Stefan Aschauer

T1 Mapping by CMR Imaging: From Histological Validation to Clinical Implication

OBJECTIVES The purpose of this study was to prospectively investigate the diagnostic and prognostic impact of cardiac magnetic resonance (CMR) T1 mapping and validate it against left ventricular biopsies. BACKGROUND Extracellular volume (ECV) expansion is a key feature of heart failure. CMR T1 mapping has been developed as a noninvasive technique to estimate ECV; however, the diagnostic and prognostic impacts of this technique have not been well established. METHODS A total of 473 consecutive patients referred for CMR (49.5% female, age 57.8 ± 17.1 years) without hypertrophic cardiomyopathy, cardiac amyloidosis, or Anderson-Fabry disease were studied. T1 mapping with the modified Look-Locker inversion recovery (MOLLI) sequence was used for ECV calculation (CMR-ECV). For methodological validation, 36 patients also underwent left ventricular biopsy, and ECV was quantified by TissueFAXS analysis (TissueFAXS-ECV). To assess the prognostic value of CMR-ECV, its association with hospitalization for cardiovascular reasons or cardiac death was tested in a multivariable Cox regression model. RESULTS TissueFAXS-ECV was 26.3 ± 7.2% and was significantly correlated with CMR-ECV (r = 0.493, p = 0.002). Patients were followed up for 13.3 ± 9.0 months and divided into CMR-ECV tertiles for Kaplan-Meier analysis (tertiles were ≤ 25.7%, 25.8% to 28.5%, and ≥ 28.6%). Significantly higher event rates were observed in patients with higher CMR-ECV (log-rank p = 0.013). By multivariable Cox regression analysis, CMR-ECV was independently associated with outcome among imaging variables (p = 0.004) but not after adjustment for clinical parameters. CONCLUSIONS CMR T1 mapping allows accurate noninvasive quantification of ECV and is independently associated with event-free survival among imaging parameters. Its prognostic value on top of established clinical risk factors warrants further investigation in long-term studies.

The right heart in heart failure with preserved ejection fraction: insights from cardiac magnetic resonance imaging and invasive haemodynamics.

Recent data indicate that right ventricular systolic dysfunction (RVSD) by cardiac magnetic resonance imaging (CMR) is a strong predictor of outcome in heart failure. However, the prognostic significance of RVSD by CMR in heart failure with preserved ejection fraction (HFpEF) is unknown.

Safety, tolerability and pharmacokinetics of liposomal curcumin in healthy humans.

INTRODUCTION Experimental studies have shown that liposomal curcumin can exert a reduction in tumor growth in pancreatic and colorectal cancer. In this phase I clinical trial we investigated the pharmacokinetics, safety, and tolerability of intravenously administered liposomal curcumin in healthy subjects. MATERIAL AND METHODS 50 male and female participants were included in this randomized, placebo-controlled double-blind phase I dose escalation study. Subjects received a single dose of liposomal curcumin (10 - 400 mg/m2; n = 2 - 6 per group) or placebo over 2 hours intravenously. RESULTS Dose-dependent increases in the plasma concentrations of curcumin and its metabolite tetrahydrocurcumin (THC) were detected. After the end of drug infusion, curcumin and THC plasma concentrations decreased within 6 - 60 minutes below the limit of quantification. Mean urinary excretion was ~ 0.1% of total systemic clearance. Liposomal curcumin was tolerated well, but a transient red blood cell echinocyte formation with concomitant increase in mean cellular volume was observed at dosages ≥ 120 mg/m2. CONCLUSION Short-term intravenous dosing of liposomal curcumin appears to be safe up to a dose of 120 mg/m2. Changes in red blood cell morphology may represent a dose limiting sign of toxicity.

Interstitial Fibrosis, Functional Status, and Outcomes in Heart Failure With Preserved Ejection FractionCLINICAL PERSPECTIVE: Insights From a Prospective Cardiac Magnetic Resonance Imaging Study

