bluuebunny/crossref_metadata_2025 huggingface dataset:
Choroidal Ischemia Sparing the Watershed Zone following Intra-Arterial Chemotherapy for Retinoblastoma
Authors: Ancona-Lezama David Arturo , Dalvin Lauren A. , Lucio-Alvarez J. Antonio , Jabbour Pascal , Shields Carol L.
Published: September 2018

Purpose: Intra-arterial chemotherapy (IAC) has become a mainstay in the management of retinoblastoma, especially in advanced or refractory disease. However, IAC is not without complications, and chemotherapy toxic effects can lead to partial or complete choroidal ischemia, often causing vision loss. Methods: This is a case report. Results: A 4-month-old girl with bilateral retinoblastoma was treated with secondary IAC (melphalan 5 mg) for recurrent tumor following intravenous chemotherapy. One month later, complete tumor control was achieved. However, she demonstrated broad choroidal ischemia in the nasal and temporal quadrants but sparing of the watershed zone superior and inferior to the optic disc and in the papillomacular region. Fluorescein angiography revealed poor perfusion of the choriocapillaris with visibility of the large choroidal vessels in the nasal and temporal areas but preserved perfusion of the watershed zone. The watershed zone remained intact on the 10-month follow-up, and the final visual acuity was fix and follow without strabismus. Conclusion: The pathophysiology of choroidal ischemia is not well understood, but the fortuitous watershed zone preservation in this case could represent uneven distribution of the chemotherapeutic drug, resulting in partial chemo-dilution of the medication in the watershed region, which represents the final downstream overlapping choroidal perfusion from both medial and lateral posterior ciliary arteries.
Effect of Interventricular Electrical Delay on Atrioventricular Optimization for Cardiac Resynchronization Therapy
Authors: Gold Michael R. , Yu Yinghong , Singh Jagmeet P. , Birgersdotter-Green Ulrika , Stein Kenneth M. , Wold Nicholas , Meyer Timothy E. , Ellenbogen Kenneth A.
Published: September 2018

Background:

Routine atrioventricular optimization (AVO) has not been shown to improve outcomes with cardiac resynchronization therapy (CRT). However, more recently subgroup analyses of multicenter CRT trials have identified electrocardiographic or lead positions associated with benefit from AVO. Therefore, the purpose of this analysis was to evaluate whether interventricular electrical delay modifies the impact of AVO on reverse remodeling with CRT.

Methods:

This substudy of the SMART-AV trial (SMARTDELAY Determined AV Optimization) included 275 subjects who were randomized to either an electrogram-based AVO (SmartDelay) or nominal atrioventricular delay (120 ms). Interventricular delay was defined as the time between the peaks of the right ventricular (RV) and left ventricular (LV) electrograms (RV-LV duration). CRT response was defined prospectively as a >15% reduction in LV end-systolic volume from implant to 6 months.

Results:

The cohort was 68% men, with a mean age of 65±11 years and LV ejection fraction of 28±8%. Longer RV-LV durations were significantly associated with CRT response (
P
<0.01) for the entire cohort. Moreover, the benefit of AVO increased as RV-LV duration prolonged. At the longest quartile, there was a 4.26× greater odds of a remodeling response compared with nominal atrioventricular delays (
P
=0.010).

Conclusions:

Baseline interventricular delay predicted CRT response. At long RV-LV durations, AVO can increase the likelihood of reverse remodeling with CRT. AVO and LV lead location optimized to maximize interventricular delay may work synergistically to increase CRT response.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00874445.
Risk of Appropriate Therapy and Death Before Therapy After Implantable Cardioverter-Defibrillator Generator Replacement
Authors: Witt Chance M. , Waks Jonathan W. , Mehta Ramila A. , Friedman Paul A. , Kramer Daniel B. , Buxton Alfred E. , Mulpuru Siva K. , Noseworthy Peter A. , Hodge David O. , Lushinsky Emilie C. , Mulholland Megan B. , Cha Yong-Mei , Gersh Bernard J. , Madhavan Malini
Published: September 2018

Background

The decision to initially implant an implantable cardioverter-defibrillator (ICD) is informed by robust randomized controlled trials, but no such data exist to guide the decision to replace an ICD generator. In this study, we aimed to determine outcomes after ICD generator replacement.

Methods

All patients with ischemic or nonischemic cardiomyopathy who underwent ICD generator replacement from 2001 to 2011 at Mayo Clinic, MN, or Beth Israel Deaconess Medical Center, MA, were included. Outcomes included (1) appropriate therapy after generator replacement and (2) death before appropriate therapy after generator replacement. Cox proportional hazards modeling was used to determine the associations between patient characteristics and outcomes.

Results

In 1421 patients undergoing ICD generator replacement (mean±SD age 69.6±12.1 years, 81% male), appropriate therapy occurred after replacement in 435 patients (30.6%) over a mean follow-up of 2.7±2.6 years. Associated factors included lower left ventricular ejection fraction and history of appropriate therapy before generator replacement. Death before appropriate ICD therapy occurred in 336 (23.7%) patients. Older age, lower left ventricular ejection fraction, and noncardiac comorbidities, including diabetes mellitus, chronic lung disease, peripheral vascular disease, lower hemoglobin, and lower glomerular filtration rate, were associated with greater risk of death before appropriate therapy. A progressive increase in mortality was observed with aggregation of these noncardiac comorbidities.

