scholarly journals Combined deletion of PR-domain containing 16 (Prdm16) in cardiomyocyte and non-cardiomyocyte lineages results in spontaneous early-onset lethality and progressive left ventricular dysfunction in mice

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
J Van Wauwe ◽  
S Craps ◽  
A Zwijsen ◽  
M Beerens ◽  
A Luttun
Keyword(s):  
Heart Failure ◽  
Early Onset ◽  
Severe Heart Failure ◽  
Fold Increase ◽  
Cell Types ◽  
Left Ventricular ◽  
Expression Levels ◽  
Cardiac Phenotype ◽  
Pr Domain ◽  
Sirius Red

Abstract Introduction PR-domain containing 16 (Prdm16) has an asymmetric expression pattern in the developing cardiovascular system, including ventricular myocardium, endocardium and arterial endothelial and smooth muscle cell (SMC) layers. Heterozygous PRDM16 mutations in humans have been linked with early-onset cardiomyopathy resulting in heart failure. Myocardial PRDM16-deficiency has been suggested as the culprit for this cardiomyopathy, however embryonic Prdm16 deletion in cardiomyocytes or their progenitors in mice only results in symptomatic cardiac defects upon metabolic stress or ageing. This suggests that Prdm16 loss in other cell types has an important co-contribution in the early heart phenotype seen in patients with causal PRDM16 variants. Purpose To investigate the adjuvant role of non-cardiomyocytes to the heart phenotype caused by Prdm16 deficiency, we used a conditional mouse model in which deletion of Prdm16 occurs in all cells expressing an Sm22-driven Cre recombinase which has a combined activity in cardiomyocyte and non-cardiomyocyte lineages in the heart, including SMCs and pericytes. Methods Mice carrying two Prdm16 alleles with a floxed exon 9 (Prdm16fl/fl) were intercrossed with the Sm22-Cre driver line. Offspring of Sm22Cre+; Prdm16fl/fl and Sm22Cre−; Prdm16fl/fl breeding pairs was monitored for Mendelian inheritance and for signs of (progressive) cardiac dysfunction by echocardiography at 5 and 16 weeks of age. Hearts were isolated and analyzed for RNA expression levels of cardiac stress markers Atrial and Brain Natriuretic Peptide (ANP and BNP) via quantitative RT-PCR and histologically for the appearance of fibrosis through Sirius red-staining. Results Genotyping at 5 weeks of age showed a loss of 60.4% of Sm22Cre+; Prdm16fl/fl offspring. Mice surviving at 5 weeks spontaneously developed signs of left ventricular diastolic and systolic dysfunction, the latter shown by a significantly reduced ejection fraction (EF; 37±3% vs. 61±3% in control Sm22Cre−; Prdm16fl/fl littermates). Cardiac expression levels of ANP and BNP were significantly increased (728-fold and 36-fold, respectively) in Sm22Cre+; Prdm16fl/fl mice which also showed perivascular fibrosis compared to control littermates. At 16 weeks of age, this aberrant cardiac phenotype further progressed (EF: 32±3% vs. 57±4%; ANP: 2,541-fold increase; BNP: 129-fold increase) and in addition to perivascular fibrosis, hearts also showed interstitial fibrosis (Sirius red+ area: 17±2% vs. 3.0±0.4% in control littermates). Conclusion Unlike recently reported mice with a Prdm16 deficiency in cardiomyocytes or their (precursor) lineages, mice with a combined loss of Prdm16 in the cardiomyocytes and certain non-cardiomyocyte lineages feature early mortality and (progressive) signs of severe heart failure. Therefore, Prdm16 expressed by non-cardiomyocytes is indispensable for proper cardiac function and its loss in these cell types co-determines the aberrant cardiac phenotype. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fonds voor Wetenschappelijk Onderzoek Strategic Basic Research pre-doctoral fellowship (1S25817N)KU Leuven Research Coordination grant (C14/19/095)

