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The handle http://hdl.handle.net/1887/61173 holds various files of this Leiden University dissertation.

Author: Höke U.

Title: Pacing in heart failure: focus on risk stratification and patient selection for cardiac resynchronization therapy

Issue Date: 2018-04-10

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PACING IN

HEART FAILURE

ULAS¸ HÖKE

Focus on Risk Stratifi cation and Patient Selection for Cardiac

Resynchronization Therapy

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Pacing in Heart Failure:

Focus on Risk Stratification and Patient Selection for Cardiac Resynchronization Therapy

Ulaş Höke

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The studies described in this thesis were performed at the Department of Cardiology of the Leiden University Medical Center, Leiden, the Netherlands.

Cover and Lay-out: Optima Grafische Communicatie, Rotterdam, The Netherlands Illustration design:

Printed by: Optima Grafische Communicatie, Rotterdam, The Netherlands ISBN: 978-94-6361-076-6

Copyright © 2018 U. Höke, Leiden, the Netherlands. All right reserved, No part of this book may be reproduced or transmitted, in any form or by any means, without prior permission of the author.

Financial support to the costs associated with publication of this thesis Astellas, Acist, Canon Medical Systems Nederland, ChipSoft, Dräger, Bayer HealthCare, Biotronik, Boehringer Ingelheim, Mediq Tefa, Medis Medical, Therabel, Pfizer, Pie Medical, Zoll Medical is greatly acknowledged.

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Pacing in Heart Failure:

Focus on Risk Stratification and Patient Selection for Cardiac Resynchronization Therapy

Proefschrift

ter verkrijging van

de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnificus prof.mr. C.J.J.M Stolker,

volgens besluit van het College voor Promoties te verdedigen op 10 april 2018

klokke 11.15 uur door Ulaş Höke geboren te Boğazliyan

in 1985

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PROMOTIECOMMISSIE

Promotores: Prof. dr. J.J. Bax Prof. dr. M.J. Schalij Co-promotor: Dr. N. Ajmone Marsan

Leden promotiecommissie

Prof. dr. Fausto J. Pinto (Head of the Department the Cardiology and Department of Heart and Vascular, University Hospital of Santa Maria/

CHLN, Lisbon, Portugal and Dean of the Faculty of Medicine, University of Lisbon, Portugal)

Prof. dr. R.J.M Klautz

Prof. dr. H.J.J. Wellens (Emeritus hoogleraar Universiteit Maastricht, Maastricht, The Netherlands)

Dr. V. Delgado

Dr. P.R.M. van Dijkman (Department of Cardiology, Haaglanden Medisch Centrum, The Hague, The Netherlands

Financial support by the Dutch Heart Foundation for the publication of this thesis is greatly acknowledged.

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Aan mijn ouders, Mehtap, Ela en Lara

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TABLE OF CONTENTS

Chapter 1 General introduction and outline of the thesis. 11

Part I: Pacemaker Therapy And Development Of Heart Failure 23

Chapter 2 Significant lead-induced tricuspid regurgitation is associated with poor prognosis at long-term follow-up.

25 Heart. 2014 Jun;100(12):960-968

Part II: Cardiac Resynchronization Therapy In Subpopulations Under-Represented In Heart Failure Randomized Clinical Trials

45

Chapter 3 Cardiac resynchronization therapy in populations underrepresented in randomized controlled trials.

47

Heart. 2015 Feb;101(3):230-239

Chapter 4 Influence of diabetes on left ventricular systolic and diastolic function and on long-term outcome after cardiac resynchronization therapy.

71

Diabetes Care. 2013 Apr;36(4):985-991

Chapter 5 Cardiac resynchronization therapy in CKD stage 4 patients. 89 Clin J Am Soc Nephrol. 2015 Oct 7;10(10):1740-1748

Chapter 6 Left ventricular reverse remodeling, device-related adverse events, and long-term outcome after cardiac resynchronization therapy in the elderly.

107

Circ Cardiovasc Qual Outcomes. 2014 May;7(3):437-444 Chapter 7 Right ventricular function and survival following cardiac

resynchronization therapy.

129

Heart. 2013 May;99(10):722-728

Chapter 8 Predictors of long-term benefit of cardiac resynchronization therapy in patients with right bundle branch block.

147 Eur Heart J. 2012 Aug;33(15):1934-1941

Part III: Optimization Of Patient Selection And Risk Stratification In Cardiac Resynchronization Therapy Management

165

Chapter 9 Usefulness of the CRT-SCORE for Shared Decision Making in Cardiac Resynchronization Therapy in Patients With a Left Ventricular Ejection Fraction of ≤35%.

167

Am J Cardiol. 2017 Dec 1;120(11):2008-2016

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Chapter 10 Assessment of left ventricular dyssynchrony by three- dimensional echocardiography: prognostic value in patients undergoing cardiac resynchronization therapy.

185

Accepted for publication in J Cardiovasc Electrophysiol. 2018 Chapter 11 Relation of myocardial contrast-enhanced T1 mapping

by cardiac magnetic resonance to left ventricular reverse remodeling after cardiac resynchronization therapy in patients with non-ischemic cardiomyopathy.

203

Am J Cardiol. 2017 May 1;119(9):1456-1462

Chapter 12 Summary, Conclusions and Future Perspectives 219 Chapter 13 Samenvatting, Conclusies en Toekomstperspectief 229

List of publications 239

Dankwoord 243

Curriculum Vitae 245

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Chapter 1

General Introduction,

Aim and Outline of the Thesis

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Chapter 1 INTRODUCTION

Heart failure is the fastest growing cardiovascular disease affecting over five mil- lion individuals annually. Despite advanced heart failure treatment, mortality rate remains high and more than 40% of patients diagnosed with heart failure die within 5 years.2 Furthermore, although heart failure hospitalization rate is decreasing both in Europe and the United States, heart failure still remains one of the most common causes for hospitalization.3

Etiology of heart failure is multifactorial but the main causes in industrialized countries are hypertension and coronary artery disease. Specific patient populations are known to be at higher risk for heart failure, although often under-represented in heart failure randomized clinical trials. Elderly patients and patients with diabetes mellitus or chronic kidney disease are for example at increased risk of developing heart failure and the presence of these comorbidities is in turn well known to be associated with higher mortality among heart failure patients.4-7

Implantation of a conventional pacemaker has also been related to an increased risk of left ventricular (LV) dysfunction, heart failure development and subsequently, mortality.60,61 Multiple factors may contribute to heart failure development or heart failure progression after pacemaker implantation. It is has been shown that right ventricular (RV) pacing results in an abnormal LV contraction with induction of intra- and inter-ventricular dyssynchrony, for which high percentages of RV pacing have been associated with heart failure events60,61 and worse long-term mortality.5,8 Furthermore, the mechanical presence of the RV lead through the tricuspid valve apparatus has been shown to lead to tricuspid regurgitation, which might play an ad- ditional role in heart failure development and progression after device implantation.

