Evaluation of systemic inflammation in response to remote ischemic preconditioning in patients undergoing transcatheter aortic valve replacement (TAVR).

BACKGROUND: Systemic inflammation can occur after transcatheter aortic valve replacement (TAVR) and correlates with adverse outcome. The impact of remote ischemic preconditioning (RIPC) on TAVR associated systemic inflammation is unknown and was focus of this study. METHODS: We performed a prospective controlled trial at a single center and included 66 patients treated with remote ischemic preconditioning (RIPC) prior to TAVR, who were matched to a control group by propensity score. RIPC was applied to the upper extremity using a conventional tourniquet. Definition of systemic inflammation was based on leucocyte count, C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6), assessed in the first 5 days following the TAVR procedure. Mortality was determined within 6 months after TAVR. RIPC group and matched control group showed comparable baseline characteristics. RESULTS: Systemic inflammation occurred in 66% of all patients after TAVR. Overall, survival after 6 months was significantly reduced in patients with systemic inflammation. RIPC, in comparison to control, did not significantly alter the plasma levels of leucocyte count, CRP, PCT or IL-6 within the first 5 days after TAVR. Furthermore, inflammation associated survival after 6 months was not improved by RIPC. Of all peri-interventional variables assessed, only the amount of the applied contrast agent was connected to the occurrence of systemic inflammation. CONCLUSIONS: Systemic inflammation frequently occurs after TAVR and leads to increased mortality after 6 months. RIPC neither reduces the incidence of systemic inflammation nor improves inflammation associated patient survival within 6 months.

The predictive role of early CRP values for one-year mortality in the first 2 d after acute myocardial infarction.

BACKGROUND: An excessive inflammatory reaction after acute myocardial infarction (AMI) is known to be harmful. New anti-inflammatory therapies are required. PURPOSE: This study assessed the predictive role of early CRP in patients with STEMI. METHODS: A total of 1003 patients with STEMI were analysed. A total of 180 patients with proven infection were excluded. CRP after 12, 24 and 48 h after pain onset were evaluated. RESULTS: Of 823 patients, 103 (12.5%) died within one year after AMI. The deceased patients showed higher CRP, even after already 12 h (6 vs. 13 mg/l, p < .001), 24 h (13 vs. 25 mg/l, p < .001) and after 48 h (40 vs. 92 mg/l, p < .001). A CRP of ≥8 mg/l, 12 h after AMI, was found in 45% and was independently associated with long-term mortality (OR: 2.7, p = .03), after 24 h: CRP ≥ 18 mg/l in 44% (OR: 2.5, p = .03), after 48 h: CRP ≥ 53 mg/l in 44% (OR 1.9, p = .03). Early CRP values correlated strongly with the later maximum value of CRP (p < .001). CONCLUSIONS: Already early CRP values are accurate for risk-prediction following AMI. By identifying patients who are beginning to develop an excessive inflammatory response, it may be possible to identify those who benefit from anti-inflammatory therapies.

Regulation of circulating chromogranin B levels in heart failure.

BACKGROUND: Chromogranin B (CGB) regulates B-type natriuretic peptide (BNP) production. Circulating CGB levels are elevated in heart failure (HF) animal models and HF patients, but also increase in healthy individuals in response to physical activity. Therefore, CGB seems to integrate information from myocardial stress and systemic neuro-endocrine activation. Substantial gaps remain in our understanding of CGB regulation in HF. METHODS AND RESULTS: We conducted a retrospective registry study including 372 patients. CGB and N-terminal pro-BNP (NT-proBNP) plasma levels were assessed in acute HF and chronic valvular HF patients and controls. CGB levels were significantly increased in acute HF and chronic valvular HF, but significantly higher in the latter. Patients in chronic valvular HF with severe mitral regurgitation (cHF-MR) showed significantly higher CGB levels than patients in chronic valvular HF with severe aortic stenosis. CGB levels progressively increased with worsening NYHA functional status and were moderately correlated to NT-proBNP, but independent of left ventricular (LV) ejection fraction (LVEF), LV mass, age and body weight. Finally, cHF-MR patients showed significant reductions of CGB levels after interventional mitral valve repair. CONCLUSION: CGB is a promising emerging biomarker in HF patients with unique potential to integrate information from myocardial stress and neuro-endocrine activation.

