bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple Sclerosis Drug Fingolimod Induces Thrombotic Microangiopathy in Deoxycorticosterone Acetate/Salt Hypertension
Authors: Iwazu Yoshitaka , Muto Shigeaki , Ioka Takashi , Watanabe Yuko , Iwazu Kana , Kusano Eiji , Nagata Daisuke
Published: September 2018

We examined whether fingolimod (FTY720), an S1PR (sphingosine-1-phosphate receptor) modulator, has beneficial or harmful effects on mineralocorticoid/salt-induced renal injury. Uninephrectomized rats on 0.9% NaCl/0.3% KCl drinking solution were randomly divided into control, control+FTY720, deoxycorticosterone acetate (DOCA), and DOCA+FTY720 groups and administered vehicle, vehicle+FTY720, DOCA+vehicle, and DOCA+FTY720 for 4 weeks, respectively. Only the DOCA+FTY720 group had reduced survival rates and showed hemolysis because of intravascular mechanical fragmentation of erythrocytes and thrombocytopenia. Both the DOCA+FTY720 and DOCA groups developed malignant hypertension, which was more severe in the DOCA+FTY720 group. In the DOCA+FTY720 group only, thrombotic microangiopathy involving severe renal arteriole endothelial cell injury was observed and was characterized by fibrinoid necrosis and onion-skin lesions in arterioles. There were fewer circulating endothelial progenitor cells in the DOCA+FTY720 group but more in the DOCA group compared with the control group. Expression levels of VEGF (vascular endothelial growth factor), S1PR1, and S1PR3 in renal arteriole endothelial cells were significantly greater in the DOCA+FTY720 and DOCA groups compared with the control group, with levels being similar between the 2 groups. Expression levels of endothelial nitric oxide synthase in renal arteriole endothelial cells were significantly lower in the DOCA+FTY720 group only. The control+FTY720 group showed reduced circulating endothelial progenitor cells but no significant functional or pathological changes in kidneys or changes in blood pressure. Exposure of uninephrectomized rats to DOCA/salt+FTY720 for 4 weeks induced renal arteriolar endothelial cell injury, resulting in the development of thrombotic microangiopathy. Consideration of this possibility is recommended when prescribing FTY720.
Tumor Cell Subtypes Based on the Intracellular Hormonal Activity in
KCNJ5
-Mutated Aldosterone-Producing Adenoma
Authors: Yamazaki Yuto , Omata Kei , Tezuka Yuta , Ono Yoshikiyo , Morimoto Ryo , Adachi Yuzu , Ise Kazue , Nakamura Yasuhiro , Gomez-Sanchez Celso E. , Shibahara Yukiko , Kitamoto Takumi , Nishikawa Tetsuo , Ito Sadayoshi , Satoh Fumitoshi , Sasano Hironobu
Published: September 2018

Aldosterone-producing adenomas (APAs) harbor marked intratumoral heterogeneity in terms of morphology, steroidogenesis, and genetics. However, an association of biological significance of morphologically identified tumor cell subtypes and genotypes is virtually unknown.
KCNJ5
mutation is most frequently detected and generally considered a curable phenotype by adrenalectomy. Therefore, to explore the biological significance of
KCNJ5
mutation in APA based on intracellular hormonal activities, 35 consecutively selected APAs (n=18;
KCNJ5
mutated, n=17; wild type) were quantitatively examined in the whole tumor areas by newly developed digital image analysis incorporating their histological and ultrastructural features (14 cells from 2
KCNJ5
-mutated APAs and 15 cells from 1 wild type) and CYP11B2 immunoreactivity. Results demonstrated that
KCNJ5
-mutated APAs had significantly lower nuclear/cytoplasm ratio and more abundant clear cells than wild type. CYP11B2 immunoreactivity was not significantly different between these genotypes, but a significant correlation was detected between the proportion of clear cells and CYP11B2 immunoreactivity in all of the APAs examined. CYP11B2 was predominantly immunolocalized in clear cells in
KCNJ5
-mutated APAs. Quantitative ultrastructural analysis revealed that
KCNJ5
-mutated APAs had significantly more abundant and smaller-sized mitochondria with well-developed cristae than wild type, whereas wild type had more abundant lipid droplets per unit area despite the small number of the cases examined. Our results did provide the novel insights into the morphological features of APA based on their biological significance.
KCNJ5
-mutated APAs were characterized by predominance of enlarged lipid-rich clear cells possibly resulting in increased neoplastic aldosterone biosynthesis.
Exposure to Maternal Diabetes Mellitus Causes Renal Dopamine D
1
Receptor Dysfunction and Hypertension in Adult Rat Offspring
Authors: Luo Hao , Chen Caiyu , Guo Li , Xu Zaicheng , Peng Xiaoyu , Wang Xinquan , Wang Jialiang , Wang Na , Li Chuanwei , Luo Xiaoli , Wang Hongyong , Jose Pedro A. , Fu Chunjiang , Huang Yu , Shi Weibin , Zeng Chunyu
Published: September 2018

Epidemiological and experimental studies suggest that maternal diabetes mellitus programs hypertension that is associated with impaired sodium excretion in the adult offspring. However, the underlying mechanisms are not clear. Because dopamine receptor function is involved in the pathogenesis of hypertension, we hypothesized that impaired renal dopamine D
1
receptor function is also involved in the hypertension in offspring of maternal diabetes mellitus. Maternal diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (35 mg/kg) to pregnant Sprague-Dawley rats at day 0 of gestation. Compared with the offspring of mothers injected with citrate buffer (control mother offspring), the diabetic mother offspring (DMO) had increased systolic blood pressure and impaired D
1
receptor-mediated diuresis and natriuresis, accompanied by increased renal PKC (protein kinase C) expression and activity, GRK-2 (G protein–coupled receptor kinase-2) expression, D
1
receptor phosphorylation, D
1
receptor/Gαs uncoupling, and loss of D
1
receptor-mediated inhibition of Na
+
-K
+
-ATPase activity in renal proximal tubule cells from DMO. Inhibition of PKC reduced the increased GRK-2 expression and normalized D
1
receptor function in primary cultures of renal proximal tubule cells from DMO. In addition, DMO, relative to control mother offspring, in vivo, had increased oxidative stress, indicated by decreased renal glutathione and increased renal malondialdehyde and urine 8-isoprostane. Normalization of oxidative stress with tempol also normalized the renal D
1
receptor phosphorylation, D
1
receptor-mediated diuresis and natriuresis, and blood pressure in DMO. Our present study indicates that maternal diabetes mellitus–programed hypertension in the offspring is caused by impaired renal D
1
receptor function because of oxidative stress that is mediated by increased PKC-GRK-2 activity.
Cellular and Genetic Causes of Idiopathic Hyperaldosteronism
Authors: Omata Kei , Satoh Fumitoshi , Morimoto Ryo , Ito Sadayoshi , Yamazaki Yuto , Nakamura Yasuhiro , Anand Sharath K. , Guo Zeng , Stowasser Michael , Sasano Hironobu , Tomlins Scott A. , Rainey William E.
Published: September 2018

