Channelopathies

Hitoshi Horigome

INTRODUCTION

Cardiac channelopathies are a group of inheritable disorders that predispose fetuses with primarily structurally normal hearts to arrhythmias through the alteration of ion channel currents of myocardial cells. Genetic variations in these channels affect their opening and closing functions, resulting in changes in the currents across the myocardial cell membranes that can lead to life-threatening arrhythmias.

The most common (˜1/2000 individuals) cardiac channelopathy is congenital long QT syndrome (LQTS). There have been rare case reports of other cardiac channelopathies presenting in fetal life, including short QT syndrome and congenital sick sinus syndrome (SSS). Still other channelopathies including Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) have not yet been reported during fetal life. This chapter will describe the current knowledge about the clinical presentation and diagnosis of the channelopathies. A discussion of genetic testing for the channelopathies can be found in Part 1, Chapter 3.

PRESENTATION OF LONG QT SYNDROME IN THE FETUS

The most common presentation of LQTS during fetal life is sinus bradycardia.¹,²,³,⁴,⁵,⁶ This bradycardia is frequently unrecognized and underappreciated because very few LQTS positive fetuses meet the obstetrical criteria for bradycardia, which is ≤110 bpm at any time during pregnancy.³ In a large study, only 17% of fetuses with genetically confirmed LQTS met the obstetrical criteria, while 70% had a fetal heart rate (FHR) < third percentile for gestational age² (FIG. 3.6.1). The degree of bradycardia seems to vary with pathogenic variant burden. For example, fetuses with homozygous KCNQ1 variants have lower FHR than those with heterozygous KCNQ1 variants⁴. In addition to sinus bradycardia, torsades de pointes (TdP), the signature rhythm of LQTS, often occurs with a 2° AV block (FIG. 3.6.2) and the two are easily recognized as abnormal.⁷ However, TdP and/or 2° AV block occur in <25% of reported fetal LQTS cases.

There are three groups of fetuses at risk for LQTS. The first group are those with a parent carrier of a known pathogenic LQTS variant (“inherited LQTS”). In general,
the fetal presentation of inherited LQTS is mild and the arrhythmia burden is less compared with de novo LQTS. Exceptions are some familial KCNH2 variants,¹,⁸,⁹,¹⁰,¹¹ fetuses with homozygous or compound heterozygous variants, those with Jervell and Lange-Nielsen syndrome (homozygous variant of KCNQ1 or KCNE1), and fetuses with maternal mosaicism for SCN5A R1623Q.¹²,¹³,¹⁴ Recurrent stillbirth is another presentation of familial LQTS; compared to the general population stillbirths are 10 times higher in familial LQTS, and not all losses carry the family variant or have a history of TdP.¹⁵ In familial LQTS, there are some genotype-phenotype-specific features. For example, fetal bradycardia is more pronounced in LQT1 (KCNQ1) and LQT2 (KCNH2) than in LQT3 (SCN5A).

FIGURE 3.6.1 Screening of long QT syndrome (LQTS) based on fetal heart rate (FHR). If FHR 110 bpm is used for screening of LQTS, only 19% of LQTS cases are included below the screening line. However, if the third percentile line is adopted, 66% of LQTS cases are picked up. Δ, family history of LQTS; •, arrhythmia. (Reprinted from Mitchell JL, Cuneo BF, Etheridge SP, Horigome H, Weng HY, Benson DW. Fetal heart rate predictors of long QT syndrome. Circulation. 2012;126:2688-2695.)

The second group of fetuses at risk for LQTS are those presenting unexpected TdP, with or without 2° AV block (FIG. 3.6.3). These fetuses most frequently have de novo variants and can be identified as early as 19 weeks of gestation. Among these cases of early-onset LQTS with high arrhythmia burden, the two most prevalent genotypes are some KCNH2 variants in the pore regions and SCN5A R1623Q or L409P variants.¹,³,¹⁶,¹⁷,¹⁸,¹⁹ The other rare but severe forms of early-onset LQTS include Timothy syndrome (CACNA1C variant)²⁰,²¹,²² and calmodulinopathy (CALM1 or CALM2 variants).²³ Pathogenic variants are not identified or are uncharacterized in about 30% of these severe and early onset cases.

The third group are pregnant women with a history of stillbirths or unexplained neonatal or infant deaths. Approximately 12% of sudden infant death victims carry LQTS variants.²⁴ For example, using molecular autopsy, Crotti et al²⁵ found LQTS-associated gene variants in 8.8% of fetal demise. The role of LQTS-variants in stillbirths has yet to
be determined, but obstetricians, perinatal health providers, and cardiologists should be aware of these early-onset life-threatening types of LQTS and consider molecular autopsy when confronted with an unexplained stillbirth.

