Holter Recordings at Initial Assessment for Long QT Syndrome: Relationship to Genotype Status and Cardiac Events.

Background: The relationship of Holter recordings of repolarization length to outcome in long QT syndrome (LQTS) is unknown. Methods: Holter recordings and initial 12 lead ECG QTc were related to outcome in 101 individuals with LQTS and 28 gene-negative relatives. Mean QTc (mQTc) and mean RTPc (R-wave to peak T-wave, mRTPc) using Bazett correction were measured, analyzing heart rates 40 to 120 bpm. Previously reported upper limit of normal (ULN) were: women and children (<15 years), mQTc 454, mRTPc 318 ms; men mQTc 446 ms, mRTPc 314 ms. Results: Measurements in LQTS patients were greatly prolonged; children and women mean mQTc 482 ms (range 406−558), mRTPc 351 ms (259−443); males > 15 years mQTc 469 ms (407−531), mRTPc 338 ms (288−388). Ten patients had cardiac arrest (CA), and 24 had arrhythmic syncope before or after the Holter. Holter values were more closely related to genotype status and symptoms than 12 lead QTc, e.g., sensitivity/specificity for genotype positive status, mRTPc > ULN (89%/86%); CA, mRTPc > 30 ms over ULN (48%/100%). Of 34 symptomatic (CA/syncope) patients, only 9 (26%) had 12 lead QTc > 500 ms, whereas 33/34 (94%) had an mRTPc or mQTc above ULN. In 10 with CA, all Holter measurements were > 15 ms above ULN, but only two had 12 lead QTc > 500 m. Conclusions: Holter average repolarization length, particularly mRTPc, reflects definite LQTS status and clinical risk better than the initial 12 lead QTc. Values below ULN indicate both a low risk of having LQTS and a low risk of cardiac events in the small percentage that do.

Pre-Test Probability and Genes and Variants of Uncertain Significance in Familial Long QT Syndrome.

The genetics underlying familial long QT syndrome (LQTS) are among the best characterised of all of the inherited heart conditions. Cohort and registry studies have demonstrated important genotype-phenotype correlations that are now essential in guiding clinical practice of patients with the most common three genotypes; KCNQ1 (LQT type 1), KCNH2 (LQT type 2) and SCN5A (LQT type 3). However, the growing number of genes-now more than 16-is confusing, and there is much doubt as to whether many actually cause LQTS at all. Furthermore, changes in sequencing techniques, evolving variant classification criteria and new scientific discoveries make all genes and variants subject to a continuous process of re-classification. This review discusses the nature of variant adjudication, the important concept of pre-test probability in interpreting a genetic result and how the nomenclature of LQTS is shifting in response to this new knowledge. It further discusses the role of deep phenotyping, the inclusion of evaluation of family members in interpreting a genetic test result, or even deciding if genetic testing should occur at all, and the role of specialist multidisciplinary teams to translate this continuously evolving knowledge into the best clinical advice, in partnership with referring cardiologists.

Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults.

BACKGROUND: Normative values for heart-rate corrected repolarisation length are not available in children and are scarce in adults. We wished to define repeatability and normative values of Holter recording measurements of repolarisation length in healthy individuals using a commercially available system, and compare measurements with those from 12-lead electrocardiograms (ECGs). METHODS: Twenty-four-hour (24-) Holter recordings were made on 99 Healthy volunteers: 52 children (7 months to 14 years) and 47 adults (≥15 yrs). Mean and peak values of QTc, and RTPc (R-wave to peak T-wave) were assessed. Bazett heart rate correction was employed for each measurement and only heart rates between 40 and 120 bpm were analysed. The end of the T-wave was defined from the zero-crossing point. QTc was also determined from 12-lead ECGs from the same population by manual measurement recording the longest QTc of leads 2 and V5. The tangent technique was used to define the end of the T-wave. RESULTS: Interobserver repeatability: mean QTc ±15 ms (CI 3.5%), peak QTc ±25 ms (CI 4.5%), mean RTPc ±3 ms (CI 1%), peak RTPc ±44 ms (CI 11%). Mean values were very similar for <15 years and all females and were therefore amalgamated: mean (±2 SD); mean QTc 424 ms (394-454), mean RTPc 291ms (263-319). Values were lower in males ≥15 years; (mean QTc 408 ms (370-446), p<0.01; mean RTPc 274 ms (234-314), p<0.01. The highest mean QTc value was 467 ms in an adult female. QTc from 12-lead ECG: females <15 years 409 ms (384-434) males <15 years 408 ms (383-433), females ≥15 years 426 ms (401-451), males ≥15 years 385 ms (362-408). CONCLUSIONS: Holter measurements of mean QTc and RTPc are highly repeatable. Males ≥15 years have shorter mean repolarisation length over 24 hours than males <15 years and all females. Mean QTc Holter values were on average 15-17 ms longer than QTc from 12-lead ECGs except in females >15 years.

Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy.

