Peter Loh

Pulmonary Vein Ostium Geometry Analysis by Magnetic Resonance Angiography

Background—During a catheter ablation procedure for selective electrical isolation of pulmonary vein (PV) ostia, the size of these ostia is usually estimated using fluoroscopic angiography. This measurement may be misleading, however, because only the projected supero/inferior ostium diameters can be measured. In this study, we analyzed 3-dimensional magnetic resonance angiographic (MRA) images to measure the minimal and maximal cross-sectional diameter of PV ostia in relation to the diameter that would have been projected on fluoroscopic angiograms during a catheter ablation procedure. Methods and Results—In 42 patients with idiopathic atrial fibrillation who were scheduled for selective electrical isolation of PV ostia, the minimal and maximal diameters of these ostia were measured from 3-dimensional MRA images. Thereafter, these images were oriented in a 45° right or left anterior oblique direction and the projected diameter of the PV ostia were measured again. The average ratio between maximal and minimal diameter was 1.5±0.4 for the left and 1.2±0.1 for the right pulmonary vein ostia. Because of the orientation and oval shape of especially the left pulmonary vein ostia, their minimal diameters were significantly smaller than the projected diameters. Conclusion—Pulmonary vein ostia, especially those at the left, are oval with the short axis oriented approximately in the antero/posterior direction. Consequently, PV ostia may sometimes be very narrow despite a rather normal appearance on angiographic images obtained during a catheter ablation procedure.

Haplotype-Sharing Analysis Implicates Chromosome 7q36 Harboring DPP6 in Familial Idiopathic Ventricular Fibrillation

Idiopathic Ventricular Fibrillation (IVF) is defined as spontaneous VF without any known structural or electrical heart disease. A family history is present in up to 20% of probands with the disorder, suggesting that at least a subset of IVF is hereditary. A genome-wide haplotype-sharing analysis was performed for identification of the responsible gene in three distantly related families in which multiple individuals died suddenly or were successfully resuscitated at young age. We identified a haplotype, on chromosome 7q36, that was conserved in these three families and was also shared by 7 of 42 independent IVF patients. The shared chromosomal segment harbors part of the DPP6 gene, which encodes a putative component of the transient outward current in the heart. We demonstrated a 20-fold increase in DPP6 mRNA levels in the myocardium of carriers as compared to controls. Clinical evaluation of 84 risk-haplotype carriers and 71 noncarriers revealed no ECG or structural parameters indicative of cardiac disease. Penetrance of IVF was high; 50% of risk-haplotype carriers experienced (aborted) sudden cardiac death before the age of 58 years. We propose DPP6 as a gene for IVF and increased DPP6 expression as the likely pathogenetic mechanism.

Activation delay and VT parameters in arrhythmogenic right ventricular dysplasia/cardiomyopathy: Toward improvement of diagnostic ECG criteria

Introduction: Desmosomal changes, electrical uncoupling, and surviving myocardial bundles embedded in fibrofatty tissue are hallmarks of activation delay in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Currently, generally accepted task force criteria (TFC) are used for clinical diagnosis. We propose additional criteria based on activation delay and ventricular tachycardia (VT) to improve identification of affected individuals.

The role of connexin40 in atrial fibrillation

Connexin40 (Cx40) is a major gap-junction protein in the atrial myocardium. In the heart, gap junctions are responsible for cell-to-cell conduction of the action potential. In several cardiac diseases, the expression of connexins is changed and is associated with increased propensity for arrhythmias. Atrial fibrillation (AF) is the most common arrhythmia in man with a diverse clinical presentation, different underlying mechanisms, and difficult treatment. The vulnerability to arrhythmias of the heart is determined by the combined presence of an arrhythmogenic substrate and initiating triggers. The arrhythmogenic substrate is formed by reduced effective refractory period, enhanced spatial dispersion of refractoriness, or abnormal atrial impulse conduction. Initiating triggers of AF most frequently originate from firing foci in the pulmonary veins and/or superior caval vein. Prolonged episodes of AF result in electrical and structural remodelling that favours the reoccurrence or perpetuation of AF. This electrical remodelling embodies changes in Cx40 expression and distribution, both in the atrial myocardium itself and in the thoracic veins. In addition, Cx40 gene mutations or polymorphisms give an inherited predisposition to AF. This review focuses on the role of Cx40 in AF, showing that abnormal Cx40 expression is correlated with both trigger formation from the thoracic veins as well as enhanced vulnerability of the atrial myocardium to AF.

