Neural Control of Heart Rate Is an Arrhythmia Risk Modifier in Long QT Syndrome
Peter J. Schwartz, MD, FACC*, , ,||,**,,*,
Emilio Vanoli, MD*,¶,
Lia Crotti, MD, PhD*,,,
Carla Spazzolini, DVM*,
Chiara Ferrandi, BSc,
Althea Goosen, BSc**,
Paula Hedley, MSc,
Marshall Heradien, MD**,
Sara Bacchini, MD*,,
Annalisa Turco, MD*,,
Maria Teresa La Rovere, MD#,
Antonella Bartoli, PharmD ,
Alfred L. George, Jr, MD and
Paul A. Brink, MD**
* Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia, Pavia, Italy
Department of Cardiology, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
Molecular Cardiology Laboratory, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
Clinical Pharmacokinetics Laboratory, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
|| Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico, Milan, Italy
¶ Department of Cardiology, Policlinico di Monza, Monza, Italy
# Centro Medico di Montescano, IRCCS Fondazione "Salvatore Maugeri," Montescano, Italy
** Department of Medicine, University of Stellenbosch, Stellenbosch, South Africa
Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, University of Cape Town, Cape Town, South Africa
US/MRC Centre for Molecular and Cellular Biology, University of Stellenbosch, Stellenbosch, South Africa
Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee.
View larger version (9K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Study Population and Outline of the Study
Flow chart of the study population showing the number of subjects, divided in subgroups by genetic status, considered in the different analyses performed on and off beta-adrenergic blockers (BBs). For the study on BB, the number of subjects was limited to those with both measurements—on- and off-treatment—available, allowing for paired comparisons. BRS = baroreflex sensitivity; HR = heart rate; MC = mutation carriers; N.M.C. = nonmutation carriers; SA = South African; WO = Wash-Out.
|
|
View larger version (14K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2 Heart Rate Values
Comparison of resting heart rate mean values off BB therapy between mutation carriers (MCs) and non-MCs (A) and between asymptomatic and symptomatic MCs (B). bpm = beats/min; other abbreviations as in Figure 1.
|
|
View larger version (8K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3 Differential Risk for Arrhythmic Events According to Resting HR
Differential risk for arrhythmic events among MCs according to resting heart rate (HR) off BB and QTc. The dashed horizontal line represents the predefined cut-off for QTc ( or >500 ms), whereas the dashed vertical line corresponds to the first tertile (60 beats/min) of the HR values distribution. Among the 56 mutation carriers included in the analysis of resting HR in the absence of BB, 1 symptomatic patient had a nonmeasurable QTc because of right bundle branch block. QTc = QT interval corrected for heart rate; other abbreviations as in Figures 1 and 2.
|
|
View larger version (11K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4 BRS Values
BRS values off-BB in the entire group under study ages 26 to 47 years (A), in MCs and in non-MCs (B), and in symptomatic and asymptomatic MCs (C). Mean and SD are shown for each subgroup. The dashed horizontal line represents the lower tertile of BRS values. CI = confidence interval; other abbreviations as in Figures 1 and 2.
|
|
View larger version (9K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 6 Impact on Arrhythmic Risk of HR and BRS
The BRS and resting HR off BB in the entire group ages 26 to 47 years. Differential probability of being symptomatic among MCs according to the combination of both BRS and HR values below or above the predefined cut-off. The gray quadrant represents the distribution of symptomatic and asymptomatic patients with relatively lower BRS (12 ms/mm Hg) and HR (60 beats/min) values in comparison with the other permutations of the 2 autonomic markers. The percentage of symptomatic MCs increases from 20% to 87.5%. Abbreviations as in Figures 1 and 2.
|
|
View larger version (8K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 7 BRS Values in MCs and Non-MCs According to Presence of ADRA2C-Del322-325 and ADRB1-G389
The BRS values in MCs and non-MCs ages 26 to 47 years. Groups A, B, and C: subjects without ADRA2C-Del322-325. Group A: subjects homozygous for ADRB1-G389. Group B: subjects heterozygous for ADRB1-G389R. Group C: subjects homozygous for ADRB1-R389. Group D: subjects with ADRA2C-Del322-325 (2 also heterozygous and 3 also homozygous for ADRB1-R389). Abbreviations as in Figures 1 and 2.
|
|
View larger version (8K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 8 BRS Values in MCs and Non-MCs According to the Presence or Absence of Adrenergic Polymorphisms
The BRS values off-BB in subjects ages 26 to 47 years (MCs and non-MCs), according to the specific genotype. Group 1: subjects with the ADRA2C-Del322-325 and subjects homozygous for ADRB1-R389, polymorphisms resulting in increased adrenergic responses. Group 2: subjects without ADRA2C-Del322-325 and not homozygous for the ADRB1-R389 allele. The solid horizontal line represents the upper tertile of BRS values. Abbreviations as in Figures 1 and 2.
|
|
|
