Metabolic acidosis in chronic kidney disease: mere consequence or also culprit?

Metabolic acidosis is a frequent complication in non-transplant chronic kidney disease (CKD) and after kidney transplantation. It occurs when net endogenous acid production exceeds net acid excretion. While nephron loss with reduced ammoniagenesis is the main cause of acid retention in non-transplant CKD patients, additional pathophysiological mechanisms are likely inflicted in kidney transplant recipients. Functional tubular damage by calcineurin inhibitors seems to play a key role causing renal tubular acidosis. Notably, experimental and clinical studies over the past decades have provided evidence that metabolic acidosis may not only be a consequence of CKD but also a driver of disease. In metabolic acidosis, activation of hormonal systems and the complement system resulting in fibrosis have been described. Further studies of changes in renal metabolism will likely contribute to a deeper understanding of the pathophysiology of metabolic acidosis in CKD. While alkali supplementation in case of reduced serum bicarbonate < 22 mmol/l has been endorsed by CKD guidelines for many years to slow renal functional decline, among other considerations, beneficial effects and thresholds for treatment have lately been under intense debate. This review article discusses this topic in light of the most recent results of trials assessing the efficacy of dietary and pharmacological interventions in CKD and kidney transplant patients.

Temperature-Dependent, Site-Specific Rate Coefficients for the Reaction of OH (OD) with Methyl Formate Isotopologues via Experimental and Theoretical Studies.

Methyl esters are an important component of combustion and atmospheric systems. Reaction with the OH radical plays an important role in the removal of the simplest methyl ester, methyl formate (MF, CH3OCHO). In this paper, the overall rate coefficients for the reactions of OH and OD with MF isotopologues, studied under pseudo-first-order conditions, are reported using two different laser flash photolysis systems with the decay of OH monitored by laser-induced fluorescence. The room-temperature rate coefficient for OH + MF, (1.95 ± 0.34) × 10-13 cm3 molecule-1 s-1, is in good agreement with the literature. The rate coefficient exhibits curved Arrhenius behavior, and our results bridge the gap between previous low-temperature and shock tube studies. In combination with the literature, the rate coefficient for the reaction of OH with MF between 230 and 1400 K can be parametrized as kOH+MF = (3.2 × 10-13) × (T/300 K)2.3 × exp(-141.4 K/T) cm3 molecule-1 s-1 with an overall estimated uncertainty of ∼30%. The reactions of OD with MF isotopologues show a small enhancement (inverse secondary isotope effect) compared to the respective OH reactions. The reaction of OH/OD with MF shows a normal primary isotope effect, a decrease in the rate coefficient when MF is partially or fully deuterated. Experimental studies have been supported by ab initio calculations at the CCSD(T)-F12/aug-cc-pVTZ//M06-2X/6-31+G** level of theory. The calculated, zero-point-corrected, barrier heights for abstraction at the methyl and formate sites are 1.3 and 6.0 kJ mol-1, respectively, and the ab initio predictions of kinetic isotope effects are in agreement with experiment. Fitting the experimental isotopologue data refines these barriers to 0.9 ± 0.6 and 4.1 ± 0.9 kJ mol-1. The branching ratio is approximately 50:50 at 300 K. Between 300 and 500 K, abstraction via the higher-energy, higher-entropy formate transition state becomes more favored (60:40). However, experiment and calculations suggest that as the temperature increases further, with higher energy, less constrained conformers of the methyl transition state become more significant. The implications of the experimental and theoretical results for the mechanisms of MF atmospheric oxidation and low-temperature combustion are discussed.

Determinants of survival in patients on extracorporeal membrane oxygenation therapy due to severe covid-19.

