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.

Identification and characterization of the new generation soluble guanylate cyclase stimulator BAY-747 designed for the treatment of resistant hypertension.

BACKGROUND AND PURPOSE: First-generation soluble guanylate cyclase (sGC) stimulators have shown clinical benefit in pulmonary hypertension (riociguat) and chronic heart failure (vericiguat). However, given the broad therapeutic opportunities for sGC stimulators, tailored molecules for distinct indications are required. EXPERIMENTAL APPROACH: We report the high-throughput screening (HTS)-based discovery of a second generation of sGC stimulators from a novel imidazo[1,2-a]pyridine lead series. An intense medicinal chemistry programme resulted in the discovery of the sGC stimulator BAY 1165747 (BAY-747). The pharmacokinetic profile of BAY-747 was determined in different species, and it was broadly characterized in pharmacological model systems relevant for vasodilatation and hypertension. KEY RESULTS: BAY-747 is a highly potent sGC stimulator in vitro. In addition, BAY-747 showed an excellent pharmacokinetic profile with long half-life and low peak-to-trough ratio. BAY-747 was investigated in experimental in vivo models of malignant and resistant hypertension (rHT). In spontaneously hypertensive (SH) rats, BAY-747 caused a dose-related and long-lasting decrease in mean arterial blood pressure (MAP). Oral treatment over 12 days resulted in a persistent decrease. BAY-747 provided additional benefit when dosed on top of losartan, amlodipine or spironolactone and even on top of triple combinations of frequently used antihypertensive drugs. In a new canine model of rHT, BAY-747 caused a dose-related and long-lasting (>6 h) MAP decrease. CONCLUSION AND IMPLICATIONS: BAY-747 is a potent, orally available sGC stimulator. BAY-747 shows long-acting pharmacodynamic effects with a very low peak-to-trough ratio. BAY-747 could be a treatment alternative for patients with hypertension, especially those not responding to standard-of-care therapy.

New Generation of sGC Stimulators: Discovery of Imidazo[1,2-a]pyridine Carboxamide BAY 1165747 (BAY-747), a Long-Acting Soluble Guanylate Cyclase Stimulator for the Treatment of Resistant Hypertension.

Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-a]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28. It turned out that BAY 1165747 (BAY-747, 28) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 (28) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.

"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.

Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC.

BACKGROUND: Oxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential. METHODS: We aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592). RESULTS: Mosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model. CONCLUSION: Inhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension.

Healthcare Providers' Knowledge of Value-Based Care in Germany: An Adapted, Mixed-Methods Approach.

BACKGROUND: Value-Based Care (VBC) is being discussed to provide better outcomes to patients, with an aim to reimburse healthcare providers (HCPs) based on the quality of care they deliver. Little is known about German HCPs' knowledge of VBC. This study aims to investigate the knowledge of HCPs of VBC and to identify potential needs for further education toward implementation of VBC in Germany. METHODS: For evidence generation, we performed a literature search and conducted an online survey among HCPs at 89 hospitals across Germany. The questionnaire was based on published evidence and co-developed with an expert panel using a mixed methods approach. RESULTS: We found HCPs to believe that VBC is more applicable in surgery than internal medicine and that well-defined cycles of care are essential for its application. HCPs believe that VBC can reduce health care costs significantly. However, they also assume that implementing VBC will be challenging. CONCLUSIONS: The concept in general is well perceived, however, HCPs do not want to participate in any financial risk sharing. Installing an authority/independent agency that measures achieved value, digital transformation, and that improves the transition between the inpatient and the outpatient sectors are top interests of HCPs.

A novel approach for quantification of the future unmet medical need in right ventricular dysfunction.

Although 'unmet medical need' (UMN) is an increasingly used term in the healthcare sector instrumental to the approximate value of drug discovery projects relevant to portfolio management, no standardized approach exists for its quantification. Especially in diseases with different comorbidities, high patient heterogeneity, and incomplete epidemiological data, it is difficult to judge the need for new therapies. The approach presented here combines an expert assessment of key UMN indicators related to the individual patient with a literature search to collect epidemiological data describing the corresponding patient population with its underlying heterogeneity. This assessment supports decision-making within the portfolio management process in larger research and development organizations.

Perspective of German medical faculties on digitization in the healthcare sector and its influence on the curriculum.

