Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome.

AMPK (adenosine monophosphate-activated protein kinase) is phosphorylated (AMPK-P) in response to low energy through allosteric activation by Adenosine mono- or diphosphate (AMP/ADP). Folliculin (FLCN) and the FLCN-interacting proteins 1 and 2 (FNIP1, 2) modulate AMPK. FNIP1 deficiency patients have a AMPK-P gain of function phenotype with hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome, myopathy of skeletal muscles and combined immunodeficiency.

Unusual variants of pre-excitation: From anatomy to ablation: Part I-Understanding the anatomy of the variants of ventricular pre-excitation.

The famous quotation of Winston Churchill, made in his radio broadcast of 1939 regarding Russia's next move, specifically "A riddle wrapped up in a mystery, inside an enigma," perfectly fits the current understanding of unusual accessory atrioventricular pathways, including the variants producing ventricular pre-excitation. It was many decades after their original descriptions that we came better to begin to understand most of their structure-function relationships. Their mysterious pathophysiology was sometimes unveiled after invasive treatments, such as surgical ablation of the atrioventricular conduction axis instead of the accessory pathway itself. Speculations made on this basis have largely been validated by subsequent clinical experience. Most of the names suggested for description of the pathways have stood well the test of time. For some of them, however, this is not the case, with the initial names becoming confusing. In a series of reviews, we re-visit those accessory pathways producing ventricular pre-excitation other than classical Wolff-Parkinson-White syndrome. To set the scene, in this initial review, we describe the development and anatomy of the normal atrioventricular conduction axis, along with the insulating tissues of the atrioventricular junctions. We have sought to illustrate our explanations by using virtual dissection of computerized tomographic datasets, since they retain the intact heart within the setting of the body. These images illustrate well the value of attitudinally appropriate terminology. Thereafter, we discuss the electrophysiological manifestations of the abnormal anatomical pathways which provide the potential for both accessory atrioventricular and intraventricular conduction.

Epicardium-derived cells in development of annulus fibrosis and persistence of accessory pathways.

BACKGROUND: The developmental mechanisms underlying the persistence of myocardial accessory atrioventricular pathways (APs) that bypass the annulus fibrosis are mainly unknown. In the present study, we investigated the role of epicardium-derived cells (EPDCs) in annulus fibrosis formation and the occurrence of APs. METHODS AND RESULTS: EPDC migration was mechanically inhibited by in ovo microsurgery in quail embryos. In ovo ECGs were recorded in wild-type (n=12) and EPDC-inhibited (n=12) hearts at Hamburger-Hamilton (HH) stages 38 to 42. Subsequently, in these EPDC-inhibited hearts (n=12) and in additional wild-type hearts (n=45; HH 38-42), ex ovo extracellular electrograms were recorded. Electrophysiological data were correlated with differentiation markers for cardiomyocytes (MLC2a) and fibroblasts (periostin). In ovo ECGs showed significantly shorter PR intervals in EPDC-inhibited hearts (45+/-10 ms) than in wild-type hearts (55+/-8 ms, 95% CI 50 to 60 ms, P=0.030), whereas the QRS durations were significantly longer in EPDC-inhibited hearts (29+/-14 versus 19+/-2 ms, 95% CI 18 to 21 ms, P=0.011). Furthermore, ex ovo extracellular electrograms (HH 38-42) displayed base-first ventricular activation in 44% (20/45) of wild-type hearts, whereas in all EPDC-inhibited hearts (100%, 12/12), the ventricular base was activated first (P<0.001). Small periostin- and MLC2a-positive APs were found mainly in the posteroseptal region of both wild-type and EPDC-inhibited hearts. Interestingly, in all (n=10) EPDC-inhibited hearts, additional large periostin-negative and MLC2a-positive APs were found in the right and left lateral free wall coursing through marked isolation defects in the annulus fibrosis until the last stages of embryonic development. CONCLUSIONS: EPDCs play an important role in annulus fibrosis formation. EPDC outgrowth inhibition may result in marked defects in the fibrous annulus with persistence of large APs, which results in ventricular preexcitation on ECG. These APs may provide a substrate for postnatally persistent reentrant arrhythmias.

