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Zusammenfassung Die Prävalenz der Fettlebererkrankung hat in den letzten Jahren auch in Deutschland erheblich zugenommen. Sie gehört mit geschätzten 18 Mio. betroffenen Bundesbürgern mittlerweile zu den großen Volkskrankheiten. Sie gilt ferner als ein relevanter unabhängiger Risikofaktor für weitere kardiovaskuläre Volkskrankheiten wie Herzinfarkt oder Schlaganfall. Schließlich begünstigt ein Diabetes mellitus die Entstehung einer Fettleber und eines ungünstigeren Verlaufs der Fettlebererkrankung. Vor dem Hintergrund der hohen Prävalenz und Komplikationen kommt das deutsche Gesundheitssystem bei der Versorgung dieser Patienten an die Grenzen seiner Ressourcen.Daher ist eine enge Abstimmung und Vernetzung aller an der Behandlung dieser Patienten beteiligten Fachgebiete und Versorgungsbereiche essenziell notwendig. In einem Expertenkonsensus unter Einbindung niedergelassener Kollegen und Krankenhausärzten der Gastroenterologie, Endokrinologie, Kardiologie, Hausärzten und Labormedizinern sowie in enger Abstimmung mit Patientenvertretern haben wir ein Konzept der Versorgung dieser Patienten im deutschen Gesundheitssystem entworfen. Darin werden auch notwendige Entwicklungen adressiert. Neben dem Nutzen als praxisnahem Leitfaden soll dies auch die gesundheitspolitische Arbeit unterstützen, insbesondere bei der Erarbeitung von praktischen Versorgungslösungen auf medizinischer Ebene.

Introduction Despite extremely high and seemingly rising prevalence of non-alcoholic fatty liver disease (NAFLD), awareness for this health condition is still low. In the present study we analyzed, if this is reflected in clinical routine for advanced diagnostic measures. Methods Retrospective data of 93 patients with histologically determined fibrosis stage and confirmed etiology was analyzed. Patients were grouped according to chronic liver disease alone (n=40), concomitant chronic liver disease and NAFLD (n=29), or NAFLD alone (n=24). Fibrosis stage and presence of cirrhosis were main outcome measures. Results Patients with NAFLD were significantly older and had significantly higher body mass index and CAP-values than patients with chronic liver disease. Significantly higher fibrosis stages were observed in patients with NAFLD than in those with chronic liver disease alone (p=0.003). Presence of cirrhosis was significantly higher in patients with NAFLD than in patients with chronic liver disease (p=0.01). This was not associated with a significantly different age distribution over fibrosis stages between chronic liver disease and NAFLD. Undergoing liver biopsy 10 years earlier could have possibly prevented progression to cirrhosis in up to 7 patients with NAFLD. This could have potentially saved 35,000 € yearly health care resources. Conclusion These findings suggest that the time course for development of liver fibrosis and cirrhosis is not fundamentally different between patients with NAFLD or with other chronic liver diseases. Higher rates of cirrhosis observed in patients with NAFLD could potentially be ameliorated by earlier diagnostic work-up and improved monitoring.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Importantly, NAFLD increases the risk for cardiovascular disease (CVD). A causal relationship has been substantiated. Given the pandemic proportions of NAFLD, a reliable scoring system for predicting the risk of NAFLD-associated CVD is an urgent medical need. We here review cumulative evidence suggesting that systemically released organokines - especially certain adipokines, hepatokines, and cardiokines - may serve this purpose. The underlying rationale is that these signalers directly communicate between white adipose tissue, liver, and heart as key players in the pathogenesis of NAFLD and resultant CVD events. Moreover, evidence suggests that these organ-specific cytokines are secreted in a biologically predetermined, cascade-like pattern. Consequently, upon pinpointing organokines of relevance, we sketch requirements to establish an algorithm predictive of the CVD risk in patients with NAFLD. Such an algorithm, as to be consolidated in the form of an applicable equation, may be improved continuously by machine learning. To the best of our knowledge, such an option has not yet been considered. Establishing and implementing a reliable algorithm for determining the NAFLD-associated CVD risk has the potential to save many NAFLD patients from life-threatening CVD events.