BACKGROUND: Severe acute respiratory distress syndrome (ARDS) due to Coronavirus Disease-19 (COVID-19) is associated with high mortality. Although survival on mechanical circulatory support has improved, determinants for better prognosis are still unclear. Here, we report on the outcome of our patient population with the need for mechanical circulatory support due to severe COVID-19 (sCOVID-19) induced ARDS. METHODS: All patients treated with extracorporeal membrane oxygenation (ECMO) for severe ARDS due to sCOVID-19 were analysed. Patients > 18 years of age at the time of initiation of ECMO were included. Pre-existing comorbidities, complications during ECMO implantation, and ECMO runtime were reviewed. The latency to intubation, proning, tracheotomy, and ECMO implantation was analysed. Furthermore, the survival and non-survival population were compared to determine factors in favour of a better outcome. RESULTS: In total, 85 patients were treated with veno-venous membrane oxygenation (vv-ECMO) for severe ARDS in our medical centre. The patient population was predominantly male (83.5%) with a mean patient age of 54.9 years. A history of cardiovascular disease (p = .01), smoking (p < .05), need for vasopressor- (p < .05), and renal replacement therapy (p < .001) was associated with a worse prognosis. Overall survival was 50%. The survival population was significantly younger (p = .004), had a significantly higher body weight (p = .02) and body mass index (BMI) (p = .01). Furthermore, survival was significantly better when vv-ECMO was initiated within 48 h after admission (p < .001). CONCLUSIONS: Pre-existing cardiovascular disease, higher age, history of nicotine abuse, and development of renal failure are associated with poor outcome. Early start of vv-ECMO therapy may lead to better survival in sCOVID-19 patients, although complications during ECMO therapy are associated with a worse prognosis.

Relevance of deceased donor proteinuria for kidney transplantation: A comprehensive national cohort study.

PURPOSE: Proteinuria is frequent in patients with nephropathies and associated with progressive kidney disease and risk for end stage kidney disease. However, the relevance of deceased donor proteinuria on transplant outcome remains uncertain. In this nationwide cohort study, we evaluated the prevalence of proteinuria in deceased donor candidates and measured the impact on outcome after kidney transplantation. METHODS: Data from the Swiss Organ Allocation System and the Swiss Transplant Cohort Study were analyzed, comprising 1725 donors and 1516 recipients transplanted between 2008 and 2019. We correlated urine findings with donor characteristics and quantified the impact of proteinuria on allograft function at 12 months and survival. RESULTS: Proteinuria influenced allocation decisions in 4.5% of nonimmunological organ declines and was the leading cause for decline in 0.2% of cases. 74.1%, 51.4%, and 35.3% of donor candidates had a baseline proteinuria above 15, 30, and 50 mg protein/mmol urine creatinine, respectively. Proteinuria above 30 mg/mmol was associated with female donor sex, mechanical resuscitation, acute kidney injury, and time delay between ICU entry and urine sampling. Donor proteinuria was not associated with patient or allograft survival, nor allograft function at 12 months. CONCLUSION: We report a high prevalence of proteinuria in donor candidates, without evidence of a deleterious impact of proteinuria on graft function and/or survival. Therefore, low-level proteinuria should not be considered a limiting contraindication for kidney allocation in deceased donor transplant.

Key characteristics impacting survival of COVID-19 extracorporeal membrane oxygenation.

BACKGROUND: Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. METHODS: 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. RESULTS: Most patients were between 50 and 70 years of age. PaO2/FiO2 ratio prior to ECMO was 72 mmHg (IQR: 58-99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41-0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28-1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. CONCLUSIONS: Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival. TRIAL REGISTRATION: Registered in the German Clinical Trials Register (study ID: DRKS00022964, retrospectively registered, September 7th 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022964 .

Different Acute Kidney Injury Patterns after Renal Ischemia Reperfusion Injury and Extracorporeal Membrane Oxygenation in Mice.

The use of extracorporeal membrane oxygenation (ECMO) is associated with acute kidney injury (AKI) in thoracic organ transplantation. However, multiple other factors contribute to AKI development after these procedures such as renal ischemia-reperfusion injury (IRI) due to hypo-perfusion of the kidney during surgery. In this study, we aimed to explore the kidney injury patterns in mouse models of ECMO and renal IRI. Kidneys of C57BL/6 mice were examined after moderate (35 min) and severe (45 min) unilateral transient renal pedicle clamping and 2 h of veno-venous ECMO. Renal injury markers, neutrophil infiltration, tubular transport function, pro-inflammatory cytokines, and renal heme oxygenase-1 (HO-1) expression were determined by immunofluorescence and qPCR. Both procedures caused AKI, but with different injury patterns. Severe neutrophil infiltration of the kidney was evident after renal IRI, but not following ECMO. Tubular transport function was severely impaired after renal IRI, but preserved in the ECMO group. Both procedures caused upregulation of pro-inflammatory cytokines in the renal tissue, but with different time kinetics. After ECMO, but not IRI, HO-1 was strongly induced in tubular cells indicating contact with hemolysis-derived proteins. After IRI, HO-1 was expressed on infiltrating myeloid cells in the tubulo-interstitial space. In conclusion, renal IRI and ECMO both caused AKI, but kidney damage after renal IRI was more pronounced including severe neutrophil infiltration and tubular transport impairment. Enhanced HO-1 expression in tubular cells after ECMO encourages limitation of hemolysis as a therapeutic approach to reduce ECMO-associated AKI.

