Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF.

AIMS: Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodeling and atrial fibrillation is frequently observed in HFpEF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial antiarrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. METHODS AND RESULTS: Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green-2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs HFpEF: 0.21±0.02 vs 0.38±0.04 mmol/L/min (N=7 vs 18); p=0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment with the CaMKII inhibitor autocamtide-2 related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with NHE1 inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. CONCLUSION: We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to antiarrhythmic effects in patients with HFpEF.

Substantial understory contribution to the C sink of a European temperate mountain forest landscape.

CONTEXT: The contribution of forest understory to the temperate forest carbon sink is not well known, increasing the uncertainty in C cycling feedbacks on global climate as estimated by Earth System Models. OBJECTIVES: We aimed at quantifying the effect of woody and non-woody understory vegetation on net ecosystem production (NEP) for a forested area of 158 km2 in the European Alps. METHODS: We simulated C dynamics for the period 2000-2014, characterized by above-average temperatures, windstorms and a subsequent bark beetle outbreak for the area, using the regional ecosystem model LandscapeDNDC. RESULTS: In the entire study area, woody and non-woody understory vegetation caused between 16 and 37% higher regional NEP as compared to a bare soil scenario over the 15-year period. The mean annual contribution of the understory to NEP was in the same order of magnitude as the average annual European (EU-25) forest C sink. After wind and bark beetle disturbances, the understory effect was more pronounced, leading to an increase in NEP between 35 and 67% compared to simulations not taking into account these components. CONCLUSIONS: Our findings strongly support the importance of processes related to the understory in the context of the climate change mitigation potential of temperate forest ecosystems. The expected increases in stand replacing disturbances due to climate change call for a better representation of understory vegetation dynamics and its effect on the ecosystem C balance in regional assessments and Earth System Models.

Effects of tropisetron, a 5-HT3 receptor antagonist, on proximal gastric motor and sensory function in nonulcer dyspepsia.

BACKGROUND: Visceral hypersensitivity is claimed to be involved in the pathogenesis of nonulcer dyspepsia (NUD). In a double-blind crossover study, we evaluated the effects of tropisetron, a 5-HT3 receptor antagonist, on gastric accommodation, reflex relaxation, and sensitivity in NUD patients. METHODS: Eight patients and 10 healthy controls received placebo or 5 mg tropisetron on separate days. On each day, gastric accommodation and relaxation were investigated using a gastric barostat. The perception during gastric distension and relaxation was scored by a verbal perception score. RESULTS: Under both medications, gastric accommodation and postprandial gastric reflex relaxation were not impaired in the NUD patients. The visceral perception was increased in the NUD patients and not substantially influenced by tropisetron. CONCLUSIONS: Tropisetron does not influence gastric accommodation, reflex relaxation, or gastric sensitivity in NUD patients and healthy controls.

Endothelin-induced conversion of embryonic heart muscle cells into impulse-conducting Purkinje fibers.

A regular heart beat is dependent on a specialized network of pacemaking and conductive cells. There has been a longstanding controversy regarding the developmental origin of these cardiac tissues which also manifest neural-like properties. Recently, we have shown conclusively that during chicken embryogenesis, impulse-conducting Purkinje cells are recruited from myocytes in spatial association with developing coronary arteries. Here, we report that cultured embryonic myocytes convert to a Purkinje cell phenotype after exposure to the vascular cytokine, endothelin. This inductive response declined gradually during development. These results yield further evidence for a role of arteriogenesis in the induction of impulse-conducting Purkinje cells within the heart muscle lineage and also may provide a basis for tissue engineering of cardiac pacemaking and conductive cells.

Circadian variation and triggers of acute coronary syndromes.