Abstract 15674: Notch3/rbpjk Signaling Pathway in the Coronary Arteries is Involved in the Development of Heart Failure in Response to Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Astrid Monfort ◽  
Hélène Ragot ◽  
Evelyne Polidano ◽  
Regine Merval ◽  
Claude Delcayre ◽  
...  
Keyword(s):  
Heart Failure ◽  
Signaling Pathway ◽  
Coronary Arteries ◽  
Severe Heart Failure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Resistance Arteries ◽  
Cardiac Phenotype ◽  
Angiopoietin 2 ◽  
And Control

Background: Notch3, a receptor expressed in vascular smooth muscle cells (VSMC), plays a key role in the integrity of resistance arteries by controlling the maturation of VSMC through RBPJk, a canonical Notch transcriptional factor. We hypothesized that Notch3 signaling pathway in the VSMCs of the coronary arteries might play a key role in the cardiac adaptation to pressure-overload. Methods: To eliminate congenital defect biases, we used mice in which conditional tamoxifen- selective deletion of RBPJk in VSMC was induced at the age of 4 weeks (SMMHC-CRE ER T2, RBP-JK loxp/loxp). Seven weeks later, hypertension was induced in control (C) mice (n= 10) and those with RBPJk deletion (SM-RBPJ-KO, n = 13) by infusion of Angiotensin 2 (Ang2) (1μg/kg/min) using Alzet minipumps after surgery. Results: In response to Ang2, SM-RBPJ-KO and control mice showed similar hypertension (159 ±7 mmHg vs 150±10 mmHg). By day 8 after surgery, SM-RBPJ-KO mice only developed a severe heart failure with anarsaca. These mice showed a decrease in shortening fraction (-42%, p<0.01), a left ventricular dilatation (+15%, p<0.01), and a ventricular hypertrophy (+12%, p<0.05) when compared to C + Ang2. As expected, C + Ang 2 hearts showed an increase in ANP, B-MHC and Gal-3 (+76%, +55%, +46%, p<0.05 respectively vs C) mRNA expressions, whereas SM-RBPJ-KO hearts exhibited even higher induction of ANP (+48%, p<0.01), Gal-3 (+74%, p<0.01), CD68 (+55%, p<0.05) and collagen-3 (+78%, p<0.01) when compared to C + Ang2. This cardiac phenotype confirmed the severe heart failure. Interestingly, immuno-morphometric analysis showed an arteriolar rarefaction in SM-RBPJ-KO + Ang2 mice associated with a lack of angiogenic signaling pathway revealed by a decrease in VEGFa and angiopoietin 2 mRNAs (-50%, and -52%, p<0.05, respectively vs. C + Ang2). Conclusion: We provide evidence that in adulthood, dysfunction of the Notch3/RBPJk signaling pathway in the coronary arteries contributes in the aggravation of heart failure in response to rapid increase in blood pressure.

Cardiac mitofusin-1 is declined in non-responding patients with idiopathic dilated cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Hsiao ◽  
I Shimizu ◽  
T Wakasugi ◽  
S Jiao ◽  
T Watanabe ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Heart Failure ◽  
Ventricular Myocytes ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Heart Failure Patients ◽  
Underlying Mechanisms ◽  
Neonatal Rat Ventricular Myocytes ◽  
Mitofusin 1

