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Introduction We aimed to study the various cardiac manifestations of the two core neuroacanthocytosis (NA) syndromes, namely chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). So far, cardiac involvement has been described as specific feature only for MLS. Methods We studied six patients with ChAc (mean age 44.5 years, five men, one woman) and six patients with MLS (mean age 57.1 years, all men). Cardiac evaluation included echocardiography and/or cardiac magnetic resonance imaging (cardiac MRI), 24-h ECG-recording and examination of cardiac biomarkers. Results Cardiac involvement of ChAc was found in four of six patients. Two patients showed mildly reduced left ventricular ejection fraction (LVEF), two other patients mild to moderate left ventricular (LV) dilatation. Neither an increase in ventricular ectopic beats nor ventricular tachycardia were evident in ChAc. Four of five MLS patients showed left ventricle dilatation and reduced left ventricular ejection fraction (LVEF). Two of these, in addition, had critical ventricular tachycardia. High sensitive troponin T was elevated in all patients, for whom data were available (n = 10). In contrast, elevation of high sensitive troponin I was found in one of six ChAc and one of two MLS patients. Conclusion For the first time, we reveal cardiac involvement in a cohort of six ChAc patients, while the risk to develop heart failure seems lower than in MLS. Our study confirms the malignant nature of MLS in terms of ventricular arrhythmias and progression to advanced heart failure. Herein, we define disease-specific recommendations for cardiac assessment in both conditions.

An excessive inflammatory reaction after acute myocardial infarction (AMI) is known to be harmful. New anti-inflammatory therapies are required. This study assessed the predictive role of early CRP in patients with STEMI. 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. 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 vs. 25 mg/l, p vs. 92 mg/l, p 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 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.

(1) Background: Wilson&rsquo, 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 &minus, 22.8 (4.8) % vs. WD patients &minus, 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.

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 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.

To investigate whether adrenal gland radiodensities alone or compared to the inferior vena cava (IVC) can correctly predict hospital mortality in patients in intensive care.One hundred thirteen intensive care patients (76 males, age: 67.2 ± 14.0 years) with an acute clinical deterioration were included in this retrospective analysis. For the venous and the arterial phase CT attenuation (Hounsfield units) of adrenal glands and IVC was ROI-based evaluated by two radiologists separately. ROC analysis, combined with the Matthews Correlation Coefficient (MCC) as a classifier, was used to assess whether one of the parameters is suitable for predicting short and medium-term mortality and, if so, which parameter is most appropriate. Interrater agreement was assessed using the intraclass correlation coefficient.Twenty-one patients (18.6%) died within three days in the ICU. Measurements of the adrenal glands in the portal venous phase yielded the highest discriminative power (=AUC) to distinguish between deceased and survivors. A threshold ratio of95.5 predicted 72-hour mortality with a sensitivity of 76.19% and a specificity of 92.39% (AUC = 0.84; p 0.0001). The positive likelihood ratio was 10.1; the positive predictive value was 69%. The predictive power for 24-hour mortality was slightly lower. Venous adrenal-to-IVC ratios and arterial measurements as a whole were substantially less suitable. All intraclass correlation coefficients indicated a high interrater agreement.In the portal venous phase, hyperattenuating of the adrenal glands on contrast-enhanced CT can predict short and intermediate ICU mortality quite well and may serve as a reproducible prognostic marker for individual patient outcomes.

BACKGROUND Left ventricular (LV) torsion is a key parameter in cardiac function and predicts functional capacity (FC) more appropriately than LV ejection fraction (EF). We sought to investigate LV torsion as a marker of hospitalization for worsening heart failure (HF) in non-ischemic dilated cardiomyopathy (DCM) patients. Methods and Results: The 91 outpatients with newly diagnosed DCM (53±13 years, 20% female) were evaluated with 3D speckle-tracking imaging and followed up for 12 months; 43 healthy sex- and age-matched volunteers served as controls. LV torsion, LVEF, right ventricular function, LV global longitudinal (GLS) and circumferential (GCS) strain values, peak oxygen uptake (peak VO2) from FC and B-type natriuretic peptide levels were measured at baseline. Peak VO2correlated successively with LV torsion, diastolic filling and GCS (r=0.70, -0.52 and -0.41, P

