A Case Series of Concomitant Cardiac Electrical Disease among Takotsubo Syndrome Patients and Literature Review.

The pathophysiology of Takotsubo Syndrome (TTS) is not completely understood and the trigger of sudden cardiac death (SCD) in TTS is not clear either. We therefore sought to find an association between TTS and primary electrical diseases. A total of 148 TTS patients were analyzed between 2003 and 2017 in a bi-centric manner. Additionally, a literature review was performed. The patients were included in an ongoing retrospective cohort database. The coexistence of TTS and primary electrical diseases was confirmed in five cases as the following: catecholaminergic polymorphic ventricular tachycardia (CPVT, 18-year-old female) (n = 1), LQTS 1 (72-year-old female and 65-year-old female) (n = 2), LQTS 2 (17-year-old female) (n = 1), and LQTS in the absence of mutations (22-year-old female). Four patients suffered from malignant tachyarrhythmia and recurrent syncope after TTS. Except for the CPVT patient and one LQTS 1 patient, all other cases underwent subcutaneous ICD implantation. An event recorder of the CPVT patient after starting beta-blocker did not detect arrhythmias. The diagnosis of primary electrical disease was in 80% of cases unmasked on a TTS event. This diagnosis triggered a family clinical and genetic screening confirming the diagnosis of primary electrical disease. A subsequent literature review identified five cases as the following: a congenital atrioventricular block (n = 1), a Jervell and Lange-Nielsen Syndrome (n = 1), and a family LQTS in the absence of a mutation (n = 2), LQTS 2 (n = 1). A primary electrical disease should be suspected in young and old TTS patients with a family history of sudden cardiac death. In suspected cases, e.g., ongoing QT interval prolongation, despite recovery of left ventricular ejection fraction a family screening is recommended.

Regulation of Ion Channel Function in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes by Cancer Cell Secretion Through DNA Methylation.

Background: Cardiac dysfunction including arrhythmias appear frequently in patients with cancers, which are expected to be caused mainly by cardiotoxic effects of chemotherapy. Experimental studies investigating the effects of cancer cell secretion without chemotherapy on ion channel function in human cardiomyocytes are still lacking. Methods: The human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from three healthy donors were treated with gastrointestinal (GI) cancer (AGS and SW480 cells) medium for 48 h. The qPCR, patch-clamp, western blotting, immunostaining, dot blotting, bisulfite sequence, and overexpression of the ten-eleven translocation (TET) enzyme were performed for the study. Results: After treated with cancer cell secretion, the maximum depolarization velocity and the action potential amplitude were reduced, the action potential duration prolonged, peak Na+ current, and the transient outward current were decreased, late Na+ and the slowly activating delayed rectifier K+ current were increased. Changes of mRNA and protein level of respective channels were detected along with altered DNA methylation level in CpG island in the promoter regions of ion channel genes and increased protein levels of DNA methyltransferases. Phosphoinositide 3-kinase (PI3K) inhibitor attenuated and transforming growth factor-ß (TGF-ß) mimicked the effects of cancer cell secretion. Conclusions: GI cancer cell secretion could induce ion channel dysfunction, which may contribute to occurrence of arrhythmias in cancer patients. The ion channel dysfunction could result from DNA methylation of ion channel genes via activation of TGF-ß/PI3K signaling. This study may provide new insights into pathogenesis of arrhythmia in cancer patients.

TRPV1 activation and internalization is part of the LPS-induced inflammation in human iPSC-derived cardiomyocytes.

The non-selective cation channel transient receptor potential vanilloid 1 (TRPV1) is expressed throughout the cardiovascular system. Recent evidence shows a role for TRPV1 in inflammatory processes. The role of TRPV1 for myocardial inflammation has not been established yet. Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (hiPSC-CM) from 4 healthy donors were incubated with lipopolysaccharides (LPS, 6 h), TRPV1 agonist capsaicin (CAP, 20 min) or the antagonist capsazepine (CPZ, 20 min). TRPV1 expression was studied by PCR and western blotting. TRPV1 internalization was analyzed by immunofluorescence. Interleukin-6 (IL-6) secretion and phosphorylation of JNK, p38 and ERK were determined by ELISA. TRPV1-associated ion channel current was measured by patch clamp. TRPV1-mRNA and -protein were expressed in hiPSC-CM. TRPV1 was localized in the plasma membrane. LPS significantly increased secretion of IL-6 by 2.3-fold, which was prevented by pre-incubation with CPZ. LPS induced TRPV1 internalization. Phosphorylation levels of ERK, p38 or JNK were not altered by TRPV1 stimulation or inhibition. LPS and IL-6 significantly lowered TRPV1-mediated ion channel current. TRPV1 mediates the LPS-induced inflammation in cardiomyocytes, associated with changes of cellular electrophysiology. LPS-induced inflammation results in TRPV1 internalization. Further studies have to examine the underlying pathways and the clinical relevance of these findings.

