Transseptal puncture for left atrial ablation: Risk factors for cardiac tamponade and a proposed causative classification system.

AIMS: Cardiac tamponade is a high morbidity complication of transseptal puncture (TSP). We examined the associations of TSP-related cardiac tamponade (TRCT) for all patients undergoing left atrial ablation at our center from 2016 to 2020. METHODS AND RESULTS: Patient and procedural variables were extracted retrospectively. Cases of cardiac tamponade were scrutinized to adjudicate TSP culpability. Adjusted multivariate analysis examined predictors of TRCT. A total of 3239 consecutive TSPs were performed; cardiac tamponade occurred in 51 patients (incidence: 1.6%) and was adjudicated as TSP-related in 35 (incidence: 1.1%; 68.6% of all tamponades). Patients of above-median age [odds ratio (OR): 2.4 (1.19-4.2), p = .006] and those undergoing re-do procedures [OR: 1.95 (1.29-3.43, p = .042] were at higher risk of TRCT. Of the operator-dependent variables, choice of transseptal needle (Endrys vs. Brockenbrough, p > .1) or puncture sheath (Swartz vs. Mullins vs. Agilis vs. Vizigo vs. Cryosheath, all p > .1) did not predict TRCT. Adjusting for operator, equipment and demographics, failure to cross the septum first pass increased TRCT risk [OR: 4.42 (2.45-8.2), p = .001], whilst top quartile operator experience [OR: 0.4 (0.17-0.85), p = .002], transoesophageal echocardiogram [TOE prevalence: 26%, OR: 0.51 (0.11-0.94), p = .023], and use of the SafeSept transseptal guidewire [OR: 0.22 (0.08-0.62), p = .001] reduced TRCT risk. An increase in transseptal guidewire use over time (2016: 15.6%, 2020: 60.2%) correlated with an annual reduction in TRCT (R2 = 0.72, p < .001) and was associated with a relative risk reduction of 70%. CONCLUSIONS: During left atrial ablation, the risk of TRCT was reduced by operator experience, TOE-guidance, and use of a transseptal guidewire, and was increased by patient age, re-do procedures, and failure to cross the septum first pass.

Chronic performance of Riata 1580 and Endotak 0158 ICD leads: A single center 10-year experience.

BACKGROUND: The long-term performance of the Riata family of leads has recently come under increasing scrutiny. We aimed to determine the long-term performance of the Riata 1580 leads compared with Endotak 0158 leads. METHODS: All patients with Riata 1580 or Endotak 0158 leads implanted from 2003 to 2008 at the Heart Hospital, UCLH were analyzed. Significant electrical changes were as follows: threshold increase >1 V at a set pulse width between pacing checks, persistent R wave fall to <2 mV or reduction in R wave >50%, noise, pacing impedance change to <300 Ω or >1500 Ω, high voltage (HV) change to <20 Ω or >200 Ω, HV change ± 15 Ω, pacing impedance change >400 Ω over 12 months. RESULTS: 333 Riata and 356 Endotak leads were implanted. Median follow-up time + interquartile range were calculated, after exclusion of censored events including loss to follow-up: Riata 3652 + 655 days, Endotak 3730 + 810 days. A total of 51 (15.9%) Riata leads and 21 (6.3%) Endotak leads were affected. A greater risk of failure was found for the Riata lead compared with the Endotak lead (P = .0001). An additional time-dependent effect was found, with the Riata lead 1.9 times more likely to fail in the first 6 years following lead implantation and 5.3 times more likely to fail after 6 years. CONCLUSIONS: Riata leads have a higher risk of failure compared to Endotak leads over time. The importance of careful ongoing performance surveillance late in the leads' lifetime is reflected in this 10-year follow-up study.

Dual-site right ventricular pacing in patients undergoing cardiac resynchronization therapy: Results of a multicenter propensity-matched analysis.

