Strong desmin immunoreactivity in the myocardial sleeves around pulmonary veins, superior caval vein and coronary sinus supports the presumed arrhythmogenicity of these regions.

Myocardial sleeve around human pulmonary veins plays a critical role in the pathomechanism of atrial fibrillation. Besides the well-known arrhythmogenicity of these veins, there is evidence that myocardial extensions into caval veins and coronary sinus may exhibit similar features. However, studies investigating histologic properties of these structures are limited. We aimed to investigate the immunoreactivity of myocardial sleeves for intermediate filament desmin, which was reported to be more abundant in Purkinje fibers than in ventricular working cardiomyocytes. Sections of 16 human (15 adult and 1 fetal) hearts were investigated. Specimens of atrial and ventricular myocardium, sinoatrial and atrioventricular nodes, pulmonary veins, superior caval vein and coronary sinus were stained with anti-desmin monoclonal antibody. Intensity of desmin immunoreactivity in different areas was quantified by the ImageJ program. Strong desmin labeling was detected at the pacemaker and conduction system as well as in the myocardial sleeves around pulmonary veins, superior caval vein, and coronary sinus of adult hearts irrespective of sex, age, and medical history. In the fetal heart, prominent desmin labeling was observed at the sinoatrial nodal region and in the myocardial extensions around the superior caval vein. Contrarily, atrial and ventricular working myocardium exhibited low desmin immunoreactivity in both adults and fetuses. These differences were confirmed by immunohistochemical quantitative analysis. In conclusion, this study indicates that desmin is abundant in the conduction system and venous myocardial sleeves of human hearts.

Pseudoaneurysm of the ascending aorta: case report of a donor-derived Pseudomonas infection in a heart transplant recipient.

BACKGROUND: Mycotic aortic pseudoaneurysm is a rare complication after heart transplantation (HTX) with remarkable mortality. Intrathoracic infection is a well-documented predisposing factor for this disease. Staphylococcus aureus, Pseudomonas aeruginosa or Candida species are commonly isolated from resected specimens of the pseudoaneurysms. We demonstrate a unique case of mycotic pseudoaneurysm caused by presumably donor-derived Pseudomonas infection in a heart transplant recipient. CASE PRESENTATION: Our 67-year-old male patient treated with diabetes mellitus underwent HTX. The donor suffered from epiglottic abscess and pneumonia with known microorganisms including Pseudomonas, therefore both the donor and recipient received targeted antimicrobial therapy and prophylaxis. Five months after the uneventful HTX, lab test of the asymptomatic patient showed moderate, increasing C-reactive protein level without obviuos source of infection. Chest computed tomography showed a large (90 mm) saccular dilatation of the tubular portion of ascending aorta. Urgent surgical intervention identified a pseudoaneurysm, histological examinations and cultures of the resected aorta verified Pseudomonas aeruginosa aortitis, while all blood cultures remained negative. Retrospective interrogation of other transplanted organs of the donor supported donor-derived infection as the transport fluid of the right kidney grew Pseudomonas. The patient received 3 weeks of ceftazidime followed by 7 months of oral ciprofloxacin therapy. One year after the operation the patient was asymptomatic with normal inflammatory markers. CONCLUSIONS: Donor-derived infection is a rare but potential cause of aortitis. Early diagnosis, surgical intervention and adjuvant antibiotic therapy seem to be the keys to successful management of mycotic pseudoaneurysms after HTX.

[Novel mechanisms in the initiation and maintenance of atrial fibrillation: tailored individual treatment]. / Új felismerések a pitvarfibrilláció genezisében és fenntartásában: az egyénre szabott kezelés lehetoségei.

