Do Electrocardiographic Changes during Dobutamine Stress Echocardiography Help Detect Coronary Allograft Vasculopathy in Heart Transplant Recipients?

The 11th Annual Scientific Meeting Methods: A continuous-flow impeller-style VAD (HeartMate II) was tested in a flow system consisting of plastic tubing and pressurized reservoirs designed to simulate the human circulation. Contrast-enhanced spectral Doppler was used to monitor the flow velocities in the inlet and outlet cannulae of the VAD. The Dopplermeasured minute flow rate (Dopp_Q) was calculated as the product of the spectral Doppler flow velocity time integral and the cannula cross-sectional area, normalized to 60-seconds. The actual minute flow rate was simultaneously measured with an ultrasonic flow meter (Q). The VAD rate was adjusted between 6,400 and 12,000 RPM in 13 steps and afterload was adjusted from none (tubing resistance only) to total occlusion in 5 steps. A total of 130 flow measurements were made, half with phasic inflow pressure and half with static inflow pressure. Results: Q ranged from -0.25 to 6.01 LPM. Dopp_Q in the outflow and inflow cannulae showed an excellent correlation with measured Q (Outlet Dopp_Q 5 1.0052*Q þ 0.048, R2 5 0.9865, and Inlet Dopp_Q 5 1.5043*Q þ 0.003, R2 5 0.9904), but the inlet Dopp_Q was 50% higher than the measured Q. This was determined to be due to different velocity profiles in the HeartMate II’s conical inlet tube compared to the uniform-diameter outflow graft, which showed plug flow. Correcting for the non-linear conical inlet tube’s velocity profiles yielded excellent correlation with measured Q (Inlet Dopp_Q 5 1.0029*Q þ 0.002, R2 5 0.9904). Phasic vs. non-phasic inflow pressure yielded results that were not statistically different. Conclusion: Non-invasive Doppler flow techniques can be used to accurately measure VAD flow, but the characteristics of the cannula velocity profiles need to be taken into account.

147 Comparison of Electrical and Mechanical Dyssynchrony To Predict the Acute Hemodynamic Response to Cardiac Resynchronization Therapy Michael R. Gold1, J. Lacy Sturdivant1, Robert B. Leman1, Barun Maskara2, Jonathan Kwok2, Yinghong Yu2; 1Medical University of South Carolina; 2Boston Scientific Corporation Hemodynamic response with cardiac resynchronization therapy (CRT) varies widely among heart failure (HF) patients (pts). Initially, QRS width and HF class were used solely to select pts. More recently, dyssynchrony was reported to predict responders more accurately. This analysis compared simple electrical and mechanical measures to predict acute hemodynamic response to CRT. Methods: We analyzed 15 pts with LBBB (65 6 11yrs, 93% NYHA Class III, 67% male, 60% ischemic) undergoing hemodynamic evaluation (LV dP/dt) during CRT implant. Variables analyzed were: intraventricular mechanical delay (septal to posterior wall motion delay), interventricular mechanical delay (time difference of opening of pulmonary and aortic valves by echocardiography), interventricular electrical delay (time difference in activation between RV and LV from intracardiac electrograms), QRS width, and LV activation time (QLV, time interval from the first deflection of surface ECG to the peak of LV free wall electrogram). A multivariate linear regression analysis of LV dP/dt improvement with CRT was used to quantify predictors of hemodynamic changes. Acute responders were defined as increase of LV dP/dt O 5% at any AV delay. Results: Stepwise multivariate analysis revealed that QLV was the only independent predictor of LV dP/dt improvement (P ! 0.001; r 5 0.82). The multivariate model demonstrated excellent sensitivity (100%), specificity (60%), positive predictive value (83%), and accuracy (87%) in predicting responders. Conclusion: Baseline electrical dyssynchrony as assessed by LV activation time predicted the magnitude of hemodynamic response to CRT. The QLV interval is easily measured at implant and may provide a simple means of selecting LV stimulation site. It predicted acute hemodynamic response to CRT better than mechanical dyssynchrony.

