Cardiovascular toxicity from therapies for light chain amyloidosis

: Amyloid light-chain (AL) amyloidosis is a hematological disorder characterized by abnormal proliferation of a plasma cell clone producing monoclonal free light chains that misfold and aggregate into insoluble fibrils in various tissues. Cardiac involvement is a common feature leading to restrictive cardiomyopathy and poor prognosis. Current first-line treatments aim at achieving hematological response by targeting the plasma cell clones, and these have been adapted from multiple myeloma therapy. Patients with AL amyloidosis often exhibit multiorgan involvement, making them susceptible to cancer therapy-related cardiovascular toxicity. Managing AL amyloidosis is a complex issue that requires enhanced knowledge of the cardio-oncological implications of hematological treatments. Future research should focus on implementing and validating primary and secondary prevention strategies and understanding the biochemical basis of oncological therapy-related damage to mitigate cardiovascular toxicity

Electrocardiographic abnormalities in patients with cardiomyopathies

Abnormalities in impulse generation and transmission are among the first signs of cardiac remodeling in cardiomyopathies. Accordingly, 12-lead electrocardiogram (ECG) of patients with cardiomyopathies may show multiple abnormalities. Some findings are suggestive of specific disorders, such as the discrepancy between QRS voltages and left ventricular (LV) mass for cardiac amyloidosis or the inverted T waves in the right precordial leads for arrhythmogenic cardiomyopathy. Other findings are less sensitive and/or specific, but may orient toward a specific diagnosis in a patient with a specific phenotype, such as an increased LV wall thickness or a dilated LV. A “cardiomyopathy-oriented” mindset to ECG reading is important to detect the possible signs of an underlying cardiomyopathy and to interpret correctly the meaning of these alterations, which differs in patients with cardiomyopathies or other conditions

Cardiovascular toxicity from therapies for light chain amyloidosis

Amyloid light-chain (AL) amyloidosis is a hematological disorder characterized by abnormal proliferation of a plasma cell clone producing monoclonal free light chains that misfold and aggregate into insoluble fibrils in various tissues. Cardiac involvement is a common feature leading to restrictive cardiomyopathy and poor prognosis. Current first-line treatments aim at achieving hematological response by targeting the plasma cell clones, and these have been adapted from multiple myeloma therapy. Patients with AL amyloidosis often exhibit multiorgan involvement, making them susceptible to cancer therapy-related cardiovascular toxicity. Managing AL amyloidosis is a complex issue that requires enhanced knowledge of the cardio-oncological implications of hematological treatments. Future research should focus on implementing and validating primary and secondary prevention strategies and understanding the biochemical basis of oncological therapy-related damage to mitigate cardiovascular toxicity

[Treatment of cardiac fibrosis: from neurohormonal antagonists to CAR-T cells]

: Cardiac fibrosis is characterized by the deposition of extracellular matrix proteins in the spaces between cardiomyocytes following both acute and chronic tissue damage events, resulting in the remodeling and stiffening of heart tissue. Fibrosis plays an important role in the pathogenesis of many cardiovascular disorders, including heart failure and myocardial infarction. Several studies have identified fibroblasts, which are induced to differentiate into myofibroblasts in response to various types of damage, as one of the most important cell types involved in the fibrotic process. There are currently no drugs with primarily antifibrotic action approved for clinical use, as the evidence of a clinical efficacy of these drugs is extremely limited, despite the numerous encouraging results from experimental studies. A new approach is represented by the use of chimeric antigen receptor T cells engineered in vivo using lipid nanoparticles containing mRNA encoding a receptor directed against the fibroblast activation protein, expressed by activated cardiac fibroblasts. This strategy has proved to be safe and effective in reducing myocardial fibrosis and improving cardiac function in mouse models of cardiac fibrosis. Clinical studies are required to test this novel approach in humans

Biomarkers of HFpEF: Natriuretic Peptides, High-Sensitivity Troponins and Beyond

Heart failure (HF) is a significant cause of morbidity and mortality worldwide. HF with preserved ejection fraction (HFpEF) is a complex syndrome, often participated by several cardiac and extracardiac conditions, including chronic kidney disease, pulmonary disease, anaemia and advanced age. Circulating biomarkers reflecting pathophysiological pathways involved in HFpEF development and progression may assist clinicians in early diagnosis and management of this condition. Natriuretic peptides (NPs) are cardioprotective hormones released by cardiomyocytes in response to pressure or volume overload and in response to activation of neuro-endocrine-immune system. The relevance of B-type NP (BNP) and N-terminal pro-B-type NP (NT-proBNP) for diagnosis and risk stratification has been extensively demonstrated, and these biomarkers are emerging tools for population screening and as guides to the start of treatment in subclinical HF. On the contrary, conflicting evidence exists on the value of NPs to guide HF therapy. Among the other biomarkers, high-sensitivity troponins and soluble suppression of tumorigenesis-2 are the most promising biomarkers for risk stratification, predicting outcome independently from NPs. In this review, some novel biomarkers are being tested in such clinical scenario, more tightly linked to specific pathophysiological processes of cardiac damage