Conclusions

The decision to replace the ICD should take into consideration not only left ventricular ejection fraction and history of ventricular arrhythmias, but also comorbid illnesses that may impact the duration and the quality of life.
Digoxin Is Associated With a Decreased Incidence of Angiodysplasia-Related Gastrointestinal Bleeding in Patients With Continuous-Flow Left Ventricular Assist Devices
Authors: Vukelic Sasa , Vlismas Peter P. , Patel Snehal R. , Xue Xiaonan , Shitole Sanyog G. , Saeed Omar , Sims Daniel B. , Chinnadurai Thiru , Shin Julia J. , Forest Stephen J. , Goldstein Daniel J. , Jorde Ulrich P.
Published: September 2018

Background:

Gastrointestinal bleeding (GIB) is one of the principal adverse events affecting patients with continuous-flow left ventricular assist devices (CF-LVADs). Despite the early recognition that GIB is commonly because of gastrointestinal angiodysplasia (GIAD), the exact pathophysiology of this process remains elusive. It has been postulated that the abnormal hemodynamic profile in CF-LVAD patients may activate the angiogenesis signaling cascade via the HIF (hypoxia-inducible factor)-1α/angiopoietin-2 pathway leading to formation of GIADs. Digoxin is a potent inhibitor of HIF-1α synthesis, and we hypothesized that its use reduces the incidence of GIAD and GIB in patients with CF-LVAD.

Methods and Results:

Charts of all adult patients implanted with CF-LVAD between February 2006 and February 2017 were reviewed with particular emphasis on occurrence and cause of GIB. Fifty-four of 199 patients (27%) experienced a GIB. Overall frequency of GIB was lower in the 64 patients receiving digoxin compared with the 135 patients not receiving digoxin (16% versus 33%,
P
=0.01). Multivariable-adjusted Cox regression analysis confirmed that digoxin use was independently associated with a reduced risk for overall GIB (hazard ratio, 0.49; 95% CI, 0.24–0.98;
P
=0.045). GIBs were then categorized as non-GIAD, GIAD, or likely GIAD. Although the incidence of non-GIAD was similar in both groups (11% versus 7%,
P
=0.41), the frequency of GIAD/likely GIAD bleeding was significantly reduced in the digoxin group (5% versus 25%,
P
=0.0003). Multivariable-adjusted analysis confirmed that digoxin use was independently associated with a reduced risk for GIAD/likely GIAD bleeding (hazard ratio, 0.18; 95% CI, 0.06–0.6;
P
=0.005). However, digoxin use was not associated with reduced risk for non-GIAD GIB (hazard ratio, 1.54; 95% CI, 0.58–4.08;
P
=0.39).

Conclusions:

Use of digoxin was associated with a significant reduction in GIAD-related GIB in patients with CF-LVAD.
Abdominal Positioning of the Next-Generation Intra-Aortic Fluid Entrainment Pump (Aortix) Improves Cardiac Output in a Swine Model of Heart Failure
Authors: Annamalai Shiva K. , Esposito Michele L. , Reyelt Lara A. , Natov Peter , Jorde Lena E. , Karas Richard H. , Kapur Navin K.
Published: September 2018

Background:

Acute heart failure refractory to medical therapy is a major cause of morbidity and mortality. The Aortix device (Procyrion Inc) is a percutaneously delivered entrainment pump positioned in the descending aorta.

Methods and Results:

Using the newest generation Aortix device in 8 adult male Yorkshire swine, we tested the hypothesis that positioning in the abdominal aorta may provide superior hemodynamic effects than thoracic positioning in a swine model of postinfarct left ventricular injury.Abdominal activation generated significantly larger transaortic gradients (proximal minus distal mean aortic pressures) than thoracic positioning at all pump speeds. Compared with baseline values, activation in the abdominal, not thoracic, position significantly increased cardiac output, reduced arterial elastance, and systemic vascular resistance at low speeds. Compared with baseline values, abdominal activation also increased transpulmonary pressure gradients at medium and high speed, which was driven by trends toward higher mean pulmonary artery pressure and lower pulmonary capillary wedge pressure.

Conclusions:

This is the first report to determine that in contrast to thoracic positioning, abdominal positioning of the newest generation Aortix device reduces left ventricular afterload and increases cardiac output at low speeds. These findings have potentially important implications for the design of early clinical studies by suggesting that device position and speed are major determinants of improved hemodynamic efficacy.
Neural Networks for Prognostication of Patients With Heart Failure
Authors: Hearn Jason , Ross Heather J , Mueller Brigitte , Fan Chun-Po , Crowdy Edgar , Duhamel Joe , Walker Mike , Alba Ana Carolina , Manlhiot Cedric
Published: September 2018

Background

Prognostication of heart failure patients from cardiopulmonary exercise test (CPET) currently involves simplification of complex time-series data into summary indices. We hypothesized that prognostication could be improved by considering the totality of the data generated during a CPET, instead of using summary indices alone.

Methods and Results

Complete data from 1156 CPETs were used to predict clinical deterioration (characterized by initiation of mechanical circulatory support, listing for heart transplantation or mortality) 1 year post-CPET. We compared the prognostic value (area under the receiver operating characteristic curve) of (1) the most predictive summary indices, (2) staged data collected at discrete intervals using multivariable regression models, and (3) breath-by-breath data using a feedforward neural network. The top-performing models were compared with the commonly used CPET risk score, using absolute net reclassification index. All models were trained and assessed using a 100-iteration Monte Carlo cross-validation. A total of 190 (16.4%) patients experienced clinical deterioration. The summary indices demonstrated subpar discriminative value (area under the receiver operating characteristic curve ≤0.800). Each multivariable model outperformed the summary indices, with the neural network incorporating breath-by-breath data achieving the best performance (area under the receiver operating characteristic curve =0.842). When compared with the CPET risk score (area under the receiver operating characteristic curve =0.759), the top-performing model obtained a net reclassification index of 4.9%.

Conclusions

The current practice of considering summary indices in isolation fails to realize the full value of CPET data. This may lead to less accurate prognostication of patients and in consequence, inaccurate selection of patients for advanced therapy. Clinical practices, like CPET prognostication, must be continuously reevaluated to ensure optimal usage of valuable (and oft-underutilized) data sources.
Clinical Outcomes of Drug-Eluting Balloon for In-Stent Restenosis Based on the Number of Metallic Layers
Authors: Yabushita Hiroto , Kawamoto Hiroyoshi , Fujino Yusuke , Tahara Satoko , Horikoshi Takeo , Tada Miho , Amano Tatsuya , Onishi Hirokazu , Nakajima Akihiro , Warisawa Takayuki , Watanabe Yusuke , Yoshizaki Toru , Mitomo Satoru , Sato Tomohiko , Naganuma Toru , Ishiguro Hisaaki , Kurita Naoyuki , Nakamura Shotarou , Hozawa Koji , Nakamura Sunao
Published: September 2018

Background:

This study assesses clinical outcomes after drug-eluting balloon treatment for recurrent in-stent restenosis lesions based on the number of metallic layers.

