The role of mononuclear phagocytes in chronic heart failure (HF) is unknown.
Our aim was to delineate monocyte, macrophage, and dendritic cell trafficking in HF and define the contribution of the ...spleen to cardiac remodeling.
We evaluated C57Bl/6 mice with chronic HF 8 weeks after coronary ligation. As compared with sham-operated controls, HF mice exhibited: (1) increased proinflammatory CD11b+ F4/80+ CD206- macrophages and CD11b+ F4/80+ Gr-1(hi) monocytes in the heart and peripheral blood, respectively, and reduced CD11b+ F4/80+ Gr-1(hi) monocytes in the spleen; (2) significantly increased CD11c+ B220- classical dendritic cells and CD11c+ low)B220+ plasmacytoid dendritic cells in both the heart and spleen, and increased classic dendritic cells and plasmacytoid dendritic cells in peripheral blood and bone marrow, respectively; (3) increased CD4+ helper and CD8+ cytotoxic T-cells in the spleen; and (4) profound splenic remodeling with abundant white pulp follicles, markedly increased size of the marginal zone and germinal centers, and increased expression of alarmins. Splenectomy in mice with established HF reversed pathological cardiac remodeling and inflammation. Splenocytes adoptively transferred from mice with HF, but not from sham-operated mice, homed to the heart and induced long-term left ventricular dilatation, dysfunction, and fibrosis in naive recipients. Recipient mice also exhibited monocyte activation and splenic remodeling similar to HF mice.
Activation of mononuclear phagocytes is central to the progression of cardiac remodeling in HF, and heightened antigen processing in the spleen plays a critical role in this process. Splenocytes (presumably splenic monocytes and dendritic cells) promote immune-mediated injurious responses in the failing heart and retain this memory on adoptive transfer.
the role of nuclear factor (NF)-κB in heart failure (HF) is not well defined. We sought to determine whether myocyte-localized NF-κB p65 activation in HF exacerbates post-infarction remodelling and ...promotes maladaptive endoplasmic reticulum (ER) stress.
non-transgenic (NTg) and transgenic (Tg) mice with myocyte-restricted overexpression of a phosphorylation-resistant inhibitor of κBα (IκBα(S32A,S36A)) underwent coronary ligation (to induce HF) or sham operation. Over 4 weeks, the remote myocardium of ligated hearts exhibited robust NF-κB activation that was almost exclusively p65 beyond 24 h. Compared with sham at 4 weeks, NTg HF hearts were dilated and dysfunctional, and exhibited hypertrophy, fibrosis, up-regulation of inflammatory cytokines, increased apoptosis, down-regulation of ER protein chaperones, and up-regulation of the ER stress-activated pro-apoptotic factor CHOP. Compared with NTg HF, Tg-IκBα(S32A,S36A) HF mice exhibited: (i) improved survival, chamber remodelling, systolic function, and pulmonary congestion, (ii) markedly diminished NF-κB p65 activation, cytokine expression, and fibrosis, and (iii) a three-fold reduction in apoptosis. Moreover, Tg-IκBα(S32A,S36A) HF hearts exhibited maintained expression of ER chaperones and CHOP when compared with sham. In cardiomyocytes, NF-κB activation was required for ER stress-mediated apoptosis, whereas abrogation of myocyte NF-κB shifted the ER stress response to one of adaptation and survival.
persistent myocyte NF-κB p65 activation in HF exacerbates cardiac remodelling by imparting pro-inflammatory, pro-fibrotic, and pro-apoptotic effects. p65 modulation of cell death in HF may occur in part from NF-κB-mediated transformation of the ER stress response from one of adaptation to one of apoptosis.
Globally, helminth infections and cardiometabolic diseases often overlap in populations and individuals. Neither the causal relationship between helminth infections and cardiometabolic diseases nor ...the effect of helminth eradication on cardiometabolic risk have been reviewed systematically in a large number of human and animal studies.
We conducted a systematic review assessing the reported effects of helminth infections and anthelmintic treatment on the development and/or severity of cardiometabolic diseases and risk factors. The search was limited to the most prevalent human helminths worldwide. This study followed PRISMA guidelines and was registered prospectively in PROSPERO (CRD42021228610). Searches were performed on December 10, 2020 and rerun on March 2, 2022 using Ovid MEDLINE ALL (1946 to March 2, 2022), Web of Science, Cochrane Library, Global Index Medicus, and Ovid Embase (1974 to March 2, 2022). Randomized clinical trials, cohort, cross-sectional, case-control, and animal studies were included. Two reviewers performed screening independently.
