Transcriptomal Insights of Heart Failure from Normality to Recovery

Abstract

Current management of heart failure (HF) is centred on modulating the progression of symptoms and severity of left ventricular dysfunction. However, specific understandings of genetic and molecular targets are needed for more precise treatments. To attain a clearer picture of this, we studied transcriptome changes in a chronic progressive HF model. Fifteen sheep (Ovis aries) underwent supracoronary aortic banding using an inflatable cuff. Controlled and progressive induction of pressure overload in the LV was monitored by echocardiography. Endomyocardial biopsies were collected throughout the development of LV failure (LVF) and during the stage of recovery. RNA-seq data were analysed using the PANTHER database, Metascape, and DisGeNET to annotate the gene expression for functional ontologies. Echocardiography revealed distinct clinical differences between the progressive stages of hypertrophy, dilatation, and failure. A unique set of transcript expressions in each stage was identified, despite an overlap of gene expression. The removal of pressure overload allowed the LV to recover functionally. Compared to the control stage, there were a total of 256 genes significantly changed in their expression in failure, 210 genes in hypertrophy, and 73 genes in dilatation. Gene expression in the recovery stage was comparable with the control stage with a well-noted improvement in LV function. RNA-seq revealed the expression of genes in each stage that are not reported in cardiovascular pathology. We identified genes that may be potentially involved in the aetiology of progressive stages of HF, and that may provide future targets for its management.

Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies

“…The study also investigated the single-nucleus transcriptome in cardiomyocytes and non-myocyte cell types and showed metabolic pathways were profoundly impaired in DCM cardiomyocytes but not HCM cardiomyocytes, suggesting the disease-specific metabolic alteration. Similarly, another paper also showed HCM- or DCM-specific impaired metabolic processes ( 67 ). Disease-specific gene sets, some of which are involved in lipid metabolism, were found to be differentially changed between DCM and HCM, such as the up-regulated APOE and the down-regulated GPT in DCM, as well as the up-regulated APOLD1 and the down-regulated STARD13 and PON3 in HCM.…”

Roles of the crucial mitochondrial DNA in hypertrophic cardiomyopathy prognosis and diagnosis: A review

“…[ 34 ] Previous studies have shown that the GnRH pathway is involved in the development of cardiomyopathies. [ 35 ] Toll-like receptors, as key factors that regulate innate immune responses, can lead to acute and chronic inflammation. [ 36 ] Inflammation is a characteristic feature of cardiac hypertrophy and mediates the important roles of toll-like receptors in the HCM process.…”

Genetic factors of heart failure (review)

“…В то же время развитие СН -это динамический процесс, в ходе которого происходит каскад метаболических изменений в миокарде и организме в целом. При моделировании прогрессирующей ХСН на овцах выявлены различия в экспрессии генов в миокарде на разных стадиях развития данного патологического состояния: по сравнению с контролем (до начала эксперимента) на стадии дилатации изменялась экспрессия 73 генов, на стадии гипертрофии -210 генов, при развитии СН -56 генов [10]. Большинство генов с измененной экспрессией на разных стадиях были уникальными и лишь незначительная их часть -общими для разных стадий.…”

“…Большинство генов с измененной экспрессией на разных стадиях были уникальными и лишь незначительная их часть -общими для разных стадий. При этом изменения в экспрессии носили обратимый характер, так как на стадии восстановления транскриптомные профили миокарда в значительной степени соответствовали таковым на стадии до начала проведения эксперимента [10]. Обратимость молекулярных изменений при развитии СН указывает на возможность управления данным патологическим процессом в случае выявления ключевых молекулярных событий.…”

“…В настоящее время активно изучается молекулярная патогенетика СН, в том числе на уровне генетических механизмов [8][9][10][11][12].…”