Comparison of diverse platelet activation markers as indicators for left atrial thrombus in atrial fibrillation.

Atrial fibrillation (AF) is well known for being a major risk factor of thromboembolic stroke. We could recently demonstrate an association of monocyte-platelet aggregates (MPAs) with the degree of thrombogenicity in patients with AF. This study investigated platelet activation markers, as potential biomarkers for the presence of left atrial (LA) thrombus in patients with AF. One hundred and eight patients with symptomatic AF underwent transesophageal echocardiography (TEE) before scheduled cardioversion or pulmonary vein isolation. In order to determine the content of MPAs by flow-cytometric quantification analyses, blood was drawn on the day of TEE. The soluble CD40 Ligand (sCD40L) and soluble P-selectin (sP-selectin) were obtained by Cytometric Bead Arrays (CBA). D-dimer levels were detected by quantitative immunological determination of fibrin degradation products. Clinical, laboratory, and echocardiographic standard parameters were obtained from all patients, including the determination of the flow in the left atrial appendage (LAA). Patients with detected LA thrombus (n = 28) compared with patients without thrombus (n = 80) showed an increased number of common risk factors, such as age, diabetes, heart failure, and coronary artery disease (CAD). The presence of LA thrombus was associated with significantly increased levels of MPAs (147 ± 12 vs. 304 ± 29 per µl; p < 0.00), sCD40L (106.3 ± 31.0 vs. 33.5 ± 2.1 pg/ml, p = 0.027), and D-dimer (0.13 ± 0.02 vs. 0.69 ± 0.21 mg FEU/l, p = 0.015). In contrast, sP-selectin showed no association with LA thrombus. A multivariate regression analysis showed that MPAs, sCD40L as well as D-dimers were independent indicators for the existence of LA thrombus. MPAs above 170 cells/µl indicated LA thrombus with a high sensitivity of 93% and a specificity of 73% (OR 62, 95% CI. 6.9-557.2, p < 0.001) in patients with AF, whereas the D-dimer lost their quality as independent indicator by using the conventional cut-off of 0.5 mg/l within the regression analysis. MPAs, as well as the D-dimer, correlated significantly negatively with the flow in the LAA measured during TEE. The content of MPAs, sCD40L, and D-dimer, but not sP-selectin showed an increased dependence on LA thrombus in patients with AF. In our study group, MPAs showed the best diagnostic test accuracy of the compared platelet markers. The different results of the examined platelet activation markers could be an indication of diverse mechanisms of LA thrombus in AF. Further studies should evaluate whether determination of MPAs in clinical routine may suffice to indicate the presence of LA thrombus in patients with AF.

Association of platelet activation markers with recurrence of atrial fibrillation after pulmonary vein isolation.

Atrial fibrillation (AF) is known to cause platelet activation. AF and its degree of thrombogenesis could be associated with monocyte-platelet aggregates (MPAs). We investigated on whether the content of MPAs or other platelet activation markers is associated with the recurrence of AF after pulmonary vein isolation (PVI). A total of 73 patients with symptomatic AF underwent PVI. After 6 months, all patients were evaluated for episodes of AF recurrence. At the same time, flow-cytometric quantification analyses were performed to determine the content of MPAs. Further platelet activation parameters were detected by using either cytometric bead arrays or quantitative immunological determination. Patients with recurrent AF (n = 20) compared to individuals without AF relapse (n = 53) were associated with an increased content of MPAs (43 ± 3% vs. 33 ± 2%, p = 0.004), as well as an increased CD41 expression on monocytes (191 ± 20 vs. 113 ± 6, p = 0.001). The level of the soluble platelet activation markers such as D-dimer, sCD40L, and sP-selectin did not differ between these groups. The content of MPAs correlated weakly with the level of sCD40L (r = 0.26, p = 0.03), but not with sP-selectin and D-dimer, whereas sP-selectin and sCD40L correlated with each other (r = 0.38, p = 0.001). Only the cellular marker of platelet activation, the content of MPAs, was increased in patients with recurrent AF after PVI. In contrast, soluble markers remained unaltered. These data indicate a distinct mechanism and level of platelet activation in AF. The clinical relevance of MPAs in identifying AF recurrence or in guiding the therapy with anticoagulants remains to be elucidated.

