The study was designed to investigate the pattern of intraventricular hemodynamic forces (HDFs) and myocardial performance during exercise in elite cyclists (ECs). Transthoracic stress echocardiography was performed on 19 ECs and 13 age-matched sedentary controls (SCs) at three incremental exercise intensities based on heart rate reserve (HRR). Left ventricular (LV) HDFs were computed from echocardiography long-axis datasets using a novel technique based on endocardial boundary tracking, both in apex-base and latero-septal directions. Pressure volume (PV) loops were noninvasively investigated using the single-beat approach. Differences between groups were investigated using mixed model analysis. At PV loops, EC showed a steeper increase in stroke work compared with SC, without acute changes in ventricular capacity (EDVI20). Contractility, measured as ventricular elastance (Ees), increased during exercise with no difference between groups (P = 0.625). At rest, EC had significantly lower heart rates and generated lower HDF than SC. However, during exercise, the pressure gradient developed by EC in systole, and therefore systolic HDF, was significantly higher than that developed by SC (P < 0.009), also showing a greater elastic rebound in late systole compared with SC (P < 0.032). Importantly, during early diastolic filling, EC showed lower HDF deceleration than SC (P < 0.043), indicating a facilitated relaxation of the left ventricle. Analysis of the HDF pattern during exercise shows the functional changes that occur in EC, characterized by increased HDF generation in systole, and facilitated relaxation in early diastole. This is the first time LV structural and functional remodeling is reported for elite cyclists during exercise.NEW & NOTEWORTHY Analysis of the hemodynamic forces shows that the functional changes that occur in elite cyclists during exercise are characterized by increased hemodynamic forces generation in systole, and facilitated relaxation in early diastole.
{"title":"Structural and functional remodeling for elite cyclists during exercise; pressure-volume loops and hemodynamic forces analysis.","authors":"Alessio Pellegrino, Loira Toncelli, Simone Vanni, Alessandra Modesti, Gianni Pedrizzetti, Pietro Amedeo Modesti","doi":"10.1152/ajpheart.00882.2024","DOIUrl":"10.1152/ajpheart.00882.2024","url":null,"abstract":"<p><p>The study was designed to investigate the pattern of intraventricular hemodynamic forces (HDFs) and myocardial performance during exercise in elite cyclists (ECs). Transthoracic stress echocardiography was performed on 19 ECs and 13 age-matched sedentary controls (SCs) at three incremental exercise intensities based on heart rate reserve (HRR). Left ventricular (LV) HDFs were computed from echocardiography long-axis datasets using a novel technique based on endocardial boundary tracking, both in apex-base and latero-septal directions. Pressure volume (PV) loops were noninvasively investigated using the single-beat approach. Differences between groups were investigated using mixed model analysis. At PV loops, EC showed a steeper increase in stroke work compared with SC, without acute changes in ventricular capacity (EDVI<sub>20</sub>). Contractility, measured as ventricular elastance (E<sub>es</sub>), increased during exercise with no difference between groups (<i>P</i> = 0.625). At rest, EC had significantly lower heart rates and generated lower HDF than SC. However, during exercise, the pressure gradient developed by EC in systole, and therefore systolic HDF, was significantly higher than that developed by SC (<i>P</i> < 0.009), also showing a greater elastic rebound in late systole compared with SC (<i>P</i> < 0.032). Importantly, during early diastolic filling, EC showed lower HDF deceleration than SC (<i>P</i> < 0.043), indicating a facilitated relaxation of the left ventricle. Analysis of the HDF pattern during exercise shows the functional changes that occur in EC, characterized by increased HDF generation in systole, and facilitated relaxation in early diastole. This is the first time LV structural and functional remodeling is reported for elite cyclists during exercise.<b>NEW & NOTEWORTHY</b> Analysis of the hemodynamic forces shows that the functional changes that occur in elite cyclists during exercise are characterized by increased hemodynamic forces generation in systole, and facilitated relaxation in early diastole.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H393-H400"},"PeriodicalIF":4.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-01-10DOI: 10.1152/ajpheart.00796.2024
Heidi Bouquin, Lauri J Suojanen, Jenni K Koskela, Essi Pietilä, Manoj Kumar Choudhary, Jukka T Mustonen, Ilkka H Pörsti
