Fibroblast Smad7 Induction Protects the Remodeling Pressure-Overloaded Heart.

BACKGROUND: Cardiac fibroblast activation contributes to adverse remodeling, fibrosis, and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-ß (transforming growth factor-ß)/Smad (small mother against decapentaplegic)-3 activation protects the pressure-overloaded heart by preserving the matrix, sustained TGF-ß activation is deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF-ß response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. We hypothesized that Smad7, an inhibitory Smad that restrains TGF-ß signaling, may be induced in the pressure-overloaded myocardium and may regulate fibrosis, remodeling, and dysfunction. METHODS: The effects of myofibroblast-specific Smad7 loss were studied in a mouse model of transverse aortic constriction, using echocardiography, histological analysis, and molecular analysis. Proteomic studies in S7KO (Smad7 knockout) and overexpressing cells were used to identify fibroblast-derived mediators modulated by Smad7. In vitro experiments using cultured cardiac fibroblasts, fibroblasts populating collagen lattices, and isolated macrophages were used to dissect the molecular signals responsible for the effects of Smad7. RESULTS: Following pressure overload, Smad7 was upregulated in cardiac myofibroblasts. TGF-ß and angiotensin II stimulated fibroblast Smad7 upregulation via Smad3, whereas GDF15 (growth differentiation factor 15) induced Smad7 through GFRAL (glial cell line-derived neurotrophic factor family receptor α-like). MFS7KO (myofibroblast-specific S7KO) mice had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to transverse aortic constriction. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased MMP (matrix metalloproteinase)-2 activity and collagen denaturation. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins and markedly increases MMP2 secretion. In contrast, Smad7 overexpression reduced MMP2 levels. In fibroblasts populating collagen lattices, the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Macrophage activation involved the combined effects of the fibroblast-derived matricellular proteins CD5L (CD5 antigen-like), SPARC (secreted protein acidic and rich in cysteine), CTGF (connective tissue growth factor), ECM1 (extracellular matrix protein 1), and TGFBI (TGFB induced). CONCLUSIONS: The antifibrotic effects of Smad7 in the pressure-overloaded heart protect from dysfunction and involve not only reduction in collagen deposition but also suppression of MMP2-mediated matrix denaturation and paracrine effects that suppress macrophage activation through inhibition of matricellular proteins.

Macrophages in the infarcted heart acquire a fibrogenic phenotype, expressing matricellular proteins, but do not undergo fibroblast conversion.

Although some studies have suggested that macrophages may secrete structural collagens, and convert to fibroblast-like cells, macrophage to fibroblast transdifferentiation in infarcted and remodeling hearts remains controversial. Our study uses linage tracing approaches and single cell transcriptomics to examine whether macrophages undergo fibroblast conversion, and to characterize the extracellular matrix expression profile of myeloid cells in myocardial infarction. To examine whether infarct macrophages undergo fibroblast conversion, we identified macrophage-derived progeny using the inducible CX3CR1CreER mice crossed with the PDGFRαEGFP reporter line for reliable fibroblast identification. The abundant fibroblasts that infiltrated the infarcted myocardium after 7 and 28 days of coronary occlusion were not derived from CX3CR1+ macrophages. Infarct macrophages retained myeloid cell characteristics and did not undergo conversion to myofibroblasts, endothelial or vascular mural cells. Single cell RNA-seq of CSF1R+ myeloid cells harvested from control and infarcted hearts showed no significant expression of fibroblast identity genes by myeloid cell clusters. Moreover, infarct macrophages did not express significant levels of genes encoding structural collagens. However, infarct macrophage and monocyte clusters were the predominant source of the fibrogenic growth factors Tgfb1 and Pdgfb, and of the matricellular proteins Spp1/Osteopontin, Thbs1/Thrombospondin-1, Emilin2, and Fn1/fibronectin, while expressing significant amounts of several other matrix genes, including Vcan/versican, Ecm1 and Sparc. ScRNA-seq data suggested similar patterns of matrix gene expression in human myocardial infarction. In conclusion, infarct macrophages do not undergo fibroblast or myofibroblast conversion and do not exhibit upregulation of structural collagens but may contribute to fibrotic remodeling by producing several fibrogenic matricellular proteins.