148 Factors Affecting Early Mortality in Patients Receiving Ventricular Assist Devices as Bridge to Transplant Amber M. Shah1, Marc A. Simon1, Duc Nguyen1, Jay Bhama1, Christian Bermudez1, Yoshiya Toyoda1, Jeffrey Teuteberg1, Kenneth McCurry1, Michael Siegenthaler1, Robert Kormos1; 1University of Pittsburgh Medical Center, Pittsburgh, PA Ventricular assist devices (VAD) are effective bridges to transplantation in patients (pts) with severe heart failure (HF) yet early post-implant mortality remains a problem. We performed this study to identify factors that predict post-implant 60-day mortality. Methods: Pre-implant clinical data were reviewed for consecutive adult HF pts receiving VADs as bridges to transplantation. Logistic regression analyses were performed to identify risk factors for post-implant 60-day mortality. Groups were created based on the number of multivariate risk factors, and mortality rates for these groups were calculated. Results: There were 154 pts implanted with VAD between 1996 and 2003 (age 49.1 6 12.5 years, 26% female, 52% ischemic cardiomyopathy (ICM), mean length of support 117.6 6 122.8 days). Devices used were 39 Novacor LVAS, 18 Heartmate LVAS VE, 27 Thoratec LVAD, 64 Thoratec BiVAD, 2 Thoratec IVAD LVAD, and 4 Thoratec RVAD. The 60-day mortality post-VAD implant was 17.5% (27/154 pts). This represents 66% of all deaths postVAD placement in this cohort. Causes of death were multi-organ failure in 11, respiratory failure in 2, right ventricular failure in 2, sepsis in 5, neurological event in 5, and non-neurological bleed in 2 pts. Univariate predictors of 60-day mortality were ICM (Odds ratio (OR) 5 5.2, 95% Confidence Interval (CI) 5 1.9e14.7),



HFSA

S117

antiarrhythmic medication other than amiodarone (OR 5 3.6, 95% CI 5 1.4e9.4), prothrombin time (PT) $ 15 seconds (OR 5 2.7, 95% CI 5 1.1e6.6), absence of implantable cardioverter-defibrillator (ICD) (OR 5 3.1, 95% CI 5 1.01e9.7), and lack of treatment with vasodilator medication (OR 5 2.8, 95% CI 5 1.1e7.0). Independent predictors of 60-day mortality in multivariate analysis were ICM (OR 5 6.1, 95% CI 5 1.9e19.4), antiarrhythmic medication other than amiodarone (OR 5 3.7, 95% CI 5 1.2e11.1), PT $ 15 seconds (OR 5 4.3, 95% CI 5 1.5e12.2) and absence of ICD (OR 5 3.9, 95% CI 5 1.1e13.8). Sixty-day mortality was 0%, 7.1%, 15.2%, 45%, and 100% in groups with 0, 1, 2, 3, and all 4 multivariate risk factors (p-value ! 0.001). Conclusions: Two thirds of all VAD mortality occurred in the first 60 days. ICM, prolonged PT, antiarrhythmic medications other than amiodarone, and absence of ICD are easily identifiable independent predictors of early mortality post-VAD implantation. Increasing number of these risk factors is strongly associated with increased early mortality in these pts.

149 Cardiac Contractility Modulation Electrical Signals Combined with b-Blockade Improve Myocardial Protein Expression of Phosphorylated Phospholamban in Dogs with Heart Failure beyond That Seen with b-Blockade Alone Sudhish Mishra1, Ramesh C. Gupta1, Mengjun Wang1, Alice Jiang1, Benny Rousso2, Yuval Mika2, Hani N. Sabbah1; 1Cardiovascular Medicine, Henry Ford Health System, Detroit, MI; 2Impulse Dynamics USA, Inc., Orangeburg, NY Background: We previously showed that chronic therapy with non-excitatory cardiac contractility modulation (CCM) electrical signals delivered to the left ventricular (LV) myocardium during the absolute refractory period improves LV ejection fraction (EF) and increases expression of phosphorylated phospholamban (P-PLB) and SERCA-2a in dogs with heart failure (HF). P-PLB acts to increase the activity of SERCA-2a in the sarcoplasmic reticulum. Reduced activity of SERCA-2a is a key maladaptation responsible for the progressive worsening of LV function in HF. We also showed that in dogs with chronic HF, CCM therapy combined with a b-blockade (BB) improves LV EF beyond that seen with BB alone. The present study examined the effects of combined therapy with CCM and BB on protein expression of P-PLB in LV tissue of dogs with intracoronary microembolization-induced HF. Methods: Tissue homogenate was prepared from LV myocardium of dogs randomized to 3 months therapy with BB alone (metoprolol succinate, 100 mg once daily), BB combined with CCM, or to no therapy at all (Control). Tissue from 6 normal (NL) dogs was used for comparison. Expression of P-PLB at serine-16 (S-16) and threonine-17 (T-17) was measured using Western blots and bands quantified in densitometric units (du). Results: P-PLB at S-16 and T-17 decreased in Control compared to NL dogs. BB alone increased expression of P-PLB at both S-16 and T-17 whereas combined therapy with BB and CCM increased P-PLB at S-16 and T-17 to levels significantly above those seen with BB alone. Conclusions: In LV myocardium of dogs with HF, combination therapy with BB and CCM affords a greater improvement in P-PLB, a key modulator of sarcoplasmic reticulum SERCA-2a. These findings provides a biochemical foundation for the observed improvement in EF seen with combination BB and CCM therapy compared to BB alone. Expression of P-PLB

