Congenital long QT syndrome: a clinician's guide

The overall treatment aim is to enable affected patients to participate in the recreations that they enjoy, while moderating their risk of morbidity and mortality. To ensure this, the patient–doctor partnership is paramount, where personalised risk–benefit assessments and management can take place.30

Non-pharmacological interventions Although the mainstay of treatment in affected individuals is pharmacological, there are important, common-sense, non-pharmacological management strategies that should be adhered to by all, including: Avoid QT prolonging states including QT prolonging medications (www.crediblemeds.org), avoiding hypokalaemia, hypomagnesaemia and hypocalcaemia. Strict electrolyte replacement with electrolyte hydration formulas should be encouraged in LQTS patients who develop diarrhoea or excessive vomiting. Lifestyle modifications in certain LQTS phenotypes can be effective. This includes avoidance, where possible, of intense exercise training (with exception in low-risk individuals based on risk-stratification described above) in LQT1, and avoiding excessive sudden auditory stimuli in post-partum women with LQT2. Engage cardiac genetic counsellor assistance for ongoing management of the significant psychological, occupational and familial burden that a LQTS diagnosis is invariably associated with.19 Pharmacological and physical interventions

Therapeutic success in LQTS is a direct reflection of our understanding of the disease. The key elements in pan-genotypic management of LQTS includes adrenergic suppression with beta-blockade, left cardiac sympathetic denervation (LCSD), as well as the judicious use of implantable cardioverter-defibrillators (ICD) (Fig. 6).13, 19, 22 Genotype-specific therapy particularly in LQT3 is becoming more mainstream; however, the evidence to guide this is still in its infancy.

image 2017 AHA/ACC/HRS consensus algorithm in instituting management in those with LQTS (with permission).19 Beta-blockers The general recommendation is that all individuals with LQTS regardless of symptom status should be on long-acting beta-blockade so long as it is tolerated. Specifically, the strongest indication (Class I) would be in those who are:19, 22, 31 Symptomatic for syncope or documented ventricular arrhythmia Asymptomatic with a QTc ≥470 ms

A recent meta-analysis of registry and time-series data of 9727 patients54 demonstrated a hazard ratio (HR) of 0.49 (P < 0.001) for reduction of all cardiac events and 0.47 (P < 0.001) for serious cardiac events with beta-blockade. In this meta-analysis, the effect of beta-blockade was seen predominantly in LQT1 (HR 0.59, P < 0.001) and LQT2 (HR 0.39, P < 0.001). Although this study was unable to appreciate a significant risk modification by beta-blockers in LQT3 individuals, a more recent cohort study of 1710 patients has shown efficacy even in the LQT3 group. Of note, even though beta-blockade lends itself to further bradycardia, it is not associated with increased cardiac events in those with LQT3.8, 10, 22, 41, 54

Nadolol followed by propranolol and atenolol are the beta-blockers with the best evidence for use. Metoprolol (in sustained-release and short-acting form) has been demonstrated to be ineffective for use in this setting, and as such is not recommended.55, 56 The heterogeneity in beta-blocker effect has been theorised to be due to the following observations: (i) nadolol is sustained release without sympathomimetic activity thereby offering sustained control without increasing risk of EAD; and (ii) nadolol and propranolol also have sodium channel blocking effects. Nadolol is preferred to propranolol in the LQT2 population due to a tendency for propranolol to block IKr.56 One trial suggested atenolol may be superior to nadolol in LQT1, but this has not been corroborated in other studies.19, 57 Although nadolol has demonstrated superiority over others in its class, there continues to be a shortage in production of nadolol worldwide.8, 19

Beta-blocker use is generally well tolerated, with the most common barriers to uptake being asthma, chronotropic incompetence leading to early fatigue and erectile dysfunction in men.8, 54, 58 The accepted starting dose for nadolol is 1–1.5 mg/kg/day (usually 40 mg to 120 mg/day given tablets are produced in 20 mg increments) as a daily dose if over the age of 12 years.59 Doses below 0.8 mg/kg/day have been shown to fail to prevent cardiac events, and dose should be up titrated to the maximal tolerated dose based on side-effect profile rather than a target heart rate.12, 55 Titrating to the maximal tolerated dose (and no further) is critical in optimising adherence.60 Optimal starting propranolol dosing is less described; however, most data showing efficacy have been at doses of 3–5 mg/kg/day split into three doses per day.12, 55

Other pharmacotherapy

Mexiletine, a sodium channel (class 1b) blocker, has been demonstrated to shorten QTc and reduce burden of cardiac events in the LQT3 population in conjunction with beta-blockade.61-63 It is recommended for use as an adjunct in LQT3 patients with ongoing symptoms or with minimal reduction in QTc with beta-blockade.19 More recent evidence demonstrates that mexiletine may also be useful in LQT2 cohorts as an adjunct to reduce QTc, though it is yet to be studied for reduction in clinical events.64 The most studied dose of mexiletine is 12–24 mg/kg/day over three doses and is tolerated well, with the most common side-effect being mild abdominal discomfort.64

