Patterns of Left Atrial Activation and Evaluation of Atrial Asynchrony in Patients with Atrial Fibrillation and Normal Controls: Factors beyond Left Atrial Dimensions

I. Extensive experimental and clinical data suggest that certain electrical and structural changes develop in the atria of patients with atrial fibrillation (AF). These alterations are commonly referred as atrial remodeling and are considered to play a crucial role in the self-perpetuation of this arrhythmia. a. A hallmark of LA structural remodeling is the LA dilatation which is a predictor for progression to chronic AF and therapeutic failure as well. However, AF is associated not only with LA enlargement but also with asymmetrical changes in the left atrial geometry. b. Furthermore, the electrical remodeling is characterized by slower and asynchronous inter- and intra-atrial conduction that also contributes to the maintenance of AF. Some studies suggested a role of the conduction block in the Bachmann’s bundle, connecting the right and left atrium, in the AF pathophysiology and LA remodeling. II. Echocardiography and especially the tissue Doppler method can provide additional insight into the nature of the LA remodeling, because it allows the characterization of the intrinsic LA velocities. a. Using pulsed-wave tissue Doppler (PW-TDI) is possible to measure the interval from the onset of the surface P wave to the A´ velocity at the lateral mitral annulus as a representation of the total interatrial conduction time (TACT). In number of studies, it was demonstrated that prolonged TACT was associated with new-onset AF, AF after open heart surgery, and AF recurrences after electrical cardioversion and catheter ablation. b. An important limitation of the previous studies is that TACT has never been validated by direct measurements of the true electrical conduction in the LA. Moreover, it was assumed that the activation of the lateral MA must be the latest LA activation site. III. In this study, we sought to evaluate the feasibility of the PW-TDI as a simple and quick method to evaluate the LA asynchrony. For the purpose, we measured the time intervals from the onset of P-wave to the A´ (P-A´) in PW-TDI at 4 different left atrial sites next to mitral annulus (septal, lateral, anterior and inferior) in patients referred for electrophysiological study and catheter ablation because of atrial fibrillation or other arrhythmias. a. The differences between the longest and shortest P-A´ (DLS-PA´), as well as the standard deviation (SD-4PA´) of all 4 values were calculated as indexes for LA asynchrony. Importantly, LA asynchrony in patients with AF was compared with a matched control group of patients without history of AF. b. Moreover, the TACT was validated by comparing it with the actual electrical activation of the left atrium measured directly in the coronary sinus. For this purpose, the intervals between the onset of the P-wave and the local LA activation at the distal electrode pair of a catheter inserted in the coronary sinus were measured. c. Having in mind the ovoid LA shape and asymmetrical changes in LA geometry observed in patients with AF, we hypothesized that the lateral mitral annulus may not always be the latest activation spot. Therefore, we sought to determine the latest LA activation site exhibiting the longest P-A´ interval, as well as to describe the sequence of LA activation in AF patients and non-AF controls. IV. One hundred and thirty patients with AF (AF group) and 70 patients without a history of AF (non-AF control group) were examined prospectively using PW-TDI. a. Both groups were matched for the baseline characteristics, including LA diameter. The P-A´ interval measured with PW-TDI at the lateral LA showed a strong, positive, linear correlation with the P-A activation at the distal poles of the CS catheter at the lateral MA: Pearson r=0.708; P=0.0001. b. Asynchrony in the AF group was more pronounced in comparison to the non-AF control group. Patients in the AF group had longer DLS-PA´ as compared to controls: 37±16 msec. vs. 28±13 msec.; P=0.0001, as well as bigger SD-4PA´: 17±7 msec. vs. 13±5 msec.; P=0.0001. c. Furthermore, distinct patterns of LA activation were observed. Most AF patients (86.5%) showed an upward LA activation with inferior LA breakthrough, whereas the non-AF controls exhibited mostly a downward LA activation (65.5%), spreading from LA roof downwards. d. ROC analysis revealed that P-A´ at anterior LA successfully discriminated patients with AF from the non-AF controls (AUC 0.85, P 55 msec. discriminated between AF patients and controls with 85% sensitivity; 81% specificity; positive predictive value of 0.898, and negative predictive value of 0.707. V. In conclusion, PW-TDI can be reliably used to assess the LA asynchrony. Patients with atrial fibrillation showed greater LA asynchrony in PW-TDI independently from the LA dimensions. For the first time, we described that LA activation showed 3 distinct patterns with the upward LA activation being the most frequently observed in patients with AF. Patients with AF demonstrated a prolonged P-A´ activation time at the anterior left atrium. P-A´ at anterior LA > 55 msec. discriminates between patients with AF and non-AF controls with high sensitivity and specificity. This method can be useful to identity patients at risk for occurrence of new-onset atrial fibrillation, as well as to assess the severity of the LA remodeling in order to improve the selection of patients for catheter ablation.:Table of Contents 1 Background 5 1.1 Mechanisms of initiation and perpetuation of atrial fibrillation 5 1.2 Left atrial remodeling in atrial fibrillation 7 1.3 Echocardiographic assessment of left atrial remodeling 8 1.4 Pathophysiology of interatrial conduction in atrial fibrillation 10 2 Objectives and methods 11 2.1 Study objectives 11 2.2 Methods 11 2.2.1 Echocardiography 13 2.2.2 Electrophysiological study 15 2.2.3 Statistical methods 16 3 Publication 17 4 Discussion 26 5 Limitations 30 6 Conclusion 31 7 Synopsis 32 8 References 36 9 Selbstständigkeitserklärung 47 10 Curriculum vitae and list of publications 48 11 Danksagung /Acknowledgments 5

