Abstract
Heart failure with preserved ejection fraction (HFpEF) patients who develop pulmonary hypertension (PH) have an increased risk of death, with combined pre- and post-capillary PH (CpcPH) having the highest risk. However, the mechanism behind PH development in HFpEF is poorly understood. We aimed to identify transcriptomic associations with PH development in HFpEF. Blood was collected from 30 HFpEF patients: 10 without PH, 10 with isolated post-capillary PH, and 10 with CpcPH. Gene expression measurements were completed using transcriptome-wide RNA sequencing. Gene expression differences were compared using a quasi-likelihood method adjusting for age, sex, race, and smoking-status. Biological pathways were compared using global gene expression differences. A replication in 34 additional heart failure patients and a validation in lung tissue from a representative mouse model were completed using quantitative PCR. Six differentially expressed genes were identified when comparing transcriptomics between subjects with CpcPH and those without PH. When tested in additional subjects, only the association with ID2 replicated. Consistent with clinical findings, Id2 expression was also upregulated in mice with HFpEF and PH. Pathway analysis identified proliferative and mitochondrial pathways associated with CpcPH. Thus, these patients may possess systemic pathophysiological differences similar to those observed in pulmonary arterial hypertension patients.
Highlights
Heart failure with preserved ejection fraction (HFpEF) patients who develop pulmonary hypertension (PH) have an increased risk of death, with combined pre- and post-capillary PH (CpcPH) having the highest risk
Four genes were significantly upregulated (ID1, ID2, RYR1, NCBP2-AS2), and two were significantly downregulated (ZNF772, ZNF132), in CpcPH patients compared to HFpEF patients without PH (FDR ≤ 0.05; Fig. 1 and Table 2)
We conducted a transcriptome-wide analysis followed by replication and validation studies to identify genes and biological pathways that may be involved in the development of PH in HFpEF patients
Summary
Heart failure with preserved ejection fraction (HFpEF) patients who develop pulmonary hypertension (PH) have an increased risk of death, with combined pre- and post-capillary PH (CpcPH) having the highest risk. Pathway analysis identified proliferative and mitochondrial pathways associated with CpcPH These patients may possess systemic pathophysiological differences similar to those observed in pulmonary arterial hypertension patients. The current standard of care is to treat comorbid disorders and concentrate on improving volume status and left ventricular relaxation properties[20] This is problematic for patients with heart failure with preserved ejection fraction, who have few treatment options available to treat their underlying disease. The aim of this study was to conduct a transcriptome-wide association study to identify gene expression signatures associated with IpcPH and CpcPH development in HFpEF patients
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