CARDIAC RESYNCHRONIZATION THERAPY

Cardiac resynchronization therapy (CRT) is an established therapy for heart failure patients with depressed LV ejection fraction (LVEF <35%), prolonged QRS duration (>120ms) and mild-to-severe heart failure symptoms despite optimal pharmacologi- cal therapy.2 The rationale behind CRT is the nullification of cardiac dyssynchrony by resynchronizing atrio-ventricular, inter-ventricular and intra (LV)-ventricular con- traction. Large clinical trials have demonstrated improvement after CRT in clinical symptoms, LV function and mitral regurgitation as well as significant reduction in all-cause and cardiac mortality rates and heart failure hospitalizations.9-15 However, up to 40% of heart failure patients do not improve after CRT and the reasons for these relatively high non-response rates still remain unclear.16,17 Research has been

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therefore focusing on identifying potential factors influencing response to CRT in order to further optimize patient selection or improve CRT efficacy. Of note, several specific patient populations, such as elderly patients, patients with diabetes or severe renal dysfunction, and presence of non-left bundle branch block QRS morphology are underrepresented in randomized clinical trials and the effects of CRT in these subpopulations remain unclear.

CARDIOVASCULAR IMAGING IN CRT

Cardiovascular imaging, including echocardiography, cardiac magnetic resonance (CMR) and nuclear imaging, is essential in the assessment of etiology, severity and prognosis of heart failure and has become therefore crucial also in the evaluation of patients referred for CRT. Particularly echocardiography, due to its wide availability and bed-side application, represents the first line imaging technique for the assess- ment of these patients.

LV volumes and function assessment

Echocardiography is the currently recommended imaging technique for quantifica- tion of LV systolic dimension and function. It is therefore also fundamental when referring patients for CRT considering the current indication criteria based on LVEF.

In addition to the biplane Simpson technique to estimate LV dimensions and sys- tolic function, it has been recommended to quantify LV volumes and LVEF using 3D imaging to provide more geometric-assumption free, accurate and reproducible measurements. Particularly, the excellent intra- and inter-operator variability of 3D echocardiography makes this modality also very suitable for the follow-up assess- ment.18 CMR is currently considered the gold standard for the quantification of LV volumes and LVEF but is not that often used in clinical practice.

LV dyssynchrony assessment

Quantification of mechanical LV dyssynchrony has been shown in single center stud- ies to be useful in the prediction of response to CRT.19,20 Whether assessment of LV dyssynchrony might improve patient selection to CRT however is still highly debated.

Recent guidelines include only QRS duration and morphology as criteria for CRT indication21 considering the inclusion criteria of the CRT randomized clinical trials.10

15,19,22 In particular, patients with left bundle branch block (LBBB) seem to have the largest benefit from CRT. However even among patients with LBBB, LV activation may change considerably as demonstrated by studies using 3D LV mapping which showed in these patients distinct patterns of LV dyssynchrony that may also influence CRT re-

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Chapter 1 sponse.23 Echocardiography permits characterization of these LV activation patterns

using different indices of LV dyssynchrony. Indices such as septal-to-posterior wall motion delay using M-Mode or time-to-peak systolic velocity using tissue Doppler imaging (TDI) were initially proposed to quantify LV dyssynchrony and to identify the site of the latest activation. The Predictors of Response to CRT (PROSPECT) trial was the first multicenter prospective trial to explore the role of several echocardio- graphic cardiac dyssynchrony parameters to predict response to CRT, including the ones derived from M-mode, conventional Doppler and TDI.24 With 498 enrolled patients, the trial demonstrated a modest accuracy to predict response to CRT for all the echocardiographic LV dyssynchrony indices.24 However, the observational study design, the inclusion of patients with LVEF>35% or LV end-diastolic dimensions <65 mm, and technical related issues (different vendors, low reproducibility, and poor acoustic window) may have had significant impact on the study results. Furthermore, several pathophysiological factors, such as the presence of myocardial scar and LV lead position were not considered in the interpretation of the results.25 Further studies and small clinical trials have in fact later shown that an integrative approach, including assessment of LV dyssynchrony with speckle tracking strain-based more automated echocardiographic approaches, quantification of myocardial scar burden and targeting the site of latest activation without transmural scar for the LV lead posi- tion, may provide a more accurate selection of patients that will benefit from CRT.26-28 Focus has been therefore shifted towards evaluation of active mechanical de- formation with speckle tracking echocardiography and towards global evaluation with 3D imaging techniques to better characterize LV mechanical dispersion or dyssynchrony.

Tracking natural acoustic markers (“speckles”) in grey-scale images, information on regional myocardial deformation, known as ‘strain’ can be obtained in radial, longitudinal, and circumferential planes.29 Radial strain has shown to be a predictor of clinical benefit in patients with ischemic cardiomyopathy in terms of LV volumet- ric changes prognosis.20,27,30 At long-term follow-up, absence of LV dyssynchrony by radial strain was associated with poor outcomes in patients with QRS duration between 120-150 ms.20

The 2D approach of speckle tracking echocardiography is based on the acquisi- tion of several views during different cardiac cycles which provides still information on each LV segment, but may be limited by a potential beat-to-beat variability in its calculation and by a failure of tracking by a out-of-plane motion of the speckles.31 In this regard, the development of 3D imaging techniques has enabled the assessment of global LV mechanical dyssynchrony in one beat and could be of incremental value for selection of CRT candidates and optimization of CRT therapy.

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One of the main LV dyssynchrony indices based on real-time 3D echocardiography was the systolic dyssynchrony index (SDI, Figure 1). From a LV 3D full volume dataset, LV endocardial border is semi-automatically defi ned at end-systole and end-diastole and a 3D LV model is derived. This model is subsequently divided into 16 or 17 seg- ments and the LV mechanical dyssynchrony is quantifi ed by calculating the standard

Figure 1. Three-dimensional echocardiographic techniques to evaluate LV dyssynchrony.