Methods and Results:

We enrolled 304 consecutive patients (333 lesions) treated with percutaneous coronary intervention using drug-eluting balloon for in-stent restenosis lesions between March 2014 and June 2015. Per the number of stent layers previously implanted to the lesion, the patients were categorized into 3 groups, 1 stent layer (1L), 166 patients; 2 stent layers (2L), 87 patients; and ≥3 stent layers (≥3L), 51 patients. The end points were major adverse cardiovascular events (MACE), including cardiac death, target lesion revascularization, myocardial infarction, and definite or probable stent thrombosis. No significant differences were observed in patients’ baseline characteristics among the groups. The 1-year MACE and target lesion revascularization rates were significantly higher in the ≥3L group than those in the 1L and 2L groups (MACE: 1L, 16.9%; 2L, 16.1%; and ≥3L, 43.1%,
P
<0.01; target lesion revascularization: 1L, 14.5%; 2L, 14.9%; and ≥3L, 41.2%,
P
<0.01). The multivariable Cox regression analysis revealed that the number of metallic layers (≥3L compared with 1L; hazard ratio, 3.17; [95% CI, 1.75–5.76];
P
<0.01 and hemodialysis [hazard ratio, 2.21; (95% CI, 1.12–4.36);
P
=0.02]) were independent predictors for MACE. No significant differences were observed in the occurrence of cardiac death among the groups (
P
=0.34).

Conclusions:

Seemingly, drug-eluting balloon is less effective for ≥3L in-stent restenosis lesions. Hemodialysis and in-stent restenosis with the number of metallic layers are independent predictors for MACE.
Established and Emerging Roles of Biomarkers in Heart Failure
Authors: Ibrahim Nasrien E. , Januzzi James L.
Published: September 2018

Heart failure (HF) is a complex syndrome with an enormous societal burden in terms of cost, morbidity, and mortality. Natriuretic peptide testing is now widely used to support diagnosis, prognostication, and management of patients with HF and are incorporated into HF clinical practice guidelines. Beyond the natriuretic peptides, novel biomarkers may supplement traditional clinical and laboratory testing to improve understanding of the complex disease process of HF and possibly to personalize care for those affected through better individual phenotyping. In this review, we will discuss natriuretic peptides and the more novel biomarkers by dividing them into categories based on the major pathophysiologic pathways they represent. Given the complex physiology in HF, it is reasonable to expect that the future of biomarker testing lies in the application of multimarker testing panels, precision medicine to improve HF care delivery, and the use of biomarkers in proteomics and metabolomics to further improve HF care.
Diminished Antioxidant Activity of High‐Density Lipoprotein–Associated Proteins in Chronic Kidney Disease
Authors: Kennedy David J. , Wilson Tang W. H. , Fan Yiying , Wu Yuping , Mann Shirley , Pepoy Michael , Hazen Stanley L.
Published: September 2018

Background

Decreased serum arylesterase activity, catalyzed by the high‐density lipoprotein–associated paraoxonase (
PON
)‐1, is associated with increased oxidant stress and atherosclerosis risk. We sought to determine the prognostic value of serum
PON
‐1 activity, as monitored by PON or arylesterase activities, in subjects with chronic kidney disease (
CKD
), particularly in relation to established cardiac biomarkers.

Methods and Results

Serum arylesterase and PON activities were measured in sequential subjects with
CKD
(n=630; estimated glomerular filtration rate [
eGFR
] <60 mL/min per 1.73 m
2
) and an age‐ and sex‐matched control group of non‐
CKD
subjects (n=315) presenting for cardiac evaluations and prospectively followed for incident (3‐year) major adverse cardiac events (composite of death, nonfatal myocardial infarction, and stroke). Serum arylesterase activity in
CKD
subjects was lower compared with that in non‐
CKD
control subjects [median (interquartile range) 94 (77 to 112) versus 103 (85 to 121) μmol(L·min) per mL,
P
<0.001]; similarly, PON activity in
CKD
subjects was lower compared with that in non‐
CKD
control subjects [median (interquartile range) 474 (275 to 936) versus 586 (301 to 1118) nmol(L·min) per mL,
P
<0.001]. Lower serum arylesterase (hazard ratio 1.8, 95% CI 1.26 to 2.57,
P
<0.01) was a predictor of poorer outcomes. After adjusting for traditional risk factors and medication use, lower serum arylesterase (hazard ratio 1.55, 95% CI 1.08 to 2.23,
P
<0.05) still conferred an increased risk of major adverse cardiac events at 3 years.

Conclusions

In patients with
CKD
, decreased serum arylesterase activity, a measure of diminished antioxidant properties of
PON
‐1, predicts higher risk of incident long‐term adverse cardiovascular events (heart attack, stroke, or death) in multivariable models adjusting for established clinical and biochemical risk factors.
Metabolic Syndrome in Adults With Congenital Heart Disease
Authors: Deen Jason F. , Krieger Eric V. , Slee April E. , Arslan Alex , Arterburn David , Stout Karen K. , Portman Michael A.
Published: September 2018

Background

Metabolic syndrome increases risk for atherosclerotic coronary artery disease, and its prevalence increases with increasing age and body mass index. Adults with congenital heart disease (
ACHD
) are now living longer and accruing coronary artery disease risk factors. However, the prevalence of metabolic syndrome in
ACHD
patients is unknown.

