Transapical access closure: the TA PLUG device

OBJECTIVES Percutaneous closure of the transapical (TA) access site for large-calibre devices is an unsolved issue. We report the first experimental data on the TA PLUG device for true-percutaneous closure following large apical access for transcatheter aortic valve implantation. METHODS The TA PLUG, a self-sealing full-core closure device, was implanted in an acute animal study in six pigs (60.2 ± 0.7 kg). All the pigs received 100 IU/kg of heparin. The targeted activated clotting time was left to normalize spontaneously. After accessing the left ventricular apex with a 39 French introducer, the closure plug device was delivered with a 33 French over-the-wire system under fluoroscopic guidance into the apex. Time to full haemostasis as well as rate of bleeding was recorded. Self-anchoring properties were assessed by haemodynamic push stress under adrenalin challenge. An additional feasibility study was conducted in four pigs (58.4 ± 1.1 kg) with full surgical exposure of the apex, and assessed device anchoring by pull-force measurements with 0.5 Newton (N) increments. All the animals were electively sacrified. Post-mortem analysis of the heart was performed and the renal embolic index assessed. RESULTS Of six apical closure devices, five were correctly inserted and fully deployed at the first attempt. One became blocked in the delivery system and was placed successfully at the second attempt. In all the animals, complete haemostasis was immediate and no leak was recorded during the 5-h observation period. Neither leak nor any device dislodgement was observed under haemodynamic push stress with repeated left ventricular peak pressure of up to 220 mmHg. In the feasibility study assessing pull-stressing, device migration occurred at a force of 3.3 ± 0.5 N corresponding to 247.5 mmHg. Post-mortem analyses confirmed full expansion of all devices at the intended target. No macroscopic damage was identified at the surrounding myocardium. The renal embolic index was zero. CONCLUSIONS True-percutaneous left ventricular apex closure following large access is feasible with the self-sealing TA PLUG. The device allows for immediate haemostasis and a reliable anchoring in the acute animal setting. This is the first report of a true-percutaneous closure for large-calibre transcatheter aortic valve implantation access.

Controversies of fetal cardiac intervention

Remarkable advances in ultrasound imaging technology have made it possible to diagnose fetal cardiovascular lesions as early as 12-14 weeks of gestation and to assess their physiological relevance by echocardiography. Moreover, invasive techniques have been developed and refined to relieve significant congenital heart disease (CHD), such as critical aortic and pulmonary stenoses in the pediatric population including neonates. Recognition of the fact that certain CHDs can evolve in utero, and early intervention may improve the outcome by altering the natural history of such conditions has led to the evolution of a new fetal therapy, i.e. fetal cardiac intervention. Two entities, pulmonary valvar atresia and intact ventricular septum (PA/IVS) and hypoplastic left heart syndrome (HLHS), are associated with significant morbidity and mortality even with postnatal surgical therapy. These cases are believed to occur due to restricted blood flow, leading to impaired growth and function of the right or left ventricle. Therefore, several centers started the approach of antenatal intervention with the primary goal of improving the blood flow through the stenotic/atretic valve orifices to allow growth of cardiac structures. Even though centers with a reasonable number of cases seem to have improved the technique and the immediate outcome of fetal interventions, the field is challenged by ethical issues as the intervention puts both the mother and the fetus at risk. Moreover, the perceived benefits of prenatal treatment have to be weighed against steadily improving postnatal surgical and hybrid procedures, which have been shown to reduce morbidity and mortality for these complex heart defects. This review is an attempt to provide a balanced opinion and an update on fetal cardiac intervention.