Panel A: LV dyssynchrony can be quantifi ed from 3-dimensional full-volume datasets of the left ven- tricle by measuring the systolic dyssynchrony index (standard deviation of time to minimum systolic volume of 16 sub-volumes [Tmsv16-SD]). The LV mechanical dispersion can also be visualized on color-coded polar maps, with the earliest activated regions coded in blue and the latest activated ar- eas coded in orange-red. In this example, the patient shows signifi cant LV dyssynchrony (Tmsv16-SD 20.05%) and the lateral and posterior LV regions as the most delayed activated areas. The time-volume curves of the 16 regional sub-volumes are plotted in a graph providing also a visual estimation of LV dyssynchrony. Panel B: Assessment of LV dyssynchrony with triplane tissue synchronization imaging.

The polar map shows the time to peak systolic velocity of 12 basal and mid-ventricular LV segments.

LV dyssynchrony is calculated as the standard deviation of time to peak systolic velocity of the 12 seg- ments. In this example, there is signifi cant LV dyssynchrony (standard deviation: 47 ms) and the mid posterolateral segment is the most delayed activated area.

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Chapter 1 deviation of time to minimum regional volume of 16 or 17 LV sub-volumes and cor-

recting it for the RR interval. A recent meta-analysis pooling data from 600 heart failure patients undergoing CRT implantation demonstrated a good accuracy of SDI to predict response to CRT.32 A weighted mean SDI of 9.8% predicted response to CRT with a sensitivity of 93% and a specificity of 75%.32

Furthermore, from TDI, triplane LV echocardiographic data can be derived and LV dyssynchrony calculated as the standard deviation of time to peak velocity of 12 basal and mid ventricular segments.33 Particularly, tissue synchronization imaging has provided a rapid and intuitive visualization of LV mechanical dyssynchrony provid- ing color-coded polar map plots of the LV activation. The earliest activated segments are color-coded in green whereas the latest activated segments are color-coded in orange (Figure 1). Using this methodology, van de Veire et al demonstrated that a standard deviation of time to peak systolic velocities ≥33 ms predicted response to CRT with 90% and 83% sensitivity and specificity, respectively.33

Finally, the recently developed 3D speckle tracking has also permitted quantifica- tion of LV dyssynchrony. Future research evaluating this promising novel technique will show it additional value for clinical practice.

CMR and nuclear imaging can also be used for the quantification of LV dyssyn- chrony with dedicated software and in centers with the specific expertise.

LV myocardial scar

Coronary artery disease is the leading cause of heart failure and current evidence shows reduced CRT benefit among patients with ischemic heart failure as compared to patients with non-ischemic heart failure.16,27,28,34 The location of transmural scar and the extent or burden of myocardial scar has shown to be of important influ- ence on the effects of CRT and particularly to target LV pacing lead position.35-37 Assessment of myocardial viability and scar with echocardiographic techniques is feasible.38 Particularly, speckle tracking echocardiographic techniques have been validated against contrast-enhanced CMR to identify transmural myocardial scar.39 Using speckle tracking radial strain echocardiography, a value of peak radial strain

<16.5% has been proposed to identify regions of transmural myocardial scar.39 In 397 ischemic heart failure patients the presence of transmural scar as assessed with speckle tracking radial strain echocardiography at the area targeted by the LV lead was independently associated with poor outcome.27 The addition of myocardial scar in the segment targeted by the LV lead had incremental prognostic value over LV dyssynchrony, LV lead position and other well-known clinical prognostic markers.27 Although the impact of macroscopic myocardial scar has been described exten- sively, the potential role of diffuse myocardial fibrosis has not been explored. Recent advances in CMR techniques with T1 mapping now permit assessment of interstitial

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myocardial fibrosis40-42 This approach has shown a good agreement with histological biopsy studies.43-45

AIM AND OUTLINE OF THE THESIS

The aim of this thesis was to study the role of pacing as potential cause but, most importantly beneficial therapy in heart failure. Particularly, it focused on optimiza- tion of selection and risk stratification of patients referred for CRT.

Part I, Chapter 2 of the thesis describes the association between tricuspid re- gurgitation and the development of heart failure after pacemaker or implantable cardioverter-defibrillator (ICD) implantation.

Part II of the thesis focuses on CRT outcomes specifically in subpopulations under- represented in randomized clinical trials in order to explore whether this therapy is still beneficial in these subgroups of patients. Chapter 3 reviews the efficacy of CRT in populations underrepresented in randomized controlled trials. Chapter 4 describes the impact of diabetes on cardiac function and long-term prognosis after CRT. In Chapter 5, the efficacy of CRT in chronic kidney disease stage 4 patients has been evaluated as compared to ICD implantation only. Chapter 6 describes CRT response, device-related adverse events and long-term outcome after CRT in the elderly. Chapter 7 focused on the changes in RV function and their impact on prognosis after CRT. In Chapter 8, predictors of long-term benefit of CRT in patients with right bundle branch block are evaluated.

In Part III of the thesis, novel approaches to optimize patient selection and risk stratification in CRT are evaluated. Chapter 9 proposes a CRT-SCORE, a multifacto- rial risk stratification score for clinical shared decision-making for application and management of CRT. The role of 3D echocardiography LV dyssynchrony is evaluated for long-term prognosis after CRT in Chapter 10. Chapter 11 describes myocardial contrast-enhanced T1 mapping for assessment of interstitial myocardial fibrosis and its potential association with unfavorable LV reverse remodeling after CRT in non- ischemic cardiomyopathy patients.

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Chapter 1 REFERENCES

1. McMurray JJ, Adamopoulos S, Anker SD, et al.

ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Associa- tion (HFA) of the ESC. European heart journal.

Jul 2012; 33(14): 1787-1847.

2. Braunwald E. Research advances in heart fail- ure: a compendium. Circulation research. Aug 30 2013; 113(6): 633-645.

3. Thrainsdottir IS, Aspelund T, Thorgeirsson G, et al. The association between glucose abnormal- ities and heart failure in the population-based Reykjavik study. Diabetes care. Mar 2005;

28(3): 612-616.

4. Auger D, Hoke U, Marsan NA, et al. Effect of induced LV dyssynchrony by right ventricular apical pacing on all-cause mortality and heart failure hospitalization rates at long-term follow-up. Journal of cardiovascular electro- physiology. Jun 2014; 25(6): 631-637.

5. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association.

Circulation. Dec 16 2015.

6. McAlister FA, Ezekowitz J, Tonelli M, Armstrong PW. Renal insufficiency and heart failure:

prognostic and therapeutic implications from a prospective cohort study. Circulation. Mar 2 2004; 109(8): 1004-1009.