BACKGROUND: Dual-site right ventricular pacing (Dual RV) has been proposed as an alternative for patients with heart failure undergoing cardiac resynchronization therapy (CRT) with a failure to deliver a coronary sinus (CS) lead. Only short-term hemodynamic and echocardiographic results of Dual RV are available. We aimed to assess the long-term results of Dual RV and its impact on survival. METHODS: Multicenter retrospective assessment of all CRT implants during a 12-year period. Patients with failed CS lead implantation, treated with Dual RV, were followed and assessed for the primary endpoint of all-cause mortality and/or heart transplant. A control group was obtained from contemporary patients using propensity matching for all available baseline variables. RESULTS: Ninety-three patients were implanted with Dual RV devices and compared with 93 matched controls. During a median of 1,273 days (interquartile range 557-2,218), intention-to-treat analysis showed that all-cause mortality and/or heart transplant was higher in the Dual RV group (adjusted hazard ratio [HR] = 1.66, 95% confidence interval [CI] 1.12-2.47, P = 0.012). As-treated analysis yielded similar results (HR = 1.97, 95% CI 1.31-2.96, P = 0.001). Cardiac device-related infections occurred seven times more frequently in the Dual RV site group (HR = 7.60, 95% CI 1.51-38.33, P = 0.014). Among Dual RV nonresponders, four had their apical leads switched off, five required an epicardial LV lead insertion, a transseptal LV lead was implanted in two, and in nine patients, after reviewing the CS venogram, a new CS lead insertion was successfully attempted. CONCLUSION: Dual RV pacing is associated with worse clinical outcomes and higher complication rates than conventional CRT.

Radiofrequency ablation of atrial tachyarrhythmias in adults with tetralogy of Fallot - predictors of success and outcome.

BACKGROUND: Adults with tetralogy of Fallot experience atrial tachyarrhythmias; however, there are a few data on the outcomes of radiofrequency ablation. We examined the characteristics, outcome, and predictors of recurrence of atrial tachyarrhythmias after radiofrequency ablation in tetralogy of Fallot patients. Methods/results Retrospective data were collected from 2004 to 2013. In total, 56 ablations were performed on 37 patients. We identified two matched controls per case: patients with tetralogy of Fallot but no radiofrequency ablation and not known to have atrial tachyarrhythmias. Acute success was 98%. Left atrial arrhythmias increased in frequency over time. The mean follow-up was 41 months; 78% were arrhythmia-free. Number of cardiac surgeries, age, and presence of atrial fibrillation were predictors of recurrence. Lone cavo-tricuspid isthmus-dependent flutter reduced the likelihood of atrial fibrillation. Right and left atria in patients with tetralogy of Fallot were larger in ablated cases than controls. NYHA class was worse in cases and improved after ablation; baseline status predicted death. Of matched non-ablated controls, a number of them had atrial fibrillation. These patients were excluded from the case-control study but analysed separately. Most of them had died during follow-up, whereas of the matched ablated cases all were alive and the majority in sinus rhythm. CONCLUSION: Patients with tetralogy of Fallot and atrial tachyarrhythmias have more dilated atria than those without atrial tachyarrhythmias. Radiofrequency ablation improves functional status. Left atrial ablation is more commonly required with repeat procedures. There is a high prevalence of atrial tachyarrhythmias, particularly atrial fibrillation, in patients with tetralogy of Fallot; early radiofrequency ablation may have a protective effect against this.

Improved electrogram attenuation during ablation of paroxysmal atrial fibrillation with the Hansen robotic system.

BACKGROUND: Robotic catheter ablation aims to improve outcomes after ablation of atrial fibrillation (AF) through improved lesion quality. This study examined electrogram attenuation as a measure of efficacy in response to robotic (ROB) and manual (MAN) ablation. METHODS: Patients with paroxysmal AF undergoing ablation as part of an ongoing randomized controlled trial were studied (Clinical Trials Registration NCT01037296). Patients underwent pulmonary vein isolation using NavX (St. Jude Medical, St. Paul, MN, USA). Patients were randomized to MAN or ROB catheter ablation using a 3.5-mm irrigated-tip catheter with standardized ablation settings. Bipolar electrogram voltage was measured at 0, 5, 10, 20, and 30 seconds after ablation onset. Distance from ablation lesion to the left atrial surface on NavX were calculated. RESULTS: Similar ablation energy was delivered in ROB and MAN groups, achieving comparable rates of PV isolation (100% vs 98%). The bipolar voltages of 4,434 electrograms from 303 ablation lesions (146 ROB, 157 MAN) were measured. At 30 seconds, signal attenuation was greater in the ROB group than MAN (mean 65 ± 4% vs 55 ± 4% of baseline voltage, P < 0.01). A total of 2,064 NavX ablation lesions were assessed (906 ROB and 1,158 MAN). ROB lesions were on average 0.52 mm further inside the geometry than MAN (P < 0.0001). CONCLUSIONS: Robotic ablation results in greater signal attenuation in man. This is achieved despite manual lesions being closer to the left atrial surface. Catheter stability and constant energy delivery may be key to achieving signal attenuation, rather than increased contact force.

