Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants.

BACKGROUND: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

A case report of primary meningococcal pericarditis secondary to Neisseria meningitidis in a young female patient.

Pericarditis is responsible for approximately 5 % of emergency admissions due to chest pain. Pericarditis secondary to Neisseria meningitidis (meningococci) was originally reported in 1918, and remains a rare diagnosis. We report a case of primary meningococcal pericarditis presenting with non-specific symptoms, illustrating the importance of considering rarer causes of pericardial effusion. A previously fit and well 23-year-old female presented to her local hospital with a 2-day history of feeling generally unwell with myalgia and fevers and was initially discharged. Four days following discharge the patient re-presented with worsening symptoms. A Computed Tomography Pulmonary Angiogram (CTPA) demonstrated a large pericardial effusion with subsequent bedside echocardiogram confirming a global pericardial effusion of up to 3 cm. This required drainage, with blood cultures and pericardial fluid showing polymerase chain reaction positivity for Neisseria meningitidis, serogroup B. Our report describes a rare case of Primary Meningococcal Pericarditis secondary to serotype B meningococcal infection. The European Society of Cardiology propose criteria that warrant hospital admission and an aetiology search for certain patients with pericardial disease. These criteria provide a useful framework to help select those minority of patients in whom a more serious underlying cause is present. Blood cultures provide vital information to allow us to complete a thorough aetiological search and empirical antibiotics can cloud the clinical picture, making it harder to identify causative organisms. To aid the early administration of appropriate therapy, it may be pertinent to recommend a low threshold for taking blood cultures in patients with pyrexia and pericarditis or pericardial effusion.

Reduction of heart failure guideline-directed medication during hospitalization: prevalence, risk factors, and outcomes.

AIMS: Optimal management of heart failure with reduced ejection fraction (HFrEF) includes titration of guideline-directed medical therapy (GDMT) to the highest tolerated dose within the licensed range. During hospitalization, GDMT doses are often significantly altered, although it is unknown whether the cause of hospitalization influences this. METHODS AND RESULTS: We recruited 711 people with stable HFrEF from specialist heart failure clinics and prospectively assessed events occurring during first unplanned hospitalization. Dose changes of ACE inhibitors or angiotensin receptor blockers (ACEi/ARB), beta-blockers, mineralocorticoid receptor antagonists, and loop diuretics were recorded during 414 hospitalizations, categorized as due to decompensated heart failure, other cardiovascular causes, infection, or other non-cardiovascular causes. Most hospitalizations resulted in no change to GDMT. ACEi/ARB dose was reduced in 21% of hospitalizations and was more common during non-cardiovascular hospitalization (25.4% vs. 13.9%; P = 0.005). ACEi/ARB dose reduction was associated with older age and lower left ventricular ejection fraction at study recruitment, and poorer renal function, lower systolic blood pressure, higher serum potassium, and less frequent care from a cardiologist during admission. People experiencing ACEi/ARB reduction had worse age-adjusted survival after discharge, without differences in heart failure re-hospitalization. De-escalation of beta-blockers occurred in 8% of hospitalizations, most often due to other non-cardiovascular causes; this was not associated with post-discharge survival or re-hospitalization with heart failure. CONCLUSIONS: De-escalation of HFrEF GDMT is more common during non-cardiovascular hospitalization and for ACEi/ARB is associated with reduced survival. Post-discharge care plans should include robust plans to consider re-escalation of GDMT in these cases.