7. Prinzen FW, Augustijn CH, Arts T, Allessie MA, Reneman RS. Redistribution of myocardial fiber strain and blood flow by asynchronous activation. The American journal of physiology.

Aug 1990; 259(2 Pt 2): H300-308.

8. Abraham WT, Hayes DL. Cardiac resynchro- nization therapy for heart failure. Circulation.

Nov 25 2003; 108(21): 2596-2603.

9. Bristow MR, Saxon LA, Boehmer J, et al. Cardi- ac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. The New England journal of medicine. May 20 2004; 350(21): 2140-2150.

10. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbid- ity and mortality in heart failure. The New Eng-

land journal of medicine. Apr 14 2005; 352(15):

1539-1549.

11. Daubert C, Gold MR, Abraham WT, et al.

Prevention of disease progression by car- diac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchro- nization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial. Journal of the American College of Cardiology. Nov 10 2009;

54(20): 1837-1846.

12. Linde C, Abraham WT, Gold MR, et al. Ran- domized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ven- tricular dysfunction and previous heart failure symptoms. Journal of the American College of Cardiology. Dec 2 2008; 52(23): 1834-1843.

13. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac- resynchronization therapy for the prevention of heart-failure events. The New England jour- nal of medicine. Oct 1 2009; 361(14): 1329-1338.

14. Tang AS, Wells GA, Talajic M, et al. Cardiac-re- synchronization therapy for mild-to-moderate heart failure. The New England journal of medicine. Dec 16 2010; 363(25): 2385-2395.

15. Bilchick KC, Kamath S, DiMarco JP, Stukenborg GJ. Bundle-branch block morphology and other predictors of outcome after cardiac re- synchronization therapy in Medicare patients.

Circulation. Nov 16 2010; 122(20): 2022-2030.

16. Delgado V, Bax JJ. Assessment of systolic dyssynchrony for cardiac resynchronization therapy is clinically useful. Circulation. Feb 15 2011; 123(6): 640-655.

17. Lang RM, Badano LP, Mor-Avi V, et al. Recom- mendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography. Jan 2015; 28(1): 1-39 e14.

18. Zareba W, Klein H, Cygankiewicz I, et al. Effec- tiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Auto-

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matic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT).

Circulation. Mar 15 2011; 123(10): 1061-1072.

19. Gorcsan J, 3rd, Oyenuga O, Habib PJ, et al. Re- lationship of echocardiographic dyssynchrony to long-term survival after cardiac resynchroni- zation therapy. Circulation. Nov 9 2010; 122(19):

1910-1918.

20. Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiol- ogy (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA).

European heart journal. Aug 2013; 34(29): 2281- 2329.

21. Gervais R, Leclercq C, Shankar A, et al. Surface electrocardiogram to predict outcome in can- didates for cardiac resynchronization therapy:

a sub-analysis of the CARE-HF trial. European journal of heart failure. Jul 2009; 11(7): 699-705.

22. Auricchio A, Fantoni C, Regoli F, et al. Char- acterization of left ventricular activation in patients with heart failure and left bundle- branch block. Circulation. Mar 9 2004; 109(9):

1133-1139.

23. Chung ES, Leon AR, Tavazzi L, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation. May 20 2008; 117(20): 2608- 2616.

24. Bax JJ, Gorcsan J, 3rd. Echocardiography and noninvasive imaging in cardiac resynchroniza- tion therapy: results of the PROSPECT (Predic- tors of Response to Cardiac Resynchronization Therapy) study in perspective. Journal of the American College of Cardiology. May 26 2009;

53(21): 1933-1943.

25. Bilchick KC, Dimaano V, Wu KC, et al. Cardiac magnetic resonance assessment of dyssynchro- ny and myocardial scar predicts function class improvement following cardiac resynchroniza- tion therapy. JACC. Cardiovascular imaging.

Sep 2008; 1(5): 561-568.

26. Delgado V, van Bommel RJ, Bertini M, et al.

Relative merits of left ventricular dyssynchrony, left ventricular lead position, and myocardial scar to predict long-term survival of ischemic heart failure patients undergoing cardiac resyn-

chronization therapy. Circulation. Jan 4 2011;

123(1): 70-78.

27. Leyva F, Foley PW, Chalil S, et al. Cardiac resynchronization therapy guided by late gado- linium-enhancement cardiovascular magnetic resonance. Journal of cardiovascular magnetic resonance: official journal of the Society for Cardiovascular Magnetic Resonance. 2011; 13:

29.

28. Notomi Y, Lysyansky P, Setser RM, et al.

Measurement of ventricular torsion by two- dimensional ultrasound speckle tracking imaging. Journal of the American College of Cardiology. Jun 21 2005; 45(12): 2034-2041.

29. Tanaka H, Nesser HJ, Buck T, et al. Dyssynchro- ny by speckle-tracking echocardiography and response to cardiac resynchronization therapy:

results of the Speckle Tracking and Resynchro- nization (STAR) study. European heart journal.

Jul 2010; 31(14): 1690-1700.

30. Mor-Avi V, Lang RM, Badano LP, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. Journal of the American Society of Echocardiography:

official publication of the American Society of Echocardiography. Mar 2011; 24(3): 277-313.

31. Kleijn SA, Aly MF, Knol DL, et al. A meta-analysis of left ventricular dyssynchrony assessment and prediction of response to cardiac resyn- chronization therapy by three-dimensional echocardiography. European heart journal car- diovascular Imaging. Sep 2012; 13(9): 763-775.

32. Van de Veire NR, Bleeker GB, De Sutter J, et al. Tissue synchronisation imaging accurately measures left ventricular dyssynchrony and predicts response to cardiac resynchronisation therapy. Heart. Sep 2007; 93(9): 1034-1039.

33. Wikstrom G, Blomstrom-Lundqvist C, Andren B, et al. The effects of aetiology on outcome in patients treated with cardiac resynchronization therapy in the CARE-HF trial. European heart journal. Apr 2009; 30(7): 782-788.

34. Adelstein EC, Tanaka H, Soman P, et al. Impact of scar burden by single-photon emission computed tomography myocardial perfusion imaging on patient outcomes following cardiac

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Chapter 1 resynchronization therapy. European heart

journal. Jan 2011; 32(1): 93-103.

35. Marsan NA, Westenberg JJ, Ypenburg C, et al.

Magnetic resonance imaging and response to cardiac resynchronization therapy: relative merits of left ventricular dyssynchrony and scar tissue. European heart journal. Oct 2009;

30(19): 2360-2367.

