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Susceptibility to Cardiac Arrhythmias and Sympathetic Nerve Growth in VEGF-B Overexpressing Myocardium.

ABSTRACT: VEGF-B gene therapy is a promising proangiogenic treatment for ischemic heart disease, but, unexpectedly, we found that high doses of VEGF-B promote ventricular arrhythmias (VAs). VEGF-B knockout, alpha myosin heavy-chain promoter (αMHC)-VEGF-B transgenic mice, and pigs transduced intramyocardially with adenoviral (Ad)VEGF- B186 were studied. Immunostaining showed a 2-fold increase in the number of nerves per field (76 vs. 39 in controls, p < 0.001) and an abnormal nerve distribution in the hypertrophic hearts of 11- to 20-month-old αMHC-VEGF-B mice. AdVEGF-B186 gene transfer (GT) led to local sprouting of nerve endings in pig myocardium (141 vs. 78 nerves per field in controls, p < 0.05). During dobutamine stress, 60% of the αMHC-VEGF-B hypertrophic mice had arrhythmias as compared to 7% in controls, and 20% of the AdVEGF-B186-transduced pigs and 100% of the combination of AdVEGF-B186- and AdsVEGFR-1-transduced pigs displayed VAs and even ventricular fibrillation. AdVEGF-B186 GT significantly increased the risk of sudden cardiac death in pigs when compared to any other GT with different VEGFs (hazard ratio, 500.5; 95% confidence interval [CI] 46.4-5,396.7; p < 0.0001). In gene expression analysis, VEGF-B induced the upregulation of Nr4a2, ATF6, and MANF in cardiomyocytes, molecules previously linked to nerve growth and differentiation. Thus, high AdVEGF-B186 overexpression induced nerve growth in the adult heart via a VEGFR-1 signaling-independent mechanism, leading to an increased risk of VA and sudden cardiac death.

SUBMITTER: Lahteenvuo J

PROVIDER: S-EPMC7335717 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Susceptibility to Cardiac Arrhythmias and Sympathetic Nerve Growth in VEGF-B Overexpressing Myocardium.

Lähteenvuo Johanna J Hätinen Olli-Pekka OP Kuivanen Antti A Huusko Jenni J Paananen Jussi J Lähteenvuo Markku M Nurro Jussi J Hedman Marja M Hartikainen Juha J Laham-Karam Nihay N Mäkinen Petri P Räsänen Markus M Alitalo Kari K Rosenzweig Anthony A Ylä-Herttuala Seppo S

Molecular therapy : the journal of the American Society of Gene Therapy 20200319 7

VEGF-B gene therapy is a promising proangiogenic treatment for ischemic heart disease, but, unexpectedly, we found that high doses of VEGF-B promote ventricular arrhythmias (VAs). VEGF-B knockout, alpha myosin heavy-chain promoter (αMHC)-VEGF-B transgenic mice, and pigs transduced intramyocardially with adenoviral (Ad)VEGF- B186 were studied. Immunostaining showed a 2-fold increase in the number of nerves per field (76 vs. 39 in controls, p < 0.001) and an abnormal nerve distribution in the hype ...[more]

PMID: 32243833

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Project description:Cardiac sympathetic denervation (CSD) is a useful therapeutic option for patients with ventricular arrhythmias (VAs) refractory to anti-arrhythmic agents and/or catheter ablation. However, the experience is mostly limited to non-structural heart disease in paediatric patients. The advent of video-assisted thoracoscopic surgery (VATS) with its reduced morbidity has encouraged the use of VATS CSD in patients with structural heart disease. In this series, we report the surgical and cardiac outcomes of VATS-guided CSD in four patients who presented with electrical storm in the setting of different structural cardiomyopathies. Four patients underwent VATS-guided CSD at our centre during the period 2019-2021 after failure of conventional medical and/or ablative treatment for the management of refractory VAs. All four patients presented with electrical storm with different cardiomyopathies including ischaemic (post-acute myocardial infarction) and non-ischaemic aetiologies (sarcoidosis, non-specific right ventricular cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy). A combined total of 349 implantable cardioverter defibrillator (ICD) shocks were registered in the 4 weeks preceding the procedure with mean shocks of 87 per patient. All four patients successfully underwent CSD through the VATS approach with no operative mortality or any major surgical morbidity. All patients had resolution of electrical storms with 75% of patients remaining free of ICD shocks at a mean follow-up of 14.87 months. One patient who remained free of ICD shocks and recurrent VAs died at 23 months after the procedure due to progressive heart failure and complications. VATS CSD is a safe and effective complementary therapeutic modality in patients with life-threatening refractory VAs and electrical storms irrespective of the underlying substrate.Supplementary informationThe online version contains supplementary material available at 10.1007/s12055-022-01361-y.

Project description:Sympathetic neurons densely innervate the myocardium with non-random topology and establish structured contacts (i.e. neuro-cardiac junctions, NCJ) with cardiomyocytes, allowing synaptic intercellular communication. Establishment of heart innervation is regulated by molecular mediators released by myocardial cells. The mechanisms underlying maintenance of cardiac innervation in the fully developed heart, are, however, less clear. Notably, several cardiac diseases, primarily affecting cardiomyocytes, are associated with sympathetic denervation, supporting the hypothesis that retrograde 'cardiomyocyte-to-sympathetic neuron' communication is essential for heart cellular homeostasis. We aimed to determine whether cardiomyocytes provide nerve growth factor (NGF) to sympathetic neurons, and the role of the NCJ in supporting such retrograde neurotrophic signalling. Immunofluorescence on murine and human heart slices shows that NGF and its receptor, tropomyosin-receptor-kinase-A, accumulate, respectively, in the pre- and post-junctional sides of the NCJ. Confocal immunofluorescence, scanning ion conductance microscopy and molecular analyses, in co-cultures, demonstrate that cardiomyocytes feed NGF to sympathetic neurons, and that this mechanism requires a stable intercellular contact at the NCJ. Consistently, cardiac fibroblasts, devoid of NCJ, are unable to sustain SN viability. ELISA assay and competition binding experiments suggest that this depends on the NCJ being an insulated microenvironment, characterized by high [NGF]. In further support, real-time imaging of tropomyosin-receptor-kinase-A vesicle movements demonstrate that efficiency of neurotrophic signalling parallels the maturation of such structured intercellular contacts. Altogether, our results demonstrate the mechanisms which link sympathetic neuron survival to neurotrophin release by directly innervated cardiomyocytes, conceptualizing sympathetic neurons as cardiomyocyte-driven heart drivers. KEY POINTS: CMs are the cell source of nerve growth factor (NGF), required to sustain innervating cardiac SNs; NCJ is the place of the intimate liaison, between SNs and CMs, allowing on the one hand neurons to peremptorily control CM activity, and on the other, CMs to adequately sustain the contacting, ever-changing, neuronal actuators; alterations in NCJ integrity may compromise the efficiency of 'CM-to-SN' signalling, thus representing a potentially novel mechanism of sympathetic denervation in cardiac diseases.

Dataset Information

Susceptibility to Cardiac Arrhythmias and Sympathetic Nerve Growth in VEGF-B Overexpressing Myocardium.

Publications

Susceptibility to Cardiac Arrhythmias and Sympathetic Nerve Growth in VEGF-B Overexpressing Myocardium.

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