ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy

Background: Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene Erbb4 is a common driving factor of PPCM. Methods: miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific Erbb4 mice ( Erbb4 F/+ αMHC-Cre + , n=9) with their age-matched nonpregnant CTRLs (n=9–10). Results: Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (−29% to −50%; P <0.05). In addition, we demonstrate that genetic cardiomyocyte-specific downregulation of Erbb4 during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL; P <0.05), increased atrial natriuretic peptide (ANP) levels (4-fold increase versus HZ-CTRL mice, P <0.001), decreased VEGF (vascular endothelial growth factor) and VE-cadherin levels (−33±17%, P =0.07; −27±20%, P <0.05 versus HZ-CTRL), and histologically enlarged cardiomyocytes (+20±21%, versus HZ-CTRL, P <0.05) but without signs of myocardial apoptosis and inflammation. Conclusions: ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00998556.

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Atorvastatin Pretreatment Inhibits Myocardial Inflammation and Apoptosis in Swine After Coronary Microembolization

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248416662348 ◽

2016 ◽

Vol 22 (2) ◽

pp. 189-195

Author(s):

Jiang-You Wang ◽

Han Chen ◽

Xi Su ◽

You Zhou ◽

Lang Li

Keyword(s):

Cardiac Function ◽

Caspase 3 ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Pathological Examination ◽

Ventricular Ejection Fraction ◽

Coronary Microembolization ◽

Myocardial Apoptosis ◽

Tnf Α ◽

Apoptosis And Inflammation

Background/Aim: In addition to its cholesterol-lowering effect, atorvastatin (ATV) has been thought to have multiple cardiovascular benefits, including anti-inflammatory and anti-apoptotic properties. The present study was undertaken to determine whether ATV pretreatment could attenuate myocardial apoptosis and inflammation and improve cardiac function in a swine model of coronary microembolization (CME). Methods: Twenty-four swine were randomly and equally divided into a sham-operated (control) group, CME group, and CME plus ATV group. Swine CME was induced by intracoronary injection of inert plastic microspheres (diameter 42 μm) into the left anterior descending coronary, with or without pretreatment of ATV. Echocardiographic measurements, a pathological examination, terminal deoxynucleotidyl transferase–mediated nick end labeling staining, and Western blotting were performed to assess the functional, morphological, and molecular effects in CME. Results: The expression levels of caspase 3 and tumor necrosis factor-α (TNF-α) were aberrantly upregulated in cardiomyocytes following CME. Downregulation of caspase 3 and TNF-α with ATV pretreatment was associated with improved cardiac function and attenuated serum cardiac troponin I (cTnI) and high-sensitivity C-reactive protein. In addition, through a Pearson correlation analysis, the left ventricular ejection fraction negatively correlated with caspase 3, TNF-α, and cTnI. Conclusion: This study demonstrated that ATV pretreatment could significantly inhibit CME-induced myocardial apoptosis and inflammation and improve cardiac function. The data generated from this study provide a rationale for the development of myocardial apoptosis and inflammation-based therapeutic strategies for CME-induced myocardial injury.

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Spatial disruption and enhanced degradation of collagen with the transition from compensated ventricular hypertrophy to symptomatic congestive heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00355.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. H1364-H1372 ◽

Cited By ~ 29

Author(s):