Provocation and localization of atrial ectopy in patients with atrial septal defects.

BACKGROUND: Atrial fibrillation (AF) is associated with atrial septal defects (ASDs), but the mechanism of arrhythmia in these patients is poorly understood. We hypothesised that right-sided atrial ectopy may predominate in this cohort. Here, we aimed to localise the origin of spontaneous and provoked atrial ectopy in ASD patients. METHODS: Following invasive calibration of P-wave axes, 24-h Holter monitoring was used to determine the chamber of origin of spontaneous atrial ectopy. Simultaneous electrogram recording from multiple intra-cardiac catheters was used to determine the chamber of origin of isoprenaline-provoked ectopy. Comparison was made to a group of non-congenital heart disease AF patients. RESULTS: Amongst ASD patients, a right-sided origin for spontaneous atrial ectopy was significantly more prevalent than a left-sided origin (24/30 patients with right-sided ectopy vs. 14/30 with left-sided ectopy, P = 0.015). Amongst AF patients, there was no difference in the prevalence of spontaneous right vs. left-sided ectopy. For isoprenaline-provoked ectopy, there was no significant difference in the proportions of patients with right-sided or left-sided ectopy in either group. CONCLUSIONS: When spontaneous atrial ectopy occurs in ASD patients, it is significantly more prevalent from a right-sided than left-sided origin. Isoprenaline infusion did not reveal the predilection for right-sided ectopy during electrophysiology study.

Initial experience of the High-Density Grid catheter in patients undergoing catheter ablation for atrial fibrillation.

PURPOSE: A significant proportion of patients undergoing catheter ablation for atrial fibrillation (AF) experience arrhythmia recurrence. This is mostly due to pulmonary vein reconnection (PVR). Whether mapping using High-Density Wave (HDW) technology is superior to standard bipolar (SB) configuration at detecting PVR is unknown. We aimed to evaluate the efficacy of HDW technology compared to SB mapping in identifying PVR. METHODS: High-Density (HD) multipolar Grid catheters were used to create left atrial geometries and voltage maps in 36 patients undergoing catheter ablation for AF (either due to recurrence of an atrial arrhythmia from previous AF ablation or de novo AF ablation). Nineteen SB maps were also created and compared. Ablation was performed until pulmonary vein isolation was achieved. RESULTS: Median time of mapping with HDW was 22.3 [IQR: 8.2] min. The number of points collected with HDW (13299.6±1362.8 vs 6952.8±841.9, p<0.001) and used (2337.3±158.0 vs 1727.5±163.8, p<0.001) was significantly higher compared to SB. Moreover, HDW was able to identify more sleeves (16 for right and 8 for left veins), where these were confirmed electrically silent by SB, with significantly increased PVR sleeve size as identified by HDW (p<0.001 for both right and left veins). Importantly, with the use of HDW, the ablation strategy changed in 23 patients (64% of targeted veins) with a significantly increased number of lesions required as compared to SB for right (p=0.005) and left veins (p=0.003). CONCLUSION: HDW technology is superior to SB in detecting pulmonary vein reconnections. This could potentially result into a significant change in ablation strategy and possibly to increased success rate following pulmonary vein isolation.

An unusual presentation of primary renal hypokalemia-hypomagnesemia (Gitelman's syndrome).