Primary aldosteronism affects ≈5% to 10% of hypertensive patients and has unilateral and bilateral forms. Most unilateral primary aldosteronism is caused by computed tomography-detectable aldosterone-producing adenomas, which express CYP11B2 (aldosterone synthase) and frequently harbor somatic mutations in aldosterone-regulating genes. The cause of the most common bilateral form of primary aldosteronism, idiopathic hyperaldosteronism (IHA), is believed to be diffuse hyperplasia of aldosterone-producing cells within the adrenal cortex. Herein, a multi-institution cohort of 15 IHA adrenals was examined with CYP11B2 immunohistochemistry and next-generation sequencing. CYP11B2 immunoreactivity in adrenal glomerulosa harboring non-nodular hyperplasia was only observed in 4/15 IHA adrenals suggesting that hyperplasia of CYP11B2-expressing cells may not be the major cause of IHA. However, the adrenal cortex of all IHA adrenals harbored at least 1 CYP11B2-positive aldosterone-producing cell cluster (APCC) or micro-aldosterone-producing adenomas. The number of APCCs per case (and individual APCC area) in IHA adrenals was significantly larger than in normotensive controls. Next-generation sequencing of DNA from 99 IHA APCCs demonstrated somatic mutations in genes encoding the L-type calcium voltage-gated channel subunit α 1-D (
CACNA1D
, n=57; 58%) and potassium voltage-gated channel subfamily J-5 (
KCNJ5
, n=1; 1%). These data suggest that IHA may result from not only hyperplasia but also the accumulation or enlargement of computed tomography-undetectable APCC harboring somatic aldosterone-driver gene mutations. The high prevalence of mutations in the
CACNA1D
L-type calcium channel provides a potential actionable therapeutic target that could complement mineralocorticoid blockade and inhibit aldosterone overproduction in some IHA patients.
Beyond Resistant Hypertension
Authors: Martínez-García Miguel-Angel , Navarro-Soriano Cristina , Torres Gerard , Barbé Ferrán , Caballero-Eraso Candela , Lloberes Patricia , Diaz-Cambriles Teresa , Somoza María , Masa Juan F. , González Mónica , Mañas Eva , de la Peña Mónica , García-Río Francisco , Montserrat Josep María , Muriel Alfonso , Selma-Ferrer Maria Jose , García Ortega Alberto , Campos-Rodriguez Francisco ,   on behalf the Spanish Sleep Network
Published: September 2018

Obstructive sleep apnea (OSA) is an independent cause of resistant hypertension (RH) but its association with refractory hypertension (RfH), a recently described form of severe hypertension, has not yet been investigated. This study seeks to analyze the association between the presence and severity of OSA/OSA syndrome with RfH and to compare it with a group of patients with OSA/OSA syndrome and RH. We conducted a multicenter, cross-sectional study of consecutive patients diagnosed with RH by means of 24-hour ambulatory blood pressure monitoring. Those patients with blood pressure levels ≥130/80 mm Hg, despite taking at least 5 antihypertensive drugs, were considered to have true RfH. All patients underwent a sleep study and completed a detailed clinical history related to OSA, current medication, and cardiovascular diseases. Overall, 229 patients were included (mean age, 58.3 years; 63% male), of whom 42 (18.3%) satisfied the criteria for RfH. Compared with those with RH, patients with RfH had a higher cardiovascular risk profile, higher blood pressure measurements, and a 2-fold greater risk of having both severe OSA (odds ratio, 2.1, with a prevalence of apnea-hypopnea index ≥15, 95.2% and apnea-hypopnea index ≥30, 64.3%) and OSA syndrome (apnea-hypopnea index ≥5+Epworth Sleepiness Scale >10; odds ratio, 1.9; 52.4% versus 37.3%;
P
=0.023), as well as higher OSA severity (apnea-hypopnea index, 41.8 versus 33.8 events/h;
P
=0.026). Patients with RfH had an even greater prevalence and severity of OSA and OSA syndrome than RH patients, highlighting the need to identify these patients to refer them to sleep units on a preferential basis.
Neonatal MicroRNA Profile Determines Endothelial Function in Offspring of Hypertensive Pregnancies
Authors: Yu Grace Z. , Reilly Svetlana , Lewandowski Adam J. , Aye Christina Y.L. , Simpson Lisa J. , Newton Laura D. , Davis Esther F. , Zhu Sha J. , Fox Willow R. , Goel Anuj , Watkins Hugh , Channon Keith M. , Watt Suzanne M. , Kyriakou Theodosios , Leeson Paul
Published: September 2018

