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Genetic Risk Scoring in a Young Myocardial Infarction (MI) Population
Abstracts
S283
Results: Long-term beta blockers were prescribed to 74 patients (82%). Side effects were intolerable in 6 (8%) and beta blockers were stopped. MPR was calculated in the remaining 68 patients over 151.7 patient years of follow-up. Median MPR was 0.79 (range 0-1.3). Suboptimal adherence (MPR<0.8) was recorded in 35 (51%). Seven patients (10%) never took up a prescription (MPR=0). Adequate adherence was present in 33 (49%), including 9 (13%) who had ideal adherence. Age, sex, clinical presentation, family history of sudden death, ethnicity and deprivation index did not predict adherence. Conclusion: Beta blocker adherence was suboptimal in half our patients with LQTS types 1 and 2. Risk factors for nonadherence could not be identified. Further research into betablocker adherence is vital in this high risk population. http://dx.doi.org/10.1016/j.hlc.2016.06.662 661 Comparative Rates of Dilatation in Genetic Aortopathies S. Krishnan ∗ , R. Jeremy University of Sydney, Sydney, Australia Aim: Long-term (>10 years) data on aortic dilatation rates in genetic aortopathy are required for clinical trial design but are not yet available. This study measured aortic geometry in Marfan (MFS), Bicuspid Aortic Valve (BAV) and Familial Thoracic Aortic Aneurysm and Dissection (TAAD) across decades of life. Methods: Prospective registry over 25 years with 2D echo measurements of aortic diameter. Data comparison by ANOVA. Results: Aortic diameter by decade was similar for MFS, BAV and TAAD (Table 1). Table 1.
Aortic Diameter, mm (n) mean±SD 2nd
3rd
4th
5th
6th
decade
decade
decade
decade
decade
............................................. MFS
(85) (105) (67) (43) (25) 36.9±5.9 41.2±6.0** 42.3±7.1** 43.1±6.4** 43.4±3.6**
BAV
(8) (32) (44) (47) (53) 32.8±6.4 39.7±5.4* 41.7±4.7** 43.1±6.0** 43.8±5.8**
TAAD
(11) (29) 36.3±6.3 38.9±4.8
(36) (49) (62) 41.5±6.4* 43.2±6.3** 44.1±4.4**
* = p<0.05, ** = p<0.01 vs. 2nd decade
Overall rate of dilatation decreased with age (trend p=0.03). However, there was considerable variability within each aortopathy group (Table 2),
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
Table 2.
Change in Aortic Diameter, mm (n) mean±SD Decade 2 to 3
Decade 3 to 4
Decade 4 to 5
Decade 5 to 6
............................................. (64) 4.0 ± 4.0
(38) 4.1 ± 3.9
(20) 2.8 ± 2.3
(13) 2.1 ± 2.0
BAV
(6) 5.7 ± 9.2
(16) 3.2 ± 4.3
(13) 2.7 ± 2.7
(19) 1.8 ± 3.4
TAAD
(6) 3.4 ± 2.3
(12) 2.1 ± 1.5
(12) 1.3 ± 3.2
(22) 1.5 ± 1.7
MFS
Conclusion: Long-term aortic dilatation rates vary with age and aortopathy type; these data can inform future clinical trial design. http://dx.doi.org/10.1016/j.hlc.2016.06.663 662 Genetic Risk Scoring in a Young Myocardial Infarction (MI) Population A. Holley 1,2,∗ , K. Matsis 3 , H. Northcott 1,2 , P. Gladding 4 , S. Harding 5 , P. Larsen 1,3 1 Wellington
Cardiovascular Research Group, Wellington, New Zealand 2 Victoria University of Wellington, New Zealand 3 University of Otago, Wellington, New Zealand 4 Theranostics (NZ) Ltd, Auckland, New Zealand 5 Wellington Hospital, Wellington, New Zealand Background: Current coronary artery disease (CAD) risk models use age as a significant component of predicting patient risk. Despite this, there is a group of relatively young patients who present with myocardial infarction (MI). Incorporation of a genetic based risk score may help improve risk stratification within this age group. This study examined a 27-genetic variant risk panel in young MI patients. Method: Patients diagnosed with an MI undergoing an invasive approach were prospectively enrolled. iPLEX Massarray Sequenom genotyping was used to generate a risk score based on 27 known genetic polymorphisms in “young MI” patients ≤50 years. Results: Of 1199 enrolled MI patients, 154 (13%) were classified as “young MI” patients. The average composite genetic risk score in this group was 1.68 (1.63-1.72), which is considerably higher than previously reported risk scores in older MI populations (mean scores 1.28). The young MI group contained a higher proportion of Maori patients than the older MI group (21% versus 10%, p<0.0001), but the genetic risk score was not elevated in Maori versus non-Maori (1.70 vs 1.67, p=0.68). We did see a significant increase in genetic risk
Abstracts
S284