Dynamic changes in the signal-averaged electrocardiogram are associated with the long-term outcomes after ablation of ischemic ventricular tachycardia

Abstract Purpose Signal-averaged ECG (SAECG) can detect inhomogeneous myocardial conduction in patients presenting with ventricular tachycardia (VT) after myocardial infarction. Radiofrequency ablation (RFCA) aims at elimination of the endocardial late potentials and non-inducibility of VT. Previously, we demonstrated that abnormal SAECG at baseline can return to normal after a successful VT ablation. The present research investigates the post-ablation changes in SAECG after RFCA of VT and their relation to the procedural long-term outcomes. Methods Thirty-three patients (31 male; age 68 ± 9 years; EF 36 ± 12%) with ischemic VT were prospectively enrolled to receive RFCA. One VT (range 1–7) per patient was ablated using substrate-guided RFCA and complete success was achieved in 28 (85%) cases. SAECG was performed before (t1), immediately after (t2), and at least 6 months (t3) after the RFCA. Results After RFCA, the amount of patients showing abnormal SAECG decreased from 82% initially (t1) to 57.6% post-interventionally (t2); P = 0.008; and remained unchanged thereafter in 57% (t3). Patients who experienced VT recurrence (VT+) during the follow-up period had broader averaged QRS (t2): (VT+) 150 ± 26 vs. (VT−) 129 ± 21 ms; P = 0.015, as well as longer LAS40 (t2): (VT+) 60 ± 26 vs. (VT−) 43 ± 18 ms; P = 0.03. Abnormal SAECG (t2) was a strong predictor for VT recurrence: HR 5.4; 95% CI 1.5–21. SAECG detected more late potentials in patients with inferior than in those with anterior scars: 95% vs. 58%; P = 0.016. Conclusions RFCA of VT in the left ventricle can improve an abnormal SAECG in some patients after myocardial infarction. Normal SAECG after RFCA of VT is associated with a lower risk for VT recurrence and death

Case Report: Four cases of cardiac sarcoidosis in patients with inherited cardiomyopathy—a phenotypic overlap, co-existence of two rare cardiomyopathies or a second-hit disease