Myocardial infarction and sudden cardiac death demonstrate a marked circadian variation with an increased risk during the morning after awakening and arising. The recognition of the morning increase of acute coronary heart disease has convinced many that morning activities can 'trigger' its onset. It is of note, however, that coronary events may occur throughout the day--even if at lower frequency compared with the morning. There is a strong association between external triggers and onset of myocardial infarction and sudden cardiac death beyond that expected by chance alone. The magnitude of this association (relative risk two- to threefold) is comparable to that of other known long term risk factors of cardiac disease. Trigger factors occur relatively frequently and may play a causative role in up to 20% of cases of acute coronary syndromes. Physical exertion, burst of anger and sexual activity have been proven to have triggering potential. Other possible triggers include external and environmental events such as earthquakes, war threat and climatic factors. The pathophysiological links between external triggers and onset of coronary syndromes are important in addressing the question of a causal relationship between triggers and disease onset and, perhaps, in improving preventive strategies.

HCV and HGV in B-cell non-Hodgkin's lymphoma.

BACKGROUND/AIMS: A causative role of hepatitis C virus infection (HCV) has been discussed in the pathogenesis of mixed cryoglobulinaemia and in B-cell non-Hodgkin's lymphoma. No data are available concerning the newly discovered hepatitis G virus (HGV) and extrahepatic manifestations such as haematological malignancies. But, HCV and HGV most probably belong to the same family of Flavivirus. Consequently, we looked for the prevalence of HCV, HGV and cryoglobulins in patients with B-cell non-Hodgkin's lymphoma. METHODS: Serum samples from 69 patients with non-Hodgkin's lymphoma were studied. Diagnosis of non-Hodgkin's lymphoma was established according to the Kiel classification. Active HCV- and HGV infections were investigated using polymerase chain reaction for detection of viral RNA. Cryoglobulins were detected from serum and monoclonal immunoglobulin components were analysed with immunofixation electrophoresis. In addition, we assessed the clinical course of HCV- and HGV-infected patients under chemotherapy. RESULTS: Three of 69 (4.3%) patients with B-cell non-Hodgkin's lymphoma were HCV-infected and nine non-Hodgkin's lymphoma patients (13.0%) were positive for hepatitis G virus RNA. All HGV infected patients were suffering from low-grade non-Hodgkin's lymphoma. No HGV-infected patient was co-infected by HCV and neither HCV- nor HGV-infected patients showed clinical signs of chronic liver disease before, during or after chemotherapy. Serum samples from all patients were devoid of cryoglobulins. CONCLUSIONS: HCV seems to have no significance for the pathogenesis of non-Hodgkin's lymphoma in Germany. The increased prevalence of hepatitis G (16.3%) in patients with low-grade non-Hodgkin's lymphoma could suggest a pathological consequence of HGV infection outside of the liver. Evidence of clinically relevant hepatic disease in HGV infected patients was not obtained. Further, chemotherapy does not seem to affect the subsequent clinical course of HGV infection.

Evaluation of the 13C-methacetin breath test for quantitative liver function testing.

Noninvasive 13C-breath tests are used for the assessment of hepatocellular dysfunction. 13C-methacetin is metabolized in the liver by O-demethylation to 13CO2 and acetaminophen. The aim of the study was to evaluate the 13C-methacetin breath test in comparison to the Child-Pugh score and other quantitative liver function tests (MEGX-test and indocyanin green-clearance). 2 mg/kg 13C-methacetin were orally given to 31 patients with histologically proven liver cirrhosis of different etiology and severity (nine Child A, 13 Child B, nine Child C), ten patients with chronic viral hepatitis and ten healthy volunteers. The increase of exhaled 13CO2 was expressed as delta over baseline (DOB; delta /1000). Different DOB-values were compared as parameters for assessing hepatocellular dysfunction. All breath test parameters analyzed provided an excellent discrimination between cirrhotic and noncirrhotic individuals. The DOB-value at 20 min showed a superior correlation with the Child-Pugh score (r = 0.67) than did MEGX-test or indocyanine green clearance results (r = 0.39 and r = 0.43, respectively). With a cut-off value of < or = 25 delta /1000 at 20 min, sensitivity and specificity to discriminate between cirrhotic and noncirrhotic individuals was 93.5% and 95%, respectively. The 13C-methacetin breath test is a safe and precise quantitative liver function test. Using one single breath sample 20 min after substrate administration, the test discriminates well between cirrhotic and noncirrhotic patients. Its prognostic value remains to be established.