Cardiac Pericytes Acquire a Fibrogenic Phenotype and Contribute to Vascular Maturation After Myocardial Infarction.

BACKGROUND: Pericytes have been implicated in tissue repair, remodeling, and fibrosis. Although the mammalian heart contains abundant pericytes, their fate and involvement in myocardial disease remains unknown. METHODS: We used NG2Dsred;PDGFRαEGFP pericyte:fibroblast dual reporter mice and inducible NG2CreER mice to study the fate and phenotypic modulation of pericytes in myocardial infarction. The transcriptomic profile of pericyte-derived cells was studied using polymerase chain reaction arrays and single-cell RNA sequencing. The role of transforming growth factor-ß (TGF-ß) signaling in regulation of pericyte phenotype was investigated in vivo using pericyte-specific TGF-ß receptor 2 knockout mice and in vitro using cultured human placental pericytes. RESULTS: In normal hearts, neuron/glial antigen 2 (NG2) and platelet-derived growth factor receptor α (PDGFRα) identified distinct nonoverlapping populations of pericytes and fibroblasts, respectively. After infarction, a population of cells expressing both pericyte and fibroblast markers emerged. Lineage tracing demonstrated that in the infarcted region, a subpopulation of pericytes exhibited transient expression of fibroblast markers. Pericyte-derived cells accounted for ~4% of PDGFRα+ infarct fibroblasts during the proliferative phase of repair. Pericyte-derived fibroblasts were overactive, expressing higher levels of extracellular matrix genes, integrins, matricellular proteins, and growth factors, when compared with fibroblasts from other cellular sources. Another subset of pericytes contributed to infarct angiogenesis by forming a mural cell coat, stabilizing infarct neovessels. Single-cell RNA sequencing showed that NG2 lineage cells diversify after infarction and exhibit increased expression of matrix genes, and a cluster with high expression of fibroblast identity markers emerges. Trajectory analysis suggested that diversification of infarct pericytes may be driven by proliferating cells. In vitro and in vivo studies identified TGF-ß as a potentially causative mediator in fibrogenic activation of infarct pericytes. However, pericyte-specific TGF-ß receptor 2 disruption had no significant effects on infarct myofibroblast infiltration and collagen deposition. Pericyte-specific TGF-ß signaling was involved in vascular maturation, mediating formation of a mural cell coat investing infarct neovessels and protecting from dilative remodeling. CONCLUSIONS: In the healing infarct, cardiac pericytes upregulate expression of fibrosis-associated genes, exhibiting matrix-synthetic and matrix-remodeling profiles. A fraction of infarct pericytes exhibits expression of fibroblast identity markers. Pericyte-specific TGF-ß signaling plays a central role in maturation of the infarct vasculature and protects from adverse dilative remodeling, but it does not modulate fibrotic remodeling.

HERV-W upregulation expression in bipolar disorder and schizophrenia: unraveling potential links to systemic immune/inflammation status.

