Heart Insufficiency Research Articles

PC013 / #607 NEUROMODULATION, STIMULATION AND REGENERATION OF THE CENTRAL NERVOUS SYSTEM WITH SHOCKWAVES: E-POSTER VIEWING

First successful extracorporeal shockwaves application in medicine was the non-invasive kidney stone disintegration in 1980. It took about 10 years to recognize that low intensity shockwaves have the ability to stimulate healing process in the body. Shockwaves proved to be efficient for the treatment of non-unions, tendon and muscular pain, delayed wound healing, heart insufficiency, erectile dysfunction and of other indications. The working principle is the mechanical stimulation of biological processes called mechanotransduction resulting in increased cell metabolism, release of nitric oxide and of numerous growth factors.

Heart Transplant Indication in Acute Heart Insufficiency with COVID-19

The report shows the evolution of a 29yr old woman who eas admitted to the hospitals because of her recent heart condition with pulmonary symptoms aswell. It was found that her COVID-19 tests were positive. As her evolution only worsened having kidney function aggravated it was decided that she had indication for a successful heart transplant. She has now 20 months of post-surgery and is being monitored by all clinical, la oratory and image exams thus being considered a successful case of serious and lifesaving heart condition due to COVID-19.

Dual-Energy Computed Tomography-Based Quantitative Bone Marrow Imaging in Non-Hematooncological Subjects: Associations with Age, Gender and Other Variables.

Background: Our aim is to assess the utility and associations of quantitative bone marrow attenuation (BMA) values measured on clinical dual-energy computed tomography (DECT) exams in non-hematooncologic subjects with skeletal regions, patient age, gender, and other clinical variables. Methods: Our local ethics committee approved this retrospective image data analysis. Between July 2019 and July 2021, 332 eligible patients (mean age, 64 ± 18 years; female, 135) were identified. Inclusion criteria were the availability of a standardized abdominopelvic DECT data set acquired on the same scanner with identical protocol. Eleven regions-of-interest were placed in the T11-L5 vertebral bodies, dorsal iliac crests, and femur necks. Patient age, gender, weight, clinical, habitual variables, inflammation markers, and anemia were documented in all cases. Results: Multi-regression analyses (all, p < 0.05) identified age as the strongest predictor of lumbar BMA (standardized coefficient: β = −0.74), followed by CRP (β = 0.11), LDH (β = 0.11), and gender (β = −0.10). In the lower thoracic spine, age was the strongest predictor (β = −0.58) of BMA, followed by gender (β = −0.09) and LDH (β = 0.12). In femoral bones, age was negatively predictive of BMA (β = −0.12), whereas LDH and anemia were positively predictive (β = 0.16 both). Heart insufficiency significantly decreased (β = 0.12, p = 0.034) a BMA value gradient from higher to lower HU values along the vertebrae T11 and L5, whereas age significantly increased this gradient (β = −0.2, p ≤ 0.001). Conclusions: DECT-based BMA measurements can be obtained from clinical CT exams. BMA values are negatively associated with patient age and influenced by gender, anemia, and inflammatory markers.

PB2145: REAL-WORLD THERAPY LINES IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) – A POPULATION-BASED ANALYSIS

Background: Real-world data on patients suffering from diffuse large B-cell lymphoma (DLBCL) in Germany treated in 1st-and 2nd-line therapies are limited. Aims: The aim of this study was to investigate the number of DLBCL pateints treated in 1st-and 2nd-line therapies in Germany. Further patients deceased or being in remission and potentially therapy-related complications were considered. Methods: A database of German health administrative anonymized claims data of statutory health insurances – comprising a total of 5,166,845 insured persons from 2015 to 2016 – was used for analyses. Newly diagnosed DLCBL-patients were defined as having at least one confirmed outpatient or inpatient main diagnosis (ICD-10-GM code C83.3), a co-existing DLCBL-specific treatment (claims for chemo-/antibody-therapy, stem cell transplantation or radiation therapy) and no DLCBL diagnosis one year before. Rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was defined as 1st-line therapy, other therapies than R-CHOP were defined as 2nd-line therapy. Patients neither deceased nor receiving a 2nd-line therapy within 3 years after 1st-line therapy were defined as patients in remission. Potential therapy-related complications were defined based on the following ICD-10-GM codes: renal insufficiency (N14, N17-N19, N99.0), heart insufficiency (I50), liver insufficiency (K71-K77), polyneuropathy (G62.0). Only newly emerged ICD-10-GM coding’s were assessed as being potentially treatment related. Burden of comorbidities was assessed using the Charlson-comorbidity-index (CCI). Results: We identified 445 DLBCL-patients (2015-2016) out of them 89.4% (n=398) were treated with R-CHOP in 1st-line therapy. Patients were on average 66 years old and mean CCI was 5.15. Out of 398 these patients, 21.1% (n=84) received a 2nd-line therapy [Ø-age: 65 y / Ø-CCI: 4.98], 23.9% (n=95) died without proceeding to 2nd-line therapy [Ø-age: 75 y / Ø-CCI: 5.89] and 55.0% (n=219) were in remission after 1st-line therapy [Ø-age: 62 y / Ø-CCI: 4.86]. Out of 398 DLCBL-patients treated with R-CHOP, 23% developed renal insufficiency, 13% heart insufficiency, 10% liver insufficiency, and 9% polyneuropathy. Deceased patients (n=95) suffered significantly more often (p<.01) from a renal (33% vs. 19%) and heart insufficiency (20% vs. 9%) than patients in remission (n=219). Summary/Conclusion: 23.9% of patients treated with 1st-line therapy R-CHOP deceased within 3 years. 10.6% of newly diagnosed DLBCL-patients were not treated with R-CHOP. Further research is need to get more insights in treatment patterns of DLBCL-patients (3rd-line therapies or use of CAR-T-cells).

