[Cardiac contractility modulation for treatment of chronic heart failure]. / Kardiale Kontraktilitätsmodulation zur Behandlung der chronischen Herzinsuffizienz.

The worldwide prevalence of heart failure is 1-2% with a portion of >10% in patients older than 70 years. In addition to treatment of causal determined factors and lifestyle modification, basic treatment consists of guideline-directed medical therapy with angiotensin-converting enzyme inhibitors (ACE), ß­blockers (BB), mineralocorticoid receptor antagonists (MRA), diuretics, digitalis (class IIb recommendation), angiotensin receptor blockers (ARB), Iƒ-channel blockers plus recently recommended in the guidelines angiotensin receptor neprilysin inhibitor (ARNI) to substitute the ACE inhibitor (class I b). Cardiac contractility modulation (CCM) is a device-based electrical therapy for the treatment of refractory heart failure symptoms. CCM signals are relatively high intensity, nonexcitatory signals applied during the absolute refractory period that have been shown to enhance the strength of left ventricular (LV) contraction and improve exercise tolerance and quality of life. The mechanisms of action appear to involve effects on myocardial gene expression and normalization of myocardial key-proteins. So far, more than 3500 CCM devices have been implanted worldwide. For patients with symptomatic heart failure and narrow QRS complex, CCM is together with baroreceptor activation the only additive electrical therapy which had been approved in Germany. Actually, for the first time, CCM has been referenced in the current Heart Failure Guidelines. Prognostic data with regard to mortality are currently being evaluated in case series; some of which have since been published. Approval by the US Food and Drug Administration (FDA) is expected within the next months.

[Cardiac contractility modulation]. / Kardiale Kontraktilitätsmodulation.

Cardiac contractility modulation (CCM) is a device-based electrical therapy for the additive treatment of chronic drug-refractory heart insufficiency. High-amplitude signals are applied during the absolute refractory period and have been shown to enhance the strength of left ventricular (LV) contraction and improve exercise tolerance and quality of life. The mechanisms of action appear to involve effects on myocardial gene expression and on normalization of key myocardial proteins. So far, more than 3500 CCM devices have been implanted worldwide. For patients with therapy refractory heart insufficiency and narrow QRS complex, CCM is together with baroreceptor activation the only additive electrical therapy which had been approved in Germany. For the first time CCM has been referenced in the current guidelines on cardiac insufficiency. Prognostic data with respect to mortality have been evaluated in case series. Ongoing randomized trials and registries will address these specific endpoints and have to a significant extent already been recently published. A Food and Drug Administration (FDA) approval is expected within the next few months.

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.

Sex differences of in-hospital outcome and long-term mortality in patients with Takotsubo cardiomyopathy.

BACKGROUND: Previous studies revealed that patients with Takotsubo cardiomyopathy (TTC) have a higher mortality rate than the general population. It is still unclear whether sex differences may influence long-term prognosis of TTC patients. The purpose of this study was to determine whether sex differences do influence the short- and long-term outcomes of TTC. METHODS AND RESULTS: A total of 114 patients with TTC were admitted to the University Medical Centre Mannheim from January 2003 to September 2015 and entered into the TTC database of the University Medical Centre Mannheim, and retrospectively analyzed. Patients were diagnosed by the Mayo Clinic criteria. All-cause mortality over mean follow-up of 1,529±1,121 days was revealed. Significantly more male patients died within long-term follow-up compared to female TTC patients (log-rank test; P=0.01). Most males died of noncardiac causes. In multivariate Cox regression analysis, the male sex (P=0.02, hazard ratio [HR] 2.8, 95% CI 1.1-7.2), the ejection fraction ≤35% (P=0.01, HR 3.3, 95% CI 1.2-9.2) and glomerular filtration rate <60 mL/min (P<0.01, HR 3.1, 95% CI 1.4-7.0) figured out as independent predictors of the adverse outcome. CONCLUSION: This study shows that males suffering from TTC reveal a higher long-term all-cause mortality rate than females over a 5 year follow-up period.

Coincidental coronary artery disease impairs outcome in patients with takotsubo cardiomyopathy.

