Clonal haematopoiesis in chronic ischaemic heart failure: prognostic role of clone size for DNMT3A- and TET2-driver gene mutations.

AIMS: Somatic mutations of the epigenetic regulators DNMT3A and TET2 causing clonal expansion of haematopoietic cells (clonal haematopoiesis; CH) were shown to be associated with poor prognosis in chronic ischaemic heart failure (CHF). The aim of our analysis was to define a threshold of variant allele frequency (VAF) for the prognostic significance of CH in CHF. METHODS AND RESULTS: We analysed bone marrow and peripheral blood-derived cells from 419 patients with CHF by error-corrected amplicon sequencing. Cut-off VAFs were optimized by maximizing sensitivity plus specificity from a time-dependent receiver operating characteristic (ROC) curve analysis from censored data. 56.2% of patients were carriers of a DNMT3A- (N = 173) or a TET2- (N = 113) mutation with a VAF >0.5%, with 59 patients harbouring mutations in both genes. Survival ROC analyses revealed an optimized cut-off value of 0.73% for TET2- and 1.15% for DNMT3A-CH-driver mutations. Five-year-mortality was 18% in patients without any detected DNMT3A- or TET2 mutation (VAF < 0.5%), 29% with only one DNMT3A- or TET2-CH-driver mutations above the respective cut-off level and 42% in patients harbouring both DNMT3A- and TET2-CH-driver mutations above the respective cut-off levels. In carriers of a DNMT3A mutation with VAF ≥ 1.15%, 5-year mortality was 31%, compared with 18% mortality in those with VAF < 1.15% (P = 0.048). Likewise, in patients with TET2 mutations, 5-year mortality was 32% with VAF ≥ 0.73%, compared with 19% mortality with VAF < 0.73% (P = 0.029). CONCLUSION: The present study defines novel threshold levels for clone size caused by acquired somatic mutations in the CH-driver genes DNMT3A and TET2 that are associated with worse outcome in patients with CHF.

Comparison of effectiveness and survival after the MitraClip or Carillon procedure for severe functional mitral regurgitation: a single-center retrospective analysis.

INTRODUCTION: Current studies suggest improved survival in patients with severe functional mitral regurgitation (FMR) treated successfully with the MitraClip (MC) compared to medical treatment alone, in addition to a significant reduction of FMR severity. Recently, the Carillon system (CS) has also been shown to significantly reduce FMR. However, whether this beneficial effect of CS also translates into a survival benefit comparable to the MC system has not been investigated so far. The aim of the study was to compare the course of FMR grade and mortality after MC or CS in a retrospective, non-randomized, single-center analysis. MATERIAL AND METHODS: A hundred and fifty-four patients with symptomatic FMR 2+ were included in this study (MC: n = 117, CS: n = 37). Baseline characteristics did not differ significantly between groups. RESULTS AND CONCLUSIONS: Initially, the degree of FMR was reduced in the MC group from 2.9 ±0.3 to 1.7 ±0.7 and from 2.7 ±0.5 to 2.1 ±0.7 in the CS group, p within and between groups < 0.01. Within 6 months, FMR remained reduced in the MC group (1.83 ±0.6) and CS group (2.1 ±0.7). One-year survival was 34.8% in the MC group and 54.8% in the CS group (p = 0.663). Median long-term survival was 1.66 years in the MC group and 3.92 years in the CS group, log rank p = 0.001.

Bone marrow and plasma FGF-23 in heart failure patients: novel insights into the heart-bone axis.

