Current Therapies and Future Horizons in Cardiac Amyloidosis Treatment.

PURPOSE OF REVIEW: Cardiac amyloidosis (CA) is a condition characterized by misfolding and extracellular deposition of proteins, leading to organ dysfunction. While numerous forms of CA exist, two subtypes dominate clinical prevalence: Transthyretin amyloid (ATTR) and immunoglobulin light chain amyloid. RECENT FINDINGS: The current scientific landscape reflects the urgency to advance therapeutic interventions with over 100 ongoing clinical trials. Heart failure treatment is affected by CA phenotype with poor tolerance of otherwise frequently used medications. Treating comorbidities including atrial fibrillation and valvular disease remains a challenge in CA, driven by technical difficulties and uncertain outcomes. Tafamidis is the first ATTR-stabilizer approved with a rapidly growing rate of clinical use. In parallel, various new therapeutic classes are in late-stage clinical trials including silencers, antibodies and genetic therapy. Managing CA is a critical challenge for future heart failure care. This review delineates the current standard-of-care and scientific landscape of CA therapy.

Screening for Occult Transthyretin Amyloidosis in Patients with Severe Aortic Stenosis and Amyloid Red Flags.

AIMS: The optimal strategy to identify transthyretin-type cardiac amyloidosis (ATTR-CA) in patients with aortic stenosis (AS) is still unclear. This study aimed to investigate if targeted screening for ATTR-CA in patients with severe AS and amyloid red flags is associated with higher detection rates. METHODS: The study prospectively enrolled patients ≥65 years with severe AS. Patients who fulfilled ≥1 major (carpal tunnel syndrome (CTS), ruptured biceps tendon, spinal stenosis, N-terminal pro B-type natriuretic peptide ≥1000 pg/mL, cardiac troponin >99th percentile) or ≥2 minor criteria (diastolic dysfunction ≥2 grade/lateral e' <10 cm/s, atrial fibrillation, atrioventricular conduction disease/pacemaker) received bone scintigraphy and biochemical analysis for light chain amyloidosis. Hypertensive patients (>140/90 mmHg) and those with interventricular septal thickness (IVSd) ≤13 mm were excluded. RESULTS: Overall, 264 patients were screened, of whom 85 were included in the analysis. Tracer uptake Perugini grade ≥1 was detected in nine patients (11%). An endomyocardial biopsy was additionally performed in four of nine patients, yielding a prevalence of 7% (n = 6). All patients with dual AS-ATTR were male. Syncope was more commonly reported in AS-ATTR patients (50% vs. 6%, p = 0.010), who also tended to have more severe hypertrophy (IVSd of 18 vs. 16 mm, p = 0.075). Pericardial effusion and CTS were more common in patients with dual pathology (67% vs. 8%, p < 0.001, and 83% vs. 24%, p = 0.003, respectively). CONCLUSION: Targeted screening for ATTR-CA in patients with AS and amyloid red flags does not yield higher detection rates than those reported previously in all comers with AS.

Post-traumatic stress disorder among COVID-19-affected high-risk cardiac patients.

BACKGROUND: During the first coronavirus disease 2019 (COVID-19) wave there was a high prevalence of mental health impairments and post-traumatic stress disorder (PTSD), particularly in patients with comorbid cardiac diseases. METHODS: During waves 2-5, all hospitalized patients with cardiac problems and suspected COVID-19 were eligible to participate in this study. RESULTS: The prevalence of PTSD was 31.4% (n=48) in 153 participants. No age- and gender-related differences for PTSD were found. CONCLUSIONS: The prevalence is lower than during the first wave but higher than in patients reported in other studies who were isolated at home. Routine mental health assessments are strongly recommended for patients at risk.

Telemetric long-term assessment of autonomic function in experimental heart failure.

