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cardio.atrial_flutter.adult-congenital-heart-disease.v1PRODUCTION
cardio.atrial_flutter.adult-congenital-heart-disease.v1

Atrial flutter / IART in adult congenital heart disease (ACHD)

cardiologyacutechronicadult
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11/12 authored

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Detailed

IART in ACHD = scar-mediated macroreentry from congenital atriotomy + chamber dilation + chronic substrate. Distinct from typical CTI flutter: slow cycle length 250–350 ms, often 1:1 AV conduction, atypical morphology, lifelong substrate. ACHD center referral MANDATORY for sustained arrhythmia in Fontan, Mustard/Senning, repaired-cyanotic patients. Rate-only strategy INADEQUATE in failing systemic RV — rhythm control preferred.

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ACHD substrate + systemic ventricular morphology documented

Patient inputs (15)

ACHD patients live decades with congenital substrate; arrhythmias typically appear in 3rd–4th decade and accelerate; informs lifelong AC + AAD planning

Fontan vs Mustard/Senning vs repaired TOF vs repaired ASD/VSD/AVSD vs Ebstein vs cc-TGA — drives substrate, ablation approach, AC threshold, and systemic ventricular dysfunction risk

Systemic LV (most repaired ACHD) vs systemic RV (Mustard/Senning, cc-TGA) vs single ventricle (Fontan) — determines GDMT applicability and rate-vs-rhythm preference

Atrial rate vs ventricular rate (often 1:1 or 2:1 in ACHD); cycle length 250–350 ms common; 1:1 conduction at HR 200–250 with hemodynamic collapse mandates DCCV

Cyanotic ACHD baseline (SpO2 80–88% in unrepaired or palliated cyanotic lesions); acute drop signals tachycardia-mediated decompensation or pulmonary embolism

Prior IART episodes, AAD trials, ablation attempts inform recurrence risk and ablation candidacy; many ACHD patients have decades of arrhythmia history

IART morphology — slow cycle length, atypical wave morphology, often 1:1 AV conduction; baseline ECG comparison essential because ACHD baseline often abnormal (RBBB, RVH, axis deviation)

DOAC + AAD dosing; contrast for 3D mapping/ablation; many ACHD patients have CKD from chronic Fontan circulation or cyanotic-nephropathy

Amiodarone toxicity baseline (TFTs, LFTs, PFTs) — required pre-amiodarone load especially given decades of anticipated treatment in young ACHD patients

Cyanotic ACHD often have erythrocytosis (Hct 50–65%) — elevated thrombosis risk + relative anemia of cyanosis if Hct lower than expected; informs AC management

Systemic ventricular function (LV vs RV vs single), valve status, residual shunts, atrial chamber size, baseline saturations; ACHD-specific echo expertise often needed

Hemodynamic stability + 1:1 AV conduction risk in Mustard/Senning drives emergent DCCV decision; SBP <90 with rapid regular tachycardia → DCCV 200 J biphasic immediately

CHA2DS2-VASc undervalues ACHD-specific stroke risk; PACES/HRS 2014 (PMID 24681262) recommends AC for any sustained atrial arrhythmia in Fontan or cyanotic patients regardless of score

HAS-BLED + ACHD-specific bleed risk (cyanotic patients have qualitative platelet dysfunction; Fontan patients have hepatic congestion → coagulopathy)

TEE or cardiac MRI to exclude atrial thrombus pre-DCCV/ablation when AFL persistent >48h and AC not therapeutic ≥3 wk; ACHD-specific anatomy often requires cardiac MRI for chamber definition

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (6)

