Imperial College London

ProfessorPeterKohl

Faculty of MedicineNational Heart & Lung Institute

Visiting Professor
 
 
 
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Contact

 

p.kohl Website

 
 
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Location

 

Heart Science CentreHarefield Hospital

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Summary

 

Publications

Publication Type
Year
to

346 results found

Scardigli M, Pásek M, Santini L, Palandri C, Conti E, Crocini C, Campione M, Loew LM, de Vries AAF, Pijnappels DA, Pavone FS, Poggesi C, Cerbai E, Coppini R, Kohl P, Ferrantini C, Sacconi Let al., 2024, Optogenetic confirmation of transverse-tubular membrane excitability in intact cardiac myocytes., J Physiol

T-tubules (TT) form a complex network of sarcolemmal membrane invaginations, essential for well-co-ordinated excitation-contraction coupling (ECC) and thus homogeneous mechanical activation of cardiomyocytes. ECC is initiated by rapid depolarization of the sarcolemmal membrane. Whether TT membrane depolarization is active (local generation of action potentials; AP) or passive (following depolarization of the outer cell surface sarcolemma; SS) has not been experimentally validated in cardiomyocytes. Based on the assessment of ion flux pathways needed for AP generation, we hypothesize that TT are excitable. We therefore explored TT excitability experimentally, using an all-optical approach to stimulate and record trans-membrane potential changes in TT that were structurally disconnected, and hence electrically insulated, from the SS membrane by transient osmotic shock. Our results establish that cardiomyocyte TT can generate AP. These AP show electrical features that differ substantially from those observed in SS, consistent with differences in the density of ion channels and transporters in the two different membrane domains. We propose that TT-generated AP represent a safety mechanism for TT AP propagation and ECC, which may be particularly relevant in pathophysiological settings where morpho-functional changes reduce the electrical connectivity between SS and TT membranes. KEY POINTS: Cardiomyocytes are characterized by a complex network of membrane invaginations (the T-tubular system) that propagate action potentials to the core of the cell, causing uniform excitation-contraction coupling across the cell. In the present study, we investigated whether the T-tubular system is able to generate action potentials autonomously, rather than following depolarization of the outer cell surface sarcolemma. For this purpose, we developed a fully optical platform to probe and manipulate the electrical dynamics of subcellular membrane domains. Our findings demonstrate that T-tu

Journal article

Sassu E, Tumlinson G, Stefanovska D, Fernández MC, Iaconianni P, Madl J, Brennan TA, Koch M, Cameron BA, Preissl S, Ravens U, Schneider-Warme F, Kohl P, Zgierski-Johnston CM, Hortells Let al., 2024, Age-related structural and functional changes of the intracardiac nervous system., J Mol Cell Cardiol, Vol: 187, Pages: 1-14

BACKGROUND: Although aging is known to be associated with an increased incidence of both atrial and ventricular arrhythmias, there is limited knowledge about how Schwann cells (SC) and the intracardiac nervous system (iCNS) remodel with age. Here we investigate the differences in cardiac SC, parasympathetic nerve fibers, and muscarinic acetylcholine receptor M2 (M2R) expression in young and old mice. Additionally, we examine age-related changes in cardiac responses to sympathomimetic and parasympathomimetic drugs. METHODS AND RESULTS: Lower SC density, lower SC proliferation and fewer parasympathetic nerve fibers were observed in cardiac and, as a control sciatic nerves from old (20-24 months) compared to young mice (2-3 months). In old mice, chondroitin sulfate proteoglycan 4 (CSPG4) was increased in sciatic but not cardiac nerves. Expression of M2R was lower in ventricular myocardium and ventricular conduction system from old mice compared to young mice, while no significant difference was seen in M2R expression in sino-atrial or atrio-ventricular node pacemaker tissue. Heart rate was slower and PQ intervals were longer in Langendorff-perfused hearts from old mice. Ventricular tachycardia and fibrillation were more frequently observed in response to carbachol administration in hearts from old mice versus those from young mice. CONCLUSIONS: On the background of reduced presence of SC and parasympathetic nerve fibers, and of lower M2R expression in ventricular cardiomyocytes and conduction system of aged hearts, the propensity of ventricular arrhythmogenesis upon parasympathomimetic drug application is increased. Whether this is caused by an increase in heterogeneity of iCNS structure and function remains to be elucidated.

