Embolization of Hemorrhoidal Arteries: A Novel Endovascular Therapy Option for the Treatment of Hemorrhoidal Disease. / Hämorrhoidenembolisation: Eine neue minimalinvasive endovaskuläre Therapieoption bei Hämorrhoidalleiden.

BACKGROUND: Hemorrhoids are a widespread disease. Treatment options range from dietary measures to open surgery. A novel treatment approach is the embolization of the hemorrhoidal arteries. METHOD: A review was performed based on a selective literature search in PubMed representing the current state of research. The keywords "hemorrhoid" and "embolization" and "emborrhoid" were used. In addition, technical details of the hemorrhoidal embolization procedure are explained. RESULTS AND CONCLUSION: Embolization of hemorrhoidal arteries is a safe treatment, which allows efficient symptom control even in patients with contraindications for open surgery. KEY POINTS: · Embolization of hemorrhoidal arteries is a new approach to the treatment of hemorrhoids.. · Embolization of hemorrhoidal arteries is feasible in patients with contraindications for open surgery such as hypercoaguable states and contraindications for general anesthesia.. · The endovascular approach causes no rectal and anal trauma and associated complications can be avoided.. · The treatment of bleeding hemorrhoids seems to be particularly effective.. · No ischemic complications have been reported so far when coils as well as particles were used.. CITATION FORMAT: · Feyen L, Freyhardt P, Schott P et al. Hämorrhoidenembolisation: Eine neue minimalinvasive endovaskuläre Therapieoption bei Hämorrhoidalleiden. Fortschr Röntgenstr 2022; 194: 266 - 271.

Control of p21Cip by BRCA1-associated protein is critical for cardiomyocyte cell cycle progression and survival.

AIMS: Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibitor p21Cip. We observed profound expressional changes of BRAP in early postnatal myocardium and investigated the impact of BRAP on cardiomyocyte cell cycle regulation. METHODS AND RESULTS: General knockout of Brap in mice evoked embryonic lethality associated with reduced myocardial wall thickness and lethal cardiac congestion suggesting a prominent role for BRAP in cardiomyocyte proliferation. αMHC-Cre driven cardiomyocyte-specific knockout of Brap also evoked lethal cardiac failure shortly after birth. Likewise, conditional cardiomyocyte-specific Brap deletion using tamoxifen-induced knockout in adult mice resulted in marked ventricular dilatation and heart failure 3 weeks after induction. Several lines of evidence suggest that Brap deletion evoked marked inhibition of DNA synthesis and cell cycle progression. In cardiomyocytes with proliferative capacity, this causes developmental arrest, whereas in adult hearts loss of BRAP-induced apoptosis. This is explained by altered signalling through p21Cip which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21Cip expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21Cip expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis. CONCLUSION: By controlling p21Cip activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes.

Radiation Dose in Prostatic Artery Embolization Using Cone-Beam CT and 3D Roadmap Software.

PURPOSE: To evaluate the radiation dose in patients undergoing prostatic artery embolization (PAE) using cone-beam CT and 3-dimensional (3D) guidance software. MATERIALS AND METHODS: In this single-center retrospective study, 100 patients with benign prostatic hyperplasia (mean prostate volume, 83.6 mL ± 44.2; 69.4 ± 9.6 years of age; body mass index, 26.5 ± 4.2) were treated using PAE between October 2016 and April 2018. Informed consent was obtained from all participants included in the study. All patients received at least 1 intraprocedural cone-beam CT per side for evaluation of the vessel anatomy and software rendering of 3D guidance for catheter guidance. Digital subtraction angiography (DSA) was performed in the distal branches only. The total dose area product (DAP), along with the DAP attributed to fluoroscopy, DSA, and cone-beam CT, were assessed. RESULTS: Bilateral embolization was achieved in 83 patients (83%). The average total DAP was 134.4 Gy ⋅ cm2 ± 69.5 (range, 44.7-410.9 Gy ⋅ cm2). Fluoroscopy, DSA, and cone-beam CT accounted for 35.5 Gy ⋅ cm2 ± 21.3 (range, 8.6-148.6 Gy ⋅ cm2) or 26.4% (percentage of total DAP), 58.2 Gy ⋅ cm2 ± 48.3 (range, 10.3-309.3 Gy ⋅ cm2) or 43.3%, and 40.7 Gy ⋅ cm2 ± 14.5 (range, 15.9-86.3 Gy ⋅ cm2) or 30.3%, respectively. Average procedure time was 89.4 ± 27.0 minutes, and the average fluoroscopy time was 30.9 ± 12.2 minutes. CONCLUSIONS: Intraprocedural cone-beam CT in combination with 3D guidance software allows for identification and catheterization of the prostatic artery in PAE. Furthermore, the results of this trial indicate that this study protocol may lead to a low overall radiation dose.