6 need judgement
  • informationallife_threateningachd_iart_with_1to1_av_conduction_in_mustard_or_senning_collapse
    IART with rapid 1:1 AV conduction (HR 200–250) in Mustard/Senning patient → sudden hemodynamic collapse → emergent synchronized DCCV 200 J biphasic now
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningachd_iart_in_failing_fontan_with_decompensation
    IART precipitates Fontan failure with low CO + congestion + protein-losing enteropathy worsening → emergent rhythm control + ACHD center + transplant team
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereachd_iart_recurrence_post_3d_mapping_ablation
    Recurrent IART within 12 months of 3D mapping ablation at ACHD center — common given complex circuits + ablation success only 50–70%
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereachd_iart_with_anticoag_bridging_during_pregnancy_or_surgery
    Periprocedural AC management for ACHD patient on lifelong AC during pregnancy, non-cardiac surgery, or repeat cardiac surgery — bleeding vs stroke tradeoff complex
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereachd_iart_with_amiodarone_toxicity_pulm_thyroid_or_lft
    New pulmonary infiltrates, thyroid dysfunction (hypo or hyper), or LFT elevation on amiodarone — switch AAD or accept AAD failure → re-ablation; matters more in young ACHD with decades of anticipated treatment
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderateachd_iart_with_sinus_node_dysfunction_post_mustard_senning
    Sinus node dysfunction post-Mustard/Senning (incidence 30–50%) limiting rate-control AAD use; pacemaker indicated before AAD escalation
    Trigger could not be auto-evaluated — needs clinician judgement.

Workflow calculators

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RISK_STRATIFICATIONrequiredDrives risk stratification
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Recommended regimen

IART in adult congenital heart disease — rhythm-control-preferred (rate-only inadequate in failing systemic RV) + universal AC (PACES/HRS 2014 override of CHA2DS2-VASc) + ACHD-center 3D electroanatomic mapping ablation pathway — ACC/AHA 2024 (Joglar PMID 38753446); PACES/HRS 2014 (Khairy PMID 24681262); 2018 ACC/AHA ACHD (Stout PMID 30121239); ESC 2020 ACHD (Baumgartner PMID 32860028)
axis: achd_iart_scar_mediated_pathway
Selected axis "IART in adult congenital heart disease — rhythm-control-preferred (rate-only inadequate in failing systemic RV) + universal AC (PACES/HRS 2014 override of CHA2DS2-VASc) + ACHD-center 3D electroanatomic mapping ablation pathway — ACC/AHA 2024 (Joglar PMID 38753446); PACES/HRS 2014 (Khairy PMID 24681262); 2018 ACC/AHA ACHD (Stout PMID 30121239); ESC 2020 ACHD (Baumgartner PMID 32860028)" by default fallback (first axis)
  • amiodarone
    first line
    class_III_AAD
    150 mg IV over 10 min then 1 mg/min × 6 h then 0.5 mg/min × 18 h; 200 mg PO daily maintenance; consider lower long-term dose (100 mg) given decades of anticipated use in young ACHD patients • IV/PO • load + daily
    triggers: achd_iart_with_systemic_ventricular_dysfunction, achd_iart_with_failing_fontan_or_systemic_RV, recurrent_iart_post_dccv, class_IC_aad_contraindicated
    Most efficacious AAD for ACHD IART with structural heart disease; class IC contraindicated per CAST (PMID 1900101); pulm/thyroid/LFT toxicity matters more in young ACHD patients with decades of anticipated treatment — ACC/AHA 2024 (PMID 38753446); PACES/HRS 2014 (PMID 24681262)
    rxcui 703
  • sotalol
    second line
    class_III_AAD_BB
    40 mg PO BID titrate to 80–160 mg BID per CrCl + QTc monitoring (REMS-equivalent inpatient initiation) • PO • BID
    triggers: amiodarone_intolerance_or_toxicity, rhythm_maintenance_with_BB_effect_desired, baseline_QTc_<440
    Alternative class III AAD with BB activity; CrCl-adjusted dosing; QTc monitoring mandatory; useful when amiodarone toxicity limits use — ACC/AHA 2024 (PMID 38753446)
    rxcui 7008
  • dofetilide
    second line
    class_III_AAD
    125–500 mcg PO BID per CrCl (REMS — inpatient initiation × 3 days minimum) • PO • BID
    triggers: amiodarone_and_sotalol_intolerance, rhythm_maintenance, baseline_QTc_<440, normal_systemic_ventricular_function
    Alternative to amiodarone/sotalol; dofetilide REMS — must be initiated inpatient with QTc + CrCl monitoring; less ventricular dysfunction risk than other class III — ACC/AHA 2024 (PMID 38753446)
    rxcui 49247
  • metoprolol
    add on
    beta_blocker_beta1_selective
    metoprolol succinate 12.5–25 mg PO daily titrate cautiously (target HR 70–90; LOWER than typical flutter due to systemic ventricular failure risk) • PO • daily
    triggers: achd_iart_for_HR_modulation_with_preserved_or_mildly_reduced_systemic_ventricular_function, no_failing_systemic_RV_or_failing_fontan
    CAUTIOUS rate control add-on; AVOID if failing systemic RV or failing Fontan (worsens forward flow); target HR 70–90 (lower than standard flutter target) — ACC/AHA 2024 (PMID 38753446); PACES/HRS 2014
    rxcui 6918
  • apixaban
    first line
    DOAC_factor_Xa
    5 mg BID (2.5 mg BID if 2 of: ≥80 yr, ≤60 kg, Cr ≥1.5) • PO • BID
    triggers: achd_iart_universal_AC_per_PACES_HRS_2014, pre_post_cardioversion, pre_post_ablation, mixed_AF_AFL_in_achd, fontan_or_cyanotic_substrate
    AC essentially universal in ACHD IART per PACES/HRS 2014 (PMID 24681262) — overrides CHA2DS2-VASc score; lifelong AC typical given lifelong substrate — ARISTOTLE (PMID 21870978); ACC/AHA 2024 Class I
    rxcui 1364430
  • warfarin
    first line
    vitamin_K_antagonist
    INR target 2–3 (or 2.5–3.5 in mechanical valve) • PO • daily
    triggers: mechanical_valve_post_repair, fontan_with_thrombosis_history, cyanotic_with_extreme_erythrocytosis, DOAC_contraindicated_or_severe_renal_impairment
    Warfarin often preferred in Fontan + complex cyanotic ACHD due to limited DOAC safety data in this population; mechanical-valve mandatory; ACC/AHA 2024 + PACES/HRS 2014
    rxcui 11289
  • unfractionated heparin
    rescue
    anticoagulant_indirect
    60 U/kg IV bolus then 12 U/kg/h to PTT 1.5–2× control (max 4000 U bolus) • IV • continuous
    triggers: pre_DCCV_AC_bridge, periprocedural_AC_for_ablation, AC_naive_with_acute_arrhythmia_>48h
    Bridge AC for acute arrhythmia management; transition to DOAC/warfarin per long-term plan — ACC/AHA 2024 + PACES/HRS 2014
    rxcui 5224

