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.

Local dose rate effects in implantable cardioverter-defibrillators with flattening filter free and flattened photon radiation.

PURPOSE: In the beam penumbra of stereotactic body radiotherapy volumes, dose rate effects in implantable cardioverter-defibrillators (ICDs) may be the predominant cause for failures in the absence of neutron-generating photon energies. We investigate such dose rate effects in ICDs and provide evidence for safe use of lung tumor stereotactic radioablation with flattening filter free (FFF) and flattened 6 Megavolt (MV) beams in ICD-bearing patients. METHODS: Sixty-two ICDs were subjected to scatter radiation in 1.0, 2.5, and 7.0 cm distance to 100 Gy within a 5â€¯× 5 cm2 radiation field. Radiation was applied with 6 MV FFF beams (constant dose rate of 1400 cGy/min) and flattened (FLAT) 6 MV beams (430 cGy/min). Local dose rates (LDR) at the position of all ICDs were measured. All ICDs were monitored continuously. RESULTS: With 6 MV FFF beams, ICD errors occurred at distances of 1.0 cm (LDR 46.8 cGy/min; maximum ICD dose 3.4 Gy) and 2.5 cm (LDR 15.6 cGy/min; 1.1 Gy). With 6 MV FLAT beams, ICD errors occurred only at 1 cm distance (LDR 16.8 cGy/min; 3.9 Gy). No errors occurred at an LDR below 7 cGy/min, translating to a safe distance of 2.5 cm (1.5 Gy) in flattened and 7 cm (0.4 Gy) in 6 MV FFF beams. CONCLUSION: A LDR in ICDs larger than 7 cGy/min may cause ICD malfunction. At identical LDR, differences between 6 MV FFF and 6 MV FLAT beams do not yield different rates of malfunction. The dominant reason for ICD failures could be the LDR and not the total dose to the ICD. For most stereotactic treatments, it is recommended to generate a planning risk volume around the ICD in which LDR larger than 7 cGy/min are avoided.

J wave syndromes in patients with spinal and bulbar muscular atrophy.

BACKGROUND: Males with X-linked recessive spinobulbar muscular atrophy (SBMA) are reported to die suddenly and a Brugada electrocardiography (ECG) pattern may be present. A hallmark of this pattern is the presence of ST segment elevations in right precordial leads associated with an increased risk of sudden cardiac death. OBJECTIVE: We aimed to detect subtle myocardial abnormalities using ECG and cardiovascular magnetic resonance imaging (CMR) in patients with SBMA. METHODS: 30 SBMA patients (55.7 ± 11.9 years) and 11 healthy male controls underwent 12-lead ECGs were recorded using conventional and modified chest leads. CMR included feature-tracking strain analysis, late gadolinium enhancement and native T1 and T2 mapping. RESULTS: Testosterone levels were increased in 6/29 patients. Abnormal ECGs were recorded in 70%, consisting of a Brugada ECG pattern, early repolarization or fragmented QRS. Despite normal left ventricular ejection fraction (66 ± 5%), SBMA patients exhibited more often left ventricular hypertrophy as compared to controls (34.5% vs 20%). End-diastolic volumes were smaller in SBMA patients (left ventricular volume index 61.7 ± 14.7 ml/m2 vs. 79.1 ± 15.5 ml/m2; right ventricular volume index 64.4 ± 16.4 ml/m2 vs. 75.3 ± 17.5 ml/m2). Tissue characterization with T1-mapping revealed diffuse myocardial fibrosis in SBMA patients (73.9% vs. 9.1%, device-specific threshold for T1: 1030 ms). CONCLUSION: SBMA patients show abnormal ECGs and structural abnormalities, which may explain an increased risk of sudden death. These findings underline the importance of ECG screening, measurement of testosterone levels and potentially CMR imaging to assess cardiac risk factors.

MicroRNA-365 regulates human cardiac action potential duration.

Abnormalities of ventricular action potential cause malignant cardiac arrhythmias and sudden cardiac death. Here, we aim to identify microRNAs that regulate the human cardiac action potential and ask whether their manipulation allows for therapeutic modulation of action potential abnormalities. Quantitative analysis of the microRNA targetomes in human cardiac myocytes identifies miR-365 as a primary microRNA to regulate repolarizing ion channels. Action potential recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes show that elevation of miR-365 significantly prolongs action potential duration in myocytes derived from a Short-QT syndrome patient, whereas specific inhibition of miR-365 normalizes pathologically prolonged action potential in Long-QT syndrome myocytes. Transcriptome analyses in these cells at bulk and single-cell level corroborate the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional action potential-regulating genes by this microRNA. Whole-cell patch-clamp experiments confirm miR-365-dependent regulation of repolarizing ionic current Iks. Finally, refractory period measurements in human myocardial slices substantiate the regulatory effect of miR-365 on action potential in adult human myocardial tissue. Our results delineate miR-365 to regulate human cardiac action potential duration by targeting key factors of cardiac repolarization.