Background: The German healthcare sector is in the process of being disrupted by digitization. Universities are asked to reflect on the consequences and develop strategies to prepare their medical students for a digitalized health care sector. The current state of research does not systematically record the associated activities of individual medical faculties in Germany. Objective: This study was designed to survey the status-quo of how German medical faculties view the digitization progress and to what extend digital capability building is already integrated into the curricula. Methods: A questionnaire with three focus areas was developed: Firstly, the general view of the medical faculties on digitization; secondly, concrete measures to prepare students for digital change and thirdly, the overarching organizational and regulatory conditions. The data was collected through short, questionnaire-based telephone interviews among those responsible for the curriculum at their faculty. The datasets collected were anonymized and statistically evaluated. Results: 30 interviews were conducted. The majority of faculty representatives agreed that digitization will change the role of physicians (87% agreement). Changes caused by individual digitization trends were however viewed to be less likely, e.g., whether medical expertise will become less important due to digital assistance systems (20% agreement), whether physician positions will be replaced by robots and algorithms (7% agreement), or whether hierarchies in hospitals will flatten (13% agreement). Digitization was seen to be of major importance for medical studies (93% agreement). Associated content should be given a higher priority in the curriculum (87% agreement). Two-thirds of faculty representatives believed that overarching institutions such as politics and medical associations ought to have more concrete plans for implementing the digital transformation and that innovations should be implemented in practice faster. Conclusion: While most faculty representatives attach great importance to the digitization of the health care system for university education, various questions about structural teaching measures to prepare students for the digital change show that there is no uniform education of medical students for a digitized health care system. We were also able to show that most faculty representatives are dissatisfied with the regulatory and organizational conditions of digitization in the medical sector.

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.

Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042).

Herein we describe the discovery, mode of action, and preclinical characterization of the soluble guanylate cyclase (sGC) activator runcaciguat. The sGC enzyme, via the formation of cyclic guanosine monophoshphate, is a key regulator of body and tissue homeostasis. sGC activators with their unique mode of action are activating the oxidized and heme-free and therefore NO-unresponsive form of sGC, which is formed under oxidative stress. The first generation of sGC activators like cinaciguat or ataciguat exhibited limitations and were discontinued. We overcame limitations of first-generation sGC activators and identified a new chemical class via high-throughput screening. The investigation of the structure-activity relationship allowed to improve potency and multiple solubility, permeability, metabolism, and drug-drug interactions parameters. This program resulted in the discovery of the oral sGC activator runcaciguat (compound 45, BAY 1101042). Runcaciguat is currently investigated in clinical phase 2 studies for the treatment of patients with chronic kidney disease and nonproliferative diabetic retinopathy.

Cardiac output improvement by pecavaptan: a novel dual-acting vasopressin V1a/V2 receptor antagonist in experimental heart failure.

AIMS: Arginine vasopressin (AVP) mediates deleterious effects via vascular V1a and renal V2 receptors in heart failure (HF). Despite positive short-term decongestive effects in phase II HF studies, selective V2 receptor antagonism has shown no long-term mortality benefit, potentially related to unopposed V1a receptor activation. We compared the novel dual V1a/V2 receptor antagonist pecavaptan with the selective V2 receptor antagonist tolvaptan in pre-clinical HF models. METHODS AND RESULTS: In vitro IC50 determination in recombinant cell lines revealed similar receptor selectivity profiles (V2:V1a) of tolvaptan and pecavaptan for human and dog AVP receptors, respectively. Two canine models were used to compare haemodynamic and aquaretic effects: (i) anaesthetised dogs with tachypacing-induced HF, and (ii) conscious telemetric dogs with a non-invasive cardiac output (CO) monitor. Tolvaptan and pecavaptan exhibited no differences in urinary output. In HF dogs, pecavaptan counteracted the AVP-induced increase in afterload and decrease in CO (pecavaptan: 1.83 ± 0.31 L/min; vs. tolvaptan: 1.46 ± 0.07 L/min, P < 0.05). In conscious telemetric animals, pecavaptan led to a significant increase in CO (+0.26 ± 0.17 L/min, P = 0.0086 vs. placebo), in cardiac index (+0.58 ± 0.39 L/min/m2 , P = 0.009 vs. placebo) and a significant decrease in total peripheral resistance (-5348.6 ± 3601.3 dyn × s/cm5 , P < 0.0001 vs. placebo), whereas tolvaptan was without any significant effect. CONCLUSIONS: Simultaneous blockade of vascular V1a and renal V2 receptors efficiently induces aquaresis and counteracts AVP-mediated haemodynamic aggravation in HF models. Dual V1a/V2 antagonism may lead to improved outcomes in HF.

Digital Competencies and Attitudes Toward Digital Adherence Solutions Among Elderly Patients Treated With Novel Anticoagulants: Qualitative Study.

