Hans Kirkels

long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay

OBJECTIVES We sought to compare the short- and long-term clinical effects of atrial synchronous pre-excitation of one (univentricular) or both ventricles (biventricular), that provide cardiac resynchronization therapy (CRT). BACKGROUND In patients with heart failure (HF) who have a ventricular conduction delay, CRT improves systolic hemodynamic function. The clinical benefit of CRT is still being investigated. METHODS Forty-one patients were randomized to four weeks of first treatment with biventricular or univentricular stimulation, followed by four weeks without treatment, and then four weeks of a second treatment with the opposite stimulation. The best CRT stimulation was continued for nine months. Cardiac resynchronization therapy was optimized by hemodynamic testing at implantation. The primary end points were exercise capacity measures. Data were analyzed by two-way repeated-measures analysis of variance. RESULTS The left ventricle was selected for univentricular pacing in 36 patients. The clinical effects of univentricular and biventricular CRT were not significantly different. The results of each method were pooled to assess sequential treatment effects. Oxygen uptake during bicycle exercise increased from 9.48 to 10.4 ml/kg/min at the anaerobic threshold (p = 0.03) and from 12.5 to 14.3 ml/kg/min at peak exercise (p < 0.001) with the first treatment, and from 10.0 to 10.7 ml/kg/min at the anaerobic threshold (p = 0.2) and from 13.4 to 15.2 ml/kg/min at peak exercise (p = 0.002) with the second treatment. The 6-min walk distance increased from 342 m at baseline to 386 m after the first treatment (p < 0.001) and to 416 m after the second treatment (p = 0.03). All improvements persisted after 12 months of therapy. CONCLUSIONS Cardiac resynchronization therapy produces a long-term improvement in the clinical symptoms of patients with HF who have a ventricular conduction delay. The differences between optimized biventricular and univentricular therapy appear to be small for short-term treatment.

Exercise Performance in Patients With End-Stage Heart Failure After Implantation of a Left Ventricular Assist Device and After Heart Transplantation An Outlook for Permanent Assisting?

OBJECTIVES We sought to study exercise capacity at different points in time after left ventricular assist device (LVAD) implantation and subsequent heart transplantation (HTx). BACKGROUND The lack of donor organs warrants alternatives for transplantation. METHODS Repeat treadmill testing with respiratory gas analysis was performed in 15 men with a LVAD. Four groups of data are presented. In group A (n = 10), the exercise capacities at 8 weeks and 12 weeks after LVAD implantation were compared. In group B (n = 15), the data at 12 weeks are presented in more detail. In group C (n = 9), sequential analysis of exercise capacity was performed at 12 weeks after LVAD implantation and at 12 weeks and one year after HTx. In group D, exercise performance one year after HTx in patients with (n = 10) and without (n = 20) a previous assist device was compared. RESULTS In group A, peak oxygen consumption (Vo2) increased from 21.3+/-3.8 to 24.2+/-4.8 ml/kg body weight per min (p < 0.003), accompanied by a decrease in peak minute ventilation/ carbon dioxide production (VE/Vco2) (39.4+/-10.1 to 36.3+/-8.2; p < 0.03). In group B, peak Vo2 12 weeks after LVAD implantation was 23.0+/-4.4 ml/kg per min. In group C, levels of peak Vo2 12 weeks after LVAD implantation and 12 weeks and one year after HTx were comparable (22.8+/-5.3, 24.6+/-3.3 and 26.2+/-3.8 ml/kg per min, respectively; p = NS). In group D, there appeared to be no difference in percent predicted peak Vo2 in patients with or without a previous LVAD (68+/-13% vs. 74+/-15%; p < 0.37), although, because of the small numbers, the power of this comparison is limited (0.45 to detect a difference of 10%). CONCLUSIONS Exercise capacity in patients with a LVAD increases over time; 12 weeks after LVAD implantation, Vo2 is comparable to that at 12 weeks and one year after HTx. Previous LVAD implantation does not seem to adversely affect exercise capacity after HTx.

Electrocardiographic remodeling in patients paced for heart failure

Congestive heart failure due to advanced coronary artery disease or dilated cardiomyopathy is often associated with intraventricular conduction delays. Electrical resynchronization is an evolving method to improve clinical and functional status. To evaluate whether pacing-induced changes in the electrocardiogram are related to hemodynamic changes, we analyzed electrocardiograms of patients enrolled in the Pacing Therapies in Congestive Heart Failure trial. The study population consisted of 42 patients, New York Heart Association functional class III-IV with a baseline QRS complex of 175 +/- 32 msec and a PR interval of 196 +/- 33 msec. The mean left ventricular ejection fraction was 0.23. Using high-resolution computer scans, we measured QRS duration of intrinsic and paced electrocardiographs at different times during the study. Results of the electrocardiographic measurements were correlated with functional results. During the crossover period, 34 episodes of biventricular pacing, 27 episodes of left ventricular pacing, and 5 episodes of right ventricular pacing occurred, each at an individual optimized atrioventricular (AV) delay. The only significant difference was that right ventricular pacing increased the QRS width by 40 msec as compared with baseline or biventricular pacing. Functional benefit, as indicated by relative increase of peak oxygen uptake (VO2) compared with baseline, was significantly correlated with shortening of paced QRS width (correlation coefficient, r = 0.55; p <0.05). After 12-month follow-up of 28 patients, we saw a slight, nonsignificant decrease of intrinsic QRS width. With regard to the underlying disease, intrinsic QRS width at baseline and at 12 months was also not significantly different between patients with coronary artery disease and dilated cardiomyopathy. This study found that right ventricular pacing causes an increase in QRS duration in patients with left bundle-branch block, whereas in left ventricular and biventricular pacing, QRS width remains unchanged. Shortening of QRS width is correlated with a pronounced relative increase of peak VO2, and thus may become a noninvasive marker of clinical efficacy. There is no evidence of remodeling of the intrinsic electrocardiogram after 12 months of pacing.

