9/12/2019 Wichter et al ARVD Therapy 1. Beta blockers (Sotalol) - - PDF document

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• 1. Beta blockers (Sotalol)
• 2. Amiodarone
• 3. Catheter ablation
• 4. AICD

M S

ARVD Therapy

Treatment for patients with ARVC

• Early drug trials involved small groups with different follow up periods
• Cohorts were inhomogeneous and involved those with sustained and

unsustained VT

• Wichter et al used serial EP testing in 81 pts with ARVC and

“established” the efficacy of Sotalol (320‐480)for these patients

Wichter et al

Marcus et al report from ARVC registry JACC 54:609 2010

• 95 pts with well documented ARVC were treated with drugs at the

discretion of the treating physician and followed for 1.3 years

• Sotalol was used in 38 pts and beta‐blockers in 58 separate pts. Amio

was used in 10

• Results Sotalol (in doses of 160‐320)were equivalent to beta‐blockers

in efficacy while Amiodarone proved most effective

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Combination therapy for treatment of VT in ARVC

• 8 patients with recurrent refractory sustained

VT were treated with Flecainide ( 50‐150 mg bid)

• All failed single drug therapy with beta

blockers,Sotalol or Amiodarone

• 4 failed prior Endocardial ablation
• 3 failed prior epi/endocardial ablation
• 6/8 were arrhythmia free for a mean follow up
• f 35.5 months.

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Shinkel metanalyses of ICD in pts with ARVC (Circ A&E 2013)

• Included 610 pts from 18 studies for pts with ARVC for primary or

secondary prevention

• After 3.8 years annualized cardiac mortality was 0.9% and transplant

rate was 0.9%

• Annualized Inappropriate ICD interventions was 3.7%,ICD related

complications include difficult lead placement 18.4%,lead malfunction 9.8% or displacement 1.4%

Treatment?

• No known pharmacotherapy to slow progression of RV dysfunction in

human

Heart Rhythm Society 2019

Decongestant Therapy and Progression of Right Ventricular Structural

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Background

• Preload reducing agents (nitrates + diuretics) has shown promising

results in preventing training‐induced development of ARVC in a murine model.

• We hypothesize that preload reducing therapy in patients with ARVC

will slow progression of RV failure.

• One of the main predictors of RVEF on CMR was found to be RV

Global Longitudinal Strain (RVGLS) on TTE

Heart Rhythm Society 2019 Shadi Kalantarian, MD, MPH

Method

• Design: Single center study (University of California San Francisco) of patients meeting

2010 Revised Task Force Criteria for ARVC.

• Inclusion Criteria: Patients with ARVC in arrhythmia phase or with symptomatic RV

dysfunction.

• Intervention:

 ISDN 10‐40 mg TID (at maximum tolerated dose) and  hydrochlorothiazide‐spironolactone 25‐25 mg daily

• Data Collection: Retrospective chart review was performed for clinical information such

as age at the time of treatment, anti‐arrhythmic treatment, genetic testing and presence

• f an ICD; history of VT classified as VT self‐terminated VT and VT requiring treatment

(i.e. anti‐tachycardia pacing or defibrillation).

Heart Rhythm Society 2019 Shadi Kalantarian, MD, MPH

Method‐Data Collection

• All subjects underwent conventional M‐mode, 2‐D and color Doppler imaging using commercially available

(Vivid 5 or 7 GE Healthcare and Philips) ultrasound systems.

• Offline analysis was performed using Syngo (Philips). Measurements including

 RVOT in parasternal long axis (PLAX)  Proximal RVOT diameter in short axis (PSAX),  RV‐end diastolic area (RVEDA),  fractional area change (FAC),  tricuspid annular plane systolic excursion (TAPSE)

were performed in accordance with American Society of Echocardiography guidelines. All measurements were performed by one physician.

• An independent experienced research sonographer blinded to treatment date performed strain analysis

twice on all available echocardiograms.

• Statistical analysis performed using paired t‐test.

Heart Rhythm Society 2019 Heart Rhythm Society 2019 Shadi Kalantarian, MD, MPH

2010 Revised Task Force Major Echo criteria

PLAX RVOT ≥32 mm PLAX/BSA ≥19 mm/m2 PSAX RVOT ≥36 mm PSAX/BSA ≥21 mm/m2 Fractional Area Change (FAC) ≤33 % (RVEDA‐RVESA) X100 RVEDA

RVEDA RVESA

FAC=

Heart Rhythm Society 2019 Shadi Kalantarian, MD, MPH

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RVGLS on TTE vs. RVEF on MRI

RVGLS is an independent predictor of RV function and RVEF on cardiac MR

Heart Rhythm Society 2019 Shadi Kalantarian, MD, MPH

Effect of Preload Reducing Therapy on RV Function in Patients with ARVC

Normal reference At baseline, mean (SD) On last follow up*on Treatment, mean (SD) p‐value** RVGLS, % >‐20% ‐14.76 (3.8) ‐14.71 (4.57) 0.98 RVEDA, cm2 11‐28 38.81 (9.4) 38.03(8.37) 0.79 RVOT PLAX, cm <3.2 4.54(1.42) 4.92(0.78) 0.39 RVOT PSAX, cm <3.6 4.56(0.78) 4.7(0.78) 0.62 RVFAC, % >32% 25.01 (5.44) 21.45(8.21) 0.26 LVEF, % >55% 61.50 (6.6) 60.33(5.54) 0.76 * Last follow up average 2.24 years (range 0.56‐5.36) ** p-value reported from two-tailed paired t-testRVGLS: RV systolic global longitudinal strain; RVFAC: RV fractional area change; RVEDA: RV end diastolic area; LVEF: LV ejection fraction; PLAX: RVOT in parasternal long axis ;PSAX: Proximal RVOT diameter in short axis.

Heart Rhythm Society 2019 Shadi Kalantarian, MD, MPH

Progression of RV dysfunction in a registry of ARVC patients

• A total of 73 patients were enrolled: 33 (45%) at UCSF and 40 (55%) at

University of Linkoping.

• The average age was 39 ± 14 years old and 56% were men.
• Each subject had a median of 3 serial ECGs and TTEs (range 2‐11

studies) available for analysis over a median follow‐up of 5.9 (IQR 3.5‐ 9.7) years .

• Genetic testing identified known pathogenic mutations in 48.0%

(n=35) of the cohort with plakophilin‐2 (PKP2) gene most commonly affected followed by desmoplakin (DSP), Desmoglein‐2 (DSG) and titin (TTN)

Heart Rhythm Society 2019 Shadi Kalantarian, MD, MPH

Echocardiographic changes in ARVC Registry

Heart Rhythm Society 2019 Shadi Kalantarian, MD, MPH

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Conclusion

• Preload reducing agents show promising results in slowing RV

enlargement and stabilizing RV function in patients with ARVC.

• To our knowledge this is the first therapy that is showing possible

disease modifying potential.

Heart Rhythm Society 2019 Shadi Kalantarian, MD, MPH