Papers by Joaquin De Haro
Clinical Medicine Insights: Cardiology, 2016
IntroductIon: Critical limb ischemia (CLI) is defined by ischemic rest pain, tissue loss, or both... more IntroductIon: Critical limb ischemia (CLI) is defined by ischemic rest pain, tissue loss, or both, secondary to arterial insufficiency, and its prevalence is increasing mainly as a result of the worldwide high prevalence of diabetes. Currently, there are no available conclusive data on the efficacy of any coadjuvant therapy after revascularization procedure benefiting amputation and patency rates. Macitentan is an orally active dual endothelin (ET) receptor antagonist that may contribute to reduce the amputation rate and improve revascularization patency in CLI. Methods/desIgn: REVASC is a proposed pilot, open-label, controlled, randomized, single-center clinical double-blind trial to be conducted in Spain on a study population of European patients with CLI, which will compare the clinical outcomes and cost-effectiveness of macitentan coadjuvant treatment after limb revascularization with the standard antiplatelet treatment strategy for severe limb ischemia. Patients are randomized 1:1 to receive macitentan or placebo for 12 weeks. The primary clinical end point will be amputation-free survival rate at 12 months, defined as the time to major (above the ankle) amputation for the index (trial) limb or death from any cause, whichever comes first. Secondary outcomes include overall survival, quality of life, in-hospital mortality and morbidity, repeat interventions, healing of tissue loss, and hemodynamic changes following revascularization. Sample size is estimated as 120 patients. The economic analysis will consist of two components: a "within-study" analysis, which will be based on study end points; and a "model-based" analysis, which will extrapolate and compare costs and effects likely to accrue beyond the study follow-up period. dIscussIon: The REVASC trial is designed to be pragmatic and represents current practice of the real-world population management after limb revascularization for CLI due to atherosclerosis. Current evidence does not support any coadjuvant treatment. A new pathway of treatment may be opened with the use of ET receptor antagonists in these patients.
There is evidence to suggest that endothelin (ET-1) is involved in the pathophysiology of periphe... more There is evidence to suggest that endothelin (ET-1) is involved in the pathophysiology of peripheral arterial disease (PAD), contributing to atherosclerotic narrowing of the lower limb arteries as well as microvascular dysfunction. This paper summarises the evidence and discusses the potential role of a promising novel therapeutic strategy for PAD focused on ET-1 pathway modification. ET-1 pathway is involved in PAD with raised plasma levels and local sources of ET-1. More recent evidence of a potential role of ET-1 in ischaemiainduced skeletal muscle damage suggests that this may be a useful target for treatment. ET antagonism may play an adjunctive role in improving endothelial function and reducing oxidative tissue damage within the affected vessels. However, in patients with advanced atherosclerotic lesions, manipulation of the ET-1 pathway is unlikely to be of a significant benefit in terms of lesion regression and improving blood flow. Results from small clinical studies suppo...
International journal of cardiology, 2018
Journal of Vascular Surgery, 2021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Clínica e Investigación en Arteriosclerosis, 2020
INTRODUCTION AND OBJECTIVES NRP1 inflammasome is crucial in endothelial dysfunction. Platelets ar... more INTRODUCTION AND OBJECTIVES NRP1 inflammasome is crucial in endothelial dysfunction. Platelets are mandatory for the inflammation that precedes it. Aspirin could inhibit NLRP1 inflammasome in endothelial cells, and clopidogrel could also provoke a reduction in vascular inflammation. A study was carried out on the influence of platelet inflammatory inhibition by P2Y receptor inhibition versus COX enzyme inhibition on the transcription of NLRP1 inflammasome in endothelial cells. METHODS An open-label, prospective, randomised crossover study with two periods of platelet inhibition enrolled 20 healthy volunteers. They received clopidogrel 75mg/day/7days and aspirin 100mg/day/7days. A venous blood sample was collected from all participants before and after this period. Human aortic endothelial cells (HAECs) were exposed for 2h in cultures. NLRP1 gene expression was then analysed in these cultures. RESULTS HAEC cultures that were exposed to baseline plasma showed higher expression of NLRP1 than HAECs exposed to plasma after one week of aspirin or clopidogrel intake [relative quantification (RQ), 1.077±0.05 vs. 1.002±0.06; OR, 1.8; 95% CI, 1.1-2.9; P<.01 and 1.077±0.05 vs. 1.04±0.03; OR, 1.7; 95% CI, 1.2-2.6; P<.001, respectively]. NLRP1 expression in HAEC cultures exposed to plasma after one week of aspirin or clopidogrel was similar to that observed in control HAECs that was no exposed to human plasma (PBS) [RQ; 1.002±0.06 vs. 1.009±0.03; OR, 0.9; 95% CI, 0.5-1.4; P=.7, and 1.04±0.03 vs. 1.009±0.03; OR, 0.8; 95% CI, 0.3-1.2; P=.5, respectively]. No difference was observed in NLRP1 percentage reduction in HAEC after aspirin or clopidogrel exposure (3.8% vs. 2.8%, P=.3, respectively). CONCLUSIONS Platelet inhibition by P2Y pathway is similar to COX pathway in NLRP1 expression inhibition in HAECs.