P-PLB at S-16 (du) P-PLB at T-17 (du)

NL

HF-Control

HFþBB

HFþBBþCCM

97 6 7 127 6 3

65 6 2* 70 6 2*

77 6 1*y 91 6 2*

91 6 4yz 110 6 6*z

* 5 p ! 0.05 vs. NL; y 5 p ! 0.05 vs. HF-Control; z 5 p ! 0.05 vs. HFþBB.

150 Do Electrocardiographic Changes during Dobutamine Stress Echocardiography Help Detect Coronary Allograft Vasculopathy in Heart Transplant Recipients? M. Obadah N. Al Chekakie1, David Thompson1, Fei Wang1, Joya Ganguly1, Ravjyot Chawla1, Joseph Akar1, John Barron1; 1Cardiovascular Medicine, Loyola University Medical Center, Maywood, IL Background: Coronary allograft vasculopathy (CAV) is the main cause of late death and re-transplantation in cardiac transplant recipients. Dobutamine stress echocardiography (DSE) has been shown to predict cardiac events and CAV in heart transplant patients. However, the role of electrocardiographic (ECG) changes during DSE in post transplant patients remains undetermined. Methods: We followed 141 consecutive heart transplant patients (age 50.5 6 11.4 yrs, 81% male) for 6.6 6 4.1 years post transplant. All patients underwent annual DSE and coronary angiography (CA) to detect CAV. A total of 436 DSE and 436 CA were performed within 6 months of each other. CAV was considered present if O 50% narrowing of lumen diameter was observed in CA. Rest e Stress echocardiographic images were obtained in 4 standard views of the left ventricle. ECG evidence of ischemia was considered present if the patient had O 1 mm horizontal or down sloping ST segment depression. A positive DSE was considered present if new wall motion abnormalities (WMA) developed or if the wall motion failed to improve with dobutamine infusion. Results: there were 94/436 angiograms demonstrating CAV. For the DSE tests performed, 51/436 had a positive DSE and 19/436 had ST changes suggestive of ischemia with dobutamine. In univariate analysis, only presence of baseline WMA predicted CAV (OR 3.3, 95% CI 1.7e6.3, p ! 0.01) while a positive DSE (OR 1.8, 95% CI 0.96e3.5, p 5 0.07] or

S118 Journal of Cardiac Failure Vol. 13 No. 6 Suppl. 2007 ST segment depression (OR 0.41, 95% CI 0.10e1.9, p 5 0.25] did not. Using multiple logistic regression to correct for other variables, only baseline WMA (OR 3.1, 95% CI 1.4e6.6, p 5 0.005) and longer time from transplant (OR 1.14, 95% CI 1.10e1.19, p ! 0.001) predicted CAV. While a positive DSE (OR 1.22, 95% CI 0.56e2.61, p 5 0.62), baseline EF ! 50% (OR 0.7, 95% CI 0.20e2.50, p 5 0.51) and ST segment depression with dobutamine (OR 0.41, 95% CI 0.10e2.1, p 5 0.26) did not. A positive DSE had 17% sensitivity, 90% specificity, 31% positive predictive value and 80% Negative predictive value to detect CAV. Conclusions: ST segment depression with dobutamine does not predict CAV in transplanted patients. The ischemic response to dobutamine stress may be altered in denervated hearts. A positive DSE has a low sensitivity to detect CAV, which is in contrast to other studies that showed a higher sensitivity. Only time from transplant and presence of baseline WMA predicts CAV.

