E.T. van der Velde

CONCOR, an initiative towards a national registry and DNA-bank of patients with congenital heart disease in the Netherlands: Rationale, design, and first results

Introduction:Survival of patients with congenital heart disease has dramatically improved after surgical repair became available 40 years ago. Instead of a mortality of 85% during childhood following the natural course, over 85% of these infants are now expected to reach adulthood. However, data on long-term outcome is scarce due to the lack of large, national registries. Moreover, little is known about the genetic basis of congenital heart defects. In 2000, the Interuniversity Cardiology Institute of the Netherlands and the Netherlands Heart Foundation have taken the initiative to develop a national registry and DNA-bank of patients with congenital heart disease in the Netherlands named CONCOR.Objectives: The aims of the CONCOR-project are to facilitate investigation of the prevalence and long-term outcome of specific congenital heart defects and their treatment, to develop an efficient organisational structure for the improvement of healthcare for patients with congenital heart disease, and to allow investigation of the molecular basis of congenital heart defects. Methods: After informed consent, research nurses enter data of participating patients into the CONCOR database using a web application. Data is transferred over the Internet via a secure connection. About 20 ml blood is withdrawn from the patient, and the DNA is isolated and stored. From each participating patient family history on congenital heart disease is obtained. Results: Within two and a half years more than 4200 patients have agreed to participate. More than 99% of the patients that were asked have given their consent to participate in CONCOR. From 60% of these patients DNA has already been obtained. Mean age of the patients included is 34 years; more than 85% of the patients are younger than 45 years. Late complications occur frequently and the incidence increases with advancing age. 18% of the patients are known with supraventricular or ventricular arrhythmias. 2% of the included patients suffered a cerebrovascular accident, 139 (3%) had endocarditis. 6% of the patients has pulmonary hypertension or Eisenmenger syndrome. More than 15% of the patients reported an affected family member with congenital heart disease in the first, second, or third degree. 6% has an affected first-degree relative, and 4% a second-degree relative. Already 10 research projects have started using the CONCOR data and DNA. Conclusion: The population of patients with congenital heart disease is young and rapidly growing. Late complications occur frequently and the incidence increases with advances age. The CONCOR registry and DNA-bank facilitates research on prevalence and long-term outcome and allows investigation of the molecular basis of congenital heart disease.

Nonlinearity and load sensitivity of end-systolic pressure-volume relation of canine left ventricle in vivo.

The effects of mechanical changes in loading conditions on the left ventricular end-systolic pressure-volume relation (ESPVR) were studied in nine open-chest dogs, including three dogs studied before and after beta-adrenergic blockade. Left ventricular pressure was measured with a micromanometer, and left ventricular volume was measured with a conductance catheter. ESPVRs were obtained by increasing left atrial inflow over wide volume ranges (as much as threefold) under three different conditions: control or high or low aortic impedance. High impedance was obtained by occlusion of the descending aorta, and low impedance was obtained by a shunt between the subclavian artery and the left atrium. In the unblocked animals in 21 of 28 runs, a second-order polynomial equation gave a better fit for the ESPVR than a linear relation. To quantify the effects of the changes in aortic impedance on the ESPVR, we calculated from the quadratic equation its volume intercept (V18) and its local slope (E18) at an end-systolic pressure (Pes) of 18 kPa. In the unblocked animals, a statistically significant difference was found in V18 between low impedance (21.50 +/- 6.27 ml) and high impedance (14.10 +/- 8.98 ml; p less than 0.005) and between control (19.14 +/- 9.58 ml) and high impedance (p less than 0.05). In most dogs, E18 was increased at high and decreased at low impedance, but not significantly. In the additional experiments with beta-blockade, the nonlinearity diminished somewhat, but the load dependency of the ESPVR remained present after beta-blockade because the same leftward shift of the ESPVR with high aortic impedance was found. Two other relations, namely, of dP/dtmax and of stroke work versus end-diastolic volume, were also investigated, which on the whole showed the same behavior as the ESPVR. These results indicate that the ESPVR and dP/dtmax-Ved and stroke work-end-diastolic volume relations, when studied over a wide volume range, are nonlinear and that changes in loading conditions influence indexes of contractility derived from these relations, especially the volume intercepts, in such a way that an increase in aortic impedance may be interpreted as an increase in contractility. Blocking the beta-adrenergic receptors did not influence the load dependency of the ESPVR but, in some cases, tended to decrease the nonlinearity in concordance with the relation between contractility and nonlinearity in isolated hearts.

