- Email: [email protected]
Overnight Holter Electrocardiography
JACC VOL. 70, NO. 6, 2017
Letters
AUGUST 8, 2017:804–10
3. Becker NP, Müller J, Göttel P, Wallukat G, Schimke I. Cardiomyopathy — an approach to the autoimmune background. Autoimmun Rev 2017;16:269–86.
findings,
4. Wallukat G, Müller J, Haberland A, et al. Aptamer BC007 for neutralization of pathogenic autoantibodies directed against G-protein coupled receptors: a vision of future treatment of patients with cardiomyopathies and positivity for those autoantibodies. Atherosclerosis 2016;244:44–7.
warranted, because our study findings raised a novel
further
investigations
regarding
the
contributory role of the Fc fragment of b1 AR-AAb are hypothesis that there might be a differential clinical impact of b1 AR-AAbs belonging to the IgG3 subclass versus the non-IgG3 subclass (1).
REPLY: Understanding Subclass Diversity of Detectable b1-Adrenergic Receptor Autoantibodies and their Clinical Impact
Yuji Nagatomo, MD Dennis M. McNamara, MD, MS *W.H. Wilson Tang, MD
We appreciate the comments raised by Dr. Boege and
*Heart and Vascular Institute
colleagues and Dr. Müller and colleagues regarding
Cleveland Clinic
our study that explored the clinical significance of
9500 Euclid Avenue
autoantibodies against the b1 -adrenergic receptor
Desk J3-4
( b1 AR-AAb) that belong to the immunoglobulin-G3
Cleveland, Ohio 44195
(IgG3) subclass (1). In this study, we reported detect-
E-mail: [email protected]
able b1 AR-AAbs in 120 of 373 patients (34%), which, to
http://dx.doi.org/10.1016/j.jacc.2017.05.065
our knowledge, had no discrepancies with previously
Please note: Dr. Nagatomo is supported by the Postdoctoral Fellowship award from the Myocarditis Foundation (MYF1401MF). Dr. McNamara is supported by grants from the National Institute of Health (HL075038, and HL69912). Dr. Tang is supported by a grant from the National Institutes of Health (1R01HL103931). P.K. Shah, MD, served as Guest Editor-in-Chief for this paper. Barry H. Greenberg, MD, served as Guest Editor for this paper.
published studies. The reported prevalence of b1 ARAAbs has a wide range, mostly without specifying subclass diversity, and may differ according to disease severity in different populations (2–4). The fundamental issue we raised in our paper is the potential subclass diversity of detectable b1 ARAAbs in subjects in terms of their physiological properties and clinical impact. We previously showed that b1 AR-AAbs detected by our methodology were significantly different between patients with dilated cardiomyopathy and healthy control subjects (2), and their clinical relevance was demonstrated in independent cohorts (3,4), including the correlation of IgG3-b 1AR-AAbs and left ventricular functional recovery after removal of AAbs by immunoabsorption (5). We demonstrated such potential differential clinical significance between IgG3- and non IgG3-
b1AR-AAb in samples collected from a prospective multicenter trial (1). To determine the clinical significance of b1 AR-AAbs in human subjects, some research groups proposed intricate methodologies (e.g., functional assay using beating cardiomyocytes and flow cytometry) to demonstrate artificially
REFERENCES 1. Nagatomo Y, McNamara DM, Alexis JD, et al. Myocardial recovery in patients with systolic heart failure and autoantibodies against b1-adrenergic receptors. J Am Coll Cardiol 2017;69:968–77. 2. Baba A. Targeted autoantibodies in apheresis treatment against severe heart failure. Jap J Apheresis 2010;29:187–93. 3. Iwata M, Yoshikawa T, Baba A, Anzai T, Mitamura H, Ogawa S. Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2001;37:418–24. 4. Nagatomo Y, Li D, Kirsop J, Borowski A, Thakur A, Tang WH. Autoantibodies specifically against beta1 adrenergic receptors and adverse clinical outcome in patients with chronic systolic heart failure in the beta-blocker era: the importance of immunoglobulin G3 subclass. J Card Fail 2016;22:417–22. 5. Baba A, Akaishi M, Shimada M, et al. Complete elimination of cardiodepressant IgG3 autoantibodies by immunoadsorption in patients with severe heart failure. Circ J 2010;74:1372–8.
