Virus-Induced Acute Respiratory Distress Syndrome Causes Cardiomyopathy Through Eliciting Inflammatory Responses in the Heart.

BACKGROUND: Viral infections can cause acute respiratory distress syndrome (ARDS), systemic inflammation, and secondary cardiovascular complications. Lung macrophage subsets change during ARDS, but the role of heart macrophages in cardiac injury during viral ARDS remains unknown. Here we investigate how immune signals typical for viral ARDS affect cardiac macrophage subsets, cardiovascular health, and systemic inflammation. METHODS: We assessed cardiac macrophage subsets using immunofluorescence histology of autopsy specimens from 21 patients with COVID-19 with SARS-CoV-2-associated ARDS and 33 patients who died from other causes. In mice, we compared cardiac immune cell dynamics after SARS-CoV-2 infection with ARDS induced by intratracheal instillation of Toll-like receptor ligands and an ACE2 (angiotensin-converting enzyme 2) inhibitor. RESULTS: In humans, SARS-CoV-2 increased total cardiac macrophage counts and led to a higher proportion of CCR2+ (C-C chemokine receptor type 2 positive) macrophages. In mice, SARS-CoV-2 and virus-free lung injury triggered profound remodeling of cardiac resident macrophages, recapitulating the clinical expansion of CCR2+ macrophages. Treating mice exposed to virus-like ARDS with a tumor necrosis factor α-neutralizing antibody reduced cardiac monocytes and inflammatory MHCIIlo CCR2+ macrophages while also preserving cardiac function. Virus-like ARDS elevated mortality in mice with pre-existing heart failure. CONCLUSIONS: Our data suggest that viral ARDS promotes cardiac inflammation by expanding the CCR2+ macrophage subset, and the associated cardiac phenotypes in mice can be elicited by activating the host immune system even without viral presence in the heart.

[Long-term effectiveness of topical analgesics]. / Langzeiteffektivität topisch applizierter Analgetika.

BACKGROUND: Neuropathic pain consistently presents a significant therapeutic challenge. Topically applied analgesics have the advantage of showing low systemic side effects, but data on long-term effectiveness are lacking. Consequently, interviews were carried out with all patients being treated with topical analgesics in hospital. METHODS: Ethics 16-5690, German Clinical Trials Register (DRKS) 00011877. Between 2008 and 2017 a total of 265 patients were treated at least once with either capsaicin 8% (C), lidocaine 5% (L) and/or perineural botulinum toxin type A (B). From this sample, 205 patients (77%) were interviewed by telephone for feedback on pain reduction (first/last treatment: low/moderate/very good), the possible reduction of analgesic prescription and if applicable the reasons for discontinuation of use (time of interview C: 26 ± 19 months, L: 61 ± 23 months, B: 11 ± 6 months after start). Further pretreatment data and diagnoses were obtained from the in-house documentation system. Responders or long-term responders were defined as patients with at least one moderate pain reduction after the first or last treatment, as long as the effect was adequately maintained. RESULTS: In all treatment groups (56 ± 13 years, 62% male, C: 80, L: 84, B: 58 patients) patients with a long history of pain (C: 60 ± 73 months, L: 59 ± 66 months, B: 67 ± 71 months) and high pain intensity (numeric rating scale, NRS, C: 7 ± 2, L: 7 ± 2, B: 6 ± 2), were predominant. The highest primary and long-term responder rates were exhibited by L (57%/60%, B: 52%/37%, C: 23%/15%). With B, long-term responders were most frequently able to reduce analgesic use (74%, C: 58%, L: 38%). DISCUSSION: Despite the long duration of the disease, the most used off-label topical drugs L and B demonstrated a high primary response rate (in contrast to C), with most benefiting from long-term treatment.

Short-Term Glucocorticoid Treatment Normalizes the Microcirculatory Response to Remote Ischemic Conditioning in Early Complex Regional Pain Syndrome.

