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1.
Eur Heart J Case Rep ; 3(1): ytz008, 2019 Mar.
Article in English | MEDLINE | ID: mdl-31020253

ABSTRACT

BACKGROUND: Peri-procedural transoesophageal echocardiography (TOE) is important in monitoring and minimizing major complications during pacing lead extraction. It is a widely accepted precautionary measure, especially in extractions considered to be higher risk. Pacing lead extraction may be challenging, and it is associated with significant risk of major bleeding from vascular trauma. CASE SUMMARY: We present a case of an 87-year-old woman who had an extraction of a ventricular pacing lead that had perforated to an extra-cardiac location, most likely to the left pleural space. Peri-procedural TOE was used as a precaution. The entire pacing lead was successfully extracted with gentle traction using standard equipment (mechanical technique). Extraction was followed by development of pneumomediastinum and a left pleural effusion, initially attributed to pulmonary injury from the pacing lead but which proved to be related to oesophageal injury from the TOE. DISCUSSION: Transoesophageal echocardiography-related complications are uncommon but should be considered in cases of unexpected post-procedural deterioration. Clinical deterioration after a seemingly uneventful procedure should prompt a thorough case review. A systematic approach should be applied to identify the offending cause and enable corrective measures to be undertaken. This case report is an important reminder to all operators utilizing TOE for peri-procedural purposes that this precautionary measure itself also independently exposes the patient to additional risk.

2.
Nat Commun ; 8(1): 1258, 2017 11 02.
Article in English | MEDLINE | ID: mdl-29097735

ABSTRACT

AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αßγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current (I f) and ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ release. In contrast, loss of γ2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior.


Subject(s)
AMP-Activated Protein Kinases/genetics , Bradycardia/genetics , Calcium/metabolism , Heart Rate/genetics , Sarcolemma/metabolism , Sinoatrial Node/metabolism , Adult , Animals , Bradycardia/metabolism , Electrocardiography, Ambulatory , Exercise , Heart/diagnostic imaging , Humans , Magnetic Resonance Imaging, Cine , Magnetic Resonance Spectroscopy , Mice , Microscopy, Electron, Transmission , Mutation , Myocardium/metabolism , Myocardium/pathology , Myocardium/ultrastructure , Physical Conditioning, Animal , Physical Endurance , Ryanodine Receptor Calcium Release Channel/metabolism , Sinoatrial Node/pathology
3.
JACC Clin Electrophysiol ; 3(5): 514-521, 2017 May.
Article in English | MEDLINE | ID: mdl-29759609

ABSTRACT

OBJECTIVES: This study assessed the feasibility of intentional coronary venous perforation and exit with subsequent pericardial carbon dioxide (CO2) insufflation as a novel method for assisting subxiphoid pericardial puncture in the setting of epicardial mapping and ablation for ventricular tachycardia. The technique required that coronary venous perforation would not lead to significant bleeding. BACKGROUND: Widespread adoption of first-line endoepicardial ventricular tachycardia ablation has not been taken up because of the risk of lacerating coronary vessels and puncturing the right ventricle with direct subxiphoid puncture. METHODS: A lateral branch of the coronary sinus was subselected using a diagnostic JR4 coronary catheter inside a steerable sheath, via femoral access, and a distal branch then perforated intentionally using a high tip load 0.014-inch angioplasty wire. Either a microcatheter or over-the-wire balloon was then passed over this into the pericardial space, allowing up to 150 ml of pericardial CO2 insufflation, which allowed direct visualization of subxiphoid anterior pericardial access using a microneedle technique. RESULTS: Intentional coronary vein exit was achieved in all 12 patients. In 1 patient, this confirmed widespread pericardial adhesions and therefore only endocardial VT ablation was undertaken. The other patients underwent successful pericardial CO2 insufflation and subxiphoid access allowing epicardial ventricular mapping and ablation. The immediate pericardial aspirate was dry or contained serous fluid in all but 1 patient. CONCLUSIONS: We report the first human transcoronary vein exit procedure. Coronary vein exit and subsequent percutaneous subxiphoid anterior access using a microneedle puncture after CO2 pericardial insufflation can be achieved reliably and safely.


