bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reducing Hypermuscularization of the Transitional Segment Between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage
Authors: Ratelade Julien , Klug Nicholas R. , Lombardi Damiano , Angelim Monara Kaelle Servulo Cruz , Dabertrand Fabrice , Domenga-Denier Valérie , Salman Rustam Al-Shahi , Smith Colin , Gerbeau Jean-Frédéric , Nelson Mark T. , Joutel Anne 
Published: March 2020

Background:
Spontaneous deep intracerebral hemorrhage (ICH) is a devastating subtype of stroke without specific treatments. It has been thought that smooth muscle cell (SMC) degeneration at the site of arteriolar wall rupture may be sufficient to cause hemorrhage. However, deep ICHs are rare in some aggressive small vessel diseases that are characterized by significant arteriolar SMC degeneration. Here we hypothesized that a second cellular defect may be required for the occurrence of ICH.

Methods:

We studied a genetic model of spontaneous deep ICH using
Col4a1

+/G498V

and
Col4a1

+/G1064D

mouse lines that are mutated for the α1 chain of collagen type IV. We analyzed cerebroretinal microvessels, performed genetic rescue experiments, vascular reactivity analysis, and computational modeling. We examined postmortem brain tissues from patients with sporadic deep ICH.

Results:

We identified in the normal cerebroretinal vasculature a novel segment between arterioles and capillaries, herein called the transitional segment (TS), which is covered by mural cells distinct from SMCs and pericytes. In
Col4a1
mutant mice, this TS was hypermuscularized, with a hyperplasia of mural cells expressing more contractile proteins, whereas the upstream arteriole exhibited a loss of SMCs. TSs mechanistically showed a transient increase in proliferation of mural cells during postnatal maturation. Mutant brain microvessels, unlike mutant arteries, displayed a significant upregulation of SM genes and
Notch3
target genes, and genetic reduction of
Notch3
in
Col4a1

+/G498V

mice protected against ICH. Retina analysis showed that hypermuscularization of the TS was attenuated, but arteriolar SMC loss was unchanged in
Col4a1

+/G498V

,
Notch3
+/−
mice. Moreover, hypermuscularization of the retinal TS increased its contractility and tone and raised the intravascular pressure in the upstream feeding arteriole. We similarly found hypermuscularization of the TS and focal arteriolar SMC loss in brain tissues from patients with sporadic deep ICH.

Conclusions:

Our results suggest that hypermuscularization of the TS, through increased Notch3 activity, is involved in the occurrence of ICH in
Col4a1
mutant mice, by raising the intravascular pressure in the upstream feeding arteriole and promoting its rupture at the site of SMC loss. Our human data indicate that these 2 mutually reinforcing vascular defects may represent a general mechanism of deep ICH.
Myocardial Energetics in Obesity
Authors: Rayner Jennifer J. , Peterzan Mark A. , Watson William D. , Clarke William T. , Neubauer Stefan , Rodgers Christopher T. , Rider Oliver J. 
Published: March 2020

Background:

Obesity is strongly associated with exercise intolerance and the development of heart failure. Whereas myocardial energetics and diastolic function are impaired in obesity, systolic function is usually preserved. This suggests that the rate of ATP delivery is maintained, but this has never been explored in human obesity. We hypothesized that ATP transfer rate through creatine kinase (CK) (
k
f
CKrest
) would be increased, compensating for depleted energy stores (phosphocreatine/ATP), but potentially limiting greater ATP delivery during increased workload. We hypothesized that these changes would normalize with weight loss.

Methods:

We recruited 80 volunteers (35 controls [body mass index 24±3 kg/m
2
], 45 obese [body mass index 35±5 kg/m
2
]) without coexisting cardiovascular disease. Participants underwent body composition analysis, magnetic resonance imaging of abdominal, liver, and myocardial fat content, left ventricular function, and
31
P magnetic resonance spectroscopy to assess phosphocreatine/ATP and CK kinetics, at rest and during dobutamine stress. Obese volunteers were assigned to a dietary weight loss intervention, before reexamination.