Increased blood pressure upon standing is considered a cardiovascular risk factor. We investigated the reproducibility of changes in aortic blood pressure, heart rate, stroke volume, cardiac output, and systemic vascular resistance during three passive head-up tilts (HUT) in 223 participants without cardiovascular medications (mean age 46 yr, BMI 28 kg/m2, 54% male). The median time gap between the first and the second HUT was 9 wk and the second and the third HUT was 4 wk. We utilized whole body impedance cardiography and radial artery tonometry as methods. The participants were divided into quartiles of the changes in each hemodynamic variable during the first HUT, and the reproducibility of these changes was tested during successive HUTs. During the first HUT, significant differences were present in all between-quartile comparisons (n = 6) of all variables. The differences persisted as follows: reduction of stroke volume in six out of six (6/6) between-quartile comparisons (P < 0.001), decrease in cardiac output (P < 0.001) and increase in heart rate in 5/6 comparisons (P < 0.001), change in systemic vascular resistance in 3/6 comparisons (P < 0.001), change in aortic systolic blood pressure in 1/6 comparisons (P = 0.043), and change in aortic diastolic blood pressure in none (P = 0.266). To conclude, the reproducibility of upright posture-induced changes is high for stroke volume, cardiac output, and heart rate, moderate for systemic vascular resistance, and modest for aortic blood pressure. Although an increase in blood pressure during upright posture may be a cardiovascular risk factor, this effect may be attributed to other underlying hemodynamic variables that exhibit more reproducible posture-related changes.NEW & NOTEWORTHY We examined the reproducibility of hemodynamic responses to three passive head-up tilts. The associated changes in stroke volume, cardiac output, and heart rate were highly reproducible. Systemic vascular resistance showed moderate reproducibility, whereas blood pressure changes during upright posture were modestly reproducible. If an exaggerated blood pressure response to upright posture is a cardiovascular risk factor, it is likely attributed to other hemodynamic variables that exhibit more reproducible posture-related changes.
{"title":"High variability in the reproducibility of key hemodynamic responses to head-up tilt.","authors":"Heidi Bouquin, Lauri J Suojanen, Jenni K Koskela, Essi Pietilä, Manoj Kumar Choudhary, Jukka T Mustonen, Ilkka H Pörsti","doi":"10.1152/ajpheart.00796.2024","DOIUrl":"10.1152/ajpheart.00796.2024","url":null,"abstract":"<p><p>Increased blood pressure upon standing is considered a cardiovascular risk factor. We investigated the reproducibility of changes in aortic blood pressure, heart rate, stroke volume, cardiac output, and systemic vascular resistance during three passive head-up tilts (HUT) in 223 participants without cardiovascular medications (mean age 46 yr, BMI 28 kg/m<sup>2</sup>, 54% male). The median time gap between the first and the second HUT was 9 wk and the second and the third HUT was 4 wk. We utilized whole body impedance cardiography and radial artery tonometry as methods. The participants were divided into quartiles of the changes in each hemodynamic variable during the first HUT, and the reproducibility of these changes was tested during successive HUTs. During the first HUT, significant differences were present in all between-quartile comparisons (<i>n</i> = 6) of all variables. The differences persisted as follows: reduction of stroke volume in six out of six (6/6) between-quartile comparisons (<i>P</i> < 0.001), decrease in cardiac output (<i>P</i> < 0.001) and increase in heart rate in 5/6 comparisons (<i>P</i> < 0.001), change in systemic vascular resistance in 3/6 comparisons (<i>P</i> < 0.001), change in aortic systolic blood pressure in 1/6 comparisons (<i>P</i> = 0.043), and change in aortic diastolic blood pressure in none (<i>P</i> = 0.266). To conclude, the reproducibility of upright posture-induced changes is high for stroke volume, cardiac output, and heart rate, moderate for systemic vascular resistance, and modest for aortic blood pressure. Although an increase in blood pressure during upright posture may be a cardiovascular risk factor, this effect may be attributed to other underlying hemodynamic variables that exhibit more reproducible posture-related changes.<b>NEW & NOTEWORTHY</b> We examined the reproducibility of hemodynamic responses to three passive head-up tilts. The associated changes in stroke volume, cardiac output, and heart rate were highly reproducible. Systemic vascular resistance showed moderate reproducibility, whereas blood pressure changes during upright posture were modestly reproducible. If an exaggerated blood pressure response to upright posture is a cardiovascular risk factor, it is likely attributed to other hemodynamic variables that exhibit more reproducible posture-related changes.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H387-H392"},"PeriodicalIF":4.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-11DOI: 10.1152/ajpheart.00893.2024
