Precision therapy in congenital long QT syndrome

Authors, Journal, Affiliations, Type, DOI

• Raquel Neves, Sahej Bains, J. Martijn Bos, Ciorsti MacIntyre, John R. Giudicessi, Michael J. Ackerman
• Trends in Cardiovascular Medicine 34 (2024) 39–47
• Mayo Clinic, Rochester, MN — Departments of Molecular Pharmacology, Pediatric Cardiology, and Cardiovascular Medicine (Windland Smith Rice Genetic Heart Rhythm Clinic)
• Retrospective cohort review; 20+ years; single quaternary LQTS specialty centre
• DOI: https://doi.org/10.1016/j.tcm.2022.06.006

Overview

This retrospective review from the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic catalogues the full spectrum of treatment configurations actually used in 1,304 patients with LQT1, LQT2, and LQT3 between 2000 and 2021. The breadth of regimens — up to 18 distinct configurations in LQT3 alone — illustrates that guideline-directed therapy (GDT) is only a starting scaffold; real-world expert practice is far more nuanced. Key non-guideline findings include intentional nontherapy for very low-risk patients, LCSD as monotherapy for BB-intolerant patients, mexiletine and intentional permanent atrial pacing (IPAP) for high-risk LQT2, and propranolol preference over nadolol in LQT3. Overall LQTS-associated mortality was 0.3% and annual breakthrough cardiac event (BCE) rate 1.2% over the 20+ year follow-up.

Keywords

Genetic testing, Long QT syndrome, Precision therapy, Sudden cardiac death

Key Takeaways

Cohort Demographics

• 1,304 patients: LQT1 n=696 (53%), LQT2 n=454 (35%), LQT3 n=154 (12%)
• 58.1% female; mean age at last visit 31±18 years; mean baseline QTc 469±39 ms
• 9.1% carried a pre-existing ICD before first Mayo Clinic evaluation — over half later underwent ICD extraction after shared-decision-making

LQT1 Treatment Configurations (10 at last follow-up)

• Most common: non-selective BB monotherapy (nadolol/propranolol) — 54% of patients
• Intentional nontherapy: 16% (113 patients) after full risk stratification
• LCSD performed in 20% of patients; 6% received LCSD monotherapy
• ICD in 11%; triple therapy (ICD+LCSD+BB) in 3%
• 31 of 33 ICDs implanted during follow-up were for primary prevention
• 8 ICDs explanted — all had been placed as primary prevention at referring centres

LQT2 Treatment Configurations (17 at last follow-up)

• Most common: non-selective BB monotherapy — 49%
• Intentional nontherapy: 16% (73 patients)
• ICD in 24%; LCSD in 12% (54 patients)
• Intentional permanent atrial pacing (IPAP) — 8% of patients: Mean resting QTc 501±49 ms; 63% had ≥1 BCE prior to visit. BCE rate dropped from 1.01 to 0.02 BCE/year (p=0.003) with IPAP. Atrial pacemaker-only device may be appropriate for some LQT2 patients without defibrillation capability
• Mexiletine in LQT2 — 19 patients (4%): Mean QTc 543±96 ms; 47% had prior BCE. Mexiletine decreased mean QTc by 65±45 ms; zero BCEs at 6.5±5.2 years follow-up. Pharmacological targeting of late sodium current effective even in potassium-channel-mediated LQT2
• SQ-ICD caution: Higher rate of inappropriate shocks from T-wave oversensing in LQT2 — SQ-ICD used rarely in this cohort
• 9 ICD extractions during follow-up (primary prevention placed elsewhere)

LQT3 Treatment Configurations (18 at last follow-up — most complex)

• Intentional nontherapy: 29% (45 patients) — highest proportion of any subtype
• Non-selective BB: 19%; mexiletine monotherapy: 14%; flecainide monotherapy: 2%
• ICD monotherapy: 13%
• Propranolol preferred over nadolol in LQT3 (22 vs 7 patients): Propranolol directly inhibits the late sodium current (INaLate) — its primary channel target in LQT3; nadolol does not
• Flecainide for p.Ile1768Val-SCN5A (3 patients): This variant increases Nav1.5 availability by accelerating recovery from inactivation; flecainide was selected to specifically target this biophysical mechanism
• Right cardiac sympathetic denervation (RCSD) — 5 patients (3%): Done incrementally after LCSD + ICD; always as an escalation step, never bilateral primary or RCSD-alone
• Cardiac transplant — 4 patients (2.6%): All LQT3; severe arrhythmogenicity with multiple ICD discharges; continuous IV lidocaine as bridge to transplant; high-risk variants: p.Arg1623Gln-SCN5A, p.Phe1486Leu-SCN5A, p.Leu618Phe-SCN5A; two represented LQT3-MEPPC overlap phenotype

