Progression of paroxysmal to persistent atrial fibrillation: 10-year follow-up in the Canadian Registry of Atrial Fibrillation.

BACKGROUND: Progression from paroxysmal to persistent atrial fibrillation (AF) has important clinical implications and is relevant to the management of patients with AF. OBJECTIVE: The purpose of this study was to define the long-term rate of progression from paroxysmal to persistent AF and the relevant clinical variables. METHODS: The Canadian Registry of Atrial Fibrillation enrolled patients after a first electrocardiographic diagnosis of paroxysmal AF. Associations between baseline characteristics and clinical outcomes were evaluated using a multivariable Cox proportional hazard model and a competing risk model accounting for death as a competing risk, where appropriate. RESULTS: We enrolled 755 patients (61.7% men) aged between 14 and 91 years (mean age 61.2 ± 14.2 years). The median follow-up was 6.35 years (interquartile range 2.93-10.04 years), with a rate of progression to persistent AF at 1, 5, and 10 years was 8.6%, 24.3%, and 36.3%, respectively. All-cause mortality was 30.3% at 10 years. Factors associated with AF progression were increasing age (hazard ratio [HR] 1.40; 95% confidence interval [CI] 1.23-1.60, for each 10-year increment), mitral regurgitation (HR 1.87; 95% CI 1.28-2.73), left atrial dilatation (HR 3.01; 95% CI 2.03-4.47), aortic stenosis (HR 2.40; 95% CI 1.05-5.48), and left ventricular hypertrophy (HR .47; 95% CI 1.04-2.08). Factors associated with a lower rate of progression were a faster heart rate during AF (HR 0.94; 95% CI 0.92-0.96 per 5-beat/min increment) and angina (HR 0.54; 95% CI 0.38-0.77). After accounting for death as a competing risk, left ventricular hypertrophy and aortic stenosis were no longer significant. CONCLUSION: Within 10 years of presenting with paroxysmal AF, >50% of patients will progress to persistent AF or be dead. Increasing age, mitral regurgitation, aortic stenosis, left ventricular hypertrophy, and left atrial dilatation were associated with progression to persistent AF.

Cardiac Abnormalities in First-Degree Relatives of Unexplained Cardiac Arrest Victims: A Report From the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry.

BACKGROUND: Unexplained cardiac arrest (UCA) may be explained by inherited arrhythmia syndromes. The Cardiac Arrest Survivors With Preserved Ejection Fraction Registry prospectively assessed first-degree relatives of UCA or sudden unexplained death victims to screen for cardiac abnormalities. METHODS AND RESULTS: Around 398 first-degree family members (186 UCA, 212 sudden unexplained death victims' relatives; mean age, 44±17 years) underwent extensive cardiac workup, including ECG, signal averaged ECG, exercise testing, cardiac imaging, Holter-monitoring, and selective provocative drug testing with epinephrine or procainamide. Genetic testing was performed when a mutation was identified in the UCA survivor or when the diagnostic workup revealed a phenotype suggestive of a specific inherited arrhythmia syndrome. The diagnostic strength was classified as definite, probable, or possible based on previously published definitions. Cardiac abnormalities were detected in 120 of 398 patients (30.2%) with 67 of 398 having a definite or probable diagnosis (17%), including Long-QT syndrome (13%), catecholaminergic polymorphic ventricular tachycardia (4%), arrhythmogenic right ventricular cardiomyopathy (4%), and Brugada syndrome (3%). The detection yield was similar for family members of UCA and sudden unexplained death victims (31% versus 27%; P=0.59). Genetic testing was performed more often in family members of UCA patients (29% versus 20%; P=0.03). Disease-causing mutations were identified in 20 of 398 relatives (5%). The most common pathogenic mutations were RyR2 (2%), SCN5A (1%), and KNCQ1 (0.8%). CONCLUSIONS: Cardiac screening revealed abnormalities in 30% of first-degree relatives of UCA or sudden unexplained death victims, with a clear working diagnosis in 17%. Long-QT, arrhythmogenic right ventricular cardiomyopathy, and catecholaminergic polymorphic ventricular tachycardia were the most common diagnoses. Systematic cascade screening and genetic testing in asymptomatic individuals will lead to preventive lifestyle and medical interventions with potential to prevent sudden cardiac death. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00292032.