Alpha 1-adrenoceptor signalling contributes to toxic effects of catecholamine on electrical properties in cardiomyocytes.

AIMS: This study aimed to investigate possible roles and underlying mechanisms of alpha-adrenoceptor coupled signalling for the pathogenesis of Takotsubo syndrome (TTS). METHODS AND RESULTS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with a toxic concentration of epinephrine (Epi, 0.5 mM for 1 h) to mimic the setting of TTS. Patch-clamp technique, polymerase chain reaction (PCR) and Fluorescence-activated cell sorting (FACS) were employed for the study. High concentration Epi suppressed the depolarization velocity, prolonged duration of action potentials and induced arrhythmic events in hiPSC-CMs. The Epi effects were attenuated by an alpha-adrenoceptor blocker (phentolamine), suggesting involvement of alpha-adrenoceptor signalling in arrhythmogenesis related to QT interval prolongation in the setting of TTS. An alpha 1-adrenoceptor agonist (phenylephrine) but not an alpha 2-adrenoceptor agonist (clonidine) mimicked Epi effects. Epi enhanced ROS production, which could be attenuated by the alpha- adrenoceptor blocker. Treatment of cells with H2O2 (100 µM) mimicked the effects of Epi on action potentials and a reactive oxygen species (ROS)-blocker (N-acetyl-I-cysteine, 1 mM) prevented the Epi effects, indicating that the ROS signalling is involved in the alpha-adrenoceptor actions. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidases were involved in alpha 1-adrenoceptor signalling. A protein kinase C (PKC) blocker suppressed the effects of Epi, phenylephrine and ROS as well, implying that PKC participated in alpha 1-adrenoceptor signalling and acted as a downstream factor of ROS. The abnormal action potentials resulted from alpha 1-adrenoceptor activation-induced dysfunctions of ion channels including the voltage-dependent Na+ and L-type Ca2+ channels. CONCLUSIONS: Alpha 1-adrenoceptor signalling plays important roles for arrhythmogenesis of TTS. Alpha-adrenoceptor blockers might be clinically helpful for treating arrhythmias in patients with TTS.

Improved Outcome of Cardiogenic Shock Triggered by Takotsubo Syndrome Compared With Myocardial Infarction.

BACKGROUND: Cardiogenic shock (CS) is a severe complication of myocardial infarction (MI) or of takotsubo syndrome (TTS). For both diseases, CS is related to a worse long-term outcome. The outcome of CS has not been studied in a direct comparison of patients with MI and patients with TTS. METHODS: Mortality and cardiovascular complications were compared in patients presenting with CS based on MI or TTS between 2003 and 2017 during a follow-up of 5 years. A total of 138 patients with TTS and 532 patients with MI were included. Of these, 66 patients with MI and 25 patients with TTS developed CS (12% vs 18%, P = 0.08). RESULTS: Patients with MI and CS had more often malignant arrhythmias (74% vs 28%, P < 0.01), and need for resuscitation (80% vs 24%, P < 0.01) or death (71% vs 24%, P < 0.01) than patients with TTS and CS during the first 30 days. Although the overall rate of death remained higher in MI than in TTS (75.8% vs 52%, log rank, P < 0.01), deaths occurred in TTS constantly throughout the follow-up time, but not in MI. The incidence of heart failure increased in MI but not in TTS (31.8% vs 4%, P < 0.01) during follow-up. CONCLUSIONS: Patients with MI and CS have a worse prognosis than patients with TTS and CS. This is driven by cardiovascular events or death during the first 30 days after the index event. However, patients with TTS and CS show high mortality as well, especially during long-term follow-up.