Atrial fibrillation affects approximately three percent of the adults. Ablation strategies targeting the isolation of the pulmonary veins are the up-to-date cornerstones for atrial fibrillation ablations. However, a one-year success rate of repeated interventions is not more than 70%. Long-term efficacy of catheter ablation is presumably limited by electrical and structural remodeling of the atria, which results in a progressive increase in the duration of atrial fibrillation to become sustained. The potential pathophysiological importance of the epicardial adipose tissue, atrial fibrosis, autonomic nervous system and arrhythmogenic foci are documented by several studies. Increased volume, inflammation induced transformation to fibrosis and myocardial infiltration of atrial subepicardial fat in obese patients result in higher risk of atrial fibrillation development. Changes in atrial autonomic innervation under some conditions including regular physical exercise strongly promote arrhythmogenesis via the mechanism of enhanced triggered activity or abbreviated atrial refractoriness. Individualized management of possible trigger and substrate mechanisms are proposed to provide a novel basis for the effective treatment of atrial fibrillation. Pro-fibrotic signalling pathways can be inhibited by the suppression of renin-angiotensin-aldosterone system. Neuromodulation strategies include renal sympathetic denervation and ganglionic plexi ablation. Anticoagulation therapy has also been shown to reduce the burden of abnormal atrial remodeling. Possible novel catheter ablation techniques are used for right or left atrial linear lesions, scar homogenization and catheter ablation of complex fractionated atrial electrograms, rotors or ectopic foci. Beside these new management strategies, clinical consideration of factors of particular risks as obesity, hyperlipidaemia, hypertension, diabetes and obstructive sleep apnoe are also essential. Orv Hetil. 2018; 159(28): 1135-1145.

Composition Profiles at the Metal Substrate-Deposit Interface Produced in Laser-Assisted Additive Manufacturing Processes.

The cross-section of various substrate-deposit metal pairs obtained with a laser-assisted additive manufacturing process has been studied by observing the composition profile with energy-dispersive spectroscopy (EDS). The EDS composition profiles observed with a sufficiently high data acquisition time revealed that the composition profile is asymmetric. By scanning toward the growth direction, a sudden composition variation was observed, which was followed by a slow decay. The character of the composition profile was the same for a number of substrate-deposit pairs, and similar trends were found in various earlier publications as well. A mathematical model for the composition variation is suggested based on the assumption that a spontaneous homogenization process takes place in the intermixing (dilution) zone of the remelted top layer of the substrate. The equation obtained makes it possible to quantitatively describe the composition profile of each component that exhibits a concentration difference between the substrate and the deposit, provided that the mole fraction difference much exceeds the scattering of the data measured. The suggested model has also been applied successfully to composition profiles published in other works, hence exhibiting general relevance. Since the variation in some physical parameters (such as hardness) along the growth direction has been reported to follow the same pattern, it is assumed that the root cause in these cases may also be the composition variation.

The Perioperative Period of Heart Transplantation Is Affected by Thyroid Hormone Status.

Background: Orthotopic heart transplantation (HTx) is a long-term surgical therapeutic approach for patients with end-stage heart failure. The objective of the present study was to uncover associations between altered thyroid hormone (TH) status and adverse outcomes after HTx. Methods: In this prospective, single-center cohort study, 283 patients underwent HTx between 2013 and 2020 at the Heart and Vascular Center of Semmelweis University in Hungary. We measured serum free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) pre- and postoperatively. TaqMan qPCR was used to measure type 2 deiodinase and type 3 deiodinase mRNA (Dio2 and Dio3, respectively) levels from the diseased heart bioptates. To assess the local TH action of the heart, mRNA levels of Hcn2 and Myh7 were measured in a subgroup of patients receiving extracorporeal membrane oxygenation (ECMO) postoperatively. Groups were compared using nonparametric tests. Cox regression analysis and logistic regression test were used to investigate the outcomes. The connection between serum TH parameters and cardiac gene expressions was assessed using linear regression. Results: Serum TSH (p = 0.009), fT3 (p < 0.001), and fT4 (p < 0.001) levels were lower after HTx than preoperatively. Levothyroxine (LT4) administered to donors was associated with better survival after 30 days (p = 0.049). LT4 replacement given to recipients after HTx was associated with better survival after 30 days (p = 0.018), 1 year (p = 0.002), and 2 years (p = 0.001). Dio3 mRNA level was significantly increased in patients who were treated with ECMO (p = 0.026), left ventricular assist device (LVAD) (p = 0.008), and biventricular assist device (BiVAD) (p = 0.013) preoperatively, and ECMO (p = 0.042) postoperatively, compared with those who did not require any type of mechanical circulatory support (MCS). We found no significant difference in the expression of the Hcn2 and Myh7 marker genes between patients on postoperative ECMO and those without MCS, and neither did they correlate with serum hormone levels (p = 0.519 and p = 0.056, respectively). Conclusions: We conclude that TH status plays an important role in HTx patients, and monitoring of TH status in the perioperative period may contribute to improved treatment outcomes. Our findings require independent confirmation in a randomized controlled clinical trial.

