Advanced echocardiographic techniques permit assessment of left ventricular dyssynchrony in overt heart failure patients and provide important prognostic data. These techniques may guide patients__... Show moreAdvanced echocardiographic techniques permit assessment of left ventricular dyssynchrony in overt heart failure patients and provide important prognostic data. These techniques may guide patients__ selection for cardiac resynchronization therapy and device optimization. Global left ventricular longitudinal 2-dimensional strain may help detect early stages of myocardial dysfunction in diabetic patients with preserved left ventricular ejection fraction. Novel cardiac magnetic resonance imaging sequence analysis may allow tissue characterization, quantification of diffuse fibrosis and detection of early alterations in ventriculo-arterial coupling. Advanced cardiac imaging provides invaluable information at every stage of the heart failure syndrome. It may help identify an earlier stage of the disease, help to select patients for cardiac resynchronization therapy, tailor therapies in selected individuals and offer important prognostic information. Show less
The general introduction of the thesis outlines the role of cardiac mechanics assessment in the evaluation and risk stratification of HF patients. Part I This part of the thesis summarizes current... Show moreThe general introduction of the thesis outlines the role of cardiac mechanics assessment in the evaluation and risk stratification of HF patients. Part I This part of the thesis summarizes current imaging techniques to assess various aspects of LV mechanics in HF patients (Chapter 2), differentiating between ischemic and non-ischemic HF (Chapter 3) and investigating its role in the selection of HF patients who are candidates to CRT (Chapters 4-6). Furthermore, the role of imaging techniques to optimize the results of CRT is summarized in Chapter 7. Part II The final part focuses on long-term prognosis of advanced HF patients. Novel echocardiographic techniques provide several parameters that have incremental prognostic value over well-recognized echocardiographic and clinical parameters (Chapters 8-11). CONCLUSIONS The study of cardiac mechanics is crucial in advanced HF patients. Particularly, using imagine techniques as speckle-tracking echocardiography, important information on the effects of CRT in heart failure patients may be derived. Moreover, studying LV mechanics may be helpful for understanding the differences in pathophysiological mechanisms of different HF aetiologies. Finally, the role of non-invasive imaging techniques for the study of LV mechanics may be paramount for the definition of long-term prognosis in advanced HF patients. Show less
Despite the impressive results of cardiac resynchronization theraphy (CRT) in recent large randomized trials a consistent number of patients fails to improve following CRT implantation when the... Show moreDespite the impressive results of cardiac resynchronization theraphy (CRT) in recent large randomized trials a consistent number of patients fails to improve following CRT implantation when the established CRT selection criteria (NYHA class III-IV heart failure, LV ejection fraction __35 % and QRS duration > 120 ms) were applied. For example, close analysis of the data from the MIRACLE trial revealed that 32% of patients did not improve or even worsened in NYHA class after 6 months of CRT. The presence of clinical non-responders to CRT has now been confirmed in several other studies and is usually around 30%. In addition, if response to CRT is defined using more objective parameters such absence of LV reverse remodeling or lack of improvement in LV ejection fraction on echocardiography at mid-term follow-up the number of non-responders is usually between 40-50%. In view of the unnecessary procedure risks and health care expenses in patients without response to CRT the percentage of non-responders among patients selected according to the current selection criteria is unacceptably high and should be reduced. Aim of the thesis: The relatively high number of patients without benefit from CRT (referred to as non-responders) indicates the need for refinement of the current selection criteria in order to 1] better identify those patients with the highest likelihood of response to CRT and 2] avoid device implantations in patients that are unlikely to respond to CRT. The aim of the current thesis was to improve and refine the current CRT selection criteria through the evaluation of the mechanismus underlying (non-) response to CRT. Show less
