A novel nonlinear afterload for ex vivo heart evaluation: Porcine experimental results

Background: Existing working heart models for ex vivo functional evaluation of donor hearts often use cardiac afterloads made up of discrete resistive and compliant elements. This approach limits the practicality of independently controlling systolic and diastolic aortic pressure to safely test the heart under multiple loading conditions. We present and investigate a novel afterload concept designed to enable such control. Methods: Six ∼70 kg pig hearts were evaluated in vivo, then ex vivo in left-ventricular working mode using the presented afterload. Both in vivo and ex vivo, the hearts were evaluated at two exertion levels: at rest and following a 20 μg adrenaline bolus, while measuring aortic pressure and flow, left ventricular pressure and volume, and left atrial pressure. Results: The afterload gave aortic pressure waveforms that matched the general shape of the in vivo measurements. A wide range of physiological systolic pressures (93 to 160 mm Hg) and diastolic pressures (73 to 113 mm Hg) were generated by the afterload. Conclusions: With the presented afterload concept, multiple physiological loading conditions could be tested ex vivo, and compared with the corresponding in vivo data. An additional control loop from the set pressure limits to the measured systolic and diastolic aortic pressure is proposed to address discrepancies observed between the set limits and the measured pressures

Identification of cardiac afterload dynamics from data

The prospect of ex vivo functional evaluation of donor hearts is considered. Particularly, the dynamics of a synthetic cardiac afterload model are compared to those of normal physiology. A method for identification of continuous-time transfer functions from sampled data is developed and verified against results from the literature. The method relies on exact gradients and Hessians obtained through automatic differentiation. This also enables straightforward sensitivity analyses. Such analyses reveal that the 4-element Windkessel model is not practically identifiable from representative data while the 3-element model underfits the data. Pressure–volume (PV) loops are therefore suggested as an alternative for comparing afterload dynamics

Prevention of ischemic myocardial contracture through hemodynamically controlled DCD

Purpose—Ischemic myocardial contracture (IMC) or ‘‘stoneheart’’ is a condition with rapid onset following circulatory death. It inhibits transplantability of hearts donated uponcirculatory death (DCD). We investigate the effectiveness of hemodynamic normalization upon withdrawal of life-sustaining therapy (WLST) in a large-animal controlled DCD model, with the hypothesis that reduction in cardiac work delays the onset of IMC. Methods—A large-animal study was conducted comprising of a control group (n = 6) receiving no therapy upon WLST, and a test group (n = 6) subjected to a protocol for fully automated computer-controlled hemodynamic drug administration. Onset of IMC within 1 h following circulatory death defined the primary end-point. Cardiac work estimates based on pressure-volume loop concepts were developed and used to provide insight into the effectiveness of the proposed computer-controlled therapy. Results—No test group individual developed IMC within 1 h, whereas all control group individuals did (4/6 within30 min). Conclusion—Automatic dosing of hemodynamic drugs in the controlled DCD context has the potential to prevent onset of IMC up to 1 h, enabling ethical and medically safe organ procurement. This has the potential to increase the use of DCD heart transplantation, which has been widely recognized as a means of meeting the growing demand for donor hearts

Closed-loop Prevention of Hypotension in the Heartbeating Brain-dead Porcine Model

Objective: The purpose of this paper is to demonstrate feasibility of a novel closed-loop controlled therapy for prevention of hypertension in the heartbeating brain-dead porcine model. Methods: Dynamic modeling and system identification were based on in-vivo data. A robust controller design was obtained for the identified models. Disturbance attenuation properties, and reliability of operation of the resulting control system, were evaluated in vivo. Results: The control system responded both predictably and consistently to external disturbances. It was possible to prevent mean arterial pressure to fall below a user-specified reference throughout 24 h of completely autonomous operation.Conclusion: Parameter variability in the identified models confirmed the benefit of closed-loop controlled administration of the proposed therapy. The evaluated robust controller was able to mitigate both process uncertainty and external disturbances. Significance: Prevention of hypertension is critical to the care of heartbeating brain-dead organ donors. Its automation would likely increase the fraction of organs suitable for transplantation from this patient group

Revision after shoulder replacement for acute fracture of the proximal humerus

Background and purpose — For more than half a century, stemmed hemiarthroplasty (SHA) has been used in the treatment of comminuted and displaced fractures of the proximal humerus. Reverse shoulder arthroplasty (RSA) has been increasingly popular in cases where it is difficult to obtain satisfactory fixation of the tuberosities. We report revision rates and reasons for revision after shoulder arthroplasty for acute fractures of the proximal humerus. Patients and methods — This study was based on a common dataset from the Nordic Arthroplasty Register Association (NARA), which includes data reported to the national shoulder arthroplasty registries in Denmark, Sweden, and Norway. We included 6,756 shoulder arthroplasties performed for acute fractures between 2004 and 2013. Results — There were 6,112 SHAs (90%) and 565 RSAs (8.4%). The cumulative arthroplasty survival rate after 5 years was 0.96 for both SHA and RSA. The relative risk of revision of RSA was 1.4 (95% CI: 0.9–2.2) with SHA as reference. For both types of arthroplasty, the most common reason for revision was infection (SHA 0.8%, RSA 2.1%). The relative risk of revision due to infection was 3.1 (95% CI: 1.6–5.9) for RSA with SHA as reference. The relative risk of revision for patients who were less than 75 years of age was 2.8 (95% CI: 2.0–3.8) compared to older patients. Interpretation — Revision after shoulder arthroplasty for acute fractures was rare. Survival rates were similar between SHA and RSA, but RSA had a statistically significant and clinically relevant higher risk of revision because of infection