Background: In current general practice, elevated serum concentrations of liver enzymes are still regarded as an indicator of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In this study, we analyzed if an adjustment of the upper limit of normal (ULN) for serum liver enzymes can improve their diagnostic accuracy. Methods: Data from 363 morbidly obese patients (42.5 ± 10.3 years old; mean BMI: 52 ± 8.5 kg/m2), who underwent bariatric surgery, was retrospectively analyzed. NAFL and NASH were defined histologically according to non-alcoholic fatty liver activity score (NAS) and according to steatosis activity fibrosis (SAF) score for 2 separate analyses, respectively. Results: In 121 women (45%) and 45 men (46%), elevated values for at least one serum parameter (ALT, AST, γGT) were present. The serum concentrations of ALT (p < 0.0001), AST (p < 0.0001) and γGT (p = 0.0023) differed significantly between NAFL and NASH, irrespective of the applied histological classification method. Concentrations of all 3 serum parameters correlated significantly positively with the NAS and the SAF score, with correlation coefficients between 0.33 (ALT/NAS) and 0.40 (γGT/SAF). The area under the curves to separate NAFL and NASH by liver enzymes achieved a maximum of 0.70 (ALT applied to NAS-based classification). For 95% specificity, the ULN for ALT would be 47.5 U/L; for 95% sensitivity, the ULN for ALT would be 17.5 U/L, resulting in 62% uncategorized patients. Conclusion: ALT, AST, and γGT are unsuitable for non-invasive screening or diagnosis of NAFL or NASH. Utilizing liver enzymes as an indicator for NAFLD or NASH should generally be questioned.

The role of visceral white adipose tissue (vWAT) in the progression of non-alcoholic liver disease (NAFLD) with its sub entities non-alcoholic fatty liver and steatohepatitis (NAFL; NASH) is underinvestigated. We thus explored mechanisms of fibrosis and regulated cell death in vWAT and liver tissue. In NAFLD, women displayed significantly more fibrosis in vWAT than men, and collagen 1α mRNA expression was significantly upregulated. The degrees of fibrosis in vWAT and liver tissue correlated significantly. The size of vWAT-resident adipocytes in NAFLD correlated negatively with the local degree of fibrosis. The extent of apoptosis, as measured by circulating M30, positively correlated with the degree of fibrosis in vWAT; necrosis-associated HMGB1 mRNA expression was significantly downregulated in vWAT and liver tissue; (iii) necroptosis-related RIPK-3 mRNA expression was significantly upregulated in vWAT; and autophagy-related LC3 mRNA expression was significantly downregulated in vWAT, while upregulated in the liver. Thus, the different cell death mechanisms in the vWAT in NAFLD are regulated independently while not ruling out their interaction. Fibrosis in vWAT may be associated with reduced adipocyte size and thus partially protective against NAFLD progression. Abbreviations: ATG5: autophagy related 5; BAS: bariatric surgery; BMI: body mass index; ELISA: enzyme-linked immunosorbent assay; EtOH: ethanol; FFAs: free fatty acids; HCC: hepatocellular carcinoma; HMGB1: high-mobility group box 1 protein; IHC: immunohistochemistry; IL: interleukin; LC3: microtubule-associated proteins 1A/1B light chain 3B; M30: neoepitope K18Asp396-NE displayed on the caspase-cleaved keratin 18 fragment; M65: epitope present on both caspase-cleaved and intact keratin 18; NAFL: non-alcoholic fatty liver; NAFLD: non-alcoholic fatty liver disease; NAS: NAFLD activity score; NASH: non-alcoholic steatohepatitis; NLRP3: nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3; qRT-PCR: quantitative real-time polymerase-chain reaction; r: Pearson’s correlation coefficient (r); rs: Spearman’s rank correlation coefficient; RIPK3: receptor-interacting serine/threonine-protein kinase 3; T2DM: type 2 diabetes mellitus (T2DM); TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling; vWAT: visceral WAT; WAT: white adipose tissue. CA extern

Background: Prevalence of non-alcoholic fatty liver disease (NAFLD) in the German population is 20–30%. Liver biopsy to detect non-alcoholic steatohepatitis (NASH) let alone for NAFLD monitoring is not feasible. Current practice regards elevated serum concentrations of liver enzymes as indicator for NAFLD or NASH. In this study we analyzed if an adjustment of the upper limit of normal (ULN) ​​for serum liver enzymes can improve their diagnostic accuracy. Methods: Data from 363 morbidly obese patients (42.5±10.3 years old; mean BMI: 52±8.5 kg/m²), who underwent bariatric surgery were retrospectively analyzed. All patients had histologically confirmed NAFL or NASH (NAS and SAF). Results: In 121 women (45%) and 45 men (46%) elevated values ​​for at least one serum parameter (ALT, AST, γGT) were present. The serum concentrations of ALT (p Conclusion: ALT, AST and GGT are unsuitable for non-invasive screening or diagnosis of NAFL or NASH. Utilizing liver enzymes as an indicator for NAFLD/NASH should generally be questioned.