The effect of lung emptying before the inhalation of aerosol drugs on drug deposition in the respiratory system.

The amount of drug depositing in the airways depends, among others, on the inhalation manoeuvre and breathing parameters. The objective of this study was to quantify the effect of lung emptying before the inhalation of drugs on the lung doses. Thirty healthy adults were recruited. Their breathing profiles were recorded while inhaling through six different emptied DPI devices without breathe-out and after comfortable or forced exhalation. The corresponding emitted doses and aerosol size distributions were derived from the literature. The Stochastic Lung Model was used to estimate the deposited doses. In general, forceful exhalation caused increased flow rate and inhaled air volume. Increased flow rate led to the increase of the average lung dose for drugs with positive lung dose-flow rate correlation (e.g. Symbicort®: relative increase of 6.7%, Bufomix®: relative increase of 9.2%). For drugs with negative correlation of lung dose with flow rate (all the studied drugs except the above two) lung emptying caused increased (Foster® by 2.7%), almost unchanged (Seebri®, Relvar®, Bretaris®) and also decreased (Onbrez® by 6.6%) average lung dose. It is worth noting that there were significant inter-individual differences, and lung dose of each drug could be increased by a number of subjects. In conclusion, the change of lung dose depends on the degree of lung emptying, but it is also inhaler and drug specific. Forceful exhalation can help in increasing the lung dose only if the above specificities are taken into account.

The effect of exhalation before the inhalation of dry powder aerosol drugs on the breathing parameters, emitted doses and aerosol size distributions.

Airway deposition of aerosol drugs is highly dependent on the breathing manoeuvre of the patients. Though incorrect exhalation before the inhalation of the drug is one of the most common mistakes, its effect on the rest of the manoeuvre and on the airway deposition distribution of aerosol drugs is not explored in the open literature. The aim of the present work was to conduct inhalation experiments using six dry powder inhalers in order to quantify the effect of the degree of lung emptying on the inhalation time, inhaled volume and peak inhalation flow. Another goal of the research was to determine the effect of the exhalation on the aerodynamic properties of the drugs emitted by the same inhalers. According to the measurements, deep exhalation before drug inhalation increased the volume of the inhaled air and the average and maximum values of the inhalation flow rate, but the extent of the increase was patient and inhaler specific. For different inhalers, the mean value of the relative increase in peak inhalation flow due to forceful exhalation was between 15.3 and 38.4% (min: Easyhaler®, max: Breezhaler®), compared to the case of normal (tidal) exhalation before the drug inhalation. The relative increase in the inhaled volume was between 36.4 and 57.1% (min: NEXThaler®, max: Turbuhaler®). By the same token, forceful exhalation resulted in higher emitted doses and smaller emitted particles, depending on the individual breathing ability of the patient, the inhalation device and the drug metered in it. The relative increase in the emitted dose varied between 0.2 and 8.0% (min: Foster® NEXThaler®, max: Bufomix® Easyhaler®), while the relative enhancement of fine particle dose ranged between 1.9 and 30.8% (min: Foster® NEXThaler®, max: Symbicort® Turbuhaler®), depending on the inhaler. All these effects and parameter values point toward higher airway doses due to forceful exhalation before the inhalation of the drug. At the same time, the present findings highlight the necessity of proper patient education on the importance of lung emptying, but also the importance of patient-specific inhaler-drug pair choice in the future.

