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Anticholinergic Medications: An Additional Contributor to Cognitive Impairment in the Heart Failure Population?
The 17th Annual Scientific Meeting Peripheral blood and urinary samples were collected in a time-course to analyze zinc concentration, cardiac enzymes and inflammation marker, interleukin-6 (IL6). In order to evaluate the cardiac function, the echocardiogram was performed at the admission in hospital and at 9 months post-AMI. Some patients who diagnosed cardiogenic shock and had a cancer and an inflammation disease were excluded in this study. Results: As the serum level of zinc in peripheral blood was within normal range (66w120mg/dl) in both groups, the zinc concentration was significantly augmented in the polaprezinc group compared to non-polaprezinc group (100.864.8 vs 72.466.2 mg/dl, p50.002). Obviously the urine zinc level of the polaprezinc group was higher than that of non-polaprezinc group (1259.76234.8 vs 464.3686.9 mg/dl, p50.008). There was no difference between two groups about the serum level and the duration of cardiac enzymes such as creatine phosphokinase (CPK) and aspartate aminotransferase (AST). However, IL-6/CPK was significantly lowered in the polaprezinc group (0.21560.068 vs 0.04260.017mg/dl, p50.033). In addition, ejection fraction (EF) of the polaprezinc group was significantly increased by echocardiogram between day 2 and 9 months post-MI (55.962.2 vs 63.463.2, p50.005). Conclusions: Medication of polaprezinc significantly reduced inflammatory cytokine and improved cardiac function post-AMI. Loaded zinc may have an effect on cardiac protection and can provide a favorable benefit on the patients with AMI.
193 S3 Amplitude Measured Using a CRT-D Is Correlated to Echocardiographic Filling Parameters in Heart Failure Patients Elizabeth Klodas1, Qi An2, Pramodsingh H. Thakur2, Ken Beck2, P.J. Vitoff3, Colleen Delaney3, Alan J. Bank4; 1Cardiovascular Imaging Consultants, Edina, MN; 2Boston Scientific, St Paul, MN; 3Boston Scientific, St Paul, MN; 4United Heart and Vascular Clinic, St Paul, MN Introduction: The third heart sound (S3) is a specific sign of ventricular diastolic dysfunction caused by elevated left ventricular filling pressure and/or depressed ventricular compliance and is known to carry significant diagnostic and prognostic information. Traditionally, S3 has been measured using an apical phonocardiogram. Whether S3 measured using an accelerometer (XL) within an implanted cardiac resynchronization therapy - defibrillator (CRT-D) in heart failure (HF) patients carries similar clinical information is unknown. In this study, we evaluated the relationship between S3 and echocardiographic filling parameters to demonstrate the clinical utility of device based acute S3 measurements. Method: PRE-SENSE study patients with a COGNISTM CRT-D implanted, were followed for 30 days. At enrollment the CRT-Ds were converted into IDE devices, via a software download enabling collection of heart sound (HS) data using the device based XL, and an echocardiographic exam was performed. An independent core laboratory measured parameters from the echo images. Off-line processing was employed to measure S3 from the HS data and differentiate patients into two groups: high S3 and low S3, where the threshold was chosen to separate upper quartile from the rest of patients. Key echocardiographic parameters including E-wave deceleration time (EDT), E deceleration rate (EDR), early diastolic velocity (E), and early diastolic mitral annulus velocity (E’), were compared between groups using Wilcoxon rank sum test as well as correlated with measured S3. Results: A total of 71 patients were enrolled at 11 centers resulting in 68 echo recordings, of which 62 had usable HS data during the echo exams. Table 1 compares key echo measures between the two groups. In addition, S3 correlated with EDT (r5-0.50, p!0.001), EDR (r50.48, p!0.001), E/A Ratio (r50.40, p50.002), E’ (r5-0.21, p50.107) and E/E’ septal ratio (r50.32, p50.011). Conclusion: S3 signals were reliably collected using implanted CRT-Ds. Group differentiation determined by acute measurement of S3 was confirmed by significant separations in a variety of echocardiographic parameters between the high S3 and low S3 groups. S3 also significantly correlated with EDT, EDR, E/A ratio and E/E’ ratio which are often used to assess LV diastolic function. Future studies are warranted to evaluate the clinical value of device-collected S3 in chronic settings.