Implantable cardioverter-defibrillator ICD therapy is indicated (class I recommendation) in:19, 22, 65 Resuscitated cardiac arrest Recurrent arrhythmogenic syncope while on beta-blockade Relative (class II) indications for ICD therapy include: Asymptomatic individuals with a very long QTc (>550 ms) especially in females with LQT2 and those with double mutations (e.g. Jervell and Lange−Nielsen syndrome) When beta-blockers are contraindicated, and high risk is established.

It is important that beta-blockade continues even with ICD placement as ICD firing is associated with significant discomfort and may lead to local adrenergic overdrive providing VT substrate. ICD have been demonstrated in longitudinal studies to prevent death, but are also associated with morbidity (inappropriate shocks, requirement for generator changes, infection) and should only be inserted after careful consideration and patient discussion.

The best ICD settings include those optimised to minimise inappropriate shocks with high detection rates and extended detection time. Subcutaneous ICD eliminate the risk associated with vascular injury and pneumothorax. Although they cannot provide anti-tachycardia pacing or bradycardia therapies, they are a good option for young patients without other indication for ventricular lead placement.66

Left cardiac sympathetic denervation LCSD can be considered in the following situations:19, 22 Recurrent ICD shocks for VT (Class I recommendation) Ongoing syncopal episodes despite optimal beta-blockade therapy (Class I recommendation) Ongoing prolonged QTc >500 ms in asymptomatic individuals on optimal beta-blockade (Class IIb recommendation) In those who cannot tolerate beta-blockers or ICD cannot be placed/not wanted (Class IIa recommendation)

LCSD involves the removal of the first four thoracic ganglia by a thoracic surgeon either thoracoscopically or with an extra-pleural approach. The cephalic portion of T1 is spared to avoid iatrogenic Horner syndrome. The rationale for LCSD has been based on its well described anti-fibrillatory effects through reduction in noradrenaline release at the ventricular level with absence of post-denervation super sensitivity without bradycardia or chronotropic incompetence.67, 68 A limiting factor in many centres is that an experienced operator is required to perform this procedure. Even with experience, side-effects can occur, including dry skin, hyperhidrosis and a Harlequin-type facial flush.69 Nevertheless, LCSD is effective in reducing up to 91% of ventricular arrhythmias despite full-dose beta-blockade in those with ongoing symptoms.70

Gene-directed therapies

Despite significant strides in unravelling the genetics accounting for LQTS, genotype-specific therapy is still in its infancy. No gene-specific therapies have, to our knowledge, been proven to be effective in reducing the risk of arrhythmogenic death.

Most headway has been in the management of LQT3 as previously discussed, where the intuitive blockade of sodium channels with mexiletine has been proven to reduce arrhythmic events while also on beta-blockade.71 Flecainide and ranolazine10 have also been described as potentially useful adjuncts. Flecainide must be used in caution given its potential to induce a Brugada phenotype.30

Other less studied therapies include oral potassium supplementation in LQT272 and potassium pump-enhancing agents such as nicorandil in LQT1,73 which require further evaluation prior to translation to practise.

Psychological burden

Among those with either asymptomatic or symptomatic LQTS, as well as family members awaiting further genetic testing, ‘cardiac anxiety’ and generalised anxiety occurs much more frequently than the general population.74, 75 Moreover, a recent Danish cohort study demonstrated an elevated risk of developing depression once being diagnosed with LQTS where the severity of depression was proportional to the severity of the LQTS phenotype.76 Anxiety and depression not only independently contribute to the overall morbidity of the condition but can worsen the phenotype in those with LQTS.47 Treatment of anxiety and depression can be challenging, given many classes of medications used including selective serotonin reuptake inhibitors (first line), serotonin noradrenaline reuptake inhibitors (second line) and tricyclic antidepressants (third line) are all listed as QTc lengthening (and listed as drugs to avoid on www.crediblemeds.org).77, 78 Despite a paucity of evidence, it appears as though citalopram78 and escitalopram79 increase the risk of cardiac events, whereas sertraline,80, 81 fluoxetine or paroxetine77 may be safer options with close QTc monitoring. Serotonin noradrenaline reuptake inhibitors and tricyclic antidepressants are not recommended in those with LQTS.77, 82

Careful consideration of the psychological impact that a provisional or confirmed LQTS diagnosis with implementation of a cardiac genetic counsellor and targeted psychological intervention is an important responsibility of the treating clinician.48, 74, 75

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