Risk factor paradox: No prognostic impact of arterial hypertension and smoking in patients with ventricular tachyarrhythmias.

BACKGROUND: Data regarding the outcome of patients with ventricular tachyarrhythmias related to arterial hypertension (AHT) and smoking is limited. The study sought to assess the prognostic impact of AHT and smoking on survival in patients presenting with ventricular tachyarrhythmias. METHODS: All consecutive patients surviving ventricular tachycardia (VT) and ventricular fibrillation (VF) upon admission to the University Medical Center Mannheim (UMM), Germany from 2002 to 2016 were included and stratified according to AHT and smoking by propensity score matching. The primary prognostic endpoint was all-cause mortality at 30 months. RESULTS: A total of 988 AHT-matched patients (494 each, with and without AHT) and a total of 872 smoking-matched patients (436 each, with and without smoking) were included. The rates of VT and VF were similar in both groups (VT: AHT 60% vs. no AHT 60%; smokers 61% vs. non-smokers 62%; VF: AHT 35% vs. no AHT 38%; smokers 39% vs. non-smokers 38%). Neither AHT nor smoking were associated with the primary endpoint of long-term all-cause mortality at 30 months (long-term mortality rates: AHT/no AHT, 26% vs. 28%; log-rank p = 0.525; smoking/non-smoking, 22% vs. 25%; log-rank p = 0.683). CONCLUSIONS: Paradoxically, neither AHT nor smoking were associated with differences of long-term all-cause mortality in patients presenting with ventricular tachyarrhythmias.

Genetic Ablation of TASK-1 (Tandem of P Domains in a Weak Inward Rectifying K+ Channel-Related Acid-Sensitive K+ Channel-1) (K2P3.1) K+ Channels Suppresses Atrial Fibrillation and Prevents Electrical Remodeling.

BACKGROUND: Despite an increasing understanding of atrial fibrillation (AF) pathophysiology, translation into mechanism-based treatment options is lacking. In atrial cardiomyocytes of patients with chronic AF, expression, and function of tandem of P domains in a weak inward rectifying TASK-1 (K+ channel-related acid-sensitive K+ channel-1) (K2P3.1) atrial-specific 2-pore domain potassium channels is enhanced, resulting in action potential duration shortening. TASK-1 channel inhibition prevents action potential duration shortening to maintain values observed among sinus rhythm subjects. The present preclinical study used a porcine AF model to evaluate the antiarrhythmic efficacy of TASK-1 inhibition by adeno-associated viral anti-TASK-1-siRNA (small interfering RNA) gene transfer. METHODS: AF was induced in domestic pigs by atrial burst stimulation via implanted pacemakers. Adeno-associated viral vectors carrying anti-TASK-1-siRNA were injected into both atria to suppress TASK-1 channel expression. After the 14-day follow-up period, porcine cardiomyocytes were isolated from right and left atrium, followed by electrophysiological and molecular characterization. RESULTS: AF was associated with increased TASK-1 transcript, protein and ion current levels leading to shortened action potential duration in atrial cardiomyocytes compared to sinus rhythm controls, similar to previous findings in humans. Anti-TASK-1 adeno-associated viral application significantly reduced AF burden in comparison to untreated AF pigs. Antiarrhythmic effects of anti-TASK-1-siRNA were associated with reduction of TASK-1 currents and prolongation of action potential durations in atrial cardiomyocytes to sinus rhythm values. Conclusions Adeno-associated viral-based anti-TASK-1 gene therapy suppressed AF and corrected cellular electrophysiological remodeling in a porcine model of AF. Suppression of AF through selective reduction of TASK-1 currents represents a new option for antiarrhythmic therapy.

Impact of ST-segment elevation on the outcome of Takotsubo syndrome.

