- Email: [email protected]
Clinical phenotype of HCN4-related sick sinus syndrome
Accepted Manuscript Commentary: Clinical Phenotype of HCN4-related Sick Sinus Syndrome Frank J. Raucci, Jr., MD, PhD, M. Benjamin Shoemaker, MD, MSCI, Bjorn C. Knollmann, MD, PhD PII:
S1547-5271(17)30164-9
DOI:
10.1016/j.hrthm.2017.02.006
Reference:
HRTHM 7033
To appear in:
Heart Rhythm
Received Date: 30 January 2017
Please cite this article as: Raucci Jr. FJ, Shoemaker MB, Knollmann BC, Commentary: Clinical Phenotype of HCN4-related Sick Sinus Syndrome, Heart Rhythm (2017), doi: 10.1016/ j.hrthm.2017.02.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Commentary: Clinical Phenotype of HCN4-related Sick Sinus Syndrome
RI PT
Frank J. Raucci, Jr., MD, PhD1,2, M. Benjamin Shoemaker, MD, MSCI1,3, Bjorn C. Knollmann, MD, PhD1,4 1 Vanderbilt Center for Arrhythmia Research and Therapeutics, 2Division of Pediatric Cardiology, 3 Division of Cardiology and 4Division of Clinical Pharmacology, Vanderbilt University Medical Center Correspondence
M AN U
Vanderbilt University School of Medicine Medical Research Building IV, Rm. 1265 2215B Garland Ave
SC
Björn C. Knollmann, M.D., Ph.D. Professor of Medicine and Pharmacology Director, Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART)
Nashville, TN 37232-0575 Office: (615) 343-6493 • Lab: (615) 936-7303 • Fax: (615) 343-4522
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Email: [email protected]
ACCEPTED MANUSCRIPT
RI PT
Sick sinus syndrome (SSS) is a clinical entity defined by chronic sinoatrial node (SAN) dysfunction with chronotropic incompetence and susceptibility to atrial tachyarrhythmias, sinus bradycardia, and sinus arrest. Patients are often symptomatic and necessitate permanent pacemaker implantation, with SSS the most common indication for pacemaker implantation in the United States accounting almost half of all implants1. SSS is common in the elderly and usually attributed to underlying structural heart disease or ischemic injury. Familial cases of SSS have also been described in children and young adults, with loss-of-function mutations in genes encoding for the cardiac Na+ channel α-subunit (SCN5A) and hyperpolarization-activated cyclic nucleotide-gated channel (HCN4) implicated as the underlying cause2-4.
M AN U
SC
HCN4 is the most abundant isoform of the HCN protein family found in the SAN and HCN tetramers form the ion channels responsible for hyperpolarization-activated “funny” current (If). Over the past decade, mutations in HCN4 have been implicated in SAN dysfunction5, 6, atrial fibrillation (AF)7, left ventricular non-compaction (LVNC)8, and atrioventricular (AV) block9. Most of the documented mutations are in the pore-forming loop between transmembrane segments 5 and 6 (S5-S6), the voltage sensing domain in segment 4 (S4), or in the C-terminus, which is where the cyclic nucleotide-binding domain is located. Documented electrophysiological effects vary based on the mutation loci but generally result in decrease in the If scaling factor (k), left shift in the steady-state activation or time constant curves, or alteration in adrenergic responsiveness to cyclic AMP (cAMP).