Experience with bisoprolol in long-QT1 and long-QT2 syndrome.

BACKGROUND: The protective effect of beta-blockers in patients with inherited Long-QT syndrome is well established. Recent reports have suggested that beta-blockers are not equally effective in Long-QT (LQT). Bisoprolol is an attractive candidate for use in LQT because of its cardioselective properties and favorable side-effect profile. METHODS: We performed a retrospective cohort study of 114 consecutive patients with gene-positive Long-QT syndrome type 1 (LQT1) or Long-QT syndrome type 2 (LQT2) treated with bisoprolol, nadolol or atenolol with a total of 580 person-years of follow-up. Electrocardiogram (ECG) parameters and cardiac events during follow-up were compared. In addition, exercise treadmill testing was performed in bisoprolol-treated patients. RESULTS: Fifty-nine patients were treated with bisoprolol, 39 with atenolol and 16 with nadolol. Overall, 59 % were females and 62 % had LQT1. Baseline heart rate and corrected QT (QTc) interval were similar between the groups. QTc shortening was observed in individuals on bisoprolol (ΔQTc -5 ± 31 ms; p = 0.049) and nadolol (ΔQTc -13 ± 16 ms; p = 0.02) but not on atenolol (ΔQTc +9 ± 24 ms; p = 0.16). Median follow-up was similar for bisoprolol and nadolol (3 years), but longer for atenolol (6 years; p = 0.03); one cardiac event occurred in the bisoprolol group (1.7 %) and two events occurred in the atenolol group (5.1 %; p = 0.45), whereas none occurred in nadolol-treated patients. Beta-blocker efficacy was not affected by the underlying genotype. The antiadrenergic effect of bisoprolol correlated with the reduction of peak heart rates at exercise testing. CONCLUSIONS: Bisoprolol treatment results in QTc shortening in gene-positive LQT1 and LQT2 patients and is well tolerated during long-term administration. The equivalence of bisoprolol for protection from ventricular arrhythmia in LQT patients compared to established beta-blockers remains unknown. Further large-scale studies are required.

Characterization of Myocardial Repolarization Reserve in Adolescent Females With Anorexia Nervosa.

BACKGROUND: Patients with anorexia nervosa exhibit abnormal myocardial repolarization and are susceptible to sudden cardiac death. Exercise testing is useful in unmasking QT prolongation in disorders associated with abnormal repolarization. We characterized QT adaptation during exercise in anorexia. METHODS AND RESULTS: Sixty-one adolescent female patients with anorexia nervosa and 45 age- and sex-matched healthy volunteers performed symptom-limited cycle ergometry during 12-lead ECG monitoring. Changes in the QT interval during exercise were measured, and QT/RR-interval slopes were determined by using mixed-effects regression modeling. Patients had significantly lower body mass index than controls; however, resting heart rates and QT/QTc intervals were similar at baseline. Patients had shorter exercise times (13.7±4.5 versus 20.6±4.5 minutes; P<0.001) and lower peak heart rates (159±20 versus 184±9 beats/min; P<0.001). The mean QTc intervals were longer at peak exercise in patients (442±29 versus 422±19 ms; P<0.001). During submaximal exertion at comparable heart rates (114±6 versus 115±11 beats/min; P=0.54), the QTc interval had prolonged significantly more in patients than controls (37±28 versus 24±25 ms; P<0.016). The RR/QT slope, best described by a curvilinear relationship, was more gradual in patients than in controls (13.4; 95% confidence interval, 12.8-13.9 versus 15.8; 95% confidence interval, 15.3-16.4 ms QT change per 10% change in RR interval; P<0.001) and steepest in patients within the highest body mass index tertile versus the lowest (13.9; 95% confidence interval, 12.9-14.9 versus 12.3; 95% confidence interval, 11.3-13.3; P=0.026). CONCLUSIONS: Despite the absence of manifest QT prolongation, adolescent anorexic females have impaired repolarization reserve in comparison with healthy controls. Further study may identify impaired QT dynamics as a risk factor for arrhythmias in anorexia nervosa.

Lead Integrity Alert Is Useful for Assessment of Performance of Biotronik Linox Leads.