BACKGROUND: Recent studies have highlighted that Takotsubo syndrome (TTS), mimicking acute coronary syndrome (ACS), is associated with poor clinical outcome. TTS is associated with different repolarization disorders including ST-segment elevation. ST elevation myocardial infarction (STEMI) in ACS is associated with declined prognosis. However, the clinical and prognostic impact of ST-segment elevation on TTS remains lacking. AIM: The aim of this study was to determine the short- and long-term prognostic impact of ST-segment elevation on TTS patients as compared with STEMI patients. PATIENTS AND METHODS: Our institutional database constituted a consecutive cohort of 138 TTS patients and 138 ACS patients matched for age and sex. TTS patients (n=41) with ST-segment elevation were compared with ACS patients with ST-segment elevation (n=64). RESULTS: Chest pain was significantly more documented in STEMI patients as compared with TTS patients (48.8% vs 78.1%; P<0.01). Cardiovascular risk factors such as diabetes mellitus (12.2% vs 29.7%; P=0.02) were significantly more presented in STEMI patients. Although the initial left ventricular ejection fraction (LVEF) was more declined in TTS patients (39%±9% vs 45%±16%; P<0.01), the LVEF was more declined in STEMI patients at follow-up (54%±10% vs 45%±16%; P=0.04). Inhospital complications such as respiratory failure were significantly more presented in TTS patients (68.3% vs 20.3%; P<0.01). The short-term as well as the long-term morality was similar in both groups. In univariate analysis, male sex, ejection fraction (EF) <35%, glomerular filtration rate (GFR) <60 mL/min, cardiogenic shock, inotropic drugs, and history of cancer were predictors of 5-year mortality. CONCLUSION: Rates of the long-term mortality in TTS patients with ST elevations are comparable with STEMI patients.

Impact of T-inversion on the outcome of Takotsubo syndrome as compared to acute coronary syndrome.

BACKGROUND: Previous studies revealed that patients with Takotsubo syndrome (TTS) have a higher mortality rate than the general population and a comparable mortality to acute coronary syndrome (ACS). Repolarisation abnormalities, namely T-wave amplitude, may provide incremental prognostic information, in addition to traditional risk factors in ACS. This study was performed to determine the short- and long-term prognostic impact of inverted T-waves in TTS patients, as compared to ACS patients. METHODS AND RESULTS: Our institutional database constituted a collective of 138 patients diagnosed with TTS from 2003 to 2017, as well as 532 patients suffering from ACS. Patients with TTS or with ACS (n = 138 per group) were matched for age and sex and assessed retrospectively and prospectively and divided into two groups, TTS with inverted T-waves (n = 123) and ACS with inverted T-waves (n = 80). In-hospital complications such as respiratory failure with the need of respiratory support (60.2% vs 6.3%; P < 0.01), thromboembolic events (13.8% vs 2.5%; P < 0.01) and cardiogenic shock (18.9% vs 8.8%; P = 0.05) were significantly more presented in TTS as compared to ACS patients. Among cardiovascular risk factors diabetes mellitus (23.6% vs 45.0%; P < 0.01) and arterial hypertension (57.7% vs 78.8%; P < 0.01) were more presented in ACS patients as compared to TTS patients. Short-term mortality was similar, however the long-term mortality of 5 years was significantly higher in the TTS group (25.2% vs 7.5%; P < 0.01). In univariate analysis were male gender, EF < 35%, GFR < 60 mL/min, cardiogenic shock, inotropic drugs and history of cancer predictors of 5-year mortality. The multivariate analysis showed only male gender (HR 2.7, 95% CI 1.1-6.5; P = 0.02), GFR < 60 mL/min (HR 2.8, 95% CI 1.2-6.0; P = 0.01) and history of cancer (HR 3.6, 95% CI 1.4-9.3; P < 0.01) as independent predictors of 5-year mortality. CONCLUSION: Rates of long-term mortality were significantly higher in TTS patients showing inverted T-waves compared with patients diagnosed with ACS with inverted T-waves. However, T-inversion was not an independent predictor of 5-year mortality in the multivariate analysis.

Differences in Short QT Syndrome Subtypes: A Systematic Literature Review and Pooled Analysis.