AC C
EP
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In this issue of Heart Rhythm, Ishikawa and colleagues evaluated the genetic mechanisms of SSS and sought to differentiate the clinical and pathophysiologic phenotype of mutations in the pacemaker channel HCN410. The main finding of this study was that the clinical SSS phenotype of HCN4 mutations is distinct from that seen with SCN5A mutations. They identified a novel HCN4 mutation (R393H) located in the S4 voltage-sensor domain, in addition to two novel SCN5A mutations (N1354K and N1372R) in their SSS patient cohort. The HCN4-R393H mutation demonstrated significantly decreased current densities when expressed as both homomeric and heteromeric channels in a heterologous expression system despite high expression in the plasma membrane. As would be expected for a loss-of-function mutation in this region, response to cAMP was preserved while the k was decreased in heteromeric channels compared to wild-type (WT), suggesting dysfunction of the activation gating mechanism. Perhaps more importantly, Ishikawa and colleagues also combined clinical and demographic data from their own SSS cohort with other cohorts of familial SSS in the literature. Unlike the phenotype previously reported for SSS with SCN5A mutations2, 3, 11, patients with HCN4 mutations had an equal gender distribution and were older at the age of diagnosis and at time of pacemaker implantation. They were also less likely to present with AV block or atrial flutter but more likely to have AF and LVNC. Overall this study was well constructed, but there are some limitations worth considering. A significant limitation is that cohorts were not age-matched, making the claim that HCN4 are associated with more AF than SCN5A mutations difficult to follow. HCN4 mutations carriers were much older, so the higher prevalence of AF could simply be the result of the age difference rather than the underlying mutation, especially since the age of AF onset was significantly earlier in SCN5A than in HCN4 carriers. More work needs to be done before concluding that
ACCEPTED MANUSCRIPT
SC
RI PT
SSS patients with HCN4 mutations are at a higher risk for AF than SCN5A mutations carriers. Another limitation is the rarity of HCN4 mutations in the broader population of SSS patients. While there does appear to be strong associations between genotype and phenotype as outlined above, most of the data were obtained from case reports of individual families or small cohorts, which may lead to selection bias that may limit the generalizability of these results. For example, although no SSS patients in this study with SCN5A mutations had LVNC, this gene has been previously associated with LVNC12. Another potential limitation is the use of recombinant heterologous expression systems for electrophysiological testing. While this is an established technique allowing for comparison of the properties of WT and mutant channels, it may not accurately reflect the in vivo function that contributes to the clinical phenotype. Future studies using induced pluripotent stem cell-derived cardiomyocytes from patients with HCN4 mutations may aid in further understanding of the underlying mechanism of these genetic variants in SSS.
M AN U
The study by Ishikawa and colleagues does bring up an interesting contrast between the clinical phenotype of different forms of familial SSS. As genotyping becomes more prevalent in clinical medicine, genotype-phenotype correlations studies like the current study could lead to more effective therapeutic targeting as well as guide timing and modality of clinical surveillance. Additionally, the study generates a rationale for studying the role of HCN4 in myocardial development to help us understand how HCN4 loss of function mutations could cause leftventricular non-compaction, which is currently not known. REFERENCES
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1. Bernstein AD and Parsonnet V. Survey of cardiac pacing and implanted defibrillator practice patterns in the United States in 1997. Pacing and clinical electrophysiology : PACE. 2001;24:842-55. 2. Abe K, Machida T, Sumitomo N, Yamamoto H, Ohkubo K, Watanabe I, Makiyama T, Fukae S, Kohno M, Harrell DT, Ishikawa T, Tsuji Y, Nogami A, Watabe T, Oginosawa Y, Abe H, Maemura K, Motomura H and Makita N. Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. Circulation Arrhythmia and electrophysiology. 2014;7:511-7. 3. Chiang DY, Kim JJ, Valdes SO, de la Uz C, Fan Y, Orcutt J, Domino M, Smith M, Wehrens XH and Miyake CY. Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture. Circulation Arrhythmia and electrophysiology. 