Gitelman's syndrome, or congenital hypokalemic hypomagnesemic hypocalciuria with metabolic alkalosis, is widely described as a benign or milder variant of Bartter's syndrome and most commonly presents with transient periods of weakness and fatigue, presyncope, vertigo, ataxia, and blurred vision, though aborted sudden cardiac death has also been rarely reported. Despite this there are limited data in the literature regarding the formal cardiac evaluation of patients with Gitelman's syndrome. We present the case of a gentleman with Gitelman's syndrome who initially presented to his primary physician with symptoms suggestive of an upper respiratory tract infection and subsequently survived a ventricular fibrillation (VF) cardiac arrest in the community. We review the literature regarding possible life-threatening cardiac complications in these patients.

Atrial tachyarrhythmias following percutaneous device closure of secundum atrial septal defects.

BACKGROUND: Atrial tachyarrhythmias (ATs) are a major source of morbidity in the atrial septal defect (ASD) patient cohort. The optimal timing and approach of anti-arrhythmic intervention is currently unclear. Here, we sought to determine the overall rate of ATs following percutaneous ASD closure and risk factors that may predict this. METHODS: A systematic search of the literature was performed using the search terms '(Secundum Atrial Septal Defects AND Atrial arrhythmias) AND (transcatheter closure or percutaneous closure or device closure)'. All studies in English reporting the rate of ATs following percutaneous closure of secundum ASDs in adult patients were included. The primary outcome was documented AT detection during follow-up ECG monitoring. A meta-regression was then performed to test for an interaction between demographic/procedural characteristics and the primary outcome. RESULTS: 13 observational studies including 2366 patients were analysed. The overall post-procedure AT event detection rate was 8.6%. Multivariate meta-regression analysis revealed that only male gender was associated with a higher rate of post-procedure AT detection while utilisation of the Amplatzer Septal Occluder device was associated with a lower AT detection rate and comprised 96.2% of all devices used. A high level of heterogeneity was observed (I2-statistic 92.3%, Q value 156.8). CONCLUSIONS: Our study illustrates that despite percutaneous ASD closure, a high proportion of adult patients have ATs with male gender correlating with higher AT rates. While the Amplatzer Septal Occluder device correlated with lower AT rates, this was the overwhelmingly the predominant device used hence comparison to other devices remains challenging.

Percutaneous left ventricular endocardial leads: adverse outcomes and a percutaneous extraction case series.

BACKGROUND: Conventional cardiac resynchronization therapy (CRT) involves the placement of an epicardial left ventricular (LV) lead through the coronary venous tree. However, alternative approaches of delivering CRT have been sought for patients who fail to respond to conventional methods or for those where coronary venous anatomy is unfavourable. Biventricular pacing through an endocardial LV lead has potential advantages; however, the long-term clinical and safety data are not known. CASE SUMMARY: This article details a case series of four patients with endocardial LV leads; three of these for previously failed conventional CRT and a fourth for an inadvertently placed defibrillator lead. DISCUSSION: We describe the clinical course and adverse events associated with left-sided leads and subsequently describe the safe and feasible method of percutaneous extraction.

Ultra-High-Density Activation Mapping to Aid Isthmus Identification of Atrial Tachycardias in Congenital Heart Disease.

OBJECTIVES: A new electroanatomic mapping system (Rhythmia, Boston Scientific, Marlborough, Massachusetts) using a 64-electrode mapping basket is now available; we systematically assessed its use in complex congenital heart disease (CHD). BACKGROUND: The incidence of atrial arrhythmias post-surgery for CHD is high. Catheter ablation has emerged as an effective treatment, but is hampered by limitations in the mapping system's ability to accurately define the tachycardia circuit. METHODS: Mapping and ablation data of 61 patients with CHD (35 males, age 45 ± 14 years) from 8 tertiary centers were reviewed. RESULTS: Causes were as follows: Transposition of Great Arteries (atrial switch) (n = 7); univentricular physiology (Fontans) (n = 8); Tetralogy of Fallot (n = 10); atrial septal defect (ASD) repair (n = 15); tricuspid valve (TV) anomalies (n = 10); and other (n = 11). The total number of atrial arrhythmias was 86. Circuits were predominantly around the tricuspid valve (n = 37), atriotomy scar (n = 10), or ASD patch (n = 4). Although the majority of peri-tricuspid circuits were cavo-tricuspid-isthmus dependent (n = 30), they could follow a complex route between the annulus and septal resection, ASD patch, coronary sinus, or atriotomy. Immediate ablation success was achieved in all but 2 cases; with follow-up of 12 ± 8 months, 7 patients had recurrence. CONCLUSIONS: We demonstrate the feasibility of the basket catheter for mapping complex CHD arrhythmias, including with transbaffle and transhepatic access. Although the circuits often involve predictable anatomic landmarks, the precise critical isthmus is often difficult to predict empirically. Ultra-high-density mapping enables elucidation of circuits in this complex anatomy and allows successful treatment at the isthmus with a minimal lesion set.

