Johan Van Cleemput

Oxidized Low Density Lipoproteins in Patients With Transplant-Associated Coronary Artery Disease

The monoclonal antibody 4E6-based ELISA was used to quantify levels of oxidized LDL in plasma of 65 control subjects, 47 patients transplanted for dilated cardiomyopathy (DCM), and 60 patients transplanted for coronary artery disease (CAD). Levels of oxidized LDL were 0.68+/-0.039 mg/dL (mean+/-SEM), 1.27+/-0.14 mg/dL (P<.001 versus control), and 1.73+/-0.13 mg/dL (P<.001 versus control and <0.01 versus DCM), respectively. Levels of oxidized LDL were significantly lower in transplanted patients with angiographically normal coronary arteries (grade 0, 1.16+/-0.053 mg/dL; n=79) than in patients with mild (grade 1, 2.13+/-0.30 mg/dL; n=18; P<.001 versus grade 0) or severe (grade 2, 3.18+/-0.45 mg/dL; n=10; P<.001 versus grade 0 and P<.05 versus grade 1) coronary artery stenosis. Logistic regression analysis identified three parameters that were significantly and independently correlated with posttransplant CAD: plasma levels of oxidized LDL (P=.0001), length of follow-up (P=.0008), and donor age (P=.047). Thus, the present study demonstrates that plasma levels of oxidized LDL correlate with the extent of CAD in heart transplant patients and suggests that elevated levels of oxidized LDL may be a marker for CAD.

Oxidized Low Density Lipoprotein Is a Prognostic Marker of Transplant-Associated Coronary Artery Disease

Retrospective studies identified oxidized low density lipoprotein (LDL) in the blood as a diagnostic marker of coronary artery disease (CAD). This prospective study sought to determine the prognostic value of oxidized LDL for CAD in cardiac transplant patients. Oxidized LDL was measured in 99 cardiac transplant patients with normal coronary angiograms at baseline and was measured again after a median follow-up of 2 years at the time of a second angiogram. Twenty-one patients developed angiographically detectable cardiac transplant vasculopathy (cases), and 78 individuals did not (controls). Cases had significantly higher baseline plasma levels of oxidized LDL than did controls: 1.18+/-0.70 versus 0.57+/-0.20 mg/dL (mean+/-SD, P<0.0001). The increase of oxidized LDL at the end of the follow-up was significantly higher in cases than in controls: 0. 75+/-0.73 mg/dL versus 0.14+/-0.27 mg/dL (P<0.0001). Baseline levels of oxidized LDL predicted cardiac transplant vasculopathy (chi(2)=16, P<0.0001) independent of pretransplant ischemic cardiomyopathy, time after transplantation, age, and serum levels of LDL and high density lipoprotein cholesterol. The development of transplant CAD was associated with a further increase of plasma levels of oxidized LDL (chi(2)=14, P=0.0002). Oxidized LDL is a prognostic marker of transplant CAD.

Peak oxygen uptake better predicts outcome than submaximal respiratory data in heart transplant candidates.

BACKGROUND Many studies have focused on the prognostic power of peak oxygen uptake VO(2) in patients with chronic heart failure, but maximal exercise testing is not without risk. The purpose of the present study was, therefore, to assess the prognostic significance of the steepness of changes in ventilation and carbon dioxide output VO(2) during submaximal exercise in comparison with VO(2). METHODS AND RESULTS The study population consisted of 284 adult heart transplant candidates who performed a graded maximal bicycle ergometer test with respiratory gas analysis. Using the respiratory data up to a gas exchange ratio of 1.0, 3 submaximal slopes were calculated in each patient. During follow-up (median, 1.33 years), 57 patients died and 149 had >/=1 cardiovascular event. When using Cox proportional hazards analysis, both peak VO(2) and submaximal respiratory slopes predicted outcome before and after accounting for age, sex, and body mass index. However, whereas the prognostic power of peak VO(2) was independent of submaximal respiratory data, the prognostic significance of the slopes was lost after controlling for peak VO(2). Stepwise regression analysis even selected peak VO(2) as an independent prognostic index among the following factors: cause of heart failure, ejection fraction, pulmonary vascular resistance, natremia, and the forced expiratory volume in 1 s. CONCLUSIONS Respiratory data during submaximal exercise are significant predictors of outcome in patients with chronic heart failure, but their prognostic power is inferior to that of peak VO(2). However, these data may be useful when maximal exercise is contraindicated or not achievable.

