Polymersome-based protein drug delivery - quo vadis?

Protein-based therapeutics are an attractive alternative to established therapeutic approaches and represent one of the fastest growing families of drugs. While many of these proteins can be delivered using established formulations, the intrinsic sensitivity of proteins to denaturation sometimes calls for a protective carrier to allow administration. Historically, lipid-based self-assembled structures, notably liposomes, have performed this function. After the discovery of polymersome-based targeted drug-delivery systems, which offer manifold advantages over lipid-based structures, the scientific community expected that such systems would take the therapeutic world by storm. However, no polymersome formulations have been commercialised. In this review article, we discuss key obstacles for the sluggish translation of polymersome-based protein nanocarriers into approved pharmaceuticals, which include limitations imparted by the use of non-degradable polymers, the intricacies of polymersome production methods, and the complexity of the in vivo journey of polymersomes across various biological barriers. Considering this complex subject from a polymer chemist's point of view, we highlight key areas that are worthy to explore in order to advance polymersomes to a level at which clinical trials become worthwhile and translation into pharmaceutical and nanomedical applications is realistic.

Contemporary choice of glucose lowering agents in heart failure patients with type 2 diabetes.

Background: The choice of glucose lowering agent in heart failure (HF)-patients can have a strong effect on HF-related adverse events, with some classes increasing and other classes reducing the risk. Little data is available about the choice of glucose lowering agents in HF-patients with type-2-diabetes.Methods: We performed a cross-sectional single centre point analysis of all patients with both a diagnoses of HF and type-2-diabetes followed in a tertiary HF-clinic. Medical records were used to determine the choice of current glucose lowering agent. Data at the time of cross-sectional analysis was used to determine potential eligibility to a sodium-glucose-linked-transporter-2-inhibitor (SGLT2-inhibitor) based on the enrolment criteria of the EMPAREG-OUTCOME-trial.Results: A total of 571 HF-patients with diabetes were assessed on June the first 2017. The majority of patients were either managed with one or two glucose lowering agents (43% respectively 34%), with metformin (N = 391;61%), Insulin (N = 278;49%) and sulfonylurea (N = 259;45%) being the most frequently employed treatments. SGLT2-inhibitor use was low (N = 7;1%). According to trial criteria 184 patients (32%) qualified for an SGLT2-inhibitor. With main reasons for ineligibility being a HbA1C < 7% (N = 324) or a glomerular-filtration-rate <30 ml/min (N = 154; of whom 101 patients overlapped with HbA1C < 7%). However 54% of patients with a HbA1C < 7% were treated with ≥2 glucose lowering agents from a class other than SGLT-2-inhibiton.Conclusion: Despite potential eligibility, SGLT2-inhibition remains an underused glucose lowering agent in this contemporary HF-population. Additional research is necessary on optimising its implementation in clinical practice, which might include switching glucose lowering therapies in patients at HbA1C-target.

Indications and diagnostic yield of endomyocardial biopsies for unexplained cardiomyopathy, a single center experience.

Background: Endomyocardial biopsies (EMBs) remain the golden standard to diagnose underlying pathophysiologic process in heart failure (HF), when potential therapeutic decisions cannot be made by non-invasive techniques. However, changes in the field of non-invasive diagnostic testing might have an impact on the need for performing an EMB in certain scenarios.Methods: We performed a retrospective analysis of consecutive EMBs performed in a single, non-academic, tertiary-care centre. EMBs were performed between February 2009 and March 2018. Baseline characteristics including non-invasive imaging and hemodynamic profile were assessed. Indications of EMBs were analysed in accordance with the 2007-AHA/ACC/ESC-scientific statement on EMBs.Results: A total of 57 patients (74% male) were included. The overall diagnostic yield was 58%, with a trend towards a higher yield in left-side (64%) versus right-side EMBs (45%; p = .346). The majority of patients (88%) underwent EMBs for a class IIa-recommendation, 9% for a class-I recommendation and the remaining patients for a class IIb-indication. Of the EMBs for a class IIa indication, 82% (n = 47) was for an unexplained restrictive cardiomyopathy, in which 53% (n = 25) revealed a diagnosis (of whom n = 23 patients had amyloidosis). Subtyping of the EMBs with a pathologic diagnosis of amyloidosis revealed that 52% (n = 12) had transthyretin amyloidosis (ATTR) and 43% (n = 10) had light-chain amyloidosis (AL). Overall one major (1.7%) and one minor (1.7%) complication occurred following the EMB-procedure.Conclusions: When following the AHA/ACC/ESC-scientific statement on EMBs, the performance of EMBs had a high diagnostic yield, with acceptable complication rates. However, in patients presenting with an unexplained restricted cardiomyopathy, technetium-labelled bone scanning could offer a non-invasive approach to establishing the diagnosis of ATTR, mitigating the need for EMBs in a subset of patients.

The Detrimental Effect of RA Pacing on LA Function and Clinical Outcome in Cardiac Resynchronization Therapy.

OBJECTIVES: This study assessed the impact of right-atrial (RA) pacing on left-atrial (LA) physiology and clinical outcome. BACKGROUND: Data for the effects of RA pacing on LA synchronicity, function, and structure after cardiac resynchronization therapy (CRT) are scarce. METHODS: The effect of RA pacing on LA function, morphology, and synchronicity was assessed in a prospective imaging cohort of heart failure (HF) patients in sinus rhythm with a guideline-based indication for CRT. Additionally, in a retrospective outcome cohort of consecutive HF patients undergoing CRT implantation, the relationship to RA pacing was assessed using various outcome endpoints. High versus low atrial pacing burden was defined as atrial pacing above or below 50% in both cohorts. RESULTS: A total of 36 patients were included in the imaging cohort (68 ± 11 years of age). Six months after CRT, patients with high RA pacing burden showed less improvement in LA maximum and minimum volumes and total emptying fraction (p < 0.05). Peak atrial longitudinal strain and reservoir and booster strain rates but not conduit strain rate improved after CRT in patients with low RA pacing burden but worsened in patients with high RA pacing burden (p < 0.05 for all). A high RA pacing burden induced significant intra-atrial dyssynchrony (maximum opposing wall delay: 44 ± 13 ms vs. 97 ± 17 ms, respectively; p = 0.022). A total of 569 patients were included in the outcome cohort. After covariate adjustments were made, a high RA pacing burden was associated with reduced LV reverse remodeling (ß = 8.738; 95% confidence interval [CI]: 3.101 to 14.374; p = 0.002) and new-onset or recurrent atrial fibrillation (41% vs. 22%, respectively, at a median of 31 months [range 22 to 44 months follow-up]; p < 0.001). There were no differences in time to first HF hospitalization or all-cause mortality (p = 0.185) after covariate adjustment. However, in a recurrent event analysis, HF readmissions were more common in patients exposed to a high RA pacing burden (p = 0.003). CONCLUSIONS: RA pacing in CRT patients negatively influences LA morphology, function, and synchronicity, which is associated with worse clinical outcome, including diminished LV reverse remodeling, increased risk for new-onset or recurrent AF and heart failure readmission. Strategies reducing RA pacing burden may be warranted.