BACKGROUND: Bipolar disorder (BD) and schizophrenia (SZ) are the two main mental disorders with unknown etiology that significantly impact individuals' quality of life. The potential pro-inflammatory role in their pathogenesis is postulated and Human Endogenous Retrovirus W (HERV-W) is an emerging candidate to modulate this pathogenic finding. HERVs, ancient retroviruses in the human genome, may play roles in inflammation and disease pathogenesis. Despite HERVs' involvement in autoimmune diseases, their influence on mental disorders remains underexplored. Therefore, the aim of this study was to assess the level of HERV-W-env expression and the systemic inflammatory profile through the concentration of IL-2, IL-4, IL-6, IL-10, TNF-α and INF-γ cytokines in BD and SZ patients. RESULTS: All participants showed HERV-W-env expression, but its expression was higher in mental disorder patients (p < 0.01) than in control. When separated, SZ individuals exhibited higher HERV-W expression than the control group (p < 0.01). Higher serum levels of TNF-α and IL-10 were found in BD (p = 0.0001 and p = 0.001, respectively) and SZ (p = 0.01) and p = 0.01, respectively) than in the control group, while SZ showed decreased levels IFN-γ and IL-2 as compared to controls (p = 0.05) and BD patients (p = 0.05), respectively. Higher TNF-α/IL-4 and TNF-α/IL-10 ratios, and lower IFN-γ/IL-10 were observed in BD and SZ patients than controls. Significant negative correlation between HERV-W-env expression and IL-10 (r=-0.47 p < 0.05), as well as positive correlations between HERV-W-env expression and TNF-α/IL-10 or IFN-γ/IL-10 ratios (r = 0.48 p < 0.05 and r = 0.46 p < 0.05, respectively) were found in BD patients. CONCLUSION: These findings suggest not only a potential link between HERV-W-env expression both in BD and SZ, but also a possible involvement of systemic inflammatory status in BD patients.

The role of endogenous Smad7 in regulating macrophage phenotype following myocardial infarction.

Smad7 restrains TGF-ß responses, and has been suggested to exert both pro- and anti-inflammatory actions that may involve effects on macrophages. Myocardial infarction triggers a macrophage-driven inflammatory response that not only plays a central role in cardiac repair, but also contributes to adverse remodeling and fibrosis. We hypothesized that macrophage Smad7 expression may regulate inflammation and fibrosis in the infarcted heart through suppression of TGF-ß responses, or via TGF-independent actions. In a mouse model of myocardial infarction, infiltration with Smad7+ macrophages peaked 7 days after coronary occlusion. Myeloid cell-specific Smad7 loss in mice had no effects on homeostatic functions and did not affect baseline macrophage gene expression. RNA-seq predicted that Smad7 may promote TREM1-mediated inflammation in infarct macrophages. However, these alterations in the transcriptional profile of macrophages were associated with a modest and transient reduction in infarct myofibroblast infiltration, and did not affect dysfunction, chamber dilation, scar remodeling, collagen deposition, and macrophage recruitment. In vitro, RNA-seq and PCR arrays showed that TGF-ß has profound effects on macrophage profile, attenuating pro-inflammatory cytokine/chemokine expression, modulating synthesis of matrix remodeling genes, inducing genes associated with sphingosine-1 phosphate activation and integrin signaling, and inhibiting cholesterol biosynthesis genes. However, Smad7 loss did not significantly affect TGF-ß-mediated macrophage responses, modulating synthesis of only a small fraction of TGF-ß-induced genes, including Itga5, Olfml3, and Fabp7. Our findings suggest a limited role for macrophage Smad7 in regulation of post-infarction inflammation and repair, and demonstrate that the anti-inflammatory effects of TGF-ß in macrophages are not restrained by endogenous Smad7 induction.

Modulation of monocyte subtypes in diabetes after non-surgical periodontal treatment.

OBJECTIVES: The current study aims to evaluate the effect of non-surgical periodontal treatment on the modulation of monocyte phenotype, in the presence or absence of diabetes. MATERIALS AND METHODS: The identification, quantification, and phenotypic characterization of monocyte subtypes (classical, intermediate, and non-classical) were performed by flow cytometry, at baseline and 1 month after the end of non-surgical periodontal treatment, in patients with periodontitis, associated or not with diabetes. RESULTS: There was an increase in non-classical monocytes after treatment and a reduction in intermediate monocytes, without differences for the classical subtype, regardless of the diabetes status. Furthermore, there was a reduction in intermediate monocytes and an increase in non-classical and classical monocytes after treatment in the diabetes group, while no significant differences were observed for classical, intermediate, and non-classical monocytes in the group without diabetes. Comparisons between the two groups showed significant differences for classical, intermediate, and non-classical monocytes at baseline; these differences were not found one month after treatment. CONCLUSIONS: Non-surgical periodontal treatment leads to modulation of monocytes to a less inflammatory phenotype, especially in individuals with diabetes. CLINICAL RELEVANCE: A better understanding of the role of these biomarkers in the periodontitis contex may constitute a new strategic target for a better treatment of patiens with diabetes associated to periodontitis. CLINICAL TRIAL REGISTRATION: Brazilian Registry of Clinical Trials-RBR-35szwc. Jhefferson Miranda Alves and Danielle Borges Germano contributed equality to this study and should be considered first authors.

