Cardiac inflammation associated with COVID-19 mRNA vaccination in patients with and without previous myocarditis.

BACKGROUND: mRNA COVID-19 vaccines have been associated with myocarditis in the general population. However, application of gold standard techniques is often missing, and data about patients with history of myocarditis have not been reported yet. METHODS: We evaluated 21 patients (median age 27, 86% males) for suspected myocarditis after receiving mRNA COVID-19 vaccine. We divided cases with previous diagnosis of myocarditis (PM, N.=7), from naïve controls (NM, N.=14). All patients were investigated thoroughly by cardiac magnetic resonance (100%) with or without endomyocardial biopsy (14%). RESULTS: Overall, 57% of patients met updated Lake Louise criteria and none fulfilled Dallas criteria, with no remarkable differences between groups. Acute coronary syndrome-like presentation was more frequent in NM with earlier normalization of troponin than PM. NM and PM already healed from myocarditis were clinically comparable, whereas PM with active inflammation had subtle presentation and were evaluated for immunosuppressive therapy modulation. None had fulminant myocarditis and/or malignant ventricular arrhythmia at presentation. No major cardiac events occurred by 3 months. CONCLUSIONS: In this study, the suspicion of mRNA COVID-19 vaccine-associated myocarditis was inconstantly confirmed by gold standard diagnostics. Myocarditis was uncomplicated in both PM and NM patients. Larger studies with longer follow-up are needed to validate COVID-19 vaccination in this population.

Three-dimensional transoesophageal echocardiography is crucial for valid assessment of mitral valve leaflet morphology in severe mitral regurgitation prior to interventional repair.

BACKGROUND: Interventional mitral valve (MV) repair of severe symptomatic mitral regurgitation (MR) is a therapeutic option in high-risk surgical or inoperable patients. Assessment of the MV remains a crucial part of pre-interventional screening. Three-dimensional transoesophageal echocardiography (3D-TOE) may compensate for well-known pitfalls that occur in 2D-TOE. PURPOSE: We investigated whether the functional length of the central segments of the posterior and anterior MV leaflets (PML-P2 and AML-A2) is more reliably determined by 3D-TOE full volume datasets (3D-MPR) or orthogonal biplane-imaging (Xplane) when compared to 2D-TOE. METHODS AND RESULTS: Between February 2014 and August 2015, 265 consecutive patients with moderate to severe symptomatic MR were screened. Seventy patients were judged suitable for interventional MV repair by the in-house Heart-Team. Eventually, 59 patients remained for data analysis. Inter-observer variability was lowest in 3D-MPR followed by Xplane (r = 0.92 and 0.90, p < .001 for both) and highest in Mplane (r = 0.82, p < .001). Mean functional PML-P2 lengths were similar in Xplane (12.6 ± 1.7 mm) and 3D-MPR (12.1 ± 2.0 mm), however, significantly different in 2D-TOE (10.0 ± 2.1 mm, p < .001). 2D-TOE underestimated PML-P2 length with a bias of -2.5 mm compared to Xplane and -1.95 mm compared to 3D-MPR. In contrast, functional AML-A2 length was determined similar across all methods. CONCLUSIONS: Our results demonstrate the superiority of 3D-TOE over 2D-TOE for accurate MV assessment in MR, especially for the determination of the functional PML length. Erroneous MV leaflet assessment may result in inadequate therapy restriction if the MV is deemed not suitable for interventional repair.

Three-Dimensional Left Ventricular Torsion in Patients With Dilated Cardiomyopathy　- A Marker of Disease Severity.