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Diagnostic Task Force Criteria Impact of New Task Force Criteria

Background —Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) diagnostic Task Force criteria (TFC) proposed in 1994 are highly specific but lack sensitivity. A new international Task Force modified criteria to improve diagnostic yield. Aim: comparison of diagnosis by 1994 TFC versus newly proposed criteria in 3 patient groups. Methods and Results —In new TFC, scoring by major and minor criteria is maintained. Structural abnormalities are quantified and TFC highly specific for ARVD/C upgraded to major. Furthermore, new criteria are added: terminal activation duration of QRS≥55ms, ventricular tachycardia with left bundle branch block morphology and superior axis, and genetic criteria. Three groups were studied: 1) 105 patients with proven ARVD/C according to 1994 TFC, 2) 89 of their family members and 3) 39 patients with probable ARVD/C (i.e. 3 points by 1994 TFC). All were screened for pathogenic mutations in desmosomal genes. Three ARVD/C patients did not meet the new sharpened criteria on structural abnormalities and thereby did not fulfill new TFC. In 62 of 105 proven ARVD/C patients mutations were found, 58 in the gene encoding Plakophilin2 ( PKP2 ), 3 in Desmoglein2, 3 in Desmocollin2 and 1 in Desmoplakin. Three patients had bigenic involvement. Ten additional relatives (11%) fulfilled new TFC: 9 (90%) were females and all carried PKP2 mutations. No relatives lost diagnosis by application of new TFC. Of probable ARVD/C patients, 25 (64%) fulfilled new TFC: 8 (40%) females and 14 (56%) carrying pathogenic mutations. Conclusions —In this first study applying new TFC to patients suspected of ARVD/C, 64% of probable ARVD/C patients and 11% of family members were additionally diagnosed. Especially ECG criteria and pathogenic mutations contributed to new diagnosis. Newly proposed TFC have a major impact in increasing diagnostic yield of ARVD/C.Background—Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Diagnostic Task Force Criteria (TFC) proposed in 1994 are highly specific but lack sensitivity. A new international task force modified criteria to improve diagnostic yield. A comparison of diagnosis by 1994 TFC versus newly proposed criteria in 3 patient groups was conducted. Methods and Results—In new TFC, scoring by major and minor criteria is maintained. Structural abnormalities are quantified and TFC highly specific for ARVD/C upgraded to major. Furthermore, new criteria are added: terminal activation duration of QRS ≥55 ms, ventricular tachycardia with left bundle-branch block morphology and superior axis, and genetic criteria. Three groups were studied: (1) 105 patients with proven ARVD/C according to 1994 TFC, (2) 89 of their family members, and (3) 39 patients with probable ARVD/C (ie, 3 points by 1994 TFC). All were screened for pathogenic mutations in desmosomal genes. Three ARVD/C patients did not meet the new sharpened criteria on structural abnormalities and thereby did not fulfill new TFC. In 62 of 105 patients with proven ARVD/C, mutations were found: 58 in the gene encoding Plakophilin2 (PKP2), 3 in Desmoglein2, 3 in Desmocollin2, and 1 in Desmoplakin. Three patients had bigenic involvement. Ten additional relatives (11%) fulfilled new TFC: 9 (90%) were female, and all carried PKP2 mutations. No relatives lost diagnosis by application of new TFC. Of patients with probable ARVD/C, 25 (64%) fulfilled new TFC: 8 (40%) women and 14 (56%) carrying pathogenic mutations. Conclusions—In this first study applying new TFC to patients suspected of ARVD/C, 64% of probable ARVD/C patients and 11% of family members were additionally diagnosed. ECG criteria and pathogenic mutations especially contributed to new diagnosis. Newly proposed TFC have a major impact in increasing diagnostic yield of ARVD/C.

