Epidermal growth factor receptor‐2 (HER‐2) is overexpressed in 20 to 25% of human breast cancers, which is associated with aggressive tumour growth and poor prognosis. Trastuzumab (Herceptin®) is a ...humanized monoclonal antibody directed against HER‐2, the first highly selective form of therapy targeting HER‐2 overexpressing tumours. Although initial trials indicated high efficacy and a favourable safety profile of the drug, the first large, randomized trial prompted a retrospective analysis of cardiac dysfunction in earlier trials utilizing trastuzumab. There has been ongoing debate on the cardiac safety of trastuzumab ever since, initiating numerous clinical and preclinical investigations to better understand the background of trastuzumab cardiotoxicity and evaluate its effects on patient morbidity. Here, we have given a comprehensive overview of our current knowledge on the cardiotoxicity of trastuzumab, primarily focusing on data from clinical trials and highlighting the main molecular mechanisms proposed.
Linked Articles
This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc
Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse ...models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1α, peroxisome proliferator-activated receptor α), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis.
Background and Aims
Hepatic cardiomyopathy, a special type of heart failure, develops in up to 50% of patients with cirrhosis and is a major determinant of survival. However, there is no reliable ...model of hepatic cardiomyopathy in mice. We aimed to characterize the detailed hemodynamics of mice with bile duct ligation (BDL)–induced liver fibrosis, by monitoring echocardiography and intracardiac pressure–volume relationships and myocardial structural alterations. Treatment of mice with a selective cannabinoid‐2 receptor (CB2‐R) agonist, known to attenuate inflammation and fibrosis, was used to explore the impact of liver inflammation and fibrosis on cardiac function.
Approach and Results
BDL induced massive inflammation (increased leukocyte infiltration, inflammatory cytokines, and chemokines), oxidative stress, microvascular dysfunction, and fibrosis in the liver. These pathological changes were accompanied by impaired diastolic, systolic, and macrovascular functions; cardiac inflammation (increased macrophage inflammatory protein 1, interleukin‐1, P‐selectin, cluster of differentiation 45–positive cells); and oxidative stress (increased malondialdehyde, 3‐nitrotyrosine, and nicotinamide adenine dinucleotide phosphate oxidases). CB2‐R up‐regulation was observed in both livers and hearts of mice exposed to BDL. CB2‐R activation markedly improved hepatic inflammation, impaired microcirculation, and fibrosis. CB2‐R activation also decreased serum tumor necrosis factor‐alpha levels and improved cardiac dysfunction, myocardial inflammation, and oxidative stress, underlining the importance of inflammatory mediators in the pathology of hepatic cardiomyopathy.
Conclusions
We propose BDL‐induced cardiomyopathy in mice as a model for hepatic/cirrhotic cardiomyopathy. This cardiomyopathy, similar to cirrhotic cardiomyopathy in humans, is characterized by systemic hypotension and impaired macrovascular and microvascular function accompanied by both systolic and diastolic dysfunction. Our results indicate that the liver–heart inflammatory axis has a pivotal pathophysiological role in the development of hepatic cardiomyopathy. Thus, controlling liver and/or myocardial inflammation (e.g., with selective CB2‐R agonists) may delay or prevent the development of cardiomyopathy in severe liver disease.