Coexistent Diabetes Is Associated With the Presence of Adverse Phenotypic Features in Patients With Hypertrophic Cardiomyopathy.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is associated with worsened clinical outcomes in hypertrophic cardiomyopathy (HCM) patients. We sought to investigate whether HCM patients with T2DM comorbidity exhibit adverse cardiac alterations in myocardial energetics, function, perfusion, or tissue characteristics. RESEARCH DESIGN AND METHODS: A total of 55 participants with concomitant HCM and T2DM (HCM-DM) (n = 20) or isolated HCM (n = 20) and healthy volunteers (HV) (n = 15) underwent 31P-MRS and cardiovascular MRI. The HCM groups were matched for HCM phenotype. RESULTS: Mean ± SD European Society of Cardiology sudden cardiac death risk scores were comparable between the HCM groups (HCM 2.2 ± 1.5%, HCM-DM 1.9 ± 1.2%; P = not significant), and sarcomeric mutations were equally common. HCM-DM patients had the highest median NT-proBNP levels (HV 42 ng/L [interquartile range 35-66], HCM 298 ng/L [157-837], HCM-DM 726 ng/L [213-8,695]; P < 0.0001). Left ventricular (LV) ejection fraction, mass, and wall thickness were similar between the HCM groups. HCM-DM patients displayed a greater degree of fibrosis burden with higher scar percentage and lower global longitudinal strain compared with HCM patients. PCr/ATP (the relative concentrations of phosphocreatine and ATP) was significantly lower in the HCM-DM group than in both HCM and HV (HV 2.17 ± 0.49, HCM 1.93 ± 0.38, HCM-DM 1.54 ± 0.27; P = 0.002). In a similar pattern, stress myocardial blood flow was significantly lower in the HCM-DM group than in both HCM and HV (HV 2.06 ± 0.42 mL/min/g, HCM 1.74 ± 0.44 mL/min/g, HCM-DM 1.39 ± 0.42 mL/min/g; P = 0.002). CONCLUSIONS: We show for the first time that HCM-DM patients display greater reductions in myocardial energetics, perfusion, and contractile function and higher myocardial scar burden and serum NT-proBNP levels compared with patients with isolated HCM despite similar LV mass and wall thickness and presence of sarcomeric mutations. These adverse phenotypic features may be important components of the adverse clinical manifestation attributable to a combined presence of HCM and T2DM.

Coronary microvascular function and visceral adiposity in patients with normal body weight and type 2 diabetes.

OBJECTIVE: This study sought to assess whether diabetes affects coronary microvascular function in individuals with normal body weight. METHODS: Seventy-five participants (30 patients with type 2 diabetes [T2D] who were overweight [O-T2D], 15 patients with T2D who were lean [LnT2D], 15 healthy volunteers who were lean [LnHV], and 15 healthy volunteers who were overweight [O-HV]) without established cardiovascular disease were recruited. Participants underwent magnetic resonance imaging for assessment of subcutaneous, epicardial, and visceral adipose tissue areas, adenosine stress myocardial blood flow (MBF), and cardiac structure and function. RESULTS: Stress MBF was reduced only in the O-T2D group (mean [SD], LnHV = 2.07 [0.47] mL/g/min, O-HV = 2.08 [0.42] mL/g/min, LnT2D = 2.16 [0.36] mL/g/min, O-T2D = 1.60 [0.28] mL/g/min; p ≤ 0.0001). Accumulation of visceral fat was evident in the LnT2D group at similar levels to the O-HV group (LnHV = 127 [53] cm2 , O-HV = 181 [60] cm2 , LnT2D = 182 [99] cm2 , O-T2D = 288 [72] cm2 ; p < 0.0001). Only the O-T2D group showed reductions in left ventricular ejection fraction (LnHV = 63% [4%], O-HV = 63% [4%], LnT2D = 60% [5%], O-T2D = 58% [6%]; p = 0.0008) and global longitudinal strain (LnHV = -15.1% [3.1%], O-HV= -15.2% [3.7%], LnT2D = -13.4% [2.7%], O-T2D = -11.1% [2.8%]; p = 0.002) compared with both control groups. CONCLUSIONS: Patients with T2D and normal body weight do not show alterations in global stress MBF, but they do show significant increases in visceral adiposity. Patients with T2D who were overweight and had no prior cardiovascular disease showed an increase in visceral adiposity and significant reductions in stress MBF.

An enormous right atrial myxoma highlights the role of echocardiography in heart failure pathways: a case report.

