients in the upper tertile of
SDC
showed higher 11‐dehydro‐TxB
2
compared with non–digoxin users (
P
=0.019). In vitro study showed an increased basal platelet activation in
patients with AF
compared with
healthy subjects
. Digoxin (2.4 ng/mL) induced calcium mobilization,
PAC
‐1 (procaspase‐activating compound 1) and platelet aggregation in
AF
patients but not in
healthy subjects
. After pretreatment with a sub‐threshold of collagen, digoxin dose‐dependent induced calcium mobilization, arachidonic acid release, TxB
2
biosynthesis,
PAC
‐1 and soluble platelet selectin expression, and platelet aggregation, which were inhibited by antibody against digoxin.

Conclusions

We found a significant in vivo correlation between
SDC
and platelet activation. Supratherapeutic
SDC
increased in vitro platelet aggregation via calcium‐related phospholipase A
2
phosphorylation. Our findings may have clinical implications for AF patients treated with digoxin.
SMAD4 Deficiency Leads to Development of Arteriovenous Malformations in Neonatal and Adult Mice
Authors: Kim Yong Hwan , Choe Se‐woon , Chae Min‐Young , Hong Suntaek , Oh S. Paul
Published: December 2018

Background

Hereditary hemorrhagic telangiectasia (
HHT
) is a rare genetic vascular disorder caused by mutations in endoglin (

ENG

), activin receptor‐like kinase 1 (

ACVRL
1

;

ALK
1

), or

SMAD
4

. Major clinical symptoms of
HHT
are arteriovenous malformations (
AVM
s) found in the brain, lungs, visceral organs, and mucosal surface. Animal models harboring mutations in
Eng
or
Alk1
recapitulate all of these
HHT
clinical symptoms and have been useful resources for studying mechanisms and testing potential drugs. However, animal models representing

SMAD
4

mutations have been lacking. The goal of this study is to evaluate
Smad4
‐inducible knockout (
iKO
) mice as an animal model of
HHT
and compare the phenotypes with other established
HHT
animal models.

Methods and Results

Global
Smad4
deletion was induced at neonatal and adult stages, and hemoglobin levels, gastrointestinal hemorrhage, and presence of aberrant arteriovenous connections were examined. Neonatal
Smad4
‐
iKO
mice exhibited signs of gastrointestinal bleeding and
AVM
s in the brain, intestine, nose, and retina. The radial expansion was decreased, and
AVM
s were detected on both distal and proximal retinal vasculature of
Smad4
‐
iKO
s. Aberrant smooth muscle actin staining was observed in the initial stage
AVM
s and their connecting veins, indicating abnormal arterial flow to veins. In adult mice,
Smad4
deficiency caused gastrointestinal bleeding and
AVM
s along the gastrointestinal tract and wounded skin.
HHT
‐related phenotypes of
Smad4
‐
iKO
s appeared to be comparable with those found in
Alk1
‐
iKO
and
Eng
‐
iKO
mice.

Conclusions

These data further confirm that
SMAD
signaling is crucial for normal arteriovenous network formation, and
Smad4
‐
iKO
will be an alternative animal model of
AVM
research associated with
HHT
.
Association of Oral Anticoagulant Type With Risk of Dementia Among Patients With Nonvalvular Atrial Fibrillation
Authors: Chen Nemin , Lutsey Pamela L. , MacLehose Richard F. , Claxton J'Neka S. , Norby Faye L. , Chamberlain Alanna M. , Bengtson Lindsay G. S. , O'Neal Wesley T. , Chen Lin Y. , Alonso Alvaro
Published: December 2018

Background

Oral anticoagulants (
OACs
) in patients with atrial fibrillation (
AF
), in addition to reducing stroke risk, could also prevent adverse cognitive outcomes. The purpose of this study was to compare the risk of dementia incidence across patients with AF initiating different
OAC
s.