Methods and Results

We conducted a retrospective cohort study of
ACHD
patients at our center to quantify the prevalence of metabolic syndrome in an
ACHD
population. Using case‐control matching, we constructed a comparable control group from a population‐based sample of 150 104 adults. International Diabetes Federation criteria were used to define metabolic syndrome. We used logistic regression to compare the risk of metabolic syndrome across the resulting cohorts, which were composed of 448
ACHD
patients and 448 controls matched by age and sex. Mean age of both groups was 32.4±11.3 years, and 51.3% were female. Obesity was present in 16.1% of the
ACHD
patients and 16.7% of the controls. Metabolic syndrome was more common in
ACHD
patients than in controls (15.0% versus 7.4%; odds ratio 1.82, 95%
CI
1.25–2.65).

Conclusions

Our data suggest that metabolic syndrome is more common among adults with congenital heart disease than in the general population. Thus, patients with congenital heart disease should be screened for metabolic syndrome and risk factors mitigated where possible to prevent atherosclerotic coronary artery disease. Preventive cardiology should be included during routine
ACHD
care.
Apocynin Attenuates Cardiac Injury in Type 4 Cardiorenal Syndrome via Suppressing Cardiac Fibroblast Growth Factor‐2 With Oxidative Stress Inhibition
Authors: Liu Yang , Liu Yu , Liu Xun , Chen Jie , Zhang Kun , Huang Feifei , Wang Jing‐Feng , Tang Wanchun , Huang Hui
Published: September 2018

Background

Type 4 cardiorenal syndrome (
CRS
) refers to the cardiac injury induced by chronic kidney disease. We aimed to assess oxidative stress and cardiac injury in patients with type 4
CRS
, determine whether the antioxidant apocynin attenuated cardiac injury in rats with type 4
CRS
, and explore potential mechanisms.

Methods and Results

A cross‐sectional study was conducted among patients with type 4
CRS
(n=17) and controls (n=16). Compared with controls, patients with type 4
CRS
showed elevated oxidative stress, which was significantly correlated with cardiac hypertrophy and decreased ejection fraction. In vivo study, male Sprague‐Dawley rats underwent 5/6 subtotal nephrectomy and sham surgery, followed with apocynin or vehicle treatment for 8 weeks. Eight weeks after surgery, the 5/6 subtotal nephrectomy rats mimicked type 4
CRS
, showing increased serum creatinine, cardiac hypertrophy and fibrosis, and decreased ejection fraction compared with sham‐operated animals. Cardiac malondialdehyde,
NADPH
oxidase activity, fibroblast growth factor‐2, and extracellular signal‐regulated kinase 1/2 (ERK1/2) phosphorylation increased significantly in the 5/6 subtotal nephrectomy rats. These changes were significantly attenuated by apocynin. In vitro study showed that apocynin reduced angiotensin
II
–induced
NADPH
oxidase–dependent oxidative stress, upregulation of fibroblast growth factor‐2 and fibrosis biomarkers, and
ERK
1/2 phosphorylation in cardiac fibroblasts. Importantly, the
ERK
1/2 inhibitor U0126 reduced the upregulation of fibroblast growth factor‐2 and fibrosis biomarkers in angiotensin
II
–treated fibroblasts.

Conclusions

Oxidative stress is a candidate mediator for type 4
CRS
. Apocynin attenuated cardiac injury in type 4
CRS
rats via inhibiting
NADPH
oxidase–dependent oxidative stress‐activated
ERK
1/2 pathway and subsequent fibroblast growth factor‐2 upregulation. Our study added evidence to the beneficial effect of apocynin in type 4
CRS
.
Serum Amyloid A Facilitates Early Lesion Development in
Ldlr

−/−

Mice
Authors: Krishack Paulette A. , Bhanvadia Clarissa V. , Lukens John , Sontag Timothy J. , De Beer Maria C. , Getz Godfrey S. , Reardon Catherine A.
Published: September 2018

Background

Atherosclerosis is a chronic inflammatory disorder, and several studies have demonstrated a positive association between plasma serum amyloid A (
SAA
) levels and cardiovascular disease risk. The aim of the study was to examine whether
SAA
has a role in atherogenesis, the underlying basis of most cardiovascular disease.

Methods and Results

Mice globally deficient in acute‐phase isoforms
Saa1
and
Saa2
(
Saa

−/−

) were crossed to
Ldlr

−/−

mice (
Saa

−/−

Ldlr

−/−

).
Saa

−/−

Ldlr

−/−

mice demonstrated a 31% reduction in lesional area in the ascending aorta but not in the aortic root or innominate artery after consuming a high‐fat, high‐cholesterol Western‐type diet for 6 weeks. The lesions were predominantly macrophage foam cells. The phenotype was lost in more mature lesions in mice fed a Western‐type diet for 12 weeks, suggesting that
SAA
is involved in early lesion development. The decreased atherosclerosis in the
Saa

−/−

Ldlr

−/−

mice occurred despite increased levels of blood monocytes and was independent of plasma lipid levels.
SAA
is produced predominantly by hepatocytes and macrophages. To determine which source of
SAA
may have a dominant role in lesion development, bone marrow transplantation was performed.
Ldlr

−/−

mice that received bone marrow from
Saa

−/−

Ldlr

−/−

mice had slightly reduced ascending aorta atherosclerosis compared with
Saa

−/−

Ldlr

−/−

mice receiving bone marrow from
Ldlr

−/−

mice, indicating that the expression of
SAA
by macrophages may have an important influence on atherogenesis.