Benefit of 3D Vena Contracta Area over 2D-Based Echocardiographic Methods in Quantification of Functional Mitral Valve Regurgitation.

BACKGROUND: The two-dimensional proximal isovelocity surface area (2D PISA) method in the quantification of an effective regurgitation orifice area (EROA) has limitations in functional mitral valve regurgitation (FMR), particularly in non-circular coaptation defects. OBJECTIVE: We aimed to validate a three-dimensional vena contracta area (3D VCA) against a conventional EROA using a 2D PISA method and anatomic regurgitation orifice area (AROA) in patients with FMR. METHODS: Both 2D and 3D full-volume color Doppler data were acquired during consecutive transoesophageal echocardiography (TEE) examinations. The EROA 2D PISA was calculated as recommended by current guidelines. Multiplanar reconstruction was used for offline analysis of the 3D VCA (with a color Doppler) and AROA (without a color Doppler). Receiver operating characteristic (ROC) analysis was used to calculate a cut-off value for the 3D VCA to discriminate between moderate and severe FMR as classified by the EROA 2D PISA. RESULTS: From 2015 to 2018, 105 consecutive patients with complete and adequate imaging data were included. The 3D VCA correlated strongly with the 2D PISA EROA and AROA (r = 0.93 and 0.94). In the presence of eccentric or multiple regurgitant jets, there was no significant difference in correlations with the 3D VCA. We found a 3D VCA cut-off of 0.43 cm2 to discriminate between moderate and severe FMR (area under curve = 0.98). The 3D VCA showed a higher interobserver agreement than the EROA 2D PISA (interclass correlation coefficient: 0.94 vs. 0.81). CONCLUSIONS: The 3D VCA has excellent validity and lower variability than the conventional 2D PISA in FMR. Compared to the 2D PISA, the 3D VCA was not affected by the presence of eccentric or multiple regurgitation jets or non-circular regurgitation orifices. With a threshold of 0.43 cm2 for the 3D VCA, we demonstrated reliable discrimination between moderate and severe FMR.

C-terminal domain of chromogranin B regulates intracellular calcium signaling.

The versatility of intracellular calcium as a second messenger is seen in its ability to mediate opposing events such as neuronal cell growth and apoptosis. A leading hypothesis used to explain how calcium regulates such divergent signaling pathways is that molecules responsible for maintaining calcium homeostasis have multiple roles. For example, chromogranin B (CGB), a calcium binding protein found in secretory granules and in the lumen of the endoplasmic reticulum, buffers calcium and also binds to and amplifies the activity of the inositol 1,4,5-trisphosphate receptor (InsP(3)R). Previous studies have identified two conserved domains of CGB, an N-terminal domain (N-CGB) and a C-terminal domain (C-CGB). N-CGB binds to the third intraluminal loop of the InsP(3)R and inhibits binding of full-length CGB. This displacement of CGB decreases InsP(3)R-dependent calcium release and alters normal signaling patterns. In the present study, we further characterized the role of N-CGB and identified roles for C-CGB. The effect of N-CGB on calcium release depended upon endogenous levels of cellular CGB, whereas the regulatory effect of C-CGB was apparent regardless of endogenous levels of CGB. When either full-length CGB or C-CGB was expressed in cells, calcium transients were increased. Additionally, the calcium signal initiation site was altered upon C-CGB expression in neuronally differentiated PC12 and SHSY5Y cells. These results show that CGB has numerous regulatory roles and that CGB is a critical component in modulating InsP(3)R-dependent calcium signaling.

Evaluation of Myocardial Strain Using Cardiac Magnetic Resonance in Patients with Wilson's Disease.