H. K. Graham ◽

A. W. Trafford

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Interstitial Fibrosis ◽

Gelatin Zymography ◽

Fold Increase ◽

Left Ventricular ◽

Collagen Content ◽

Tissue Inhibitor Of Metalloproteinase ◽

Internal Diameter ◽

Structural Reorganization

The cardiac extracellular matrix (ECM) maintains the structural and mechanical integrity of the myocardium. We determined the alterations in the composition of the ECM coincident with the transition from compensated left ventricular (LV) hypertrophy (LVH) to symptomatic congestive heart failure (CHF) and the mechanisms underlying such changes. Heart failure was induced in ferrets by aortic banding. Myocardial collagen content was assessed by HPLC and histological analysis. Matrix metalloproteinase (MMP) activity and tissue inhibitor of metalloproteinase (TIMP) expression were evaluated using gelatin zymography and Western blotting, respectively. LV free wall thickness increased by 29% in asymptomatic LVH and was associated with a 20% increase in interstitial fibrosis ( P < 0.05). CHF was coincident with increased plasma angiotensin II levels (149 ± 48, 40 ± 19, and 5.6 ± 1 pg/ml for CHF, LVH, and sham, respectively; P < 0.01, CHF vs. sham and LVH), ventricular dilatation (LV internal diameter = 15 ± 0.4 vs. 9 ± 0.1 mm, P < 0.05), increased active MMP-9 (3.0- and 2.2-fold increase over sham and LVH, respectively, n = 5–10 animals per group, P < 0.01), and reduced myocardial total collagen content (3.5 ± 0.4, 2.6 ± 0.3, and 2.2 ± 0.3% in sham, LVH, and CHF, respectively, P < 0.05). In CHF the distribution of collagen was markedly altered, becoming punctate in nature. No difference in MMP-2 activity, TIMP-1, TIMP-2, TIMP-3, or TIMP-4 expression, or collagen cross-linking was found at any time. The present work demonstrates structural reorganization and loss of collagen from cardiac ECM during the transition to decompensated CHF. The enhanced MMP-9 activity coincident with the transition to CHF provides potential therapeutic opportunities for managing the progression from asymptomatic LVH to symptomatic CHF.

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Anesthetic Challenges in the Management of Intracranial Aneurysm Clipping in a Patient with Hypertrophic Cardiomyopathy

Journal of Neuroanaesthesiology and Critical Care ◽

10.1055/s-0040-1716425 ◽

2020 ◽

Author(s):

Sakshi Duggal ◽

Priyanka Khurana ◽

Pragati Ganjoo ◽

Nilima Das

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Perioperative Complications ◽

Artery Aneurysm ◽

Ventricular Outflow Tract ◽

Left Ventricular ◽

Anterior Communicating Artery ◽

Drug Selection ◽

Aneurysm Clipping ◽

Left Ventricular Outflow ◽

Life Threatening

AbstractAneurysmal surgeries are high-risk procedures due to potential for occurrence of fatal perioperative complications. This risk is exaggerated in the presence of co-existing hypertrophic cardiomyopathy (HCM). It involves asymmetrical hypertrophy of left ventricle with mitral valve dysfunction, leading to left ventricular outflow tract obstruction. Various perioperative factors may precipitate this obstruction resulting in life-threatening consequences. We report the management of a patient with HCM undergoing anterior communicating artery aneurysm clipping and discuss the anesthetic concerns. Comprehensive approach with careful drug selection, vigilant monitoring, and preparedness for complications enabled patient safety and a good neurological outcome.

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Unilateral mydriasis in a child with a ventriculoperitoneal shunt for obstructive hydrocephalus: a diagnostic dilemma

BMJ Case Reports ◽

10.1136/bcr-2020-237257 ◽

2020 ◽

Vol 13 (12) ◽

pp. e237257

Author(s):

Monidipa Banerjee ◽

Eiman Haj Ahmed ◽

Kathryn Foster ◽

Arundoss Gangadharan

Keyword(s):

Ipratropium Bromide ◽

Obstructive Hydrocephalus ◽

Sudden Onset ◽

Unique Case ◽

Diagnostic Dilemma ◽

Vp Shunt ◽

Life Threatening ◽

Unilateral Mydriasis ◽

The Brain ◽

Rule Out

There are several causes for sudden onset unilateral mydriasis, however impending transtentorial uncal herniation needs to be ruled out. This unique case highlights an uncommon adverse response to a common mode of treatment that leads to a diagnostic dilemma. A 3-year-old boy with a ventriculoperitoneal (VP) shunt for an obstructive hydrocephalus presented with an acute respiratory distress. He developed unilateral mydriasis with absent light reflex during treatment with nebulisers. An urgent CT scan of the brain did not show any new intracranial abnormality. A case of pharmacological anisocoria was diagnosed that resolved completely within 24 hours of discontinuation of ipratropium bromide. Although ipratropium-induced anisocoria has been reported in children, but to our knowledge none in a child with VP shunt for hydrocephalus. This emphasises the urgency in evaluating unilateral mydriasis to rule out life-threatening conditions. Clinicians should remember that ipratropium administered through ill-fitting face masks could cause this completely reversible adverse effect.

