Sponge-like Chitosan Based Porous Monolith for Uraemic Toxins Sorption

More than three million patients are treated for kidney failure world-wide. Haemodialysis, the most commonly used treatment, requires large amounts of water and generates mountains of non-recyclable plastic waste. To improve the environmental footprint, dialysis treatments need to develop absorbents to regenerate the waste dialysate. Whereas conventional dialysis clears water-soluble toxins, it is not so effective in clearing protein-bound uraemic toxins (PBUTs), such as indoxyl sulfate (IS). Thus, developing absorption devices to remove both water-soluble toxins and PBUTs would be advantageous. Vapour induced phase separation (VIPS) has been used in this work to produce polycaprolactone/chitosan (PCL/CS) composite symmetric porous monoliths with extra porous carbon additives to increase creatinine and albumin-bound IS absorption. Moreover, these easy-to-fabricate porous monoliths can be formed into the required geometry. The PCL/CS porous monoliths absorbed 436 μg/g of albumin-bound IS and 2865 μg/g of creatinine in a single-pass perfusion model within 1 h. This porous PCL/CS monolith could potentially be used to absorb uraemic toxins, including PBUTs, and thus allow the regeneration of waste dialysate and the development of a new generation of environmentally sustainable dialysis treatments, including wearable devices.

Prognostic value of pulmonary transit time by cardiac magnetic resonance in patients with heart failure with preserved ejection fraction

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): National Institute for Health Research Leicester Cardiovascular Biomedical Research Centre Background Quantifying pulmonary transit time (PTT) from cardiac magnetic resonance (CMR) first pass perfusion imaging is a novel technique for the evaluation of haemodynamic congestion in heart failure. Previous studies have demonstrated that PTT is prolonged in patients with heart failure with reduced ejection fraction (HFrEF) and that it provides independent prognostic information in this patient group. However, the potential diagnostic and prognostic roles of PTT assessment in patients with heart failure with preserved ejection fraction (HFpEF) remain to be established. Aim To compare PTT in healthy controls and in patients with HFpEF, and to determine the prognostic value of PTT in HFpEF. Methods In a prospective, observational study, HFpEF and age-matched control subjects underwent multi-parametric CMR at 3-Tesla, comprising quantitative left ventricular volumetric assessment using a standard steady-state free precession (SSFP) pulse sequence, and first-pass perfusion imaging at rest using a T1-weighted segmented inversion recovery gradient echo sequence (following injection of 0.04mmol/kg of contrast). PTT was calculated as the time interval between the peaks of signal intensity curves in the right and left ventricular blood pools (defined on the basal slice of the rest perfusion images). The primary endpoint was the composite of death or hospitalisation with heart failure. Results 88 HFpEF patients (age 73 ± 9 years, 51% male, EF 56.4 ± 5.6%) and 40 controls (age 73 ± 5 years, 43% male, EF 58.5 ± 4.7%) were studied. PTT was comparable in HFpEF patients (7.7 ± 3.8s) and in healthy controls (7.5 ± 1.8, p = 0.69). Normalised to cardiac cycle lengths, PTT remained comparable in HFpEF patients and healthy controls (8.5 ± 4.0 cardiac cycles versus 7.8 ± 1.6 cardiac cycles, respectively, p = 0.19). In the HFpEF group, during median follow-up of 3.4 years, there were 38 events (25 hospitalisations with heart failure, 13 deaths); a significant relationship between survival and PTT was not demonstrated (HR 1.06 [0.99,1.14] for a one-unit increase, p = 0.098). Conclusion In HFpEF, PTT is not prolonged compared with PTT in healthy subjects. Unlike in HFrEF, PTT does not appear to be diagnostically or prognostically significant in HFpEF. Figure 1: Graph showing signal intensity curves in the right (red) and left (green) ventricular blood pools Figure 2: Kaplan-Meier plot showing comparable rates of the composite endpoint in patients with PTT greater/less than median PTT (8 cardiac cycles)

Magnetic resonance imaging derived cardiac first pass perfusion in cryptogenic ischemic stroke in the young