Cardiomyocyte death in patients with end-stage heart failure before and after support with a left ventricular assist device: low incidence of apoptosis despite ubiquitous mediators

BACKGROUND Left ventricular assist device (LVAD) implantation in patients with end-stage heart failure results in impressive hemodynamic improvement. The effects on myocardial apoptosis and its mediators are unknown. METHODS Myocardial biopsies from 17 patients at the time of LVAD implantation and after explantation, at the time of heart transplantation (HTx), were examined by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) reaction and with antibodies against Fas ligand (FasL), Fas, tumor necrosis factor (TNF)-alpha receptor 1 (TNF-R1), TNF-alpha receptor 2 (TNF-R2), TNF-alpha, TNF-alpha-converting enzyme (TACE), poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) (PAR), caspase-3 and FLICE inhibitory protein (FLIP). RESULTS Apoptosis incidence was low: 0.8% (range 0% to 3%) positive cardiomyocytes nuclei before support, and 0.1% (range 0% to 0.6%) after support (p < 0.01). This was accompanied by low expression of caspase-3 and high expression of the DNA repair enzyme, PARP. Its product, PAR, increased after support. Mediators and receptors inducing apoptosis as well as FLIP were widely present before and after support. CONCLUSIONS Despite the abundant presence of mediators and receptors inducing apoptosis, the incidence of apoptosis itself was low before and after mechanical support. The abundant expression of FLIP may suggest an important role for this protein in the inhibition of cardiomyocyte death.

T Cell Apoptosis in Human Heart Allografts : Association with Lack of Co-Stimulation?

It is unclear whether the intracardial immune reactivity after heart transplantation influences the peripheral immunological status (activation or nonresponsiveness) of the patient. Co-stimulation and activation-induced cell death (AICD) or apoptosis play an important role in determining the balance between lymphocyte reactivity and nonreactivity. Therefore, we studied the expression of co-stimulatory molecules and the process of apoptosis in biopsies of human heart allografts, using immunohistochemistry. Although a normal expression of co-stimulatory molecules on antigen-presenting cells was observed, the expression of their counter-structures on T cells was absent. This may be due to chronic T cell activation, which can lead to the induction of apoptosis via the Fas/Fas ligand pathway. In the infiltrates, a considerable percentage of the lymphocytes, but not the macrophages, were apoptotic. Apoptosis was confirmed by DNA fragmentation analysis. Increased numbers of Bax-expressing versus decreased numbers of Bcl2-expressing lymphocytes in comparison with normal lymphoid tissue confirmed a imbalance in favor of apoptosis. Apoptosis was biased towards CD4+ T cells (65.7% versus 26.6% in CD8+ T cells). Fas was expressed on most of the infiltrating cells. Fas ligand expression was also observed, not only on most of the T cells but also on all macrophages. Because macrophages were often detected in close contact with T cells, they may play a role in T cell regulation via the Fas/Fas ligand pathway. This study indicates that, during rejection, not only is tissue damage induced by infiltrating T cells, but also the infiltrating lymphocytes themselves are actively down-regulated (eg, AICD) by one another and by macrophages in the infiltrate. This regulatory process may affect the immunological status of the patient after heart transplantation.

Functional and haemodynamic recovery after implantation of continuous-flow left ventricular assist devices in comparison with pulsatile left ventricular assist devices in patients with end-stage heart failure.

Caused by ageing of the population, better survival from ischaemic heart disease, and improved treatment of chronic heart disease, the incidence of heart failure has increased enormously. Worldwide, left ventricular assist devices (LVADs) are increasingly being used as a bridge or alternative to heart transplantation. In this study, we investigated whether there is difference in functional and haemodynamic recovery after implantation of pulsatile and continuous‐flow pumps.

Distinct phenotypes of cardiac allograft vasculopathy after heart transplantation: A histopathological study

INTRODUCTION Long-term survival after heart transplantation (HTx) is hampered by cardiac allograft vasculopathy (CAV). Better understanding of the pathophysiological mechanisms of CAV might have considerable consequences for therapeutic approaches in the future. The aim of the present study was to investigate the histological phenotypes of CAV in relation with clinical patient characteristics. METHODS AND RESULTS Coronary cross-sections from 51 HTx patients were obtained at autopsy. CAV was observed in 42 patients (82%). Three histological CAV phenotypes were identified (H-CAV 1-3). No CAV (H-CAV 0) is as seen in normal coronary arteries; intimal thickening consisting of a layer of longitudinal oriented smooth muscle cells. In H-CAV 1 to 3 a second intimal layer is formed, on top of the longitudinal oriented smooth muscle cell layer, with predominantly mononuclear inflammatory infiltrate in loose connective tissue (H-CAV 1), smooth muscle cells in different orientation (H-CAV 2), or a fibrotic intimal lesion (H-CAV 3). H-CAV type was significantly related with time after transplantation, age at transplantation, the amount of atherosclerotic disease and the occurrence of infection. In addition, morphometric analysis revealed that higher H-CAV types have a relatively larger intimal area, that is compensated for by expansive arterial remodeling of the artery. CONCLUSION CAV in an ongoing process that can be classified into three different phenotypes; inflammatory lesions, lesions rich of smooth muscle cells and fibrotic lesions. Our results suggest that these phenotypes are related to time after transplantation, age at transplantation, the amount of atherosclerotic disease and the occurrence of infection.