Despite medical advances in the treatment of heart failure (HF), mortality remains high. It has been shown that alterations of the autonomic-nervous-system (ANS) are associated with HF progression and increased mortality. Preclinical models are required to evaluate the effectiveness of novel treatments modulating the autonomic imbalance. However, there are neither standard models nor diagnostic methods established to measure sympathetic and parasympathetic outflow continuously. Digital technologies might be a reliable tool for continuous assessment of autonomic function within experimental HF models. Telemetry devices and pacemakers were implanted in beagle dogs (n = 6). HF was induced by ventricular pacing. Cardiac hemodynamics, plasma catecholamines and parameter describing the ANS ((heart rate variability (HRV), deceleration capacity (DC), and baroreflex sensitivity (BRS)) were continuously measured at baseline, during HF conditions and during recovery phase. The pacing regime led to the expected depression in cardiac hemodynamics. Telemetric assessment of the ANS function showed a significant decrease in Total power, DC, and Heart rate recovery, whereas BRS was not significantly affected. In contrast, plasma catecholamines, revealing sympathetic activity, showed only a significant increase in the recovery phase. A precise diagnostic of the ANS in the context of HF is becoming increasingly important in experimental models. Up to now, these models have shown many limitations. Here we present the continuous assessment of the autonomic function in the progression of HF. We could demonstrate the advantage of highly resolved ANS measurement by HR and BP derived parameters due to early detection of an autonomic imbalance in the progression of HF.

Impact of extended-course oral nirmatrelvir/ritonavir (Paxlovid) in established Long COVID: Case series and research considerations.

Background: Prior case series suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) benefits some people with Long COVID, within and/or outside of the context of an acute reinfection. To the best of our knowledge, there have been no prior case series of people with Long COVID who have attempted longer courses of nirmatrelvir/ritonavir. Methods: We documented a case series of 13 individuals with Long COVID who initiated extended courses (>5 days; range: 7.5-30 days) of oral nirmatrelvir/ritonavir outside (n=11) of and within (n=2) the context of an acute SARS-CoV-2 infection. Participants reported on symptoms and health experiences before, during, and after their use of nirmatrelvir/ritonavir. Results: Among those who took a long course of nirmatrelvir/ritonavir outside of the context of an acute infection, some experienced a meaningful reduction in symptoms, although not all benefits persisted; others experienced no effect on symptoms. One participant reported intense stomach pain that precluded her from continuing her course. Among the two participants who took a long course of nirmatrelvir/ritonavir within the context of an acute reinfection, both eventually returned to their pre-re-infection baseline. Discussion: Long courses of nirmatrelvir/ritonavir may have meaningful benefits for some people with Long COVID but not others. We encourage researchers to study who, how, and why nirmatrelvir/ritonavir benefits some and what course length is most effective, with the goal of informing clinical recommendations for using nirmatrelvir/ritonavir and/or other antivirals as a potential treatment for Long COVID.

Association between different dimensions of anger and symptoms of post-traumatic stress disorder in at-risk cardiovascular patients during the COVID-19 pandemic.

Introduction: The common connecting factor between PTSD and cardiovascular diseases lies in the disruption of the stress processing system. The COVID-19 pandemic has led to an increase in stress levels worldwide. Due to the life-threatening situation of affected risk patients, this also led to the accumulation of post-traumatic stress symptoms (PTSS). The influence of anger on cardiovascular diseases has hardly been investigated so far. The focus of this study is on anger regulation in cardiovascular risk patients. The COVID-19 pandemic is considered as an additional stressor in this study, but not as a separate entity. The hypothesis is that individuals with inward anger are more prone to post-traumatic stress disorder (PTSD). Methods: As part of the routine examination, all patients who were hospitalized between January 1st, 2021 and May 31st, 2022 with high-risk cardiovascular diseases were included. A total of N = 153 (84.1%) subjects participated in the study. On admission, anger (STAXI-2) and PTSD (PCL-5) were assessed using questionnaires. The relationship between different domains of anger and PTSS was examined. Results: Inwardly directed anger was more pronounced in this population than in a standard sample (+1 SD) and had a significant impact on the presence of PTSD (B = -0.72, p < 0.001). Additionally, correlations were found between inward-directed anger and PTSD, as well as all other anger expressions studied and the PTSD total score. Discussion: It can be assumed that anger and its regulation are relevant factors for both cardiac diseases and PTSD. The study results can be used for prevention, rehabilitation and therapeutic measures. However, the impact of inner anger on PTSD is theoretical and based on statistical testing. A confirmatory longitudinal study is needed to substantiate these results.

Sex-Related Differences among Adults with Hypertrophic Obstructive Cardiomyopathy Undergoing Transcoronary Ablation of Septal Hypertrophy.