Outcome of kidney transplantation from very senior donors in Switzerland - a national cohort study.

Kidney transplantation from older and marginal donors is effective to confront organ shortage. However, limitations after transplantation of kidneys from very marginal kidney donors remain unclear. We compared patient and graft outcome, achieved allograft function and quality of life of renal transplantations from Very Senior Donors (VSD, defined as donors aged 70 years and older) with Senior Donors (SD, aged 60-70 years) and Regular Donors (RD, aged younger than 60 years) in Switzerland. We evaluated the outcome of 1554 adult recipients of deceased donor kidney transplantations from 05/2008 to 12/2019; median follow-up was 4.7 years. Failure-free survival (freedom from graft loss or death), glomerular filtration rate (eGFR), and quality of life at 12 months were analyzed for RD (reference group, n = 940), SD (n = 404), and VSD (n = 210). Failure-free survival decreased with increasing donor age, mainly attributable to premature graft loss. Still, overall 5-year failure-free survival reached 83.1%, 81.0%, and 64.0% in the RD, SD, and VSD subgroups, respectively. eGFR 12 months post-transplantation was significantly higher in RD compared with SD and VSD. The acceptance rate of donor candidates for kidney TPL was 78% for the entire cohort (87% for RD, 79% for SD, and 56% for VSD). Deceased donor kidney transplantation from donors aged 70 years or older is associated with an inferior, yet acceptable failure-free outcome, with sustained quality of life.

Impact of unilateral diaphragm elevation on postoperative outcomes in bilateral lung transplantation - a retrospective single-center study.

This study evaluated the impact of unilateral diaphragm elevation following bilateral lung transplantation on postoperative course. Patient data for all lung transplantations performed at our institution between 01/2010 and 12/2019 were reviewed. Presence of right or left diaphragm elevation was retrospectively evaluated using serial chest X-rays performed while patients were standing and breathing spontaneously. Right elevation was defined by a > 40 mm difference between right and left diaphragmatic height. Left elevation was present if the left diaphragm was at the same height or higher than the right diaphragm. In total, 1093/1213 (90%) lung transplant recipients were included. Of these, 255 (23%) patients exhibited radiologic evidence of diaphragm elevation (right, 55%; left 45%; permanent, 62%). Postoperative course did not differ between groups. Forced expiratory volume in 1 second, forced vital capacity and total lung capacity were lower at 1-year follow-up in patients with permanent than in patients with transient or absent diaphragmatic elevation (P = 0.038, P < 0.001, P = 0.002, respectively). Graft survival did not differ between these groups (P = 0.597). Radiologic evidence of diaphragm elevation was found in 23% of our lung transplant recipients. While lung function tests were worse in patients with permanent elevation, diaphragm elevation did not have any relevant impact on outcomes.