Severe aortic stenosis and coronary artery disease

Coronary artery disease (CAD) and aortic stenosis (AS) share pathophysiological mechanisms and risk factors. Moreover, the prevalence of CAD increases among elderly patients with severe AS since disease progression is strongly associated with age for both CAD and AS. These factors contribute to the frequent coexistence of CAD and AS. Patients with concomitant AS and CAD are characterised by higher baseline risk profiles with a larger number of comorbidities as compared to patients with isolated AS. Therefore, adequate therapeutic strategies are crucial for the treatment of these patients. The number of patients undergoing concomitant coronary artery bypass grafting (CABG) and surgical aortic valve replacement (SAVR) doubled during the last decade. Moreover, the development and rapid integration of transcatheter aortic valve implantation (TAVI) into clinical practice in western European countries has further extended invasive treatment of AS to elderly high-risk patients not considered suitable candidates for SAVR, frequently presenting with CAD. The aim of this review article is to provide an overview on CAD prevalence, impact on clinical outcomes, and treatment strategies in patients with severe AS requiring SAVR or TAVI.

Electrocardiographic characteristics of patients with Ebstein's anomaly before and after ablation of an accessory atrioventricular pathway

UNLABELLED The abnormal development of the tricuspid valve in patients with Ebstein's anomaly results in several activation abnormalities including delayed intraatrial conduction, right bundle branch block (RBBB), and ventricular preexcitation. The aim of the present study was to define the ECG characteristics before and after ablation of an accessory A-V pathway (AP) in patients with Ebstein's anomaly. METHODS A series of 226 consecutive patients with Ebstein's anomaly was studied. Sixty-four patients (28%) had documented tachycardia. Thirty-three patients with recurrent tachycardia were found to have a single right-sided AP that was successfully ablated (study group). Thirty patients without tachycardia served as the control group. RESULTS Only 21 of 33 patients (62%) had a typical ECG pattern of preexcitation. In addition, none of the patients had an ECG pattern of RBBB during sinus rhythm. In contrast, 28 of 30 (93%) patients in the control group had RBBB (P < 0.001). Radiofrequency catheter ablation resulted in appearance of RBBB in 31 of 33 (94%) patients. The absence of RBBB in patients with Ebstein's anomaly and recurrent tachycardia had a 98% sensitivity and 92% specificity for the diagnosis of an AP. The positive predictive value was 91% (0.77, 0.97 CI 95%) and the negative predictive value was 98% (0.85, 0.99 CI 95%). CONCLUSION One-third of patients with Ebstein's anomaly and symptomatic tachyarrhythmias have minimal or absent ECG features of ventricular preexcitation. In these patients, the absence of RBBB pattern is a strong predictor of an AP.

Radiofrequency catheter ablation of idiopathic ventricular tachycardia originating in the main stem of the pulmonary artery.

We report the case of a patient in whom successful radiofrequency catheter ablation of an idiopathic ventricular tachycardia (VT) originating in the main stem of the pulmonary artery was performed. After successful ablation of the index arrhythmia, which was an idiopathic right ventricular outflow tract VT, a second VT with a different QRS morphology was reproducibly induced. Mapping of the second VT revealed the presence of myocardium approximately 2 cm above the pulmonary valve. Application of radiofrequency energy at this site resulted in termination and noninducibility of this VT. After 6-month follow-up, the patient remained free from VT recurrences.

Trigger activity more than three years after left atrial linear ablation without pulmonary vein isolation in patients with atrial fibrillation.

OBJECTIVES The aim of this study was to analyze trigger activity in the long-term follow-up after left atrial (LA) linear ablation. BACKGROUND Interventional strategies for curative treatment of atrial fibrillation (AF) are targeted at the triggers and/or the maintaining substrate. After substrate modification using nonisolating linear lesions, the activity of triggers is unknown. METHODS With the LA linear lesion concept, 129 patients were treated using intraoperative ablation with minimal invasive surgical techniques. Contiguous radiofrequency energy-induced lesion lines involving the mitral annulus and the orifices of the pulmonary veins without isolation were placed under direct vision. RESULTS After a mean follow-up of 3.6 +/- 0.4 years, atrial ectopy, atrial runs, and reoccurrence of AF episodes were analyzed by digital 7-day electrocardiograms in 30 patients. Atrial ectopy was present in all patients. Atrial runs were present in 25 of 30 patients (83%), with a median number of 9 runs per patient/week (range 1 to 321) and a median duration of 1.2 s/run (range 0.7 to 25), without a significant difference in atrial ectopy and atrial runs between patients with former paroxysmal (n = 17) or persistent AF (n = 13). Overall, 87% of all patients were completely free from AF without antiarrhythmic drugs. CONCLUSIONS A detailed rhythm analysis late after specific LA linear lesion ablation shows that trigger activity remains relatively frequent but short and does not induce AF episodes in most patients. The long-term success rate of this concept is high in patients with paroxysmal or persistent AF.