BACKGROUND: Isolated cardiac arrhythmia due to a variant in CACNA1C is of recent knowledge. Most reports have been of singleton cases or of quite small families, and estimates of penetrance and expressivity have been difficult to obtain. We here describe a large pedigree, from which such estimates have been calculated. METHODS: We studied a five-generation family, in which a CACNA1C variant c.2573G>A p.Arg858His co-segregates with syncope and cardiac arrest, documenting electrocardiographic data and cardiac symptomatology. The reported patients/families from the literature with CACNA1C gene variants were reviewed, and genotype-phenotype correlations are drawn. RESULTS: The range of phenotype in the studied family is wide, from no apparent effect, through an asymptomatic QT interval prolongation on electrocardiography, to episodes of presyncope and syncope, ventricular fibrillation, and sudden death. QT prolongation showed inconsistent correlation with functional cardiology. Based upon analysis of 28 heterozygous family members, estimates of penetrance and expressivity are derived. CONCLUSIONS: These estimates of penetrance and expressivity, for this specific variant, may be useful in clinical practice. Review of the literature indicates that individual CACNA1C variants have their own particular genotype-phenotype correlations. We suggest that, at least in respect of the particular variant reported here, "arrhythmogenic channelopathy" may be a more fitting nomenclature than long QT syndrome.

Predictors of ß-blocker adherence in cardiac inherited disease.

Objective: The cardiac inherited disease (CID) population has suboptimal adherence to long-term ß-blocker therapy, which is known to be a risk for sudden cardiac death. This study aimed to identify the clinical and psychosocial variables associated with non-adherence in this population. Methods: 130 individuals (aged 16-81 years, median: 54) from the New Zealand Cardiac Inherited Disease Registry taking ß-blockers participated: 65 (50%) long QT syndrome, 42 (32%) hypertrophic cardiomyopathy and 23 (18%) other. Participants completed one questionnaire recording self-reported adherence, anxiety, depression, confidence in taking medication, illness perceptions and medication beliefs. Demographic and clinical variables were taken from the registry. Results: 21 participants (16%) were classed as non-adherent. Bivariate analysis showed that self-reported adherence was worse in those who were younger (p<0.001), had a channelopathy not cardiomyopathy (p<0.01), reported lower confidence in taking ß-blockers (p<0.001), had high concerns (p<0.05) and low necessity beliefs about their ß-blocker (p<0.001), a poorer understanding of their CID (p<0.01), and lower treatment control beliefs (p<0.01). These variables accounted for 37% of the variance in adherence in a linear regression model. Stronger beliefs around medication necessity and higher confidence in their ability to take their medication predicted ß-blocker adherence. Conclusions: Factors associated with ß-blocker non-adherence in patients with CID include young age, having a channelopathy, negative medication beliefs, low confidence in taking medication and poor illness perceptions. These findings present an opportunity to develop targeted interventions to improve adherence.

ß-Blocker Adherence in Familial Long QT Syndrome.

BACKGROUND: Long-term uninterrupted ß-blockade significantly reduces cardiac events in long QT syndrome (LQTS). Despite this, data on nonadherence are scarce and quantified only on the day of cardiac arrest in LQTS literature. We aimed to describe ß-blocker adherence, and predictors thereof, among patients with LQTS types 1 and 2. METHODS AND RESULTS: Electronic health records and pharmacy dispensing data were reviewed for 90 patients with LQTS 1 and 2 who reside in Auckland, New Zealand, during a 34-month period. For each patient, the medication possession ratio (MPR: proportion of follow-up days patients were dispensed ß-blocker) was calculated. Adequate adherence was characterized by an MPR ≥0.8 and ideal as MPR=1.0. Clinical and demographic features were assessed to determine whether they predicted adherence. Long-term ß-blockers were prescribed to 74 patients (82%). Side effects were described as intolerable by 6 (8%) and their ß-blockers were stopped. MPR was calculated in the remaining 68 patients >151.7 patient-years of follow-up. Median MPR was 0.79 (range, 0-1.3). Suboptimal adherence (MPR<0.8) was recorded in 35 (51%). Seven patients (10%) never took up a prescription (MPR=0). Adequate adherence was present in 33 (49%), including 9 (13%) who had ideal adherence. Age, sex, clinical presentation, family history of sudden death, ethnicity, and deprivation index did not predict adherence. CONCLUSIONS: Adherence to ß-blockers in LQTS is suboptimal in half of those with LQTS 1 and 2. Risk factors for nonadherence could not be identified in our population. Further research into ß-blocker adherence is imperative in this high-risk population.

Update on the Diagnosis and Management of Familial Long QT Syndrome.

This update was reviewed by the CSANZ Continuing Education and Recertification Committee and ratified by the CSANZ board in August 2015. Since the CSANZ 2011 guidelines, adjunctive clinical tests have proven useful in the diagnosis of LQTS and are discussed in this update. Understanding of the diagnostic and risk stratifying role of LQTS genetics is also discussed. At least 14 LQTS genes are now thought to be responsible for the disease. High-risk individuals may have multiple mutations, large gene rearrangements, C-loop mutations in KCNQ1, transmembrane mutations in KCNH2, or have certain gene modifiers present, particularly NOS1AP polymorphisms. In regards to treatment, nadolol is preferred, particularly for long QT type 2, and short acting metoprolol should not be used. Thoracoscopic left cardiac sympathectomy is valuable in those who cannot adhere to beta blocker therapy, particularly in long QT type 1. Indications for ICD therapies have been refined; and a primary indication for ICD in post-pubertal females with long QT type 2 and a very long QT interval is emerging.