Results:

At rest, although myocardial phosphocreatine/ATP was 14% lower in obesity (1.9±0.3 versus 2.2±0.2,
P
<0.001),
k
f
Ckrest
was 33% higher (0.23±0.07 s
–1
versus 0.16±0.08 s
–1
,
P
=0.002), yielding no difference in overall resting ATP delivery (obese 2.5±0.9 µmol·g
–1
·s
–1
versus control 2.2±1.1 µmol·g
–1
·s
–1
,
P
=0.232). In controls, increasing cardiac workload led to an increase in both
k
f
CK
(+86%,
P
<0.001) and ATP delivery (+80%,
P
<0.001). However, in obesity, similar stress led to no significant increase in either
k
f
CK
(
P
=0.117) or ATP delivery (
P
=0.608). This was accompanied by reduced systolic augmentation (absolute increase in left ventricular ejection fraction, obese +16±7% versus control +21±4%,
P
=0.031). Successful weight loss (–11±5% body weight) was associated with improvement of these energetic changes such that there was no significant difference in comparison with controls.

Conclusions:
In the obese resting heart, the myocardial CK reaction rate is increased, maintaining ATP delivery despite reduced phosphocreatine/ATP. During increased workload, although the nonobese heart increases ATP delivery through CK, the obese heart does not; this is associated with reduced systolic augmentation and exercise tolerance. Weight loss reverses these energetic changes. This highlights myocardial energy delivery through CK as a potential therapeutic target to improve symptoms in obesity-related heart disease, and a fascinating modifiable pathway involved in the progression to heart failure, as well.
Secretome Analysis of Cardiomyocytes Identifies PCSK6 (Proprotein Convertase Subtilisin/Kexin Type 6) as a Novel Player in Cardiac Remodeling After Myocardial Infarction
Authors: Kuhn Tim Christian , Knobel Johannes , Burkert-Rettenmaier Sonja , Li Xue , Meyer Ingmar Sören , Jungmann Andreas , Sicklinger Florian , Backs Johannes , Lasitschka Felix , Müller Oliver J. , Katus Hugo A. , Krijgsveld Jeroen , Leuschner Florian 
Published: March 2020

Background:
Acute occlusion of a coronary artery results in swift tissue necrosis. Bordering areas of the infarcted myocardium can also experience impaired blood supply and reduced oxygen delivery, leading to altered metabolic and mechanical processes. Although transcriptional changes in hypoxic cardiomyocytes are well studied, little is known about the proteins that are actively secreted from these cells.

Methods:
We established a novel secretome analysis of cardiomyocytes by combining stable isotope labeling and click chemistry with subsequent mass spectrometry analysis. Further functional validation experiments included ELISA measurement of human samples, murine left anterior descending coronary artery ligation, and adeno-associated virus 9–mediated in vivo overexpression in mice.

Results:
The presented approach is feasible for analysis of the secretome of primary cardiomyocytes without serum starvation. A total of 1026 proteins were identified to be secreted within 24 hours, indicating a 5-fold increase in detection compared with former approaches. Among them, a variety of proteins have not yet been explored in the context of cardiovascular pathologies. One of the secreted factors most strongly upregulated upon hypoxia was PCSK6 (proprotein convertase subtilisin/kexin type 6). Validation experiments revealed an increase of PCSK6 on mRNA and protein level in hypoxic cardiomyocytes. PCSK6 expression was elevated in hearts of mice after 3 days of ligation of the left anterior descending artery, a finding confirmed by immunohistochemistry. ELISA measurements in human serum also indicate distinct kinetics for PCSK6 in patients with acute myocardial infarction, with a peak on postinfarction day 3. Transfer of PCSK6-depleted cardiomyocyte secretome resulted in decreased expression of collagen I and III in fibroblasts compared with control treated cells, and small interfering RNA–mediated knockdown of PCSK6 in cardiomyocytes impacted transforming growth factor-β activation and SMAD3 (mothers against decapentaplegic homolog 3) translocation in fibroblasts. An adeno-associated virus 9–mediated, cardiomyocyte-specific overexpression of PCSK6 in mice resulted in increased collagen expression and cardiac fibrosis, as well as decreased left ventricular function, after myocardial infarction.