Background and aims: Hepatic steatosis is the basis of non-alcoholic fatty liver disease (NALFD). Mere fat accumulation within hepatocytes is considered the mild form of NAFLD, but can progress in some patients to advanced steatohepatitis (NASH), which may lead to fibrosis, cirrhosis or hepatocellular carcinoma. However, even hepatic steatosis alone may be a risk factor for cardiovascular disease (CVD). Patients and methods: In the present real life study 106 patients from the outpatient clinic of the Department for Gastroenterology and Hepatology with either NAFLD (n = 60) or other typical diagnoses (n = 46) were included. Ultrasound examination identified 77 patients with hepatic steatosis. Liver enzymes, lipid profile, surrogate cell death markers, and adiponectin were determined. Transient elastography (Fibroscan®) and bioelectrical impedance analysis (BIA) were performed. Results: Mean patient age was 46 years (23 - 62) for non-NAFLD and 53 years (18 - 71) for the NAFLD group. ALT and AST did not differ significantly between the two groups. Adiponectin and HDL were significantly lower in NAFLD (p

Introduction: Liver parameters are associated with cardiovascular disease risk and severity of stenosis. It is unclear whether liver parameters could predict the long-term outcome of patients after acute myocardial infarction (AMI). We performed an unbiased analysis of the predictive value of serum parameters for long-term prognosis after AMI. Material and methods: In a retrospective, observational, single-center, cohort study, 569 patients after AMI were enrolled and followed up until 6 years for major adverse cardiovascular events, including cardiac death. Patients were classified into non-survivors (n = 156) and survivors (n = 413). Demographic and laboratory data were analyzed using ensemble feature selection (EFS) and logistic regression. Correlations were performed for serum parameters. Results: Age (73; 64; p < 0.01), alanine aminotransferase (ALT; 93 U/l; 40 U/l; p < 0.01), aspartate aminotransferase (AST; 162 U/l; 66 U/l; p < 0.01), C-reactive protein (CRP; 4.7 U/l; 1.6 U/l; p < 0.01), creatinine (1.6; 1.3; p < 0.01), γ-glutamyltransferase (GGT; 71 U/l; 46 U/l; p < 0.01), urea (29.5; 20.5; p < 0.01), estimated glomerular filtration rate (EGFR; 49.6; 61.4; p < 0.01), troponin (13.3; 7.6; p < 0.01), myoglobin (639; 302; p < 0.01), and cardiovascular risk factors (hypercholesterolemia p < 0.02, family history p < 0.01, and smoking p < 0.01) differed significantly between non-survivors and survivors. Age, AST, CRP, EGFR, myoglobin, sodium, urea, creatinine, and troponin correlated significantly with death (r = -0.29; 0.14; 0.31; -0.27; 0.20; -0.13; 0.33; 0.24; 0.12). A prediction model was built including age, CRP, EGFR, myoglobin, and urea, achieving an AUROC of 77.6% to predict long-term survival after AMI. Conclusions: Non-invasive parameters, including liver and renal markers, can predict long-term outcome of patients after AMI. CA - Canbay

Ischemic postconditioning (PoCo) reduces infarct size following myocardial ischemia/reperfusion. To protect, PoCo must be performed early during reperfusion, and causal cardioprotective signaling must occur then. The role of microRNA (miRNA) in PoCo is unclear. Anesthetized pigs were subjected to 60 min left anterior descending coronary artery (LAD) occlusion and 180 min reperfusion. Immediate full reperfusion (IFR, n = 5) was compared to PoCo (four cycles of 60 s/60 s reperfusion/reocclusion, n = 5). Transmural myocardial biopsies from the LAD territory were sampled at baseline, 60 min ischemia, 10 and 180 min reperfusion. RNA was isolated. The expression of 11 miRNAs, including muscle-specific (miRNA-1, -133a, -206, -208b, -214, and -499), fibrosis- (miRNA-21, -24, and -29b), neovascularization- (miRNA-92a), and inflammation-associated (miRNA-146b) candidates, was quantified using real-time PCR (RT-PCR). mRNA expression at baseline and 180 min reperfusion was quantified and validated (microarray and RT-PCR). PoCo reduced infarct size from 44.9 ± 7.7 to 34.8 ± 5.3 % of the area at risk. The expression of miRNA-1, -24, -29b, -133a, -146b, -208b, and -499 was increased at 10 min reperfusion with PoCo vs. IFR; however, that of miRNA-1, -24, -208b, and -499 was already increased at 60 min ischemia and probably reflects falsely positive results. Five mRNAs were different with PoCo vs. IFR. In silico analysis identified a tentative connection between three miRNAs and five mRNAs with the biological functions “cell death”, “inflammatory response” and/or “glucose metabolism”. If at all, only miRNA-29b, -133a, and -146b fulfill the minimal temporal requirements for a potential causal involvement in cardioprotection by PoCo.