Methods and Results

We identified patients with nonvalvular
AF
initiating
OAC
s in 2
US
healthcare claim databases, MarketScan (2007–2015) and Optum Clinformatics (2009–2015). Dementia, comorbidities, and use of medications were defined on the basis of inpatient and outpatient claims. We performed head‐to‐head comparisons of warfarin, dabigatran, rivaroxaban, and apixaban in propensity score–matched cohorts. We calculated hazard ratios (
HR
s) and 95% confidence intervals (
CI
s) of incident dementia for each propensity score–matched cohort and meta‐analyzed database‐specific results. We analyzed 307 099 patients with AF from the MarketScan database and 161 346 from the Optum database, of which 6572 and 4391, respectively, had a diagnosis of incident dementia. The mean follow‐up of each cohort ranged between 0.7 and 2.2 years. Patients initiating direct OACs experienced lower rates of dementia than those initiating warfarin (dabigatran:
HR
, 0.85; 95%
CI
, 0.71–1.01; rivaroxaban:
HR
, 0.85; 95%
CI
, 0.76–0.94; apixaban:
HR
, 0.80; 95%
CI
, 0.65–0.97). There were no differences in rates of dementia comparing direct OAC user groups (dabigatran versus rivaroxaban:
HR
, 1.02; 95%
CI
, 0.79–1.32; dabigatran versus apixaban:
HR
, 0.92; 95%
CI
, 0.63–1.36; apixaban versus rivaroxaban:
HR
, 1.01; 95%
CI
, 0.86–1.19).

Conclusions

Patients with
AF
initiating direct OACs experienced lower rates of incident dementia than warfarin users. No obvious benefit was observed for any particular direct OAC in relation to dementia rates.
Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice
Authors: Yao Yuyu , Li Bing , Liu Chang , Fu Cong , Li Pengfei , Guo Youming , Ma Genshan , Liu Naifeng , Chao Lee , Chao Julie
Published: December 2018

Background

Kallistatin exerts beneficial effects on organ injury by inhibiting oxidative stress and inflammation. However, the role of kallistatin in atherosclerosis is largely unknown. Here, we investigated the role and mechanisms of kallistatin in patients with coronary artery disease (
CAD
), atherosclerotic plaques of apoE
−/−
mice, and endothelial activation.

Methods and Results

Plasma kallistatin levels were analyzed in 453 patients at different stages of
CAD
. Kallistatin levels were significantly lower in patients with
CAD
and negatively associated with
CAD
severity and oxidative stress. Human kallistatin
cDNA
in an adenoviral vector was injected intravenously into apoE
−/−
mice after partial carotid ligation, with or without nitric oxide synthase inhibitor (N
ω
‐nitro‐L‐arginine methyl ester) or sirtuin 1 inhibitor (nicotinamide). Kallistatin gene delivery significantly reduced macrophage deposition, oxidative stress, and plaque volume in the carotid artery, compared with control adenoviral injection. Kallistatin administration increased endothelial nitrous oxide synthase, sirtuin 1, interleukin‐10, superoxide dismutase 2, and catalase expression in carotid plaques. The beneficial effects of kallistatin in mice were mitigated by N
ω
‐nitro‐L‐arginine methyl ester or nicotinamide. Furthermore, human kallistatin protein suppressed tumor necrosis factor‐α–induced
NADPH
oxidase activity and increased endothelial nitrous oxide synthase and sirtuin 1 expression in cultured human endothelial cells. These effects were also abolished by N
ω
‐nitro‐L‐arginine methyl ester or nicotinamide.

Conclusions

This was the first study to demonstrate that reduced plasma kallistatin levels in patients are associated with
CAD
severity and oxidative stress. Kallistatin treatment prevents carotid atherosclerotic plaque formation in mice by stimulating the sirtuin 1/endothelial nitrous oxide synthase pathway. These findings indicate the potential protective effects of kallistatin on atherosclerosis in human subjects and mouse models.
Inpatient and Outpatient Infection as a Trigger of Cardiovascular Disease: The ARIC Study
Authors: Cowan Logan T. , Lutsey Pamela L. , Pankow James S. , Matsushita Kunihiro , Ishigami Junichi , Lakshminarayan Kamakshi
Published: December 2018

Background

Acute infections are known cardiovascular disease (
CVD
) triggers, but little is known regarding how
CVD
risk varies following inpatient versus outpatient infections. We hypothesized that in‐ and outpatient infections are associated with
CVD
risk and that the association is stronger for inpatient infections.

