Left Ventricular T-Cell Recruitment Contributes to the Pathogenesis of Heart Failure

Nevers, Tania; Salvador, Ane M.; Grodecki-Pena, Anna; Knapp, Andrew; Velázquez, Francisco; Aronovitz, Mark; Kapur, Navin K.; Karas, Richard H.; Blanton, Robert M.; Alcaide, Pilar

doi:10.1161/circheartfailure.115.002225

Cited by 221 publications

(282 citation statements)

References 51 publications

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“…3E), as previously demonstrated in WT mice (Nevers et al. 2015). Taken together, these data indicate that the contribution of EC‐MR to systolic dysfunction in response to TAC is independent of cardiac adhesion molecule expression and LV CD4+ T cell and CD11b+ monocyte infiltration.…”

Section: Resultsmentioning

confidence: 99%

“…2009; Nevers et al. 2015). Moreover, the amount of TUNEL+ cells was comparable between TAC EC‐MR +/+ mice and TAC EC‐MR −/− at this time (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…2015). Although TAC EC‐MR −/− mice had similar T‐cell infiltration as their TAC WT littermates, we next evaluated LV expression of proinflammatory cytokines in EC‐MR −/− mice.…”

Section: Resultsmentioning

confidence: 99%

“…4 weeks after TAC, mice were euthanized and tissues were harvested for further analysis as described (Nevers et al. 2015; Salvador et al. 2016).…”

Section: Methodsmentioning

confidence: 99%

“…We recently showed using the TAC model, that ICAM‐1 is necessary for recruitment of T cells and proinflammatory monocytes to the heart in response to pressure overload and that this mechanism is necessary for progression to systolic dysfunction and HF (Nevers et al. 2015; Salvador et al. 2016).…”

Section: Introductionmentioning

confidence: 99%

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Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

et al. 2017

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Heart Failure (HF) is associated with increased circulating levels of aldosterone and systemic inflammation. Mineralocorticoid receptor (MR) antagonists block aldosterone action and decrease mortality in patients with congestive HF. However, the molecular mechanisms underlying the therapeutic benefits of MR antagonists remain unclear. MR is expressed in all cell types in the heart, including the endothelial cells (EC), in which aldosterone induces the expression of intercellular adhesion molecule 1 (ICAM‐1). Recently, we reported that ICAM‐1 regulates cardiac inflammation and cardiac function in mice subjected to transverse aortic constriction (TAC). Whether MR specifically in endothelial cells (EC) contributes to the several mechanisms of pathological cardiac remodeling and cardiac dysfunction remains unclear. Basal cardiac function and LV dimensions were comparable in mice with MR selectively deleted from ECs (EC‐MR −/−) and wild‐type littermate controls (EC‐MR +/+). MR was specifically deleted in heart EC, and in EC‐containing tissues, but not in leukocytes of TAC EC‐MR −/− mice. While EC‐MR −/− TAC mice showed preserved systolic function and some alterations in the expression of fetal genes, the proinflammatory cytokine TNF α and the endothelin receptors in the LV as compared to EC‐MR +/+ TAC mice, no difference was observed between both TAC groups in overall cardiac hypertrophy, ICAM‐1 LV expression and leukocyte infiltration, cardiac fibrosis or capillary rarefaction, all hallmarks of pathological cardiac remodeling. Our data indicate that EC‐MR contributes to the transition of cardiac hypertrophy to systolic dysfunction independently of other maladaptive changes induced by LV pressure overload.

