Dataset Information

Cardiac resynchronization therapy reduces expression of inflammation-promoting genes related to interleukin-1? in heart failure.

ABSTRACT:

Aims

In light of recent data regarding inflammatory signalling pathways in cardiovascular disease and the recently demonstrated impact of pharmacologic inhibition of interleukin-1? (IL-1?) in heart failure, the primary aim was to assess the physiologic effects of cardiac resynchronization therapy (CRT) on the expression of systemic inflammatory, immune-modulatory, metabolic, and apoptotic genes in peripheral blood mononuclear cells (PBMCs) of patients with heart failure.

Methods and results

We used RNA sequencing (RNA-Seq) and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) to identify gene expression changes in PBMCs in response to CRT. In total, 27 patients were analysed: 12 with heart failure undergoing CRT, 6 with heart failure undergoing standard implanted cardioverter defibrillators, and 9 with coronary artery disease but not heart failure. In CRT patients (median age 65.5?years, interquartile range 63.0-66.8?years, 33% female), RNA-Seq analysis identified 40 genes, including multiple genes associated with the IL-1? pathway, with significant correlations (false discovery rate < 0.05) with four key CRT response measures. CRT was associated with suppression of PBMC expression of IL-1? (1.80-fold decrease, P?=?0.047), FOS proto-oncogene (FOS) (3.25-fold decrease, P?=?0.01), dual specificity phosphatase 1 (DUSP1) (2.05-fold decrease, P?=?0.001), and early growth response 1 (EGR1) (7.38-fold decrease, P?=?0.03), and suppression was greater in responders vs. non-responders (P?=?0.03 for IL-1?, P?=?0.02 for FOS, P?=?0.02 for DUSP1, and P?=?0.11 for EGR1). Baseline FOS and DUSP-1 levels were greater in responders vs. non-responders (6.15-fold higher, FOS, P?=?0.002; 2.60-fold higher, DUSP1, P?=?0.0001). CRT responders but not non-responders showed higher baseline gene expression of FOS (P?=?0.04) and DUSP1 (P?=?0.06) compared with control patients without heart failure. Baseline serum high-sensitivity C-reactive protein levels were 3.47-fold higher in CRT responders vs. non-responders (P?=?0.008).

Conclusion

Treatment of heart failure with CRT resulted in decreased PBMC expression of genes linked to inflammation. Moreover, CRT responders had higher expression of these inflammatory genes prior to CRT and greater suppression of these genes after CRT compared with non-responders.

SUBMITTER: Bilchick K

PROVIDER: S-EPMC7849974 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Cardiac resynchronization therapy reduces expression of inflammation-promoting genes related to interleukin-1β in heart failure.

Bilchick Kenneth K Kothari Hema H Narayan Aditya A Garmey James J Omar Abdullah A Capaldo Brian B McNamara Coleen C

Cardiovascular research 20200601 7

<h4>Aims</h4>In light of recent data regarding inflammatory signalling pathways in cardiovascular disease and the recently demonstrated impact of pharmacologic inhibition of interleukin-1β (IL-1β) in heart failure, the primary aim was to assess the physiologic effects of cardiac resynchronization therapy (CRT) on the expression of systemic inflammatory, immune-modulatory, metabolic, and apoptotic genes in peripheral blood mononuclear cells (PBMCs) of patients with heart failure.<h4>Methods and r ...[more]

PMID: 31612215

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Project description:Background Patients with recurring heart failure (HF) following cardiac resynchronization therapy fare poorly. Their management is undecided. We tested remote hemodynamic-guided pharmacotherapy. Methods and Results We evaluated cardiac resynchronization therapy subjects included in the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association Class III Heart Failure Patients) trial, which randomized patients with persistent New York Heart Association Class III symptoms and ≥1 HF hospitalization in the previous 12 months to remotely managed pulmonary artery (PA) pressure-guided management (treatment) or usual HF care (control). Diuretics and/or vasodilators were adjusted conventionally in control and included remote PA pressure information in treatment. Annualized HF hospitalization rates, changes in PA pressures over time (analyzed by area under the curve), changes in medications, and quality of life (Minnesota Living with Heart Failure Questionnaire scores) were assessed. Patients who had cardiac resynchronization therapy (n=190, median implant duration 755 days) at enrollment had poor hemodynamic function (cardiac index 2.00±0.59 L/min per m2), high comorbidity burden (67% had secondary pulmonary hypertension, 61% had estimated glomerular filtration rate <60 mL/min per 1.73 m2), and poor Minnesota Living with Heart Failure Questionnaire scores (57±24). During 18 months randomized follow-up, HF hospitalizations were 30% lower in treatment (n=91, 62 events, 0.46 events/patient-year) versus control patients (n=99, 93 events, 0.68 events/patient-year) (hazard ratio, 0.70; 95% CI, 0.51-0.96; P=0.028). Treatment patients had more medication up-/down-titrations (847 versus 346 in control, P<0.001), mean PA pressure reduction (area under the curve -413.2±123.5 versus 60.1±88.0 in control, P=0.002), and quality of life improvement (Minnesota Living with Heart Failure Questionnaire decreased -13.5±23 versus -4.9±24.8 in control, P=0.006). Conclusions Remote hemodynamic-guided adjustment of medical therapies decreased PA pressures and the burden of HF symptoms and hospitalizations in patients with recurring Class III HF and hospitalizations, beyond the effect of cardiac resynchronization therapy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00531661.

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