AIMS: Fibroblast growth factor 23 (FGF-23) is known to be elevated in patients with congestive heart failure (CHF). As FGF-23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF-23 in CHF remains unclear. It is also unclear if FGF-23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF-23 levels measured in bone marrow plasma (FGF-23-BM) and in peripheral blood (FGF-23-P) in CHF patients to gain further insights into the heart-bone axis of FGF-23 expression. We also investigated possible associations between FGF-23-BM as well as FGF-23-P and outcome in CHF patients. METHODS AND RESULTS: We determined FGF-23-P and FGF-23-BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF-23-BM and FGF-23-P with all-cause mortality in CHF patients, 32 events, median follow-up 1673 days, interquartile range [923, 1828]. FGF-23-P (median 60.3 vs. 22.0 RU/mL, P < 0.001) and FGF-23-BM (median 130.7 vs. 93.1 RU/mL, P < 0.001) levels were higher in CHF patients compared with healthy controls. FGF-23-BM levels were significantly higher than FGF-23-P levels in both CHF patients and in healthy controls (P < 0.001). FGF-23-P and FGF-23-BM correlated significantly with LVEF (r = -0.37 and r = -0.33, respectively), N terminal pro brain natriuretic peptide levels (r = 0.57 and r = 0.6, respectively), New York Heart Association status (r = 0.28 and r = 0.25, respectively), and estimated glomerular filtration rate (r = -0.43 and r = -0.41, respectively) (P for all <0.001) and were independently associated with all-cause mortality in CHF patients after adjustment for LVEF, estimated glomerular filtration rate, New York Heart Association status, and N terminal pro brain natriuretic peptide, hazard ratio 2.71 [confidence interval: 1.18-6.20], P = 0.018, and hazard ratio 2.80 [confidence interval: 1.19-6.57], P = 0.018, respectively. CONCLUSIONS: In CHF patients, FGF-23 is elevated in bone marrow plasma and is independently associated with heart failure severity and all-cause mortality. The failing heart seems to interact via FGF-23 within a heart-bone axis.

Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure.

Importance: Somatic mutations causing clonal expansion of hematopoietic cells (clonal hematopoiesis of indeterminate potential [CHIP]) are increased with age and associated with atherosclerosis and inflammation. Age and inflammation are the major risk factors for heart failure, yet the association of CHIP with heart failure in humans is unknown. Objective: To assess the potential prognostic significance of CHIP in patients with chronic heart failure (CHF) owing to ischemic origin. Design, Setting, and Participants: We analyzed bone marrow-derived mononuclear cells from 200 patients with CHF by deep targeted amplicon sequencing to detect the presence of CHIP and associated such with long-term prognosis in patients with CHF at University Hospital Frankfurt, Frankfurt, Germany. Data were analyzed between October 2017 and April 2018. Results: Median age of the patients was 65 years. Forty-seven mutations with a variant allele fraction (VAF) of at least 0.02 were found in 38 of 200 patients with CHF (18.5%). The somatic mutations most commonly occurred in the genes DNMT3A (14 patients), TET2 (9 patients), KDM6A (4 patients), and BCOR (3 patients). Patients with CHIP were older and more frequently had a history of hypertension. During a median follow-up of 4.4 years, a total of 53 patients died, and 23 patients required hospitalization for heart failure. There was a significantly worse long-term clinical outcome for patients with either DNMT3A or TET2 mutations compared with non-CHIP carriers. By multivariable Cox proportional regression analysis, the presence of somatic mutations within TET2 or DNMT3A (HR, 2.1; 95% CI, 1.1-4.0; P = .02, for death combined with heart failure hospitalization) and age (HR, 1.04; 95% CI, 1.01-1.07 per year; P = .005) but not a history of hypertension remained independently associated with adverse outcome. Importantly, there was a significant dose-response association between VAF and clinical outcome. Conclusions and Relevance: Our data suggest that somatic mutations in hematopoietic cells, specifically in the most commonly mutated CHIP driver genes TET2 and DNMT3A, may be significantly associated with the progression and poor prognosis of CHF. Future studies will have to validate our findings in larger cohorts and address whether targeting specific inflammatory pathways may be valuable for precision medicine in patients with CHF carrying specific mutations encoding for CHIP.

Use of Antiplatelet Agents Is Inversely Associated With Liver Fibrosis in Patients With Cardiovascular Disease.