INTRODUCTION: Medtronic's Lead Integrity Alert (LIA) software algorithm is useful for detecting abnormal parameters across various ICD-lead families. However, its utility in the assessment of the Biotronik Linox™ family of high-voltage (HV) leads is unknown. METHODS: We conducted a retrospective cohort study to assess the performance of the LIA algorithm to detect abnormalities and lead failure in Linox ICD-leads. All LIA-enabled Medtronic devices connected to an active Linox lead were included. The alerts were adjudicated by 2 blinded electrophysiologists and correlated with clinical data. RESULTS: Between 2008 and 2012, data from 208 patients with 564 patient-years of follow-up were available for analysis. The median follow-up duration was 32 (IQR 21-41 months). Twenty-one LIA triggers were noted in 20 different patients. The median delay until a positive LIA was 32 months (IQR 21-41 months) postimplant with a 5-year lead survival free from LIA of 76%. Ninety-five percent (19/20) LIA alerts were true lead failures. The most common LIA triggers were short V-V intervals (85%) and nonsustained ventricular tachycardia (85%). Abrupt changes of the ICD-lead impedance occurred in 5/20 triggers. Inappropriate ICD-shocks were strongly associated with a positive LIA (30% vs. 7.4%; P = 0.006). Of the explanted Linox leads 53% had visible abnormalities. The sensitivity, specificity, and positive predictive value for lead failure in the presence of a LIA trigger were 87%, 99.5%, and 95.2%, respectively. CONCLUSIONS: A positive LIA trigger in Biotronik Linox ICD-leads is highly predictive of lead failure. LIA is useful in ongoing surveillance of lead performance.

Preventing cardiac implantable electronic device infections.

Cardiac implantable electronic devices (CIEDs) have dramatically improved clinical outcomes in patients with heart disease, and the number of CIED-related procedures being performed continues to grow. Unfortunately, the rate of device-related infection (DRI) is increasing disproportionately to the rate of implantation, with DRI rates of >2% in many series. This increase in DRI is a consequence of the increased number of patients with a higher burden of comorbidities, who are more susceptible to infection and are undergoing more complex device procedures. Identification of high-risk patients is an important component of procedural planning, and targeted therapy and surveillance may be beneficial in certain groups. An understanding of the pathophysiology of DRI has facilitated more effective and widespread use of prophylactic antibiotics; however, current guidelines for antibiotic prophylaxis are based on a relatively small evidence base. Clinical equipoise remains regarding the optimal prophylactic regimen, and we are continuing to learn how best to manage these patients. In this review, we discuss the epidemiology and pathophysiology of DRI and its clinical presentation, the risk factors for DRI, and the existing and emerging evidence supporting strategies to prevent DRI.

Early failure of the Biotronik Linox implantable cardioverter defibrillator lead.

INTRODUCTION: The Linox and Durata implantable cardioverter defibrillator (ICD) leads were introduced to British Columbia (BC) in 2008. We determined their performance and the potential risk factors for lead failure in a large population-based patient registry. METHODS AND RESULTS: We used the BC Cardiac Registry, a mandatory Governmental database of ICD implants, to identify all recipients of Linox and Durata leads in BC between October 2008 and April 2012, and those subsequently undergoing reoperation. Lead failure was defined as recurrent nonphysiological high-rate sensing unrelated to external electromagnetic interference or T-wave oversensing; a sudden rise in impedance unrelated to perforation or lead dislodgement; or abnormal lead parameters with definite evidence of lead fracture or insulation failure. We determined the estimated cumulative lead survival by the Kaplan-Meier method, and the risk factors for lead failure in a proportional hazards model. Over a median of 39 (27-50) months, the Linox failed more frequently than the Durata (16/477 [3.4%] vs. 4/838 [0.4%]; P < 0.001), and had a significantly lower estimated cumulative survival (91.6 [80.6-96.5]% vs. 99.4 [98.4-99.8]% at 5 years; P < 0.0001). Linox failure was characterized by high-rate nonphysiological sensing (11 cases), and/or a sudden impedance rise (7 cases). Insulation failure was clearly confirmed in 6 cases of Linox failure. Female sex was a significant risk factor for Linox failure (adjusted HR = 2.1[1.3-3.4]; P = 0.004). CONCLUSIONS: This multicenter registry indicates a high rate of Linox lead failure, particularly in female patients. Ongoing surveillance of the Linox ICD lead performance is recommended.