36. Xu YZ, Cha YM, Feng D, et al. Impact of myocardial scarring on outcomes of cardiac resynchronization therapy: extent or location?

Journal of nuclear medicine: official publica- tion, Society of Nuclear Medicine. Jan 2012;

53(1): 47-54.

37. Becker M, Zwicker C, Kaminski M, et al. Depen- dency of cardiac resynchronization therapy on myocardial viability at the LV lead position.

JACC. Cardiovascular imaging. Apr 2011; 4(4):

366-374.

38. Becker M, Hoffmann R, Kuhl HP, et al. Analysis of myocardial deformation based on ultrasonic pixel tracking to determine transmurality in chronic myocardial infarction. European heart journal. Nov 2006; 27(21): 2560-2566.

39. Nacif MS, Turkbey EB, Gai N, et al. Myocar- dial T1 mapping with MRI: comparison of look-locker and MOLLI sequences. Journal of magnetic resonance imaging: JMRI. Dec 2011;

34(6): 1367-1373.

40. Gai N, Turkbey EB, Nazarian S, et al. T1 mapping of the gadolinium-enhanced myocardium:

adjustment for factors affecting interpatient comparison. Magnetic resonance in medicine:

official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. May 2011; 65(5): 1407- 1415.

41. Ng AC, Auger D, Delgado V, et al. Association between diffuse myocardial fibrosis by cardiac magnetic resonance contrast-enhanced T(1) mapping and subclinical myocardial dysfunc- tion in diabetic patients: a pilot study. Circula- tion. Cardiovascular imaging. Jan 2012; 5(1):

51-59.

42. Iles L, Pfluger H, Phrommintikul A, et al.

Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. Journal of the American College of Cardiology. Nov 4 2008;

52(19): 1574-1580.

43. Sibley CT, Noureldin RA, Gai N, et al. T1 Mapping in cardiomyopathy at cardiac MR:

comparison with endomyocardial biopsy.

Radiology. Dec 2012; 265(3): 724-732.

44. aus dem Siepen F, Buss SJ, Messroghli D, et al.

T1 mapping in dilated cardiomyopathy with cardiac magnetic resonance: quantification of diffuse myocardial fibrosis and comparison with endomyocardial biopsy. European heart journal cardiovascular Imaging. Feb 2015; 16(2):

210-216.

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Part 1

Heart Failure as a Complication of

Pacemaker Therapy

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Chapter 2

Significant Lead-induced Tricuspid Regurgitation is Associated with Poor Prognosis at Long Term Follow-up

Ulaş Höke MD*,†, Dominique Auger MD*, Joep Thijssen MD*, Ron Wolterbeek MD, Enno T. van der Velde PhD*, Eduard R Holman MD PhD*, Martin J. Schalij MD PhD*, Jeroen J. Bax MD PhD*, Victoria Delgado MD PhD*, Nina Ajmone Marsan MD PhD*.

*Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands. Interuniversity Cardiology Institute of The Netherlands, Utrecht, The Netherlands. Department of Biostatistics, Leiden University Medical Centre, Leiden, The Netherlands.

Heart. 2014 Jun;100(12):960-8

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Chapter 2 Trivial tricuspid regurgitation (TR) is a common echocardiographic finding in healthy

individuals.46 However, significant TR (grade ≥2) has been demonstrated to be as- sociated with poor prognosis, regardless of the underlying cardiac pathology.47 Significant TR can be a primary valvular disease (due to valve lesion) or secondary to tricuspid annular dilatation and/or right ventricular (RV) remodeling. In addition, placement of a RV (trans-tricuspid) lead has also been associated with a higher risk of TR. However, the incidence of lead-induced TR, time course and effects on long-term outcome remain unknown.48-53 Previous studies have reported the incidence of TR immediately after implantation, focusing on the potential mechanisms of valve dys- function (perforation, impingement, adherence to the leaflets).49,54 However, data on the long-term incidence of TR after device implantation and, more importantly, data on the impact of significant TR on cardiac performance and clinical outcome are still lacking. Expanding indications for device therapy and aging of the population, with growing numbers of implanted pacemakers (PM) and cardioverter-defibrillators (ICD), may result in increased incidence of lead-induced TR with important clinical consequences in the near future.55-58 Therefore, the objective of this evaluation was first to assess the incidence of significant lead-induced TR at long-term follow-up. In addition, the impact of significant lead-induced TR on cardiac performance and on long-term prognosis was evaluated.

METHODS

Patients

Patients undergoing an ICD or PM implantation at the Leiden University Medi- cal Center between January 2002 and June 2009 were included in the present analysis. Data on baseline patient characteristics, implantation procedure, device characteristics and settings, and all follow-up visits were prospectively collected in the departmental Cardiology Information System (EPD-Vision, Leiden University Medical Center, Leiden, the Netherlands) and retrospectively analyzed. Indication for device implantation based on international guidelines was primary and second- ary prevention of sudden cardiac death in ICD recipients, and sick sinus syndrome and advanced degree atrioventricular (AV) block in PM recipients.58 Due to evolving guidelines, particularly on prevention of sudden cardiac death, eligibility for device implantation in this population might have changed over time, based on the results of landmark clinical trials.58-60

Patients with de novo implantation of pacing devices were included. Exclusion criteria were: 1) previous transvenous (temporary) cardiac pacing system implanta- tion, cardiac valve surgery, congenital heart disease or organic TR, in order to exclude

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other causes of TR prior to device implantation; 2) absence of an echocardiographic evaluation within 6 months before device implantation, in order to allow appropri- ate comparison between pre and post-implantation evaluations; 3) presence of an echocardiographic evaluation only in the first 6 months after the procedure (evalua- tion mainly in relation with procedure-related complications) or only more than 1.5 year after implantation (evaluation mainly driven by a new clinical event), in order to avoid selection bias; 4) occurrence of heart failure hospitalization or other major cardiac events in the period between the 2 echocardiographic evaluations, in order to exclude potential confounding factors in the comparison of TR before and after device implantation; 5) upgrades of systems to CRT (with or without ICD capabilities) to avoid the potential beneficial effect of resynchronization on cardiac performance.

To evaluate whether lead placement might have induced significant TR and in order to ensure enough time for potential lead-related structural or functional changes to occur, only patients with a follow-up echocardiographic evaluation within 1-1.5 year after the implantation (according to standard follow-up visits) and with a minimal follow-up of 1 year after the echocardiographic evaluation were included.