Optical imaging of spiral waves: pharmacological modification of spiral-type excitations in a 2-dimensional layer of ventricular myocardium.

Differential effects of sodium channel blockers, an I(Kr) blocker (nifekalant) and amiodarone on the spiral-type reentry, were investigated in rabbit hearts by using a high-resolution optical mapping system. Two-dimensional subepicardial layer of left ventricular myocardium with uniform anisotropy was prepared by endocardial cryoablation. During ventricular tachycardia (VT) elicited by cross-field stimulation, spiral-type excitations rotating around functional block lines (FBLs) were visualized. All the sodium channel blockers stabilized rotors; VT duration was prolonged in association with increases of FBLs and VT cycle length. The rotors in the presence of nifekalant were characterized by large meandering, long FBLs, and frequent front-tail interactions generating wave breaks. Amiodarone (acute application) increased FBLs and VT cycle length, but shortened the VT duration with minimal front-tail interaction. These results suggest that multifaceted drug action on both depolarization and repolarization may be required for the early termination of spiral-type reentry without causing breakup of rotors.

Ventricular preexcitation in children and young adults: atrial myocarditis as a possible trigger of sudden death.

BACKGROUND: Sudden death (SD) in ventricular preexcitation (VP) syndrome is believed to be the result of atrial fibrillation with rapid ventricular response over the accessory pathway. Previous reports are anecdotal and often lack autopsy validation. METHODS AND RESULTS: Prevalence and clinicopathological features of VP were investigated in a series of 273 SDs in children and young adults (aged

Late onset postpartum eclampsia without pre-eclamptic prodromi: clinical and neuroradiological presentation in two patients.

In two patients eclampsia started 9 days postpartum. Headache and visual disturbances preceded seizures but none of the classic pre-eclamptic signs oedema, proteinuria, and hypertension were present until shortly before seizure onset. Brain herniation (patient 1) and status epilepticus (patient 2) necessitated neurointensive care management. Brain MRI initially showed only frontal sulcal effacement in one patient but later showed white matter hyperintensities on T2 weighted images and a previously undescribed pattern of cortical-subcortical postgadolinium enhancement on T1 weighted images in both. Neurological deficits and MRI findings were reversed with therapy in both patients. It is concluded that late postpartum eclampsia can manifest without classic prodromi and that characteristic MRI findings may lag behind clinical manifestation.

Anatomy of the atrioventricular junctions with regard to ventricular preexcitation.

In the normal heart, the atrioventricular junctions surround the orifices of the mitral and tricuspid valves. The septal area of the junctions is much smaller than generally thought, being made up of the fibrous membranous septum and the muscular atrioventricular septum. The left atrioventricular junction gives the potential for muscular atrioventricular contiguities only in relation to the mural leaflet of the mitral valve. The right junction extends from the area posterior to the muscular atrioventricular septum to the supraventricular crest of the right ventricle. Anomalous pathways for conduction, which produce pre-excitation, can be found anywhere within these atrioventricular junctions. The pathways usually are the muscular accessory connections responsible for the Wolff-Parkinson-White syndrome, which can exist in the left, septal, or right junctions. Specific muscular connections are found in the presence of Purkinje cell tumors, diverticulums of the coronary sinus, or when taking origin from nodes of Kent at the acute margin of the ventricular mass. The latter connections are responsible for most examples of so-called Mahaim conduction, and are also described as atriofascicular tracts. The true Mahaim fibers are best described as nodoventricular or fasciculo-ventricular connections, while the pathway previously labelled as atriofascicular by the European Study Group is now best distinguished as an atrio-Hisian tract. The slow and fast pathways into the atrioventricular node are composed or ordinary atrial myocardium, the orientation of the fibers probably producing preferential conduction.