151 Assist Devices Fail To Induce Reverse Fetal-Pattern Gene Expression Despite Administration of Beta Blockers Norman Gray1, Brian D. Lowes1, Mihail Calalb1, Ron Zolty1, Andreas Brieke1, JoAnn Lindenfeld1, Simon Shakar1, Eugene Wolfel1, Joe Cleveland1, Michael R. Bristow1; 1Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO

No difference in the degree of change of Cr by calcineurin use, duration of sirolimus, start of sirolimus post TX year ! 2 v. O 2, or baseline Cr ! 2.5 v. O5 2.5 mg/dL.

153 Background: Heart failure is associated with reversal to a fetal gene expression pattern of contractile and metabolic genes. Substantial recovery of ventricular function with assist devices is rare. The role of Hypoxia-Inducible Factor (HIF) has generated great interest in its potential to alter unfavorable gene expression patterns including those involved in glycolysis, angiogenesis, and other as yet defined responses. Betablockers are known to improve myocardial function in heart failure but whether there effect on function is due to change in heart-failure associated gene expression remains largely unknown. Hypothesis: Despite increases in LVEF and administration of therapies (beta-blockers) known to favorably affect gene programs, assist devices fail to produce sustained myocardial recovery because of persistent fetal-pattern gene expression. Methods: Human heart tissue was obtained from the left ventricular apex at the time of assist device implantation and again from the left ventricular free wall during cardiac transplantation. Non-failing tissue was obtained from unutilized hearts from human donors. Gene expression was measured with the Affymetrix 133 plus 2 Array. HIF-1a was measured by Western blotting with commercially available antibodies. Results: In the failing heart, the elevated expression of HIF is reversed with unloading of the heart by assist device placement (p ! 0.05). Failing heart samples were associated with a decrease in a-myosin heavy chain (P ! 0.05) sacoplasmic reticulum-Caþþ ATPase mRNA expression, and with an increase in skeletal tropomyosin (p ! 0.05). This pattern persisted after assist device therapy. Heart failure was also associated with abnormalities in regulatory metabolic genes including GLUT1. These patterns also persisted after assist device therapy despite a reduction in ANP expression (p ! 0.05) and normalization of HIF-1a. Conclusions: Unloading of the failing heart with assist devices while on beta-blockade does not produce sustained recovery of myocardial contractile function, which may be in part to persistent fetal transcriptional patterns of contractile and metabolic genes.

152 Long-Term Change in Creatinine among Cardiac Transplant Patients with Dose Reduced Calcineurin after the Addition of Sirolimus Michael Shullo1, Sameer Khandhar2, Hemal Shah2, Colleen Yost2, Rachelle Zomak2, Meghan Rebel2, Dennis McNamara2, Robert Kormos3, Kenneth McCurry3, Jeffrey Teuteberg2; 1Department of Pharmacy and Therapeutics, University of Pittsburgh Medical Center, Pittsburgh, PA; 2Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA; 3Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, PA Purpose: The development or worsening of renal insufficiency is a common complication of chronic calcineurin use after cardiac transplantation (TX). Adding sirolimus allows for calcineurin dose reduction and may retard the progression of renal insufficiency. Methods: All TX patients at a single center from 1/82 until 12/06 started on sirolimus in place of azathioprine (AZA) or mycophenolate mofetil (MMF) for either the development of renal insufficiency or transplant vasculopathy. Minimum duration of sirolimus treatment was 30 days. Results: 51 patients met inclusion criteria (mean age 52 years, 78% male, 86% white, 45% ischemic). Donors: mean age 33 years, 71% male, 73% white. Transplant: 195 minutes, CMV mismatch (Dþ/R-) 16%, induction 10%. At sirolimus switch calcineurin was tacrolimus 67%; mean days post TX 2067 (þ/- 1700); indication for the switch was renal insufficiency 57%, transplant vasculopathy 43%. Conversion: AZA or MMF stopped, sirolimus 6mg load then 2mg/day, goal level 5, once sirolimus therapeutic and if no rejection, then calcineurin dose decreased, biopsies at weeks 2, 4, and 6. Mean duration of sirolimus treatment was 727 days (þ/- 555, range 56-1668). The mean creatinine (Cr) in mg/dL prior to the change was 2.06 and at 30, 60, 180 days, 1 and 2 years was: 2.13, 2.19, 2.23, 2.50, and 2.54 respectively (p 5 0.3461). The degree of change in Cr at each time period is a seen in Figure 1. Conclusions: The addition of sirolimus with calcineurin dose reduction resulted in stabilization of renal function over the subsequent two years. Better predictors are required for those who may benefit the most from such an intervention.