Device implantation, settings and interrogations

All pacing and defibrillator systems were transvenously implanted and in all patients the RV lead was implanted in the RV apex. The PM settings were individually tailored based on the indication for cardiac stimulation. All patients were followed up every 3–6 months after implantation and devices were interrogated at the implanting cen- tre. For the evaluation of the potential confounding effect of pacing on outcome, the last percentage of pacing prior to the follow-up echocardiography was used.

Echocardiographic evaluation

Echocardiographic assessment was performed with patients in the left lateral decu- bitus position, using a commercially available system (Vivid 7 and E9, GE-Vingmed Ultrasound, Horton, Norway). Standard 2-dimensional and Doppler images were recorded and saved in cine-loop format for off-line analysis (EchoPac, version 110.0.0, GE-Vingmed, Horton, Norway). Echocardiographic evaluation was per- formed according to the most recent recommendations and included quantification of LV end-diastolic and end-systolic volumes and of LV ejection fraction (LVEF) by biplane Simpson’s method.61,62 LV diastolic function was evaluated according to current recommendations, using transmitral flow Doppler velocities and tissue Doppler imaging-derived mitral annular velocities.63 Transmitral early (E) and late (A) diastolic velocities and the E-wave deceleration time were measured using the pulsed-wave Doppler recordings at the apical four-chamber view with a 2-mm sample volume at the tips of the mitral leaflets. Using tissue Doppler imaging, the

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Chapter 2 peak early diastolic myocardial velocities at septal and lateral borders of the mitral

annulus were measured and averaged to calculate the mean early diastolic myo- cardial velocities (E′). The E/E′ ratio was therefore derived as a measure of LV filling pressures. Mitral regurgitation severity was graded according to a multiparametric approach as recommended.61 In addition, left atrial volume was measured using the Simpson’s method and indexed to body surface area. Furthermore, RV dimension was assessed by tricuspid annular diameter and RV end-diastolic area, while RV function was quantified by RV fractional area change and tricuspid annular plane systolic excursion (TAPSE).62,64 Right atrial (RA) diameter was also measured and RA pressure was estimated using the inferior vena cava size and collapsibility. Systolic pulmonary arterial pressure (sPAP) estimated as the sum of the RA pressure and the peak pressure gradient between RV and right atrium, as measured on the TR spectral continuous-wave Doppler signal.64 TR severity was graded by multiparametric ap- proach including the assessment of vena contracta width and regurgitant jet area by color Doppler, the evaluation of TR continuous-wave Doppler signal intensity and the pattern of the systolic blood flow in the hepatic veins.61,64

Definition of significant lead-induced TR

In order to evaluate the presence and impact of a significant lead-induced TR, pa- tients with stable TR, improved TR or clinically irrelevant deterioration of TR (grade 0 or 1) at 1-1.5 year after implantation (no significant lead-induced TR) were compared with patients with significant TR increase at follow-up reaching a grade ≥2 (significant lead-induced TR).

Long-term follow-up and end points

Long-term follow-up was performed by chart review and telephone contact with the general practitioner. Survival data were obtained by reviewing medical records and retrieval of survival status through the municipal civil registries. The primary end point was all-cause mortality. The secondary end point was defined as the combined end point of all-cause mortality and heart failure related events: hospitalization for heart failure, surgical LV restoration, surgical tricuspid valvuloplasty or upgrade to cardiac resynchronization therapy (whichever comes first).

Statistical analysis

Variables are presented as mean values ± standard deviation when normally dis- tributed, as median and interquartile range (IQR) when non-normally distributed, or as frequencies and percentages when variables were categorical or ordinal. Dif- ferences in baseline characteristics between the two groups were evaluated using the unpaired Student t-test (continuous variables) and χ2 (categorical data) and Wil-

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coxon rank sum test (non-normally distributed continuous variables) as appropriate.

Wilcoxon matched-pairs signed-rank test was used to test the significance change in the ordinal variables at follow-up. Differences in echocardiographic variables within and between the patient-groups were compared by repeated-measures ANOVA, including interaction between group and time. Generalized estimating equations (GEE) was used to compare changes in non-normally distributed echocardiographic parameters or ordinal echocardiographic parameters. Cumulative incidences with 95% confidence intervals (CI) of all-cause mortality and heart failure related events were analyzed using the method of Kaplan−Meier with log-rank tests for compari- son between groups. The follow-up onset was set at the moment of the follow-up echocardiographic evaluation. In addition, in patients with LVEF <40% at baseline was a subgroup analysis performed to evaluate the impact of significant lead- induced TR on the primary and secondary end points. To assess whether significant lead-induced TR was associated with an increased mortality and/or heart failure related events, Cox proportional hazards modeling was used. Univariate analysis was performed among clinical and echocardiographic variables at the time of the follow-up echocardiography and subsequently, all variables with a p-value of <0.05 and no similarity to other parameters (concerning LV and RV dimension and func- tion parameters), were included in the multivariable model. A p-value of <0.05 was considered statistically significant. All statistical analyses were performed by using IBM PASW Statistics, version 20.0 (SPSS Inc, Chicago, IL).

RESULTS

Patients

A total of 239 patients (184 male, mean age 60±14 years, 191 ICD devices) were in- cluded in the present analysis. Clinical and echocardiographic characteristics of the patient population before implantation are summarized in Table 1. Indication for ICD was primary prevention in 119 (62%) patients, while indication for cardiac stimulation was sick sinus syndrome in 27 (56%) and AV block in 21 (44%) in PM patients.

Significant lead-induced TR

At baseline, some degree of TR (defined as grades I-II) was present in 153 patients (64%) patients and the distribution of TR grades in the whole patient population before (and after) lead implantation is summarized in Figure 1. A significant worsen- ing of TR was observed after lead implantation in the whole population (Wilcoxon p<0.001) and in particular significant lead-induced TR was observed in 91 (38%) patients. Pre-implantation clinical and echocardiographic characteristics of patients

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Chapter 2 Table 1. Baseline clinical and echocardiographic characteristics of the patient population

Overall (n=239)

No significant lead-induced TR

(n=148)

Lead-induced significant TR

(n=91)

p-value

Age, years 60±14 60±14 61±13 0.893

Male, n(%) 184(77) 114(77) 70(77) 0.985

Ischemic heart disease, n(%) 153(64) 96(65) 57(63) 0.728

QRS duration, ms 114±28 112±28 116±28 0.362

PM/ICD, n (%) 48(20) / 191(80) 29(20) / 119(80) 19(21) / 72(79) 0.810 PM indication: SSS/AV block, n(%) 27(56) / 21(44)† 16(55) / 13(45)† 11(58) / 8(42)† 0.955 ICD indication: primary prevention n(%) 119(62)* 78(66)* 41 (57)* 0.183 Percentage of pacing for PM, median [IQR] 100 [100-100] 100 [100-100] 100 [97-100] 0.065 Percentage of pacing for ICD, median [IQR] 0 [0-1] 0 [0-0] 0 [0-2] 0.149