BACKGROUND: LV twist has a key role in maintaining left ventricular (LV) contractility during exercise. The purpose of this study was to investigate LV torsion instead of twist as a surrogate marker of peak oxygen uptake (peak V̇O2) assessed by cardiopulmonary exercise testing (CPET) in patients with non-ischemic dilated cardiomyopathy (DCM).Methods and Results:We evaluated 45 outpatients with DCM (50±12 years, 24% females) with 3D speckle-tracking electrocardiography prior to CPET. LV torsion, LV ejection fraction (EF), LV diastolic function, LV global longitudinal (GLS) and circumferential (GCS) strain were quantified. A reduced functional capacity (FC) was defined as a peak V̇O2<20 mL/kg/min. LV torsion correlated most strongly with peak V̇O2(r=0.76, P<0.001). LV torsion instead of twist was an independent predictor of peak V̇O2(B: 0.59 to 0.71, P<0.001) in multivariable analyses. Impaired LV torsion <0.61 degrees/cm was able to predict a reduced FC with higher sensitivity and specificity (0.91 and 0.81; area under the curve (AUC): 0.88, P<0.001) than LV EF, GLS or GCS (AUC 0.64, 0.63 and 0.66; P<0.05 for differences in AUC). CONCLUSIONS: Peak V̇O2correlated more strongly with LV torsion than with LV diastolic function, LV EF, GLS or GCS. LV torsion had high accuracy in identifying patients with a reduced FC.

Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.

There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4(+) helper T cells (TH17 cells) has a pivotal role in autoimmune diseases. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23-TH17 pathway. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-α and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.

Interferon-γ signaling inhibition ameliorates angiotensin II-induced cardiac damage.

Angiotensin (Ang) II induces vascular injury in part by activating innate and adaptive immunity; however, the mechanisms are unclear. We investigated the role of interferon (IFN)-γ and interleukin (IL)-23 signaling. We infused Ang II into IFN-γ receptor (IFN-γR) knockout mice and wild-type controls, as well as into mice treated with neutralizing antibodies against IL-23 receptor and IL-17A. Ang II-treated IFN-γR knockout mice exhibited reduced cardiac hypertrophy, reduced cardiac macrophage and T-cell infiltration, less fibrosis, and less arrhythmogenic electric remodeling independent of blood pressure changes. In contrast, IL-23 receptor antibody treatment did not reduce cardiac hypertrophy, fibrosis, or electric remodeling despite mildly reduced inflammation. IL-17A antibody treatment behaved similarly. In the kidney, IFN-γR deficiency reduced inflammation and tubulointerstitial damage and improved glomerular filtration rate. Nonetheless, albuminuria was increased compared with Ang II-treated wild-type controls. The glomeruli of Ang II-treated IFN-γR knockout mice exhibited fewer podocytes, less nephrin and synaptopodin staining, and impaired podocyte autophagy. Thus, IFN-γ blockade, but not IL-23 receptor antibody treatment, protects from Ang II-induced cardiac damage and electric remodeling. In the kidney, IFN-γ signaling acts in a cell type-specific manner. Glomerular filtration rate is preserved in the absence of the IFN-γR, whereas podocytes may require the IFN-γR in the presence of Ang II for normal integrity and function.

Immune-related effects in hypertension and target-organ damage.

PURPOSE OF REVIEW: Several studies published in the past three decades have suggested that inflammation and activation of immunity are central features in the pathogenesis of atherosclerosis, ischemic myocardial injury, and also in hypertension-induced target organ damage. A better understanding of this field could help us to explain the increased cardiovascular risk in patients with chronic inflammation. RECENT FINDINGS: Recent studies have demonstrated that macrophages and various T-cell subtypes play a pivotal role in the regulation of blood pressure and target organ damage. Hypertensive stimuli such as the effector molecule of the renin-angiotensin system, angiotensin II, not only regulate vascular tone and sodium balance, but also activate immune cells and promote cell infiltration into target organs. Experimental and clinical evidence show that adaptive transfer of immune cells, rendering mice deficient for a certain subset of immune cells, or immunosuppressive treatment affects blood pressure and ameliorates target organ damage. SUMMARY: The aim of this review is to summarize and discuss some of the more recent insights as to how immune cells might affect the regulation of blood pressure and the pathogenesis of hypertension-induced target organ damage.

Differential effect of ischaemic preconditioning on mobilisation and recruitment of haematopoietic and mesenchymal stem cells in porcine myocardial ischaemia-reperfusion.

