UNRAVEL: big data analytics research data platform to improve care of patients with cardiomyopathies using routine electronic health records and standardised biobanking.

INTRODUCTION: Despite major advances in our understanding of genetic cardiomyopathies, they remain the leading cause of premature sudden cardiac death and end-stage heart failure in persons under the age of 60 years. Integrated research databases based on a large number of patients may provide a scaffold for future research. Using routine electronic health records and standardised biobanking, big data analysis on a larger number of patients and investigations are possible. In this article, we describe the UNRAVEL research data platform embedded in routine practice to facilitate research in genetic cardiomyopathies. DESIGN: Eligible participants with proven or suspected cardiac disease and their relatives are asked for permission to use their data and to draw blood for biobanking. Routinely collected clinical data are included in a research database by weekly extraction. A text-mining tool has been developed to enrich UNRAVEL with unstructured data in clinical notes. PRELIMINARY RESULTS: Thus far, 828 individuals with a median age of 57 years have been included, 58% of whom are male. All data are captured in a temporal sequence amounting to a total of 18,565 electrocardiograms, 3619 echocardiograms, data from over 20,000 radiological examinations and 650,000 individual laboratory measurements. CONCLUSION: Integration of routine electronic health care in a research data platform allows efficient data collection, including all investigations in chronological sequence. Trials embedded in the electronic health record are now possible, providing cost-effective ways to answer clinical questions. We explicitly welcome national and international collaboration and have provided our protocols and other materials on www.unravelrdp.nl .

Stent thrombosis in real-world patients: a comparison of drug-eluting with bare metal stents.

BACKGROUND: Although the introduction of drugeluting stents (DES) has been associated with an impressive reduction in target vessel revascularisation, there has been concern about the safety profile. The aim of this study was to determine the incidence of stent thrombosis in real-world patients and evaluate the contribution of drug-eluting stents. METHODS: A prospective observational cohort study was conducted at a high-volume centre in Utrecht, the Netherlands. All patients who underwent a percutaneous coronary intervention (PCI) between 1 January and 31 December 2005 were evaluated. The patients were pretreated with aspirin and clopidogrel, which was continued for six months in bare metal stents (BMS) and 12 months in DES. RESULTS: In 2005, 1309 patients underwent a percutaneous coronary intervention procedure with stent implantation. After a median follow-up of nine months, 1.8% (n=23) of the patients had suffered from stent thrombosis. Two cases could be attributed to incorrect use of antiplatelet agents. In 8/23 cases, a technical reason was found such as an unrecognised dissection or stent underexpansion. The timing of stent thrombosis was acute in 1/23 patients, subacute in 20/23 patients and late in 2/23 patients. In both cases of late stent thrombosis, a BMS had been used. There were no differences in stent thrombosis rates between DES and BMS (1.4 vs. 1.9%, ns.). This is remarkable since DES were used in more complex and longer lesions. CONCLUSION: The use of DES in routine daily practice does not appear to be associated with a higher rate of stent thrombosis than BMS. (Neth Heart J 2007;15:382-6.Neth Heart J 2007;15:382-6).

Activation delay after premature stimulation in chronically diseased human myocardium relates to the architecture of interstitial fibrosis.

BACKGROUND: Progressive activation delay starting at long coupling intervals of premature stimuli has been shown to correlate with sudden cardiac death in patients with hypertrophic cardiomyopathy. The purpose of this study was to elucidate the mechanism of increased activation delay in chronically diseased myocardium. METHODS AND RESULTS: High-resolution unipolar mapping (105, 208, or 247 recording sites with interelectrode distances of 0.8, 0.5, or 0.3 mm, respectively) of epicardial electrical activity was carried out during premature stimulation in 11 explanted human hearts. The hearts came from patients who underwent heart transplantation and were in the end stage of heart failure (coronary artery disease, 4; hypertrophic cardiomyopathy, 1; and dilated cardiomyopathy, 6). Eight hearts were Langendorff-perfused. Epicardial sheets were taken from the remaining hearts and studied in a tissue bath. Activation maps and conduction curves were constructed and correlated with histology. Conduction curves revealing prominent increase of activation delay were associated with zones of dense, patchy fibrosis with long fibrotic strands. Dense, diffuse fibrosis with short fibrotic strands only marginally affected conduction curves. The course of conduction curves in patchy fibrotic areas greatly depended on the direction of propagation relative to fiber direction. CONCLUSIONS: The study demonstrates that in chronically diseased human myocardium, nonuniform anisotropic characteristics imposed by long fibrotic strands cause a progressive increase of activation delay, starting at long coupling intervals of premature stimuli. The increase strongly depends on the direction of the wave front with respect to fiber direction and the architecture of fibrosis.

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.

Pacing Therapies in Congestive Heart Failure II study.

Ventricular resynchronization therapy (VRT) by left or biventricular stimulation is gaining increasing acceptance as a new therapy in addition to drugs in patients with advanced heart failure and intraventricular conduction disturbances. Several studies have demonstrated acute hemodynamic benefit of VRT in these patients, although there are only limited long-term data in small patient cohorts. Many open questions remain: whether to pace both ventricles or the left ventricle alone, the optimal left ventricular pacing site, the criteria used to identify the optimal candidate for VRT (e.g., QRS width), and the importance of an integrated defibrillator function in a VRT device. The Pacing Therapy in Congestive Heart Failure (PATH-CHF) II study is a prospective, randomized, cross-over study currently investigating the potential benefit of VRT in a population with advanced heart failure, with or without an accepted indication for an implantable defibrillator. It focuses on the effects of optimized univentricular pacing in these patients, and both acute hemodynamic and chronic functional effects are assessed. Acute hemodynamic testing mainly investigates the impact of different left ventricular pacing sites, alone or combined with right ventricular sites, on hemodynamic performance. Primary endpoint of the study is an improvement in functional capacity as assessed by cardiopulmonary exercise testing and 6-minute walk distance; secondary endpoints include improvement in quality of life (assessed by Minnesota quality of life score, New York Heart Association (NYHA) functional class, and hospitalization frequency), and improvements in prognostic and hemodynamic parameters. The trial aims to enroll 64 patients with full datum sets (separately in 2 groups with a QRS of < or = 150 or > 150 msec, respectively) in 9 European centers. The enrollment began September 1998, and is expected to conclude in summer 2000 to reach the number of necessary datum sets.

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.

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.