BACKGROUND Red blood cell (RBC) aggregation influences blood flow properties, impacts blood microcirculation and consequently oxygen delivery. Different methods are established to determine RBC aggregation: under static conditions (i.e. the RBC adhesiveness/aggregation test (EAAT)) or under shear conditions (i.e. the laser-assisted optical rotational cell analyzer (LORCA)). OBJECTIVE Comparison of these two different methods in detecting the RBC aggregation of patients with coronary artery disease (CAD) and of healthy controls. METHODS RBC aggregation was quantified in peripheral venous blood of patients with CAD and healthy controls using EAAT and LORCA. RESULTS Both methods detected an increased RBC aggregation in patients with CAD compared to the healthy control group: the ratio of clot-free area to whole area (rCFA) detected with EAAT (15.65 vs. 11.30%), and aggregation index (66.33 vs. 53.90%), shear rate of disaggregation (SDA) (105.59 vs. 69.21 s-1), and upstroke/ttop (0.03 vs. 0.02 au/s) detected with LORCA device were increased, aggregation half time (detected with LORCA) was decreased (2.11 vs. 3.60 s). rCFA (EAAT) correlated with SDA (LORCA). CONCLUSIONS Both methods determine an increased RBC aggregation in patients with CAD. However, only one measurement parameter of the LORCA seems to reflect the same RBC aggregation properties as the EAAT.

Stent implantation into aortocoronary saphenous vein grafts (SVG) releases particulate debris and soluble vasoactive mediators, for example, serotonin. We now analyzed effects of the soluble mediators released into the coronary arterial blood during stent implantation on vasomotion of isolated rat epicardial coronary artery segments and on coronary flow and left ventricular developed pressure in isolated perfused rat hearts. Coronary blood was retrieved during percutaneous SVG intervention using a distal occlusion/aspiration protection device in nine symptomatic patients with stable angina pectoris and a flow-limiting SVG stenosis. The blood was separated into particulate debris and plasma. Responses to coronary plasma were determined in isolated rat epicardial coronary arteries and in isolated, constant pressure-perfused rat hearts (±nitric oxide synthase [NOS] inhibition and ±serotonin receptor blockade, respectively). Coronary aspirate plasma taken after stent implantation induced a stronger vasoconstriction of rat epicardial coronary arteries (52 ± 8% of maximal potassium chloride induced vasoconstriction [% KClmax = 100%]) than plasma taken before stent implantation (12 ± 8% of KClmax); NOS inhibition augmented this vasoconstrictor response (to 110 ± 15% and 24 ± 9% of KClmax). Coronary aspirate plasma taken after stent implantation reduced in isolated perfused rat hearts only under NOS inhibition coronary flow by 17 ± 3% and left ventricular developed pressure by 25 ± 4%. Blockade of serotonin receptors abrogated these effects. Coronary aspirate plasma taken after stent implantation induces vasoconstriction in isolated rat epicardial coronary arteries and reduces coronary flow and left ventricular developed pressure in isolated perfused rat hearts with pharmacologically induced endothelial dysfunction. CA Kleinbongard

Objective Stent implantation into atherosclerotic coronary vessels induces the release of particulate debris and soluble vasoactive substances, which impair downstream microvascular function. Microvascular perfusion, however, is also determined by hemorheological parameters. We therefore analyzed now changes in erythrocyte (RBC) aggregation in coronary arterial blood during stent implantation. Methods Symptomatic male patients with stable angina pectoris and stenosis in their native right coronary artery (RCA) or saphenous vein graft on right coronary artery (SVG-RCA) were enrolled. Coronary arterial blood was taken before and coronary aspirate during stent implantation with a distal occlusion/aspiration device. RBC aggregation was determined using the erythrocyte adhesiveness/aggregation test. The ratio of clot-free area to whole area of a spread blood drop was quantified (rCFA). To evaluate the impact of soluble factors within aspirate plasma on RBC aggregation, separated RBCs of healthy volunteers were exposed to patients' coronary arterial blood and aspirate samples. Results rCFA was comparably increased in coronary aspirate of RCAs and SVG-RCAs after stent implantation (RCA: 25.7±2.1 vs. 32.2±2.1%; SVG-RCA: 28.9±1.9 vs. 33.3±2.0%, P

