Katherine Sattler

Prevalence of cancer in Takotsubo cardiomyopathy: Short and long-term outcome

BACKGROUND Takotsubo Cardiomyopathy (TTC) is a transient disorder of ventricular wall dysfunction, mostly induced by physical or emotional stress. TTC may be associated with adverse cardiac events. The association of cancer and its clinical impact in TTC patients has not been described yet. METHODS In 114 consecutive patients presenting with TTC between January 2003 and September 2015, we studied the frequency of cancer diagnosis, and compared the clinical course and the occurrence of a clinical endpoint of cancer and non-cancer patients during a follow up of 4.2years. RESULTS Of the 114 patients, 16 (14.0%) had a malignancy already diagnosed at TTC, and further 11 patients received the diagnosis during follow up. Cancer patients had higher frequency of atrial fibrillation and lower hemoglobin levels at admission than patients without cancer. While the occurrence of in-hospital events was comparable, the diagnosis of cancer at TTC event or during follow up was predictive for a higher rate of the composite endpoint. In the Kaplan-Meier analysis, malignant diseases were strongly associated not only with overall mortality but also with worsened time of event-free survival during the long-term outcome. CONCLUSIONS Prevalence of malignant diseases is high in TTC patients, and is a risk factor for worse outcome. Screening for malignancies should be recommended in all patients presenting with TTC. Further studies are needed to define the association on molecular levels.

Interventional Left Atrial Appendage Closure Affects the Metabolism of Acylcarnitines

Background: Left atrial appendage closure (LAAC) represents the interventional alternative to oral anticoagulation for stroke prevention in atrial fibrillation (AF). The metabolism of acylcarnitines was shown to affect cardiovascular diseases. This study evaluates the influence of successful LAAC on the metabolism of acylcarnitines. Methods: Patients undergoing successful LAAC were enrolled prospectively. Peripheral blood samples for metabolomics measurements were collected immediately before (i.e., index) and six months after LAAC (i.e., mid-term). A targeted metabolomics analysis based on electrospray ionization–liquid chromatography–mass spectrometry (ESI–LC–MS/MS) and MS/MS measurements was performed. Results: 44 patients with non-valvular AF (median CHA2DS2-VASc score 4, median HAS-BLED score 4) and successful LAAC were included. Significant changes in acylcarnitine levels were found in the total cohort, which were mainly attributed to patients with impaired left ventricular and renal function, elevated amino-terminal pro-brain natriuretic peptide (NT-proBNP) and diabetes mellitus. Adjusted multivariable regression models revealed significant changes of five metabolites over mid-term follow-up: C2, C14:1, C16, and C18:1 decreased significantly (each p < 0.05); short-chain C5 acylcarnitine plasma levels increased significantly (p < 0.05). Conclusion: This study demonstrates that successful LAAC affects the metabolism of acylcarnitines at mid-term follow-up. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02985463.

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.

Percutaneous Closure of Left Atrial Appendage significantly affects Lipidome Metabolism

Patients with non-valvular atrial fibrillation (AF) and a high risk for oral anticoagulation can be treated by percutaneous implantation of left atrial appendage occlusion devices (LAAC) to reduce the risk of cardio-embolic stroke. This study evaluates whether LAAC may influence lipid metabolism, which has never been investigated before. Patients with successful LAAC were included consecutively. Venous peripheral blood samples of patients were collected immediately before (T0, baseline) and 6 months after (T1, mid-term) LAAC. A targeted metabolomics approach based on electrospray ionization liquid chromatography–mass spectrometry (ESI-LC-MS/MS) and MS/MS measurements was performed. A total of 34 lipids revealed a significant change from baseline to mid-term follow-up after successful LAAC. Subgroup analysis revealed confounding influence by gender, age, diabetes mellitus type II, body mass index, left ventricular ejection fraction, creatinine and NT-proBNP. After multivariable adjustment within logistic regression models, these 34 lipids were still significantly altered after LAAC. Successful percutaneous LAAC may affect lipid metabolism and thereby may potentially affect pro-atherogenic and cardio-toxic effects.