Platelets participate in the development of liver fibrosis in animal models, but little is known about the benefit of antiplatelet agents in preventing liver fibrosis in humans. We therefore explored the relationship between the use of antiplatelet agents and liver fibrosis in a prospective cohort study of patients at high risk of liver fibrosis and cardiovascular events. Consecutive patients undergoing elective coronary angiography at the University Hospital Frankfurt were prospectively included in the present study. Associations between use of antiplatelet agents (acetyl salicylic acid, P2Y12 receptor antagonists) and liver fibrosis were assessed in regression models, and the relationship between platelet-derived growth factor beta (PDGF-ß) serum concentration, platelets, liver fibrosis, and use of antiplatelet agents was characterized. Out of 505 included patients, 337 (67%) received antiplatelet agents and 134 (27%) had liver fibrosis defined as a FibroScan transient elastography (TE) value ≥7.9 kPa. Use of antiplatelet agents was inversely associated with the presence of liver fibrosis in univariate and multivariate analyses (multivariate odds ratio [OR], 0.67; 95% confidence interval [CI], 0.51-0.89; P = 0.006). Use of antiplatelet agents was also inversely associated with FibroTest values (beta, -0.38; SD beta, 0.15; P = 0.02). Furthermore, there was a significant correlation between platelet counts and PDGF-ß serum concentration (rho, 0.33; P < 0.0001), but PDGF-ß serum levels were not affected by antiplatelet agents. Conclusion: There is a protective association between the use of antiplatelet agents and occurrence of liver fibrosis. A randomized controlled trial is needed to explore causality and the potential of antiplatelet agents as antifibrotic therapy in patients at risk for liver fibrosis progression.

Patatin-like phospholipase domain containing 3 variants differentially impact metabolic traits in individuals at high risk for cardiovascular events.

Single nucleotide polymorphism (SNP) rs738409 C>G in the patatin-like phospholipase domain containing 3 (PNPLA3) gene results in an amino acid exchange from isoleucin to methionine at position I148M of PNPLA3. The expression of this loss-of-function mutation leads to impaired hepatocellular triglyceride hydrolysis and is associated with the development of liver steatosis, fibrosis, and hepatocellular carcinoma. In contrast to these well-established associations, the relationship of the PNPLA3 rs738409 variant with other metabolic traits is incompletely understood. We therefore assessed the association of the PNPLA3 rs738409 genotype with relevant metabolic traits in a prospective study of patients at high risk for cardiovascular events, i.e., patients undergoing coronary angiography. In a total of 270 patients, known associations of the PNPLA3 rs738409 GG genotype with nonalcoholic steatohepatitis and liver fibrosis were confirmed. In addition, we found an association of the PNPLA3 rs738409 G allele with the presence of diabetes (22% versus 28% versus 58% for CC versus CG versus GG genotype, respectively; P = 0.02). In contrast to its association with nonalcoholic fatty liver disease, liver fibrosis, and diabetes, the minor G allele of PNPLA3 rs738409 was inversely associated with total serum cholesterol and low-density lipoprotein serum levels (P = 0.003 and P = 0.02, respectively). Finally, there was a trend toward an inverse association between the presence of the PNPLA3 rs738409 G allele and significant coronary heart disease. Comparable trends were observed for the transmembrane 6 superfamily member 2 (TM6SF2) 167 K variant, but the sample size was too small to evaluate this rarer variant. Conclusion: The PNPLA3 rs738409 G allele is associated with liver disease but also with a relatively benign cardiovascular risk profile. (Hepatology Communications 2018;2:798-806).

Severity of coronary artery disease is associated with non-alcoholic fatty liver dis-ease: A single-blinded prospective mono-center study.

BACKGROUND AND AIMS: Liver steatosis has shown to be associated with coronary artery disease (CAD). The aim of our study was to evaluate the association between the presence and severity of CAD and Non-alcoholic fatty liver disease (NAFLD) assessed by transient elastography (TE) and controlled attenuation parameter (CAP). METHODS: 576 Patients undergoing coronary angiography were enrolled in this prospective study, receiving at least 10 TE and CAP measurements using the FibroScan® M-probe. Clinically relevant CAD (CAD 3) was defined as stenosis with ≥75% reduction of the luminal diameter. NAFLD was determined by CAP ≥234 dB/m. NAFLD with advanced fibrosiswas determined by TE-values ≥7.9kPa in the presence of NAFLD and absence of congestive or right-sided heart failure. Rates and 95% confidence intervals are shown. RESULTS: 505 patients were available for analysis of NAFLD. However, only 392 patients were available for analysis of NAFLD with advanced fibrosis, since 24 patients had to be excluded due to non valid TE-measurements and 89 patients due to congestive or right-sided heart failure or suspected concomitant liver disease, respectively. 70.5% (66.3%-74.4%) of patients had CAD 3, 71.5% (67.3%-75.4%) were diagnosed with NAFLD, and 11.2% (8.3%-14.8%) with NAFLD with advanced fibrosis. Patients with CAD 3 had higher median CAP-values (273±61 vs. 260±66 dB/m; p = 0.038) and higher degrees of steatosis as compared to patients without CAD 3. While NAFLD was significantly more often diagnosed in patients with CAD 3 (75.0% vs. 63.1%, p = 0.0068), no significant difference was found for NAFLD with advanced fibrosis (10.7% vs. 12.5%, p = 0.60). CONCLUSIONS: Clinically relevant CAD is frequently associated with the presence of NAFLD, but not NAFLD with advanced fibrosis.