Comparison of anticoagulation strategies for veno-venous ECMO support in acute respiratory failure.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) support in acute respiratory failure may be lifesaving, but bleeding and thromboembolic complications are common. The optimal anticoagulation strategy balancing these factors remains to be determined. This retrospective study compared two institutional anticoagulation management strategies focussing on oxygenator changes and both bleeding and thromboembolic events. METHODS: We conducted a retrospective observational cohort study between 04/2015 and 02/2020 in two ECMO referral centres in Germany in patients receiving veno-venous (VV)-ECMO support for acute respiratory failure for > 24 h. One centre routinely applied low-dose heparinization aiming for a partial thromboplastin time (PTT) of 35-40 s and the other routinely used a high-dose therapeutic heparinization strategy aiming for an activated clotting time (ACT) of 140-180 s. We assessed number of and time to ECMO oxygenator changes, 15-day freedom from oxygenator change, major bleeding events, thromboembolic events, 30-day ICU mortality, activated clotting time and partial thromboplastin time and administration of blood products. Primary outcome was the occurrence of oxygenator changes depending on heparinization strategy; main secondary outcomes were the occurrence of severe bleeding events and occurrence of thromboembolic events. The transfusion strategy was more liberal in the low-dose centre. RESULTS: Of 375 screened patients receiving VV-ECMO support, 218 were included in the analysis (117 high-dose group; 101 low-dose group). Disease severity measured by SAPS II score was 46 (IQR 36-57) versus 47 (IQR 37-55) and ECMO runtime was 8 (IQR 5-12) versus 11 (IQR 7-17) days (P = 0.003). There were 14 oxygenator changes in the high-dose group versus 48 in the low-dose group. Freedom from oxygenator change at 15 days was 73% versus 55% (adjusted HR 3.34 [95% confidence interval 1.2-9.4]; P = 0.023). Severe bleeding events occurred in 23 (19.7%) versus 14 (13.9%) patients (P = 0.256) and thromboembolic events occurred in 8 (6.8%) versus 19 (19%) patients (P = 0.007). Mortality at 30 days was 33.3% versus 30.7% (P = 0.11). CONCLUSIONS: In this retrospective study, ECMO management with high-dose heparinization was associated with lower rates of oxygenator changes and thromboembolic events when compared to a low-dose heparinization strategy. Prospective, randomized trials are needed to determine the optimal anticoagulation strategy in patients receiving ECMO support.

Improvement of renal function after transcatheter aortic valve replacement and its impact on survival.

BACKGROUND: Chronic kidney disease as well as acute kidney injury are associated with adverse outcomes after transcatheter aortic valve replacement (TAVR). However, little is known about the prognostic implications of an improvement in renal function after TAVR. METHODS: Renal improvement (RI) was defined as a decrease in postprocedural creatinine in µmol/l of ≥1% compared to its preprocedural baseline value. A propensity score representing the likelihood of RI was calculated to define patient groups which were comparable regarding potential confounders (age, sex, BMI, NYHA classification, STS score, log. EuroSCORE, history of atrial fibrillation/atrial flutter, pulmonary disease, previous stroke, CRP, creatinine, hsTNT and NT-proBNP). The cohort was stratified into 5 quintiles according to this propensity score and the survival time after TAVR was compared within each subgroup. RESULTS: Patients in quintile 5 (n = 93) had the highest likelihood for RI. They were characterized by higher creatinine, lower eGFR, higher NYHA class, higher NT-proBNP, being mostly female and having shorter overall survival time. Within quintile 5, patients without RI had significantly shorter survival compared to patients with RI (p = 0.002, HR = 0.32, 95% CI = [0.15-0.69]). There was no survival time difference between patients with and without RI in the whole cohort (p = 0.12) and in quintiles 1 to 4 (all p > 0.16). Analyses of specific subgroups showed that among patients with NYHA class IV, those with RI also had a significant survival time benefit (p < 0.001, HR = 0.15; 95%-CI = [0.05-0.44]) compared to patients without RI. CONCLUSIONS: We here describe a propensity score-derived specific subgroup of patients in which RI after TAVR correlated with a significant survival benefit.

Periprocedural safety and outcome after pump implantation for intravenous treprostinil administration in patients with pulmonary arterial hypertension.

METHODS: In this retrospective observational study, we analyzed all patients with pulmonary arterial hypertension undergoing LenusPro® pump implantation between November 2013 and October 2019 at our center. Periprocedural safety was assessed by describing all complications that occurred within 28 days after surgery; complications that occurred later were described to assess long-term safety. Clinical outcomes were measured by comparison of clinical parameters and echocardiographic measurements of right ventricular function from baseline to 6-months-follow-up. RESULTS: Fifty-four patients underwent LenusPro® pump implantation for intravenous treprostinil treatment during the investigation period. Periprocedural complications occurred in 5 patients; the only anesthesia-related complication (right heart failure with recovery after prolonged intensive care and death in the further course) occurred in the only patient who underwent general anesthesia. All other patients underwent local anesthesia with or without short-acting (analgo-) sedation. Eighteen long-term complications occurred in 15 patients, most notably pump pocket or catheter related problems. Transplant-free survival rates at 1, 2, and 3 years were 77 %, 56 %, and 48 %, respectively. CONCLUSIONS: Subcutaneous pump implantation under local anesthesia and conscious analgosedation while avoiding intubation and mechanical ventilation is feasible in patients with advanced PAH. Controlled studies are needed to determine the safest anesthetic approach for this procedure. BACKGROUND/OBJECTIVES: Intravenous treprostinil treatment via a fully implantable pump is a treatment option for patients with advanced pulmonary arterial hypertension. However, there is no consensus on the preferred anesthetic approach for the implantation procedure. Primary objective was to assess periprocedural safety with particular attention to feasibility of local anesthesia and conscious analgosedation instead of general anesthesia. Long-term safety and clinical outcomes were secondary endpoints.