Modeling Short QT Syndrome Using Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Background Short QT syndrome (SQTS), a disorder associated with characteristic ECG QT‐segment abbreviation, predisposes affected patients to sudden cardiac death. Despite some progress in assessing the organ‐level pathophysiology and genetic changes of the disorder, the understanding of the human cellular phenotype and discovering of an optimal therapy has lagged because of a lack of appropriate human cellular models of the disorder. The objective of this study was to establish a cellular model of SQTS using human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs). Methods and Results This study recruited 1 patient with short QT syndrome type 1 carrying a mutation (N588K) in KCNH2 as well as 2 healthy control subjects. We generated hiPSCs from their skin fibroblasts, and differentiated hiPSCs into cardiomyocytes (hiPSC‐CMs) for physiological and pharmacological studies. The hiPSC‐CMs from the patient showed increased rapidly activating delayed rectifier potassium channel current (IK r) density and shortened action potential duration compared with healthy control hiPSC‐CMs. Furthermore, they demonstrated abnormal calcium transients and rhythmic activities. Carbachol increased the arrhythmic events in SQTS but not in control cells. Gene and protein expression profiling showed increased KCNH2 expression in SQTS cells. Quinidine but not sotalol or metoprolol prolonged the action potential duration and abolished arrhythmic activity induced by carbachol. Conclusions Patient‐specific hiPSC‐CMs are able to recapitulate single‐cell phenotype features of SQTS and provide novel opportunities to further elucidate the cellular disease mechanism and test drug effects.

Interventional left atrial appendage closure may affect metabolism of essential amino acids and bioenergetic efficacy

BACKGROUND Interventional closure of left atrial appendage (LAAC) represents an alternative for stroke prevention in patients with non-valvular atrial fibrillation. Whether LAAC may affect metabolomic pathways has not been investigated yet. This study evaluates the impact of LAAC on the metabolism of essential amino acids, kynurenine and creatinine. METHODS Peripheral blood samples of prospectively enrolled patients undergoing successful LAAC were taken before (T0) and 6 months after (T1, mid-term follow-up). Targeted metabolomic profiling was performed using electrospray ionization liquid chromatography-mass spectrometry (ESI-LC-MS/MS) and MS/MS measurements focusing on metabolism of essential amino acids. RESULTS 44 patients with non-valvular AF (mean CHA2DS2-VASc score 4, mean HAS-BLED score 4) were enrolled. Changes in metabolites of essential amino acids, myocardial contraction and bioenergetic efficacy, such as phenylalanine (percentage change 8.2%, p = 0.006), tryptophan (percentage change 20.3%, p = 0.0006), tyrosine (percentage change 20.2%, p = 0.0001), creatinine (percentage change 7.2%, p > 0.05) and kynurenine (percentage change 8.3%, p = 0.0239) were found at mid-term follow-up. CONCLUSIONS LAAC may affect the metabolism of essential amino acids and bioenergetic efficacy. ClinicalTrials.gov Identifier: NCT02985463.

Ion Channel Dysfunctions in Dilated Cardiomyopathy in Limb-Girdle Muscular Dystrophy

Background: Limb-Girdle muscular dystrophies (LGMD) are a heritable group of genetically determined disorders with a primary involvement of the pelvic or shoulder girdle musculature with partially cardiac manifestation, such as dilated cardiomyopathy (DCM) and life-threatening tachyarrhythmia. We report here that human induced pluripotent stem cell (hiPSC)–derived cardiomyocytes from a patient with LGMD2I and DCM associated with recurrent ventricular tachycardia displayed ion channel dysfunction and abnormality of calcium homeostasis. Methods: Dermal fibroblasts obtained from a patient with LGMD2I harboring a fukutin-related protein gene mutation (826C>A; Leu276Ile) and 3 healthy donors were reprogrammed to hiPSCs. The hiPSCs were differentiated into cardiomyocytes and used for biological and electrophysiological studies. Results: Compared with hiPSC cardiomyocytes from the healthy donors, the hiPSC cardiomyocytes from the patient exhibited abnormal action potentials characterized by reduced amplitude and upstroke velocity. The peak and late Na channel currents (INa) as well as the peak L-type calcium channel currents were significantly reduced. The expression of SCN5A and CACNA1C was reduced in DCM cardiomyocytes, consistent with reduction of INa and L-type calcium channel currents. In addition, the rapidly activating delayed rectifier potassium current (IKr) was reduced, whereas the transient outward current (Ito) and slowly activating delayed rectifier potassium current (IKs) were similar in DCM and control cardiomyocytes. Finally, a significant reduction of systolic and diastolic intracellular Ca2+ concentrations was detected in DCM cardiomyocytes. Conclusions: This study demonstrates that patient-specific hiPSC cardiomyocytes can recapitulate some phenotypic properties of LGMD2I with DCM and provide a platform for studies on the cardiac events in LGMD.