Conclusions

The results indicate that
SAA
produced by macrophages promotes early lesion formation in the ascending aorta.
Short‐Term, High‐Dose Fish Oil Supplementation Increases the Production of Omega‐3 Fatty Acid–Derived Mediators in Patients With Peripheral Artery Disease (the OMEGA‐PAD I Trial)
Authors: Grenon S. Marlene , Owens Christopher D. , Nosova Emily V. , Hughes‐Fulford Millie , Alley Hugh F. , Chong Karen , Perez Sandra , Yen Priscilla K. , Boscardin John , Hellmann Jason , Spite Matthew , Conte Michael S.
Published: September 2018

Background

Patients with peripheral artery disease (
PAD
) experience significant morbidity and mortality. The
OMEGA
‐
PAD
I Trial, a randomized, double‐blinded, placebo‐controlled trial, addressed the hypothesis that short‐duration, high‐dose n‐3 polyunsaturated fatty acids (n‐3
PUFA
) oral supplementation improves endothelial function and inflammation in
PAD
.

Methods and Results

Eighty patients with stable claudication received 4.4 g of fish oil or placebo for 1 month. The primary end point was endothelial function as measured by brachial artery flow‐mediated vasodilation. Secondary end points included biomarkers of inflammation, n‐3 polyunsaturated fatty acids metabolome changes, lipid profile, and walking impairment questionnaires. Although there was a significant increase in FMD in the fish oil group following treatment (0.7±1.8% increase from baseline,
P
=0.04), this response was not different then the placebo group (0.6±2.5% increase from baseline,
P
=0.18; between‐group
P
=0.86) leading to a negative finding for the primary endpoint. There was, however, a significant reduction in triglycerides (fish oil: −34±46 mg/
dL
,
P
<0.001; placebo −10±43 mg/
dL
,
P
=0.20; between‐group differential
P
‐value: 0.02), and an increase in the omega‐3 index of 4±1% (
P
<0.001) in the fish oil group (placebo 0.1±0.9%,
P
=0.49; between‐group
P
<0.0001). We observed a significant increase in the production of pathway markers of specialized pro‐resolving mediators generated from n‐3 polyunsaturated fatty acids in the fish oil group.

Conclusions

High‐dose, short‐duration fish oil supplementation did not lead to a different response in the primary end point of endothelial function between the treatment and placebo group, but improved serum triglycerides and increased the production of downstream n‐3 polyunsaturated fatty acids–derived products and mediators in patients with
PAD
.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov/
. Unique identifier:
NCT
01310270.
Manganese‐Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri‐Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia–Reperfusion Model
Authors: Dash Rajesh , Kim Paul J. , Matsuura Yuka , Ikeno Fumiaki , Metzler Scott , Huang Ngan F. , Lyons Jennifer K. , Nguyen Patricia K. , Ge Xiaohu , Wong Po Foo Cheryl , McConnell Michael V. , Wu Joseph C. , Yeung Alan C. , Harnish Phillip , Yang Phillip C.
Published: September 2018

Background

The exact mechanism of stem cell therapy in augmenting the function of ischemic cardiomyopathy is unclear. In this study, we hypothesized that increased viability of the peri‐infarct region (
PIR
) produces restorative benefits after stem cell engraftment. A novel multimodality imaging approach simultaneously assessed myocardial viability (manganese‐enhanced magnetic resonance imaging [
MEMRI]
), myocardial scar (delayed gadolinium enhancement
MRI
), and transplanted stem cell engraftment (positron emission tomography reporter gene) in the injured porcine hearts.

Methods and Results

Twelve adult swine underwent ischemia–reperfusion injury. Digital subtraction of
MEMRI
‐negative myocardium (intrainfarct region) from delayed gadolinium enhancement
MRI
–positive myocardium (
PIR
and intrainfarct region) clearly delineated the
PIR
in which the
MEMRI
‐positive signal reflected
PIR
viability. Human amniotic mesenchymal stem cells (
hAMSC
s) represent a unique population of immunomodulatory mesodermal stem cells that restored the murine
PIR
. Immediately following
hAMSC
delivery,
MEMRI
demonstrated an increased
PIR
viability signal compared with control. Direct
PIR
viability remained higher in
hAMSC
‐treated hearts for >6 weeks. Increased
PIR
viability correlated with improved regional contractility, left ventricular ejection fraction, infarct size, and
hAMSC
engraftment, as confirmed by immunocytochemistry. Increased
MEMRI
and positron emission tomography reporter gene signal in the intrainfarct region and the
PIR
correlated with sustained functional augmentation (global and regional) within the
hAMSC
group (mean change, left ventricular ejection fraction:
hAMSC
85±60%, control 8±10%;
P
<0.05) and reduced chamber dilatation (left ventricular end‐diastole volume increase:
hAMSC
24±8%, control 110±30%;
P
<0.05).

Conclusions

The positron emission tomography reporter gene signal of
hAMSC
engraftment correlates with the improved
MEMRI
signal in the
PIR
. The increased
MEMRI
signal represents
PIR
viability and the restorative potential of the injured heart. This in vivo multimodality imaging platform represents a novel, real‐time method of tracking
PIR
viability and stem cell engraftment while providing a mechanistic explanation of the therapeutic efficacy of cardiovascular stem cells.
Effects of Cardiac Resynchronization Therapy on Cardiac Remodeling and Contractile Function: Results From Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE)
Authors: St. John Sutton Martin , Cerkvenik Jeffrey , Borlaug Barry A. , Daubert Claude , Gold Michael R. , Ghio Stefano , Chirinos Julio A. , Linde Cecilia , Ky Bonnie
Published: September 2018

Background

Cardiac resynchronization therapy results in improved ejection fraction in patients with heart failure. We sought to determine whether these effects were mediated by changes in contractility, afterload, or volumes.