Dietary cholesterol withdrawal reduces vascular inflammation and induces coronary plaque stabilization in miniature pigs

OBJECTIVE To study the effect of dietary cholesterol withdrawal on size and composition of LDL-hypercholesterolemia-induced coronary plaques in miniature pigs. METHODS Pigs were on normal chow (control group), on a cholesterol-rich diet for 37 weeks (hypercholesterolemic group) or on a cholesterol-rich diet followed by normal chow for 26 weeks (cholesterol withdrawal group). Endothelial function was assessed with quantitative angiography after intracoronary infusion of acetylcholine, plaque load with intra-coronary ultrasound and plaque composition with image analysis of cross-sections. The effect of porcine serum on coronary smooth muscle cell (SMC) function was studied in vitro. RESULTS Cholesterol-rich diet caused LDL-hypercholesterolemia, increased plasma levels of oxidized LDL (ox-LDL) and C-reactive protein (CRP), and induced endothelial dysfunction and coronary atherosclerosis. Dietary cholesterol withdrawal lowered LDL, ox-LDL and CRP. It restored endothelial function, did not affect plaque size but decreased lipid, ox-LDL and macrophage content. Smooth muscle cells and collagen accumulated within the plaque. Increased smoothelin-to-alpha-smooth muscle actin ratio indicated a more differentiated SMC phenotype. Cholesterol lowering reduced proliferation and apoptosis. In vitro, hypercholesterolemic serum increased SMC apoptosis and decreased SMC migration compared to non-hypercholesterolemic serum. CONCLUSIONS Cholesterol lowering induced coronary plaque stabilization as evidenced by a decrease in lipids, ox-LDL, macrophages, apoptosis and cell proliferation, and an increase in differentiated SMC and collagen. Increased migration and decreased apoptosis of SMC may contribute to the disappearance of the a-cellular core after lipid lowering.

Timing and quantification of bone loss in cardiac transplant recipients

To evaluate osteopenic bone disease in heart transplant patients, we prospectively measured bone mineral density (BMD) in 33 consecutive male recipients before hospital discharge and 1 year later, using dual photon absorptiometry. At hospital discharge BMD measurement at the lumbar spine was only 90% of that expected in healthy age- and sex-matched controls (P=0.005). One year later BMD had further decreased by 8.5% at the lumbar spine and by 10.4% at the femoral neck (P=0.0001). Five patients suffered vertebral compression fractures during the 1st post-operative year. Our results indicate that osteopenia of the lumbar spine is already present at the time of hospital discharge after transplantation and that further bone loss occurs at a considerable rate during the 1st postoperative year at the lumbar spine and at the femoral neck.

Long-Term Outcomes After Medical and Invasive Treatment in Patients With Hypertrophic Cardiomyopathy

OBJECTIVES The aim of this study was to determine the long-term outcomes (all-cause mortality and sudden cardiac death [SCD]) after medical therapy, alcohol septal ablation (ASA), and myectomy in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Therapy-resistant obstructive HCM can be treated both surgically and percutaneously. But there is no consensus on the long-term effects of ASA, especially on SCD. METHODS This study included 1,047 consecutive patients with HCM (mean age 52 ± 16 years, 61% men) from 3 tertiary referral centers. A total of 690 patients (66%) had left ventricular outflow tract gradients ≥ 30 mm Hg, of whom 124 (12%) were treated medically, 316 (30%) underwent ASA, and 250 (24%) underwent myectomy. Primary endpoints were all-cause mortality and SCD. Kaplan-Meier graphs and Cox regression models were used for statistical analyses. RESULTS The mean follow-up period was 7.6 ± 5.3 years. Ten-year survival was similar in medically treated patients (84%), ASA patients (82%), myectomy patients (85%), and patients with nonobstructive HCM (85%) (log-rank p = 0.50). The annual rate of SCD was low after invasive therapy: 1.0%/year in the ASA group and 0.8%/year in the myectomy group. Multivariate analysis demonstrated that the risk for SCD was lower after myectomy compared with the ASA group (hazard ratio: 2.1; 95% confidence interval: 1.0 to 4.4; p = 0.04) and the medical group (hazard ratio: 2.3; 95% confidence interval: 1.0 to 5.2; p = 0.04). CONCLUSIONS Patients with obstructive HCM who are treated at referral centers for HCM care have good survival and low SCD risk, similar to that of patients with nonobstructive HCM. The SCD risk of patients after myectomy was lower than after ASA or in the medical group.

Heart rate variability after cardiac transplantation in humans

The reappearance of cardiac innervation after cardiac transplantation remains a matter of debate. We evaluated the ability of heart rate variability (HRV) analysis to detect the extent and time course of functional cardiac allograft reinnervation. Time‐ and frequency‐domain analysis of heart rate was performed on Holter recordings of 120 heart transplant and four heart‐lung transplant recipients. A high frequency (HF) component was clearly distinguished on visual inspection of power spectral density in 42 patients. In eight patients an HF component of normal magnitude was detected. The other 34 patients in this group, including all four heart‐lung transplants, presented with a very small HF component. The other 82 patients showed a flat spectrum. The group with an HF component of normal amplitude was significantly different, compared to the other groups, for all HRV parameters. Serial plotting of HRV parameters of the patients with an HF component of normal amplitude against time posttransplant, revealed, from 12 months onwards, a progressive increase of parameters denoting HF variability. In five heart transplant patients with acute allograft rejection, the use of HRV analysis for rejection monitoring was unsuccessful. These results suggest that, inasmuch as the HF component of HRV is caused by parasympathetic cardiac innervation, the HF component of normal amplitude, observed in only a minority of cardiac transplant recipients (6%), is a marker for parasympathetic reinnervation. The evolution over time of this HF component is compatible with a biological phenomenon as gradual parasympathetic reinnervation of the sinus node.

