Simvastatin restores contractile function and reduces cardiac remodeling in cardiomyopathy

The Journal of Heart and Lung Transplantation Volume 22, Number 1S detectable in 2 hours and to 2.1⫾0.2 fold in 10 hours by RT-PCR and the fluorescent image of Green Fluorescence Protein expression was able to be observed within 8 hours. In conclusion: these results suggest that this new EP-mediated gene transfer technique may be potentially applicable for gene delivery in human heart. 103 IMMUNOLOGY PROPERTIES OF RAT VASCULAR ENDOTHELIUM M. Riha, D. Kreisel, A.S. Krupnick, K.R. Balsara, B.R. Rosengard, Harrison Department of Surgical Research, University of Pennsylvania, Philadelphia, PA Introduction: Vascular endothelium is now recognized as an immunologically active tissue and has been shown to activate T lymphocytes in numerous large and small animal models. Our goal was to evaluate the ability of rat vascular endothelium to activate allogeneic T lymphocytes due to the importance of this animal model in the study of cardiac immunology. Methods: Vascular endothelial cells were isolated from adult PVG rats using a modification of previously described protocols and surface phenotype was evaluated utilizing flow cytometry. Standard CFSE proliferation assays were carried out using purified allogeneic DA CD4⫹ and CD8⫹ T lymphocytes activated by PVG vascular endothelium. Results: Rat endothelial cells express typical phenotypic (CD 31, CD 54, CD 106) markers of vascular endothelium. After activation with IFN-␥ the rat vascular endothelium expresses high levels of upregulated MHC Class I and MHC Class II. Furthermore these cells express the accessory molecule CD 80, while there is no evidence of CD 86, which provide them the ability to function as antigen presenting cells. Alloreactive CD4⫹ and CD8⫹ T lymphocytes demonstrate proliferation after co-culture with activated vascular endothelium. Proliferation of CD4⫹ T lymphocytes was 10.4% (N⫽4) while proliferation of CD8⫹ T lymphocytes was 32.3% (N⫽4). Conclusion: Our data clearly demonstrate that purified rat vascular endothelium can activate unprimed CD8 and CD4 T lymphocytes in vitro. This important pathway of allorecognition need to be taken in to account when utilizing the rat model of heart transplantation for immunological studies. 104 EVALUATION OF CHANGES IN FUNCTIONAL CAPACITY, QUALITY OF LIFE AND HOSPITAL DAYS FOLLOWING PARTICIPATION IN CARDIOPULMONARY REHAB IN PATIENTS WITH CONGESTIVE HEART FAILURE L. Houston-Feenstra, J.T. Heywood, K. Jutzy, R.V. Jutzy, Cardiology, Loma Linda University Medical Center, Loma Linda, CA Controversy exits in the management of congestive heart failure(CHF), regarding the association between functional improvement, quality of life and the impact these factors have on health care costs. This study was designed to evaluate changes in functional capacity, quality of life and hospital days, following participation in a non-traditional rehabilitation program, in patients with CHF. Thirty five patients were studied with an average ejection fraction of 20%, patients were followed for 2 years following completion of rehab for determination of incidence of rehospitalization. Treadmill testing and assessment of quality of life using the Minnesota Living with Heart Failure tool (lower score ⫽ better quality of life) were collected prior to and after completion of rehab. Data for hospital days was obtained from patient records and subject interviews. The American Heart Association published estimates of the average Hospital charge per day for patients with a diagnosis of CHF, this estimate of $2500.00 per day was used to calculate “estimated hospital charges”.

