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.

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.

Conditioned pain modulation (CPM) is not impaired in the early phase of complex regional pain syndrome (CRPS) and neuralgia. Only in CRPS higher CPM was associated with lower cold pain thresholds.

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.

Remote ischaemic conditioning leads to a decrease of blood flow. This decrease inversely correlates with the oxygen extraction in patients with CRPS.

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.

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.

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. Graphic abstract