Neurofibromin 1 controls metabolic balance and Notch-dependent quiescence of murine juvenile myogenic progenitors.

Patients affected by neurofibromatosis type 1 (NF1) frequently show muscle weakness with unknown etiology. Here we show that, in mice, Neurofibromin 1 (Nf1) is not required in muscle fibers, but specifically in early postnatal myogenic progenitors (MPs), where Nf1 loss led to cell cycle exit and differentiation blockade, depleting the MP pool resulting in reduced myonuclear accretion as well as reduced muscle stem cell numbers. This was caused by precocious induction of stem cell quiescence coupled to metabolic reprogramming of MPs impinging on glycolytic shutdown, which was conserved in muscle fibers. We show that a Mek/Erk/NOS pathway hypersensitizes Nf1-deficient MPs to Notch signaling, consequently, early postnatal Notch pathway inhibition ameliorated premature quiescence, metabolic reprogramming and muscle growth. This reveals an unexpected role of Ras/Mek/Erk signaling supporting postnatal MP quiescence in concert with Notch signaling, which is controlled by Nf1 safeguarding coordinated muscle growth and muscle stem cell pool establishment. Furthermore, our data suggest transmission of metabolic reprogramming across cellular differentiation, affecting fiber metabolism and function in NF1.

The role of intravascular imaging in chronic total occlusion percutaneous coronary intervention.

Chronic total occlusions (CTOs) represent the most complex subset of coronary artery disease and therefore careful planning of CTO percutaneous coronary recanalization (PCI) strategy is of paramount importance aiming to achieve procedural success, and improve patient's safety and post CTO PCI outcomes. Intravascular imaging has an essential role in facilitating CTO PCΙ. First, intravascular ultrasound (IVUS), due to its higher penetration depth compared to optical coherence tomography (OCT), and the additional capacity of real-time imaging without need for contrast injection is considered the preferred imaging modality for CTO PCI. Secondly, IVUS can be used to resolve proximal cap ambiguity, facilitate wire re-entry when dissection and re-entry strategies are applied and most importantly to guide stent deployment and optimization post implantation. The role of OCT during CTO PCI is currently limited to stent sizing and optimization, however, due to its high spatial resolution, OCT is ideal for detecting stent edge dissections and strut malapposition. In this review, we describe the use of intravascular imaging for lesion crossing, plaque characterization and wire tracking, extra- or intra-plaque, and stent sizing and optimization during CTO PCI and summarize the findings of the major studies in this field.

Differential Expression of Circulating Damage-Associated Molecular Patterns in Patients with Coronary Artery Ectasia.

Coronary artery ectasia (CAE) is defined as abnormal dilation of a coronary artery with a diameter exceeding that of adjacent normal arterial segment by >1.5 times. CAE is a pathological entity of the coronary arteries and characterized as a variant of coronary atherosclerosis. CAE frequently coexists with coronary artery disease (CAD). While inflammation appears to be involved, the pathophysiology of CAE remains unclear. Damage-associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue, are deemed as alarm signals by the innate immune system. Inflammatory agents can generate DAMPs and DAMPs can create a pro-inflammatory state. In a prospective cross-sectional study, we enrolled 29 patients with CAE and non-obstructive CAD, 19 patients with obstructive CAD without CAE, and 14 control subjects with normal (control) coronary arteries age- and sex-matched with the CAE patients, to investigate the differential expression of plasma DAMPs. Patients with CAE and non-obstructive CAD had increased plasma levels of the DAMPs S100B, S100A12, HMGB1, and HSP70, the DAMPs receptor TLR4, and miR328a-3p compared to CAD and controls. Plasma levels of the mir328a-3p target the protective soluble form of the DAMPs receptor for advanced glycation end products (sRAGE), and the antioxidant DJ-1 was decreased in both CAE and CAD compared to controls. In an in vitro human umbilical vein endothelial cells model, circulating levels of S100B, HMGB1, HSP70 as well as CAE patient plasma induced inflammatory responses. The differential expression of the DAMPs S100B, HSP70, HMGB1, and their receptors TLR4 and sRAGE in CAE versus CAD makes them attractive novel biomarkers as therapeutic targets and therapeutics.

The Emerging Role of Combined Brain/Heart Magnetic Resonance Imaging for the Evaluation of Brain/Heart Interaction in Heart Failure.