Bioimpedance based determination of cardiac index does not show enough trueness for point of care use in patients with systolic heart failure.

Cardiac output (CO) is a key parameter in diagnostics and therapy of heart failure (HF). The thermodilution method (TD) as gold standard for CO determination is an invasive procedure with corresponding risks. As an alternative, thoracic bioimpedance (TBI) has gained popularity for CO estimation as it is non-invasive. However, systolic heart failure (HF) itself might worsen its validity. The present study validated TBI against TD. In patients with and without systolic HF (LVEF ≤ 50% or > 50% and NT-pro-BNP < 125 pg/ml, respectively) right heart catheterization including TD was performed. TBI (Task Force Monitor©, CNSystems, Graz, Austria) was conducted semi-simultaneously. 14 patients with and 17 patients without systolic HF were prospectively enrolled in this study. In all participants, TBI was obtainable. Bland-Altman analysis indicated a mean bias of 0.3 L/min (limits of agreement ± 2.0 L/min, percentage error or PE 43.3%) for CO and a bias of -7.3 ml (limits of agreement ± 34 ml) for cardiac stroke volume (SV). PE was markedly higher in patients with compared to patients without systolic HF (54% vs. 35% for CO). Underlying systolic HF substantially decreases the validity of TBI for estimation of CO and SV. In patients with systolic HF, TBI clearly lacks diagnostic accuracy and cannot be recommended for point-of-care decision making. Depending on the definition of an acceptable PE, TBI may be considered sufficient when systolic HF is absent.Trial registration number: DRKS00018964 (German Clinical Trial Register, retrospectively registered).

Permanent pacing in a very long-term follow-up after orthotopic heart transplantation: A matter of when or why?

BACKGROUND: Orthotopic heart transplantation (OHT) is associated with a high incidence of conduction disturbances (CD) leading to permanent pacemaker (PPM) implantation. However, the improved posttransplant survival raises the question about the pacemaker dependence (PD) in a prolonged follow-up. HYPOTHESIS: The prevalence of PPM in OHT is high but not all patients are PD in a very long-term follow-up. Device implantation has no prognostic relevance. METHODS: We performed a retrospective analysis of patient medical records focusing on device interrogation data at the most recent follow-up. RESULTS: The study population consisted of 183 patients with a mean follow-up of 15.0 ± 6.8 years. One-fourth of the patients had undergone PPM implantation (n = 49, 26.8%). Among these, two-thirds were PD at last follow-up (n = 32, 65.3%). PPM was more often in biatrial OHT and cardiac allograft vasculopathy (OR 3.0, 95% CI 1.26-7.29, p = .013 and OR 2.0, 95% CI 1.03-3.87, p = .041, respectively). Early sinus node dysfunction (SND) was the most persistent CD. PPM was associated with a poorer outcome in OHT (HR 1.9, 95% CI 1.06-3.46, p = .031) and a higher rate of fatal septicemia (HR 5.1, 95% CI 1.41-18.14, p = .013). CONCLUSIONS: One-fourth of the OHT recipients develop CD requiring PPM implantation, although one-third among these are not PD in follow-up. Early SND is associated with a higher rate of PD. PPM is associated with an inferior prognosis.