outpatient playbook — drug actions (2)

  1. 1. continue lifelong AC per PACES/HRS 2014 ACHD override
    rxcui 1364430
    apixaban 5 mg BID OR warfarin INR 2–3 (Fontan/cyanotic) • PO • BID or daily
    trigger: ACHD IART substrate is lifelong
    Lifelong AC — PACES/HRS 2014 (PMID 24681262); ACC/AHA 2024 Class I
  2. 2. continue amiodarone if ablation incomplete
    rxcui 703
    100–200 mg PO daily (consider lower long-term dose in young ACHD) • PO • daily
    trigger: AAD-dependent rhythm maintenance
    Lower recurrence than other AAD; lower dose long-term to limit toxicity — ACC/AHA 2024

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Sustained atrial tachycardia / IART in adult with prior Fontan palliation (single-ventricle physiology) — high-risk hemodynamic substrate; ACHD center referral mandatory; Sustained atrial tachycardia / IART in adult with prior Mustard or Senning atrial-switch repair for d-TGA — risk of 1:1 AV conduction and systemic RV failure; Sustained atrial tachycardia / IART in adult with repaired tetralogy of Fallot, ASD, VSD, AVSD, or other congenital lesion with atrial scar substrate.

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Atrial flutter / IART in adult congenital heart disease (ACHD)** (cardio.atrial_flutter.adult-congenital-heart-disease.v1).
Scope: IART in ACHD = scar-mediated macroreentry from congenital atriotomy + chamber dilation + chronic substrate. Distinct from typical CTI flutter: slow cycle length 250–350 ms, often 1:1 AV conduction, atypical morphology, lifelong substrate. ACHD center referral MANDATORY for sustained arrhythmia in Fontan, Mustard/Senning, repaired-cyanotic patients. Rate-only strategy INADEQUATE in failing systemic RV — rhythm control preferred.