Abstract Background/Introduction Mitochondria are dynamic regulators of cellular metabolism and homeostasis. The dysfunction of mitochondria has long been considered a major contributor to aging and age-related diseases. The prognosis of severe heart failure is still unacceptably poor and it is urgent to establish new therapies for this critical condition. Some patients with heart failure do not respond to established multidisciplinary treatment and they are classified as “non-responders”. The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Purpose Studies indicate mitochondrial dysfunction has causal roles for metabolic remodeling in the failing heart, but underlying mechanisms remain to be explored. This study tried to elucidate the role of Mitofusin-1 in a failing heart. Methods We examined twenty-two heart failure patients who underwent endomyocardial biopsy of intraventricular septum. Patients were classified as non-responders when their left-ventricular (LV) ejection fraction did not show more than 10% improvement at remote phase after biopsy. Fourteen patients were classified as responders, and eight as non-responders. Electron microscopy, quantitative PCR, and immunofluorescence studies were performed to explore the biological processes or molecules involved in failure to respond. In addition to studies with cardiac tissue specific knockout mice, we also conducted functional in-vitro studies with neonatal rat ventricular myocytes. Results Twenty-two patients with IDCM who underwent endomyocardial biopsy were enrolled in this study, including 14 responders and 8 non-responders. Transmission electron microscopy (EM) showed a significant reduction in mitochondrial size in cardiomyocytes of non-responders compared to responders. Quantitative PCR revealed that transcript of mitochondrial fusion protein, Mitofusin-1, was significantly reduced in non-responders. Studies with neonatal rat ventricular myocytes (NRVMs) indicated that the beta-1 adrenergic receptor-mediated signaling pathway negatively regulates Mitofusin-1 expression. Suppression of Mitofusin-1 resulted in a significant reduction in mitochondrial respiration of NRVMs. We generated left ventricular pressure overload model with thoracic aortic constriction (TAC) in cardiac specific Mitofusin-1 knockout model (c-Mfn1 KO). Systolic function was reduced in c-Mfn1 KO mice, and EM study showed an increase in dysfunctional mitochondria in the KO group subjected to TAC. Conclusions Mitofusin-1 becomes a biomarker for non-responders with heart failure. In addition, our results suggest that therapies targeting mitochondrial dynamics and homeostasis would become next generation therapy for severe heart failure patients. Funding Acknowledgement Type of funding source: None

Anaemia and heart failure

Open Medicine ◽  
2011 ◽  
Vol 6 (1) ◽  
pp. 11-25
Author(s):  
Enrico Vizzardi ◽  
Tania Bordonali ◽  
Elena Tanghetti ◽  
Marco Metra ◽  
Livio Cas
Keyword(s):  
Heart Failure ◽  
Ventricular Dysfunction ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Favourable Effect ◽  
Heart Failure Trial ◽  
Patients With Heart Failure ◽  
Darbepoetin Alpha ◽  
Main Determinants ◽  
Independent Determinant

AbstractAnaemia is one of the most frequent co-morbidities in patients with heart failure. Its prevalence increases from 4% to7% in subjects with asymptomatic left ventricular dysfunction to >30% in patients with severe heart failure. Renal insufficiency, activation of inflammatory mediators and treatment with renin-angiotensin antagonists seem to be its main determinants. The results of many studies agree in providing evidence that anaemia is a powerful independent determinant of survival in patients with heart failure. However, the mechanisms of this relation are still not fully understood. Moreover a favourable effect of the correction of anaemia on prognosis has not yet been shown. Also In addition to this, controlled studies assessing its effects on exercise tolerance have yielded controversial results. Further research is needed to assess the effect of correcting anaemia in chronic heart failure (CHF) patients; ongoing reduction of events with RED-HF (Darbepoetin alpha in heart failure) trial will help define the role.

scholarly journals Linearity of the left ventricular end-systolic pressure-volume relation in patients with severe heart failure

1989 ◽  
Vol 14 (1) ◽  
pp. 127-134 ◽  
Author(s):  
Constantine N. Aroney ◽  
Howard C. Herrmann ◽  
Marc J. Semigran ◽  
G. William ◽  
Charles A. Boucher ◽  
...  
Keyword(s):  
Heart Failure ◽  
Severe Heart Failure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Volume Relation

Abstract 1876: Functional Effect of Chronic Urotensin II Receptor Antagonist on L-Type Ca 2+ Current in Mouse Model of Progressive Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Peng Zhou ◽  
Heng-Jie Cheng ◽  
Michael Cross ◽  
Michael F Callahan ◽  
Bridget Brosnihan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Receptor Antagonist ◽  
Weight Ratio ◽  
Heart Association ◽  
Cell Voltage ◽  
Fold Increase ◽  
Left Ventricular ◽  
Lv Function ◽  
List Type ◽  
Urotensin Ii