Table I. Key echocardiographic measures between high and low S3 groups Measure LVEDD (cm) LVEDV (mL) LVESD (cm) LVESV (mL) LVEF (%) LAEDV (mL) E (cm/s) EDT (ms) EDR (m/s^2) E/A ratio E/E’ septal ratio E’ septal (cm/s)
Low S3 (n548)
High S3 (n514)
p-values
5.57 134.8 4.35 83.5 41.5 72.1 62.8 279.5 2.63 0.89 13.2 5.31
6.71 182.6 5.81 134.6 28.4 101.1 89.0 193.3 5.02 1.49 19.4 4.29
!0.001 0.005 !0.001 0.003 0.004 0.006 0.006 !0.001 !0.001 0.020 0.003 0.162
HFSA
S67
194 Anticholinergic Medications: An Additional Contributor to Cognitive Impairment in the Heart Failure Population? Arslan Shaukat1, Amir Habib1, Kathleen A. Lane2, Changyu Shen2, Yaron M. Hellman3, Irmina Gradus-Pizlo3, Mohammed A. Hadi3, Malaz Boustani4, Adnan S. Malik3; 1Indiana University School of Medicine, Indianapolis, IN; 2Indiana University School of Medicine, Indianapolis, IN; 3Indiana University School of Medicine, Indianapolis, IN; 4Indiana University School of Medicine, Indianapolis, IN Introduction: Patients with congestive heart failure (CHF) have a high prevalence of cognitive impairment and the association is multi-factorial. In general, the burden of anticholinergic drugs has consistently been shown to be a risk factor for cognitive impairment in the elderly. However, there is a lack of studies assessing the anticholinergic cognitive burden of drugs in patients with CHF. Objective: The aim of this study was to assess the cognitive burden of medications in patients with CHF. Methods: Patients who presented to a comprehensive heart failure clinic during the month of September 2012 were included in this cross-sectional, retrospective, single-center study. Patients were being treated for CHF due to systolic dysfunction (ischemic and non-ischemic), diastolic dysfunction, and congenital heart disease. The primary outcomes of interest were mean anticholinergic cognitive burden (ACB) score of all medications and CHF medications (ACB-CHF), calculated based on the anticholinergic cognitive burden scoring scale. The ACB-CHF score was further dichotomized as 0 or 1 (low anticholinergic burden) versus 2 or 3 (high anticholinergic burden). Descriptive statistics were used to summarize patient characteristics. Linear and logistic regression models were used to investigate associations between the ACB and dichotomized ACB-CHF scores and various subject characteristics including age, duration, type and severity of CHF, co-morbid conditions, and diagnosis of depression, dementia, or cognitive impairment. Results: A total of 182 patients were included. The mean ACB and ACB-CHF scores were 2.4 (range 0-13) and 1.0 (range 0-4) respectively, while 25.8% of patients had an ACBCHF score of 2 or 3. Co-morbidities of diabetes mellitus (p50.005), chronic kidney disease (p50.04) and anemia (p50.04), and having a diagnosis of depression (p50.02) were associated with significantly higher ACB scores. There was no association found between ejection fraction (EF) in patients with systolic heart failure and the ACB (p50.28) or ACB-CHF (p50.62) score. NYHA functional class of I was found to have significantly lower ACB-CHF scores (p50.02) compared to class IV. No other associations were statistically significant. Conclusions: Patients with CHF have a substantial exposure to anticholinergic medications with adverse cognitive effects. This may be another important contributor to the increased prevalence of cognitive impairment in these patients. Prospective studies are needed to assess the long-term impact from the cognitive burden of medications in this population.
195 Combined Use of a PI3K-mTOR Dual Inhibitor and Doxorubicin Induced Cardiac Hypertrophy and Early Death in Mice Xinhua Yan1, Yongyao Yang1, Juyong Lee1, Jillian Onufrak1, Sharath Sasi1, John Fuseler2, Robert L. Price2, Thomas K. Borg2, James P. Morgan1, David A. Goukassian1, Joseph Carrozza1; 1St. Elizabeth’s Medical Center, Boston, MA; 2 University of South Carolina School of Medicine, Columbia, SC The HER2-PI3K-mTOR pathway is pivotal for protecting the heart from chemotherapy drug doxorubicin (DOX). Studies from us and others have shown that the HER2 receptor and PI3Ks protect cardiomyocytes from DOX-induced apoptosis and loss of cardiac troponins. Currently, drugs targeting the HER2-PI3K-mTOR pathway are either approved or being tested in clinical trials for cancer therapy. It is, therefore, important to evaluate the cardiac effects of using these drugs alone or in combined with DOX. Methods: Three-month old female FVB/n mice were treated with BEZ235 (BEZ, a PI3K-mTOR dual inhibitor) alone or with DOX for 6-7 weeks. Cardiac function was monitored by echocardiography and hemodynamic measurements. Cardiac morphology was assessed by confocal microscopy and transmission electron microscopy. The activation of signaling molecules were measured by Western blot analysis. Results: BEZ alone induced cardiac hypertrophy and subsequent heart failure in a course of 17 months. Combination of BEZ with DOX, either concurrently or sequentially, induced cardiac hypertrophy which was associated with a higher mortality rate compared to DOX alone. Neuregulin1(an HER receptor ligand) worsened, while Lapatinib (an HER2 inhibitor) alleviated, cardiac hypertrophy in these mice. Lapatinib increased the activation of AMPK in DOX+BEZ treated hearts. The cardiac effect of lapatinib was blocked by Compound C, an AMPK inhibitor. Metformin, an AMPK activator, alleviated DOX+BEZ induced cardiac hypertrophy. Conclusions: BEZ alone induced irreversible cardiac dysfunction in mice. Combined use of BEZ and DOX induced cardiac hypertrophy and early mortality, which were prevented by lapatinib. The cardioprotective effects of lapatinib may rely on activating AMPK in the heart.