IGF-binding protein-2 protects against the development of obesity and insulin resistance.

Proliferation of adipocyte precursors and their differentiation into mature adipocytes contributes to the development of obesity in mammals. IGF-I is a potent mitogen and important stimulus for adipocyte differentiation. The biological actions of IGFs are closely regulated by a family of IGF-binding proteins (IGFBPs), which exert predominantly inhibitory effects. IGFBP-2 is the principal binding protein secreted by differentiating white preadipocytes, suggesting a potential role in the development of obesity. We have generated transgenic mice overexpressing human IGFBP-2 under the control of its native promoter, and we show that overexpression of IGFBP-2 is associated with reduced susceptibility to obesity and improved insulin sensitivity. Whereas wild-type littermates developed glucose intolerance and increased blood pressure with aging, mice overexpressing IGFBP-2 were protected. Furthermore, when fed a high-fat/high-energy diet, IGFBP-2-overexpressing mice were resistant to the development of obesity and insulin resistance. This lean phenotype was associated with decreased leptin levels, increased glucose sensitivity, and lower blood pressure compared with wild-type animals consuming similar amounts of high-fat diet. Our in vitro data suggest a direct effect of IGFBP-2 preventing adipogenesis as indicated by the ability of recombinant IGFBP-2 to impair 3T3-L1 differentiation. These findings suggest an important, novel role for IGFBP-2 in obesity prevention.

The role of IGF-I and its binding proteins in the development of type 2 diabetes and cardiovascular disease.

Patients with insulin resistance and type 2 diabetes have an excessive risk of cardiovascular disease (CVD); this increased risk is not fully explained by traditional risk factors such as hypertension and dyslipidaemias. There is now compelling evidence to suggest that abnormalities of insulin-like growth factor-I (IGF-I) and one of its binding proteins, insulin-like growth factor-binding protein-1 (IGFBP-1), occur in insulin-resistant states and may be significant factors in the pathophysiology of CVD. We reviewed articles and relevant bibliographies following a systematic search of MEDLINE for English language articles between 1966 and the present, using an initial search strategy combining the MeSH terms: IGF, diabetes and CVD. Our aim was first to review the role of IGF-I in vascular homeostasis and to explore the mechanisms by which it may exert its effects. We also present an overview of the physiology of the IGF-binding proteins, and finally, we sought to summarize the evidence to date describing the changes in the insulin/IGF-I/IGFBP-1 axis that occur in type 2 diabetes and CVD; in particular, we have focused on the potential vasculoprotective effects of both IGF-I and IGFBP-1. We conclude that this system represents an interesting and novel therapeutic target in the prevention of CVD in type 2 diabetes.

Inter-Rater Reliability and Downstream Financial Implications of Electrocardiography Screening in Young Athletes.