Funding Acknowledgements Type of funding sources: None. Introduction Up to 50% of ischemic strokes in adults aged between 18 and 50 are cryptogenic by nature. Heart has been a hypothesised source. Purpose: Purpose of the study was to investigate the wash in and wash out of gadolinium based contrast agent in the left atrial appendage, and cardiac chambers in first pass cardiac magnetic resonance imaging. Methods The study comprised 30 patients with first-ever cryptogenic ischemic stroke and 30 age and gender matched stroke-free controls included in the prospective multicenter study Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers and Outcome (SECRETO; NCT01934725). Cardiac magnetic resonance imaging was performed on all participants with a 1.5T magnetic resonance system. Dynamic contrast enhanced T1 weighted first pass perfusion images were acquired in the superior vena cava, the left atrial appendage (Fig. 1), and the left ventricle. The images were analyzed for time-intensity curves (Fig. 2), and results were normalised to individual heart rate. Arrival times, peak times, areas under the curves, relative blood flows (defined as area under the curve/full width at half maximum), and maximum and minimum rates of bolus wash in / wash out were calculated. Results The wash in of the contrast agent bolus was similar in patients and controls. Arrival times and peak timings showed similar characteristics in patients and controls in the left atrial appendage (arrival time: 12.4 [2.3] vs. 13.5 [3.6] cardiac cycles, p = 0.657; peak time: 19.6 [5.1] vs. 19.8 [6.9] cardiac cycles, p = 0.929) and the left atrium (arrival time: 12.2 [2.8] vs. 13.0 [3.6] cardiac cycles, p = 0.535; peak time: 18.7 [5.5] vs. 18.1 [5.2] cardiac cycles, p = 0.790). Areas under under the curves and relative blood flows were similar in patients and controls. A significant difference between patients and controls was found in the wash out rate of gadolinium in the left ventricle (-28 [11] vs. -36 [13] 1/cardiac cycles, p = 0.012), indicating slightly slower wash out in the patients. Conclusions Cryptogenic ischemic stroke in the young is not associated with prolonged blood flow in the left atrial appendage or left atrium. There were no significant differences in the first pass perfusion between subjects and healthy controls. However, there might be a slight tendency for stagnation of blood flow in the left ventricles of cryptogenic stroke patients.

Initial investigation of free-breathing 3D whole-heart stress myocardial perfusion MRI

Objective: Myocardial first-pass perfusion imaging with MRI is well-established clinically. However, it is potentially weakened by limited myocardial coverage compared to nuclear medicine. Clinical evaluations of whole-heart MRI perfusion by 3D methods, while promising, have to date had the limit of breathhold requirements at stress. This work aims to develop a new free-breathing 3D myocardial perfusion method, and to test its performance in a small patient population. Methods: This work required tolerance to respiratory motion for stress investigations, and therefore employed a “stack-of-stars” hybrid Cartesian-radial MRI acquisition method. The MRI sequence was highly optimised for rapid acquisition and combined with a compressed sensing reconstruction. Stress and rest datasets were acquired in four healthy volunteers, and in six patients with coronary artery disease (CAD), which were compared against clinical reference information.Results: This free-breathing method produced datasets that appeared consistent with clinical reference data in detecting moderate-to-strong induced perfusion abnormalities. However, the majority of the mild defects identified clinically were not detected by the method, potentially due to the presence of transient myocardial artefacts present in the images. Discussion: The feasibility of detecting CAD using this 3D first-pass perfusion sequence during free-breathing is demonstrated. Good agreement on typical moderate-to-strong CAD cases is promising, however, questions still remain on the sensitivity of the technique to milder cases.