Soluble IL-33 receptor predicts survival in acute kidney injury.

Introduction: The prediction of acute kidney injury (AKI)-related outcomes remains challenging. Herein we prospectively quantified soluble ST2 (sST2), the circulating isoform of the IL-33 receptor, in hospitalized patients with AKI. Methods: In-hospital subjects with AKI of various etiology were identified through the in-hospital AKI alert system of the Brandenburg University hospital. sST2 was measured within a maximum of 48 hours from the time of diagnosis of AKI. The following endpoints were defined: in-hospital death, dialysis, recovery of kidney function until demission. Results: In total, 151 individuals were included in the study. The in-hospital mortality was 16.6%, dialysis therapy became mandatory in 39.7%, no recovery of kidney function occurred in 27.8%. sST2 was significantly higher in nonsurvivors (p = 0.024) but did not differ in the two other endpoints. The level of sST2 increased significantly with the severity of AKI. Further differences were detected in subjects with heart insufficiency (lower sST2), and in patients that required ICU treatment, or ventilatory therapy, or vasopressors (all higher). Conclusions: The current study suggests sST2 as biomarker of “acute distress”: it predicts post-AKI survival and substantially increases in subjects with a higher degree of cumulative morbidity under acute circumstances (e.g., ICU therapy, vasopressor administration).

PROSPECTIVE ANALYSIS OF THE PHYSIOLOGICAL CHANGES CAUSED BY PROLONGED USE OF N95-TYPE MASKS

TYPE: Late Breaking Abstract TOPIC: Pulmonary Physiology PURPOSE: INTRODUCTION: The clinical and physiological effects of long-duration use of N95-type masks without ventilation valves, on healthcare workers during the Coronavirus Disease-2019 (COVID-19) pandemic were evaluated. METHODS: All volunteering personnel working in operating theater using non-ventilated N95 type respiratory masks, minimum for a 2-hour non-interrupted duration were observed. The partial oxygen saturation (SpO2) and heart rate (HR) were recorded before wearing the N95 mask, and at 1st and 2nd hour. Volunteers were then questioned for any symptoms. RESULTS: Total of 116 measurements were completed in 29 (13 male, 16 female) eligible volunteers, each having 4 measurements, on different days. Median age was 32.5. Pre-mask, 1st hour, and 2nd hour median values for SpO2 were 98%, 97% and 96%, respectively (p<0.001). Median HR was 75 pre-mask, 79 at 1st hour, and 84/min at 2nd hour (p<0.001). Significant difference between all-three consecutive measurements of HR was achieved. Statistical difference was only reached between pre-mask and other SpO2 measurements (1st and 2nd hour). Complaints seen in group were head ache (34%), shortness of breath (23%), palpitation (19%), and nausea feeling (3%). Two individuals took off their masks to breathe, on 87th and 105th minutes, respectively. CONCLUSIONS: Long duration (>1 hour) use of N95-type masks cause significant reduction in SpO2 measurements and increase in heart rate. CLINICAL IMPLICATIONS: .Despite being a crucial personal protective equipment in COVID-19 pandemic, especially for health workers in operating rooms, it should be used with caution in people with known heart and/or pulmonary insufficiency, and with short intermittent time periods. DISCLOSURE: No significant relationships. KEYWORD: COVID-19

