1865
Letters to the Editor
Conflict of interest: none declared.
References 1. Finsterer J, Sto¨llberger C. Are RYR2 exon-3 deletions truly causative for non-compaction? Europace 2014; 16:1864. 2. Ohno S, Omura M, Kawamura M, Kimura H, Itoh H, Makiyama T et al. Exon 3 deletion of RYR2 encoding cardiac ryanodine receptor is associated with left ventricular non-compaction. Europace 2014;16: 1646 –54. 3. Tang Y, Tian X, Wang R, Fill M, Chen SR. Abnormal termination of Ca2+ release is a common defect of RyR2 mutations associated with cardiomyopathies. Circ Res 2012;110:968 –977. 4. Osmonov D, Ozcan KS, Ekmekci A, Gungor B, Alper AT, Gurkan K. Tachycardia-induced cardiomyopathy due to repetitive monomorphic ventricular ectopy in association with isolated left ventricular non-compaction. Cardiovasc J Afr 2013;24:1– 3. 5. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed
modification of the task force criteria. Circulation 2010;121:1533 –1541.
Seiko Ohno and Minoru Horie* Department of cardiovascular, Shiga University of Medical Sciences, Ohtsu, Japan *Corresponding author. Tel: +81 77 548 2213; fax: +81 77 543 5839. E-mail address: [email protected]
doi:10.1093/europace/euu152 Published online 17 July 2014
Iterative method for atrioventricular optimization of cardiac resynchronization therapy: is beauty only in the eye of the beholder? In a well-designed study evaluating the reproducibility of the iterative technique for cardiac resynchronization therapy (CRT) optimization of the atrioventricular (AV) delay, Jones et al. 1 showed that this method provides poor interobserver agreement. The authors can be commended for their rigorous methodology and the results—for the optimization technique studied—cannot be refuted. Based upon their findings, the authors question the utility of iterative AV optimization for clinical practise and for research purposes. This interpretation may lead the reader to erroneously conclude that evaluation of transmitral flow in CRT patients is of little use (despite clinical evidence proving the contrary).2 I would therefore like to make the following points: (i) When performing the iterative technique, the authors not only evaluated the presence of transmitral A-wave truncation (which is obviously undesirable), but also of EA separation. Even though separation of the E and A waves prolongs diastolic filling time, it is not so much the filling duration but the velocity–time integral (which is a surrogate for the volume of blood flow) that will determine ventricular filling (and thereby cardiac output). There is no evidence to my knowledge that confirms that EA separation has any importance whatsoever in patients with CRT (indeed, EA separation may be affected by other factors, such as heart rate). It is likely that much of the inter-observer disagreement observed in the study may have stemmed from the ‘optimal’ EA separation. (ii) The authors have defined four different patterns of transmitral flow and state that
only 40% of the patients had flow patterns that were suitable for AV optimization. I respectfully disagree with this statement, as it can be clearly seen in Figure 2 that the AV interval programmed to 40 ms is too short in all fourcases asthere is A-wave truncation. (iii) Transmitral flow only evaluates ventricular filling; it may therefore not be the best parameter to optimize cardiac output. The utility of this parameter, however, is to screen for A-wave truncation, which is detrimental and requires prolonging the AV interval. Thus, even if out-of-the box settings are frequently used in clinical practice, a simplified screening of transmitral flow in CRT patients may be useful, as stipulated in the guidelines.3,4 Screening for A-wave truncation may however not always be easy (e.g. in case a pre-implantation study in intrinsic rhythm displaying baseline A-wave duration is not available). It would be of clinical interest that the authors perform an evaluation of their dataset to determine (i) inter-observer agreement of AV optimization using the iterative method but evaluating only the presence of A-wave truncation (and not optimal EA separation) (ii) inter-observer agreement on whether the A-wave is truncated or not on a blinded dataset, and (iii) whether a cut-off value of A-wave duration may be proposed for screening purposes. Conflict of interest: none declared.