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Heart Failure Results in Inspiratory Muscle Dysfunction Irrespective of Left Ventricular Ejection Fraction.

BACKGROUND: Exercise intolerance in heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) results from both cardiac dysfunction and skeletal muscle weakness. Respiratory muscle dysfunction with restrictive ventilation disorder may be present irrespective of left ventricular ejection fraction and might be mediated by circulating pro-inflammatory cytokines. OBJECTIVE: To determine lung and respiratory muscle function in patients with HFrEF/HFpEF and to determine its associations with exercise intolerance and markers of systemic inflammation. METHODS: Adult patients with HFrEF (n = 22, 19 male, 61 ± 14 years) and HFpEF (n = 8, 7 male, 68 ± 8 years) and 19 matched healthy control subjects underwent spirometry, measurement of maximum mouth occlusion pressures, diaphragm ultrasound, and recording of transdiaphragmatic and gastric pressures following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. New York Heart Association (NYHA) class and 6-min walking distance (6MWD) were used to quantify exercise intolerance. Levels of circulating interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured using ELISAs. RESULTS: Compared with controls, both patient groups showed lower forced vital capacity (FVC) (p < 0.05), maximum inspiratory pressure (PImax), maximum expiratory pressure (PEmax) (p < 0.05), diaphragm thickening ratio (p = 0.01), and diaphragm strength (twitch transdiaphragmatic pressure in response to supramaximal cervical magnetic phrenic nerve stimulation) (p = 0.01). In patients with HFrEF, NYHA class and 6MWD were both inversely correlated with FVC, PImax, and PEmax. In those with HFpEF, there was an inverse correlation between amino terminal pro B-type natriuretic peptide levels and FVC (r = -0.77, p = 0.04). In all HF patients, IL-6 and TNF-α were statistically related to FVC. CONCLUSIONS: Irrespective of left ventricular ejection fraction, HF is associated with respiratory muscle dysfunction, which is associated with increased levels of circulating IL-6 and TNF-α.

Effects of central apneas on sympathovagal balance and hemodynamics at night: impact of underlying systolic heart failure.

BACKGROUND: Increased sympathetic drive is the key determinant of systolic heart failure progression, being associated with worse functional status, arrhythmias, and increased mortality. Central sleep apnea is highly prevalent in systolic heart failure, and its effects on sympathovagal balance (SVB) and hemodynamics might depend on relative phase duration and background pathophysiology. OBJECTIVE: This study compared the effects of central apneas in patients with and without systolic heart failure on SVB and hemodynamics during sleep. METHODS: During polysomnography, measures of SVB (heart rate and diastolic blood pressure variability) were non-invasively recorded and analyzed along with baroreceptor reflex sensitivity and hemodynamic parameters (stroke volume index, cardiac index, total peripheral resistance index). Data analysis focused on stable non-rapid eye movement N2 sleep, comparing normal breathing with central sleep apnea in subjects with and without systolic heart failure. RESULTS: Ten patients were enrolled per group. In heart failure patients, central apneas had neutral effects on SVB (all p > 0.05 for the high, low, and very low frequency components of heart rate and diastolic blood pressure variability). Patients without heart failure showed an increase in very low and low frequency components of diastolic blood pressure variability in response to central apneas (63 ± 18 vs. 39 ± 9%; p = 0.001, 43 ± 12 vs. 31 ± 15%; p = 0.002). In all patients, central apneas had neutral hemodynamic effects when analyzed over a period of 10 min, but had significant acute hemodynamic effects. CONCLUSION: Effects of central apneas on SVB during sleep depend on underlying systolic heart failure, with neutral effects in heart failure and increased sympathetic drive in idiopathic central apneas.

Validity of transit time-based blood pressure measurements in patients with and without heart failure or pulmonary arterial hypertension across different breathing maneuvers.