Minute Myocardial Injury as Measured by High-Sensitive Troponin T Serum Levels Predicts the Response to Intracoronary Infusion of Bone Marrow-Derived Mononuclear Cells in Patients With Stable Chronic Post-Infarction Heart Failure: Insights From the TOPCARE-CHD Registry.

RATIONALE: Cell-based therapies are a promising option in patients with chronic postinfarction heart failure (ischemic cardiomyopathy [ICM]). However, the responses after intracoronary infusion of autologous bone marrow-derived mononuclear cells (BMCs) are heterogeneous, which may be related to impaired cell retention in patients with ICM. Ischemic injury is associated with upregulation of prototypical chemoattractant cytokines mediating retention and homing of circulating cells. The development of ultrasensitive tests to measure high-sensitive troponin T (hs-TnT) serum levels revealed the presence of ongoing minute myocardial injury even in patients with stable ICM. OBJECTIVE: To test the hypothesis that serum levels of hs-TnT correlate with cell retention and determine the response to intracoronary BMC application in patients with ICM. METHODS AND RESULTS: About 157 patients with stable ICM and no substantial impairment of kidney function received intracoronary BMC administration. Immediately prior to cell application, hs-TnT levels to measure myocardial injury and NT-proBNP levels as marker of left ventricular wall stress were determined. Patients with elevated hs-TnT were older and had more severe heart failure. Importantly, only patients with elevated baseline hs-TnT≥15.19 pg/mL (upper tertile) demonstrated a significant (P=0.04) reduction in NT-proBNP serum levels (-250 [-1465; 33] pg/mL; relative reduction -24%) 4 months after BMC administration, whereas NT-proBNP levels remained unchanged in patients in the 2 lower hs-TnT tertiles. The absolute decrease in NT-proBNP at 4 months was inversely correlated with baseline hs-TnT (r=-0.27, P=0.001). Finally, retention of intracoronarily infused, 111Indium-labeled cells within the heart was closely associated with hs-TnT levels in patients with chronic ischemic heart failure (P=0.0008, n=10, triple measurements). CONCLUSIONS: The extent of ongoing myocardial injury as measured by serum levels of hs-TnT predicts the reduction of NT-proBNP serum levels at 4 months after intracoronary BMC administration in patients with ICM, suggesting that the beneficial effects of BMC application on LV remodeling and wall stress are confined to patients with ongoing minute myocardial injury. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00962364.

Elevated Serum Glial Fibrillary Acidic Protein (GFAP) is Associated with Poor Functional Outcome After Cardiopulmonary Resuscitation.

