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Articolo in rivista, 2024, ENG, 10.1016/j.jacc.2023.10.029

Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure

Alessio Alogna 1 , Leonhard Berboth 2 , Alessandro Faragli 2 , Jens Ötvös 2 , Francesco Paolo Lo Muzio 2 , Vittoria di Mauro 3 , Jessica Modica 3 , Eride Quarta 4 , Lukas Semmler 2 , Peter Maximilian Deißler 2 , Yannic Wanja Berger 2 , Khai Liem Tran 2 , Beatrice de Marchi 5 , Gianluigi Longinotti-Buitoni 5 , Lorenzo Degli Esposti 6 , Etienne Guillot 7 , Didier Bazile 7 , Michele Iafisco 6 , Alessandro Dotti 8 , Marie-Louise Bang 3 , Claudio de Luca 9 , Christina Brandenberger 10 , Louise Benazzi 11 , Dario di Silvestre 11 , Antonella de Palma 11 , Uwe Primeßnig 12 , Felix Hohendanner 12 , Simone Perna 13 , Francesca Buttini 14 , Paolo Colombo 4 , Christian Mühlfeld 15 , Paul Steendijk 16 , Pierluigi Mauri 11 , Carsten Tschöpe 2 , Barry Borlaug 17 , Burkert M Pieske 12 , Philipp Attanasio 18 , Heiner Post 2 , Frank R Heinzel 19 , Daniele Catalucci 20

1 Deutsches Herzzentrum der Charité, Department of Cardiology, Angiology and Intensive Care Medicine, Campus Virchow-Klinikum, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany; German Centre for Cardiovascular Research, Berlin, Germany. Electronic address: alessio.alogna@dhzc-charite.de. 2 Deutsches Herzzentrum der Charité, Department of Cardiology, Angiology and Intensive Care Medicine, Campus Virchow-Klinikum, Berlin, Germany. 3 Institute of Genetic and Biomedical Research, National Research Council of Italy, Milan Unit, Milan, Italy; Humanitas Cardio Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy. 4 Department of Food and Drugs, University of Parma, Parma, Italy; PlumeStars, Parma, Italy. 5 L.I.F.E. Italia, Milan, Italy. 6 Institute of Science, Technology and Sustainability for Ceramics (ISSMC), National Research Council, Faenza, Italy. 7 Sanofi R&D, Chilly-Mazarin, France. 8 Fin-Ceramica Faenza, Faenza (Ravenna), Italy. 9 NanoPhoria, Milano, Italy. 10 Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany; Charité-Universitätsmedizin Berlin, Institute of Functional Anatomy, Campus Charité Mitte, Berlin, Germany. 11 Proteomics and Metabolomic Lab, Institute for Biomedical Technologies, National Research Council, Segrate (Milan), Italy. 12 Deutsches Herzzentrum der Charité, Department of Cardiology, Angiology and Intensive Care Medicine, Campus Virchow-Klinikum, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany; German Centre for Cardiovascular Research, Berlin, Germany. 13 Department of Biology, College of Science, Sakhir Campus, University of Bahrain, Zallaq, Bahrain. 14 Department of Food and Drugs, University of Parma, Parma, Italy. 15 Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, Hannover, Germany. 16 Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. 17 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA. 18 Department of Cardiology, Campus Benjamin Franklin, Charité-Universitätsmedizin, Berlin, Germany. 19 Deutsches Herzzentrum der Charité, Department of Cardiology, Angiology and Intensive Care Medicine, Campus Virchow-Klinikum, Berlin, Germany; German Centre for Cardiovascular Research, Berlin, Germany. 20 Institute of Genetic and Biomedical Research, National Research Council of Italy, Milan Unit, Milan, Italy; Humanitas Cardio Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy.

Background: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. Objectives: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. Methods: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. Results: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. Conclusions: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.

Journal of the American College of Cardiology (Print) 83 (1), pp. 47–59