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Fetal-adult cardiac transcriptome analysis in rats with contrasting left ventricular mass reveals new candidates for cardiac hypertrophy.

ABSTRACT: Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.e. the stroke-prone spontaneously hypertensive rat (SHRSP). To this end we performed genome-wide transcriptome analysis in SHRSP to identify differences in expression patterns between day 20 of fetal development (E20) and adult animals in week 14 in comparison to a normotensive rat strain with contrasting low LV mass, i.e. Fischer (F344). 15232 probes were detected as expressed in LV tissue obtained from rats at E20 and week 14 (p < 0.05) and subsequently screened for differential expression. We identified 24 genes with SHRSP specific up-regulation and 21 genes with down-regulation as compared to F344. Further bioinformatic analysis presented Efcab6 as a new candidate for LVH that showed only in the hypertensive SHRSP rat differential expression during development (logFC = 2.41, p < 0.001) and was significantly higher expressed in adult SHRSP rats compared with adult F344 (+ 76%) and adult normotensive Wistar-Kyoto rats (+ 82%). Thus, it represents an interesting new target for further functional analyses and the elucidation of mechanisms leading to LVH. Here we report a new approach to identify candidate genes for cardiac hypertrophy by combining the analysis of gene expression differences between strains with a contrasting cardiac phenotype with a comparison of fetal-adult cardiac expression patterns.

SUBMITTER: Grabowski K

PROVIDER: S-EPMC4315412 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Fetal-adult cardiac transcriptome analysis in rats with contrasting left ventricular mass reveals new candidates for cardiac hypertrophy.

Grabowski Katja K Riemenschneider Mona M Schulte Leonard L Witten Anika A Schulz Angela A Stoll Monika M Kreutz Reinhold R

PloS one 20150203 2

Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.e. the stroke-prone ...[more]

PMID: 25646840

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Project description:AimsA waiting period of more than 3 months is recommended for patients before undergoing cardiac resynchronization therapy (CRT). However, due to an anticipated high mortality rate, early implementation of CRT might be beneficial for some patients. We aimed to evaluate the rate and the probability of left ventricular (LV) function improvement and their predictors in patients with heart failure (HF) with indications for CRT.Methods and resultsFrom March 2011 to February 2014, a total of 5625 hospitalized patients for acute HF were consecutively enrolled in 10 tertiary hospitals. Among them, we analysed 1792 patients (mean age 63.96 ± 15.42 years, female 63.1%) with left ventricular ejection fraction (LVEF) ≤ 35% at the baseline echocardiography and divided them into three groups: 144 with left bundle branch block (LBBB), 136 with wide QRS complexes without LBBB, and 1512 not having these findings (control). We compared and analysed these three groups for improvement of LV function at follow-up echocardiography. In patients who met CRT indications (patients with LBBB or wide QRS complexes without LBBB), logistic regression was performed to identify risk factors for no improvement of LV. No improvement of LV was defined as LVEF ≤ 35% at follow-up echocardiography or the composite adverse outcomes: death, heart transplantation, extracorporeal membrane oxygenation, or use of a ventricular assist device before follow-up echocardiography. A classification tree was established using the binary recursive partitioning method to predict the outcome of patients who met CRT indications. In a median follow-up of 11 months, LVEF improvement was observed in 24.3%, 15.4%, and 40.5% of patients with LBBB, wide QRS complexes without LBBB, and control, respectively. Patients meeting CRT indications had higher 3 month mortality rates than the control (24.6% vs. 17.7%, P = 0.002). Multivariable logistic regression analysis revealed that large LV end-systolic dimension [odds ratio (OR) 1.10, 95% confidence interval (CI) 1.05-1.15, P < 0.001], low LVEF (OR 0.92, 95% CI 0.87-0.98, P = 0.006), diabetes requiring insulin (OR 6.49, 95% CI 2.53-19.33, P < 0.001), and suboptimal medical therapy (OR 6.85, 95% CI 3.21-15.87, P < 0.001) were significant factors predictive of no improvement. A decision tree analysis was consistent with these results.ConclusionsPatients with CRT indications had higher mortality during their follow-up compared with control. LV function improvement was rare in this population, especially when they had some risk factors. These results suggest that the uniform waiting period before CRT implantation could be reconsidered and individualized.

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Fetal-adult cardiac transcriptome analysis in rats with contrasting left ventricular mass reveals new candidates for cardiac hypertrophy.

Publications

Fetal-adult cardiac transcriptome analysis in rats with contrasting left ventricular mass reveals new candidates for cardiac hypertrophy.

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