European Journal of Vascular and Endovascular Surgery, 2019
European Journal of Vascular and Endovascular Surgery, 2019
European Journal of Vascular and Endovascular Surgery, 2019
Therapeutic Advances in Chronic Disease, 2018
Background: Although the management of carotid disease is well established for symptomatic lesion... more Background: Although the management of carotid disease is well established for symptomatic lesions ⩾70%, carotid revascularization for symptomatic low-grade (⩽50%) stenosis is not actually supported by data from randomized clinical trials. Such patients may occasionally have recurrent neurological symptoms despite optimal medical treatment owing to vulnerable plaques. In such cases, carotid artery stenting (CAS) may represent an option for treatment but this has not been tested in clinical trials. This study analyzed early and long-term outcomes of CAS performed in patients with low-grade symptomatic recurrent carotid stenosis. Methods: From a prospective registry of 322 carotid revascularization in symptomatic patients, 21 consecutive patients with low-grade symptomatic recurrent carotid stenosis who underwent CAS with proximal cerebral protection device Mo.Ma, after ruling out any other source of cerebral embolization, were involved in the study. All patients had suggestive eviden...
Therapeutic Advances in Cardiovascular Disease, 2018
NLRP1 and NLRP3 inflammasomes might differentially mediate the chronic inflammatory response in a... more NLRP1 and NLRP3 inflammasomes might differentially mediate the chronic inflammatory response in abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD). We measure differential relative gene expression of NLRP1 and NLRP3 inflammasomes in aortic tissues from 30 patients undergoing AAA open repair compared to aortic biopsies from 30 patients undergoing surgery to treat AOD. Aortic wall samples from autopsy without aortic disease were used as controls. NLRP3 was overexpressed in patients with AAA and AOD (RQ 1.185 ± 0.15, and 1.098 ± 0.05, respectively) compared to donors (RQ 1.001 ± 0.08) (OR 2.8, 95% CI 1.2–4.3, p < 0.05 for AAA and OR 2.1, 95% CI 1.1–3.8, p < 0.05 for AOD). NLRP1 gene expression was significantly upregulated in patients with AOD (RQ 1.197 ± 0.09). Meanwhile, NLRP1 was normal expressed in AAA (RQ 1.003 ± 0.07) as well as in autopsy aortic specimens (RQ 1.005 ± 0.11). Enhanced NLRP1 expression in AOD was even significant when compared to AAA (OR 2.3, ...
Atherosclerosis Supplements, 2010
Annals of translational medicine, 2017
International Journal of Cardiology, 2017
The American journal of cardiology, Jan 26, 2017
Carotid stenting (CAS) has been mainly offered to those patients considered at "high risk&qu... more Carotid stenting (CAS) has been mainly offered to those patients considered at "high risk" for open carotid endarterectomy based on available data from large randomized clinical trials. However, several recent studies have called medical "high risk" into question for CAS indication. The REAL-1 trial evaluated the safety and perioperative and long-term effectiveness in patients with significant carotid artery stenosis with "high-risk" criteria treated with CAS and proximal protection device (MOMA) compared with those with standard surgical-risk features. This nonrandomized double-arm registry included 125 patients (40% symptomatic), 71 (56%) with "standard-risk" and 54 (44%) with "high-risk" criteria. The primary end point was the cumulative incidence of any major adverse event, a composite of stroke, myocardial infarction, and death within 30 days after the intervention or ipsilateral stroke after 30 days and up to 4 years. There was...