Voltage-gated Ca 2+ channels play fundamental roles in the regulation of cardiac function by various neurotransmitters. Recently, we have shown that urotensin II (UII), a potent vasoconstrictor, inhibits L-type Ca 2+ current (I Ca,L ) and produces negative inotropic action. In heart failure (HF), the UII-mediated pathway is upregulated, suggesting a therapeutic value of UII receptor antagonist (UII-ANT) for HF. However, the role and mechanism of chronic UII-ANT in HF is unclear. We tested the hypothesis that chronic UII-ANT may improve cardiac I Ca,L , preventing β-adrenergic deregulation on I Ca,L and limit HF progression. We examined plasma levels of norepinephrine (NE), left ventricular (LV) function, and myocyte I Ca,L responses to isoproterenol (ISO) in 3 age-matched groups of mice: HF (n = 7), 2 months after ISO (150 mg/kg sq for 2 days); HF/UII-ANT (n = 11), 1 month after receiving ISO, then urantide, a potent UII-ANT (10 −5 M/kg/day, sq via implanted osmotic mini pump), given for 1 month; and Controls (n = 7). I Ca,L was measured using whole-cell voltage clamp technique. Compared with controls, ISO-treated mice progressed to HF with 4.7-fold increase in plasma NE (18975 vs 4066 pg/ml) and LV dilatation associated with increased myocyte length (ML, 155 vs120 μm) and heart-to-body weight ratio (H/BW, 7.6 vs 5.5 g/kg). Stroke volume (SV, 30.3 vs 61.4 μl) and ejection fraction (EF, 39% vs 60%) were decreased. Compared with normal myocytes, in HF myocytes, I Ca,L was reduced (50%, 3.7 ± 0.2 vs 7.4 ± 0.2 pA/pF), and I Ca,L response to β-AR stimulation (ISO, 10 −8 M) was attenuated (11% vs 35%) (p < 0.01). In HF/UII-ANT mice, plasma NE (5148 pg/ml), SV (57.9 μl), and EF (57%) returned close to control levels with retained normal ML (124 μm) and H/BW (5.9 g/kg). Moreover, compared with controls, in HF/UII-ANT mice, ISO caused similar increases in the peak I Ca,L (32% vs 35%). Chronic UII-ANT treatment normalizes LV L-type Ca 2+ channel basal function and β-adrenergic regulation, leading to regression of LV and myocyte dysfunction and remodeling in mice with ISO-induced HF. This research has received full or partial funding support from the American Heart Association, AHA National Center.

Abstract 16574: Heart Failure Biomarkers (NT-proBNP, Gal-3, sST2) Correlate With Right Ventricular Systolic Pressure and Provide Insight to Poor CRT Response: A BIOCRT Substudy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Roderick C Deaño ◽  
Jackie Szymonifka ◽  
Qing Zhou ◽  
Jigar H Contractor ◽  
Zachary Lavender ◽  
...  
Keyword(s):  
Heart Failure ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Fold Increase ◽  
Left Ventricular ◽  
Cardiac Resynchronization ◽  
Cardiac Transplant ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Crt Response