Background: Following myocardial infarction (MI), apoptosis occurs early in the remote myocardium and contributes to the processes of myocardial remodelling. Increased nitrosative stress is a well-known and potent inductor of myocardial apopto¬sis. Excess activation of endothelial nitric oxide synthase (eNOS) increases its uncoupling potential and results in nitrosative stress via formation of peroxynitrite. However, the pathophysiological role of eNOS signalling in the remote myocardium after MI is as yet undefined. Aim: The impact of eNOS activation on pro- and anti-apoptotic signalling in the remote myocardium and the influence of pretreatment with the eNOS cofactor tetrahydrobiopterin (BH4) on eNOS activation, nitrosative stress level, and apoptosis induction and execution were studied in a rat MI model in vivo. Results: Twenty-four hours after anterior MI, eNOS activity in animals treated with left anterior descending coronary artery ligation (LIG) significantly increased in the posterior left ventricular (LV) myocardium as did protein nitrosylation when com¬pared to sham treatment. This was paralleled by induction of apoptosis via the extrinsic and intrinsic pathways. Moreover, anti-apoptotic signalling via protein kinase B/Akt and glycogen synthase-kinase 3 beta was suppressed. Notably, pretreatment with the eNOS cofactor BH4 reduced eNOS activation, prevented excess protein nitrosylation, blunted apoptosis induction, facilitated anti-apoptotic signalling, and eventually prevented apoptosis execution. Conclusions: Here we showed that 24 h after experimental MI in rats in vivo, apoptosis was induced in the posterior non-in¬farcted LV wall. Evidence is presented that pretreatment with the eNOS cofactor BH4 resulted in less nitrosative stress and weakened apoptotic processes, although the stabilisers contained did participate in this phenomenon. Because apoptosis is a crucial component of myocardial remodelling, influencing eNOS signalling might be an interesting pharmacological target for the development of novel anti-remodelling therapies.

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.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.CGB is a promising emerging biomarker in HF patients with unique potential to integrate information from myocardial stress and neuro-endocrine activation.

BACKGROUND Interventional mitral valve (MV) repair of severe symptomatic mitral regurgitation (MR) is a therapeutic option in high-risk surgical or inoperable patients. Assessment of the MV remains a crucial part of pre-interventional screening. Three-dimensional transoesophageal echocardiography (3D-TOE) may compensate for well-known pitfalls that occur in 2D-TOE. PURPOSE We investigated whether the functional length of the central segments of the posterior and anterior MV leaflets (PML-P2 and AML-A2) is more reliably determined by 3D-TOE full volume datasets (3D-MPR) or orthogonal biplane-imaging (Xplane) when compared to 2D-TOE. METHODS AND RESULTS Between February 2014 and August 2015, 265 consecutive patients with moderate to severe symptomatic MR were screened. Seventy patients were judged suitable for interventional MV repair by the in-house Heart-Team. Eventually, 59 patients remained for data analysis. Inter-observer variability was lowest in 3D-MPR followed by Xplane (r = 0.92 and 0.90, p