Theodore M DeConne, Colleen M Sitlani, Kevin P Decker, Joseph A Delaney, Bruce M Psaty, Margaret F Doyle, Petra Buzkova, Alan L Landay, Sally A Huber, Timothy M Hughes, David Herrington, Jingzhong Ding, Nels C Olson
Background: Endothelial dysfunction has emerged as a risk factor for many age-related diseases such as cardiovascular disease and Alzheimer's disease and related dementias. T-lymphocytes (T-cells) have been identified as important regulators of endothelial function in multiple murine models, and pro-inflammatory and senescent T-cell subsets have been associated with endothelial dysfunction in middle-aged adults with hypertension. However, there is little data on the relationships between T-cell subsets and endothelial function in large, multi-ethnic, population-based cohorts free from cardiovascular diseases. Therefore, the purpose of this study was to determine whether T-cell subsets were associated with endothelial function in participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methods: Endothelial function was assessed using flow-mediated dilation (FMD) of the brachial artery by duplex ultrasound at the baseline exam. Baseline peripheral blood T-cell subsets were measured using flow cytometry (N=968). Two analyses were employed. The primary analysis examined associations of Th1 (CD4+ interferon-γ+ (IFN-γ+)) and CD4+CD28-CD57+ T-cells, specified as a priori hypotheses, with FMD using multivariable linear regression. Secondary analyses examined associations between 27 additional immune cell populations with FMD. Results: Th1 and CD4+CD28-CD57+ T-cells were not associated with FMD. In secondary analyses, a 1-SD higher value of pan CD4+ and pan CD8+ T-cells were associated with lower and higher FMD, respectively. Conclusions: These results may suggest regulation of endothelial function by T-cells in pre-clinical models is conserved in humans. The findings warrant additional longitudinal human studies with greater T-cell phenotyping to further understand the influence of CD4+ and CD8+ T-cell balance on endothelial function.
{"title":"Associations of circulating T-cell subsets with endothelial function: the Multi-Ethnic Study of Atherosclerosis.","authors":"Theodore M DeConne, Colleen M Sitlani, Kevin P Decker, Joseph A Delaney, Bruce M Psaty, Margaret F Doyle, Petra Buzkova, Alan L Landay, Sally A Huber, Timothy M Hughes, David Herrington, Jingzhong Ding, Nels C Olson","doi":"10.1152/ajpheart.00893.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00893.2024","url":null,"abstract":"<p><p><b>Background:</b> Endothelial dysfunction has emerged as a risk factor for many age-related diseases such as cardiovascular disease and Alzheimer's disease and related dementias. T-lymphocytes (T-cells) have been identified as important regulators of endothelial function in multiple murine models, and pro-inflammatory and senescent T-cell subsets have been associated with endothelial dysfunction in middle-aged adults with hypertension. However, there is little data on the relationships between T-cell subsets and endothelial function in large, multi-ethnic, population-based cohorts free from cardiovascular diseases. Therefore, the purpose of this study was to determine whether T-cell subsets were associated with endothelial function in participants of the Multi-Ethnic Study of Atherosclerosis (MESA). <b>Methods:</b> Endothelial function was assessed using flow-mediated dilation (FMD) of the brachial artery by duplex ultrasound at the baseline exam. Baseline peripheral blood T-cell subsets were measured using flow cytometry (N=968). Two analyses were employed. The primary analysis examined associations of Th1 (CD4<sup>+</sup> interferon-γ<sup>+</sup> (IFN-γ<sup>+</sup>)) and CD4<sup>+</sup>CD28<sup>-</sup>CD57<sup>+</sup> T-cells, specified as a priori hypotheses, with FMD using multivariable linear regression. Secondary analyses examined associations between 27 additional immune cell populations with FMD. <b>Results:</b> Th1 and CD4<sup>+</sup>CD28<sup>-</sup>CD57<sup>+</sup> T-cells were not associated with FMD. In secondary analyses, a 1-SD higher value of pan CD4<sup>+</sup> and pan CD8<sup>+</sup> T-cells were associated with lower and higher FMD, respectively. <b>Conclusions:</b> These results may suggest regulation of endothelial function by T-cells in pre-clinical models is conserved in humans. The findings warrant additional longitudinal human studies with greater T-cell phenotyping to further understand the influence of CD4<sup>+</sup> and CD8<sup>+</sup> T-cell balance on endothelial function.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-11DOI: 10.1152/ajpheart.00871.2024
Lauren E Parker, Kyriakos N Papanicolaou, Stephanie Zalesak-Kravec, Eva M Weinberger, Maureen A Kane, D Brian Foster
