Volker Liebe

Subcutaneous implantable cardioverter-defibrillator: First single-center experience with other cardiac implantable electronic devices

BACKGROUND The subcutaneous implantable cardioverter-defibrillator (S-ICD) is an implantable device for antiarrhythmic therapy with no intravascular leads. OBJECTIVE The purpose of this study was to describe the technical feasibility of combining the S-ICD with other cardiac implantable electronic devices (CIEDs), including pacemakers with transvenous or epicardial electrodes. We also provide the first experience of combining an S-ICD with catheter-based therapies, including cardiac contractility modulation (CCM) and vagus nerve stimulation. METHODS Between July 2011 and November 2014, 6 patients received a CCM device and S-ICD, 3 patients with a single-chamber pacemaker using either transvenous or epicardial pacing electrodes received and S-ICD, and 1 patient with an implanted S-ICD received vagus nerve stimulation. In all patients, intraoperative S-ICD testing, crosstalk tests, and postoperative ergometric testing were performed. RESULTS In all 10 patients, device implantations were successfully performed without complications. S-ICD therapy was shown to be technically feasible with concomitant CIED. Mean follow-up was nearly 17 months. S-ICD testing and crosstalk testing before and during exercise enabled device programming across a broad range of test conditions and was associated with no subsequent evidence of adverse device interaction. None of the devices required permanent inactivation or removal, and no patient received an inappropriate shock. CONCLUSION In suitable patients, combining an S-ICD with CCM or pacemaker may provide an acceptable means to reduce the number of transvascular leads. S-ICD appeared safe with CCM over an intermediate follow-up period. Additional prospective randomized controlled trials examining S-ICD in conjunction with CIEDs are warranted.

A new therapeutic option by subcutaneous recombinant hirudin in patients with heparin-induced thrombocytopenia type II: A pilot study

We prospectively studied 15 patients suffering from acute heparin-induced thrombocytopenia (HIT) type II with and without thromboembolic events and 4 patients with anamnestically known HIT type II recurrently requiring thromboprophylaxis in order to develop new therapeutic strategies by subcutaneous recombinant hirudin administration. Patients with acute venous or arterial thromboembolism were treated with aPTT-controlled intravenous (mean: 19.3 days) followed by subcutaneous r-hirudin (mean: 22.5 days). Patients without thromboembolism were treated with subcutaneous r-hirudin (mean: 25.9 days). Four patients were readmitted to subcutaneous r-hirudin (mean: 32 days). When r-hirudin was administered subcutaneously following intravenous treatment, mean baseline (prior to the injection) and mean peak (1.5-2.5 hours after the injection) aPTT ratios were 1.1 (+/-0.2) to 1.7 (+/-0.48) and 2. 48 (+/-0.43) to 2.52 (+/-0.4) times normal value, respectively. Mean baseline and mean peak ECT ratios were 1.2 (+/-0.12) to 1.9 (+/-0. 22) and 2.2 (+/-0.25) to 2.6 (+/-0.11) times the upper normal value, respectively. When r-hirudin was initially administered subcutaneously, mean baseline and mean peak aPTT ratios were 1.41 (+/-0.25) to 1.61 (+/-00.28) and 1.88 (+/-0.26) to 2.06 (+/-0.09) times the normal value, respectively. Mean baseline and mean peak ECT ratios were 1.25 (+/-0.2) to 1.5 (+/-0.38) and 2.01 (+/-0.21) to 2.23 (+/-0.25) times the upper limit of normal, respectively. Patients who received recurrent subcutaneous r-hirudin had mean baseline and peak aPTT values of 1.5 (+/-0.35) to 1.75 (+/-0.156) and 2.0 (+/-0.33) to 2.1 (+/-0.18) times the normal value, respectively. Mean baseline and peak ECT ratios were 1.3 (+/-0.26) to 1.65 (+/-0.09) and 1.94 (+/-0.256) to 2.7 (+/-0.23) times the upper limit of normal, respectively. The overall cumulative incidence of r-hirudin antibodies was 12/19 (63%) with a significant accumulation of r-hirudin in antibody-positive patients compared to antibody-negative patients (p<0.05). No patient suffered a new thromboembolic or major bleeding event. Subcutaneous administration of recombinant hirudin provides a long-term thromboprophylaxis regimen in HIT type II patients after passivation of acute thromboembolism.