Proteome changes in CaMKIIδC-overexpressing cardiac myocytes.

Recent studies have demonstrated that the expression as well as the activity of Ca/calmodulin-dependent protein kinase IIδ(C) (CaMKIIδ(C)) is increased in heart failure. Transgenic overexpression of CaMKIIδ(C) in mouse hearts results in severe dilated cardiomyopathy. So far, little is known about CaMKIIδ(C)-induced changes in gene expression and proteome alteration. We hypothesize that proteome changes similar to those found in advanced heart failure can be assessed even after short term overexpression of CaMKIIδ(C) in an in vitro culture model. Thus, we designed a study using a proteomic approach combined with adenovirus-mediated gene transfer of CaMKIIδ(C) to identify early CaMKIIδ(C)-induced changes in cardiac myocyte phenotype on proteome level. CaMKIIδ(C) was overexpressed by adenovirus-mediated gene transfer in isolated cardiac myocytes of adult rabbits for 48 h. Proteome changes were analyzed by two-dimensional gel electrophoresis and mass spectrometry (MS). Overexpression of CaMKIIδ(C) resulted in a decreased expression of 21 proteins (at least twofold change of expression, P<.05, n=10). Using in-gel digest and MS, we identified 13 out of these 21 proteins. CaMKIIδ(C) overexpression leads to a reduced abundance of NADH dehydrogenase, lactate dehydrogenase, pyruvate kinase, dihydrolipoamide succinyltransferase, creatine kinase M, heat shock protein 70, elongation factor Tu, and superoxide dismutase. The profile of the proteome changes induced by CaMKIIδ(C) overexpression after 48 h displayed striking alterations of metabolic proteins, cell-protecting proteins including antioxidants, and proteins involved in protein synthesis. Interestingly, the observed proteome changes are in common with the phenotype of failing cardiac myocytes on the protein level. These altered proteins may act individually as contributors to heart failure, which is observed after overexpression of CaMKIIδ(C) in genetically altered mice.

Myocardial adaptation of energy metabolism to elevated preload depends on calcineurin activity : a proteomic approach.

Chronic hemodynamic overload on the heart results in pathological myocardial hypertrophy, eventually followed by heart failure. Phosphatase calcineurin is a crucial mediator of this response. Little is known, however, about the role of calcineurin in response to acute alterations in loading conditions of the heart, where it could be mediating beneficial adaptational processes. We therefore analyzed proteome changes following a short-term increase in preload in rabbit myocardium in the absence or presence of the calcineurin inhibitor cyclosporine A. Rabbit right ventricular isolated papillary muscles were cultivated in a muscle chamber system under physiological conditions and remained either completely unloaded or were stretched to a preload of 3 mN/mm(2), while performing isotonic contractions (zero afterload). After 6 h, proteome changes were detected by two-dimensional gel electrophoresis and ESI-MS/MS. We identified 28 proteins that were upregulated by preload compared to the unloaded group (at least 1.75-fold regulation, all P < 0.05). Specifically, mechanical load upregulated a variety of enzymes involved in energy metabolism (i.e., aconitase, pyruvate kinase, fructose bisphosphate aldolase, ATP synthase alpha chain, acetyl-CoA acetyltransferase, NADH ubiquinone oxidoreductase, ubiquinol cytochrome c reductase, hydroxyacyl-CoA dehydrogenase). Cyclosporine A treatment (1 micromol/l) abolished the preload-induced upregulation of these proteins. We demonstrate for the first time that an acute increase in the myocardial preload causes upregulation of metabolic enzymes, thereby increasing the capacity of the myocardium to generate ATP production. This short-term adaptation to enhanced mechanical load appears to critically depend on calcineurin phosphatase activity.

Relevance of brain natriuretic peptide in preload-dependent regulation of cardiac sarcoplasmic reticulum Ca2+ ATPase expression.

