Heart Rate and Cardiac Allograft Vasculopathy in Heart Transplant Recipients

Transcription

1 ESC Congress 2011 Paris August Heart Rate and Cardiac Allograft Vasculopathy in Heart Transplant Recipients M.T. La Rovere, F. Olmetti, G.D. Pinna, R. Maestri, D. Lilleri, A. D Armini, M. Viganò, O. Febo Fondazione S. Maugeri, IRCCS, Istituto Scientifico di Montescano (Pavia), and Policlinico San Matteo, IRCCS, Pavia, Italy No conflict of interest to declare

2 Background Elevated resting Heart Rate is an independent predictor of all cause and cardiovascular mortality in the general population and pathologic conditions Sustained elevation in resting HR might play a role in the progression and severity of coronary atherosclerosis

3 Minimum Heart Rate and Coronary Atherosclerosis Coronary atherosclerosis score (%) r= 0.70, P< Minimum heart rate (bpm) A Perski et al. Am Heart J 1988;116:

4 Heart Rate and Development of Coronary Atherosclerosis Monkeys fed an atherogenic high colesterol diet for 6 months 60 Coronary Atherosclerosis (%) P<0.02 Sinus Node Ablation 0 High Heart Rate Low Heart Rate PA Beere et al, Science 1984; 226:

5 Heart Rate and Atherosclerosis: Coronary Plaque Rupture n=106; two coronary angiography; 6 months; 24-hour ECG Multivariate analysis of association with coronary plaque disruption OR (95% CI) P Left ventricular mass >270 g 4.92 ( ) 0.02 Mean heart rate >80 bpm 3.19 ( ) Blocker use 0.32 ( ) 0.02 Wall thickness IVS 1.68 ( ) 0.06 Fractional pulse pressure 1.81 ( ) 0.07 ACE inhibitors 0.51 ( ) 0.06 Statins 0.42 ( ) 0.06 UE Heidland, BE Strauer. Circulation 2001;104:

6 Heart Rate Control Sympathetic + Parasympathetic Autonomic Blockade Intrinsic Heart Rate 100 bpm PG Katona et al, J Appl Physiol 1982: 52:1652

7 Cardiac Allograft Vasculopathy Up to 50% of all transplanted hearts in the first 5 yrs following surgery Immunologic and non-immunologic factors Risk factors: hyperlipemia, age and sex of donor heart, obesity, cause of heart failure, ischemic time

8 Heart Transplant Recipients Unique model to study the role of heart rate in the development of coronary atherosclerosis

9 Population Under Study 244 patients alive at 1 year after HTx ( ): CARDIAC ALLOGRAFT VASCULOPATHY at biannual follow-up coronary angiography: > 50% obstruction in a major coronary vessel or diffuse concentric narrowing of the whole vessel 24-HOLTER Recording obtained in all patients at 1 year. Mean Heart Rate = heart rate burden Mean Heart Rate > 90 bpm = SINUS TACHYCARDIA

10 Population Under Study Clinical and laboratory parameters known to be related to CAV donor s age, recipient s age human cytomegalovirus infection, acute rejection during the first year after HTx ischemic time heart failure etiology smoking habit obesity, arterial hypertension, diabetes, cholesterol level left ventricular end diastolic wall thickness immunosoppressive regimen baseline medications after HTx including beta-blockers and calcium-antagonist

11 Clinical Characteristics at 1 year Donor s Age (years), mean±sd 48.2±13.4 Recipient s Age (years), mean±sd 36.1±14.5 Ischemic Time (min) 140±53 Ischemic Cause, n (%) 70 (28) Arterial Hypertension, n (%) 119 (49) Diabetes Mellitus, n (%) 27 (12) Hyperlipidemia, n (%) 89 (36) Current Tobacco smoker, n (%) 26 (11) Chronic Renal Failure, n (%) 99 (41) Hyperlipidemia, n (%) 89 (36) Cyclosporine, n (%) 187 (77) Azathioprine, n (%) 118 (48) Steroids, n (%) 223 (91) Mycophenolate mofetil, n (%) 37 (15) Tacrolimus, n (%) 51 (21) Calcium Mean antagonist, Heart n Rate, (%) beats/min 85 ± 14 (6) 11.6 Beta-blocker, n (%) 37 (15) LV end-diastolic wall thickness, (mm) mean±sd 20.6±2.7

12 Follow-up Data Median 96 months (range months) [%] [%] Chronic Graft Failure Causes of Death Malignancies Sudden death Infections Other CAV Death Repeat HTx

13 Cox Univariate Analysis Hazard Ratio (95% CI) p value Donor s Age 1.02 ( ) Recipient s Age 1.02 ( ) 0.11 Ischemic Time 0.99 ( ) 0.22 HF etiology dichotomized 1.12 ( ) 0.68 Arterial Hypertension 1.23 ( ) 0.42 Diabets Mellitus 1.02 ( ) 0.97 Hyperlipidemia 1.28 ( ) 0.34 Current Tabacco Smoker 1.47 ( ) 0.27 Chronic Renal Failure 1.77 ( ) 0.02 Acute Rejections 0.91 ( ) 0.77 HCMV Infection 0.66 ( ) 0.25 LV End-diast Wall Thickness 1.16 ( ) Mean Heart Rate > 90 bpm 0.55 ( ) 0.039

14 Event free survival 1.0 KM Curves for CAV Development 0.9 Mean HR > 90 bpm (n=91) Mean HR < 90 bpm (n=153) Log-rank = 7.97 p = Time (months)

15 Multivariable Cox Model for CAV Development Hazard Ratio p value (95% CI) Donor s Age 1.02 ( ) Chronic Renal Failure LV End-Diastolic Wall Thickness Mean Heart Rate > 90 beats/min 1.90 ( ) ( ) ( ) 0.22

16 Bivariate Cox Models Exploring the Relationship between Mean Heart Rate and the significant predictors HR (95% CI) p value Mean Heart Rate > 90 beats/min 0.51 ( ) 0.02 Chronic Renal Failure 1.89 ( ) 0.01 HR (95% CI) p value Mean Heart Rate > 90 beats/min 0.59 ( ) 0.06 LV End-Diastolic Wall Thickness 1.15 ( ) HR (95% CI) p value Mean Heart Rate > 90 beats/min 0.71 ( ) 0.27 Donor s Age 1.02 ( ) 0.01

17 Age-Related Decline in Intrinsic Heart Rate J Yanni et al, J Mol Cell Cardiol 2010

18 MEAN INTRINSIC HEART RATE (bpm) Age-Related Decline in Intrinsic Heart Rate B Marcus et al Am Heart J 1990 AD Jose et al, Cardiovasc Res 1970 P Alboni et al, Circulation 1982 SA Jones, J Pharm Pharmacol YEARS

19 Conclusions In the denervated heart, sinus tachycardia is not a risk factor for coronary atherosclerosis Heart Rate in heart transplant patients simply reflects intrinsic heart rate and is a simple epiphenomenon of the donor s age