No severity triggers fired against current inputs.

Plan

Regimen axis: **IART in adult congenital heart disease — rhythm-control-preferred (rate-only inadequate in failing systemic RV) + universal AC (PACES/HRS 2014 override of CHA2DS2-VASc) + ACHD-center 3D electroanatomic mapping ablation pathway — ACC/AHA 2024 (Joglar PMID 38753446); PACES/HRS 2014 (Khairy PMID 24681262); 2018 ACC/AHA ACHD (Stout PMID 30121239); ESC 2020 ACHD (Baumgartner PMID 32860028)**.
1. amiodarone 150 mg IV over 10 min then 1 mg/min × 6 h then 0.5 mg/min × 18 h; 200 mg PO daily maintenance; consider lower long-term dose (100 mg) given decades of anticipated use in young ACHD patients IV/PO load + daily (class_III_AAD, first line) — Most efficacious AAD for ACHD IART with structural heart disease; class IC contraindicated per CAST (PMID 1900101); pulm/thyroid/LFT toxicity matters more in young ACHD patients with decades of anticipated treatment — ACC/AHA 2024 (PMID 38753446); PACES/HRS 2014 (PMID 24681262)
2. sotalol 40 mg PO BID titrate to 80–160 mg BID per CrCl + QTc monitoring (REMS-equivalent inpatient initiation) PO BID (class_III_AAD_BB, second line) — Alternative class III AAD with BB activity; CrCl-adjusted dosing; QTc monitoring mandatory; useful when amiodarone toxicity limits use — ACC/AHA 2024 (PMID 38753446)
3. dofetilide 125–500 mcg PO BID per CrCl (REMS — inpatient initiation × 3 days minimum) PO BID (class_III_AAD, second line) — Alternative to amiodarone/sotalol; dofetilide REMS — must be initiated inpatient with QTc + CrCl monitoring; less ventricular dysfunction risk than other class III — ACC/AHA 2024 (PMID 38753446)
4. metoprolol metoprolol succinate 12.5–25 mg PO daily titrate cautiously (target HR 70–90; LOWER than typical flutter due to systemic ventricular failure risk) PO daily (beta_blocker_beta1_selective, add on) — CAUTIOUS rate control add-on; AVOID if failing systemic RV or failing Fontan (worsens forward flow); target HR 70–90 (lower than standard flutter target) — ACC/AHA 2024 (PMID 38753446); PACES/HRS 2014
5. apixaban 5 mg BID (2.5 mg BID if 2 of: ≥80 yr, ≤60 kg, Cr ≥1.5) PO BID (DOAC_factor_Xa, first line) — AC essentially universal in ACHD IART per PACES/HRS 2014 (PMID 24681262) — overrides CHA2DS2-VASc score; lifelong AC typical given lifelong substrate — ARISTOTLE (PMID 21870978); ACC/AHA 2024 Class I
6. warfarin INR target 2–3 (or 2.5–3.5 in mechanical valve) PO daily (vitamin_K_antagonist, first line) — Warfarin often preferred in Fontan + complex cyanotic ACHD due to limited DOAC safety data in this population; mechanical-valve mandatory; ACC/AHA 2024 + PACES/HRS 2014
7. unfractionated heparin 60 U/kg IV bolus then 12 U/kg/h to PTT 1.5–2× control (max 4000 U bolus) IV continuous (anticoagulant_indirect, rescue) — Bridge AC for acute arrhythmia management; transition to DOAC/warfarin per long-term plan — ACC/AHA 2024 + PACES/HRS 2014

Setting playbook (outpatient) — Long-term ACHD-center surveillance: lifelong AC (PACES/HRS 2014 override), AAD continuation if ablation incomplete, recurrence + concomitant-AF screening, systemic ventricular function surveillance, Fontan-failure surveillance, pregnancy counseling, transplant evaluation if disease progression — ACC/AHA 2024 (PMID 38753446); PACES/HRS 2014 (PMID 24681262); Stout PMID 30121239
8. continue lifelong AC per PACES/HRS 2014 ACHD override apixaban 5 mg BID OR warfarin INR 2–3 (Fontan/cyanotic) PO BID or daily — ACHD IART substrate is lifelong (Lifelong AC — PACES/HRS 2014 (PMID 24681262); ACC/AHA 2024 Class I)
9. continue amiodarone if ablation incomplete 100–200 mg PO daily (consider lower long-term dose in young ACHD) PO daily — AAD-dependent rhythm maintenance (Lower recurrence than other AAD; lower dose long-term to limit toxicity — ACC/AHA 2024)