Quantitative dobutamine stress echocardiography for the early detection of cardiac allograft vasculopathy in heart transplant recipients

Background: A non-invasive method to detect the presence of cardiac allograft vasculopathy (CAV) remains an important goal in clinical cardiology. Objective: To assess the value of quantitative dobutamine stress echocardiography (DSE) for the early detection of CAV. Methods: 42 heart transplant recipients underwent DSE with acquisition of both conventional two-dimensional and colour tissue Doppler data. All studies were analysed conventionally and quantitatively using regional deformation parameters—that is, peak systolic longitudinal strain (∊peak sys), strain rate (SRpeak sys) and post-systolic strain index. Myocardial segments were classified as normal, mildly abnormal or severely abnormal based on correlative angiographic findings. Results: At baseline, ∊peak sys was significantly lower in severely abnormal segments than in normal ones. However, at peak stress, ∊peak sys was able to separate three groups of segments. Receiver operating characteristic analysis showed an SRpeak sys response of <0.5/s to identify patients with CAV with a sensitivity of 88%, specificity of 85% and a negative predictive value of 92%. Conclusion: Regional myocardial function is impaired in heart transplant recipients with CAV even when the disease is considered to be non-significant on conventional angiography. Systolic deformation parameters tended to detect the existence of CAV more accurately than conventional visual DSE assessment. Strain rate imaging during stress can therefore safely be used as a non-invasive screening test for detecting CAV in heart transplant recipients.

Different evolutions in heart rate variability after heart transplantation: 10-year follow-up

Background. After heart transplantation, the donor heart is extrinsically denervated. No input of sympathetic or vagal nerves can influence the heart rate, resulting in a flat power spectrum of the beat-to-beat variability. The occurrence and the significance of reinnervation remain controversial. Methods and Results. We monitored the evolution of heart rate variability (HRV) after heart transplantation, starting from a few weeks postoperatively up to 10 years after surgery. Twenty–four-hour Holter recordings of 216 heart-transplant patients were analyzed using time and frequency domain analysis of HRV. Analysis of all data revealed an increase in 24-hour and night-time total power starting from 2 years after transplantation. Low-frequency oscillations calculated over the total 24 hours, day- and nighttime increased significantly starting from year 4 and onward (year 4–8: P<0.005). No evolution was found in high-frequency power. Subgroup analysis revealed a group with a clear spectral component (n=16), a group with a small component (n=124), and a group with a flat spectrum (n=76). Only the first group revealed an evolution in both high- and low-frequency power. Conclusion. These results indicate three different types of evolution in HRV, with reinnervating patterns present in only a minority of the patients. The vast majority of the patients show no signs of reinnervation.

Validation of the 2014 European Society of Cardiology Guidelines Risk Prediction Model for the Primary Prevention of Sudden Cardiac Death in Hypertrophic Cardiomyopathy

Background—The recently released 2014 European Society of Cardiology guidelines of hypertrophic cardiomyopathy (HCM) use a new clinical risk prediction model for sudden cardiac death (SCD), based on the HCM Risk-SCD study. Our study is the first external and independent validation of this new risk prediction model. Methods and Results—The study population consisted of a consecutive cohort of 706 patients with HCM without prior SCD event, from 2 tertiary referral centers. The primary end point was a composite of SCD and appropriate implantable cardioverter-defibrillator therapy, identical to the HCM Risk-SCD end point. The 5-year SCD risk was calculated using the HCM Risk-SCD formula. Receiver operating characteristic curves and C-statistics were calculated for the 2014 European Society of Cardiology guidelines, and risk stratification methods of the 2003 American College of Cardiology/European Society of Cardiology guidelines and 2011 American College of Cardiology Foundation/American Heart Association guidelines. During follow-up of 7.7±5.3 years, SCD occurred in 42 (5.9%) of 706 patients (ages 49±16 years; 34% women). The C-statistic of the new model was 0.69 (95% CI, 0.57–0.82; P=0.008), which performed significantly better than the conventional risk factor models based on the 2003 guidelines (C-statistic of 0.55: 95% CI, 0.47–0.63; P=0.3), and 2011 guidelines (C-statistic of 0.60: 95% CI, 0.50–0.70; P=0.07). Conclusions—The HCM Risk-SCD model improves the risk stratification of patients with HCM for primary prevention of SCD, and calculating an individual risk estimate contributes to the clinical decision-making process. Improved risk stratification is important for the decision making before implantable cardioverter-defibrillator implantation for the primary prevention of SCD.