Time courses and quantitative analysis of atrial fibrillation episode number and duration after circular plus linear left atrial lesions: trigger elimination or substrate modification: early or delayed cure?

OBJECTIVES We sought to analyze the time course of atrial fibrillation (AF) episodes before and after circular plus linear left atrial ablation and the percentage of patients with complete freedom from AF after ablation by using serial seven-day electrocardiograms (ECGs). BACKGROUND The curative treatment of AF targets the pathophysiological corner stones of AF (i.e., the initiating triggers and/or the perpetuation of AF). The pathophysiological complexity of both may not result in an "all-or-nothing" response but may modify number and duration of AF episodes. METHODS In patients with highly symptomatic AF, circular plus linear ablation lesions were placed around the left and right pulmonary veins, between the two circles, and from the left circle to the mitral annulus using the electroanatomic mapping system. Repetitive continuous 7-day ECGs administered before and after catheter ablation were used for rhythm follow-up. RESULTS In 100 patients with paroxysmal (n = 80) and persistent (n = 20) AF, relative duration of time spent in AF significantly decreased over time (35 +/- 37% before ablation, 26 +/- 41% directly after ablation, and 10 +/- 22% after 12 months). Freedom from AF stepwise increased in patients with paroxysmal AF and after 12 months measured at 88% or 74% depending on whether 24-h ECG or 7-day ECG was used. Complete pulmonary vein isolation was demonstrated in <20% of the circular lesions. CONCLUSIONS The results obtained in patients with AF treated with circular plus linear left atrial lesions strongly indicate that substrate modification is the main underlying pathophysiologic mechanism and that it results in a delayed cure instead of an immediate cure.

Direct Democracy: Protest Catalyst or Protest Alternative?

This paper presents the first investigation of whether direct democracy supplements or undermines the attendance of demonstrations as a form of protest behavior. A first approach assumes that direct democracy is associated with fewer protests, as they function as a valve that integrates voters’ opinions, preferences, and emotions into the political process. A competing hypothesis proposes a positive relationship between direct democracy and this unconventional form of political participation due to educative effects. Drawing on individual data from recent Swiss Electoral Studies, we apply multilevel analysis and estimate a hierarchical model of the effect of the presence as well as the use of direct democratic institutions on individual protest behavior. Our empirical findings suggest that the political opportunity of direct democracy is associated with a lower individual probability to attend demonstrations.

Seasonal changes in the behaviour and respiration physiology of the freshwater duck mussel, Anodonta anatina.

For low-energy organisms such as bivalves, the costs of thermal compensation of biological rates (synonymous with acclimation or acclimatization) may be higher than the benefits. We therefore conducted two experiments to examine the effect of seasonal temperature changes on behaviour and oxygen consumption. In the first experiment, we examined the effects of seasonal temperature changes on the freshwater bivalve Anodonta anatina, taking measurements each month for a year at the corresponding temperature for that time of year. There was no evidence for compensation of burrowing valve closure duration or frequency, or locomotory speed. In the second experiment, we compared A. anatina at summer and winter temperatures (24 and 4°C, respectively) and found no evidence for compensation of the burrowing rate, valve closure duration or frequency, or oxygen consumption rates during burrowing, immediately after valve closure or at rest. Within the experimental limits of this study, the evidence suggests that thermal compensation of biological rates is not a strategy employed by A. anatina. We argue that this is due to either a lack of evolutionary pressure to acclimatize, or evolutionary pressure to not acclimatize. Firstly, there is little incentive to increase metabolic rate to enhance predatory ability given that these are filter feeders. Secondly, maintained low energetic demand, enhanced at winter temperatures, is essential for predator avoidance, i.e. valve closure. Thus, we suggest that the costs of acclimatization outweigh the benefits in A. anatina.