Offspring of hypertensive pregnancies are at increased risk of developing hypertension in adulthood. In the neonatal period, they display endothelial cell dysfunction and altered microvascular development. MicroRNAs, as important endothelial cellular regulators, may play a role in this early endothelial dysfunction. Therefore, we identified differential microRNA patterns in endothelial cells from offspring of hypertensive pregnancies and determined their role in postnatal vascular cell function. Studies were performed on human umbilical vein endothelial cell samples from 57 pregnancies. Unbiased RNA sequencing identified 30 endothelial related microRNAs differentially expressed in human umbilical vein endothelial cells from hypertensive compared with normotensive pregnancies. Quantitative reverse transcription polymerase chain reaction confirmed a significant higher expression level of the top candidate, miR-146a. Combined miR-146a–targeted gene expression and pathway analysis revealed significant alterations in genes involved in inflammation, angiogenesis, and immune response in the same human umbilical vein endothelial cells. Elevated miR-146a expression level at birth identified cells with reduced ability for in vitro vascular tube formation, which was rescued by miR-146a inhibition. In contrast, miR-146a overexpression significantly reduced vascular tube formation in human umbilical vein endothelial cells from normotensive pregnancies. Finally, we confirmed that miR-146a levels at birth predicted in vivo microvascular development during the first 3 postnatal months. Offspring of hypertensive pregnancy have a distinct endothelial regulatory microRNA profile at birth, which is related to altered endothelial cell behavior and predicts patterns of microvascular development during the first 3 months of life. Modification of this microRNA profile in vitro can restore impaired vascular cell function.
Programmed Cell Death 5 Provides Negative Feedback on Cardiac Hypertrophy Through the Stabilization of Sarco/Endoplasmic Reticulum Ca
2+
-ATPase 2a Protein
Authors: Ye Jingjing , Zheng Qiaoxia , Jia Shi , Qiao Xue , Cao Yangpo , Xu Chunling , Weng Lin , Zhao Lifang , Chen Yingyu , Liu Jian , Wang Tianbing , Cheng Heping , Zheng Ming
Published: September 2018

PDCD5 (programmed cell death 5) is ubiquitously expressed in tissues, including the heart; however, the mechanism underlying the cardiac function of PDCD5 has not been understood. We investigated the mechanisms of PDCD5 in the pathogenesis of cardiac hypertrophy. Cardiac-specific PDCD5 knockout mice developed severe cardiac hypertrophy and impaired cardiac function, whereas PDCD5 protein was significantly increased in transverse aortic constriction mouse hearts and phenylephrine-stimulated cardiomyocytes. Overexpression of PDCD5 inhibited phenylephrine-induced cardiomyocyte hypertrophy, and knockdown of PDCD5 induced cardiomyocyte hypertrophy and aggravated phenylephrine-induced hypertrophy. The expression of PDCD5 protein was regulated by NFATc2 (nuclear factor of activated T cells c2) during hypertrophy. SERCA2a (sarco/endoplasmic reticulum Ca
2+
-ATPase 2a) expression was decreased in PDCD5-deficient mouse hearts because of increased ubiquitination. PDCD5-deficient cardiomyocytes displayed decreased calcium uptake rate, slowed decay of Ca
2+
transients, decreased calcium stores, and diastolic dysfunction. Moreover, reintroduction of PDCD5 in PDCD5-deficient mouse hearts reserved SERCA2a protein, suppressed NFATc2 protein, and rescued the hypertrophy and cardiac dysfunction. Our results revealed that PDCD5 is a novel target of NFATc2 in the hypertrophic heart and provides negative feedback to protect the heart against excessive hypertrophy via the stabilization of SERCA2a protein.
Maternal Allopurinol Prevents Cardiac Dysfunction in Adult Male Offspring Programmed by Chronic Hypoxia During Pregnancy
Authors: Niu Youguo , Kane Andrew D. , Lusby Ciara M. , Allison Beth J. , Chua Yi Yi , Kaandorp Joepe J. , Nevin-Dolan Rhiannon , Ashmore Thomas J. , Blackmore Heather L. , Derks Jan B. , Ozanne Susan E. , Giussani Dino A.
Published: September 2018

Integrating functional and molecular levels, we investigated the effects of maternal treatment with a xanthine oxidase inhibitor on the programming of cardiac dysfunction in adult offspring using an established rat model of hypoxic pregnancy. Female Wistar rats were divided into normoxic or hypoxic (13% O
2
) pregnancy±maternal allopurinol treatment (30 mg kg
-1
d
-1
). At 4 months, hearts were isolated from 1 male per litter per outcome variable to determine cardiac function and responses to ischemia-reperfusion in a Langendorff preparation. Sympathetic dominance, perfusate CK (creatine kinase) and LDH (lactate dehydrogenase) and the cardiac protein expression of the β
1
-adrenergic receptor, the M
2
Ach receptor (muscarinic type-2 acetylcholine receptor), and the SERCA2a (sarcoplasmic reticulum Ca
2+
ATPase 2a) were determined. Relative to controls, offspring from hypoxic pregnancy showed elevated left ventricular end diastolic pressure (+34.7%), enhanced contractility (dP/dt
max
, +41.6%), reduced coronary flow rate (−21%) and an impaired recovery to ischemia-reperfusion (left ventricular diastolic pressure, area under the curve recovery −19.1%; all
P
<0.05). Increased sympathetic reactivity (heart rate, +755.5%; left ventricular diastolic pressure, +418.9%) contributed to the enhanced myocardial contractility (
P
<0.05). Perfusate CK (+431%) and LDH (+251.3%) and the cardiac expression of SERCA2a (+71.4%) were also elevated (
P
<0.05), further linking molecular markers of cardiac stress and injury to dysfunction. Maternal allopurinol restored all functional and molecular indices of cardiac pathology. The data support a link between xanthine oxidase–derived oxidative stress in hypoxic pregnancy and cardiac dysfunction in the adult offspring, providing a target for early intervention in the developmental programming of heart disease.
Morning Home Blood Pressure and Cardiovascular Events in Japanese Hypertensive Patients
Authors: Kario Kazuomi , Iwashita Mikio , Okuda Yasuyuki , Sugiyama Mitsunori , Saito Ikuo , Kushiro Toshio , Teramukai Satoshi , Shimada Kazuyuki
Published: September 2018

SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated the benefit of achieving strict blood pressure control with a lower target blood pressure level in high-risk patients with hypertension. The aim of this post hoc analysis was to investigate the relationship between the 2-year average on-treatment home blood pressure and cardiovascular disease risk in subgroups stratified by risk status using data from the HONEST study (Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure). Participants in the HONEST study (n=21 591) were stratified according to risk level as follows: SPRINT population (n=5823)—patients (≥50 years of age) without diabetes mellitus or prior stroke, with SPRINT-defined cardiovascular risk and systolic blood pressure (SBP) of ≥130 mm Hg; SPRINT-excluded high-risk population (n=5481)—patients with diabetes mellitus or prior stroke; and non-SPRINT low-risk population—all other patients in the HONEST study (n=10 287). Cardiovascular disease event risk was 6.32 events per 1000 person-years in the SPRINT population, which was higher than in the non-SPRINT low-risk (3.39;
P
<0.001) and lower than the SPRINT-excluded high-risk (12.41;
P
<0.001) populations. In the SPRINT and the SPRINT-excluded high-risk populations, a lower home SBP achieved was associated with lower cardiovascular disease risk, with the lowest risk in patients with a home SBP <125 mm Hg. The non-SPRINT low-risk population showed a J-curve association between on-treatment home SBP and cardiovascular disease risk with the lowest risk at a home SBP of 135 to <145 mm Hg. Intensive therapy targeting home SBP of <125 mm Hg would be beneficial for high-risk hypertensive patients.

Clinical Trial Registration—

URL:
http://www.umin.ac.jp/ctr/index.htm
. UMIN Clinical Trials Registry, trial no.: UMIN000002567.
Association Between Inflammatory Markers and Myocardial Fibrosis
Authors: Marques Mateus D. , Nauffal Victor , Ambale-Venkatesh Bharath , Vasconcellos Henrique D. , Wu Colin , Bahrami Hossein , Tracy Russell P. , Cushman Mary , Bluemke David A. , Lima João A.C.
Published: September 2018

Inflammation promotes adverse ventricular remodeling. T1 mapping has been used to noninvasively assess interstitial myocardial fibrosis. We examined the association of baseline markers of systemic inflammation with interstitial myocardial fibrosis measured by extracellular volume fraction (ECV) and native T1 mapping at 10-year follow-up in the MESA (Multi-Ethnic Study of Atherosclerosis). Seven hundred seventy-two participants had complete baseline data and underwent cardiac magnetic resonance imaging. All analyses were stratified by sex. Multivariable linear regression models were constructed to assess the associations of baseline CRP (C-reactive protein), IL (interleukin)-6, and fibrinogen with native T1 time and ECV. Longer native T1 times and higher percentages of ECV represent increasing myocardial fibrosis. A 1-SD increment of log-transformed IL-6 levels was associated with 0.4% higher ECV in men (β=0.4;
P
=0.05). CRP and fibrinogen were not associated to ECV. A 1-SD increment in the log-transformed CRP levels was associated with 4.9 ms higher native T1 (β=4.9;
P
=0.03). In women, the inflammatory markers did not demonstrate association with native T1 nor ECV. Higher IL-6 and CRP levels are associated with increased interstitial myocardial fibrosis assessed by cardiac magnetic resonance in men. However, no inflammatory markers were associated to myocardial fibrosis in women.
Extracellular Ubiquitin(1–76) and Ubiquitin(1–74) Regulate Cardiac Fibroblast Proliferation
Authors: Jackson Edwin K. , Mi Eric , Ritov Vladimir B. , Gillespie Delbert G.
Published: September 2018

SDF-1α (stromal cell–derived factor-1α) is a CXCR4-receptor agonist and DPP4 (dipeptidyl peptidase 4) substrate. SDF-1α, particularly when combined with sitagliptin to block the metabolism of SDF-1α by DPP4, stimulates proliferation of cardiac fibroblasts via the CXCR4 receptor; this effect is greater in cells from spontaneously hypertensive rats versus Wistar-Kyoto normotensive rats. Emerging evidence indicates that ubiquitin(1–76) exists in plasma and is a potent CXCR4-receptor agonist. Therefore, we hypothesized that ubiquitin(1–76), similar to SDF-1α, should increase proliferation of cardiac fibroblasts. Contrary to our working hypothesis, ubiquitin(1–76) did not stimulate cardiac fibroblast proliferation, yet unexpectedly antagonized the proproliferative effects of SDF-1α combined with sitagliptin. In this regard, ubiquitin(1–76) was more potent in spontaneously hypertensive versus Wistar-Kyoto cells. In the presence of 6bk (selective inhibitor of insulin-degrading enzyme [IDE]; an enzyme known to convert ubiquitin(1–76) to ubiquitin(1–74)), ubiquitin(1–76) no longer antagonized the proproliferative effects of SDF-1α/sitagliptin. Ubiquitin(1–74) also antagonized the proproliferative effects of SDF-1α/sitagliptin, and this effect of ubiquitin(1–74) was not blocked by 6bk and was >10-fold more potent compared with ubiquitin(1–76). Neither ubiquitin(1–76) nor ubiquitin(1–74) inhibited the proproliferative effects of the non-CXCR4 receptor agonist neuropeptide Y (activates Y
1
receptors). Cardiac fibroblasts expressed IDE mRNA, protein, and activity and converted ubiquitin(1–76) to ubiquitin(1–74). Spontaneously hypertensive fibroblasts expressed greater IDE activity. Extracellular ubiquitin(1–76) blocks the proproliferative effects of SDF-1α/sitagliptin via its conversion by IDE to ubiquitin(1–74), a potent CXCR4 antagonist. Thus, IDE inhibitors, particularly when combined with DPP4 inhibitors or hypertension, could increase the risk of cardiac fibrosis.
Hypertension, Anxiety, and Blood-Brain Barrier Permeability Are Increased in Postpartum Severe Preeclampsia/Hemolysis, Elevated Liver Enzymes, and Low Platelet Count Syndrome Rats
Authors: Wallace Kedra , Bean Cynthia , Bowles Teylor , Spencer Shauna-Kay , Randle Wisdom , Kyle Patrick B. , Shaffery James
Published: September 2018