Methods and Results

In 610 patients with New York Heart Association class I/
II
heart failure from the
Re
synchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (
REVERSE
) study, we performed detailed quantitative echocardiography assessment prior to and following cardiac resynchronization therapy. We derived measures of contractility (the slope [end‐systolic elastance] and the volume intercept of the end‐systolic pressure–volume relationship, stroke work, and preload recruitable stroke work), measures of arterial load and ventricular–arterial coupling, and measures of chamber size (volume intercept, end‐systolic and end‐diastolic volumes). At 6 and 12 months, cardiac resynchronization therapy was associated with a reduction in the volume intercept and end‐systolic and end‐diastolic volumes (
P
<0.01). There were no consistent effects on end‐systolic elastance, stroke work, preload recruitable stroke work, or ventricular–arterial coupling. In the active cardiac resynchronization therapy population, baseline measures of arterial load were associated with the clinical composite score (odds ratio 1.30, 95%
CI
1.04 to 1.63,
P
=0.02). The volume intercept was associated with mortality (hazard ratio 1.90, 95%
CI
1.01 to 3.59,
P
=0.047) and more modestly with the combined end point of mortality or heart failure hospitalization (hazard ratio 1.48, 95%
CI
0.8 to 2.25,
P
=0.06). In contrast, end‐systolic elastance, stroke work, preload recruitable stroke work, and ventricular–arterial coupling were not associated with any outcomes.

Conclusion

In patients with
NYHA
Class I/
II
heart failure, cardiac resynchronization therapy exerts favorable changes in left ventricular end‐systolic and end‐diastolic volumes and the volume intercept. The volume intercept may be useful to gain insight into prognosis in heart failure.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov/
. Unique identifier:
NCT
00271154.
Thiosulfate Mediates Cytoprotective Effects of Hydrogen Sulfide Against Neuronal Ischemia
Authors: Marutani Eizo , Yamada Marina , Ida Tomoaki , Tokuda Kentaro , Ikeda Kohei , Kai Shinichi , Shirozu Kazuhiro , Hayashida Kei , Kosugi Shizuko , Hanaoka Kenjiro , Kaneki Masao , Akaike Takaaki , Ichinose Fumito
Published: September 2018

Background

Hydrogen sulfide (H
2
S) exhibits protective effects in various disease models including cerebral ischemia–reperfusion (I/R) injury. Nonetheless, mechanisms and identity of molecules responsible for neuroprotective effects of H
2
S remain incompletely defined. In the current study, we observed that thiosulfate, an oxidation product of H
2
S, mediates protective effects of an H
2
S donor compound sodium sulfide (Na
2
S) against neuronal I/R injury.

Methods and Results

We observed that thiosulfate in cell culture medium is not only required but also sufficient to mediate cytoprotective effects of Na
2
S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (
SH
‐
SY
5Y) and murine primary cortical neurons. Systemic administration of sodium thiosulfate (
STS
) improved survival and neurological function of mice subjected to global cerebral I/R injury. Beneficial effects of
STS
, as well as Na
2
S, were associated with marked increase of thiosulfate, but not H
2
S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating “carrier” molecule of beneficial effects of H
2
S. Protective effects of thiosulfate were associated with inhibition of caspase‐3 activity by persulfidation at Cys163 in caspase‐3. We discovered that an
SLC
13 family protein, sodium sulfate cotransporter 2 (
SLC
13A4, NaS‐2), facilitates transport of thiosulfate, but not sulfide, across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of Na
2
S and
STS
.

Conclusions

The protective effects of H
2
S are mediated by thiosulfate that is transported across cell membrane by NaS‐2 and exerts antiapoptotic effects via persulfidation of caspase‐3. Given the established safety track record, thiosulfate may be therapeutic against ischemic brain injury.
Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo
Authors: Kobayashi Hatasu , Matsuda Yoshiko , Hitomi Toshiaki , Okuda Hiroko , Shioi Hirotomo , Matsuda Tetsuya , Imai Hirohiko , Sone Masakatsu , Taura Daisuke , Harada Kouji H. , Habu Toshiyuki , Takagi Yasushi , Miyamoto Susumu , Koizumi Akio
Published: September 2018

Background

P.R4810K of

RNF
213

(mysterin: rs112735431), which is an
AAA
+
ATP
ase, is the susceptibility polymorphism for moyamoya disease (
MMD
) in East Asians. However, the role of
RNF
213 R4810K in the etiology of
MMD
is unknown.

Methods and Results

To clarify the role of
RNF
213 in known angiogenic pathways,
RNF
213 expression was analyzed in endothelial cells (
EC
s) treated with several angiogenic and antiangiogenic factors, including interferons (
IFN
s).
RNF
213 was upregulated by
IFN
‐β through signal transducer and activator of transcription x in the promoter and mediated antiangiogenic activity of
IFN
‐β.
RNF
213 wild‐type (
WT
) overexpression could not lower angiogenesis without
IFN
‐β, but
RNF
213 R4810K overexpression could. To correlate biochemical function as
ATP
ase and the role of
RNF
213 oligomer formation with antiangiogenic activity, we investigated the effects of mutations in the
AAA
+
module. A mutation of the Walker B motif (
WEQ
), which stabilizes oligomerization, inhibited angiogenesis, but
AAA
+
module deletion, which cannot initiate oligomerization, did not. Intriguingly, R4810K, similar to
WEQ
, decreased
ATP
ase activity, suggesting its antiangiogenic activity through stabilizing oligomers. To confirm the antiangiogenic effect of
RNF
213 upregulation in vivo, vascular
EC
‐ or smooth muscle cell‐specific Rnf213 R4757K (R4810K ortholog) or
WT
transgenic (Tg) mice were exposed to hypoxia. Cerebral angiogenesis by hypoxia was suppressed in EC‐specific Rnf213 R4757K Tg mice, whereas it was not suppressed in other mice.

Conclusions

This study suggests the importance of inflammatory signals as environmental factors and R4810K carriers for susceptibility to cerebral hypoxia. A specific inhibitor of
ATP
binding to the first
AAA
+
could be a promising therapeutic candidate for
MMD
.
Association of Acute and Chronic Hyperglycemia With Acute Ischemic Stroke Outcomes Post‐Thrombolysis: Findings From Get With The Guidelines‐Stroke
Authors: Masrur Shihab , Cox Margueritte , Bhatt Deepak L. , Smith Eric E. , Ellrodt Gray , Fonarow Gregg C. , Schwamm Lee
Published: September 2018

Background

Hyperglycemia has been associated with adverse outcomes in patients with acute ischemic stroke (
AIS
) and may influence outcomes after tissue plasminogen activator (
tPA
). We sought to analyze the association of acute and chronic hyperglycemia on clinical outcomes in
tPA‐
treated patients.