Gender aspects in cardiooncology.

BACKGROUND: Cardiooncology is a relatively new subspeciality, investigating the side effects of cytoreductive therapies on the cardiovascular (CV) system. Gender differences are well known in oncological and CV diseases, but are less elucidated in cardiooncological collectives. METHODS: Five hundred and fifty-one patients (278 male, 273 female) with diagnosed cancer who underwent regular cardiological surveillance were enrolled in the 'MAnnheim Registry for CardioOncology' and followed over a median of 41 (95% confidence interval: 40-43) months. RESULTS: Female patients were younger at the time of first cancer diagnosis [median 60 (range 50-70) vs. 66 (55-75), P = 0.0004], while the most common tumour was breast cancer (49.8%). Hyperlipidaemia was more often present in female patients (37% vs. 25%, P = 0.001). Male patients had a higher cancer susceptibility than female patients. They suffered more often from hypertension (51% vs. 67%, P = 0.0002) or diabetes (14% vs. 21%, P = 0.02) and revealed more often vitamin D deficiency [(U/l) median 26.0 (range 17-38) vs. 16 (9-25), P = 0.002] and anaemia [(g/dl) median 11.8 (range 10.4-12.9) vs. 11.7 (9.6-13.6), P = 0.51]. During follow-up, 140 patients died (male 77, female 63; P = 0.21). An increased mortality rate was observed in male patients (11.4% vs. 14%, P = 0.89), with even higher mortality rates of up to 18.9% vs. 7.7% (P = 0.02) considering tumours that can affect both sexes compared. CONCLUSIONS: Although female patients were younger at the time of first cancer diagnosis, male patients had both higher cancer susceptibility and an increased mortality risk. Concomitant CV diseases were more common in male 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.

Multiple breath washout (MBW) testing using sulfur hexafluoride: reference values and influence of anthropometric parameters.

BACKGROUND: Multiple breath washout (MBW) using sulfur hexafluoride (SF6) has the potential to reveal ventilation heterogeneity which is frequent in patients with obstructive lung disease and associated small airway dysfunction. However, reference data are scarce for this technique and mostly restricted to younger cohorts. We therefore set out to evaluate the influence of anthropometric parameters on SF6-MBW reference values in pulmonary healthy adults. METHODS: We evaluated cross-sectional data from 100 pulmonary healthy never-smokers and smokers (mean 51 (SD 20), range 20-88 years). Lung clearance index (LCI), acinar (Sacin) and conductive (Scond) ventilation heterogeneity were derived from triplicate SF6-MBW measurements. Global ventilation heterogeneity was calculated for the 2.5% (LCI2.5) and 5% (LCI5) stopping points. Upper limit of normal (ULN) was defined as the 95th percentile. RESULTS: Age was the only meaningful parameter influencing SF6-MBW parameters, explaining 47% (CI 33% to 59%) of the variance in LCI, 32% (CI 18% to 47%) in Sacin and 10% (CI 2% to 22%) in Scond. Mean LCI increases from 6.3 (ULN 7.4) to 8.8 (ULN 9.9) in subjects between 20 and 90 years. Smoking accounted for 2% (CI 0% to 8%) of the variability in LCI, 4% (CI 0% to 13%) in Sacin and 3% (CI 0% to 13%) in Scond. CONCLUSION: SF6-MBW outcome parameters showed an age-dependent increase from early adulthood to old age. The effect was most pronounced for global and acinar ventilation heterogeneity and smaller for conductive ventilation heterogeneity. No influence of height, weight and sex was seen. Reference values can now be provided for all important SF6-MBW outcome parameters over the whole age range. TRIAL REGISTRATION NUMBER: NCT04099225.

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.

Blood Cholesterol and Outcome of Patients with Cancer under Regular Cardiological Surveillance.

