Martin Kostelka

Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides

Co-ordinated electrical activation of the heart is maintained by intercellular coupling of cardiomyocytes via gap junctional channels located in the intercalated disks. These channels consist of two hexameric hemichannels, docked to each other, provided by either of the adjacent cells. Thus, a complete gap junction channel is made from 12 protein subunits, the connexins. While 21 isoforms of connexins are presently known, cardiomyocytes typically are coupled by Cx43 (most abundant), Cx40 or Cx45. Some years ago, antiarrhythmic peptides were discovered and synthesised, which were shown to increase macroscopic gap junction conductance (electrical coupling) and enhance dye transfer (metabolic coupling). The lead substance of these peptides is AAP10 (H-Gly-Ala-Gly-Hyp-Pro-Tyr-CONH2), a peptide with a horseshoe-like spatial structure as became evident from two-dimensional nuclear magnetic resonance studies. A stable d-amino-acid derivative of AAP10, rotigaptide, as well as a non-peptide analogue, gap-134, has been developed in recent years. Antiarrhythmic peptides act on Cx43 and Cx45 gap junctions but not on Cx40 channels. AAP10 has been shown to enhance intercellular communication in rat, rabbit and human cardiomyocytes. Antiarrhythmic peptides are effective against ventricular tachyarrhythmias, such as late ischaemic (type IB) ventricular fibrillation, CaCl2 or aconitine-induced arrhythmia. Interestingly, the effect of antiarrhythmic peptides is higher in partially uncoupled cells and was shown to be related to maintained Cx43 phosphorylation, while arrhythmogenic conditions like ischaemia result in Cx43 dephosphorylation and intercellular decoupling. It is still a matter of debate whether these drugs also act against atrial fibrillation. The present review outlines the development of this group of peptides and derivatives, their mode of action and molecular mechanisms, and discusses their possible therapeutic potential.

Reducing the incidence and severity of pericardial adhesions with a sprayable polymeric matrix.

PURPOSE This study was undertaken to evaluate the antiadhesive properties of a polymeric agent in infants undergoing staged surgical correction of congenital heart abnormalities. DESCRIPTION Sixteen infants having staged surgical repair were treated with a polymeric matrix at the completion of the initial surgery. There were 5 untreated controls. The tenacity and extent of adhesions at five separate regions of the heart were evaluated at the follow-up surgery. EVALUATION For all sites combined, there was a threefold difference in median tenacity scores in favor of the experimental treatment (1.0 vs 3.0, p < 0.01). Significant differences were achieved separately at the right ventricle and the anterior surface of the great vessels (p = 0.02 for both comparisons). Analysis of adhesion scores reflecting the extent of adhesions similarly favored the experimental treatment for all sites (80 vs 270, p < 0.01), with significant differences persisting at the right atrium (p < 0.01) and the anterior surface of the great vessels (p = 0.04). There were no treatment-related adverse events. CONCLUSIONS Use of this polymeric agent at the completion of open cardiac surgery may prevent the occurrence or reduce the severity of pericardial adhesions.

Secundum ASD closure using a right lateral minithoracotomy: Five-Year experience in 122 patients

BACKGROUND Surgical closure of secundum atrial septal defect (ASD) is a standard procedure associated with very low mortality and morbidity. We evaluated outcomes in the era of catheter-based interventional closure and minimally invasive techniques. METHODS From May 1996, February 2002, 177 patients with a body weight of more than 30 kg underwent surgical ASD closure. A right lateral minithoracotomy (LMT) was used in 122 patients and a conventional approach, in 55. Diagnoses included secundum ASD in 106 patients in the LMT group and 40 in the conventional group, sinus venosus ASD in 13 patients in each group, and status post interventional closure in 3 and 2 patients, respectively. Mean age was 37 +/- 17 years in the LMT group and 43 +/- 20 years, in the conventional group and mean body weight was 66 +/- 17 kg and 70 +/- 16 kg, respectively. In the LMT group, femoral cannulation was performed for cardiopulmonary bypass. RESULTS Direct ASD closure was carried out in 67.2% of patients in the LMT group and 58.2% of those in the conventional group. The remaining patients had pericardial patch closure. There was one death: A patient in the conventional group who required explantation of an Amplatzer device because of infection died postoperatively. Average stay in the intensive care unit was 1.2 +/- 0.5 days. Two patients required reoperation for residual ASD after direct closure; 1 sustained a temporary neurological deficit that resolved completely. On postoperative echocardiography, a minimal residual shunt was seen in only 3 patients. All patients were in good clinical condition with improved functional status at discharge from the hospital. CONCLUSIONS Secundum ASD closure by LMT has become as standard and safe an operation as the conventional technique and achieves good perioperative results and satisfactory long-term outcomes. Thus LMT is an attractive option for patients who are not suitable for closure using catheter-based devices.