MO289: IL33 Exerts Toxicity in the Heart as Secreted by Renal Inflammation

Abstract BACKGROUND AND AIMS Acute kidney injury (AKI) is a major cardiovascular risk factor, regardless of the severity or the origin of the AKI. Among this risk, AKI imparts an array of signals and long-term physiologic alterations that can precipitate heart insufficiency and hypertrophy. However, few direct molecular mechanisms have been identified that show how AKI leads to cardiac disease and maladaptation. The aims of this project are to assess the role of IL33 in remote cardiac damage after AKI. METHOD AKI was induced in mice by ischemia–reperfusion injury of both right and left kidneys by 30min of reversible artery occlusion. To examine the role of renal inflammation more specifically, we used the unilateral ureteral obstruction (UUO) model, which does not cause acute injury. For UUO, an incision was made in the lower left quadrant of the abdomen and the left ureter was isolated and ligated permanently. Mice were treated to manipulate select signaling pathways with either Adenovirus-associated virus 9 (AAV9) or recombinant proteins. We generated AAV9 carrying the IL33 gene or an empty vector (EV) under a CMV promoter and injected 1012 viral particles intrathoracically in 6 to 9 days old pups. Recombinant IL33 (rIL33) or vehicle were injected intraperitoneally in IL33 KO adult mice after AKI (at D0, D1 and D2). Echocardiography was performed either at baseline or after 28 days of surgery. Hearts were fixed in 4% paraformaldehyde overnight and paraffin-embedded for fibrosis (picrosirius staining) and cardiomyocyte area measurement (WGA staining and ImageJ software). IL33 citrine reporter mice (IL33cit) in the heterozygous state were used to show IL33 expression. RESULTS Our data showed that UUO and AKI were strong inducers of cardiac dysfunction after 28 days in adult mice, measured with echocardiography (mean ejectional fraction (EF): 58, 46, 47% in Sham, AKI and UUO group respectively, P &amp;lt; .05). Cardiac pathology was also present such as increased fibrosis in hearts from WT mice after AKI compared with Sham (2.3%, 4.5%, 8.3% of fibrosis area in Sham, AKI and UUO respectively, P &amp;lt; 0.05) and an increased mean cardiomyocyte area indicative of hypertrophy (333, 597, 1246 µm2 in Sham, AKI and UUO respectively, P &amp;lt; .05). However, cardiac function and architecture were preserved either after 28 days of AKI or UUO in IL33 KO mice. In parallel, WT mice injected with AAV9-CMV-IL33 showed impaired cardiac function compared with mice injected with a control AAV9-empty vector after 8 weeks (EF 58% versus 42% in AAV-EV and AAV-IL33 respectively, P &amp;lt; .05). After AKI, AAV9-IL33 mice had even more impaired cardiac function compared to AAV-empty control mice (EF 42% versus 35% in AAV-EV and AAV-IL33 respectively). In IL33 KO mice, the injection of 1 µg of rIL33 in the early days of AKI restored cardiac dysfunction and fibrosis after 28 days of AKI (EF 59 versus 43% in Sham and AKI respectively, P &amp;lt; .05), yet vehicle injected mice were still protected. IL33 expression viewed with the Citrine reporter mice showed that it was locally downregulated in the heart after AKI, which was strictly localized in pericytes in the heart (PDGFRß+ cells). ELISA for protein levels of IL33 confirmed the reduction of this cytokine in hearts from WT AKI and UUO mice after 28 days compared with Sham (29.6, 4.2 and 2.7 fg of IL33/µg of protein in Sham, AKI and UUO hearts respectively, P &amp;lt; .05). CONCLUSION IL33 seems to exert toxicity in the heart as secreted by renal inflammation, which is against some previous reports in the literature where it was suggested to be a protective factor to the heart (whether released from the kidney or from within the heart).

Short peptide pharmacophores developed from protein phosphatase-1 disrupting peptides (PDPs)

PP1 is a major phosphoserine/threonine-specific phosphatase that is involved in diseases such as heart insufficiency and diabetes. PP1-disrupting peptides (PDPs) are selective modulators of PP1 activity that release its catalytic subunit, which then dephosphorylates nearby substrates. Recently, PDPs enabled the creation of phosphatase-recruiting chimeras, which are bifunctional molecules that guide PP1 to a kinase to dephosphorylate and inactivate it. However, PDPs are 23mer peptides, which is not optimal for their use in therapy due to potential stability and immunogenicity issues. Therefore, we present here the sequence optimization of the 23mer PDP to a 5mer peptide, involving several attempts considering structure-based virtual screening, high throughput screening and peptide sequence optimization. We provide here a strong pharmacophore as lead structure to enable PP1 targeting in therapy or its use in phosphatase-recruiting chimeras in the future.