Background—Myocardial extracellular volume (ECV) accumulation is one of the key pathophysiologic features of heart failure with preserved ejection fraction (HFpEF). Our aims were to (1) measure ECV by cardiac magnetic resonance T1 mapping using the modified Look-Locker inversion recovery (MOLLI) sequence, (2) validate MOLLI-ECV against histology, and (3) investigate the relationship between MOLLI-ECV and prognosis in HFpEF. Methods and Results—One-hundred seventeen consecutive HFpEF patients underwent cardiac magnetic resonance imaging, coronary angiography, and invasive hemodynamic assessments at baseline. Eighteen patients also underwent left ventricular biopsy for histological analysis (Histo-ECV). To assess the prognostic impact of MOLLI-ECV, its association with hospitalization for heart failure/cardiac death was tested by multivariable Cox regression analysis. Histo-ECV was 30.1±4.6% and was significantly correlated with MOLLI-ECV (R=0.494, P=0.037). Patients were followed for 24.0 months (6.0–32.0 months), during which 34 had a cardiac event. By Kaplan–Meier analysis, patients with MOLLI-ECV ≥ the median (28.9%) had shorter event-free survival (log-rank, P=0.028). MOLLI-ECV significantly correlated with N-terminal prohormone of brain natriuretic peptide (P<0.001), 6-minute walk distance (P=0.004), New York Heart Association functional class (P=0.009), right atrial pressure (P=0.037), and stroke volume (P=0.043). By multivariable Cox regression analysis, MOLLI-ECV was associated with outcome among imaging variables (P=0.038) but not after adjustment for clinical and invasive hemodynamic parameters. Conclusions—We demonstrate that MOLLI-ECV in HFpEF accurately reflects histological ECV, correlates with markers of disease severity, and is associated with outcome among cardiac magnetic resonance parameters but not after adjustment for important clinical and invasive hemodynamic parameters. Nevertheless, MOLLI-ECV has the potential of becoming an important biomarker in HFpEF.

Human Pharmacokinetics of High Dose Oral Curcumin and Its Effect on Heme Oxygenase-1 Expression in Healthy Male Subjects

Purpose. Heme oxygenase-1 (HO-1) has been proposed to exert pharmacological benefits by its antioxidative and anti-inflammatory effects. HO-1 expression may be affected by the GT length polymorphism in the promoter region of the HO-1 gene. We investigated the inducibility of HO-1 by orally administered curcumin in healthy male subjects and its correlation with the GT length polymorphism. Methods. In an open label uncontrolled phase-1 pilot study, ten male subjects received 12 g of oral curcumin. To investigate the effects of the GT length polymorphism on the inducibility of HO-1, five subjects with homozygous short and five with homozygous long GT genotypes were studied. Plasma concentrations of curcumin, bilirubin, HO-1 mRNA, and protein expression in peripheral blood mononuclear cells (PBMCs) were analyzed over 48 hours. Results. At a detection limit of 1 µg/mL curcumin could not be detected in plasma of any subject. Compared to baseline, HO-1 mRNA and protein levels were not induced in PBMCs at any time point up to 48 hours. There was no correlation between any of the parameters and GT length polymorphism. Conclusions. Oral curcumin administration has low bioavailability and does not induce HO-1 on mRNA or protein level in PBMCs.

Diastolic Pressure Gradient Predicts Outcome in Patients With Heart Failure and Preserved Ejection Fraction.

Approximately 50% of patients presenting with clinical signs of heart failure are diagnosed with heart failure with preserved ejection fraction (HFpEF) [(1)][1]. Pulmonary hypertension (PH) is a common feature of HFpEF and predicts poor outcome. According to the diastolic pressure gradient (DPG),

Outcome in Heart Failure with Preserved Ejection Fraction: The Role of Myocardial Structure and Right Ventricular Performance

Background Heart failure with preserved ejection fraction (HFpEF) is recognized as a major cause of cardiovascular morbidity and mortality. Thus, a profound understanding of the pathophysiologic changes in HFpEF is needed to identify risk factors and potential treatment targets in this specific patient population. Therefore, we aimed to comprehensively assess the impact of left- and right-ventricular function and hemodynamics on long-term mortality and morbidity in order to improve risk prediction in patients with HFpEF. Methods and Results We prospectively included 142 consecutive patients with HFpEF into our observational, non-interventional registry. Echocardiography, cardiac magnetic resonance imaging and invasive hemodynamic assessments including myocardial biopsy were performed at baseline. We detected significant correlations between left ventricular extracellular matrix and left ventricular end-diastolic diameter (r = -0.64;p = 0.03) and stroke volume (r = -0.53;p = 0.04). Hospitalization for heart failure and/or cardiac death was observed over a median follow up of 10 months. The strongest risk factors were reduced right ventricular function (adj. HR 6.62;95%CI 3.12- 14.02;p<0.001), systolic pulmonary arterial pressure (adj. HR per 1-SD 1.55;95%CI 1.15- 2.09;p = 0.004) and the pulmonary artery wedge pressure (adj. HR per 1-SD 1.51;95%CI 1.09–2.08; p = 0.012). The area under the ROC curve for right ventricular function was 0.63, for systolic pulmonary arterial pressure 0.75, and for pulmonary artery wedge pressure 0.68. Conclusion The current study emphasizes the importance of right ventricular function and pulmonary pressures on outcome in patients with HFpEF providing pathophysiological insights into the hemodynamic changes in HFpEF.

