Long-Term Outcomes of Permanent Pacemaker Implantation in Bicaval Heart Transplant Recipients.

BACKGROUND: Permanent pacemakers (PPMs) may be necessary in up to 10% of patients after heart transplantation (HT). OBJECTIVES: The purpose of this study was to evaluate long-term outcomes and clinical courses of heart transplant recipients who received PPM. METHODS: All patients who required PPM after bicaval HT at Columbia University between January 2005 and December 2021 were included. Cases were compared to matched heart transplant recipients by age, sex, and year of transplantation. Patient and device characteristics including complications and device interrogations were reviewed. Outcomes of re-transplantation or graft failure/death were compared between groups. RESULTS: Of 1,082 heart transplant recipients, 41 (3.8%) received PPMs. The median time from transplantation to PPM was 118 days (IQR: 18-920 days). The most common indications were sinus node dysfunction (60%, n = 25) and atrioventricular (AV) nodal disease (41.5%, n = 17). Post-implantation complications included pocket hematoma (n = 3), lead under-sensing (n = 2), and pocket infection requiring explant (n = 1). Rates of death and re-transplantation at 10 years post-HT were similar between groups. In multivariable analysis, after adjustment for mechanical circulatory support, pretransplantation amiodarone use, donor ischemic time and age, only older donor age was associated with increased risk of PPM implantation (P = 0.03). There was a significant decrease in PPM placement after 2018 (1.2% vs 4.4%, P = 0.02), largely driven by a decline in early PPM placement. There were no differences in mortality or need for re-transplantation between groups. CONCLUSIONS: PPMs are implanted after HT for sinus and atrioventricular node dysfunctions with low incidence of device-related complications. Our study shows a decrease in PPM implantation after 2018, likely attributable to expectant management in the early postoperative period.

A combinatorial cis-regulatory logic restricts color-sensing Rhodopsins to specific photoreceptor subsets in Drosophila.

Color vision in Drosophila melanogaster is based on the expression of five different color-sensing Rhodopsin proteins in distinct subtypes of photoreceptor neurons. Promoter regions of less than 300 base pairs are sufficient to reproduce the unique, photoreceptor subtype-specific rhodopsin expression patterns. The underlying cis-regulatory logic remains poorly understood, but it has been proposed that the rhodopsin promoters have a bipartite structure: the distal promoter region directs the highly restricted expression in a specific photoreceptor subtype, while the proximal core promoter region provides general activation in all photoreceptors. Here, we investigate whether the rhodopsin promoters exhibit a strict specialization of their distal (subtype specificity) and proximal (general activation) promoter regions, or if both promoter regions contribute to generating the photoreceptor subtype-specific expression pattern. To distinguish between these two models, we analyze the expression patterns of a set of hybrid promoters that combine the distal promoter region of one rhodopsin with the proximal core promoter region of another rhodopsin. We find that the function of the proximal core promoter regions extends beyond providing general activation: these regions play a previously underappreciated role in generating the non-overlapping expression patterns of the different rhodopsins. Therefore, cis-regulatory motifs in both the distal and the proximal core promoter regions recruit transcription factors that generate the unique rhodopsin patterns in a combinatorial manner. We compare this combinatorial regulatory logic to the regulatory logic of olfactory receptor genes and discuss potential implications for the evolution of rhodopsins.

Single-base pair differences in a shared motif determine differential Rhodopsin expression.

The final identity and functional properties of a neuron are specified by terminal differentiation genes, which are controlled by specific motifs in compact regulatory regions. To determine how these sequences integrate inputs from transcription factors that specify cell types, we compared the regulatory mechanism of Drosophila Rhodopsin genes that are expressed in subsets of photoreceptors to that of phototransduction genes that are expressed broadly, in all photoreceptors. Both sets of genes share an 11-base pair (bp) activator motif. Broadly expressed genes contain a palindromic version that mediates expression in all photoreceptors. In contrast, each Rhodopsin exhibits characteristic single-bp substitutions that break the symmetry of the palindrome and generate activator or repressor motifs critical for restricting expression to photoreceptor subsets. Sensory neuron subtypes can therefore evolve through single-bp changes in short regulatory motifs, allowing the discrimination of a wide spectrum of stimuli.