When Pulmonary Hypertension Complicates Heart Failure.

Pulmonary hypertension (PH) often complicates chronic left-sided heart failure, with a remarkable impact on quality of life, exercise capacity, and survival. PH in chronic left-sided heart failure (PH-LHD) is not only caused by backward transmission of pressures but also involves impairment of atrial function, inflammation, and vasoconstriction. Once the left atrium loses its reservoir capacity, usually pulmonary vascular resistances increase. Right atrial dilation commonly represents the first sign of PH-LHD, before right ventricle dilatation and systolic dysfunction develop, leading to right heart insufficiency, and ultimately, right heart failure.

In Vivo Evaluation of a Novel Control Algorithm for Left Ventricular Assist Devices Based Upon Ventricular Stroke Work.

The physical fitness of patients with terminal heart failure and an implanted left ventricular assist device (LVAD) might be improved by load-adaptive control of the LVAD. In this study, three control strategies for LVAD were compared in eight pigs: (1) a constant stroke work (CSW) control strategy that ensures a constant ventricular load using ventricular stroke work as the control variable; (2) a work ratio (WR) controller that maintains a constant ratio of ventricular work to hydraulic pump work; and (3) a controller that maintains the pump pace at a constant speed (CS). Biventricular heart insufficiency was induced by increased isoflurane application, and preload, afterload, and contractility alterations were performed. LVAD speed changes were significantly more pronounced in all load interventions with the CSW control strategy (preload: P < 0.001 vs. CS and P = 0.004 vs. WR; afterload: P < 0.001 vs. CS and P < 0.001 vs. WR; contractility: P < 0.001 vs. CS and P < 0.001 vs. WR). However, a significant difference in systemic flow only became evident in the experiments upon afterload increase ( P < 0.001 vs. CS and P = 0.004 vs. WR). An implementation of an evolved version of the CSW control strategy that dispenses with invasively measured parameters might be feasible for clinical use.

P 31 Long-term results with TPS (Transcranial Pulse Stimulation) treatment of Alzheimer's disease

Introduction Low intensity shockwaves proofed to be efficient for the treatment of non-unions, tendon and muscular pain, wound healing, heart insufficiency, erectile dysfunction and since 1990 also neurological indications. The working principle is the mechanical stimulation of biological processes called mechanotransduction resulting in increased cell metabolism, release of nitric oxide (eNO) and numerous growth factors like VGEF, TGF, BNDF and others. There is also an anti-inflammatory effect, stimulation of stem cells and of the innate immune system. Transcranial Pulse Stimulation (TPS) uses shockwave pulses for mechanical stimulation of the brain tissue. Detailed animal evaluation conformed the experience from years of shockwave applications in other medical disciplines that the treatment is safe. There have been no negative side effect observed. Materials & Methods 6 Alzheimer’s disease patients have been treated with TPS since 2010. The treatment consisted of a booster block of 6 treatment sessions within 2 weeks and one re-treatment session per month after 3 months follow-up. 6000 shockwave pulses with energy flux density of 0.2mJ/mm2 were applied in one session. Second booster treatment (6 sessions) has been administred after 2 years. Results The CERAD score was improved by 12.8% within the first 3 months. The achieved improvement was maintained for one year by monthly re-treatments. Nevertheless, afterwards the CERAD score started to decrease significantly and achieved the baseline after 12 months. Second booster treatment (6 sessions) has not been as successful as the first one. Still after another year, the CERAD score was still better than the expected disease level of an untreated patient. Conclusion The achieved results allow the assumption that more frequent booster treatments might maintain the improved CERAD score also after the first year of treatment. The current experience proves that the treatment is safe and effective. A two-center trial has been successfully completed with 35 patients. Still, further trials with larger number of patients are necessary. A placebo controlled, randomized trial is ongoing.

Stachytine Hydrochloride Improves Cardiac Function in Mice with ISO-Induced Heart Failure by Inhibiting the α-1,6-Fucosylation on N-Glycosylation of β1AR.

