Innate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts

Olson, Nels C.; Sitlani, Colleen M.; Doyle, Margaret F.; Huber, Sally A.; Landay, Alan; Tracy, Russell P.; Psaty, Bruce M.; Delaney, Joseph

doi:10.1016/j.atherosclerosis.2020.03.011

Cited by 33 publications

(63 citation statements)

References 48 publications

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“…Details regarding design, recruitment, and objectives of MESA are described elsewhere [ 13 ]. We designed a case-cohort study to test the primary hypothesis that immune cells subsets were risk factors for CHD [ 10 ]. We then leveraged the data from the case-cohort study to consider other scientific questions using the same study population [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…We then leveraged the data from the case-cohort study to consider other scientific questions using the same study population [ 14 ]. We selected a case-cohort sample of 1195 participants, with case status (n = 476) based on incident myocardial infarction or incident angina events during study follow-up [ 10 ] with the remainder of the participants being selected by simple random sampling.…”

Section: Methodsmentioning

confidence: 99%

“…To investigate the links between immune cell subsets and cardiovascular disease (CVD), we used cryopreserved peripheral blood mononuclear cells (PBMC) to phenotype a range of immune cells by flow cytometry in the MESA cohort [ 10 ]. We leveraged the availability of this data for a secondary analysis of the relationships between 30 immune cell subsets and repeated SBP measures measured over 10-years.…”

Section: Introductionmentioning

confidence: 99%

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Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA)

Delaney

Olson

Sitlani

et al. 2021

BMC Cardiovasc Disord

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Background Hypertension is a major source of cardiovascular morbidity and mortality. Recent evidence from mouse models, genetic, and cross-sectional human studies suggest increased proportions of selected immune cell subsets may be associated with levels of systolic blood pressure (SBP). Methods We assayed immune cells from cryopreserved samples collected at the baseline examination (2000–2002) from 1195 participants from the multi-ethnic study of atherosclerosis (MESA). We used linear mixed models, with adjustment for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and cytomegalovirus titers, to estimate the associations between 30 immune cell subsets (4 of which were a priori hypotheses) and repeated measures of SBP (baseline and up to four follow-up measures) over 10 years. The analysis provides estimates of the association with blood pressure level. Results The mean age of the MESA participants at baseline was 64 ± 10 years and 53% were male. A one standard deviation (1-SD) increment in the proportion of γδ T cells was associated with 2.40 mmHg [95% confidence interval (CI) 1.34–3.42] higher average systolic blood pressure; and for natural killer cells, a 1-SD increment was associated with 1.88 mmHg (95% CI 0.82–2.94) higher average level of systolic blood pressure. A 1-SD increment in classical monocytes (CD14++CD16−) was associated with 2.01 mmHG (95% CI 0.79–3.24) lower average systolic blood pressure. There were no associations of CD4+ T helper cell subsets with average systolic blood pressure. Conclusion These findings suggest that the innate immune system plays a role in levels of SBP whereas there were no associations with adaptive immune cells.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA)

Delaney

Olson

Sitlani

et al. 2021

BMC Cardiovasc Disord

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“…Our understanding of immune cell function on cardiovascular events continues to advance. In 2004, it was reported that elevated leukocyte numbers may be used in risk factor assessment of coronary heart disease [161] but more recently, a detailed panel of 34 myeloid and lymphoid subpopulations from peripheral blood showed leukocyte quantity had no predictive value of future MI and correlate better with atherosclerosis [162]. A meta-analysis of 24 studies with 43,725 individuals, showed that shorter leukocyte telomere length, a bio-marker for aging, was associated with coronary heart disease [163].…”

