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A Simple Porcine Model of Inducible Sustained Atrial Fibrillation.

ABSTRACT: The surgical management of atrial fibrillation (AF) is an evolving field with a history of testing various lesion sets and ablation technologies. Previous animal models of AF require a chronic intervention to make AF reliably inducible. Our objective was to create an acute, reliable, and reproducible porcine model of sustained AF. To accomplish this, 21 adult domestic pigs underwent median sternotomy. Methods to induce AF were then performed sequentially: manual stimulation, rapid pacing (200 beats per minute), and then rapid pacing of 8 beats with a cycle length of 300 milliseconds, followed by an extra stimulus at decreasing cycle lengths. If AF was not induced, burst pacing was performed at a cycle length of 90 milliseconds for 30 seconds. If AF was still not induced, intravenous neostigmine was administered, and the process was repeated. Atrial fibrillation was considered sustained after 1 minute. Attempts at AF induction were successful in 18 (86%) of 21. Atrial fibrillation was induced during manual stimulation in four (19%), during rapid pacing in five (24%), during burst pacing in five (24%), and after the administration of neostigmine in four (19%). Mean (SD) duration of AF was 3.6 (2.6) minutes. Of the 18, 14 (78%) reverted to sinus rhythm spontaneously and 4 (22%) required an antiarrhythmic. This technique of inducing AF can easily be used to evaluate new technologies and lesion sets without the need for creating a chronic animal model.

SUBMITTER: Lee AM

PROVIDER: S-EPMC5551441 | biostudies-other | 2016 Jan-Feb

REPOSITORIES: biostudies-other

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Project description:Transgenic porcine cancer models bring novel possibilities for research. Their physical similarities with humans enable the use of surgical procedures and treatment approaches used for patients, which facilitates clinical translation. Here, we aimed to develop an inducible oncopig model of intestinal cancer. Transgenic (TG) minipigs were generated using somatic cell nuclear transfer by handmade cloning. The pigs encode two TG cassettes: (a) an Flp recombinase-inducible oncogene cassette containing KRAS-G12D, cMYC, SV40LT - which inhibits p53 - and pRB and (b) a 4-hydroxytamoxifen (4-OHT)-inducible Flp recombinase activator cassette controlled by the intestinal epithelium-specific villin promoter. Thirteen viable transgenic minipigs were born. The ability of 4-OHT to activate the oncogene cassette was confirmed in vitro in TG colonic organoids and ex vivo in tissue biopsies obtained by colonoscopy. In order to provide proof of principle that the oncogene cassette could also successfully be activated in vivo, three pigs were perorally treated with 400 mg tamoxifen for 2 × 5 days. After two months, one pig developed a duodenal neuroendocrine carcinoma with a lymph node metastasis. Molecular analysis of the carcinoma and metastasis confirmed activation of the oncogene cassette. No tumor formation was observed in untreated TG pigs or in the remaining two treated pigs. The latter indicates that tamoxifen delivery can probably be improved. In summary, we have generated a novel inducible oncopig model of intestinal cancer, which has the ability to form metastatic disease already two months after induction. The model may be helpful in bridging the gap between basic research and clinical usage. It opens new venues for longitudinal studies of tumor development and evolution, for preclinical assessment of new anticancer regimens, for pharmacology and toxicology assessments, as well as for studies into biological mechanisms of tumor formation and metastasis.

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A Simple Porcine Model of Inducible Sustained Atrial Fibrillation.

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