Effects of ischaemic preconditioning (IP) on the mobilisation and recruitment of haematopoietic (HSCs) and mesenchymal stem (MSC) cells were determined in porcine coronary occlusion/reperfusion. Thirty-three pigs underwent percutaneous occlusion of the left anterior descending coronary artery (LAD) for 90 minutes (min), followed by 120 min reperfusion. IP was performed in 16 of the 33 pigs by two cycles of 5 min balloon occlusion/reperfusion prior to the 90 min occlusion (group IP vs. group C). Peripheral blood and myocardial tissue concentration of bone marrow origin HSCs (characterised by coexpression of CD31+, CD90+, CD45+) and MSCs (characterised by coexpression of CD44+, CD90+, CD45-) were measured by flow cytometry in the early phase of IP. Plasma/serum levels of stem cell mobilisation factors (stromal cell-derived factor-1a [SDF-1a], vascular endothelial growth factor [VEGF], tumour necrosis factor a[TNF-a] and interleukin-8 [IL-8]) were measured. IP led to a significant increase in circulating HSCs as compared with the group C (475 +/- 233 vs. 281 +/- 264 /ml, p=0.032) in the early phase of IP. In contrast, a rapid and prolonged decrease in level of circulating MSCs was observed in group IP as compared with group C (19 +/- 12 vs. 32 +/- 17 /ml, p=0.015). The recruitment of HSCs and MSCs in infarct and border zone was significantly greater in IP group, indicating a faster homing of MSCs as compared with the rate of mobilisation. Rapid increase in VEGF, TNF-a and IL-8 levels was induced by IP, which, however, was not correlated with the levels of circulating SCs. In conclusion, IP resulted in differential mobilisation and recruitment of HSCs and MSCs in the early phase of cardioprotection.

Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system.

Angiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with the angiotensin II type-1 receptor (AT1R), which contributes to blood pressure regulation and development of hypertension but may also mediate effects on the immune system. Here we study the role of the RAS in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model mimicking many aspects of multiple sclerosis. Quantitative RT-PCR analyses showed an up-regulation of renin, angiotensin-converting enzyme, as well as AT1R in the inflamed spinal cord and the immune system, including antigen presenting cells (APC). Treatment with the renin inhibitor aliskiren, the angiotensin II converting-enzyme inhibitor enalapril, as well as preventive or therapeutic application of the AT1R antagonist losartan, resulted in a significantly ameliorated course of MOG-EAE. Blockade of AT1R did not directly impact on T-cell responses, but significantly reduced numbers of CD11b+ or CD11c+ APC in immune organs and in the inflamed spinal cord. Additionally, AT1R blockade impaired the expression of CCL2, CCL3, and CXCL10, and reduced CCL2-induced APC migration. Our findings suggest a pivotal role of the RAS in autoimmune inflammation of the central nervous system and identify RAS blockade as a potential new target for multiple sclerosis therapy.

Regulatory T cells ameliorate angiotensin II-induced cardiac damage.

BACKGROUND: Hypertensive target organ damage, especially cardiac hypertrophy with heart failure and arrhythmia, is a major source of morbidity and mortality. Angiotensin II, a major mediator of hypertension and cardiac damage, has proinflammatory properties. Inflammation and activation of the immune system play a pivotal role in pathogenesis of hypertensive target organ damage. However, the role of immunosuppressive CD4+CD25+ regulatory T (Treg) cells in the pathogenesis of hypertensive target organ damage is unexplored. METHODS AND RESULTS: We conducted adoptive transfer of Treg cells into angiotensin II-infused hypertensive mice. Treg cell recipients exhibited improved cardiac hypertrophy and less cardiac fibrosis despite sustained hypertension. Amelioration of cardiac morphology was accompanied by an improvement in arrhythmogenic electric remodeling, indicating the functional significance of the enhanced cardiac morphology. Delocalization of the connexin 43 gap junction protein is one of the major pathomechanisms in electric remodeling. Pronounced connexin 43 immunoreactivity was found at the lateral borders of cardiomyocytes in angiotensin II-treated mice. In contrast, connexin 43 was restricted to the intercalated disk regions in sham controls. Surprisingly, angiotensin II+Treg-treated mice showed normal connexin 43 gap junction protein localization. Adoptive Treg cell transfer resulted in a marked reduction in cardiac CD4+, CD8+, and CD69+ cell and macrophage infiltration. CONCLUSIONS: Immunosuppressive effects of transferred Treg cells ameliorated cardiac damage and accounted for the improved electric remodeling independently of blood pressure-lowering effects. Our results provide new insights into the pathogenesis of hypertensive cardiac damage and could therefore lead to new therapeutic approaches that involve manipulation of the immune system.