BACKGROUND AND AIM: Takotsubo cardiomyopathy (TC) is an important differential diagnosis of coronary artery disease (CAD), mimicking acute coronary syndrome in clinical symptoms, biomarker profiles and ST-elevation in ECG. Absence of occlusive coronary disease is an essential criterion distinguishing both diseases. The aim of the study was to explore the influence of co-existing incidental CAD on poorer clinical outcomes and all-cause mortality in TC. DESIGN, METHODS AND RESULTS: Our mono-centric study cohort constituted 114 consecutive patients diagnosed with TC between 2003 and 2015. The primary endpoint was the all-cause mortality. Additionally, we compared the incidence of thromboembolic events, life-threatening arrhythmias, cardiogenic shock and in-hospital death. There was no significant difference in gender distribution or mean age in both groups. Patients diagnosed with a co-existing CAD (n = 22), had a more pronounced cardiovascular risk profile. The all-cause mortality among patients with co-existing CAD after a 2-year follow-up was higher than those diagnosed with lone TC (22.7 vs. 5.4 %, P = 0.07). In a multivariate cox regression analysis CAD (HR 3.5, 95 %CI 1.0-11.6; P = 0.04), LVEF ≤ 35% (HR 3.8, 95% CI 0.0-0.6, P = 0.01) and cardiogenic shock (HR 3.8, 95% CI 1.2-11.3; P = 0.01) were independent predictors of the primary endpoint. CONCLUSION: Our study reveals that co-existing CAD impairs the outcome in patients with TC. The diagnostic work-up for TC should therefore not necessarily hinge on ruling out CAD.

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.

[Current impact of cardiac implantable electronic devices]. / Aktueller Stellenwert der Device-Therapie.

Sudden cardiac death and chronic heart failure are among the main contributors to persisting high mortality rates in Germany. In addition to removal of causal factors and guideline-conform pharmacological therapy, therapy with cardiac implantable electronic devices (CIED) is of undisputed importance. Subcutaneous defibrillators have the advantage that they do not have intracardiac electrodes but still have the same efficacy and safety. For patients with a wide QRS complex and reduced ejection fraction, cardiac resynchronization has led to a reduction of morbidity and mortality. For patients with a normal QRS complex, cardiac contractility modulation had been shown to improve the quality of life, exercise capacity and left ventricular function. As a procedure for autonomic modulation in patients with reduced cardiac strength, the data for baroreceptor stimulation are the most convincing.

[Sudden cardiac death : Epidemiology, pathophysiology and risk stratification]. / Plötzlicher Herztod : Epidemiologie, Pathophysiologie und Risikostratifizierung.

Sudden cardiac death (SCD) remains a major public health burden despite revolutionary progress in the last three decades in the treatment of ventricular tachyarrhythmia with the use of implantable cardioverter defibrillator (ICD) therapy. Survivors of sudden cardiac arrest are at high risk for recurrent tachyarrhythmia events. Early recognition of low left ventricular ejection fractions (≤35%) as a strong predictor of mortality and the causal association between ventricular tachyarrhythmia and SCD has led to a significant development of not only pharmacological antiarrhythmic therapy but also device-based prevention of SCD. The ICD therapy is nowadays routinely used for primary prevention of SCD in patients with significant structural cardiomyopathy and primary electrical arrhythmia syndromes, which are associated with high a risk and secondary prevention in survivors of sudden cardiac arrest. Additionally, effective approaches exist to significantly reduce the recurrence rate of ventricular tachyarrhythmia of various origins by complex electrophysiological endocardial and epicardial catheter ablation procedures.

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

BACKGROUND: Left atrial appendage (LAA) closure (LAAC) by implantation of an occlusion device is an established cardiac intervention to reduce risk of stroke while avoiding intake of oral anticoagulation medication during atrial fibrillation. Cardiac interventions can alter local or systemic gene and protein expression. Effects of LAAC on systemic metabolism have not been studied yet. OBJECTIVES: We aimed to study the effects of interventional LAAC on systemic metabolism. METHODS: Products of glycolysis, tricarboxylic acid and urea metabolism were analyzed by ESI-LC-MS/MS and MS/MS using the AbsoluteIDQ™ p180 Kit in plasma of 44 patients undergoing successful interventional LAAC at baseline (T0) and after 6 months (T1). RESULTS: During follow up, plasma concentrations of several parameters of glycolysis and tricarboxylic acid cycle (TCA) and urea metabolism increased (alanine, hexose, proline, sarcosine), while others decreased (aspartate, glycine, SDMA, serine). Multivariate linear regression analysis showed that time after interventional LAAC was an independent predictor for metabolite changes, including the decrease of SDMA (beta -0.19, p < 0.01) and the increase of sarcosine (beta 0.16, p < 0.01). CONCLUSIONS: Successful interventional LAAC affects different pathways of the metabolome, which are probably related to cardiac remodeling. The underlying mechanisms as well as the long term effects have to be studied in the future.