FIGURE 3.6.2 2° atrioventricular block observed in a fetus with long QT syndrome. A: Pulsed Doppler waveforms of ejection flow in the fetal aorta, showing fixed A-A (p-p) intervals with alternate atrioventricular (AV) conduction (2:1 AV block) due to extremely prolonged refractory period of the ventricle. The A rate is 106 bpm, and V rate is 53 bpm. SVC, inverse flow due to atrial contraction in the superior vena cava; Ao, ejection flow due to ventricular contraction in the aorta. B: Electrocardiogram recorded after birth in the same patient as A. Findings show that half of the P-waves are located on the T-waves without AV conduction due to extremely prolonged QT intervals (700 ms). PP (0.62 s) and VV (1.25 s) intervals are both regular.

Literature Summary of Fetal LQTS Presentation (Table 3.6.1)

A search of English-language journals for case reports or series of LQTS diagnosed in utero revealed 55 cases, including 10 cases with LQT1, 23 with LQT2, 15 with LQT3, 3 with calmodulinopathy, 3 unknown, and 1 with multiple pathogenic variants. Investigation of the genotype-phenotype correlations revealed that all LQT1 fetuses showed only sinus bradycardia, whereas the frequencies of 2:1 AV block and TdP reached
approximately 60% and 80%, respectively, in both LQT2 and LQT3 fetuses. Babies with LQT2 and LQT3 were delivered at a gestational age of 27 to 38 (median 35) weeks, via cesarean delivery in ˜75% of the pregnancies of which one-third were emergency cesarean deliveries.

FIGURE 3.6.3 Torsade de pointes (TdP) observed in a fetus with long QT syndrome. A: M-mode fetal echocardiogram. The atrial wall movement is faster than that of the ventricular wall without any correlations, indicating ventricular tachycardia. Ventricular wall motion is a little irregular with a rate of 210 bpm. IVS, interventricular septum. B: Typical waveforms of TdP recorded with fetal magnetocardiography, showing polymorphic ventricular tachycardia (VT) with an irregular rhythm and QRS morphology. C: Pulsed Doppler waveforms of ejection flow in the fetal aorta, showing irregular intervals and amplitudes, which suggest polymorphic VT (TdP).

