The long-term outcome of athletes with frequent ventricular premature complexes (VPCs) and apparently normal heart has not been fully clarified. To evaluate the clinical and prognostic significance ...of VPCs and the influence of continuing sports activity during follow-up, we studied 120 healthy athletes (96 men; median age 16 years) in whom frequent VPCs (>100 VPCs/24 hours) were discovered by chance during preparticipation screening. All athletes were followed up for a median of 84 months. During follow-up, 96 underwent serial 24-hour Holter recording and 62 underwent serial echocardiography. The median number of VPCs/24 hours on basal Holter was 3,760. During follow-up, 81 athletes continued sports activity, whereas 39 did not. No athlete died or developed overt heart disease. The median number of VPCs/24 hours decreased in both athletes who continued sports activity and those who did not (from 3,805 to 1,124, p <0.0001 and from 5,787 to 1,298, p <0.0001, respectively). During follow-up, left ventricular ejection fraction slightly decreased to <55% in 9 of 62 athletes who, in respect to the remaining 53, had more VPCs/24 hours both in the basal state (12,000 vs 3,880) and during follow-up (10,702 vs 1,368), and a longer follow-up (95 vs 36 months). In conclusion, (1) frequent VPCs in athletes without heart disease have a long-term benign prognostic significance, (2) sporting activity does not modify this benign outcome, (3) during follow-up, the burden of VPCs decreases whether or not subjects continue sports activity, and (4) in 14.5% of athletes, ejection fraction slightly decreases over time.
Aims. LBBB is rare in healthy young adults, and its long-term prognosis is uncertain. Methods. 56 subjects (aged <50 years), in whom an LBBB was discovered by chance in the absence of clinical and ...echocardiographic evidence of heart disease, were collected in a multicenter registry. Results. 69% were males. Mean age at the time of discovery of LBBB was 37 ± 11 years. Mean QRS duration was 149 ± 17 m sec and 35% had left axis deviation. All patients had a normal echocardiogram, except for left ventricular dyssynchrony; 37 patients underwent coronary angiography (30) or myocardial scintigraphy during effort Eriksson and Wilhelmsen (2005), and in all cases obstructive coronary artery disease was excluded. In 2/30 patients who underwent coronary angiography, an anomalous origin of the CX artery from the right coronary sinus was found. Thirty patients underwent cardiac magnetic resonance; in 60% it was normal, while in 40% it revealed late enhancement, which in 33% was localized in the basal septum, suggesting fibrosis of the left bundle branch. During follow-up (12+/10 years, median 10 years) no sudden death occurred. At the end of follow-up, all patients were alive, except for one who suffered accidental death. Two patients (3.5%) underwent PM implantation owing to syncope. The echocardiogram at the end of follow-up revealed LV dysfunction in only one patient. Conclusions. In young adults without apparent heart disease, LBBB is a heterogeneous condition. In the vast majority of cases, the prognosis is good and no ventricular dysfunction occurs over time. However, as only 18% of our patients were aged >60 years at the end of follow-up, we cannot establish the prognosis in older age-groups.
Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and non-alcoholic steatohepatitis (NASH) are chronic liver diseases (CLDs) of distinct etiologies that represent a public health risk ...with limited therapeutic options. A common feature among CLDs is an aggressive T cell response resulting in destruction of liver tissue and fibrosis. Here, we assessed the presence and nature of T cell inflammation in late-stage human AIH, PSC and NASH and examined whether targeting the T cell response can improve disease pathology in a mouse model (Traf6ΔTEC) of spontaneous AIH. T cell infiltration and ensuing inflammatory pathways were present in human AIH and PSC and to a lesser extent in NASH. However, we observed qualitative differences in infiltrating T cell subsets and upregulation of inflammatory pathways among these diseases, while mouse and human AIH exhibited similar immunogenic signatures. While gene expression profiles differed among diseases, we identified 52 genes commonly upregulated across all diseases that included the JAK3 tyrosine kinase. Therapeutic targeting of chronic AIH with the JAK inhibitor tofacitinib reduced hepatic T cell infiltration, AIH histopathology and associated immune parameters in treated Traf6ΔTEC mice. Our results indicate that targeting T cell responses in established hepatic autoimmune inflammation is a feasible strategy for developing novel therapeutic approaches to treat AIH and possibly other CLDs irrespective of etiology.