BACKGROUND: Preparticipation screening for cardiovascular disease in young athletes with electrocardiography is endorsed by the European Society of Cardiology and several major sporting organizations. One of the concerns of the ECG as a screening test in young athletes relates to the potential for variation in interpretation. We investigated the degree of variation in ECG interpretation in athletes and its financial impact among cardiologists of differing experience. METHODS AND RESULTS: Eight cardiologists (4 with experience in screening athletes) each reported 400 ECGs of consecutively screened young athletes according to the 2010 European Society of Cardiology recommendations, Seattle criteria, and refined criteria. Cohen κ coefficient was used to calculate interobserver reliability. Cardiologists proposed secondary investigations after ECG interpretation, the costs of which were based on the UK National Health Service tariffs. Inexperienced cardiologists were more likely to classify an ECG as abnormal compared with experienced cardiologists (odds ratio, 1.44; 95% confidence interval, 1.03-2.02). Modification of ECG interpretation criteria improved interobserver reliability for categorizing an ECG as abnormal from poor (2010 European Society of Cardiology recommendations; κ=0.15) to moderate (refined criteria; κ=0.41) among inexperienced cardiologists; however, interobserver reliability was moderate for all 3 criteria among experienced cardiologists (κ=0.40-0.53). Inexperienced cardiologists were more likely to refer athletes for further evaluation compared with experienced cardiologists (odds ratio, 4.74; 95% confidence interval, 3.50-6.43) with poorer interobserver reliability (κ=0.22 versus κ=0.47). Interobserver reliability for secondary investigations after ECG interpretation ranged from poor to fair among inexperienced cardiologists (κ=0.15-0.30) and fair to moderate among experienced cardiologists (κ=0.21-0.46). The cost of cardiovascular evaluation per athlete was $175 (95% confidence interval, $142-$228) and $101 (95% confidence interval, $83-$131) for inexperienced and experienced cardiologists, respectively. CONCLUSIONS: Interpretation of the ECG in athletes and the resultant cascade of investigations are highly physician dependent even in experienced hands with important downstream financial implications, emphasizing the need for formal training and standardized diagnostic pathways.

A systematic review of ICD complications in randomised controlled trials versus registries: is our 'real-world' data an underestimation?

Implantable cardioverter defibrillator (ICD) implantation carries a significant risk of complications, however published estimates appear inconsistent. We aimed to present a contemporary systematic review using meta-analysis methods of ICD complications in randomised controlled trials (RCTs) and compare it to recent data from the largest international ICD registry, the US National Cardiovascular Data Registry (NCDR). PubMed was searched for any RCTs involving ICD implantation published 1999-2013; 18 were identified for analysis including 6433 patients, mean follow-up 3 months-5.6 years. Exclusion criteria were studies of children, hypertrophic cardiomyopathy, congenital heart disease, resynchronisation therapy and generator changes. Total pooled complication rate from the RCTs (excluding inappropriate shocks) was 9.1%, including displacement 3.1%, pneumothorax 1.1% and haematoma 1.2%. Infection rate was 1.5%.There were no predictors of complications but longer follow-up showed a trend to higher complication rates (p=0.07). In contrast, data from the NCDR ICD, reporting on 356 515 implants (2006-2010) showed a statistically significant threefold lower total major complication rate of 3.08% with lead displacement 1.02%, haematoma 0.86% and pneumothorax 0.44%. The overall ICD complication rate in our meta-analysis is 9.1% over 16 months. The ICD complication reported in the NCDR ICD registry is significantly lower despite a similar population. This may reflect under-reporting of complications in registries. Reporting of ICD complications in RCTs and registries is very variable and there is a need to standardise classification of complications internationally.

Catheter ablation of atrial fibrillation-patient satisfaction from a single-center UK experience.

BACKGROUND: Patient satisfaction is an indicator of quality of care and a key factor for patients' healthcare choices. Although atrial fibrillation (AF) ablation is now common, there are no published data on patient satisfaction during this procedure. METHODS: Anonymous patient satisfaction questionnaires were distributed to consecutive AF ablation patients over 6 months at a single center. RESULTS: Of 101 questionnaires returned, 51 % related to a first procedure. Pre-operative clinic experiences were good. Prior to ablation, 53 % reported receiving information leaflets, while 55 % reported using the Internet to search for further information. Mean anxiety pre-procedurally on a ten-point scale was 3.1 ± 2.9 and 97 % of patients felt prepared. Afterwards, however, 31 % found the experience not as expected, mainly due to being in more pain or more awake. A large number of patients recalled the procedure in detail, despite use of conscious sedation. Overall cath lab experience was good or excellent for the majority (79 %). Patients felt less well than expected immediately post-procedure and perceived a higher complication rate immediately after ablation (24 %) and at home (32 %) than reported by physicians (4.5 %). Despite this, 89 % would recommend an AF ablation to a friend or relative, and 96 % would recommend our institution. CONCLUSION: Our findings suggest that most patients are satisfied with the AF ablation experience, but this is not solely dependent on procedural success. Dissatisfaction occurs due to unmet expectations, particularly excess pain, i.e. greater than expected, during and after ablation. An improved consent process may improve patient experience. Physicians should also address initiatives to reduce pain during AF ablation.