Implantation of bare metal stents (BMS) induces the release not only of particulate debris, but also of soluble vasoconstrictors which contribute to microvascular impairment. So this study aimed at addressing the potential attenuation of such vasoconstriction using paclitaxel eluting stents (PES). Using a distal protection/aspiration device, coronary arterial blood was retrieved before and during stent [n = 14 BMS, n = 14 PES, n = 3 sirolimus eluting stents (SES)] implantation in patients with saphenous vein aorto-coronary bypass stenosis and analyzed for plasma serotonin and thromboxane B(2) concentrations. The vasoconstriction of rat mesenteric arteries with intact (+E) and denuded (-E) endothelium in response to coronary arterial or aspirate plasma was quantified and normalized to that by potassium chloride (KCl(max) = 100%). Coronary arterial plasma before stent implantation induced a vasoconstriction of 30-43%, which was independent of endothelial integrity. Serotonin-release was 2.2 ± 0.5 μmol/l with BMS and 2.0 ± 0.4 μmol/l with PES, thromboxane B(2)-release was 26 ± 5 pg/ml with BMS and 22 ± 8 pg/ml with PES. BMS- and SES-aspirate plasma induced a vasoconstriction of 68 ± 18% (+E)/93 ± 14% (-E) and 81 ± 17% (+E)/124 ± 14% (-E), respectively. In contrast, PES-aspirate plasma induced only minor vasoconstriction of 8 ± 3% (+E)/12 ± 5% (-E). Addition of paclitaxel to BMS-aspirate plasma attenuated vasoconstriction. PES-aspirate induced microtubular condensation in immunofluorescence microscopy. Results indicate that aspirate from PES implantation attenuates vasoconstriction, possibly secondary to microtubular stabilization. Such acute downstream vascular paralysis could be beneficial in preventing a no-reflow phenomenon in patients undergoing stenting.

Supplemental Digital Content is available in the text, Detection of high-risk subjects in acute myocardial infarction (AMI) by noninvasive means would reduce the need for intracardiac catheterization and associated complications. Liver enzymes are associated with cardiovascular disease risk. A potential predictive value for liver serum markers for the severity of stenosis in AMI was analyzed. Patients with AMI undergoing percutaneous coronary intervention (PCI; n = 437) were retrospectively evaluated. Minimal lumen diameter (MLD) and percent stenosis diameter (SD) were determined from quantitative coronary angiography. Patients were classified according to the severity of stenosis (SD ≥ 50%, n = 357; SD

Aims Myocardial injury reflected by a post-procedural increase of serum troponin I (TnI) occurs frequently during transcatheter aortic valve implantation (TAVI). It is potentially caused by intraprocedural hypotension, periprocedural coronary microembolisation and post-procedural (para)valvular leakages (PVLs). We invasively assessed coronary flow dynamics including coronary flow velocity reserve (CFVR), embolic high-intensity transient signals (HITS) as well as rapid pacing induced hypotension and post-procedural PVLs to determine their contribution to post-procedural TnI increases. Methods and results In 15 transfemoral TAVI patients, TnI was measured serially, and cardiac MRIs with late gadolinium enhancement (LGE) were performed pre- and post-interventionally. There were no significant correlations between coronary flow dynamics, CFVR and the area under the curve (AUC) of TnI over 72 hours. Despite the detection of HITS in all patients and during all procedural steps, there was also no correlation between the amount of HITS and the AUC of TnI. However, there were positive correlations between the duration of rapid pacing as well as the time of subsequent blood pressure recovery and the AUC of TnI. Both LGE and more than mild PVL were observed in a single case only. Conclusions Myocardial injury after TAVI appears to be related more to hypoperfusion-induced ischaemia than to periprocedural microembolisation.