TABLE 3.6.1 LITERATURE SUMMARY OF FETAL LONG QT SYNDROME

Author (y)	Origin of LQTS	Hx of Fetal Loss	GA (wk)	Rhythm	Delivery (wk)	Variant
1. Vigliani (1995)	Mother	ND	38	Brady	VD (40)	ND
2. Donofrio (1999)		ND	32	Brady		ND
3. Hamada (1999)	Mother	No	37	Brady	VD (38)	KCNQ1 A341V
4. Cuneo (2003)	De novo	No	30	VT, 2:1 AV block, SB (110 bpm)	CS (34)	SCN5A R1623Q
5. Johnson (2003)	Mother	ND	38	VT, SB (120 bpm)	ND (38)	KCNH2 R725Q
6. Miller (2004)	Maternal mosaicism	SB × 2	28	VT², SB, 2:1 AV block	ECS (32)	SCN5A R1623Q
7. Chang (2004)	De novo	ND	ND	Tachy-brady	ND (38)	SCN5A V1763M
8. Lupoglazoff (2004)	Mother	ND	˜30	2:1 AV block	ND	KCNH2 T613M
9.	Mother	ND	˜30	VT, 2:1 AV block	ND	KCNH2 D501N
10.	M + F	ND	˜30	VT, 2:1 AV block	ND	Multiple
11.	De novo	ND	˜30	VT, 2:1 AV block	ND	KCNH2 G628S
12.	De novo	ND	˜30	VT, 2:1 AV block	ND	KCNH2 Y93C
13.	Mother	ND	˜30	SB	ND	KCNQ1 R231C
14.	Mother	ND	˜30	SB	ND	KCNQ1 G325R
15.	Mother	ND	˜30	SB	ND	KCNQ1 R231C
16.	Mother	ND	˜30	SB	ND	KCNQ1 R231C
17.	Mother	ND	˜30	SB	ND	KCNQ1 G1258 insA
18. Schultz-Bahr (2004)	De novo	Primip	ND	Tachy-brady	CS (35)	SCN5A P1332L
19. Schneider (2005)	Mother	ND	32	SB	VD (38)	KCNQ1 CTG to CCG
20. Ten Harkel (2005)	De novo	ND	29	Irregular	CS (33)	SCN5A R1623Q
21. Tomek (2008)	Father	Primip	22	2° AV block, SB
			26	VT	CS (31)	SCN5A ND
22. Bhuiyan (2008)	M + F Consanguineous	MC × 2 SB × 2 homoz	22	2:1 AV block
			29	PVC, VT	CS (32)	Homoz KCNH2 Q1070X
23. Wang (2008)	Novel de novo		32	Arrhythmia	ECS (32)
	Novel de novo		34	VT	ND	SCN5A G1631D
24. Simpson (2009)	De novo	No	30	VT¹,²,³	ND (32)	KCNH2 T613M
25. Horigome (2010)	+ FH	ND	ND	SB	ND	KCNQ1 Thr587Met
26.	? de novo	ND	ND	SB	ND	KCNQ1 Ala341Val
27.	? de novo	ND	ND	VT, 2:1 AV block	ND	KCNH2 Gly628Ser
28.	? de novo	ND	ND	VT	ND	KCNH2 Del(7) (q32qter)
29.	+ FH	ND	ND	ND	ND	KCNH2 Ser243 + 112x
30.	? de novo	ND	ND	VT, 2:1 AV block	ND	KCNH2 GM628Ala
31.	? de novo	ND	ND	VT, 2:1 AV block	ND	KCNH2 Thr613met
32.	? de novo	ND	28	2:1 AV block	ND	SCN5A Ala1186Thr
33.	? de novo	ND	ND	VT, 2:1 AV block	ND	SCN5A Asn1774Asp
34. Murphy (2011)	De novo	No	19	VT¹,²,³	FD(25)	SCN5A L409B
35. Donofrio (2012)	De novo	No	19	Irregular
			26	2:1 AV block
			30	VT¹,², 2:1 AV block	ECS (30)	SCN5A R1623Q
36. Chabaneix (2012)	ND (but no FH)	No	36	PVCs, VT, SB (120 bpm)
			37	VT¹, 2:1 AV block	ND (37)	KCHN2 Gly628Ser
37. Kormarlu (2012)	Father	Primip		Tachy¹,²,³	ECS	KCNH2 ND
38. Theeuws (2013)	De novo	No	32	VT¹,²,³	ECS (32)	UK
39. Crotti (2013)	De novo	No	21	SB (110 bpm)
			27	SB (90 bpm)	CS (37)	CALM2 D96V
40. Cuneo (2013)	De novo	ND	28	VT, 2:1 AV block	CS (33)	KCNH2 G628S
41.	Mother novel	1 SB	34	VT, 2:1 AV block	NSVD (38)	KCNH2 Thr613Lys Lys897Thr
42.	De novo	ND	30	VT, 2:1 AV block	CS (35)	SCN5A R1623Q
43.	De novo twins	ND	30	VT¹,³, 2:1 AV block	ECS (31)	SCN5A R1623Q
44. Flock (2014)	Mother	Prim	29	SB	CS (39)	KCNQ1 G350V
45.	De novo	No	27	VT¹,²,³, SB, 2:1 AV block	ECS (27)	KCNH2 G682S
46.	Mother	Prim	27	SB, 2:1 AV block	CS (38)	KCNH2 T613M
47. Priest (2014)	Father	No	ND	Brady	CS (38)	KCNH2 T613M
48. Reed (2015)	De novo	No		Brady	VD (38)	CALM3 D130G
49. Chaix (2016)	De novo	30		SB (109 bpm)
		36		2:1 AV block
		37		SB (85 bpm)	CS (37)	CALM3
50. Magnusson (2017)	Mother	MC × 1 SB × 1	ND	ND	VD	SCN5A C1231G>A
51. Blais (2017)	De novo	No	26	VT, 2:1 AV block	CS (37)	SCN5A R1623Q
52. Miyake (2017)	De novo	MC × 1	28	2:1 AV block
			30	VT³, SB	CS (35)	KCNH2 S624R
53.	Father	ND	24	VT, SB
			26	VT³, SB	CS (37)	KCNH2 T613M
54. Tuveng (2018)	Mother, novel variant	Fetal loss × 1	ND	SB	ND	KCNH2 R62Q
55. Crimmins (2018)	De novo	None	27	VT, 2:1 AV block	CS (30)	KCNH2 G628S
Brady, bradycardia; CS, cesarean section; ECS, emergency cesarean section; FD, fetal demise; +FH, positive family history; homoz, homozygous for the LQTS variant; M + F, mother and father; MC, miscarriage; ND, no data; prim, primiparous mother; SB, sinus bradycardia; Tachy-brady, tachycardia and bradycardia; UK, tested for common variants but negative; VD, vaginal delivery; VT, ventricular tachycardia; 1, cardiac dysfunction; 2, biventricular hypertrophy; 3, hydrops.

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Tags: Diagnosis and Management of Fetal Arrhythmias

Dec 30, 2020 | Posted by drzezo in CARDIOLOGY | Comments Off

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