Proteasome Inhibitors (PI) have now become the cornerstone of treatment of multiple myeloma (MM). Carfilzomib has been demonstrated to cause more frequent cardiovascular side effects such as dyspnea, ...hypertension, and heart failure. Recent pre-clinical studies have investigated the effects of proteasome on myocardial and vascular cells, but the pathogenic mechanism underlying the effects of proteasome inhibition on these cells is poorly understood. We reviewed the evidence from clinical trials, post-hoc analysis and small observational studies currently available and summarized the data from experimental, focusing on the pathogenic mechanisms potentially implicated in the cardiovascular toxicity of proteasome inhibitor, particularly of carfilzomib that is most responsible for cardiovascular side effects. Finally, we tried to suggest future perspectives for diagnostic and therapeutic approach to this type of cardiovascular damage.
It has been widely reported that the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) attaches human cells by using the Angiotensin Converting Enzyme 2 (ACE2) receptor, but vascular ...impairment described during coronavirus disease 2019 (COVID-19) infection is primarily due to the direct involvement of the endothelial cells by the virus or secondarily to the inflammatory host response is currently unknown. We therefore aimed to demonstrate in vivo the presence of endothelial dysfunction in six COVID-19 patients without cardiovascular risk factors or pre-existing cardiac condition, using the Endo-PAT 2000, a device able to measure endothelial vasodilation function in a rapid and non-invasive way. Four patients were positive for endothelial dysfunction, with RHI values between 1.13-1.56 (average value 1.32, normal values >1.67); in one of the two negative patients the reported RHI value was slightly above the cutoff (1.72). Our findings confirm that COVID-19 patients are at higher risk of developing endothelial dysfunction. In addition, our results demonstrate that endothelial impairment may occur even in the absence of cardiovascular risk factors.
Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of multiple myeloma. Besides heart failure, angina and myocardial ischemia occurred following administration of CFZ, which is ...not contraindicated in patients with recent myocardial infarction/unstable angina excluded from the safety trials.
To test the effects of CFZ (10−9 to 10−7mol/L) on vascular tone and reactivity in the isolated rabbit heart and aorta.
CFZ administered by bolus injection to the isolated heart increased coronary perfusion pressure (CPP) at all tested concentrations and mildly raised left ventricular pressure and heart rate, only at the highest concentration. Addition of CFZ directly into the organ bath increased the basal tone of isolated aortic strips with contraction plateau reached after 10min. This spasmogenic effect doubled following ablation of the endothelium. Pretreatment with CFZ amplified the vasospastic action exerted by KCl, noradrenaline (NA) and angiotensin II (A) on aortic strips, and impaired vasodilation following administration of nitroglycerin (NTG) and nifedipine (NFP) on the contraction plateau induced by KCl, NA and A. Aortic strips pretreated with CFZ exhibited impaired relaxation, as compared to untreated strips, following administration of acetylcholine (Ach), an endothelium-dependent vasodilating agent, on the plateau of NA contraction (p<0.05).
CFZ increased CPP, resting vasoconstricting tone and the spasmogenic effect of different agents. Preincubation with CFZ decreased the anti-spasmogenic activity of NTG and NFP, as well as reduced by over 50% the vasodilating effect of Ach, suggesting that CFZ can impair vasodilation via an endothelium dependent mechanism. Further studies are warranted to establish its clinical safety in patients with known CAD and prior history of coronary spasm.
•In the isolated aorta, carfilzomib increased basal tone and vasospastic action of KCl, noradrenaline and angiotensin II.•In the isolated aorta, carfilzomib impaired the anti-spasmogenic activity of nitroglycerin, nifedipine and acetylcholine.•In the isolated heart, carfilzomib increased coronary perfusion pressure, and mildly left ventricular pressure and heart rate.
Carfilzomib is a new chemotherapeutic agent used for the treatment of multiple myeloma. Our study shows that carfilzomib increases coronary perfusion pressure, resting vasoconstricting tone, and the spasmogenic effect of noradrenaline and angiotensin II, while it curbs the vasodilatory action of nitroglycerine and nifedipine. Our findings are relevant to human health as they warrant caution in the use of carfilzomib in elderly patients with cardiovascular risk factors and, even more importantly, in those with preexisting heart conditions, who are also eligible to receive carfilzomib, even though they were excluded from the safety trials, based on which carfilzomib use was approved.
Heart failure (HF) is a clinical syndrome defined by specific symptoms and signs due to structural and/or functional heart abnormalities, which lead to inadequate cardiac output and/or increased ...intraventricular filling pressure. Importantly, HF becomes progressively a multisystemic disease. However, in August 2021, the European Society of Cardiology published the new Guidelines for the diagnosis and treatment of acute and chronic HF, according to which the left ventricular ejection fraction (LVEF) continues to represent the pivotal parameter for HF patients' evaluation, risk stratification and therapeutic management despite its limitations are well known. Indeed, HF has a complex pathophysiology because it first involves the heart, progressively becoming a multisystemic disease, leading to multiorgan failure and death. In these terms, HF is comparable to cancer. As for cancer, surviving, morbidity and hospitalisation are related not only to the primary neoplastic mass but mainly to the metastatic involvement. In HF, multiorgan involvement has a great impact on prognosis, and multiorgan protective therapies are equally important as conventional cardioprotective therapies. In the light of these considerations, a revision of the HF concept is needed, starting from its definition up to its therapy, to overcome the old and simplistic HF perspective.
Many patients with heart failure with preserved ejection fraction (HFpEF) are women. Exploring mechanisms underlying the sex differences may improve our understanding of the pathophysiology of HFpEF. ...Studies focusing on sex differences in circulating proteins in HFpEF patients are scarce.