193 S3 Amplitude Measured Using a CRT-D Is Correlated to Echocardiographic Filling Parameters in Heart Failure Patients Elizabeth Klodas1, Qi An2, Pramodsingh H. Thakur2, Ken Beck2, P.J. Vitoff3, Colleen Delaney3, Alan J. Bank4; 1Cardiovascular Imaging Consultants, Edina, MN; 2Boston Scientific, St Paul, MN; 3Boston Scientific, St Paul, MN; 4United Heart and Vascular Clinic, St Paul, MN Introduction: The third heart sound (S3) is a specific sign of ventricular diastolic dysfunction caused by elevated left ventricular filling pressure and/or depressed ventricular compliance and is known to carry significant diagnostic and prognostic information. Traditionally, S3 has been measured using an apical phonocardiogram. Whether S3 measured using an accelerometer (XL) within an implanted cardiac resynchronization therapy - defibrillator (CRT-D) in heart failure (HF) patients carries similar clinical information is unknown. In this study, we evaluated the relationship between S3 and echocardiographic filling parameters to demonstrate the clinical utility of device based acute S3 measurements. Method: PRE-SENSE study patients with a COGNISTM CRT-D implanted, were followed for 30 days. At enrollment the CRT-Ds were converted into IDE devices, via a software download enabling collection of heart sound (HS) data using the device based XL, and an echocardiographic exam was performed. An independent core laboratory measured parameters from the echo images. Off-line processing was employed to measure S3 from the HS data and differentiate patients into two groups: high S3 and low S3, where the threshold was chosen to separate upper quartile from the rest of patients. Key echocardiographic parameters including E-wave deceleration time (EDT), E deceleration rate (EDR), early diastolic velocity (E), and early diastolic mitral annulus velocity (E’), were compared between groups using Wilcoxon rank sum test as well as correlated with measured S3. Results: A total of 71 patients were enrolled at 11 centers resulting in 68 echo recordings, of which 62 had usable HS data during the echo exams. Table 1 compares key echo measures between the two groups. In addition, S3 correlated with EDT (r5-0.50, p!0.001), EDR (r50.48, p!0.001), E/A Ratio (r50.40, p50.002), E’ (r5-0.21, p50.107) and E/E’ septal ratio (r50.32, p50.011). Conclusion: S3 signals were reliably collected using implanted CRT-Ds. Group differentiation determined by acute measurement of S3 was confirmed by significant separations in a variety of echocardiographic parameters between the high S3 and low S3 groups. S3 also significantly correlated with EDT, EDR, E/A ratio and E/E’ ratio which are often used to assess LV diastolic function. Future studies are warranted to evaluate the clinical value of device-collected S3 in chronic settings.