Nearly 70 years after studies first showed that the offspring of vitamin A (retinol, ROL) -deficient rats exhibit structural cardiac defects and over 20 years since the role of vitamin A's potent bioactive metabolite hormone, all-trans retinoic acid (ATRA), was elucidated in embryonic cardiac development, the role of the Vitamin A metabolites, or retinoids, in adult heart physiology as well as heart and vascular disease, remains poorly understood. Studies have shown that low serum levels of retinoic acid correlate with higher all-cause and cardiovascular mortality, though the relationship between circulating retinol and ATRA levels, cardiac tissue ATRA levels, and intracellular cardiac ATRA signaling in the context of heart and vascular disease has only begun to be addressed. We have recently shown that patients with idiopathic dilated cardiomyopathy show a nearly 40% decline of in situ cardiac ATRA levels, despite adequate local stores of retinol. Moreover, we and others have shown that the administration of ATRA forestalls the development of heart failure (HF) in rodent models. In this review, we summarize key facets of retinoid metabolism and signaling and discuss mechanisms by which impaired ATRA signaling contributes to several HF hallmarks including hypertrophy, contractile dysfunction, poor calcium handling, redox imbalance, and fibrosis. We highlight unresolved issues in cardiac ATRA metabolism whose pursuit will help refine therapeutic strategies aimed at restoring ATRA homeostasis.
{"title":"Retinoic Acid Signaling & Metabolism in Heart Failure.","authors":"Lauren E Parker, Kyriakos N Papanicolaou, Stephanie Zalesak-Kravec, Eva M Weinberger, Maureen A Kane, D Brian Foster","doi":"10.1152/ajpheart.00871.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00871.2024","url":null,"abstract":"<p><p>Nearly 70 years after studies first showed that the offspring of vitamin A (retinol, ROL) -deficient rats exhibit structural cardiac defects and over 20 years since the role of vitamin A's potent bioactive metabolite hormone, all-trans retinoic acid (ATRA), was elucidated in embryonic cardiac development, the role of the Vitamin A metabolites, or retinoids, in adult heart physiology as well as heart and vascular disease, remains poorly understood. Studies have shown that low serum levels of retinoic acid correlate with higher all-cause and cardiovascular mortality, though the relationship between circulating retinol and ATRA levels, cardiac tissue ATRA levels, and intracellular cardiac ATRA signaling in the context of heart and vascular disease has only begun to be addressed. We have recently shown that patients with idiopathic dilated cardiomyopathy show a nearly 40% decline of in situ cardiac ATRA levels, despite adequate local stores of retinol. Moreover, we and others have shown that the administration of ATRA forestalls the development of heart failure (HF) in rodent models. In this review, we summarize key facets of retinoid metabolism and signaling and discuss mechanisms by which impaired ATRA signaling contributes to several HF hallmarks including hypertrophy, contractile dysfunction, poor calcium handling, redox imbalance, and fibrosis. We highlight unresolved issues in cardiac ATRA metabolism whose pursuit will help refine therapeutic strategies aimed at restoring ATRA homeostasis.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10DOI: 10.1152/ajpheart.00363.2024
Ninette Shenouda, Joseph M Stock, Nicholas V Chouramanis, Zoe R Lincoln, Megan M Wenner, Julio A Chirinos, David G Edwards
Increased arterial wave reflections can increase left ventricular wasted pressure effort (WPE) and cardiovascular disease risk. Naturally menstruating women experience fluctuations in sex hormones with known cardioprotective effects. We sought to determine whether hormonal fluctuations alter arterial hemodynamics or wave reflections, and thereby WPE, or contribute to sex differences. We hypothesized that premenopausal women would have favorable wave reflection changes and reduced WPE during high- vs. low-hormone cycle phases and compared to men. We tested 13 women (28±7 yrs) during the early follicular (EF, day 3±1), late follicular (LF, day 12±2) and mid-luteal phases (ML, day 22±3). Eleven men (28±3 yrs) underwent time-matched visits. Sex hormones and arterial hemodynamics were measured at all visits. Wave reflection indices and WPE were assessed via aortic pressure-flow analyses. We observed sex-by-visit interactions for WPE and total peripheral resistance (TPR; both p<0.01). Women showed favorable reductions in WPE (EF: 2758±966 and LF: 2489±1230 vs. ML: 1954±1085 mmHg*ms, both p<0.05) and TPR (EF: 1885±271 vs. ML: 1699±255 dynes*s*cm-5, p=0.01) from low- to high-hormone phases. These reductions were not observed in men and were not paralleled in classic wave reflection indices (p>0.05). Increased estradiol predicted a reduction in TPR (R2=0.45, p<0.001), whereas TPR, reflected wave amplitude and timing of wave reflection predicted reductions in WPE (R2=0.71, p<0.001). These data suggest a role of estradiol on the vasculature leading to reduced left ventricular WPE, and consideration for cycle phases when assessing ventricular load in naturally menstruating women.