in patients with family history of premature CAD compared to those without (1.76 vs 1.60, p<0.0001). Conclusion: We report a 13% rate of young MI patients who have high genetic risk scores. Genetic risk was not associated with ethnicity, but was linked to family history of CAD. How to incorporate genetic risk scores into current risk models, particularly in the young, requires further evaluation. http://dx.doi.org/10.1016/j.hlc.2016.06.664 663 Genotype and Prediction of Aortic Dissection in Marfan Syndrome R. Jeremy 1,∗ , C. Bakkers 2 1 University
of Sydney, Sydney, Australia University, Rotterdam, The Netherlands
2 Erasmus
Background: risk assessment for aortic dissection in patients with Marfan syndrome is difficult. Aortic diameter is widely used, however the relationship between aortic diameter and occurrence of dissection is variable. Increasing evidence supports family history of dissection as an adverse prognostic predictor, suggesting that specific FBN1 mutations may carry increased risk for dissection. Purpose: this study examined the relationship between FBN1 mutation type and dissection risk in Marfan syndrome. Methods: the study group included all patients with Marfan syndrome and known FBN1 mutations collated from the clinic at our hospital, comprehensive literature search (PubMed) and review of published databases (ClinVar, UMD and HGMD). When patients were identified in published databases, the original clinical reports were reviewed whenever possible. Each mutation was included only once. Occurrence of aortic dissection with a mutation was recorded once, even when multiple dissections had occurred. Polymorphisms considered non-pathogenic were excluded. Mutations were grouped as missense (no cysteine affected), missense (cysteine affected), premature stop codon, frameshift and splice defects. Results: a total of 2223 mutations were identified - 619 missense (no cysteine); 663 missense (cysteine); 611 stop; 152 frameshift and 178 splice. There were 195 (8.8%) mutations associated with aortic dissection. Aortic dissection was more frequently associated with stop/frameshift/splice mutations (99/941) than with missense mutations, with or without cysteine affected, 96/1282 (p=0.015). Missense mutations affecting cysteine were not associated with increased risk of dissection. Risk of dissection for patients with stop/frameshift/splice mutations was related to position of the mutation within FBN1 (Table). Conclusions: FBN1 mutations of stop/splice/frameshift type are associated with greater risk of aortic dissection, particularly when occurring towards amino terminus of the encoded protein.
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
FBN1 Mutation and Dissection Risk Risk of Dissection Mutation Location
Missense ± Cysteine
Stop/ Relative Frameshift/ Risk Splice
p value
............................................. 9/145 (0.06)
22/155 (0.142)
2.29
0.037
Exons 1-20
19/365 (0.05)
44/289 (0.152)
2.92
<0.0001
Exons 1-30
39/602 (0.06)
53/447 (0.119)
1.83
0.002
Exons 1-40
51/799 (0.06)
67/593 (0.113)
1.77
0.002
Exons 1-50
67/1000 (0.07)
78/716 (0.109)
1.64
0.002
Exons 1-65
96/1282 (0.07)
99/941 (0.105)
1.40
0.015
Exons 1-10
http://dx.doi.org/10.1016/j.hlc.2016.06.665 664 Long QT Syndrome Associated With a Mutation in the 3 Subunit of the Cardiac Sodium Channel (SCN3B) Gene in Two Siblings K. Lau ∗ , P. Martin, K. Chia, J. McGaughran, J. Atherton Royal Brisbane and Womens Hospital, Brisbane, Australia Abstract: A 22-year-old female who was 10 weeks postpartum received successful resuscitation by her husband and defibrillation from QAS following out-of-hospital cardiac arrest during sleep with documented ventricular fibrillation. 12-lead ECG following arrest showed prolonged QTc 500ms. Echocardiography revealed mildly dilated left ventricle and moderate systolic dysfunction (EF 35-40%) with preserved basal function, which normalised within seven days. CT pulmonary angiogram, cardiac catheter study and cardiac MRI were normal. Implantable cardioverter defibrillator was inserted and the patient commenced on beta blockers. The proband’s 26-year-old brother presented three years later for evaluation of atypical chest pain. He reported one episode of unwitnessed loss of consciousness on awakening. ECG confirmed sinus rhythm and was within normal limits (QTc 402ms). Echocardiogram, cardiac MRI and CT coronary angiogram were normal. Electrophysiological study revealed normal conduction and sinus node recovery times, with no inducible ventricular arrhythmias. Atrial fibrillation was induced with high right atrial catheter placement.