Cardiovascular (CV) diseases and cancer share several similarities, including common risk factors. In the present investigation we assessed the relationship between cholesterol levels and mortality in a cardiooncological collective. In total, 551 patients receiving anticancer treatment were followed over a median of 41 (95% CI 40, 43) months and underwent regular cardiological surveillance. A total of 140 patients (25.4%) died during this period. Concomitant cardiac diseases were more common in patients who deceased (53 (37.9%) vs. 67 (16.3%), p < 0.0001), as well as prior stroke. There were no differences in the distribution of classical CV risk factors, such as hypertension, diabetes or nicotine consumption. While total cholesterol (mg/dL) was significantly lower in patients who deceased (157 ± 59 vs. 188 ± 53, p < 0.0001), both HDL and LDL cholesterol were not differing. In addition, cholesterol levels varied between different tumour entities; lowest levels were found in patients with tumours of the hepatopancreaticobiliary system (median 121 mg/dL), while patients with melanoma, cerebral tumours and breast cancer had rather high cholesterol levels (median > 190 mg/dL). Cholesterol levels were significantly lower in patients who died of cancer; lowest cholesterol levels were observed in patients who died of tumours with higher mitotic rate (mesenchymal tumours, cerebral tumours, breast cancer). Cox regression analysis revealed a significant mortality risk for patients with stem cell transplantation (HR 4.31) and metastasised tumour stages (HR 3.31), while cardiac risk factors were also associated with a worse outcome (known cardiac disease HR 1.58, prior stroke/TIA HR 1.73, total cholesterol HR 1.70), with the best discriminative performance found for total cholesterol (p = 0.002).

Prognostic Impact of Pretherapeutic Hemoglobin Levels on All-cause Mortality in Cardiooncology.

BACKGROUND/AIM: We investigated the prognostic impact of hemoglobin (Hb) levels in tumour patients receiving routine cardiological surveillance during anticancer treatment. The aim of the study was to identify independent predictors of all-cause mortality in a cardio-oncological collective. PATIENTS AND METHODS: A total of 551 patients (273 males, 278 females) were enrolled in the Mannheim Registry for Cardiooncology and were included in the present analysis. Median follow-up was 41 months (95% CI=40-43). RESULTS: Patients were grouped according to a pretherapeutic Hb-threshold (determined by ROC analysis) into cohorts with Hb<11.4 g/dl (n=232, 42.1%) and Hb >11.4 g/dl (n=319, 57.9%). Patients with lower Hb levels were older at the time of first diagnosis (63.8±14.4 vs. 59.9±15.4 years, p=0.003) and were more likely to have advanced tumour stages (92 (39.7%) vs. 83 (26.0%), p=0.0007). There were no differences regarding cardiovascular comorbidities such as hypertension or diabetes, while chronic kidney disease was more common in patients with lower Hb. Anticoagulants were used more often in patients with lower Hb (88 (37.9%) vs. 84 (26.3%), p=0.01). Left ventricular ejection fraction (LVEF) was lower in patients with Hb <11.4 g/dl (51.9±11.0% vs. 55.1±9.7%, p=0.003). Correlation analysis revealed a significant correlation of Hb levels and LVEF (R2=0.07, p<0.0001). During follow-up, a total of 140 patients (25.4%) were deceased, with significantly more deaths occurring in the group of patients with low Hb values [108 (46.6%) vs. 32 (10.0%), p<0.0001]. In multivariable analysis, Hb was identified as independent predictor for mortality (OR=5.3, CI=0.41-0.89, p<0.0001). CONCLUSION: Low Hb levels were identified as an independent predictor of mortality in patients with cancer. There was a significant correlation of Hb and LVEF, suggesting that low Hb values are not solely due to anaemia, but rather reflect the severity of cancer.

Left atrial appendage closure in patients with chronic kidney disease: results from the German multicentre LAARGE registry.

OBJECTIVES: Chronic kidney disease (CKD) is associated with an increased complication rate after cardiac interventions. Although CKD has a high prevalence among atrial fibrillation patients, the impact of CKD on periprocedural complications and the outcome after an interventional left atrial appendage closure (LAAC) is unclear. The present study, therefore, aimed to investigate whether CKD influences the procedure's effectiveness and safety. METHODS: LAARGE is a prospective, non-randomised registry. LAAC was conducted with different standard commercial devices, and the follow-up period was one year. CKD was defined by an eGFR < 60 mL/min/1.73 m2, and subgroups were further analysed (i.e. eGFR < 15, 15-29, and 30-59 mL/min/1.73 m2, respectively). RESULTS: Two hundred ninety-nine of 623 patients (48.0%) revealed a CKD. The prevalence of cardiovascular comorbidity, CHA2DS2-VASc score (4.9 vs. 4.2), and HAS-BLED score (4.3 vs. 3.5) was significantly higher in CKD patients (each p < 0.001). Implantation success was similarly high across all GFR groups (97.9%). Periprocedural MACCE (0.7 vs. 0.3%), and other major complications (4.7 vs. 3.7%) were comparably infrequent. Survival free of stroke was significantly lower among CKD patients within 1 year (82.0 vs. 93.0%; p < 0.001; consistent after adjustment for confounding factors), without significant accentuation in advanced CKD (i.e. eGFR < 30 mL/min/1.73 m2; p > 0.05 vs. eGFR 30-59 mL/min/1.73 m2). Non-fatal strokes were absolutely infrequent during follow-up (0 vs. 1.1%). Severe non-fatal bleedings were observed only among CKD patients (1.4 vs. 0%; p = 0.021). CONCLUSIONS: Despite an increased cardiovascular risk profile of CKD patients, device implantation was safe, and LAAC was associated with effective stroke prevention across all CKD stages.