Physiologic and hematologic concerns of rotary blood pumps: what needs to be improved?

Over the past few decades, advances in ventricular assist device (VAD) technology have provided a promising therapeutic strategy to treat heart failure patients. Despite the improved performance and encouraging clinical outcomes of the new generation of VADs based on rotary blood pumps (RBPs), their physiologic and hematologic effects are controversial. Currently, clinically available RBPs run at constant speed, which results in limited control over cardiac workload and introduces blood flow with reduced pulsatility into the circulation. In this review, we first provide an update on the new challenges of mechanical circulatory support using rotary pumps including blood trauma, increased non-surgical bleeding rate, limited cardiac unloading, vascular malformations, end-organ function, and aortic valve insufficiency. Since the non-physiologic flow characteristic of these devices is one of the main subjects of scientific debate in the literature, we next emphasize the latest research regarding the development of a pulsatile RBP. Finally, we offer an outlook for future research in the field.

Importance of the collagen adhesin ace in pathogenesis and protection against Enterococcus faecalis experimental endocarditis.

Ace is an adhesin to collagen from Enterococcus faecalis expressed conditionally after growth in serum or in the presence of collagen. Here, we generated an ace deletion mutant and showed that it was significantly attenuated versus wild-type OG1RF in a mixed infection rat endocarditis model (P<0.0001), while no differences were observed in a peritonitis model. Complemented OG1RFDeltaace (pAT392::ace) enhanced early (4 h) heart valve colonization versus OG1RFDeltaace (pAT392) (P = 0.0418), suggesting that Ace expression is important for early attachment. By flow cytometry using specific anti-recombinant Ace (rAce) immunoglobulins (Igs), we showed in vivo expression of Ace by OG1RF cells obtained directly from infected vegetations, consistent with our previous finding of anti-Ace antibodies in E. faecalis endocarditis patient sera. Finally, rats actively immunized against rAce were less susceptible to infection by OG1RF than non-immunized (P = 0.0004) or sham-immunized (P = 0.0475) by CFU counts. Similarly, animals given specific anti-rAce Igs were less likely to develop E. faecalis endocarditis (P = 0.0001) and showed fewer CFU in vegetations (P = 0.0146). In conclusion, we have shown for the first time that Ace is involved in pathogenesis of, and is useful for protection against, E. faecalis experimental endocarditis.

Contribution of the collagen adhesin Acm to pathogenesis of Enterococcus faecium in experimental endocarditis.

Enterococcus faecium is a multidrug-resistant opportunist causing difficult-to-treat nosocomial infections, including endocarditis, but there are no reports experimentally demonstrating E. faecium virulence determinants. Our previous studies showed that some clinical E. faecium isolates produce a cell wall-anchored collagen adhesin, Acm, and that an isogenic acm deletion mutant of the endocarditis-derived strain TX0082 lost collagen adherence. In this study, we show with a rat endocarditis model that TX0082 Deltaacm::cat is highly attenuated versus wild-type TX0082, both in established (72 h) vegetations (P < 0.0001) and for valve colonization 1 and 3 hours after infection (P or=50-fold reduction relative to an Acm producer) were found in three of these five nonadherent isolates, including the sequenced strain TX0016, by quantitative reverse transcription-PCR, indicating that acm transcription is downregulated in vitro in these isolates. However, examination of TX0016 cells obtained directly from infected rat vegetations by flow cytometry showed that Acm was present on 40% of cells grown during infection. Finally, we demonstrated a significant reduction in E. faecium collagen adherence by affinity-purified anti-Acm antibodies from E. faecium endocarditis patient sera, suggesting that Acm may be a potential immunotarget for strategies to control this emerging pathogen.

Optical imaging of postsynaptic odor representation in the glomerular layer of the mouse olfactory bulb.