S283
Results: Long-term beta blockers were prescribed to 74 patients (82%). Side effects were intolerable in 6 (8%) and beta blockers were stopped. MPR was calculated in the remaining 68 patients over 151.7 patient years of follow-up. Median MPR was 0.79 (range 0-1.3). Suboptimal adherence (MPR<0.8) was recorded in 35 (51%). Seven patients (10%) never took up a prescription (MPR=0). Adequate adherence was present in 33 (49%), including 9 (13%) who had ideal adherence. Age, sex, clinical presentation, family history of sudden death, ethnicity and deprivation index did not predict adherence. Conclusion: Beta blocker adherence was suboptimal in half our patients with LQTS types 1 and 2. Risk factors for nonadherence could not be identified. Further research into betablocker adherence is vital in this high risk population. http://dx.doi.org/10.1016/j.hlc.2016.06.662 661 Comparative Rates of Dilatation in Genetic Aortopathies S. Krishnan ∗ , R. Jeremy University of Sydney, Sydney, Australia Aim: Long-term (>10 years) data on aortic dilatation rates in genetic aortopathy are required for clinical trial design but are not yet available. This study measured aortic geometry in Marfan (MFS), Bicuspid Aortic Valve (BAV) and Familial Thoracic Aortic Aneurysm and Dissection (TAAD) across decades of life. Methods: Prospective registry over 25 years with 2D echo measurements of aortic diameter. Data comparison by ANOVA. Results: Aortic diameter by decade was similar for MFS, BAV and TAAD (Table 1). Table 1.
Aortic Diameter, mm (n) mean±SD 2nd
3rd
4th
5th
6th
decade
decade
decade
decade
decade
............................................. MFS
(85) (105) (67) (43) (25) 36.9±5.9 41.2±6.0** 42.3±7.1** 43.1±6.4** 43.4±3.6**
BAV
(8) (32) (44) (47) (53) 32.8±6.4 39.7±5.4* 41.7±4.7** 43.1±6.0** 43.8±5.8**
TAAD
(11) (29) 36.3±6.3 38.9±4.8
(36) (49) (62) 41.5±6.4* 43.2±6.3** 44.1±4.4**
* = p<0.05, ** = p<0.01 vs. 2nd decade
Overall rate of dilatation decreased with age (trend p=0.03). However, there was considerable variability within each aortopathy group (Table 2),
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
Table 2.
Change in Aortic Diameter, mm (n) mean±SD Decade 2 to 3
Decade 3 to 4
Decade 4 to 5
Decade 5 to 6
............................................. (64) 4.0 ± 4.0
(38) 4.1 ± 3.9
(20) 2.8 ± 2.3
(13) 2.1 ± 2.0
BAV
(6) 5.7 ± 9.2
(16) 3.2 ± 4.3
(13) 2.7 ± 2.7
(19) 1.8 ± 3.4
TAAD
(6) 3.4 ± 2.3
(12) 2.1 ± 1.5
(12) 1.3 ± 3.2
(22) 1.5 ± 1.7
MFS
Conclusion: Long-term aortic dilatation rates vary with age and aortopathy type; these data can inform future clinical trial design. http://dx.doi.org/10.1016/j.hlc.2016.06.663 662 Genetic Risk Scoring in a Young Myocardial Infarction (MI) Population A. Holley 1,2,∗ , K. Matsis 3 , H. Northcott 1,2 , P. Gladding 4 , S. Harding 5 , P. Larsen 1,3 1 Wellington
Cardiovascular Research Group, Wellington, New Zealand 2 Victoria University of Wellington, New Zealand 3 University of Otago, Wellington, New Zealand 4 Theranostics (NZ) Ltd, Auckland, New Zealand 5 Wellington Hospital, Wellington, New Zealand Background: Current coronary artery disease (CAD) risk models use age as a significant component of predicting patient risk. Despite this, there is a group of relatively young patients who present with myocardial infarction (MI). Incorporation of a genetic based risk score may help improve risk stratification within this age group. This study examined a 27-genetic variant risk panel in young MI patients. Method: Patients diagnosed with an MI undergoing an invasive approach were prospectively enrolled. iPLEX Massarray Sequenom genotyping was used to generate a risk score based on 27 known genetic polymorphisms in “young MI” patients ≤50 years. Results: Of 1199 enrolled MI patients, 154 (13%) were classified as “young MI” patients. The average composite genetic risk score in this group was 1.68 (1.63-1.72), which is considerably higher than previously reported risk scores in older MI populations (mean scores 1.28). The young MI group contained a higher proportion of Maori patients than the older MI group (21% versus 10%, p<0.0001), but the genetic risk score was not elevated in Maori versus non-Maori (1.70 vs 1.67, p=0.68). We did see a significant increase in genetic risk
Abstracts
S284