In this thesis the surgical options for treatment of functional mitral regurgitation (MR) are described. In functional MR, the mitral valve has a normal anatomy, which distinguishes this type of... Show moreIn this thesis the surgical options for treatment of functional mitral regurgitation (MR) are described. In functional MR, the mitral valve has a normal anatomy, which distinguishes this type of insufficiency from organic MR. Regurgitation in functional MR is related to an abnormal geometry of the left ventricle, which can be the result of an infarction or ischaemia, or may be caused by another__intrinsic__disease of the myocardium. Based on aetiology, we can distinguish ischaemic and non-ischaemic functional MR. Patients with functional MR often present with signs and symptoms of heart failure. Current guidelines do not offer clear treatment algorithms for these patients, and an intervention on the mitral valve is often discouraged, mainly because of contradictory results from studies on surgical interventions on the valve. In this thesis, the role of surgery in the multidisciplinary treatment of patients with functional MR, typically associated with heart failure, is evaluated with regard to clinical and echocardiographic outcomes. The ultimate goal is to establish an individualised medico-surgical approach to this pathology. As such, this thesis results from close collaboration between the departments of Cardiothoracic Surgery and Cardiology of the Leiden University Medical Center. Show less
In this thesis the development of a pathophysiology-based method for the early evaluation of anthracycline-induced cardiotoxicity was described. We evaluated a comprehensive array of biomarkers,... Show moreIn this thesis the development of a pathophysiology-based method for the early evaluation of anthracycline-induced cardiotoxicity was described. We evaluated a comprehensive array of biomarkers, representing several aspects of anthracycline-induced cardiotoxicity, including cardiac injury and remodeling, free radical overload and the inflammation accompanying the injury. It was shown that predominantly the markers of cardiac injury may be suitable for the early detection of anthracycline-induced cardiotoxicity. In the second part of this thesis we evaluated a new, free-radical scavenging compound against anthracycline-induced cardiotoxicity using this approach. The failure of this compound to show efficacy against anthracycline-induced cardiotoxicity in our model suggests that a broader approach toward the mechanism of anthracycline-induced cardiotoxicity is necessary Show less
Right ventricular (RV) dysfunction is important determinant of prognosis in patients at increased risk for development of RV overload. RV dysfunction in patients before and after surgical left... Show moreRight ventricular (RV) dysfunction is important determinant of prognosis in patients at increased risk for development of RV overload. RV dysfunction in patients before and after surgical left ventricular restoration is associated with a worse prognosis. RV overload in liver transplantation recipients was also associated with decreased survival. Furthermore, patients with congenital heart disease and an systemic RV are at increased risk for long-term complications caused by RV overload. No unique golden standard for the quantification of RV dysfunction exists. The combination of echocardiographic RV parameters yields additional prognostic information in heart failure patients undergoing surgical left ventricular restoration. In systemic sclerosis the electrical ventricular gradient can accurately detect RV overload and is consistent with other screening parameters in patients with limited organ involvement. Optimization of loading conditions can improve clinical status and RV function in patients with RV dysfunction. RV function can be improved in LVAD patients by optimizing the synergy between the LVAD and intrinsic cardiac function. Furthermore, interventions in complex congenital heart disease patients with pulmonary hypertension can improve RV loading conditions and true pulmonary flow and can improve RV loading conditions and clinical functioning. Show less
The aim of this thesis is to provide new insights on catheter ablation of VT in patients with prior MI. Improved understanding of the VT substrate in different types of MI, and in particular, in... Show moreThe aim of this thesis is to provide new insights on catheter ablation of VT in patients with prior MI. Improved understanding of the VT substrate in different types of MI, and in particular, in contemporary non-transmural reperfused infarctions, a critical reassessment of the value of non-inducibility as ablation endpoint and the development of new physiologically meaningful endpoints for substrate modification will hopefully contribute to optimize procedural outcomes in this patient population. In addition, recognition of the limitations of the technique will aid in patient selection and will help to consider alternative treatment options in some individuals. Show less