References 1. Jones S, Shun-Shin MJ, Cole GD, Sau A, March K, Williams S et al. Applicability of the iterative technique for cardiac resynchronization therapy optimization: full-disclosure, 50-sequential-patient dataset of transmitral Doppler traces, with implications for future research design and guidelines. Europace 2014;16: 541 –50. 2. Mullens W, Grimm RA, Verga T, Dresing T, Starling RC, Wilkoff BL et al. Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program. J Am Coll Cardiol 2009;53:765 –73. 3. Gorcsan J III, Abraham T, Agler DA, Bax JJ, Derumeaux G, Grimm RA et al. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting—a report from the American Society of Echocardiography Dyssynchrony Writing Group endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr 2008;21:191–213. 4. Daubert J-C, Saxon L, Adamson PB, Auricchio A, Berger RD, Beshai JF et al. 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. Europace 2012;14:1236–86.
Haran Burri* Cardiology Service, University Hospital of Geneva, Rue Gabrielle Perret Gentil 4, 1205 Geneva, Switzerland
Downloaded from by guest on November 14, 2015
Neither of our two probands who were clinically diagnosed as having CPVT underwent EP stimulation studies. Because VT in CPVT patients would presumably have Purkinje fiber network origins, a few cases would be candidates for ablation therapy. Furthermore, the symptoms of our mutation carriers were ameliorated by medication and pacemaker treatments. Therefore, only two carriers were implanted with ICD. Although RYR2 mutations are reportedly the cause of ARVC/D, the detection rate in ARVC/D patients is very low and our patients did not fulfil the ARVC/D criteria.5 To our knowledge, no RYR2 gene mutation has been identified in patients with myopathy or malignant hyperthermia, and our mutation carriers had no clinical history of either myopathy or malignant hyperthermia. It remains difficult to ascertain whether LVNC is congenital or acquired in our patients, because the cardiac echo and magnetic resonance imaging studies in our patients are limited to only a few years period. In these families, however, we detected LVNC in seven mutation carriers, including a 1-year-old boy and an 80-year-old woman. This wide range of ages means that the mutation is likely related to congenital LVNC. At present, there is no history of heart failure or stroke/embolism in our patients. This might be attributable to early detection of arrhythmias, allowing them to benefit from medications and/or pacemaker implantation, and these early interventions could thereby have prevented heart failure. Though our report suggests an association between the RYR2 exon 3 deletion mutation and LVNC, further investigation to elucidate the mechanistic relationship is needed.
1866
Letters to the Editor
*Corresponding author. Tel: +41 22 372 72 00; fax: +41 22 372 72 29. E-mail address: [email protected]
doi:10.1093/europace/euu179 Published online 17 July 2014
Author reply 1
We thank Prof. Burri for opening discussion on the iterative method for atrioventricular delay (AVD) optimization following our 50-patient full-disclosure study2 and our previous multiobserverstudy.3 We address his three points. (1) Prof. Burri observes that ‘there is no evidence to my knowledge that confirms that E/A separation has any importance whatsoever in patients with CRT’. We too cannot find any experimental evidence that the degree of E/A wave separation indicates an optimal AVD. Presumably he shares our disappointment, therefore, that the guidelines nevertheless do focus on E/Aseparation:4
(a) E and A waves are clearly identified and separated, and (b) Termination of the A wave occurs at least 40 milliseconds before QRS onset . . . . . . AV optimization is recommended if any of the following are observed: A wave is not identified, E and A waves are merged, or A wave is truncated by mitral closure. E and A waves merge when the AV pacing delay is set too long In our study, operators followed the guideline method.4 Prof. Burri proposes ignoring E/A wave separation and looking only at A-wave truncation, hoping to reduce inter-observer
(2) We agree with Prof. Burri that A-wave truncation is often seen at short AVDs. Our observation was that, across a broad range of AVDs, the E/A wave does not change in the way required to follow existing optimization protocols. Moreover, since only 5% of AVD selections were 60 ms,2 the problem of a wide range of seemingly suitable AVDs would persist without the 60 ms option. (3) We agree with Prof. Burri that transmitral flow may not be the best parameter to optimize cardiac output and have proposed alternative solutions.5 We are grateful for Prof. Burri’s support and observations. We show ‘all the data, all the time’ to allow any reader to run further experiments with the same data. We encourage them to do so and publish the results. Science thrives in openness. We are not confident that algorithms removing short-AVD, truncated-A-wave traces will resolve the problem we describe. Our dataset allows this (or any other) approach to be tested thoroughly in a systematic manner as we have previously described. Even mere executability of the decisionmaking protocol across numerous expert observers3 appears so disappointing that the very concept of iterative Doppler AV optimization might be doubted. We hope the guideline
writers will soon show the experimental data underlying the guideline or, if it has been mislaid, cancel the recommendation, to help our field move forward.