BACKGROUND: Nonadherence to medication is a driver of morbidity and mortality, and complex medication regimens in patients with chronic diseases foster the problem. Digital technology might help, but despite numerous solutions being developed, none are currently widely used, and acceptance rates remain low, especially among the elderly. OBJECTIVE: This study aimed to better understand and operationalize how new digital solutions can be evaluated. Particularly, the goal was to identify factors that help digital approaches targeting adherence to become more widely accepted. METHODS: A qualitative study using a conceptual grounded theory approach was conducted. We included patients aged 65 years and older who routinely took new oral anticoagulants. To generate theses about the digital competencies of the target group with daily medication intake, face-to-face interviews were conducted, recorded, and anonymized. After coding the interviews, categories were generated, discussed, and combined with several theses until saturation of the statements was reached. RESULTS: The methodological approach led to the finding that after interviews in 20 of 77 potentially available patients, a saturation of statements was reached. The average patient's age was 75 years, and 50% (10/20) of the subjects were female. The data identified five main coding categories-Diseases and medicine, Technology, Autonomy, Patient narrative, and Attitude toward technologies-each including positive and negative subcategories. Main categories and subcategories were summarized as Adherence Radar, which can be considered as a framework to assess the potential of adherence solutions in the process of prototyping and can be applied to all adherence tools in a holistic manner. CONCLUSIONS: The Adherence Radar can be used to increase the acceptance rate of digital solutions targeting adherence. For a patient-centric design, an app should be adapted to the individual patient's needs. According to our results, this application should be based on gender and educational background as well as the individual physician-patient relationship. If used in a proper, individualized manner, digital adherence solutions could become a new cornerstone for the treatment of chronically ill individuals.

Perception of the Progressing Digitization and Transformation of the German Health Care System Among Experts and the Public: Mixed Methods Study.

BACKGROUND: Health care systems worldwide are struggling to keep rising costs at bay with only modest outcome improvement among many diseases. Digitization with technologies like Artificial Intelligence or Machine Learning algorithms might address this. Although digital technologies have been successfully applied in clinical studies the effect on the overall health care system so far was limited. The regulatory ecosystem or data privacy might be responsible, but other reasons may also predominate. OBJECTIVE: We analyzed how the digitization of the German health care market is currently perceived among different stakeholders and investigated reasons for its slow adaption. METHODS: This was a mixed methods study split into a qualitative Part A using the conceptual approach of the Grounded Theory and a quantitative Part B using the Delphi method. For Part A we interviewed experts in the health care system and converted the results into 17 hypotheses. The Delphi method consisted of an online survey which was sent to the participants via email and was available for three months. For the assessment of the 17 hypotheses, the participants were given a six-point Likert scale. The participants were grouped into patients, physicians, and providers of services within the German health care market. RESULTS: There was a strong alignment of opinions on the hypotheses between experts (N=21) and survey participants (N=733), with 70.5% overall agreement on 12/17 hypotheses. Physicians demonstrated the lowest level of agreement with the expert panel at 88% (15/17) disagreement, with the hypotheses "H8: Digitization in the health care system will free up jobs," and "H6: Digitization in the health care system will empower the patients," perceived to be in profound disagreement (P=.036 and P<.001, respectively). CONCLUSIONS: Despite the firm agreement among participants and experts regarding the impact of digitization on the health care system, physicians demonstrated a more negative attitude. We assume that this might be a factor contributing to the slow adoption of digitization in practice. Physicians might be struggling with changing power structures, so future measures to transform the market should involve them to a larger degree.

Test-Retest Reliability of Non-Invasive Cardiac Output Measurement during Exercise in Healthy Volunteers in Daily Clinical Routine / Confiabilidade Teste-Reteste de Medição Não-Invasiva de Débito Cardíaco durante Exercício em Voluntários Saudáveis sob Condições Clínicas de Rotina

Abstract Background: Thoracic bioreactance (TB), a noninvasive method for the measurement of cardiac output (CO), shows good test-retest reliability in healthy adults examined under research and resting conditions. Objective: In this study, we evaluate the test-retest reliability of CO and cardiac power (CPO) output assessment during exercise assessed by TB in healthy adults under routine clinical conditions. Methods: 25 test persons performed a symptom-limited graded cycling test in an outpatient office on two different days separated by one week. Cardiorespiratory (power output, VO2peak) and hemodynamic parameters (heart rate, stroke volume, CO, mean arterial pressure, CPO) were measured at rest and continuously under exercise using a spiroergometric system and bioreactance cardiograph (NICOM, Cheetah Medical). Results: After 8 participants were excluded due to measurement errors (outliers), there was no systematic bias in all parameters under all conditions (effect size: 0.2-0.6). We found that all noninvasively measured CO showed acceptable test-retest-reliability (intraclass correlation coefficient: 0.59-0.98; typical error: 0.3-1.8). Moreover, peak CPO showed better reliability (intraclass correlation coefficient: 0.80-0.85; effect size: 0.9-1.1) then the TB CO, thanks only to the superior reliability of MAP (intraclass correlation coefficient: 0.59-0.98; effect size: 0.3-1.8). Conclusion: Our findings preclude the clinical use of TB in healthy subject population when outliers are not identified.

