Proefschriften 2010

Promotie MollemaEchocardiographic evaluation of left ventricular function in ischemic heart disease

Sjoerd A. Mollema

Promotores: Prof. dr. J.J. Bax, Prof. dr. M.J. Schalij

9 december2010

The aim of this thesis was to evaluate the role of 2-dimensional (2D) echocardiography to evaluate left ventricular (LV) function in ischemic heart disease. In Part I recently introduced echocardiographic parameters to describe LV function were studied and their importance for prognosis after myocardial infarction (MI) was evaluated. The introduction of tissue Doppler imaging (TDI) and speckle-tracking strain imaging has resulted in additional prognostic parameters, such as LV strain (rate) and dyssynchrony. In 124 patients with acute MI underwent, within 48 h of primary percutaneous coronary intervention (PCI), 2D echocardiography to assess LV volumes, LV ejection fraction and wall motion score index (WMSI) plus LV dyssynchrony by TDI. At 6-months follow-up, 2D echocardiography was repeated and showed that 91% of the patients with substantial LV dyssynchrony at baseline developed LV remodelling compared to 2% in the patients without substantial LV dyssynchrony. Thus, LV dyssynchrony within 48 h after onset of acute MI was strongly related to the extent of long-term LV dilatation at 6-months follow-up. Patients showing LV remodelling at 6-months follow-up had comparable baseline characteristics to patients without LV remodelling except for higher peak troponin-T levels, peak CK levels, WMSI, E/E' ratio, and a larger extent of LV dyssynchrony. Multivariate analysis demonstrated that LV dyssynchrony was superior in predicting LV remodelling. Global longitudinal peak systolic strain assessed with novel automated function imaging (AFI) is related to peak levels of cardiac troponin T and biplane LV ejection fraction. Global and regional longitudinal strain are associated with global and regional (transmural) extent of scar tissue on contrast-enhanced MRI. Regional strain is able to discriminate between segments with viable myocardium and those with transmural scar tissue on contrast-enhanced MRI. Global longitudinal peak systolic strain early after acute MI reflects myocardial viability and predicts recovery of LV function after 1-year follow-up. Moreover, global longitudinal peak systolic strain assessed with AFI is an independent predictor of recovery of LV function. Strain and strain rate provide strong prognostic information in patients after acute MI.

In Part II of the thesis the role of echocardiography in the decision making around advanced treatment options in heart failure such as cardiac resynchronization therapy (CRT) and cardiac surgery was explored. Baseline QRS duration is not predictive for clinical and echocardiographic response to CRT at 6-months follow-up. In contrast, LV resynchronization following CRT is an acute phenomenon and predicts response to CRT at 6-months follow-up. In addition, global LV longitudinal strain reflects myocardial scar and predicts response to CRT in patients with heart failure.

These studies demonstrate that echocardiography provides prognostic information with regard to LV function and LV remodeling in patients with recent MI. The development of LV dilatation and heart failure during 6-months follow-up is dependent of early LV dyssynchrony which identifies the patient who is a candidate for CRT.

promotie DelgadoNovel cardiac imaging technologies: implications in clinical decision making

Victoria Delgado

Promotores: Prof. dr. J.J. Bax, Prof. dr. M.J. Schalij

11 november 2010

cum laude

The aims of this thesis were to investigate the role of novel cardiac imaging technologies in the current clinical daily practice with the advent of novel therapies. Currently, left ventricular (LV) ejection fraction is one of the most important parameters for risk stratification and clinical decision making. However, LV performance can be evaluated by means of myocardial deformation, LV fluid dynamics and ultrastructural changes in myocardial tissue. Speckle tracking echocardiography have permitted angle-independent multidirectional evaluation of myocardial deformation. In patients with coronary artery disease and varying LV ejection fractions, global LV longitudinal strain and LV ejection fraction are not identical, but rather reflect different aspects of systolic LV function. Indeed, the assessment of active myocardial deformation reflects closely the contractile properties of the myocardium, whereas LV ejection fraction merely reflects stroke volume.

In addition, these contractile properties of the LV have an influence on LV hydrodynamics. The assessment of vortex formation with contrast echocardiography yields a novel measurement of LV diastolic performance. Indeed, vortex formation time and morphology were well correlated with infarct size (r=0.63 and r=0.71, respectively) and with LV untwisting rate (r=0.65 and r=0.61, respectively).