Olfactory glomeruli are the loci where the first odor-representation map emerges. The glomerular layer comprises exquisite local synaptic circuits for the processing of olfactory coding patterns immediately after their emergence. To understand how an odor map is transferred from afferent terminals to postsynaptic dendrites, it is essential to directly monitor the odor-evoked glomerular postsynaptic activity patterns. Here we report the use of a transgenic mouse expressing a Ca(2+)-sensitive green fluorescence protein (GCaMP2) under a Kv3.1 potassium-channel promoter. Immunostaining revealed that GCaMP2 was specifically expressed in mitral and tufted cells and a subpopulation of juxtaglomerular cells but not in olfactory nerve terminals. Both in vitro and in vivo imaging combined with glutamate receptor pharmacology confirmed that odor maps reported by GCaMP2 were of a postsynaptic origin. These mice thus provided an unprecedented opportunity to analyze the spatial activity pattern reflecting purely postsynaptic olfactory codes. The odor-evoked GCaMP2 signal had both focal and diffuse spatial components. The focalized hot spots corresponded to individually activated glomeruli. In GCaMP2-reported postsynaptic odor maps, different odorants activated distinct but overlapping sets of glomeruli. Increasing odor concentration increased both individual glomerular response amplitude and the total number of activated glomeruli. Furthermore, the GCaMP2 response displayed a fast time course that enabled us to analyze the temporal dynamics of odor maps over consecutive sniff cycles. In summary, with cell-specific targeting of a genetically encoded Ca(2+) indicator, we have successfully isolated and characterized an intermediate level of odor representation between olfactory nerve input and principal mitral/tufted cell output.

Evaluation of Recurrence Risks for Left-Sided Cardiac Lesions

It is widely accepted that hypoplastic left heart syndrome (HLHS), aortic valve stenosis with or without bicuspid aortic valve (AS/BAV) and coarctation of the aorta (CoA) occur in families more commonly with each other than with any other congenital heart defect (CHD). Genetic counseling for CHDs is currently based on empiric risk estimates derived from data collected on all types of CHDs between 1968 and 1990. Additionally, for the specific group of defects described above, termed left-sided lesions, estimates are available for sibling recurrence. Utilizing family history data from 757 probands recruited between 1997 and 2007 from The Children’s Hospital of Philadelphia, this study reassessed the pre/recurrence risks for LSLs specifically. Sibling pre/recurrence risks for HLHS (5.5%, 95% CI: 3.1%-8.9%), CoA (4.0%, 95% CI: 2.1%-6.7%), and AS/BAV (6.0%, 95% CI: 3.3%-9.8%) were higher than currently quoted risks based on sibling data for individual LSLs. Additionally, the prevalence of BAV in 202, apparently unaffected, parents of 134 probands was assessed by echocardiography. BAV, which occurs at a frequency of 1% in the general population, was found to occur in approximately 10% of parents of LSL probands. Lastly, among affected first-degree relative pairs (i.e. siblings, parent-offspring), the majority (65%-70%) were both affected with a LSL. Defect specific concordance rates were highest for AS/BAV. Together, these findings suggest that over the past 20 years with changing diagnostic capabilities and environmental/maternal conditions (e.g. folic acid fortification, increased maternal diabetes and obesity) recurrence risks may have increased, as compared to current LSL specific risk estimates. Based on these risk estimate increases and prior studies, a protocol for screening first-degree relatives of LSL probands should be devised.

Hemodynamics and Flow Characteristics of a New Dialysis Port

Renal replacement therapy by hemodialysis requires a permanent vascular access. Implantable ports offer a potential alternative to standard vascular access strategies although their development is limited both in number and extent. We explored the fluid dynamics within two new percutaneous bone-anchored dialysis port prototypes, both by in vitro experiments and computer simulation. The new port is to be fixed to bone and allows the connection of a dialysis machine to a central venous catheter via a built-in valve. We found that the pressure drop induced by the two ports was between 20 and 50 mmHg at 500 ml/min, which is comparable with commercial catheter connectors (15–80 mmHg). We observed the formation of vortices in both geometries, and a shear rate in the physiological range (<10,000s-1), which is lower than maximal shear rates reported in commercial catheters (up to 13,000s-1). A difference in surface shear rate of 15% between the two ports was obtained.