Heart failure (HF) patients frequently develop brain deficits that lead to cognitive dysfunction (CD), which may ultimately also affect survival. There is an important interaction between brain and heart that becomes crucial for survival in patients with HF. Our aim was to review the brain/heart interactions in HF and discuss the emerging role of combined brain/heart magnetic resonance imaging (MRI) evaluation. A scoping review of published literature was conducted in the PubMed EMBASE (OVID), Web of Science, Scopus and PsycInfo databases. Keywords for searches included heart failure, brain lesion, brain, cognitive, cognitive dysfunction, magnetic resonance imaging cardiovascular magnetic resonance imaging electroencephalogram, positron emission tomography and echocardiography. CD testing, the most commonly used diagnostic approach, can identify neither subclinical cases nor the pathophysiologic background of CD. A combined brain/heart MRI has the capability of diagnosing brain/heart lesions at an early stage and potentially facilitates treatment. Additionally, valuable information about edema, fibrosis and cardiac remodeling, provided with the use of cardiovascular magnetic resonance, can improve HF risk stratification and treatment modification. However, availability, familiarity with this modality and cost should be taken under consideration before final conclusions can be drawn. Abnormal CD testing in HF patients is a strong motivating factor for applying a combined brain/heart MRI to identify early brain/heart lesions and modify risk stratification accordingly.

Cavotricuspid isthmus ablation guided by force-time integral - A randomized study.

BACKGROUND: Force-time integral (FTI) is an ablation marker of lesion quality and transmurality. A target FTI of 400 gram-seconds (gs) has been shown to improve durability of pulmonary vein isolation, following atrial fibrillation ablation. However, relevant targets for cavotricuspid isthmus (CTI) ablation are lacking. HYPOTHESIS: We sought to investigate whether CTI ablation with 600 gs FTI lesions is associated with reduced rate of transisthmus conduction recovery compared to 400 gs lesions. METHODS: Fifty patients with CTI-dependent flutter were randomized to ablation using 400 gs (FTI400 group, n = 26) or 600 gs FTI lesions (FTI600 group, n = 24). The study endpoint was spontaneous or adenosine-mediated recovery of transisthmus conduction, after a 20-min waiting period. RESULTS: The study endpoint occurred in five patients (19.2%) in group FTI400 and in four patients (16.7%) in group FTI600, p = .81. First-pass CTI block was similar in both groups (50% in FTI400 vs. 54.2% in FTI600, p = .77). There were no differences in the total number of lesions, total ablation time, procedure time and fluoroscopy duration between the two groups. There were no major complications in any group. In the total population, patients not achieving first-pass CTI block had significantly higher rate of acute CTI conduction recovery, compared to those with first-pass block (29.2% vs. 7.7% respectively, p = .048). CONCLUSIONS: CTI ablation using 600 gs FTI lesions is not associated with reduced spontaneous or adenosine-mediated recurrence of transisthmus conduction, compared to 400 gs lesions.

Cardiogenic shock with highly complicated course after influenza A virus infection treated with vva-ECMO and Impella CP (ECMELLA): a case report.

BACKGROUND: The value of mechanical circulatory support (MCS) in cardiogenic shock, especially the combination of the ECMELLA approach (Impella combined with ECMO), remains controversial. CASE PRESENTATION: A previously healthy 33-year-old female patient was submitted to a local emergency department with a flu-like infection and febrile temperatures up to 39 °C. The patient was tested positive for type-A influenza, however negative for SARS-CoV-2. Despite escalated invasive ventilation, refractory hypercapnia (paCO2: 22 kPa) with severe respiratory acidosis (pH: 6.9) and a rising norepinephrine rate occurred within a few hours. Due to a Horovitz-Index < 100, out-of-centre veno-venous extracorporeal membrane oxygenation (vv-ECMO)-implantation was performed. A CT-scan done because of anisocoria revealed an extended dissection of the right vertebral artery. While the initial left ventricular function was normal, echocardiography revealed severe global hypokinesia. After angiographic exclusion of coronary artery stenoses, we geared up LV unloading by additional implantation of an Impella CP and expanded the vv-ECMO to a veno-venous-arterial ECMO (vva-ECMO). Clinically relevant bleeding from the punctured femoral arteries resulted in massive transfusion and was treated by vascular surgery later on. Under continued MCS, LVEF increased to approximately 40% 2 days after the initiation of ECMELLA. After weaning, the Impella CP was explanted at day 5 and the vva-ECMO was removed on day 9, respectively. The patient was discharged in an unaffected neurological condition to rehabilitation 25 days after the initial admission. CONCLUSIONS: This exceptional case exemplifies the importance of aggressive MCS in severe cardiogenic shock, which may be especially promising in younger patients with non-ischaemic cardiomyopathy and potentially reversible causes of cardiogenic shock. This case impressively demonstrates that especially young patients may achieve complete neurological restoration, even though the initial prognosis may appear unfavourable.