Section: Consequences Of Hsc Aging On Heart Repair and Prospective Thmentioning

confidence: 99%

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

Tobin

Alibhai

Weisel

et al. 2020

Cells

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The importance of the immune system for cardiac repair following myocardial infarction is undeniable; however, the complex nature of immune cell behavior has limited the ability to develop effective therapeutics. This limitation highlights the need for a better understanding of the function of each immune cell population during the inflammatory and resolution phases of cardiac repair. The development of reliable therapies is further complicated by aging, which is associated with a decline in cell and organ function and the onset of cardiovascular and immunological diseases. Aging of the immune system has important consequences on heart function as both chronic cardiac inflammation and an impaired immune response to cardiac injury are observed in older individuals. Several studies have suggested that rejuvenating the aged immune system may be a valid therapeutic candidate to prevent or treat heart disease. Here, we review the basic patterns of immune cell behavior after myocardial infarction and discuss the autonomous and nonautonomous manners of hematopoietic stem cell and immune cell aging. Lastly, we identify prospective therapies that may rejuvenate the aged immune system to improve heart function such as anti-inflammatory and senolytic therapies, bone marrow transplant, niche remodeling and regulation of immune cell differentiation.

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“…CD27 -CD28 -CD45RO + CD4 + T cells, for example, were associated with increased mortality from coronary heart disease. 16 In contrast, a large analysis combining participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) found that circulating lymphocytes (CD4 + , CD8 + , CD19 + ) and monocytes (CD14 + ) were not associated with future myocardial infarction in otherwise healthy adults 17 . Among PLWH, lower CD4 + T cell counts have been linked with higher rates of non-AIDS diseases, including CVD.…”

Section: Introductionmentioning

confidence: 99%

Digital spatial profiling of coronary plaques from persons living with HIV reveals high levels of STING and CD163 in macrophage enriched regions

Wanjalla

Guo

Fuller

et al. 2020

Preprint

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BackgroundChronic innate and adaptive immune activation may contribute to high prevalence of cardiovascular disease in persons living with HIV (PLWH).MethodsWe assessed coronary plaques from deceased PLWH (n=6) and HIV-negative (n=6) persons matched by age and gender. Formalin-fixed, paraffin-embedded 5μm thick sections were processed using Movat, hematoxylin and eosin, immunohistochemical and immunofluorescence stains. Immune cell populations were measured using surface antibodies, and immune-related protein expression from macrophage rich, T-cell rich and perivascular adipose tissue regions using GeoMx® digital spatial profiling.ResultsCoronary plaques from PLWH and HIV-negative persons had similar plaque area and percent stenosis. Percent CD163+ cells as measured by immunohistochemical staining was significantly higher in PLWH, median 0.29% (IQR 0.11-0.90) vs. 0.01% (IQR 0.0013-0.11) in HIV-negative plaque, p = 0.02 (Figure 1A). Other surface markers of innate cells (CD68 +, p=0.18), adaptive immune cells (CD3+, p=0.39; CD4+, p=0.09; CD8+, p=0.18) and immune trafficking markers (CX3CR1+, p=0.09) within the coronary plaque trended higher in HIV-positive plaques but did not reach statistical significance. GeoMx® digital spatial profiling showed higher differential protein expression of CD163 (scavenger receptor for hemoglobin-haptoglobin complex), stimulator of interferon gamma (STING, a cytosolic DNA sensor), CD25 and granzyme-B in the HIV-positive compared to HIV-negative, p<0.05(Figure 1B).ConclusionsIncreased inflammation within the coronary plaques of PLWH is characterized by more innate and adaptive immune cells. Higher STING expression in PLWH suggests that immune response to viral antigens within the plaque might be a driver above other stimulants. STING inhibitors are available and could be investigated as a future therapeutic target in PWH if these results are replicated with a larger number of plaques.Graphical AbstractHighlightsImmunohistochemical and fluorescent stains combined with GeoMx® digital spatial profiling allowed for deep characterization of immune cells within intact coronary plaques and perivascular adipose tissueCoronary plaques from HIV-positive persons had higher proportion of CD163+ immune cells compared to HIV-negative personsDifferential protein expression of immune-rich regions of interest within intact 5μm sections of coronary plaques revealed higher levels of stimulator of interferon gamma (STING) in HIV-positive persons

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Innate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts

Cited by 33 publications

References 48 publications

Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA)

Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA)

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

Digital spatial profiling of coronary plaques from persons living with HIV reveals high levels of STING and CD163 in macrophage enriched regions

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