{"title":"Favorable alterations in ventricular-arterial interactions across the menstrual cycle in healthy premenopausal women.","authors":"Ninette Shenouda, Joseph M Stock, Nicholas V Chouramanis, Zoe R Lincoln, Megan M Wenner, Julio A Chirinos, David G Edwards","doi":"10.1152/ajpheart.00363.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00363.2024","url":null,"abstract":"<p><p>Increased arterial wave reflections can increase left ventricular wasted pressure effort (WPE) and cardiovascular disease risk. Naturally menstruating women experience fluctuations in sex hormones with known cardioprotective effects. We sought to determine whether hormonal fluctuations alter arterial hemodynamics or wave reflections, and thereby WPE, or contribute to sex differences. We hypothesized that premenopausal women would have favorable wave reflection changes and reduced WPE during high- vs. low-hormone cycle phases and compared to men. We tested 13 women (28±7 yrs) during the early follicular (EF, day 3±1), late follicular (LF, day 12±2) and mid-luteal phases (ML, day 22±3). Eleven men (28±3 yrs) underwent time-matched visits. Sex hormones and arterial hemodynamics were measured at all visits. Wave reflection indices and WPE were assessed via aortic pressure-flow analyses. We observed sex-by-visit interactions for WPE and total peripheral resistance (TPR; both p<0.01). Women showed favorable reductions in WPE (EF: 2758±966 and LF: 2489±1230 vs. ML: 1954±1085 mmHg*ms, both p<0.05) and TPR (EF: 1885±271 vs. ML: 1699±255 dynes*s*cm<sup>-5</sup>, p=0.01) from low- to high-hormone phases. These reductions were not observed in men and were not paralleled in classic wave reflection indices (p>0.05). Increased estradiol predicted a reduction in TPR (R<sup>2</sup>=0.45, p<0.001), whereas TPR, reflected wave amplitude and timing of wave reflection predicted reductions in WPE (R<sup>2</sup>=0.71, p<0.001). These data suggest a role of estradiol on the vasculature leading to reduced left ventricular WPE, and consideration for cycle phases when assessing ventricular load in naturally menstruating women.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10DOI: 10.1152/ajpheart.00687.2024
Garrett Jensen, Xinjie Wang, Jacob Kuempel, Nicolas Palaskas, Zhishi Chen, Wei Yu, Yanping Chen, Haseeb Mohammed, Weijia Luo, Jiang Chang
The most fatal side effect associated with revolutionary immune checkpoint inhibitor (ICI) cancer therapies is myocarditis, a rare and devastating complication with a mortality rate approaching 40%. This review comprehensively examines the limited knowledge surrounding this recently recognized condition, emphasizing the absence of evidence-based therapeutic strategies, diagnostic modalities, and reliable biomarkers that hinder effective management. It explores advancements in preclinical models that are uncovering disease mechanisms and enabling the identification of therapeutic targets. These efforts have informed the design of early clinical trials aimed at reducing mortality. With the growing prevalence of ICI therapies in oncology, addressing critical gaps-such as long-term outcomes and risk stratification-has become increasingly urgent. By synthesizing current evidence, this work seeks to enhance understanding and guide the development of strategies to improve patient outcomes and ensure the continued safe use of ICIs in cancer care.