Abstracts

S107

Results

Pre Rehab Post Rehab P Score

Maximum Exercise Duration

VO2/KG

Quality of Life: Total Score

Hospital Days

4.8 Min 8.0 Min .0001

11.0 13.9 .006

78 45 .002

9.6 2.8 .0001

Estimated Hospital charges: ONE YEAR pre rehab ⫽ $24,000.00 per patient, TWO YEARS post rehab $7000.00 per pateint. Conclusions: 1. Non-Traditional Cardiopulmonary Rehab resulted in a significant improvement in both functional capacity and Quality of life for all patients. 2. All patients demonstrated a significant decrease in the number of hospital days following rehab. 105 CAN CHANGES OVER TIME IN ECHOCARDIOGRAPHIC MEASUREMENTS; CARDIOPULMONARY EXERCISE TESTING AND RADIONUCLIDE VENTRICULOGRAPHY PREDICT OUTCOME IN PATIENTS WITH CHRONIC HEART FAILURE? ¨ berfuhr,2 B. Reichart,2 K. Theisen,1 H.-U. Stempfle,1 A. Alt,1 P. U 1 Cardiology, Med. Klinik - Innenstadt, Munich, Germany; 2Cardiac Surgery, Klinikum Grosshadern, Munich, Germany Single measurements of hemodynamic parameters including peak VO(2), VE/VCO(2) and left ventricular ejection fraction (LVEF) have significant prognostic importance in patients with chronic heart failure. In contrast, the predictive value of hemodynamic changes over time is less defined. Therefore the aim of this study was to evaluate changes over time in serial echocardiographic, cardiopulmonary exercise and radionuclide ventriculography testings to predict mortality in patients with chronic heart failure. Methods: 145 patients with chronic heart failure (127 men, mean age: 52⫾10 years, mean peak oxygen consumption (peak VO2)⫽15.2⫾4.5 ml/kg/min, percental peak VO2⫽50⫾14%, maximal work load⫽91⫾30W, peak systolic blood pressure (SBP)⫽142⫾32mmHg, anaerobic threshold (AT)⫽13.7⫾3.7mlO(2)/min, mean LVEF⫽26⫾9%, right ventricular EF⫽41⫾9 %, fractional shortening (FS)⫽15⫾6 %, LV enddiastolic diameter (LVED)⫽73⫾10mm, LV endsystolic diameter (LVES)⫽62⫾11 mm) underwent echocardiographic, treadmill exercise testing and radionuclear examination on 4.4⫾2.8 occasions with a mean follow-up of 23⫾17 months (range 3-88 months). Results: During the follow-up period, 15 patients (10%) died and 46 (32%) underwent heart transplantation. Changes over time in percental peak VO(2) (p⬍0.001), peak VO(2) (p⫽0.001), peak SBP (p⬍0.01), maximal work load (p⬍0.01), LVED and LVES (p⬍0.05) were significant prognostic markers for non-transplanted survival. In contrast, changes in RV- as well as LVEF, FS, AT and maximal work load were not significantly different between non-transplanted survival and death/ heart transplantation. Conclusions: Changes over time in parameters of cardiopulmonary exercise testing and LV diameter can add additional prognostic information in patients with chronic heart failure. Changes in myocardial contractility measured by FS or EF showed however, no prognostic value. 106 SIMVASTATIN RESTORES CONTRACTILE FUNCTION AND REDUCES CARDIAC REMODELING IN CARDIOMYOPATHY J.C. Osorio, S.S. Abraham, B.D. Kaufman, S. Homma, S. Mital, Pediatrics, Columbia University, New York, NY

S108

Abstracts

Background: B2 kinin receptor (B2R) stimulation activates endothelial nitric oxide synthase (eNOS). Disruption of the B2R results in dilated cardiomyopathy which may be related to decreased NO. Simvastatin (Sim) increases cardiac NO production through increased expression and/or phosphorylation of eNOS. We evaluated the ability of Sim to upregulate NO production and reduce contractile dysfunction and cardiac remodeling in mice lacking the B2R. Methods: 2 month old, male mice with genetic disruption of the B2R (B2RKO) (n⫽16) and wild-type controls (B2RWT) (n⫽20) were studied. Half the mice in each group were treated with Sim (20mg/kg/ day oral) for 6 weeks. 2D echocardiography was performed at baseline and 6 weeks to measure cardiac function and dimensions. At 6 weeks, eNOS, phospho-eNOS and phospho-Akt expression was measured in myocardium. Results: B2RKO mice developed LV hypertrophy compared to WT (LV mass 6.6⫾0.3 vs 5.6⫾0.3 mg/m2; mass/volume ratio 0.7⫾0.01 vs 0.63⫾0.02) with increase in LV volume (9.6⫾0.4 vs 8.0⫾0.5 ml/m2), LV end-systolic diameter (16.3⫾0.9 vs 13.4⫾0.8 cm/m2) and decrease in LV shortening fraction (SF 48⫾2% vs 57⫾2%) (p⬍0.05 vs WT). Sim treatment lowered LV mass (5.6⫾2 mg/m2), volume (8.2⫾0.3 ml/m2), systolic diameter (1.4⫾0.5) and increased SF (57⫾1%) in KO mice compared to untreated group (p⬍0.01). Phospho-eNOS expression was lower in KO mice compared to WT (p⫽0.05). Sim treatment decreased eNOS (p⫽0.006) but increased phospho-eNOS expression (p⬍0.05) compared to untreated KO. Phospho-Akt, which phosphorylates eNOS, was also higher in the Sim treated KO. Conclusion: Disruption of the B2R results in reduced eNOS activation and progressive cardiac remodeling and dysfunction. Sim reduces contractile dysfunction and cardiac remodeling by increasing Aktmediated eNOS phosphorylation. Since B2R and eNOS expression is reduced in human heart failure, this novel effect of Sim may be potentially beneficial in the treatment of heart failure. 107 THE DIFFERENTIAL IMPACT OF SPIRONOLACTONE ON PATTERNS OF PRO-INFLAMMATORY CYTOKINE EXPRESSION IN ADVANCED HEART FAILURE J.R. Becker, M.E. Keebler, P.A. Uber, M.H. Park, R.L. Scott, M.R. Mehra, Cardiomyopathy and Heart Transplantation Ctr, Ochsner Clinic Foundation, New Orleans, LA Background: The aldosterone antagonist spironolactone is presumed to increase survival in advanced heart failure by a number of mechanisms including reduced cardiac collagen turnover, improvement in heart variability, and reduction in ventricular arrhythmias. The effects of spironolactone on patterns of proinflammatory cytokine expression has not been previously elucidated. Methods: We prospectively examined 33 patients with advanced heart failure (LV ejection fraction (mean ⫾ SD) 23 ⫾ 13%, age 64 ⫾ 12yrs, 70% men, 51% on spironolactone). Plasma levels of tumor necrosis factor-alpha, interleukin-6, and soluble intercellular adhesion molecule-1 were determined by enzyme-linked immunoassay. In addition, detailed clinical data and whole blood B-type natriuretic peptide levels were analyzed. Results: Those receiving spironolactone (n⫽18) or not (n⫽15) did not differ with regard to age and gender, clinical severity (NYHA class III), or LV ejection fraction (23 ⫾ 13 vs 24 ⫾ 14%, p⫽ns), but trended toward higher B-type natriuretic peptide levels (539 ⫾ 455 vs 334 ⫾ 350 pg/ml, p⫽0.1), respectively. Similarly, no differences (p⫽ns) in the groups with regard to the use of ACE inhibitors (83 vs 93%), beta blockers (72 vs 80%) and amiodarone (17 vs 27%) were noted. See table for cytokine and soluble adhesion molecule data.