Percutaneous coronary intervention causes a rapid but transient mobilisation of CD34(+)CD45(-) cells.

OBJECTIVE: Circulating CD34(+)CD45(-) cell concentrations are increased in patients with coronary artery disease, however their pathophysiological significance is unknown. We determined CD34(+)CD45(-) cell concentrations following percutaneous coronary intervention (PCI) in order to explore their role in acute vascular injury. METHODS: In a prospective time-course analysis, we quantified using flow cytometry circulating CD34(+)CD45(-) cells, traditional CD34(+)VEGFR-2(+) putative endothelial progenitor cells (EPCs), CD14(+) VEGFR(-) 2(+)Tie-2(+) angiogenic monocytes and intercellular adhesion molecule expression (CXCR-4 and CD18) in patients, before and during the first week following diagnostic angiography (n=13) or PCI (n=23). Vascular endothelial growth factor-A (VEGF-A) and C reactive protein (CRP) were quantified by ELISA. RESULTS: Unlike diagnostic angiography, PCI increased circulating neutrophil and CRP concentrations at 24 and 48 h, respectively (p<0.002 for both). CD34(+)CD45(-) cell concentrations were unaffected by angiography (p>0.4), but were transiently increased 6 h following PCI (median (IQR) 0.93 (0.43-1.49) vs 1.51 (0.96-2.15)×10(6) cells/L; p=0.01), returning to normal by 24 h. This occurred in the absence of any change in serum VEFG-A concentration, adhesion molecule expression on CD34(+) cells, or mobilisation of traditional EPCs or angiogenic monocytes (p>0.1 for all). CONCLUSIONS: PCI transiently increases circulating CD34(+)CD45(-) cells, without increasing CD34(+) adhesion molecule expression or VEGF-A concentrations, suggesting that CD34(+)CD45(-) cells may be mobilised from the vessel wall directly as a result of mechanical injury. Traditional putative EPC and angiogenic monocytes are unaffected by PCI, and are unlikely to be important in the acute response to vascular injury.

Three coronary arteries arising from the right coronary cusp with a malignant sub-pulmonary course of the left anterior descending artery.

We describe a case of a 45-year-old man presenting with acute myocardial infarction investigated by computed tomography coronary angiography. Interestingly all three coronary arteries arose from the right coronary cusp. The left anterior descending artery (LAD) subtended an acute angle from the aortic root, associated with significant kinking and stenosis at the ostium, before passing anteriorly, taking a sub-pulmonic course and descending in the anterior interventricular groove. The distal vessel was small with an atrophic appearance. The circumflex artery followed a retro-aortic route, before trifurcating to supply the lateral and posterior walls of the left ventricle. The right coronary artery was normal. Given his unstable presentation and the potentially lethal course of the LAD, he was referred for grafting of the LAD vessel which successfully ameliorated his symptoms and has thus far prevented recurrent myocardial infarction. .

Endothelial progenitor cells in patients with chronic obstructive pulmonary disease.

The pathogenesis of chronic obstructive pulmonary disease is not fully understood. The objective of this study was to compare circulating endothelial progenitor cells in patients with chronic obstructive pulmonary disease to age, sex, and cigarette smoking matched healthy controls. Patients with chronic obstructive pulmonary disease (n = 37) and healthy controls (n = 19) were matched by age, sex, and smoking status. Circulating hematopoietic progenitor cells (CD34(+) or CD133(+) mononuclear cells) and endothelial progenitor cells (CD34(+)KDR(+) or CD34(+)CD133(+)KDR(+) mononuclear cells) were quantified by flow cytometry. Endothelial cell-colony forming units from peripheral blood mononuclear cells were quantified in vitro and phenotypic analysis carried out using immunocytochemistry. Patients with chronic obstructive pulmonary disease had more circulating mononuclear cells compared with controls (8.4 ± 0.6 vs. 5.9 ± 0.4 × 10(9) cells/l; P = 0.02). CD34(+) hematopoietic progenitor cells were reduced as a proportion of mononuclear cells in patients compared with controls (0.99 ± 0.12 vs. 1.9 ± 0.12%; P = 0.02); however, there were no differences in the absolute number of CD34(+), CD34(+)KDR(+), or CD34(+)CD133(+)KDR(+) cells (P > 0.05 for all). Endothelial cell-colony forming units were increased in patients with chronic obstructive pulmonary disease compared with controls (13.7 ± 5.2 vs. 2.7 ± 0.9 colonies; P = 0.048). In contrast to previous studies, the number of circulating progenitor cells was not reduced in patients with chronic obstructive pulmonary disease compared with carefully matched controls. It seems unlikely that circulating endothelial progenitor cells or failure of angiogenesis plays a central role in the development of emphysema.

