Rationale Fibrosis is an important structural contributor to formation of atrial fibrillation (AF) substrate in heart failure (HF). TGF-β signaling is thought to be intricately involved in creation of atrial fibrosis. Objective We hypothesized that gene-based expression of dominant-negative type II TGF-β receptor (TGF-β-RII-DN) in the posterior left atrium (PLA) in a canine HF model will sufficiently attenuate fibrosis induced changes in atrial conduction and/or restitution to decrease AF. Since AF electrograms (EGMs) are thought to reflect AF substrate, we further hypothesized that TGF-β-RII-DN would lead to increased fractionation and decreased organization of AF EGMs. Methods and Results 21 dogs underwent injection + electroporation in the PLA of plasmid expressing a dominant negative TGF-β type II receptor (pUBc-TGFβ-DN-RII) (N=9) or control vector (pUBc-LacZ) (N=12), followed by 3–4 weeks of right ventricular tachypacing (VTP) (240 bpm). Compared to controls, dogs treated with pUBC-TGFβ-DN-RII demonstrated an attenuated increase in conduction inhomogeneity (CI), flattening of restitution slope and decreased duration of induced AF, with AF EGMs being more fractionated and less organized in pUBc-TGFβ-DN-RII versus pUBc-LacZ dogs. Tissue analysis revealed a significant decrease in replacement/interstitial fibrosis, pSMAD2/3 and pERK1/2. Conclusions Targeted, gene-based reduction of TGF-β signaling in the PLA – with resulting decrease in replacement fibrosis – led to beneficial remodeling of both conduction and restitution characteristics of the PLA, translating into a decrease in AF and increased complexity of AF EGMs. In addition to providing mechanistic insights, this data may have important diagnostic and therapeutic implications for AF.

Introduction We report the case of a woman who developed hyperlipidemia on lorlatinib therapy found to have minimal change disease. We review therapies for cancer known to alter the lipid profile, in addition to reviewing secondary hyperlipidemia workup. We also propose a mechanism for lorlatinib-induced hyperlipidemia. Case report A 63 year old woman with non-small cell lung adenocarcinoma on lorlatinib therapy develops marked hyperlipidemia. Management & outcome: A secondary hyperlipidemia workup is performed which reveals nephrotic range proteinuria. Minimal change disease is found on renal biopsy. The hyperlipidemia was initially responsive to statin therapy, then required addition of ezetimibe. Discussion This is a case of hyperlipidemia in a patient on lorlatinib. The case highlights that therapies for lung cancer and other malignancies have the potential to alter the lipid profile. We propose minimal change disease as a possible mechanism for lorlatinib-induced dyslipidemia. Additionally, we discuss the crucial aspects of secondary hyperlipidemia workup.

Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor used in the treatment of various B-cell malignancies, including chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), relapsed or refractory Mantle cell lymphoma, relapsed or refractory marginal zone lymphoma, Waldenstrom macroglobulinemia, chronic graft-versus-host disease, and additional off-label uses. 1,2 Ibrutinib has been associated with the development of atrial fibrillation (AF) in approximately 6%-16% of patients, 1 though a recent

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