PURPOSE: Pulse transit time (PTT) derived by ECG and plethysmographic signal can be a promising alternative to invasive or oscillometry-based blood pressure (BP) monitoring in sleep laboratories because it does not cause arousals from sleep. Therefore, this study assessed the validity of PTT for BP monitoring under sleep laboratory-like conditions. METHODS: Ten volunteers (55.8 ± 19.6 years), 12 patients with heart failure with reduced ejection fraction (HFrEF; 67.3 ± 8.6 years), and 14 patients with Nizza class I pulmonary arterial hypertension (PAH; 59.5 ± 13.4 years) performed different breathing patterns to simulate nocturnal sleep-disordered breathing (SDB). BP was measured at least every 15 min over 1 h using oscillometry (Task Force Monitor™) and PTT (SOMNOscreen™) devices in free breathing conditions and during SDB simulation (alternating phases of hyperventilation and apneas). RESULTS: One hundred forty-two points of measurements were collected. No difference was found in both mean systolic BP (SBP) and diastolic BP (DBP) between oscillometric PTT-based BP measurements in the whole population and throughout the whole recording (SBP 111.3 ± 15.1 mmHg versus 110.0 ± 14.7 mmHg, p = 0.051; DBP 69.9 ± 12.2 versus 69.9 ± 14.2 mmHg, p = 0.701). Likewise, no significant difference in SBP and DBP was found between the two methods in the subgroups of healthy subjects, HFrEF patients and PAH patients, both in free breathing conditions (p > 0.05) and during SDB simulation (p > 0.05). CONCLUSIONS: When monitoring BP in healthy subjects, and in patients with HFrEF or PAH, PTT provides a BP estimation comparable with oscillometric measurement, though slightly inaccurate, both in the condition of regular and unstable breathing.

Correction to: Validity of transit time-based blood pressure measurements in patients with and without heart failure or pulmonary arterial hypertension across different breathing maneuvers.

After the publication of the original manuscript we found that the calculation of the supplemental data regarding the capacity of PTT-based blood pressure (BP) recordings to detect changes in systolic and diastolic BP in different cohorts of patients was incorrect. These errors occured when data were transformed from MS Excel to Sigma-Plot tables. In this correction, the affected data and the respective figures were now revised.

Neurosarcoidosis As a Rare Differential Diagnosis for Single Or Multiple Lesions of the Nervous System.

Objective: Sarcoidosis is a multisystemic granulomatous disease of unknown cause which affects the lung or bilateral hilar lymphadenopathy in over 90% of the cases. Neurosarcoidosis (NS) is rare and accounts for approximately 5 - 15% of the cases. Involvement of all parts of the central and peripheral nervous system is possible with various clinical symptoms, e. g. seizures, hydrocephalus, optic/facial nerve palsy or hearing loss.Methods: We screened the neuropathological data bases and the medical records of two neurosurgical university hospitals for cases of NS. All these cases had been verified by surgical biopsy. We retrospectively evaluated the patient's records with special regard to the histopathology reports and specific clinical symptoms.Results: We identified 9 cases of NS between 1994 and 2014 (3 female, 6 male patients). The average age at the time of diagnosis of NS was 41,4 years. Various clinical symptoms like hydrocephalus (n = 3), seizures (n = 1), meningitis (n = 1), optical nerve involvment with vision disorder (n = 1), myelitis with paraplegia (n = 1), mastoiditis with hearing loss (n = 1), back pain syndrome (n = 2) were present. 7 patients were treated with corticosteroids, 1 patient with cyclophosphamide and 1 with a combination of corticosteroids and methotrexate.Conclusion: NS is a rare but potentially life-threatening disease. It is difficult to distinguish sarcoidosis from other granulomatous diseases, infectious diseases like tuberculosis, multiple sclerosis or neoplasm. For a definite diagnosis, a neurosurgical biopsy with histological evidence of noncaseating epithelioid cell granulomas is required, followed by multidisciplinary treatment.

Impact of Simulated Hyperventilation and Periodic Breathing on Sympatho-Vagal Balance and Hemodynamics in Patients with and without Heart Failure.