Subject(s)
Catheter Ablation/methods , Coronary Vessels/surgery , Insufflation/methods , Tachycardia, Ventricular/surgery , Adult , Aged , Aged, 80 and over , Carbon Dioxide/administration & dosage , Cardiomyopathies/complications , Epicardial Mapping/methods , Female , Humans , Insufflation/instrumentation , Male , Middle Aged , Myocardial Ischemia/complications , Pericardium/surgery , Punctures/instrumentation , Punctures/methods , Tachycardia, Ventricular/complications , Xiphoid Bone
6.
Hypertension ; 64(3): 523-9, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24914196

ABSTRACT

ATP-sensitive potassium channels (KATP) regulate a range of biological activities by coupling membrane excitability to the cellular metabolic state. In particular, it has been proposed that KATP channels and specifically, the channel subunits Kir6.1 and SUR2B, play an important role in the regulation of vascular tone. However, recent experiments have suggested that KATP channels outside the vascular smooth muscle compartment are the key determinant of the observed behavior. Thus, we address the importance of the vascular smooth muscle KATP channel, using a novel murine model in which it is possible to conditionally delete the Kir6.1 subunit. Using a combination of molecular, electrophysiological, in vitro, and in vivo techniques, we confirmed the absence of Kir6.1 and KATP currents and responses specifically in smooth muscle. Mice with conditional deletion of Kir6.1 showed no obvious arrhythmic phenotype even after provocation with ergonovine. However, these mice were hypertensive and vascular smooth muscle cells failed to respond to vasodilators in a normal fashion. Thus, Kir6.1 underlies the vascular smooth muscle KATP channel and has a key role in vascular reactivity and blood pressure control.


Subject(s)
Blood Pressure/physiology , KATP Channels/physiology , Muscle, Smooth, Vascular/physiology , Animals , Calcitonin Gene-Related Peptide/pharmacology , Disease Models, Animal , Hypertension/physiopathology , In Vitro Techniques , KATP Channels/deficiency , KATP Channels/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Patch-Clamp Techniques , Pinacidil/pharmacology , Vasodilator Agents/pharmacology
7.
Dev Biol ; 369(2): 277-85, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22790009

ABSTRACT

The sympathetic nervous system (SNS) arises from neural crest (NC) cells during embryonic development and innervates the internal organs of vertebrates to modulate their stress response. NRP1 and NRP2 are receptors for guidance cues of the class 3 semaphorin (SEMA) family and are expressed in partially overlapping patterns in sympathetic NC cells and their progeny. By comparing the phenotypes of mice lacking NRP1 or its ligand SEMA3A with mice lacking NRP1 in the sympathetic versus vascular endothelial cell lineages, we demonstrate that SEMA3A signalling through NRP1 has multiple cell-autonomous roles in SNS development. These roles include neuronal cell body positioning, neuronal aggregation and axon guidance, first during sympathetic chain assembly and then to regulate the innervation of the heart and aorta. Loss of NRP2 or its ligand SEMA3F impaired sympathetic gangliogenesis more mildly than loss of SEMA3A/NRP1 signalling, but caused ectopic neurite extension along the embryonic aorta. The analysis of compound mutants lacking SEMA3A and SEMA3F or NRP1 and NRP2 in the SNS demonstrated that both signalling pathways cooperate to organise the SNS. We further show that abnormal sympathetic development in mice lacking NRP1 in the sympathetic lineage has functional consequences, as it causes sinus bradycardia, similar to mice lacking SEMA3A.


Subject(s)
Neurogenesis/physiology , Neuropilin-1/metabolism , Neuropilin-2/metabolism , Sympathetic Nervous System/embryology , Sympathetic Nervous System/metabolism , Animals , Aorta/embryology , Aorta/innervation , Aorta/metabolism , Axons/metabolism , Cell Lineage , Female , Fetal Heart/embryology , Fetal Heart/innervation , Fetal Heart/metabolism , Ganglia, Sympathetic/growth & development , Ganglia, Sympathetic/metabolism , Male , Membrane Proteins/deficiency , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Knockout , Mice, Transgenic , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neural Crest/embryology , Neural Crest/metabolism , Neurites/metabolism , Neurogenesis/genetics , Neuropilin-1/deficiency , Neuropilin-1/genetics , Neuropilin-2/deficiency , Neuropilin-2/genetics , Pregnancy , Semaphorin-3A/deficiency , Semaphorin-3A/genetics , Semaphorin-3A/metabolism , Signal Transduction , Sympathetic Nervous System/cytology
8.
Circ Res ; 111(2): e19-31, 2012 Jul 06.
Article in English | MEDLINE | ID: mdl-22647876