(1) Background: The transcoronary ablation of septal hypertrophy (TASH) is an established therapy for hypertrophic obstructive cardiomyopathy (HOCM). Previous studies on this topic are characterised by a consistent male predominance and show a worse prognosis in females. (2) Methods: This study is a retrospective analysis of all TASH procedures conducted between 2006 and 2021 at a tertiary academic centre. A solution of 75 µm microspheres (Embozene®, Boston Scientific, Marlborough, MA, USA) was used as an embolising agent. The outcomes of interest were left ventricular outflow tract (LVOT) gradient reduction and symptom improvement among males vs. that among females. Secondarily, we analysed the sex-related differences in procedural safety outcomes and mortality. (3) Results: The study population consisted of 76 patients, with a median age of 61 years. Females comprised 57% of the cohort. We observed no sex-related differences in the baseline LVOT gradients at rest or under provocation (p = 0.560 and p = 0.208, respectively). Females were significantly older at the time of the procedure (p < 0.001), had lower tricuspid annular systolic excursion (TAPSE) (p = 0.009), presented a worse clinical status according to the NYHA functional classification (for NYHA ≥ 3, p < 0.001), and were more often on diuretics (p < 0.001). We did not observe sex-related differences in absolute gradient reduction at rest (p = 0.147) and under provocation (p = 0.709). There was a reduction in the NYHA class by a median value of 1 (p = 0.636) at follow-up for both sexes. Postprocedural access site complications were documented in four cases (two of which concerned females), and complete atrioventricular block was noted in five patients (three of which concerned females). The 10-year survival rates were comparable between the sexes (85% in females and 88% in males). The female sex was not associated with enhanced mortality according to multivariate analysis after adjusting for the confounding variables (HR 0.94; 95% CI 0.376-2.350; p = 0.895), but we observed age-related differences in long-term mortality (HR 1.035; 95% CI 1.007-1.063; p = 0.015). (4) Conclusions: TASH is safe and effective in both sexes, irrespective of their clinical differences. Women present at an advanced age and with more severe symptoms. An advanced age at the time of the intervention is an independent predictor of mortality.

Long COVID: major findings, mechanisms and recommendations.

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.

"Digital biomarkers" in preclinical heart failure models - a further step towards improved translational research.

Innovations in the development of novel heart failure therapies are essential to further increase the predictive value of early research findings. Animal models are still playing a pivotal role in 'translational research'. In recent years, the transferability from animal studies has been more and more critically discussed due to persistent high attrition rates in clinical trials. However, there is an increasing trend to implement mobile health devices in preclinical studies. These devices can increase the predictive value of animal models by providing more accurate and translatable data and protect from confounding factors. This review outlines the current prevalence and opportunities of these techniques in preclinical heart failure research studies to accelerate the integration of these important tools. A literature screening for preclinical heart failure studies in large animals implementing telemetry devices over the last decade was performed. Twelve out of 43 publications were included. A variety of different hemodynamic and cardiac parameters can be recorded in conscious state by means of telemetry devices in both, the animal model and the patient. The measurement quality is consistently rated as valid and robust. Mobile health technologies functioning as digital biomarkers represent a more predictive approach compared to the traditionally used invasive measurement techniques, due to the possibility of continuous data collection in the conscious animal. Furthermore, they help to implement the 3R concept (reduction, refinement, replacement) in animal research. Despite this, the use of these techniques in preclinical research has been restrained to date.

Toward the fabrication of a 5-µm-resolution Wolter microscope for the National Ignition Facility (invited).

Advancements in computer-controlled polishing, metrology, and replication have led to an x-ray mirror fabrication process that is capable of producing high-resolution Wolter microscopes. We present the fabrication and test of a nickel-cobalt replicated full-shell x-ray mirror that was electroformed from a finely figured and polished mandrel. This mandrel was designed for an 8-m source-to-detector-distance microscope, with 10× magnification, and was optimized to reduce shell distortions that occur within 20 mm of the shell ends. This, in combination with an improved replication tooling design and refined bath parameters informed by a detailed COMSOL Multiphysics® model, has led to reductions in replication errors in the mirrors. Mandrel surface fabrication was improved by implementing a computer-controlled polishing process that corrected the low-frequency mandrel figure error and achieved <2.0 nm RMS convergence error. X-ray tests performed on a pair of mirror shells replicated from the mandrel have demonstrated <10 µm full-width at half-maximum (FWHM) spatial resolution. Here, we discuss the development process, highlight results from metrology and x-ray testing, and define a path for achieving a program goal of 5 µm FWHM resolution.

Pseudoaneurysm Repair With a Septal Occluder.