{"title":"Immune checkpoint inhibitor-associated myocarditis.","authors":"Garrett Jensen, Xinjie Wang, Jacob Kuempel, Nicolas Palaskas, Zhishi Chen, Wei Yu, Yanping Chen, Haseeb Mohammed, Weijia Luo, Jiang Chang","doi":"10.1152/ajpheart.00687.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00687.2024","url":null,"abstract":"<p><p>The most fatal side effect associated with revolutionary immune checkpoint inhibitor (ICI) cancer therapies is myocarditis, a rare and devastating complication with a mortality rate approaching 40%. This review comprehensively examines the limited knowledge surrounding this recently recognized condition, emphasizing the absence of evidence-based therapeutic strategies, diagnostic modalities, and reliable biomarkers that hinder effective management. It explores advancements in preclinical models that are uncovering disease mechanisms and enabling the identification of therapeutic targets. These efforts have informed the design of early clinical trials aimed at reducing mortality. With the growing prevalence of ICI therapies in oncology, addressing critical gaps-such as long-term outcomes and risk stratification-has become increasingly urgent. By synthesizing current evidence, this work seeks to enhance understanding and guide the development of strategies to improve patient outcomes and ensure the continued safe use of ICIs in cancer care.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-07DOI: 10.1152/ajpheart.00728.2024
Jan Traub, Niklas Beyersdorf, Roxanne Sell, Stefan Frantz, Stefan Störk, Guido Stoll, Anna Frey
TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a transmembrane protein expressed on myeloid cells, including macrophages and microglia, and is involved in modulating inflammation and lipid metabolism. Elevated plasma levels of soluble TREM2 (sTREM2) have been associated with heart failure (HF) and neurodegenerative diseases such as Alzheimer's disease (AD). This post-hoc analysis explored the association of plasma sTREM2 with cognition and mortality in the Cognition.Matters-HF cohort of 148 chronic HF patients. Plasma sTREM2 levels were measured using a bead-based immunoassay, and the cohort was split into high and low sTREM2 groups based on a median concentration of 16.6 ng/ml. Higher sTREM2 levels were associated with worse cognitive performance, particularly in working memory (T = -2.67, p = 0.009) and visual/verbal memory (T = -2.16, p = 0.032), but not with cardiac function. In univariate cox regression, a higher plasma sTREM2 concentration was linked to increased mortality (HR = 1.28, 95% CI 1.05-1.57, p = 0.015), although this association did not remain significant after adjusting for age and heart failure severity (adjusted HR = 0.95, 95% CI 0.70-1.28, p = 0.720). These findings suggest that plasma sTREM2 reflects cognitive impairment more than cardiac dysfunction in HF, highlighting its potential as a biomarker for neuroinflammation in HF patients.
{"title":"Plasma levels of soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) in chronic heart failure - predictors and prognostic relevance.","authors":"Jan Traub, Niklas Beyersdorf, Roxanne Sell, Stefan Frantz, Stefan Störk, Guido Stoll, Anna Frey","doi":"10.1152/ajpheart.00728.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00728.2024","url":null,"abstract":"<p><p>TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a transmembrane protein expressed on myeloid cells, including macrophages and microglia, and is involved in modulating inflammation and lipid metabolism. Elevated plasma levels of soluble TREM2 (sTREM2) have been associated with heart failure (HF) and neurodegenerative diseases such as Alzheimer's disease (AD). This post-hoc analysis explored the association of plasma sTREM2 with cognition and mortality in the Cognition.Matters-HF cohort of 148 chronic HF patients. Plasma sTREM2 levels were measured using a bead-based immunoassay, and the cohort was split into high and low sTREM2 groups based on a median concentration of 16.6 ng/ml. Higher sTREM2 levels were associated with worse cognitive performance, particularly in working memory (T = -2.67, p = 0.009) and visual/verbal memory (T = -2.16, p = 0.032), but not with cardiac function. In univariate cox regression, a higher plasma sTREM2 concentration was linked to increased mortality (HR = 1.28, 95% CI 1.05-1.57, p = 0.015), although this association did not remain significant after adjusting for age and heart failure severity (adjusted HR = 0.95, 95% CI 0.70-1.28, p = 0.720). These findings suggest that plasma sTREM2 reflects cognitive impairment more than cardiac dysfunction in HF, highlighting its potential as a biomarker for neuroinflammation in HF patients.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-07DOI: 10.1152/ajpheart.00845.2024
A Wentzel, W Smith, E Jansen van Vuren, R Kruger, Y Breet, E Wonkamtinitang, N A Hanchard, S T Chung
Sustained stress, assessed as a high allostatic load score (ALS), is an independent cardiovascular disease (CVD) risk factor in older adults but its associations in young people are undefined. Since neurological maturation impacts stress adaptation and CVD risk, we assessed the relationship of ALS with CVD profile using a tiered approach stratified by age (emerging adults 20-24y, EA vs. young adults 25-30y, YA) and ALS (high vs. low). In 1054 healthy African-PREDICT participants, we determined: 1) ALS in EA vs. YA; 2) the relationship between ALS with cardiovascular health; and 3) the odds of high ALS>4 to identify masked hypertension and prediabetes as cardiometabolic outcomes. A 9-component four-domain ALS was compiled: neuro-endocrine (dehydroepiandrosterone, cortisol), inflammatory (interleukin-6, C-reactive protein), cardiovascular (systolic and diastolic-blood pressure), and metabolic (total cholesterol, HDL-cholesterol, body mass index). Retinal vessel caliber, pulse wave velocity (PWV), cardiac structure and function were assessed. Median ALS was 3 (range:1-9). A high-ALS>4 was more common in YA vs. EA (47%vs.35%, P=0.032). Higher ALS associated with narrower retinal arteries (P<0.01), greater PWV (P=<0.01), lower diastolic (P<0.01) and left ventricular function (P<0.01). High-ALS increased the odds of having masked hypertension, prediabetes, narrower retinal arteries, higher LV mass, poorer diastolic and ventricular function (all P≤0.01) in EA and YA independent of traditional CVD risk factors. The composite ALS identified early stress dysregulation in cardiometabolic health and higher odds for prediabetes and masked hypertension in young adults. Cumulative stress may be a modifiable independent cardiometabolic risk factor in younger populations that needs further investigation.