Objective Stent implantation into atherosclerotic coronary vessels impacts on downstream microvascular function and induces the release of particulate debris and soluble substances, which differs qualitatively and quantitatively between native right coronary arteries (RCAs) and saphenous vein grafts on right coronary arteries (SVG-RCAs). We have now quantified the release of microparticles (MPs) during stent implantation into stable atherosclerotic lesions and compared the release between RCAs and SVG-RCAs. Methods In symptomatic, male patients with stable angina and a stenosis in their RCA or SVG-RCA, respectively (n = 14/14), plaque volume and composition were analyzed using intravascular ultrasound before stent implantation. Coronary aspirate was retrieved during stent implantation with a distal occlusion/aspiration device and divided into particulate debris and plasma. Particulate debris was weighed. Platelet-derived MPs (PMPs) were distinguished by flow cytometry as CD41+, endothelium-derived MPs (EMPs) as CD144+, CD62E+ and CD31+/CD41-, leukocyte-derived MPs as CD45+, and erythrocyte-derived MPs as CD235+. Results In patients with comparable plaque volume and composition in RCAs and SVG-RCAs, intracoronary PMPs and EMPs were increased after stent implantation into their RCAs and SVG-RCAs (CD41+: 2729.6±645.6 vs. 4208.7±679.4 and 2355.9±503.9 vs. 3285.8±733.2 nr/µL; CD144+: 451.5±87.9 vs. 861.7±147.0 and 444.6±74.8 vs. 726.5±136.4 nr/µL; CD62E+: 1404.1±247.7 vs. 1844.3±378.6 and 1084.6±211.0 vs. 1783.8±384.3 nr/µL, P

Background: A postprocedural increase of the serum troponin I concentration (TnI) reflects myocardial injury and occurs frequently during transcatheter aortic valve implantation (TAVI). Periprocedural coronary microembolization is a potential cause of such injury. We therefore evaluated each step of the transfemoral TAVI procedure for coronary embolization using intracoronary Doppler (ICD) in the left anterior descending (LAD) artery. Methods: 15 high-risk patients with severe, symptomatic aortic valve stenosis (age 79 ± 45 yrs; EuroScore 17 ± 4%) who underwent transfemoral TAVI using the balloon-expandable Edwards bioprosthesis were included. ICD examinations were recorded and evaluated off-line for high-intensity transient signals (HITS). Perioperative concentrations of TnI were serially measured within the first 72 h after TAVI, and a cardiac MRI with late gadolinium-enhancement (LGE) was performed within 7 days. Results: HITS were detected in all patients (figure 1), mostly during the initial crossing of the native valve and positioning of the prosthesis with subsequent implantation. TnI peaked at 24 h after TAVI (3.17 ng/ml), and LGE was observed in only one single case. There was no correlation between amount of HITS and TnI area under the curve in the first 72 h after TAVI. Conclusions: Procedural HITS were detected by ICD in all patients undergoing transfemoral TAVI. The highest amount of HITS was observed during initial valve passage and positioning of the prosthesis with subsequent implantation. However, no association was found between the number of HITS and myocardial injury, as reflected by increased serum TnI concentrations or LGE on cardiac MRI.

Background: A postprocedural increase of the serum troponin I concentration (TnI) reflects myocardial injury and occurs frequently during transcatheter aortic valve implantation (TAVI). Periprocedural coronary microembolization is a potential cause of such injury. We therefore evaluated each step of the transfemoral TAVI procedure for coronary embolization using intracoronary Doppler (ICD) in the left anterior descending (LAD) artery. Methods: 15 high-risk patients with severe, symptomatic aortic valve stenosis (age 79 ± 45 yrs; EuroScore 17 ± 4%) who underwent transfemoral TAVI using the balloon-expandable Edwards bioprosthesis were included. ICD examinations were recorded and evaluated off-line for high-intensity transient signals (HITS). Perioperative concentrations of TnI were serially measured within the first 72 h after TAVI, and a cardiac MRI with late gadolinium-enhancement (LGE) was performed within 7 days. Results: HITS were detected in all patients (figure 1), mostly during the initial crossing...

Stent implantation into atherosclerotic coronary arteries releases particulate debris and soluble substances that contribute to impaired microvascular perfusion. Here we addressed the potential for microvascular obstruction in patients with stenotic native right coronary arteries (nRCA) compared with saphenous vein grafts on right coronary arteries (SVG-RCA). We enrolled symptomatic, male patients with stable angina pectoris and a flow-limiting stenosis in their nRCA or SVG-RCA ( n = 18/18). Plaque volume and composition were analyzed using intravascular ultrasound before stent implantation. Coronary aspirate was retrieved during stent implantation under protection with a distal occlusion/aspiration device and divided into particulate debris and plasma. The release of catecholamines, endothelin, serotonin, thromboxane B2, and tumor necrosis factor-α was measured. The response of rat mesenteric arteries with intact (+E) and denuded (−E) endothelium to aspirate plasma (without and with selective endothelin receptor blockade) was normalized to that by potassium chloride (KClmax = 100%). Plaque volume and composition were not different between nRCA and SVG-RCA. There was less particulate debris (65 ± 8 vs. 146 ± 23 mg; P < 0.05) and more endothelin release (5.8 ± 0.8 vs. 1.3 ± 0.7 pg/ml; P < 0.05) in nRCA than in SVG-RCA, whereas the release of the other mediators was not different. Aspirate from nRCA induced stronger vasoconstriction than that from SVG-RCA [nRCA, 78 ± 6% (+E)/84 ± 5% (−E); SVG-RCA, 59 ± 6% (+E)/68 ± 3% (−E); P < 0.05 nRCA vs. SVG-RCA], which was attenuated by a nonspecific endothelin and a specific endothelin receptor A antagonist. Thus coronary aspirate from stented nRCA is characterized by less debris but more endothelin and stronger vasoconstrictor response than that from SVG-RCA.

