- Email: [email protected]
HOSPITAL-RELATED CARDIAC MORBIDITY AMONG SURVIVORS OF BREAST CANCER: LONG-TERM RISKS AND PREDICTORS
S122
Canadian Journal of Cardiology Volume 30 2014
133 TETRANDRINE REVERSES HUMAN CARDIAC MYOFIBROBLAST ACTIVATION AND MYOCARDIAL FIBROSIS G Teng, H Duff, D Belke, J Turnbull, C Meijndert, Y Chen, E O’Brien, PW Fedak Calgary, Alberta
Myocardial fibrosis is an important therapeutic target given its contribution to chamber dilatation, progression of heart failure and lethal cardiac arrhythmias. Myocardial fibrosis is mediated by persistent activation of resident (myo)fibroblasts that secrete extracellular matrix (ECM). Tetrandrine (TTD) is a calcium channel blocker (CCB) with documented anti-fibrotic actions believed to be secondary to its effects on lowering blood pressure. In this study, for the first time, we identified that TTD can directly reverse in vitro human cardiac fibroblast activation and limits in vivo myocardial fibrosis independent of hemodynamic load. METHODS AND RESULTS: IN VITRO: Human atrial biopsies were obtained from cardiac surgery patients (N¼10). Cardiac fibroblasts were isolated, expanded in culture, and seeded in 3D collagen matrices. Cell-collagen constructs were exposed to TGFb1 (10 ng/mL), with or without TTD (1 or 5mM) for 48 hours. Extent of collagen gel contraction, myofibroblast activation (a-SMA expression), expression of pro-fibrotic mRNAs and rate of collagen protein synthesis was compared. TTD exposure significantly decreased TGF-b1 induced human cardiac myofibroblast mediated collagen gel contraction (79.661.28 control; 67.053.91 TTD1mM; 60.058.85 TTD5mM; both P< 0.01). Cell viability was similar between groups (annexin positive cells: control 1.7%, TTD (1mM) 1.1% and TTD(5mM) 1.4%). TTD significantly attenuated myofibroblast activation as assessed by aSMA expression using flow cytometer. TTD decreased collagen synthesis ([3H]-proline incorporation 171 (control); 119 (TTD1uM); and 43 (TTD5mM) DPM/mg protein) and expression of a-SMA and collagen mRNAs (ACTA2; Col1A1; Col1A2). TTD inhibited collagen gel contraction in the presence of T-type and L-type CCB (Mibefradil (5mM) or verapamil (20mM)), and a calcium chelator BAPTA-AM (15mM) suggesting that the observed effects are not mediated by calcium channel blockade. IN VIVO: Dahl salt-sensitive rat model of pressure-overload was employed. Animals were divided into untreated controls and compared to TTD treatment groups (7.5mg; 15mg; 30mg/kg by IP injection over 4 weeks). Systemic blood pressure was monitored by tail cuff. Left ventricular compliance and myocardial fibrosis was assessed by passive pressure-volume analysis, echocardiography and PSR staining. Myocardial fibrosis was attenuated and LV compliance preserved after 4 weeks of TTD 30mg/kg treatment as compared to untreated controls (% collagen area: 4.210.56 versus 2.130.31, P<0.01). TTD-induced changes in fibrosis and chamber compliance independent of hemodynamic load. CONCLUSION: TTD reverses human cardiac myofibroblast activation and myocardial fibrosis independent of calcium channel blockade and hemodynamic load. The mechanisms that mediate the anti-fibrotic activity of TTD should be further explored and leveraged for its therapeutic potential. BACKGROUND:
134 HOSPITAL-RELATED CARDIAC MORBIDITY AMONG SURVIVORS OF BREAST CANCER: LONG-TERM RISKS AND PREDICTORS MK Davis, D Li, E Wai, S Tyldesley, C Simmons, C Baliski, ML McBride Vancouver, British Columbia BACKGROUND:
Advances in the early detection and treatment of breast cancer have resulted in dramatically improved cancer survival, with five-year survival rates of 88% in Canada in 2013. Many survivors face ongoing health issues, including cardiovascular disease, as a result of comorbid conditions and late treatment effects. METHODS: Demographic and clinical records of all 3-year breast cancer survivors in BC, diagnosed between 1986 and 2005, were linked to provincial administrative inpatient records; for each survivor, two gender and birth-year matched comparators without prior breast cancer, were randomly selected from the provincial health insurance plan registry and similarly linked. Cardiac morbidity was ascertained from hospital diagnosis codes. Poisson regression was used to assess RR of morbidity, adjusting for sociodemographic characteristics; logistic regression was used to assess clinical and other risk factors. RESULTS: Median follow-up to 2008 was 9 years, with maximum follow-up 20 years. Compared to the population sample, nonrelapsed survivors diagnosed age 18-39 (N¼1,158) had 2.5 times the risk of cardiac morbidity (RR 2.51, 95% CI 1.83-3.49); those with a relapse (N¼580) had over 7 times the risk (RR 7.18, 95% CI 4.81-10.71). Among those diagnosed age 40, non-relapsed survivors (N¼20,473) had a 13% increase in cardiac risk (RR 1.13, 95%CI 1.08-1.17), and relapsed survivors (N¼5,223) had 52% increased risk (RR 1.52, 95% CI 1.37-1.69). The most common diagnoses seen were cardiac dysrhythmias, heart failure, and acute myocardial infarction for those diagnosed at age 40 or older; and for those diagnosed aged 18-39 the most common diagnoses were diseases of pericardium and acute pulmonary heart disease. Among non-relapsed survivors, those diagnosed with a higher stage cancer showed increased risk. Those non-relapsed survivors diagnosed aged 40 who received combined treatment of surgery, systemic and radiation had slightly lower risk of cardiac morbidity, compared to surgery alone (RR ¼ 0.84, 95% CI 0.74-0.95).