(1) Background: Wilson's disease (WD) is an inherited autosomal recessive disorder with the excessive deposition of copper into different organs, including the heart. Previous studies showed structural cardiac changes even in patients with no signs of heart failure. The aim of this study was to perform cardiac magnetic resonance-based strain analysis in WD patients, as it is a powerful independent predictor of mortality. (2) Methods: We conducted a prospective cardiac magnetic resonance study that included 61 patients and 61 age and sex-matched controls, and performed strain analysis of the left and right ventricle. (3) Results: Left ventricular global longitudinal strain (GLS) as a prognostic marker of increased mortality was not altered (control -22.8 (4.8) % vs. WD patients -21.8 (5.1) %, p = 0.124). However, 4 of the 61 patients had a markedly reduced GLS. Global circumferential strain did not significantly differ between the groups either (p = 0.534). WD patients had significantly reduced global radial strain (p = 0.002). Right ventricular GLS was also significantly reduced in WD patients (p = 0.01). (4) Conclusions: Strain analysis revealed functional impairment of the left and right ventricle in a small number of patients as a potential early sign of cardiac manifestation in asymptomatic WD patients.

Myocardial strain analysis using cardiac magnetic resonance in patients with calpainopathy.

BACKGROUND: Limb-girdle muscular dystrophy (LGMD) is a genetically and clinically heterogeneous group of rare muscular dystrophies. Subtype 2A (LGMD2A) also known as "calpainopathy" is an inherited autosomal recessive gene defect. Cardiac dysfunction is common in several forms of LGMD. Cardiac involvement in LGMD2A, however, is not clear. The aim of this study was to perform cardiac magnetic resonance (CMR)-based strain analysis in LGMD2A patients, as this is a diagnostic parameter of subclinical cardiac involvement and a powerful independent predictor of mortality. We conducted the largest prospective cardiac magnetic resonance study to date, including 11 genetically verified LGMD2A patients and 11 age- and sex-matched control subjects and performed CMR-based strain analysis of the left and right ventricles. RESULTS: Left and right global longitudinal strain (GLS) were not significantly different between the two groups and within normal reference ranges (left ventricle: control - 21.8 (5.1) % vs. patients - 22.3 (3.2) %, p = 0.38; right ventricle: control - 26.3 (7.2) % vs. patients - 26.8 (5.8) %, p = 0.85). Also, global circumferential and radial strains did not significantly differ between the two groups (p = 0.95 and p = 0.86, respectively). LGMD2A patients did not show relevant amounts of late gadolinium enhancement (LGE) or malignant ventricular arrhythmias. CONCLUSIONS: No evidence of even subtle cardiac dysfunction is evident form CMR-based strain analysis in LGMD2A patients. Malignant ventricular arrhythmias were not detected. Thus, in case of non-pathological initial echocardiographic and electrocardiographic examination, a less frequent or even no cardiac follow-up may be acceptable in these patients. However, if there are signs and symptoms that suggest an underlying cardiac condition (e.g. palpitations, angina, shortness of breath), this approach needs to be individualized to account for the unknown.

Spatio-temporal regulation of calpain activity after experimental myocardial infarction in vivo.

BACKGROUND: Calpains are calcium activated cysteine proteases that play a pivotal role in the pathophysiology of cardiac remodeling. METHODS: Here, we performed left anterior descending coronary artery ligation in rats as a model for ischemic systolic heart failure and examined the time- and region-specific regulation of calpain-1 and calpain-2 in the left ventricular myocardium. RESULTS: Following anterior wall myocardial infarction, calpain activity was significantly increased restricted to the ischemic anterior area at days 1, 5 and 14. No changes in calpain activity at neither time point were detected in the borderzone and remote posterior area of the left ventricle. Of note, calpain activity in the infarcted anterior myocardium was regulated differentially in the acute vs. subacute and chronic phase. In the acute phase, calpain translocation to the plasma membrane and attenuation of the expression of its endogenous inhibitor, calpastatin, were identified as the driving forces. In the subacute and chronic phase, calpain activity was regulated at the level of protein expression that was shown to be essentially independent of transcriptional activity. CONCLUSIONS: We conclude that myocardial infarction leads to a distinct calpain regulation pattern in the left ventricular myocardium that is region specific and time dependent. Considering the results from our previous studies, a spatio-temporal interaction between calpains and calcium dependent natriuretic peptide production in the infarcted myocardium is possible. GENERAL SIGNIFICANCE: Our results shed more light in the differential regulation of calpain activity in the myocardium and might aid in the development of targeted post-infarct and/or heart failure therapeutics.