Seroconversion after SARS-CoV-2 vaccination is protective against severe COVID-19 disease in heart transplant recipients.

BACKGROUND: Heart transplant (HTX) recipients are prone to develop complications after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Vaccination is often ineffective due to weaker immunogenicity. In this high-volume single-center study, we aimed to determine factors influencing seroconversion after vaccination and predictors of severe SARS-CoV-2 infection. METHODS: Two hundred twenty-nine HTX recipients were enrolled. Type of the first two vaccine doses included messenger RNA (mRNA), vector, and inactivated vaccines. We carried out analyses on seroconversion after the second and third doses of vaccination and on severity of infection. Antispike protein SARS-CoV-2 immunoglobulin G (IgG) was measured after the second and third vaccines and serostatus was defined. Effect of the first two vaccine doses was studied on patients who did not suffer SARS-CoV-2 infection before antibody measurement (n = 175). The effectivity of the third vaccine was evaluated among seronegative recipients after the second vaccine (n = 53). Predictors for severe infection defined as pneumonia, hospitalization or death were assessed in all patients who contracted SARS-CoV-2 infection (n = 92). RESULTS: 62% of the recipients became seropositive after the second vaccination. Longer time between HTX and vaccination (odds ratio [OR]: 2.35) and mRNA vaccine (OR: 4.83) were predictors of seroconversion. 58% of the nonresponsive patients became seropositive after receiving the third vaccine. Male sex increased the chance of IgG production after the third dose (OR: 5.65). Clinical course of SARS-CoV-2 infection was severe in 32%. Of all parameters assessed, only seropositivity before infection was proven to have a protective effect against severe infection (OR: 0.11). CONCLUSIONS: We found that longer time since HTX, mRNA vaccine type, and male sex promoted seroconversion after SARS-CoV-2 vaccination in HTX recipients. Seropositivity-but not the number of vaccine doses-seemed to be protective against severe SARS-CoV-2 infection. Screening of HTX patients for anti-SARS-COV-2 antibodies may help to identify patients at risk for severe infection.

Comprehensive Analysis of Two H13-Type Starting Materials Used for Laser Cladding and Aerosol Particles Formed in This Process.

Laser cladding with H13 steel powders was performed and the related material transformations were studied for the particles emitted during this process. Fractions of various sizes of the aerosol particles formed during the laser cladding were collected on a cascade impactor, while the electromobility and the aerodynamic size of the particles were measured using a scanning mobility particle spectrometer and an aerodynamic particle sizer, respectively. The aerosol particles deposited onto the impactor plates were analyzed using scanning electron microscopy−energy-dispersive X-ray spectroscopy, as well as total-reflection X-ray fluorescence and X-ray absorption near-edge structure spectroscopy. Both the concentration and mean oxidation state of the major components were correlated with the aerosol particle size. The ultrafine aerosol particles (with a diameter less than about 100 nm) were predominantly oxidized and formed as the result of an evaporation−oxidation−condensation process sequence. The larger particles (>200 nm in geometric diameter) were primarily the residues of the original metal powder and exhibited a composition change as compared to the as-received metal powder. Correlations between the changes in the concentration ratio of the components were detected and explained.

Inflammasome activation in end-stage heart failure-associated atrial fibrillation.