in patients with family history of premature CAD compared to those without (1.76 vs 1.60, p<0.0001). Conclusion: We report a 13% rate of young MI patients who have high genetic risk scores. Genetic risk was not associated with ethnicity, but was linked to family history of CAD. How to incorporate genetic risk scores into current risk models, particularly in the young, requires further evaluation. http://dx.doi.org/10.1016/j.hlc.2016.06.664 663 Genotype and Prediction of Aortic Dissection in Marfan Syndrome R. Jeremy 1,∗ , C. Bakkers 2 1 University
of Sydney, Sydney, Australia University, Rotterdam, The Netherlands
2 Erasmus
Background: risk assessment for aortic dissection in patients with Marfan syndrome is difficult. Aortic diameter is widely used, however the relationship between aortic diameter and occurrence of dissection is variable. Increasing evidence supports family history of dissection as an adverse prognostic predictor, suggesting that specific FBN1 mutations may carry increased risk for dissection. Purpose: this study examined the relationship between FBN1 mutation type and dissection risk in Marfan syndrome. Methods: the study group included all patients with Marfan syndrome and known FBN1 mutations collated from the clinic at our hospital, comprehensive literature search (PubMed) and review of published databases (ClinVar, UMD and HGMD). When patients were identified in published databases, the original clinical reports were reviewed whenever possible. Each mutation was included only once. Occurrence of aortic dissection with a mutation was recorded once, even when multiple dissections had occurred. Polymorphisms considered non-pathogenic were excluded. Mutations were grouped as missense (no cysteine affected), missense (cysteine affected), premature stop codon, frameshift and splice defects. Results: a total of 2223 mutations were identified - 619 missense (no cysteine); 663 missense (cysteine); 611 stop; 152 frameshift and 178 splice. There were 195 (8.8%) mutations associated with aortic dissection. Aortic dissection was more frequently associated with stop/frameshift/splice mutations (99/941) than with missense mutations, with or without cysteine affected, 96/1282 (p=0.015). Missense mutations affecting cysteine were not associated with increased risk of dissection. Risk of dissection for patients with stop/frameshift/splice mutations was related to position of the mutation within FBN1 (Table). Conclusions: FBN1 mutations of stop/splice/frameshift type are associated with greater risk of aortic dissection, particularly when occurring towards amino terminus of the encoded protein.
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
FBN1 Mutation and Dissection Risk Risk of Dissection Mutation Location
Missense ± Cysteine
Stop/ Relative Frameshift/ Risk Splice
p value
............................................. 9/145 (0.06)
22/155 (0.142)
2.29
0.037
Exons 1-20
19/365 (0.05)
44/289 (0.152)
2.92
<0.0001
Exons 1-30
39/602 (0.06)
53/447 (0.119)
1.83
0.002
Exons 1-40
51/799 (0.06)
67/593 (0.113)
1.77
0.002
Exons 1-50
67/1000 (0.07)
78/716 (0.109)
1.64
0.002
Exons 1-65
96/1282 (0.07)
99/941 (0.105)
1.40
0.015
Exons 1-10
http://dx.doi.org/10.1016/j.hlc.2016.06.665 664 Long QT Syndrome Associated With a Mutation in the 3 Subunit of the Cardiac Sodium Channel (SCN3B) Gene in Two Siblings K. Lau ∗ , P. Martin, K. Chia, J. McGaughran, J. Atherton Royal Brisbane and Womens Hospital, Brisbane, Australia Abstract: A 22-year-old female who was 10 weeks postpartum received successful resuscitation by her husband and defibrillation from QAS following out-of-hospital cardiac arrest during sleep with documented ventricular fibrillation. 12-lead ECG following arrest showed prolonged QTc 500ms. Echocardiography revealed mildly dilated left ventricle and moderate systolic dysfunction (EF 35-40%) with preserved basal function, which normalised within seven days. CT pulmonary angiogram, cardiac catheter study and cardiac MRI were normal. Implantable cardioverter defibrillator was inserted and the patient commenced on beta blockers. The proband’s 26-year-old brother presented three years later for evaluation of atypical chest pain. He reported one episode of unwitnessed loss of consciousness on awakening. ECG confirmed sinus rhythm and was within normal limits (QTc 402ms). Echocardiogram, cardiac MRI and CT coronary angiogram were normal. Electrophysiological study revealed normal conduction and sinus node recovery times, with no inducible ventricular arrhythmias. Atrial fibrillation was induced with high right atrial catheter placement.