Journal article

Kohl P, 2023, Hello, Goodbye., J Physiol, Vol: 601, Pages: 4645-4646

Journal article

Steffens S, Schroeder K, Krueger M, Maack C, Streckfuss-Boemeke K, Backs J, Backofen R, Baessler B, Devaux Y, Gilsbach R, Heijman J, Knaus J, Kramann R, Linz D, Lister AL, Maatz H, Maegdefessel L, Mayr M, Meder B, Nussbeck SY, Rog-Zielinska EA, Schulz MH, Sickmann A, Yigit G, Kohl Pet al., 2023, The challenges of research data management in cardiovascular science: a DGK and DZHK position paper-executive summary, CLINICAL RESEARCH IN CARDIOLOGY, ISSN: 1861-0684

Journal article

Becker C, Hardarson J, Hoelzer A, Geisler A, Schulz T, Reichl C, Burton NCC, Schuler T, Kohl P, Zgierski-Johnston Cet al., 2023, Evaluation of cervical lymph nodes using multispectral optoacoustic tomography: a proof-of-concept study, EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY, Vol: 280, Pages: 4657-4664, ISSN: 0937-4477

Journal article

Fuerniss HE, Wuelfers EM, Iaconianni P, Ravens U, Kroll J, Stiller B, Kohl P, Rog-Zielinska EA, Peyronnet Ret al., 2023, Disease severity, arrhythmogenesis, and fibrosis are related to longer action potentials in tetralogy of Fallot, CLINICAL RESEARCH IN CARDIOLOGY, ISSN: 1861-0684

Journal article

Fürniss HE, Wülfers EM, Iaconianni P, Ravens U, Kroll J, Stiller B, Kohl P, Rog-Zielinska EA, Peyronnet Ret al., 2023, Disease severity, arrhythmogenesis, and fibrosis are related to longer action potentials in tetralogy of Fallot., Clin Res Cardiol

BACKGROUND: Arrhythmias may originate from surgically unaffected right ventricular (RV) regions in patients with tetralogy of Fallot (TOF). We aimed to investigate action potential (AP) remodelling and arrhythmia susceptibility in RV myocardium of patients with repaired and with unrepaired TOF, identify possible correlations with clinical phenotype and myocardial fibrosis, and compare findings with data from patients with atrial septal defect (ASD), a less severe congenital heart disease. METHODS: Intracellular AP were recorded ex vivo in RV outflow tract samples from 22 TOF and three ASD patients. Arrhythmias were provoked by superfusion with solutions containing reduced potassium and barium chloride, or isoprenaline. Myocardial fibrosis was quantified histologically and associations between clinical phenotype, AP shape, tissue arrhythmia propensity, and fibrosis were examined. RESULTS: Electrophysiological abnormalities (arrhythmias, AP duration [APD] alternans, impaired APD shortening at increased stimulation frequencies) were generally present in TOF tissue, even from infants, but rare or absent in ASD samples. More severely diseased and acyanotic patients, pronounced tissue susceptibility to arrhythmogenesis, and greater fibrosis extent were associated with longer APD. In contrast, APD was shorter in tissue from patients with pre-operative cyanosis. Increased fibrosis and repaired-TOF status were linked to tissue arrhythmia inducibility. CONCLUSIONS: Functional and structural tissue remodelling may explain arrhythmic activity in TOF patients, even at a very young age. Surprisingly, clinical acyanosis appears to be associated with more severe arrhythmogenic remodelling. Further research into the clinical drivers of structural and electrical myocardial alterations, and the relation between them, is needed to identify predictive factors for patients at risk. Central illustration: summary diagram of essential study results. Note that not all results are depict

Journal article

Simon-Chica A, Wülfers EM, Kohl P, 2023, Nonmyocytes as electrophysiological contributors to cardiac excitation and conduction., Am J Physiol Heart Circ Physiol, Vol: 325, Pages: H475-H491

Although cardiac action potential (AP) generation and propagation have traditionally been attributed exclusively to cardiomyocytes (CM), other cell types in the heart are also capable of forming electrically conducting junctions. Interactions between CM and nonmyocytes (NM) enable and modulate each other's activity. This review provides an overview of the current understanding of heterocellular electrical communication in the heart. Although cardiac fibroblasts were initially thought to be electrical insulators, recent studies have demonstrated that they form functional electrical connections with CM in situ. Other NM, such as macrophages, have also been recognized as contributing to cardiac electrophysiology and arrhythmogenesis. Novel experimental tools have enabled the investigation of cell-specific activity patterns in native cardiac tissue, which is expected to yield exciting new insights into the development of novel or improved diagnostic and therapeutic strategies.

