The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Nebivolol is a third-generation, highly cardioselective and lipophilic β1-adrenoceptor antagonist. Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis. The reason why nebivolol exerted a myofilament Ca2+ desensitizing effect in KI strips at both 1 and 10 μM, whereas in WT strips only 10 μM had an effect and no effect at all in human HCM tissues remains unclear. 422, 175–180. However, the effects of nebivolol were never evaluated in HCM models with increased myofilament Ca2+ sensitivity. (2014). Ther. To counteract this hypercontractility, guideline therapies advocate treatment with beta-adrenoceptor and Ca2+ channel blockers. Nebivolol reduces mortality and morbidity in patients with heart failure and left ventricular dysfunction, including cases caused by IDC. Am. Our study will investigate whether treatment with nebivolol, as compared to another medication called metoprolol, in African Americans with hypertension will be more effective in protecting blood vessels against the harmful effects of high blood pressure. Heart J. Advances in medical treatment of hypertrophic cardiomyopathy. doi: 10.1097/00005344-200007000-00017, Keywords: nebivolol, myofilament, Ca2+ sensitivity, hypertrophic cardiomyopathy, Mybpc3, mouse, human, epigallocatechin-3-gallate, Citation: Stücker S, Kresin N, Carrier L and Friedrich FW (2017) Nebivolol Desensitizes Myofilaments of a Hypertrophic Cardiomyopathy Mouse Model. The binary endocardial appearance is a poor discriminator of Anderson-Fabry disease from familial hypertrophic cardiomyopathy. doi: 10.1007/s00395-009-0053-z, Liou, Y. M., Kuo, S. C., and Hsieh, S. R. (2008). Gene therapy. Cell Motil. (4) Even though we did not observe any nebivolol effect in the human strips in this study, this observation cannot be generalized to all HCM patients since the number of tissues was low and they were derived from HCM patients carrying only mutations in MYBPC3. Int J Cardiol. The findings are contradictory but could be explained by either differences (i) between species (rabbit vs. mouse vs. human), (ii) in experimental setups, (iii) the functional status of the tissues (non-failing vs. failing), or (iv) a combination of it. FHL2 expression and variants in hypertrophic cardiomyopathy. As mentioned before, discrepancies concerning the effects of nebivolol on maximal force development and myofilament Ca2+ sensitivity in cardiac muscle strips have been previously described. As controls, Mybpc3 WT mice of the same background were used. (B) pCa50 representing the negative logarithm of the calcium concentration needed for half-maximal activation ±nebivolol 1 and 10 μM. Genet. 118, 3893–3903. To counteract this hypercontractility, guideline therapies advocate treatment with beta-adrenoceptor and Ca2+ channel blockers. (2008). Am. Methods and Results: Nebivolol effects were tested on contractile parameters and force-Ca2+ relationship of skinned ventricular muscle strips isolated from Mybpc3-targeted knock-in (KI), wild-type (WT) mice and cardiac strips of three HCM patients with MYBPC3 mutations. Contractile parameters of permeabilized cardiac muscle strips of three human HCM patients carrying different Mybpc3 mutations in the absence or presence of nebivolol. Nebivolol, a commonly used beta-adrenoceptor antagonist, has been reported to lower maximal force development and myofilament Ca2+ sensitivity in rabbit and human heart tissues. Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction. USA.gov. 69, 370–380. (2014). All experimental procedures were in accordance with the German Law for the Protection of Animals and the protocol was approved by the Ministry of Science and Public Health of the City State of Hamburg, Germany (Org 653). Cumulative exercise-induced left ventricular systolic and diastolic dysfunction in hypertrophic cardiomyopathy… Edes, I., Kiss, E., Kitada, Y., Powers, F. M., Papp, J. G., Kranias, E. G., et al. Dimensions of strips were 2.91 ± 0.14 mm in length, 0.36 ± 0.01 mm in width and 0.11 ± 0.01 mm2 in cross-sectional area (CSA), calculated by 2πr2 assuming a circular shape, nWT = 17, nKI = 18, nhuman = 57. J. Pharmacol. Circ. Epub 2020 Apr 9. Recent data suggest that the effect of nebivolol is similar in HF patients with reduced and preserved EF (van Veldhuisen et al., 2009). Since it was shown to attenuate