Immune profiling of mouse and human chronic liver diseases (CLDs) identifies targets for therapeutic treatment of autoimmune hepatitis (AIH). Late-stage human CLDs exhibit CD4+ and CD8+ T cell infiltration and disease-specific T cell inflammatory pathways. AIH and primary sclerosing cholangitis (PSC) exhibit enhanced T cell inflammatory responses compared to non-alcoholic steatohepatitis (NASH). Immune transcriptomic profiling identifies gene targets for therapeutic intervention against CLDs including the JAK3 kinase. Treatment of Traf6ΔTEC mice with chronic AIH with the JAK inhibitor tofacitinib inhibits disease histopathology Display omitted
•Late-stage human chronic liver diseases (CLDs) exhibit robust T cell responses.•T cell responses are qualitatively different among CLDs of distinct etiologies.•Genes upregulated in mouse and human CLDs can be targeted to mitigate inflammation.•Validation of the Traf6ΔTEC mouse model as a useful tool to test drug therapeutic efficacy.
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort ...from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.
Cardiovascular disease is the main cause of death in the world. The underlying cause in most cases is atherosclerosis, which is in part a chronic inflammatory disease. Experimental atherosclerosis ...studies have elucidated the role of cholesterol and inflammation in the disease process. This has led to successful clinical trials with pharmaceutical agents that reduce clinical manifestations of atherosclerosis. Careful and well-controlled experiments in mouse models of the disease could further elucidate the pathogenesis of the disease, which is not fully understood. Standardized lesion analysis is important to reduce experimental variability and increase reproducibility. Determining lesion size in aortic root, aortic arch, and brachiocephalic artery are common endpoints in experimental atherosclerosis. This protocol provides a technical description for evaluation of atherosclerosis at all these sites in a single mouse. The protocol is particularly useful when material is limited, as is frequently the case when genetically modified animals are being characterized.
Atherosclerosis progression is modulated by interactions with the adaptive immune system. Humoral immunity can help protect against atherosclerosis formation; however, the existence, origin, and ...function of putative atherogenic antibodies are controversial. How such atherosclerosis-promoting antibodies could affect the specific composition and stability of plaques, as well as the vasculature generally, remains unknown.
We addressed the overall contribution of antibodies to atherosclerosis plaque formation, composition, and stability in vivo (1) with mice that displayed a general loss of antibodies, (2) with mice that had selectively ablated germinal center-derived IgG production, or (3) through interruption of T-B-cell interactions and further studied the effects of antibody deficiency on the aorta by transcriptomics.
Here, we demonstrate that atherosclerosis-prone mice with attenuated plasma cell function manifest reduced plaque burden, indicating that antibodies promote atherosclerotic lesion size. However, the composition of the plaque was altered in antibody-deficient mice, with an increase in lipid content and decreases in smooth muscle cells and macrophages, resulting in an experimentally validated vulnerable plaque phenotype. Furthermore, IgG antibodies enhanced smooth muscle cell proliferation in vitro in an Fc receptor-dependent manner, and antibody-deficient mice had decreased neointimal hyperplasia formation in vivo. These IgG antibodies were shown to be derived from germinal centers, and mice genetically deficient for germinal center formation had strongly reduced atherosclerosis plaque formation. mRNA sequencing of aortas revealed that antibodies are required for the sufficient expression of multiple signal-induced and growth-promoting transcription factors and that aortas undergo large-scale metabolic reprograming in their absence. Using an elastase model, we demonstrated that absence of IgG results in an increased severity of aneurysm formation.
We propose that germinal center-derived IgG antibodies promote the size and stability of atherosclerosis plaques, through promoting arterial smooth muscle cell proliferation and maintaining the molecular identity of the aorta. These results could have implications for therapies that target B cells or B-T-cell interactions because the loss of humoral immunity leads to a smaller but less stable plaque phenotype.
Inflammation is important for antimicrobial defense and for tissue repair after trauma. The inflammatory response and its resolution are both active processes that must be tightly regulated to ...maintain homeostasis. Excessive inflammation and nonresolving inflammation cause tissue damage and chronic disease, including autoinflammatory and cardiovascular diseases. An improved understanding of the cellular and molecular mechanisms that regulate inflammation has supported development of novel therapies for several inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. Many of the specific anticytokine therapies carry a risk for excessive immunosuppression and serious side effects. The discovery of the inflammatory reflex and the increasingly detailed understanding of the molecular interactions between homeostatic neural reflexes and the immune system have laid the foundation for bioelectronic medicine in the field of inflammatory diseases. Neural interfaces and nerve stimulators are now being tested in human clinical trials and may, as the technology develops further, have advantages over conventional drugs in terms of better compliance, continuously adaptable control of dosing, better monitoring, and reduced risks for unwanted side effects. Here, we review the current mechanistic understanding of common autoinflammatory conditions, consider available therapies, and discuss the potential use of increasingly capable devices in the treatment of inflammatory disease.