Awareness of the involvement of the right ventricle in both common and rare cardiovascular diseases has grown. Recent developments in echocardiography and electrocardiography have contributed... Show moreAwareness of the involvement of the right ventricle in both common and rare cardiovascular diseases has grown. Recent developments in echocardiography and electrocardiography have contributed to further insight into the pathophysiology of the right ventricle as well as its relation to the pulmonary circulation and the left ventricle. Because echocardiography is accessible, non-invasive, and inexpensive it is an ideal technique for the assessment of the right ventricle and can be used for screening patients at risk of right ventricular dysfunction as well as monitor therapeutic responses. Furthermore, advanced echocardiographic techniques such as 2-dimensional speckle-tracking imaging may add to a better understanding of right ventricular mechanics. Integrated application of echocardiographic and electrocardiographic techniques could provide further understanding into the different pathophysiological aspects of right ventricular function. These insights could be used to identify risk factors, prognostic factors and monitor response to therapy through serial assessment in patients at risk for right ventricular dysfunction and failure such as patients with pulmonary hypertension, heart failure and those undergoing cardiac surgery. Furthermore, a better understanding of the mechanisms that lead to right ventricular remodeling may aid to the development of right ventricular specific therapies that improve survival in patients with right ventricular dysfunction. Show less
The Fontan procedure is currently the palliative solution for children born with a univentricular heart. Despite an improved survival rate, many patients still suffer from complications, such as... Show moreThe Fontan procedure is currently the palliative solution for children born with a univentricular heart. Despite an improved survival rate, many patients still suffer from complications, such as heart failure. For this reason, both patients with and without heart failure are often treated with angiotensin-converting enzyme (ACE) inhibitors, although the effectiveness is unclear. In this thesis, we investigated various aspects of the Fontan circulation to assess not only the efficacy and side effects of ACE inhibition, but also the limitations of exercise capacity and the response of the circulation of these patients to acute volume loading tests. We showed that short-term ACE inhibition had no positive effects on exercise capacity, haemodynamics and cardiac function. It also appeared to have no negative effect on the Fontan circulation, apart from side effects during the titration period. Furthermore, we found that even relatively healthy young Fontan patients have reduced exercise capacity associated with diastolic dysfunction and aortic stiffness. Nevertheless, we found that paediatric Fontan patients are able to respond adequately to acute volume changes and they seem to adapt well to the Fontan circulation. Show less
Various non-invasive imaging techniques are available for the diagnosis of coronary artery disease (CAD). Multi-slice computed tomography (MSCT) is an upcoming technique that allows direct... Show moreVarious non-invasive imaging techniques are available for the diagnosis of coronary artery disease (CAD). Multi-slice computed tomography (MSCT) is an upcoming technique that allows direct visualization of the coronary arteries. Apart from the assessment of atherosclerosis, MSCT can also provide important information on the global and regional left ventricular (LV) function. However, it should be realized that the hemodynamic consequences of atherosclerosis can not be obtained by MSCT imaging, and that functional testing, with for example nuclear imaging, will remain necessary to determine therapeutic strategy. CAD is the most common cause of chronic heart failure. Recently, cardiac resynchronization therapy (CRT) has become implemented in the treatment of patients with severe heart failure. Although the improvement in systolic function after CRT implantation can be considerable, 20% to 30% of patients do not respond to CRT. It has been shown that the presence of LV dyssynchrony is an important predictor of response to CRT. Gated SPECT allows not only the assessment of myocardial perfusion (scar tissue and viable myocardium) but also the evaluation of LV dyssynchrony. As many patients with heart failure undergo nuclear imaging with SPECT, integrated assessment of LV dyssynchrony, viability and scar tissue may be an attractive option. Show less