Conclusions:
A novel mass spectrometry–based approach allows investigation of the secretome of primary cardiomyocytes. Analysis of hypoxia-induced secretion led to the identification of PCSK6 as being crucially involved in cardiac remodeling after acute myocardial infarction.
White Blood Cells and Blood Pressure
Authors: Siedlinski Mateusz , Jozefczuk Ewelina , Xu Xiaoguang , Teumer Alexander , Evangelou Evangelos , Schnabel Renate B. , Welsh Paul , Maffia Pasquale , Erdmann Jeanette , Tomaszewski Maciej , Caulfield Mark J. , Sattar Naveed , Holmes Michael V. , Guzik Tomasz J. 
Published: March 2020

Background:
High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension.

Methods:
We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ≈750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP.

Results:

A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm Hg for neutrophil counts; all
P
<10
–50
). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19–1.20] and 0.56 [95% CI, 0.23–0.90] of mm Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the
SH2B3
locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio.

Conclusions:
Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP.
Self-Reported Fatigue Predicts Incident Stroke in a General Population
Authors: Barlas Genevieve , Luben Robert L. , Neal Samuel R. , Wareham Nicholas J. , Khaw Kay-Tee , Myint Phyo K. 
Published: March 2020

Background and Purpose—
Fatigue is a common symptom among stroke survivors and in general practice. However, the clinical significance of fatigue and its relationship to incident stroke is unclear. The aim of this study was to examine the relationship between self-reported fatigue and the incidence of stroke in a general population.

Methods—
This was a prospective, population-based study. The study population was 15 654 men and women aged 39 to 79 years recruited in 1993 to 1997 and followed till March 2016. Fatigue was assessed at 18 months after baseline using the vitality domain of the Short Form 36 questionnaire. Cox proportional hazard models were constructed to describe the prospective relationship between baseline fatigue and incident stroke adjusting for age, sex, systolic blood pressure, cholesterol, physical activity, smoking status, alcohol consumption, fruit and vegetable consumption, diabetes mellitus, body mass index, vitamin supplement use, education level, Townsend deprivation index, and occupational social class. Incident stroke was ascertained using death certificates and hospital record linkage data.

Results—
Through 249 248 person-years of follow-up, 1509 incident strokes occurred. Participants who reported the highest level of fatigue (quartile 4) were more likely to be women, to be multimorbid, and to perceive their health as fair or poor. We observed ≈50% relative risk increase in stroke risk (hazard ratio, 1.49 [95% CI, 1.29–1.71]) in those who reported the highest level of fatigue compared with those who reported the lowest level of fatigue (Q4 versus Q1). This relationship remained unaltered regardless of anemia status, the presence or absence of chronic bronchitis, thyroid dysfunction, or depression.

Conclusions—
Self-report fatigue assessed by the vitality domain of the Short Form 36 questionnaire predicts the risk of future stroke at the general population level. Identifying and addressing stroke risk factors in those who report fatigue in general practice may have substantial benefit at the population level.
Whole-Exome Sequencing in 22 Young Ischemic Stroke Patients With Familial Clustering of Stroke
Authors: Ilinca Andreea , Martinez-Majander Nicolas , Samuelsson Sofie , Piccinelli Paul , Truvé Katarina , Cole John , Kittner Steven , Soller Maria , Kristoffersson Ulf , Tatlisumak Turgut , Puschmann Andreas , Putaala Jukka , Lindgren Arne 
Published: March 2020

Backgrounds and Purpose—
Although new methods for genetic analyses are rapidly evolving, there are currently knowledge gaps in how to detect Mendelian forms of stroke.

Methods—
We performed whole-exome sequencing in 22 probands, under 56 years at their first ischemic stroke episode, from multi-incident stroke families. With the use of a comprehensive stroke-gene panel, we searched for variants in stroke-related genes. The probands’ clinical stroke subtype was related to clinical characteristics previously associated with pathogenic variants in these genes. Relatives were genotyped in 7 families to evaluate stroke-gene variants of unknown significance. In 2 larger families with embolic stroke of unknown source, whole-exome sequencing was performed in additional members to examine the possibility of identifying new stroke genes.