The four-electrode resistivity technique in anisotropic media: theoretical analysis and application on myocardial tissue in vivo

Several aspects of the 4-electrode resistivity technique were studied with special emphasis on the theoretical determination of penetration depth and sample volume in anisotropic media such as (cardiac) muscle. Moreover, the presence of a thin disturbing layer on top of the medium under study was analyzed. A 4-electrode sensor was developed for the measurement of local myocardial resistivity in 2 orthogonal directions. The sensor was applied to the epicardium of anesthetized open chest dogs and, as an example, results are given on the frequency dependence (5-60 kHz) and the changes during the cardiac cycle of longitudinal and transverse myocardial resistivity.<<ETX>>

Heart failure admissions in adults with congenital heart disease; risk factors and prognosis

BACKGROUND Heart failure (HF) is a serious complication and often the cause of death in adults with congenital heart disease (CHD). Therefore, our aims were to determine the frequency of HF-admissions, and to assess risk factors of first HF-admission and of mortality after first HF-admission in adults with CHD. METHODS The Dutch CONCOR registry was linked to the Hospital Discharge Registry and National Mortality Registry to obtain data on HF-admissions and mortality. Risk factors for both HF-admission and mortality were assessed using Cox regression models. RESULTS Of 10,808 adult patients (49% male), 274 (2.5%) were admitted for HF during a median follow-up period of 21 years. The incidence of first HF-admission was 1.2 per 1000 patient-years, but the incidence of HF itself will be higher. Main defect, multiple defects, and surgical interventions in childhood were identified as independent risk factors of HF-admission. Patients admitted for HF had a five-fold higher risk of mortality than patients not admitted (hazard ratio (HR)=5.3; 95% confidence interval 4.2-6.9). One- and three-year mortality after first HF-admission were 24% and 35% respectively. Independent risk factors for three-year mortality after first HF-admission were male gender, pacemaker implantation, admission duration, non-cardiac medication use and high serum creatinine. CONCLUSIONS The incidence of HF-admission in adults with CHD is 1.2 per 1000 patient-years. Mortality risk is substantially increased after HF-admission, which emphasises the importance to identify patients at high risk of HF-admission. These patients might benefit from closer follow-up and earlier medical interventions. The presented risk factors may facilitate surveillance.

The End-Systolic Pressure-Volume Relationship in the Newborn Lamb: Effects of Loading and Inotropic Interventions

ABSTRACT: Indices of global systolic performance of the newborn left ventricle exceed those of the adult, despite isolated tissue studies showing immature contractile mechanisms. To evaluate contractility in situ, we investigated the end-systolic pressure-volume relationship (ESPVR) by the conductance technique in nine newborn lambs. After percutaneous placement of catheters, we generated ESPVR by inferior vena cava occlusion, aortic occlusion, and volume infusion in two control states, during three levels of dobutamine infusion, and after propranolol. We performed linear and nonlinear regression analyses of the end-systolic points and derived the slope (Ees) and volume at 14 kPa pressure. We found that reliable ESPVR could be obtained in almost all inferior vena cava and aortic occlusions (50 of 51 in each), but in only 18 of 27 volume infusions. Overall, linear regressions adequately defined the ESPVR (75 of 102 were not statistically different than nonlinear regressions; of those different, the mean linear R2 was 0.934 ± 0.048). By multiple regression analysis, neither Ees nor volume at 14 kPa significantly changed with dobutamine, but both changed after propranolol (23% less than control and 54% greater, respectively), supporting previous studies showing a limited contractile reserve in the newborn secondary to high resting β-adrenergic tone. Neither Ees nor volume at 14 kPa was different between control states. However, Ees was 25% less steep when generated by inferior vena cava than by aortic occlusion. We conclude that the ESPVR can be generated reliably and reproducibly in the newborn lamb and is relatively linear and sensitive to changes in contractility, but that it is also sensitive to the technique of load intervention.

Dependence of anisotropic myocardial electrical resistivity on cardiac phase and excitation frequency.

SummaryKnowledge of myocardial electrical resistivity is of interest because passive electrical properties govern the electrotonic spread of current through the myocardium and influence the shape and velocity of the excitation wave. In addition, measurements of myocardial resistivity may provide information about tissue structure and components. The aim of the present study was to determine the excitation frequency dependence and the changes during the cardiac cycle of anisotropic myocardial electrical resistivity. Longitudinal and transverse myocardial resistivity were measured using an epicardial sensor in four open-chest dogs with excitation frequencies in the range of 5–60 kHz. Mean longitudinal resistivity gradually decreased from 313±49 Ω·cm at 5 kHz to 212±32 Ω·cm at 60 kHz, transverse resistivity decreased from 487±49 to 378±53 Ω·cm. To analyze the phasic changes, we compared mean resistivity (averaged over the full cardiac cycle) with resistivity during four cardiac phases: pre-ejection, ejection, early diastole and late diastole. Longitudinal resistivity was significantly higher during the ejection phase (+9.6±4.1 Ω·cm) and lower during late diastole (−6.9±2.9 Ω·cm). Transverse resistivity was significantly higher during late diastole (+4.0±2.3 Ω·m). The values during the other cardiac phases were not significantly different from mean resistivity. The phasic changes in longitudinal and transverse resistivity during the cardiac cycle were independent of the excitation frequency. We speculate that these changes are related to geometrical changes, especially to changes in myocardial blood volume.