In addition, these changes in myocardial deformation properties reflect structural changes that can be evaluated by integrated backscatter imaging. The extent of fibrosis as assessed with calibrated integrated backscatter imaging was a strong determinant of favorable cardiac resynchronization response in ischemic heart failure patients.

These echocardiographic imaging techniques can be applied to study the myocardial tissue properties of the left atrium (LA). The efficacy of radiofrequency catheter ablation can be predicted with the assessment of LA wall fibrosis and the mechanical properties. In 170 consecutive patients undergoing radiofrequency catheter ablation for atrial fibrillation (AF), LA fibrosis as assessed with calibrated integrated backscatter provided an incremental value over LA size and type of AF to predict the outcome of radiofrequency catheter ablation.

Finally, the advent of novel transcatheter valvular repair/implantation techniques has emerged as feasible therapies for patients who are deemed not operable. Real-time 3-dimensional echocardiography and multi-detector row computed tomography have provided accurate visualization of the valvular structures with important implications in the pre-procedural screening and during the procedure. Particularly, in percutaneous aortic valve implantation procedures the position and deployment of the prosthesis determine the presence of post-procedural aortic valve regurgitation. Multi-detector row computed tomography provides exact information on the mechanisms that may explain the presence of post-procedural aortic regurgitation.

Promotie BorleffsImplantable cardioverter defibrillator treatment: benefits and pitfalls in the currently indicated population

C.J.W. Borleffs

Promotores: Prof. dr. M.J. Schalij, Prof. dr. J.J. Bax

Date: September 30, 2010

cum laude

The aim of this thesis was to improve understanding of several important clinical issues concerning treatment with the inplantable cardioverter defibrillator (ICD) in daily clinical care by studying a large population of ICD patients outside the setting of a clinical trial. In Part I the population currently receiving treatment was assessed and long-term follow-up, as well as possibilities for baseline risk stratification, were evaluated. In 676 patients with myocardial infarction (MI) treated according to current guidelines only 6% met the criteria for implantation of an ICD within the first year post-MI. These patients suffered from more extensive infarctions and had more LAD-related infarctions compared to the patients without ICD implantation. In 456 patients with ischemic heart disease who received ICD therapy for secondary prevention of sudden cardiac death appropriate ICD therapy was noted in 47% of whom 30% for fast, potentially life-threatening ventricular arrhythmias (VAs). Independent predictors of life-threatening VAs were a history of atrial fibrillation (AF) or flutter, ventricular tachycardia as presenting arrhythmias, wide QRS, and poor left ventricular (LV) ejection fraction. In addition, it was not impossible to identify a group which exhibited no risk of recurrence of potentially life-threatening VAs. If patients with symptomatic heart failure developed new onset AF after having received a cardiac resynchronisation therapy-defibrillator (CRT-D) device, they showed less reverse remodeling of the LV and less improvement of LV ejection fraction compared to the patients who maintained sinus rhythm during follow-up. In an attempt to identify patients who do not benefit from ICD treatment as they died prior to appropriate ICD therapy, a baseline risk score was constructed to estimate risk of non-benefit in 900 ischemic primary prevention ICD recipients. Predictors were age ≥75 years, LV ejection fraction ≤25%, diabetes, NYHA functional class III-IV, and history of smoking. Five-year cumulative incidence for non-benefit ranged from 12% in low-risk patients to 49% in high-risk patients.

In Part II new parameters to improve risk stratification within the population currently treated with an ICD have been studied. In separate studies heterogeneity of infarct tissue on contrast-enhanced MRI, subnormal intensity of 123I-MIBG imaging, a spatial QRS-T angle >100o, and a right ventricular stimulus threshold ≥1V were found to be independent predictors of occurrence of VAs triggering appropriate ICD therapy, appropriate shocks, and mortality.

In Part III several complications accompanying ICD treatment were studied, particularly the failure of coronary sinus leads and defibrillation leads. An ICD replacement is associated with a doubled risk for pocket-related surgical re-interventions.

