Estudo caso-controle para avaliar influência autonômica na bradicardia dos pacientes com a mutação R302Q no gene PRKAG2

Abstract

Background: It has been shown that bradycardia in the mutant murine model with ɣ2- AMPK mutation is caused by sinus node remodeling. We aim to assess the autonomic nervous system (ANS) phenotype in a cohort of carriers of R302Q PRKAG2 gene mutation and to assess its role in the sinus bradycardia occurring in PRKAG2 cardiomyopathy. Methods: This case-control cross-sectional study included twenty-seven individuals from five families, carriers of ɣ2 subunit PRKAG2 mutation and 27 relatives without the mutation, matched by sex and age as a control group, who underwent ANS evaluation by means of heart rate (HR) variability assessment using time and frequency domain parameters during 10 minutes supine resting and 24-hour Holter, resting and post phenylephrine baroreflex sensitivity, Valvalsa and respiratory maneuvers, Handgrip, head-up tilt table testing, basal and post orthostatism serum epinephrine, norepinephrine, and dopamine, serum NTproBNP, and pharmacologic dual autonomic blockade with atropine and propranolol (we classified in 3 types of response, 1 being normal, 2 with mildly abnormal intrinsic HR, 3 with severely abnormal intrinsic HR plus no response to atropine). Results: Control and PRKAG2 Groups had 55.6% females and similar age (36.3+14 vs 36.8+14.6 years, p=0.8). Holter HRV parameters were significantly higher in PRKAG2 group, particularly SDNN, SDRR and RMSSD and Total Power, as well as higher incidence of frequent atrial ectopy (7.4% vs 48.1%, p= 0.016). Systolic BP during Valsalva phase1 was higher among PRKAG2 subjects (124.80±13.72 vs 133.59±15.28, p=0.031). Results from baroreflex sensitivity, Valsalva and respiratory maneuvers, Handgrip, head-up tilt table testing did not differ among study Groups. Total peripheral resistance (TPRI) group was higher in PRKAG2 subjects at rest (3.406.77+1309.59 dyn.sec.cm-5 ; p< 0.0001) as well as after phenylephrine bolus (5717.19 + 2231.52 vs 3569.30 + 1292.32 dyn.sec.cm-5 ; p< .0001). PRKAG2 subjects had a slower HR at rest (52.2+8.2 vs 64.4+14.5 beats/ min; p= 0.0006), after atropine (92.8+19 vs 116.7+18.2 beats/ min; p< 0.0001), and intrinsic HR (67.6+21.4 vs 95.7+13.5 beats/ min; p<0.0001). After 1 year of follow-up 3 type-2 patients (20%) (PRKAG2 Group) had a major cardiac event (1 sudden death and 2 pacemakers). Conclusions: The autonomic nervous system plays no role in the bradycardia associated with PRKAG2 cardiomyopathy. There is evidence in favor of a heightened sympathetic drive in PRKAG2 subjects, which could have an impact in the risk of sudden death. Type 2 response to pharmacologic ANS blockade predicted major arrhythmic events in one year.