Kontext: Starsi studie prokazaly, že se objem, hmota a funkce leve (LK) a prave komory (PK) srdecni významně lisi podle toho, zda se při výpoctu těchto parametrů zahrnou svalove tramce a papilarni svaly (trabeculae papillary and papillary muscle, TPM).Metody: V kohortě 101 pacientů bylo provedeno vysetřeni srdce magnetickou rezonanci (cardiac magnetic resonance, CMR). Kohorta zahrnovala celkem 26 pacientů bez patologických nalezů na CMR (referencni skupina), pacienty s ischemickou kardiomyopatii (IKMP), s dilatacni kardiomyopatii (DKMP) a pacienty s hypertrofii leve komory (vždy po 25 pacientech). Parametry LK a PK se stanovovaly pomoci dřive zavedených metod: 1. metoda zahrnujici TPM a 2. metoda nezahrnujici TPM do objemu přislusneho srdecniho oddilu.Výsledky: Ve srovnani s výpoctem při zahrnuti TPM znamenalo vylouceni TPM z celkoveho objemu LK a PK významně mensi objem na konci diastoly a systoly (end-diastolic and end-systolic volume, EDV, ESV) a hmotu myokardu, a vyssi hodnoty tepoveho objemu (stroke volume, SV) a ejekcni frakce (EF) (p = 0.001). Podil TPM na hmotě LK a PK byl větsi u DKMP (18,4 ± 3,8 %) a IKMP (17,8 ± 3,2 %) než u referencni skupiny (15,2 ± 2,5 %; oboji p < 0,05); výsledkem byl statisticky významně větsi rozdil mezi oběma použitým metodami (1. metoda - 2. metoda) při výpoctu ESV, EDV, SV, EF a hmoty myokardu u nemocných s DKMP a IKMP oproti referencni skupině.Zavěr: Hodnoty parametrů LK při vysetřeni srdce MR významně ovlivňuje to, zda jsou TPM považovany za soucast krevniho poolu LK nebo za soucast hmoty LK. Aby se zabranilo chybne interpretaci výsledků vysetřeni a chybným rozhodnutim, může být při dlouhodobem sledovani pacientů naprosto zasadni systematicke použivani jedne z obou metod delineace LK.

Background In the first three months after Transcatheter aortic valve implantation (TAVI), a remarkable number of patients have an unfavorable outcome. An inflammatory response after TAVI is suspected to have negative effects. The exact mechanisms remain unclear. We examined the influence of monocyte subpopulations on the clinical outcome, along with the degree of monocyte activation and further parameters of inflammation and platelet activation. Methods Flow-cytometric quantification analyses of peripheral blood were done in 120 consecutive patients who underwent TAVI (one day before TAVI and on day 1 and 7 after TAVI). Monocyte-subsets were defined by their CD14 and CD16 expression, monocyte-platelet-aggregates (MPA) by CD14/CD41 co-expression. The extent of monocyte activation was determined by quantification of CD11b-expression (activation epitope). Additionally, pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, C-reactive protein were measured with the cytometric bead array method or standard laboratory tests. Results Elevated Mon2 (CD14++CD16+) - monocytes (38 vs. 62 cells/μl, p Conclusions Elevated Mon2-monocytes and a high level of monocyte activation before TAVI are associated with early mortality after TAVI. Chronic inflammation in aging patients seems to be an important risk factor after 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 &lt, 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.

Background Wilson's disease (WD) is an inherited autosomal recessive disorder resulting from abnormal copper metabolism. Relatively little is known about the effects of copper accumulation on the heart. Objective We aimed to determine if patients with Wilson's disease show signs of cardiac involvement and structural heart disease. Methods In this prospective trial, we studied 61 patients with Wilson's disease and compared them to 61 age- and gender-matched healthy controls. Results While left ventricular function assessed by global longitudinal and global radial strain did not differ significantly between the groups, Wilson's disease patients had significantly reduced global radial strain (table 1). Wilson's disease patients demonstrated significantly more late gadolinium enhancement than the control patients (4.9±1.4 vs. 1.1±0.2% p The severity of Wilson's disease, based on the Unified Wilson's Disease Rating Scale, was significantly correlated with the extent of late gadolinium enhancement (r=0.53, P=0.001), cardiac troponin (r=0.56, P=0.001), the number of premature ventricular contraction (r=0.66, P=0.001). Table 1. Myocardial strain and CMR characteristics of patients and controls Parameter Patients (n=61) Controls (n=61) p value Left ventricular parameters GLS, % −22.8 (4.8) −21.8 (5.1) 0.124 GRS, % 43.2 (13.2) 51.6 (13.8) 0.002 GCS, % −29.2 (5.2) −28.6 (4.7) 0.534 Late gadolinium enhancement LGE, %* 4.9 (1.4) 1.1 (0.2) 0.003 LGE at RVIP, n (%) 58 (95) 3 (5) Conclusion Our data demonstrate that cardiac involvement in Wilson's disease is possible and those patients who are severely affected by the disease carry a higher risk of developing structural heart disease.

