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Objectives: We examined for differences in pre-left ventricular assist device (LVAD) implantation myocardial transcriptome signatures among patients with different degrees of mitral regurgitation (MR)., Methods: Between January 2018 and October 2019, we collected left ventricular (LV) cores during durable LVAD implantation (n = 72). A retrospective chart review was performed. Total RNA was isolated from LV cores and used to construct cDNA sequence libraries. The libraries were sequenced with the NovaSeq system, and data were quantified using Kallisto. Gene Set Enrichment Analysis (GSEA) and Gene Ontology analyses were performed, with a false discovery rate <0.05 considered significant., Results: Comparing patients with preoperative mild or less MR (n = 30) and those with moderate-severe MR (n = 42), the moderate-severe MR group weighted less (P = .004) and had more tricuspid valve repairs (P = .043), without differences in demographics or comorbidities. We then compared both groups with a group of human donor hearts without heart failure (n = 8). Compared with the donor hearts, there were 3985 differentially expressed genes (DEGs) for mild or less MR and 4587 DEGs for moderate-severe MR. Specifically altered genes included 448 DEGs for specific for mild or less MR and 1050 DEGs for moderate-severe MR. On GSEA, common regulated genes showed increased immune gene expression and reduced expression of contraction and energetic genes. Of the 1050 genes specific for moderate-severe MR, there were additional up-regulated genes related to inflammation and reduced expression of genes related to cellular proliferation., Conclusions: Patients undergoing durable LVAD implantation with moderate-severe MR had increased activation of genes related to inflammation and reduction of cellular proliferation genes. This may have important implications for myocardial recovery., (Published by Elsevier Inc.)

Objective: Primary mitral regurgitation is a valvular lesion in which the left ventricular ejection fraction remains preserved for long periods, delaying a clinical trigger for mitral valve intervention. In this study, we sought to investigate whether adverse left ventricular remodeling occurs before a significant fall in ejection fraction and characterize these changes., Methods: Sixty-five rats were induced with severe mitral regurgitation by puncturing the mitral valve leaflet with a 23-G needle using ultrasound guidance. Rats underwent longitudinal cardiac echocardiography at biweekly intervals and hearts explanted at 2 weeks (n = 15), 10 weeks (n = 15), 20 weeks (n = 15), and 40 weeks (n = 15). Sixty age- and weight-matched healthy rats were used as controls. Unbiased RNA-sequencing was performed at each terminal point., Results: Regurgitant fraction was 40.99 ± 9.40%, with pulmonary flow reversal in the experimental group, and none in the control group. Significant fall in ejection fraction occurred at 14 weeks after mitral regurgitation induction. However, before 14 weeks, end-diastolic volume increased by 93.69 ± 52.38% (P < .0001 compared with baseline), end-systolic volume increased by 118.33 ± 47.54% (P < .0001 compared with baseline), and several load-independent pump function indices were reduced. Transcriptomic data at 2 and 10 weeks before fall in ejection fraction indicated up-regulation of myocyte remodeling and oxidative stress pathways, whereas those at 20 and 40 weeks indicated extracellular matrix remodeling., Conclusions: In this rodent model of mitral regurgitation, left ventricular ejection fraction was preserved for a long duration, yet rapid and severe left ventricular dilatation, and biological remodeling occurred before a clinically significant fall in ejection fraction., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: It is difficult to achieve rhythm control in patients with long-standing persistent atrial fibrillation (AF). The radiofrequency maze procedure is an effective means in curing AF with a variable recurrence rate depending on patient characteristics and AF duration. In these patients, the characteristics of the atrial substrate have not been well investigated. Because the inflammatory process has been shown to be important in the pathogenesis of AF, we sought to characterize the proinflammatory gene expression in left atria obtained from patients with AF undergoing mitral valve surgery combined with the maze procedure to distinguish the changes associated with AF and its recurrence after the surgical ablation., Methods: Left atrial appendages from 35 patients receiving mitral valve surgery were used for study. Ten patients had sinus rhythm (SR) and 25 patients had persistent AF for more than 1 year and underwent the maze procedure. Among the AF patients, 13 patients remained in SR (AF-SR) and 12 patients had recurrent AF during the 1-year clinical follow-up (AF-AF). The nCounter Human Inflammation Array (NanoString Technologies, Seattle, Wash) was used for evaluating proinflammatory gene expression. Quantitative polymerase chain reaction, Western blot, and immunohistochemistry were applied for studying messenger RNA and protein expression., Results: Of 144 expressed proinflammatory genes, the inflammation array analysis revealed that 32 genes were differentially expressed between AF (including AF-SR and AF-AF) and SR. Thirteen genes were differentially expressed between AF-SR and AF-AF. The array and quantitative polymerase chain reaction produced parallel results in analyzing the expression of particular genes. Concordant with the gene expression difference between AF and SR patients, rapid pacing increased the expressions of SHC1, RHOA, PDGFA, and TRAF2 in HL-1 myocytes, implicating a causative effect of tachyarrhythmia on these genes. Compared with AF-SR, AF-AF expressed more intense oxidative stress, upregulations of collagen, transforming growth factor beta 1, and intranuclear nuclear factor of activated T-cells. Regression analysis showed that increased left atrial diameter was associated with the expression of RHOA and STAT1., Conclusions: Differential expression profiles of proflammatory genes were presented between SR and AF and between maintained SR and recurrent AF after the maze procedure. The identified inflammatory molecules associated with AF and failed surgical ablation may provide clues for developing new potential therapeutic targets to improve AF rhythm control., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Scarring and collagen deposition in the valves and destruction of myocytes may result from the combined effects of a smoldering rheumatic process and a constant trauma to the mitral valve or aortic valve by the turbulent flow in rheumatic heart disease (RHD). Transforming growth factor-beta1 (TGF-beta1) may be responsible for the increased valvular fibrosis and calcification in the pathogenesis of RHD. However, the role of TGF-beta1 genetic variant in RHD has not been studied. This case-controlled study was carried out to investigate the possible relationship between the TGF-beta1 gene C-509T and T869C polymorphisms and RHD among the Chinese population in Taiwan., Methods: A group of 115 patients with RHD documented by using echocardiography and 100 age- and sex-matched healthy control patients were studied. TGF-beta1 gene C-509T and T869C polymorphisms were identified with polymerase chain reaction-based restriction analysis., Results: A significant difference was seen in the distribution of genotypes between patients with RHD and control patients for either TGF-beta1 C-509T polymorphism (P <.0001) or T869C polymorphism (P <.0001). The frequency of TGF-beta1 C-509T CC genotype was lower in the RHD group than in the control group (chi2 = 19.05, P <.0001), which suggests that this genotype may confer protective effects against RHD. A significant difference was seen in the distribution of allelic frequency between patients with RHD and control patients for TGF-beta1 T869C polymorphism (P =.04). The odds ratio (OR) for risk of RHD associated with TGF-beta1 T869C T allele was 1.49 (95% CI, 1.02-2.19). Further categorization of patients with RHD into mitral valve disease and combined valve disease subgroups revealed no statistical difference in these gene polymorphisms when compared with the 2 subgroups., Conclusions: Patients with RHD have a lower frequency of TGF-beta1 C-509T CC genotype and a higher frequency of T869C T allele, which supports a role for the TGF-beta1 gene C-509T and T869C polymorphisms in determining the risk/protection of RHD in Taiwan Chinese patients.