BACKGROUND: Myxomata are rare, benign, primary tumours of the heart which can present with a variety of symptoms depending on size, location, and mobility. Here, we report a case of enormous right atrial myxoma, obliterating the right atrial and right ventricular cavities presenting with symptoms of heart failure. CASE SUMMARY: A 66-year-old Caucasian female presented to primary care with symptoms of right heart failure and was found to have elevated N-terminal pro B-type natriuretic peptide of 2829 ng/L (normal value <125 ng/L). The patient was referred for urgent evaluation to the integrated heart failure service at our institution. Echocardiography revealed an enormous mobile mass attached to the right atrial septum, extending into the right ventricle and inferior vena cava measuring 90 × 42 mm. The patient underwent urgent surgical resection. Perioperative transoesophageal echocardiography demonstrated severe tricuspid regurgitation, which was treated with tricuspid annuloplasty ring. The patient made an uneventful recovery and was discharged. Subsequent imaging showed a reduction in right ventricular dimensions and improved systolic function. DISCUSSION: This case serves to remind us of the critical role of echocardiography in the diagnosis and management of people with breathlessness and raised natriuretic peptides. Therapies for heart failure are guided by ejection fraction, therefore timely and accurate diagnosis is critical. Moreover, as in this case, echocardiography can also identify other features of critical relevance to patient care.

Prospective Longitudinal Characterization of the Relationship between Diabetes and Cardiac Structural and Functional Changes.

OBJECTIVES: In a cohort of type 2 diabetic (T2D) patients who underwent baseline cardiac magnetic resonance (CMR) and biomarker testing, during a median follow-up of 6 years, we aimed to determine longitudinal changes in the phenotypic expression of heart disease in diabetes, report clinical outcomes, and compare baseline clinical characteristics and CMR findings of patients who experienced major adverse cardiovascular events (MACE) to those remaining MACE free. BACKGROUND: T2D increases the risk of heart failure (HF) and cardiovascular mortality. The long-term impact of T2D on cardiac phenotype in the absence of cardiovascular disease and other clinical events is unknown. METHODS: Patients with T2D (n = 100) with no history of cardiovascular disease or hypertension were recruited at baseline. Biventricular volumes, function, and myocardial extracellular volume fraction (ECV) were assessed by CMR, and blood biomarkers were taken. Follow-up CMR was repeated in those without interim clinical events after 6 years. RESULTS: Follow-up was successful in 83 participants. Of those, 29 experienced cardiovascular/clinical events (36%). Of the remaining 59, 32 patients who experienced no events received follow-up CMR. In this cohort, despite no significant changes in blood pressure, weight, or glycated hemoglobin, significant reductions in biventricular end-diastolic volumes and ejection fractions occurred over time. The mean ECV was unchanged. Baseline plasma high-sensitivity cardiac troponin T (hs-cTnT) was significantly associated with a change in left ventricular (LV) ejection fraction. Patients who experienced MACE had higher LV mass and greater LV concentricity than those who remained event free. CONCLUSIONS: T2D results in reductions in biventricular size and systolic function over time even in the absence of cardiovascular/clinical events.

A 30-Year-Old Man With Primary Cardiac Angiosarcoma.

A previously fit and well 30-year-old man presented with palpitations, fever, and pleuritic chest pain. Multimodality imaging and histopathology confirmed the diagnosis of primary cardiac angiosarcoma. We present the details of the presentation, diagnostic process using multimodality imaging, and clinical management. (Level of Difficulty: Beginner.).

Detrimental Immediate- and Medium-Term Clinical Effects of Right Ventricular Pacing in Patients With Myocardial Fibrosis.