Gastric hypersensitivity in nonulcer dyspepsia: an inconsistent finding.

Visceral hypersensitivity is claimed to be involved in the pathogenesis of nonulcer dyspepsia (NUD). We evaluated whether gastric hypersensitivity is a consistent finding in an unselected group of NUD patients. In 11 patients and 20 healthy controls, a standardized gastric distension was performed using a gastric barostat. Perception was scored by a questionnaire and compared between the two groups. There was a linear pressure/volume relationship during gastric distension in both groups. The pain threshold in NUD patients was significantly lower compared to controls [5.5 +/- 4.0 mm Hg above minimal distending pressure (mdp) and 10.2 +/- 2.2 mm Hg above mdp, respectively, P < 0.004], irrespective of the H. pylori status. However, more than 50% of the NUD perception scores were in the control range at most distension levels. Gastric hypersensitivity could be confirmed in NUD patients as a group. However, there is a considerable overlap concerning perception in response to distension between unselected NUD patients and controls.

Proximal gastric motility functions are normal in severe obesity.

The role of altered gastric motor functions for the development of obesity is still unclear. In this study, we investigated whether severe obesity is related to gastric dysfunctions or to abnormal perception in response to distension. 31 obese patients and 20 healthy volunteers were studied using an electronic barostat. Basal gastric tone, gastric accommodation, and perception in response to distension were not altered in obese patients. The median minimal distending pressure, reflecting the intra-abdominal pressure, was significantly elevated in obese patients, being 12 versus 7 mm Hg, respectively (p < 0.0001). We conclude that the proximal gastric motility, including perception and accommodation in response to intragastric distension, is not impaired in severe obesity. Whether disturbances of gastric reflex relaxation in response to a meal are involved in the pathogenesis of obesity remains to be established.

Clinical evaluation of the faecal elastase test in the diagnosis and staging of chronic pancreatitis.

OBJECTIVE: To test the diagnostic accuracy of faecal elastase (FE), a new test of exocrine pancreatic function, in a large prospective population of patients with abdominal complaints. METHODS: Between January 1994 and December 1995, 131 patients (age range 17-82 years) were submitted for exocrine pancreatic function testing. Sixty-three patients had a firm diagnosis of chronic pancreatitis (CP) at stage I-III according to endoscopic retrograde cholangiopancreatography (ERCP). Twenty patients suffered from other pancreatic diseases (PD), and 48 patients had various other gastrointestinal diseases (GD). Fifty-seven healthy controls (HC) were also investigated. Stool specimens were analysed for FE by enzyme-linked immunosorbent assay (ELISA) and for faecal chymotrypsin (FC). The pancreolauryl serum test (PLT) was also performed in 97 patients and 23 healthy controls. RESULTS: FE was 200; 45-500 micrograms/g (median; range) in CP-I (n = 19), 94; 0-400 micrograms/g in CP-II (n = 14) and 38; 0-135 micrograms/g in CP-III patients (n = 30). With a cutoff of 200 micrograms/g, abnormal test results were found in 47% of CP-I, 79% of CP-II and 100% of CP-III patients; in 30% of PD patients, in 38% of GD patients and in 7% of HC. Sensitivity of abnormal FE in diagnosing CP was 79% (FC: 48%; PLT: 71%). The specificity of only 62% (FC: 73%; PLT: 67%) in the GD group increased to 78% (FC: 81%; PLT: 77%) when patients with small bowel diseases and diarrhoea (n = 22) were excluded. CONCLUSION: Faecal elastase is more sensitive than chymotrypsin and comparable to the pancreolauryl test in the diagnosis of chronic pancreatitis. Indirect exocrine pancreatic function tests are not helpful to differentiate between pancreatic and small bowel diseases in a prospective population of patients with abdominal complaints.