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 β-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.

Aims It is hypothesized that inflammation could promote structural and electrical remodelling processes in atrial fibrillation (AF). Atrial infiltration of monocytes and granulocytes has been shown to be dependent on CD11b expression. The aim of this study was to investigate whether treatment of AF by pulmonary vein isolation (PVI) may lead to reduced inflammation, as indicated by a decrease of CD11b expression on monocytes and granulocytes. Methods and results Flow-cytometric quantification analysis and determination of systemic inflammatory markers of peripheral blood were performed in 75 patients undergoing PVI 1 day before and 6 months after PVI. The extent of activation of monocytes and granulocytes was measured by quantifying the cell adhesion molecule CD11b. The mean expression of CD11b on monocytes (20.9 ± 2.5 vs. 10.2 ± 1.4; P

Pacient s cevnim typem Ehlersova-Danlosova syndromu a s implantovanou mechanickou chlopni byl hospitalizovan pro dyspnoe a bolest na hrudi. Po vylouceni infarktu myokardu nasledovalo vysetřeni CT angiografii, ktere prokazalo spontanni rupturu jedne z mezižebernich tepen s nasledným vznikem hemothoraxu a rozvojem kompresivni atelektazy. Celý připad komplikovala soucasna antikoagulacni lecba warfarinem po implantaci mechanicke chlopně. Po neuspěsne konzervativni lecbě byl připad řesen chirurgicky. Jak ukazuje nase kasuistika, může implantace mechanicke chlopně s nezbytnou odpovidajici a dlouhodobou antikoagulaci warfarinem u těchto pacientů představovat nežadouci přidatne riziko.

Purpose To assess the type and frequency of vascular changes in the superior mesenteric artery (SMA) associated with the hypovolemic shock complex (HSC). Methods Twenty-six patients (14 males, 70.6 ± 11.2 years) meeting the criteria for hypovolemic shock complex in computed tomography were examined for the presence of angiographic signs of non-occlusive mesenteric ischemia (NOMI) in the SMA: the string of sausages sign and spasms of the arcades of mesenteric arteries on coronal maximum intensity projection images (MIP). Interrater agreement was assessed using weighted kappa (κ). Results Vascular changes of the SMA were visible in almost all of the patients with HSC with a frequency of 88.5 %–96.2 %. Intraclass correlation coefficients indicated a substantial to almost perfect interrater agreement. Conclusions Using computed tomography, it is possible to reliably and reproducibly detect vascular changes in SMA known from angiography in the context of hypoperfusion. The pathological vascular changes also occur more frequently than other classic signs of a CT hypoperfusion complex. Since the qualitative assessment of the SMA requires only a small amount of time, it is suitable as a further criterion for the presence of the CT hypoperfusion complex.

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.

AIMS We aimed to evaluate possible detrimental effects of transoesophageal echocardiography (TEE) on the oesophageal tissue during percutaneous mitral valve repair (PMVR). METHODS AND RESULTS From March 2014 to July 2015, 186 patients were treated for severe mitral regurgitation with PMVR using the MitraClip system. In 40 patients, oesophago-gastro-duodenoscopy was performed due to symptoms related to the gastrointestinal tract. Based on the procedure duration, patients were classified into group 1 (>60 minutes, n=23) or into group 2 (

Patient: Male, 50 Final Diagnosis: Exudative enteropathy Symptoms: Abdominal pain • diarrhea • fever • hyponatremia • lymphadenopathy • weight loss Medication: — Clinical Procedure: — Specialty: — Objective: Unusual clinical course Background: Protein-losing enteropathy is a rare cause of hypoproteinemia. Erosive and non-erosive gastrointestinal diseases as well as vascular disorders that result in increased central venous pressure or mesenteric lymphatic obstruction may result in protein loss via the gastrointestinal tract. Case Report: We present the case of a 50-year-old man with protein-losing enteropathy, who had profuse diarrhea, abdominal pain, lymphadenopathy, fever, and a weight loss of 10 kg in the preceding 2 months. Extensive work-up revealed infection with Giardia lamblia. We review clinical signs and symptoms, laboratory findings, and imaging studies, and discuss potential pitfalls in establishing the diagnosis. Conclusions: To the best of our knowledge, this represents one of the few published cases of intestinal giardiasis as a cause of protein-losing enteropathy in an immunocompetent adult. The diagnosis of lambliasis should be based on a combination of stool cultures and serum serology, and in cases of high clinical suspicion, an endoscopy and biopsy of the upper GI tract is recommended.