Coprevalence and Incidence of Lung Cancer in Patients Screened for Abdominal Aortic Aneurysm.

BACKGROUND/AIM: Lung diseases are common in patients with abdominal aortic aneurysms (AAA). This study evaluates the prevalence of lung cancer (LC) in high-risk patients screened for AAA. PATIENTS AND METHODS: Six hundred and one male patients (≥65 years of age, cardiovascular high-risk profile) were enrolled and followed prospectively over a median of 16.5 months. RESULTS: In 29 patients (4.8%) LC and in another 50 patients (8.3%) AAA were found. The prevalence of LC among patients with AAA was even higher (9 of 50, 18.0%). Twenty-one patients had an initial diagnosis of LC, with an incidence of 12.0% (6 of 50) in patients with AAA. During follow-up, 14 of 70 patients with AAA and/ or LC (20.0%) deceased. The highest mortality was found in patients with LC only (8 of 20, 40.0%), followed by patients with both AAA and LC (3 of 9, 33.3%), while patients with AAA only had the lowest mortality rate (3 of 41, 7.3%). CONCLUSION: In patients with a high cardiovascular risk profile, a high prevalence of both AAA and LC were found, whereby the prognosis is largely determined by the LC. Therefore, LC is of particular importance in the setting of screening and surveillance of AAA.

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.

Current evidence of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction.

Heart failure (HF) is one of the most common reasons for hospital admission in western countries. The measurement of the left ventricular ejection fraction is essential for the classification of HF and deciding on HF treatment. The treatment of HF has been improved in both diagnostic and therapeutic fields over the past two decades. The angiotensin receptor-neprilysin inhibitor decreased the cardiovascular mortality in patients with chronic HF with reduced ejection fraction. Sacubitril/valsartan (LCZ696) improves the imbalance between the renin-angiotensin-aldosterone and natriuretic peptide systems. We present the clinical efficacy, real-world experience, safety and tolerability, the relevance of etiology of cardiomyopathy, and gender differences and regulatory affairs of LCZ696 in the treatment of patients with HF with reduced ejection fraction.

Effectivity and applicability of the German DEGRO/DGK-guideline for radiotherapy in CIED-bearing patients.

BACKGROUND AND PURPOSE: No evidence has been presented until now whether recommendations given in recently issued guidelines concerning CIED-bearing patients significantly decrease RT-related complications. MATERIALS AND METHODS: 160 RT-cases were prospectively treated with 3D-CRT, IMRT, SBRT using exclusively 6 MV photons (n = 146) and electrons (n = 14) according to the 2015 issued German DEGRO/DGK-guideline for CIED-bearing patients and compared to 40 RT-cases (3D-CRT, 10-23 MV photons (n = 39) and electrons (n = 1)) of CIED-bearing patients which were treated in concordance to the 1994 issued AAPM-guideline. RESULTS: With AAPM-recommendations, complications occurred in 7/39 (17.95%) photon-RT cases, one patient experienced inadequate defibrillation therapy. For all patients treated with photon energies between 6 and 23 MV, a relative risk for CIED failure if treated with > 6 MV was calculated to be 9.03 (95% CI 5.24-15.55). After implementation of the DEGRO/DGK guideline, no complications were noted in 147 cases treated with photons, even though CIED-doses were as high as 5.37 Gy. In 13 cases treated with electrons, one PM lost patient-related data in a patient receiving antiproliferative RT to mammary glands. CONCLUSIONS: Implementation of the German DEGRO/DGK-guideline effectively prevented radiation-associated CIED failures in patients treated with photons. Limitation of photon energy to 6 MV, suspension of defibrillation therapy in ICDs, surveillance of patients according to risk stratification and avoidance of direct irradiation of CIEDs should become standard of care.

Interaction between CIEDs and modern radiotherapy techniques: Flattening filter free-VMAT, dose-rate effects, scatter radiation, and neutron-generating energies.