Improved General and Oral Health in Diabetic Patients by an Okinawan-Based Nordic Diet:A Pilot Study

Periodontal disease, periodontitis as well as the preceding gingivitis, has been associated with both obesity and diabetes. Studies have shown that diet changes can lead to a lower incidence of such inflammation. The aim of the present case series over four weeks was to study the effects on medical and dental conditions in patients with type 2 diabetes of the consumption of the Okinawan-based Nordic Diet (OBND®). Medical and dental examinations were performed to estimate the general health and gingivitis/periodontitis. Serum cytokine levels were assessed using Luminex technology. Eight of ten study participants completed the study. All participants lost weight (p = 0.012). Six out of seven that were treated with insulin could reduce their insulin intake after two weeks with OBND®. The reduction was about 16 units which corresponds to a 34% relative reduction compared to the starting point (range 15–63%). Fasting blood glucose values fell (p = 0.035). Hemoglobin A1c (HbA1c) (p = 0.01), triglycerides (p = 0.05), and low-density lipoprotein (LDL) (p = 0.05) were also reduced. Bleeding on probing changed from ~28% before any dietary changes to ~13% after two weeks with OBND® (p = 0.01). The reduction in gingival bleeding was as substantial as might be expected from one session of professional tooth cleaning. Markers of inflammation were also reduced. The OBND® thus showed significant promise in alleviating the impact of diabetes on dental as well as general health

Familial aggregation of atrial fibrillation: a study in Danish twins

BACKGROUND: Heritability may play a role in non-familial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared to a dizygotic (DZ) twin in the same situation. METHODS AND RESULTS: A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) where one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of gender, 22.0% vs. 11.6% (p<0.0001). In a Cox regression of event free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included, when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event free survival time (hazard ratio: 2.0 (95% confidence interval (CI): 1.3 – 3.0)) thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62 % (55 % – 68 %), due to additive genetics. There were no significant differences across genders. CONCLUSION: All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both genders. The recurrence risk for co-twins (12–22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF

Tolerability and pharmacokinetic profile of a novel benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride in dogs with malignant mammary tumours

The pharmacokinetic profile, tolerability and efficacy of benzene‐poly‐carboxylic acids complex with cis‐diammineplatinum (II) dichloride (BP‐C1) were studied in dogs with mammary cancer. A three‐level response surface pathway designed trial was performed on seven dogs. At each level BP‐C1 was administered subcutaneously daily for 7 days followed by a 7‐day rest period in a dose escalating manner. Adverse events according to VCOG‐CTCAE, performance status and tumour progression were recorded. The pharmacokinetic profile followed a two‐compartment model with rapid absorption, short distribution, and a slow elimination phase. The overall elimination half‐life was 125 h. The maximum tolerated dose of BP‐C1 was estimated to be above 0.46 mg kg−1. A significant reduction in VCOG‐CTCAE toxicity which correlated negatively with increasing dose was found. The dogs' general performance status remained unchanged. No decrease in total tumour burden was found, although temporary tumour reduction was seen in some target tumours.Tolerability and pharmacokinetic profile of a novel benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride in dogs with malignant mammary tumourspublishedVersio

Biased Signaling of the Angiotensin II Type 1 Receptor Can Be Mediated through Distinct Mechanisms

Seven transmembrane receptors (7TMRs) can adopt different active conformations facilitating a selective activation of either G protein or β-arrestin-dependent signaling pathways. This represents an opportunity for development of novel therapeutics targeting selective biological effects of a given receptor. Several studies on pathway separation have been performed, many of these on the Angiotensin II type 1 receptor (AT1R). It has been shown that certain ligands or mutations facilitate internalization and/or recruitment of β-arrestins without activation of G proteins. However, the underlying molecular mechanisms remain largely unresolved. For instance, it is unclear whether such selective G protein-uncoupling is caused by a lack of ability to interact with G proteins or rather by an increased ability of the receptor to recruit β-arrestins. Since uncoupling of G proteins by increased ability to recruit β-arrestins could lead to different cellular or in vivo outcomes than lack of ability to interact with G proteins, it is essential to distinguish between these two mechanisms.We studied five AT1R mutants previously published to display pathway separation: D74N, DRY/AAY, Y292F, N298A, and Y302F (Ballesteros-Weinstein numbering: 2.50, 3.49-3.51, 7.43, 7.49, and 7.53). We find that D74N, DRY/AAY, and N298A mutants are more prone to β-arrestin recruitment than WT. In contrast, receptor mutants Y292F and Y302F showed impaired ability to recruit β-arrestin in response to Sar1-Ile4-Ile8 (SII) Ang II, a ligand solely activating the β-arrestin pathway.Our analysis reveals that the underlying conformations induced by these AT1R mutants most likely represent principally different mechanisms of uncoupling the G protein, which for some mutants may be due to their increased ability to recruit β-arrestin2. Hereby, these findings have important implications for drug discovery and 7TMR biology and illustrate the necessity of uncovering the exact molecular determinants for G protein-coupling and β-arrestin recruitment, respectively