Results—

Six of 22 probands carried pathogenic or possibly pathogenic variants in genes reported to be associated with their stroke subtype. A known pathogenic variant in
NOTCH3
and a possibly pathogenic variant in
ACAD9
gene were identified. A novel
JAK2
:c.3188G>A (p.Arg1063His) mutation was seen in a proband with embolic stroke of undetermined source and prothrombotic status. However, penetrance in the family was incomplete.
COL4A2:
c.3368A>G (p.Glu1123Gly) was detected in 2 probands but did not cosegregate with the disease in their families. Whole-exome sequencing in multiple members of 2 pedigrees with embolic stroke of undetermined source revealed possibly pathogenic variants in genes not previously associated with stroke,
GPR142:
c.148C>G (p.Leu50Val), and
PTPRN2
:c.2416A>G (p.Ile806Val);
LRRC1
c.808A>G (p.Ile270Val),
SLC7A10
c.1294dupG (p.Val432fs),
IKBKB
: c.1070C>T (p.Ala357Val), and
OXGR1
c.392G>A (p.Arg131His), respectively.

Conclusions—
Screening with whole-exome sequencing using a comprehensive stroke-gene panel may identify rare monogenic forms of stroke, but careful evaluation of clinical characteristics and potential pathogenicity of novel variants remain important. In our study, the majority of individuals with familial aggregation of stroke lacked any identified genetic causes.
Trends of r-tPA (Recombinant Tissue-Type Plasminogen Activator) Treatment and Treatment-Influencing Factors in Acute Ischemic Stroke
Authors: Marko Martha , Posekany Alexandra , Szabo Simon , Scharer Sebastian , Kiechl Stefan , Knoflach Michael , Serles Wolfgang , Ferrari Julia , Lang Wilfried , Sommer Peter , Greisenegger Stefan ,   for the Austrian Stroke Unit Registry Collaborators
Published: March 2020

Background and Purpose—
Frequencies of treatment with r-tPA (recombinant tissue-type plasminogen activator) are increasing over the past 15 years. However, published data on the influence of various demographic and clinical factors on r-tPA treatment as well as estimates of future trajectories are limited. We evaluated time trends and future trajectories of r-tPA treatment in patients with acute stroke and the influence of various factors on r-tPA treatment by analyzing data of 103 970 patients enrolled in the Austrian Stroke Unit Registry from 2006 to 2018, of which 18 953 were treated with r-tPA.

Methods—
Time trends of r-tPA-treatment were investigated in predefined subgroups (minor/major stroke, age, anterior/posterior circulation stroke); limited exponential time series models were calculated to estimate future trends of r-tPA-treatment. Logistic regression models were calculated to estimate the influence of clinical variables on r-tPA-treatment.

Results—
Overall, r-tPA treatment frequencies increased from 9.9% in 2006 to 21.8% in 2018. We observed a particular increase in patients >80 years, patients presenting with a National Institutes of Health Stroke Scale Score of 2 to 3, patients with posterior circulation stroke, patients with wake-up stroke, and patients without atrial fibrillation. Forecast of overall r-tPA frequencies predicted a further but flattened increase up to 24% by 2025. Logistic regression of time-dependent associations of clinical variables with r-tPA-treatment revealed increasing odds of r-tPA-treatment in patients with a posterior circulation stroke and decreasing odds of r-tPA-treatment in patients with atrial fibrillation.

Conclusions—
We observed a positive development of r-tPA-treatment frequencies mirroring increasing confidence with intravenous thrombolysis in clinical practice; however, decreasing odds of r-tPA-treatment over time in patients with atrial fibrillation deserve particular attention.
Impact of Body Temperature Before and After Endovascular Thrombectomy for Large Vessel Occlusion Stroke
Authors: Diprose William K. , Liem Bernard , Wang Michael T.M. , Sutcliffe James A. , Brew Stefan , Caldwell James R. , McGuinness Ben , Campbell Doug , Barber P. Alan 
Published: March 2020

Background and Purpose—
In ischemic stroke, body temperature is associated with functional outcome. However, the relationship between temperature and outcome may differ in the intraischemic and postischemic phases of stroke. We aimed to determine whether body temperature before or after endovascular thrombectomy (EVT) for large vessel occlusion stroke is associated with clinical outcomes.

Methods—
Consecutive EVT patients were identified from a prospective registry. Temperature measurements within 24 hours of admission were stratified into pre-EVT (preprocedural and intraprocedural) and post-EVT measurements, which served as surrogates for the intraischemic and postischemic phases of large vessel occlusion stroke, respectively. The primary outcome was functional independence, defined as a modified Rankin Scale score of 0, 1, or 2 at 3 months. Secondary outcomes included the ordinal shift of modified Rankin Scale scores at 3 months, symptomatic intracerebral hemorrhage, and mortality at 3 months.

