Sex-Related Differences in Dilated Cardiomyopathy with a Focus on Cardiac Dysfunction in Oncology.

PURPOSE OF REVIEW: The aim of this report is to describe the main aspects of sex-related differences in non-ischemic dilated cardiomyopathies (DCM), focusing on chemotherapy-induced heart failure (HF) and investigating the possible therapeutic implications and clinical management applications in the era of personalized medicine. RECENT FINDINGS: In cardio-oncology, molecular and multimodality imaging studies confirm that sex differences do exist, affecting the therapeutic cardioprotective strategies and, therefore, the long-term outcomes. Interestingly, compelling evidences suggest that sex-specific characteristics in drug toxicity might predict differences in the therapeutic response, most likely due to the tangled interplay between cancer and HF, which probably share common underlying mechanisms. Cardiovascular diseases show many sex-related differences in prevalence, etiology, phenotype expression, and outcomes. Complex molecular mechanisms underlie this diverse pathological manifestations, from sex-determined differential gene expression to sex hormone interaction with their receptors in the heart. Non-ischemic DCM is an umbrella definition that incorporates several etiologies, including chemotherapy-induced cardiomyopathies. The role of sex as a risk factor for cardiotoxicity is poorly explored. However, understanding the various features of disease manifestation and outcomes is of paramount importance for a prompt and tailored evaluation.

Oral anticoagulants in fragile patients with percutaneous endoscopic gastrostomy and atrial fibrillation: the ORIGAMI pilot investigation.

BACKGROUND: Extensive data support the superior safety without any trade-off in efficacy of direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKA) in patients with nonvalvular atrial fibrillation, deep venous thrombosis or pulmonary embolism. Whether DOACs may be successfully used to treat complex and fragile patients with percutaneous endoscopic gastrostomy (PEG) remains to be proven. The purpose of this pilot study was to evaluate the feasibility, anticoagulant effect, and preliminary safety/efficacy profile of edoxaban administered via PEG in patients with an indication for long-term oral anticoagulation. METHODS: In this prospective, single-arm, pilot study, 12 patients with PEG and guideline-recommended indication for anticoagulation for nonvalvular atrial fibrillation were prospectively enrolled. Crushed edoxaban at approved doses was administered via PEG. Quantitative measures of edoxaban's antifactor Xa activity were performed at steady state. Thromboembolic and bleeding events were assessed at one-month follow-up. RESULTS: Steady state edoxaban plasma levels were at therapeutic range in all patients; mean plasma concentration was 208.5 (±78.6) ng/mL. At one month follow-up, none had suffered a thromboembolic event; one developed minor bleeding, and one died from non-cardiovascular death, owing to sudden worsening of a pre-existing underlying severe condition. CONCLUSIONS: In this pilot investigation, we report for the first time that crushed edoxaban, administered at approved doses through PEG in fragile and complex patients, is feasible, results in therapeutic edoxaban concentrations, and is apparently effective and safe.

Angiotensin receptor-neprilysin inhibitor in symptomatic patients with Duchenne dilated cardiomyopathy: A primetime.

AIMS: Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder, characterized by significant long-term cardiac involvement. Dilated cardiomyopathy (DCM) is the main cause of death in DMD, and angiotensin-converting enzyme inhibitors (ACEi) and beta-blockers (BB) are first-line treatments in DCM. It is unknown whether angiotensin receptor-neprilysin inhibitor (ARNi) could provide greater benefits in this setting. Our aim is to assess whether ARNi use may prevent deterioration in ejection fraction (EF) or is associated with EF improvement compared with ACEi in DMD patients with heart failure and to report the tolerability of ARNi in this group of patients. METHODS AND RESULTS: We followed 22 DMD patients, 6 of them with an EF < 40% and 16 with an EF > 40%. The first group received ARNi on top of BB, while the control group started or continued first-line therapy with ACEi ± BB. From December 2016 to December 2021, we recorded EF values at baseline and at follow-up, comparing EF changes. Median follow-up was 7 months (interquartile range 4.7-9.1). At baseline, the mean of EF (%) in the ARNi group was 31 ± 2%, while it was 59 ± 9% in the control group. At follow-up, we recorded an EF improvement in the ARNi group (38 ± 6%, P-value < 0.05). Among controls, EF at follow-up was substantially unchanged from baseline. CONCLUSIONS: Our data suggest that the use of ARNi in DMD patients with DCM and an EF < 40% might be associated with an EF improvement and a safe tolerability profile.