Journal article

Chiang C-J, Kim H, Jonson-Reid M, Yang M, Moon CK, Kohl Pet al., 2023, Risk Factors and Neglect Subtypes: Findings From a Nationally Representative Data Set, AMERICAN JOURNAL OF ORTHOPSYCHIATRY, ISSN: 0002-9432

Journal article

Lother A, Kohl P, 2023, The heterocellular heart: identities, interactions, and implications for cardiology, BASIC RESEARCH IN CARDIOLOGY, Vol: 118, ISSN: 0300-8428

Journal article

Darkow E, Yusuf D, Rajamani S, Backofen R, Kohl P, Ravens U, Peyronnet Ret al., 2023, Meta-Analysis of Mechano-Sensitive Ion Channels in Human Hearts: Chamber- and Disease-Preferential mRNA Expression, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 24, ISSN: 1661-6596

Journal article

Bailey DM, Berg RMG, Stewart A, Adams JC, Kohl Pet al., 2023, Sharpey-Schafer, Langley and Sherrington: 'swordsmen' of physiology. A historical look to the future, EXPERIMENTAL PHYSIOLOGY, Vol: 108, Pages: 655-658, ISSN: 0958-0670

Journal article

Karoutas A, Szymanski W, Rausch T, Guhathakurta S, Rog-Zielinska EA, Peyronnet R, Seyfferth J, Chen H-R, de Leeuw R, Herquel B, Kimura H, Mittler G, Kohl P, Medalia O, Korbel JO, Akhtar Aet al., 2023, The NSL complex maintains nuclear architecture stability via lamin A/C acetylation (vol 21, pg 1248, 2019), NATURE CELL BIOLOGY, Vol: 25, Pages: 626-626, ISSN: 1465-7392

Journal article

Kubo Y, Kohl P, 2023, Congratulations, celebrations, invitations!, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 601, Pages: 1047-1047, ISSN: 0022-3751

Journal article

Cameron BA, Kohl P, Quinn TA, 2023, Cellular and Subcellular Mechanisms of Ventricular Mechano-Arrhythmogenesis, Cardiac and Vascular Biology, Pages: 265-298

Intrinsic regulation of cardiac electrical and mechanical activity allows the heart to adjust its function to meet the metabolic demand of the body. This includes the acute feedback of cardiac mechanics to electrics (‘mechano-electric coupling’, MEC), which is achieved primarily through cellular and subcellular elements, including mechano-sensitive ion channels, biophysical signal transmitters and mechano-sensitive biochemical signalling pathways. While MEC is normally involved in fine-tuning of cardiac function, in disease states characterised by perturbations in the cardiac mechanical environment, myocardial mechanics or elements of MEC, it can instead drive arrhythmogenic changes in electrophysiology (‘mechano-arrhythmogenesis’), which can result in sustained ventricular tachyarrhythmias. This chapter briefly reviews essential aspects of MEC, discusses clinical evidence and experimental studies of ventricular mechano-arrhythmogenesis and describes the underlying cellular and subcellular elements involved. It then puts mechano-arrhythmogenesis into a clinical context by focussing on two pathological states that highlight the spatio-temporal dependence of mechano-arrhythmogenesis in the whole heart: one that is characterised by acute, local changes in cardiac electro-mechanics and MEC (acute regional myocardial ischaemia) and one that involves chronic, global changes (hypertension). Overall, an improved understanding of the mechanisms driving ventricular mechano-arrhythmogenesis is critical for the development of anti-arrhythmic therapies targeting MEC, such as modulation of tissue mechanics or alteration of subcellular mechano-sensitive components.