Comparison and outcome analysis of patients with apical and non-apical takotsubo cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy (TTC) is a relevant differential diagnosis in patients presenting with signs of an acute coronary syndrome. Although recent literature has highlighted some salient features of this disorder, there has been little information elucidating the differences in clinical features, electrocardiographic findings, echocardiographic data and TTC-related complications associated with the different variants of TTC. METHODS AND RESULTS: Our institutional database constituted a collective of 114 patients diagnosed with TTC between 2003 and 2015 and these patients were subsequently divided into two groups based on the presence (n = 82, 72%) or absence (n = 32, 28%) of the apical form of TTC. The protocol for our proposed study was approved by the Ethics Committee of the University Medical Centre in Mannheim. It was noticed that the patients presenting with the apical form of TTC belonged to an older age group as compared to those presenting with the non-apical form (61.1 ± 8.9 years vs. 69.5 ± 11.2; P < 0.01). The QTc interval prolongation at index-event was observed to be quantifiably greater in the 'apical variant' patients group (484.8 ± 57 ms vs. 464 ± 34.1 ms; P = 0.06). With respect to cardiovascular risk factors, patients with arterial hypertension did have a higher predilection to present with the apical form (63.4% vs. 43.7%; P = 0.06), however, the impact of smoking was less pronounced in this patient group (24.4% vs. 50%, P = 0.01). Furthermore, our study highlighted a significant impact on ejection fraction (EF), with a compromised left ventricular function (36 ± 9% vs. 42.4 ± 9.7%, P < 0.01) and greater involvement of the right ventricle in the apical variant patients group (23% vs. 3%, P = 0.04). Patients with the apical form also showed a greater tendency to develop TTC-related complications such as cardiogenic shock and required longer monitoring and care in comparison. CONCLUSIONS: The apical and non-apical variants of TTC are manifestations of the same syndrome. They differ significantly, however, in their clinical presentation, related complications and prognosis.

[Chronic cervical vagal stimulation. Mechanisms of action and clinical relevance for heart failure]. / Chronische zervikale vagale Stimulation. Mechanismen und momentaner klinischer Stellenwert bei der Herzinsuffizienz.

Increased sympathetic nerve activity and reduced vagal activity are associated with increased mortality in patients after myocardial infarction and patients with chronic heart failure; furthermore, vagal withdrawal has been documented to precede acute decompensation. Experimental studies have indicated that increased parasympathetic activity by means of vagal stimulation may reduce mortality in animal models of postinfarction sudden cardiac death and of chronic heart failure. First clinical results have demonstrated that chronic vagus nerve stimulation in heart failure patients with severe systolic dysfunction appears to be safe and tolerable and may improve the quality of life and left ventricular (LV) function. Vagus nerve stimulation gives rise to these potential clinical benefits by multiple mechanisms of action, including reduced heart rate, restoration of heart rate variability and baroreflex sensitivity, suppression of proinflammatory cytokines and antiarrhythmic effects. First clinical results suggest that vagal nerve stimulation is safe and tolerable and could lead to a marked clinical improvement but discrepancies in the findings due to different study designs warrant further discussion.

[The subcutaneous cardioverter-defibrillator: When less is more]. / Der subkutane Kardioverter-Defibrillator : Weniger ist mehr.

INTRODUCTION: In the last few decades, defibrillator therapy has revolutionized treatment of patients at risk for sudden cardiac death. Multiple clinical trials have shown the benefit of implantable cardioverter-defibrillators (ICD) for primary and secondary prevention of sudden cardiac death. Being an entirely subcutaneous system, the S-ICD® avoids important periprocedural and long-term complications associated with transvenous implantable cardioverter-defibrillator (TV-ICD) systems as well as the need for fluoroscopy during implant surgery. METHODS AND RESULTS: In patients with challenging anatomic conditions or after infection, the S-ICD® might be reasonable. In multicenter studies and registries efficacy and safety of the S-ICD® was equal or better to transvenous implantable defibrillators. The cardiac rhythm is detected by the use of 1 of the 3 potential vectors. The S-ICD® automatically selects the most suitable vector for rhythm detection. If ventricular tachyarrhythmia is detected, the device is able to deliver up to five shocks of 80 J, while postshock pacing is available at 50 bpm for 30 s. The implantation technique is different from that of conventional ICDs, but easily learnable by experienced cardiologists. Initially observed hurdles (e.g., inappropriate shocks or infections) have been overcome by standardized implantation techniques, operator learning curves, and modification of algorithms. CONCLUSIONS: The S-ICD® predominately might be suitable in all patients with ICD indication except patients with pacing or cardiac resynchronization therapy (CRT) indication, ventricular tachycardia < 170 bpm, negative screening, or in the occasional patient whose arrhythmia might be suppressed by overdrive pacing. The system received CE certification in 2009 and was approved by the FDA in 2012. Currently, in Germany the S-ICD® has been integrated into the DRG system and can be reimbursed as a single chamber ICD.