BACKGROUND: Short QT syndrome (SQTS) is a rare syndrome and affects different types of genes. However, data on differences of clinical profile and outcome of different SQTS types are sparse. METHODS: We conducted a pooled analysis of 110 SQTS patients. Patients have been diagnosed between 2000 and 2017 at our institution (n = 12) and revealed using a literature review (n = 98). 29 studies were identified by analysing systematic data bases (PubMed, Web of Science, Cochrane Libary, Cinahl). RESULTS: 67 patients with genotype positive SQTS origin and 43 patients with genotype negative origin were found. A significant difference is documented between the sex with a higher predominance of male in genotype negative SQTS patients and predominance of females in genotype positive SQTS patients (male 52% versus 84%, female 45% versus 14%; p = 0.0016). No relevant difference of their median age (genotype positive 27 ± 19 versus genotype negative 29 ± 15; p = 0.48) was found. Asymptomatic patients and patients reporting symptoms such as syncope, sudden cardiac death, atrial flutter and ventricular fibrillation documented in both groups were similar except atrial fibrillation (genotype positive 19% versus genotype negative 0%; p = 0.0055). The QTc interval was not significantly different in both groups (genotype positive 315 ± 32 versus genotype negative 320 ± 19; p = 0.30). The treatments (medical treatment and ICD implantation) in both groups were comparable. Electrophysiology studies were not significantly higher documented in patients with genotype positive and negative origin (24% versus 9%; p = 0.075). Events at follow up such as VT, VF, and SCD were not higher presented in patients with genotype positive (13% versus 9%) (p = 0.25). 54% of genotype positive SQTS patients showed SQTS 1 followed by STQS 2 (21%) and SQTS 3 (10%). CONCLUSIONS: The long-term risk of a malignant arrhythmic event is not higher in patients with genotype positive. However, patients with genotype positive present themselves more often with AF with a female predominance. Also, other events at follow up such as syncope, atrial flutter and palpitation were not significantly higher (9% versus 0%; p = 0.079).

Therapy optimization in patients with heart failure: the role of the wearable cardioverter-defibrillator in a real-world setting.

BACKGROUND: The wearable cardioverter-defibrillator (WCD) has emerged as a valuable tool to temporarily protect patients at risk for sudden cardiac death (SCD). The aim of this study was to determine the value of the WCD for therapy optimization of heart failure patients. METHODS: One hundred five consecutive patients that received WCD between 4/2012 and 9/2016 were included in the study. All patients were followed for clinical outcome and echocardiographic parameters during WCD therapy and had continued follow-up after WCD therapy, irrespective of subsequent implantable cardioverter-defibrillator (ICD) implantation. RESULTS: The most common indication for WCD were newly diagnosed ischemic (ICM) or non-ischemic cardiomyopathy (NICM) with left ventricular ejection fraction (LVEF) ≤35%. Mean WCD wear time was 68.8 ± 50.4 days with a mean daily use of 21.5 ± 3.5 h. Five patients (4.8%) received a total of five appropriate WCD shocks. During WCD wear, patients with ICM and NICM showed significant improvement in LVEF, reducing the proportion of patients with a need for primary preventive ICD implantation to 54.8% (ICM) and 48.8% (NICM). An ICD was finally implanted in 51.4% of the study patients (24 trans-venous ICDs, 30 subcutaneous ICDs). After discontinuation of WCD therapy, all patients were followed for a mean of 18.6 ± 12.3 months. 5.6% of patients with implanted ICDs received appropriate therapies. No patient with subcutaneous ICD needed change to a trans-venous device. None of the patients without an implanted ICD suffered from ventricular tachyarrhythmias and no patient died suddenly. In patients with NICM a significant LVEF improvement was observed during long-term follow-up (from 34.8 ± 11.1% to 41.0 ± 10.2%). CONCLUSIONS: WCD therapy successfully bridged all patients to either LVEF recovery or ICD implantation. Following WCD, ICD implantation could be avoided in almost half of the patients. In selected patients, prolongation of WCD therapy beyond 3 months might further prevent unnecessary ICD implantation. The WCD as an external monitoring system contributed important information to optimize device selection in patients that needed ICD implantation.

Electrical dysfunctions in human-induced pluripotent stem cell-derived cardiomyocytes from a patient with an arrhythmogenic right ventricular cardiomyopathy.

