A large body of evidence produced during decades of research indicates that myocardial injury activates innate immunity. On the one hand, innate immunity both aggravates ischemic injury and impedes ...remodeling after myocardial infarction (MI). On the other hand, innate immunity activation contributes to myocardial healing, as exemplified by monocytes' central role in the formation of a stable scar and protection against intraventricular thrombi after acute infarction. Although innate leukocytes can recognize a wide array of self-antigens via pattern recognition receptors, adaptive immunity activation requires highly specific cooperation between antigen-presenting cells and distinct antigen-specific receptors on lymphocytes. We have only recently begun to examine lymphocyte activation's relationship to adaptive immunity and significance in the context of ischemic myocardial injury. There is some experimental evidence that CD4(+) T-cells contribute to ischemia-reperfusion injury. Several studies have shown that CD4(+) T-cells, especially CD4(+) T-regulatory cells, improve wound healing after MI, whereas depleting B-cells is beneficial post MI. That T-cell activation after MI is induced by T-cell receptor signaling implicates autoantigens that have not yet been identified in this context. Also, the significance of lymphocytes in humans post MI remains unclear, primarily as a result of methodology. This review summarizes current experimental evidence of lymphocytes' activation, functional role, and crosstalk with innate leukocytes in myocardial ischemia-reperfusion injury, wound healing, and remodeling after myocardial infarction.
The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated ...with a wide array of mechanisms subsumed under the term “inflammation”. Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-α led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective.
The aim of this study was to investigate the impact of myocardial fibrosis in Fabry disease. Seventy-three patients with genetically confirmed Fabry disease were followed for 4.8 ± 2.4 years. In ...accordance with current guidelines, 57 patients received enzyme replacement therapy (ERT) after study inclusion, whereas 16 did not. At baseline and latest possible follow-up, myocardial fibrosis was assessed noninvasively by cardiac magnetic resonance, and biomarkers of collagen metabolism were determined. Holter electrocardiography and clinical follow-up at yearly intervals were used to monitor malignant ventricular arrhythmias (MVAs; nonsustained and sustained ventricular tachycardia and sudden cardiac death). In total, 48 patients (66%) showed fibrosis assessed by late enhancement (LE) at baseline, and 4 patients developed new LE during follow-up, 2 of them despite ERT. The 2 patients receiving ERT (1.4 ± 1.9% vs 2.5 ± 2.6%, p <0.001) and the patients not receiving ERT (0.5 ± 0.8% vs 0.7 ± 1.0%, p = 0.035) showed a progression of LE during follow-up. None of the patients displayed reductions of LE during follow-up. Collagen biomarkers were elevated in patients with and without LE but did not correlate with LE amount. Thirteen LE-positive patients at the baseline examination had documented MVAs (including 5 sudden cardiac deaths), whereas none of the patients without LE had MVAs. The yearly increase in fibrosis was 0.9 ± 0.6% in patients with MVAs and 0.2 ± 0.3% in patients without MVAs (p <0.001). Logistic multivariate regression analysis revealed that the annual increase in fibrosis during follow-up was the only independent predictor of MVAs. In conclusion, myocardial fibrosis in Fabry disease is progressive, apparently not modified by ERT, and a crucial outcome determinant.
Myocardial infarction is a prevalent major cardiovascular event that arises from myocardial ischemia with or without reperfusion, and basic and translational research is needed to better understand ...its underlying mechanisms and consequences for cardiac structure and function. Ischemia underlies a broad range of clinical scenarios ranging from angina to hibernation to permanent occlusion, and while reperfusion is mandatory for salvage from ischemic injury, reperfusion also inflicts injury on its own. In this consensus statement, we present recommendations for animal models of myocardial ischemia and infarction. With increasing awareness of the need for rigor and reproducibility in designing and performing scientific research to ensure validation of results, the goal of this review is to provide best practice information regarding myocardial ischemia-reperfusion and infarction models. Listen to this article's corresponding podcast at ajpheart.podbean.com/e/guidelines-for-experimental-models-of-myocardial-ischemia-and-infarction/.