The Journal of Heart and Lung Transplantation January 2003

Group

Spironolactone No Spironolactone p Value

Tumor Necrosis Factor Alpha (pg/ml)

Interleukin-6 (pg/ml)

sICAM-1 (ng/ml)

2.6 ⫾ 1.1 3.7 ⫾ 1.8 0.03

7.5 ⫾ 5.5 6.9 ⫾ 3.6 0.7

258 ⫾ 118 298 ⫾ 159 0.42

Conclusion: Spironolactone therapy in advanced heart failure is associated with decreased TNF-Alpha but not IL-6 or sICAM-1. Thus, this investigation suggests that at least some of the benefits of aldosterone antagonism in severe heart failure may be mediated via effects on cytokine expression.

108 THE INTRINSIC MITOCHONDRIAL OXIDATIVE CAPACITY OF THE FAILING HEART IS DEPRESSED AND RELATES TO MARKERS OF DISEASE SEVERITY B. Mettauer,2 J. Zoll,1 B. N’Guessan,1 F. Ribera,1 O. Roth,2 J.P. Mazzucotelli,4 E. Epailly,4 E. Lampert,1 R. Ventura-Clapier,3 B. Geny,1 1Physiology, Faculty of Medicine, Strasbourg, France; 2 Cardiology, Hopitaux Civils de Colmar, Colmar, France; 3ISERM U446, Faculty of Pharmacy, Chatenay-Malabry, France; 4 Cardiovascular Surgery, University Hospital, Strasbourg, France As in the failing heart(FH) the myocyte suffers from energetic imbalance but the intrinsic in-situ mitochondria(MI) properties remain poorly known we have determined in samples from 19 explanted FH (LVEF:24⫾1%) at the time of heart transplantation the left(LV) and right(RV) ventricular maximal ADP-stimulated MI respiration(Vm, ␮molO2/min/g) in an oxigraphic cell after saponine-skinning, and compared it to Vm of LV samples from 5 unfailing control(C) hearts, procured during surgery for acute mitral valve regurgitation (LVEF: 69⫾3%). The Michaelis constant(Km, ␮M) was calculated by stepwise ADP increase as index of ADP sensibility. Correlations were sought between these parameters and clinical or neuro-hormonal indexes of disease severity. Results (means⫾SEM) are presented in table with the p value for comparisons between the FH and C corresponding parameters. Vm from the LV and RV inversely correlated to natriuretic peptides (LV Vm vs ANP r⫽-0.49, p⫽0.03; LV Vm vs BNP r⫽-0.44, P⫽0.1; RV Vm vs BNP r⫽-0.5, p⫽0.06) and Vm from the RV correlated with exercise capacity (RV Vm vs max.VO2 r⫽0.53, p⫽0.03; RV Vm vs VO2 at ventilatory threshold r⫽0.89, p⫽0.006). None of the MI respiration parameters were related to LVEF, Minnesota heart failure score, hemodynamics and plasma catecholamines. We conclude that the energetic imbalance of the severely failing heart not only results from a defective O2 and substrate supply or from deleterious remodeling processes but also from an intrinsic defect in MI oxidative capacity that relate to indexes of disease severity. However these MI keep regulatory properties of a highly oxidative muscle (high Km). FH LV Vm

FH LV Km

FH RV Vm

FH RV Km

C LV Vm

C LV Km

11.7 ⫾ 0.8 p ⫽ 0.02

483 ⫾ 48 p ⫽ 0.08

11.8 ⫾ 1.1 p ⫽ 0.06

487 ⫾ 54 p ⫽ 0.07

16.3 ⫾ 2.1

572 ⫾ 44

109 DOES QRS WIDTH REALLY IMPACT ON CARDIAC RESYNCHRONIZATION BENEFIT IN HEART FAILURE PATIENTS? E. Gronda,1 A. Municino `,1 L. Genovese,1 M. Mangiavacchi,1 B. Andreuzzi,1 D. Pini,1 P. Galimberti,1 C. Klersy,2 F. Faletra,1