Conflict of interest: none declared.
References 1. Burri H. Iterative method for atrioventricular optimization of cardiac resynchronization therapy: is beauty only in the eye of the beholder? Europace 2014;16:1865. 2. Jones S, Shun-Shin MJ, Cole GD, Sau A, March K, Williams S et al. Applicability of the iterative technique for cardiac resynchronization therapy optimization: full-disclosure, 50-sequential-patient dataset of transmitral Doppler traces, with implications for future research design and guidelines. Europace 2014;16: 541 – 50. 3. Raphael CE, Kyriacou A, Jones S, Pabari P, Cole G, Baruah R et al. Multinational evaluation of the interpretability of the iterative method of optimisation of AV delay for CRT. Int J Cardiol 2013; 168:407 – 13. 4. Gorcsan J III, AbrahamT, Agler DA, Bax JJ, Derumeaux G, Grimm RA et al. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting—a report from the American Society of Echocardiography Dyssynchrony Writing Group endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr 2008;21:191 –213. 5. Whinnett ZI, Davies JE, Willson K, Chow AW, Foale RA, Davies DW et al. Determination of optimal atrioventricular delay for cardiac resynchronization therapy using acute non-invasive blood pressure. Europace 2006;8:358 – 66.
Siana Jones*, Matthew J. Shun-Shin, Graham D. Cole, Zachary I. Whinnett and Darrel P. Francis International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, 59-61 North Wharf Road, London W2 1LA, UK *Corresponding author. Tel: +44 207 679 9442; fax: +44 207 594 1706. E-mail address: siana. [email protected]
Downloaded from by guest on November 14, 2015
. . . Step 3: Examine mitral inflow pattern. No AV optimization protocol is required if:
variability. For example, by blanking out the E-waves from all the images, our study could be repeated to establish variability of optima based only on A-wave truncation. The blanking out is important because another finding of our study2 is that operators utilize collateral information beyond what they are asked to look at. Therefore, operators are unlikely to be able to ignore E/A wave separation simply through being asked to do so.
Letters to the Editor
Conflict of interest: none declared.
References 1. Finsterer J, Sto¨llberger C. Are RYR2 exon-3 deletions truly causative for non-compaction? Europace 2014; 16:1864. 2. Ohno S, Omura M, Kawamura M, Kimura H, Itoh H, Makiyama T et al. Exon 3 deletion of RYR2 encoding cardiac ryanodine receptor is associated with left ventricular non-compaction. Europace 2014;16: 1646 –54. 3. Tang Y, Tian X, Wang R, Fill M, Chen SR. Abnormal termination of Ca2+ release is a common defect of RyR2 mutations associated with cardiomyopathies. Circ Res 2012;110:968 –977. 4. Osmonov D, Ozcan KS, Ekmekci A, Gungor B, Alper AT, Gurkan K. Tachycardia-induced cardiomyopathy due to repetitive monomorphic ventricular ectopy in association with isolated left ventricular non-compaction. Cardiovasc J Afr 2013;24:1– 3. 5. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed
modification of the task force criteria. Circulation 2010;121:1533 –1541.
