Johan Vanhaecke

Oxidized LDL and Malondialdehyde-Modified LDL in Patients With Acute Coronary Syndromes and Stable Coronary Artery Disease

BACKGROUND The association between oxidative modifications of LDL and coronary artery disease (CAD) is suspected but not established. Therefore, the association between plasma levels of oxidized LDL and malondialdehyde (MDA)-modified LDL and acute coronary syndromes and stable CAD was investigated. METHODS AND RESULTS The study population contained 63 patients with acute coronary syndromes (45 with acute myocardial infarction and 18 with unstable angina pectoris), 35 nontransplanted patients with angiographically confirmed stable angina, 28 heart transplant patients with posttransplant CAD, 79 heart transplant patients without CAD, and 65 control subjects. After correction for age, sex, and LDL and HDL cholesterol, plasma levels of oxidized LDL and MDA-modified LDL were significantly higher in patients with CAD than in individuals without CAD (r2=0.57 and r2=0.26, respectively; both P=0.0001). Plasma levels of MDA-modified LDL were significantly higher in patients with acute coronary syndromes than in individuals with stable CAD (r2=0.65; P=0.0001) and were associated with increased levels of troponin I and C-reactive protein (r2=0.39 and r2=0.34, respectively; both P=0.0001). Plasma levels of oxidized LDL were not associated with increased levels of troponin I and C-reactive protein (r2=0.089 and r2=0.063, respectively). CONCLUSIONS Elevated plasma levels of oxidized LDL are associated with CAD. Elevated plasma levels of MDA-modified LDL suggest plaque instability and may be useful for the identification of patients with acute coronary syndromes.

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

Background— Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results— We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74–0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52–0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro–B-type natriuretic peptide and troponin) versus enalapril. Conclusions— Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Growing pains: Non‐adherence with the immunosuppressive regimen in adolescent transplant recipients

Abstract:  One‐year graft and patient survival are better in adolescent transplant recipients (age 11–19 years) than in younger (age < 11 years) pediatric transplant recipients. However, several groups found that long‐term outcomes (> i.e. 5 year post‐transplant) in the adolescent age group are significantly worse than in younger transplant recipients.

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.

Pretransplant predictors of posttransplant adherence and clinical outcome: an evidence base for pretransplant psychosocial screening.

Introduction. There is growing awareness, yet scant prospective evidence that pretransplant (TX) psychosocial factors may predict post-TX outcome. We examined which pre-TX psychosocial factors predict post-TX nonadherence with immunosuppression (NA) and clinical outcomes in heart, liver, and lung TX. Methodology. We prospectively followed 141 patients (28 heart, 61 liver, and 52 lung) from pre-TX until 1 year post-TX. Multivariable analyses determined which pre-TX factors (i.e., anxiety, depression, personality traits, social support, adherence with medication, and smoking status) predict poor post-TX outcome (i.e., NA, late acute rejection, graft loss, and resource utilization), controlling for medical predictors of poor outcome. Results. Pre-TX self-reported medication nonadherence (odds ratio [OR]=7.9), lower received social support (OR=0.9), a higher education (OR=2.7), and lower “conscientiousness” (OR=0.8) were independent predictors of post-TX NA. Not living in a stable relationship predicted graft loss (OR=4.9). Pre-TX medication NA was the only predictor for presence of late acute rejection (OR=4.4). No other pre-TX predictors for poor outcome could be found. Conclusion. This is the first prospective study demonstrating that selected pre-TX psychosocial factors predict post-TX NA and poor clinical outcome, implying that pre-TX screening should include this set of factors in addition to traditional medical criteria.

Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice

Background— Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction in transgenic mice with cardiomyocyte-specific overexpression of PDE5 (PDE5-TG). Methods and Results— Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes, predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening, and calcium handling in isolated cardiomyocytes and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates. Ten days after myocardial infarction, LV cGMP levels had increased to a greater extent in wild-type mice than in PDE5-TG mice (P<0.05). Ten weeks after myocardial infarction, LV end-systolic and end-diastolic volumes were larger in PDE5-TG than in wild-type mice (57±5 versus 39±4 and 65±6 versus 48±4 &mgr;L, respectively; P<0.01 for both). LV systolic dysfunction and diastolic dysfunction were more marked in PDE5-TG than in wild-type mice, associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium. Conclusions— Increased PDE5 expression predisposes mice to adverse LV remodeling after myocardial infarction. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.

Predictors of fatal and non-fatal outcomes in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) : incremental value of apolipoprotein A-1, high-sensitivity C-reactive peptide and N-terminal pro B-type natriuretic peptide

Few prognostic models in heart failure have been developed in typically elderly patients treated with modern pharmacological therapy and even fewer included simple biochemical tests (such as creatinine), new biomarkers (such as natriuretic peptides), or, especially, both. In addition, most models have been developed for the single outcome of all‐cause mortality.

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.

Frequency dependence of Ca2+ release from the sarcoplasmic reticulum in human ventricular myocytes from end-stage heart failure

OBJECTIVES Human cardiac muscle from failing heart shows a decrease in active tension development and a rise in diastolic tension at stimulation frequencies above 50-60 beats/min due to both systolic and diastolic dysfunction. We have investigated underlying changes in cellular [Ca2+]i regulation. METHODS Single ventricular myocytes were isolated enzymatically from the explanted hearts of transplant recipients with ischemic cardiomyopathy (nhearts = 5 ncells = 15) or dilated cardiomyopathy (nhearts = 6, ncells = 19). Cells were studied during whole-cell patch clamp with fluo-3 and fura-red as [Ca2+]i indicators (36 +/- 1 degrees C). RESULTS In current clamp mode (action potential recording), the amplitude of Ca2+ release from the sarcoplasmic reticulum (SR) decreased at stimulation frequencies above 0.5 Hz; this decrease was more pronounced for cells from dilated cardiomyopathy. Diastolic [Ca2+]i increased at 1 and 2 Hz for both groups. Action potential duration (APD90) decreased with frequency in all cells; in addition there was a drop in plateau potential of 10 +/- 1 mV for cells from ischemic cardiomyopathy and of 13 +/- 2 mV for cells from dilated cardiomyopathy. In voltage clamp mode the L-type Ca2+ current showed reversible decrease during stimulation at 1 and 2 Hz. Recovery from inactivation during a double pulse protocol was slow (75 +/- 3% at 500 ms, 89 +/- 3% at 1000 ms) and followed the decay of the [Ca2+]i transient. CONCLUSIONS The negative force-frequency relation of the failing human heart is due to a decrease in Ca2+ release of the cardiac myocytes at frequencies > or = 0.5 Hz, more pronounced in dilated than in ischemic cardiomyopathy. Inhibition of ICaL at higher frequencies, at least partially related to an increase in diastolic [Ca2+]i, will contribute to this negative staircase because of a decrease in the trigger for Ca2+ release, and of decreased loading of the SR.

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.