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The association between neutrophil-to-lymphocyte ratio and contrast-induced acute kidney injury in patients with carotid artery stenting

Vascular ◽

10.1177/17085381211012562 ◽

2021 ◽

pp. 170853812110125

Author(s):

Altuğ Ösken ◽

Ahmet Öz ◽

Muhammed Keskin ◽

Evliya Akdeniz ◽

Hasan Şahan ◽

...

Keyword(s):

Acute Kidney Injury ◽

Carotid Artery ◽

Carotid Artery Stenting ◽

Kidney Injury ◽

Fold Increase ◽

Multivariate Regression Analysis ◽

Neutrophil To Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Life Threatening ◽

Prolonged Hospital

Objectives Contrast-induced acute kidney injury (CI-AKI) is a life-threatening complication that leads to comorbidities and prolonged hospital stay lengths in the setting of peripheral interventions. The presence of some CI-AKI risk factors has already been investigated. In this study, we evaluated the predictors of CI-AKI after carotid artery stenting. Methods A total of 389 patients with 50% to 99% carotid artery stenosis who underwent carotid artery stenting were included in this study. Patients were grouped according to CI-AKI status. Results CI-AKI developed in 26 (6.6%) patients. Age, baseline creatinine level, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio were higher and estimated glomerular filtration rate, haemoglobin and lymphocyte count were lower in CI-AKI patients. In the multivariate regression analysis, the neutrophil-to-lymphocyte ratio triggered a 1.39- to 2.63-fold increase in the risk of CI-AKI onset ( p < 0.001). Conclusions The neutrophil-to-lymphocyte ratio may be a significant predictor of CI-AKI in patients with carotid artery stenting and higher neutrophil-to-lymphocyte ratio values may be independently associated with CI-AKI.

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Echocardiographic Assessment of Cardiac Structural and Functional Indices in Broiler Chickens Treated with Silver Nanoparticles

The Scientific World JOURNAL ◽

10.1155/2013/931432 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5 ◽

Cited By ~ 8

Author(s):

Hamid Raieszadeh ◽

Vahid Noaman ◽

Mehrdad Yadegari

Keyword(s):

Broiler Chickens ◽

Interventricular Septum ◽

Left Ventricular ◽

Internal Diameter ◽

Treatment Groups ◽

Randomized Design ◽

Linear Probe ◽

Significant Difference ◽

Echocardiographic Assessment ◽

Fractional Shortening

270 Ross broiler chickens of twenty days old were housed in 18-floor pens in a completely randomized design with six treatment groups and three replicate groups and fifteen chicks per each pen. The treatment groups (1–6) consisted of 0, 10, 20, 30, 50, and 70 ppm of nanocide in drinking water, respectively. At 26 days of age, 3 chickens were selected randomly for echocardiography using a 7.5 MHz linear probe, and the left ventricular internal diameter at the end of diastole (LVIDd), left ventricular internal diameter at the end of systole (LVIDs), left ventricular fractional shortening (LVFS), ejection fraction (EF), stroke volume (SV), interventricular septum thickness at the end of systole (IVSTs), and interventricular septum thickness at the end of diastole (IVSTd) were evaluated. LVIDd and LVIDs in group six were of higher rate than other groups and showed statistically significant differences with groups two, three, and four (P<0.05). LVFS, percentage of EF, and IVSTd were minimum in group six and had significant difference with other groups (P<0.05). The results of this study showed that prescription of high dosage of nanocide leads to cardiovascular problems with decrease in myocardial contractility and increase in the internal diameter of left ventricle.