BACKGROUND: The early phase of complex regional pain syndrome (CRPS) is characterized by an inflammatory state and therefore often treated with anti-inflammatory acting glucocorticoids. Recently, we demonstrated that remote ischemic conditioning (RIC), a cyclic application of nondamaging ischemia on a remote extremity, reduces blood flow and increases oxygen extraction in the CRPS-affected extremity. AIM: The aim of the presented study was to analyze the effect of short-term pain treatment including glucocorticoid pulse treatment on the RIC-induced perfusion parameters. METHOD: Independently from the study, pain treatment was started with an oral glucocorticoid pulse (180 to 360 mg prednisolone) in 12 patients with CRPS (disease duration < 1 year). RIC was conducted before and after pulse treatment. Three cycles of 5 minutes ischemia and 10 minutes reperfusion were applied to the contralateral limb. Blood flow, tissue oxygenation, and oxygen extraction fraction were assessed ipsilateral before and during RIC. Current pain was assessed on the numeric rating scale (0 to 10), and finger-palm distance was measured. RESULTS: Pain level (5.8 ± 1.5 vs. 3.1 ± 1.1) and finger-palm distance (5 ± 1.9 cm vs. 3.7 ± 1.9 cm) were decreased significantly by the treatment. RIC decreased blood flow by 32.8% ± 42.8% (P < 0.05) and increased oxygen extraction fraction by 8.5% ± 10.3% (P < 0.05) solely before the treatment. After treatment, all parameters remained unchanged after RIC (P < 0.05 vs. before), comparable to healthy subjects. CONCLUSION: Confirming previous results, RIC presumably unmasks luxury perfusion in untreated CRPS patients. In accordance with the clinical improvement, the short-term pain treatment with glucocorticoids as major component normalizes impaired perfusion. These results might underline the rationale for anti-inflammatory treatment in early-phase CRPS.

Impaired autonomic function and somatosensory disturbance in patients with treated autoimmune thyroiditis.

Despite treatment with levothyroxine, hypothyroidism and autoimmune thyroiditis (AIT) may be associated with reduced quality of life (QoL), an enigmatic condition referred to as "syndrome T". Peripheral neuropathy, described in untreated thyroid disease, could be a contributing mechanism. We analysed autonomic and somatosensory function in 29 patients with AIT and treated hypothyroidism and 27 healthy volunteers. They underwent heart rate variability (HRV) analysis and quantitative sensory testing (n = 28), comprising 13 parameters of small and large nerve fibre function and pain thresholds. Autonomic cardiovascular function was assessed in rest, deep respiration and orthostasis. Additionally, biomarkers for autoimmunity and thyroid function were measured. Anxiety, depression and QoL were assessed using validated questionnaires. 36% of the patients showed at least one sign of somatosensory small or large fibre dysfunction. 57% presented with mild hyperalgesia to at least one stimulus. Several markers of autonomic function and some detection thresholds were related to the antibody titres. Anxiety, depression scores and QoL correlated to antibody titres and HRV measures. Autonomic and somatosensory dysfunction indicate that in treated hypothyroidism and AIT a subgroup of patients suffers from neuropathic symptoms leading to impaired QoL. Additionally, mild hyperalgesia as a possible sensitisation phenomenon should be considered a target for symptomatic treatment.

Clinical implications and risk factors for QRS prolongation over time in heart failure patients.

