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Clinical Correlates of Post-Exercise Heart Rate Recovery in Chronic Heart Failure
The 10th Annual Scientific Meeting of 141 genes (9.8%) while phenylbutyrateþcaptopril reversed 1131 (79.0%) (both p ! 0.01 vs. SHR-F). Although combined treatment induced changes in gene expression involving many cell processes, changes were most closely associated with a prominent suppression of apoptosis and proteolysis related genes. Thus, captopril stabilizes hemodynamics with heart failure and provides a window to treat underlying cardiac dysfunction, but did not improve intrinsic contractile function. The addition of phenylbutyrate to ACE inhibitor resulted in reversal of changes in transcripts, hypertrophy and myocardial dysfunction associated with heart failure. LV/Body Weight (ratio) SHR-NF SHR-F SHR-FþC SHR-FþCP
3.6 3.8 3.3 2.7
6 6 6 6
V0.1 (muscle lengths/s)
AT (g/mm2)
0.4 0.3 0.4 0.2*,y
4.3 2.5 2.7 5.3
6 6 6 6
0.3 0.7* 0.4* 1.8y,x
1.4 0.7 0.9 1.6
6 6 6 6
0.4 0.2* 0.2* 0.2y,x
Fibrosis (%) 12.5 21.9 22.8 18.4
6 6 6 6
Gene Expression (number)
3.5 3.6* 713[* 718Y* 3.1* 42Yy 99[y 4.0* 485Yy,x 646[y,x
AT 5 active tension; V0.1 5 shortening velocity mean 6 SD. *p ! 0.05 vs. SHR-NF. y p ! 0.01 vs. SHR-F. x p ! 0.01 vs. SHR-FþC.
Clinical Correlates of Post-Exercise Heart Rate Recovery in Chronic Heart Failure Thomas Dewland1, Detlef Wencker1, Ana Silvia Androne1, Katarzyna Hrniewicz1, Stuart D. Katz1; 1Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT Background: Autonomic imbalance is thought to play an important role in the progression of chronic heart failure (CHF). Deceleration of heart rate in the first minute post-exercise (heart rate recovery, HRR) is modulated primarily by augmentation of parasympathetic tone and therefore is an easily obtainable measure of autonomic function. In non-CHF populations, reduced post-exercise HRR is associated with increased mortality risk. The current study was undertaken to characterize the clinical correlates of post-exercise HRR in CHF patients. Methods: We collected post-exercise HRR data from all subjects who performed a cardiopulmonary exercise test at the Yale CHF center between 2002-2005. We used a standardized post-exercise recovery protocol in which the treadmill was stopped immediately at the end of a maximal exercise test and post-exercise HRR data were collected in the seated position. Post-exercise HRR@1 minute was calculated as the difference between the heart rates at peak exercise and at 1 minute post-exercise (beats/min (bpm)). Results: Exercise tests were analyzed in 156 CHF patients (mean age 44 yrs) and 31 non-CHF controls (mean age 39 yrs). Peak heart rate, percent predicted maximum heart rate, peak oxygen uptake and post-exercise HRR@1 minute were reduced in CHF when compared with controls (Table, all p-values ! 0.001). Respiratory exchange ratio (RER) at peak exercise did not differ between groups. Reduced post-exercise heart rate recovery was significantly associated with worsening NYHA class (30 bpm Class I, 26 bpm Class II, and 20 bpm Class III, p 5 0.001 for linear trend) and reduced peak oxygen uptake (r 5 0.41, p ! 0.001). The relationship between HRR and peak oxygen uptake was not altered in multivariate analyses adjusting for age, peak heart rate, or the use of beta-blockers. Conclusions: Post-exercise heart rate recovery is impaired in patients with CHF when compared with non-CHF control subjects and is associated with severity of impairment of functional capacity. These findings suggest that parasympathetic tone is diminished in patients with CHF when compared with non-CHF controls. Since this easily obtained measure of autonomic function is known to be independently associated with clinical outcomes in non-CHF subjects, additional studies are warranted to determine the relationship between post-exercise HRR and clinical outcomes in CHF.
