Search Results (13)

Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29–96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment. Full article

Multifocal ectopic Purkinje-related premature contractions (MEPPC) syndrome is a recently recognized rare form of arrhythmia involving the entire His–Purkinje system and often coinciding with dilated cardiomyopathy (DCM). Certain variants in the SCN5A gene may be linked to MEPPC syndrome. We present a case of a 32-year-old Caucasian female who exhibited a high burden of premature ventricular contractions (PVCs) and non-sustained episodes of ventricular tachycardia (NSVT) with an alternating QRS pattern, and who was resistant to traditional medical therapy and radiofrequency catheter ablation (RFCA), necessitating implantation of a cardioverter-defibrillator (ICD). A positive family history (father’s death at the age of 40 years) and the rapid deterioration of left ventricular function parameters echocardiographically during recurrent arrhythmic episodes raised concern about a potentially complex disease scenario. Genetic testing revealed a heterozygous variant of the SCN5A gene, c.2440C>T, p.(Arg814Trp), confirming the diagnosis of MEPPC syndrome. Treatment with a combination of class I antiarrhythmic drugs, flecainide and mexiletine, concomitant with beta blockers, led to symptomatic improvement, a reduction of PVCs (from 66 491 (44%) to 858 (1%)), and the restoration of left ventricular function (LV EF from 44% to 53%). A lack of defined diagnostic criteria hampers timely diagnosis, leading to ineffective interventions and delayed initiation of treatment with antiarrhythmic drugs. MEPPC patients remain at significant risk for severe heart failure and sudden cardiac death. Our clinical case report underscores the importance of accurate and timely diagnosis, which allows effective treatment with a combination of antiarrhythmic drugs and mitigates the risk associated with MEPPC syndrome. Full article

The human heart controls blood flow, and therewith enables the adequate supply of oxygen and nutrients to the body. The correct function of the heart is coordinated by the interplay of different cardiac cell types. Thereby, one can distinguish between cells of the working myocardium, the pace-making cells in the sinoatrial node (SAN) and the conduction system cells in the AV-node, the His-bundle or the Purkinje fibres. Tissue-engineering approaches aim to generate hiPSC-derived cardiac tissues for disease modelling and therapeutic usage with a significant improvement in the differentiation quality of myocardium and pace-making cells. The differentiation of cells with cardiac conduction system properties is still challenging, and the produced cell mass and quality is poor. Here, we describe the generation of cardiac cells with properties of the cardiac conduction system, called conduction system-like cells (CSLC). As a primary approach, we introduced a CrispR-Cas9-directed knockout of the NKX2-5 gene in hiPSC. NKX2-5-deficient hiPSC showed altered connexin expression patterns characteristic for the cardiac conduction system with strong connexin 40 and connexin 43 expression and suppressed connexin 45 expression. Application of differentiation protocols for ventricular- or SAN-like cells could not reverse this connexin expression pattern, indicating a stable regulation by NKX2-5 on connexin expression. The contraction behaviour of the hiPSC-derived CSLCs was compared to hiPSC-derived ventricular- and SAN-like cells. We found that the contraction speed of CSLCs resembled the expected contraction rate of human conduction system cells. Overall contraction was reduced in differentiated cells derived from NKX2-5 knockout hiPSC. Comparative transcriptomic data suggest a specification of the cardiac subtype of CSLC that is distinctly different from ventricular or pacemaker-like cells with reduced myocardial gene expression and enhanced extracellular matrix formation for improved electrical insulation. In summary, knockout of NKX2-5 in hiPSC leads to enhanced differentiation of cells with cardiac conduction system features, including connexin expression and contraction behaviour. Full article

The ventricular conduction or His-Purkinje system (VCS) mediates the rapid propagation and precise delivery of electrical activity essential for the synchronization of heartbeats. Mutations in the transcription factor Nkx2-5 have been implicated in a high prevalence of developing ventricular conduction defects or arrhythmias with age. Nkx2-5 heterozygous mutant mice reproduce human phenotypes associated with a hypoplastic His-Purkinje system resulting from defective patterning of the Purkinje fiber network during development. Here, we investigated the role of Nkx2-5 in the mature VCS and the consequences of its loss on cardiac function. Neonatal deletion of Nkx2-5 in the VCS using a Cx40-CreERT2 mouse line provoked apical hypoplasia and maturation defects of the Purkinje fiber network. Genetic tracing analysis demonstrated that neonatal Cx40-positive cells fail to maintain a conductive phenotype after Nkx2-5 deletion. Moreover, we observed a progressive loss of expression of fast-conduction markers in persistent Purkinje fibers. Consequently, Nkx2-5-deleted mice developed conduction defects with progressively reduced QRS amplitude and RSR’ complex associated with higher duration. Cardiac function recorded by MRI revealed a reduction in the ejection fraction in the absence of morphological changes. With age, these mice develop a ventricular diastolic dysfunction associated with dyssynchrony and wall-motion abnormalities without indication of fibrosis. These results highlight the requirement of postnatal expression of Nkx2-5 in the maturation and maintenance of a functional Purkinje fiber network to preserve contraction synchrony and cardiac function. Full article