Methods and Results

Coronary heart disease (CHD) and ischemic stroke cases were identified and adjudicated in the ARIC (Atherosclerosis Risk in Communities Study). Hospital discharge diagnosis codes and Medicare claims data were used to identify infections diagnosed in in‐ and outpatient settings. A case‐crossover design and conditional logistic regression were used to compare in‐ and outpatient infections among
CHD
and ischemic stroke cases (14, 30, 42, and 90 days before the event) with corresponding control periods 1 and 2 years previously. A total of 1312 incident
CHD
cases and 727 incident stroke cases were analyzed. Inpatient infections (14‐day odds ratio [
OR
]=12.83 [5.74, 28.68], 30‐day
OR
=8.39 [4.92, 14.31], 42‐day
OR
=6.24 [4.02, 9.67], and 90‐day
OR
=4.48 [3.18, 6.33]) and outpatient infections (14‐day
OR
=3.29 [2.50, 4.32], 30‐day
OR
=2.69 [2.14, 3.37], 42‐day
OR
=2.45 [1.97, 3.05], and 90‐day
OR
=1.99 [1.64, 2.42]) were more common in all
CHD
case periods compared with control periods and inpatient infection was a stronger
CHD
trigger for all time periods (
P
<0.05). Inpatient infection was also a stronger stroke trigger with the difference borderline statistically significant (
P
<0.10) for the 42‐ and 90‐day time periods.

Conclusions

In‐ and outpatient infections are associated with
CVD
risk. Patients with an inpatient infection may be at particularly elevated
CVD
risk and should be considered potential candidates for
CVD
prophylaxis.
Low‐Voltage Type 1 ECG Is Associated With Fatal Ventricular Tachyarrhythmia in Brugada Syndrome
Authors: Nagase Satoshi , Kamakura Tsukasa , Kataoka Naoya , Wada Mitsuru , Yamagata Kenichiro , Ishibashi Kohei , Inoue Yuko Y. , Miyamoto Koji , Noda Takashi , Aiba Takeshi , Izumi Chisato , Noguchi Teruo , Yasuda Satoshi , Shimizu Wataru , Kamakura Shiro , Kusano Kengo
Published: December 2018

Background

Epicardial mapping can reveal low‐voltage areas on the right ventricular outflow tract in patients with Brugada syndrome with several ventricular fibrillation (
VF
) episodes. A type 1
ECG
is associated with an abnormal electrogram on right ventricular outflow tract epicardium. This study investigated the clinical significance of the amplitude of type 1
ECGs
in patients with Brugada syndrome.

Methods and Results

In 209 patients with Brugada syndrome with a spontaneous type 1
ECG
(26 resuscitated from
VF
, 54 with syncope, and 129 asymptomatic), the amplitude of the
ECG
in leads exhibiting type 1 was measured among V1 to V3 leads positioned in the standard and upper 1 and 2 intercostal spaces. The number of ECG leads exhibiting type 1 did not differ among groups. The averaged amplitude of type 1
ECG
was, however, significantly smaller in the group resuscitated from
VF
than in the asymptomatic group (
P
<0.05). Moreover, the minimum amplitude of type 1
ECG
was significantly smaller in the group resuscitated from
VF
than in the group with syncope and the asymptomatic group (
P
<0.05 and
P
<0.01, respectively). During follow‐up (56±48 months),
VF
occurred in 29 patients. Kaplan‐Meier analysis revealed that patients with the minimum amplitude of type 1
ECG
lower than or at the median value had a higher incidence of
VF
(log‐rank test,
P
<0.01). In multivariate analysis, syncope, past
VF
episode, and minimum amplitude of type 1
ECG
≤0.8
mV
were independent predictors of
VF
events during follow‐up.

Conclusions

Low‐voltage type 1
ECG
is highly and independently related to fatal ventricular tachyarrhythmia in patients with Brugada syndrome.
Estradiol Treatment Initiated Early After Ovariectomy Regulates Myocardial Gene Expression and Inhibits Diastolic Dysfunction in Female Cynomolgus Monkeys: Potential Roles for Calcium Homeostasis and Extracellular Matrix Remodeling
Authors: Michalson Kristofer T. , Groban Leanne , Howard Timothy D. , Shively Carol A. , Sophonsritsuk Areepan , Appt Susan E. , Cline J. Mark , Clarkson Thomas B. , Carr J. Jeffrey , Kitzman Dalane W. , Register Thomas C.
Published: December 2018

Background

Left ventricular (
LV
) diastolic dysfunction often precedes heart failure with preserved ejection fraction, the dominant form of heart failure in postmenopausal women. The objective of this study was to determine the effect of oral estradiol treatment initiated early after ovariectomy on
LV
function and myocardial gene expression in female cynomolgus macaques.