BACKGROUND: The effects of hyperventilation and hyperventilation in the context of periodic breathing (PB) on sympatho-vagal balance (SVB) and hemodynamics in conditions of decreased cardiac output and feedback resetting, such as heart failure (HF) or pulmonary arterial hypertension (PAH), are not completely understood. OBJECTIVES: To investigate the effects of voluntary hyperventilation and simulated PB on hemodynamics and SVB in healthy subjects, in patients with systolic HF and reduced or mid-range ejection fraction (HFrEF and HFmrEF) and in patients with PAH. METHODS: Study participants (n = 20 per group) underwent non-invasive recording of diastolic blood pressure, heart rate variability (HRV), baroreceptor-reflex sensitivity (BRS), total peripheral resistance index (TPRI) and cardiac index (CI). All measurements were performed at baseline, during voluntary hyperventilation and during simulated PB with different length of the hyperventilation phase. RESULTS: In healthy subjects, voluntary hyperventilation led to a 50% decrease in the mean BRS slope and a 29% increase in CI compared to baseline values (p < 0.01 and p < 0.05). Simulated PB did not alter TPRI or CI and showed heterogeneous effects on BRS, but analysis of dPBV revealed decreased sympathetic drive in healthy volunteers depending on PB cycle length (p < 0.05). In HF patients, hyperventilation did not affect BRS and TPRI but increased the CI by 10% (p < 0.05). In HF patients, simulated PB left all of these parameters unaffected. In PAH patients, voluntary hyperventilation led to a 15% decrease in the high-frequency component of HRV (p < 0.05) and a 5% increase in CI (p < 0.05). Simulated PB exerted neutral effects on both SVB and hemodynamic parameters. CONCLUSIONS: Voluntary hyperventilation was associated with sympathetic predominance and CI increase in healthy volunteers, but only with minor hemodynamic and SVB effects in patients with HF and PAH. Simulated PB had positive effects on SVB in healthy volunteers but neutral effects on SVB and hemodynamics in patients with HF or PAH.

Sarcoidosis of the paranasal sinuses.

BACKGROUND: Sarcoidosis is a chronic disease, which predominantly affects the lung. Since sinonasal sarcoidosis is rare, little is known about the sarcoidosis manifestation at this site. Therefore, the aim of our study was to detect the prevalence of sinonasal sarcoidosis, its clinical occurrence, diagnosis, and therapy. METHODS: The database of all patients having visited the otorhinolaryngology departments of the universities in Göttingen and in Bonn between 2003 and 2016 was searched for the diagnosis of sinonasal sarcoidosis. RESULTS: Thirteen patients with a biopsy-proven sinonasal sarcoidosis were identified. Most patients presented non-specific clinical symptoms, which are also found in acute and chronic sinusitis. None of the patients was suspected to have sinonasal sarcoidosis by the ENT doctor before histological validation. The mean diagnostic delay was 262 (± 195) days. An additional pulmonary involvement was detected in four of six patients. CONCLUSIONS: Sinonasal sarcoidosis is presenting with heterogeneous clinical presentations. An early biopsy of granulomatous lesions is mandatory. A multidisciplinary approach is needed to exclude serious lung or heart manifestations, because even asymptomatic organ involvement is possible. A CT-scan may be useful even if unspecific. Local or systemic therapy has to be prepared individually using local and systemic corticosteroids, antimetabolites, or anti-TNF-alpha.

Monocyte subtypes and the CCR2 chemokine receptor in cardiovascular disease.