Table I. Key echocardiographic measures between high and low S3 groups Measure LVEDD (cm) LVEDV (mL) LVESD (cm) LVESV (mL) LVEF (%) LAEDV (mL) E (cm/s) EDT (ms) EDR (m/s^2) E/A ratio E/E’ septal ratio E’ septal (cm/s)
Low S3 (n548)
High S3 (n514)
p-values
5.57 134.8 4.35 83.5 41.5 72.1 62.8 279.5 2.63 0.89 13.2 5.31
6.71 182.6 5.81 134.6 28.4 101.1 89.0 193.3 5.02 1.49 19.4 4.29
!0.001 0.005 !0.001 0.003 0.004 0.006 0.006 !0.001 !0.001 0.020 0.003 0.162
HFSA
S67
194 Anticholinergic Medications: An Additional Contributor to Cognitive Impairment in the Heart Failure Population? Arslan Shaukat1, Amir Habib1, Kathleen A. Lane2, Changyu Shen2, Yaron M. Hellman3, Irmina Gradus-Pizlo3, Mohammed A. Hadi3, Malaz Boustani4, Adnan S. Malik3; 1Indiana University School of Medicine, Indianapolis, IN; 2Indiana University School of Medicine, Indianapolis, IN; 3Indiana University School of Medicine, Indianapolis, IN; 4Indiana University School of Medicine, Indianapolis, IN Introduction: Patients with congestive heart failure (CHF) have a high prevalence of cognitive impairment and the association is multi-factorial. In general, the burden of anticholinergic drugs has consistently been shown to be a risk factor for cognitive impairment in the elderly. However, there is a lack of studies assessing the anticholinergic cognitive burden of drugs in patients with CHF. Objective: The aim of this study was to assess the cognitive burden of medications in patients with CHF. Methods: Patients who presented to a comprehensive heart failure clinic during the month of September 2012 were included in this cross-sectional, retrospective, single-center study. Patients were being treated for CHF due to systolic dysfunction (ischemic and non-ischemic), diastolic dysfunction, and congenital heart disease. The primary outcomes of interest were mean anticholinergic cognitive burden (ACB) score of all medications and CHF medications (ACB-CHF), calculated based on the anticholinergic cognitive burden scoring scale. The ACB-CHF score was further dichotomized as 0 or 1 (low anticholinergic burden) versus 2 or 3 (high anticholinergic burden). Descriptive statistics were used to summarize patient characteristics. Linear and logistic regression models were used to investigate associations between the ACB and dichotomized ACB-CHF scores and various subject characteristics including age, duration, type and severity of CHF, co-morbid conditions, and diagnosis of depression, dementia, or cognitive impairment. Results: A total of 182 patients were included. The mean ACB and ACB-CHF scores were 2.4 (range 0-13) and 1.0 (range 0-4) respectively, while 25.8% of patients had an ACBCHF score of 2 or 3. Co-morbidities of diabetes mellitus (p50.005), chronic kidney disease (p50.04) and anemia (p50.04), and having a diagnosis of depression (p50.02) were associated with significantly higher ACB scores. There was no association found between ejection fraction (EF) in patients with systolic heart failure and the ACB (p50.28) or ACB-CHF (p50.62) score. NYHA functional class of I was found to have significantly lower ACB-CHF scores (p50.02) compared to class IV. No other associations were statistically significant. Conclusions: Patients with CHF have a substantial exposure to anticholinergic medications with adverse cognitive effects. This may be another important contributor to the increased prevalence of cognitive impairment in these patients. Prospective studies are needed to assess the long-term impact from the cognitive burden of medications in this population.
195 Combined Use of a PI3K-mTOR Dual Inhibitor and Doxorubicin Induced Cardiac Hypertrophy and Early Death in Mice Xinhua Yan1, Yongyao Yang1, Juyong Lee1, Jillian Onufrak1, Sharath Sasi1, John Fuseler2, Robert L. Price2, Thomas K. Borg2, James P. Morgan1, David A. Goukassian1, Joseph Carrozza1; 1St. Elizabeth’s Medical Center, Boston, MA; 2 University of South Carolina School of Medicine, Columbia, SC The HER2-PI3K-mTOR pathway is pivotal for protecting the heart from chemotherapy drug doxorubicin (DOX). Studies from us and others have shown that the HER2 receptor and PI3Ks protect cardiomyocytes from DOX-induced apoptosis and loss of cardiac troponins. Currently, drugs targeting the HER2-PI3K-mTOR pathway are either approved or being tested in clinical trials for cancer therapy. It is, therefore, important to evaluate the cardiac effects of using these drugs alone or in combined with DOX. Methods: Three-month old female FVB/n mice were treated with BEZ235 (BEZ, a PI3K-mTOR dual inhibitor) alone or with DOX for 6-7 weeks. Cardiac function was monitored by echocardiography and hemodynamic measurements. Cardiac morphology was assessed by confocal microscopy and transmission electron microscopy. The activation of signaling molecules were measured by Western blot analysis. Results: BEZ alone induced cardiac hypertrophy and subsequent heart failure in a course of 17 months. Combination of BEZ with DOX, either concurrently or sequentially, induced cardiac hypertrophy which was associated with a higher mortality rate compared to DOX alone. Neuregulin1(an HER receptor ligand) worsened, while Lapatinib (an HER2 inhibitor) alleviated, cardiac hypertrophy in these mice. Lapatinib increased the activation of AMPK in DOX+BEZ treated hearts. The cardiac effect of lapatinib was blocked by Compound C, an AMPK inhibitor. Metformin, an AMPK activator, alleviated DOX+BEZ induced cardiac hypertrophy. Conclusions: BEZ alone induced irreversible cardiac dysfunction in mice. Combined use of BEZ and DOX induced cardiac hypertrophy and early mortality, which were prevented by lapatinib. The cardioprotective effects of lapatinib may rely on activating AMPK in the heart.