Methods and Results

Monkeys were ovariectomized and randomized to receive placebo (control) or oral estradiol at a human‐equivalent dose of 1 mg/day for 8 months. Monkeys then underwent conventional and tissue Doppler imaging to assess cardiac function, followed by transcriptomic and histomorphometric analyses of
LV
myocardium. Age, body weight, blood pressure, and heart rate were similar between groups. Echocardiographic mitral early and late inflow velocities, mitral annular velocities, and mitral E deceleration slope were higher in estradiol monkeys (all
P
<0.05), despite similar estimated
LV
filling pressure. MCP1 (monocyte chemoattractant protein 1) and
LV
collagen staining were lower in estradiol animals (
P
<0.05). Microarray analysis revealed differential myocardial expression of 40 genes (>1.2‐fold change; false discovery rate,
P
<0.05) in estradiol animals relative to controls, which implicated pathways associated with better calcium ion homeostasis and muscle contraction and lower extracellular matrix deposition (
P
<0.05).

Conclusions

Estradiol treatment initiated soon after ovariectomy resulted in enhanced
LV
diastolic function, and altered myocardial gene expression towards decreased extracellular matrix deposition, improved myocardial contraction, and calcium homeostasis, suggesting that estradiol directly or indirectly modulates the myocardial transcriptome to preserve cardiovascular function.
Pathological Remodeling of Mitral Valve Leaflets from Unphysiologic Leaflet Mechanics after Undersized Mitral Annuloplasty to Repair Ischemic Mitral Regurgitation
Authors: Sielicka Alicja , Sarin Eric L. , Shi Weiwei , Sulejmani Fatiesa , Corporan Daniella , Kalra Kanika , Thourani Vinod H. , Sun Wei , Guyton Robert A. , Padala Muralidhar
Published: December 2018

Background

Undersized ring annuloplasty is a commonly used surgical repair for ischemic mitral regurgitation, in which annular downsizing corrects regurgitation, but alters valve geometry and elevates tissue stresses. In this study, we investigated if unphysiological leaflet kinematics after annuloplasty might cause pathogenic biological remodeling of the mitral valve leaflets, and if preserving physiologic leaflet kinematics with a better technique can moderate such adverse remodeling.

Methods and Results

Twenty‐nine swine were induced with ischemic mitral regurgitation, and survivors were assigned to groups: 7 underwent annuloplasty, 12 underwent annuloplasty with papillary‐muscle approximation, 6 underwent papillary‐muscle approximation, and 3 were sham controls. Pre‐and post‐surgery leaflet kinematics were measured, and valve tissue was explanted after 3 months to assess biological changes. Anterior leaflet excursion was unchanged across groups, but persistent tethering was observed with annuloplasty. Posterior leaflet was vertically immobile after annuloplasty, better mobile with the combined approach, and substantially (
P
=0.0028) mobile after papillary‐muscle approximation. Procollagen‐1 was higher in leaflets from annuloplasty compared with the other groups. Heat shock protein‐47 and lysyl oxidase were higher in groups receiving annuloplasty compared with sham. α‐
SMA
was elevated in leaflets from animals receiving an annuloplasty, indicating activation of quiescent valve interstitial cells, paralleled by elevated transforming growth factor‐β expression.

Conclusions

This is the first study to demonstrate that surgical valve repairs that impose unphysiological leaflet mechanics have a deleterious, pathological impact on valve biology. Surgeons may need to consider restoring physiologic leaflet stresses as well as valve competence, while also exploring pharmacological methods to inhibit the abnormal signaling cascades.
Relationship Between Electrocardiographic Findings and Cardiac Magnetic Resonance Phenotypes in Arrhythmogenic Cardiomyopathy
Authors: De Lazzari Manuel , Zorzi Alessandro , Cipriani Alberto , Susana Angela , Mastella Giulio , Rizzo Alessandro , Rigato Ilaria , Bauce Barbara , Giorgi Benedetta , Lacognata Carmelo , Iliceto Sabino , Corrado Domenico , Perazzolo Marra Martina
Published: December 2018

Background

The new designation of arrhythmogenic cardiomyopathy defines a broader spectrum of disease phenotypes, which include right dominant, biventricular, and left dominant variants. We evaluated the relationship between electrocardiographic findings and contrast‐enhanced cardiac magnetic resonance phenotypes in arrhythmogenic cardiomyopathy.