Methods and Results

We identified 58 265
AIS
patients from 1408 sites who received
tPA
from 2009 to 2013 in Get With The Guidelines‐Stroke. Acute hyperglycemia at admission was defined as a plasma glucose level >140 mg/dL. Chronic hyperglycemia was defined by plasma glycosylated hemoglobin (HbA1c) >6.5%. Post‐
tPA
outcomes were analyzed using logistic regression. Blood glucose >140 mg/dL and HbA1c >6.5 were associated with worse clinical outcomes (symptomatic intracranial hemorrhage [
sICH
], life‐threatening hemorrhage, and in‐hospital mortality and length of stay) in diabetic and nondiabetic patients. Among patients with documented history of diabetes, increasing admission glucose up to 200 mg/dL was associated with increased adjusted odds ratio (
aOR
) of in‐hospital mortality (
aOR,
1.07) and
sICH
(
aOR,
1.05) per 10 mg/dL increase in blood glucose. Increasing HbA1C to 8% was associated with increased odds of in‐hospital mortality (
aOR,
1.19) and
sICH
(
aOR,
1.16) per 1% increase in HbA1c. Similar findings were observed in patients without a documented history of diabetes. There was no further increase in poor outcomes above the blood glucose level of 200 mg/dL or HbA1c >8.

Conclusion

Acute and chronic hyperglycemia are both associated with increased mortality and worse clinical outcomes in
AIS
patients treated with
tPA
. Controlled trials are needed to determine whether acute correction of hyperglycemia can improve outcomes after thrombolysis.
Metformin and Myocardial Injury in Patients With Diabetes and ST‐Segment Elevation Myocardial Infarction: A Propensity Score Matched Analysis
Authors: Basnet Suresh , Kozikowski Andrzej , Makaryus Amgad N. , Pekmezaris Renee , Zeltser Roman , Akerman Meredith , Lesser Martin , Wolf‐Klein Gisele
Published: September 2018

Background

Although animal studies have documented metformin's cardioprotective effects, the impact in humans remains elusive. The study objective was to explore the association between metformin and myocardial infarct size in patients with diabetes presenting with
ST
‐segment elevation myocardial infarction.

Methods and Results

Data extraction used the National Cardiovascular Data Cath
PCI
Registry in all patients with diabetes aged >18 years presenting with
ST
‐segment elevation myocardial infarction at 2 academic medical centers from January 2010 to December 2013. The exposure of interest was ongoing metformin use before the event. Propensity score matching was used for the metformin and nonmetformin groups on key prognostic variables. All matched pairs had acceptable D scores of <10%, confirming an efficient matching procedure. The primary outcome was myocardial infarct size, reflected by peak serum creatine kinase–myocardial band, troponin T, and hospital discharge left ventricular ejection fraction. Of all 1726
ST
‐segment elevation myocardial infarction cases reviewed, 493 patients had diabetes (28.5%), with 208 metformin users (42.1%) and 285 nonusers. Matched pairs analysis yielded 137 cases per group. The difference between metformin and nonmetformin groups was −18.1 ng/mL (95%
CI
−55.0 to 18.8;
P
=0.56) for total peak serum creatine kinase–myocardial band and −1.1 ng/mL (95%
CI
−2.8 to 0.5;
P
=0.41) for troponin T. Median discharge left ventricular ejection fraction in both groups was 45, and the difference between metformin and nonmetformin users was 0.7% (95%
CI
−2.2 to 3.6;
P
=0.99).

Conclusions

No statistically significant association of cardioprotection was found between metformin and myocardial infarct size in patients with diabetes and acute
ST
‐segment elevation myocardial infarction.
Adherence to Antihypertensive Medication in Treatment‐Resistant Hypertension Undergoing Renal Denervation
Authors: Schmieder Roland E. , Ott Christian , Schmid Axel , Friedrich Stefanie , Kistner Iris , Ditting Tilmann , Veelken Roland , Uder Michael , Toennes Stefan W.
Published: September 2018

Background

Adherence to medication has been repeatedly proposed to represent a major cause of treatment‐resistant hypertension (
TRH
); however, treatment decisions such as treating
TRH
with renal denervation depend on accurate judgment of adherence. We carefully analyzed adherence rates to medication before and after renal denervation and its effect on blood pressure (
BP
) control.

Methods and Results

Eighty patients with
TRH
were included in 2 prospective observational studies that assessed the difference of potential antihypertensive and nephroprotective effects of renal denervation. To compare prescribed with actual medication intake (representing a measure of adherence), we analyzed urine samples collected at baseline and at 6 months after renal denervation for antihypertensive compounds or metabolites (by liquid chromatography–mass spectrometry). In addition to office
BP
, 24‐hour ambulatory
BP
and central hemodynamics (central systolic pressure, central pulse pressure) were assessed. Informed consent for analyses of urine metabolites was obtained from 79 of 80 patients. Actual intake of all antihypertensive drugs was detected at baseline and at 6 months after renal denervation in 44 (56%) and 52 (66%) patients, respectively; 1 drug was missing in 22 (28%) and 17 (22%) patients, respectively, and ≥2 drugs were missing in 13 (16%) and 10 (13%) patients, respectively. At baseline, 24‐hour ambulatory BP (
P
=0.049) and central systolic
BP
(
P
=0.012) were higher in nonadherent patients. Adherence did not significantly change overall (McNemar‐Bowker test,
P
=0.362). An increase in adherence was observed in 21 patients, and a decrease was observed in 11 patients. The decrease in 24‐hour ambulatory
BP
was not different in those with stable adherence 6 months after renal denervation (n=41, −7±13 mm Hg) compared with those with increased adherence (n=21, −10±13 mm Hg) and decreased adherence (n=11, −7±14 mm Hg) (
P
>0.20). Our study is limited by the relatively small sample size and potentially by the specific health environment of our university center (Northern Bavaria, Germany).