Frailty is associated with chronic inflammation and pro-inflammatory monocyte subpopulations.

AIM OF THE STUDY: Frail patients with high grade aortic valve stenosis (AS) undergoing Transcatheter Aortic Valve Implantation (TAVI) have an increased mortality. A connection between frailty and inflammation has been suggested. Monocyte subpopulations are associated with both cardiovascular diseases and chronic inflammatory diseases. This study investigates the association of frailty with monocyte subpopulations and systemic inflammatory parameters in elderly patients undergoing TAVI. METHODS: A total of 120 patients with symptomatic AS was examined. Before TAVI implantation, frailty was assessed by a bedside evaluation (eyeball test). In all patients a flow cytometry analysis has been performed. Monocyte subpopulations were defined as follows: classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++). Expression of CD11b was measured as a marker for monocyte activation. Pro-inflammatory cytokines such as interleukin IL-8, as well as CRP were measured with Cytometric Bead Array or standard laboratory methods. RESULTS: 28 out of 120 patients were frail. These patients showed both, signs of elevated chronic systemic inflammation reflected by elevated CRP (3.7 (1.4-5.4) vs. 5.9 (3.7-29.1), p = 0.001) and an elevated level of intermediate monocytes (37 (24-54) vs. 53 (47-63), p = 0.001). At 6 months after TAVI, 19 of 120 patients died, primarily without relevant dysfunction of the implanted aortic valve. Mortality was significantly higher in the frail as compared with non-frail patients (9 of 28 frail patients vs. 10 of 92 non frail patients, p < 0.001). A binary logistic regression analysis validated frailty and intermediate monocytes as independent predictors for early mortality after TAVI. CONCLUSION: Chronic systemic inflammation and increased levels of intermediate monocytes are associated with frailty in old patients with severe aortic valve stenosis. Both the syndrome of frailty and elevated intermediate monocytes showed an association with early mortality after TAVI.

Paclitaxel accelerates spontaneous calcium oscillations in cardiomyocytes by interacting with NCS-1 and the InsP3R.

Paclitaxel (Taxol) is a microtubule-stabilizing compound that is used for cancer chemotherapy. However, Taxol administration is limited by serious side effects including cardiac arrhythmia, which cannot be explained by its microtubule-stabilizing effect. Recently, neuronal calcium sensor 1 (NCS-1), a calcium binding protein that modulates the inositol-1,4,5-trisphosphate receptor (InsP(3)R), was described as a binding partner of Taxol and as a substrate of calpain. We examined calcium signaling processes in cardiomyocytes after treatment with Taxol to investigate the basis of Taxol-induced cardiac arrhythmia. After treating isolated neonatal rat ventricular myocytes with a therapeutic concentration of Taxol for several hours live cell imaging experiments showed that the frequency of spontaneous calcium oscillations significantly increased. This effect was not mimicked by other tubulin-stabilizing agents. However, it was prevented by inhibiting the InsP(3)R. Taxol treated cells had increased expression of NCS-1, an effect also detectable after Taxol administration in vivo. Short hairpin RNA mediated knockdown of NCS-1 decreased InsP(3)R dependent intracellular calcium release, whereas Taxol treatment, that increased NCS-1 levels, increased InsP(3)R dependent calcium release. The effects of Taxol were ryanodine receptor independent. At the single channel level Taxol and NCS-1 mediated an increase in InsP(3)R activity. Calpain activity was not affected by Taxol in cardiomyocytes suggesting a calpain independent signaling pathway. In short, our study shows that Taxol impacts calcium signaling and calcium oscillations in cardiomyocytes through NCS-1 and the InsP(3)R.

Chromogranin B regulates calcium signaling, nuclear factor kappaB activity, and brain natriuretic peptide production in cardiomyocytes.