Methods and Results

We studied a consecutive cohort of patients with a definite diagnosis of arrhythmogenic cardiomyopathy, according to 2010 International Task Force criteria, who underwent electrocardiography and contrast‐enhanced cardiac magnetic resonance. Both depolarization and repolarization electrocardiographic abnormalities were correlated with the severity of dilatation/dysfunction, either global or regional, of both ventricles and the presence and regional distribution of late gadolinium enhancement. The study population included 79 patients (60% men). There was a statistically significant relationship between the presence and extent of T‐wave inversion across a 12‐lead
ECG
and increasing values of median right ventricular (
RV
) end‐diastolic volume (
P
<0.001) and decreasing values of
RV
ejection fraction (
P
<0.001). The extent of T‐wave inversion to lateral leads predicted a more severe
RV
dilatation rather than a left ventricular involvement because of the leftward displacement of the dilated
RV
, as evidenced by contrast‐enhanced cardiac magnetic resonance. A terminal activation delay of >55 ms in the right precordial leads (V1‐V3) was associated with higher
RV
volume (
P
=0.014) and lower
RV
ejection fraction (
P
=0.053). Low
QRS
voltages in limb leads predicted the presence (
P
=0.004) and amount (
P
<0.001) of left ventricular late gadolinium enhancement.

Conclusions

The study results indicated that electrocardiographic abnormalities predict the arrhythmogenic cardiomyopathy phenotype in terms of severity of
RV
disease and left ventricular involvement, which are among the most important determinants of the disease outcome.
Myocardial Oxygen Consumption and Efficiency in Patients With Cardiac Amyloidosis
Authors: Clemmensen Tor Skibsted , Soerensen Jens , Hansson Nils Henrik , Tolbod Lars Poulsen , Harms Hendrik J. , Eiskjær Hans , Mikkelsen Fabian , Wiggers Henrik , Andersen Niels Frost , Poulsen Steen Hvitfeldt
Published: December 2018

Background

This study evaluated myocardial oxygen consumption (MVO
2
) and myocardial external efficiency (MEE) in patients with cardiac amyloidosis (CA). Furthermore, we compared MEE and MVO
2
in subjects with light chain amyloidosis versus transthyretin (ATTR) amyloidosis.

Methods and Results

The study population comprised 40 subjects: 25 patients with confirmed CA and 15 control subjects. All subjects underwent an
11
C‐acetate positron emission tomography. Furthermore, the CA patients underwent comprehensive echocardiography and right heart catheterization during a symptom‐limited, semi‐supine exercise test. MEE was calculated from
11
C‐acetate positron emission tomography as the ratio of left ventricular (LV) stroke work and the energy equivalent of MVO
2
. Myocardial work efficiency was calculated as echocardiography‐derived work pressure product divided by three‐dimensional LV mass. CA patients had significantly lower LV‐ejection fraction (54±13% versus 63±4%,
P
<0.05) and LV‐global longitudinal strain (LVGLS) (12±4% versus 19±2%,
P
<0.0001) and a more restrictive filling pattern (E/e′‐ratio 18 [12–25] versus 8 [7–9],
P
<0.0001) than controls. MEE was severely reduced (13±5% versus 22±5%,
P
<0.0001) whereas total MVO
2
was higher (18±6 mL/min versus 13±3 mL/min,
P
<0.01) in CA patients than controls. MEE decreased with increasing New York Heart Association symptom burden (
P
<0.0001). We found a good relationship between MEE and peak exercise systolic performance (LVGLS:
R
2
=0.60,
P
<0.0001; myocardial work efficiency:
R
2
=0.48,
P
<0.0001; cardiac index:
R
2
=0.52,
P
<0.0001) and between MEE and myocardial blood flow (
R
2
=0.44,
P
<0.0001).

Conclusion

Myocardial oxidative metabolism is disturbed in CA patients with increased total MVO
2
and reduced MEE. MEE correlated significantly with echocardiographic derived systolic parameters such as myocardial work efficiency and LVGLS that might be used as surrogate MEE markers.
Adjudicated Heart Failure in HIV‐Infected and Uninfected Men and Women
Authors: Feinstein Matthew J. , Steverson Alexandra B. , Ning Hongyan , Pawlowski Anna E. , Schneider Daniel , Ahmad Faraz S. , Sanders Jes M. , Sinha Arjun , Nance Robin M. , Achenbach Chad J. , Christopher Delaney J. A. , Heckbert Susan R. , Shah Sanjiv J. , Hanna David B. , Hsue Priscilla Y. , Bloomfield Gerald S. , Longenecker Chris T. , Crane Heidi M. , Lloyd‐Jones Donald M.
Published: December 2018

Background

HIV is associated with elevated risk of heart failure (
HF
). Despite poor agreement between automated, administrative code–based
HF
definitions and physician‐adjudicated
HF
, no studies have evaluated incident adjudicated
HF
for people living with
HIV
(
PLWH
).