Identification of translational and/or post-translational modifications of cardiac proteins after acute myocardial infarction (AMI) or during the progression to congestive heart failure (CHF) is... Show moreIdentification of translational and/or post-translational modifications of cardiac proteins after acute myocardial infarction (AMI) or during the progression to congestive heart failure (CHF) is relevant to gain insight into the pathological mechanisms. Characterization of the release kinetics of these cardiac proteins from the reversibly or irreversibly injured myocardium into the circulation may lead to new diagnostic biomarkers. Although cardiac Troponin I (cTnI) is a well-known biomarker of irreversible myocardial damage in acute myocardial infarction, we demonstrated that the release of cTnI also occurs from viable cardiomyocytes by a stretch-related mechanism, mediated by integrin stimulation. This finding may explain why in several pathological conditions, such as CHF, plasma cTnI levels are elevated in the absence of myocardial necrosis. In addition, we investigated the role of Tenascin-C re-expression during the development of heart failure and the relevance of TNC as a biomarker of ventricular remodeling. In animals with pressure-overload induced ventricle dilatation, TNC gene expression was upregulated, resulting in re-expression of myocardial TNC protein levels and elevated TNC plasma levels, correlating with cardiac function. Plasma TNC levels in patients with CHF declined during cardiac resynchronization therapy. This study indicates that serial plasma TNC levels can be used as a marker of adverse or reverse ventricular remodeling. Show less
Evaluation of patients with ischemic heart disease using echocardiography is indispensable. Both in the acute setting of STEMI, at follow-up and in the chronic phase during the possible development... Show moreEvaluation of patients with ischemic heart disease using echocardiography is indispensable. Both in the acute setting of STEMI, at follow-up and in the chronic phase during the possible development of heart failure, routine echocardiographic assessment is an essential part of daily clinical practice. Show less
This thesis is the result of several studies into the clinical and echocardiographic outcome of both open and hybrid surgical ventricular reconstruction for the treatment of ischemic cardiomyopathy... Show moreThis thesis is the result of several studies into the clinical and echocardiographic outcome of both open and hybrid surgical ventricular reconstruction for the treatment of ischemic cardiomyopathy. Additionally, predictors for a favorable outcome and important associated issues such as management and late outcome of functional mitral regurgitation and the use of LV ejection fraction as a selection criterium for indication for a implantable cardioverter defibrillator for the primary prevention ofventricular arrhythmias after surgical ventricular reconstruction were studied. In chapter 2 the early and late outcome of different types of open left ventricular reconstruction surgery by means of a meta-analysis are presented. Chapter 3 describesthe use of echocardiographic wall motion score index to predict mortality and functional results after surgical ventricular reconstruction for advanced ischemic heart failure. In chapter 4 the management of functional mitral regurgitation during left ventricular reconstruction is presented followed by a landmark analysis into the 10-year outcome of functional mitral regurgitation after left ventricular reconstruction. Chapter 5 discusses the use of the improved LV ejection fraction after SVR as an indication for a implantable cardioverter defibrillator for the primary prevention of ventricular arrhythmias after surgical ventricular reconstruction in heart failure patients. Chapter 6 discusses the early experience with a minimal-invasive hybrid transcatheter surgical ventricular reconstruction technique. First the technique of hybrid transcatheter left ventricular reconstruction is described. Followed by the preliminary results of this technique from 2 cardiac centres in the Netherland. Finally, the multicenter European results of hybrid less invasive reconstruction on clinical, functional and echocardiographic outcome are presented. Show less
The main challenge of this thesis was to evaluate whether the reperfused heart induced systemic effects postoperatively, contributing to morbidity and mortality after cardiac surgery. We identified... Show moreThe main challenge of this thesis was to evaluate whether the reperfused heart induced systemic effects postoperatively, contributing to morbidity and mortality after cardiac surgery. We identified preexisting processes in patients with heart failure, such as complement activation and influx of inflammatory cells in the myocardium. These changes in their turn altered the post-reperfusion response of the myocardium after cardiac surgery. Moreover, preexisting low-grade endothelial cell activation predicted the development of post-cardiac surgery vasoplegia. No evidence was found for oxidative damage after reperfusion in contrast to the current theory. As expected, targeting the inflammatory resposne with sevoflurane resulted in attenuation of pro-inflammatory markers, although no cardioprotective effects were observed. A stepwise approach in future research via preclinical to clinical studies, and vice versa, is ne cessary to ensure the integration of advancements in pathophysiological science with clinical trials Show less