INTRODUCTION: New treatment options, like endovascular aortic repair, reduced the mortality rate of patients suffering from complications after an acute type A aortic dissection repair. Nevertheless, initial successful treatment of an aortic dissection does not fully eliminate the risk of later adverse aortic events like anastomotic pseudoaneurysm. Pseudoaneurysm of the anastomosis between the ascending and the arch graft could initiate complications like peripheral embolization, dysphagia or compression of mediastinum organs. Re-operation via re-sternotomy bears enormous morbidity and mortality for these patients. There is a high unmet need for percutaneous therapeutic options to treat pseudoaneurysms. CASE PRESENTATION: A 59-year-old-man treated 15 years ago for type A aortic dissection, was hospitalized due to intermittent abdominal pain. A detailed examination revealed 2 pseudoaneurysms: 1 symptomatic at the level of the reimplanted celiac trunk and 1 asymptomatic at the anastomosis between the brachiocephalic trunk and the aortic arch graft. Due to multiple co-morbidities and previous operations, the risk for surgery was considered too high. Both pseudoaneurysm were treated percutaneously, the symptomatic 1 with covered stent and the asymptomatic with Amplatzer™ septal-occluder. DISCUSSION: We present an alternative percutaneous therapy approach for treatment of pseudoaneurysm using a septal-occluder. A follow-up computed tomography 3 months later showed successfully excluded pseudoaneurysm.

Chemical recycling: A critical assessment of potential process approaches.

Increased media coverage of plastic pollution in the environment and import bans on plastic waste in several countries have resulted in plastic waste becoming one of the most discussed waste streams in recent years. In the European Union (EU), only about one-third of the post-consumer plastic waste is recycled; the rest goes to energy recovery and landfilling in equal parts. In connection to the necessary increase in efforts to achieve the ambitious EU recycling targets, chemical recycling is currently receiving more and more attention. The assumption is that chemical recycling processes could open up new waste streams for recycling and generate valuable raw materials for the chemical industry. Although there exists no legal definition for chemical recycling, there is more or less agreement that it covers the conversion of plastic polymers into their monomers or chemical building blocks. Techniques such as gasification, pyrolysis and liquefaction as well as solvolysis can be used for chemical recycling. So far, only few large-scale plants for chemical recycling exist worldwide. This article presents the different processes by means of examples from (formerly) running installations and their suitability for plastics recycling is assessed. However, to date, only few chemical recycling plants are in continuous operation, and further scientific evidence for the ecological and economic benefits is still necessary for final evaluation.

Probing the axion-nucleon coupling with the next generation of axion helioscopes.

A finite axion-nucleon coupling, nearly unavoidable for QCD axions, leads to the production of axions via the thermal excitation and subsequent de-excitation of 57 Fe isotopes in the sun. We revise the solar bound on this flux adopting the up to date emission rate, and investigate the sensitivity of the proposed International Axion Observatory IAXO and its intermediate stage BabyIAXO to detect these axions. We compare different realistic experimental options and discuss the model dependence of the signal. Already BabyIAXO has sensitivity far beyond previous solar axion searches via the nucleon coupling and IAXO can improve on this by more than an order of magnitude.

Proximity to COVID-19 on Mental Health Symptoms among Hospital Medical Staff.

BACKGROUND: Exposure to patients with COVID-19 can have a significant impact on mental health of hospital medical staff. The aim of this study was to examine the influence of proximity to patients with COVID-19 considering occupational position and gender on the mental health of hospital staff. SUBJECTS AND METHODS: N=78 participants were included in the study, with n=40 of them with direct contact to patients with COVID-19 (51%); eight had contact with patients suspected of having COVID-19 (10%), and n=30 with no direct contact to people with COVID-19 (39%). RESULTS: Multinomial regression analyses showed that proximity had a negative (inverse) influence on avoidance behaviour as part of PTSD, physical symptoms, somatization, compulsiveness and anger expression-in as tendency to suppress anger. In addition, there was a significant impact of the female gender on increased physical symptoms, while age, work experience and occupation had no further influence. CONCLUSIONS: These results that hospital medical staff is less psychologically stressed when closer to COVID-19 patients are inconsistent with previous studies. Self-efficacy and locus of control in these situations are relevant for processing the trauma. In summary, perception of personal risk is essential. Proximity is believed to be a proxy variable for personal risk perception. As a synopsis of these results, regular briefings of the hospital staff are recommended to prevent psychological impairment. They should contain specific information about conditions in the affected wards and the risk of infection, which could help reduce risk perception of medical personnel.

Iridium thin-film coatings for the BabyIAXO hybrid X-ray optic.