Book chapter

Kohl P, Zgierski-Johnston CM, 2023, Assessment of Tissue Viability by Functional Imaging of Membrane Potential., Methods Mol Biol, Vol: 2644, Pages: 423-434

Electrical activity plays a key role in physiology, in particular for signaling and coordination. Cellular electrophysiology is often studied with micropipette-based techniques such as patch clamp and sharp electrodes, but for measurements at the tissue or organ scale, more integrated approaches are needed. Epifluorescence imaging of voltage-sensitive dyes ("optical mapping") is a tissue non-destructive approach to obtain insight into electrophysiology with high spatiotemporal resolution. Optical mapping has primarily been applied to excitable organs, especially the heart and brain. Action potential durations, conduction patterns, and conduction velocities can be determined from the recordings, providing information about electrophysiological mechanisms, including factors such as effects of pharmacological interventions, ion channel mutations, or tissue remodeling. Here, we describe the process for optical mapping of Langendorff-perfused mouse hearts, highlighting potential issues and key considerations.

Journal article

Chleilat E, Walz TP, Kohl P, Seemann G, Zgierski-Johnston Cet al., 2022, New insights into reperfusion arrhythmia mechanism and means to circumvent perivascular excitation tunnelling-based rhythm disturbance, 24th World Congress of the International-Society-for-Heart-Research, Publisher: ELSEVIER SCI LTD, Pages: S25-S26, ISSN: 0022-2828

Conference paper

Kohl P, 2022, Opinion matters, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 600, Pages: 5169-5169, ISSN: 0022-3751

Journal article

Peyronnet R, Desai A, Edelmann J-C, Cameron BA, Emig R, Kohl P, Dean Det al., 2022, Simultaneous assessment of radial and axial myocyte mechanics by combining atomic force microscopy and carbon fibre techniques., Philos Trans R Soc Lond B Biol Sci, Vol: 377

Cardiomyocytes sense and shape their mechanical environment, contributing to its dynamics by their passive and active mechanical properties. While axial forces generated by contracting cardiomyocytes have been amply investigated, the corresponding radial mechanics remain poorly characterized. Our aim is to simultaneously monitor passive and active forces, both axially and radially, in cardiomyocytes freshly isolated from adult mouse ventricles. To do so, we combine a carbon fibre (CF) set-up with a custom-made atomic force microscope (AFM). CF allows us to apply stretch and to record passive and active forces in the axial direction. The AFM, modified for frontal access to fit in CF, is used to characterize radial cell mechanics. We show that stretch increases the radial elastic modulus of cardiomyocytes. We further find that during contraction, cardiomyocytes generate radial forces that are reduced, but not abolished, when cells are forced to contract near isometrically. Radial forces may contribute to ventricular wall thickening during contraction, together with the dynamic re-orientation of cells and sheetlets in the myocardium. This new approach for characterizing cell mechanics allows one to obtain a more detailed picture of the balance of axial and radial mechanics in cardiomyocytes at rest, during stretch, and during contraction. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.

Journal article

Quinn TA, Kohl P, 2022, The Bainbridge effect: stretching our understanding of cardiac pacemaking for more than a century, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 600, Pages: 4377-4379, ISSN: 0022-3751

Journal article

Kohl P, Greiner J, Rog-Zielinska EA, 2022, Electron microscopy of cardiac 3D nanodynamics: form, function, future, NATURE REVIEWS CARDIOLOGY, Vol: 19, Pages: 607-619, ISSN: 1759-5002

Journal article

Emig R, Hoess P, Cai H, Kohl P, Peyronnet R, Weber W, Hoerner Met al., 2022, Benchmarking of Cph1 Mutants and <i>Dr</i>BphP for Light-Responsive Phytochrome-Based Hydrogels with Reversibly Adjustable Mechanical Properties, ADVANCED BIOLOGY, Vol: 6, ISSN: 2701-0198

Journal article

Giardini F, Olianti C, Biasci V, Arecchi G, Zaglia T, Mongillo M, Cerbai E, Zgierski-Johnston C, Kohl P, Sacconi Let al., 2022, Correlating electrical dysfunctions and structural remodeling in Arrhythmogenic Mouse Hearts by advanced optical methods, Publisher: OXFORD UNIV PRESS, ISSN: 0008-6363