Monocytes circulate in the blood and migrate to inflammatory tissues, but their functions can be either detrimental or beneficial, depending on their phenotypes. In humans, classical monocytes are inflammatory cluster of differentiation (CD)14++CD16-CCR2++ cells originated from the bone marrow or spleen reservoirs and comprise ≥92% of monocytes. Intermediate monocytes (CD14++CD16+CCR2+) are involved in the production of anti-inflammatory cytokines [such as interleukin (IL)-10], reactive oxygen species (ROS), and proinflammatory mediators [such as tumor necrosis factor-α (TNF-α) and IL-1ß). Nonclassical monocytes (CD14+CD16++CCR2-) are patrolling cells involved in tissue repair and debris removal from the vasculature. Many studies in both humans and animals have shown the importance of monocyte chemoattractant protein-1 (MCP-1) and its receptor [chemokine receptor of MCP-1 (CCR2)] in pathologies, such as atherosclerosis and myocardial infarction (MI). This review presents the importance of these monocyte subsets in cardiovascular diseases (CVDs), and sheds light on new strategies for the blocking of the MCP-1/CCR2 axis as a therapeutic goal for treating vascular disorders.

Increased vascular occlusion in patients with pseudoxanthoma elasticum.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an autosomal recessive inherited multisystem disorder of the connective tissue caused by a loss-of-function mutation of the ABCC6 gene. It can affect the cardiovascular system, presumably leading to a high prevalence of atherosclerosis. PATIENTS AND METHODS: 46 PXE patients and 18 controls underwent an angiological examination consisting of measurement of ankle-brachial index (ABI), strain-gauge arterial reserve (SGAR), arterial resting perfusion, pulse wave index (PWI), central pulse wave velocity, and ultrasound examination. RESULTS: With an average age of 51.4 ± 12.4 years, 35/46 (76.1 %) of the PXE patients had atherosclerotic lesions, and 10 of them (28.6 %) had a chronic vascular occlusion of one or more peripheral vessels. 34/46 (73.9 %) had a pathologic ABI < 0.9, 15/42 (35.7 %) had a pathological SGAR < 10 mL/100 mL tissue/min, and 23/38 (60.5 %) had a pathological PWI > 180. The differences between the groups were statistically significant for ABI, arterial reserve, and PWI. CONCLUSIONS: In PXE patients atherosclerosis was found with a much higher prevalence than expected. Moreover, they were at very high risk for total vessel occlusions.
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Challenges Facing the Use of Endothelial Progenitor Cells in Stem Cell Therapies.

The paper summarizes the difficulties to study the rare population of endothelial progenitor cells in clinical trials, based on the experience of our group in many publications in this area.

Recurrent Chronic Obstructive Pulmonary Disease Exacerbations after Endobronchial Valve Implantation Are Associated with the Presence of Pseudomonas aeruginosa.

BACKGROUND: Endoscopic lung volume reduction by means of endobronchial valve implantation is an established therapy in patients with severe emphysema. However, long-term complications such as chronic obstructive pulmonary disease (COPD) exacerbations are a limitation of this method. OBJECTIVES: As the mechanisms underlying increased rates of COPD exacerbations are unknown, the aim of our study was to determine whether infectious or inflammatory factors may contribute to these events and to investingate the consequent need for valve explantation. METHODS: Tissue surrounding explanted endobronchial Zephyr valves was examined by microbiological, histological and cytological methods. Additionally, we performed a microbiological analysis of tracheal aspirates before both valve implantation and valve explantation. Moreover, blood samples were collected for the analysis of inflammatory markers. RESULTS: Endobronchial valves were explanted from 16 patients. Reasons for explantation were frequent postprocedural COPD exacerbations (group 1: 8 patients) or loss of clinical benefit (group 2: 8 patients). Compared to group 2, the microbiological examinations of valve lavage and tracheal aspirates from patients in group 1 showed a higher detection of Gram-negative bacteria. In particular, infection with Pseudomonas aeruginosa was more predominant in group 1, while no presence could be detected in group 2. Blood inflammatory markers tended to be slightly higher in group 1 than in group 2; however, without reaching statistical significance. CONCLUSIONS: Increased rates of COPD exacerbations after endobronchial valve implantation are associated with the presence of P. aeruginosa. The finding warrants further investigation.