Levels of oxidized low-density lipoproteins are increased in patients with severe sepsis

BACKGROUND It was hypothesized that the inflammatory response of patients with severe sepsis may result in changes of plasma levels of oxidized low-density lipoproteins (ox-LDLs) and that drotrecogin alpha (activated) (DAA) (Xigris, Eli Lilly and Company [Indiana 46285, USA]) may influence ox-LDL levels. MATERIALS AND METHODS The ox-LDL levels were measured in severe septic patients on day 1, 4, and 7 of severe sepsis. Patients were treated either with or without DAA. RESULTS The ox-LDL levels increased significantly (P < .05) from day 1 to day 7 (day 1, mean +/- SEM, 25.4 +/- 1.8 U/L; day 4, mean +/- SEM, 34.3 +/- 2.1 U/L; day 7, mean +/- SEM, 38.3 +/- 2.1 U/L) in all patients (n = 68). The ox-LDL levels increased significantly from day 1 to day 7 both in patients treated with (n = 31) and without DAA (n = 37) (P < .001) (DAA-group: day 1, mean +/- SEM, 24.4 +/- 2.8 U/L; day 4, mean +/- SEM, 35.5 +/- 2.9 U/L; day 7, mean +/- SEM, 40.7 +/- 3.2 U/L) (control group: day 1, mean +/- SEM, 26.3 +/- 2.8 U/L; day 4, mean +/- SEM, 33.2 +/- 2.9 U/L; day 7, mean +/- SEM, 36.4 +/- 2.9 U/L). No significant differences of ox-LDL levels were observed between both groups at any point of time (P > .05). CONCLUSIONS The ox-LDL concentrations increase significantly during the first week of severe sepsis and are not affected by administration of drotrecogin alpha (activated) (Xigris).

Recombinant human activated protein C upregulates the release of soluble fractalkine from human endothelial cells

Fractalkine is a unique endothelial cell‐derived chemokine that functions both as a chemoattractant and as an adhesion molecule. Recent findings suggest that fractalkine plays an important role in inflammatory diseases by modulating leucocyte endothelial cell interactions. A modulating effect on the immune system in severe sepsis has been suggested for recombinant human activated protein C (rhAPC). However, a little is known about the effect of rhAPC on the endothelial release of soluble fractalkine. The effect of rhAPC (50 ng/ml to 10 μg/ml) and protein C (in equimolar concentrations) on the synthesis of fraktalkine‐mRNA and release of soluble protein in human umbilical vein endothelial cells (HUVEC) was determined by reverse transcription‐polymerase chain reaction and by an enzyme‐linked immunosorbent assay. rhAPC at supra‐pharmacological concentrations (1–10 μg/ml) stimulated fractalkine‐messenger RNA‐gene transcription and release of soluble fractalkine in a time‐ and dose‐dependent manner, whereas the zymogen protein C was ineffective. As shown by experiments using monoclonal antibodies against the thrombin receptor, protease‐activated receptor‐1 (PAR‐1), PAR‐2 and against the endothelial protein C receptor (EPCR), the effect of rhAPC on fractalkine upregulation was mediated by binding to the EPCR‐receptor and signalling via PAR‐1. These in vitro data demonstrate that induction of fractalkine release is an important response of HUVEC to stimulation with rhAPC and may lead to a better understanding of the molecular pathways involved in the mode of action of rhAPC. Further clinical trials are needed to confirm the in vivo relevance of these data.

Simultaneous Non-Invasive Epicardial and Endocardial Mapping in Patients With Brugada Syndrome: New Insights Into Arrhythmia Mechanisms.

Background The underlying mechanisms of Brugada syndrome (BrS) are not completely understood. Recent studies provided evidence that the electrophysiological substrate, leading to electrocardiogram abnormalities and/or ventricular arrhythmias, is located in the right ventricular outflow tract (RVOT). The purpose of this study was to examine abnormalities of epicardial and endocardial local unipolar electrograms by simultaneous noninvasive mapping in patients with BrS. Methods and Results Local epicardial and endocardial unipolar electrograms were analyzed using a novel noninvasive epi‐ and endocardial electrophysiology system (NEEES) in 12 patients with BrS and 6 with right bundle branch block for comparison. Fifteen normal subjects composed the control group. Observed depolarization abnormalities included fragmented electrograms in the anatomical area of RVOT endocardially and epicardially, significantly prolonged activation time in the RVOT endocardium (65±20 vs 38±13 ms in controls; P=0.008), prolongation of the activation‐recovery interval in the RVOT epicardium (281±34 vs 247±26 ms in controls; P=0.002). Repolarization abnormalities included a larger area of ST‐segment elevation >2 mV and T‐wave inversions. Negative voltage gradient (−2.5 to −6.0 mV) between epicardium and endocardium of the RVOT was observed in 8 of 12 BrS patients, not present in patients with right bundle branch block or in controls. Conclusions Abnormalities of epicardial and endocardial electrograms associated with depolarization and repolarization properties were found using NEEES exclusively in the RVOT of BrS patients. These findings support both, depolarization and repolarization abnormalities, being operative at the same time in patients with BrS.