Hemodynamically optimized temporary cardiac pacing after surgery for congenital heart defects.

Disturbance of normal AV synchrony and dyssynchronous ventricular contraction may be deleterious in patients with otherwise compromised hemodynamics. This study evaluated the effect of hemodynamically optimized temporary dual chamber pacing in patients after surgery for congenital heart disease. Pacing was performed in 23 children aged 5 days to 7.7 years (median 7.3 months) with various postoperative dysrhythmias, low cardiac output, and/or high inotropic support and optimized to achieve the highest systolic and mean arterial pressures. The following four pacing modes were used: (1) AV synchronous or AV sequential pacing with individually optimized AV delay in 11 patients with first‐to third‐degree AV block; (2) AV sequential pacing using transesophageal atrial pacing in combination with a temporary DDD pacemaker for atrial tracking and ventricular pacing in three patients with third‐degree A V block and junctional ectopic tachycardia, respectively, who had poor signal and exit block on atrial epicardial pacing wires; (3) R wave synchronized atrial pacing in eight patients with junctional ectopic tachycardia and impaired antegrade AV conduction precluding the use of atrial overdrive pacing; (4) Atrio‐biventricular sequential pacing in two patients. Pressures measured during optimized pacing were compared to baseline values at underlying rhythm (13 patients with first‐degree AV block or junctional ectopic tachycardia) or during pacing modes commonly used in the given clinical situation: AAI pacing (1 patient with slow junctional rhythm and first‐degree AV block during atrial pacing), WI pacing (2 patients with third‐degree A V block and exit block and poor sensing on epicardial atrial pacing wires) and dual‐chamber pacing with AV delays set to 100 ms (atrial tracking) or 150 rns (AV sequential pacing) in 7 patients with second‐ to third‐degree A V block and functional atrial pacing wires. Optimized pacing led to a significant increase in arterial systolic (mean) pressure from 71.5 ± 12.5 (52.3 ± 9.0) to 80.5 ± 12.2 (59.7 ± 9.1) mmHg (P < 0.001 for both) and a decrease in central venous (left atrial) pressure from 12.3 ± 3.4 (10.5 ± 3.2) to 11.0 ± 3.0 (9.2 ± 2.7) mmHg (P < 0.001 and < 0.005, respectively). In conclusion, several techniques of individually optimized temporary dual chamber pacing leading to optimal AV synchrony and/or synchronous ventricular contraction were successfully used to improve hemodynamics in patients with heart failure and selected dysrhythmias after congenital heart surgery.

Differential effects of the site of permanent epicardial pacing on left ventricular synchrony and function in the young: implications for lead placement

AIMS To analyse left ventricular (LV) synchrony and function with respect to the epicardial pacing site in the young. METHODS AND RESULTS Left ventricular function and synchrony (M-mode, speckle tracking) were evaluated during mid-term follow-up in 32 children with complete non-surgical (n = 15) or surgical (n = 17) atrioventricular block (structural heart disease in 21/32) paced from LV apex (n = 19), right ventricular (RV) apex (n = 7), and RV free wall (n = 6), respectively. Data are in the following order: LV apical, RV apical, and RV free wall pacing. Septal to posterior wall motion delay (SPWMD) = median 0, 69, and 136 ms (P < 0.001), septal to lateral mechanical delay = 54 +/- 29, 73 +/- 24, and 129 +/- 70 ms (P = 0.001), apical to basal mechanical delay = 96 +/- 37, 106 +/- 50, and 79 +/- 18 ms (P NS), and LV ejection fraction (LVEF) = 57 +/- 9, 49 +/- 12, and 33 +/- 10% (P < 0.001), respectively. Left ventricular ejection fraction correlated negatively with SPWMD (R(2) = 0.454, P < 0.001) and septal to lateral mechanical delay (R(2) = 0.320, P < 0.001) but not with apical to basal mechanical delay. Right ventricular free wall pacing (P = 0.014) and SPWMD (P = 0.044) were negative multivariable predictors of LVEF. CONCLUSION Compared with other sites, LV apical pacing preserves septal to lateral LV synchrony and systolic function and may be the preferred epicardial pacing site in the young.