Ion Channel Expression and Characterization in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Background Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are providing new possibilities for the biological study, cell therapies, and drug discovery. However, the ion channel expression and functions as well as regulations in hiPSC-CMs still need to be fully characterized. Methods Cardiomyocytes were derived from hiPS cells that were generated from two healthy donors. qPCR and patch clamp techniques were used for the study. Results In addition to the reported ion channels, INa, ICa-L, ICa-T, If, INCX, IK1, Ito, IKr, IKs IKATP, IK-pH, ISK1–3, and ISK4, we detected both the expression and currents of ACh-activated (KACh) and Na+-activated (KNa) K+, volume-regulated and calcium-activated (Cl-Ca) Cl−, and TRPV channels. All the detected ion currents except IK1, IKACh, ISK, IKNa, and TRPV1 currents contribute to AP duration. Isoprenaline increased ICa-L, If, and IKs but reduced INa and INCX, without an effect on Ito, IK1, ISK1–3, IKATP, IKr, ISK4, IKNa, ICl-Ca, and ITRPV1. Carbachol alone showed no effect on the tested ion channel currents. Conclusion Our data demonstrate that most ion channels, which are present in healthy or diseased cardiomyocytes, exist in hiPSC-CMs. Some of them contribute to action potential performance and are regulated by adrenergic stimulation.

Long term outcome of patients suffering from cancer and Takotsubo syndrome or myocardial infarction

Background The pathophysiology of takotsubo syndrome (TTS) is unclear so far. There is strong association of the occurrence of TTS and malignant diseases. An association between malignant diseases and myocardial infarction (MI) was found recently and ascribed to common molecular and lifestyle mechanisms. Aim To compare the outcome of patients with MI or TTS and malignant diseases in a matched cohort. Methods Patients with TTS or with MI (n = 138 per group) were matched for age and sex and assessed retrospectively and prospectively. Occurrence of malignant diseases and clinical outcome was followed up over 4 years. Results At the time of the index event, 8 (5.8%) MI patients and 17 (12.3%) TTS patients were already diagnosed with cancer. During follow up, the rate of patients who developed cancer was significantly higher in the TTS group than in the MI group (log rank P = 0.01). Mortality was higher in the TTS group, but also in the subgroup of TTS patients with cancer (log rank P < 0.05). In the multivariate analysis, male gender, renal impairment and the history of cancer was associated with an increased risk for death. Conclusions Patients with TTS have more often malignant diseases than patients with MI. Cancer patients with TTS have a worse clinical outcome. The underlying mechanism is unclear yet, but the results point at TTS being the syndrome of an extracardiac disease rather than a disease of cardiac origin. Longer and closer follow up of patients with TTS and further studies addressing the mechanism of TTS are needed.

Correction to: Occlusion of left atrial appendage affects metabolomic profile: focus on glycolysis, tricarboxylic acid and urea metabolism

The article Occlusion of left atrial appendage aff ects metabolomic profile:focus on glycolysis, tricarboxylic acid and urea metabolism, written by K. Sattler, M. Behnes, C. Barth, A. Wenke, B. Sartorius, I. El-Battrawy, K. Mashayekhi, J. Kuschyk, U. Hoffmann, T. Papavasiliu, C. Fastner, S. Baumann, S. Lang, X. Zhou, G. Yücel, M. BorggrefeI, Akin, was originally published Online First without open access.