BACKGROUND AND PURPOSE: Providing evidence for radiotherapy (RT)-induced effects on cardiac implantable electric devices (CIEDs) with focus on flattening filter free-volumetric modulated arc therapy (FFF-VMAT) at 6 and 10 MV as well as 3D-conformal radiotherapy (3D-CRT) at 18 MV. MATERIALS AND METHODS: 68 CIEDs (64 implantable cardioverter-defibrillators (ICDs) and 4 cardiac pacemakers (PMs)) were located on the left chest position on a slab phantom and irradiated under telemetrical surveillance either directly, or distant to 3D-CRT or FFF-VMAT, dose-rate 2500 cGy/min, and target dose of 150 Gy. Devices were placed within, close by (2.5 cm and 5 cm), and distant (35 cm) to the radiation field. Scatter radiation (SR) and photon neutrons (PN) were recorded. CIEDs were investigated in following groups: 1a) 18 MV 3D-CRT - 4 ICDs/4 PMs out of radiation field, 1b) 18 MV open field - 4 ICDs/4 PMs within radiation field, 2) 6 MV FFF-VMAT, 15 ICDs in 35 cm distance to VMAT, 3) 10 MV-FFF VMAT, 15 ICDs in 35 cm distance to VMAT, 4) 6 MV FFF-VMAT, 15 ICDs in 2.5 cm distance to VMAT, 5) 10 MV FFF-VMAT, 15 ICDs in 2.5 cm distance to VMAT. RESULTS: No incidents occurred at 6 MV FFF. 10 MV FFF-VMAT and 18 MV 3D-CRT resulted in data loss, reset, and erroneous sensing with inhibition of pacing (leading to inadequate defibrillation) in 8/34 ICDs and 2/4 PMs which were not located within radiation. Direct radiation triggered instantaneous defibrillation in 3/4 ICDs. CONCLUSIONS: 6 MV FFF-VMAT is safe even at high dose-rates of 2500 cGy/min, regardless whether CIEDs are located close (2.5 cm) or distant (35 cm) to the radiation beam. CIEDs should never be placed within radiation and energy should always be limited to 6 MV. At 6 MV, VMAT at high dose-rates can be used to treat tumors, which are located close to CIEDs.

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.

Prevalence of abdominal aortic aneurysm and associated lower extremity artery aneurysm in men hospitalized for suspected or known cardiopulmonary disease.

BACKGROUND: AAA is a disease affecting predominantly male patients ≥65 years and its dreaded complications such as rupture led to population-based screening programs as preventive measure. Nonetheless, the supposed prevalence may have been overestimated, so that targeted screening of high risk populations may be more effective. This study was performed to evaluate the prevalence of abdominal aortic aneurysm (AAA) of an inpatient high-risk cohort and to estimate the co-prevalence of lower extremity arterial aneurysms. METHODS: Participants: 566 male inpatients, ≥ 65 years of age, hospitalized for suspected or known cardiopulmonary disease. Primary and secondary outcome measures: Maximal infrarenal aortic diameters using abdominal ultrasound (leading edge to leading edge method). Upon detection of an AAA (diameter ≥ 30 mm), the lower extremity arteries were examined with regard to associated aneurysms. RESULTS: In 40 of 566 patients (7.1%) AAAs were detectable. Fourteen patients (2.5%) had a first diagnosis of AAA, none of which was large (> 55 mm), the remaining 26 patients were either already diagnosed (14 patients, 2.5%) or previously repaired (12 patients, 2.1%). The three most common main diagnoses at discharge were acute coronary syndrome (43.3%), congestive heart failure (32.2%), and chronic obstructive pulmonary disease (12%). The cohort showed a distinct cardiovascular risk profile comprising arterial hypertension (82.9%), diabetes mellitus (44.4%), and a history of smoking (57.6%). In multivariate analysis, three-vessel coronary artery disease (Odds ratio (OR): 4.5, 95% confidence interval (CI): 2.3-8.9, p <  0.0001) and history of smoking (OR: 3.7, CI: 1.6-8.6, p <  0.01) were positively associated with AAA, while diabetes mellitus (OR: 0.5, CI: 0.2-0.9, p = 0.0295) showed a negative association with AAA. Among the subjects with AAA, we found two large iliac and two large popliteal aneurysms. CONCLUSION: Ultrasound screening in male inpatients, hospitalized for suspected or known cardiopulmonary disease, revealed a high AAA prevalence in comparison to the present epidemiological screening programs. There was a moderate proportion of newly-screen detected AAA and additional screening of the lower extremity arteries yielded some associated aneurysms with indication for possible intervention.

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.