These studies provide novel information to identify patients who, although currently indicated for ICD treatment, have a very low occurrence of VAs during follow-up and should possibly be reconsidered for implantation. Additionally, clinically applicable risk scores are proposed to make patient-tailored estimations of mortality risk and of the risk for mortality prior to a first ICD discharge. Finally, these studies have indicated several drawbacks of ICD treatment such as inappropriate shocks and their prognostic importance, lead failure and replacement of ICDs.

Promotie RoesMagnetic resonance imaging techniques for risk stratification in cardiovascular disease

S.D. Roes

Promotores: Prof. dr. A. de Roos, Prof. dr. J.J. Bax

24 juni2010

The aim of this thesis was to evaluate and optimise magnetic resonance imaging (MRI) techniques for the purpose of risk stratification in patients with cardiovascular disease. After the description of several novel methods to acquire images without disturbance of respiratory motion and heart rate variability, accuracy and reproducibility were tested of blood flow velocity in the coronary arteries, blood flow across mitral and tricuspid valves, and blood flow through all four heart valves without and with valve regurgitation. Patients with the metabolic syndrome had impaired left ventricular (LV) diastolic function and elevated aortic pulse wave velocity (PWV) compared to subjects without the metabolic syndrome, and plasma high-density cholesterol (HDL) level was correlated negatively with aortic PWV and with E wave deceleration mean and E wave deceleration time. If patients with the metabolic syndrome underwent intensive lifestyle intervention including a diet and physical exercise for a year, their LV mass index (LVMI) decreased with 9.4% (p<0.001) whereas LVMI of patients with metabolic syndrome who were treated with rosiglitazone, a PPAR-γ agonist, remained unchanged.

In patients with severe ischemic LV dysfunction contrast-enhanced MRI and nuclear imaging with 99mTc-tetrofosmin and 18F-deoxyglucose showed high agreement for viability assessment in segments without scar tissue and in segments with transmural scar tissue, but disagreement was evident in segments with subendocardial scar tissue which illustrates that the non-enhanced epicardial rim may contain either normal or ischemically jeopardized myocardium. On contrast-enhanced MRI, global extent of scar tissue was correlated with global LV strain as assessed by 2D speckle tracking. A cut-off value of -4.5% for regional strain discriminated between segments with viable myocardium and segments with transmural scar on contrast-enhanced MRI with good sensitivity and specificity. The extent of infarct tissue heterogeneity on contrast-enhanced MRI predicted for the occurrence of spontaneous ventricular arrhythmias in patients with previous myocardial infarction who received implantable cardioverter-defibrillator therapy, and predictive value of infarct tissue heterogeneity exceeded that of total infarct size, LV function and LV volumes. In a separate study with 231 patients with healed myocardial infarction long-term mortality was predicted better by infarct size assessment than by LV ejection fraction and LV volumes. In patients with large myocardial scar, the presence of contractile reserve, representing hibernating myocardium, on low-dose dobutamine MRI is a more important predictor of long-term event-free survival than infarct size on contrast-enhanced MRI.

This thesis demonstrates the potential of MRI for (1) detection of altered cardiac and aortic function, (2) assessment of flow in arteries and across valves, and (3) risk stratification in cardiovascular disease.

Promotie TrompetGenes, inflammation, and age-related diseases

S. Trompet

Promotores: Prof. dr. J.W. Jukema, Prof. dr. R.G.J. Westendorp

2 juni 2010

A dramatic increase in mean and maximal life span, coupled with a significant reduction in early mortality, has led to a large increase in the number of elderly people in modern societies. Progression of age is associated with a reduction of the response to environmental stimuli and, in general, is associated with an increased predisposition to illness and death. The high incidence of death due to infections, cardiovascular disease, and cancer underlies a common feature in these pathologies that is represented by dysregulation of both systemic and innate immunity. Ageing is accompanied by a chronic low-grade inflammation state as reflected by a 2-4-fold increase in serum levels of pro-inflammatory mediators. This pro-inflammatory state, interacting with the genetic background, potentially triggers the onset of age-related inflammatory diseases like atherosclerosis, dementia, and cancer. Genetic epidemiology is an important tool to investigate the association between innate immunity and age-related diseases.

