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Cardiovascular Risk Factors in Familial Hypercholesteroaemia in the FHWA Program: Is Risk Solely Mediated by Hypercholesterolaemia?
S26
Abstracts CSANZ Abstracts 2011
Heart, Lung and Circulation 2011;20S:S1–S155
ABSTRACTS
63 Aromatase Deficiency Influences the Acute Response to Myocardial Ischaemic Insult in Female Mice—A Matter of Local Sex Steroid Balance? J. Bell 1,∗ , A. Wollerman 1 , K. Mellor 1 , W. Meachem 2 , E. Simpson 2 , L. Delbridge 1
Ip 1 , S.
1 University 2 Prince
of Melbourne, Australia Henry’s Institute, Australia
Sex differences exist in ischaemic heart disease, and the conventional view is that estrogen confers cardioprotection. Oestrogen synthesis depends on androgen availability, with aromatase regulating conversion of testosterone to estradiol. Extra-gonadal aromatase expression has been shown to mediate estrogen production in some tissues, but a role for local steroid conversion has not yet been demonstrated in the heart. The aim of this study was to determine whether aromatase deficiency influences myocardial function and ischaemic resilience. RT-PCR analysis of C57Bl/6 mouse hearts confirmed cardiac-specific aromatase expression in adult females. Functional performance of isolated hearts from female aromatase knockout (ArKO) and wild-type (ArWT) mice were compared. In aerobic perfusion, left ventricular developed pressures (LVDP) were similar, but dP/dt max was modestly reduced in ArKO hearts (4272 ± 154 mmHg/s vs 3725 ± 144 mmHg/s, p < 0.05).Though the incidence of reperfusion-induced ventricular premature beats was increased in ArKO hearts (VPB; 46 ± 6 vs 194 ± 70, p < 0.05) immediately following 25 minute ischaemia, recovery of LVDP was substantially improved at the end of 60 minute reperfusion (%basal; 30 ± 6% vs 62 ± 8%, p < 0.05). Hypercontracture was attenuated (end diastolic pressure; 51 ± 1 mmHg vs 25 ± 5 mmHg, p < 0.05) and LDH content of coronary effluent was reduced throughout reperfusion in ArKO hearts. This was associated with a hyper-phosphorylation of phospholamban and a reduction in phosphorylated Akt. These observations indicate more robust functional recovery, reduced cellular injury and modified cardiomyocyte Ca-handling in aromatase deficient hearts. Our findings challenge the notion that estrogen deficiency is deleterious in relation to ischaemia/reperfusion performance, and suggest that cardioprotection may be facilitated by a shift in the myocardial testosterone/estrogen balance. doi:10.1016/j.hlc.2011.05.066 64 BNP Signal Peptide and High Sensitivity Troponin T Response During Dobutamine Stress Echocardiography M. Siriwardena ∗ , V. Campbell, N. Kitson, T. Yandle, M. Richards, C. Pemberton Christchurch Cardioendocrine Research Group, New Zealand Purpose: B-type Natriuretic Peptide Signal Peptide (BNP-SP) is a novel biomarker identified in the circulation. Emerging evidence suggests BNP-SP may be a marker
of cardiac ischaemia. In this study, we documented the release of BNP-SP and high sensitivity troponin T (Trop T hs) during dobutamine stress echocardiography (DSE) in those with coronary artery disease (CAD) and healthy volunteers. Methods: Sixteen patients with CAD and 10 healthy volunteers were recruited. Plasma samples were collected just prior to the DSE and then half hourly for a total of four hours after DSE. At each time point, BNP-SP levels were determined by our published radioimmunoassay, whereas Trop T hs levels were determined on a Roche Elecsys analyser. Results: The majority of patients with CAD remained on anti-anginals including B blockers at the time of the DSE (11/16). A clear significant rise was seen in both groups in both markers above the 99th percentile upper normal range (25 pmol/l for BNP-SP and 14 pg/ml for Trop T hs). The two markers had very different temporal profiles of release with BNPSP peaking at 0.5 h, whereas Trop T hs peaked at 3.5–4.0 hours. There was no significant difference in the pattern of release between groups for either marker as determined by two way repeat ANOVA analysis (BNP-SP, P = 0.34; Trop T hs, P = 0.34).