Non-CHF controls CHF
Peak HR
%Pred. MaxHR
Peak VO2
RER
HRR@1 minute
179 6 2 134 6 2
96 6 1 76 6 1
38 6 3 19 6 1
1.12 6 .02 1.14 6 .01
35 6 2 23 6 1
041 Depressed Regional Circumferential Strain Is Associated with Increased BNP in Heart Failure Howard V. Dinh1,2, Juan Alvergue1, Carissa Fonseca2, Gregg Fonarow1, Divya Shokeen1, Miguel Valderrabano1, Kalyanam Shivkumar1,2, Paul Finn1,2; 1Medicine/ Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, CA; 2 Radiology/Diagnostic Cardiovascular Imaging Section, David Geffen School of Medicine, UCLA, Los Angeles, CA Regional circumferential strain is a measure of mechanical contractile property of myocardium. The clinical significance of circumferential strain (Sc), Sc heterogeneity, and their relationship to the heart failure (HF) biomarker BNP is poorly
HFSA
S13
understood. Hypothesis: Regional Sc heterogeneity is greater in HF compared to healthy subjects and Sc correlates with BNP. Methods: HF patients being considered for cardiac resynchronization therapy (CRT) (n 5 18, age 49.8 6 13.5, BNP 466pg/ ml 6 592, MVO2 14.8ml/kg 6 4, NYHA Class 2.6 6 0.9) and age-matched volunteers (n 5 20, age 43 6 14) were scanned with a 1.5T MRI using 2D-FLASH spatial modulation of magnetism sequence with grid tags (1mm diameter, 7mm space) and temporal resolution of 46 ms. The basal, mid and apical short axes were imaged with Sc assessed off-line by strain analysis software (Cardiac Imaging Modeler V5). Sc was calculated for all 16 segments of the LV. The strain index of heterogeneity (Ish) is defined as the segmental strain standard deviation at the time of peak global strain/average Sc x 100%. Result: HF patients demonstrated reduced LVEF and peak Sc. Ish values were significantly higher for HF compared to controls (Table). Mid LV Sc correlated with BNP level (r 5 0.72, p ! 0.01). Representative mid-LV Sc graph and end sytolic images for an individual control and HF subject is shown (Figure). Conclusion: HF patients have depressed Sc and increased regional Sc heterogeneity. Depressed Sc correlates with increased BNP level. Studies are on-going to assess whether these findings offer an incremental benefit in predicting responders to CRT. HF (n 5 18)
040
EF(%) Sc Apex Sc Mid Sc Base Ish Apex Ish Mid Ish Base
26 11 10 8.8 61.0 36.4 62.7
6 6 6 6 6 6 6
14 5 4 4 76.1 32.3 64
Control (n520) 63 23 21 16 14.0 20.4 28
6 6 6 6 6 6 6
7 3.6 5 5 7.47 31.5 24.9
p #0.001 #0.001 #0.001 #0.001 #0.05 #0.05 #0.05
Sc 5 circumferential strain (%)); Ish 5 Index of strain heterogeneity (%).
042 Real-Time In Vivo Detection of Myocyte Apoptosis M. Grosso1, M. Ranji1, S. Kanemoto1, M. Matsubara1, B. Chance1, R. Gorman1, J. Gorman1; 1Dept. Surg. Research, Univ.PA, Phila., PA Therapy to treat post infarction heart failure(CHF) has done little to improve survival. Effort is being spent on developing preventative therapies for post-MI CHF but effective techniques need to be developed to identify those patients at risk for ventricular remodeling(LVR) and CHF. Apoptosis in non-ischemic myocytes beyond the infarct are associated with LVR-CHF. Identifying apoptotic myocytes requires tissue biopsy- limiting its clinical usefulness. We have developed an in vivo method utilizing UV spectroscopy to detect myocyte apoptosis in real time. Methods: A rabbit ischemia- reperfusion (IR) injury producing a strong apoptotic stimulus was utilized. Adult rabbits (3-5 kg) were anesthetized and instrumented; via a thoracotomy the heart was exposed. A specially designed 3 mm fiber-optic probe was used to transmit and capture the specific UV frequencies of the mitochondrial fluorophores flavoprotein (FP) and nicotinamide adenine dinucleotide (NADH). With the probe on the heart surface, real-time, non- tissue destructive signals were captured allowing intrinsic tissue mitochondrial redox stateexpressed as (Fp/ Fp þNADH). Chance has shown ratio increases correlate strongly with apoptosis. The probe was placed on separate LV areas for baseline measures. The distal LAD artery was snare occluded-30 mins, followed by 180 mins of RP. Probe measurements (3X, 5 locations, 6 time points n 5 90) were obtained from non-ischemic (n 53) and ischemic (n 52) zones during I/R. Results: Fig/Table. Conclusions: Apoptosis, as indicated by a rise in the redox ratio (Fp/Fp þ NADH) was detected during late reperfusion. Detection was in real-time without tissue destruction utilizing a surface held optical probe. This technique may serve as a clinical non-invasive technology to assess the progression of apoptosis and may help identify patients who would benefit from early therapy after MI to prevent LVR/CHF.