Methods and Results

We analyzed
PLWH
and uninfected controls receiving care in an urban medical system from January 1, 2000, to July 12, 2016. Physicians reviewed data from medical records to adjudicate
HF
diagnoses. We used multivariable‐adjusted Cox models to analyze incident
HF
for
PLWH
versus controls and
HIV
‐related factors associated with incident
HF
. We also analyzed the performance of automated versus physician‐adjudicated
HF
definitions. Incident adjudicated
HF
occurred in 97 of 4640
PLWH
(2.1%; mean: 6.8 years to
HF
) and 55 of 4250 controls (1.3%; mean: 6.7 years to
HF
; multivariable‐adjusted hazard ratio: 2.10; 95% confidence interval, 1.38–3.21). Among
PLWH
, higher
HIV
viral load (
hazard ratio
per log
10
higher time‐updated viral load: 1.22; 95%
confidence interval,
1.11–1.33) was associated with greater
HF
risk and higher
CD
4+ T cell count was associated with lower
HF
risk (
hazard ratio
per 100 cells/mm
3
higher time‐updated
CD
4 count: 0.80; 95%
confidence interval,
0.69–0.92). In exploratory analyses, the most accurate automated
HF
definitions had sensitivities of 67% to 75% and positive predictive values of 54% to 60%.

Conclusions

In a cohort with rigorous
HF
adjudication,
PLWH
had greater risks of
HF
than uninfected people after adjustment for demographics and cardiovascular risk factors. Higher
HIV
viral load and lower
CD
4+ T cell count were associated with higher
HF
risk among
PLWH
. Automated methods of
HF
ascertainment exhibited poor accuracy for
PLWH
and uninfected people.
Temperature and Precipitation Associate With Ischemic Stroke Outcomes in the United States
Authors: Chu Stacy Y. , Cox Margueritte , Fonarow Gregg C. , Smith Eric E. , Schwamm Lee , Bhatt Deepak L. , Matsouaka Roland A. , Xian Ying , Sheth Kevin N.
Published: December 2018

Background

There is disagreement in the literature about the relationship between strokes and seasonal conditions. We sought to (1) describe seasonal patterns of stroke in the United States, and (2) determine the relationship between weather variables and stroke outcomes.

Methods and Results

We performed a cross‐sectional study using Get With The Guidelines‐Stroke data from 896 hospitals across the continental United States. We examined effects of season, climate region, and climate variables on stroke outcomes. We identified 457 638 patients admitted from 2011 to 2015 with ischemic stroke. There was a higher frequency of admissions in winter (116 862 in winter versus 113 689 in spring, 113 569 in summer, and 113 518 in fall;
P
<0.0001). Winter was associated with higher odds of in‐hospital mortality (odds ratio [OR] 1.08 relative to spring, confidence interval [
CI
] 1.04–1.13,
P
=0.0004) and lower odds of discharge home (
OR
0.92,
CI
0.91–0.94,
P
<0.0001) or independent ambulation at discharge (
OR
0.96,
CI
0.94–0.98,
P
=0.0006). These differences were attenuated after adjusting for climate region and case mix and became inconsistent after controlling for weather variables. Temperature and precipitation were independently associated with outcome after multivariable analysis, with increases in temperature and precipitation associated with lower odds of mortality (
OR
0.95,
CI
0.93–0.97,
P
<0.0001 and
OR
0.95,
CI
0.90–1.00,
P
=0.035, respectively).