Cardiac sarcoidosis (CS), a rare condition characterized by non-caseating granulomas, can manifest with symptoms such as atrioventricular block and ventricular tachycardia (VT), as well as mimic inherited cardiomyopathies. A 48-year-old male presented with recurrent VT. The initial 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) scan showed uptake of the mediastinal lymph node. Cardiovascular magnetic resonance (CMR) demonstrated intramyocardial fibrosis. The follow-up 18FDG-PET scan revealed the presence of tracer uptake in the left ventricular (LV) septum, suggesting the likelihood of CS. Genetic testing identified a pathogenic LMNA variant. A 47-year-old female presented with complaints of palpitations and syncope. An Ajmaline provocation test confirmed Brugada syndrome (BrS). CMR revealed signs of cardiac inflammation. An endomyocardial biopsy (EMB) confirmed the diagnosis of cardiac sarcoidosis. Polymorphic VT was induced during an electrophysiological study, and an implantable cardioverter-defibrillator (ICD) was implanted. A 58-year-old woman presented with sustained VT with a prior diagnosis of hypertrophic cardiomyopathy (HCM). A genetic work-up identified the presence of a heterozygous MYBC3 variant of unknown significance (VUS). CMR revealed late gadolinium enhancement (LGE), while the 18FDG-PET scan demonstrated LV tracer uptake. The immunosuppressive therapy was adjusted, and no further VTs were observed. A 28-year-old male athlete with right ventricular dilatation and syncope experienced a cardiac arrest during training. Genetic testing identified a pathogenic mutation in PKP2. The autopsy has confirmed the presence of ACM and a distinctive extracardiac sarcoidosis. Cardiac sarcoidosis and inherited cardiomyopathies may interact in several different ways, altering the clinical presentation. Overlapping pathologies are frequently overlooked. Delayed or incomplete diagnosis risks inadequate treatment. Thus, genetic testing and endomyocardial biopsies should be recommended to obtain a clear diagnosis

Results of catheter ablation of atrial fibrillation in hypertrophied hearts – Comparison between primary and secondary hypertrophy

AbstractBackground and purposeApproximately 20–25% of the patients with hypertrophic cardiomyopathy (HCM) develop atrial fibrillation (AF) during the clinical course of the disease, a percentage significantly larger than that of the general population. The purpose of the present study was to report on the procedural results of patients with AF and either primary or secondary left ventricular hypertrophy (LVH).Methods and subjectsTwenty-two consecutive HCM patients (55% male, mean age 57±8 years) with symptomatic AF, having undergone AF ablation procedures between September 2009 and July 2012 were compared with respect to procedural outcome and follow-up characteristics with 22 matched controls with secondary cardiac hypertrophy (64% male, 63±10 years) from our prospective AF catheter ablation registry.Results and conclusionRadiofrequency catheter ablation (RFCA) was successful in restoring long-term sinus rhythm in patients with LVH due to HCM and due to secondary etiology. However, patients with HCM needed more RFCA procedures and frequently additional antiarrhythmic drug therapy in order to maintain sinus rhythm

EHRA expert consensus document on the management of arrhythmias in frailty syndrome, endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA).

There is an increasing proportion of the general population surviving to old age with significant chronic disease, multi-morbidity, and disability. The prevalence of pre-frail state and frailty syndrome increases exponentially with advancing age and is associated with greater morbidity, disability, hospitalization, institutionalization, mortality, and health care resource use. Frailty represents a global problem, making early identification, evaluation, and treatment to prevent the cascade of events leading from functional decline to disability and death, one of the challenges of geriatric and general medicine. Cardiac arrhythmias are common in advancing age, chronic illness, and frailty and include a broad spectrum of rhythm and conduction abnormalities. However, no systematic studies or recommendations on the management of arrhythmias are available specifically for the elderly and frail population, and the uptake of many effective antiarrhythmic therapies in these patients remains the slowest. This European Heart Rhythm Association (EHRA) consensus document focuses on the biology of frailty, common comorbidities, and methods of assessing frailty, in respect to a specific issue of arrhythmias and conduction disease, provide evidence base advice on the management of arrhythmias in patients with frailty syndrome, and identifies knowledge gaps and directions for future research