Abstracts CONCLUSION:
Survivors of breast cancer are at an increased risk of a cardiac morbidity years after diagnosis. This underscores the need for long-term surveillance, improved models of survivorship care and continued survivorship research.
S123
diastolic dysfunction found in the treated and controlled nondippers. Assessment of both diastolic function using ECHO and nighttime BP with 24hr ABPM may be useful in elderly patients with treated and controlled hypertension.
Canadian Cardiovascular Society (CCS) Oral TRANSLATIONAL APPROACHES TO HYPERTENSION Saturday, October 25, 2014 135 DIASTOLIC FUNCTION IN NORMOTENSIVE DIPPERS AND NON DIPPERS USING 24HR ABPM J Meloche, U Jurt, D Brouillard, M Matangi Kingston, Ontario BACKGROUND:
The purpose of this analysis was to determine the difference in LV diastolic function in the normotensive and controlled hypertensive population depending on their nighttime dipper and non-dipper feature as determined by 24hr ABPM. METHODS: Our cardiology database, CARDIOfile was searched for all patients who underwent a 24hr ABPM and an ECHO within 180 days. A night time dipper was defined as a >10% fall in average nighttime systolic BP when compared to average daytime systolic BP. Normal systolic BP was defined as an average 24hr systolic BP of 130mmHg. Patients were further defined as either normotensive or controlled hypertensive with antihypertensive drugs. Normal diastolic function was defined as an E/e’ <9 or an E/e’ of 9-14 with an LA volume index <34ml/m2. Only patients with an LVEF >55% and absence of valve disease were included. ANOVA was used to determine differences between the means and Tukey-Kramer inter-comparisons testing was carried out if the P value for ANOVA was <0.05. Chi-squared analysis was used to determine differences between proportions. RESULTS: See Table 1 and bar graph. There were 752 patients who met the entry criteria. Two hundred and nineteen were normotensive. Of these 127 were nighttime dippers and 92 were non-dippers. Five hundred and thirty-three were controlled hypertensives on medication. Of these, 254 were nighttime dippers and 279 were non-dippers. ANOVA showed no significant difference in LVEF or average 24hr SBP, but a highly significant difference in age (P<0.0001) between the 4 groups, Table 1. There was a highly significant difference in the proportion of patients with abnormal diastolic function between the 4 groups, Chi-squared, P<0.0001, figure1. CONCLUSION: Only 24hr ABPM can be used to classify patients with normal systolic BP or controlled hypertension as either nighttime dippers or non-dippers. Overall, there is a gradual increase in the proportion with abnormal diastolic function within the four groups defined. There is a correlation between loss of nocturnal dipping and worsening diastolic function. The lowest incidence of diastolic dysfunction is in the normotensive dippers with the highest incidence of
136 CARDIAC REMODELING IN RUGBY AND FOOTBALL LINE PLAYERS IS ASSOCIATED WITH BOTH SUBCLINICAL SYSTOLIC AND DIASTOLIC DYSFUNCTION A Pellissier, E Larochelle, L Krsticevic, E Baron, V Le, A Roy, A Deragon, M Cote, P Laramée, S Leclerc, D Garcia, F Tournoux Montréal, Québec BACKGROUND:
American style football player linemen are known to develop hypertension and concentric cardiac remodeling during training. It is unclear whether such cardiac remodeling is linked to hypertension or to the development of an athlete’s heart. The goal of this study was to demonstrate whether such cardiac remodeling was associated or not with subclinical cardiac dysfunction. METHODS: Forty-two line position athletes (25 male football players, 9 female rugby players and 8 male rugby players) were scanned using a Vivid q echo machine (General Electrics). For each participant, left ventricle mass, systolic function (ejection
Canadian Journal of Cardiology Volume 30 2014
133 TETRANDRINE REVERSES HUMAN CARDIAC MYOFIBROBLAST ACTIVATION AND MYOCARDIAL FIBROSIS G Teng, H Duff, D Belke, J Turnbull, C Meijndert, Y Chen, E O’Brien, PW Fedak Calgary, Alberta