Effect of coronary occlusion and reperfusion on local electrical resistivity of myocardium in dogs

SummaryThe effect of coronary occlusion and reperfusion on myocardial electrical resistivity was studied in nine anesthetized open-chest dogs. Anisotropic resistivity was measured on the anterior free wall of the left ventricle (LV) before (control) and during transient occlusion of the left anterior descending (LAD) coronary artery, and during reperfusion. To measure local resistivity longitudinal (RL) and transverse (RT) to epicardial muscle fiber direction, a sensor was developed based on the four electrode (FE) technique with an electrode distance of 1 mm. Previous calculations showed that measurements with this system were confined to a 2-mm-thick epicardial layer. Control values for RL and RT were 243±32Ω·cm and 358±45Δ·cm (mean±SD, n=9) respectively. During a 2-min LAD occlusion, RL increased gradually by 12.4% (p<0.05) and RT by 7.8% (p<0.05) above the preceding control values. During a 5-min reperfusion period resistivities returned towards control values, but tended to remain elevated. RL showed a slight initial further increase during the first min of reperfusion and remained significantly above control values during 3 min of reperfusion. RT returned to values not significantly different from control after about 1 min of reperfusion.

A new approach to determine parallel conductance for left ventricular volume measurements

OBJECTIVES To determine absolute ventricular volume with the conductance catheter technique, the electrical conductance of tissues and fluids (parallel conductance) around the ventricle should be determined precisely. METHODS A new objective method to estimate parallel conductance based on analysis of the dilution curve of hypertonic saline was investigated. The parallel conductances obtained with the new method (G(a)(p)) were compared to those obtained with the conventional method (G(l)(p)). The study was performed in the left ventricle of 12 patients. RESULTS G(a)(p) was not significantly different from G(l)(p). For the G(l)(p) method the average percentage difference between duplicate values, both taken as absolute values, was 15.06% and for the G(a)(p) method it was 4. 01%. Thus the reproducibility of the method is a factor four better than that of the method. This difference appeared to be significant. CONCLUSION We conclude that a smaller number of injections will be required to obtain the same precision using our method.

Implementing national guidelines on risk prediction and primary prevention of coronary heart disease in a cardiology information system

Recently the Dutch Institute for Healthcare Improvement (CBO) published a national consensus concerning both risk prediction and guidelines for primary prevention of coronary heart disease (CHD). The risk prediction algorithm used by the CBO was, after validating, taken as an input for an application, as part of the cardiology information system (CARIS) of the Leiden University Medical Center. By selecting the patient, the risk factors that are available in CARIS are filled in automatically. The remaining items are imported from the hospital information system. After that, the absolute risk on CHD is calculated and a treatment advice is presented Since no manual input is necessary, the risk estimation tool is quick and easy to use. With this predictive tool for clinical decision support, the physician can opt for an intervention to minimize disease risk, or prevent risk factor development in the future.

The volume-dependency of parallel conductance throughout the cardiac cycle and its consequence for volume estimation of the left ventricle in patients

OBJECTIVE To study the hypothesis that the electrical conductance of tissues and fluids (parallel conductance (G(p))) around the ventricle depends on left ventricular volume throughout the cardiac cycle. METHODS We extended a recently developed method to determine G(p) throughout the cardiac cycle. First, we compared the estimates of parallel conductances obtained with the new method (G(a)(p)) with those of the conventional one (G(1)(p)), both averaged over the cardiac cycles. Secondly, G(a)(p) was determined throughout the cardiac cycle and its volume dependency was assessed. Thirdly, the factor alpha was calculated as the ratio between stroke volume, obtained by the conductance method using G(1)(p), and that obtained by a thermodilution method. Because the non-homogeneous field was indicated to be the reason for the dependency of G(p) on left ventricular volume as well as for the need for alpha, we tested whether the hypothesis implies that a correction with alpha is not needed if G(p) is determined throughout the cardiac cycle. RESULTS We found a negative linear relation between G(p) and left ventricular volume. This relation appeared to be reproducible within each patient. Furthermore, we found that alpha deviates from 1 primarily due to the dependency of G(p) on left ventricular volume. CONCLUSION To obtain stroke volume or to determine absolute left ventricular volume continuously within a cardiac cycle, G(p) should be determined throughout each cardiac cycle and if a constant G(p) throughout the cardiac cycle is used a correction with the factor alpha should be made to correct for a possible influence of electrical field heterogeneity.