Wilson’s disease (WD) is an inherited autosomal recessive disorder which leads to reduced copper excretion and excessive deposition of the copper into different organs. However, relatively little is known about the effects of copper accumulation on the heart. Cardiac involvement in WD has

Background: MitraClip therapy has recently gained clinical attention after EU and US approval. The Dresdner MitraClip registry reflects real world clinical demographic findings and midterm outcomes in an older patient cohort at high or prohibitive surgical risk with mixed mitral regurgitation (MR) etiology. Methods and results: A retrospective data analysis was conducted for consecutive patients with severe MR treated with the MitraClip system in a single institution between 08/2012 and 08/2015. 160 patients (46% ischemic cardiomyopathy (ICM), 22% dilative cardiomyopathy (DCM) and 32% degenerative mitral regurgitation (DMR) participated in this study. Patients in the ICM group had a significantly higher EURO-II-Score (22 (ICM) vs. 15 (DCM) vs 13 (DMR), p

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.

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.

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.

Calcium (Ca(2+)) release from intracellular stores plays a crucial role in many cellular functions in the brain. These intracellular signals have been shown to be transmitted within and between cells. We report a non-uniform distribution of proteins essential for Ca(2+) signaling in acutely prepared brain slice preparations and organotypic slice cultures, both made from rat hippocampus. The Type I inositol-1,4,5 trisphosphate receptor (InsP(3)R1) is the main InsP(3)R subtype in neurons. Immunohistochemistry experiments showed a prominent expression of InsP(3)R1 in the CA1 region of the hippocampus whereas the CA3 region and dentate gyrus (DG) showed only moderate immunoreactivity. In contrast, chromogranin B (CGB), a protein binding to the InsP(3)R1 on the luminal side of the endoplasmic reticular membrane was enriched in the CA3 region whereas DG and the CA1 region showed only faint CGB signals. The neuronal kinases leading to the formation of inositol-1,4,5 trisphosphate (InsP(3)), phosphatidylinositol-4-kinase (PI4K), and phosphatidylinositol-4-phosphate-5-kinase (PIPK), showed strong immunoreactivity throughout all hippocampal cell fields with differences in the subcellular distribution. Moreover, a distinct band of strong CGB and PIPK immunoreactivity was observed in the CA3 region that coincides with the mossy fiber tract (stratum lucidum). These data show differential expression of the components of the signaling toolkit leading to InsP(3)-mediated Ca(2+) release in cells of the hippocampus. The regulation of these differences may play an important role in various neuropathologic conditions such as Alzheimer's disease, epilepsy, or schizophrenia.

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 (Ins P 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 Ins P 3 receptor (Ins P 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 Ins P 3 -mediated Ca 2+ signaling. Inhibition of the Ca 2+ -activated protease μ-calpain prevented alterations in phosphoinositide-mediated Ca 2+ signaling and NCS-1 protein levels. We also found that NCS-1 is readily degraded by μ-calpain in vitro and that μ-calpain activity is increased in Taxol but not vehicle-treated cells. From these results, we conclude that prolonged exposure to Taxol activates μ-calpain, which leads to the degradation of NCS-1, which, in turn, attenuates Ins P 3 mediated Ca 2+ signaling. These findings provide a previously undescribed approach to understanding and treating Taxol-induced peripheral neuropathy.