Role of the immune system in hypertensive target organ damage.

Recent advances in our understanding of cardiovascular diseases clearly show that inflammation and activation of immunity are central features in the pathogenesis of atherosclerosis, ischemic myocardial injury, and also in hypertension-induced target organ damage. However, the idea that special immune cells could regulate immune responses in these conditions in favor of minimizing disease is a novel concept. Regulatory T cells have unique immune modulatory properties that offer an attractive alternative to common immunosuppressant drugs. Their application in animal models of autoimmunity and neoplastic conditions offers exciting therapeutic avenues. Thus, with the use of regulatory T cells in hypertension-induced target organ damage enables new insights into the pathophysiologic mechanisms and widen our knowledge of the role of the immune system in cardiovascular disease. The aim of this review was to summarize and discuss some of the most recent insights and put them into a perspective based on well-known interactions between immunity and hypertensive damage.

Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide.

The recently cloned (pro)renin receptor [(P)RR] mediates renin-stimulated cellular effects by activating mitogen-activated protein kinases and promotes nonproteolytic prorenin activation. In vivo, (P)RR is said to be blocked with a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP). We tested whether human prorenin and renin induce extracellular signal-regulated kinase (ERK) 1/2 activation and whether the direct renin inhibitor aliskiren or the HRP inhibits the receptor. We detected the (P)RR mRNA and protein in isolated human monocytes and in U937 monocytes. In U937 cells, we found that both human renin and prorenin induced a long-lasting ERK 1/2 phosphorylation despite angiotensin II type 1 and 2 receptor blockade. In contrast to angiotensin II-ERK signaling, renin and prorenin signaling did not involve the epidermal growth factor receptor. A mitogen-activated protein kinase kinase 1/2 inhibitor inhibited both renin and prorenin-induced ERK 1/2 phosphorylation. Neither aliskiren nor HRP inhibited binding of (125)I-renin or (125)I-prorenin to (P)RR. Aliskiren did not inhibit renin and prorenin-induced ERK 1/2 phosphorylation and kinase activity. Fluorescence-activated cell sorter analysis showed that, although fluorescein isothiocyanate-labeled HRP bound to U937 cells, HRP did not inhibit renin or prorenin-induced ERK 1/2 activation. In conclusion, prorenin and renin-induced ERK 1/2 activation are independent of angiotensin II. The signal transduction is different from that evoked by angiotensin II. Aliskiren has no (P)RR blocking effect and did not inhibit ERK 1/2 phosphorylation or kinase activity. Finally, we found no evidence that HRP affects renin or prorenin binding and signaling.

Fractalkine receptor polymorphisms V2491 and T280M as genetic risk factors for restenosis.

The chemokine fractalkine (FKN) recruits leukocytes into lesions of the arterial wall, which may lead to restenosis after stenting. FKN also regulates proliferation of smooth muscle cells, another mechanism pivotal to neointimal thickening. We assessed the hypothesis that functionally important polymorphisms of the FKN receptor CX3CR1 influence restenosis after coronary stenting. Three hundred and sixty-five patients undergoing coronary stenting were genotyped for the CX3CR1 polymorphisms V2491 and T280M. Restenosis occurred in 25% of patients, and recurrent (> 1) restenosis at the target lesion in 8%. The allele 1249 was associated with an increased risk of restenosis (adjusted odds ratio 2.4, 95% confidence interval: 1.3-4.2, P = 0.003) and recurrent restenosis (odds ratio 2.7, 95% confidence interval: 1.3-5.9, P = 0.011). Particularly, patients with 1249 lacking the allele M280 were at an elevated risk of restenosis (P = 0.006) and, accordingly, the haplotype containing 1249 but not M280 was more frequent in patients with restenosis (P = 0.001). In conclusion, the CX3CR1 1249 allele is associated with an increased risk of restenosis while the CX3CR1 M280 allele might counteract the harmful influence of 1249. These findings show the importance of the chemokine FKN and genetic variations of its receptor for restenosis after coronary stenting. Recognition of these inherited risk modifiers may help to individualize treatment of coronary stenosis.