The constituents and mechanisms of generation of 'endothelial cell--colony forming units'.

AIMS: The formation of endothelial cell-colony forming units (EC-CFUs) is increased by vascular injury, although their function in vivo is unclear. We, therefore, examined the constituents of EC-CFUs and the mechanisms of their generation. METHODS AND RESULTS: We performed immunohistochemical characterization of EC-CFUs and their mononuclear precursors. Using fluorescent-activated cell sorting, we evaluated the capacity of mononuclear subpopulations to generate EC-CFUs, and monitored their migratory behaviour when co-incubated with EC-CFUs. Time-lapse microscopy was used to observe colony maturation. Cellular proliferation within EC-CFUs was assessed using bromodeoxyuridine (BrdU) and anti-proliferative agents. EC-CFUs exhibited typical endothelial characteristics; however, several endothelial markers were weakly expressed or absent. Macrophage and lymphocyte antigens were intensely expressed. EC-CFUs readily incorporated BrdU, and failed to develop in the presence of anti-proliferative agents (P < 0.01; n = 12). Time-lapse microscopy demonstrated that the characteristic EC-CFU 'spindle cells' are not EC-CFU progeny, but are mononuclear cells migrating towards, and incorporating into colonies. Only CD14(+) monocytes were necessary for EC-CFU formation. CD14 expression was progressively down-regulated during colony maturation (P < 0.001; n = 6). Although unable to generate EC-CFUs directly, CD34(+) cells could differentiate into CD14(+) cells and potentiate EC-CFU formation. CONCLUSIONS: EC-CFUs exhibit endothelial characteristics, but are predominantly CD14(+) derived macrophages and are a potent stimulus for lymphocyte migration. Proliferation is necessary for EC-CFU generation; however, colony growth also occurs as a result of leucocyte migration. Although confirmatory in vivo studies are required, EC-CFU formation likely reflects leucocyte activation as a reparatory response to vascular denudation or tissue ischaemia.

GPIb VNTR C/C genotype may predict embolic events in infective endocarditis.

BACKGROUND AND AIM OF THE STUDY: Infective endocarditis (IE) is frequently complicated by septic embolism, a need for valve replacement, and death. The development of these complications is associated with the presence, size and mobility of cardiac vegetations, which may form as a result of bacterium-platelet interactions mediated by the platelet glycoprotein GPIb receptor. Variable number tandem repeat (VNTR) and single nucleotide polymorphisms of the gene encoding the GPIb receptor have been described, but their correlation with platelet function, development of vegetations and complications of IE is unknown. METHODS: The GPIb Kozak T/C, VNTR and human platelet antigen-2a/2b (HPA-2a/2b) genotype of healthy volunteers (n = 156) and patients with IE (n = 35) was determined, and the influence of these polymorphisms on Staphylococcus aureus-induced platelet aggregation in vitro, platelet activation in vivo and clinical outcome in IE was then investigated. RESULTS: The GPIb VNTR C/C genotype was associated with an increased risk of embolism (p = 0.039), with no influence on platelet activation or aggregation, vegetation characteristics or mortality (p > 0.05 for all). The GPIb Kozak T/C and HPA-2a/2b polymorphisms did not influence the development of complications in patients with IE (all p > 0.05). CONCLUSION: The results of these exploratory studies suggest that the GPIb VNTR C/C genotype may predict the development of septic emboli in patients with IE. This hypothesis should be analyzed in larger studies and, if confirmed, would represent an important clinical finding, as it implies that early surgery in patients with the GPIb VNTR C/C genotype could reduce morbidity and mortality in IE.

Cardiovascular effects of tumour necrosis factor α antagonism in patients with acute myocardial infarction: a first in human study.