Seiko Ohno and Minoru Horie* Department of cardiovascular, Shiga University of Medical Sciences, Ohtsu, Japan *Corresponding author. Tel: +81 77 548 2213; fax: +81 77 543 5839. E-mail address: [email protected]
doi:10.1093/europace/euu152 Published online 17 July 2014
Iterative method for atrioventricular optimization of cardiac resynchronization therapy: is beauty only in the eye of the beholder? In a well-designed study evaluating the reproducibility of the iterative technique for cardiac resynchronization therapy (CRT) optimization of the atrioventricular (AV) delay, Jones et al. 1 showed that this method provides poor interobserver agreement. The authors can be commended for their rigorous methodology and the results—for the optimization technique studied—cannot be refuted. Based upon their findings, the authors question the utility of iterative AV optimization for clinical practise and for research purposes. This interpretation may lead the reader to erroneously conclude that evaluation of transmitral flow in CRT patients is of little use (despite clinical evidence proving the contrary).2 I would therefore like to make the following points: (i) When performing the iterative technique, the authors not only evaluated the presence of transmitral A-wave truncation (which is obviously undesirable), but also of EA separation. Even though separation of the E and A waves prolongs diastolic filling time, it is not so much the filling duration but the velocity–time integral (which is a surrogate for the volume of blood flow) that will determine ventricular filling (and thereby cardiac output). There is no evidence to my knowledge that confirms that EA separation has any importance whatsoever in patients with CRT (indeed, EA separation may be affected by other factors, such as heart rate). It is likely that much of the inter-observer disagreement observed in the study may have stemmed from the ‘optimal’ EA separation. (ii) The authors have defined four different patterns of transmitral flow and state that
only 40% of the patients had flow patterns that were suitable for AV optimization. I respectfully disagree with this statement, as it can be clearly seen in Figure 2 that the AV interval programmed to 40 ms is too short in all fourcases asthere is A-wave truncation. (iii) Transmitral flow only evaluates ventricular filling; it may therefore not be the best parameter to optimize cardiac output. The utility of this parameter, however, is to screen for A-wave truncation, which is detrimental and requires prolonging the AV interval. Thus, even if out-of-the box settings are frequently used in clinical practice, a simplified screening of transmitral flow in CRT patients may be useful, as stipulated in the guidelines.3,4 Screening for A-wave truncation may however not always be easy (e.g. in case a pre-implantation study in intrinsic rhythm displaying baseline A-wave duration is not available). It would be of clinical interest that the authors perform an evaluation of their dataset to determine (i) inter-observer agreement of AV optimization using the iterative method but evaluating only the presence of A-wave truncation (and not optimal EA separation) (ii) inter-observer agreement on whether the A-wave is truncated or not on a blinded dataset, and (iii) whether a cut-off value of A-wave duration may be proposed for screening purposes. Conflict of interest: none declared.
References 1. Jones S, Shun-Shin MJ, Cole GD, Sau A, March K, Williams S et al. Applicability of the iterative technique for cardiac resynchronization therapy optimization: full-disclosure, 50-sequential-patient dataset of transmitral Doppler traces, with implications for future research design and guidelines. Europace 2014;16: 541 –50. 2. Mullens W, Grimm RA, Verga T, Dresing T, Starling RC, Wilkoff BL et al. Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program. J Am Coll Cardiol 2009;53:765 –73. 3. Gorcsan J III, Abraham T, Agler DA, Bax JJ, Derumeaux G, Grimm RA et al. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting—a report from the American Society of Echocardiography Dyssynchrony Writing Group endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr 2008;21:191–213. 4. Daubert J-C, Saxon L, Adamson PB, Auricchio A, Berger RD, Beshai JF et al. 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. Europace 2012;14:1236–86.
Haran Burri* Cardiology Service, University Hospital of Geneva, Rue Gabrielle Perret Gentil 4, 1205 Geneva, Switzerland
Downloaded from by guest on November 14, 2015
Neither of our two probands who were clinically diagnosed as having CPVT underwent EP stimulation studies. Because VT in CPVT patients would presumably have Purkinje fiber network origins, a few cases would be candidates for ablation therapy. Furthermore, the symptoms of our mutation carriers were ameliorated by medication and pacemaker treatments. Therefore, only two carriers were implanted with ICD. Although RYR2 mutations are reportedly the cause of ARVC/D, the detection rate in ARVC/D patients is very low and our patients did not fulfil the ARVC/D criteria.5 To our knowledge, no RYR2 gene mutation has been identified in patients with myopathy or malignant hyperthermia, and our mutation carriers had no clinical history of either myopathy or malignant hyperthermia. It remains difficult to ascertain whether LVNC is congenital or acquired in our patients, because the cardiac echo and magnetic resonance imaging studies in our patients are limited to only a few years period. In these families, however, we detected LVNC in seven mutation carriers, including a 1-year-old boy and an 80-year-old woman. This wide range of ages means that the mutation is likely related to congenital LVNC. At present, there is no history of heart failure or stroke/embolism in our patients. This might be attributable to early detection of arrhythmias, allowing them to benefit from medications and/or pacemaker implantation, and these early interventions could thereby have prevented heart failure. Though our report suggests an association between the RYR2 exon 3 deletion mutation and LVNC, further investigation to elucidate the mechanistic relationship is needed.