{"title":"Allostatic load and cardiometabolic health in a young adult South African population: The African-PREDICT study.","authors":"A Wentzel, W Smith, E Jansen van Vuren, R Kruger, Y Breet, E Wonkamtinitang, N A Hanchard, S T Chung","doi":"10.1152/ajpheart.00845.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00845.2024","url":null,"abstract":"<p><p>Sustained stress, assessed as a high allostatic load score (ALS), is an independent cardiovascular disease (CVD) risk factor in older adults but its associations in young people are undefined. Since neurological maturation impacts stress adaptation and CVD risk, we assessed the relationship of ALS with CVD profile using a tiered approach stratified by age (emerging adults 20-24y, EA vs. young adults 25-30y, YA) and ALS (high vs. low). In 1054 healthy African-PREDICT participants, we determined: 1) ALS in EA vs. YA; 2) the relationship between ALS with cardiovascular health; and 3) the odds of high ALS>4 to identify masked hypertension and prediabetes as cardiometabolic outcomes. A 9-component four-domain ALS was compiled: neuro-endocrine (dehydroepiandrosterone, cortisol), inflammatory (interleukin-6, C-reactive protein), cardiovascular (systolic and diastolic-blood pressure), and metabolic (total cholesterol, HDL-cholesterol, body mass index). Retinal vessel caliber, pulse wave velocity (PWV), cardiac structure and function were assessed. Median ALS was 3 (range:1-9). A high-ALS>4 was more common in YA vs. EA (47%vs.35%, <i>P</i>=0.032). Higher ALS associated with narrower retinal arteries (P<0.01), greater PWV (<i>P</i>=<0.01), lower diastolic (<i>P</i><0.01) and left ventricular function (<i>P</i><0.01). High-ALS increased the odds of having masked hypertension, prediabetes, narrower retinal arteries, higher LV mass, poorer diastolic and ventricular function (all <i>P</i>≤0.01) in EA and YA independent of traditional CVD risk factors. The composite ALS identified early stress dysregulation in cardiometabolic health and higher odds for prediabetes and masked hypertension in young adults. Cumulative stress may be a modifiable independent cardiometabolic risk factor in younger populations that needs further investigation.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-07DOI: 10.1152/ajpheart.00681.2024
Malak Abbas, Amadou Gaye
This review comprehensively examines the diverse roles of non-coding RNAs (ncRNAs) in the pathogenesis and treatment of cardiovascular disease (CVD), focusing on microRNA (miRNA), long non-coding RNA (lncRNA), piwi-interacting RNA (piRNA), small interfering RNA (siRNA), circular RNA (circRNA), and vesicle-associated RNAs. These ncRNAs are integral regulators of key cellular processes, including gene expression, inflammation, and fibrosis, and they hold great potential as both diagnostic biomarkers and therapeutic targets. The review highlights novel insights into how these RNA species, particularly miRNAs, lncRNAs, and piRNAs, contribute to various CVDs such as hypertension, atherosclerosis, and myocardial infarction. Additionally, it explores the emerging role of extracellular vesicles (EVs) in intercellular communication and their therapeutic potential in cardiovascular health. The review underscores the need for continued research into ncRNAs and RNA-based therapies, with a focus on advancing delivery systems and expanding personalized medicine approaches to improve cardiovascular outcomes.