Cardiac contractility modulation: first experience in heart failure patients with reduced ejection fraction and permanent atrial fibrillation

AIMS Cardiac contractility modulation (CCM) is an electrical therapy for heart failure (HF) with reduced ejection fraction. Sinus rhythm is deemed necessary for effective treatment because the current CCM signal delivery algorithm requires sequential sensing of a p wave, followed by depolarizations at each ventricular lead. In case of atrial fibrillation (AF) CCM is inhibited. This study demonstrates the feasibility of CCM therapy in patients with permanent AF by circumventing the requirement for sensing of a natural p wave. METHODS AND RESULTS Five CCM patients with AF received a pacemaker or implantable cardioverter/defibrillator (ICD) upgrade to cardiac resynchronization therapy (CRT) with low atrial sensitivity, which resulted in compulsory atrial stimulation followed by biventricular pacing. The CCM system recognized the atrial stimuli as p waves, which led to CCM signal delivery. Three patients developed permanent AF after a mean follow-up of 40 months of CCM therapy. Two patients had permanent AF at the time of CCM device implantation. All pacemaker or ICD devices were successfully upgraded to CRT. Cardiac resynchronization therapy stimulation rates of ≥96% and CCM stimulation rates between 60% and 95% were achieved. Clinical condition of the patients improved (mean NYHA class -0.7, left ventricular ejection fraction +2%, Minnesota living with HF questionnaire -15.6 points). CONCLUSION CCM signal delivery is feasible in HF patients with permanent AF by sequential atrial-ventricular pacing, so that the atrial pacing spike is interpreted as a p wave by the CCM signal delivery algorithm. This experimental approach can be considered in individual cases. A new CCM algorithm, which does not require an atrial electrode, is desirable.

Prognostic value of platelet-derived growth factor in patients with severe sepsis.

Primary objective: Platelet-derived growth factor-BB (PDGF-BB) has been shown to promote the structural integrity of the vessel wall and to increase wound healing capacity. Aim of the present study was to determine the role of PDGF-BB in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C (rhAPC) on plasma levels of PDGF-BB in severe sepsis was evaluated as well as the in vitro effect of rhAPC on PDGF-BB-release from human endothelial cells (HUVEC). Research design, methods and procedures: PDGF-BB levels were measured in 46 patients on day 3 of severe sepsis. Twenty-one of these patients received treatment with rhAPC. The in vitro effect of rhAPC on PDGF-BB-messenger RNA synthesis and release of PDGF-BB into supernatants was measured by reverse transcriptase-polymerase chain reaction and ELISA-methods. Main outcomes and results: Survivors of severe sepsis presented with higher PDGF-BB levels than non-survivors (p < 0.05). Septic patients with PDGF-BB levels below 200 pg/ml were 7.3 times more likely (RR = 7.3, 95% CI: 1.4–44.5; p < 0.05) to die from sepsis than patients with higher PDGF-BB values. RhAPC (1–10 μg/ml) stimulated endothelial PDGF-BB-messenger RNA transcription and PDGF-BB-release in vitro. Plasma levels of PDGF-BB in patients receiving rhAPC were significantly (p < 0.01) higher (median 277.7; 25–75th percentiles: 150.5–414.4 pg/ml) than in patients not treated with rhAPC (median: 125.6; 25–75th percentiles: 55.3–344.7 pg/ml). Conclusions: The ability of rhAPC to upregulate endothelial PDGF-BB production may represent a new molecular mechanism by which rhAPC controls vessel wall homeostasis and increases tissue healing capacity in severe sepsis. PDGF-BB may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis.