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Penetrating Atherosclerotic Ulcer of the Aorta

Journal of Endovascular Therapy ◽

10.1177/152660280100800517 ◽

2001 ◽

Vol 8 (5) ◽

pp. 534-538 ◽

Cited By ~ 4

Author(s):

Aditya K. Samal ◽

Christopher J. White ◽

James B. Kot

Keyword(s):

Computed Tomography ◽

Ventricular Hypertrophy ◽

Sudden Onset ◽

Left Ventricular ◽

Descending Thoracic Aorta ◽

Penetrating Atherosclerotic Ulcer ◽

Severe Chest Pain ◽

Mediastinal Hematoma ◽

History Of ◽

Mediastinal Widening

Purpose: To describe a case of penetrating atherosclerotic ulcer of the aorta with a review of its natural history, diagnosis and management. Case Report: An elderly patient with a history of hypertension presented to the emergency room with the sudden onset of severe chest pain radiating to the back. The electrocardiogram showed left ventricular hypertrophy; the chest radiograph revealed mediastinal widening. Computed tomography was suspicious for a mediastinal hematoma without aortic dissection. Transesophageal echocardiography was also negative for dissection. An aortogram revealed a penetrating atherosclerotic ulcer of the descending thoracic aorta. The patient underwent successful resection and repair of the lesion. Conclusions: Penetrating atherosclerotic ulcer of the aorta is a potentially lethal lesion that must be promptly diagnosed and treated.

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Successful thrombolysis in essential thrombocythemia-related acute ischaemic stroke

BMJ Case Reports ◽

10.1136/bcr-2021-242925 ◽

2021 ◽

Vol 14 (5) ◽

pp. e242925

Author(s):

Ishita Desai ◽

Ashutosh Tiwari ◽

Mritunjai Kumar Singh ◽

Niraj Kumar

Keyword(s):

Ischaemic Stroke ◽

Essential Thrombocythemia ◽

Acute Ischaemic Stroke ◽

Jak2 V617f ◽

Preliminary Evidence ◽

Sudden Onset ◽

Left Ventricular ◽

Interesting Case ◽

Increased Risk ◽

Successful Thrombolysis

Essential thrombocythemia (ET)-related acute ischaemic stroke (AIS) may account for approximately 0.25%–0.5% of all ischaemic strokes. If left undiagnosed and untreated, patients with ET carry an increased risk of recurrent thrombosis involving major organs including the brain. We report an interesting case of a 67-year-old man, who was successfully thrombolysed for AIS resulting from ET. He presented with sudden onset of left-sided hemiparesis with a left-ventricular clot. His subsequent investigations including positive JAK2 V617F mutation confirmed the diagnosis of ET. He made a significant recovery with thrombolysis, anticoagulation, antiplatelet and hydroxyurea. A fear of post-thrombolytic haemorrhagic complications appears the major reason for the lack of reports of thrombolysis in ET-related AIS. Although the diagnosis of ET was confirmed on subsequent investigations, successful thrombolysis in our case provides preliminary evidence that ET-related AIS cases can undergo successful thrombolysis using tenecteplase. To date, ours is only the second case of ET-related AIS being thrombolysed.

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Abstract 16154: Baseline Left Ventricular Diameter Predicts Recovery in New Systolic Heart Failure Syndromes

Circulation ◽

10.1161/circ.142.suppl_3.16154 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Daniel Gold ◽

Nathan Kong ◽

Matthew Gold ◽

Tess Allan ◽

Anand Shah ◽

...