BACKGROUND: The neurological prognosis of patients after cardiopulmonary resuscitation (CPR) is difficult to assess. GFAP is an astrocytic intermediate filament protein released into bloodstream in case of cell death. We performed a prospective study aiming to compare the predictive potential of GFAP after resuscitation to the more widely used biomarker neuron-specific enolase (NSE). METHODS: One hundred patients were included at 48 h (tolerance interval ±12 h) after cardiac arrest. A serum sample was collected immediately after study inclusion. We determined serum levels of GFAP and NSE by means of immunoassays. Primary outcome was the modified Glasgow outcome scale at 4 weeks. Values below four were considered as a poor functional outcome. RESULTS: Median GFAP levels in poor outcome (n = 61) and good outcome (n = 39) patients were 0.03 µg/L (interquartile range 0.01-0.07 µg/L) and 0.02 µg/L (0.01-0.03 µg/L; p = 0.014), respectively. GFAP revealed a sensitivity of 60.7% and a specificity of 66.7% to predict a poor functional outcome. All patients having a GFAP level >0.08 µg/L had a poor functional outcome. For NSE, sensitivity was 44.3% and specificity was 100.0% for predicting a poor outcome. Multivariate regression analysis revealed GFAP, NSE, and the Karnofsky index to be independent predictors of outcome. CONCLUSIONS: The release patterns of GFAP and NSE after CPR show differences. GFAP levels above 0.08 µg/L were associated with a poor outcome in all cases, and patients with strongly elevated values (>3 µg/L) consistently had severe brain damage on brain imaging. Both biomarkers independently contribute to outcome prediction after CPR.

Safety of transient elastography in patients with implanted cardiac rhythm devices.

BACKGROUND: At present the use of transient elastography (TE) in patients with pacemaker (PM) or implantable cardioverter defibrillator (ICD) devices is not recommended, since the safety due to the electromagnet embarked in the vibrator for producing the shearwave has not been evaluated. However, no adverse events of sonographic examinations in this patient group have been reported. AIMS: The aim of the present study was to evaluate the safety of TE in patients with PM or ICD. METHODS: In a prospective study we evaluated safety and function of such devices during TE. In 17 patients with PM and 17 patients with ICD, the function of the device was checked prior to and after TE examination. RESULTS: In none of the 34 patients changes in stimulation thresholds, electrode impedance and sensing were detected. CONCLUSION: Our findings support the assumption that the potential harm of TE in patients with PM and ICD is rare.

A Decade of Transapical Aortic Valve Implantation.

BACKGROUND: Transcatheter-based aortic valve procedures have undergone tremendous evolution during the past decade and have led to great changes in the treatment of valvular heart disease. The Hospital of the Johann Wolfgang Goethe University, Frankfurt am Main, Germany is one of the three pioneering centers that started performing transapical transcatheter aortic valve implantation (TA-TAVI) back in 2005, and this study reviews the 10-year institutional experience with this approach. METHODS: From January 2005 through January 2015, 312 consecutive high-risk patients underwent TA-TAVI. Echocardiographic follow-up at discharge, at 6 and 12 months, and yearly thereafter was 100% complete. Structural behavior of the balloon-expandable valves in 11 patients with a mean follow-up time beyond 8 years was additionally evaluated at latest follow-up using computed tomography measurements. RESULTS: The age of the patients in this study was 79.8 ± 5.8 years, and the mean logistic EuroSCORE II and The Society of Thoracic Surgeons score were 23.9% ± 17.2% and 9.8% ± 8.6%, respectively. Perioperative, 30-day, and in-hospital mortality rates were 1.3%, 8.2%, and 9.5%, respectively, with a decrease in 30-day mortality to 4.2% in 2014. The incidence of neurologic complications was 3.2%. Mean length of hospital stay was 8.7 ± 4.3 days. Echocardiographic results demonstrated a significant and persistent increase of effective aortic valve orifice area (preoperative: 0.69 ± 0.1 cm(2) vs. late-follow-up: 1.52 ± 0.2 cm(2); p = 0.04) and a decrease in mean transvalvular gradient (preoperative: 49.5 ± 8.2 mm Hg vs. late-follow-up: 13.8 ± 4.3 mm Hg; p = 0.03) after a mean follow-up time of 4.1 ± 2.3 years. Overall survival rates were 73% ± 2% and 56% ± 6% at 3 and 5 years, respectively. Computed tomography measurements have not shown any signs of stress fracture of balloon-expandable stents up to 8 years of follow-up. CONCLUSIONS: A decade after clinical introduction of TA-TAVI, procedural and technical advances have made it an established alternative to classic aortic valve replacement in high-risk patients with aortic valve stenosis. Despite limited worldwide data on hemodynamic and structural valve behavior beyond 8 years, 11 patients from our early experience who were followed up for 8 years in the current report did not have any signs of structural valve dysfunction.

