Effect of external counterpulsation on coronary collateral artery growth and myocardial blood flow in patients with stable coronary artery disease [Elektronische Ressource] / von Nikolaos Pagonas

Aus dem Zentrum für Innere Medizin mit Schwerpunkt Kardiologie (CC13),
Richard-Thoma-Laboratorien für Arteriogenese und Center for
Cardiovascular Research (CCR) der Medizinischen Fakultät Charité –
Universitätsmedizin Berlin


DISSERTATION


Effect of external counterpulsation on coronary collateral
artery growth and myocardial blood flow in patients with
stable coronary artery disease



zur Erlangung des akademischen Grades
Doctor medicinae (Dr. med.)

vorgelegt der Medizinischen Fakultät
Charité – Universitätsmedizin Berlin

von

Nikolaos Pagonas
aus Athen, Griechenland


















Gutachter: 1. Priv. - Doz. Dr. med. I. Buschmann
2. Prof. Dr. Dr. med. B. M. Harnoss
3. Prof. Dr. med. K.- L. Schulte



Datum der Promotion: 04.02.2011
2












Meinen Eltern in Dankbarkeit gewidmet










3Table of Contents
1 INTRODUCTION ............................................................................................................................................. 6
1.1 CORONARY ARTERY DISEASE....................................................................................................................... 6
1.1.1 Epidemiology...................... 6
1.1.2 Pathophysiology.................................................................................................................................... 6
1.1.3 Clinical features of stable coronary disease.......................................................................................... 7
1.1.4 Diagnostic tests ..................................................................................................................................... 8
1.1.5 Therapy for stable CAD ...................................................................................................................... 10
1.2 ARTERIOGENESIS ...................................................................................................................................... 12
1.2.1 Terminology of vascular growth.......................................................................................................... 12
1.2.2 Collateral artery growth and the role of shear stress.......................................................................... 13
1.2.3 The protective role of coronary collateral circulation......................................................................... 15
1.2.4 Assessment of cardiac collateral arteries............................................................................................ 16
1.2.5 Clinical trials for the stimulation of arteriogenesis.. 19
1.3 EXTERNAL COUNTERPULSATION............................................................................................................... 20
1.3.1 Introduction......................................................................................................................................... 20
1.3.2 Technique of ECP................. 21
1.3.3 Mechanism of the action and review of the literature ......................................................................... 22
2 THE STUDY’S HYPOTHESIS...................................................................................................................... 29
3 PATIENTS AND METHODS......................................................................................................................... 30
3.1 STUDY POPULATION .................................................................................................................................. 30
3.1.1 Inclusion and exclusion criteria.......................................................................................................... 30
3.2 THE STUDY DESIGN.... 31
3.3 CLINICAL ENDPOINTS AND NON-INVASIVE MEASUREMENTS...................................................................... 34
3.3.1 History and clinical examination......... 34
3.3.2 Clinical laboratory evaluation ............................................................................................................ 34
3.3.3 Exercise test......................................................................................................................................... 35
3.3.4 Cardiac magnetic resonance imaging................................................................................................. 35
3.4 INVASIVE MEASUREMENTS AND ENDPOINTS.............................................................................................. 36
3.4.1 Fractional Flow Reserve (FFR).......................................................................................................... 36
3.4.2 Collateral flow index (CFIp)............................................................................................................... 38
3.4.3 Index of microcirculatory resistance (IMR) ........................................................................................ 40
3.4.4 Quantitative coronary angiography...... 42
3.4.5 Protocol of cardiac catheterization and invasive measurements ........................................................ 42
3.4.6 Performance of the invasive measurements ........................................................................................43
3.4.7 Calculation of the invasive endpoints ................................................................................................. 44
3.5 EXTERNAL COUNTERPULSATION THERAPY (ECP) 45
3.6 SAMPLE SIZE AND STATISTICAL ANALYSIS................................................................................................. 45
44 RESULTS ......................................................................................................................................................... 47
4.1 PAT I E N T S................................................................................................................................................... 47
4.1.1 Characteristics of the study population............................................................................................... 47
4.1.2 Adverse events and compliance........................................................................................................... 49
4.2 ENDPOINTS AT BASELINE........................................................................................................................... 49
4.2.1 Clinical characteristics of the patients................................................................................................ 49
4.2.2 Hemodynamic effect of ECP................................................................................................................ 51
4.2.3 Non-invasive diagnostic tests at baseline............................................................................................ 51
4.2.4 Invasive endpoints at baseline............................................................................................................. 53
4.3 ENDPOINTS AT WEEK 8 .............................................................................................................................. 56
4.3.1 Clinical endpoints ............................................................................................................................... 56
4.3.2 Specific hemodynamic parameters...................................................................................................... 58
4.3.3 Exercise test......................................................................................................................................... 60
4.3.4 CMR .................................................................................................................................................... 61
4.3.5 Invasive measurements........................................................................................................................ 61
4.3.6 Univariate analysis ............................................................................................................................. 64
5 DISCUSSION................................................................................................................................................... 65
5.1 ESTABLISHMENT AND FEASIBILITY OF THE THERAPY................................................................................. 65
5.2 CLINICAL BENEFIT OF ECP ....................................................................................................................... 66
5.3 EXERCISE TEST AND ECP.......................................................................................................................... 68
5.4 ECP, ARTERIOGENESIS AND MYOCARDIAL BLOOD FLOW ........................................................................... 69
5.4.1 Stimulation of arteriogenesis by ECP ................................................................................................. 69
5.4.2 ECP compared to pharmacologic stimulation of arteriogenesis......................................................... 70
5.4.3 Collateral and myocardial blood flow...... 71
5.4.4 Clinical impact of ECP treatment ..................................................