The general objective of this thesis was to investigate associations between genetic variants involved in inflammation and epigenetics and age-related diseases in an elderly cohort to get ore insights in the pathophysiological mechanisms involved in age-related diseases, like cardiovascular disease, cognitive decline, and cancer. For all analyses we used data of the participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Single nucleotide polymorphisms (SNPs) in candidate genes were assessed with Sequonom Mass Array technology and associated with these various age-related diseases. The thesis shows that subjects carrying genetic variants coding for a high pro-inflammatory profile or a low anti-inflammatory profile have an increased risk to develop cardiovascular disease and cognitive decline. Moreover, they tend to have an increased risk of dying from cancer.

Furthermore, the author has provided first evidence that the process of epigenetics can play an important role in the pathophysiology of age-related diseases. A SNP within the p300/CBP-associated factor (PCAF) gene showed a large decrease in mortality risk in three independent study cohorts. Functional analysis showed that this polymorphism is located in a functional region of the PCAF promoter, and modulation of PCAF gene expression was detectable in an animal model of reactive vascular stenosis. These studies promote the concept that epigenetic processes are under genetic control and that, other than environment, genetic variation in genes encoding histone acyltransferases (HATs) may determine susceptibility to coronary heart disease outcomes and mortality. In future clinical practice anti-inflammatory and immunosuppressive mechanisms may be attractive targets for disease prevention and/or treatment.

Promotie TopsMultimodality imaging to guide; cardiac interventional procedures

Laurens F. Tops

Promotores: Prof. dr. J.J. Bax, Prof. dr. M.J. Schalij

15 april2010

cum laude

The aim of the thesis was to explore the role of multimodality imaging in cardiac interventional procedures. In Part I, the integration of different imaging modalities during catheter ablation procedures for atrial fibrillation (AF) was studied. In addition, the effects of these procedures on left atrial (LA) and left ventricular (LV) size and function were investigated. In patients undergoing catheter ablation for drug-refractory AF pre-procedural acquired multi-slice computed tomography (MSCT) images, intracardiac echocardiography, and electroanatomic maps were fused to facilitate catheter ablation procedures in LA and pulmonary veins (PV). The presence of right-sided complex PV anatomy was associated with an improved outcome of the catheter ablation procedure, whereas LA dilatation was associated with a worse outcome. If after catheter ablation for AF patients maintained sinus rhythm, LA size decreased significantly, but in case of recurrent AF LA size increased. LA reverse remodelling was associated with improvements of LA active function and LA reservoir function.

Part II studied the effects of right ventricular (RV) apical pacing on LV dyssynchrony and mechanics, and the effect of upgrade to cardiac resynchronisation therapy (CRT). RV pacing in patients with complete AV-block for a mean of 3.8±1.7 year led to LV dyssynchrony in 49% of the patients and in those patients LV ejection fraction decreased from 48±7 to 43±7% (p<0.05), whereas it remained unchanged in patients without LV dyssynchrony (from 49±6 to 49±8%, n.s.). These detrimental effects of RV pacing may (partly) occur immediately after onset of pacing. In patients who underwent an upgrade of RV pacing to CRT LV dyssynchrony disappeared and LV ejection fraction improved from 30±8 to 39±7% (p<0.001).

In Part III the role of imaging in new percutaneous procedures to treat severe mitral regurgitation (MR) and aortic stenosis (AS) was explored. MSCT was used to assess coronary sinus anatomy to test feasibility of mitral valve annulus remodelling. Contraindications for this therapy are a large distance between the coronary sinus and mitral valve annulus, and a circumflex artery that courses between the coronary sinus and the mitral valve annulus. In assessment of aortic root anatomy, MSCT revealed a large variation in the distance between the aortic annulus and the left coronary ostium (range 7.1 to 22.7 mm) and the right coronary ostium (range 9.2 to 26.3 mm).

This thesis demonstrates that for interventional procedures, such as invasive treatment of AF, cardiac pacing and the percutaneous treatment of valvular heart disease, tremendous advances in multimodality imaging have been made. The selection of patients for these procedures, the procedures themselves, and the follow-up of patients may be greatly facilitated by the use of imaging modalities. Importantly, the integration of different imaging techniques may enhance visualization of critical anatomic structures during the interventional procedures.