3.6 3.8 3.3 2.7
6 6 6 6
V0.1 (muscle lengths/s)
AT (g/mm2)
0.4 0.3 0.4 0.2*,y
4.3 2.5 2.7 5.3
6 6 6 6
0.3 0.7* 0.4* 1.8y,x
1.4 0.7 0.9 1.6
6 6 6 6
0.4 0.2* 0.2* 0.2y,x
Fibrosis (%) 12.5 21.9 22.8 18.4
6 6 6 6
Gene Expression (number)
3.5 3.6* 713[* 718Y* 3.1* 42Yy 99[y 4.0* 485Yy,x 646[y,x
AT 5 active tension; V0.1 5 shortening velocity mean 6 SD. *p ! 0.05 vs. SHR-NF. y p ! 0.01 vs. SHR-F. x p ! 0.01 vs. SHR-FþC.
Clinical Correlates of Post-Exercise Heart Rate Recovery in Chronic Heart Failure Thomas Dewland1, Detlef Wencker1, Ana Silvia Androne1, Katarzyna Hrniewicz1, Stuart D. Katz1; 1Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT Background: Autonomic imbalance is thought to play an important role in the progression of chronic heart failure (CHF). Deceleration of heart rate in the first minute post-exercise (heart rate recovery, HRR) is modulated primarily by augmentation of parasympathetic tone and therefore is an easily obtainable measure of autonomic function. In non-CHF populations, reduced post-exercise HRR is associated with increased mortality risk. The current study was undertaken to characterize the clinical correlates of post-exercise HRR in CHF patients. Methods: We collected post-exercise HRR data from all subjects who performed a cardiopulmonary exercise test at the Yale CHF center between 2002-2005. We used a standardized post-exercise recovery protocol in which the treadmill was stopped immediately at the end of a maximal exercise test and post-exercise HRR data were collected in the seated position. Post-exercise HRR@1 minute was calculated as the difference between the heart rates at peak exercise and at 1 minute post-exercise (beats/min (bpm)). Results: Exercise tests were analyzed in 156 CHF patients (mean age 44 yrs) and 31 non-CHF controls (mean age 39 yrs). Peak heart rate, percent predicted maximum heart rate, peak oxygen uptake and post-exercise HRR@1 minute were reduced in CHF when compared with controls (Table, all p-values ! 0.001). Respiratory exchange ratio (RER) at peak exercise did not differ between groups. Reduced post-exercise heart rate recovery was significantly associated with worsening NYHA class (30 bpm Class I, 26 bpm Class II, and 20 bpm Class III, p 5 0.001 for linear trend) and reduced peak oxygen uptake (r 5 0.41, p ! 0.001). The relationship between HRR and peak oxygen uptake was not altered in multivariate analyses adjusting for age, peak heart rate, or the use of beta-blockers. Conclusions: Post-exercise heart rate recovery is impaired in patients with CHF when compared with non-CHF control subjects and is associated with severity of impairment of functional capacity. These findings suggest that parasympathetic tone is diminished in patients with CHF when compared with non-CHF controls. Since this easily obtained measure of autonomic function is known to be independently associated with clinical outcomes in non-CHF subjects, additional studies are warranted to determine the relationship between post-exercise HRR and clinical outcomes in CHF.