Differential Regulation of Circulating Soluble Receptor for Advanced Glycation End Products (sRAGEs) and Its Ligands S100A8/A9 Four Weeks Post an Exercise Intervention in a Cohort of Young Army Recruits.

Apart from its beneficial effects on cardiovascular risk factors, an anti-inflammatory effect of exercise is strongly implicated. Yet, data regarding the effect of an exercise intervention on healthy individuals are limited and contradictory. The present study aimed to investigate the effects of a physical activity intervention on the soluble form of the receptor for advanced glycation end products (sRAGEs) and its ligands S100A8/A9. A total of 332 young army recruits volunteered and 169 completed the study. The participants underwent the standard basic training of Greek army recruits. IL-6, IL-1ß, S100A8/A9, and sRAGEs were measured at the beginning and at the end of the training period. Primary rodent adult aortic smooth muscle cells (ASMCs) were analyzed for responsiveness to direct stimulation with S100A8/A9 alone or in combination with sRAGEs. At the end of the training period, we observed a statistically significant reduction in S100A8/A9 (630.98 vs. 472.12 ng/mL, p = 0.001), IL-1ß (9.39 [3.8, 44.14] vs. 5.03 [2.44, 27.3] vs. pg/mL, p = 0.001), and sRAGEs (398.38 vs. 220.1 pg/mL, p = 0.001). IL-6 values did not change significantly after exercise. S100A8/A9 reduction was positively correlated with body weight (r = 0.236 [0.095, 0.370], p = 0.002) and BMI (r = 0.221 [0.092, 0.346], p = 0.004). Direct stimulation of ASMCs with S100A8/A9 increased the expression of IL-6, IL-1ß, and TNF-α and, in the presence of sRAGEs, demonstrated a dose-dependent inhibition. A 4-week military training resulted in significant reduction in the pro-inflammatory cytokines IL-1ß and S100A8/A9 complex. The observed reduction in sRAGEs may possibly reflect diminished RAGE axis activation. Altogether, our findings support the anti-inflammatory properties of physical activity.

Cytoprotective Mechanisms of DJ-1: Implications in Cardiac Pathophysiology.

DJ-1 was originally identified as an oncogene product while mutations of the gene encoding DJ-1/PARK7 were later associated with a recessive form of Parkinson's disease. Its ubiquitous expression and diversity of function suggest that DJ-1 is also involved in mechanisms outside the central nervous system. In the last decade, the contribution of DJ-1 to the protection from ischemia-reperfusion injury has been recognized and its involvement in the pathophysiology of cardiovascular disease is attracting increasing attention. This review describes the current and gaps in our knowledge of DJ-1, focusing on its role in regulating cardiovascular function. In parallel, we present original data showing an association between increased DJ-1 expression and antiapoptotic and anti-inflammatory markers following cardiac and vascular surgical procedures. Future studies should address DJ-1's role as a plausible novel therapeutic target for cardiovascular disease.

Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Evolution of epidemiological characteristics of infective endocarditis in Greece.

OBJECTIVE: The clinical profile, management and outcome of infective endocarditis (IE) may be influenced by socioeconomic issues. METHODS: A nationwide prospective study evaluated IE during the era of deep economic crisis in Greece. Epidemiological data and factors associated with 60-day mortality were analyzed through descriptive statistics, logistic and Cox-regression models. RESULTS: Among 224 patients (male 72.3%, mean age 62.4 years), Staphylococcus aureus (n = 62; methicillin-resistant S. aureus (MRSA) 33.8%) predominated in the young without impact on mortality (p = 0.593), whilst Enterococci (n = 36) predominated in the elderly. Complications of IE were associated with mortality: heart failure [OR 2.415 (95% CI: 1.159-5.029), p = 0.019], stroke [OR 3.206 (95% CI: 1.190-8.632), p = 0.018] and acute kidney injury [OR 2.283 (95% CI: 1.085-4.805), p = 0.029]. A 60-day survival benefit was solely related to cardiac surgery for IE during hospitalization [HR 0.386 (95% CI: 0.165-0.903), p = 0.028] and compliance with antimicrobial treatment guidelines [HR 0.487 (95% CI: 0.259-0.916), p = 0.026]. Compared with a previous country cohort study, history of rheumatic fever and native valve predisposition had declined, whilst underlying renal disease and right-sided IE had increased (p < 0.0001); HIV infection had emerged (p = 0.002). No difference in rates of surgery and outcome was assessed. CONCLUSIONS: A country-wide survey of IE highlighted emergence of HIV, right-sided IE and predominance of MRSA in the youth during a severe socioeconomic crisis. Compliance with treatment guidelines promoted survival.