Objective: Patients with heart failure (HF) and pulmonary hypertension (PH) have worse outcomes after cardiac resynchronization therapy (CRT). The relationship of circulating HF biomarkers and right ventricular systolic pressure (RVSP) may provide insight to the mechanism between PH and poor CRT response. Methods: In 90 patients (age 65 ± 13, 78% male, EF 26 ± 8%, RVSP 44 ± 12 mmHg) undergoing CRT, we measured baseline RVSP by echocardiography and obtained peripheral blood samples drawn at the time of device implantation. We measured levels of established and emerging HF biomarkers (Table 1). CRT non-response was defined as no improvement of adjudicated HF Clinical Composite Score at 6 months. Major adverse cardiac event (MACE) was defined as composite endpoint of death, cardiac transplant, left ventricular assist device, and HF hospitalization within 2 years. Results: There were 34% CRT non-responders and 27% had MACE. Per 1 unit increase in log-transformed RVSP, there was an 11-fold increase risk of having CRT non-response (odd ratio [OR] 11.0, p=0.01) and over 5-fold increase of developing 2-year MACE (hazard ratio [HR] 5.8, p=0.02). When comparing patients with severe PH (RVSP>60 mmHg) to those without PH (RVSP < 35 mmHg), there was an 8-fold increase in CRT nonresponse (OR 8.4, p=0.03) but no difference in MACE (p=NS). RVSP was correlated with increased biomarker levels of myocardial stretch and fibrosis, but not myocardial necrosis (Table 1). Conclusions: Higher RVSP is associated with greater rates of CRT non-response and adverse clinical outcomes. The mechanistic association between severe PH and CRT nonresponse may be explained by the biomarker profile reflective of myocardial wall stretch and fibrosis.

scholarly journals Levosimendan treatment of severe acute congestive heart failure refractory to dobutamine/milrinone in children

2011 ◽  
Vol 68 (11) ◽  
pp. 979-984
Author(s):  
Sergej Prijic ◽  
Sanja Rakic ◽  
Ljubica Nikolic ◽  
Bosiljka Jovicic ◽  
Mila Stajevic ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Myocardial Contractility ◽  
Severe Heart Failure ◽  
Oxygen Demand ◽  
Left Ventricular ◽  
Myocardial Oxygen Demand ◽  
Univentricular Heart ◽  
Dilatative Cardiomyopathy ◽  
Hemodynamic Improvement

Introduction. Levosimendan is a novel positive inotropic agent which, improves myocardial contractility through its calcium-sensitizing action, without causing an increase in myocardial oxygen demand. Also, by opening ATP-sensitive potassium channels, it causes vasodilatation with the reduction in both afterload and preload. Because of the long halflife, its effects last for up 7 to 9 days after 24-hour infusion. Case report. We presented three patients 2, 15 and 17 years old. All the patients had severe acute deterioration of the previously diagnosed chronic heart failure (dilatative cardiomyopathy; univentricular heart with bidirectional Glenn anastomosis and restrictive bulboventricular foramen; bacterial endocarditis on artificial aortic valve with severe stenosis and regurgitation). Signs and symptoms of severe heart failure, cardiomegaly (cardio-thoracic index 0.65) and left ventricular dilatation (end-diastolic diameter z-score 2.6; 4.1 and 4.0) were confirmed on admission. Also, myocardial contractility was poor with ejection fraction (EF - 27%, 25%, 35%), fractional shortening (FS - 13%, 11%, 15%) and stroke volume (SV - 40, 60, 72 mL/m2). The treatment with standard intravenous inotropic agents resulted in no improvement but in clinical deterioration. Thus, standard intravenous inotropic support was stopped and levosimendan treatment was introduced. All the patients received a continuous 24-h infusion 0.1 ?g/kg/min of levosimendan. In a single patient an initial loading dose of 11 ?g/kg over 10 min was administrated, too. Levosimendan treatment resulted in both clinical and echocardiography improvement with the improved EF (42%, 34%, 44%), FS (21%, 16%, 22%) and SV (59, 82, 93 mL/m2). Hemodynamic improvement was registered too, with the reduction in heart rate in all the treated patients from 134-138 bpm before, to less than 120 bpm after the treatment. These parameters were followed by the normalization of lactate levels. Nevertheless, left ventricular end-diastolic diameter did not change after the levosimendan treatment. Conclusion. Our initial experience demonstrates that administration of levosimendan in patients with severe chronic heart failure not responsive to standard intravenous inotropic treatment might result in a significant clinical and hemodynamic improvement and that, in selected patients, it might be life saving. According to our best knowledge patients presented are the first pediatric patients treated with levosimendan in our country.