BACKGROUND: QRS prolongation is an established prognostic marker in heart failure (HF). In contrast, the role of QRS width progression over time has been incompletely explored. The current study investigates the role of QRS width progression over time on clinical status and identifies underlying predictors. METHODS: Datasets of ≥ 2 consecutive visits from 100 attendees to our HF clinic between April and August 2021 were analysed for changes in QRS complex duration. RESULTS: In total 240 datasets were stratified into tertiles based on change in QRS duration (mm/month) (1st tertile: - 1.65 [1.50] 'regression'; 2nd tertile 0.03 [0.19] 'stable', 3rd tertile 3.57 [10.11] 'progression'). The incidence of the combined endpoint HF hospitalisation and worsening of symptomatic heart failure was significantly higher in the group with QRS width progression (3rd tertile) compared with the stable group (2nd tertile; log-rank test: p = 0.013). These patients were characterised by higher plasma NT-pro-BNP levels (p = 0.008) and higher heart rate (p = 0.007). A spline-based prediction model identified patients at risk of QRS width progression when NT-pro-BNP and heartrate were > 837 pg/ml and > 83/bpm, respectively. These markers were independent of guideline-directed medical HF therapy. Patients beyond both thresholds had a 14-fold increased risk of QRS width progression compared to those with neither or either alone (HR: 14.2 [95% 6.9 - 53.6]; p < 0.0001, p for interaction = 0.016). CONCLUSIONS: This pilot study demonstrates that QRS width progression is associated with clinical deterioration of HF. NTproBNP plasma levels and heart rate indicate patients at risk QRS width progression, independently of HF therapy.

Investigation of Inter- and Intra-Day Variability of Tear Fluid Regarding Flow Rate, Protein Concentration as well as Protein Composition.

Purpose: The purpose of this study was to present the determination of inter- and intra-day variations in tear flow rate, and tear fluid protein concentration, as well as protein composition regarding their impact for future biomarker studies. Methods: Tear fluid was collected noninvasively from 18 healthy subjects by performing Schirmer tests at 4 different time points repetitive in a period of 2 days. The tear flow rate on the Schirmer test strips was measured. Proteins were extracted from strips and quantified using amino acid analysis. Protein composition was analyzed by the strips data-independent (DIA) based mass spectrometry. To exclude any impairments to health, volunteers underwent a detailed neurological as well as an ophthalmological examination. Results: Whether tear fluid was collected from oculus sinister or oculus dexter did not affect the tear flow rate (P ≈ 0.63) or protein concentration (P ≈ 0.97) of individual subjects. Moreover, protein concentration was independent from the tear volume, so that a change in volume may only influence the total protein amount. When the examination days were compared, investigation of tear flow rate (P ≈ 0.001) and protein concentration (P ≈ 0.0003) indicated significant differences. Further, mass spectrometric analysis of tear fluid revealed 11 differentially regulated proteins when comparing both examination days. Conclusions: Our findings provide evidence of inter-day variation in tear flow rate, tear proteome concentration, and composition in healthy subjects, suggesting that inter-day variation needs to be taken into consideration in biomarker research of tear fluid. Identified proteins were assigned to functions in the immune response, oxidative and reducing processes, as well as mannose metabolism.

Recruited macrophages elicit atrial fibrillation.

Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and SPP1+ macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in Ccr2-∕- HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting Spp1 reduced atrial fibrillation in HOMER mice. These results identify SPP1+ macrophages as targets for immunotherapy in atrial fibrillation.

Treating heart failure in patients with diabetes: The view of the cardiologist.

Diabetes is a very important comorbidity in patients with heart failure. When both diseases coexist cardiovascular morbidity and mortality is greatly increased. Therefore, it is of clinical importance to treat both diseases as early as possible with an optimal therapy. Hitherto, heart failure therapy did not differ if a patient had concomitant diabetes. However, with SGLT-2 inhibitors having demonstrated to reduce hospitalization of heart failure independent of diabetes state and expected to be included into the ESC heart failure treatment guidelines in 2021 coexisting diabetes potentially will make a difference when to start therapy. In this article we provide an overview of current recommendations and also provide clinical considerations for the therapy of heart failure with concomitant diabetes.

Gut-Derived Metabolite Indole-3-Propionic Acid Modulates Mitochondrial Function in Cardiomyocytes and Alters Cardiac Function.