Abstract—

Hypertension and inflammation during pregnancy are suggested to contribute to the development of postpartum depression and anxiety. Using a rat model of severe preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome, which displays both hypertension and inflammation during pregnancy, we evaluated whether rats were prone to develop depression or anxiety in the postpartum period. On gestational day 12, miniosmotic pumps infusing sFlt-1 (soluble fms-like tyrosine kinase-1) and sEng (soluble endoglin) were placed into rats, a subset of these rats was infused with 2 mg/kg of Orencia (abatacept) the following day to determine whether immune suppression via T-cell depletion prevented any changes in maternal depression or anxiety-like behavior. All rats, including normal pregnant (NP) controls, delivered between gestational days 21 and 22. Postpartum severe preeclamptic rats buried significantly more marbles compared with NP rats (
P
=0.002) and Orencia-treated rats (
P
=0.05). Severe preeclamptic rats spent significantly more time in closed arms of the elevated plus maze compared with NP rats (
P
=0.009) and Orencia-treated rats (
P
=0.05). Severe preeclamptic rats were hypertensive compared with NP (
P
=0.03) and Orencia-treated rats (
P
=0.01). Finally, severe preeclamptic rats had increased blood-brain barrier permeability compared with NP rats (
P
=0.03), which was reversed in Orencia-treated rats (
P
=0.008). These results suggest that severe preeclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome during pregnancy contributes to an increase in anxiety-like behavior, blood-brain barrier permeability, and hypertension in the postpartum. The current results suggest that T-cell suppression during pregnancy can also help prevent chronic hypertension and increased anxiety in the postpartum period.
Shock Index Predicts Patient‐Related Clinical Outcomes in Stroke
Authors: Myint Phyo Kyaw , Sheng Shubin , Xian Ying , Matsouaka Roland A. , Reeves Mathew J. , Saver Jeffrey L. , Bhatt Deepak L. , Fonarow Gregg C. , Schwamm Lee H. , Smith Eric E.
Published: September 2018

Background

The prognostic value of shock index (
SI
), heart rate divided by systolic blood pressure, in stroke for clinical outcomes other than mortality is not well understood.

Methods and Results

We examined the Get With The Guidelines–Stroke (
GWTG
‐Stroke) data to explore the usefulness of
SI
in predicting in‐hospital outcomes in 425 808 acute stroke cases (mean age: 71.0±14.5 years; 48.8% male; 89.7% ischemic stroke and 10.3% intracerebral hemorrhage) admitted between October 2012 and March 2015. Compared with patients with
SI
of 0.5 to 0.7, patients with
SI
>0.7 (13.6% of the sample) had worse outcomes, with adjusted odds ratios of 2.00 (95% confidence interval [
CI
], 1.92–2.08) for in‐hospital mortality, 1.46 (95%
CI
, 1.43–1.49) for longer length of hospital stay >4 days, 1.50 (95%
CI
, 1.47–1.54) for discharge destination other than home, 1.41 (95%
CI
, 1.38–1.45) for inability to ambulate independently at discharge, and 1.52 (95%
CI
, 1.47–1.57) for modified Rankin Scale score of 3 to 6 at discharge. Results were similar when analyses were confined to those with available National Institutes of Health Stroke Scale (NIHSS) or within individual stroke subtypes or when
SI
was additionally included in the models with or without blood pressure components. Every 0.1 increase in
SI
>0.5 was associated with significantly worse outcomes in linear spline models. The addition of
SI
to existing
GWTG
‐Stroke mortality prediction models without
NIHSS
demonstrated modest improvement, but little to no improvement was noted in models with
NIHSS
.

Conclusions

SI
calculated at the point of care may be a useful prognostic indicator to identify those with high risk of poor outcomes in acute stroke, especially in hospitals with limited experience with
NIHSS
assessment.
Bedside Ultrasound Assessment of Jugular Venous Compliance as a Potential Point‐of‐Care Method to Predict Acute Decompensated Heart Failure 30‐Day Readmission
Authors: Simon Marc A. , Schnatz Rick G. , Romeo Jared D. , Pacella John J.
Published: September 2018

Background

Heart failure is one of the most costly diagnosis‐related groups, largely because of hospital readmissions. Objective assessment of volume status to ensure optimization before hospital discharge could significantly reduce readmissions. We previously demonstrated an ultrasound method of quantifying percentage of cross‐sectional area (
CSA
) change of the right internal jugular vein with Valsalva that reliably estimates central venous pressure.

Methods and Results

Patients admitted with acute decompensated heart failure (
ADHF
) underwent ultrasound measurements of the right internal jugular vein at end‐expiration and during the strain phase of Valsalva to determine a percentage of
CSA
change. An initial subgroup of patients with right heart catheterization and accompanying ultrasound measurements of the right internal jugular vein identified a percentage of
CSA
change predictive of right atrial pressure (
RAP
) ≥12 mm Hg. Images of admitted
ADHF
patients were obtained at admission and discharge for final analysis. Simultaneous right heart catheterization and right internal jugular vein ultrasound measurements demonstrated that a <66%
CSA
change predicted
RAP
≥12 mm Hg (positive predictive value: 87%;
P
<0.05, receiver operating characteristic curve). Elevated admission
RAP
by percentage of
CSA
change normalized by discharge (
P
<0.05), indicating that this test is significantly responsive to therapeutic interventions. Using the cutoff value of 66%
CSA
change, normal
RAP
at discharge had 91% predictive value for patients avoiding 30‐day readmission (
P
<0.05).

Conclusions

This bedside ultrasound technique strongly correlates to invasive
RAP
measurement in
ADHF
patients, identifies restoration of euvolemia, and is predictive of 30‐day
ADHF
readmission. This tool could help guide inpatient
ADHF
treatment and may lead to reduced readmissions.
Fibroblast Growth Factor‐23 and Heart Failure With Reduced Versus Preserved Ejection Fraction: MESA
Authors: Almahmoud Mohamed Faher , Soliman Elsayed Z. , Bertoni Alain G. , Kestenbaum Bryan , Katz Ronit , Lima João A. C. , Ouyang Pamela , Miller P. Elliott , Michos Erin D. , Herrington David M.
Published: September 2018

Background

Higher fibroblast growth factor‐23 (
FGF
‐23) levels are associated with incident heart failure (
HF
) in MESA (the Multiethnic Study of Atherosclerosis).
FGF
‐23 is also associated with left ventricular hypertrophy. Whether the
FGF
‐23 association with
HF
is similar for heart failure with reduced ejection fraction (
HF
r
EF
) and heart failure with preserved ejection fraction (
HF
p
EF
) is not well established.