BMP-4, a member of the TGF-beta superfamily of growth factors, is involved in various developmental processes. We investigated the effects of BMP-4 and its antagonist Noggin on axolotl trunk development. Implantation of BMP-4-coated microbeads caused inhibition of muscle and dorsal fin formation in the vicinity of the microbeads. At some distance, myotomes developed with reduced height but increased width, which was accompanied by increased cell proliferation. These effects could be modulated by co-implanting Noggin-coated beads. Immunostaining of Pax7 further revealed that although the dermomyotome was absent in the vicinity of BMP-4-coated beads, at some distance from them, it was thicker than in controls, indicating that moderate amounts of BMP-4 stimulate this layer of undifferentiated cells. In contrast, Noggin generally inhibited the dermomyotome, possibly indicating premature differentiation of dermomyotome cells. We conclude that BMP-4 and Noggin are involved in the regulation of cell proliferation and differentiation during somite development.

In this interesting report, Dardas et al1 describe another case of a rare yet potentially life-threatening complication of interventional atrial septal defect closure with a 20-mm Amplatzer septal occluder device. Transesophageal echocardiography revealed a 15-mm atrial septal defect complicated by a deficient aortic rim and a bicuspid aortic valve, along with aortic root dilation (42 mm). At the routine 6-month follow-up, transesophageal echocardiography showed device perforation into the aortic root. We previously described a series of 2 patients who underwent primarily uncomplicated interventional patent foramen ovale closure by a Cardia Star …

A 79-year-old woman was admitted to our center for atypical angina pectoris with chest pains worse at coughing. Her medical history revealed a dorsal stabilization of 3 lumbar vertebral bodies, 5 months ago. Laboratories showed moderate elevation of high-sensitive troponin T. Therefore, a coronary angiography was performed and ruled out significant coronary artery stenoses. However, fluoroscopy showed a toothpick-shaped structure of ≈9 cm reaching from the superior vena cava down to the diaphragmal base of the right ventricle (RV; Figure [A] and [B]). Chest x-ray and 3-dimensional echocardiography confirmed the presence of a toothpick-like structure within the RV, along with a small pericardial effusion (Figure [C–E]; see Movie IA and IB in the Data Supplement). In-depth investigation of the patient’s medical record revealed usage of bone cement (polymethylmethacrylate [PMMA]) during the orthopedic procedure 5 months ago. A computed tomographic scan was performed, and 3-dimensional reconstruction showed multiple pulmonary emboli of identical Hounsfield units in addition to the structure in the RV (Figure [F] and [G]). Considering the patient’s medical history, we hypothesized the visualized structures being PMMA fragments accidentally penetrating into the paravertebral venous system causing consecutive cardiopulmonary embolism after the orthopedic procedure. For retrieval, open heart surgery was declined by the patient. …

It was with great interest that we read the comprehensive study by Signore et al1 addressing the impact of inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3Rs) on the electromechanical behavior of mouse cardiomyocytes and human ventricular myocardium. Published in the September 17, 2013, issue of Circulation , this article provides compelling evidence that the Gαq-protein–coupled receptor (GPCR)/InsP3R axis plays a critical role in the regulation of cardiomyocyte calcium homeostasis, electric stability, and contractile performance. The authors demonstrate that GPCR agonists generate InsP3, which activates InsP3Rs to liberate calcium from internal stores, resulting in decreased resting membrane potential, prolongation of myocyte action potential, and the …

To the Editor: It was with great interest that we read this focused review by Patterson and colleagues on the role of calpains in cardiac hypertrophy. Succinctly, the authors provide a comprehensive overview on the current body of evidence of how calpains are believed to be implicated in the regulation of the development of cardiac, specifically ventricular, hypertrophy and go further on to discuss potential therapeutic strategies.1 In 2008, we studied the mechanism by which angiotensin II (Ang II) activates nuclear factor (NF)-κB in cardiomyocytes to drive the hypertrophic signaling pathway and showed that this activation depends on calcium release by the inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R).2 Importantly, we identified the calcium storage protein chromogranin B (CGB) to be of crucial importance in shaping this InsP3-dependent release of calcium. Our in vitro results were supported by in vivo experiments that showed …

To The Editor: In the March 28, 2008 issue of Circulation Research , Letavernier et al assessed the effects of calpain inhibition on angiotensin (Ang) II–induced cardiovascular remodeling.1 These authors used transgenic mice expressing high levels of calpastatin to inhibit Ang II–dependent calpain activation. They show that prevention of Ang II–induced calpain activation is associated with impaired nuclear factor (NF)-κB activation in heart tissue, which eventually leads to decreased Ang II–induced cardiac hypertrophy. This finding adds substantial novel information to our understanding of how calpains might be involved in the complex regulation of cardiac hypertrophy. However, compelling evidence as to how calpains are activated by Ang II in the myocardium and how the calpain/calpastatin system is linked to NF-κB activation is not provided. In the May 23, 2008 issue of Circulation Research , we show that Ang II induces calcium release via the inositol 1,4,5-trisphosphate receptor …

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 κB 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 κB activity, and BNP production.

