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

Bilchick, Kenneth C.; Kothari, Hema; Narayan, Aditya; Garmey, James C.; Omar, Abdullah; Capaldo, Brian J.; McNamara, Coleen A.

doi:10.1093/cvr/cvz232

Cited by 12 publications

(6 citation statements)

References 55 publications

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“…We observed that global miRNA expression decreases with worsening RV enlargement. A similar finding has been seen in other reports evaluating miRNA signatures found in plasma of heart failure patients [ 17 , 38 ] where the authors suggest that as patients develop worsening volume overload, a dilutional effect can lead to a reduction in measured plasma miRNA. Although this may play a role in miRNA measured in plasma, it seems less likely in the buffy coat.…”

Section: Discussionsupporting

confidence: 89%

Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot

et al. 2020

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Introduction The adult congenital heart disease population with repaired tetralogy of Fallot (TOF) is subject to chronic volume and pressure loading leading to a 40% probability of right ventricular (RV) failure by the 3rd decade of life. We sought to identify a non-invasive signature of adverse RV remodeling using peripheral blood microRNA (miRNA) profiling to better understand the mechanisms of RV failure. Methods Demographic, clinical data, and blood samples were collected from adults with repaired TOF (N = 20). RNA was isolated from the buffy coat of peripheral blood and whole genome miRNA expression was profiled using Agilent’s global miRNA microarray platform. Fold change, pathway analysis, and unbiased hierarchical clustering of miRNA expression was performed and correlated to RV size and function assessed by echocardiography performed at or near the time of blood collection. Results MiRNA expression was profiled in the following groups: 1. normal RV size (N = 4), 2. mild/moderate RV enlargement (N = 11) and 3. severe RV enlargement (N = 5). 267 miRNAs were downregulated, and 66 were upregulated across the three groups (fold change >2.0, FDR corrected p<0.05) as RV enlargement increased and systolic function decreased. qPCR validation of a subset of these miRNAs identified increasing expression of miRNA 28-3p, 433-3p, and 371b-3p to be associated with increasing RV size and decreasing RV systolic function. Unbiased hierarchical clustering of all patients based on miRNA expression demonstrates three distinct patient clusters that largely coincide with progressive RV enlargement. Pathway analysis of dysregulated miRNAs demonstrates up and downregulation of cell cycle pathways, extracellular matrix proteins and fatty acid synthesis. HIF 1α signaling was downregulated while p53 signaling was predicted to be upregulated. Conclusion Adults with TOF have a distinct miRNA profile with progressive RV enlargement and dysfunction implicating cell cycle dysregulation and upregulation in extracellular matrix and fatty acid metabolism. These data suggest peripheral blood miRNA can provide insight into the mechanisms of RV failure and can potentially be used for monitoring disease progression and to develop RV specific therapeutics to prevent RV failure in TOF.

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Section: Discussionsupporting

confidence: 89%

Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot

et al. 2020

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“…The c-FOS and c-JUN are family of AP-1, which regulate the MAPK pathway, and can be inhibited by SIRT3 ( 196 ). EGR1 and c-FOS are also associated with the release of IL-1β ( 197 ). SP-1 can regulate immune responses, but it is a non-specific transcription factor involved in many other cellular processes and indicates transcriptional activation; (2) Regulation of metabolism.…”

Section: Link Between Heart Failure and Comorbiditiesmentioning

confidence: 99%

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

Zhao

Wang

2021

Front. Cardiovasc. Med.

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Heart failure (HF) patients often suffer from multiple comorbidities, such as diabetes, atrial fibrillation, depression, chronic obstructive pulmonary disease, and chronic kidney disease. The coexistance of comorbidities usually leads to multi morbidity and poor prognosis. Treatments for HF patients with multi morbidity are still an unmet clinical need, and finding an effective therapy strategy is of great value. HF can lead to comorbidity, and in return, comorbidity may promote the progression of HF, creating a vicious cycle. This reciprocal correlation indicates there may be some common causes and biological mechanisms. Metabolism remodeling and chronic inflammation play a vital role in the pathophysiological processes of HF and comorbidities, indicating metabolism and inflammation may be the links between HF and comorbidities. In this review, we comprehensively discuss the major underlying mechanisms and therapeutic implications for comorbidities of HF. We first summarize the potential role of metabolism and inflammation in HF. Then, we give an overview of the linkage between common comorbidities and HF, from the perspective of epidemiological evidence to the underlying metabolism and inflammation mechanisms. Moreover, with the help of bioinformatics, we summarize the shared risk factors, signal pathways, and therapeutic targets between HF and comorbidities. Metabolic syndrome, aging, deleterious lifestyles (sedentary behavior, poor dietary patterns, smoking, etc.), and other risk factors common to HF and comorbidities are all associated with common mechanisms. Impaired mitochondrial biogenesis, autophagy, insulin resistance, and oxidative stress, are among the major mechanisms of both HF and comorbidities. Gene enrichment analysis showed the PI3K/AKT pathway may probably play a central role in multi morbidity. Additionally, drug targets common to HF and several common comorbidities were found by network analysis. Such analysis has already been instrumental in drug repurposing to treat HF and comorbidity. And the result suggests sodium-glucose transporter-2 (SGLT-2) inhibitors, IL-1β inhibitors, and metformin may be promising drugs for repurposing to treat multi morbidity. We propose that targeting the metabolic and inflammatory pathways that are common to HF and comorbidities may provide a promising therapeutic strategy.

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“…Similar to the IL-1β blockade by anakinra, Van Tassell et al found an improvement of LV pressures as assessed by echocardiography after 12 weeks of treatment [43]. Corroborating a potential circulating factor and IL-1β implication, Bilchik et al demonstrated that cardiac resynchronization therapy (CRT) in HF responder patients reduced the expression of inflammation-promoting genes related to IL-1 β in PBMC [44].…”

Section: Potential Mechanisms Involved In Impaired Mitochondrial Respiration Of Pbmc In Hfmentioning

confidence: 91%

Pathophysiology of Heart Failure: A Role for Peripheral Blood Mononuclear Cells Mitochondrial Dysfunction?

Sauer

Riou

Charles

et al. 2022

JCM

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Heart failure (HF) is a leading cause of hospitalization in patients aged more than 65 years and is associated with high mortality rates. A better comprehension of its physiopathology is still needed, and, in addition to neurohormonal systems and sodium glucose co-transporter 2 modulations, recent studies focus on the mitochondrial respiration of peripheral blood circulating cells (PBMCs). Thus, cardiovascular metabolic risk factors and cellular switch with an increased neutrophil/lymphocytes ratio might favor the decreased PBMC mitochondrial respiration observed in relation with HF severity. PBMCs are implicated in the immune system function and mitochondrial dysfunction of PBMC, potentially induced by their passage through a damaged heart and by circulating mitoDAMPs, which can lead to a vicious circle, thus sustaining negative cardiac remodeling during HF. This new approach of HF complex pathophysiology appears to be a promising field of research, and further studies on acute and chronic HF with reduced or preserved LVEF are warranted to better understand whether circulating PBMC mitochondrial function and mitoDAMPs follow-ups in HF patients might show diagnosis, prognosis or therapeutic usefulness.

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

Cited by 12 publications

References 55 publications

Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot

Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

Pathophysiology of Heart Failure: A Role for Peripheral Blood Mononuclear Cells Mitochondrial Dysfunction?

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