Intrahepatic high-grade malignant non-Hodgkin lymphoma in a patient with chronic hepatitis C infection.

A 61-year-old white female with chronic hepatitis C virus (HCV) infection first diagnosed in 1994 was admitted with two newly discovered lesions in the liver suspected to represent hepatocellular carcinoma. The alpha-1-fetoprotein (AFP) level was within normal limits and there was neither clinical nor sonographic evidence of liver cirrhosis. Fine needle aspiration, however, showed an high-grade malignant centroblastic non-Hodgkin lymphoma (NHL). Staging failed to confirm extrahepatic involvement. Both a cryoglobulinemia and HIV infection were ruled out. Although the coincidence of HCV infection and NHL is not well recognized, recent studies have indicated an increased incidence of NHL and hepatitis C in up to 38% of patients with cryoglobulinemia. In these patients, the diagnosis is always one of a low-grade lymphoma. Based on its lymphoproliferative characteristics, an etiologic role for HCV in the development of NHL has been discussed, though the exact pathogenesis remains unclear.

[Multicentric gastric carcinoid in autoimmune gastritis]. / Multizentrisches Magenkarzinoid bei Autoimmungastritis.

HISTORY AND FINDINGS: A now 54-year-old woman was 32 years ago found to have immune thrombocytopenia and 3 years ago ANA-positive and HBsAg-negative hepatitis with cirrhotic metaplasia. Numerous small asymptomatic carcinoids with marked hypergastrinaemia (1626 ng/l) were also first found 3 years ago. No gastrinoma could be found. Severe arthralgia was the main symptom on admission. INVESTIGATIONS: Gastroscopy revealed a polypoid carcinoid, 1 cm in diameter. There was total achlorhydria. No pernicious anaemia or carcinoid syndrome was found. TREATMENT AND COURSE: Total gastrectomy with construction of a jejunal substitute stomach was performed. Histology showed typical chronic-atrophic gastritis type A, all stages of an argyrophilic endocrine cell hyperplasia, as well as microcarcinoidosis and multicentric carcinoid, in part with submucosal infiltration and lymph node metastases. Immunohistology revealed immune reaction for the global endocrine marker. No specific hormones were demonstrable in the carcinoid cells. The postoperative course was without complications. Serum gastrin levels have since been normal. CONCLUSIONS: The case confirms the possibility of an achlorhydria-hypergastrinaemia-carcinoid sequence. Now new stage-related therapeutic guidelines for this disease are needed.

[Are emergency physicians' diagnoses accurate?]. / Sind Notarztdiagnosen zuverlässig?

METHODS AND AIM OF THE STUDY: The on-scene performance during all missions of the emergency physician-operated rescue helicopter and mobile intensive care unit based at a large-city hospital over a period of 1 year was retrospectively analysed; 2,254 hospital discharge reports were available (92% of the patients treated by the emergency physicians [n = 2,493]). The following parameters were investigated: reliability of the primary diagnosis established by the emergency physician (by comparison with the discharge diagnoses); initial on-scene therapeutic measures; means of transportation (with or without accompanying emergency physician); and level of care of the target hospital. RESULTS: The most common reasons for a mission were cardiopulmonary diseases (55%), neurological disorders (18%), and traumatic events (7%). The diagnoses, therapeutic measures, and mode of transportation were correct in 2,033 (90%) patients with a discharge report. Severe errors of assessment by the emergency physician were identified in 73 patients (3%): life-threatening conditions were not recognised and/or grossly incorrect therapeutic measures were taken and/or the chosen means of transportation was unsuitable. Relative errors in assessment occurred in 4% (n = 83): the most crucial diagnosis was not made, but the patient was escorted by the emergency physician (without therapeutic errors) to a suitable hospital. In 3% (n = 65) of the cases, the patient's condition was overestimated by the emergency physician as suggested by the obviously exaggerated on-scene therapy. Underestimations of the severity were most common in patients with cardiopulmonary diseases and increased in frequency and severity with increasing age and the presence of a concomitant neurologic deficit. Underestimations of a severe condition in younger patients were extremely rare; overestimations of the severity and consequent overtreatment were particularly common in traumatised patients independent of age. CONCLUSIONS: In the context of quality management measures, a careful evaluation of on-scene diagnoses, therapeutic measures, and decisions made by the emergency physician is a suitable procedure for identifying systematic errors. A high percentage of correct diagnoses and therapy at the emergency site can only be ensured by clinically experienced physicians who constantly deal with patients with acutely life-threatening conditions.