Overnight Holter Electrocardiography
created signaling, which could be even more difficult
An Opportunity for Early Sleep Apnea
to standardize and is impractical as a clinical diag-
Diagnosis and Treatment
nostic. It remains unclear whether these complex methodologies would be necessary (or even sufficient) to determine the clinical significance of detec-
We have read the paper by Javaheri et al. (1) with
ted b 1AR-AAbs. Although not tested in our study, the
great interest. We agree with the investigators that
clinical significance of b 1AR-AAbs and their subclass
treatment of sleep apnea (SA) may be extremely
diversity against the first extracellular loop of b1 AR
beneficial to many groups of patients with cardio-
has also not been validated. Therefore, we agree with
vascular disease (CVD) (1). We would like to point out
Dr. Boege and colleagues and Dr. Müller and col-
that early diagnosis of SA may play an important role
leagues that various issues need to be addressed to
in preventing CVD morbidity. Importantly, the pres-
clarify the assay requirements and clinical impact of
ence of SA is associated with characteristic cyclic
targeting b1AR-AAbs. However, in the light of our
variation of heart rate (CVHR) patterns, which can be
809
810
JACC VOL. 70, NO. 6, 2017
Letters
AUGUST 8, 2017:804–10
found on Holter electrocardiographic (ECG) monitoring. It has been shown that the number of CVHRs per hour (CVHR index) is strongly correlated with the
4. Stein PK, Duntley SP, Domitrovich PP, Nishith P, Carney RM. A simple method to identify sleep apnea using Holter recordings. J Cardiovasc Electrophysiol 2003;14:467–73.
apnea hypopnea index (AHI) (2). In patients with heart failure, the CVHR score was also shown to
REPLY: Overnight Holter Electrocardiography
correlate with the respiratory disturbance index,
An Opportunity for Early Sleep Apnea
which was closely correlated with the AHI obtained
Diagnosis and Treatment
by polysomnography (3). Obstructive sleep apnea (OSA) and Cheyne-Stokes respiration with central
We appreciate the interest of Drs. Matusik and Stein
sleep apnea (CSA) differ in regard to autonomic heart
in our paper (1), and are familiar with the excellent
rate control. The greatest heart rate changes are seen
work of Stein et al. (2) and other investigators
during the apneic phase of OSA. In contrast, in CSA,
who used the variability patterns of heart rate as a
heart rate changes are nearly absent during apnea (3).
screening tool for sleep apnea. Because of word
These abnormal heart rate patterns are distinct from
limitations, we were not able to cover several car-
respiratory sinus arrhythmia and may be easily
diovascular aspects of sleep apnea. Characteristic
differentiated by visual analysis of beat-to-beat heart
patterns of heart rate fluctuations during Holter
rate tachograms (4).
monitoring may well be useful, particularly in
Patients with SA risk factors and/or CVD frequently
patients with a high pre-test probability of having
undergo Holter monitoring for various clinical in-
sleep apnea. Caveats include patients with auto-
dications. Wide introduction of specific continuous
nomic neuropathy in whom heart rate changes may
ECG-based SA indexes into clinical practice (2,3) or
be blunted. Further validation of this method will
even simple screening of patterns derived from
be important to enable its widespread use. Perhaps
Holter ECG tachograms (4) may be a way to identify
the addition of overnight oximetry to Holter moni-
those patients who may benefit from detailed SA
toring in selected patients may further improve
diagnostics and treatment.
sensitivity of screening for sleep apnea in those patients with cardiovascular disease, who could
Paweł T. Matusik, MD, PhD *Phyllis K. Stein, PhD
potentially benefit from treatment of any comorbid sleep apnea.
*Department of Medicine
Saint Louis, Missouri 63110
*Shahrokh Javaheri, MD Virend K. Somers, MD, PhD Francisco Campos-Rodriguez, MD
E-mail: [email protected]
*Bethesda Sleep Laboratory
http://dx.doi.org/10.1016/j.jacc.2017.04.069
Pulmonology and Sleep
Cardiovascular Division Washington University School of Medicine
Please note: This work was supported by the Faculty of Medicine of Jagiellonian University Medical College (Leading National Research Centre 2012–2017). The supporting institution had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the paper. Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES
10535 Montgomery Road, Suite 200 Cincinnati, Ohio 45242 E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2017.05.066 Please note: All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
1. Javaheri S, Barbe F, Campos-Rodriguez F, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol 2017;69:841–58.
REFERENCES
2. Hayano J, Tsukahara T, Watanabe E, et al. Accuracy of ECG-based screening for sleep-disordered breathing: a survey of all male workers in a transport company. Sleep Breath 2013;17:243–51.
1. Javaheri S, Barbe F, Campos-Rodriguez F, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol 2017; 69:841–58.
3. Shimizu T, Yoshihisa A, Iwaya S, et al. Cyclic variation in heart rate score by Holter electrocardiogram as screening for sleep-disordered breathing in subjects with heart failure. Respir Care 2015;60:72–80.
2. Stein PK, Duntley SP, Domitrovich PP, Nishith P, Carney RM. A simple method to identify sleep apnea using Holter recordings. J Cardiovasc Electrophysiol 2003;14:467–73.