Background: The gut microbiome has been linked to the onset of cardiometabolic diseases, in part facilitated through gut microbiota-dependent metabolites such as trimethylamine-N-oxide. However, molecular pathways associated to heart failure mediated by microbial metabolites remain largely elusive. Mitochondria play a pivotal role in cellular energy metabolism and mitochondrial dysfunction has been associated to heart failure pathogenesis. Aim of the current study was to evaluate the impact of gut-derived metabolites on mitochondrial function in cardiomyocytes via an in vitro screening approach. Methods: Based on a systematic Medline research, 25 microbial metabolites were identified and screened for their metabolic impact with a focus on mitochondrial respiration in HL-1 cardiomyocytes. Oxygen consumption rate in response to different modulators of the respiratory chain were measured by a live-cell metabolic assay platform. For one of the identified metabolites, indole-3-propionic acid, studies on specific mitochondrial complexes, cytochrome c, fatty acid oxidation, mitochondrial membrane potential, and reactive oxygen species production were performed. Mitochondrial function in response to this metabolite was further tested in human hepatic and endothelial cells. Additionally, the effect of indole-3-propionic acid on cardiac function was studied in isolated perfused hearts of C57BL/6J mice. Results: Among the metabolites examined, microbial tryptophan derivative indole-3-propionic acid could be identified as a modulator of mitochondrial function in cardiomyocytes. While acute treatment induced enhancement of maximal mitochondrial respiration (+21.5 ± 7.8%, p < 0.05), chronic exposure led to mitochondrial dysfunction (-18.9 ± 9.1%; p < 0.001) in cardiomyocytes. The latter effect of indole-3-propionic acids could also be observed in human hepatic and endothelial cells. In isolated perfused mouse hearts, indole-3-propionic acid was dose-dependently able to improve cardiac contractility from +26.8 ± 11.6% (p < 0.05) at 1 µM up to +93.6 ± 14.4% (p < 0.001) at 100 µM. Our mechanistic studies on indole-3-propionic acids suggest potential involvement of fatty acid oxidation in HL-1 cardiomyocytes. Conclusion: Our data indicate a direct impact of microbial metabolites on cardiac physiology. Gut-derived metabolite indole-3-propionic acid was identified as mitochondrial modulator in cardiomyocytes and altered cardiac function in an ex vivo mouse model.

Compared to limb pain of other origin, ultrasonographic osteodensitometry reveals loss of bone density in complex regional pain syndrome.

Local osteopenia and altered bone metabolism are major complications of complex regional pain syndrome (CRPS), but quantitative assessment is difficult unless using X-ray or dual-energy X-ray absorptiometry. Ultrasound-based measurement of bone density (UBD) is a possible alternative but has never been used to detect unilateral disease such as CRPS. Therefore, the main outcome measure of this prospective study was the diagnostic utility of UBD in patients with lower-limb CRPS. Second, we compared the extent of unilateral and contralateral calcaneal bone density to that of other conditions with unilateral pain, general osteoporosis, and healthy subjects. Calcaneal osteodensitometry was bilaterally examined using ultrasound-based methodology. Bone mineral density values were converted to Z-scores based on age- and sex-dependent reference values. All patients completed a functional and an osteoporosis risk questionnaire. In patients with CRPS (n = 18), the bone mineral density values and Z-scores were significantly lower in both the affected (mean ± SD: 0.40 ± 0.08 and -1.1 ± 0.8, respectively) and nonaffected (0.46 ± 0.09 and -0.6 ± 0.9, respectively) limbs than in patients (n = 40) with other unilateral pain syndromes (affected: 0.51 ± 0.1 and -0.2 ± 1.1, respectively; nonaffected: 0.54 ± 0.11 and 0 ± 0.9, respectively) and healthy subjects (right side: 0.6 ± 0.1 and 0.1 ± 0.9, respectively). Conversely, in patients with known systemic osteoporosis, the Z-scores were lower bilaterally with smaller side-to-side differences than in those with CRPS (P < 0.05). Compared with subjects suffering from long-term CRPS (≥2.4 years), patients with shorter disease duration exhibited significantly lower Z-scores (P < 0.05). In conclusion, UBD revealed that CRPS is associated with both local and systemic alterations of bone metabolism.