Aims: Our aim is to investigate the arrhythmogenic mechanism in arrhythmogenic right ventricular cardiomyopathy (ARVC)-patients by using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and results: Human-induced pluripotent stem cell-derived cardiomyocytes were generated from human skin fibroblasts of two healthy donors and an ARVC-patient with a desmoglein-2 (DSG2) mutation. Patch clamp, quantitative polymerase chain reaction, and calcium imaging techniques were employed for the study. The amplitude and maximal upstroke velocity (Vmax) of action potential (AP) in ARVC-cells were smaller than that in healthy donor cells, whereas the resting potential and AP duration (APD) was not changed. The reduced Vmax resulted from decreased peak sodium current. The reason for undetected changes in APD may be the counter-action of reduced transient outward, small conductance Ca2+-activated, adenosine triphosphate-sensitive, Na/Ca exchanger (INCX) currents, and enhanced rapidly delayed rectifier currents. Isoprenaline (Iso) reduced INCX and shortened APD in both donor and ARVC-hiPSC-CMs. However, the effects of Iso in ARVC-cells are significantly larger than that in donor cells. In addition, ARVC-hiPSC-CMs showed more frequently than donor cells arrhythmogenic events induced by adrenergic stimulation. Conclusion: Cardiomyocytes derived from the ARVC patient with a DSG2 mutation displayed multiple ion channel dysfunctions and abnormal cellular electrophysiology as well as enhanced sensitivity to adrenergic stimulation. These may underlie the arrhythmogenesis in ARVC patients.

Estradiol protection against toxic effects of catecholamine on electrical properties in human-induced pluripotent stem cell derived cardiomyocytes.

BACKGROUND AND PURPOSE: Previous studies revealed that Takotsubo cardiomyopathy (TTC), a transient disorder of ventricular dysfunction affecting predominantly postmenopausal women, is associated with acquired long QT syndrome and arrhythmias, but the exact pathophysiologic mechanism is unknown. Our aim is to investigate the electrophysiological mechanism for QT-prolongation in TTC-patients by using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS: hiPSC-CMs, which were generated from human skin fibroblasts of three healthy donors, were treated by estradiol (10µM for one week) and a toxic concentration of isoprenaline (Iso, 1mM for 2h). Patch clamp techniques, qPCR and fluorescence-activated cell sorting (FACS) were employed for the study. KEY RESULTS: Iso enhanced late INa and suppressed Ito and thus prolonged the action potential duration (APD), suggesting possible reasons for arrhythmias in TTC. Iso elevated the production of reactive oxygen species (ROS). N-acetylcystein (1mM), a ROS-blocker, abolished the effects of Iso on late INa and Ito. H2O2 (100µM) mimicked Iso effects on late INa and Ito. These data indicate that the effects of Iso were mediated by ROS. Metoprolol (1mM), a beta-blocker, prevented the effects of Iso on late INa and APD, confirming the adrenoceptor-dependent effects of Iso. Estradiol treatment prevented the APD-prolongation, attenuated the enhancement of INa, diminished the reduction of Ito, suppressed ROS-production induced by Iso and reduced the expression levels of adrenoceptors, suggesting protective effects of estragon against toxic effects of catecholamine. CONCLUSIONS: Estradiol has protective effects against catecholamine excess and hence reduction in estrogen level may increase the risk of acquired long QT syndrome in TTC.

Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.

Aims: Recent studies have highlighted that takotsubo syndrome (TTS) is associated with a poor clinical outcome. Our study was conducted to determine the short- and long-term prevalence, recurrence rate and impact of life-threatening arrhythmias (LTA) on the clinical outcome of TTS. Methods and results: Our institutional database constituted a collective of 114 patients diagnosed with TTS between 2003 and 2015. The patient groups, divided according to the presence (n = 13, 11.4%) or absence (n = 101, 88.6%) of LTAs, were followed-up over a period of 3 years so as to determine the clinical outcome. Our analyses suggest that patients comprising the LTA group suffered significantly more often from an acute cardiovascular event including cases of a newly diagnosed atrial fibrillation (38.4% vs. 2.9%), cardiogenic shock with use of inotropic agents (53.8% vs. 14.8%) and cardiopulmonary resuscitation (61.5% vs. 1%). The short-term recurrence rate of a LTA episode was 15.3%, while the long-term recurrence rate of any LTA was around 5%. Whereas, in-hospital mortality was significantly higher in TTS associated with LTAs, the overall survival rate over 3 years was similar. A multivariate Cox regression analysis suggested atrial fibrillation, EF ≤ 35%, cardiogenic shock, and glomerular filtration rate <60 mL/min. as independent predictors of adverse outcome. Conclusion: The short- as well as the long-term prevalence and recurrence of LTAs in TTS patients is high. The long-term mortality rates were similar to the TTS patients presenting without any LTAs. LTAs in TTS could be triggered by a concomitant atrial fibrillation.

