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.

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.

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.

Effect of endothelium-specific insulin resistance on endothelial function in vivo.

OBJECTIVE: Insulin resistance is an independent risk factor for the development of cardiovascular atherosclerosis. A key step in the development of atherosclerosis is endothelial dysfunction, manifest by a reduction in bioactivity of nitric oxide (NO). Insulin resistance is associated with endothelial dysfunction; however, the mechanistic relationship between these abnormalities and the role of impaired endothelial insulin signaling versus global insulin resistance remains unclear. RESEARCH DESIGN AND METHODS: To examine the effects of insulin resistance specific to the endothelium, we generated a transgenic mouse with endothelium-targeted overexpression of a dominant-negative mutant human insulin receptor (ESMIRO). This receptor has a mutation (Ala-Thr(1134)) in its tyrosine kinase domain that disrupts insulin signaling. Humans with the Thr(1134) mutation are insulin resistant. We performed metabolic and vascular characterization of this model. RESULTS: ESMIRO mice had preserved glucose homeostasis and were normotensive. They had significant endothelial dysfunction as evidenced by blunted aortic vasorelaxant responses to acetylcholine (ACh) and calcium ionophore. Furthermore, the vascular action of insulin was lost in ESMIRO mice, and insulin-induced endothelial NO synthase (eNOS) phosphorylation was blunted. Despite this phenotype, ESMIRO mice demonstrate similar levels of eNOS mRNA and protein expression to wild type. ACh-induced relaxation was normalized by the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride. Endothelial cells of ESMIRO mice showed increased superoxide generation and increased mRNA expression of the NADPH oxidase isoforms Nox2 and Nox4. CONCLUSIONS: Selective endothelial insulin resistance is sufficient to induce a reduction in NO bioavailability and endothelial dysfunction that is secondary to increased generation of reactive oxygen species. This arises independent of a significant metabolic phenotype.

Catheter ablation of premature ventricular contraction-induced cardiomyopathy.

BACKGROUND: A 44-year-old female presented with a long history of chest pain, palpitations and increasing dyspnea. Electrocardiography and 24 h Holter monitoring revealed multiple premature ventricular complexes (PVCs), and echocardiography demonstrated significant left ventricular dilatation and systolic impairment. After further investigation it was concluded that this cardiomyopathy was secondary to the observed multiple PVCs and that these represented a potential target for treatment. INVESTIGATIONS: Electrocardiography, echocardiography, cardiac MRI, 24 h Holter monitoring, coronary angiography, tilt testing and invasive electrophysiological testing using a multielectrode array catheter. DIAGNOSIS: PVC-induced dilated cardiomyopathy. MANAGEMENT: Electrophysiological mapping and cryoablation of the focus of the ventricular ectopy.

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.

Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species.

Insulin resistance is well established as an independent risk factor for the development of type 2 diabetes and cardiovascular atherosclerosis. Most studies have examined atherogenesis in models of severe insulin resistance or diabetes. However, by the time of diagnosis, individuals with type 2 diabetes already demonstrate a significant atheroma burden. Furthermore, recent studies suggest that, even in adolescence, insulin resistance is a progressive disorder that increases cardiovascular risk. In the present report, we studied early mechanisms of reduction in the bioavailability of the antiatheroscerotic molecule nitric oxide (NO) in very mild insulin resistance. Mice with haploinsufficiency for the insulin receptor (IRKO) are a model of mild insulin resistance with preserved glycemic control. We previously demonstrated that 2-mo-old (Young) IRKO mice have preserved vasorelaxation responses to ACh. This remained the case at 4 mo of age. However, by 6 mo, despite no significant deterioration in glucose homeostasis (Adult), IRKO mice had marked blunting of ACh-mediated vasorelaxation [IRKO maximum contraction response (E(max)) 66 +/- 5% vs. wild type 87 +/- 4%, P < 0.01]. Despite the endothelial dysfunction demonstrated, aortic endothelial nitric oxide synthase (eNOS) mRNA levels were similar in Adult IRKO and wild-type mice, and, interestingly, aortic eNOS protein levels were increased, suggesting a compensatory upregulation in the IRKO. We then examined the potential role of reactive oxygen species in mediating early endothelial dysfunction. The superoxide dismutase mimetic Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP) restored ACh relaxation responses in the Adult IRKO (E(max) to ACh with MnTMPyP 85 +/- 5%). Dihydroethidium fluorescence of aortas and isolated coronary microvascular endothelial cells confirmed a substantial increase in endothelium-derived reactive oxygen species in IRKO mice. These data demonstrate that mild insulin resistance is a potent substrate for accelerated endothelial dysfunction and support a role for endothelial cell superoxide production as a mechanism underlying the early reduction in NO bioavailability.

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.