ABSTRACT

RATIONALE: Nkx2.5 is one of the most widely studied cardiac-specific transcription factors, conserved from flies to man, with multiple essential roles in both the developing and adult heart. Specific dominant mutations in NKX2.5 have been identified in adult congenital heart disease patients presenting with conduction system anomalies and recent genome-wide association studies implicate the NKX2.5 locus, as causative for lethal arrhythmias ("sudden cardiac death") that occur at a frequency in the population of 1 in 1000 per annum worldwide. Haploinsufficiency for Nkx2.5 in the mouse phenocopies human conduction disease pathology yet the phenotypes, described in both mouse and man, are highly pleiotropic, implicit of unknown modifiers and/or factors acting in epistasis with Nkx2.5/NKX2.5. OBJECTIVE: To identify bone fide upstream genetic modifier(s) of Nkx2.5/NKX2.5 function and to determine epistatic effects relevant to the manifestation of NKX2.5-dependent adult congenital heart disease. METHODS AND RESULTS: A study of cardiac function in prospero-related homeobox protein 1 (Prox1) heterozygous mice, using pressure-volume loop and micromannometry, revealed rescue of hemodynamic parameters in Nkx2.5(Cre/+); Prox1(loxP/+) animals versus Nkx2.5(Cre/+) controls. Anatomic studies, on a Cx40(EGFP) background, revealed Cre-mediated knock-down of Prox1 restored the anatomy of the atrioventricular node and His-Purkinje network both of which were severely hypoplastic in Nkx2.5(Cre/+) littermates. Steady state surface electrocardiography recordings and high-speed multiphoton imaging, to assess Ca(2+) handling, revealed atrioventricular conduction and excitation-contraction were also normalized by Prox1 haploinsufficiency, as was expression of conduction genes thought to act downstream of Nkx2.5. Chromatin immunoprecipitation on adult hearts, in combination with both gain and loss-of-function reporter assays in vitro, revealed that Prox1 recruits the corepressor HDAC3 to directly repress Nkx2.5 via a proximal upstream enhancer as a mechanism for regulating Nkx2.5 function in adult cardiac conduction. CONCLUSIONS: Here we identify Prox1 as a direct upstream modifier of Nkx2.5 in the maintenance of the adult conduction system and rescue of Nkx2.5 conduction disease phenotypes. This study is the first example of rescue of Nkx2.5 function and establishes a model for ensuring electrophysiological function within the adult heart alongside insight into a novel Prox1-HDAC3-Nkx2.5 signaling pathway for therapeutic targeting in conduction disease.


Subject(s)
Epistasis, Genetic/genetics , Heart Conduction System/physiopathology , Heart Diseases/genetics , Heart Diseases/metabolism , Histone Deacetylases/genetics , Homeodomain Proteins/genetics , Phenotype , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics , Animals , Heart Diseases/physiopathology , Histone Deacetylases/physiology , Homeobox Protein Nkx-2.5 , Homeodomain Proteins/physiology , Mice , Mice, Transgenic , NIH 3T3 Cells , Transcription Factors/physiology , Tumor Suppressor Proteins/physiology
9.
Eur Heart J ; 33(15): 1942-53, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22240500

ABSTRACT

AIMS: Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin. METHODS AND RESULTS: Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S(1)-S(2) protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation-repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P = 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution. CONCLUSION: Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction-repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Desmoplakins/genetics , Mutation/genetics , Adult , Aged , Animals , Case-Control Studies , Desmoplakins/deficiency , Electrocardiography , Female , Gene Deletion , Heart Conduction System/physiology , Heterozygote , Humans , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction , Sodium Channels/physiology , Young Adult
10.
J Mol Cell Cardiol ; 47(1): 133-41, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19376125