Revisiting the prognostic value of monocyte chemotactic protein 1 and interleukin-6 in the sepsis-3 era.

BACKGROUND: Monocyte Chemotactic Protein 1 (MCP1) and latest sepsis-3 criteria are poorly represented within studies evaluating biomarkers in sepsis. Therefore, this study evaluates the prognostic value of MCP-1 compared to interleukin-6 (IL-6) in patients with sepsis and septic shock according to sepsis-3 criteria. METHODS: 136 patients with sepsis or septic shock were included within 24h of intensive care unit (ICU) admission. MCP-1, IL-6, procalcitonin (PCT), C-reactive protein (CRP) and white blood cells (WBC) were measured on days 1, 3 and 8. All-cause mortality was followed up at 30days and 6months. RESULTS: Both MCP-1 and IL-6 levels revealed valuable prognostic discrimination of 30-day and 6-months all-cause mortality on day 1 and 3 (MCP-1: range of AUCs 0.62-0.65, p<0.039; IL-6: range of AUCs 0.65-0.70, p<0.021) compared to PCT, CRP, SOFA and APACHE II score. MCP-1 levels within the 4th quartile revealed the highest mortality at 30days and 6months compared to patients with lower levels (range of hazard ratio (HR)=2.1-3.3, p<0.041). The prognostic value of MCP-1 sustained in multivariate regression models and was comparable to that of IL-6. CONCLUSION: Both MCP-1 and IL-6 revealed prognostic value for short- and mid-term all-cause mortality in patients with sepsis and septic shock according to latest sepsis-3 definitions.

Comparative analysis of high-sensitivity cardiac troponin I and T for their association with coronary computed tomography-assessed calcium scoring represented by the Agatston score.

BACKGROUND: This study evaluates the association between high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) and coronary calcium concentration (CAC) detected by coronary computed tomography (CCT) and evaluated with the Agatston score in patients with suspected coronary artery disease (CAD). METHODS: Patients undergoing CCT during routine clinical care were enrolled prospectively. CCT was indicated for patients with a low to intermediate pretest probability for CAD. Within 24 h of CCT examination, peripheral blood samples were taken to measure cardiac biomarkers hs-cTnI and hs-cTnT. RESULTS: A total of 76 patients were enrolled including 38% without detectable CAC, 36% with an Agatston score from 1 to 100, 17% from 101 to 400, and 9% with values ≥ 400. hs-cTnI was increasing alongside Agatston score and was able to differentiate between different groups of Agatston scores. Both hs-cTn discriminated values greater than 100 (hs-cTnI, AUC = 0.663; p = 0.032; hs-cTnT, AUC = 0.650; p = 0.048). In univariate and multivariate logistic regression models, hs-cTnT and hs-cTnI were significantly associated with increased Agatston scores. Patients with hs-cTnT ≥ 0.02 µg/l and hs-cTnI ≥ 5.5 ng/l were more likely to reveal values ≥ 400 (hs-cTnT; OR = 13.4; 95% CI 1.545-116.233; p = 0.019; hs-cTnI; OR = 8.8; 95% CI 1.183-65.475; p = 0.034). CONCLUSION: The present study shows that the Agatston score was significantly correlated with hs cardiac troponins, both in univariable and multivariable linear regression models. Hs-cTnI is able to discriminate between different Agatston values. The present results might reveal potential cut-off values for hs cardiac troponins regarding different Agatston values. Trial registration Cardiovascular Imaging and Biomarker Analyses (CIBER), NCT03074253 https://clinicaltrials.gov/ct2/show/record/NCT03074253.

Diagnostic value of Pentraxin-3 in patients with sepsis and septic shock in accordance with latest sepsis-3 definitions.