Conference paper

Khokhlova A, Solovyova O, Kohl P, Peyronnet Ret al., 2022, Single cardiomyocytes from papillary muscles show lower preload-dependent activation of force compared to cardiomyocytes from the left ventricular free wall, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 166, Pages: 127-136, ISSN: 0022-2828

Journal article

Kohl P, 2022, Ask not what The Journal can do for you, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 600, Pages: 1537-1538, ISSN: 0022-3751

Journal article

Duerschmied D, Hilgendorf I, Kohl P, Rog-Zielinska E, Verheyen Jet al., 2022, SFB1425-The heterocellular nature of cardiac lesions: Identities, interactions, implications, KARDIOLOGIE, Vol: 16, Pages: 128-135, ISSN: 2731-7129

Journal article

Rog-Zielinska EA, Kohl P, 2022, Cardiomyocyte t-tubular fluid pumping, Publisher: CELL PRESS, Pages: 155A-155A, ISSN: 0006-3495

Conference paper

Simon-Chica A, Fernandez MC, Wuelfers EM, Lother A, Hilgendorf I, Seemann G, Ravens U, Kohl P, Schneider-Warme Fet al., 2022, Novel insights into the electrophysiology of murine cardiac macrophages: relevance of voltage-gated potassium channels, Cardiovascular Research, Vol: 118, Pages: 798-813, ISSN: 0008-6363

AimsMacrophages (MΦ), known for immunological roles, such as phagocytosis and antigen presentation, have been found to electrotonically couple to cardiomyocytes (CM) of the atrioventricular node via Cx43, affecting cardiac conduction in isolated mouse hearts. Here, we characterize passive and active electrophysiological properties of murine cardiac resident MΦ, and model their potential electrophysiological relevance for CM.Methods and resultsWe combined classic electrophysiological approaches with 3D florescence imaging, RNA-sequencing, pharmacological interventions, and computer simulations. We used Cx3creYFP/+1 mice wherein cardiac MΦ are fluorescently labelled. FACS-purified fluorescent MΦ from mouse hearts were studied by whole-cell patch-clamp. MΦ electrophysiological properties include: membrane resistance 2.2±0.1 GΩ (all data mean±SEM), capacitance 18.3±0.1 pF, resting membrane potential −39.6±0.3 mV, and several voltage-activated, outward or inwardly rectifying potassium currents. Using ion channel blockers (barium, TEA, 4-AP, margatoxin, XEN-D0103, and DIDS), flow cytometry, immuno-staining, and RNA-sequencing, we identified Kv1.3, Kv1.5, and Kir2.1 as channels contributing to observed ion currents. MΦ displayed four patterns for outward and two for inward-rectifier potassium currents. Additionally, MΦ showed surface expression of Cx43, a prerequisite for homo- and/or heterotypic electrotonic coupling. Experimental results fed into development of an original computational model to describe cardiac MΦ electrophysiology. Computer simulations to quantitatively assess plausible effects of MΦ on electrotonically coupled CM showed that MΦ can depolarize resting CM, shorten early and prolong late action potential duration, with effects depending on coupling strength and individual MΦ electrophysiological properties, in particular resting membrane potential and presence/absence of

Journal article

Greiner J, Schiatti T, Kaltenbacher W, Dente M, Semenjakin A, Kok T, Fiegle DJ, Seidel T, Ravens U, Kohl P, Peyronnet R, Rog-Zielinska EAet al., 2022, Consecutive-Day Ventricular and Atrial Cardiomyocyte Isolations from the Same Heart: Shifting the Cost-Benefit Balance of Cardiac Primary Cell Research, CELLS, Vol: 11

Journal article

Muellenbroich MC, Kelly A, Acker C, Bub G, Bruegmann T, Di Bona A, Entcheva E, Ferrantini C, Kohl P, Lehnart SE, Mongillo M, Parmeggiani C, Richter C, Sasse P, Zaglia T, Sacconi L, Smith GLet al., 2021, Novel Optics-Based Approaches for Cardiac Electrophysiology: A Review, FRONTIERS IN PHYSIOLOGY, Vol: 12

Journal article

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