Recognizing and managing permanent junctional reciprocating tachycardia in the catheter ablation era.

There is general agreement that an orthodromic AV reentry using a concealed slow conducting accessory pathway as the retrograde limb of the circuit constitutes the underlying mechanism of the permanent form of junctional reciprocating tachycardia (PJRT). In this arrhythmia, the standard ECG typically shows a "long R-P' tachycardia" with retrograde P wave negative in the inferior leads. A careful electrophysiologic evaluation is necessary to confirm the diagnosis of PJRT. Recent reports have demonstrated that the radiofrequency current catheter technique provides a safe and highly effective therapeutic tool for patients suffering from this arrhythmia.

Successful and unsuccessful sites of radiofrequency catheter ablation of accessory atrioventricular connections.

Local electrograms from 47 consecutive patients who underwent successful radiofrequency catheter ablation of 49 accessory atrioventricular (AV) connections were analyzed. One hundred twenty-two local electrograms were recorded at 27 successful and 95 unsuccessful sites immediately before radiofrequency catheter ablation of 27 manifest accessory AV connections during preexcited sinus rhythm or atrial pacing. Continuous electric activity was found in 96% of successful sites versus 71% of unsuccessful sites (p < 0.01). Possible accessory pathway (AP) potentials were present only in 15% of successful and 2% of unsuccessful sites, respectively (p < 0.05). All measured time intervals were significantly shorter for successful sites as compared to unsuccessful sites of ablation of manifest accessory AV connections. Unipolar electrograms from the tip of the ablation catheter of each successful and unsuccessful ablation site were available for the last 16 patients with manifest accessory AV connections. A PQS pattern of the unipolar electrogram was associated with a higher success rate, whereas a PrS pattern never resulted in successful ablation of an accessory AV connection. Multivariate logistic regression analysis of the local electrogram characteristics of rapidly conducting, concealed accessory AV connections revealed the interval between the onset of the local ventricular and atrial electrogram (VoAo interval) as the only independent variable associated with successful sites for radiofrequency catheter ablation. The only study patient with a slowly conducting, concealed accessory AV connection underwent successful ablation with the first lesion of radiofrequency energy at the site with the shortest VoAo interval. We conclude that (1) the shortest local AV intervals and local ventricular electrograms preceding the earliest onset of the delta wave in any surface lead are predictive of successful ablation of manifest accessory AV connections; (2) the shortest local VA intervals during orthodromic AV reentry tachycardia or right ventricular pacing are predictive of successful ablation of concealed accessory AV connections; and (3) unipolar recordings from the tip of the ablation catheter should be recorded routinely during mapping of manifest accessory AV connections to identify appropriate target sites for radiofrequency energy applications.

Anatomy, histology, and pathology of the cardiac conduction system--Part IV.

Metastatic tumor involvement of the heart as a basis for the genesis of various cardiac arrhythmias is reviewed. The morphologic basis of pre-excitation syndromes and right ventricular dysplasia are also reviewed.

[The inheritance of disorders of heart rhythm in 3 generations (a family history)]. / Nasledovanie narushenii serdechnogo ritma v trekh pokoleniiakh (opisanie sem'i).

The paper is concerned with the description of a family where father suffered from right bundle-branch block, his daughter--from Wolff-Parkinson-White syndrome (type B) with attacks of supraventricular paroxysmal tachycardia, one granddaughter--from Clerc-Lévy-Cristesco syndrome with attacks of sinus tachycardia, the two other granddaughters had a short P-R interval. Medicogenetic investigation revealed not only the inheritance of myocardial conduction changes of autosomal dominant type but also of syndromes characterizing primary dysplasia of connective tissue in 3 generations.

The pathologic basis of cardiac arrhythmias.

Besides the anatomoclinical correlates of disturbances in impulse formation and conduction, this article also considers the three mechanisms now known to underlie tachyarrhythmias: focally enhanced automaticity, triggered activity, and, in particular, reentry.