Mechanical circulatory support in refractory cardiogenic shock due to influenza virus-related myocarditis.

BACKGROUND: There is scarce evidence for mechanical circulatory support (MCS) in patients with influenza-related myocarditis complicated by refractory cardiogenic shock (rCS). We sought to investigate the impact of MCS using combined veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and micro-axial flow pumps (the ECMELLA concept) in influenza-related myocarditis complicated by rCS. METHODS: This is a prospective, observational analysis from the single centre HAnnover Cardiac Unloading REgistry (HACURE) from two recent epidemic influenza seasons. We analysed patients with verified influenza-associated myocarditis complicated by rCS who were admitted to our intensive care unit (ICU) on MCS. Subsequently, we performed a propensity score (PS) matched analysis to patients with acute myocardial infarction (AMI) complicated by rCS and non-ischaemic cardiomyopathy (DCM) related rCS. RESULTS: We describe a series of seven patients with rCS-complicated influenza-related myocarditis (mean age 56±10 years, 58% male, influenza A (n=2)/influenza B (n=5)). No patient had been vaccinated prior to the influenza season. MCS was provided using combined VA-ECMO and Impella micro-axial flow pump. In two patients with out-of-hospital cardiac arrest, VA-ECMO had been implanted for extracorporeal cardiopulmonary resuscitation. All patients died within 18 days of hospital admission. By PS-based comparison to patients with AMI- or DCM-related rCS and combined MCS, 30-day mortality was significantly higher in influenza-related rCS. CONCLUSION: Despite initial stabilisation with combined MCS in patients with rCS-complicated influenza-related myocarditis, the detrimental course of shock could not be stopped and all patients died. Influenza virus infection potentially critically affects other organs besides the heart, leading to irreversible end-organ damage that MCS cannot compensate for and, therefore, results in a devastating outcome.

Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension.

Intensive care of patients with pulmonary hypertension (PH) and right-sided heart failure includes treatment of factors causing or contributing to heart failure, careful fluid management, and strategies to reduce ventricular afterload and improve cardiac function. Extracorporeal membrane oxygenation (ECMO) should be considered in distinct situations, especially in candidates for lung transplantation (bridge to transplant) or, occasionally, in patients with a reversible cause of right-sided heart failure (bridge to recovery). ECMO should not be used in patients with end-stage disease without a realistic chance for recovery or for transplantation. For patients with refractory disease, lung transplantation remains an important treatment option. Patients should be referred to a transplant centre when they remain in an intermediate- or high-risk category despite receiving optimised pulmonary arterial hypertension therapy. Meticulous peri-operative management including the intra-operative and post-operative use of ECMO effectively prevents graft failure. In experienced centres, the 1-year survival rates after lung transplantation for PH now exceed 90%.

Group body psychotherapy for the treatment of somatoform disorder - a partly randomised-controlled feasibility pilot study.