International Journal of Cardiology, 2017
Journal of the American Geriatrics Society, 2016
Rodriguez-Padilla: acquisition, analysis, and interpretation of data; critical revision; final ap... more Rodriguez-Padilla: acquisition, analysis, and interpretation of data; critical revision; final approval of version to be published. de Haro: conception and design, analysis and interpretation of data, drafting the article, and critical revision for important intellectual content, final approval of version to be published. Varela: conception and design, analysis and interpretation of data, critical revision, final approval of the version to be published. Bleda: analysis and interpretation of data, critical revision, final approval of version to be published. Gonzalez-Hidalgo: analysis and interpretation of data, critical revision, final approval of version to be published. Michel: analysis and interpretation of data, critical revision, final approval of version to be published. Acin: analysis and interpretation of data, critical revision, final approval of version to be published.
Annals of Vascular Surgery, 2016
Inflammatory stress stimuli in the plasma of patients with peripheral artery disease (PAD) are ab... more Inflammatory stress stimuli in the plasma of patients with peripheral artery disease (PAD) are able to trigger the expression of NLRP1 inflammasome in human aortic endothelial cells (HAECs). Our objective was to elucidate the effect of simvastatin treatment on NLRP1 inflammasome expression in endothelial cells exposed to the plasma of PAD patients. The study included 81 patients with PAD, 24 of them treated with simvastatin (20 mg/day) and 57 without statin therapy. HAECs between passages 3 and 6 were stimulated for 2 hr using the plasma samples of the study participants. NLRP1 gene transcription of HAECs exposed to the plasma of PAD patients was quantificated. HAECs exposed to the plasma of PAD patients with simvastatin therapy showed significantly higher expression of the NLRP1 gene compared with those exposed to the plasma of PAD patients without this treatment (relative quantitation [RQ] 1.12 ± 0.06 vs. 1.06 ± 0.07, P = 0.03). Furthermore, HAECs exposed to the plasma of patients with critical limb ischemia and treated with simvastatin responded with a higher NLRP1 expression than those exposed to the plasma of simvastatin-treated patients with claudication (RQ 1.1 ± 0.3 vs. 0.99 ± 0.14, P &lt; 0.001). Simvastatin intake in PAD patients increases in vitro reactivity of NLRP1 inflammasome gene expression in HAECs, especially in critical limb ischemia patients.
International Journal of Cardiology, 2016
Background: Soluble stimuli present in the plasma of patients with peripheral arterial disease (P... more Background: Soluble stimuli present in the plasma of patients with peripheral arterial disease (PAD) are capable of directly stimulating intracellular signalling in endothelium. Oxidized-LDL (oxLDL) induces NLRP3 inflammasome activation in macrophages. However, it is not clear how lipid profile affect NLRP1 inflammasome gene expression in endothelial cells. In this study, the effect of cholesterol and TG of plasma of patients with PAD on NLRP1 inflammasome gene expression in human arterial endothelial cells (HAECS) was assessed. Methods: We included 113 patients with symptomatic PAD. HAECs were stimulated for 2 h using the plasma samples of the study participants. The NLRP1 quantification of the transcription was carried out on the 7500 real-time PCR system using the Taqman® Universal PCR Master Mix and Assays on demand. Relative quantification of the NLRP1 expression was carried out using the ΔΔCt (threshold cycle) comparative method. Results: Plasma from patients with elevated VLDL-cholesterol levels (N33.6 mg/dL, the median value of the sample) provoked a higher expression of NLRP1 inflammasome in HAECs (RQ = 1.15 ± 0.23 vs. 1.05 ± 0.69; p = 0.045), as well as plasma from patients with elevated TGs levels (N 168 mg/dL, the median value of the sample) (RQ = 1.15 ± 0.23 vs. 1.05 ± 0.69; p = 0.045). A positive correlation was found between NLRP1 inflammasome expression and VLDL-cholesterol plasma levels (r = 0.4; p b 0.001) as between NLRP1 inflammasome expression and TG levels (r = 0.4; p b 0.001). Conclusions: Plasma TG and VLDL cholesterol of patients with atherosclerosis, manifested as PAD, promote the in vitro NLRP1 inflammasome expression in HAECs.
Angiología, 2015
Conclusiones: La MMP-2 y el TIMP-2 están aumentados, en aorta y fascia de pacientes con AAA, sobr... more Conclusiones: La MMP-2 y el TIMP-2 están aumentados, en aorta y fascia de pacientes con AAA, sobre todo, en los de mediano tamaño, lo que indica cierto papel en la etiología. El incremento de MMP-2 y TIMP-2 en presencia de hernia potencia la idea de un mecanismo patogénico común.
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Papers by Joaquin De Haro