[Experiences with an alternative distension medium in oral contrast imaging of the small intestine]. / Erfahrungen mit einem alternativen Distensionsmittel in der oralen Dünndarmkontrastierung.

PURPOSE: The image quality of oral small bowel imaging is often poor on account of the small bowel enema. A new contrast medium should increase the image quality due to better compliance of patient because of the better taste of substance. The loading of patient with radiation or time should not increase. METHODS AND PATIENTS: We investigated prospectively 40 patients, randomized in two groups of 20 patients each. Two different substances were used as contrast medium: barium-methylcellulose and Barium-Mucofalk, respectively. The quality of the double contrast, profile of the mucosa, duration of radiation, duration of examination, dose-area product, and taste of the substance were judged for significance. RESULTS: The taste of the new contrast medium was judged to be better: twice as often as "good" and five times less often as "bad", the difference was not significant due to the small number of patients. There is no significant difference in the other criterias. CONCLUSION: Mucofalk is an alternative contrast medium for oral small bowel radiology in cases of difficult placement of the tube for enema. The quality of double contrast and visualization of the profile of mucosa are the same while the taste is better.

[Clinical relevance of mammography in men]. / Klinische Relevanz der Mammographie beim Mann.

PURPOSE: During a period of four years 104 mammograms were performed in 89 men. Mastectomies were carried out on 23 men (group 1). 66 patients (group 2) were followed up clinically and in 15 patients serial mammograms were obtained. MATERIAL AND METHOD: In group 1 there were 5 patients with bilateral gynaecomastia, 9 with unilateral gynaecomastia and two with pseudogynaecomastia and there were 7 patients with malignancies. In group 2 there were 46 patients with bilateral gynaecomastia and 10 patients with unilateral gynaecomastia. Pseudogynaecomastia was found in 25 patients. There were 7 malignancies, of which 5 had been suspected clinically and one had been diagnosed as gynaecomastia by mammography. Two carcinomas in situ were missed clinically and also by mammography. CONCLUSION: When malignancy is not suspected on clinical grounds the first examination should be sonography, mammography being reserved for cases of doubt. Where, however, malignancy is suspected, and for follow-up, mammography retains its primary position.

Gallbladder dynamics in chronic pancreatitis. Relationship to exocrine pancreatic function, CCK, and PP release.