Patterns of Left Atrial Activation and Evaluation of Atrial Asynchrony in Patients with Atrial Fibrillation and Normal Controls: Factors beyond Left Atrial Dimensions

I. Extensive experimental and clinical data suggest that certain electrical and structural changes develop in the atria of patients with atrial fibrillation (AF). These alterations are commonly referred as atrial remodeling and are considered to play a crucial role in the self-perpetuation of this arrhythmia. a. A hallmark of LA structural remodeling is the LA dilatation which is a predictor for progression to chronic AF and therapeutic failure as well. However, AF is associated not only with LA enlargement but also with asymmetrical changes in the left atrial geometry. b. Furthermore, the electrical remodeling is characterized by slower and asynchronous inter- and intra-atrial conduction that also contributes to the maintenance of AF. Some studies suggested a role of the conduction block in the Bachmann’s bundle, connecting the right and left atrium, in the AF pathophysiology and LA remodeling. II. Echocardiography and especially the tissue Doppler method can provide additional insight into the nature of the LA remodeling, because it allows the characterization of the intrinsic LA velocities. a. Using pulsed-wave tissue Doppler (PW-TDI) is possible to measure the interval from the onset of the surface P wave to the A´ velocity at the lateral mitral annulus as a representation of the total interatrial conduction time (TACT). In number of studies, it was demonstrated that prolonged TACT was associated with new-onset AF, AF after open heart surgery, and AF recurrences after electrical cardioversion and catheter ablation. b. An important limitation of the previous studies is that TACT has never been validated by direct measurements of the true electrical conduction in the LA. Moreover, it was assumed that the activation of the lateral MA must be the latest LA activation site. III. In this study, we sought to evaluate the feasibility of the PW-TDI as a simple and quick method to evaluate the LA asynchrony. For the purpose, we measured the time intervals from the onset of P-wave to the A´ (P-A´) in PW-TDI at 4 different left atrial sites next to mitral annulus (septal, lateral, anterior and inferior) in patients referred for electrophysiological study and catheter ablation because of atrial fibrillation or other arrhythmias. a. The differences between the longest and shortest P-A´ (DLS-PA´), as well as the standard deviation (SD-4PA´) of all 4 values were calculated as indexes for LA asynchrony. Importantly, LA asynchrony in patients with AF was compared with a matched control group of patients without history of AF. b. Moreover, the TACT was validated by comparing it with the actual electrical activation of the left atrium measured directly in the coronary sinus. For this purpose, the intervals between the onset of the P-wave and the local LA activation at the distal electrode pair of a catheter inserted in the coronary sinus were measured. c. Having in mind the ovoid LA shape and asymmetrical changes in