Objective- Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic ...inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. Approach and Results- We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe
mice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Conclusions- Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis.
Cardiovascular disease is one of the leading causes of death worldwide. A major cause is atherosclerosis, which is a chronic inflammatory disease of medium and large size arteries characterized by ...the accumulation of cholesterol rich low-density lipoprotein (LDL) particles in the sub-endothelium layer of the vessel.Retention and modification of LDL triggers a systemic inflammatory response sustained by the humoral and cellular branches of the immune system. Early atherosclerosis initiation is often in the form of fatty streaks whilst necrotic core formation, inflammation, fibrosis and stenosis are characteristics of advanced atherosclerotic plaques.A protective humoral immune response is induced upon vaccination against oxidized LDL in experimental models of atherosclerosis, whilst studies on follicular B cells report an opposite pathogenic function of this subset. Furthermore, association studies on cardiovascular disease risk and antibody titers against oxidized LDL provide inconsistent results. Given these seemingly contradictory observations, the role of B cells and antibodies in atherosclerosis is still poorly understood.Atherosclerosis can develop as a silent disease over decades, and asymptomatic plaques usually have a robust fibrotic cap consisting of collagen and extracellular matrix deposited by smooth muscle cells. However, sudden clinical symptoms can occur in terms of myocardial infarction and stroke when the stability of the cap is impaired and the content of the plaque is released into the bloodstream.In this thesis we identify a potential mechanism involved in regulating the growth and the stability of atherosclerotic lesions. We first demonstrate that a germinal center response occurs promptly upon acute hypercholesterolemia, and is associated with an autoimmune-like deposition of immune complexes and systemic autoantibody production. Secondly, we characterize the effects of B cells in late stage atherosclerosis and we show that antibodies promote increased lesion size. Furthermore, we illustrate how these effects are depending on germinal center-derived antibodies. Thirdly, we observe that antibodies originating from the germinal center reaction induce a stable atherosclerotic plaque phenotype, in part through promoting smooth muscle cell proliferation. Finally, we report that antibodies regulate transcriptional pathways involved in maintaining the integrity, function and stability of the aorta.Collectively, the findings presented in this thesis identify germinal center B cells as an important factor affecting the composition, size and stability of the atherosclerotic plaque.
Medullary thymic epithelial cells (mTECs) induce T cell tolerance in the thymus through the elimination of self-reactive thymocytes. Commensal bacteria are also critical for shaping T cell responses ...in the gut and distal organs. We previously showed that mice depleted of mTECs (Traf6ΔTEC) generated autoreactive T cells and developed autoimmune hepatitis (AIH). In this report, we found that Toll-like receptor (TLR)-mediated microbial sensing on liver hematopoietic cells and the gut microbiota contributed to AIH development in Traf6ΔTEC mice. While adoptive transfer of thymic Traf6ΔTEC T cells in immune-deficient mice was sufficient for AIH development, colonization of germ-free mice with Traf6ΔTEC microbiota failed to induce AIH, suggesting that the gut microbiota contributes to but is not sufficient for AIH development. Microbiota-mediated exacerbation of AIH associated with increased numbers of hepatic Foxp3+ T cells and their increase was proportional to the degree of inflammation. The contribution of the gut microbiota to AIH development associated with an altered microbial signature whose composition was influenced by the qualitative nature of the thymic T cell compartment. These results suggest that aberrant selection of T cells in the thymus can induce changes in the gut microbiota that lead to exacerbation of organ-specific autoimmunity and AIH. Our results add to our understanding of the mechanisms of AIH development and create a platform towards developing novel therapeutic approaches for treating this disease.
•The thymus-gut-liver axis regulates development of murine autoimmune hepatitis (AIH).•Aberrant thymic T cell selection induces AIH and alters the gut microbiota.•Hepatic microbial sensing and the gut microbiota exacerbate AIH.•Microbiota-mediated hepatic Foxp3+ T cell production associates with AIH severity.
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