Increasing circulating IGFBP1 levels improves insulin sensitivity, promotes nitric oxide production, lowers blood pressure, and protects against atherosclerosis.

Low concentrations of insulin-like growth factor (IGF) binding protein-1 (IGFBP1) are associated with insulin resistance, diabetes, and cardiovascular disease. We investigated whether increasing IGFBP1 levels can prevent the development of these disorders. Metabolic and vascular phenotype were examined in response to human IGFBP1 overexpression in mice with diet-induced obesity, mice heterozygous for deletion of insulin receptors (IR(+/-)), and ApoE(-/-) mice. Direct effects of human (h)IGFBP1 on nitric oxide (NO) generation and cellular signaling were studied in isolated vessels and in human endothelial cells. IGFBP1 circulating levels were markedly suppressed in dietary-induced obese mice. Overexpression of hIGFBP1 in obese mice reduced blood pressure, improved insulin sensitivity, and increased insulin-stimulated NO generation. In nonobese IR(+/-) mice, overexpression of hIGFBP1 reduced blood pressure and improved insulin-stimulated NO generation. hIGFBP1 induced vasodilatation independently of IGF and increased endothelial NO synthase (eNOS) activity in arterial segments ex vivo, while in endothelial cells, hIGFBP1 increased eNOS Ser(1177) phosphorylation via phosphatidylinositol 3-kinase signaling. Finally, in ApoE(-/-) mice, overexpression of hIGFBP1 reduced atherosclerosis. These favorable effects of hIGFBP1 on insulin sensitivity, blood pressure, NO production, and atherosclerosis suggest that increasing IGFBP1 concentration may be a novel approach to prevent cardiovascular disease in the setting of insulin resistance and diabetes.

Vascular insulin-like growth factor-I resistance and diet-induced obesity.

Obesity and type 2 diabetes mellitus are characterized by insulin resistance, reduced bioavailability of the antiatherosclerotic signaling molecule nitric oxide (NO), and accelerated atherosclerosis. IGF-I, the principal growth-stimulating peptide, which shares many of the effects of insulin, may, like insulin, also be involved in metabolic and vascular homeostasis. We examined the effects of IGF-I on NO bioavailability and the effect of obesity/type 2 diabetes mellitus on IGF-I actions at a whole-body level and in the vasculature. In aortic rings IGF-I blunted phenylephrine-mediated vasoconstriction and relaxed rings preconstricted with phenylephrine, an effect blocked by N(G)-monomethyl L-arginine. IGF-I increased NO synthase activity to an extent similar to that seen with insulin and in-vivo IGF-I led to serine phosphorylation of endothelial NO synthase (eNOS). Mice rendered obese using a high-fat diet were less sensitive to the glucose-lowering effects of insulin and IGF-I. IGF-I increased aortic phospho-eNOS levels in lean mice, an effect that was blunted in obese mice. eNOS activity in aortae of lean mice increased 1.6-fold in response to IGF-I compared with obese mice. IGF-I-mediated vasorelaxation was blunted in obese mice. These data demonstrate that IGF-I increases eNOS phosphorylation in-vivo, increases eNOS activity, and leads to NO-dependent relaxation of conduit vessels. Obesity is associated with resistance to IGF-I at a whole-body level and in the endothelium. Vascular IGF-I resistance may represent a novel therapeutic target to prevent or slow the accelerated vasculopathy seen in humans with obesity or type 2 diabetes mellitus.