Conclusions: We have demonstrated important differences in profiles of two potential early markers of cardiac ischaemia. Although either marker is unlikely to improve accuracy of DSE, the differences may prove beneficial in other settings. doi:10.1016/j.hlc.2011.05.067 65 Cardiovascular Risk Factors in Familial Hypercholesteroaemia in the FHWA Program: Is Risk Solely Mediated by Hypercholesterolaemia? D. Chan 1,∗ , Y. Lo 1 , A. Juniper 2 , L. Southwell 1 , S. Burrows 1 , T. Bates 1 , F. Van Bockxmeer 1 , T. Redgrave 1 , J. Burnett 1 , G. Watts 1 1 University
of Western Australia, Australia of Health WA, Australia
2 Department
Background: Familial hypercholesterolaemia (FH) is classically due to LDL receptor mutations that result in marked hypercholesterolaemia and premature cardiovascular disease (CVD). The contribution that other CV risk factors in FH is unclear. Methods: We carried out a cross-sectional study of 255 phenotypically defined patients with FH (139 women and 118 men, age 49 ± 16 years, Dutch FH Score 3–32,
73% LDLR mutation positive of 186 tested, 82% treated with statins) in the FHWA Program. We recorded details of smoking, diabetes mellitus, hypertension (>140/90 mmHg), obesity (BMI >30 kg/m2 ), low HDLcholesterol (<1.0 mmol/L, men; <1.3 mmol/L, women), high LDL-cholesterol (>4 mmol/L) and clinical evidence of CVD. Associations explored by logistic regression analyses. Results: The prevalence of CV risk factors was: current/ex-smokers 53%, obesity 26%, hypertension 27%, low-HDL-cholesterol 29%, diabetes mellitus 6%, highLDL-cholesterol 50% and CVD 33% (angina 15%, bypass grafting 13%, peripheral/cerebrovascular disease 15%); 92% of patients had at least 1 CV risk factor. In univariate regression, smoking (OR 2.03, P = 0.01), diabetes mellitus (OR 5.71, P < 0.01), hypertension (OR 3.96, P < 0.001) and obesity (OR 1.91, P = 0.02) were all significantly associated with prior CVD. In multivariate regression, smoking (OR 1.98, P = 0.023), diabetes mellitus (OR 3.92, P = 0.023) and hypertension (OR 3.42, P < 0.001) remained significant predictors of CVD. Age, gender, elevated LDL-cholesterol, presence of an LDLR mutation and Dutch FH Score were not significant predictors of CVD. Conclusions: In treated patients with FH, the spectrum of modifiable CV risk factors extends beyond hypercholesterolaemia. Smoking, hypertension, obesity and diabetes are widely prevalent and together with LDL-cholesterol lowering need to be aggressively treated in FH. doi:10.1016/j.hlc.2011.05.068 66 Clinical Characteristics of Patients with Inducible Coronary Artery Spasm D. Di Fiore ∗ , C. Poh, J. Beltrame, C. Zeitz The Queen Elizabeth Hospital, Australia Background: Coronary artery spasm (CAS) is the hallmark of vasospastic angina and can be diagnosed with provocative spasm testing during coronary angiography. The objective of this study was to identify the clinical features of patients with inducible CAS. Methods: We undertook acetylcholine provocation testing in 83 patients undergoing cardiac catheterisation for investigation of chest pain where non-obstructive coronary artery disease (CAD) was found. Vasoactive cardiac medications had been withheld for 48 hours prior to the procedure. Acetylcholine (ACh) was delivered by intracoronary injection at escalating doses of 25, 50 and 100 m until either a positive result was achieved, or the maximum dose given. Patients were classified as having a positive provocation test if they had occlusive or sub-occlusive vasoconstriction to ACh (i.e. ≥90% vasoconstriction). Vasoconstriction <90% was classified as a negative provocation test. Clinical characteristics were examined in order to detect possible predictors of a positive provocation test.