scholarly journals Increasing veno-arterial extracorporeal membrane oxygenation flow reduces electrical impedance of the lung regions in porcine acute heart failure

2020 ◽  
pp. 609-620 ◽  
Author(s):  
M Popková ◽  
E Kuriščák ◽  
P Hála ◽  
D Janák ◽  
L Tejkl ◽  
...  
Keyword(s):  
Heart Failure ◽  
Extracorporeal Membrane Oxygenation ◽  
Acute Heart Failure ◽  
Electrical Impedance ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Fluid Accumulation ◽  
Impedance Tomography ◽  
Membrane Oxygenation ◽  
Ventricular Afterload

Veno-arterial extracorporeal membrane oxygenation (VA ECMO) is a technique used in patients with severe heart failure. The aim of this study was to evaluate its effects on left ventricular afterload and fluid accumulation in lungs with electrical impedance tomography (EIT). In eight swine, incremental increases of extracorporeal blood flow (EBF) were applied before and after the induction of ischemic heart failure. Hemodynamic parameters were continuously recorded and computational analysis of EIT was used to determine lung fluid accumulation. With an increase in EBF from 1 to 4 l/min in acute heart failure the associated increase of arterial pressure (raised by 44 %) was accompanied with significant decrease of electrical impedance of lung regions. Increasing EBF in healthy circulation did not cause lung impedance changes. Our findings indicate that in severe heart failure EIT may reflect fluid accumulation in lungs due to increasing EBF.

Abstract 5935: Influence of Recent Advances in the Management of Heart Failure and Ventricular Arrhythmias on Survival in Patients with Cardiac Sarcoidosis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yoshikazu Yazaki ◽  
Mitsuaki Horigome ◽  
Kazunori Aizawa ◽  
Takeshi Tomita ◽  
Hiroki Kasai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Tachycardia ◽  
Cardiac Sarcoidosis ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Cardiac Resynchronization ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Predictors Of Mortality ◽  
Recent Advances

Background : We previously described severity of heart failure and ventricular tachycardia (VT) as independent predictors of mortality in patients with cardiac sarcoidosis (CS). Medical treatment for chronic heart failure has been established over the last few decades. Prophylactic use of implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT or CRT-D) have been introduced in patients with severe heart failure. We therefore hypothesized that the prognosis of CS improves due to such advances in the management of heart failure and VT. Methods : To confirm our hypothesis, we analyzed 43 CS patients diagnosed between 1988 and 2006 and treated with corticosteroids. We classified two sequential referral patients diagnosed between 1988 and 1997 (n=19) and between 1998 and 2006 (n=24), and compared treatment and prognosis between the two cohorts. Results : Left ventricular ejection fraction (LVEF) and dimensions were similar between the two cohorts. Although age in the 1988–1997 referral cohort was significantly younger than that in the 1998–2006 referral cohort (54±14years versus 62±10years, p<0.05), survival in the earlier cohort was significantly worse (log-rank=4.41, p<0.05). The 1- and 5-year mortality rates were 88% and 71% in the 1988–1997 referral cohort, and 96% and 92% in the 1998–2006 referral cohort, respectively. The 1998–2006 referral cohort showed significantly higher incidence of ICD or CRT-D implantation (29% versus 6%, p<0.05), β-blocker use (46% versus 6%, p<0.01) and addition of methotrexate (21% versus 0%, p<0.05), and increased maintenance dose (7.0±1.9mg/day versus 5.0±0.9mg/day, p<0.01) compared to the 1988–1997 referral cohort. Multivariate analysis including age, LVEF, and sustained ventricular tachycardia (sVT) identified diagnosis between 1988 and 1997 (hazard ratio [HR]: 19.8, p<0.01) and LVEF (HR: 0.83/1% increase, p<0.01) as independent predictors of mortality. Conclusions : Survival in the recent CS patients is significantly better than previously described. Recent advances in the device therapies and medical treatments including modified immunosuppression alter the clinical outcome in patients with CS.

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