2015;8:1105-12. 4. Verkerk AO and Wilders R. Pacemaker activity of the human sinoatrial node: an update on the effects of mutations in HCN4 on the hyperpolarization-activated current. International journal of molecular sciences. 2015;16:3071-94. 5. Milanesi R, Baruscotti M, Gnecchi-Ruscone T and DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. The New England journal of medicine. 2006;354:151-7. 6. Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O and Isbrandt D. Pacemaker channel dysfunction in a patient with sinus node disease. The Journal of clinical investigation. 2003;111:1537-45. 7. Duhme N, Schweizer PA, Thomas D, Becker R, Schroter J, Barends TR, Schlichting I, Draguhn A, Bruehl C, Katus HA and Koenen M. Altered HCN4 channel C-linker interaction is
ACCEPTED MANUSCRIPT
Acknowledgement
TE D
M AN U
SC
RI PT
associated with familial tachycardia-bradycardia syndrome and atrial fibrillation. European heart journal. 2013;34:2768-75. 8. Milano A, Vermeer AM, Lodder EM, Barc J, Verkerk AO, Postma AV, van der Bilt IA, Baars MJ, van Haelst PL, Caliskan K, Hoedemaekers YM, Le Scouarnec S, Redon R, Pinto YM, Christiaans I, Wilde AA and Bezzina CR. HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. Journal of the American College of Cardiology. 2014;64:745-56. 9. Zhou J, Ding WG, Makiyama T, Miyamoto A, Matsumoto Y, Kimura H, Tarutani Y, Zhao J, Wu J, Zang WJ, Matsuura H and Horie M. A novel HCN4 mutation, G1097W, is associated with atrioventricular block. Circulation journal : official journal of the Japanese Circulation Society. 2014;78:938-42. 10. Ishikawa T, Ohno S, Murakami T, Yoshida K, Mishima H, Fukuoka T, Kimoto H, Sakamoto R, Ohkusa T, Aiba T, Nogami A, Sumitomo N, Shimizu W, Yoshiura KI, Horigome H, Horie M and Makita N. Sick Sinus Syndrome with HCN4 Mutations Shows Early Onset and Frequent Association with Atrial Fibrillation and Left Ventricular Non-compaction. Heart rhythm : the official journal of the Heart Rhythm Society. 2017. 11. Vitved T, Lianee HT, Stovring B, Sigurd BM and Christiansen M. [Mutations in the heart's pacemaker channels--a new cause of sick sinus node syndrome and long-QT syndrome]. Ugeskrift for laeger. 2008;170:929-33. 12. Shan L, Makita N, Xing Y, Watanabe S, Futatani T, Ye F, Saito K, Ibuki K, Watanabe K, Hirono K, Uese K, Ichida F, Miyawaki T, Origasa H, Bowles NE and Towbin JA. SCN5A variants in Japanese patients with left ventricular noncompaction and arrhythmia. Molecular genetics and metabolism. 2008;93:468-74.
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EP
This work was supported in part by grants from the National Institutes of Health (R01HL128044, R01HL124935, R01HL108173) to BCK
S1547-5271(17)30164-9
DOI:
10.1016/j.hrthm.2017.02.006
Reference:
HRTHM 7033
To appear in:
Heart Rhythm
Received Date: 30 January 2017
Please cite this article as: Raucci Jr. FJ, Shoemaker MB, Knollmann BC, Commentary: Clinical Phenotype of HCN4-related Sick Sinus Syndrome, Heart Rhythm (2017), doi: 10.1016/ j.hrthm.2017.02.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Commentary: Clinical Phenotype of HCN4-related Sick Sinus Syndrome
RI PT
Frank J. Raucci, Jr., MD, PhD1,2, M. Benjamin Shoemaker, MD, MSCI1,3, Bjorn C. Knollmann, MD, PhD1,4 1 Vanderbilt Center for Arrhythmia Research and Therapeutics, 2Division of Pediatric Cardiology, 3 Division of Cardiology and 4Division of Clinical Pharmacology, Vanderbilt University Medical Center Correspondence
M AN U
Vanderbilt University School of Medicine Medical Research Building IV, Rm. 1265 2215B Garland Ave
SC
Björn C. Knollmann, M.D., Ph.D. Professor of Medicine and Pharmacology Director, Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART)
Nashville, TN 37232-0575 Office: (615) 343-6493 • Lab: (615) 936-7303 • Fax: (615) 343-4522
AC C
EP
TE D
Email: [email protected]
ACCEPTED MANUSCRIPT
RI PT
Sick sinus syndrome (SSS) is a clinical entity defined by chronic sinoatrial node (SAN) dysfunction with chronotropic incompetence and susceptibility to atrial tachyarrhythmias, sinus bradycardia, and sinus arrest. Patients are often symptomatic and necessitate permanent pacemaker implantation, with SSS the most common indication for pacemaker implantation in the United States accounting almost half of all implants1. SSS is common in the elderly and usually attributed to underlying structural heart disease or ischemic injury. Familial cases of SSS have also been described in children and young adults, with loss-of-function mutations in genes encoding for the cardiac Na+ channel α-subunit (SCN5A) and hyperpolarization-activated cyclic nucleotide-gated channel (HCN4) implicated as the underlying cause2-4.