BACKGROUND: In heart failure (HF), ventricular myocardium expresses brain natriuretic peptide (BNP). Despite the association of elevated serum levels with poor prognosis, BNP release is considered beneficial because of its antihypertrophic, vasodilating, and diuretic properties. However, there is evidence that BNP-mediated signaling may adversely influence cardiac remodeling, with further impairment of calcium homeostasis. METHODS AND RESULTS: We studied the effects of BNP on preload-dependent myocardial sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) expression. In rabbit isolated muscle strips stretched to high preload and shortening isotonically over 6 hours, the SERCA/glyceraldehyde phosphate dehydrogenase mRNA ratio was enhanced by 168% (n=8) compared with unloaded preparations (n=8; P<0.001). Recombinant human BNP at a concentration typically found in end-stage HF patients (350 pg/mL) abolished SERCA upregulation by stretch (n=9; P<0.0001 versus BNP free). Inhibition of cyclic guanosine 3',5' monophosphate (cGMP)-phosphodiesterase-5 mimicked this effect, whereas inhibition of cGMP-dependent protein kinase restored preload-dependent SERCA upregulation in the presence of recombinant human BNP. Furthermore, in myocardium from human end-stage HF patients undergoing cardiac transplantation (n=15), BNP expression was inversely correlated with SERCA levels. Moreover, among 23 patients treated with left ventricular assist devices, significant SERCA2a recovery occurred in those downregulating BNP. CONCLUSIONS: Our data indicate that preload stimulates SERCA expression. BNP antagonizes this mechanism via guanylyl cyclase-A, cGMP, and cGMP-dependent protein kinase. This novel action of BNP to uncouple preload-dependent SERCA expression may adversely affect contractility in patients with HF.

Pressure overload and neurohumoral activation differentially affect the myocardial proteome.

Treatment with monocrotaline causes pulmonary hypertension in rats. This results in severe pressure overload-induced hypertrophy of the right ventricles, whilst the normally loaded left ventricles do not hypertrophy. Both ventricles are affected by enhanced neuroendocrine stimulation in this model. We analyzed in this model load-induced and catecholamine-induced changes of right and left ventricular proteome by two-dimensional gel electrophoresis, tryptic in-gel digest, and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. All analyzed animals showed right ventricular hypertrophy without signs of heart failure. Changes of 27 proteins in the right and 21 proteins in the left ventricular myocardium were found. Given the hemodynamic features of this animal model, proteome changes restricted to the right ventricle are caused by pressure overload. We describe for the first time a potentially novel pathway (BRAP2/BRCA1) that is involved in myocardial hypertrophy. Furthermore, we demonstrate that increased afterload-induced hypertrophy leads to striking changes in the energy metabolism with down-regulation of pyruvate dehydrogenase (subunit beta E1), isocitrate dehydrogenase, succinyl coenzyme A ligase, NADH dehydrogenase, ubiquinol-cytochrome C reductase, and propionyl coenzyme A carboxylase. These changes go in parallel with alterations of the thin filament proteome (troponin T, tropomyosin), probably associated with Ca(2+) sensitization of the myofilaments. In contrast, neurohumoral stimulation of the left ventricle increases the abundance of proteins relevant for energy metabolism. This study represents the first in-depth analysis of global proteome alterations in a controlled animal model of pressure overload-induced myocardial hypertrophy.

Excessive sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression causes increased sarcoplasmic reticulum Ca2+ uptake but decreases myocyte shortening.

BACKGROUND: Increasing sarcoplasmic/endoplasmic reticulum (SR) Ca2+-ATPase (SERCA) uptake activity is a promising therapeutic approach for heart failure. We investigated the effects of different levels of SERCA1a expression on contractility and Ca2+ cycling. We tested whether increased SERCA1a expression levels enhance myocyte contractility in a gene-dose-dependent manner. METHODS AND RESULTS: Rabbit isolated cardiomyocytes were transfected at different multiplicities of infection (MOIs) with adenoviruses encoding SERCA1a (or beta-galactosidase as control). Myocyte relaxation half-time was decreased by 10% (P=0.052) at SERCA1a MOI 10 and by 28% at MOI 50 (P<0.05). Myocyte fractional shortening was increased by 12% at MOI 10 (P<0.05) but surprisingly decreased at MOI 50 (-22%, P<0.05) versus control. SR Ca2+ uptake (in permeabilized myocytes) demonstrated a gene-dose-dependent decrease in K(m) by 29% and 46% and an increase in Vmax by 37% and 72% at MOI 10 and MOI 50, respectively (all P<0.05 versus control). Ca2+ transient amplitude was increased in Ad-SERCA1a-infected myocytes at MOI 10 (by 121%, P<0.05), but at MOI 50, the Ca2+ transient amplitude was not significantly changed. Caffeine-induced Ca2+ transients indicated significantly increased SR Ca2+ content in Ad-SERCA1a-infected cells, by 72% at MOI 10 and by 87% at MOI 50. Mathematical simulations demonstrate that the functional increase in SR Ca2+-ATPase uptake activity at MOI 50 (and increased cytosolic Ca2+ buffering) is sufficient to curtail the Ca2+ transient amplitude and explain the reduced contraction. CONCLUSIONS: Moderate SERCA1a gene transfer and expression improve contractility and Ca(2+) cycling. However, higher SERCA1a expression levels can impair myocyte shortening because of higher SERCA activity and Ca2+ buffering.