Abstracts CSANZ Abstracts 2011
S27
Results: Characteristic
Positive Test For Vasospasm
%
Negative Test For Vasospasm
%
Number Age Female gender Current smoker Hypercholesterolaemia Migraine history Rest Angina Previous ACS presentation
37 52.1 + 10.3 27 9 26 2 32 13
45
46 50.8 + 11.9 35 12 22 7 22 16
55
73 24 70 5 87 35
76 26 48 15 48 35
P Value
0.30 0.75 0.85 0.04 0.15 0.0002 0.97
Conclusion: In a selected group of patients with chest pain and no obstructive coronary artery disease, those with inducible coronary spasm were more likely to have a history of hypercholesterolaemia and experience rest angina. This contrasts with similar Japanese studies where only cigarette smoking and rest angina were predictive. doi:10.1016/j.hlc.2011.05.069 67 Clinical Impact of High Sensitive Troponin T (HsTnT) on Diagnosis of Acute Coronary Syndrome (ACS) J. Mazhar ∗ , V. Pera, A. Siddiqui, J. Bouwhuis, S. Du Toit, G. Devlin Waikato Hospital, Hamilton, New Zealand Background: HsTnT assay has a lower cut-off (14 ng/L) resulting in a new clinically challenging group of patients with minimally elevated HsTnT (14–53 ng/L), previously reported as normal with the fourth generation troponin T(4GTnT). A rise and/or fall of HsTnT is important to increase specificity, particularly at lower levels. Our aim was to assess impact of HsTnT on diagnosis of ACS. Methods: 143 consecutive patients admitted with possible ACS were enrolled. Patients were diagnosed and treated based on 4GTnT. HsTnT was added to all samples and treating cardiologists were blinded to these results. Results: Mean age was 62 with 86 (60%) male. 89 (62%) had non cardiac chest pain (NCCP), 16 (11%) angina, 11 (8%) unstable angina, 22 (15%) NSTEMI, 5 (3%) STEMI. Using a single HsTnT, identified 21 new patients with elevated HsTnT but normal 4GTnT (see table). HsTnT ranged from 15 to 52 ng/L. Thirteen patients discharged as NCCP had minimally elevated HsTnT. Stress testing was done in 9 (69%) of this group and was negative in all. Only one of the 21 patients fulfilled the diagnosis of NSTEMI with a rise and/or fall of HsTnT. Diagnosis NCCP Angina Unstable angina
Diagnosis based on 4GTnT 89 (62%) 16 (11%) 11 (8%)
HsTnT > 14 ng/L in Each Group
Rise and/or Fall of HsTnT
13 4 4
0 0 1
Conclusion: Use of HsTnT increases the incidence of troponin positive presentations significantly by detecting levels between 14 and 53 ng/L. Specificity is increased by diagnostic algorithms requiring a rise and/or fall. Education of health professionals in interpretation of HsTnT is essential to avoid unnecessary investigations. doi:10.1016/j.hlc.2011.05.070
ABSTRACTS
Heart, Lung and Circulation 2011;20S:S1–S155
Abstracts CSANZ Abstracts 2011
Heart, Lung and Circulation 2011;20S:S1–S155
ABSTRACTS
63 Aromatase Deficiency Influences the Acute Response to Myocardial Ischaemic Insult in Female Mice—A Matter of Local Sex Steroid Balance? J. Bell 1,∗ , A. Wollerman 1 , K. Mellor 1 , W. Meachem 2 , E. Simpson 2 , L. Delbridge 1
Ip 1 , S.
1 University 2 Prince
of Melbourne, Australia Henry’s Institute, Australia
Sex differences exist in ischaemic heart disease, and the conventional view is that estrogen confers cardioprotection. Oestrogen synthesis depends on androgen availability, with aromatase regulating conversion of testosterone to estradiol. Extra-gonadal aromatase expression has been shown to mediate estrogen production in some tissues, but a role for local steroid conversion has not yet been demonstrated in the heart. The aim of this study was to determine whether aromatase deficiency influences myocardial function and ischaemic resilience. RT-PCR analysis of C57Bl/6 mouse hearts confirmed cardiac-specific aromatase expression in adult females. Functional performance of isolated hearts from female aromatase knockout (ArKO) and wild-type (ArWT) mice were compared. In aerobic perfusion, left ventricular developed pressures (LVDP) were similar, but dP/dt max was modestly reduced in ArKO hearts (4272 ± 154 mmHg/s vs 3725 ± 144 mmHg/s, p < 0.05).Though the incidence of reperfusion-induced ventricular premature beats was increased in ArKO hearts (VPB; 46 ± 6 vs 194 ± 70, p < 0.05) immediately following 25 minute ischaemia, recovery of LVDP was substantially improved at the end of 60 minute reperfusion (%basal; 30 ± 6% vs 62 ± 8%, p < 0.05). Hypercontracture