BACKGROUND: Long-term right ventricular (RV) pacing leads to heart failure or a decline in left ventricular (LV) function in up to a fifth of patients. We aimed to establish whether patients with focal fibrosis detected on late gadolinium enhancement cardiovascular magnetic resonance (CMR) have deterioration in LV function after RV pacing. METHODS: We recruited 84 patients with LV ejection fraction ≥40% into 2 observational CMR studies. Patients (n=34) with a dual-chamber device and preserved atrioventricular conduction underwent CMR in 2 asynchronous pacing modes (atrial asynchronous and dual-chamber asynchronous) to compare intrinsic atrioventricular conduction with forced RV pacing. Patients (n=50) with high-grade atrioventricular block underwent CMR before and 6 months after pacemaker implantation to investigate the medium-term effects of RV pacing. RESULTS: The key findings were (1) initiation of RV pacing in patients with fibrosis, compared with those without, was associated with greater immediate changes in both LV end-systolic volume index (5.3±3.5 versus 2.1±2.4 mL/m2; P<0.01) and LV ejection fraction (-5.7±3.4% versus -3.2±2.6%; P=0.02); (2) medium-term RV pacing in patients with fibrosis, compared with those without, was associated with greater changes in LV end-systolic volume index (8.0±10.4 versus -0.6±7.3 mL/m2; P=0.008) and LV ejection fraction (-12.3±7.9% versus -6.7±6.2%; P=0.012); (3) patients with fibrosis did not experience an improvement in quality of life, biomarkers, or functional class after pacemaker implantation; (4) after 6 months of RV pacing, 10 of 50 (20%) patients developed LV ejection fraction <35% and were eligible for upgrade to cardiac resynchronization according to current guidelines. All 10 patients had fibrosis on their preimplant baseline scan and were identified by >1.1 g of fibrosis with 90% sensitivity and 70% specificity. CONCLUSIONS: Fibrosis detected on CMR is associated with immediate- and medium-term deterioration in LV function following RV pacing and could be used to identify those at risk of heart failure before pacemaker implantation.

Insight Into Myocardial Microstructure of Athletes and Hypertrophic Cardiomyopathy Patients Using Diffusion Tensor Imaging.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) remains the commonest cause of sudden cardiac death among young athletes. Differentiating between physiologically adaptive left ventricular (LV) hypertrophy observed in athletes' hearts and pathological HCM remains challenging. By quantifying the diffusion of water molecules, diffusion tensor imaging (DTI) MRI allows voxelwise characterization of myocardial microstructure. PURPOSE: To explore microstructural differences between healthy volunteers, athletes, and HCM patients using DTI. STUDY TYPE: Prospective cohort. POPULATION: Twenty healthy volunteers, 20 athletes, and 20 HCM patients. FIELD STRENGTH/SEQUENCE: 3T/DTI spin echo. ASSESSMENT: In-house MatLab software was used to derive mean diffusivity (MD) and fractional anisotropy (FA) as markers of amplitude and anisotropy of the diffusion of water molecules, and secondary eigenvector angles (E2A)-reflecting the orientations of laminar sheetlets. STATISTICAL TESTS: Independent samples t-tests were used to detect statistical significance between any two cohorts. Analysis of variance was utilized for detecting the statistical difference between the three cohorts. Statistical tests were two-tailed. A result was considered statistically significant at P ≤ 0.05. RESULTS: DTI markers were significantly different between HCM, athletes, and volunteers. HCM patients had significantly higher global MD and E2A, and significantly lower FA than athletes and volunteers. (MDHCM = 1.52 ± 0.06 × 10-3 mm2 /s, MDAthletes = 1.49 ± 0.03 × 10-3 mm2 /s, MDvolunteers = 1.47 ± 0.02 × 10-3 mm2 /s, P < 0.05; E2AHCM = 58.8 ± 4°, E2Aathletes = 47 ± 5°, E2Avolunteers = 38.5 ± 7°, P < 0.05; FAHCM = 0.30 ± 0.02, FAAthletes = 0.35 ± 0.02, FAvolunteers = 0.36 ± 0.03, P < 0.05). HCM patients had significantly higher E2A in their thickest segments compared to the remote (E2Athickest = 66.8 ± 7, E2Aremote = 51.2 ± 9, P < 0.05). DATA CONCLUSION: DTI depicts an increase in amplitude and isotropy of diffusion in the myocardium of HCM compared to athletes and volunteers as reflected by increased MD and decreased FA values. While significantly higher E2A values in HCM and athletes reflect steeper configurations of the myocardial sheetlets than in volunteers, HCM patients demonstrated an eccentric rise in E2A in their thickest segments, while athletes demonstrated a concentric rise. Further studies are required to determine the diagnostic capabilities of DTI. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY STAGE: 2.

Implantable cardioverter-defibrillator therapy to reduce sudden cardiac death in adults with congenital heart disease: A registry study.