Severe secondary MR is known to be associated with a worse prognosis, whilst the effect of reducing MR on prognosis has still been unclear. The question remains what influences the prognosis of... Show moreSevere secondary MR is known to be associated with a worse prognosis, whilst the effect of reducing MR on prognosis has still been unclear. The question remains what influences the prognosis of these patients: is it the LV or the valve (i.e. the MR)? Characterization and risk-stratification of patients with secondary MR therefore remains challenging. Until recently the decision to intervene for secondary MR was based also on the LVEF. However, LVEF is subject to many limitations. Advanced echocardiography, such as speckle tracking echocardiography, from which LVGLS could be derived has shown to be of much more diagnostic and prognostic value in various valvular heart disease and is currently being implemented more in valvular heart disease guidelines. This supports the fact that LVGLS can detect LV dysfunction in an earlier stage and therefore guide physicians to refer patients for intervention before it is too late. Also the mitral valve geometry has an important role in the technical feasibility of intervention, but also could elaborate on which specific transcatheter intervention is more appropriate according to their targets (i.e. leaflets, annulus or sub apparatus). Additionally, multimodality imaging remains key in characterization and quantification of secondary MR and may help further risk-stratification. Show less
In this PhD thesis we have studied left ventricular systolic deformation with novel cardiovascular magnetic resonance (CMR) algorithm called feature-tracking in patients with acute myocardial... Show moreIn this PhD thesis we have studied left ventricular systolic deformation with novel cardiovascular magnetic resonance (CMR) algorithm called feature-tracking in patients with acute myocardial infarction (MI). We have shown that left ventricular strain with feature-tracking CMR offers an incremental value above conventional imaging parameters in the assessment of prognosis of patients with acute MI. In addition, left ventricular strain analysis confirmed a clear clinical benefit of early intravenous betablocker treatment in patients with acute MI. Moreover, we have explored the feasibility of novel automated 3D echocardiographic algorithm in the assessment of the aortic root anatomy in patients with severe aortic stenosis prior to transcatheter aortic valve replacement (TAVR). The 3D echocardiographic algorithm performed excellent against the gold standard multidetector row computed tomography to determine the aortic annulus size and to choose the correct TAVR prosthesis size; however, the accuracy was a bit lower in patients with severely calcified aortic valves. In addition, we have explored the advantages and limitations of different cardiac imaging techniques in the assessment of patients with TAVR, the role of multimodality imaging in patients with combined valvular heart disease and heart failure, and the role of myocardial fibrosis assessment with CMR in valvular heart disease. Show less
With increasing age, incidence and prevalence of cardiovascular disease increase. Many physicians face the dilemma whether or not to start preventive treatment in old age. To help physicians decide... Show moreWith increasing age, incidence and prevalence of cardiovascular disease increase. Many physicians face the dilemma whether or not to start preventive treatment in old age. To help physicians decide whether to advise preventive medication to their older patients, prediction of those at highest or lowest (relative) risk using (preferably) inexpensive and easy to use cardiovascular risk factors is important. However, in old age there is a lack of good cardiovascular risk predictors. This thesis shows that the use of multiple blood pressure measurements expressed in the variability (in diastolic blood pressure) or trends in blood pressure can identify older persons with high cardiovascular risk. It also shows that in the oldest old, the absence or presence of heart failure does not influence the prognostic value of low systolic blood pressure regarding risk of death. The serological biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) is found to be an interesting candidate in cardiovascular risk prediction in old age, especially in secondary prevention. In the oldest old, an increase in NT-proBNP still reflects increased risk of (cardiovascular) death, independent of decreasing renal function and is associated with incident heart failure and atrial fibrillation. Show less