Intentional Nontherapy — 231 patients (18% of all LQTS)

• Mean age 34±22 years; mean resting QTc 451±30 ms
• Criterion: asymptomatic adult (post-pubertal), normal resting QTc, normal QTc during recovery phase of stress test, and free of events for ≥23 years if previously symptomatic
• Precautionary measures: QT-prolonging drug avoidance, electrolyte correction, fever reduction
• Zero lethal events; mean 7.5±4.3 years follow-up

LCSD Monotherapy — 60 patients (5%)

• 42 (70%) LQT1, 18 (30%) LQT2; mean QTc 465±28 ms
• Primary indication: BB intolerance (90% of patients)
• Only 3 patients (5%) experienced a non-lethal post-LCSD BCE; zero lethal events
• Data from specialised centres suggest LCSD monotherapy is safe and effective for select low-risk patients

ICD Delivery Principles

• ICD configuration (transvenous vs SQ-ICD vs epicardial) decided through shared decision-making incorporating: LQTS subtype, age, athletic lifestyle, patient preference
• SQ-ICD: rarely used, especially in LQT2 (T-wave oversensing risk)
• Epicardial ICD: used for athletes in high-velocity collision sports
• ICD never provided as a "sports-enabling" intervention; implantation based solely on phenotypic risk
• ~24% of patients with ICD received at least one appropriate VF-terminating therapy

Overall Programme Outcomes

• LQTS-associated mortality: 0.3% (4 deaths) over 20+ years
• Annual BCE rate: 1.2%
• 4 cardiac transplants (all LQT3)
• Lethal event rate = zero in intentional nontherapy and LCSD-monotherapy groups

High-Risk Genetic Variants Observed

• LQT1: compound heterozygous p.Val524Gly-KCNQ1 + p.Leu191fs[*]90-KCNQ1 → required most aggressive therapy
• LQT2: pore-localising variants p.Asn633Ser-KCNH2 and p.Gly604Ser-KCNH2 → most aggressive therapy
• LQT3: transplant variants p.Arg1623Gln-SCN5A, p.Phe1486Leu-SCN5A, p.Leu618Phe-SCN5A; two also carry MEPPC overlap

Limitations of the document

• Single quaternary referral centre (Mayo Clinic) — highly selected, not representative of average LQTS patient; outcomes may not generalise
• Only LQT1/2/3 included; minor subtypes (~5% of LQTS) excluded
• Retrospective design; treatment was not randomised
• Some therapies (mexiletine, nadolol) have limited availability in Europe — further limits generalisability
• Follow-up duration varies by patient and therapy escalation timing

Key Concepts Mentioned

• concepts/Left-Cardiac-Sympathetic-Denervation — LCSD monotherapy outcomes for BB-intolerant low-risk patients
• concepts/Precision-Medicine-LQTS — core thesis: 20+ distinct configurations required; no one-size-fits-all

Key Entities Mentioned

• entities/Long-QT-Syndrome — comprehensive precision treatment data for LQT1/2/3
• entities/SCN5A — LQT3 specific management; propranolol INaLate blockade; transplant variants
• entities/KCNQ1 — LQT1 treatment spectrum; compound heterozygous high-risk variants
• entities/KCNH2 — LQT2 treatment including IPAP and mexiletine off-label; SQ-ICD caution

Wiki Pages Updated

• wiki/sources/precision-lqts-tcm-2024.md (created)
• wiki/entities/Long-QT-Syndrome.md (updated — precision therapy section added under Management)
• wiki/concepts/Left-Cardiac-Sympathetic-Denervation.md (updated — LCSD monotherapy outcomes added)
• wiki/sourceindex.md (updated)