BACKGROUND: Pentraxin-3 (PTX-3) is an acute-phase protein involved in inflammatory and infectious processes. This study assesses its diagnostic and prognostic value in patients with sepsis or septic shock in a medical intensive care unit (ICU). METHODS: The study includes 213 ICU patients with clinical criteria of sepsis and septic shock. 77 donors served as controls. Plasma levels of PTX-3, procalcitonin (PCT) and interleukin-6 were measured on day 1, 3 and 8. RESULTS: PTX-3 correlated with higher lactate levels as well as with APACHE II and SOFA scores (p = 0.0001). PTX-3 levels of patients with sepsis or septic shock were consistently significantly higher than in the control group (p ≤ 0.001). Plasma levels were able to discriminate sepsis and septic shock significantly on day 1, 3 and 8 (range of AUC 0.73-0.92, p = 0.0001). Uniform cut-off levels were defined at ≥5 ng/ml for at least sepsis, ≥9 ng/ml for septic shock (p = 0.0001). CONCLUSION: PTX-3 reveals diagnostic value for sepsis and septic shock during the first week of intensive care treatment, comparable to interleukin-6 according to latest Sepsis-3 definitions. TRIAL REGISTRATION: NCT01535534 . Registered 14.02.2012.

Inverse remodelling of K2P3.1 K+ channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy.

AIMS: Atrial fibrillation (AF) prevalence increases with advanced stages of left ventricular (LV) dysfunction. Remote proarrhythmic effects of ventricular dysfunction on atrial electrophysiology remain incompletely understood. We hypothesized that repolarizing K2P3.1 K+ channels, previously implicated in AF pathophysiology, may contribute to shaping the atrial action potential (AP), forming a specific electrical substrate with LV dysfunction that might represent a target for personalized antiarrhythmic therapy. METHODS AND RESULTS: A total of 175 patients exhibiting different stages of LV dysfunction were included. Ion channel expression was quantified by real-time polymerase chain reaction and Western blot. Membrane currents and APs were recorded from atrial cardiomyocytes using the patch-clamp technique. Severely reduced LV function was associated with decreased atrial K2P3.1 expression in sinus rhythm patients. In contrast, chronic (c)AF resulted in increased K2P3.1 levels, but paroxysmal (p)AF was not linked to significant K2P3.1 remodelling. LV dysfunction-related suppression of K2P3.1 currents prolonged atrial AP duration (APD) compared with patients with preserved LV function. In individuals with concomitant LV dysfunction and cAF, APD was determined by LV dysfunction-associated prolongation and by cAF-dependent shortening, respectively, consistent with changes in K2P3.1 abundance. K2P3.1 inhibition attenuated APD shortening in cAF patients irrespective of LV function, whereas in pAF subjects with severely reduced LV function, K2P3.1 blockade resulted in disproportionately high APD prolongation. CONCLUSION: LV dysfunction is associated with reduction of atrial K2P3.1 channel expression, while cAF leads to increased K2P3.1 abundance. Differential remodelling of K2P3.1 and APD provides a basis for patient-tailored antiarrhythmic strategies.

Histology-based prediction of lymph node metastases in early gastric cancer as decision guidance for endoscopic resection.

BACKGROUND: Selected cases of early gastric cancer (EGC) can be successfully treated by endoscopic therapy if the risk of concurrent lymph node metastases (LNM) is negligible. Criteria for endoscopic resection based on risk factor analyses for LNM have been established mainly in Asia. However, it is not clear to what extent these recommendations can be transferred to Western collectives. The aim of this study was to analyze predictors for LNM in EGC in a Western study population. METHODS: From our institutional archive, we selected all patients with gastric adenocarcinoma who had undergone gastrectomy with lymphadenectomy (1972 - 2005). Among 1970 patients 275 cases with EGC were identified. Clinical and pathological data were collected and logistic regression analyses performed. RESULTS: LNM were present in 36/275 (13.1%) patients. With deeper invasion proportion of LNM increased. At submucosa level (sm1), patients were almost five times more likely to have LNM than at mucosa levels.Multivariable logistic regression analysis revealed lymphovascular invasion, diffuse- and mixed-type, and invasion depth as significant independent histopathological predictors of LNM. In patients with intestinal type according to Lauren and no lymphovascular invasion, we found only one LNM-positive case out of 43 patients in the pT1b (sm1 and sm2) groups. CONCLUSIONS: Our results underline the recommendation of most guidelines that endoscopic resection is sufficient for pT1a ECG because of the low incidence of LNM in this group. However, there seems also a role for endoscopic therapy in cases of pT1b (sm1/2) EGC with intestinal type differentiation and no lymphovascular invasion.