Mechanical load-dependent regulation of gene expression in monocrotaline-induced right ventricular hypertrophy in the rat.

Rats treated with monocrotaline (MCT) develop pulmonary hypertension. Their right ventricles (RVs) exhibit severe pressure overload-induced hypertrophy, whereas the left ventricles (LVs) are normally loaded. In contrast, enhanced neuroendocrine stimulation during the transition to heart failure affects both ventricles. We assessed gene expression levels of Ca2+-regulating proteins in RVs and LVs of control and MCT rats in transition to heart failure to identify biomechanical load-regulated genes. In MCT RVs, both mRNA and protein levels of the Ca2+-ATPase of the sarcoplasmic/endoplasmic reticulum (SERCA2a) were reduced by 36% (P=0.001) and 17% (P=0.016), respectively, compared with control RVs. Phospholamban and ryanodine receptor mRNA levels likewise were reduced (by 27% [P=0.05] and 21% [P=0.011], respectively) in MCT RVs, whereas sarcolemmal Na+-Ca2+ exchanger expression was not altered. MCT LVs exhibited no significant expression changes compared with control LVs. Isometrically contracting MCT intact RV trabeculae showed enhanced baseline force development. Although control RV preparations exhibited a positive force-frequency relationship, MCT RVs showed a negative force-frequency relationship and blunted postrest potentiation. Contractile function of MCT LV trabeculae was normal. Maximum Ca2+-activated tension was enhanced by 64% in permeabilized RV MCT preparations (P=0.013). beta-Myosin heavy chain protein was upregulated in MCT RVs (P<0.001) but unaltered in MCT LVs. Degradation of troponin T was prominent in MCT RVs, a phenomenon not observed in the LV. Enhanced biomechanical load is necessary to induce the gene expression changes associated with the hypertrophic phenotype of the pressure-overloaded RV. Neuroendocrine factors, which equally affect both chambers, are not sufficient to alter the expression of Ca2+-cycling proteins.

Is laparoscopy an advantage in the diagnosis of cirrhosis in chronic hepatitis C virus infection?

AIM: To evaluate the potential of laparoscopy in the diagnosis of cirrhosis and outcome of interferon treatment in HCV-infected patients. METHODS: In this retrospective study, diagnostic laparoscopy with laparoscopic liver biopsy was performed in 72 consecutive patients with chronic HCV infection. The presence or absence of cirrhosis was analyzed macroscopically by laparoscopy and microscopically by liver biopsy specimens. Clinical and laboratory data and outcome of interferon-alfa treatment were compared between cirrhotic and noncirrhotic patients. RESULTS: Laparoscopically, cirrhosis was seen in 29.2 % (21/72) and non-cirrhosis in 70.8 % (51/72) of patients. Cirrhotic patients were significantly older with a significant longer duration of HCV infection than noncirrhotic patients. Laboratory parameters (AST, y-GT, y-globulin fraction) were measured significantly higher as well as significantly lower (prothrombin index, platelet count) in cirrhotic patients than in non-cirrhotic patients. Histologically, cirrhosis was confirmed in 11.1 % (8/72) and non cirrhosis in 88.9 % (64/72). Patients with macroscopically confirmed cirrhosis (n=21) showed histologically cirrhosis in 38.1 % (8/21) and histologically non-cirrhosis in 61.9 % (13/21). In contrast, patients with macroscopically non-cirrhosis (n=51) showed histologically non cirrhosis in all cases (51/51). Thirty-nine of 72 patients were treated with interferon-alfa, resulting in 35.9 % (14/39) patients with sustained response and 64.1 % (25/39) with non response. Non-responders showed significantly more macroscopically cirrhosis than sustained responders. In contrast, there were no significant histological differences between non-responders and sustained responders. CONCLUSION: Diagnostic laparoscopy is more accurate than liver biopsy in recognizing cirrhosis in patients with chronic HCV infection. Liver biopsy is the best way to assess inflammatory grade and fibrotic stage. The invasive marker for staging, prognosis and management, and treatment outcome of chronic HCV-infected patients need further research and clinical trials. Laparoscopy should be performed for recognition of cirrhosis if this parameter is found to be of prognostic and therapeutic relevance in patients with chronic HCV infection.