Atrial fibrillation, n(%) 75(32) 40(27) 35(39) 0.056

Diabetes, n(%) 42(18) 29(20) 13(15) 0.308

NYHA functional class 2 [1-2] 2 [1-2] 2 [1-2] 0.727

LVEDV, ml 151±63 149±58 151±71 0.808

LVESV, ml 95±54 96±49 95±61 0.892

LVEF,% 39±14 38±14 40±13 0.356

E/A ratio 1.0 [0.7-1.4] 1.1 [0.8-1.6] 1.0 [0.7-1.4] 0.748

E-wave deceleration time, ms 225±74 217±73 238±75 0.053

Average E’ (cm/s) 6.49±2.41 6.22±2.16 6.93±2.72 0.096

E/E’ ratio 11 [8-15] 11 [8-15] 12 [8-16] 0.737

Mitral regurgitation grade ≥2** 62(29) 40(29) 22(27) 0.723

Left atrial volume (ml/m²) 36±7 36±7 37±8 0.443

RV end-diastolic area, mm² 16.1±5.0 16.5±5.1 15.3±4.8 0.074

RV fractional area change,% 39±12 38±13 41±11 0.082

TAPSE, mm 17.0±4 17.0±4.4 17.4±4.5 0.481

Right atrial diameter, cm 3.5±0.9 3.6±0.9 3.5±0.9 0.298

Tricuspid annular diameter, cm 3.6±0.8 3.6±0.8 3.6±0.8 0.931

sPAP, mmHg 33±12 32.9±12.0 33.0±11.0 0.916

Tricuspid regurgitation grade 0 81(33.9) 57(38.5) 24(26.4) 0.056

Tricuspid regurgitation grade 1 131(54.8) 71(48.0) 60(65.9)

Tricuspid regurgitation grade 2 22(9.2) 16(10.8) 6(6.6)

Tricuspid regurgitation grade 3 5(2.1) 4(2.7) 1(1.1)

Values are mean±SD or median [interquartile range]. AV-block=atrioventricular block; GFR= glomeru- lar filtration rate; ICD=implantable cardioverter defibrillator; IQR= interquartile range; LVEDV=left ventricular end-diastolic volume; LVEF=left ventricular ejection fraction; LVESV=left ventricular end- systolic volume; NYHA= New York heart association; PM=permanent pacemaker; RV=right ventricular;

sPAP=systolic pulmonary arterial pressure; SSS=sick sinus syndrome; TAPSE=tricuspid annular plane systolic excursion. † among patients with PM, * among patients with ICD, ** MR grade was available in 217 patients.

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with significant lead-induced TR and no significant lead-induced TR were compared in Table 1. No significant differences were observed between the 2 groups, except for a trend (non-significant) of more frequent atrial fibrillation (AF), a higher prevalence of TR grade 1, and a higher RV fractional area change with a smaller RV end-diastolic area among patients with significant lead-induced TR.

Impact of significant lead-induced TR on cardiac performance

Echocardiographic changes after lead placement in patients with and without signifi- cant lead-induced TR are summarized in Table 2. Similar changes over time in LVEF and diastolic function severity were observed between the two groups (see interac- tion group and time p-value in Table 2). Similar changes over time in LVEF, diastolic function and in mitral regurgitation severity were observed between the two groups (see interaction group and time p-value in Table 2). Although no significant changes over time in RV function (TAPSE and RV fractional area change) were observed in both groups, RV size significantly increased over time only in patients with significant lead-induced TR. In addition, an enlargement of RA diameter was observed in this group of patients. Finally, pulmonary pressures increased over time only in patients with lead induced significant TR (from 33±11 to 41±15 mmHg versus 33±12 to 33±10 mmHg, see interaction group and time p-value in Table 2).

Impact of significant lead-induced TR on long-term prognosis

The relation between significant lead-induced TR and the primary (all-cause mortal- ity) and secondary (all-cause mortality and heart failure related events) end points was evaluated over a median long-term follow-up of 58 months (IQR 35-76 months) after the repeated echocardiographic evaluation. During the follow-up period, a to- tal of 62 deaths (26%) were observed. A higher all-cause mortality rate (primary end Figure 1. Distribution of tricuspid regurgitation (TR) grade in the study population before and after right ventricular (RV) lead implantation.

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Chapter 2

point) was observed in patients with significant lead-induced TR (log rank p=0.038;

Figure 2A). In the univariate Cox proportional hazard ratio (HR) analysis, significant lead-induced TR reached a HR of 1.687 (95%-CI: 1.023-2.780,p=0.040) (Table 3).

After adjustment for the other clinical and echocardiographic characteristics, sig- nificant lead-induced TR was independently associated with survival (with adjusted HR of 1.749[95%-CI: 1.008-3.035], p=0.047) together with age, percentage of pacing and LVEF.

Similarly, as shown in Figure 2B, the secondary end point (combination of all- cause mortality and heart failure related events) was observed in 90 (38%) patients.

The secondary end point was more frequent in lead-induced significant TR patients Table 2. Changes in echocardiographic variables over time (from baseline to 1-1.5 year follow-up) in patients with and without significant lead-induced TR.