Methods and Results

We studied 6542 participants (mean age 62±10 years, 53% women, mean estimated glomerular filtration rate of 81±18 mL/min per 73 m
2
) from MESA who were free of cardiovascular disease at baseline (2000–2002).
HF
events were ascertained by an adjudication committee for a median follow‐up of 12.1 years. We classified
HF
events as
HF
r
EF
(ejection fraction [
EF
] <50%) or
HF
p
EF
[
EF
] ≥50%) at the time of diagnosis. Cox proportional hazard regression was used to compute hazard ratios and 95% confidence intervals for the association between baseline serum
FGF
‐23 and incident
HF
r
EF
and
HF
p
EF
. A total of 134 events were classified as
HF
p
EF
, 151
HF
r
EF
, and 49 unknown
EF
. Following imputation, 149 were classified as
HF
p
EF
, 176
HF
r
EF
, and 291 participants had
HF
(34 participants had
HF
p
EF
then
HF
r
EF
). In the fully adjusted model, higher
FGF
‐23 levels were associated with incident
HF
p
EF
but not with
HF
r
EF
(hazard ratio 1.29, 95% confidence interval, 1.08–1.54) versus (hazard ratio 1.04, 95% confidence interval, 0.84–1.29) for each 20 pg/mL higher serum
FGF
‐23 concentration.

Conclusions

FGF
‐23 association with
HF
is driven by the association with
HF
p
EF
but not with
HF
r
EF
in a population‐based cohort. Further studies are needed to determine the pathological mechanisms mediating this association.
Trastuzumab in Female Breast Cancer Patients With Reduced Left Ventricular Ejection Fraction
Authors: Nowsheen Somaira , Aziz Khaled , Park Jae Yoon , Lerman Amir , Villarraga Hector R. , Ruddy Kathryn Jean , Herrmann Joerg
Published: September 2018

Background

Trastuzumab is life‐extending therapy for breast cancer patients overexpressing the human epidermal growth factor receptor 2 (
HER
2+), but has known cardiotoxic risk. We sought to determine if trastuzumab can be administered to patients with reduced baseline cardiac function at no higher cardiotoxicity risk than in those with normal cardiac function at baseline.

Methods and Results

We performed a retrospective study of women treated with trastuzumab for human epidermal growth factor receptor 2 breast cancer at Mayo Clinic Rochester between January 1, 2000 and August 31, 2015 with pre‐ and on‐therapy echocardiograms available for review. A left ventricular ejection fraction (LVEF) <53% was considered abnormal, and a ≥10% decline in
LVEF
as evidence of cardiotoxicity based on the criteria of the American Society of Echocardiography. A total of 428 women were identified; 408 had a normal cardiac function (
LVEF
63.4±5%) and 20 had an impaired cardiac function (
LVEF
45.4±7%) before trastuzumab. Seven women (35%) with reduced
LVEF
at baseline had a ≥10% reduction in
LVEF
, compared with 179 (43.9%) of those with normal
LVEF
before trastuzumab initiation (
P
=
NS
). Symptomatic heart failure developed more often in patients with reduced versus normal baseline
LVEF
(25% versus 4.2%,
P
<0.05). After adjusting for patient age and breast cancer disease stage, survival rates over 5 years from time of diagnosis were found to be lower for patients with reduced baseline
LVEF
compared with patients with normal baseline
LVEF
(
P
<0.001); the adjusted proportion of patients surviving at 5 years for those with low
LVEF
at baseline was 79% and for those with normal
LVEF
was 93%.

Conclusions

Women undergoing trastuzumab therapy for breast cancer with impaired baseline cardiac function experience no higher risk of
LVEF
decline, but more frequently develop symptomatic heart failure. While trastuzumab could be considered, these patients should be co‐managed by a cardiologist.
9‐Year Trend in the Management of Acute Heart Failure in Japan: A Report From the National Consortium of Acute Heart Failure Registries
Authors: Shiraishi Yasuyuki , Kohsaka Shun , Sato Naoki , Takano Teruo , Kitai Takeshi , Yoshikawa Tsutomu , Matsue Yuya
Published: September 2018

Background

Acute heart failure (
AHF
) is a heterogeneous condition, and its characteristics and management patterns differ by region. Furthermore, limited evidence is available on
AHF
outside of Western countries. A project by the National Consortium of Acute Heart Failure Registries was designed to evaluate the trends over time in patient backgrounds, in‐hospital management patterns, and long‐term outcomes of patients with
AHF
over 9 years in Japan.

Methods and Results

Between 2007 and 2015, registry data for patients with
AHF
were collected from 3 large‐scale quality
AHF
registries (
ATTEND
/
WET
‐
HF
/
REALITY
‐
AHF
). Predefined end points were trends over time in age, sex, and clinical outcomes, including short‐ and long‐term mortality and readmission for heart failure. The final data set consisted of 9075 patients with
AHF
. No significant differences in patient backgrounds and laboratory findings (eg, anemia or renal function) were observed, with the exception of patient age; mean age became substantially higher over 9 years (71.6–77.0 years;
P
for trend, <0.001). On the contrary, length of hospital stay became shorter (mean, 26–16 days). These changes were not associated with in‐hospital mortality (4.7–7.5%) or 30‐day heart failure readmission rate (4.8–5.4%), as well as 1‐year mortality and heart failure readmission rate (20.1–23.3% and 23.6–26.2%, respectively).