The main aim of this thesis is to explore risk factors associated to an increased risk of adverse outcomes for heart failure (HF) patients and improve the early re-admission or mortality prediction... Show moreThe main aim of this thesis is to explore risk factors associated to an increased risk of adverse outcomes for heart failure (HF) patients and improve the early re-admission or mortality prediction in HF. Data from two studies (OPERA-HF study in the UK and SAPHIRE study in US) has been used to explore a wide range of variables as potential risk factors. We found that depression is a significant and independent predictor of all-cause mortality among HF patients. Depression was also significantly associated with recurrent events: unplanned readmission or mortality. Other psychosocial or non-clinical variables independently associated with increasing risk of recurrent events in the year following discharge after a HF hospital admission were: presence of frailty, moderate-to-severe anxiety, living alone and the presence of cognitive impairment. We then used data from the OPERA-HF study to develop a 30-day composite outcome model and to explore the added predictive value of non-clinical predictors to early outcomes: 30-day unplanned readmission or mortality. The performance of the model improved by including physical frailty and social support next to clinical variables. The transportability of the model to a different geography was proved in the external validation of the model on the SAPHIRE study data. Show less
In this thesis, we evaluated the acute and chronic hemodynamic effects of non-pharmacological heart failure therapies. In particular, the effects of surgical treatment and biventricular pacing... Show moreIn this thesis, we evaluated the acute and chronic hemodynamic effects of non-pharmacological heart failure therapies. In particular, the effects of surgical treatment and biventricular pacing therapy were investigated by left ventricular pressure-volume loop analyses. We demonstrated that restrictive mitral annuloplasty effectively restored mitral leaflet coaptation without inducing significant acute changes in ventricular function. This indicates that this procedure can be safely applied in patients with heart failure. Surgical ventricular restoration was shown to achieve acute normalisation of left ventricular volumes, improved systolic function, and decreased left ventricular wall stress and mechanical dyssynchrony. At the expense of a higher diastolic pressure resulting from altered diastolic properties, stroke work and cardiac output were not importantly altered, but mechanical efficiency was significantly improved. Chronically, surgical therapy resulted in improved clinical status evidenced by improved NYHA class, quality of life score, and 6-min walking distance. Left ventricular function and dyssynchrony remained significantly improved at 6 months follow-up. In addition, we observed a decrease in pulmonary artery pressure, right ventricular reverse remodeling and reduced tricuspid regurgitation. Acute and chronic hemodynamic effects of cardiac resynchronization therapy (biventricular pacing) were demonstrated by pressure-volume loop analysis. Hemodynamic improvements, previously only shown in acute studies, were shown to be maintained at 6 months follow-up. In addition, ventricular-arterial coupling, mechanical efficiency, and chronotropic responses were improved. In conclusion, the acute and chronic hemodynamic effects of these non-pharmacological heart failure therapies were demonstrated by ventricular pressure-volume analysis. These findings provide insight in the underlying mechanisms and help to explain improved functional status achieved with these therapies. Show less
In neonatal rat ventricular cardiomyocytes (NRVCs), we activated integrins by RGD to test whether integrin stimulation produced hypertrophy. Effect of RGD was compared with pro-hypertrophic effects... Show moreIn neonatal rat ventricular cardiomyocytes (NRVCs), we activated integrins by RGD to test whether integrin stimulation produced hypertrophy. Effect of RGD was compared with pro-hypertrophic effects of phenylephrine (chapter 2). Ventricular failure is associated with disturbed collagen turnover. Myocardial collagen turnover can be assessed by plasma PINP, PIIINP, and ICTP representing collagen synthesis (PINP, PIIINP) or degradation (ICTP). We investigated the effects of cardiac resynchronization therapy (CRT) on collagen turnover in patients at baseline and after 6 months of CRT (chapter 3). Monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and RV failure are associated with MMP activation in RV, we investigated whether NO plays role in RV hypertrophy and failure (chapter 4). In chapter 5 we reviewed novel approaches to treat experimental PAH. We investigated whether MCT-induced PAH and RV failure can be treated with mesenchymal stem cells (MSCs) from donor rats with PAH caused by MCT. At day 14 after MCT, recipient rats were treated with MSCs. In chapters 6,7 the effects of MSCs on pulmonary pathology and RV function were examined. Isolated cardiomyocytes were investigated for PAH-related changes in excitability. In chapter 8 we reported on excitability properties dependent on Kv-channel expression, proposed to play a role in arrhythmias. Show less
