Figure 4.

Inflammasome activation is required for Tet2-enhanced AF inducibility in nonaccelerated atherogenic models. A, Lethally irradiated Ldlr WT (CD45.1) mice were transplanted with bone marrow with hematopoietic-specific inactivation of Tet2 (Tet2KO) or WT controls and fed WD. B, Hematopoietic-specific Tet2 inactivation did not increase number of mice with AF (left; number of mice with AF/total mice in the group)or AF inducibility (right) in Ldlr WT mice. C, Hematopoietic-specificTet2 deficiency did not affect RA APD90 in Ldlr WT recipient mice after 6 to 9 weeks of WD. Representative tracing to the left. D, After feeding WD >40 weeks, AF was provoked in all hematopoietic-specific inactivated Tet2 (Tet2KO) bone marrow recipients but none of the WT bone marrow recipients (left; number of mice with AF/total mice in the group), and there was a marked difference in AF inducibility (right). E, Tet2KO bone marrow recipients had a shorter RA APD90 compared with WT counterparts. Representative tracing to the left. F, Lethally irradiated Ldlr WT mice or Nlrp3^−/− mice were transplanted with bone marrow with hematopoietic-specific inactivation of Tet2 (Tet2KO) or WT controls and then fed WD >40 weeks. G, There were no significant differences in number of mice with AF (number of mice with AF/total mice in the group); however, H, there was a significant difference in AF inducibility among the 3 groups. Statistical testing: Fisher exact test for B and D; 2-tailed Student t test and mean (SD) for C and E; χ² test for G and H. AF indicates atrial fibrillation; KO, knockout; LDLR, low-density lipoprotein receptor; NLRP3, NLR (NACHT, LRR [leucine rich repeat]) family pyrin domain containing protein 3; RA APD90, right atrial action potential duration at 90% repolarization; TET2, tet methylcystosine dioxygenase 2; WD, Western diet; and WT, wild-type.