Focus on the road to modelling cardiomyopathy in muscular dystrophy.

Alterations in the DMD gene, which codes for the protein dystrophin, cause forms of dystrophinopathies such as Duchenne muscular dystrophy, an X-linked disease. Cardiomyopathy linked to DMD mutations is becoming the leading cause of death in patients with dystrophinopathy. Since phenotypic pathophysiological mechanisms are not fully understood, the improvement and development of new disease models, considering their relative advantages and disadvantages, is essential. The application of genetic engineering approaches on induced pluripotent stem cells, such as gene-editing technology, enables the development of physiologically relevant human cell models for in vitro dystrophinopathy studies. The combination of induced pluripotent stem cells-derived cardiovascular cell types and 3D bioprinting technologies hold great promise for the study of dystrophin-linked cardiomyopathy. This combined approach enables the assessment of responses to physical or chemical stimuli, and the influence of pharmaceutical approaches. The critical objective of in vitro microphysiological systems is to more accurately reproduce the microenvironment observed in vivo. Ground-breaking methodology involving the connection of multiple microphysiological systems comprised of different tissues would represent a move toward precision body-on-chip disease modelling could lead to a critical expansion in what is known about inter-organ responses to disease and novel therapies that have the potential to replace animal models. In this review, we will focus on the generation, development, and application of current cellular, animal, and potential for bio-printed models, in the study of the pathophysiological mechanisms underlying dystrophin-linked cardiomyopathy in the direction of personalized medicine.

Feasibility, effectiveness, and safety of edoxaban administration through percutaneous endoscopic gastrostomy: 12-months follow up of the ORIGAMI study.

Background and aims: Edoxaban proved to be safe and effective also in fragile patients, but its administration through percutaneous endoscopic gastrostomy (PEG) has not been previously investigated. The purpose of this study was to evaluate the feasibility and the preliminary safety and efficacy profiles of edoxaban administered via PEG in patients with an indication for long-term oral anticoagulation. Methods: ORIGAMI was a prospective, single-arm, observational study (NCT04271293). Patients with PEG and an indication for long-term anticoagulation were prospectively enrolled. Crushed edoxaban at approved doses was administered via PEG. The primary endpoint was the composite of cardio-embolic events consisting of ischemic stroke, systemic embolism, or symptomatic deep venous thrombosis/pulmonary embolism (DVT/PE). Secondary endpoints were the number of bleeding events and edoxaban plasma concentrations at steady state. We here report the 12-month results. Results: A total of 12 patients were enrolled. The main indication for PEG implantation was amyotrophic lateral sclerosis (10/12). The primary endpoint of cardio-embolic events did not occur in any patients at 12 months. All patients were in the therapeutic range of steady-state edoxaban plasma levels. Three minor bleedings were observed, while no major bleedings occurred during the observational period. A total of five patients died. All deaths were from non-cardiovascular causes and were consistent with the natural history of the pre-existing severe disease. Conclusion: Our study suggests that edoxaban administration via PEG is feasible and appears safe and effective in fragile, comorbid patients, resulting in therapeutic plasma concentrations of edoxaban. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT04271293].

Gender-differences in antithrombotic therapy across the spectrum of ischemic heart disease: Time to tackle the Yentl syndrome?