Background Patients with diabetes mellitus (DM) have an increased risk for periprocedural complications and adverse cardiac events after percutaneous coronary intervention. We addressed the potential for coronary microvascular obstruction and restenosis in patients with and without DM undergoing stenting for saphenous vein bypass graft (SVG) stenosis under protection with a distal occlusion/aspiration device. Methods SVG plaque volume and composition were analyzed using intravascular ultrasound before stent implantation. Percent diameter stenosis was determined from quantitative coronary angiography before, immediately after and 6 months after stent implantation. Coronary aspirate was retrieved during stent implantation and divided into particulate debris and plasma. Total calcium, several vasoconstrictors, and tumor necrosis factor (TNF)α in particulate debris and coronary aspirate plasma were determined. Results Patients with and without DM had similar plaque volume, but larger necrotic core and greater particulate debris release in patients with than without DM (20.3±2.7 vs. 12.7±2.6% and 143.9±19.3 vs. 75.1±10.4 mg, Pvs. 5.1±2.4 pmol/mg and 2.2±0.7 vs. 1.1±0.2 pmol/L, Pvs. 6.34±1.11%, PP Conclusion In diabetics, particulate debris and coronary aspirate plasma contained more TNFα, which might reflect the activity of the underlying atherosclerotic process. Trial registration URL: http://www.clinicaltrials.gov/ct2/results?term=NCT01430884; unique identifier: NCT01430884

Plaque vulnerability plays an important role in acute coronary events and in coronary microembolization during percutaneous coronary intervention (PCI). Modern intravascular imaging modalities were used to identify vulnerable lesions, potentially predicting periinterventional coronary microembolization. In 14 patients undergoing PCI, optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS) were performed to evaluate plaque vulnerability. After PCI, imaging was repeated with the aim to depict signs of coronary microembolization like plaque ruptures and protrusions. Lesions with ≥ 2 features of plaque vulnerability in OCT (thin fibrous cap, microvessels, thrombus, plaque rupture) were associated with a higher lipid core content in NIRS, compared to lesions with only few of these features: lipid core burden index of the lesion (LCBIlesion) and the maximal 4-mm LCBI (LCBI4 mm) were 152±37 vs. 68±18 (p

Atherosclerotic coronary arteries are more calcified in patients with than without chronic kidney disease (CKD). We addressed the potential for coronary microvascular obstruction in patients with and without CKD during stenting for saphenous vein aorto-coronary graft (SVG) stenosis under protection with a distal occlusion/aspiration device. In patients with and without CKD (n = 20/20), SVG plaque composition was analyzed from virtual histology using intravascular ultrasound analysis before stent implantation. There was more dense calcium and more necrotic core in patients with than without CKD (14 ± 3 vs. 3 ± 1 % and 21 ± 3 vs. 12 ± 2 % of plaque volume, respectively). Coronary aspirate was retrieved during stent implantation and divided into particulate debris and plasma. Patients with CKD had more particulate debris and calcium release than patients without CKD. In contrast, the release of serotonin was less in patients with than without CKD (0.4 ± 0.1 vs. 1.2 ± 0.3 μmol/L), whereas that of catecholamines, endothelin, tissue factor, thromboxane, tumor necrosis factor α, and C reactive protein was not significantly different. Confirming the biochemical results, aspirate plasma from patients with CKD induced less vasoconstriction of rat mesenteric arteries than that from patients without CKD (with endothelium (+E), 26 ± 7 %; without endothelium (−E): 28 ± 7 % vs. +E, 68 ± 12 %; −E: 95 ± 16 % of maximum KCl-induced vasoconstriction). Graft atherosclerosis of patients with CKD is more degenerated and releases more particulate debris and calcium, but the aspirate has surprisingly less serotonin and vasoconstrictor potential.