Variables

No significant lead- induced TR (n=148)

Lead-induced significant TR (n=91)

p-value

Baseline Follow-up Baseline Follow-up interaction group and time

LVEDV, ml 149±58 156±65 151±71 163±65* 0.507

LVESV, ml 96±49 103±59* 95±61 107±56* 0.441

LVEF,% 38±14 37±12 40±13 36±11* 0.064

E/A ratio 1.1 [0.8-1.6] 0.9 [0.7-1.4] 1.0 [0.7-1.4] 1.1 [0.6-1.9] 0.961

E-wave deceleration time, ms 217±73 234±72 238±75 238±87 0.227

Average E’ (cm/s) 6.22±2.16 5.93±1.91 6.93±2.72 6.95±2.70 0.680

E/E’ ratio 11 [8-15] 11 [8-19] 12 [8-16] 11 [8-18] 0.603

Mitral regurgitation grade 0 † 51(38) 44(32) 30(37) 27(33) 0.276

Mitral regurgitation grade 1 45(33) 48(35) 29(36) 30(37) Mitral regurgitation grade 2 31(23) 33(24) 16(20) 18(22)

Mitral regurgitation grade 3 7(5) 10(7) 6(7) 6(7)

Mitral regurgitation grade 4 2(2) 3(2) - 1(1)

Left atrial volume (ml/m²) 36±7 38±7 37±8 40±9 0.366

RV end-diastolic area, mm² 17±5 16±5 15±5 17±6* 0.009

RV fractional area change,% 38±13 37±11 41±11 37±13* 0.154

TAPSE, mm 17±4 16±4* 17±5 17±5 0.849

Right atrium diameter, mm 36±9 36±8 35±9 39±10* <0.001

Tricuspid annular diameter, mm

36±8 36±8 36±8 39±9* 0.074

sPAP, mmHg 33±12 33±10 33±11 41±15* <0.001

Values are mean±SD or median [interquartile range]. Bold p-values are statistically significant.

LVEDV=left ventricular end-diastolic volume; LVEF=left ventricular ejection fraction; LVESV=left ven- tricular end-systolic volume; RV=right ventricular; sPAP=systolic pulmonary arterial pressure. *p<0.05, baseline vs. follow-up. † Mitral regurgitation grade was available in 217 patients at baseline and in 220 patients at follow-up.

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(log rank p=0.017). In the univariate analysis, significant lead-induced TR was associ- ated with worse outcome with a HR of 1.641 (95%-CI: 1.087-2.480,p=0.019) (Table 4). In the multivariate model, significant lead-induced TR was independently associ- ated with the occurrence of the secondary end point (adjusted HR of 1.649, 95%-CI:

1.043-2.599,p=0.032) together with age, LVEF and mitral regurgitation.

0 20 40 60 80

0 20 40 60 80 100

log rank Chi square:

4.299 p=0.038

Significant lead-induced TR

Patients at risk

No significant lead-induced TR 148 135 109 71 34 Significant lead-induced TR 91 83 59 41 18

No significant lead-induced TR

A

Follow-up (months)

CumulativeSurvival(%)

0 20 40 60 80

0 20 40 60 80 100

Patients at risk

No significant lead-induced TR 148 124 98 60 27 Significant lead-induced TR 91 70 47 32 13

B

log rank Chi square:

5.656 p=0.017

Significant lead-induced TR No significant lead-induced TR

Follow-up (months)

CumulativeSurvival(%)

Figure 2. (A) Kaplan-Meier survival curves for the time to the primary end point (all-cause mortality) in patients with and without significant lead-induced TR with the follow-up onset at time of the follow-up echocardiography. (B) Kaplan-Meier survival curves for the time to the secondary end point (all-cause mortality and heart failure related events) in patients with and without significant lead-induced TR with the follow-up onset at time of the follow-up echocardiography

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Chapter 2 The subgroup analysis in patients with baseline LVEF<40% demonstrated that signifi-

cant lead-induced TR was associated with poor survival free from the primary end point (HR 2.184 [95%-CI: 1.112-4.288], Figure 3A) but not with survival free from the secondary end point (HR 1.428 [95%-CI: 0.832-2.451], Figure 3B).

Table 3. Univariate and multivariate Cox regression survival analysis for the primary endpoint (all-cause mortality)

Variable

Univariate analysis Multivariate analysis

HR 95%-CI p-value HR 95%-CI p-value

Age, per year 1.079 1.048-1.112 <0.001 1.064 1.032-1.098 <0.001

Male sex 1.194 0.635-2.246 0.582

Ischemic etiology 1.684 0.963-2.944 0.068

Atrial fibrillation 1.373 0.823-2.290 0.224

Diabetes 1.705 0.963-3.018 0.067

ICD system(versus PM) 0.897 0.507-1.589 0.710

Percentage of pacing, per % 1.007 1.002-1.013 0.006 1.008 1.002-1.015 0.008

LVEDV, per ml 1.005 1.002-1.009 0.001

LVESV, per ml 1.007 1.004-1.011 <0.001

LVEF, per % 0.968 0.946-0.990 0.005 0.973 0.947-0.999 0.041

Mitral regurgitation grade 0 (reference group)

0.028 0.510

Mitral regurgitation grade 1 (vs.

reference group)

0.449 0.219-0.922 1.185 0.522-2.691

Mitral regurgitation grade 2 (vs.

reference group)

0.840 0.409-1.727 1.445 0.626-3.336

Mitral regurgitation grade 3 (vs.

reference group)

1.815 0.737-4.468 2.067 0.695-6.146

Mitral regurgitation grade 4 (vs.

reference group)

2.695 0.632-11.483 2.634 0.662-10.488

RV end-diastolic area, per mm² 1.069 1.025-1.114 0.002 RV fractional area change, per % 0.975 0.953-0.996 0.022

TAPSE, per mm 0.914 0.856-0.976 0.007 0.974 0.910-1.042 0.447

Right atrial diameter, per mm 1.412 1.071-1.861 0.014 Tricuspid annular diameter, per mm 1.748 1.325-2.306 <0.001

sPAP, per mmHg 1.046 1.029-1.063 <0.001

Significant lead-induced TR 1.687 1.023-2.780 0.040 1.749 1.008-3.035 0.047 Bold values are statistically significant. ICD=implantable cardioverter-defibrillators; LVEDV=left ven- tricular end-diastolic volume; LVEF=left ventricular ejection fraction; LVESV=left ventricular end-sys- tolic volume; RV=right ventricular; sPAP=systolic pulmonary arterial pressure; TAPSE=tricuspid annular plane systolic excursion; TR=tricuspid regurgitation.

Bold values are statistically significant. ICD=implantable cardioverter-defibrillators; LVEDV=left ven- tricular end-diastolic volume; LVEF=left ventricular ejection fraction; LVESV=left ventricular end-sys- tolic volume; RV=right ventricular; sPAP=systolic pulmonary arterial pressure; TAPSE=tricuspid annular plane systolic excursion; TR=tricuspid regurgitation.

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Figure 3. Subgroup analysis in patients with LVEF <40% before device implantation (A) Kaplan-Meier survival curves for the time to the primary end point (all-cause mortality) in patients with and without signifi cant lead-induced TR with the follow-up onset at the second echocardiography. (B) Kaplan-Mei- er survival curves for the time to the secondary end point (all-cause mortality and heart failure related events) in patients with and without signifi cant lead-induced TR with the follow-up onset at the second echocardiography.

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