The incidence and clinical presentation of ischemic heart disease (IHD), as well as thrombotic and bleeding risks, appear to differ between genders. Compared with men, women feature an increased thrombotic risk, probably related to an increased platelet reactivity, higher level of coagulation factors, and sex-associated unique cardiovascular risk factors, such as pregnancy-related (i.e., pre-eclampsia and gestational diabetes), gynecological disorders (i.e., polycystic ovary syndrome, early menopause) and autoimmune or systemic inflammatory diseases. At the same time, women are also at increased risk of bleeding, due to inappropriate dosing of antithrombotic agents, smaller blood vessels, lower body weight and comorbidities, such as diabetes and chronic kidney disease. Pharmacological strategies focused on the personalization of antithrombotic treatment may, therefore, be particularly appealing in women in light of their higher bleeding and ischemic risks. Paradoxically, although women represent a large proportion of cardiovascular patients in our practice, adequate high-quality clinical trial data on women remain scarce and inadequate to guide decision-making processes. As a result, IHD in women tends to be understudied, underdiagnosed and undertreated, a phenomenon known as a "Yentl syndrome." It is, therefore, compelling for the scientific community to embark on dedicated clinical trials to address underrepresentation of women and to acquire evidence-based knowledge in the personalization of antithrombotic therapy in women.

Colchicine in ischemic heart disease: the good, the bad and the ugly.

Inflammation is the main pathophysiological process involved in atherosclerotic plaque formation, progression, instability, and healing during the evolution of coronary artery disease (CAD). The use of colchicine, a drug used for decades in non-ischemic cardiovascular (CV) diseases and/or systemic inflammatory conditions, stimulated new perspectives on its potential application in patients with CAD. Previous mechanistic and preclinical studies revealed anti-inflammatory and immunomodulatory effects of colchicine exerted through its principal mechanism of microtubule polymerization inhibition, however, other pleiotropic effects beneficial to the CV system were observed such as inhibition of platelet aggregation and suppression of endothelial proliferation. In randomized double-blinded clinical trials informing our clinical practice, low doses of colchicine were associated with the significant reduction of cardiovascular events in patients with stable CAD and chronic coronary syndrome (CCS) while in patients with a recent acute coronary syndrome (ACS), early initiation of colchicine treatment significantly reduced major adverse CV events (MACE). On the other hand, the safety profile of colchicine and its potential causal relationship to the observed increase in non-CV deaths warrants further investigation. For these reasons, postulates of precision medicine and patient-tailored approach with regards to benefits and harms of colchicine treatment should be employed at all times due to potential toxicity of colchicine as well as the currently unresolved signal of harm concerning non-CV mortality. The main goal of this review is to provide a balanced, critical, and comprehensive evaluation of currently available evidence with respect to colchicine use in the setting of CAD.

ORal anticoagulants In fraGile patients with percutAneous endoscopic gastrostoMy and atrIal fibrillation: the (ORIGAMI) study.

AIMS: The ORal anticoagulants In fraGile patients with percutAneous endoscopic gastrostoMy and atrIal fibrillation (ORIGAMI) study investigates the safety and efficacy of Edoxaban administered via PEG in patients with atrial fibrillation and a clinical indication for a long-term anticoagulation. DESIGN: In this prospective, single-centre observational study, 12 PEG-treated patients with indication to anticoagulation will receive edoxaban via PEG and will be followed up to 6 months. Plasma antifactor Xa activity and edoxaban concentrations will be assessed. Thromboembolic (ischaemic stroke, systemic embolism, venous thromboembolism) and bleeding events (Bleeding Academic Research Consortium and Thrombolysis in Myocardial Infarction) will be recorded at 1 and 6 months. PRELIMINARY RESULTS: A retrospective analysis of five atrial fibrillation cases undergoing PEG implantation at our Institution who received edoxaban via PEG showed plasma anti-FXa levels at a steady state of 146 ±â€Š15 ng/ml, without major adverse event at a mean follow-up of 6 months. CONCLUSION: ORIGAMI prospectively investigates PEG-administration of edoxaban in PEG-treated patients requiring long-term anticoagulation. Our preliminary retrospective data support this route of DOAC administration. CLINICALTRIALSGOV IDENTIFIER: NCT04271293.