Stroke Volume Alterations in Patients Undergoing Left Ventricular Reconstructive Surgery: A Meta-Analysis of 3,131 Cases Lon S. Annest1, Danial Burkhoff2, Ulrich P. Jorde3, Andrew S. Wechsler4; 1 BioVentrix, San Ramon, CA; 2Impulse Dynamics, Tel Aviv, Israel; 3New York Presbyterian Columbia University; 4Cardiothoracic Surgery, Drexel University College of Medicine, Philadelphia, PA Background: Left ventricular reconstruction (LVR) is an emerging treatment modality in advanced heart failure (HF) due to ischemic cardiomyopathy. Substantial improvement is NYHA functional class has been reported, along with significant reductions in end-diastolic volume (EDV) and increases in ejection fraction (EF). However, the impact of LVR on the pumping capacity of the reconstructed LV is not known. Hypothesis: Increase in EF does not explain observed functional improvement after LVR, and resting cardiac output does not increase post operatively. Methods: An investigation of published literature was conducted with the search terms ‘‘ventricular-reconstruction-restoration-remodeling-aneurysmectomy-Dor ‘‘ and those reporting outcomes of the surgical procedure, along with pre and post operative ventricular volume data, were analyzed. Mean pre and post operative EF, enddiastolic (EDVI) , end-systolic (ESVI) and stroke volumes (SVI), each indexed to body surface area, were calculated. Results: A total of 3,131 patients from 24 publications are included. While post op volumes decreased significantly and EF increased by almost 11 absolute percentage points, SV was decreased in the resting post op state (Table 1). Conclusion: SVR, by its intrinsic design reduces LVEDVI significantly. A significant rise in ejection fraction (observed) is required to preserve stroke volume. Consistent improvement in functional class has been assumed to be the consequence of enhanced cardiac index when heart rate is not significantly different. This study challenges this mechanism for functional improvement and directs future attention toward quantitation of peak exercise cardiac output and/or maximal oxygen consumption, both important indices of cardiac hydraulic function and both unstudied, to date. Table 1. Parameter ESVI EDVI SVI EF

Pre Op 121.2 166.0 44.8 27.8%

6 6 6 6

34.1 43.8 13.9 5.4%

Post Op

Percentage Change

6 6 6 6

-46.6% -36.9% -10.5% 40.6%

64.7 104.8 40.1 39.1%

16.8 23.6 8.8 4.9%

ESVI 5 end systolic volume index cc/m2 EDVI 5 end diastolic volume index cc/m2 SVI 5 stroke volume index cc/m2.

154 Incidence of Rejection after Adding Sirolimus to a Dose Reduced Calcineurin Inhibitor after Cardiac Transplantation Michael Shullo2, Sameer J. Khandhar1, Hemal Shah1, Rachelle Zomak3, Colleen Yost3, Meghan Rebel3, Dennis McNamara1, Robert Kormos3, Kenneth McCurry3, Jeffrey J. Teuteberg1; 1Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA; 2Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, PA; 3Heart, Lung, and Esophageal Institute, University of Pittsburgh, Pittsburgh, PA Purpose: Evidence supporting a role for sirolimus after cardiac transplantation (CTX) is growing. The long-term safety of changing to a regimen utilizing sirolimus has not been well described. Methods: All CTX at a single center from 1/1/1982 until 12/31/06 started on sirolimus in place of azathioprine (AZA) or mycophenolate mofetil (MMF) and the duration of treatment with sirolimus O 30 days. Results: A total of 78 patients met inclusion criteria (mean age 50 years, 68% male, white