Conclusions

Length of hospital stay in patients with
AHF
shortened over the 9‐year period despite the increasing age of the patients. However, short‐ and long‐term outcomes do not seem to be affected; continuous efforts to monitor clinical outcomes in patients with
AHF
are needed.
Reasons for Guideline Nonadherence at Heart Failure Discharge
Authors: Gilstrap Lauren G. , Stevenson Lynne W. , Small Roy , Parambi Ron , Hamershock Rose , Greenberg Jeffrey , Carr Christina , Ghazinouri Roya , Rathman Lisa , Han Elizabeth , Mehra Mandeep R. , Desai Akshay S.
Published: September 2018

Background

Cardiology has advanced guideline development and quality measurement. Recognizing the substantial benefits of guideline‐directed medical therapy, this study aims to measure and explain apparent deviations in heart failure (
HF
) guideline adherence by clinicians at hospital discharge and describe any impact on readmission rates.

Methods and Results

The extent of decongestion and prescription of neurohormonal therapy were recorded prospectively for 226
HF
discharges, including 132 (58%) from an academic hospital and 94 (42%) from a community hospital. Among all discharges, 25% were discharged with residual congestion (30% academic versus 18% community,
P
=0.070). Among discharges of patients with HF with reduced ejection fraction, 37% (45% academic versus 18% community,
P
<0.001) were discharged without β‐blocker therapy or with lower doses than at admission. Moreover, 46% of patients with HF with reduced ejection fraction (48% academic versus 39% community,
P
=0.390) were discharged without an angiotensin‐converting enzyme inhibitor or angiotensin
II
receptor blocker or with lower doses than at admission. Renal dysfunction was the most common reason for discharge with congestion, and hypotension the most common reason for discharge with no or decreased neurohormonal therapy. There was a trend toward higher 90‐day readmission rates after discharge with residual congestion.

Conclusions

Clinicians frequently deviate from guidelines in both academic and community hospitals; however, this deviation may not always indicate poor quality. Application of guidelines recommended for stable populations is increasingly limited for hospitalized patients by hypotension, renal dysfunction, and inotrope use. Patients with renal dysfunction, hypotension, and recent inotrope use merit further study to determine best practices and possibly to adjust quality metrics for
HF
severity.
Tako‐Tsubo Cardiomyopathy in Severe Sepsis: Nationwide Trends, Predictors, and Outcomes
Authors: Vallabhajosyula Saraschandra , Deshmukh Abhishek J. , Kashani Kianoush , Prasad Abhiram , Sakhuja Ankit
Published: September 2018

Background

There are limited data on the presentation of Takotsubo cardiomyopathy (
TTC
) in severe sepsis.

Methods and Results

This was a retrospective cohort study using the National Inpatient Sample database (2007–2013) of all adults with severe sepsis.
TTC
was identified in patients with severe sepsis using previously validated administrative codes. The primary outcome was in‐hospital mortality, and secondary outcomes included resource utilization and discharge disposition. Regression analysis was performed for the entire cohort and a propensity‐matched sample. An exploratory analysis was performed for predictors of
TTC
incidence and mortality in
TTC
. During this 7‐year period, in 7.1‐million hospitalizations for severe sepsis,
TTC
was diagnosed in 10 746 (0.15%) admissions.
TTC
was noted more commonly in whites, females, and among 65‐ to 79‐year‐old individuals.
TTC
was independently associated with lower in‐hospital mortality in severe sepsis (odds ratio, 0.58; 95% confidence interval, 0.51–0.65). This association was more prominent in females (odds ratio, 0.51; 95% confidence interval, 0.44–0.59]) compared with males (odds ratio, 0.69; 95% confidence interval, 0.55–0.85]). Presentation in later years of the study period, middle‐age, female sex, and white race were independent predictors for the diagnosis of
TTC
. Age ≥80 years, black race, greater comorbidity, and multiorgan dysfunction were independently associated with higher in‐hospital mortality among
TTC
admissions.

Conclusions

TTC
is observed with increasing frequency in severe sepsis and was associated with a significantly lower in‐hospital mortality compared with patients without
TTC
. Presentation in later years of the study period, middle age, female sex, and white race were independent predictors for the diagnosis of
TTC
in severe sepsis.
Myocardial Perfusion Is Impaired and Relates to Cardiac Dysfunction in Patients With Atrial Fibrillation Both Before and After Successful Catheter Ablation
Authors: Wijesurendra Rohan S. , Liu Alexander , Notaristefano Francesco , Ntusi Ntobeko A. B. , Karamitsos Theodoros D. , Bashir Yaver , Ginks Matthew , Rajappan Kim , Betts Tim R. , Jerosch‐Herold Michael , Ferreira Vanessa M. , Neubauer Stefan , Casadei Barbara
Published: September 2018

Background

Atrial fibrillation (
AF
) is associated with myocardial infarction, and patients with
AF
and no obstructive coronary artery disease can present with symptoms and evidence of cardiac ischemia. We hypothesized that microvascular coronary dysfunction underlies these observations.

Methods and Results

Myocardial blood flow (
MBF
) at baseline and during adenosine stress and left ventricular and left atrial function were evaluated by magnetic resonance in 49 patients with
AF
(25 paroxysmal, 24 persistent) with no history of epicardial coronary artery disease or diabetes mellitus, before and 6 to 9 months after ablation. Findings were compared with those obtained in matched controls in sinus rhythm (n=25). Before ablation, patients with
AF
had impaired left atrial function and left ventricular ejection fraction and strain indices (all
P
<0.05 versus controls).
MBF
was impaired in patients both under baseline conditions (1.21±0.24 mL/min per g·[mm Hg·bpm/10
4
]
−1
versus 1.34±0.28 mL/min per g·[mm Hg·bpm/10
4
]
−1
in controls,
P
=0.044) and during adenosine stress (2.29±0.48 mL/min per g versus 2.73±0.37 mL/min per g in controls,
P
<0.001). Under baseline conditions,
MBF
correlated with left ventricular strain and left atrial function (all
P
≤0.001), so that cardiac function was most impaired in patients with the lowest
MBF
. Baseline and stress
MBF
remained unchanged postablation (both
P
=ns), and baseline
MBF
showed similar correlations with functional indices to those present preablation (all
P
≤0.001).