Resumo Fundamento: A biorreatância torácica (BT), um método não invasivo destinado à medição do débito cardíaco (DC), mostra boa confiabilidade teste-reteste em adultos saudáveis examinados em condições de pesquisa e repouso. Objetivo: No presente estudo, avaliamos a confiabilidade teste-reteste da avaliação do DC e trabalho cardíaco (TC) durante exercício, avaliado por BT em adultos saudáveis sob condições clínicas de rotina. Métodos: 25 indivíduos realizaram teste ergométrico gradual sintoma-limitante em ambiente ambulatorial em dois dias diferentes, com intervalo de uma semana. Parâmetros cardiorrespiratórios (trabalho cardíaco, VO2máx) e hemodinâmicos (frequência cardíaca, volume sistólico, DC, pressão arterial média, TC) foram medidos em repouso e continuamente sob exercício utilizando sistema espiroergométrico e cardiógrafo de biorreatância (NICOM, Cheetah Medical). Resultados: Após 8 participantes terem sido excluídos devido a erros de medição (outliers), não houve viés sistemático em nenhum dos parâmetros em todas as condições (tamanho do efeito: 0,2-0,6). Observamos que todos os débitos cardíacos medidos de forma não invasiva apresentaram níveis aceitáveis de confiabilidade teste-reteste (coeficiente de correlação intraclasse: 0,59-0,98; erro típico: 0,3-1,8). Além disso, TC máximo apresentou melhor confiabilidade (coeficiente de correlação intraclasse: 0,80-0,85; tamanho do efeito: 0,9-1,1), seguido do DC pela BT, graças apenas à confiabilidade superior da PAM (coeficiente de correlação intraclasse: 0,59-0,98; tamanho do efeito: 0,3-1,8). Conclusão: Nossos achados impedem o uso clínico da BT em indivíduos saudáveis quando outliers não forem identificados.

Vascular Protection and Decongestion Without Renin-Angiotensin-Aldosterone System Stimulation Mediated by a Novel Dual-Acting Vasopressin V1a/V2 Receptor Antagonist.

Increased plasma vasopressin levels have been shown to be associated with the progression of congestive heart failure. Vasopressin mediates water retention by renal tubular V2 receptor activation as well as vasoconstriction, cardiac hypertrophy, and fibrosis through V1a receptor activation. Therefore, we developed a novel, dual-acting vasopressin receptor antagonist, BAY 1753011, with almost identical Ki-values of 0.5 nM at the human V1a receptor and 0.6 nM at the human V2 receptor as determined in radioactive binding assays. Renal V2 antagonism by BAY 1753011 was compared with the loop diuretic furosemide in acute diuresis experiments in conscious rats. Similar diuretic efficacy was found with 300-mg/kg furosemide (maximal diuretic response) and 0.1-mg/kg BAY 1753011. Furosemide dose-dependently induced plasma renin and angiotensin I levels, while an equiefficient diuretic BAY 1753011 dose did not activate the renin-angiotensin system. BAY 1753011 dose-dependently decreased the vasopressin-induced expression of the profibrotic/hypertrophic marker plasminogen activator inhibitor-1 and osteopontin in rat cardiomyocytes, while the selective V2 antagonist satavaptan was without any effect. The combined vascular V1a-mediated and renal V2-mediated properties as well as the antihypertrophic/antifibrotic activity enable BAY 1753011 to become a viable treatment option for oral chronic treatment of congestive heart failure.

Test-Retest Reliability of Non-Invasive Cardiac Output Measurement during Exercise in Healthy Volunteers in Daily Clinical Routine.