Can optimization of pacing settings compensate for a non-optimal left ventricular pacing site?

AIMS Optimal left ventricular (LV) lead position improves the response to cardiac resynchronization therapy (CRT). However, in some patients it is not possible to position the LV lead at an optimal pacing site. The aim of this study was to determine whether optimization of the pacing settings atrioventricular delay (AVD) and interventricular delay (VVD) can compensate for a non-optimal LV pacing site. METHODS AND RESULTS In 16 patients with heart failure [New York Heart Association class III (13) or IV (3), median QRS duration of 172 ms and median LV ejection fraction of 20%] the acute haemodynamic effect of biventricular pacing was assessed at > or =2 pacing sites by the increase in maximum rate of LV pressure rise (%dP/dt(max)). At each site the AVD and VVD were optimized. Biventricular pacing with nominal settings at a non-optimal LV pacing site improved dP/dt(max) by 12.8% (-0.5 to 23.2%). This could be further improved by 6.5 percentage points (1.2-13.9) by optimization of pacing settings (P = 0.001) and by 9.9 percentage points (3.7-13.3, P = 0.004) by optimization of pacing site. Optimization of the LV pacing site and pacing settings together improved %dP/dt(max) by 16.2 per cent points (10.0-21.8, P < 0.001). CONCLUSION Optimization of the AVD and VVD can partly compensate for a non-optimal LV pacing site. However, a combination of an optimal LV pacing site and optimized pacing settings gives the best acute haemodynamic response.

Founder mutations in the Netherlands: familial idiopathic ventricular fibrillation and DPP6

In this part of a series on founder mutations in the Netherlands, we review familial idiopathic ventricular fibrillation linked to the DPP6 gene. Familial idiopathic ventricular fibrillation determines an intriguing subset of the inheritable arrhythmia syndromes as there is no recognisable phenotype during cardiological investigation other than ventricular arrhythmias highly associated with sudden cardiac death. Until recently, it was impossible to identify presymptomatic family members at risk for fatal events. We uncovered several genealogically linked families affected by numerous sudden cardiac deaths over the past centuries, attributed to familial idiopathic ventricular fibrillation. Notably, ventricular fibrillation in these families was provoked by very short coupled monomorphic extrasystoles. We were able to associate their phenotype of lethal arrhythmic events with a haplotype harbouring the DPP6 gene. While this gene has not earlier been related to cardiac arrhythmias, we are now able, for the first time, to identify and to offer timely treatment to presymptomatic family members at risk for future fatal events solely by genetic analysis. Therefore, when there is a familial history of unexplained sudden cardiac deaths, a link to the DPP6 gene may be explored as it may enable risk evaluation of the remaining family members. In addition, when closely coupled extrasystoles initiate ventricular fibrillation in the absence of other identifiable causes, a link to the DPP6 gene should be suspected.

Cardiac resynchronization therapy beyond nominal settings: who needs individual programming of the atrioventricular and interventricular delay?

AIMS This study aimed to determine the additional acute haemodynamic effect of atrioventricular (AV) and interventricular (VV) delay optimization compared with current nominal cardiac resynchronization therapy (CRT) device settings, and to explore whether clinical characteristics correlate to the effect of optimization. METHODS AND RESULTS Fifty CRT patients were prospectively enrolled. The optimal AV and VV delays were guided by relative improvement in maximum rate of left ventricular (LV) pressure rise (%dP/dt(max)). A significant improvement in %dP/dt(max) was obtained by optimization in 23-33% (sensed AV delay), 32-57% (paced AV delay), and 45% of patients (VV delay). Adjustment of the device nominal VV delay from 0 to 40 ms LV pre-activation would diminish the proportion of patients with additional effect of individual optimization from 45 to 15%. Heart failure aetiology [ischaemic 2 ± 2 vs. non-ischaemic 1 ± 1 percentage points (PP) %dP/dt(max), P= 0.013], gender (men 2 ± 2 vs. women 1 ± 1 PP %dP/dt(max), P= 0.012) and intrinsic PR interval (R= 0.49, P= 0.002) correlated to the degree of effect of AV delay optimization. Women yielded more effect of VV delay optimization (4 ± 3 vs. 2 ± 1 PP %dP/dt(max), P= 0.026). CONCLUSION Compared with the best of the currently available device nominal AV and VV delays, 23-45% of CRT patients can yield additional acute haemodynamic effect by individual optimization of the delays. A new nominal VV delay of 40 ms LV pre-activation is recommended. Male gender, ischaemic aetiology, and longer PR interval are associated with a larger effect of individual optimization.