The electrical depolarization of the heart passes through various structures of the cardiac conduction system, which modify its conduction to different extents. In this study, we investigated the relationship between the atrioventricular conduction time (AV interval) and its contributors, the atrioventricular node (AVN) and the His–Purkinje system (HPS), as represented by the AH and HV intervals, respectively. We also compared sex differences in these intervals and their relations. Resting intracardiac tracings lasting 5 min were obtained from 64 patients (33 women) during an invasive electrophysiological study. The aforementioned intervals were measured for all consecutive beats. The mean AH interval was 85.9 ms, HV 43.7 ms, and AV 129.6 ms. Men had longer AH (80.0 vs. 65.9 ms), HV (38.4 vs. 35.3 ms), and AV intervals (124.7 vs. 108.5 ms) than women. The AV intervals were linearly correlated with AH intervals in all patients (r² = 0.65). No significant correlation was found between AV and HV intervals in all patients (r² = 0.05). There were no sex differences in these associations. Our results suggest that the atrioventricular conduction time depends mainly on the conduction through the AVN and less on the HPS. These relations are similar in both sexes, although men had longer conduction times through the AVN, HPS, and total atrioventricular conduction time. Full article

Background: Bundle branch re-entrant ventricular tachycardia (BBRVT) is a monomorphic ventricular arrhythmia with wide QRS complexes caused by re-entrant tachycardia between both bundle branches. BBRVT can occur in a variety of cardiac pathologies with His–Purkinje system (HPS) conduction abnormalities such as dilated cardiomyopathy, coronary artery disease, hypertrophic cardiomyopathy, valvular heart disease and even after aortic valve surgery. Case report: A 62-year-old male patient with an ischemic cardiomyopathy and implantable cardioverter defibrillator (ICD) underwent minimal invasive aortic valve replacement (Yil-AVR) and coronary artery bypass graft (CABG). He was remitted a week later because of relapsing sustained ventricular tachycardia (VT). Electrocardiogram showed a wide QRS tachycardia, which was remarkably similar to the patient’s sinus rhythm. Analysis of ICD revealed the presence of BBRVT. Catheter ablation of the right bundle branch (RBB) was performed. He is currently in clinical follow-up and no reoccurrence of VT has been recorded so far. Conclusion: Patients with known cardiomyopathy can develop BBRVT early after cardiac surgery. To our knowledge, this is the first time that BBRVT occurred after Yil-AVR. Full article

The rapid propagation of electrical activity through the ventricular conduction system (VCS) controls spatiotemporal contraction of the ventricles. Cardiac conduction defects or arrhythmias in humans are often associated with mutations in key cardiac transcription factors that have been shown to play important roles in VCS morphogenesis in mice. Understanding of the mechanisms of VCS development is thus crucial to decipher the etiology of conduction disturbances in adults. During embryogenesis, the VCS, consisting of the His bundle, bundle branches, and the distal Purkinje network, originates from two independent progenitor populations in the primary ring and the ventricular trabeculae. Differentiation into fast-conducting cardiomyocytes occurs progressively as ventricles develop to form a unique electrical pathway at late fetal stages. The objectives of this review are to highlight the structure–function relationship between VCS morphogenesis and conduction defects and to discuss recent data on the origin and development of the VCS with a focus on the distal Purkinje fiber network. Full article

His bundle pacing is performed at our centre since 2017 and has been adopted in tertiary centres accross Switzerland. It provides true physiological stimulation, thereby avoiding avoiding the detrimental effects of right ventricular pacing. However, relatively high incidences of lead revision and increases in capture thresholds have been reported. An alternative technique, practiced at our centre since 2020, is left bundle area pacing, which provides excellent electrical parameters. However, long-term data on lead performance and extractibility are lacking. Furthermore, although these techniques are conceptually very attractive, there is a dire need for studies randomizing conduction system pacing with right ventricular / biventricular pacing, before they can be considered as becoming the gold standard. Full article

The mammalian ventricular myocardium forms a functional syncytium due to flow of electrical current mediated in part by gap junctions localized within intercalated disks. The connexin (Cx) subunit of gap junctions have direct and indirect roles in conduction of electrical impulse from the cardiac pacemaker via the cardiac conduction system (CCS) to working myocytes. Cx43 is the dominant isoform in these channels. We have studied the distribution of Cx43 junctions between the CCS and working myocytes in a transgenic mouse model, which had the His-Purkinje portion of the CCS labeled with green fluorescence protein. The highest number of such connections was found in a region about one-third of ventricular length above the apex, and it correlated with the peak proportion of Purkinje fibers (PFs) to the ventricular myocardium. At this location, on the septal surface of the left ventricle, the insulated left bundle branch split into the uninsulated network of PFs that continued to the free wall anteriorly and posteriorly. The second peak of PF abundance was present in the ventricular apex. Epicardial activation maps correspondingly placed the site of the first activation in the apical region, while some hearts presented more highly located breakthrough sites. Taken together, these results increase our understanding of the physiological pattern of ventricular activation and its morphological underpinning through detailed CCS anatomy and distribution of its gap junctional coupling to the working myocardium. Full article