ABSTRACT

Elevated levels of the cardiac transcription factor Hand1 have been reported in several adult cardiac diseases but it is unclear whether this change is itself maladaptive with respect to heart function. To test this possibility, we have developed a novel, inducible transgenic system, and used it to overexpress Hand1 in adult mouse hearts. Overexpression of Hand1 in the adult mouse heart leads to mild cardiac hypertrophy and a reduction in life expectancy. Treated mice show no significant fibrosis, myocyte disarray or congestive heart failure, but have a greatly reduced threshold for induced ventricular tachycardia, indicating a predisposition to cardiac arrhythmia. Within 48 h, they show a significant loss of connexin43 protein from cardiac intercalated discs, with increased intercalated disc beta-catenin expression at protein and RNA levels. These changes are sustained during prolonged Hand1 overexpression. We propose that cardiac overexpression of Hand1 offers a useful mouse model of arrhythmogenesis and elevated HAND1 may provide one of the molecular links between the failing heart and arrhythmia.


Subject(s)
Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/metabolism , Basic Helix-Loop-Helix Transcription Factors/physiology , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Cardiomegaly/genetics , Cardiomegaly/metabolism , Electrophysiology , Heart Failure/genetics , Heart Failure/metabolism , Humans , Immunohistochemistry , In Vitro Techniques , Male , Mice , Mice, Transgenic , Reverse Transcriptase Polymerase Chain Reaction
11.
Curr Opin Pharmacol ; 9(2): 154-9, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19109070

ABSTRACT

Putative druggable targets to selectively enhance cardiac conduction can be considered from the level of the ion channels determining the initiation and duration of the cardiac action potential to the gap junction proteins responsible for optimal cellular electrical coupling. Nature has provided a number of inherited disorders of conduction, the pathophysiology of which offer novel insights into future therapeutic targets. This review will focus upon the potential cellular and molecular targets for drug development based upon our knowledge of their pathophysiological impact.


Subject(s)
Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/therapeutic use , Heart/physiology , Heart/physiopathology , Animals , Ankyrins/physiology , Brugada Syndrome/drug therapy , Brugada Syndrome/physiopathology , Drug Delivery Systems , GTP-Binding Proteins/physiology , Gap Junctions/drug effects , Gap Junctions/physiology , Heart Conduction System/physiology , Humans , Ion Channels/drug effects , Ion Channels/physiopathology , Long QT Syndrome/drug therapy , Myocardium/metabolism , Potassium Channels/physiology
12.
Obstet Gynecol ; 105(5 Pt 2): 1218-21, 2005 May.
Article in English | MEDLINE | ID: mdl-15863588

ABSTRACT

BACKGROUND: A large luteinized follicular cyst can rupture or twist during pregnancy. However, in the absence of those complications a simple ovarian cyst can often be managed conservatively, provided that sonographic evaluation of the cyst is benign. Rapid growth of a simple follicular cyst is rare but may occasionally complicate pregnancy. CASE: A 25-year-old primigravida had a simple-appearing adnexal mass detected by sonogram early in pregnancy. She was followed with serial sonograms. Because of the clear sonolucent appearance of the mass and the patient's preference, a conservative management was elected. The cyst grew in size as her pregnancy progressed, became symptomatic, and necessitated surgical intervention. Cystectomy and cesarean delivery at 36+ weeks relieved the symptoms and achieved delivery of a healthy infant. CONCLUSION: Solitary luteinized follicular cysts of pregnancy have the potential to grow to a very large size and create complications related to their size alone. Conservative management of simple adnexal cysts in pregnancy, based on their sonographic appearance, can avoid risks of abdominal surgery in the second trimester of pregnancy, but in the third trimester, a large cyst can create significant complications requiring surgical intervention.


Subject(s)
Ovarian Cysts/surgery , Ovarian Follicle/surgery , Pregnancy Complications/surgery , Pregnancy Outcome , Adult , Cesarean Section , Female , Follow-Up Studies , Gestational Age , Humans , Ovarian Cysts/diagnostic imaging , Ovarian Follicle/pathology , Pregnancy , Pregnancy Complications/diagnostic imaging , Pregnancy Complications/pathology , Risk Assessment , Severity of Illness Index , Treatment Outcome , Ultrasonography, Prenatal
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