Background: Cardiovascular diseases have become a major public health problem that seriously threatens human health. The cumulative effects of various cardiovascular events will eventually develop into chronic heart insufficiency and even heart failure, and the β1 adrenergic receptor signal pathway plays an important role in this process. Stachytine hydrochloride is the main active ingredient of Yimucao, which is a traditional Chinese medicine used to treat gynecological diseases. Modern studies have found that stachytine hydrochloride has a good cardioprotective effect, but it is still unclear whether stachytine hydrochloride has an effect on the β1 adrenergic receptor signal pathway. The purpose of this study is to explore the effect of stachytine hydrochloride on the β1 adrenergic receptor signal pathway. Method: In this study, a continuous infusion of isoproterenol (40 mg/kg/day) was administered to mice and ventricular myocytes explored the potential mechanism of stachytine hydrochloride (12 mg/kg/day) on the β1 adrenergic receptor signal pathway in the heart. Evaluate changes in cardiac morphology and function by echocardiography, cardiac hemodynamics, and histological methods, and detect molecular changes by Western blot and immunofluorescence. Treat primary cultured adult mouse or neonatal rat ventricular myocytes with or without isoproterenol (0.1 μMol), PNGase F (10–2 units/ml), and stachytine hydrochloride (10 μMol) at different time points. Detect α-1,6-fucosylation on N-glycosylation, calcium transient, contraction, and relaxation function and related signals. Results: Stachytine hydrochloride reduces cardiac remodeling and modulates hemodynamic parameters during chronic β1 adrenergic receptor activation in vivo. The N-glycosylation of β1 adrenergic receptors decreased after continuous isoproterenol stimulation, while stachytine hydrochloride can increase the N-glycosylation of β1AR in the heart of mice with isoproterenol-induced heart failure. Decreased N-glycosylation of β1 adrenergic receptors will downregulate the cAMP/PKA signal pathway and inhibit myocardial excitation and contraction coupling. Stachytine hydrochloride significantly reduced isoproterenol-induced cardiac N-linked glycoproteins with α-1,6-fucosylation. Conclusion: Our results show that stachytine hydrochloride inhibits the synthesis of α-1,6-fucosylation on the N-terminal sugar chain by reducing α-1,6-fucosyltransferase (FUT8) and α-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase A (MGAT4a), upregulating the N-glycosylation level on β1 adrenergic receptors, and maintaining cAMP/PKA signal pathway activation.

A rapid and quantitative detection method for plasma soluble growth stimulating gene protein 2 based on time resolved fluorescence immunochromatography.

Background: plasma soluble growth stimulating gene protein 2 (sST2) is a new generation biomarker in heart failure (HF), which is an independent predictor of adverse outcomes of heart failure. Thus, the establishment of a rapid and sensitive method for detecting sST2 is urgently needed. Methods: lanthanide element Eu3+ coated fluorescent nanometer microspheres (Eu3+@FMN) can be used as markers to label monoclonal mouse anti-human sST2 antibody ST-01 (ST-01-Eu3+@FMN). When the immune sandwich complex formed between the monoclonal mouse anti-human sST2 antibody ST-02 and ST-01-Eu3+@FMN on the test band with the appearance of target object sST2, we can detect the fluorescence intensity of Eu3+ on the test band and the quality control band using a dry fluorescence analyzer. We calculated the T/C value (T/C = fluorescence intensity of the test band/fluorescence intensity of the quality control band), fitted to the calibration curve, and measured the concentration value of sST2 in the corresponding sample. Results: the best reaction time was 15 min after condition exploration, and the optimal sample volume was 80 μL. The detection sensitivity of the scheme was 2.14 ng mL-1. The calibration curve of the assay was y = 0.0113x + 0.0033, and the linear range was 5-200 ng mL-1. No cross reaction was found when the samples contained BNP, NT-proBNP, and galectin-3, indicating a good specificity. The precision was good with a relative deviation < 15%. The coefficient of variation of detection results of low-concentration samples and high-concentration samples was 4.20% and 3.30% respectively in the same batch of strip tests, so the intra-assay CV was set as <10%; when different batches of strips were used for testing, the coefficient of variation of detection results of low-concentration samples and high-concentration samples was 10.06% and 8.38% respectively, so the inter-assay CV was set as <15%. Stability test results showed that the relative deviation of test results at each time node was <15%, indicating good stability of the assay strips. The correlation coefficient between the ST-01-Eu3+@FMN based time-resolved fluorescence immunochromatography analysis and sST2 ELISA kit was 0.98. To confirm the usage of our proposed TRF-ICA for clinical samples, it was used to determine the concentration of sST2 in samples obtained from 34 patients with heart insufficiency, acute and chronic heart failure. As a result, we successfully detected a minimal concentration of 5.21 ng mL-1 and a maximum concentration of 184.26 ng mL-1 for sST2. Conclusion: this technique provides a rapid, simple and quantitative detection method for sST2 in clinics. It can help clinicians to predict the incidence of adverse events in patients with HF.