INTRODUCTION: The adult congenital heart disease (ACHD) population is rapidly expanding. However, a significant proportion of these patients suffer sudden cardiac death. Recommending implantable cardioverter-defibrillator (ICD) insertion requires balancing the need for appropriate therapy in malignant arrhythmia against the consequences of inappropriate therapy and procedural complications. Here we present long-term follow-up data for ICD insertion in patients with ACHD from a large Level 1 congenital cardiac center. METHODS AND RESULTS: All patients with ACHD undergoing ICD insertion over an 18-year period were identified. Data were extracted for baseline characteristics including demographics, initial diagnosis, ventricular function, relevant medication, and indication for ICD insertion. Details regarding device insertion were gathered along with follow-up data including appropriate and inappropriate therapy and complications. A total of 136 ICDs were implanted during this period: 79 for primary and 57 for secondary prevention. The most common congenital cardiac conditions in both groups were tetralogy of Fallot and transposition of the great arteries. Twenty-two individuals in the primary prevention group received appropriate antitachycardia pacing (ATP), 14 underwent appropriate cardioversion, 17 received inappropriate ATP, and 15 received inappropriate cardioversion. In the secondary prevention group, 18 individuals received appropriate ATP, 8 underwent appropriate cardioversion, 8 received inappropriate ATP, and 7 were inappropriately cardioverted. Our data demonstrate low complication rates, particularly with leads without advisories. CONCLUSION: ICD insertion in the ACHD population involves a careful balance of the risks and benefits. Our data show a significant proportion of patients receiving appropriate therapy indicating that ICDs were inserted appropriately.

A case report of acute myopericarditis associated with Graves' thyrotoxicosis.

BACKGROUND: The effects of hyperthyroidism on the heart are well documented, primarily consisting of supraventricular tachycardias, congestive heart failure, and dilated cardiomyopathy. Acute myopericarditis resulting from a hyperthyroid state is an uncommon but recognized association. CASE SUMMARY: A 29-year-old man with a history of Graves' disease presented with chest pain and electrocardiogram changes suggestive of an infero-lateral ST-elevation myocardial infarction. However, emergent coronary angiography and bedside echocardiography were normal. Troponin-I was found to be >25 000 ng/L (normal value <57). Thyroid function tests showed a significantly raised free T4 and undetectable thyroid-stimulating hormone. Cardiovascular magnetic resonance (CMR) showed extensive myocardial oedema and late gadolinium enhancement (LGE) in keeping with acute myopericarditis, alongside an enlarged thyroid gland consistent with goitre. Propylthiouracil in combination with an angiotensin-converting enzyme inhibitor and beta-blocker were commenced and eventually definitive treatment with thyroidectomy was performed. Follow-up CMR at 6 months showed complete resolution of the prior noted oedema and a reduction in the location and extent of LGE with significant residual fibrosis. DISCUSSION: Acute myopericarditis is a common diagnosis in young patients presenting with symptoms of chest pain with elevated troponin and is frequently related to a viral illness. Hyperthyroid states are also associated with acute myopericarditis and should be particularly considered in patients with a pre-existing thyroid condition or in those with symptoms suggestive of hyperthyroidism. Given the specific treatments required in a case of myopericarditis associated with hyperthyroidism, it is important to be aware of this association and consider screening where appropriate.

Endothelial Insulin Receptor Restoration Rescues Vascular Function in Male Insulin Receptor Haploinsufficient Mice.

Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We investigated whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor knockout (IRKO) mice were crossed with mice expressing a human insulin receptor endothelial cell-specific overexpression (hIRECO) to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO mice in glucose and insulin tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO mice exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild type littermates. These phenotypic changes were associated with increased basal- and insulin-stimulated nitric oxide production. IRKO-hIRECO mice also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling.

Socioeconomic deprivation and mode-specific outcomes in patients with chronic heart failure.