Altered regulation of signaling pathways can lead to pathologies including cardiac hypertrophy and heart failure. We report that neonatal and adult cardiomyocytes express chromogranin B (CGB), a Ca(2+) binding protein that modulates Ca(2+) release by the inositol 1,4,5-trisphosphate receptor (InsP(3)R). Using fluorescent Ca(2+) indicator dyes, we found that CGB regulates InsP(3)-dependent Ca(2+) release in response to angiotensin II, an octapeptide hormone that promotes cardiac hypertrophy. ELISA experiments and luciferase reporter assays identified angiotensin II as a potent inducer of brain natriuretic peptide (BNP), a hormone that recently emerged as an important biomarker in cardiovascular disease. CGB was found to regulate angiotensin II-stimulated and basal secretion, expression and promoter activity of BNP that depend on the InsP(3)R. Moreover, we provide evidence that CGB acts via the transcription activity of nuclear factor kappaB in an InsP(3)/Ca(2+)-dependent manner but independent of nuclear factor of activated T cells. In vivo experiments further showed that cardiac hypertrophy induced by angiotensin II, a condition characterized by increased ventricular BNP production, is associated with upregulation of ventricular CGB expression. Overexpression of CGB in cardiomyocytes, in turn, induced the BNP promoter. The evidence presented in this study identifies CGB as a novel regulator of cardiomyocyte InsP(3)/Ca(2+)-dependent signaling, nuclear factor kappaB activity, and BNP production.

Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation.

Paclitaxel (Taxol) is a well established chemotherapeutic agent for the treatment of solid tumors, but it is limited in its usefulness by the frequent induction of peripheral neuropathy. We found that prolonged exposure of a neuroblastoma cell line and primary rat dorsal root ganglia with therapeutic concentrations of Taxol leads to a reduction in inositol trisphosphate (InsP(3))-mediated Ca(2+) signaling. We also observed a Taxol-specific reduction in neuronal calcium sensor 1 (NCS-1) protein levels, a known modulator of InsP(3) receptor (InsP(3)R) activity. This reduction was also found in peripheral neuronal tissue from Taxol treated animals. We further observed that short hairpin RNA-mediated NCS-1 knockdown had a similar effect on phosphoinositide-mediated Ca(2+) signaling. When NCS-1 protein levels recovered, so did InsP(3)-mediated Ca(2+) signaling. Inhibition of the Ca(2+)-activated protease mu-calpain prevented alterations in phosphoinositide-mediated Ca(2+) signaling and NCS-1 protein levels. We also found that NCS-1 is readily degraded by mu-calpain in vitro and that mu-calpain activity is increased in Taxol but not vehicle-treated cells. From these results, we conclude that prolonged exposure to Taxol activates mu-calpain, which leads to the degradation of NCS-1, which, in turn, attenuates InsP(3)mediated Ca(2+) signaling. These findings provide a previously undescribed approach to understanding and treating Taxol-induced peripheral neuropathy.

The infarction zone rather than the noninfarcted remodeling zone overexpresses angiotensin II receptor type 1 and is the main source of ventricular atrial natriuretic peptide.

Chromogranin B and inositol 1,4,5-trisphosphate-associated calcium signaling leading to increased natriuretic peptide production has been described in cardiac hypertrophy. Here, we performed left anterior descending coronary artery ligation in rats as a model for systolic heart failure and examined protein and gene expression clusters in the infarcted and noninfarcted myocardium and moreover under treatment with metoprolol. We found that atrial natriuretic peptide gene transcription was significantly more elevated in the infarcted compared with the noninfarcted myocardium. Chromogranin B, which facilitates calcium release from internal stores through the inositol 1,4,5-trisphosphate receptor, was upregulated in both areas. Interestingly, angiotensin II receptor type 1 gene transcription was significantly upregulated in the infarcted and unchanged in the noninfarcted myocardium. Nuclear factor ĸappa B as a calcium-dependent transcription factor showed increased activity in the infarction zone. The ß-adrenergic axis does not seem to be involved, as metoprolol treatment did not have a significant impact on any of these results. We conclude that region-specific upregulation of angiotensin II receptor type 1 is a major factor for increased atrial natriuretic peptide production in the infarcted anterior wall. This effect is most likely achieved through inositol 1,4,5-trisphosphate-mediated cytosolic calcium increase and subsequent nuclear factor ĸappa B activation, which is a known transcription factor for natriuretic peptides.