Conclusions

Admissions for ischemic stroke were more frequent in the winter. Warmer and wetter weather conditions were independently associated with better outcomes. Further studies should aim to identify sensitive populations and inform public health measures aimed at resource allocation, readiness, and adaptive strategies.
Atrial Fibrillation Is Associated With Higher Overall Mortality in Patients With Implantable Cardioverter‐Defibrillator: A Systematic Review and Meta‐Analysis
Authors: Mustafa Usman , Dherange Parinita , Reddy Rohit , DeVillier Joseph , Chong Jessica , Ihsan Alarozia , Jones Ryan , Duddyala Narendra , Reddy Pratap , Dominic Paari
Published: December 2018

Background

Implantable cardioverter‐defibrillator (
ICD
) improves survival when used for primary or secondary prevention of sudden cardiac death. Whether the benefits of
ICD
in patients with atrial fibrillation (
AF)
are similar to those with normal sinus rhythm (
NSR
) is not well established. The aim of this study is to investigate whether
ICD
patients with
AF
are at higher risk of mortality and appropriate shock therapy compared with patients with
NSR
.

Methods and Results

Literature was searched and 25 observational studies with 63 283 patients were included in this meta‐analysis. We compared the outcomes of (1) all‐cause mortality and appropriate shock therapy among
AF
and
NSR
patients who received
ICD
for either primary or secondary prevention and (2) all‐cause mortality among
AF
patients with
ICD
versus guideline directed medical therapy. All‐cause mortality (odds ratio, 2.11; 95% confidence interval, 1.73–2.56;
P
<0.001) and incidence of appropriate shock therapy (odds ratio, 1.77; 95% confidence interval, 1.47–2.13;
P
<0.001) were significantly higher in
ICD
patients with
AF
as compared to
NSR
. There was no statistically significant mortality benefit from
ICD
compared with medical therapy in
AF
patients (odds ratio, 0.69; 95% confidence interval, 0.42–1.11;
P
=0.12) based on a separate meta‐analysis of 3 studies with 387 patients.

Conclusions

Overall mortality and appropriate shock therapy are higher in
ICD
patients with AF as compared with
NSR
. The impact of
ICD
on all‐cause mortality in
AF
patients when compared to goal‐directed medical therapy is unclear, and randomized controlled trials are needed comparing
AF
patients with
ICD
and those who have indications for
ICD,
but are only on medical therapy.
Temporary Mechanical Circulatory Support for Refractory Cardiogenic Shock Before Left Ventricular Assist Device Surgery
Authors: Vallabhajosyula Saraschandra , Arora Shilpkumar , Lahewala Sopan , Kumar Varun , Shantha Ghanshyam P. S. , Jentzer Jacob C. , Stulak John M. , Gersh Bernard J. , Gulati Rajiv , Rihal Charanjit S. , Prasad Abhiram , Deshmukh Abhishek J.
Published: December 2018

Background

There are limited data on the role of temporary mechanical circulatory support (
MCS
) devices for cardiogenic shock before left ventricular assist device (
LVAD
) surgery. This study sought to evaluate the trends of use and outcomes of
MCS
in cardiogenic shock before
LVAD
surgery.

Methods and Results

This was a retrospective cohort study from 2005 to 2014 using the National Inpatient Sample (20% stratified sample of US hospitals). This study identified admissions undergoing
LVAD
surgery with preoperative cardiogenic shock. Admissions for other cardiac surgery and heart transplant were excluded. Temporary
MCS
was identified using administrative codes. The primary outcome was hospital mortality and secondary outcomes were hospital costs and lengths of stay in admissions with and without
MCS
use. In this 10‐year period, 9753 admissions were identified with 40.6% requiring pre‐
LVAD MCS
. There was a temporal increase in the frequency of cardiogenic shock associated with an increase in non–intra‐aortic balloon pump
MCS
devices. The cohort receiving
MCS
had greater in‐hospital myocardial infarction, ventricular arrhythmias, and use of coronary angiography. On multivariable analysis, older age, myocardial infarction, and need for
MCS
devices were independently predictive of higher in‐hospital mortality. In 696 propensity‐matched pairs, use of
MCS
was predictive of higher in‐hospital mortality (odds ratio 1.4 [95% confidence interval 1.1–1.6];
P
=0.02) and higher hospital costs, but similar lengths of stay.

Conclusions

In patients with cardiogenic shock bridged to
LVAD
therapy, there was a steady increase in preoperative
MCS
use. Use of
MCS
identified patients at higher risk for in‐hospital mortality and greater resource utilization.
Occurrence of Postpericardiotomy Syndrome: Association With Operation Type and Postoperative Mortality After Open‐Heart Operations
Authors: Lehto Joonas , Kiviniemi Tuomas , Gunn Jarmo , Airaksinen Juhani , Rautava Päivi , Kytö Ville
Published: December 2018

Background

Postpericardiotomy syndrome (
PPS
) is a common complication after cardiac surgery. However, large‐scale epidemiological studies about the effect of procedure type on the occurrence of
PPS
and mortality of patients with PPS have not yet been performed.