1866
Letters to the Editor
*Corresponding author. Tel: +41 22 372 72 00; fax: +41 22 372 72 29. E-mail address: [email protected]
doi:10.1093/europace/euu179 Published online 17 July 2014
Author reply 1
We thank Prof. Burri for opening discussion on the iterative method for atrioventricular delay (AVD) optimization following our 50-patient full-disclosure study2 and our previous multiobserverstudy.3 We address his three points. (1) Prof. Burri observes that ‘there is no evidence to my knowledge that confirms that E/A separation has any importance whatsoever in patients with CRT’. We too cannot find any experimental evidence that the degree of E/A wave separation indicates an optimal AVD. Presumably he shares our disappointment, therefore, that the guidelines nevertheless do focus on E/Aseparation:4
(a) E and A waves are clearly identified and separated, and (b) Termination of the A wave occurs at least 40 milliseconds before QRS onset . . . . . . AV optimization is recommended if any of the following are observed: A wave is not identified, E and A waves are merged, or A wave is truncated by mitral closure. E and A waves merge when the AV pacing delay is set too long In our study, operators followed the guideline method.4 Prof. Burri proposes ignoring E/A wave separation and looking only at A-wave truncation, hoping to reduce inter-observer
(2) We agree with Prof. Burri that A-wave truncation is often seen at short AVDs. Our observation was that, across a broad range of AVDs, the E/A wave does not change in the way required to follow existing optimization protocols. Moreover, since only 5% of AVD selections were 60 ms,2 the problem of a wide range of seemingly suitable AVDs would persist without the 60 ms option. (3) We agree with Prof. Burri that transmitral flow may not be the best parameter to optimize cardiac output and have proposed alternative solutions.5 We are grateful for Prof. Burri’s support and observations. We show ‘all the data, all the time’ to allow any reader to run further experiments with the same data. We encourage them to do so and publish the results. Science thrives in openness. We are not confident that algorithms removing short-AVD, truncated-A-wave traces will resolve the problem we describe. Our dataset allows this (or any other) approach to be tested thoroughly in a systematic manner as we have previously described. Even mere executability of the decisionmaking protocol across numerous expert observers3 appears so disappointing that the very concept of iterative Doppler AV optimization might be doubted. We hope the guideline
writers will soon show the experimental data underlying the guideline or, if it has been mislaid, cancel the recommendation, to help our field move forward.
Conflict of interest: none declared.
References 1. Burri H. Iterative method for atrioventricular optimization of cardiac resynchronization therapy: is beauty only in the eye of the beholder? Europace 2014;16:1865. 2. Jones S, Shun-Shin MJ, Cole GD, Sau A, March K, Williams S et al. Applicability of the iterative technique for cardiac resynchronization therapy optimization: full-disclosure, 50-sequential-patient dataset of transmitral Doppler traces, with implications for future research design and guidelines. Europace 2014;16: 541 – 50. 3. Raphael CE, Kyriacou A, Jones S, Pabari P, Cole G, Baruah R et al. Multinational evaluation of the interpretability of the iterative method of optimisation of AV delay for CRT. Int J Cardiol 2013; 168:407 – 13. 4. Gorcsan J III, AbrahamT, Agler DA, Bax JJ, Derumeaux G, Grimm RA et al. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting—a report from the American Society of Echocardiography Dyssynchrony Writing Group endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr 2008;21:191 –213. 5. Whinnett ZI, Davies JE, Willson K, Chow AW, Foale RA, Davies DW et al. Determination of optimal atrioventricular delay for cardiac resynchronization therapy using acute non-invasive blood pressure. Europace 2006;8:358 – 66.
Siana Jones*, Matthew J. Shun-Shin, Graham D. Cole, Zachary I. Whinnett and Darrel P. Francis International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, 59-61 North Wharf Road, London W2 1LA, UK *Corresponding author. Tel: +44 207 679 9442; fax: +44 207 594 1706. E-mail address: siana. [email protected]
Downloaded from by guest on November 14, 2015
. . . Step 3: Examine mitral inflow pattern. No AV optimization protocol is required if:
variability. For example, by blanking out the E-waves from all the images, our study could be repeated to establish variability of optima based only on A-wave truncation. The blanking out is important because another finding of our study2 is that operators utilize collateral information beyond what they are asked to look at. Therefore, operators are unlikely to be able to ignore E/A wave separation simply through being asked to do so.