Inpatient detection of cardiac-inherited disease: the impact of improving family history taking.

OBJECTIVES: 'Idiopathic' cardiac conditions such as dilated cardiomyopathy (DCM) and resuscitated sudden cardiac death (RSCD) may be familial. We suspected that inpatient cardiology services fail to recognise this. Our objective was to compare diagnostic value of family histories recorded by inpatient cardiology teams with a multigenerational family tree obtained by specially trained allied professionals. METHODS: 2 experienced cardiology nurses working in 2 tertiary adult cardiac units were trained in cardiac-inherited diseases and family history (FHx) taking, and established as regional coordinators for a National Cardiac Inherited Disease Registry. Over 6 months they sought 'idiopathic' cardiology inpatients with conditions with a possible familial basis, reviewed the FHx in the clinical records and pursued a minimum 3-generation family tree for syncope, young sudden death and cardiac disease (full FHx). RESULTS: 37 patients (22 males) were selected: mean age 51 years (range 15-79). Admission presentations included (idiopathic) RSCD (14), dyspnoea or heart failure (11), ventricular tachycardia (2), other (10). 3 patients had already volunteered their familial diagnosis to the admitting team. FHx was incompletely elicited in 17 (46%) and absent in 20 (54%). 29 patients (78%) provided a full FHx to the coordinator; 12 of which (41%) were strongly consistent with a diagnosis of a cardiac-inherited disease (DCM 7, hypertrophic cardiomyopathy 3, long QT 1, left ventricular non-compaction 1). Overall, a familial diagnostic rate rose from 3/37(8%) to 12/37 (32%). CONCLUSIONS: Adult cardiology inpatient teams are poor at recording FHx and need to be reminded of its powerful diagnostic value.

Physical and Psychological Consequences of Left Cardiac Sympathetic Denervation in Long-QT Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Left cardiac sympathetic denervation reduces risk in long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia. Side effects and patient satisfaction have not been systematically analyzed in patients who underwent left cardiac sympathetic denervation. Aims of this study included documenting physical and psychological consequences and patient satisfaction after left cardiac sympathetic denervation in LQTS or catecholaminergic polymorphic ventricular tachycardia. METHODS AND RESULTS: Patients with LQTS (N=40) and catecholaminergic polymorphic ventricular tachycardia (N=7) underwent video-assisted thoracoscopic left cardiac sympathetic denervation, with a median follow-up of 29 months (range, 1-67 months). Clinical records were reviewed; 44 patients completed a telephone survey. Of 47 patients (53%), 25 were preoperatively symptomatic (15 syncope, 7 near-drowning, and 3 resuscitated sudden death). Indications for left cardiac sympathetic denervation included ß-blocker intolerance (15; 32%) or nonadherence (10; 21%) and disease factors (18; 38%; catecholaminergic polymorphic ventricular tachycardia [6], near-drowning [2], exertional syncope [1], symptoms on therapy [2], LQT3 [1], QTc>520 ms [6]). Other indications were competitive sports participation (2), family history of sudden death (1), and other (1). Median QTc did not change among patients with LQTS (461±60 to 476±54 ms; P=0.49). Side effects were reported by 42 of 44 (95%). Twenty-nine patients (66%) reported dryness on left side, 26 (59%) a Harlequin-type (unilateral) facial flush, 24 (55%) contralateral hyperhidrosis, 17 (39%) differential hand temperatures, 5 (11%) permanent and 4 (9%) transient ptosis, 5 (11%) thermoregulation difficulties, 4 (9%) a sensation of left arm paresthesia, and 3 (7%) sympathetic flight/fright response loss. Majority of the patients were satisfied postoperatively: 38 (86%) were happy with the procedure, 33 (75%) felt safer, 40 (91%) recommended the procedure to others, and 40 (91%) felt happy with their scar appearance. CONCLUSIONS: Despite significant morbidity resulting from left cardiac sympathetic denervation, patients with LQTS and CPVT have high levels of postoperative satisfaction.

Must every child with long QT syndrome take a beta blocker?

Long QT syndrome is the most commonly recognised cause of sudden cardiac death in children. With a prevalence of 1 in 2000, family screening is identifying large numbers of hitherto asymptomatic gene carriers in the community, about a third of whom have a normal QT interval. The mainstay of treatment is long term uninterrupted beta blocker therapy, a treatment with many potential side effects. This article reviews the evidence and suggests a cohort who may, after assessment in a specialised cardiac-genetic clinic, be spared this treatment because of very low baseline risk. These are asymptomatic boys and prepubertal girls with a heart rate corrected QT interval persistently less than 470 ms who do not indulge in high risk activities (especially swimming) and do not have a missense mutation in the c-loop region of the KCNQ1 (long QT 1) gene.