Metabolism Regulates Cellular Functions of Bone Marrow-Derived Cells used for Cardiac Therapy.

Administration of bone marrow-derived mononuclear cells (BMC) may increase cardiac function after myocardial ischemia. However, the functional capacity of BMC derived from chronic heart failure (CHF) patients is significantly impaired. As modulation of the energy metabolism allows cells to match the divergent demands of the environment, we examined the regulation of energy metabolism in BMC from patients and healthy controls (HC). The glycolytic capacity of CHF-derived BMC is reduced compared to HC, whereas BMC of metabolically activated bone marrow after acute myocardial infarction reveal increased metabolism. The correlation of metabolic pathways with the functional activity of cells indicates an influence of metabolism on cell function. Reducing glycolysis without profoundly affecting ATP-production reversibly reduces invasion as well as colony forming capacity and abolishes proliferation of CD34(+) CD38(-) lin(-) hematopoietic stem and progenitor cells (HSPC). Ex vivo inhibition of glycolysis further reduced the pro-angiogenic activity of transplanted cells in a hind limb ischemia model in vivo. In contrast, inhibition of respiration, without affecting total ATP production, leads to a compensatory increase in glycolytic capacity correlating with increased colony forming capacity. Isolated CD34(+) , CXCR4(+) , and CD14(+) cells showed higher glycolytic activity compared to their negative counterparts. Metabolic activity was profoundly modulated by the composition of media used to store or culture BMC. This study provides first evidence that metabolic alterations influence the functional activity of human HSPC and BMC independent of ATP production. Changing the balance between respiration and glycolysis might be useful to improve patient-derived cells for clinical cardiac cell therapy. Stem Cells 2016;34:2236-2248.

Occurrence and prognostic impact of systemic inflammatory response syndrome in transfemoral and transapical aortic valve implantation with balloon- and self-expandable valves.

AIMS: Transcatheter aortic valve implantation (TAVI) is an alternative therapeutic option for patients with severe aortic valve stenosis (AS) and elevated surgical risk. Previous studies have suggested that the occurrence of systemic inflammatory response syndrome (SIRS) in patients undergoing TAVI is associated with an unfavourable outcome. We sought to assess the impact of different interventional access routes (transapical [TA] vs. transfemoral [TF]) and valve types (Medtronic CoreValve® [CV] vs. Edwards SAPIEN XT® [ES]) on the incidence of SIRS. In addition, the prognostic value of SIRS was evaluated. METHODS AND RESULTS: Between January 2009 and July 2011 a total of 192 (out of 228) consecutive patients with severe aortic stenosis underwent TAVI at the University Hospital Frankfurt and were included in the current retrospective analysis. SIRS criteria were evaluated within the first 48 hours after TAVI. SIRS was defined according to existing definitions of the ACCP/SCCM Consensus Conference. A total of 75 (39.1%) patients developed SIRS at some time during the first 48 hours following TAVI. The occurrence of SIRS was independent from access route (TA 42.3% vs. TF 37.0%; p=0.28) as well as from type of valve used (ES 42.5% vs. CV 32.3%; p=0.11). However, the occurrence of SIRS was associated with a more than twofold higher one-year mortality rate (21.3%) compared to patients without SIRS in the first 48 hours (5.3%; p=0.04). CONCLUSIONS: The occurrence of SIRS in the first 48 hours post procedure is associated with impaired prognosis following TAVI, but is independent from the chosen valve type and access route.

The challenges of autologous cell therapy: systemic anti-thrombotic therapies interfering with serum coagulation may disable autologous serum-containing cell products for therapeutical use.

Cell therapy of acute myocardial infarction (AMI) with bone marrow-derived mononuclear cells (BMC) resulted in a modest improvement of cardiac function, but clinical trial results were heterogeneous. After isolation, BMC are maintained in medium supplemented with complements such as autologous serum to maintain optimal cell viability until administration. In the REPAIR-AMI trial, serum was prepared using tubes containing coagulation accelerators, but the regulatory agency recommended using additive-free tubes for the pivotal BAMI trial. Here, we show that serum obtained from patients with anti-thrombotic therapy in tubes without coagulation accelerators induces clotting, thereby rendering the cell product unsuitable for intra-coronary application. Specifically, systemic treatment of patients with low doses of heparin prevented efficient coagulation ex vivo, and the resulting partially clotted plasma induced cell aggregation within 1-18 h in the cell product. Utmost care has to be taken to test autologous components of cell products before clinical use. The development of media including the appropriate recombinant growth factors for maintaining cell functionality ex vivo may be warranted.