A plea for the single-lead ICD with atrial sensing due to anatomical considerations.

We present the case of a 46-year old male patient suffering from non-ischemic cardiomyopathy and intermittent atrial tachycardia. According to guidelines an implantable cardioverter defibrillator (ICD) was planned to implant through the left subclavian vein. During the procedure the angiography revealed a persistent left superior vena cava (PLSVC) with moderate stenosis of the subclavian vein. Due to this we decided not to implant a dual chamber ICD but to implant a single chamber lead with additional atrial sensing capacity. The procedure as well as the follow-up was uneventful. Follow-up revealed good ventricular as well as atrial signals.

CMR-derived TAPSE measurement: a semi-quantitative method of right ventricular function assessment in patients with hypertrophic cardiomyopathy.

AIM: To compare cardiovascular magnetic resonance (CMR)-derived right ventricular fractional shortening (RVFS), tricuspid annular plane systolic excursion with a reference point within the right ventricular apex (TAPSEin) and with one outside the ventricle (TAPSEout) with the standard volumetric approach in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: 105 patients with HCM and 20 healthy subjects underwent CMR. In patients with HCM, TAPSEin (r = 0.31, p = 0.001) and RVFS (r = 0.35, p = 0.0002) revealed a significant but weak correlation with right ventricular ejection fraction (RVEF), whereas TAPSEout (r = 0.57, p < 0.0001) showed a moderate correlation with RVEF. The ability to predict RVEF < 45 % in HCM patients was best for TAPSEout. In patients with hypertrophic obstructive cardiomyopathy (HOCM), RVEF showed a significant but weak correlation with TAPSEout (r = 0.36, p = 0.02) and no correlation with TAPSEin (r = 0.05, p = 0.07) and RVFS (r = 0.02, p = 0.2). In patients with hypertrophic non-obstructive cardiomyopathy (HNCM), there was a moderate correlation between RVEF and TAPSEout (r = 0.57, p < 0.0001) and a weak correlation with TAPSEin (r = 0.39, p = 0.001) and RVFS (r = 0.38, p = 0.002). In the 20 healthy controls, there was a strong correlation between RVEF and all semi-quantitative measurements. CONCLUSION: CMR-derived TAPSEin is not suitable to determine right ventricular function in HCM patients. TAPSEout showed a good correlation with RVEF in HNCM patients but only a weak correlation in HOCM patients. TAPSEout might be used for screening but the detection of subtle changes in RV function requires the 3D volumetric approach.

Insights into the location of type I ECG in patients with Brugada syndrome: correlation of ECG and cardiovascular magnetic resonance imaging.

BACKGROUND: Brugada syndrome is characterized by ST-segment abnormalities in V1-V3. Electrocardiogram (ECG) leads placed in the 3rd and 2nd intercostal spaces (ICSs) increased the sensitivity for the detection of a type I ECG pattern. The anatomic explanation for this finding is pending. OBJECTIVE: The purpose of the study was to correlate the location of the Brugada type I ECG with the anatomic location of the right ventricular outflow tract (RVOT). METHODS: Twenty patients with positive ajmaline challenge and 10 patients with spontaneous Brugada type I ECG performed by using 12 right precordial leads underwent cardiovascular magnetic resonance imaging (CMRI). The craniocaudal and lateral extent of the RVOT and maximal RVOT area were determined. Type I ECG pattern and maximal ST-segment elevation were correlated to extent and maximal RVOT area, respectively. RESULTS: In all patients, Brugada type I pattern was found in the 3rd ICS in sternal and left-parasternal positions. RVOT extent determined by using CMRI included the 3rd ICS in all patients. Maximal RVOT area was found in 3 patients in the 2nd ICS, in 5 patients in the 4th ICS, and in 22 patients in the 3rd ICS. CMRI predicted type I pattern with a sensitivity of 97.2%, specificity of 91.7%, positive predictive value of 88.6%, and negative predictive value of 98.0%. Maximal RVOT area coincided with maximal ST-segment elevation in 29 of 30 patients. CONCLUSION: RVOT localization determined by using CMRI correlates highly with the type I Brugada pattern. Lead positioning according to RVOT location improves the diagnosis of Brugada syndrome.