Remote Ischemic Preconditioning Neither Improves Survival nor Reduces Myocardial or Kidney Injury in Patients Undergoing Transcatheter Aortic Valve Implantation (TAVI).

BACKGROUND: Peri-interventional myocardial injury occurs frequently during transcatheter aortic valve implantation (TAVI). We assessed the effect of remote ischemic preconditioning (RIPC) on myocardial injury, acute kidney injury (AKIN) and 6-month mortality in patients undergoing TAVI. METHODS: We performed a prospective single-center controlled trial. Sixty-six patients treated with RIPC prior to TAVI were enrolled in the study and were matched to a control group by propensity-score. RIPC was applied to the upper extremity using a conventional tourniquet. Myocardial injury was assessed using high-sensitive troponin-T (hsTnT), and kidney injury was assessed using serum creatinine levels. Data were compared with the Wilcoxon-Rank and McNemar tests. Mortality was analysed with the log-rank test. RESULTS: TAVI led to a significant rise of hsTnT across all patients (p < 0.001). No significant inter-group difference in maximum troponin release or areas-under-the-curve was detected. Medtronic CoreValve and Edwards Sapien valves showed similar peri-interventional troponin kinetics and patients receiving neither valve did benefit from RIPC. AKIN occurred in one RIPC patient and four non-RIPC patients (p = 0.250). No significant difference in 6-month mortality was observed. No adverse events related to RIPC were recorded. CONCLUSION: Our data do not show a beneficial role of RIPC in TAVI patients for cardio- or renoprotection, or improved survival.

Influence of the plasminogen activator system on necrosis in acute myocardial infarction: analysis of urokinase- and urokinase receptor-knockout mouse models.

Serine proteases and G-protein-coupled receptors have been studied extensively as effectors of cell death. However, their roles in myocardial infarction have not been determined. In this study, we investigated the influence of the plasminogen activator system involving urokinase and urokinase receptor on necrosis after acute myocardial infarction. Myocardial infarction and reperfusion were induced in mouse hearts using the in vitro Langendorff model. DNA fragmentation and cleaved caspase-3 activity in urokinase- (uPA-/-) and urokinase receptor-knockout mice (uPAR-/-) were determined and compared with those in wild-type mice using in situ nick-end DNA labeling (TUNEL) and enzyme-linked immunosorbent assays, respectively. Infarct sizes were determined using propidium iodide and fluorescent microspheres. Following regional ischemia and reperfusion, a significant increase in the number of TUNEL-positive nuclei was observed in the ischemic zone in mouse hearts and to a lesser degree in regions remote from the ischemic area in wild-type, uPAR-/-, and uPA-/- groups compared with those in directly removed hearts. No significant differences were observed between uPAR-/- and wild-type mice. Conversely, a significant reduction in DNA fragmentation was observed in ischemic and nonischemic regions after acute myocardial infarction in uPA-/- mice when compared with that in wild-type and uPAR-/- groups. The resulting infarct sizes were significantly smaller in uPA-/- mice than in uPAR-/- and wild-type mice. These data demonstrated the involvement of uPA, but not uPAR, in protecting against necrosis during acute myocardial infarction.

Left ventricular clefts - incidental finding or pathologic sign of Wilson's disease?

BACKGROUND: Wilson's disease is an inherited autosomal recessive multi-systemic disorder characterized by reduced excretion and consequently excessive accumulation of copper in different organs, such as the heart. RESULTS: In a prospective controlled trial, which is the largest to date, we evaluated 61 patients with Wilson's disease, age- and sex-matched to 61 healthy patients, for cardiac manifestation using cardiac magnetic resonance imaging. Patients were under stable disease and had no signs of heart failure at the time of examination. We detected a left ventricular cleft, an invagination penetrating more than 50% wall thickness of the adjoining compact myocardium in diastole, in 20% of the patients (12 out of 61) compared to 5% among control patients (3 out of 61, p = 0.013). No correlation between the incidence of cleft and a certain genotype of Wilson's disease was found. All described cases were incidental findings and none of the patients showed other signs of cardiac involvement. CONCLUSIONS: To conclude, the results of this study suggests that the increased occurrence of left ventricular clefts is due to Wilson's disease. Large studies with a long observation period are needed for further evaluation.