hydroxyl radical-induced myocardial damage which has been associated with altered intracellular calcium handling and calcium overload of the myocytes (Josephson et al., 1991; Janssen et al., 1999; Piccini et al., 2012), it was proposed that nebivolol has direct free-radical scavenging properties (Janssen et al., 1999). Biochem. Current pharmacological treatment of HCM mainly relies on beta-adrenoceptor (AR) and Ca2+ channel blockers, which improve clinical symptoms, partially prevent arrhythmias and improve diastolic dysfunction by prolonging left ventricular (LV) filling time and reducing outflow tract obstruction (Maron et al., 2003; Gersh et al., 2011; Spoladore et al., 2012; Hamada et al., 2014; Tardiff et al., 2015). Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in heterozygous knock-in mice. Exclusion criteria included the presence of cardiomyopathy (dilated, restrictive or hypertrophic) detected by baseline echocardiography, coronary heart disease, moderate or severe aortic and/or mitral valve disease, prior chemotherapy or radiotherapy, alcohol abuse, any contraindications to nebivolol, bundle branch block, atrial fibrillation and dyslipidemia. Association between use of beta-blockers and outcomes in patients with heart failure and preserved ejection fraction. 101, 928–938. 2018 Feb;32(1):478-487. doi: 10.1053/j.jvca.2017.05.035. Comparison of the effects of a truncating and a missense MYBPC3 mutation on contractile parameters of engineered heart tissue. J. Clin. Hypertrophic Cardiomyopathy, Sudden Death, and Endocarditis. Heart Circ. Whether such an indirect effect is the main reason for a decrease in myofilament Ca2+ sensitivity or another direct mechanism on the moyfilaments, such as binding to the C-terminal region of cardiac troponin C altering the interaction between cTnC and cTnI as in the case of the positive control compound EGCg (Liou et al., 2008; Robertson et al., 2009), exists, remains to be shown. In a double-blind randomized study of 25 hypertensive patients, nebivolol 5 mg administered once daily significantly increased stroke volume compared with atenolol 100 mg once daily. 9 … Circulation 119, 1473–1483. Hypertrophic cardiomyopathy (HCM) is the most frequent cardiac genetic disease primarily caused by mutations in sarcomeric protein genes (Friedrich and Carrier, 2012; Maron et al., 2014; Ho et al., 2015). Am. 110, 841–850. Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice. Pflugers Arch. Running one of the largest drug safety studies in the world, eHealthMe is able to enable everyone to run personal clinical trial. J. Hum. Impact Factor 3.367 | CiteScore 4.3More on impact ›, Connecting Sarcomere Protein Mutations to Pathogenesis in Myopathies Genet. Cell. Faber L, Welge D, Fassbender D, et al. Often, only one part of the heart is thicker than the other parts. doi: 10.1016/j.jacc.2014.05.003, Mearini, G., Stimpel, D., Geertz, B., Weinberger, F., Kramer, E., Schlossarek, S., et al. The aim of this study was to evaluate whether nebivolol would exert similar effects in permeabilized myofilaments of an Mybpc3 HCM mouse model and of HCM patients with mutations in the most frequently mutated gene MYBPC3. Solution structure of human cardiac troponin C in complex with the green tea polyphenol, (–)-epigallocatechin 3-gallate. Invest. Cardiovasc. Hypertrophic cardiomyopathy: prognostic factors hypertrophic cardiomyopathy. Epigallocatechin-3-gallate accelerates relaxation and Ca2+ transient decay and desensitizes myofilaments in healthy and mybpc3-targeted knock-in cardiomyopathic mice. Pharmacol. (3) 10 μM nebivolol induced myofilament Ca2+ desensitization in both WT and KI strips and this effect was more pronounced in KI muscle strips, respectively. The Genetic and Molecular Bases for Hypertrophic Cardiomyopathy: The Role for Calcium Sensitization. Neither 1 nor 10 μM nebivolol had an effect on Ca2+ sensitivity in cardiac muscle strips of three HCM patients with MYBPC3 mutations, whereas epigallocatechin-gallate induced a right shift in the force-Ca2+ curve. Nebivolol exerts the highest β 1 ‐selectivity in human myocardium, displaying a 40.7‐fold selectivity ratio . J. Physiol. J Hered 1947;38:294 –298.  |  Circulation 126, 2200–2207. 