BACKGROUND: Thoracic bioreactance (TB), a noninvasive method for the measurement of cardiac output (CO), shows good test-retest reliability in healthy adults examined under research and resting conditions. OBJECTIVE: In this study, we evaluate the test-retest reliability of CO and cardiac power (CPO) output assessment during exercise assessed by TB in healthy adults under routine clinical conditions. METHODS: 25 test persons performed a symptom-limited graded cycling test in an outpatient office on two different days separated by one week. Cardiorespiratory (power output, VO2peak) and hemodynamic parameters (heart rate, stroke volume, CO, mean arterial pressure, CPO) were measured at rest and continuously under exercise using a spiroergometric system and bioreactance cardiograph (NICOM, Cheetah Medical). RESULTS: After 8 participants were excluded due to measurement errors (outliers), there was no systematic bias in all parameters under all conditions (effect size: 0.2-0.6). We found that all noninvasively measured CO showed acceptable test-retest-reliability (intraclass correlation coefficient: 0.59-0.98; typical error: 0.3-1.8). Moreover, peak CPO showed better reliability (intraclass correlation coefficient: 0.80-0.85; effect size: 0.9-1.1) then the TB CO, thanks only to the superior reliability of MAP (intraclass correlation coefficient: 0.59-0.98; effect size: 0.3-1.8). CONCLUSION: Our findings preclude the clinical use of TB in healthy subject population when outliers are not identified.

How soon will digital endpoints become a cornerstone for future drug development?

Digital technologies are transforming healthcare and will provide the basis for more patient-centric innovation in the pharmaceutical industry. Digital endpoints in clinical studies have the potential to drive innovation and reduce costly late-stage failures. This is also currently under consideration by regulatory agencies, such as the US Food and Drug Administration (FDA). The academic-industrial collaboration MOBILISED-D aims to implement and validate real-world walking speed (RWS) as a digital endpoint accepted by regulatory authorities as a first of its class. Previous work has shown that loss of mobility driven by chronic illness and frailty in older patients can be a relevant readout or effect of different diseases and various organ systems.

Remote Left Ventricular Hemodynamic Monitoring Using a Novel Intracardiac Sensor.

BACKGROUND: Heart failure (HF) remains the most common reason for hospital admission in patients aged >65 years. Despite modern drug therapy, mortality and readmission rates for patients hospitalized with HF remain high. This necessitates further research to identify early patients at risk for readmission to limit hospitalization by timely adjustment of medical therapy. Implantable devices can monitor left ventricular (LV) hemodynamics and remotely and continuously detect the early signs of decompensation to trigger interventions and reduce the risk of hospitalization for HF. Here, we report the first preclinical study validating a new batteryless and easy to implant LV-microelectromechanical system to assess LV performance. METHODS AND RESULTS: A miniaturized implantable wireless pressure sensor was adapted for implantation in the LV apex. The LV-microelectromechanical system sensor was tested in a canine model of HF. The wireless pressure sensor measurements were compared with invasive left heart catheter-derived measurements at several time points. During different pharmacological challenge studies with dobutamine or vasopressin, the device was equally sensitive compared with invasive standard procedures. No adverse events or any observable reaction related to the implantation and application of the device for a period of 35 days was observed. CONCLUSIONS: Our miniaturized wireless pressure sensor placed in the LV (LV-microelectromechanical system) has the potential to become a new telemetric tool to earlier identify patients at risk for HF decompensation and to guide the treatment of patients with HF.

Digital Transformation and Disruption of the Health Care Sector: Internet-Based Observational Study.

BACKGROUND: Digital innovation, introduced across many industries, is a strong force of transformation. Some industries have seen faster transformation, whereas the health care sector only recently came into focus. A context where digital corporations move into health care, payers strive to keep rising costs at bay, and longer-living patients desire continuously improved quality of care points to a digital and value-based transformation with drastic implications for the health care sector. OBJECTIVE: We tried to operationalize the discussion within the health care sector around digital and disruptive innovation to identify what type of technological enablers, business models, and value networks seem to be emerging from different groups of innovators with respect to their digital transformational efforts. METHODS: From the Forbes 2000 and CBinsights databases, we identified 100 leading technology, life science, and start-up companies active in the health care sector. Further analysis identified projects from these companies within a digital context that were subsequently evaluated using the following criteria: delivery of patient value, presence of a comprehensive and distinctive underlying business model, solutions provided, and customer needs addressed. RESULTS: Our methodological approach recorded more than 400 projects and collaborations. We identified patterns that show established corporations rely more on incremental innovation that supports their current business models, while start-ups engage their flexibility to explore new market segments with notable transformations of established business models. Thereby, start-ups offer higher promises of disruptive innovation. Additionally, start-ups offer more diversified value propositions addressing broader areas of the health care sector. CONCLUSIONS: Digital transformation is an opportunity to accelerate health care performance by lowering cost and improving quality of care. At an economic scale, business models can be strengthened and disruptive innovation models enabled. Corporations should look for collaborations with start-up companies to keep investment costs at bay and off the balance sheet. At the same time, the regulatory knowledge of established corporations might help start-ups to kick off digital disruption in the health care sector.