Differences in itch and pain behaviors accompanying the irritant and allergic contact dermatitis produced by a contact allergen in mice.

INTRODUCTION: Irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD) are inflammatory skin diseases accompanied by itch and pain. Irritant contact dermatitis is caused by chemical irritants eliciting an innate immune response, whereas ACD is induced by haptens additionally activating an adaptive immune response: After initial exposure (sensitization) to the hapten, a subsequent challenge can lead to a delayed-type hypersensitivity reaction. But, the sensory and inflammatory effects of sensitization (ICD) vs challenge of ACD are insufficiently studied. Therefore, we compared itch- and pain-like behaviors and inflammatory reactions evoked in mice during the sensitization (ICD) vs challenge phase (ACD) of application of the hapten, squaric acid dibutylester (SADBE). OBJECTIVES: Our aim was to compare itch- and pain-like behaviors and inflammatory reactions evoked in mice during the sensitization (ICD) vs challenge phase (ACD) of application of the hapten, squaric acid dibutylester (SADBE). METHODS: Mice were sensitized on the abdomen with 1% SADBE (ACD) or vehicle treated (ICD, control). Spontaneous and stimulus-evoked itch- and pain-like behaviors were recorded in mice before and after 3 daily challenges of the cheek with 1% SADBE (ACD, ICD). Cutaneous inflammation was evaluated with clinical scoring, ultrasound imaging, skin thickness, histology, and analyses of selected biomarkers for contact dermatitis, IL-1ß, TNF-α, CXCL10, and CXCR3. RESULTS: Allergic contact dermatitis vs ICD mice exhibited more spontaneous site-directed scratching (itch) and wiping (pain). Allergic contact dermatitis-but not ICD-mice exhibited allodynia and hyperalgesia to mechanical and heat stimuli. Inflammatory mediators IL-1ß and TNF-α were upregulated in both groups as well as the chemokine receptor, CXCR3. CXCL10, a CXCR3 ligand, was upregulated only for ACD. Inflammatory responses were more pronounced in ACD than ICD. CONCLUSION: These findings provide new information for differentiating the behavioral and inflammatory reactions to hapten-induced ICD and ACD.

Neuroimaging markers of clinical progression in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: One of the main goals of novel, noninvasive imaging techniques like high-resolution nerve ultrasound (HRUS) and corneal confocal microscopy (CCM) is the prediction of treatment response for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A total of 17 patients with CIDP were examined prospectively at baseline and every 9 months over a period of 18 months using CCM to quantify corneal nerve degeneration markers and immune cell infiltration as well as HRUS to detect changes of the cross-sectional area (CSA) of the peripheral nerves. Additionally, skin biopsy of the distal and proximal leg as well as quantitative sensory testing were performed at the first follow-up visit. RESULTS: A value of more than 30 total corneal cells/mm2 in CCM at baseline identified patients with clinical progression with a sensitivity/specificity of 100% in our cohort. Corneal nerve fiber density and length remained low and stable over the study period and intra-epidermal fiber density was markedly reduced in the majority of the patients. Furthermore, an increase in Bochum ultrasound score (BUS), which summarizes the CSA of the ulnar nerve in Guyons' canal, the ulnar nerve in the upper arm, the radial nerve in the spiral groove and the sural nerve between the gastrocnemius muscle, and a maximum BUS of 4 at study initiation identified patients with disease progression (sensitivity 80%, specificity 88%). CONCLUSIONS: BUS and corneal total cell infiltration seem to represent early markers for clinical progression in CIDP, thus having the potential to identify at-risk patients and impact treatment decisions.