M AN U
SC
HCN4 is the most abundant isoform of the HCN protein family found in the SAN and HCN tetramers form the ion channels responsible for hyperpolarization-activated “funny” current (If). Over the past decade, mutations in HCN4 have been implicated in SAN dysfunction5, 6, atrial fibrillation (AF)7, left ventricular non-compaction (LVNC)8, and atrioventricular (AV) block9. Most of the documented mutations are in the pore-forming loop between transmembrane segments 5 and 6 (S5-S6), the voltage sensing domain in segment 4 (S4), or in the C-terminus, which is where the cyclic nucleotide-binding domain is located. Documented electrophysiological effects vary based on the mutation loci but generally result in decrease in the If scaling factor (k), left shift in the steady-state activation or time constant curves, or alteration in adrenergic responsiveness to cyclic AMP (cAMP).
AC C
EP
TE D
In this issue of Heart Rhythm, Ishikawa and colleagues evaluated the genetic mechanisms of SSS and sought to differentiate the clinical and pathophysiologic phenotype of mutations in the pacemaker channel HCN410. The main finding of this study was that the clinical SSS phenotype of HCN4 mutations is distinct from that seen with SCN5A mutations. They identified a novel HCN4 mutation (R393H) located in the S4 voltage-sensor domain, in addition to two novel SCN5A mutations (N1354K and N1372R) in their SSS patient cohort. The HCN4-R393H mutation demonstrated significantly decreased current densities when expressed as both homomeric and heteromeric channels in a heterologous expression system despite high expression in the plasma membrane. As would be expected for a loss-of-function mutation in this region, response to cAMP was preserved while the k was decreased in heteromeric channels compared to wild-type (WT), suggesting dysfunction of the activation gating mechanism. Perhaps more importantly, Ishikawa and colleagues also combined clinical and demographic data from their own SSS cohort with other cohorts of familial SSS in the literature. Unlike the phenotype previously reported for SSS with SCN5A mutations2, 3, 11, patients with HCN4 mutations had an equal gender distribution and were older at the age of diagnosis and at time of pacemaker implantation. They were also less likely to present with AV block or atrial flutter but more likely to have AF and LVNC. Overall this study was well constructed, but there are some limitations worth considering. A significant limitation is that cohorts were not age-matched, making the claim that HCN4 are associated with more AF than SCN5A mutations difficult to follow. HCN4 mutations carriers were much older, so the higher prevalence of AF could simply be the result of the age difference rather than the underlying mutation, especially since the age of AF onset was significantly earlier in SCN5A than in HCN4 carriers. More work needs to be done before concluding that
ACCEPTED MANUSCRIPT
SC
RI PT
SSS patients with HCN4 mutations are at a higher risk for AF than SCN5A mutations carriers. Another limitation is the rarity of HCN4 mutations in the broader population of SSS patients. While there does appear to be strong associations between genotype and phenotype as outlined above, most of the data were obtained from case reports of individual families or small cohorts, which may lead to selection bias that may limit the generalizability of these results. For example, although no SSS patients in this study with SCN5A mutations had LVNC, this gene has been previously associated with LVNC12. Another potential limitation is the use of recombinant heterologous expression systems for electrophysiological testing. While this is an established technique allowing for comparison of the properties of WT and mutant channels, it may not accurately reflect the in vivo function that contributes to the clinical phenotype. Future studies using induced pluripotent stem cell-derived cardiomyocytes from patients with HCN4 mutations may aid in further understanding of the underlying mechanism of these genetic variants in SSS.