LA geometry observed in patients with AF, we hypothesized that the lateral mitral annulus may not always be the latest activation spot. Therefore, we sought to determine the latest LA activation site exhibiting the longest P-A´ interval, as well as to describe the sequence of LA activation in AF patients and non-AF controls. IV. One hundred and thirty patients with AF (AF group) and 70 patients without a history of AF (non-AF control group) were examined prospectively using PW-TDI. a. Both groups were matched for the baseline characteristics, including LA diameter. The P-A´ interval measured with PW-TDI at the lateral LA showed a strong, positive, linear correlation with the P-A activation at the distal poles of the CS catheter at the lateral MA: Pearson r=0.708; P=0.0001. b. Asynchrony in the AF group was more pronounced in comparison to the non-AF control group. Patients in the AF group had longer DLS-PA´ as compared to controls: 37±16 msec. vs. 28±13 msec.; P=0.0001, as well as bigger SD-4PA´: 17±7 msec. vs. 13±5 msec.; P=0.0001. c. Furthermore, distinct patterns of LA activation were observed. Most AF patients (86.5%) showed an upward LA activation with inferior LA breakthrough, whereas the non-AF controls exhibited mostly a downward LA activation (65.5%), spreading from LA roof downwards. d. ROC analysis revealed that P-A´ at anterior LA successfully discriminated patients with AF from the non-AF controls (AUC 0.85, P<0.0001). A cut off value for P-A´ anterior > 55 msec. discriminated between AF patients and controls with 85% sensitivity; 81% specificity; positive predictive value of 0.898, and negative predictive value of 0.707. V. In conclusion, PW-TDI can be reliably used to assess the LA asynchrony. Patients with atrial fibrillation showed greater LA asynchrony in PW-TDI independently from the LA dimensions. For the first time, we described that LA activation showed 3 distinct patterns with the upward LA activation being the most frequently observed in patients with AF. Patients with AF demonstrated a prolonged P-A´ activation time at the anterior left atrium. P-A´ at anterior LA > 55 msec. discriminates between patients with AF and non-AF controls with high sensitivity and specificity. This method can be useful to identity patients at risk for occurrence of new-onset atrial fibrillation, as well as to assess the severity of the LA remodeling in order to improve the selection of patients for catheter ablation.:Table of Contents 1 Background 5 1.1 Mechanisms of initiation and perpetuation of atrial fibrillation 5 1.2 Left atrial remodeling in atrial fibrillation 7 1.3 Echocardiographic assessment of left atrial remodeling 8 1.4 Pathophysiology of interatrial conduction in atrial fibrillation 10 2 Objectives and methods 11 2.1 Study objectives 11 2.2 Methods 11 2.2.1 Echocardiography 13 2.2.2 Electrophysiological study 15 2.2.3 Statistical methods 16 3 Publication 17 4 Discussion 26 5 Limitations 30 6 Conclusion 31 7 Synopsis 32 8 References 36 9 Selbstständigkeitserklärung 47 10 Curriculum vitae and list of publications 48 11 Danksagung /Acknowledgments 5

