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I<jats:sub>f<\/jats:sub> is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic <jats:italic>mice<\/jats:italic> (<jats:italic>HCN4<\/jats:italic><jats:sup>tg\/wt<\/jats:sup>) to assess functional consequences of <jats:italic>HCN4<\/jats:italic> overexpression-mediated I<jats:sub>f<\/jats:sub> increase in cardiomyocytes to levels observed in <jats:italic>human<\/jats:italic> heart failure. <jats:italic>HCN4<\/jats:italic><jats:sup>tg\/wt<\/jats:sup> animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. I<jats:sub>f<\/jats:sub> augmentation induces a diastolic Na<jats:sup>+<\/jats:sup> influx shifting the Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup> exchanger equilibrium towards \u2018reverse mode\u2019 leading to increased [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>. Changed Ca<jats:sup>2+<\/jats:sup> homeostasis results in significantly higher systolic [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> transients and stimulates apoptosis. Pharmacological inhibition of I<jats:sub>f<\/jats:sub> prevents the rise of [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and protects from ventricular remodeling. Here we report that augmented myocardial I<jats:sub>f<\/jats:sub> alters intracellular Ca<jats:sup>2+<\/jats:sup> homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial I<jats:sub>f<\/jats:sub><jats:italic>per se<\/jats:italic> may constitute a therapeutic mechanism to prevent cardiomyopathy.<\/jats:p>","DOI":"10.1038\/s41467-019-11261-2","type":"journal-article","created":{"date-parts":[[2019,7,23]],"date-time":"2019-07-23T10:03:15Z","timestamp":1563876195000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1419-0741","authenticated-orcid":false,"given":"Pessah","family":"Yampolsky","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Koenen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7744-9138","authenticated-orcid":false,"given":"Matias","family":"Mosqueira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascal","family":"Geschwill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1216-9511","authenticated-orcid":false,"given":"Sebastian","family":"Nauck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9576-3523","authenticated-orcid":false,"given":"Monika","family":"Witzenberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Seyler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Fink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathieu","family":"Kruska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claus","family":"Bruehl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6050-0045","authenticated-orcid":false,"given":"Alexander P.","family":"Schwoerer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3465-7185","authenticated-orcid":false,"given":"Heimo","family":"Ehmke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rainer H. 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