The interventional implantation of a stent into an atherosclerotic coronary artery is a unique and paradigmatic scenario of plaque rupture in humans. The use of protection devices not only prevents the released plaque particles and the superimposed thrombotic material from being washed and embolized into the coronary microcirculation of the individual patient, but permits also the retrieval and ex vivo analysis of particulate plaque debris and soluble substances. The particulate debris comprises typical cholesterol crystals, foam cells, hyalin material and calcium deposits from the atheroma as well as platelets and coagulation material; soluble substances include vasoconstrictors, such as serotonin and thromboxane, as well as inflammatory mediators, such as TNFα which amplifies vasoconstriction by inducing endothelial dysfunction. The vasoconstriction observed in a bioassay ex vivo correlates to clinical symptoms, angiographic stenosis and plaque burden, as assessed by intravascular ultrasound. The release of TNFα into the aspirate correlates to restenosis. Detailed analysis of the human coronary aspirate may promote a better understanding of the pathophysiology of the vulnerable atherosclerotic plaque and help to better antagonize the microvascular consequences of coronary microembolization, including the no reflow phenomenon. This article is part of a Special Issue entitled "Coronary Blood Flow."

The present article briefly reviews the processes underlying excitation-contraction coupling in cardiomyocytes and vascular smooth muscle cells, their perturbations during reversible and irreversible myocardial ischemia and reperfusion, notably the pathogenetic role of increased intracellular calcium concentrations, and finally the beneficial effects of calcium antagonists on the impairment of coronary vasomotor tone, on cardiac contractile dysfunction and on myocardial infarction.

Coronary flow velocity reserve (CVR) is reduced in patients with severe symptomatic aortic stenosis, contributing to ischemic clinical symptoms. We evaluated coronary flow dynamics assessed by intracoronary Doppler surveillance of the blood flow in the left anterior descending (LAD) artery during

Rationale: Stent implantation into atherosclerotic plaques releases, apart from particulate debris, soluble substances that contribute to impaired microvascular perfusion. Objective: To quantify the release of vasoconstrictors and to determine the efficacy of coronary dilators to attenuate their action. Methods and Results: Using a distal protection/aspiration device, coronary arterial blood was retrieved before and during stenting in 22 patients with severe saphenous vein aorto-coronary bypass stenoses. The release of catecholamines, endothelin, serotonin, thromboxane B 2 , and tumor necrosis factor (TNF)α was measured. The response of rat mesenteric arteries with intact (+E) and denuded (−E) endothelium to aspirate plasma was normalized to that by KCl. Responses to selective receptor blockade, adenosine, nitroprusside, and verapamil against the aspirate-induced constriction were determined. The coronary arterial plasma withdrawn before stenting induced 21±5% and the aspirate plasma after stenting induced 95±8% of maximum KCl-induced vasoconstriction. Serotonin, thromboxane B 2 , and TNFα release into aspirate plasma increased by 1.9±0.2 μmol/L, 25.6±3.1 pg/mL, and 19.7±6.1 pg/mL, respectively, during stenting. The aspirate-induced vasoconstriction was largely antagonized by selective serotonin receptor blockade, with little further antagonism by additional thromboxane receptor blockade. TNFα did not induce constriction per se but potentiated the constriction with serotonin and the thromboxane-analog U-46619 in arteries +E. The concentrations to induce half-maximal vasodilation were comparable for nitroprusside (+E, 3.3×10 −8 ; −E, 1.9×10 −8 mol/L) and verapamil (+E, 8.3×10 −8 ; −E, 7.8×10 −8 mol/L), and the vasoconstriction was eventually eliminated. The vasodilator response to adenosine was dependent on functional endothelium and weaker. Conclusion: Serotonin is the main coronary vasoconstrictor after stenting, and thromboxane and TNFα somewhat potentiate the serotonin response. Nitroprusside and verapamil are more potent than adenosine to attenuate the aspirate plasma-induced vasoconstriction, and they are not dependent on functional endothelium.

A 62-year-old male patient with hypertrophic obstructive cardiomyopathy (HOCM) under treatment with β-blockers and calcium antagonists was admitted for dyspnoea (NYHA III). Heart rate was 45 b.p.m. ( Panel A ) and echocardiography revealed left ventricular outflow tract obstruction (estimated pressure gradient at rest 70 mmHg; after exercise 89 mmHg) and systolic anterior motion of the mitral leaflet. Cardiac magnetic …

Periprocedural microembolization (PM) during a percutaneous coronary intervention (PCI) induces myocardial injury, ranging from asymptomatic increases in cardiac biomarkers to life-threatening situations. Intracoronary imaging can identify distinct plaque characteristics, which may predict PM. We