BACKGROUND: Clinical outcomes for patients with heterogeneous somatoform disorder (bodily distress disorder, including medically unexplained symptoms) are suboptimal, new treatments are required to improve acceptance. Body-oriented psychological therapy approaches have been identified as potentially beneficial additions to the portfolio of treatments. This study was aiming to assess the acceptability, the potential benefits, and associated change processes of manualised group body psychotherapy (BPT) for outpatients with Somatoform Disorder. METHODS: A randomized controlled feasibility trial was carried out with follow-up at 6 months after baseline assessments using the Primary Health Questionnaire (PHQ), Somatic Symptom Screening Scale (SOMS-7), quality of life ratings (Short-Form Health Survey-36; SF-36) and body image measures (Dresden Body Image Questionnaire). Acceptance was assessed with the Helping Alliance Scale (HAS). RESULTS: A total of 24 patients were recruited to participate. Sixteen patients were randomly assigned to receive either manualised BPT or TAU, eight patients were directly assigned to BPT. Drop-out rates were acceptable, patients reported to be highly satisfied with the group intervention. Somatic symptom levels reduced significantly in the BPT group. Additionally, a significant effect on self-acceptance and the mental component of quality of life was observed. CONCLUSION: Group body psychotherapy is a feasible and acceptable treatment for patients with somatoform disorder and a larger trial studying the effectiveness of BPT in these patients should be conducted. TRIAL REGISTRATION: Retrospectively registered SRCTN12277345 ; Trial Registraton Date: 27/03/2019.

Wearable Cardioverter-Defibrillators following Cardiac Surgery-A Single-Center Experience.

BACKGROUND: A wearable cardioverter-defibrillator (WCD) can terminate ventricular fibrillation and ventricular tachycardias via electrical shock and thus give transient protection from sudden cardiac death. We investigated its role after cardiac surgery. METHODS: We retrospectively analyzed all patients who were discharged with a WCD from cardiac surgery department. The WCD was prescribed for patients with a left ventricular ejection fraction (LVEF) of ≤35% or an explanted implantable cardioverter-defibrillator (ICD). RESULTS: A total of 100 patients were included in this study, the majority (n = 59) had received coronary artery bypass graft surgery. The median wearing time of a WCD patient was 23.5 hours per day. LVEF was 28.9 ± 8% after surgery and improved in the follow-up to 36.7 ± 11% (p < 0.001). Three patients were successfully defibrillated. Ten patients experienced ventricular tachycardias. No inappropriate shocks were given. An ICD was implanted in 25 patients after the WCD wearing period. CONCLUSION: Ventricular arrhythmias occurred in 13% of the investigated patients. LVEF improved significantly after 3 months, and thus a permanent ICD implantation was avoided in several cases. Sternotomy did not impair wearing time of the WCD. A WCD can effectively protect patients against ventricular tachyarrhythmias after cardiac surgery.

Minimally Invasive Surgery in Mitral Valve Endocarditis.

BACKGROUND: To minimize the surgical damage, minimally invasive mitral valve surgery (MIMVS) has become the therapy of choice. However, this approach is technically more challenging, especially in endocarditis. The data on MIMVS in endocarditis are scarce, we therefore retrospectively analyzed the result at our institute. METHODS: From January 2011 and July 2017, 420 MIMVS were performed, out of which 44 (10%) were for endocarditis. Mean age was 55 ± 17 years and 41% (n = 18) were male. RESULTS: Euroscore II was 7.3 (range: 2-38). Operation times, cardiopulmonary bypass times, and clamp times were 230 (±77), 158 (±56), and 84 (±39) minutes, respectively. Seven cases (16%) were cardiac redo operations. Mitral valve repair and replacement was performed in 46 (n = 20) and 54% (n = 24) of patients, respectively. Overall in-hospital mortality, apoplexy, and reoperation rates (all for bleeding) were 7 (n = 3), 0 (n = 0), and 11% (n = 5), respectively. New onset of dialysis was required in three patients (7%). No patient developed superficial wound infection. Overall intensive care unit and hospital stay was 3 (±3) and 24 (±32) days, respectively. CONCLUSION: MIMVS can be performed with acceptable outcome and low perioperative morbidity in patients with mitral valve endocarditis. Especially absence of any postoperative wound infections and low rate of endocarditis recurrence; use of MIMVS must be encouraged as an eligible approach in most cases.

The novel cardiac z-disc protein CEFIP regulates cardiomyocyte hypertrophy by modulating calcineurin signaling.