Conclusions

Baseline and stress
MBF
are significantly impaired in patients with
AF
but no epicardial coronary artery disease. Reduction in
MBF
is proportional to severity of left ventricular and left atrial dysfunction, even after successful ablation. Coronary microvascular dysfunction may be a relevant pathophysiological mechanism in patients with a history of
AF
.
Measurement of Low‐Density Lipoprotein Cholesterol Levels in Primary and Secondary Prevention Patients: Insights From the PALM Registry
Authors: Lowenstern Angela M. , Li Shuang , Navar Ann Marie , Roger Veronique L. , Robinson Jennifer G. , Goldberg Anne C. , Virani Salim S. , Lee L. Veronica , Wilson Peter W. F. , Louie Michael J. , Peterson Eric D. , Wang Tracy Y.
Published: September 2018

Background

The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommended testing low‐density lipoprotein cholesterol (
LDL
‐C) to identify untreated patients with
LDL
‐C ≥190 mg/dL, assess lipid‐lowering therapy adherence, and consider nonstatin therapy. We sought to determine whether clinician lipid testing practices were consistent with these guidelines.

Methods and Results

The
PALM
(Patient and Provider Assessment of Lipid Management) registry enrolled primary and secondary prevention patients from 140 US cardiology, endocrinology, and primary care offices in 2015 and captured demographic data, lipid treatment history, and the highest
LDL
‐C level in the past 2 years. Core laboratory lipid levels were drawn at enrollment. Among 7627 patients, 2787 (36.5%) had no
LDL
‐C levels measured in the 2 years before enrollment. Patients without chart‐documented
LDL
‐C levels were more often women, nonwhite, uninsured, and non–college graduates (all
P
<0.01). Patients without prior lipid testing were less likely to receive statin treatment (72.6% versus 76.0%;
P
=0.0034), a high‐intensity statin (21.5% versus 24.3%;
P
=0.016), nonstatin lipid‐lowering therapy (24.8% versus 27.3%;
P
=0.037), and had higher core laboratory
LDL
‐C levels at enrollment (median 97 versus 92 mg/dL;
P
<0.0001) than patients with prior
LDL
‐C testing. Of 166 individuals with core laboratory
LDL
‐C levels ≥190 mg/dL, 36.1% had no
LDL
‐C measurement in the prior 2 years, and 57.2% were not on a statin at the time of enrollment.

Conclusions

In routine clinical practice,
LDL
‐C testing is associated with higher‐intensity lipid‐lowering treatment and lower achieved
LDL
‐C levels.
Atrial Fibrillation Detection Using a Novel Cardiac Ambulatory Monitor Based on Photo‐Plethysmography at the Wrist
Authors: Bonomi Alberto G. , Schipper Fons , Eerikäinen Linda M. , Margarito Jenny , van Dinther Ralph , Muesch Guido , de Morree Helma M. , Aarts Ronald M. , Babaeizadeh Saeed , McManus David D. , Dekker Lukas R.C.
Published: September 2018

Background

Long‐term continuous cardiac monitoring would aid in the early diagnosis and management of atrial fibrillation (
AF
). This study examined the accuracy of a novel approach for
AF
detection using photo‐plethysmography signals measured from a wrist‐based wearable device.

Methods and Results

ECG
and contemporaneous pulse data were collected from 2 cohorts of
AF
patients:
AF
patients (n=20) undergoing electrical cardioversion (
ECV
) and
AF
patients (n=40) that were prescribed for 24 hours
ECG
Holter in outpatient settings (
HOL
). Photo‐plethysmography and acceleration data were collected at the wrist and processed to determine the inter‐pulse interval and discard inter‐pulse intervals in presence of motion artifacts. A Markov model was deployed to assess the probability of
AF
given irregular pattern in inter‐pulse interval sequences. The
AF
detection algorithm was evaluated against clinical rhythm annotations of
AF
based on
ECG
interpretation. Photo‐plethysmography recordings from apparently healthy volunteers (n=120) were used to establish the false positive
AF
detection rate of the algorithm. A total of 42 and 855 hours (AF: 21 and 323 hours) of photo‐plethysmography data were recorded in the
ECV
and
HOL
cohorts, respectively.
AF
was detected with >96% accuracy (
ECV,
sensitivity=97%;
HOL
, sensitivity=93%; both with specificity=100%). Because of motion artifacts, the algorithm did not provide
AF
classification for 44±16% of the monitoring period in the
HOL
group. In healthy controls, the algorithm demonstrated a <0.2% false positive
AF
detection rate.

Conclusions

A novel
AF
detection algorithm using pulse data from a wrist‐wearable device can accurately discriminate rhythm irregularities caused by
AF
from normal rhythm.
Differential Impact of Acute Lesions Versus White Matter Hyperintensities on Stroke Recovery
Authors: Hawe Rachel L. , Findlater Sonja E. , Kenzie Jeffrey M. , Hill Michael D. , Scott Stephen H. , Dukelow Sean P.
Published: September 2018

Background

Understanding how the size of acute lesions and white matter hyperintensities (
WMH
) impact stroke recovery can improve our ability to predict outcomes and tailor treatments. The aim of this exploratory study was to investigate the role of acute lesion volume and
WMH
volume on longitudinal recovery of specific sensory, motor, and cognitive impairments after stroke using robotic and clinical measures.

Methods and Results

Eighty‐two individuals were assessed at 1, 6, 12, and 26 weeks poststroke with robotic tasks and commonly used clinical measures. The volumes of acute lesions and
WMH
were measured on fluid‐attenuated inversion recovery images. Linear mixed models were used to investigate the role of acute lesions and
WMH
on parameters derived from the robotic tasks and clinical measures. Regression analysis determined the added value of acute lesion and
WMH
volumes along with measures of initial performance to predict outcomes at 6 months. Acute lesion volume has widespread effects on sensory, motor, and overall functional recovery poststroke. The impact of
WMH
was specific to cognitive impairments. Apart from the robotic position sense task, neither lesion volume nor
WMH
measure had significant ability to predict outcomes at 6 months over using initial impairment as measured by robotic assessments alone.

Conclusions

While acute lesion volume and
WMH
may impact different impairments poststroke, their clinical utility in predicting outcomes at 6 months poststroke is limited.