New therapies are required to reduce myocardial infarct (MI) size and prevent the onset of heart failure in patients presenting with acute myocardial infarction (AMI), one of the leading causes of ...death and disability globally. In this regard, the immune cell response to AMI, which comprises an initial pro-inflammatory reaction followed by an anti-inflammatory phase, contributes to final MI size and post-AMI remodelling changes in left ventricular (LV) size and function. The transition between these two phases is critical in this regard, with a persistent and severe pro-inflammatory reaction leading to adverse LV remodelling and increased propensity for developing heart failure. In this review article, we provide an overview of the immune cells involved in orchestrating the complex and dynamic inflammatory response to AMI-these include neutrophils, monocytes/macrophages, and emerging players such as dendritic cells, lymphocytes, pericardial lymphoid cells, endothelial cells, and cardiac fibroblasts. We discuss potential reasons for past failures of anti-inflammatory cardioprotective therapies, and highlight new treatment targets for modulating the immune cell response to AMI, as a potential therapeutic strategy to improve clinical outcomes in AMI patients. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
The innate immune system detects highly conserved, relatively invariant structural motifs of pathogens. Toll-like receptors (TLRs) have been identified as the primary innate immune receptors. TLRs ...distinguish between different patterns of pathogens and activate a rapid innate immune response; however, TLRs can also be activated by host-derived molecules. In addition to being expressed in immune cells, TLRs are expressed in other tissues, such as those of the cardiovascular system. TLRs could, therefore, be a key link between cardiovascular disease development and the immune system. Indeed, evidence that TLR activation contributes to the development and progression of atherosclerosis, cardiac dysfunction in sepsis, and congestive heart failure, is convincing. Although much has been learned about TLR activation in cellular components of the cardiovascular system, the role individual TLR family members have in the pathophysiology of cardiovascular diseases and hence in clinical practice remains to be defined. Here we review the rapid progress that has been made in this field, which has improved our understanding of vascular as well as myocardial TLR function in basic and clinical science.
Isoprostanes are free radical‐catalysed PG‐like products of unsaturated fatty acids, such as arachidonic acid, which are widely recognized as reliable markers of systemic lipid peroxidation and ...oxidative stress in vivo. Moreover, activation of enzymes, such as COX‐2, may contribute to isoprostane formation. Indeed, formation of isoprostanes is considerably increased in various diseases which have been linked to oxidative stress, such as cardiovascular disease (CVD), and may predict the atherosclerotic burden and the risk of cardiovascular complications in the latter patients. In addition, several isoprostanes may directly contribute to the functional consequences of oxidant stress via activation of the TxA2 prostanoid receptor (TP), for example, by affecting endothelial cell function and regeneration, vascular tone, haemostasis and ischaemia/reperfusion injury. In this context, experimental and clinical data suggest that selected isoprostanes may represent important alternative activators of the TP receptor when endogenous TxA2 levels are low, for example, in aspirin‐treated individuals with CVD. In this review, we will summarize the current understanding of isoprostane formation, biochemistry and (patho) physiology in the cardiovascular context.
Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ...ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR(MLCCre)) that were generated with a conditional MR allele (MR(flox)) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter.
Control (MR(flox/flox), MR(flox/wt)) and MR(MLCCre) mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR(MLCCre) mice. Chronically infarcted MR(MLCCre) mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O(2)(·-) production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR(MLCCre) mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-κB and reduced apoptosis early after myocardial infarction.
Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression.
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Picrosirius red (PSR) staining is a commonly used histological technique to visualize collagen in paraffin-embedded tissue sections. PSR stained collagen appears red in light ...microscopy. However it is largely unknown that PSR stained collagen also shows a red fluorescence, whereas live cells have a distinct green autofluorescence. Both emission patterns can be detected using standard filter sets as found in conventional fluorescence microscopes. Here we used digital image addition and subtraction to determine the relative area of the pure collagen and live cell content in heart tissue in a semi-automated process using standard software. This procedure, which considers empty spaces (holes) within the section, can be easily adapted to quantify the collagen and live cell areas in healthy or fibrotic tissues as aorta, lung, kidney or liver by semi-automated planimetry exemplified herein for infarcted heart tissue obtained from the mouse myocardial infarction model.
•Use of conventional PSR stained paraffin-embedded tissue sections for fluorescence analysis.•PSR and autofluorescence images are used to calculate area of collagen and area of live cells in the tissue; empty spaces (holes) in tissue are considered.•High throughput analysis of collagen and live cell content in tissue for statistical purposes.
Amyloidosis is a rare multi-system disorder associated with frequently delayed diagnosis, enormous disease burden and psychosocial distress.
Systematic assessment of needs was performed by a ...subtype-spanning questionnaire-based survey within the AMY-NEEDS research and care program.
118 patients with proven amyloidosis (62.7% ATTR, 22.0% AL, 15.3% other forms) were included in August 2020 until February 2021 (mean age 71.2 ±11.3 years; 30% women). The median diagnostic delay between onset of symptoms and diagnosis was 9.0 (range: 2.5; 33.0) months. Local health care providers (HCPs) play a central role on the way to diagnosis. Diagnosis itself typically requires a clinical but not necessarily a university setting. In the treatment phase, the focus moves to the amyloidosis centre as primary contact and coordinator, with general practitioners (GPs) acting predominantly as a contact point in crisis and link to additional services. About half of patients reported impaired quality of life and one third suffering from anxiety and depressed mood, respectively. The majority of patients talk about their concerns with close caregivers and local HCPs. Advance care planning is a relevant, yet insufficiently met need.
The journey of patients with amyloidotic disease, their contact partners and needs at different stages were characterized in detail within the German health care system. An amyloidosis-specific care concept has to master the multitude of interfaces connecting the numerous treatment providers involved with the amyloidosis centre and GPs as key players. Telemedical approaches could be a promising and well-accepted option allowing optimal coordination and communication.
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