Keyword(s):

Left Ventricular ◽

Medical Decision ◽

Left Ventricular Ejection ◽

Internal Diameter ◽

Event Free Survival ◽

Short Term Treatment ◽

Ventricular Ejection Fraction ◽

Free Survival ◽

Advanced Therapies

Introduction: It is unknown how often patients with very advanced left ventricular (LV) dilation at initial presentation demonstrate meaningful recovery with medical therapy. Understanding short term treatment outcomes may impact medical decision making and counseling. Hypothesis: Patients with left ventricular end diastolic internal diameter (LVEDD) > 6.5cm will be less likely to recover left ventricular ejection fraction (LVEF) as compared to patients with LVEDD < 6.5cm. Methods: Patients were retrospectively identified by a database search of echocardiogram studies obtained at the University of Chicago between 2008-2018. Manual review was performed to ensure new diagnosis of systolic dysfunction with LVEF ≤ 35% and follow up echocardiogram study within 3 to 9 months of index study. LVEDD was determined from parasternal long axis views per routine. LVEF recovery was specified as LVEF > 35%. Chart review was done to assess for composite death, hospice, transplant, left ventricular assist device, and sustained ventricular tachycardia. Chi-square, multivariable logistic regression, and Kaplan-Meier survival were used for analysis. Results: Out of 100 patients included for analysis, mean age was 59.7 years, 41 were female and 82 were African American. 17.7% of patients’ with LVEDD > 6.5 cm had LVEF recovery compared to 53.0% of patients’ with LVEDD ≤ 6.5 cm (p = 0.008). LVEDD > 6.5 cm was associated with less LVEF recovery even when adjusted for age, gender, hypertension, and diabetes (adjusted odds ratio 0.18, 95% CI 0.04 to 0.65). LVEDD > 6.5cm was associated with worse event free survival (p = 0.004) with a median follow-up time of 2.4 years. Conclusions: An LVEDD of > 6.5cm is associated with diminished LVEF recovery and event free survival when compared to those patients with an LVEDD ≤ 6.5cm. Delaying consideration for advanced therapies and device based therapies in hopes of recovery may be inappropriate for many such patients.

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Abstract P709: Risk Factors Associated With Atrial Fibrillation Detection by Mobile Cardiac Outpatient Telemetry Following Acute Ischemic Stroke

Stroke ◽

10.1161/str.52.suppl_1.p709 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Ovais Inamullah ◽

Alec McConnell ◽

Hussein Al-khalidi ◽

Gerald S Bloomfield ◽

Shreyansh Shah

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Patient Selection ◽

Left Atrial ◽

Cryptogenic Stroke ◽

Left Ventricular ◽

Stepwise Logistic Regression ◽

Internal Diameter ◽

Atrial Area

Background: Mobile Cardiac outpatient telemetry (MCOT) is often used for patients (pts) with cryptogenic ischemic stroke following hospital discharge to detect atrial fibrillation (AFib) but criteria for patient selection remains a subject of debate. Methods: We identified 297 pts hospitalized with acute ischemic stroke who had an inpatient transthoracic echocardiogram (TTE) and underwent MCOT upon discharge between 2016 and 2018 at a large academic comprehensive stroke center. Pts characteristics between AFib vs. no AFib were compared by Fisher’s exact test for categorical and Wilcoxon rank-sum test for continuous variables. A multivariable stepwise logistic regression model was developed to determine the predictors of AFib detection. Statistical hypotheses were tested as two-sided at 0.05 level of significance. Results: Of the 297 pts, AFib was detected in 24 (8.1%) on 30-day MCOT. Pts with AFib detected were older, white, and have had a larger left atrial area (Table). The final logistic model demonstrated that white race (vs. non-white) (OR 4.86, 1.53-15.41), left atrial area (OR 1.15, 1.05-1.25) and left ventricular internal diameter in diastole (OR 0.33, 0.16-0.67) were associated with AFib detection by MCOT. Conclusion: Although rates of AFib detection on 30-day MCOT post-discharge was low, there are important patient characteristics and TTE features that can improve patient selection. Further studies are needed to determine if this data can be used prospectively to clinically decide which pts with cryptogenic stroke should be given 30-day MCT to detect atrial fibrillation.

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