Eighty-four animal and human studies were included in the final analysis. Most studies reported on lipids (45), metabolic syndrome (38), and diabetes (30), with fewer on blood pressure (18), atherosclerotic cardiovascular disease (11), high-sensitivity C-reactive protein (hsCRP, 5), and non-atherosclerotic cardiovascular disease (4). Fifteen different helminth infections were represented. On average, helminth-infected participants had less dyslipidemia, metabolic syndrome, diabetes, and atherosclerotic cardiovascular disease. Eleven studies examined anthelmintic treatment, of which 9 (82%) reported post-treatment increases in dyslipidemia, metabolic syndrome, and diabetes or glucose levels. Results from animal and human studies were generally consistent. No consistent effects of helminth infections on blood pressure, hsCRP, or cardiac function were reported except some trends towards association of schistosome infection with lower blood pressure. The vast majority of evidence linking helminth infections to lower cardiometabolic diseases was reported in those with schistosome infections.
Helminth infections may offer protection against dyslipidemia, metabolic syndrome, diabetes, and atherosclerotic cardiovascular disease. This protection may lessen after anthelmintic treatment. Our findings highlight the need for mechanistic trials to determine the pathways linking helminth infections with cardiometabolic diseases. Such studies could have implications for helminth eradication campaigns and could generate new strategies to address the global challenge of cardiometabolic diseases.
Heme oxygenase-1 (HO-1) is an inducible stress-response protein that imparts antioxidant and antiapoptotic effects. However, its pathophysiological role in cardiac remodeling and chronic heart ...failure (HF) is unknown. We hypothesized that induction of HO-1 in HF alleviates pathological remodeling.
Adult male nontransgenic and myocyte-restricted HO-1 transgenic mice underwent either sham operation or coronary ligation to induce HF. Four weeks after ligation, nontransgenic HF mice exhibited postinfarction left ventricular (LV) remodeling and dysfunction, hypertrophy, fibrosis, oxidative stress, apoptosis, and reduced capillary density, associated with a 2-fold increase in HO-1 expression in noninfarcted myocardium. Compared with nontransgenic mice, HO-1 transgenic HF mice exhibited significantly (P<0.05) improved postinfarction survival (94% versus 57%) and less LV dilatation (end-diastolic volume, 46+/-8 versus 85+/-32 microL), mechanical dysfunction (ejection fraction, 65+/-9% versus 49+/-16%), hypertrophy (LV/tibia length 4.4+/-0.4 versus 5.2+/-0.6 mg/mm), interstitial fibrosis (11.2+/-3.1% versus 18.5+/-3.5%), and oxidative stress (3-fold reduction in tissue malondialdehyde). Moreover, myocyte-specific HO-1 overexpression in HF promoted tissue neovascularization and ameliorated myocardial p53 expression (2-fold reduction) and apoptosis. In isolated mitochondria, mitochondrial permeability transition was inhibited by HO-1 in a carbon monoxide (CO)-dependent manner and was recapitulated by the CO donor tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). HO-1-derived CO also prevented H2O2-induced cardiomyocyte apoptosis and cell death. Finally, in vivo treatment with CORM-3 alleviated postinfarction LV remodeling, p53 expression, and apoptosis.
HO-1 induction in the failing heart is an important cardioprotective adaptation that opposes pathological LV remodeling, and this effect is mediated, at least in part, by CO-dependent inhibition of mitochondrial permeability transition and apoptosis. Augmentation of HO-1 or its product, CO, may represent a novel therapeutic strategy for ameliorating HF.
In the failing heart, iNOS is expressed by both macrophages and cardiomyocytes. We hypothesized that inflammatory cell-localized iNOS exacerbates left ventricular (LV) remodeling. Wild-type (WT) ...C57BL/6 mice underwent total body irradiation and reconstitution with bone marrow from iNOS
−/−
mice (iNOS
−/−
c) or WT mice (WTc). Chimeric mice underwent coronary ligation to induce large infarction and ischemic heart failure (HF), or sham surgery. After 28 days, as compared with WTc sham mice, WTc HF mice exhibited significant (
p
< 0.05) mortality, LV dysfunction, hypertrophy, fibrosis, oxidative/nitrative stress, inflammatory activation, and iNOS upregulation. These mice also exhibited a ~twofold increase in circulating Ly6C
hi
pro-inflammatory monocytes, and ~sevenfold higher cardiac M1 macrophages, which were primarily CCR2
–
cells. In contrast, as compared with WTc HF mice, iNOS
−/−
c HF mice exhibited significantly improved survival, LV function, hypertrophy, fibrosis, oxidative/nitrative stress, and inflammatory activation, without differences in overall cardiac iNOS expression. Moreover, iNOS
−/−
c HF mice exhibited lower circulating Ly6C
hi
monocytes, and augmented cardiac M2 macrophages, but with greater infiltrating monocyte-derived CCR2
+
macrophages vs. WTc HF mice. Lastly, upon cell-to-cell contact with naïve cardiomyocytes, peritoneal macrophages from WT HF mice depressed contraction, and augmented cardiomyocyte oxygen free radicals and peroxynitrite. These effects were not observed upon contact with macrophages from iNOS
−/−
HF mice. We conclude that leukocyte iNOS is obligatory for local and systemic inflammatory activation and cardiac remodeling in ischemic HF. Activated macrophages in HF may directly induce cardiomyocyte contractile dysfunction and oxidant stress upon cell-to-cell contact; this juxtacrine response requires macrophage-localized iNOS.