OBJECTIVE: To characterise the association between socioeconomic deprivation and adverse outcomes in patients with chronic heart failure (CHF). METHODS: We prospectively observed 1802 patients with CHF and left ventricular ejection fraction (LVEF) ≤45%, recruited in four UK hospitals between 2006 and 2014. We assessed the association between deprivation defined by the UK Index of Multiple Deprivation (IMD) and: mode-specific mortality (mean follow-up 4 years); mode-specific hospitalisation; and the cumulative duration of hospitalisation (after 1 year). RESULTS: A 45-point difference in mean IMD score was noted between patients residing in the least and most deprived quintiles of geographical regions. Deprivation was associated with age, sex and comorbidity, but not CHF symptoms, LVEF or prescribed drug therapy. IMD score was associated with the risk of age-sex adjusted all-cause mortality (6% higher risk per 10-unit increase in IMD score; 95% CI 2% to 10%; P=0.004), and non-cardiovascular mortality (9% higher risk per 10-unit increase in IMD score; 95% CI 3% to 16%; P=0.003), but not cardiovascular mortality. All-cause, but not heart failure-specific, hospitalisation was also more common in the most deprived patients. Overall, patients spent a cumulative 3.3 days in hospital during 1 year of follow-up, with IMD score being associated with the age-sex adjusted cumulative duration of hospitalisations (4% increase in duration per 10-unit increase in IMD score; 95% CI 3% to 6%; P<0.0005). CONCLUSIONS: Socioeconomic deprivation in people with CHF is linked to increased risk of death and hospitalisation due to an excess of non-cardiovascular events.

Insulinlike Growth Factor-Binding Protein-1 Improves Vascular Endothelial Repair in Male Mice in the Setting of Insulin Resistance.

Insulin resistance is associated with impaired endothelial regeneration in response to mechanical injury. We recently demonstrated that insulinlike growth factor-binding protein-1 (IGFBP1) ameliorated insulin resistance and increased nitric oxide generation in the endothelium. In this study, we hypothesized that IGFBP1 would improve endothelial regeneration and restore endothelial reparative functions in the setting of insulin resistance. In male mice heterozygous for deletion of insulin receptors, endothelial regeneration after femoral artery wire injury was enhanced by transgenic expression of human IGFBP1 (hIGFBP1). This was not explained by altered abundance of circulating myeloid angiogenic cells. Incubation of human endothelial cells with hIGFBP1 increased integrin expression and enhanced their ability to adhere to and repopulate denuded human saphenous vein ex vivo. In vitro, induction of insulin resistance by tumor necrosis factor α (TNFα) significantly inhibited endothelial cell migration and proliferation. Coincubation with hIGFBP1 restored endothelial migratory and proliferative capacity. At the molecular level, hIGFBP1 induced phosphorylation of focal adhesion kinase, activated RhoA and modulated TNFα-induced actin fiber anisotropy. Collectively, the effects of hIGFBP1 on endothelial cell responses and acceleration of endothelial regeneration in mice indicate that manipulating IGFBP1 could be exploited as a putative strategy to improve endothelial repair in the setting of insulin resistance.

Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop.

RATIONALE: In the endothelium, insulin stimulates endothelial NO synthase (eNOS) to generate the antiatherosclerotic signaling radical NO. Insulin-resistant type 2 diabetes mellitus is associated with reduced NO availability and accelerated atherosclerosis. The effect of enhancing endothelial insulin sensitivity on NO availability is unclear. OBJECTIVE: To answer this question, we generated a mouse with endothelial cell (EC)-specific overexpression of the human insulin receptor (hIRECO) using the Tie2 promoter-enhancer. METHODS AND RESULTS: hIRECO demonstrated significant endothelial dysfunction measured by blunted endothelium-dependent vasorelaxation to acetylcholine, which was normalized by a specific Nox2 NADPH oxidase inhibitor. Insulin-stimulated phosphorylation of protein kinase B was increased in hIRECO EC as was Nox2 NADPH oxidase-dependent generation of superoxide, whereas insulin-stimulated and shear stress-stimulated eNOS activations were blunted. Phosphorylation at the inhibitory residue Y657 of eNOS and expression of proline-rich tyrosine kinase 2 that phosphorylates this residue were significantly higher in hIRECO EC. Inhibition of proline-rich tyrosine kinase 2 improved insulin-induced and shear stress-induced eNOS activation in hIRECO EC. CONCLUSIONS: Enhancing insulin sensitivity specifically in EC leads to a paradoxical decline in endothelial function, mediated by increased tyrosine phosphorylation of eNOS and excess Nox2-derived superoxide. Increased EC insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide. Inhibition of proline-rich tyrosine kinase 2 restores insulin-induced and shear stress-induced NO production. This study demonstrates for the first time that increased endothelial insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide.