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Section: Resultsmentioning

confidence: 99%

“…2009; Nevers et al. 2015). Moreover, the amount of TUNEL+ cells was comparable between TAC EC‐MR +/+ mice and TAC EC‐MR −/− at this time (Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…4 weeks after TAC, mice were euthanized and tissues were harvested for further analysis as described (Nevers et al. 2015; Salvador et al. 2016).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

et al. 2017

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Epigenetics of Aberrant Cardiac Wound Healing

Russell‐Hallinan

Watson

Baugh

2018

Comprehensive Physiology

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Remodeling of cardiac tissue architecture is essential for normal organ development and maintaining homeostasis after injury. Injurious insults to the heart, such as hypertension and myocardial infarction, promote cellular responses including stimulation of resident inflammatory cells, activation of endothelial cells and recruitment of immune cells, hypertrophy of cardiomyocytes, and activation of fibroblasts. The physiological goal of this coordinated cellular response is to repair damaged tissue while maintaining or restoring cardiac contractile function. Persistent uncontrolled inflammation, hypertrophy, and fibrosis in the heart due to hyperactive wound healing are detrimental and impair cardiac performance, facilitating the progression to heart failure. Abnormal changes in gene expression promote acquisition of aberrant cellular phenotypes that drive cardiac remodeling. DNA methylation and histone modifications are epigenetic mechanisms that critically regulate chromatin structure and gene expression, and are essential for normal physiology and development. Increasing clinical and experimental evidence suggests that these epigenetic mechanisms are involved in driving aberrant wound healing and the development of heart failure. While most of our knowledge to date is on the heart as a whole, the precise contribution of DNA methylation and histone modifications in regulating aberrant cardiac remodeling at the cellular level is less defined. Therefore, this overview aims to summarize the role of DNA methylation and histone modifications (acetylation and methylation) in heart failure and to comprehensively dissect the role these mechanisms play in regulating the function of cardiomyocytes, fibroblasts, and immune cells in response to injury. © 2018 American Physiological Society. Compr Physiol 8:451-491, 2018.

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Leucocyte count predicts cardiovascular risk in heart failure with preserved ejection fraction: insights from TOPCAT Americas

et al. 2020

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Aims Prior evidence has implicated leucocyte expansion in several cardiovascular disorders, including heart failure (HF) with reduced ejection fraction (rEF). However, the prognostic importance of leucocyte count in HF with preserved EF (HFpEF) remains largely unexplored. Methods and results The Americas cohort of the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT-Americas) was used to evaluate the association between total leucocyte count and clinical outcomes in HFpEF. The primary outcome was a composite of aborted cardiac arrest, cardiovascular mortality, or hospitalization for HF. Secondary outcomes were hospitalization for HF, aborted cardiac arrest, stroke, non-fatal myocardial infarction (MI), cardiovascular mortality, non-cardiovascular mortality, and all-cause mortality. Survival models were used to identify the risk of the primary and secondary outcomes in those with leucocyte count above the median (7100 cells/μL), as compared to those with leucocyte count below the median, during the follow-up period. A total of 1746 (out of 1767; 99%) patients from TOPCAT-Americas were available for the analyses with a median follow up of 2.4 (25th to 75th percentile 1.4-3.9) years. Patients with leucocyte count >7100 cells/μL were 36% more likely to experience the primary endpoint compared to those with ≤7100 cells/μL (hazard ratio: 1.36, 95% confidence interval: 1.14-1.61). This association remained significant after extensive adjustment for potential confounders (hazard ratio: 1.27, 95% confidence interval: 1.06-1.52). We also observed a greater incidence of HF hospitalization and non-fatal MI in patients with higher leucocyte count. These associations remained robust on sensitivity analyses, suggesting a low probability of confounding. Exploratory analyses suggested that both higher leucocyte count (integrating the combined influence of both myeloid and lymphoid immune cells) and augmented platelet count (as a surrogate for myeloid immune cell expansion) in the same model were associated with the primary outcome (both P < 0.05). Conclusions Leucocyte count >7100 cells/μL was independently associated with adverse clinical outcomes in HFpEF patients from TOPCAT-Americas. These results were primarily driven by the HF hospitalization outcome but were also accompanied by an excess of non-fatal MI. Further research is needed to define the mechanisms underlying our findings and their prognostic implications.

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Left Ventricular T-Cell Recruitment Contributes to the Pathogenesis of Heart Failure

Cited by 221 publications

References 51 publications

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

Epigenetics of Aberrant Cardiac Wound Healing

Leucocyte count predicts cardiovascular risk in heart failure with preserved ejection fraction: insights from TOPCAT Americas

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