M AN U
The study by Ishikawa and colleagues does bring up an interesting contrast between the clinical phenotype of different forms of familial SSS. As genotyping becomes more prevalent in clinical medicine, genotype-phenotype correlations studies like the current study could lead to more effective therapeutic targeting as well as guide timing and modality of clinical surveillance. Additionally, the study generates a rationale for studying the role of HCN4 in myocardial development to help us understand how HCN4 loss of function mutations could cause leftventricular non-compaction, which is currently not known. REFERENCES
AC C
EP
TE D
1. Bernstein AD and Parsonnet V. Survey of cardiac pacing and implanted defibrillator practice patterns in the United States in 1997. Pacing and clinical electrophysiology : PACE. 2001;24:842-55. 2. Abe K, Machida T, Sumitomo N, Yamamoto H, Ohkubo K, Watanabe I, Makiyama T, Fukae S, Kohno M, Harrell DT, Ishikawa T, Tsuji Y, Nogami A, Watabe T, Oginosawa Y, Abe H, Maemura K, Motomura H and Makita N. Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. Circulation Arrhythmia and electrophysiology. 2014;7:511-7. 3. Chiang DY, Kim JJ, Valdes SO, de la Uz C, Fan Y, Orcutt J, Domino M, Smith M, Wehrens XH and Miyake CY. Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture. Circulation Arrhythmia and electrophysiology. 2015;8:1105-12. 4. Verkerk AO and Wilders R. Pacemaker activity of the human sinoatrial node: an update on the effects of mutations in HCN4 on the hyperpolarization-activated current. International journal of molecular sciences. 2015;16:3071-94. 5. Milanesi R, Baruscotti M, Gnecchi-Ruscone T and DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. The New England journal of medicine. 2006;354:151-7. 6. Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O and Isbrandt D. Pacemaker channel dysfunction in a patient with sinus node disease. The Journal of clinical investigation. 2003;111:1537-45. 7. Duhme N, Schweizer PA, Thomas D, Becker R, Schroter J, Barends TR, Schlichting I, Draguhn A, Bruehl C, Katus HA and Koenen M. Altered HCN4 channel C-linker interaction is
ACCEPTED MANUSCRIPT
Acknowledgement
TE D
M AN U
SC
RI PT
associated with familial tachycardia-bradycardia syndrome and atrial fibrillation. European heart journal. 2013;34:2768-75. 8. Milano A, Vermeer AM, Lodder EM, Barc J, Verkerk AO, Postma AV, van der Bilt IA, Baars MJ, van Haelst PL, Caliskan K, Hoedemaekers YM, Le Scouarnec S, Redon R, Pinto YM, Christiaans I, Wilde AA and Bezzina CR. HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. Journal of the American College of Cardiology. 2014;64:745-56. 9. Zhou J, Ding WG, Makiyama T, Miyamoto A, Matsumoto Y, Kimura H, Tarutani Y, Zhao J, Wu J, Zang WJ, Matsuura H and Horie M. A novel HCN4 mutation, G1097W, is associated with atrioventricular block. Circulation journal : official journal of the Japanese Circulation Society. 2014;78:938-42. 10. Ishikawa T, Ohno S, Murakami T, Yoshida K, Mishima H, Fukuoka T, Kimoto H, Sakamoto R, Ohkusa T, Aiba T, Nogami A, Sumitomo N, Shimizu W, Yoshiura KI, Horigome H, Horie M and Makita N. Sick Sinus Syndrome with HCN4 Mutations Shows Early Onset and Frequent Association with Atrial Fibrillation and Left Ventricular Non-compaction. Heart rhythm : the official journal of the Heart Rhythm Society. 2017. 11. Vitved T, Lianee HT, Stovring B, Sigurd BM and Christiansen M. [Mutations in the heart's pacemaker channels--a new cause of sick sinus node syndrome and long-QT syndrome]. Ugeskrift for laeger. 2008;170:929-33. 12. Shan L, Makita N, Xing Y, Watanabe S, Futatani T, Ye F, Saito K, Ibuki K, Watanabe K, Hirono K, Uese K, Ichida F, Miyawaki T, Origasa H, Bowles NE and Towbin JA. SCN5A variants in Japanese patients with left ventricular noncompaction and arrhythmia. Molecular genetics and metabolism. 2008;93:468-74.
AC C
EP
This work was supported in part by grants from the National Institutes of Health (R01HL128044, R01HL124935, R01HL108173) to BCK