Results—

Four hundred thirty-two participants were included (59% men, mean±SD age 65.6±15.7 years). Multivariable logistic regression demonstrated that higher median pre-EVT temperature (per 1°C increase) was an independent predictor of reduced functional independence (odds ratio [OR], 0.66 [95% CI, 0.46–0.94];
P
=0.02), poorer modified Rankin Scale scores (common OR, 1.42 [95% CI, 1.08–1.85];
P
=0.01), and increased mortality (OR, 1.65 [95% CI, 1.02–2.69];
P
=0.04). Peak post-EVT temperature (per 1°C increase) was a significant predictor of elevated modified Rankin Scale scores (common OR, 1.39 [95% CI, 1.03–1.90];
P
=0.03) and higher mortality (OR, 1.66 [95% CI, 1.04–2.67];
P
=0.03).

Conclusions—
In patients with large vessel occlusion stroke treated with EVT, higher body temperatures during both the intraischemic and postischemic phases were associated with poorer clinical outcomes. Future research investigating the maintenance of normothermia or therapeutic hypothermia in patients needing to be transferred from primary to EVT-capable stroke centers could be considered.
Reduced Cognitive Assessment Scores Among Individuals With Magnetic Resonance Imaging–Detected Vascular Brain Injury
Authors: Anand Sonia S. , Friedrich Matthias G. , Desai Dipika , Schulze Karleen M. , Awadalla Philip , Busseuil David , Dummer Trevor J.B. , Jacquemont Sébastien , Dick Alexander , Kelton David , Kirpalani Anish , Lear Scott A. , Leipsic Jonathan , Noseworthy Michael D. , Parker Louise , Parraga Grace , Poirier Paul , Robson Paula , Tardif Jean-Claude , Teo Koon , Vena Jennifer , Yusuf Salim , Moody Alan R. , Black Sandra E. , Smith Eric E. ,   on behalf of the Canadian Alliance for Healthy Hearts and Minds Cohort
Published: March 2020

Background and Purpose—
Little is known about the association between covert vascular brain injury and cognitive impairment in middle-aged populations. We investigated if scores on a cognitive screen were lower in individuals with higher cardiovascular risk, and those with covert vascular brain injury.

Methods—
Seven thousand five hundred forty-seven adults, aged 35 to 69 years, free of cardiovascular disease underwent a cognitive assessment using the Digital Symbol Substitution test and Montreal Cognitive Assessment, and magnetic resonance imaging (MRI) to detect covert vascular brain injury (high white matter hyperintensities, lacunar, and nonlacunar brain infarctions). Cardiovascular risk factors were quantified using the INTERHEART (A Global Study of Risk Factors for Acute Myocardial Infarction) risk score. Multivariable mixed models tested for independent determinants of reduced cognitive scores. The population attributable risk of risk factors and MRI vascular brain injury on low cognitive scores was calculated.

Results—

The mean age of participants was 58 (SD, 9) years; 55% were women. Montreal Cognitive Assessment and Digital Symbol Substitution test scores decreased significantly with increasing age (
P
<0.0001), INTERHEART risk score (
P
<0.0001), and among individuals with high white matter hyperintensities, nonlacunar brain infarction, and individuals with 3+ silent brain infarctions. Adjusted for age, sex, education, ethnicity covariates, Digital Symbol Substitution test was significantly lowered by 1.0 (95% CI, −1.3 to −0.7) point per 5-point cardiovascular risk score increase, 1.9 (95% CI, −3.2 to −0.6) per high white matter hyperintensities, 3.5 (95% CI, −6.4 to −0.7) per nonlacunar stroke, and 6.8 (95% CI, −11.5 to −2.2) when 3+ silent brain infarctions were present. No postsecondary education accounted for 15% (95% CI, 12–17), moderate and high levels of cardiovascular risk factors accounted for 19% (95% CI, 8–30), and MRI vascular brain injury accounted for 10% (95% CI, −3 to 22) of low test scores.

Conclusions—
Among a middle-aged community-dwelling population, scores on a cognitive screen were lower in individuals with higher cardiovascular risk factors or MRI vascular brain injury. Much of the population attributable risk of low cognitive scores can be attributed to lower educational attainment, higher cardiovascular risk factors, and MRI vascular brain injury.