New ECG Criteria in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Background—Desmosomal changes, electric uncoupling, and surviving myocardial bundles in fibrofatty tissue characterize arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Resultant activation delay is pivotal for reentry and thereby ventricular tachycardia (VT). Current task force criteria (TFC) for diagnosis have limited sensitivity. The aim of this study was to assess the diagnostic value of additional criteria on activation delay and VT to improve identification of affected individuals. Methods and Results—ECG criteria were studied, while off drugs, in 50 index patients with proven ARVD/C according to TFC (TFC ≥4 points) and 33 patients with probable ARVD/C (TFC 3 points, or TFC3), being 21 index patients and 12 family members of proven ARVD/C patients. Newly proposed additional criteria are (1) prolonged terminal activation duration in V1–V3, an indicator of activation delay, (2) VT with left bundle-branch block morphology and superior axis, and (3) multiple VT morphologies. All index patients were screened for mutations in ARVD/C-related genes encoding desmosomal proteins. Altogether, 23 of 33 (70%) TFC3 patients fulfilled ARVD/C diagnosis when newly proposed criteria were applied additionally to current TFC. VT with left bundle-branch block morphology and superior axis or multiple VT morphologies were recorded in 12 and 9 of 33 TFC3 patients, respectively, all being index patients. When applying prolonged terminal activation duration additionally to TFC on depolarization/conduction abnormalities, 14 (42%) TFC3 patients fulfilled ARVD/C diagnosis. Results were not significantly different between mutation carriers and noncarriers. Conclusions—Adding the newly proposed criteria to current TFC for ARVD/C will improve identification of affected individuals importantly, independent of outcome of DNA analyses.

Pulmonary vein antrum isolation leads to a significant decrease of left atrial size

AIMS Pulmonary vein antrum isolation (PVAI) is an effective treatment for atrial fibrillation (AF); however, its impact on left atrial (LA) size is unknown. This study evaluates the impact of PVAI on LA size, and whether LA size differs between patients with a successful outcome and patients with AF recurrences. METHODS AND RESULTS Seventy-nine patients (76% male, mean age 56 ± 8 years) with symptomatic, drug refractory AF (70% paroxysmal, 30% persistent/permanent) underwent radiofrequency PVAI. Ablation lesions were created encircling right and left pulmonary venous ostia in pairs. The endpoint was complete isolation of all pulmonary veins. Magnetic resonance imaging was performed before and 4 months after PVAI and LA volume was measured by manually tracing the LA area. Clinical follow-up was at 1, 3, 6, 12, and 24 months. Rhythm status was determined by history, electrocardiogram, and 48 h Holter monitoring. After a mean follow-up of 12 ± 5 months, 62 patients (78%) were free of AF (72% without antiarrhythmic drugs). In the total group, LA volume decreased from 104 ± 27 mL to 91 ± 25 mL, P < 0.001. Patients with a successful outcome showed a decrease in LA volume of 103 ± 27 mL to 89 ± 24 mL, P < 0.001. Among patients with AF recurrences, LA volume decreased from 105 ± 29 mL to 95 ± 27 mL, P = 0.012. No significant difference was seen between the change in LA volume in both subgroups, P = 0.27. CONCLUSION Pulmonary vein antrum isolation in patients with AF resulted in a significant decrease of LA size. There was no relation between the decrease in LA size and the recurrence of AF after PVAI.