Patterns of Left Atrial Activation and Evaluation of Atrial Asynchrony in Patients with Atrial Fibrillation and Normal Controls: Factors beyond Left Atrial Dimensions

I. Extensive experimental and clinical data suggest that certain electrical and structural changes develop in the atria of patients with atrial fibrillation (AF). These alterations are commonly referred as atrial remodeling and are considered to play a crucial role in the self-perpetuation of this arrhythmia. a. A hallmark of LA structural remodeling is the LA dilatation which is a predictor for progression to chronic AF and therapeutic failure as well. However, AF is associated not only with LA enlargement but also with asymmetrical changes in the left atrial geometry. b. Furthermore, the electrical remodeling is characterized by slower and asynchronous inter- and intra-atrial conduction that also contributes to the maintenance of AF. Some studies suggested a role of the conduction block in the Bachmann’s bundle, connecting the right and left atrium, in the AF pathophysiology and LA remodeling. II. Echocardiography and especially the tissue Doppler method can provide additional insight into the nature of the LA remodeling, because it allows the characterization of the intrinsic LA velocities. a. Using pulsed-wave tissue Doppler (PW-TDI) is possible to measure the interval from the onset of the surface P wave to the A´ velocity at the lateral mitral annulus as a representation of the total interatrial conduction time (TACT). In number of studies, it was demonstrated that prolonged TACT was associated with new-onset AF, AF after open heart surgery, and AF recurrences after electrical cardioversion and catheter ablation. b. An important limitation of the previous studies is that TACT has never been validated by direct measurements of the true electrical conduction in the LA. Moreover, it was assumed that the activation of the lateral MA must be the latest LA activation site. III. In this study, we sought to evaluate the feasibility of the PW-TDI as a simple and quick method to evaluate the LA asynchrony. For the purpose, we measured the time intervals from the onset of P-wave to the A´ (P-A´) in PW-TDI at 4 different left atrial sites next to mitral annulus (septal, lateral, anterior and inferior) in patients referred for electrophysiological study and catheter ablation because of atrial fibrillation or other arrhythmias. a. The differences between the longest and shortest P-A´ (DLS-PA´), as well as the standard deviation (SD-4PA´) of all 4 values were calculated as indexes for LA asynchrony. Importantly, LA asynchrony in patients with AF was compared with a matched control group of patients without history of AF. b. Moreover, the TACT was validated by comparing it with the actual electrical activation of the left atrium measured directly in the coronary sinus. For this purpose, the intervals between the onset of the P-wave and the local LA activation at the distal electrode pair of a catheter inserted in the coronary sinus were measured. c. Having in mind the ovoid LA shape and asymmetrical changes in LA geometry observed in patients with AF, we hypothesized that the lateral mitral annulus may not always be the latest activation spot. Therefore, we sought to determine the latest LA activation site exhibiting the longest P-A´ interval, as well as to describe the sequence of LA activation in AF patients and non-AF controls. IV. One hundred and thirty patients with AF (AF group) and 70 patients without a history of AF (non-AF control group) were examined prospectively using PW-TDI. a. Both groups were matched for the baseline characteristics, including LA diameter. The P-A´ interval measured with PW-TDI at the lateral LA showed a strong, positive, linear correlation with the P-A activation at the distal poles of the CS catheter at the lateral MA: Pearson r=0.708; P=0.0001. b. Asynchrony in the AF group was more pronounced in comparison to the non-AF control group. Patients in the AF group had longer DLS-PA´ as compared to controls: 37±16 msec. vs. 28±13 msec.; P=0.0001, as well as bigger SD-4PA´: 17±7 msec. vs. 13±5 msec.; P=0.0001. c. Furthermore, distinct patterns of LA activation were observed. Most AF patients (86.5%) showed an upward LA activation with inferior LA breakthrough, whereas the non-AF controls exhibited mostly a downward LA activation (65.5%), spreading from LA roof downwards. d. ROC analysis revealed that P-A´ at anterior LA successfully discriminated patients with AF from the non-AF controls (AUC 0.85, P 55 msec. discriminated between AF patients and controls with 85% sensitivity; 81% specificity; positive predictive value of 0.898, and negative predictive value of 0.707. V. In conclusion, PW-TDI can be reliably used to assess the LA asynchrony. Patients with atrial fibrillation showed greater LA asynchrony in PW-TDI independently from the LA dimensions. For the first time, we described that LA activation showed 3 distinct patterns with the upward LA activation being the most frequently observed in patients with AF. Patients with AF demonstrated a prolonged P-A´ activation time at the anterior left atrium. P-A´ at anterior LA > 55 msec. discriminates between patients with AF and non-AF controls with high sensitivity and specificity. This method can be useful to identity patients at risk for occurrence of new-onset atrial fibrillation, as well as to assess the severity of the LA remodeling in order to improve the selection of patients for catheter ablation.:Table of Contents 1 Background 5 1.1 Mechanisms of initiation and perpetuation of atrial fibrillation 5 1.2 Left atrial remodeling in atrial fibrillation 7 1.3 Echocardiographic assessment of left atrial remodeling 8 1.4 Pathophysiology of interatrial conduction in atrial fibrillation 10 2 Objectives and methods 11 2.1 Study objectives 11 2.2 Methods 11 2.2.1 Echocardiography 13 2.2.2 Electrophysiological study 15 2.2.3 Statistical methods 16 3 Publication 17 4 Discussion 26 5 Limitations 30 6 Conclusion 31 7 Synopsis 32 8 References 36 9 Selbstständigkeitserklärung 47 10 Curriculum vitae and list of publications 48 11 Danksagung /Acknowledgments 5