Non-pharmacologic actions:
- ACHD-specific lifestyle: exercise prescription with ACHD experience, weight management, alcohol limit
- Vaccinations + secondary prevention bundle (ACC/AHA 2024)
- Annual ACHD-center EP review for repeat ablation consideration if recurrence
- Pregnancy counseling: very high-risk in ACHD with IART + AC; multidisciplinary high-risk obstetric + ACHD cardiology team mandatory if pregnancy desired
- Transplant evaluation if Fontan failure or systemic RV failure progresses
- Mental-health continuity care

AVOID / contraindication checks:
- Flecainide_propafenone_CONTRAINDICATED_in_systemic_ventricular_dysfunction_or_complex_congenital_substrate (CAST PMID 1900101; PACES/HRS 2014)
- Non_DHP_CCB_avoid_EF_below_40_common_in_failing_fontan_or_systemic_RV (ACC/AHA 2024)
- Dofetilide_REMS_inpatient_initiation_minimum_3_days_with_QTc_monitoring (ACC/AHA 2024)
- Sotalol_REMS_equivalent_inpatient_initiation_with_QTc_monitoring (FDA label)
- Amiodarone_monitor_pulm_thyroid_LFT_PFTs_baseline_then_q6m_lifelong (ACC/AHA 2024)
- Rate_only_strategy_INADEQUATE_in_failing_systemic_RV_or_failing_fontan_use_rhythm_control (PACES/HRS 2014 PMID 24681262)
- DOAC_limited_safety_data_in_fontan_or_complex_cyanotic_ACHD_warfarin_often_preferred (PACES/HRS 2014)
- Ablation_at_ACHD_center_only_with_3D_electroanatomic_mapping_capability (Stout PMID 30121239; PACES/HRS 2014)

Monitoring

Regimen monitoring:
- telemetry continuous acute with baseline ACHD ECG for comparison (ACC/AHA 2024)
- HR target 70-90 LOWER than standard flutter due to systemic ventricular failure risk (PACES/HRS 2014)
- QTc serial dofetilide sotalol amiodarone (FDA label)
- PFTs TFTs LFTs baseline then q6m lifelong on amiodarone (ACC/AHA 2024 — matters more in young ACHD)
- lifelong AC essentially universal per PACES HRS 2014 override (PACES/HRS 2014 PMID 24681262)
- systemic ventricular function surveillance q6m via TTE (Stout PMID 30121239)
- sinus node function assessment post Mustard or Senning for pacemaker indication (PACES/HRS 2014)
- cyanotic erythrocytosis Hct and hyperviscosity symptoms (Stout PMID 30121239)
- fontan failure surveillance BNP LFTs protein loss q6m (Stout PMID 30121239)

Setting (outpatient) monitoring:
- ACHD-center cardiology q3–6 mo lifelong (Stout PMID 30121239)
- Holter at 3, 6, 12 mo post-ablation then annually (Aliot PMID 19324313)
- Annual TFTs / LFTs / PFTs on amiodarone (ACC/AHA 2024)
- CBC + eGFR q6m on DOAC (ESC 2024)
- INR weekly if warfarin until stable then monthly
- Annual TTE with systemic ventricular function
- Annual Fontan-failure surveillance if applicable

Follow-up plan: ACHD-center cardiology q3–6 mo; AC continuation indefinite (lifelong); post-ablation 4-week ECG + Holter at 3/6/12 mo for IART/AF screen; pacemaker interrogation if applicable; systemic ventricular function surveillance; pregnancy counseling (high-risk in ACHD with arrhythmia + AC); cardiac rehab (ACHD-specific protocol); mental-health support (chronic-disease anxiety high in ACHD)
- Close-out criterion: lifelong follow-up booked at ACHD center + AC + AAD plan documented