Non-CHF controls CHF
Peak HR
%Pred. MaxHR
Peak VO2
RER
HRR@1 minute
179 6 2 134 6 2
96 6 1 76 6 1
38 6 3 19 6 1
1.12 6 .02 1.14 6 .01
35 6 2 23 6 1
041 Depressed Regional Circumferential Strain Is Associated with Increased BNP in Heart Failure Howard V. Dinh1,2, Juan Alvergue1, Carissa Fonseca2, Gregg Fonarow1, Divya Shokeen1, Miguel Valderrabano1, Kalyanam Shivkumar1,2, Paul Finn1,2; 1Medicine/ Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, CA; 2 Radiology/Diagnostic Cardiovascular Imaging Section, David Geffen School of Medicine, UCLA, Los Angeles, CA Regional circumferential strain is a measure of mechanical contractile property of myocardium. The clinical significance of circumferential strain (Sc), Sc heterogeneity, and their relationship to the heart failure (HF) biomarker BNP is poorly
HFSA
S13
understood. Hypothesis: Regional Sc heterogeneity is greater in HF compared to healthy subjects and Sc correlates with BNP. Methods: HF patients being considered for cardiac resynchronization therapy (CRT) (n 5 18, age 49.8 6 13.5, BNP 466pg/ ml 6 592, MVO2 14.8ml/kg 6 4, NYHA Class 2.6 6 0.9) and age-matched volunteers (n 5 20, age 43 6 14) were scanned with a 1.5T MRI using 2D-FLASH spatial modulation of magnetism sequence with grid tags (1mm diameter, 7mm space) and temporal resolution of 46 ms. The basal, mid and apical short axes were imaged with Sc assessed off-line by strain analysis software (Cardiac Imaging Modeler V5). Sc was calculated for all 16 segments of the LV. The strain index of heterogeneity (Ish) is defined as the segmental strain standard deviation at the time of peak global strain/average Sc x 100%. Result: HF patients demonstrated reduced LVEF and peak Sc. Ish values were significantly higher for HF compared to controls (Table). Mid LV Sc correlated with BNP level (r 5 0.72, p ! 0.01). Representative mid-LV Sc graph and end sytolic images for an individual control and HF subject is shown (Figure). Conclusion: HF patients have depressed Sc and increased regional Sc heterogeneity. Depressed Sc correlates with increased BNP level. Studies are on-going to assess whether these findings offer an incremental benefit in predicting responders to CRT. HF (n 5 18)
040
EF(%) Sc Apex Sc Mid Sc Base Ish Apex Ish Mid Ish Base
26 11 10 8.8 61.0 36.4 62.7
6 6 6 6 6 6 6
14 5 4 4 76.1 32.3 64
Control (n520) 63 23 21 16 14.0 20.4 28
6 6 6 6 6 6 6
7 3.6 5 5 7.47 31.5 24.9
p #0.001 #0.001 #0.001 #0.001 #0.05 #0.05 #0.05
Sc 5 circumferential strain (%)); Ish 5 Index of strain heterogeneity (%).
042 Real-Time In Vivo Detection of Myocyte Apoptosis M. Grosso1, M. Ranji1, S. Kanemoto1, M. Matsubara1, B. Chance1, R. Gorman1, J. Gorman1; 1Dept. Surg. Research, Univ.PA, Phila., PA Therapy to treat post infarction heart failure(CHF) has done little to improve survival. Effort is being spent on developing preventative therapies for post-MI CHF but effective techniques need to be developed to identify those patients at risk for ventricular remodeling(LVR) and CHF. Apoptosis in non-ischemic myocytes beyond the infarct are associated with LVR-CHF. Identifying apoptotic myocytes requires tissue biopsy- limiting its clinical usefulness. We have developed an in vivo method utilizing UV spectroscopy to detect myocyte apoptosis in real time. Methods: A rabbit ischemia- reperfusion (IR) injury producing a strong apoptotic stimulus was utilized. Adult rabbits (3-5 kg) were anesthetized and instrumented; via a thoracotomy the heart was exposed. A specially designed 3 mm fiber-optic probe was used to transmit and capture the specific UV frequencies of the mitochondrial fluorophores flavoprotein (FP) and nicotinamide adenine dinucleotide (NADH). With the probe on the heart surface, real-time, non- tissue destructive signals were captured allowing intrinsic tissue mitochondrial redox stateexpressed as (Fp/ Fp þNADH). Chance has shown ratio increases correlate strongly with apoptosis. The probe was placed on separate LV areas for baseline measures. The distal LAD artery was snare occluded-30 mins, followed by 180 mins of RP. Probe measurements (3X, 5 locations, 6 time points n 5 90) were obtained from non-ischemic (n 53) and ischemic (n 52) zones during I/R. Results: Fig/Table. Conclusions: Apoptosis, as indicated by a rise in the redox ratio (Fp/Fp þ NADH) was detected during late reperfusion. Detection was in real-time without tissue destruction utilizing a surface held optical probe. This technique may serve as a clinical non-invasive technology to assess the progression of apoptosis and may help identify patients who would benefit from early therapy after MI to prevent LVR/CHF.