10 μM nebivolol induced myofilament Ca2+ desensitization in WT strips and to a greater extent in KI strips. Nebivolol is a third-generation beta-AR antagonist that exhibits vasodilating properties, most likely due to stimulation of nitric oxide synthase (Cockcroft et al., 1995). In the treatment of myocardial infarction, beta-blockers are contraindicated in patients with hypotension (SBP < 100 mmHg). doi: 10.1161/01.CIR.0000066323.15244.54, Robertson, I. M., Li, M. X., and Sykes, B. D. (2009). Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. A cardiac MRI was performed which showed increased ratio of noncompacted wall to compacted wall (2.5:1) in addition to global hypokinesis of the left ventricle. At baseline, KI strips showed no difference in maximal force development compared to WT mouse heart strips. J Physiol. Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy. Crossref Medline Google Scholar; 22 Papapetropoulos A, Garcia-Cardena G, Madri JA, Sessa WC. (2) Our study does not explain the precise mechanism of Ca2+-desensitization of nebivolol in mouse heart tissue. Hypertrophic cardiomyopathy is a heterogeneous cardiac disease with a diverse clinical presentation and course. An established HCM mouse model carrying the human c.772G>A MYBPC3 mutation is the Mybpc3 KI mouse model (Vignier et al., 2009). Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiac disorders (affecting ~ 1 in 500 people) and is the number one … Author information: (1)Department … Concentration response curves were fitted to the data points and force-pCa relationship comparison was done by using extra sum-of-squares F-test (GraphPad, Prism 6). The hemodynamic profile of nebivolol is differ-entfromthatofotherb-blockers. J. Physiol. Cardiol. doi: 10.1152/ajpheart.00705.2013, Stohr, A., Friedrich, F. W., Flenner, F., Geertz, B., Eder, A., Schaaf, S., et al. doi: 10.1007/s10974-009-9174-0, Jagatheesan, G., Rajan, S., Petrashevskaya, N., Schwartz, A., Boivin, G., Arteaga, G. M., et al. Cell. NIH Nebivolol is a highly selective β 1 ‐adrenergic receptor blocker that induces vasodilation through stimulation of the endothelial nitric oxide/ l ‐arginine pathway. To examine the effect of the beta 1 ‐selective beta‐blocker nebivolol, administered as add‐on therapy, on left ventricular function in 260 elderly patients (>65 years) with chronic heart failure (CHF).. Methods. and survival analysis in 128 Egyptian patients. |, http://www.nc3rs.org.uk/arrive-animal-research-reporting-vivo-experiments, https://clinicaltrials.gov/ct2/show/NCT02619526, Creative Commons Attribution License (CC BY). (2014). Drugs Ther. We thank Julia Münch and Monica Patten (University Heart Center Hamburg, Hamburg, Germany) for patients' recruitment, Elisabeth Krämer, Giulia Mearini, and Frederik Flenner (UKE-Pharmacology, Hamburg, Germany) for help in preservation of human septal myectomies and database maintenance. Sexual dimorphic response to exercise in hypertrophic cardiomyopathy-associated MYBPC3-targeted knock-in mice. The study has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). doi: 10.1093/cvr/cvv023, Tardiff, J. C., Hewett, T. E., Palmer, B. M., Olsson, C., Factor, S. M., Moore, R. L., et al. To counteract this hypercontractility, guideline therapies advocate treatment with beta-AR and Ca2+ channel blockers. 38(Suppl. J. 2. Cell. The phase IV clinical study is created by eHealthMe based on reports of 15,231 people who have side effects while taking Bystolic from the FDA, and is updated regularly. Many publications have been written about medical treatment of hypertrophic cardiomyopathy (HCM) in past. Approaches to High-Throughput Analysis of Cardiomyocyte Contractility. . Res. In mice, nebivolol did not influence maximal force development. Since nebivolol has been reported to desensitize human myofilaments for Ca2+ and since both 1 and 10 μM nebivolol had induced a right-ward shift of the force-pCa curves in Mybpc3 KI cardiac muscle strips we sought to investigate whether it would also affect myofilament Ca2+ sensitivity in human HCM tissue. (F) pCa50 ±EGCg 30 μM. (A) Force-Ca2+ relationship in WT (left) and KI (right) strips ±nebivolol 1 and 10 μM. 85–23, revised 2011 published by National Research Council) and comply with the ARRIVE guidelines (http://www.nc3rs.org.uk/arrive-animal-research-reporting-vivo-experiments). Sudden death in young athletes profile of an established HCM Mybpc3 mouse model expressing a heterozygous mutation! 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