Age-dependent changes of cardiac neuronal noradrenaline reuptake transporter (uptake1) in the human heart ☆

OBJECTIVES The purpose of this study was to elucidate whether the neuronal noradrenaline reuptake transporter (uptake1) undergoes age-dependent regulation in the human heart. BACKGROUND Aging is associated with various alterations in cardiovascular function. METHODS We determined uptake1 density (by [3H]-nisoxetine binding to membranes) and activity (by accumulation of [3H]-noradrenaline into tissue slices) in the right atria (RA) of 42 patients (age range 3 months to 76 years) undergoing open-heart surgery without apparent heart failure. Moreover, the effects of 1 micromol/l desipramine on the noradrenaline-induced positive inotropic effect were assessed in the isolated, electrically driven RA trabeculae of these patients. RESULTS There was a significant negative correlation between RA uptake1 density and age; moreover, RA uptake1 activity was significantly reduced in elderly patients. Desipramine (1 micromol/l) significantly shifted noradrenaline concentration-response curves to the left; this shift was significantly more pronounced in younger patients than in older patients. CONCLUSIONS With increasing age, human myocardial uptake1 activity decreases, possibly because of age-dependent downregulation of uptake1 density.

Results of primary and two-stage repair of interrupted aortic arch

OBJECTIVE Early results of primary and two-stage repair of interrupted aortic arch have improved. Experience with different surgical approaches should be analysed and compared. METHODS Forty neonates and infants with interrupted aortic arch underwent primary repair (19 patients) or palliative operation (21 patients). Twenty (50%) patients were followed-up for 5.1+/-4.3 years. All patients were regularly examined with the aim of determining clinical development, presence of residual lesions or complications and need for re-intervention. Aortic arch and the left ventricular outflow tract growth were assessed by echocardiographic examination. Data from hospital and outpatient department records were analysed. RESULTS The early mortality was 61.9% after palliative operations and 36.8% after the primary repair. Presence of complications (P < 0.001), earlier year of surgery (P < 0.01), bad clinical condition and acidosis (P < 0.05) represented statistically significant risk factors for death in the whole series. In seven (87.5%) out of eight early survivors, after the initial palliative operation, closure of ventricular septal defect and debanding were done, and in three (37.5%) patients, re-operation for aortic arch obstruction was also required. Out of 12 patients, after the primary repair, one required early re-operation for persistent left ventricular outflow tract obstruction and two needed late re-intervention for left bronchus obstruction. In three (25%) patients, after the primary repair, left ventricular outflow tract obstruction with a maximal systolic pressure gradient higher than 30 mmHg developed. At present, all 20 early survivors are alive. Five patients, after palliative operation, are in NYHA class 1, but in three patients, who are in class III or IV, the outcome is influenced by severe complications. All patients after the primary repair are in class I or II. CONCLUSIONS Our experience confirmed better results after the primary repair of interrupted aortic arch, which was associated with lower mortality, prevalence of severe complications and need for re-intervention. Higher prevalence of subaortic stenosis after primary repair could be explained by patient selection early in our experience. We recommend the primary repair of interrupted aortic arch and associated heart lesions in neonates, however, in unfavourable conditions an individualised surgical approach with initial palliative surgery should be considered.