was attenuated (end diastolic pressure; 51 ± 1 mmHg vs 25 ± 5 mmHg, p < 0.05) and LDH content of coronary effluent was reduced throughout reperfusion in ArKO hearts. This was associated with a hyper-phosphorylation of phospholamban and a reduction in phosphorylated Akt. These observations indicate more robust functional recovery, reduced cellular injury and modified cardiomyocyte Ca-handling in aromatase deficient hearts. Our findings challenge the notion that estrogen deficiency is deleterious in relation to ischaemia/reperfusion performance, and suggest that cardioprotection may be facilitated by a shift in the myocardial testosterone/estrogen balance. doi:10.1016/j.hlc.2011.05.066 64 BNP Signal Peptide and High Sensitivity Troponin T Response During Dobutamine Stress Echocardiography M. Siriwardena ∗ , V. Campbell, N. Kitson, T. Yandle, M. Richards, C. Pemberton Christchurch Cardioendocrine Research Group, New Zealand Purpose: B-type Natriuretic Peptide Signal Peptide (BNP-SP) is a novel biomarker identified in the circulation. Emerging evidence suggests BNP-SP may be a marker
of cardiac ischaemia. In this study, we documented the release of BNP-SP and high sensitivity troponin T (Trop T hs) during dobutamine stress echocardiography (DSE) in those with coronary artery disease (CAD) and healthy volunteers. Methods: Sixteen patients with CAD and 10 healthy volunteers were recruited. Plasma samples were collected just prior to the DSE and then half hourly for a total of four hours after DSE. At each time point, BNP-SP levels were determined by our published radioimmunoassay, whereas Trop T hs levels were determined on a Roche Elecsys analyser. Results: The majority of patients with CAD remained on anti-anginals including B blockers at the time of the DSE (11/16). A clear significant rise was seen in both groups in both markers above the 99th percentile upper normal range (25 pmol/l for BNP-SP and 14 pg/ml for Trop T hs). The two markers had very different temporal profiles of release with BNPSP peaking at 0.5 h, whereas Trop T hs peaked at 3.5–4.0 hours. There was no significant difference in the pattern of release between groups for either marker as determined by two way repeat ANOVA analysis (BNP-SP, P = 0.34; Trop T hs, P = 0.34).
Conclusions: We have demonstrated important differences in profiles of two potential early markers of cardiac ischaemia. Although either marker is unlikely to improve accuracy of DSE, the differences may prove beneficial in other settings. doi:10.1016/j.hlc.2011.05.067 65 Cardiovascular Risk Factors in Familial Hypercholesteroaemia in the FHWA Program: Is Risk Solely Mediated by Hypercholesterolaemia? D. Chan 1,∗ , Y. Lo 1 , A. Juniper 2 , L. Southwell 1 , S. Burrows 1 , T. Bates 1 , F. Van Bockxmeer 1 , T. Redgrave 1 , J. Burnett 1 , G. Watts 1 1 University
of Western Australia, Australia of Health WA, Australia
2 Department
Background: Familial hypercholesterolaemia (FH) is classically due to LDL receptor mutations that result in marked hypercholesterolaemia and premature cardiovascular disease (CVD). The contribution that other CV risk factors in FH is unclear. Methods: We carried out a cross-sectional study of 255 phenotypically defined patients with FH (139 women and 118 men, age 49 ± 16 years, Dutch FH Score 3–32,
73% LDLR mutation positive of 186 tested, 82% treated with statins) in the FHWA Program. We recorded details of smoking, diabetes mellitus, hypertension (>140/90 mmHg), obesity (BMI >30 kg/m2 ), low HDLcholesterol (<1.0 mmol/L, men; <1.3 mmol/L, women), high LDL-cholesterol (>4 mmol/L) and clinical evidence of CVD. Associations explored by logistic regression analyses. Results: The prevalence of CV risk factors was: current/ex-smokers 53%, obesity 26%, hypertension 27%, low-HDL-cholesterol 29%, diabetes mellitus 6%, highLDL-cholesterol 50% and CVD 33% (angina 15%, bypass grafting 13%, peripheral/cerebrovascular disease 15%); 92% of patients had at least 1 CV risk factor. In univariate regression, smoking (OR 2.03, P = 0.01), diabetes mellitus (OR 5.71, P < 0.01), hypertension (OR 3.96, P < 0.001) and obesity (OR 1.91, P = 0.02) were all significantly associated with prior CVD. In multivariate regression, smoking (OR 1.98, P = 0.023), diabetes mellitus (OR 3.92, P = 0.023) and hypertension (OR 3.42, P < 0.001) remained