Hyperthermia Influences the Effects of Sodium Channel Blocking Drugs in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Introduction Fever can increase the susceptibility to supraventricular and ventricular arrhythmias, in which sodium channel dysfunction has been implicated. Whether fever influences the efficacy of sodium channel blocking drugs is unknown. The current study was designed to investigate the temperature dependent effects of distinct sodium channel blocking drugs on the sodium currents in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and Results hiPSC-CMs were generated from human skin fibroblasts of a healthy donor. The peak and late sodium currents (INa), steady-state activation, inactivation and recovery from inactivation of INa in hiPSC-CMs were analyzed using the whole-cell patch clamp technique. The effects of different concentrations of the antiarrhythmic drugs flecainide, lidocaine, ajmaline and the antianginal drug ranolazine on INa were tested at 36°C and 40°C. Increasing the temperature of the bath solution from 36°C to 40°C enhanced the inhibition of peak INa but reduced the inhibition of late INa by flecainide and lidocaine. By contrast, increasing the temperature reduced the effect of ajmaline and ranolazine on the peak INa but not late INa. None of the tested drugs showed temperature-dependent effects on the steady-state activation and inactivation as well as on the recovery from inactivation of INa in hiPSC-CMs. Conclusions Temperature variation from the physiological to the febrile range apparently influences the effects of sodium channel blockers on the sodium currents. This may influence their antiarrhythmic efficacy in patients suffering from fever.

Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism

IntroductionThere are no published data on the status of endogenous activated protein C (APC) in pulmonary embolism (PE), and no data on the effect of drotrecogin alfa (activated) (DAA) given in addition to therapeutic dose enoxaparin.MethodsIn this double-blind clinical trial, 47 patients with computed tomography (CT)-confirmed acute submassive PE treated with 1 mg/kg body weight of enoxaparin twice daily were randomized to groups receiving a 12-hour intravenous infusion of 6, 12, 18, or 24 μg/kg/hour of DAA or a placebo. Blood samples were drawn before starting DAA infusion, after 4, 8 and 12 hours (at the end of the infusion period), and on treatment days 2, 3, 4, 5 and 6.ResultsInitial endogenous plasma activated protein C (APC) levels were 0.36 ± 0.48 ng/ml (<0.10 to 1.72 ng/ml) and remained in the same range in the placebo group. APC levels in patients treated with DAA were 13.67 ± 3.57 ng/ml, 32.71 ± 8.76 ng/ml, 36.13 ± 7.60 ng/ml, and 51.79 ± 15.84 ng/ml in patients treated with 6, 12, 18, and 24 μg/kg/hour DAA, respectively. In patients with a D-dimer level >4 mg/L indicating a high level of acute fibrin formation and dissolution, DAA infusion resulted in a more rapid drop in soluble fibrin, D-dimer, and fibrinogen/fibrin degradation products (FDP) levels, compared to enoxaparin alone. There was a parallel decline of soluble fibrin, D-dimer, FDP, and plasmin-plasmin inhibitor complex (PPIC) in response to treatment with enoxaparin ± DAA, with no evidence of a systemic profibrinolytic effect of the treatment.ConclusionsIn patients with acute submassive PE endogenous APC levels are low. DAA infusion enhances the inhibition of fibrin formation.Trial registrationClinicalTrials.gov: NCT00191724

Cardiac impact of R-wave triggered irreversible electroporation therapy

BACKGROUND Irreversible electroporation (IRE) is a novel tumor ablative therapy technique, using electric fields to induce apoptosis in target tissues. Whether these electric pulses of high field strength can cause cardiac damage and/or ablation-induced arrhythmias is unclear. OBJECTIVE The purpose of this study was to systematically evaluate the safety of electrocardiogram (ECG)-gated IRE with regard to cardiac side effects. METHODS In all patients, 12-lead ECG and signal-averaged ECG (SAECG) recordings were performed before and after IRE and 24-hour Holter recording on the day of the IRE procedure. Venous blood samples (N-terminal pro-brain-type natriuretic peptide [NT-proBNP], high-sensitive troponin I [hsTnI]) were obtained before and 4 and 16 hours after the procedure. Patients with abnormal findings were reevaluated after 3 months. RESULTS In total, 26 patients with an oncologic indication for IRE (11 females, mean age 62.9 years) were prospectively enrolled. Nine patients (34.6%) showed an increase in hsTnI and 21 patients (80.8%) an increase in NT-proBNP after ablation. Fifteen patients (57%) developed arrhythmias related to the procedure. One patient, in whom hsTnI and NT-proBNP had increased, developed multiple, nonsustained ventricular tachycardia events. In another patient, atrial fibrillation was triggered twice in 2 separate procedures. Twelve patients had clinically benign arrhythmias. SAECG was negative in all patients. CONCLUSION Subclinical myocardial injury and nonfatal cardiac arrhythmias can occur in the context of IRE treatment. Although no sustained cardiac injuries could be found at 3-month follow-up, we propose implementation of a cardiac safety algorithm consisting of cardiac biomarkers and ECG monitoring when IRE is conducted.