Selected aspects of the application of the hybrid circulatory system in the analysis of heart insufficiency

Purpose: There are many causes of heart failure, one of them being valvular heart disease. In this case, the stage and type of the disease can significantly affect the hemodynamic parameters of the left ventricle of the heart. In turn, these parameters can significantly influence the mode, type and strategy of clinical treatment. The aim of the study was to analyze and map the hydrodynamic conditions of the heart using a hybrid-digital model of the circulatory system. Methods: The tests performed using the circulatory system model allowed for the simulation of the failure of both heart’s left ventricle and a set of arteries in the systemic circulation. Furthermore, the changes in hemodynamic parameters for valvular anomalies at various heartbeats were obtained. Results: The results suggested that a higher heartbeat should be sustained in such cases of complex mitral-aortic anomalies in the clinical practice. When observing low aortic pressures, heartbeat should be increased to compensate for the valvular insufficiencies. Conclusions: Extending the already conducted research could result in constituting a wide database for clinicians who are treating the insufficiency of the left ventricle of the heart. Moreover, the information included in this paper may be used for a comparison of the clinical anomalies, which facilitates a correct diagnosis. The test-stand used in the research can be applied to predict the anomalies of the circulation system for a quick and precise analysis of a clinical anomaly of a patient without physical presence.

Parkinson’s disease treatment with shockwaves

Abstract Shockwaves have been first successfully used for extracorporeal kidney stone disintegration in 1980. Meanwhile, low intensity shockwaves proved to be efficient for the treatment of non-unions, tendon- and muscular pain, wound healing, heart insufficiency, erectile dysfunction and aesthetics. Spasticity is treated since 1990, followed by the treatment of spinal cord injuries and unresponsive wakefulness. The working principle is the mechanical activation of biological processes called mechanotransduction resulting in anti-inflammatory effect, increased cell metabolism, release of nitric oxide (eNO) and of numerous growth factors. From 2010 to 2013, 18 patients with Parkinson’s disease were off-label treated. First, in order to determine an appropriate treatment rhythm and the energy dosage. A further 3 patients followed in 2017. The treatment was performed with focused shockwave generator and consisted of 6 approximately 30 minutes sessions within two weeks. 6000 pulses with energy flux density of 0.2mJ/mm2 at 5Hz were applied during each session in the region of interest of the brain. After the initial treatment block, the disease symptoms assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) improved by over 50%. The symptomatic improvements remained stable to date by regular monthly re-treatments (1 session) in one of the patients for 8 years and in the 3 other patients over 3 years. The UPDRS, motoric part decreased by more than 50% within the treatment period. The UPDRS, all 3 items, was reduced by 44%. There were no negative side effects. Parkinson’s disease treatment with shockwaves is safe and effective. The broad scope of shockwave stimulated biological effects in the brain seems to be an interesting and promising option as an extension to the established treatments. Further clinical trials with larger number of patients are necessary for regulatory clearance. A placebo controlled, randomized trial is ongoing. Keywords: Parkinson' disease, shockwaves, mechanotransduction, brain

Impact of comorbidities and ablation strategy on outcome after pulmonary vein isolation with cryo-balloon in patients with non- paroxysmal atrial fibrillation

Abstract Background Presence of several comorbidities in patients with atrial fibrillation is well known, but impact of them on outcome after pulmonary vein isolation with cryo-balloon is not enough investigated. First aim of the study was analysis of the impact of comorbidities on long term outcome after PVI with cryo-balloon new generation (CBA) and secondary goal was evaluation of the impact of additional posterior roof ablation (PRA) in these patients. Methods Patients with non-paroxysmal AF ablated with CBA in our institution since May 2012 and completed follow up &amp;gt;3 months were enrolled in the study. The history of AF, cardiac comorbidities (CAD, Non ischemic-cardiomyopathy, heart insufficiency, right ventricular dysfunction) diabetes mellitus, and renal failure were assessed at admission, all patients received echocardiographic examination and blood test. After a single trans-septal access and PV angiography PVI was performed using a 28-mm CBA. Mapping of PV signals before, during, and after each cryo application was performed with a 3F lasso catheter. The procedural endpoint after PVI was defined as complete elimination of all fragmented signals at the PV antrum with verification of entrance and exit block. In some patients PRA was performed additionally to PVI at discretion of physician. The primary endpoint of this study was the first documented recurrence of atrial tachyarrhythmia (&amp;gt;30 sec.), hospitalization due to cardio-vascular cause, re-do procedure or re-administration of anti-arrhythmic drugs. Results Among 560 patients 78 (13.9%) had no comorbidity and 299 (53.4%) were lasted with &amp;gt;1 comorbidity. A total of 260 (46.4%) recurrences were obtained within median follow up of 28 (12–57) months. Female gender, long time from first diagnosis &amp;gt;12 months and cardiac comorbidity were revealed to be independent predictors for long term recurrences whereas additional PRA performed in 176 pts independently improved outcome (61.9% vs 49.7%). Conclusion Cardiac comorbidities increased probability of post ablation recurrences, but performing of additional posterior roof ablation improved outcome in our cohort. These results should be confirmed in multi-center randomized study Funding Acknowledgement Type of funding sources: None.