Complications associated with the prehospital use of laryngeal tubes--a systematic analysis of risk factors and strategies for prevention.

OBJECTIVE: With the increasing spread of laryngeal tubes (LT) in emergency medicine, complications and side-effects are observed. We sought to identify complications associated with the use of LTs in emergency medicine, and to develop strategies to prevent these incidents. METHODS: In a prospective clinical study, all patients who had their airways managed in the field with a LT and who were admitted through the emergency department of the Frankfurt University Hospital during a 6 year period were evaluated using anonymised data collection sheets. A team of experts was available 24/7 and was requested whenever a patient was admitted with a LT in place. This team evaluated the condition of the patients with respect to prehospital airway management and was responsible for further advanced airway management. All complications were analysed, and strategies for prevention developed. RESULTS: One hundred eighty nine patients were included and analysed. The initial cuff pressure of the LTs was 10 0 cm H2O on the median. Complications consisted of significant tongue swelling (n=73; 38.6%), resulting in life-threatening cannot ventilate, cannot intubate scenarios in two patients (1.0%) and the need for surgical tracheostomy in another patient, massive distension of the stomach (n=20, 10.6%) with ventilation difficulties when LTs without gastric drainage were used; malposition of the LT in the piriform sinus (n=1, 0.5%) and significant bleeding from soft tissue injuries (n=4, 2.1%). CONCLUSIONS: The prehospital use of LTs may result in severe and even life-threatening complications. Likely, such complications could have been prevented by using gastric drainage and cuff pressure adjustment. Both, prehospital health care providers and emergency department staff should develop a greater awareness of such complications to best avoid them in the future.

Thorax, trachea, and lung ultrasonography in emergency and critical care medicine: assessment of an objective structured training concept.

Background and Study objective. Focused lung ultrasound (LUS) examinations are important tools in critical care medicine. There is evidence that LUS can be used for the detection of acute thoracic lesions. However, no validated training method is available. The goal of this study was to develop and assess an objective structured clinical examination (OSCE) curriculum for focused thorax, trachea, and lung ultrasound in emergency and critical care medicine (THOLUUSE). Methods. 39 trainees underwent a one-day training course in a prospective educational study, including lectures in sonoanatomy and -pathology of the thorax, case presentations, and hands-on training. Trainees' pre- and posttest performances were assessed by multiple choice questionnaires, visual perception tests by interpretation video clips, practical performance of LUS, and identification of specific ultrasound findings. Results. Trainees postcourse scores of correct MCQ answers increased from 56 ± 4% to 82 ± 2% (mean± SD; P < 0.001); visual perception skills increased from 54 ± 5% to 78 ± 3% (P < 0.001); practical ultrasound skills improved, and correct LUS was performed in 94%. Subgroup analysis revealed that learning success was independent from the trainees' previous ultrasound experience. Conclusions. THOLUUSE significantly improves theoretical and practical skills for the diagnosis of acute thoracic lesions. We propose to implement THOLUUSE in emergency medicine training.

MicroRNAs in stem cell function and regenerative therapy of the heart.

MicroRNAs are small noncoding RNAs that posttranscriptionally control gene expression by targeting mRNAs. Distinct microRNAs regulate stem and progenitor cell functions, thereby modulating cell survival and homing or controlling differentiation and maturation. Experimental studies additionally show that microRNAs regulate endogenous repair and might potentially be useful to enhance the regeneration of the heart. This review summarizes the current studies that address the use of microRNAs to either improve cellular therapies or that might be targeted for enhancing endogenous tissue repair and regeneration after myocardial infarction.

Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial.