Long-Term Results After Repair of Complete Atrioventricular Septal Defect With Two-patch Technique

BACKGROUND Surgical management of patients with complete atrioventricular septal defect (AVSD) has advanced over the last decades. Definitive early surgical repair for AVSD has become the treatment of choice at many centers. This trend has contributed to the recent decline in postoperative mortality and good long-term results. METHODS We reviewed long-term results of 100 consecutive patients with complete AVSD undergoing definitive early repair with a two-patch technique and complete cleft closure operated on between June 1999 and June 2009. Valve performance, mortality, morbidity, and indications for reoperation were retrospectively studied. RESULTS Median age at operation was 3.8 months (range, 15 days to 4.7 years); median weight was 5.0 kg (range, 3.0 to 19 kg). Follow-up was 99% complete (mean 58 months; range, 1 to 120 months). Early definitive repair was performed in all patients who initially presented to our institution over the study period. There was no perioperative, in-hospital mortality, or late mortality. At the latest follow up, left atrioventricular valve (LAVV) regurgitation was absent or trace in 80 patients (80%), mild to moderate in 15 patients (15%), and moderate to severe in 4 patients (4%). Right AV valve regurgitation was none or trace in 86 patients (86%), mild to moderate in 11 patients (11%), and moderate to severe in 2 patients (2%). Actuarial freedom from reoperation for LAVV dysfunction at 1, 3, 5, and 10 years was 98%, 95%, 94%, and 94%, respectively. Actuarial freedom from reoperation for left ventricular outflow tract obstruction at 1, 3, 5, and 10 years was 100%, 99%, and remained constant by 99% at 5 and 10 years. CONCLUSIONS Definitive early repair for complete AVSD can be performed with excellent results. The two-patch technique with complete cleft closure is a safe and reproducible surgical method that can achieve very low mortality and stable long-term outcomes, even in neonates.

Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias.

Coordinated electrical activation of the heart is essential for the maintenance of a regular cardiac rhythm and effective contractions. Action potentials spread from one cell to the next via gap junction channels. Because of the elongated shape of cardiomyocytes, longitudinal resistivity is lower than transverse resistivity causing electrical anisotropy. Moreover, non-uniformity is created by clustering of gap junction channels at cell poles and by non-excitable structures such as collagenous strands, vessels or fibroblasts. Structural changes in cardiac disease often affect passive electrical properties by increasing non-uniformity and altering anisotropy. This disturbs normal electrical impulse propagation and is, consequently, a substrate for arrhythmia. However, to investigate how these structural changes lead to arrhythmias remains a challenge. One important mechanism, which may both cause and prevent arrhythmia, is the mismatch between current sources and sinks. Propagation of the electrical impulse requires a sufficient source of depolarizing current. In the case of a mismatch, the activated tissue (source) is not able to deliver enough depolarizing current to trigger an action potential in the non-activated tissue (sink). This eventually leads to conduction block. It has been suggested that in this situation a balanced geometrical distribution of gap junctions and reduced gap junction conductance may allow successful propagation. In contrast, source-sink mismatch can prevent spontaneous arrhythmogenic activity in a small number of cells from spreading over the ventricle, especially if gap junction conductance is enhanced. Beside gap junctions, cell geometry and non-cellular structures strongly modulate arrhythmogenic mechanisms. The present review elucidates these and other implications of passive electrical properties for cardiac rhythm and arrhythmogenesis.

Knock-down of endothelial connexins impairs angiogenesis

Connexins (Cx) are suggested to play important roles in growth and differentiation. Aim of our study was to investigate the role of endothelial Cx in the angiogenic process. Several parameters of angiogenesis were assessed in 18 h Matrigel in vitro angiogenesis assays with human umbilical vein endothelial cells (HUVEC). Prior to culture on Matrigel cells were treated with nicotine or the gap junction inhibitor palmitoleic acid (PA), or siRNA-knock-down of either Cx37, Cx40 or Cx43 was performed. Changes in Cx expression and their effects on gap-junctional communication were investigated using immunofluorescence microscopy, Western blot and Lucifer Yellow dye transfer. Knock-down of each Cx-isoform significantly reduced the amount of specific Cx protein in HUVEC. Cx-knock-down as well as treatment with PA impaired intercellular communication via gap junctions and diminished significantly the number of capillary branches. Knock-down of Cx43 and Cx40 or treatment with PA reduced complexity pattern in the angiogenesis assay. Nicotine significantly reduced expression of Cx43 and Cx37 as well as average length of capillary branches, number of branches and pattern in the Matrigel assay. We can conclude that connexins are involved in angiogenesis, in particular in branch formation. This can partly explain the changes in angiogenesis seen under nicotine treatment.