We hypothesize that the inositol 1,4,5-trisphosphate receptor (InsP3R) signaling pathway is crucial for the development of cardiac arrhythmia caused by paclitaxel treatment. Paclitaxel, a well established drug used for cancer chemotherapy, constrains tumor growth through a microtubule stabilizing mechanism. However, use of paclitaxel is limited by serious side effects including bradycardia, which cannot be explained by its effect on microtubules. Recently, a new binding partner of paclitaxel was described - neuronal calcium sensor-1 (NCS-1), a protein that modulates the function of the InsP3R and that we found to be expressed in cardiomoycytes. After treating neonatal ventricular cardiomyocytes from rats with a therapeutic dose of paclitaxel for several hours, NCS-1 levels were markedly elevated. The same effect was also detectable in vivo, in hearts extracted from adult mice chronically injected with paclitaxel. Using live cell imaging, we observed an increase in the peak of the intracellular calcium signal and a significant decrease in the spontaneous calcium oscillation frequency in paclitaxel treated cardiomyocytes compared to control. The changes could not be explained by the function of ryanodine receptors (RyR) because there is no functional interaction between NCS-1 and RyR, as previously shown in bilayer experiments, and no paclitaxel-dependent change in RyR expression. However, co-immunoprecipitation confirmed a direct interaction between NCS-1 and InsP3R type 2, the predominant isoform in cardiomyocytes. To test whether this interaction is functionally relevant, we stimulated cardiomyocytes with endothelin, an activator of the InsP3 signaling cascade and found a difference in calcium transients between paclitaxel-treated and untreated cardiomyocytes. NCS-1 knockdown in cardiomyocytes by shRNA validated our findings. Taken together, our results suggest that paclitaxel-induced cardiac arrhythmia in patients is mediated by the interaction of NCS-1 and the InsP3R. This gives us a new understanding of the pathomechanism and provides a new approach for reducing the side effects of paclitaxel treatment and optimizing cancer chemotherapy.

Chromogranin B (CGB) is a low affinity, high capacity calcium binding protein belonging to the granin family. It is located in the lumen of the endoplasmic reticulum (ER) and is also found in secretory granules. Addition of CGB amplifies calcium release from ER stores and increases the activity of the inostiol (1,4,5)-trisphohsphate receptor (InsP3R). We previously demonstrated that CGB is non-uniformly distributed within neurons, and its spatial localization is cell type specific. We also showed that stimulation of the InsP3R in neurons leads to initiation of intracellular calcium release where the concentration of CGB is highest. When we expressed the N-terminal region of CGB, which binds to the third intralumenal loop of the InsP3R, the functional interaction between CGB and the InsP3R was disrupted and the initiation site of calcium release was altered. We now report that a 20 amino acid fragment of the C-terminal region plays a critical role in regulating calcium transients from the InsP3R. Addition of the C-terminal region of CGB increased the activity of single InsP3R currents in lipid bilayers. When intracellular calcium transients were monitored in 3T3 cells lacking CGB, InsP3R dependent calcium release was markedly amplified after expression of full length CGB or expression of the C-terminal region. In contrast, expression of the N-terminal region was unable to amplify the intracellular calcium transients. In SHSY5Y cells with endogenous CGB, expression of the C-terminal region induced a prolonged response to extracelluar agonists compared to native cells whereas expression of the N-terminal region depressed calcium signaling and altered the signal initiation site. These effects of CGB on calcium transients in neuronal cells indicate its importance in physiological processes and will guide investigation into pathophysiological processes.