Background: Many evidences show that elevated plasma levels of uric acid (UA) are associated to the increased risk of developing athero-thrombotic cardiovascular events. Hyperuricemia is a risk factors for endothelial dysfunction (ED). ED is involved in the pathophysiology of athero-thrombosis since dysfunctional cells lose their physiological, antithrombotic properties. We have investigated whether UA might promote ED by modulating the TF/TFPI balance finally changing the antithrombotic characteristics of endothelial cells. Methods: Human Umbilical Vein Endothelial Cells (HUVEC) were incubated with increasing doses of UA (up to 9 mg/dl). TF gene and protein expression were evaluated by Real-Time PCR and Western Blot. Surface expression and procoagulant activity were assessed by FACS analysis and coagulation assay. The mRNA and protein levels of TF physiological inhibitor, TFPI were measured by Real-Time PCR and Western Blot. The role of inflammasome and of NF-B as possible mechanism(s) of action of the UA on TF/TFPI balance were also investigated. Results: UA significantly increased TF gene and protein levels, surface expression and procoagulant activity. In parallel, TFPI levels were significantly reduced. The NF-κB pathways appeared involved in modulating these phenomena. Additionally, also inflammasome might play a role. Conclusions: The present in vitro study, shows that one of the mechanisms by which high levels of UA contributes to ED might be the imbalance between TF/TFPI levels in endothelial cells, shifting them to a non-physiological, pro-thrombotic phenotype. These UA effects might hypothetically explain, at least in part, the relationship observed between elevated plasma levels of UA and cardiovascular events.
Background We previously demonstrated that an Italian family affected by a severe dilated cardiomyopathy (DCM) with history of sudden deaths at young age, carried a mutation in the Lmna gene encoding for a truncated variant of the Lamin A/C protein (LMNA), R321X. When expressed in heterologous systems, such variant accumulates into the endoplasmic reticulum (ER), inducing the activation of the PERK-CHOP pathway of the unfolded protein response (UPR), ER dysfunction and increased rate of apoptosis. The aim of this work was to analyze whether targeting the UPR can be used to revert the ER dysfunction associated with LMNA R321X expression in HL-1 cardiac cells. Methods HL-1 cardiomyocytes stably expressing LMNA R321X were used to assess the ability of 3 different drugs targeting the UPR, salubrinal, guanabenz and empagliflozin to rescue ER stress and dysfunction. In these cells, the state of activation of both the UPR and the pro-apoptotic pathway were analyzed monitoring the expression levels of phospho-PERK, phospho-eIF2α, ATF4, CHOP and PARP-CL. In addition, we measured ER-dependent intracellular Ca2+ dynamics as indicator of proper ER functionality. Results We found that salubrinal and guanabenz increased the expression levels of phospho-eIF2α and downregulated the apoptosis markers CHOP and PARP-CL in LMNA R321X-cardiomyocytes, maintaining the so-called adaptive UPR. These drugs also restored ER ability to handle Ca2+ in these cardiomyocytes. Interestingly, we found that empagliflozin downregulated the apoptosis markers CHOP and PARP-CL shutting down the UPR itself through the inhibition of PERK phosphorylation in LMNA R321X-cardiomyocytes. Furthermore, upon empagliflozin treatment, ER homeostasis, in terms of ER ability to store and release intracellular Ca2+ was also restored in these cardiomyocytes. Conclusions We provided evidence that the different drugs, although interfering with different steps of the UPR, were able to counteract pro-apoptotic processes and to preserve the ER homeostasis in R321X LMNA-cardiomyocytes. Of note, two of the tested drugs, guanabenz and empagliflozin, are already used in the clinical practice, thus providing preclinical evidence for ready-to-use therapies in patients affected by the LMNA R321X associated cardiomyocytes.
Background: Isotretinoin or 13-cis-retinoic acid (RA) is one of the most effective and widely used drug for the treatment of severe acne vulgaris. Despite deemed safe, no definite consensus has been reached on the cardiovascular risk of RA derivatives. We describe the first case of concomitant dilated cardiomyopathy (DCM) and renal infarction after 5 months of isotretinoin use in a previously healthy 18-years old man. Case Summary: An18-years-old man, with history of acne vulgaris, presented in August 2021 to our emergency department because of left iliac fossa pain and effort dyspnea. Computed tomography scan revealed left renal infarction and echocardiogram demonstrated global left ventricular (LV) dilatation with severely reduced LV-ejection fraction (LVEF: 29%). Coronary artery disease, autoimmune, infective, or heritable causes of DCM were ruled out. Cardiac magnetic resonance evidenced LV circumferential mid-wall late gadolinium enhancement and ECG monitoring revealed several non-sustained ventricular tachycardia episodes. Thus, Bisoprolol, Sacubitril/Valsartan, and Eplerenone were started and up titrated until maximum tolerated doses, with only poor LVEF improvement. Conclusion: Our case aims to raise awareness on rare life-threatening cardiovascular events associated with isotretinoin use for the treatment of severe acne in young patients. To the best of our knowledge, this is the first described case of renal thromboembolism and DCM requiring S-ICD implantation and cardiac transplant program listing occurring in the course of isotretinoin treatment.
Isotretinoin or 13-cis-retinoic acid (RA) is one of the most effective and widely used drugs for the treatment of severe acne vulgaris. Despite being deemed safe, no definite consensus has been reached on the cardiovascular risk of RA derivatives. We report a case of heart failure due to dilated cardiomyopathy (DCM) and concomitant renal infarction occurring after 5 months of isotretinoin use in a previously healthy 18-year-old male. The patient, with a history of acne vulgaris, presented to our emergency department with left iliac fossa pain and effort dyspnea. A trans-thoracic echocardiogram showed DCM and severely reduced left ventricle ejection fraction (LVEF: 29%). During hospitalization, a total body computed tomography (CT) showed an ischemic lesion in the left kidney. Ischemic, autoimmune, infective, and heritable causes of DCM were ruled out. Cardiac magnetic resonance (CMR) evidenced LV circumferential mid-wall late gadolinium enhancement. Heart failure therapy was promptly started and up-titrated, but only poor LVEF improvement was detected overtime. Our case aims to raise awareness on rare life-threatening cardiovascular events possibly associated with isotretinoin use. To the best of our knowledge, this is the first described case of renal thromboembolism and severe DCM leading to implantable cardioverter-defibrillator (ICD) implantation occurring during isotretinoin treatment.
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