Letters
AUGUST 8, 2017:804–10
3. Becker NP, Müller J, Göttel P, Wallukat G, Schimke I. Cardiomyopathy — an approach to the autoimmune background. Autoimmun Rev 2017;16:269–86.
findings,
4. Wallukat G, Müller J, Haberland A, et al. Aptamer BC007 for neutralization of pathogenic autoantibodies directed against G-protein coupled receptors: a vision of future treatment of patients with cardiomyopathies and positivity for those autoantibodies. Atherosclerosis 2016;244:44–7.
warranted, because our study findings raised a novel
further
investigations
regarding
the
contributory role of the Fc fragment of b1 AR-AAb are hypothesis that there might be a differential clinical impact of b1 AR-AAbs belonging to the IgG3 subclass versus the non-IgG3 subclass (1).
REPLY: Understanding Subclass Diversity of Detectable b1-Adrenergic Receptor Autoantibodies and their Clinical Impact
Yuji Nagatomo, MD Dennis M. McNamara, MD, MS *W.H. Wilson Tang, MD
We appreciate the comments raised by Dr. Boege and
*Heart and Vascular Institute
colleagues and Dr. Müller and colleagues regarding
Cleveland Clinic
our study that explored the clinical significance of
9500 Euclid Avenue
autoantibodies against the b1 -adrenergic receptor
Desk J3-4
( b1 AR-AAb) that belong to the immunoglobulin-G3
Cleveland, Ohio 44195
(IgG3) subclass (1). In this study, we reported detect-
E-mail: [email protected]
able b1 AR-AAbs in 120 of 373 patients (34%), which, to
http://dx.doi.org/10.1016/j.jacc.2017.05.065
our knowledge, had no discrepancies with previously
Please note: Dr. Nagatomo is supported by the Postdoctoral Fellowship award from the Myocarditis Foundation (MYF1401MF). Dr. McNamara is supported by grants from the National Institute of Health (HL075038, and HL69912). Dr. Tang is supported by a grant from the National Institutes of Health (1R01HL103931). P.K. Shah, MD, served as Guest Editor-in-Chief for this paper. Barry H. Greenberg, MD, served as Guest Editor for this paper.
published studies. The reported prevalence of b1 ARAAbs has a wide range, mostly without specifying subclass diversity, and may differ according to disease severity in different populations (2–4). The fundamental issue we raised in our paper is the potential subclass diversity of detectable b1 ARAAbs in subjects in terms of their physiological properties and clinical impact. We previously showed that b1 AR-AAbs detected by our methodology were significantly different between patients with dilated cardiomyopathy and healthy control subjects (2), and their clinical relevance was demonstrated in independent cohorts (3,4), including the correlation of IgG3-b 1AR-AAbs and left ventricular functional recovery after removal of AAbs by immunoabsorption (5). We demonstrated such potential differential clinical significance between IgG3- and non IgG3-
b1AR-AAb in samples collected from a prospective multicenter trial (1). To determine the clinical significance of b1 AR-AAbs in human subjects, some research groups proposed intricate methodologies (e.g., functional assay using beating cardiomyocytes and flow cytometry) to demonstrate artificially
REFERENCES 1. Nagatomo Y, McNamara DM, Alexis JD, et al. Myocardial recovery in patients with systolic heart failure and autoantibodies against b1-adrenergic receptors. J Am Coll Cardiol 2017;69:968–77. 2. Baba A. Targeted autoantibodies in apheresis treatment against severe heart failure. Jap J Apheresis 2010;29:187–93. 3. Iwata M, Yoshikawa T, Baba A, Anzai T, Mitamura H, Ogawa S. Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2001;37:418–24. 4. Nagatomo Y, Li D, Kirsop J, Borowski A, Thakur A, Tang WH. Autoantibodies specifically against beta1 adrenergic receptors and adverse clinical outcome in patients with chronic systolic heart failure in the beta-blocker era: the importance of immunoglobulin G3 subclass. J Card Fail 2016;22:417–22. 5. Baba A, Akaishi M, Shimada M, et al. Complete elimination of cardiodepressant IgG3 autoantibodies by immunoadsorption in patients with severe heart failure. Circ J 2010;74:1372–8.