IMPORTANCE: The modest effects of clinical studies using intracoronary administration of autologous bone marrow-derived mononuclear cells (BMCs) in patients with chronic postinfarction heart failure may be attributed to impaired homing of BMCs to the target area. Extracorporeal shock wave treatment has been experimentally shown to increase homing factors in the target tissue, resulting in enhanced retention of applied BMCs. OBJECTIVE: To test the hypothesis that targeted cardiac shock wave pretreatment with subsequent application of BMCs improves recovery of left ventricular ejection fraction (LVEF) in patients with chronic heart failure. DESIGN, SETTING, AND PARTICIPANTS: The CELLWAVE double-blind, randomized, placebo-controlled trial conducted among patients with chronic heart failure treated at Goethe University Frankfurt, Germany, between 2006 and 2011. INTERVENTIONS: Single-blind low-dose (n = 42), high-dose (n = 40), or placebo (n = 21) shock wave pretreatment targeted to the left ventricular anterior wall. Twenty-four hours later, patients receiving shock wave pretreatment were randomized to receive double-blind intracoronary infusion of BMCs or placebo, and patients receiving placebo shock wave received intracoronary infusion of BMCs. MAIN OUTCOMES AND MEASURES: Primary end point was change in LVEF from baseline to 4 months in the pooled groups shock wave + placebo infusion vs shock wave + BMCs; secondary end points included regional left ventricular function assessed by magnetic resonance imaging and clinical events. RESULTS: The primary end point was significantly improved in the shock wave + BMCs group (absolute change in LVEF, 3.2% [95% CI, 2.0% to 4.4%]), compared with the shock wave + placebo infusion group (1.0% [95% CI, -0.3% to 2.2%]) (P = .02). Regional wall thickening improved significantly in the shock wave + BMCs group (3.6% [95% CI, 2.0% to 5.2%]) but not in the shock wave + placebo infusion group (0.5% [95% CI, -1.2% to 2.1%]) (P = .01). Overall occurrence of major adverse cardiac events was significantly less frequent in the shock wave + BMCs group (n = 32 events) compared with the placebo shock wave + BMCs (n = 18) and shock wave + placebo infusion (n = 61) groups (hazard ratio, 0.58 [95% CI, 0.40-0.85]; P = .02). CONCLUSIONS AND RELEVANCE: Among patients with postinfarction chronic heart failure, shock wave-facilitated intracoronary administration of BMCs vs shock wave treatment alone resulted in a significant, albeit modest, improvement in LVEF at 4 months. Determining whether the increase in contractile function will translate into improved clinical outcomes requires confirmation in larger clinical end point trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00326989.

Impact of intracoronary reinfusion of bone marrow-derived mononuclear progenitor cells on cardiopulmonary exercise capacity in patients with chronic postinfarction heart failure.

INTRODUCTION: Intracoronary infusion of bone marrow-derived progenitor cells (BMC) in patients with chronic ischaemic heart failure (CHF) is associated with improvement in left ventricular ejection fraction (LVEF), reduction of NT-proBNP levels and improved prognosis. However, effects of this therapy on cardiopulmonary exercise capacity have not been investigated separately so far. PATIENTS AND METHODS: One hundred and fifty-four patients with ischaemic heart failure (mean LVEF 40.3 ± 10.9 %, NT-proBNP 1,103 ± 1,436 pg/ml) underwent cardiopulmonary exercise capacity testing (CPX) before and 3 months after intracoronary infusion of autologous BMC. Thirty patients with a potential bias on the CPX course as concomitant coronary intervention, bypass surgery, new onset of arrhythmias or implantation of cardiac resynchronization devices were excluded from further analysis. RESULTS: The remaining 124 patients showed an increase in exercise time and peak workload by 16.8 and 6 %. Peak oxygen uptake and oxygen uptake efficiency slope also improved by 2.9 and 12.9 %, whereas other parameters like peak oxygen pulse and the slope of minute ventilation versus CO2 elimination remained unchanged. Analysis of patients with poor, moderate and conserved CPX results prior to cell therapy documented that patients in tertiles with lowest initial exercise capacity showed the largest improvements in CPX after therapy. The differences in response to cell therapy were detectable in all investigated CPX parameters and became significant for exercise time, peak oxygen uptake and peak oxygen pulse. These findings indicate that intracoronary BMC therapy improves exercise capacity in CHF patients with more advanced heart failure.