A prediction tool for initial out-of-hospital cardiac arrest survivors

AIM Improvement in predicting survival after out-of-hospital cardiac arrest is of major medical, scientific and socioeconomic interest. The current study aimed at developing an accurate outcome-prediction tool for patients following out-of-hospital cardiac arrests. METHODS This retrospective cohort study was based on a cardiac arrest registry. From out-of-hospital cardiac arrest patients (n=1932), a set of variables established before restoration of spontaneous circulation was explored using multivariable logistic regression. To obtain reliable estimates of the classification performance the patients were allocated to training (oldest 80%) and validation (most recent 20%) sets. The main performance parameter was the area under the ROC curve (AUC), classifying patients into survivors/non-survivors after 30 days. Based on rankings of importance, a subset of variables was selected that would have the same predictive power as the entire set. This reduced-variable set was used to derive a comprehensive score to predict mortality. RESULTS The average AUC was 0.827 (CI 0.793-0.861) for a logistic regression model using all 21 variables. This was significantly better than the AUC for any single considered variable. The total amount of adrenaline, number of minutes to sustained restoration of spontaneous circulation, patient age and first rhythm had the same predictive power as all 21 variables. Based on this finding, our score was built and had excellent predictive accuracy (the AUC was 0.810), discriminating patients into 10%, 30%, 50%, 70%, and 90% survival probabilities. CONCLUSION The current results are promising to increase prognostication accuracy, and we are confident that our score will be helpful in the daily clinical routine.

Effect of systemic high dose vitamin C therapy on forearm blood flow reactivity during endotoxemia in healthy human subjects

OBJECTIVE Acute inflammation induced by administration of Escherichia coli lipopolysaccharide endotoxin (LPS) reduces plasma concentrations of vitamin C and impairs vascular endothelium-derived nitric oxide (NO) bioactivity. We tested the hypothesis that systemically administered high dose vitamin C restores the endogenous anti-oxidant potential and improves NO-dependent vasodilatation in the forearm vasculature. DESIGN & SETTING 36 male subjects were enrolled in this balanced, placebo controlled cross-over study. Forearm blood flow (FBF) reactivity to acetylcholine (ACh) and glyceryl-trinitrate (GTN), a sensitive test for endothelial function, was assessed at baseline and 4h after LPS-administration (20 IU/kg i.v). The effect of two different doses of intravenous vitamin C (Vitamin C-Injektopas®), 320 mg/kg and 480 mg/kg over 2h, or placebo on forearm vascular function was studied after LPS. MAIN RESULTS LPS caused transient flu-like symptoms, decreased plasma vitamin C concentrations and reduced the ACh-dependent increase in FBF by up to 76%. Vitamin C at a mean plasma concentration of 3.2 or 4.9 mmol/L restored the response to ACh compared to baseline. CONCLUSION High dose systemic vitamin C recovers LPS-induced endothelium-dependent vasodilation in the forearm resistance vasculature. This provides a rationale for a further clinical study of the systemic vitamin C effect under inflammatory conditions.

Modes of death in patients with heart failure and preserved ejection fraction

BACKGROUND Recent studies suggest that reduced right ventricular function is an important predictor of outcome in patients with heart failure and preserved ejection fraction (HFpEF). Because affected patients suffer from a broad spectrum of non-cardiac co-morbidities, it remains unclear, whether they actually die from right heart failure (RHF) or as a consequence of other conditions. METHODS Consecutive patients with a confirmed diagnosis of HFpEF were enrolled in this prospective registry. Local and external medical records, as well as telephone interviews with relatives were used to ascertain modes of death. RHF was accepted as a mode of death, if the following criteria were met: 1. right ventricular dysfunction assessed by transthoracic echocardiography, and 2. clinical signs of right heart decompensation at the time of death. RESULTS Out of 230 patients with complete follow-up, 16.5% (n=38) died after a mean of 30±17months. 60.5% deaths were classified as cardiovascular and 34.2% as non-cardiovascular. In 5.3% patients, the reason for death remained unknown. Of the cardiovascular cases (n=23), 91.4% of deaths were attributed to RHF, 4.3% died from stroke and 4.3% from sudden cardiac death. Of the non-cardiovascular deaths (n=13), 46.2% of deaths were attributed to major infections and 38.4% deaths were related to cancer. Other reasons for death included ileus (7.7%) and major bleeding (7.7%). CONCLUSION In our well-characterised HFpEF cohort, more than half of all deaths could directly be attributed to RHF. The right ventricle seems to be a meaningful therapeutic target in a subset of patients.