Association of Arg16Gly Polymorphism of the Beta-2 Adrenergic receptor with Baroreflex Sensitivity and Indices of Autonomic Cardiovascular Modulation

Transcription

1 Association of Arg16Gly Polymorphism of the Beta-2 Adrenergic receptor with Baroreflex Sensitivity and Indices of Autonomic Cardiovascular Modulation Ochoa JE 1,2, Correa M 1,5, Gallo J 3,5, McEwen J 1,3, Bilo G 4, Aristizabal D 1,5, Parati G 2,4 1. Cellular and Molecular Biology Unit, Corporación para Investigaciones Biológicas, Medellín, Colombia. 2. Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Milan, Italy. 3. School of Medicine, University of Antioquia, Medellín-Colombia. 4. Department of Cardiology, S. Luca Hospital, Istituto Auxologico Italiano, Milan, Italy. 5. Department of Preventive Cardiology, Clínica Medellín, Medellín, Colombia.

2 The β-adrenergic receptor: First element in the signal transduction chain mediating the response of the heart to adrenergic stimulation. Both, B1 and B2 subtypes of the β-adr are present in the heart

3 β2-adrenergic receptor: Presynaptically: - sympathetic nerve terminals - cardiac NE release. Postsynaptically - myocardium: HR and contractility - vascular smooth muscle: relaxation β2 β2

4 Functional effects of polymorphism Arg 16Gly

5 Functional effects of polymorphism Arg 16Gly Reduced expression and down-regulation of the B2ADR Reduced response to sympathetic agonists Influences the pathogenesis of hypertension and other CVD. Limited information on the effects of Arg 16Gly on ANS function, as reflected in autonomic indices derived from the analysis of BRS and HRV.

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7 Assess the possible effects of Arg16Gly polymorphism on indices of cardiac autonomic modulation derived from the time and frequency domain analysis of BRS and HRV.

8 Methods

9 Frequency (number of individuals) DBP distribution curve (n=800) Individuals at or above 70 th percentile (DBP 85 mmhg). Not on antihypertensive medication A total of 92 individuals were included Diastolic BP (mmhg)

10 Genotyping 1. Selection of a 450 bp DNA fragment of the ADRB2 gene containing 5 SNP of interest 2. PCR amplification 3. Direct sequencing

11 Autonomic and hemodynamic assessment Task Force Monitor CNSystems

12 Beat-to-beat monitoring of BP, ECG and SV

13 Supine Study Protocol Individual stands up Standing Intervention time (min)

14 Time domain analysis of HRV RRI (ms) SD RRI (ms) NN50 (count) pnn50 (%) RMSSD RRI (ms)

15 Frequency domain analysis of HRV (Spectral technique, Parati G et al 1995) LF, HF and RRI total power (PSD) (ms 2 ) LF and HF (%) LF/HF ratio

16 Time Domain analysis of BRS: The sequence method Up Sequence Down Sequence up-sequences (Up-BRS) down-sequences (Down-BRS) up+down-sequences (BRS) Parati et al 1988

17 Frequency domain analysis of BRS (Alpha Coefficient) LF HF RRI spectrum Frequency regions where PI and SBP powers are coherent (>0.5) SBP spectrum Pagani M et al 1988 Parati G et al. 1993

18 Autonomic Parameters HRV (time domain) Indirect Indices of Sympathetic cardiac modulation Indirect Indices of Parasympathetic cardiac modulation SDRRI RMSSD NN50 pnn50 HRV (frequency domain) LF (mostly upright ) LF/HF HF LF BRS (time domain) BRS (frequency domain) alpha-lf alpha-hf alpha-lf Sequence up slope Sequence down slope Sequence Total slope

19 Results

20 Genotypic Distribution of Arg16Gly Polymorphism n=800 HWE=p>0.05 Allelic Frequency: A(50%), G (50%) n=92 HWE:p>0.05 Allelic Frequency: A(53%), G (47%)

21 Clinical characteristics of study participants by Arg16Gly genotype Variable Arg/Arg (n=31) Arg/Gly (n=37) Gly/Gly (n=24) P value Age (years) 50.3 ± ± ± Weight (Kg) 68.0 ± ± ± BMI 26.5 ± ± ± Sex (M/F) 12/17 22/15 14/ Smokers (%) 4/31 (13%) 8/37 (21%) 4/24 (16%) 0.82 SBP (mmhg) ± ± ± DBP (mmhg) 86.8 ± ± ± HR (bpm) 73.0 ± ± ±

22 Time-domain indices of HRV (Supine) P= 0,001 P= 0,0001 P= 0,003 P= 0,009

23 Frequency-domain indices of HRV (Supine) P= 0,001 P= 0,001 P= 0,001

24 Time domain indices of BRS (Supine) P= 0,001 P= 0,01 P= 0,002

25 Frequency-domain indices of BRS (Supine) P= 0,006* P= 0,34* *Arg/Arg vs. Gly/Gly

26 Changes in cardiac autonomic modulation from supine to standing GG subjects displayed a significant reduction in ALL HRV and BRS indices on shifting from supine to standing While AA subjects showed little or no change, indicating a blunted postural modulation of HRV and BRS indices

27 Conclusions 1 Based on HRV and BRS analysis, subjects with high normal or elevated BP who carry Arg16 allele are characterized by : - A significantly enhanced cardiac sympathetic modulation. - A significantly reduced cardiac parasympathetic modulation.

28 Conclusions 2 These results indicate that Arg16Gly polymorphism may be involved in the modulation of cardiac baroreflex and HRV in humans. Further studies on a larger number of subjects are needed to confirm these findings, also considering different populations.

29 Thanks