Chagas is a parasitic disease caused by Trypanosoma cruzi. It is commonly asymptomatic in the acute phase. Chronically, it can lead to heart block, cardiomyopathy, and/or megaesophagus/colon. ...Vertical transmission occurs in 1-10% of births and is under-recognized and rarely screened. In a survey of obstetrician-gynecologists in the US, only 8% knew the risk of congenital infection and 78% never considered a diagnosis of Chagas disease among patients from endemic countries. Here Cricco-Lizza et al present the case of an 81-year-old man from the US with a history of complete heart block who presented with chronic abdominal distention.
Background
The long-term prevalence and risk factors for post-acute COVID-19 sequelae (PASC) are not well described and may have important implications for unvaccinated populations and policy makers.
...Objective
To assess health status, persistent symptoms, and effort tolerance approximately 1 year after COVID-19 infection
Design
Retrospective observational cohort study using surveys and clinical data
Participants
Survey respondents who were survivors of acute COVID-19 infection requiring Emergency Department presentation or hospitalization between March 3 and May 15, 2020.
Main Measure(s)
Self-reported health status, persistent symptoms, and effort tolerance
Key Results
The 530 respondents (median time between hospital presentation and survey 332 days IQR 325–344) had mean age 59.2±16.3 years, 44.5% were female and 70.8% were non-White. Of these, 41.5% reported worse health compared to a year prior, 44.2% reported persistent symptoms, 36.2% reported limitations in lifting/carrying groceries, 35.5% reported limitations climbing one flight of stairs, 38.1% reported limitations bending/kneeling/stooping, and 22.1% reported limitations walking one block. Even those without high-risk comorbid conditions and those seen only in the Emergency Department (but not hospitalized) experienced significant deterioration in health, persistent symptoms, and limitations in effort tolerance. Women (adjusted relative risk ratio aRRR 1.26, 95% CI 1.01–1.56), those requiring mechanical ventilation (aRRR 1.48, 1.02–2.14), and people with HIV (aRRR 1.75, 1.14–2.69) were significantly more likely to report persistent symptoms. Age and other risk factors for more severe COVID-19 illness were not associated with increased risk of PASC.
Conclusions
PASC may be extraordinarily common 1 year after COVID-19, and these symptoms are sufficiently severe to impact the daily exercise tolerance of patients. PASC symptoms are broadly distributed, are not limited to one specific patient group, and appear to be unrelated to age. These data have implications for vaccine hesitant individuals, policy makers, and physicians managing the emerging longer-term yet unknown impact of the COVID-19 pandemic.
The U.S. government has named post-acute sequelae of COVID-19 (longCOVID) as influential on disability rates. We previously showed that COVID-19 carries a medical/functional burden at 1 year, and ...that age and other risk factors of severe COVID-19 were not associated with increased longCOVID risk. Long-term longCOVID brain fog (BF) prevalence, risk factors and associated medical/functional factors are poorly understood, especially after mild SARS-CoV-2 infection.
A retrospective observational cohort study was conducted at an urban tertiary-care hospital. Of 1,032 acute COVID-19 survivors from March 3-May 15, 2020, 633 were called, 530 responded (59.2 ± 16.3 years, 44.5% female, 51.5% non-White) about BF prevalence, other longCOVID, post-acute ED/hospital utilization, perceived health/social network, effort tolerance, disability.
At approximately 1-year, 31.9% (
= 169) experienced BF. Acute COVID-19 severity, age, and premorbid cardiopulmonary comorbidities did not differ between those with/without BF at 1 year. Patients with respiratory longCOVID had 54% higher risk of BF than those without respiratory longCOVID. BF associated with sleep disturbance (63% with BF vs.29% without BF,
< 0.0001), shortness of breath (46% vs.18%,
< 0.0001), weakness (49% vs.22%,
< 0.0001), dysosmia/dysgeusia (12% vs.5%,
< 0.004), activity limitations (
< 0.001), disability/leave (11% vs.3%,
< 0.0001), worsened perceived health since acute COVID-19 (66% vs.30%,
< 0.001) and social isolation (40% vs.29%,
< 0.02), despite no differences in premorbid comorbidities and age.
A year after COVID-19 infection, BF persists in a third of patients. COVID-19 severity is not a predictive risk factor. BF associates with other longCOVID and independently associates with persistent debility.