Monoclonal antibodies and amyloid removal as a therapeutic strategy for cardiac amyloidosis

: Cardiac amyloidosis (CA) is an infiltrative disease caused by progressive deposition of amyloid fibres in the heart. The most common forms include immunoglobulin light-chain and transthyretin amyloidosis. Current therapies for CA either stabilize or block the production of amyloidogenic precursors, preventing further amyloid deposition. This approach, while reducing cell damage and disease progression, does not target pre-existing amyloid deposits. Conversely, amyloid removal might stimulate functional recovery of the affected organ, thus improving quality of life and survival. A therapeutic strategy based on monoclonal antibodies capable of selectively binding amyloid deposits and inducing their removal has recently been tested in various clinical trial, with promising results, and could represent a key treatment for CA in the near future

Treatment of cardiac fibrosis : from neuro-hormonal inhibitors to CAR-T cell therapy

Cardiac fibrosis is characterized by the deposition of extracellular matrix proteins in the spaces between cardiomyocytes following both acute and chronic tissue damage events, resulting in the remodeling and stiffening of heart tissue. Fibrosis plays an important role in the pathogenesis of many cardiovascular disorders, including heart failure and myocardial infarction. Several studies have identified fibroblasts, which are induced to differentiate into myofibroblasts in response to various types of damage, as the most important cell types involved in the fibrotic process. Some drugs, such as inhibitors of the renin-angiotensin-aldosterone system, have been shown to be effective in reducing cardiac fibrosis. There are currently no drugs with primarily anti-fibrotic action approved for clinical use, as well as the evidence of a clinical efficacy of these drugs is extremely limited, despite the numerous encouraging results from experimental studies. A new approach is represented by the use of CAR-T cells engineered in vivo using lipid nanoparticles containing mRNA coding for a receptor directed against the FAP protein, expressed by cardiac myofibroblasts. This strategy has proved to be safe and effective in reducing myocardial fibrosis and improving cardiac function in mouse models of cardiac fibrosis. Clinical studies are required to test this novel approach in humans

Transthyretin Stabilizers and Seeding Inhibitors as Therapies for Amyloid Transthyretin Cardiomyopathy

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive and increasingly recognized cause of heart failure which is associated with high mortality and morbidity. ATTR-CM is characterized by the misfolding of TTR monomers and their deposition within the myocardium as amyloid fibrils. The standard of care for ATTR-CM consists of TTR-stabilizing ligands, such as tafamidis, which aim at maintaining the native structure of TTR tetramers, thus preventing amyloid aggregation. However, their efficacy in advanced-staged disease and after long-term treatment is still a source of concern, suggesting the existence of other pathogenetic factors. Indeed, pre-formed fibrils present in the tissue can further accelerate amyloid aggregation in a self-propagating process known as “amyloid seeding”. The inhibition of amyloidogenesis through TTR stabilizers combined with anti-seeding peptides may represent a novel strategy with additional benefits over current therapies. Finally, the role of stabilizing ligands needs to be reassessed in view of the promising results derived from trials which have evaluated alternative strategies, such as TTR silencers and immunological amyloid disruptors

Machiavelli: tempo e conflitto

Il carattere perturbante del pensiero di Machiavelli, che ne ha sovradeterminato l'interpretazione dalle origini cinquecentesche del machiavellismo fino alla critica novecentesca di Leo Strauss, nasce non soltanto dalla nota elisione di qualsiasi regola morale dal campo della politica, ma anche, se non soprattutto, dallo spazio assegnato nei testi machiavelliani alla dimensione del conflitto; uno spazio che acquisisce una valenza positiva (ancorch\ue9 problematica), in contrapposizione tanto a una tradizione che individuava nello scioglimento "armonico" delle discordie interne ed esterne il fine ultimo della politica, quanto, nei secoli successivi, al progetto di un ordine che neutralizzasse ogni elemento polemico della societ\ue0. Questa problematica centralit\ue0 del "conflittualismo" machiavelliano emerge in piena evidenza quando venga ricondotta alla concezione della temporalit\ue0: una concezione la cui originalit\ue0 \ue8 stata oggetto privilegiato di alcune tra le pi\uf9 importanti letture novecentesche, da Gramsci ad Althusser fino a J.G.A. Pocock, che tutte hanno evidenziato, seppure da prospettive e con esiti assai diversi, la continua messa in discussione da parte del fiorentino di una presunta unicit\ue0 del tempo della politica, e con essa dell'unit\ue0 di un ordine necessario e trascendente rispetto alla contingenza dell'agire umano. \uc8 su questi intrecci di "tempo" e "conflitto" che si interrogano gli interventi raccolti nel volume