Myocardial fibrosis is an important therapeutic target given its contribution to chamber dilatation, progression of heart failure and lethal cardiac arrhythmias. Myocardial fibrosis is mediated by persistent activation of resident (myo)fibroblasts that secrete extracellular matrix (ECM). Tetrandrine (TTD) is a calcium channel blocker (CCB) with documented anti-fibrotic actions believed to be secondary to its effects on lowering blood pressure. In this study, for the first time, we identified that TTD can directly reverse in vitro human cardiac fibroblast activation and limits in vivo myocardial fibrosis independent of hemodynamic load. METHODS AND RESULTS: IN VITRO: Human atrial biopsies were obtained from cardiac surgery patients (N¼10). Cardiac fibroblasts were isolated, expanded in culture, and seeded in 3D collagen matrices. Cell-collagen constructs were exposed to TGFb1 (10 ng/mL), with or without TTD (1 or 5mM) for 48 hours. Extent of collagen gel contraction, myofibroblast activation (a-SMA expression), expression of pro-fibrotic mRNAs and rate of collagen protein synthesis was compared. TTD exposure significantly decreased TGF-b1 induced human cardiac myofibroblast mediated collagen gel contraction (79.661.28 control; 67.053.91 TTD1mM; 60.058.85 TTD5mM; both P< 0.01). Cell viability was similar between groups (annexin positive cells: control 1.7%, TTD (1mM) 1.1% and TTD(5mM) 1.4%). TTD significantly attenuated myofibroblast activation as assessed by aSMA expression using flow cytometer. TTD decreased collagen synthesis ([3H]-proline incorporation 171 (control); 119 (TTD1uM); and 43 (TTD5mM) DPM/mg protein) and expression of a-SMA and collagen mRNAs (ACTA2; Col1A1; Col1A2). TTD inhibited collagen gel contraction in the presence of T-type and L-type CCB (Mibefradil (5mM) or verapamil (20mM)), and a calcium chelator BAPTA-AM (15mM) suggesting that the observed effects are not mediated by calcium channel blockade. IN VIVO: Dahl salt-sensitive rat model of pressure-overload was employed. Animals were divided into untreated controls and compared to TTD treatment groups (7.5mg; 15mg; 30mg/kg by IP injection over 4 weeks). Systemic blood pressure was monitored by tail cuff. Left ventricular compliance and myocardial fibrosis was assessed by passive pressure-volume analysis, echocardiography and PSR staining. Myocardial fibrosis was attenuated and LV compliance preserved after 4 weeks of TTD 30mg/kg treatment as compared to untreated controls (% collagen area: 4.210.56 versus 2.130.31, P<0.01). TTD-induced changes in fibrosis and chamber compliance independent of hemodynamic load. CONCLUSION: TTD reverses human cardiac myofibroblast activation and myocardial fibrosis independent of calcium channel blockade and hemodynamic load. The mechanisms that mediate the anti-fibrotic activity of TTD should be further explored and leveraged for its therapeutic potential. BACKGROUND:
134 HOSPITAL-RELATED CARDIAC MORBIDITY AMONG SURVIVORS OF BREAST CANCER: LONG-TERM RISKS AND PREDICTORS MK Davis, D Li, E Wai, S Tyldesley, C Simmons, C Baliski, ML McBride Vancouver, British Columbia BACKGROUND:
Advances in the early detection and treatment of breast cancer have resulted in dramatically improved cancer survival, with five-year survival rates of 88% in Canada in 2013. Many survivors face ongoing health issues, including cardiovascular disease, as a result of comorbid conditions and late treatment effects. METHODS: Demographic and clinical records of all 3-year breast cancer survivors in BC, diagnosed between 1986 and 2005, were linked to provincial administrative inpatient records; for each survivor, two gender and birth-year matched comparators without prior breast cancer, were randomly selected from the provincial health insurance plan registry and similarly linked. Cardiac morbidity was ascertained from hospital diagnosis codes. Poisson regression was used to assess RR of morbidity, adjusting for sociodemographic characteristics; logistic regression was used to assess clinical and other risk factors. RESULTS: Median follow-up to 2008 was 9 years, with maximum follow-up 20 years. Compared to the population sample, nonrelapsed survivors diagnosed age 18-39 (N¼1,158) had 2.5 times the risk of cardiac morbidity (RR 2.51, 95% CI 1.83-3.49); those with a relapse (N¼580) had over 7 times the risk (RR 7.18, 95% CI 4.81-10.71). Among those diagnosed age 40, non-relapsed survivors (N¼20,473) had a 13% increase in cardiac risk (RR 1.13, 95%CI 1.08-1.17), and relapsed survivors (N¼5,223) had 52% increased risk (RR 1.52, 95% CI 1.37-1.69). The most common diagnoses seen were cardiac dysrhythmias, heart failure, and acute myocardial infarction for those diagnosed at age 40 or older; and for those diagnosed aged 18-39 the most common diagnoses were diseases of pericardium and acute pulmonary heart disease. Among non-relapsed survivors, those diagnosed with a higher stage cancer showed increased risk. Those non-relapsed survivors diagnosed aged 40 who received combined treatment of surgery, systemic and radiation had slightly lower risk of cardiac morbidity, compared to surgery alone (RR ¼ 0.84, 95% CI 0.74-0.95).