OBJECTIVE: The inflammatory cytokine, tumour necrosis factor α (TNF-α), exerts deleterious cardiovascular effects. We wished to determine the effects of TNF-α antagonism on endothelial function and platelet activation in patients with acute myocardial infarction. DESIGN AND SETTING AND PATIENTS: A double-blind, parallel group, randomised controlled trial performed in a tertiary referral cardiac centre. 26 patients presenting with acute myocardial infarction randomised to receive an intravenous infusion of etanercept (10 mg) or saline placebo. MAIN OUTCOME MEASURES: Leucocyte count, plasma cytokine concentrations, flow cytometric measures of platelet activation and peripheral vasomotor and fibrinolytic function were determined before and 24 h after study intervention. RESULTS: Consistent with effective conjugation of circulating TNF-α, plasma TNF-α concentrations increased in all patients following etanercept (254 ± 15 vs 0.12 ± 0.02 pg/ml; p < 0.0001), but not saline infusion. Etanercept treatment reduced neutrophil (7.4 ± 0.6 vs 8.8 ± 0.6 × 10(9) cells/l; p = 0.03) and plasma interleukin-6 concentrations (5.8 ± 2.0 vs 10.6 ± 4.0 pg/ml; p = 0.012) at 24 h but increased platelet-monocyte aggregation (30 ± 5 vs 20 ± 3%; p = 0.02). Vasodilatation in response to substance P, acetylcholine and sodium nitroprusside, and acute tissue plasminogen activator release were unaffected by either treatment (p > 0.1 for all). CONCLUSIONS: Following acute myocardial infarction, etanercept reduces systemic inflammation but increases platelet activation without affecting peripheral vasomotor or fibrinolytic function. We conclude that TNF-α antagonism is unlikely to be a beneficial therapeutic strategy in patients with acute myocardial infarction.

Endothelial progenitor cells, atheroma burden and clinical outcome in patients with coronary artery disease.

OBJECTIVE: We wished to determine the effect of an acute coronary syndrome (ACS) on putative endothelial progenitor cell (EPC) populations, and define their relationship to coronary artery disease (CAD) severity and clinical outcome, in order to clarify their clinical relevance. DESIGN AND SETTING: A prospective cohort study conducted in a tertiary referral cardiac centre. PATIENTS: Two-hundred-and-one patients undergoing coronary angiography for suspected angina or ACS. MAIN OUTCOME MEASURES: Putative EPC populations were determined by flow cytometry. CAD was quantified using the Gensini scoring system. Survival free from revascularisation, recurrent myocardial infarction and death were determined at 3 years. RESULTS: Circulating CD34(+)VEGFR-2(+) and CD34(+)VEGFR-2(+)CD133(+) cells were rare (<0.007% of mononuclear cells), were not increased in patients with ACS, and were unrelated CAD severity or clinical outcome (p>0.1 for all). By contrast, CD34(+)CD45(-) cells were increased in patients with CAD compared with those with normal coronary arteries (p=0.008) and correlated with atheroma burden (r=0.44, p<0.001). Increased concentrations of circulating CD34(+)CD45(-) cells were associated with a shorter cumulative event-free survival (p<0.02). Proangiogenic monocytes (CD14(+)VEGFR-2(+)Tie-2(+)) and endothelial cell-colony forming units were increased in patients with ACS (p<0.01 for both), however, concentrations reflected myocardial necrosis, and did not predict the extent of CAD or clinical outcome. CONCLUSIONS: Traditional EPC populations, CD34(+)VEGFR-2(+) and CD34(+)VEGFR-2(+)CD133(+) are not related to the extent of CAD or clinical outcome. However, CD34(+)CD45(-) cells are increased in patients with CAD and predict future cardiovascular events. It is likely that CD34(+)CD45(-) concentrations reflect the extent of vascular injury and atheroma burden.

Novel biopolymers to enhance endothelialisation of intra-vascular devices.

Rapid endothelisation is of critical importance in the prevention of adverse remodelling after device implantation. Currently, there is a need for alternative strategies to promote re-endothelialisation for intravascular stents and vascular grafts. Using polymer microarray technology 345 polymers are comprehensively assessed and a matrix is identified that specifically supports both progenitor and mature endothelial cell activity in vitro and in vivo while minimising platelet attachment.