Performance of 2014 NICE defibrillator implantation guidelines in heart failure risk stratification.

OBJECTIVE: Define the real-world performance of recently updated National Institute for Health and Care Excellence guidelines (TA314) on implantable cardioverter-defibrillator (ICD) use in people with chronic heart failure. METHODS: Multicentre prospective cohort study of 1026 patients with stable chronic heart failure, associated with left ventricular ejection fraction (LVEF) ≤45% recruited in cardiology outpatient departments of four UK hospitals. We assessed the capacity of TA314 to identify patients at increased risk of sudden cardiac death (SCD) or appropriate ICD shock. RESULTS: The overall risk of SCD or appropriate ICD shock was 2.1 events per 100 patient-years (95% CI 1.7 to 2.6). Patients meeting TA314 ICD criteria (31.1%) were 2.5-fold (95% CI 1.6 to 3.9) more likely to suffer SCD or appropriate ICD shock; they were also 1.5-fold (95% CI 1.1 to 2.2) more likely to die from non-cardiovascular causes and 1.6-fold (95% CI 1.1 to 2.3) more likely to die from progressive heart failure. Patients with diabetes not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients without diabetes who met TA314 criteria. Patients with ischaemic cardiomyopathy not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients with non-ischaemic cardiomyopathy who met TA314 criteria. CONCLUSIONS: TA314 can identify patients with reduced LVEF who are at increased relative risk of sudden death. Clinicians should also consider clinical context and the absolute risk of SCD when advising patients about the potential risks and benefits of ICD therapy.

The investigation and management of broad complex tachycardia and ventricular standstill presenting in pregnancy: A case report.

A 23 year old pregnant lady at 35 weeks gestation presented to accident and emergency with worsening dyspnoea, palpitations and dizziness. Twelve lead electrocardiogram, routine bloods and echocardiography were normal. Ambulatory monitoring previously had shown an episode of monomorphic broad complex tachycardia (BCT) and a short episode of ventricular standstill. She was admitted for cardiac monitoring until delivery. Several episodes of ventricular standstill and self-terminating BCT were recorded, which were not associated with symptoms. The patient's symptoms either corresponded with sinus rhythm or supraventricular tachycardia. She underwent elective caesarean section at 37 weeks with no complications. The patient's symptoms reduced considerably post delivery, and she was discharged three days later. Unfortunately she then had a presyncopal episode whilst holding her baby. Due to concern regarding the safety of her baby she had a permanent pacemaker implanted to allow safe beta-blockade. She remains asymptomatic six months later.

Importance of insulin resistance to vascular repair and regeneration.

Metabolic insulin resistance is apparent across a spectrum of clinical disorders, including obesity and diabetes, and is characterized by an adverse clustering of cardiovascular risk factors related to abnormal cellular responses to insulin. These disorders are becoming increasingly prevalent and represent a major global public health concern because of their association with significant increases in atherosclerosis-related mortality. Endogenous repair mechanisms are thought to retard the development of vascular disease, and a growing evidence base supports the adverse impact of the insulin-resistant phenotype upon indices of vascular repair. Beyond the impact of systemic metabolic changes, emerging data from murine studies also provide support for abnormal insulin signaling at the level of vascular cells in retarding vascular repair. Interrelated pathophysiological factors, including reduced nitric oxide bioavailability, oxidative stress, altered growth factor activity, and abnormal intracellular signaling, are likely to act in conjunction to impede vascular repair while also driving vascular damage. Understanding of these processes is shaping novel therapeutic paradigms that aim to promote vascular repair and regeneration, either by recruiting endogenous mechanisms or by the administration of cell-based therapies.