Adenosine stress native T1 mapping demonstrates impaired myocardial perfusion reserve in non-ischemic dilated cardiomyopathy

Background Impaired myocardial perfusion reserve has been demonstrated in non-ischemic dilated cardiomyopathy (NIDCM) by positron emission tomography (PET) and adenosine-stress first-pass perfusion cardiac magnetic resonance (CMR) imaging. Adenosine stress native T1 mapping is a novel CMR technique able to assess myocardial perfusion without the use of contrast agents. The aim of the present study was to determine the clinical utility of this novel CMR technique in NIDCM. Methods A total of 20 consecutive patients (mean age 61±12 years, 80% males) with diagnosis of NIDCM who consented to be enrolled in the UHSM CMR registry were included in the present study. CMR at 3T including 1. cine imaging for the assessment of LV volumes, mass and global longitudinal strain (GLS) by tissue-tracking imaging; 2. rest and stress (adenosine 140 mcg/kg/min) MOLLI T1 mapping of mid-ventricular slice for the assessment of rest and stress T1 values and T1 reactivity (ΔT1%); 3. first-pass perfusion imaging for the assessment of myocardial perfusion reserve index (MPRI) and 4. late gadolinium enhancement (LGE) imaging for the assessment of myocardial replacement fibrosis, was performed. Twenty control patients without history of known coronary artery disease and evidence of reversible ischemia or previous myocardial infarct on CMR imaging were included for comparison purposes. Results NIDCM patients had significantly higher native T1 value (1263±47 ms vs. 1234±38 ms, p=0.031), significantly lower ΔT1% (3.2±1.5% vs. 5.7±1.7%, p<0.001, Figure A), significantly lower MPRI (1.32±0.18 vs. 1.67±0.13, p<0.001) and significantly impaired GLS (−10±4% vs. −16±2%, p<0.001) as compared to controls. A significant strong relation between ΔT1% and MPRI (β=0.76, p<0.001, Figure B) and significant moderate relation between ΔT1% and GLS (β=−0.54, p<0.001) were observed. Conclusion T1 reactivity, myocardial perfusion reserve and GLS are significantly reduced in NIDCM patients compared to controls. Adenosine stress T1 mapping holds promise for detection of impaired myocardial perfusion reserve in NIDCM without the requirement for contrast agents. Funding Acknowledgement Type of funding source: None

Simultaneous Determination of Telmisartan and Pitavastatin Calcium in Intestinal Perfusate by HPLC: Application to Intestinal Absorption Interaction Study

Background: Hypertension and hypercholesterolemia are two main physiological risk factors of cardiovascular disease, and commonly occur in combination. Multicompound combination therapy is rational for the treatment of concurrent hypertension and hypercholesterolemia, while telmisartan and pitavastatin calcium can be used as a potential drug combination. Objective: The aim of this paper is to study the intestinal absorption and absorption interaction of telmisartan and pitavastatin calcium. Methods: An HPLC method was developed and validated to determine telmisartan and pitavastatin calcium in intestinal perfusate simultaneously. The in situ single-pass perfusion in rats was utilized to investigate the effects of concentrations, intestinal segment (duodenum, jejunum, ileum and colon) and co-administrated drugs on absorption. Results: The effective permeability coefficient and the absorption rate constant of telmisartan were higher in the duodenum as compared to other intestinal segments. However, the intestinal absorption of pitavastatin calcium was not segmental dependent. The effective permeability coefficient and absorption rate constant have no significant difference among three concentrations of telmisartan, pitavastatin calcium individually and their combination. Conclusion: The results showed that telmisartan and pitavastatin calcium were transported passively, and telmisartan and pitavastatin calcium could be absorbed well in all intestinal segments. The intestinal absorption parameters revealed the absence of any intestinal absorption interaction when co-administered. Lay Summary: Co-administration of telmisartan and pitavastatin calcium can provide a potential therapeutic strategy for the treatment of concurrent hypertension and hypercholesterolemia. We are investigating the intestinal interaction of these two drugs in rats using the developed HPLC method and in situ single-pass perfusion technology. We will calculate some parameters after administrating two types of drugs either separately or together, which help reflect changes regarding intestinal absorption and penetration. Compared with telmisartan and pitavastatin calcium administrated separately, if parameters significantly change after co-administration, it proves the existence of the intestinal interactions. Moreover, the results might contribute to clinic drug monitoring.