Monitoring phase: Telemetry continuous; QTc on amiodarone / sotalol; post-ablation observation for groin hematoma, tamponade, AV block (more common in ACHD ablation), atrioesophageal fistula (rare with right-sided ACHD ablation); AC adherence; cyanotic erythrocytosis monitoring; Fontan-failure surveillance

Disposition

Current setting: outpatient — Long-term ACHD-center surveillance: lifelong AC (PACES/HRS 2014 override), AAD continuation if ablation incomplete, recurrence + concomitant-AF screening, systemic ventricular function surveillance, Fontan-failure surveillance, pregnancy counseling, transplant evaluation if disease progression — ACC/AHA 2024 (PMID 38753446); PACES/HRS 2014 (PMID 24681262); Stout PMID 30121239

Disposition criteria:
- Continue lifelong ACHD-center surveillance with this engine; cross-link to cardio.afib.core.v1 if AF predominant; cross-link to cardio.hf.core.v1 if systemic ventricular failure

Escalation triggers (move to higher acuity):
- Recurrent IART despite ablation → repeat 3D EP mapping at ACHD center (Aliot PMID 19324313)
- New AF detected → AF management via cardio.afib.core.v1 with ACHD modifiers
- Amiodarone toxicity (pulm fibrosis, thyroid, LFT) → switch to sotalol or dofetilide; re-ablation consideration — ACC/AHA 2024
- Stroke / TIA on AC → workup + reassess regimen; consider antiphospholipid screen — ACC/AHA 2024
- Failing Fontan or systemic RV → transplant team
- Pregnancy detected → STAT high-risk obstetric + ACHD cardiology consult

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] IART with rapid 1:1 AV conduction (HR 200–250) in Mustard/Senning patient → sudden hemodynamic collapse → emergent synchronized DCCV 200 J biphasic now
- [LIFE_THREATENING] IART precipitates Fontan failure with low CO + congestion + protein-losing enteropathy worsening → emergent rhythm control + ACHD center + transplant team
- [SEVERE] Recurrent IART within 12 months of 3D mapping ablation at ACHD center — common given complex circuits + ablation success only 50–70%

Citations

- 2024 ACC/AHA/ACCP/HRS AF + AFL Joint Guideline ACHD subsection (Joglar Circulation 2024 PMID 38753446); 2018 ACC/AHA ACHD Management Guideline (Stout Circulation 2018 PMID 30121239); PACES/HRS 2014 Expert Consensus on Recognition and Management of Arrhythmias in ACHD (Khairy Heart Rhythm 2014 PMID 24681262); 2020 ESC Adult Congenital Heart Disease Guideline (Baumgartner EHJ 2021 PMID 32860028) [PMID:38753446](https://pubmed.ncbi.nlm.nih.gov/38753446/)
- Cited evidence (PMID 30121239) [PMID:30121239](https://pubmed.ncbi.nlm.nih.gov/30121239/)
- Cited evidence (PMID 24681262) [PMID:24681262](https://pubmed.ncbi.nlm.nih.gov/24681262/)
- Cited evidence (PMID 25051961) [PMID:25051961](https://pubmed.ncbi.nlm.nih.gov/25051961/)
- Cited evidence (PMID 32860028) [PMID:32860028](https://pubmed.ncbi.nlm.nih.gov/32860028/)

Last reconciled with current guidelines: 2026-05-15.
References
  • 2024 ACC/AHA/ACCP/HRS AF + AFL Joint Guideline ACHD subsection (Joglar Circulation 2024 PMID 38753446); 2018 ACC/AHA ACHD Management Guideline (Stout Circulation 2018 PMID 30121239); PACES/HRS 2014 Expert Consensus on Recognition and Management of Arrhythmias in ACHD (Khairy Heart Rhythm 2014 PMID 24681262); 2020 ESC Adult Congenital Heart Disease Guideline (Baumgartner EHJ 2021 PMID 32860028) — PMID:38753446
  • Cited evidence (PMID 30121239) — PMID:30121239
  • Cited evidence (PMID 24681262) — PMID:24681262
  • Cited evidence (PMID 25051961) — PMID:25051961
  • Cited evidence (PMID 32860028) — PMID:32860028