The z-disc is a structural component at the lateral borders of the sarcomere and is important for mechanical stability and contractility of both cardiac and skeletal muscles. Of note, the sarcomeric z-disc also represents a nodal point in cardiomyocyte function and signaling. Mutations of numerous z-disc proteins are associated with cardiomyopathies and muscle diseases. To identify additional z-disc proteins that might contribute to cardiac disease, we employed an in silico screen for cardiac-enriched cDNAs. This screen yielded a previously uncharacterized protein named cardiac-enriched FHL2-interacting protein (CEFIP), which exhibited a heart- and skeletal muscle-specific expression profile. Importantly, CEFIP was located at the z-disc and was up-regulated in several models of cardiomyopathy. We also found that CEFIP overexpression induced the fetal gene program and cardiomyocyte hypertrophy. Yeast two-hybrid screens revealed that CEFIP interacts with the calcineurin-binding protein four and a half LIM domains 2 (FHL2). Because FHL2 binds calcineurin, a phosphatase controlling hypertrophic signaling, we examined the effects of CEFIP on the calcineurin/nuclear factor of activated T-cell (NFAT) pathway. These experiments revealed that CEFIP overexpression further enhances calcineurin-dependent hypertrophic signal transduction, and its knockdown repressed hypertrophy and calcineurin/NFAT activity. In summary, we report on a previously uncharacterized protein CEFIP that modulates calcineurin/NFAT signaling in cardiomyocytes, a finding with possible implications for the pathogenesis of cardiomyopathy.

Simultaneous dual-isotope solid-state detector SPECT for improved tracking of white blood cells in suspected endocarditis.

Aims: High-energy resolution and sensitivity of novel cadmium-zinc-telluride (CZT) detector equipped SPECT systems facilitate simultaneous imaging of multiple isotopes and may enhance the detection of molecular/cellular signals. This may refine the detection of endocarditis. This study was designed to determine the feasibility and diagnostic accuracy of simultaneous imaging of inflammation with 111In-labeled white blood cells (WBCs) and myocardial perfusion with 99mTc-sestamibi, for localization of WBCs relative to the valve plane in suspected endocarditis. Methods and results: A dedicated cardiac CZT camera (Discovery 530c, GE Healthcare) was employed. Anthropomorphic thorax phantom studies were followed by clinical studies in 34 patients with suspected infection of native valves (n = 12) or implants (n = 22). Simultaneous 111In-WBC/99mTc perfusion imaging was performed, and compared with standard 111In-WBC planar scintigraphy and SPECT-CT. Phantom studies ruled out significant radioisotope crosstalk. Downscatter on 99mTc images was not observed for 111In activity as high as 2.5*99mTc activity. In patients, image quality was superior for CZT imaging vs. conventional SPECT-CT and planar scintigraphy (P < 0.01). Cadmium-zinc-telluride dual isotope imaging improved reader confidence for detection of inflammatory foci. Diagnostic accuracy based on surgery or Duke Criteria during follow-up was highest for CZT imaging (P < 0.001). Conclusion: Novel CZT SPECT technology improves the accuracy of molecular/cellular cardiac imaging. Simultaneous multi-isotope imaging with 111In and 99mTc is feasible and aids in the workup of suspected endocarditis.

Myozap Deficiency Promotes Adverse Cardiac Remodeling via Differential Regulation of Mitogen-activated Protein Kinase/Serum-response Factor and ß-Catenin/GSK-3ß Protein Signaling.

The intercalated disc (ID) is a "hot spot" for heart disease, as several ID proteins have been found mutated in cardiomyopathy. Myozap is a recent addition to the list of ID proteins and has been implicated in serum-response factor signaling. To elucidate the cardiac consequences of targeted deletion of myozap in vivo, we generated myozap-null mutant (Mzp(-/-)) mice. Although Mzp(-/-) mice did not exhibit a baseline phenotype, increased biomechanical stress due to pressure overload led to accelerated cardiac hypertrophy, accompanied by "super"-induction of fetal genes, including natriuretic peptides A and B (Nppa/Nppb). Moreover, Mzp(-/-) mice manifested a severe reduction of contractile function, signs of heart failure, and increased mortality. Expression of other ID proteins like N-cadherin, desmoplakin, connexin-43, and ZO-1 was significantly perturbed upon pressure overload, underscored by disorganization of the IDs in Mzp(-/-) mice. Exploration of the molecular causes of enhanced cardiac hypertrophy revealed significant activation of ß-catenin/GSK-3ß signaling, whereas MAPK and MKL1/serum-response factor pathways were inhibited. In summary, myozap is required for proper adaptation to increased biomechanical stress. In broader terms, our data imply an essential function of the ID in cardiac remodeling beyond a mere structural role and emphasize the need for a better understanding of this molecular structure in the context of heart disease.