[Vagus stimulation. Mechanisms and current clinical importance in heart failure]. / Vagusstimulation. Mechanismen und momentaner klinischer Stellenwert bei der Herzinsuffizienz.

Increased sympathetic activity and reduced vagal activity are associated with increased mortality both after myocardial infarction and in heart failure; furthermore, vagal withdrawal has been documented to precede acute decompensation. Experimental studies indicate that increased parasympathetic activity by means of vagal stimulation may reduce mortality in animal models of post-infarction sudden cardiac death and of chronic heart failure. Initial clinical results demonstrate that chronic vagus nerve stimulation in heart failure patients with severe systolic dysfunction appears to be safe and tolerable and may improve quality of life, submaximal exercise capacity, and LV function. Vagus nerve stimulation derives these potential clinical benefits from multiple mechanisms of action. These include reduced heart rate, restoration of heart rate variability and baroreflex sensitivity, suppression of pro-inflammatory cytokines, and antiarrhythmic effects.

[Magnetic navigation in invasive electrophysiological diagnostic and therapy]. / Magnetische Navigation in der elektrophysiologischen Diagnostik und Therapie.

Electrophysiological stimulation and ablation is currently performed with manually deflectable catheters of different lengths and curves. Disadvantages of conventional therapy are catheter stiffness, limited local stability, risk of dislocation or perforation, and reduced tissue contact in regions with difficult access. Fluoroscopy to control catheter movement and position may require substantial radiation times. Magnetic navigation was first applied for right heart catherization in congenital heart disease in 1991; the first electrophysiological application took place in 2003. Today, an ablation electrode with small magnets is aligned in the patient's heart by two external magnets positioned at both sides of the thorax. Antegrade and retrograde movement of the distal catheter tip are performed via an external device on the patient's thigh. Three-dimensional MRI scans acquired before intervention can be merged with electroanatomical reconstruction, leading to further reductions of radiation burden. During treatment of supraventricular tachyarrhythmias high local precision of magnetically guided catheters, good local stability, and a substantially reduced radiation time have been reported. First applications in ventricular tachyarrhythmias and complex congenital cardiac defects indicate a comparable effect. Limitations of this therapy are the application in left atrial procedures (open irrigated ablation catheters not yet available), difficult transaortic retrograde approach (high lead flexibility), and the considerable costs. Magnet-assisted navigation is feasible during percutaneous coronary interventions of tortuous coronary arteries and in positioning guidewires in coronary sinus side branches for resynchronisation therapy. Future applications will be complex left atrial procedures, magnetically guided cardiac stem cell therapy, local drug application, and extracardiac vessel therapy.

[Primary electrical heart disease in adulthood--electrophysiological findings and therapy]. / Primär elektrische Herzerkrankungen im Erwachsenenalter--Elektrophysiologische Befunde und Therapie.

Sudden cardiac death accounts for 100,000 victims in Germany per year. Predominantly, patients with structural heart disease such as coronary artery disease or dilated cardiomyopathy are affected. However, approximately 5-10% of sudden deaths hit patients without structural disease of the heart. The proportion of young patients (< 40 years of age) in this group is even higher (10-20%). In younger patients significantly more diseases like hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia and primary electrical diseases of the heart could be observed such as long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. The primary electrical diseases are different concerning their electrocardiographical pattern, clinical triggers of arrhythmias, results of invasive diagnostics and therapy. Meanwhile, molecular genetic screening can reveal specific mutations of ion channels and can identify consecutive functional defects. The significance of programmed ventricular stimulation is at present unclear concerning risk stratification in patients with Brugada syndrome and short QT syndrome and of no significance in long QT syndrome and catecholaminergic polymorphic ventricular tachycardias. The implantable cardioverter defibrillator is the therapy of choice in most symptomatic patients. With increasing knowledge as a result of sophisticated molecular genetic screening, identification of underlying ion channel defects and new details of the mechanisms of arrhythmogenesis, a potential genotype-guided therapy will gain more importance in the future.