Gallbladder dynamics, cholecystokinin (CCK), and pancreatic polypeptide (PP) release were studied in 14 patients with chronic pancreatitis (CP) (2 females, 12 males; age range 24-56 years) and 12 control subjects (4 females, 8 males, 21-50 years). On day 1, gallbladder contractility was investigated after ceruletide intravenous infusion (2.5 ng/kg/min for 10 min). On day 2, a mixed standard test meal (1450 kJ) was administered orally. Gallbladder volume was assessed at three time intervals before (-30, -15, 0 min) and at 5, 10, 20, 30, 40, 50, 60, 80, 100 and 120 min after stimulation by means of ultrasonography. CCK and PP plasma levels were determined at each time interval. Exocrine pancreatic function was assessed using the pancreolauryl serum test (PLT). Six patients with CP had severe exocrine pancreatic insufficiency (EPI) (PLT < 1.8 micrograms/ml) with steatorrhea, eight patients had mild-moderate EPI. Fasting gallbladder volume was increased in CP (32.3 +/- 3.1 cm3) as compared to controls (20.5 +/- 1.2 cm3) (P < 0.01). Peak gallbladder contraction (percent of initial volume) in CP ranged from 5 to 55% (controls: 8-46%) following ceruletide and from 17 to 86% (controls: 27-80%) following the test meal (NS). There was no correlation between the degree of EPI according to PLT and peak gallbladder contraction. Gallbladder emptying in CP patients was not different from controls, although the postprandial CCK response was significantly impaired (P < 0.01). Postprandial PP response in CP was correlated with the PLT result (r = 0.78; P < 0.01) but not with gallbladder emptying or refilling time.(ABSTRACT TRUNCATED AT 250 WORDS)

[Is pre-hospital thrombolysis in acute myocardial infarct valuable as a routine measure?]. / Ist die prästationäre Thrombolyse bei akutem Myokardinfarkt als Routinemassnahme sinnvoll?

UNLABELLED: In 4920 consecutive missions of the mobile intensive care unit Klinikum Steglitz, 1226 patients (25%) had chest pain of presumed cardiac origin. In 272 patients (22%) an acute myocardial infarction (AMI) was diagnosed in the field. In four patients the diagnosis was wrong; 11 patients with proven coronary artery disease had significant ST-segment elevation, but did not develop AMI. In hospital, a total of 406 patients had evidence of AMI; 173 of these (41%) were seen by an emergency physician in the field already within the first hour after onset of symptoms. In 6%, diagnostic ST-elevation was not recognized by the emergency physician; 27% had non-diagnostic ECG changes (11% bundle-branch block). Prehospital thrombolysis within 4 h after symptom onset was performed in 126 of 205 patients (61%); 74 of these patients were seen by the emergency physician within the first hour. The main reason for exclusion was advanced age. Inclusion of older patients and also those with bundle-branch block could further increase the prehospital thrombolysis rate. CONCLUSION: With an effective emergency medical system a large proportion of all patients with AMI can correctly be identified and properly treated with a thrombolytic drug in the field. The time gain is considerable.

[Sonographic study of gallbladder function: exogenous or endogenous stimulation?]. / Sonographische Untersuchung der Gallenblasenfunktion: Exogene oder endogene Stimulation?

Eleven patients (8 male, 3 female, age 21-53 years) with dyspeptic symptoms and no gastrointestinal organic diseases were studied for their gallbladder contractile function. A comparative sonographic study of gallbladder contraction was performed after exogenous and endogenous stimulation. On day 1, ceruletide was infused at a dose of 2.5 ng/kg/min about 10 minutes. On day 2, a semi-liquid test meal of 1450 kJ (44 kJ% carbohydrates, 24 kJ% protein, 32 kJ% fat) was administered. Gallbladder volume was determined for 30 minutes before and 5, 10, 20, 30, 40, 60, 80, 100 and 120 minutes after both stimulations by means of realtime ultrasonography. Three diameters in two plains were measured for calculation of gallbladder volume. Following ceruletide, peak gallbladder contraction (range 7-48% of initial volume) was observed within 10 (n = 5) or 20 (n = 6) minutes. Following the test meal, peak gallbladder contraction ranged from 27-80% and was observed within 30 to 100 minutes. Variations in time and amount of peak gallbladder contraction does hardly allow to establish normal values. No significant correlation was found between both types of stimulation concerning peak gallbladder contraction or time to peak contraction. We conclude that for the assessment of gallbladder contractility, ceruletide infusion and determination of gallbladder volume after 20 minutes (upper range 48% of initial volume) is the most valuable procedure. Impaired gallbladder contractility can be diagnosed with certainty only after exogenous stimulation.