{"title":"Emerging Roles of Non-coding RNAs in Cardiovascular Pathophysiology.","authors":"Malak Abbas, Amadou Gaye","doi":"10.1152/ajpheart.00681.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00681.2024","url":null,"abstract":"<p><p>This review comprehensively examines the diverse roles of non-coding RNAs (ncRNAs) in the pathogenesis and treatment of cardiovascular disease (CVD), focusing on microRNA (miRNA), long non-coding RNA (lncRNA), piwi-interacting RNA (piRNA), small interfering RNA (siRNA), circular RNA (circRNA), and vesicle-associated RNAs. These ncRNAs are integral regulators of key cellular processes, including gene expression, inflammation, and fibrosis, and they hold great potential as both diagnostic biomarkers and therapeutic targets. The review highlights novel insights into how these RNA species, particularly miRNAs, lncRNAs, and piRNAs, contribute to various CVDs such as hypertension, atherosclerosis, and myocardial infarction. Additionally, it explores the emerging role of extracellular vesicles (EVs) in intercellular communication and their therapeutic potential in cardiovascular health. The review underscores the need for continued research into ncRNAs and RNA-based therapies, with a focus on advancing delivery systems and expanding personalized medicine approaches to improve cardiovascular outcomes.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kawasaki disease (KD) is an acute vasculitis that mostly affects children and is characterized by inflammation of medium-sized arteries, particularly the coronary arteries. The absent in melanoma 2 (AIM2) inflammasome senses cytosolic dsDNA and regulates IL-1β-driven inflammation. We investigated the role of AIM2 in Candida albicans water-soluble fraction (CAWS)-induced vasculitis in a murine model mimicking KD. Aim2-/- mice exhibited reduced vasculitis, inflammatory cell infiltration, and vascular fibrosis in the aorta and coronary arteries. In addition, dsDNA damage was detected in Dectin-2+ cells infiltrating vasculitis areas. In vitro experiments showed that CAWS induced dsDNA damage in Dectin-2+ bone marrow-derived dendritic cells (BMDC) isolated from wild-type (WT) and Aim2-/- mice. Furthermore, CAWS induces nuclear membrane deformation and DNA leakage into the cytosol, leading to AIM2 inflammasome activation and subsequent IL-1β production in WT BMDC. These findings suggest that AIM2 inflammasome activation in dendritic cells, triggered by dsDNA damage and leakage, contributes to the development of CAWS-induced vasculitis, and provides important insights into the inflammatory mechanisms underlying KD.
{"title":"AIM2 Targeting of Nuclear DNA Leakage in Dendritic Cells Exacerbates Vasculitis in a Murine Model of Kawasaki Disease.","authors":"Chintogtokh Baatarjav, Takanori Komada, Yoshitaka Gunji, Satoko Komori, Hidetoshi Aizawa, Noriko Nagi-Miura, Tadayoshi Karasawa, Masafumi Takahashi","doi":"10.1152/ajpheart.00901.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00901.2024","url":null,"abstract":"<p><p>Kawasaki disease (KD) is an acute vasculitis that mostly affects children and is characterized by inflammation of medium-sized arteries, particularly the coronary arteries. The absent in melanoma 2 (AIM2) inflammasome senses cytosolic dsDNA and regulates IL-1β-driven inflammation. We investigated the role of AIM2 in <i>Candida albicans</i> water-soluble fraction (CAWS)-induced vasculitis in a murine model mimicking KD. <i>Aim2<sup>-/-</sup></i> mice exhibited reduced vasculitis, inflammatory cell infiltration, and vascular fibrosis in the aorta and coronary arteries. In addition, dsDNA damage was detected in Dectin-2<sup>+</sup> cells infiltrating vasculitis areas. <i>In vitro</i> experiments showed that CAWS induced dsDNA damage in Dectin-2<sup>+</sup> bone marrow-derived dendritic cells (BMDC) isolated from wild-type (WT) and <i>Aim2<sup>-/-</sup></i> mice. Furthermore, CAWS induces nuclear membrane deformation and DNA leakage into the cytosol, leading to AIM2 inflammasome activation and subsequent IL-1β production in WT BMDC. These findings suggest that AIM2 inflammasome activation in dendritic cells, triggered by dsDNA damage and leakage, contributes to the development of CAWS-induced vasculitis, and provides important insights into the inflammatory mechanisms underlying KD.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}