Methods and Results

We studied the association of
PPS
occurrence with operation type and postoperative mortality in a nationwide follow‐up analysis of 28 761 consecutive patients entering coronary artery bypass grafting, aortic valve replacement, mitral valve replacement, or ascending aortic surgery. Only
PPS
episodes severe enough to result in hospital admission or to contribute as a cause of death were included. Data were collected from mandatory Finnish national registries between 2005 and 2014. Of all the patients included, 493 developed
PPS
during the study period. The occurrence of
PPS
was significantly higher after aortic valve replacement (hazard ratio, 1.97; 95% confidence interval, 1.58–2.46;
P
<0.001), mitral valve replacement (hazard ratio, 1.62; 95% confidence interval, 1.22–2.15;
P
<0.001), and aortic surgery (hazard ratio, 3.06; 95% confidence interval, 2.24–4.16;
P
<0.001), when compared with coronary artery bypass grafting in both univariable and multivariable analyses. The occurrence of PPS decreased significantly with aging (
P
<0.001). The occurrence of PPS was associated with an increased risk of mortality within the first year after the surgery (adjusted hazard ratio, 1.78; 95% confidence interval, 1.12–2.81;
P
=0.014).

Conclusions

The occurrence of
PPS
was higher after aortic valve replacement, mitral valve replacement, and aortic surgery when compared with the coronary artery bypass grafting procedure. Aging decreased the risk of
PPS
. The development of
PPS
was associated with higher mortality within the first year after cardiac or ascending aortic surgery.
GLP‐1 Is a Coronary Artery Vasodilator in Humans
Authors: Clarke Sophie J. , Giblett Joel P. , Yang Lucy L. , Hubsch Annette , Zhao Tian , Aetesam‐ur‐Rahman Muhammad , West Nick E. J. , O'Sullivan Michael , Figg Nichola , Bennett Martin , Wewer Albrechtsen Nicolai J. , Deacon Carolyn F. , Cheriyan Joseph , Hoole Stephen P.
Published: December 2018

Background

The mechanism underlying the beneficial cardiovascular effects of the incretin GLP‐1 (glucagon‐like peptide 1) and its analogues in humans is elusive. We hypothesized that activating receptors located on vascular smooth muscle cells to induce either peripheral or coronary vasodilatation mediates the cardiovascular effect of
GLP
‐1.

Methods and Results

Ten stable patients with angina awaiting left anterior descending artery stenting underwent forearm blood flow measurement using forearm plethysmography and post–percutaneous coronary intervention coronary blood flow measurement using a pressure‐flow wire before and after peripheral
GLP
‐1 administration. Coronary sinus and artery bloods were sampled for
GLP
‐1 levels. A further 11 control patients received saline rather than
GLP
‐1 in the coronary blood flow protocol.
GLP
‐1 receptor (GLP‐1R) expression was assessed by immunohistochemistry using a specific
GLP
‐1R monoclonal antibody in human tissue to inform the physiological studies. There was no effect of
GLP
‐1 on absolute forearm blood flow or forearm blood flow ratio after
GLP
‐1, systemic hemodynamics were not affected, and no binding of
GLP
‐1R monoclonal antibody was detected in vascular tissue.
GLP
‐1 reduced resting coronary transit time (mean [
SD
], 0.87 [0.39] versus 0.63 [0.27] seconds;
P
=0.02) and basal microcirculatory resistance (mean [
SD
], 76.3 [37.9] versus 55.4 [30.4] mm Hg/s;
P
=0.02), whereas in controls, there was an increase in transit time (mean [SD], 0.48 [0.24] versus 0.83 [0.41] seconds;
P
<0.001) and basal microcirculatory resistance (mean [SD], 45.9 [34.7] versus 66.7 [37.2] mm Hg/s;
P
=0.02).
GLP
‐1R monoclonal antibody binding was confirmed in ventricular tissue but not in vascular tissue, and transmyocardial
GLP
‐1 extraction was observed.

Conclusions

GLP
‐1 causes coronary microvascular dilation and increased flow but does not influence peripheral tone.
GLP
‐1R immunohistochemistry suggests that
GLP
‐1 coronary vasodilatation is indirectly mediated by ventricular‐coronary cross talk.