Overnight Holter Electrocardiography
created signaling, which could be even more difficult
An Opportunity for Early Sleep Apnea
to standardize and is impractical as a clinical diag-
Diagnosis and Treatment
nostic. It remains unclear whether these complex methodologies would be necessary (or even sufficient) to determine the clinical significance of detec-
We have read the paper by Javaheri et al. (1) with
ted b 1AR-AAbs. Although not tested in our study, the
great interest. We agree with the investigators that
clinical significance of b 1AR-AAbs and their subclass
treatment of sleep apnea (SA) may be extremely
diversity against the first extracellular loop of b1 AR
beneficial to many groups of patients with cardio-
has also not been validated. Therefore, we agree with
vascular disease (CVD) (1). We would like to point out
Dr. Boege and colleagues and Dr. Müller and col-
that early diagnosis of SA may play an important role
leagues that various issues need to be addressed to
in preventing CVD morbidity. Importantly, the pres-
clarify the assay requirements and clinical impact of
ence of SA is associated with characteristic cyclic
targeting b1AR-AAbs. However, in the light of our
variation of heart rate (CVHR) patterns, which can be
809
810
JACC VOL. 70, NO. 6, 2017
Letters
AUGUST 8, 2017:804–10
found on Holter electrocardiographic (ECG) monitoring. It has been shown that the number of CVHRs per hour (CVHR index) is strongly correlated with the
4. Stein PK, Duntley SP, Domitrovich PP, Nishith P, Carney RM. A simple method to identify sleep apnea using Holter recordings. J Cardiovasc Electrophysiol 2003;14:467–73.
apnea hypopnea index (AHI) (2). In patients with heart failure, the CVHR score was also shown to
REPLY: Overnight Holter Electrocardiography
correlate with the respiratory disturbance index,
An Opportunity for Early Sleep Apnea
which was closely correlated with the AHI obtained
Diagnosis and Treatment
by polysomnography (3). Obstructive sleep apnea (OSA) and Cheyne-Stokes respiration with central
We appreciate the interest of Drs. Matusik and Stein
sleep apnea (CSA) differ in regard to autonomic heart
in our paper (1), and are familiar with the excellent
rate control. The greatest heart rate changes are seen
work of Stein et al. (2) and other investigators
during the apneic phase of OSA. In contrast, in CSA,
who used the variability patterns of heart rate as a
heart rate changes are nearly absent during apnea (3).
screening tool for sleep apnea. Because of word
These abnormal heart rate patterns are distinct from
limitations, we were not able to cover several car-
respiratory sinus arrhythmia and may be easily
diovascular aspects of sleep apnea. Characteristic
differentiated by visual analysis of beat-to-beat heart
patterns of heart rate fluctuations during Holter
rate tachograms (4).
monitoring may well be useful, particularly in
Patients with SA risk factors and/or CVD frequently
patients with a high pre-test probability of having
undergo Holter monitoring for various clinical in-
sleep apnea. Caveats include patients with auto-
dications. Wide introduction of specific continuous
nomic neuropathy in whom heart rate changes may
ECG-based SA indexes into clinical practice (2,3) or
be blunted. Further validation of this method will
even simple screening of patterns derived from
be important to enable its widespread use. Perhaps
Holter ECG tachograms (4) may be a way to identify
the addition of overnight oximetry to Holter moni-
those patients who may benefit from detailed SA
toring in selected patients may further improve
diagnostics and treatment.
sensitivity of screening for sleep apnea in those patients with cardiovascular disease, who could
Paweł T. Matusik, MD, PhD *Phyllis K. Stein, PhD
potentially benefit from treatment of any comorbid sleep apnea.
*Department of Medicine
Saint Louis, Missouri 63110
*Shahrokh Javaheri, MD Virend K. Somers, MD, PhD Francisco Campos-Rodriguez, MD
E-mail: [email protected]
*Bethesda Sleep Laboratory
http://dx.doi.org/10.1016/j.jacc.2017.04.069
Pulmonology and Sleep
Cardiovascular Division Washington University School of Medicine
Please note: This work was supported by the Faculty of Medicine of Jagiellonian University Medical College (Leading National Research Centre 2012–2017). The supporting institution had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the paper. Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES
10535 Montgomery Road, Suite 200 Cincinnati, Ohio 45242 E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2017.05.066 Please note: All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
1. Javaheri S, Barbe F, Campos-Rodriguez F, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol 2017;69:841–58.
REFERENCES
2. Hayano J, Tsukahara T, Watanabe E, et al. Accuracy of ECG-based screening for sleep-disordered breathing: a survey of all male workers in a transport company. Sleep Breath 2013;17:243–51.
1. Javaheri S, Barbe F, Campos-Rodriguez F, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol 2017; 69:841–58.
3. Shimizu T, Yoshihisa A, Iwaya S, et al. Cyclic variation in heart rate score by Holter electrocardiogram as screening for sleep-disordered breathing in subjects with heart failure. Respir Care 2015;60:72–80.
2. Stein PK, Duntley SP, Domitrovich PP, Nishith P, Carney RM. A simple method to identify sleep apnea using Holter recordings. J Cardiovasc Electrophysiol 2003;14:467–73.