Bisphenol A removal and degradation pathways in microorganisms with probiotic properties.

Bisphenol-A (BPA) is a constituent of polycarbonate plastics and epoxy resins, widely applied on food packaging materials. As BPA exposure results in health hazards, its efficient removal is of crucial importance. In our study five potentially probiotic microorganisms, namely Lactococcus lactis, Bacillus subtilis, Lactobacillus plantarum, Enterococcus faecalis, and Saccharomyces cerevisiae, were tested for their toxicity tolerance to BPA and their BPA removal ability. Although BPA toxicity, evident on all microorganisms, presented a correlation to both BPA addition time and its concentration, all strains exhibited BPA-removal ability with increased removal rate between 0 and 24 h of incubation. BPA degradation resulted in the formation of two dimer products in cells while the compounds Hydroquinone (HQ), 4-Hydroxyacetophenone (HAP), 4-Hydroxybenzoic acid (HBA) and 4-Isopropenylphenol (PP) were identified in the culture medium. In the proposed BPA degradation pathways BPA adducts formation appears as a common pattern, while BPA decomposition as well as the formation, and the levels of its end products present differences among microorganisms. The BPA degradation ability of the tested beneficial microorganisms demonstrates their potential application in the bioremediation of BPA contaminated foods and feeds and provides a means to suppress the adverse effects of BPA on human and animal health.

Cardiac amyloidosis: in search of the ideal diagnostic tool.

BACKGROUND: Cardiac amyloidosis (CA) is due to amyloid deposition in the myocardium. Transthyretin (ATTR) and light-chain (AL) amyloidosis are the main types of CA. Here, we present the clinical and imaging findings in patients with CA and discuss the controversies with the aim of finding the ideal diagnostic tool. METHODS: Ten patients suspected of having CA on the basis of electrocardiographic (ECG) and echocardiographic findings were evaluated via cardiovascular magnetic resonance imaging (CMR; 1.5 T) using cine, late gadolinium enhancement (LGE), T1, T2 mapping, and extracellular volume fraction. N­terminal pro-B-type natriuretic peptide (NT-proBNP) levels were also assessed in all patients. RESULTS: All ten patients had an echocardiogram suggestive of CA. The CMR study documented ventricular hypertrophy leading to small ventricular volumes, as assessed by echocardiography. Diffuse subendocardial LGE, supporting the diagnosis of CA, was identified in all except one patient, who had subepicardial LGE due to myocarditis that was verified by endomyocardial biopsy (EMB). Right ventricular (RV) involvement was identified in four of the ten patients, whose condition deteriorated rapidly over the next 6 months. The NT-proBNP levels were >332 pg/ml in all except two patients. Light-chain amyloidosis was identified via fat tissue biopsy in two patients and through renal biopsy in one patient. In two patients with positive technetium-99m, EMB confirmed the diagnosis of ATTR. CONCLUSION: NT-proBNP may be a sensitive but nonspecific biomarker for assessing CA. However, CMR is the only imaging modality that can assess the pathophysiologic background of cardiac hypertrophy and the severity of CA, irrespective of NT-proBNP level.

Cardiac imaging in cardiotoxicity: a focus on clinical practice.

Cancer therapeutics induced cardiotoxicity has emerged as an important factor of long-term adverse cardiovascular outcomes in survivors of various malignant diseases. Early detection of myocardial injury in the setting of cancer treatment is important for the initiation of targeted cardioprotective therapy, in order to prevent irreversible cardiac dysfunction and heart failure, while not withholding a potentially life-saving cancer therapy. Cardiac imaging techniques including echocardiography, cardiac magnetic resonance, and nuclear cardiac imaging are the main tools for the identification of cardiotoxicity. There is also growing evidence for the detection of subclinical cardiac dysfunction in cancer patients by speckle tracking echocardiography. In this review article, we focus on current and emerging data regarding the role of cardiac imaging for the detection of changes in myocardial function related with cancer treatment in clinical practice.