Although radial access is the current gold standard for the implementation of percutaneous coronary interventions (PCI), post-procedural radial compression devices are seldom compared with each other ...in terms of safety or efficacy. Our group aimed to compare a cost effective and potentially green method to dedicated radial compression devices, with respect to access site complications combined in a device oriented complex endpoint (DOCE), freedom from which served as our primary endpoint. Patients undergoing PCI were randomized to receive either the cost effective or a dedicated device, either of which were removed using patent hemostasis. Twenty-four hours after the procedure, radial artery ultrasonography was performed to evaluate the access site. The primary endpoint was assessed using a non-inferiority framework with a non-inferiority margin of five percentage points, which was considered as the least clinically meaningful difference. The cost-effective technique and the dedicated devices were associated with a comparably low rate of complications (freedom from DOCE: 83.3% vs. 70.8%, absolute risk difference: 12.5%, one-sided 95% confidence interval (CI): 1.11%). Composition of the DOCE (i.e., no complication, hematoma, pseudoaneurysm, and radial artery occlusion) and compression time were also assessed in superiority tests as secondary endpoints. Both the cost-effective technique and the dedicated devices were associated with comparably low rates of complications:
= 0.1289. All radial compression devices performed similarly when considering the time to complete removal of the respective device (120.0 (inter-quartile range: 100.0-142.5) for the vial vs. 120.0 (inter-quartile range: 110.0-180) for the dedicated device arm, with a median difference of 95% CI: 7.0 -23.11 to 2.00 min,
= 0.2816). In conclusion, our cost-effective method was found to be non-inferior to the dedicated devices with respect to safety, therefore it is a safe alternative to dedicated radial compression devices, as well as seeming to be similarly effective.
Cardiogenic shock (CS) in acute coronary syndrome (ACS) is a critical disease with high mortality rates requiring complex treatment to maximize patient survival chances. Emergent coronary ...revascularization along with circulatory support are keys to saving lives. Mechanical circulatory support may be instigated in severe, yet still reversible instances. Of these, the peripheral veno-arterial extracorporeal membrane oxygenator (pVA-ECMO) is the most widely used system for both circulatory and respiratory support. The aim of our work is to provide a review of our current understanding of the pVA-ECMO when used in the catheterization laboratory in a CS ACS setting. We detail the workings of a Shock Team: pVA-ECMO specifics, circumstances, and timing of implantations and discuss possible complications. We place emphasis on how to select the appropriate patients for potential pVA-ECMO support and what characteristics and parameters need to be assessed. A detailed, stepwise implantation algorithm indicating crucial steps is also featured for practitioners in the catheter laboratory. To provide an overall aspect of pVA-ECMO use in CS ACS we further gave pointers including relevant human resource, infrastructure, and consumables management to build an effective Shock Team to treat CS ACS via the pVA-ECMO method.
Aims
Heart failure with preserved ejection fraction (HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate (cGMP) signalling has been intensively ...investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long‐term preventive application of the phosphodiesterase‐5A (PDE5A) inhibitor vardenafil in diabetic cardiomyopathy‐associated HFpEF.
Methods and results
Zucker diabetic fatty (ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular (LV) pressure–volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro‐oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV/cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G (PKG) activity, increased nitro‐oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV/cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro‐oxidative stress, myocardial hypertrophy and fibrotic remodelling.
Conclusions
We report that vardenafil successfully prevented the development of diabetes mellitus‐associated HFpEF. Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus.
COPD is one of the most common pulmonary diseases and one of the leading causes of death worldwide. Exacerbations of COPD include acute worsening that could lead to hospitalization and death. In this ...study, our objective was to investigate the natural course of moderate and severe exacerbations (SAE) and mortality in the Hungarian population in the past decade.
A retrospective financial database analysis was performed to examine the risk of additional SAEs and death after the first ever SAE in COPD patients, using the financial database of the Hungarian National Health Insurance Fund (NHIF). Patients were enrolled between 2009.01.01. and 2019.12.31. if they had received at least one inhaled drug (LABA, LAMA, ICS or SABA/SAMA) and had been hospitalized for a COPD exacerbation (ICD-10 code J44).
A total of 63,037 patients with COPD were enrolled after their first SAE. Of them, 27,095 patients suffered at least one subsequent SAE, and 32,120 patients died during the 10-year follow-up. The median survival was 4.7 years. The risk of subsequent hospitalizations increased significantly after each SAE, with hazard ratios ranging from 1.65 to 5.01. The risk for mortality was increased after each SAE, but did not increase further with the number of SAEs. Moreover, the risk for subsequent SAE and death increased with moderate exacerbations; however, this risk did not increase further with each event.
Despite a relevant improvement in COPD treatment, the natural course of exacerbations remained unchanged. This result highlights the importance of preventing exacerbations and the need for more research to better predict them.