AIMS: Inflammatory pathways are increasingly recognized as an important factor in the pathophysiology of both heart failure (HF) and atrial fibrillation (AF). However, there is no data about inflammation-related histological and molecular alterations in HF-associated AF. The objective of our study was to investigate inflammatory pathways and fibrosis in end-stage HF-associated AF. METHODS AND RESULTS: Left atrial samples of 24 male patients with end stage ischemic HF undergoing heart transplantation were analysed. Twelve patients suffered from sustained AF while the others had no documented AF. The expression of inflammasome sensors and their downstream signalling were investigated by Western blot. No differences were observed in the expression of inflammasome sensors between the two groups, while cleaved caspase-1 increased tendentiously in the AF group (P = 0.051). Cleaved caspase-1 also showed significant correlation with the expression of interleukin-1ß and its cleaved form in the total population and in the AF group (P < 0.05). The presence of myocardial and epicardial macrophages were assessed by ionized calcium-binding adaptor molecule 1 (Iba1) immunostaining. Number of macrophages showed a tendency towards elevation in the left atrial myocardium and epicardium of AF compared with SR group. The amount of total and interstitial fibrosis was determined on Masson's trichrome-stained sections. Histological assessment revealed no difference between AF and SR groups in the amount of either total or interstitial fibrosis. CONCLUSIONS: This is the first study on inflammation-related differences between HF with SR or AF showing elevated inflammasome activity and enhanced macrophage infiltration in left atrial samples of patients with AF.

Admission lactate level and the GRACE 2.0 score are independent and additive predictors of 30-day mortality of STEMI patients treated with primary PCI-Results of a real-world registry.

BACKGROUND: In many of the risk estimation algorithms for patients with ST-elevation myocardial infarction (STEMI), heart rate and systolic blood pressure are key predictors. Yet, these parameters may also be altered by the applied medical treatment / circulatory support without concomitant improvement in microcirculation. Therefore, we aimed to investigate whether venous lactate level, a well-known marker of microcirculatory failure, may have an added prognostic value on top of the conventional variables of the "Global Registry of Acute Coronary Events" (GRACE) 2.0 model for predicting 30-day all-cause mortality of STEMI patients treated with primary percutaneous coronary intervention (PCI). METHODS: In a prospective single-center registry study conducted from May 2020 through April 2021, we analyzed data of 323 cases. Venous blood gas analysis was performed in all patients at admission. Nested logistic regression models were built using the GRACE 2.0 score alone (base model) and with the addition of venous lactate level (expanded model) with 30-day all-cause mortality as primary outcome measure. Difference in model performance was analyzed by the likelihood ratio (LR) test and the integrated discrimination improvement (IDI). Independence of the predictors was evaluated by the variance inflation factor (VIF). Discrimination and calibration was characterized by the c-statistic and calibration intercept / slope, respectively. RESULTS: Addition of lactate level to the GRACE 2.0 score improved the predictions of 30-day mortality significantly as assessed by both LR test (LR Chi-square = 8.7967, p = 0.0030) and IDI (IDI = 0.0685, p = 0.0402), suggesting that the expanded model may have better predictive ability than the GRACE 2.0 score. Furthermore, the VIF was 1.1203, indicating that the measured lactate values were independent of the calculated GRACE 2.0 scores. CONCLUSIONS: Our results suggest that admission venous lactate level and the GRACE 2.0 score may be independent and additive predictors of 30-day all-cause mortality of STEMI patients treated with primary PCI.

Establishment of relationships between native and inhalation device specific spirometric parameters as a step towards patient tailored inhalation device selection.

INTRODUCTION: Drug emission from DPIs is dependent on the inspiratory flow parameters through them, which are not directly measured by standard spirometry. Their estimation based on native spirometric data could help in choosing the appropriate device and optimizing the drug deposition. OBJECTIVES: The aim of this study was to survey patient preferences and to find correlations between breathing parameters of COPD patients through DPI devices and their baseline spirometric data, age, gender, disease severity and anthropometric characteristics. Another objective was to establish relationships between peak inspiratory flows (PIFdev) through Breezhaler®, Genuair® and Turbuhaler® inhalers and their determinants. METHODS: Breathing parameters of 49 patients with previously diagnosed COPD and currently using one of the above inhalers were recorded by normal spirometry and while inhaling through the selected DPIs. Statistical analysis of the measured data was completed. All specific data are provided as (mean ±â€¯standard deviation). RESULTS: More than 60% of the patients stated that their current device is the easiest to use. The means of the measured PIFdev values were 91.4 L/min, 77.1 L/min and 77.5 L/min for Breezhaler®, Genuair®, and Turbuhaler®, respectively. PIFdev values were significantly higher for males than for females, but differences upon age, BMI and disease severity group were not significant (at p = 0.05). Peak inspiratory flows through the inhalers (PIFdev) correlated best with their native spirometric counterparts (PIF) and linear PIFdev-PIF relationships could be determined (Breezhaler®: r = 0.60, p = 0.002, Genuair®: r = 0.55, p = 0.001, Turbuhaler®: r = 0.57, p = 0.002). Physical background of the deduced equations was also provided. CONCLUSIONS: Present correlations may be used to assess the success of inhalation of COPD patients through the studied devices and to choose the appropriate device for each patient. As a consequence, the amount of the drug emitted by the device can be optimized, the deposition efficiency within the lungs increased and the related therapeutic effect improved.