Robert H. Anderson is one of the most important and accomplished cardiac anatomists of the last decades, having made major contributions to our understanding of the anatomy of normal hearts and the pathologies of acquired and congenital heart diseases. While cardiac anatomy as a research discipline has become largely subservient to molecular biology, anatomists like Professor Anderson demonstrate anatomy has much to offer. Here, we provide cases of early anatomical insights on the heart that were rediscovered, and expanded on, by molecular techniques: migration of neural crest cells to the heart was deduced from histological observations (1908) and independently shown again with experimental interventions; pharyngeal mesoderm is added to the embryonic heart (1973) in what is now defined as the molecularly distinguishable second heart field; chambers develop from the heart tube as regional pouches in what is now considered the ballooning model by the molecular identification of regional differentiation and proliferation. The anatomical discovery of the conduction system by Purkinje, His, Tawara, Keith, and Flack is a special case because the main findings were never neglected in later molecular studies. Professor Anderson has successfully demonstrated that sound knowledge of anatomy is indispensable for proper understanding of cardiac development. Full article

In this paper, we propose an improvement of the cardiac conduction system based on three modified Van der Pol oscillators. Each oscillator represents one of the components of the heart conduction system: Sino-Atrial node (SA), Atrio-Ventricular node (AV) and His–Purkinje system (HP). However, while SA and AV nodes can be modelled through a single oscillator, the modelling of HP by using a single oscillator is a rough simplification of the cardiac behaviour. In fact, the HP bundle is composed of Right (RB) and Left Bundle (LB) branches that serve, respectively, the right and left ventricles. In order to describe the behaviour of each bundle branch, we build a phenomenological model based on four oscillators: SA, AV, RB and LB. For the characterization of the atrial and ventricular muscles, we used the modified FitzHugh–Nagumo (FHN) equations. The numerical simulation of the model has been implemented in Simulink. The simulation results show that the new model is able to reproduce the heart dynamics generating, besides the physiological signal, also the pathological rhythm in case of Right Bundle Branch Block (RBBB) and Left Bundle Branch Block (LBBB). In particular, our model is able to describe the communication interruption of the conduction system, when one of the HP bundle branches is damaged. Full article

Many diseases that result in dysfunction and dysmorphology of the heart originate in the embryo. However, the embryonic heart presents a challenging subject for study: especially challenging is its electrophysiology. Electrophysiological maturation of the embryonic heart without disturbing its physiological function requires the creation and deployment of novel technologies along with the use of classical techniques on a range of animal models. Each tool has its strengths and limitations and has contributed to making key discoveries to expand our understanding of cardiac development. Further progress in understanding the mechanisms that regulate the normal and abnormal development of the electrophysiology of the heart requires integration of this functional information with the more extensively elucidated structural and molecular changes. Full article

Aims: Though indicated in guidelines, AAI1 pacemakers are scarcely used in patients with sick sinus syndrome (SSS) due to fear of AV block during follow-up, necessitating device upgrade. The Wenckebach block point (WBP) is often used to determine AV nodal conduction at implant. Our aims were therefore to determine the upgrade rate of AAI pacemakers over time and to study both the stability of WBP over time and its usefulness as a predictor for upgrades. Methods: In this single-centre study, patients with AAI pacemakers were followed regarding need for upgrade and predictors were explored. An AAI system was implanted in patients with SSS without evidence of conduction delay in the His-Purkinje system. WBP was measured at implant and at every follow-up visit. Changes in WBP during long-term follow-up were studied in patients with complete data. Results: We included 140 patients, 87 patients (62%) were female and age at implantation was 74 ± 13 years. Mean follow-up was 3.6 ± 3.3 years. Intraoperative WBP was 134 ± 16 bpm, for patients with complete follow-up it was 129 ± 18 bpm. Mean WBP remained stable during long-term follow-up within a range of 120 to 140 bpm. No changes in WBP behaviour were seen with increasing age. System upgrade was performed in 8 patients (5.7%) mainly due to higher degree AV block. The annual upgrade rate was 1.6%. None of intraoperative WBP, age at implant, presence of atrial fibrillation at implant and gender were predictive for future upgrade. Conclusion: AAI pacemakers evince a very reasonable long-term performance in patients with SSS, with very few patients needing an upgrade. WBP is stable during long-term follow-up and well into old age. No predictors for the development of higher-degree AV block were found. Thus AAI pacemakers may be considered more frequently in patients with SSS and without signs of atrioventricular conduction disease. Full article