Abstract Background To preserve the benefit of atrial sensing without the implantation of an additional lead, a single-lead ICD system with a floating atrial dipole (VDD or DX ICD) has been ...developed. Purpose The purpose of this nationwide survey was to provide an overview of the current key influences of device selection focusing on DX ICD systems and to test the applicability of a previously published decision-making flowchart of ICD type selection in the daily clinical practice. Methods An online questionnaire was sent to all implanting centers in Hungary. In total, 10 centers participated in the survey and reported data from 361 DX ICD and 10 CRT-DX systems implantations between February 2021 and May 2023. Results The most important influencing clinical factors indicated by the participating doctors were elevated risk of atrial fibrillation/stroke (56%), risk of sinus/supraventricular tachycardias (42%), and a potential need for CRT upgrade in the future (36%). The DX ICD was considered in the majority of cases instead of the VVI system (87%), and only in a small proportion instead of a DDD ICD (13%). 60% of the patients with DX ICDs were also included into remote monitoring-based follow-up. In 83% of the cases, good (>2 mV) or excellent (>5) atrial signal amplitude was recorded within 6 weeks after the implantation. Results In the current nationwide survey, the most important influencing clinical factors indicated by the responding doctors for selecting a DX ICD were the elevated risk of stroke or sinus/supraventricular tachycardias and a potential need for CRT upgrade in the future. These findings support the use of a previously published decision-making flowchart.Graphical abstract
Radial artery approach angiography is the current gold standard for coronary status diagnostics and eventual percutaneous revascularization (PCI). Currently, application of adequate, patent ...hemostasis based physical torniquets are used for puncture site control, to avoid bleeding, radial artery occlusion and damage (RAO and RAD). The Radial Artery Puncture Hemostasis Evaluation (RAPHE) is a prospective, randomized, multicenter clinical trial designed to investigate new, simplified techniques of radial artery hemostasis utilizing physical compression free methods.
The RAPHE study has been designed to evaluate the efficacy and safety of two non-compression based radial artery hemostasis methods: a 100% chitosan bioactive hemostatic dressing and a purpose-built radial potassium-ferrate based topical hemostasis disc. These devices will be investigated in a standalone configuration. Control group is a standard pneumatic airbladder-based compression device. A total of 600 patients will be enrolled in a three-way randomization (1:1:1) with two study and one control groups. Safety and efficacy endpoints are RAO, puncture site hematoma formation and RAD respectively, consisting of dissection, (pseudo)aneurism and/or fistula formation, measured post-procedure and at sixty days.
The results from this trial will provide valuable information on new, simplified methods of radial artery hemostasis options and possibly simplify post-puncture management of patients.
www.ClinicalTrials.gov, identifier NCT04857385.
Envisioned 5G applications and services, such as Tactile Internet, Industry 4.0 use-cases, remote control of drone swarms, pose serious challenges to the underlying networks and cloud platforms. On ...the one hand, evolved cloud infrastructures provide the IT basis for future applications. On the other hand, networking is in the middle of a momentous revolution and important changes are mainly driven by Network Function Virtualization (NFV) and Software Defined Networking (SDN). A diverse set of cloud and network resources, controlled by different technologies and owned by cooperating or competing providers, should be coordinated and orchestrated in a novel way in order to enable future applications and fulfill application level requirements. In this paper, we propose a novel cross domain orchestration system which provides wholesale XaaS (Anything as a Service) services over multiple administrative and technology domains. Our goal is threefold. First, we design a novel orchestration system exploiting a powerful information model and propose a versatile embedding algorithm with advanced capabilities as a key enabler. The main features of the architecture include i) efficient and multi-purpose service embedding algorithms which can be implemented based on graph models, ii) inherent multidomain support, iii) programmable aggregation of different resources, iv) information hiding together with flexible delegation of certain requirements enabling multi-operator use-cases, and v) support for legacy technologies. Second, we present our proof-of-concept prototype implementing the proposed system. Third, we establish a dedicated test environment spanning across multiple European sites encompassing sandbox environments from both operators and the academia in order to evaluate the operation of the system. Dedicated experiments confirm the feasibility and good scalability of the whole framework.
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