Presence of cardiomyocytes exhibiting Purkinje-type morphology and prominent connexin45 immunoreactivity in the myocardial sleeves of cardiac veins.

BACKGROUND: Pulmonary vein (PV) myocardium is a known source of atrial fibrillation. A debated question is whether myocardial extensions into caval veins and coronary sinus (CS) have similar properties. No studies have documented specific pacemaker and/or conducting properties of human extracardiac myocardium. OBJECTIVE: The purpose of this study was to characterize the histology and immunohistochemical features of myocardial sleeves in the wall of cardiac veins. METHODS: Sections of 32 human hearts were investigated. Specimens of PVs, superior caval vein (SVC), CS, sinoatrial and atrioventricular nodes, and left ventricle were stained with Best's Carmine for selective staining of intracellular glycogen. Anti-connexin45 (Cx45)- and Cx43-specific antibodies were used to determine the conduction properties of extracardiac myocardium. RESULTS: Myocardial sleeve was found in the wall of PVs of 15 of 16 hearts, 21 of 22 SVCs, and 8 of 8 CSs. Bundles of glycogen-positive cardiomyocytes exhibiting pale cytoplasm and peripheral myofibrils were observed in the venous sleeves. Strong Cx45 and weak Cx43 labeling was detected in the extracardiac myocardium. Similar staining pattern was observed for the pacemaker and conduction system, whereas ventricular myocardium exhibited prominent Cx43 and no Cx45 immunoreactivity. CONCLUSION: Myocardial fibers of PVs, SVC, and CS exhibit morphology similar to that of Purkinje fibers and are enriched in glycogen. We provide data for the first time on prominent positive staining for Cx45 in the extracardiac myocardium, indicating its potential pacemaker and/or conducting nature.

Effect of delayed pMDI actuation on the lung deposition of a fixed-dose combination aerosol drug.

Lack of coordination between the beginning of the inhalation and device triggering is one of the most frequent errors reported in connection with the use of pMDI devices. Earlier results suggested a significant loss in lung deposition as a consequence of late actuation. However, most of our knowledge on the effect of poor synchronization is based on earlier works on CFC devices emitting large particles with high initial velocities. The aim of this study was to apply numerical techniques to analyse the effect of late device actuation on the lung dose of a HFA pMDI drug emitting high fraction of extrafine particles used in current asthma and COPD therapy. A computational fluid and particle dynamics model was combined with stochastic whole lung model to quantify the amount of drug depositing in the extrathoracic airways and in the lungs. High speed camera measurements were also performed to characterize the emitted spray plume. Our results have shown that for the studied pMDI drug late actuation leads to reasonable loss in terms of lung dose, unless it happens in the second half of the inhalation period. Device actuation at the middle of the inhalation caused less than 25% lung dose reduction relative to the value characterizing perfect coordination, if the inhalation time was between 2 and 5 s and inhalation flow rate between 30 and 150 L/min. This dose loss is lower than the previously known values of CFC devices and further support the practice of triggering the device shortly after the beginning of the inhalation instead of forcing a perfect synchronization and risking mishandling and poor drug deposition.