A total of 415 proteins were analyzed in 392 HFpEF patients included in The Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure study (MEDIA-DHF). Sex differences in these proteins were assessed using adjusted logistic regression analyses. The associations between candidate proteins and cardiovascular (CV) death or CV hospitalization (with sex interaction) were assessed using Cox regression models.
We found 9 proteins to be differentially expressed between female and male patients. Women expressed more LPL and PLIN1, which are markers of lipid metabolism; more LHB, IGFBP3, and IL1RL2 as markers of transcriptional regulation; and more Ep-CAM as marker of hemostasis. Women expressed less MMP-3, which is a marker associated with extracellular matrix organization; less NRP1, which is associated with developmental processes; and less ACE2, which is related to metabolism. Sex was not associated with the study outcomes (adj. HR 1.48, 95% CI 0.83-2.63), p = 0.18.
In chronic HFpEF, assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients. These findings may help further investigations into potential pathophysiological processes contributing to HFpEF.
The combination of risk stratification by assessment of conventional risk factors for cardiovascular disease (CVD) with not only a morphological assessment of vascular damage (such as carotid ...ultrasound examination) but also vascular function tests may be a useful strategy for the management of CVD and its related risk factors. Endothelial dysfunction is present in a great variety of pathological conditions: it is considered the first alteration of vascular function in atherosclerosis and one of the phenomena involved in the progression of heart failure. Assessing endothelial function with noninvasive methods could have a central role for evaluation of treatment, prognostic stratification, and pharmacological studies in CVD. In this review, we focus on noninvasive techniques that have recently become available to assess endothelial function and express the possible clinical role in different clinical settings.
La miocardite acuta è una rara ma clinicamente significativa potenziale complicanza della malattia da coronavirus 2019 (COVID-19), causata dal virus della sindrome respiratoria acuta grave ...coronavirus 2 (SARS-CoV-2). La miocardite COVID-19 correlata sembra avere meccanismi fisiopatologici e caratteristiche infiammatorie peculiari. Recenti studi hanno significativamente contribuito alla comprensione di prevalenza, caratteristiche cliniche e significato prognostico della patologia, mediante utilizzo sistematico di risonanza magnetica nucleare cardiaca e l’analisi di ampie popolazioni di pazienti ospedalizzati per COVID-19. Sono inoltre disponibili i risultati di studi che hanno valutato la sicurezza del ritorno all’attività sportiva dopo COVID-19 e il rischio di miocardite correlata a vaccinazione COVID19. La nostra revisione si propone di riassumere le nuove evidenze a tal riguardo.
The purpose of this study is to evaluate long-term effects of spironolactone, an affordable and widely used aldosterone receptor blocker, in patients with heart failure (HF) and mild or no symptoms.
...The study is a single-blind, placebo-controlled, blinded endpoint, randomized study. Patients with New York Heart Association (NYHA) classes I to II HF and left ventricular ejection fraction < 40% were randomized to spironolactone or placebo in addition to optimal therapy. The primary endpoint was the composite of death from any cause or cardiovascular hospitalization.
A total of 130 patients were randomized to spironolactone (n = 65) or placebo (n = 65). Patients on spironolactone had a better event-free survival for cardiovascular death or cardiovascular hospitalizations and for cardiovascular hospitalizations alone. At multivariable analysis, only spironolactone therapy, left ventricular ejection fraction and serum creatinine levels had an independent prognostic value for the combined endpoint, whereas only spironolactone therapy and serum creatinine levels had an independent prognostic value for cardiovascular hospitalizations alone.
Administration of spironolactone reduced the composite of death and cardiovascular hospitalization in patients with NYHA classes I to II HF. These results suggest that spironolactone could be beneficial when administered on top of optimal therapy among patients with HF and mild or no symptoms.
Recent data suggest that n-3 PUFA exert beneficial effects on endothelial progenitor cell (EPC) biology. We sought to investigate whether these effects might be mediated by enhanced EPC in vitro ...function and/or in vivo bioavailability.
CACs and late-outgrowth EPCs were isolated from peripheral blood mononuclear cells obtained from 12 donor buffy-coats. The effect of n-3 PUFA (EPA:DHA = 0.9:1.5; 9 μM EPA plus 15 μM DHA) was tested on CAC/EPC viability, function (tube-formation) and pro-inflammatory molecule expression. Circulating EPC (cells positive for CD34, CD133 and kinase insert domain receptor - KDR cell-surface antigens by flow cytometry) number was evaluated in 20 healthy subjects (10 F/10 M, 32 ± 5 years), randomized to receive 4 mackerel or sardine portions per week for 6 weeks followed by a 6 week free-diet period. N-3 PUFA improved CAC and late-outgrowth EPC viability (p < 0.05) and the capacity to form tube-like structures in CACs (+38%; p < 0.05) and late-outgrowth EPCs (+15%; p < 0.05). ICAM-1 expression was reduced in both CACs (p < 0.05) and late-outgrowth EPCs (p < 0.05) and VCAM-1 in late-outgrowth EPCs (p < 0.005). N-3 PUFA significantly decreased TNF-α and MCP-1 expression in CACs and IL-8, TNF-α and MCP-1 in late-outgrowth EPCs (p < 0.05). Circulating EPC number significantly improved after 6 weeks of a fish-enriched diet (p < 0.01) and returned to baseline levels after a 6 week free-diet period (p < 0.01). Plasma EPA levels were independently and positively associated with EPC levels (p < 0.005).
Our findings support the case of a beneficiary role played by n-3 PUFA in EPC function and bioavailability.
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