Abstracts CONCLUSION:
Survivors of breast cancer are at an increased risk of a cardiac morbidity years after diagnosis. This underscores the need for long-term surveillance, improved models of survivorship care and continued survivorship research.
S123
diastolic dysfunction found in the treated and controlled nondippers. Assessment of both diastolic function using ECHO and nighttime BP with 24hr ABPM may be useful in elderly patients with treated and controlled hypertension.
Canadian Cardiovascular Society (CCS) Oral TRANSLATIONAL APPROACHES TO HYPERTENSION Saturday, October 25, 2014 135 DIASTOLIC FUNCTION IN NORMOTENSIVE DIPPERS AND NON DIPPERS USING 24HR ABPM J Meloche, U Jurt, D Brouillard, M Matangi Kingston, Ontario BACKGROUND:
The purpose of this analysis was to determine the difference in LV diastolic function in the normotensive and controlled hypertensive population depending on their nighttime dipper and non-dipper feature as determined by 24hr ABPM. METHODS: Our cardiology database, CARDIOfile was searched for all patients who underwent a 24hr ABPM and an ECHO within 180 days. A night time dipper was defined as a >10% fall in average nighttime systolic BP when compared to average daytime systolic BP. Normal systolic BP was defined as an average 24hr systolic BP of 130mmHg. Patients were further defined as either normotensive or controlled hypertensive with antihypertensive drugs. Normal diastolic function was defined as an E/e’ <9 or an E/e’ of 9-14 with an LA volume index <34ml/m2. Only patients with an LVEF >55% and absence of valve disease were included. ANOVA was used to determine differences between the means and Tukey-Kramer inter-comparisons testing was carried out if the P value for ANOVA was <0.05. Chi-squared analysis was used to determine differences between proportions. RESULTS: See Table 1 and bar graph. There were 752 patients who met the entry criteria. Two hundred and nineteen were normotensive. Of these 127 were nighttime dippers and 92 were non-dippers. Five hundred and thirty-three were controlled hypertensives on medication. Of these, 254 were nighttime dippers and 279 were non-dippers. ANOVA showed no significant difference in LVEF or average 24hr SBP, but a highly significant difference in age (P<0.0001) between the 4 groups, Table 1. There was a highly significant difference in the proportion of patients with abnormal diastolic function between the 4 groups, Chi-squared, P<0.0001, figure1. CONCLUSION: Only 24hr ABPM can be used to classify patients with normal systolic BP or controlled hypertension as either nighttime dippers or non-dippers. Overall, there is a gradual increase in the proportion with abnormal diastolic function within the four groups defined. There is a correlation between loss of nocturnal dipping and worsening diastolic function. The lowest incidence of diastolic dysfunction is in the normotensive dippers with the highest incidence of
136 CARDIAC REMODELING IN RUGBY AND FOOTBALL LINE PLAYERS IS ASSOCIATED WITH BOTH SUBCLINICAL SYSTOLIC AND DIASTOLIC DYSFUNCTION A Pellissier, E Larochelle, L Krsticevic, E Baron, V Le, A Roy, A Deragon, M Cote, P Laramée, S Leclerc, D Garcia, F Tournoux Montréal, Québec BACKGROUND:
American style football player linemen are known to develop hypertension and concentric cardiac remodeling during training. It is unclear whether such cardiac remodeling is linked to hypertension or to the development of an athlete’s heart. The goal of this study was to demonstrate whether such cardiac remodeling was associated or not with subclinical cardiac dysfunction. METHODS: Forty-two line position athletes (25 male football players, 9 female rugby players and 8 male rugby players) were scanned using a Vivid q echo machine (General Electrics). For each participant, left ventricle mass, systolic function (ejection