significant predictors of CVD. Age, gender, elevated LDL-cholesterol, presence of an LDLR mutation and Dutch FH Score were not significant predictors of CVD. Conclusions: In treated patients with FH, the spectrum of modifiable CV risk factors extends beyond hypercholesterolaemia. Smoking, hypertension, obesity and diabetes are widely prevalent and together with LDL-cholesterol lowering need to be aggressively treated in FH. doi:10.1016/j.hlc.2011.05.068 66 Clinical Characteristics of Patients with Inducible Coronary Artery Spasm D. Di Fiore ∗ , C. Poh, J. Beltrame, C. Zeitz The Queen Elizabeth Hospital, Australia Background: Coronary artery spasm (CAS) is the hallmark of vasospastic angina and can be diagnosed with provocative spasm testing during coronary angiography. The objective of this study was to identify the clinical features of patients with inducible CAS. Methods: We undertook acetylcholine provocation testing in 83 patients undergoing cardiac catheterisation for investigation of chest pain where non-obstructive coronary artery disease (CAD) was found. Vasoactive cardiac medications had been withheld for 48 hours prior to the procedure. Acetylcholine (ACh) was delivered by intracoronary injection at escalating doses of 25, 50 and 100 m until either a positive result was achieved, or the maximum dose given. Patients were classified as having a positive provocation test if they had occlusive or sub-occlusive vasoconstriction to ACh (i.e. ≥90% vasoconstriction). Vasoconstriction <90% was classified as a negative provocation test. Clinical characteristics were examined in order to detect possible predictors of a positive provocation test.
Abstracts CSANZ Abstracts 2011
S27
Results: Characteristic
Positive Test For Vasospasm
%
Negative Test For Vasospasm
%
Number Age Female gender Current smoker Hypercholesterolaemia Migraine history Rest Angina Previous ACS presentation
37 52.1 + 10.3 27 9 26 2 32 13
45
46 50.8 + 11.9 35 12 22 7 22 16
55
73 24 70 5 87 35
76 26 48 15 48 35
P Value
0.30 0.75 0.85 0.04 0.15 0.0002 0.97
Conclusion: In a selected group of patients with chest pain and no obstructive coronary artery disease, those with inducible coronary spasm were more likely to have a history of hypercholesterolaemia and experience rest angina. This contrasts with similar Japanese studies where only cigarette smoking and rest angina were predictive. doi:10.1016/j.hlc.2011.05.069 67 Clinical Impact of High Sensitive Troponin T (HsTnT) on Diagnosis of Acute Coronary Syndrome (ACS) J. Mazhar ∗ , V. Pera, A. Siddiqui, J. Bouwhuis, S. Du Toit, G. Devlin Waikato Hospital, Hamilton, New Zealand Background: HsTnT assay has a lower cut-off (14 ng/L) resulting in a new clinically challenging group of patients with minimally elevated HsTnT (14–53 ng/L), previously reported as normal with the fourth generation troponin T(4GTnT). A rise and/or fall of HsTnT is important to increase specificity, particularly at lower levels. Our aim was to assess impact of HsTnT on diagnosis of ACS. Methods: 143 consecutive patients admitted with possible ACS were enrolled. Patients were diagnosed and treated based on 4GTnT. HsTnT was added to all samples and treating cardiologists were blinded to these results. Results: Mean age was 62 with 86 (60%) male. 89 (62%) had non cardiac chest pain (NCCP), 16 (11%) angina, 11 (8%) unstable angina, 22 (15%) NSTEMI, 5 (3%) STEMI. Using a single HsTnT, identified 21 new patients with elevated HsTnT but normal 4GTnT (see table). HsTnT ranged from 15 to 52 ng/L. Thirteen patients discharged as NCCP had minimally elevated HsTnT. Stress testing was done in 9 (69%) of this group and was negative in all. Only one of the 21 patients fulfilled the diagnosis of NSTEMI with a rise and/or fall of HsTnT. Diagnosis NCCP Angina Unstable angina
Diagnosis based on 4GTnT 89 (62%) 16 (11%) 11 (8%)
HsTnT > 14 ng/L in Each Group
Rise and/or Fall of HsTnT
13 4 4
0 0 1
Conclusion: Use of HsTnT increases the incidence of troponin positive presentations significantly by detecting levels between 14 and 53 ng/L. Specificity is increased by diagnostic algorithms requiring a rise and/or fall. Education of health professionals in interpretation of HsTnT is essential to avoid unnecessary investigations. doi:10.1016/j.hlc.2011.05.070
ABSTRACTS
Heart, Lung and Circulation 2011;20S:S1–S155