Euglycemic ketoacidosis - rare condition on the rise

SGLT2 inhibitors have been developed as antidiabetics. Large randomized prospective studies have shown prognostic benefit in patients with heart and/or renal insufficiency regarding cardiovascular and general endpoints - even in absence of type 2 diabetes mellitus. This extends the indication to large groups of multimorbid patients. SGLT2 inhibitors induce ketogenesis comparable to fasting conditions. This may - in presence of additional catabolic factors - deteriorate into life-threatening ketoacidosis - probably due to increased reabsorption of ketone bodies from urine as well as the blockage of SGLT2 receptors on α-cells of the pancreas. Euglycaemic ketoacidosis (eKA) under SGLT2 inhibition occurs in about 2:1000 years of treatment. The diagnosis is challenging: in eKA, blood sugar levels are often normal, and ketone detection in urinalysis can be falsely negative, while glucosuria is excessive compared to euglycemic blood-glucose. The management corresponds to classical diabetic ketoacidosis, but special features of blood glucose target, hydration and potassium management should be considered. SGLT2 inhibitors should be paused if a longer fasting period is expected ("sick-day-break"). Due to the soaring number of prescriptions, a significant increase in the prevalence of eKA is expected. Immediate diagnosis and therapy are essential in emergency and intensive care medicine.

Effects of the Wenyang Zhenshuai Granule on the Expression of LncRNA-MiR143HG/miR-143 Regulating ERK5 in H9C2 Cardiomyocytes.

Chronic heart failure (CHF) is a complex clinical syndrome caused by a variety of heart problems, with a high incidence. The 5-year survival rate of patients with clinical symptoms is similar to that of malignant tumors. Wenyang Zhenshuai granules are a safe and effective granule of traditional Chinese medicine components, including aconite, dried ginger, licorice, and red ginseng. In contemporary clinical applications, it is widely used in acute and chronic heart insufficiency, coronary heart disease, and arrhythmia. This research cultured H9C2 cardiomyocytes and divided them into the normal control group, LncRNA-MiR143HG overexpression group, LncRNA-MiR143HG silence group, Adriamycin (ADR) group, ADR + medicated serum group, ADR + LncRNA-MiR143HG overexpression + medicated serogroup, and ADR + LncRNA-MiR143HG silence + medicated serogroup. The cells of each group were treated differently, and the survival rate of each group of cells and the expression levels of LncRNA-MiR143HG/miR-143 and ERK5 were detected at the end of the experiment, and the expression of LncRNA-MiR143HG/miR-143 in H9C2 cardiomyocytes was regulated by Wenyang Zhenshuai granules' impact. The results of this study showed that, in the doxorubicin-induced H9C2 cardiomyocyte injury model, the expression of miR-143 was upregulated, and the expression of LncRNA-MiR143HG and ERK5 was significantly downregulated. Wenyang Zhenshuai granules can downregulate the expression of miR-143 to promote ERK5 protein expression and phosphorylation. The process is regulated by LncRNA-MiR143HG/miR-143, which may be one of its important mechanisms for the treatment of chronic heart failure.

Exercise-Training Regulates Apolipoprotein B in Drosophila to Improve HFD-Mediated Cardiac Function Damage and Low Exercise Capacity.