Conclusions

Nonadherence to medication among patients with
TRH
was relatively low: ≈1 of 6 patients with
TRH
did not take ≥2 of the prescribed drugs. Adherence pattern did not change significantly after renal denervation and had no impact on the overall observed
BP
changes, supporting the concept that renal denervation is an effective treatment in patients with
TRH
.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifiers:
NCT
00888433,
NCT
01442883 and
NCT
01687725.
Early Access to the Cardiac Catheterization Laboratory for Patients Resuscitated From Cardiac Arrest Due to a Shockable Rhythm: The Minnesota Resuscitation Consortium Twin Cities Unified Protocol
Authors: Garcia Santiago , Drexel Todd , Bekwelem Wobo , Raveendran Ganesh , Caldwell Emily , Hodgson Lucinda , Wang Qi , Adabag Selcuk , Mahoney Brian , Frascone Ralph , Helmer Gregory , Lick Charles , Conterato Marc , Baran Kenneth , Bart Bradley , Bachour Fouad , Roh Steven , Panetta Carmelo , Stark Randall , Haugland Mark , Mooney Michael , Wesley Keith , Yannopoulos Demetris
Published: September 2018

Background

In 2013 the Minnesota Resuscitation Consortium developed an organized approach for the management of patients resuscitated from shockable rhythms to gain early access to the cardiac catheterization laboratory (CCL) in the metro area of Minneapolis‐St. Paul.

Methods and Results

Eleven hospitals with 24/7 percutaneous coronary intervention capabilities agreed to provide early (within 6 hours of arrival at the Emergency Department) access to the CCL with the intention to perform coronary revascularization for outpatients who were successfully resuscitated from ventricular fibrillation/ventricular tachycardia arrest. Other inclusion criteria were age >18 and <76 and presumed cardiac etiology. Patients with other rhythms, known do not resuscitate/do not intubate, noncardiac etiology, significant bleeding, and terminal disease were excluded. The primary outcome was survival to hospital discharge with favorable neurological outcome. Patients (315 out of 331) who were resuscitated from VT/VF and transferred alive to the Emergency Department had complete medical records. Of those, 231 (73.3%) were taken to the CCL per the Minnesota Resuscitation Consortium protocol while 84 (26.6%) were not taken to the CCL (protocol deviations). Overall, 197 (63%) patients survived to hospital discharge with good neurological outcome (cerebral performance category of 1 or 2). Of the patients who followed the Minnesota Resuscitation Consortium protocol, 121 (52%) underwent percutaneous coronary intervention, and 15 (7%) underwent coronary artery bypass graft. In this group, 151 (65%) survived with good neurological outcome, whereas in the group that did not follow the Minnesota Resuscitation Consortium protocol, 46 (55%) survived with good neurological outcome (adjusted odds ratio: 1.99; [1.07–3.72],
P
=0.03).

Conclusions

Early access to the CCL after cardiac arrest due to a shockable rhythm in a selected group of patients is feasible in a large metropolitan area in the United States and is associated with a 65% survival rate to hospital discharge with a good neurological outcome.
Primary Prevention Implantable Cardioverter Defibrillator (ICD) Therapy in Women—Data From a Multicenter French Registry
Authors: Providência Rui , Marijon Eloi , Lambiase Pier D. , Bouzeman Abdeslam , Defaye Pascal , Klug Didier , Amet Denis , Perier Marie‐Cécile , Gras Daniel , Algalarrondo Vincent , Deharo Jean‐Claude , Leclercq Christophe , Fauchier Laurent , Babuty Dominique , Bordachar Pierre , Sadoul Nicolas , Piot Olivier , Boveda Serge , Providencia Rui , Beganton Frankie , Perier Marie‐Cecile
Published: September 2018

Background

There are limited data describing sex specificities regarding implantable cardioverter defibrillators (ICDs) in the real‐world European setting.

Methods and Results

Using a large multicenter cohort of consecutive patients referred for ICD implantation for primary prevention (2002–2012), in ischemic and nonischemic cardiomyopathy, we examined the sex differences in subjects' characteristics and outcomes. Of 5539 patients, only 837 (15.1%) were women and 53.8% received cardiac resynchronization therapy. Compared to men, women presented a significantly higher proportion of nonischemic cardiomyopathy (60.2% versus 36.2%,
P
<0.001), wider QRS complex width (QRS >120 ms: 74.6% versus 68.5%,
P
=0.003), higher New York Heart Association functional class (≥III in 54.2%♀ versus 47.8%♂,
P
=0.014), and lower prevalence of atrial fibrillation (18.7% versus 24.9%,
P
<0.001). During a 16 786 patient‐years follow‐up, overall, fewer appropriate therapies were observed in women (hazard ratio=0.59, 95% CI 0.45–0.76;
P
<0.001). By contrast, no sex‐specific interaction was observed for inappropriate shocks (odds ratio ♀=0.84, 95% CI 0.50–1.39,
P
=0.492), early complications (odds ratio=1.00, 95% CI 0.75–1.32,
P
=0.992), and all‐cause mortality (hazard ratio=0.87 95% CI 0.66–1.15,
P
=0.324). Analysis of sex‐by‐ cardiac resynchronization therapy interaction shows than female cardiac resynchronization therapy recipients experienced fewer appropriate therapies than men (hazard ratio=0.62, 95% CI 0.50–0.77;
P
<0.001) and lower mortality (hazard ratio=0.68, 95% CI 0.47–0.97;
P
=0.034).

Conclusions

In our real‐life registry, women account for the minority of ICD recipients and presented with a different clinical profile. Whereas female cardiac resynchronization therapy recipients had a lower incidence of appropriate ICD therapies and all‐cause death than their male counterparts, the observed rates of inappropriate shocks and early complications in all ICD recipients were comparable.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov/
. Unique identifier: NCT01992458.