Reflective coatings are an essential feature of X-ray telescopes. Their overall performance relies heavily on substrate compatibility and how well they conform to the optics assembly processes. We use X-ray reflectometry (XRR) to demonstrate the compatibility of shaping flat substrates coated with iridium, and show that specular and nonspecular reflectance before and after shaping is on par with traditional hot-slumped coated substrates. From 1.487 and 8.048keV measurements, we find that the substrates have rms roughness of 0.38nm and magnetron sputtered iridium deposits with rms surface roughness of 0.27-0.35nm. A hydrocarbon overlayer from atmospheric contamination is present with a thickness of 1.4-1.6nm and a density of 1.2-1.6g/cm3. Both the traditional hot slumped and the flat substrates undergoing post-coating shaping have a similar characteristic surface morphology and are equally well-suited for use with X-ray optics. Finally, we demonstrate by simulation the improved effective area achieved by using a low-Z overlayer, and illustrate the performance of a hybrid optic coated with optimized bilayers for a Primakoff axion spectrum emitted by the sun.

sGC stimulation lowers elevated blood pressure in a new canine model of resistant hypertension.

Therapy-resistant hypertension is a serious medical problem, causing end-organ damage, stroke, and heart failure if untreated. Since the standard of care fails in resistant hypertension patients, there is still a substantial unmet medical need for effective therapies. Active stimulation of soluble guanylyl cyclase via novel soluble guanylyl cyclase stimulators might provide an effective treatment option. To test this hypothesis, we established a new experimental dog model and investigated the effects of the soluble guanylyl cyclase-stimulator BAY 41-2272. In beagle dogs, a resistant hypertension phenotype was established by combining unilateral renal wrapping with the occlusion of the renal artery in the contralateral kidney. The most frequently used antihypertensive drugs were administered orally, either alone or in combination, and their acute effect on telemetric measured blood pressure was assessed and compared with that of BAY 41-2272. The chosen disease stimulus led to a moderate and stable increase in blood pressure. Even high doses of standard-of-care antihypertensives only slightly decreased blood pressure. In contrast, the administration of the soluble guanylyl cyclase stimulator BAY 41-2272 as standalone therapy led to a dose-dependent reduction in blood pressure (-14.1 ± 1.8 mmHg). Moreover, BAY 41-2272 could also further decrease blood pressure in addition to a triple combination of standard-of-care antihypertensives (-28.6 ± 13.2 mmHg). BAY 41-2272 was highly efficient as a standalone treatment in resistant hypertension but was also effective in addition to standard-of-care treatment. These data strongly suggest that soluble guanylyl cyclase stimulators might provide an effective pharmacologic therapy for patients with resistant hypertension.

Gender Differences in Anger Among Hospital Medical Staff Exposed to Patients with COVID-19.

Purpose: Occupational exposure to patients with COVID-19 is a stress factor. The aim of this study was to assess gender differences in anger among medical hospital staff. Methods: N=78 hospital employees with direct or indirect contact to patients with COVID-19 completed State-Trait Inventory-2. Results: Female personnel showed higher scores in the main "trait anger" scale and its subscale "anger temperament," whereas "anger control-out" was significant lower. Direct patient contact had no influence. Conclusion: More specific training for female hospital staff could achieve health-related equity. Focusing on anger as a leading indicator could lead to better prevention and self-monitoring. Registered at Clinicaltrials.gov (NCT04368312).

In oxygen-deprived tumor cells ERp57 provides radioprotection and ensures proliferation via c-Myc, PLK1 and the AKT pathway.

The disulfide isomerase ERp57, originally found in the endoplasmic reticulum, is located in multiple cellular compartments, participates in diverse cell functions and interacts with a huge network of binding partners. It was recently suggested as an attractive new target for cancer therapy due to its critical role in tumor cell proliferation. Since a major bottleneck in cancer treatment is the occurrence of hypoxic areas in solid tumors, the role of ERp57 in cell growth was tested under oxygen depletion in the colorectal cancer cell line HCT116. We observed a severe growth inhibition when ERp57 was knocked down in hypoxia (1% O2) as a consequence of downregulated c-Myc, PLK1, PDPK1 (PDK1) and AKT (PKB). Further, irradiation experiments revealed also a radiosensitizing effect of ERp57 depletion under oxygen deprivation. Compared to ERp57, we do not favour PDPK1 as a suitable pharmaceutical target as its efficient knockdown/chemical inhibition did not show an inhibitory effect on proliferation.