Apolipoprotein B plays an essential role in systemic lipid metabolism, and it is closely related to cardiovascular diseases. Exercise-training can regulate systemic lipid metabolism, improve heart function, and improve exercise capacity, but the molecular mechanisms involved are poorly understood. We used a Drosophila model to demonstrate that exercise-training regulates the expression of apoLpp (a homolog of apolipoprotein B) in cardiomyocytes, thereby resisting heart insufficiency and low exercise capacity caused by obesity. The apoLpp is an essential lipid carrier produced in the heart and fat body of Drosophila. In a Drosophila genetic screen, low expression of apoLpp reduced obesity and cardiac dysfunction induced by a high-fat diet (HFD). Cardiac-specific inhibition indicated that reducing apoLpp in the heart during HFD reduced the triglyceride content of the whole-body and reduced heart function damage caused by HFD. In exercise-trained flies, the result was similar to the knockdown effect of apoLpp. Therefore, the inhibition of apoLpp plays an important role in HFD-induced cardiac function impairment and low exercise capacity. Although the apoLpp knockdown of cardiomyocytes alleviated damage to heart function, it did not reduce the arrhythmia and low exercise capacity caused by HFD. Exercise-training can improve this condition more effectively, and the possible reason for this difference is that exercise-training regulates climbing ability in ways to promote metabolism. Exercise-training during HFD feeding can down-regulate the expression of apoLpp, reduce the whole-body TG levels, improve cardiac recovery, and improve exercise capacity. Exercise-training can downregulate the expression of apoLpp in cardiomyocytes to resist cardiac function damage and low exercise capacity caused by HFD. The results revealed the relationship between exercise-training and apoLpp and their essential roles in regulating heart function and climbing ability.

Medical recommender systems based on continuous-valued logic and multi-criteria decision operators, using interpretable neural networks

BackgroundOut of the pressure of Digital Transformation, the major industrial domains are using advanced and efficient digital technologies to implement processes that are applied on a daily basis. Unfortunately, this still does not happen in the same way in the medical domain. For this reason, doctors usually do not have the time or knowledge to evaluate all alternative treatment options for each patient accurately and individually. However, physicians can reduce their workload by using recommender systems, still having every decision under control. In this way, they also get an insight into how other physicians make treatment decisions in each situation. In this work, we report the development of a novel recommender system that uses predicted outcomes based on continuous-valued logic and multi-criteria decision operators. The advantage of this methodology is that it is transparent, since the model outcomes emulate logical decision processes based on the hierarchy of relevant physiological parameters, and second, it is safer against adversarial attacks than conventional deep learning methods since it drastically reduces the number of trainable parameters.MethodsWe test our methodology in a patient population with diabetes and heart insufficiency that becomes a therapy (beta-blockers, ACE or Aspirin). The original database (Pakistan database) is publicly available and accessible via the internet. However, to explore methods to protect the patient's identity and guarantee data privacy we implemented a methodology on a variable-by-variable basis by fitting a sequence of regression models and drawing synthetic values from the corresponding predictive distributions using linear regressions and norm rank. Furthermore, we implemented a deep-learning model based on logical gates modeled by perceptrons with fixed weights and biases. While a first trainable layer automatically recognizes a meaningful parameter hierarchy, the implemented Logic-Operator Neuronal Network (LONN) simulates cognitive processes like a rational, logical thinking process, considering that this logic is joined by fuzziness, i.e., logical operations are not exact but essentially fuzzy due to the implemented continuous-valued operators. The predicted outcomes of the model (kind of therapy-ACE, Aspirin or beta-blocker- and expected therapy time of the patient) are then implemented in a recommender system that compares two different models: model 1 trained on a population excluding negative outcomes (patient group 1, with no patient dead and long therapy times) and a model 2 trained on the whole patient population (patient group 2). In this way, we provide a recommendation of the best possible therapy based on the outcome of the model and the confidence of this recommendation when the outcome of model 1 is compared with the outcome of model 2.ResultsWith the applied method for data synthetization, we obtained an error of about 1% for all the relevant parameters. Furthermore, we demonstrate that the LONN models reach an accuracy of about 75%. After comparing the LONN models against conventional deep-learning models we observe that our implemented models are less accurate (accuracy loss of about 8%). However, the loss of accuracy is compensated by the fact that LONN models are transparent and safe because the freezing of training parameters makes them less prone to adversarial attacks. Finally, we predict the best therapy as well as the expected therapy time. We were able to predict individualized therapies, which were classified as optimal (binary value) when the prediction fully matched predictions made with models 1 and 2. The results provided by the recommender system are displayed using a graphical interface. The current is a proof of concept to improve the quality of the disease management, while the methods are continuously visualized to preserve transparency for the customers.ConclusionsThis work contributes to simplify administrative functions and boost the quality of management of patients improving the quality of healthcare with models that are both transparent and safe. Our methodology can be extended to different clinical scenarios where recommender systems can be applied. The acceptance and further development of the app is one of the next important steps and still requires further development depending on specific requirements of the health management, the physicians or health professionals, and the patent population.