Temporary atrial septal defect balloon occlusion test as a must in the elderly.

BACKGROUND: Atrial septal defect (ASD) can often remain asymptomatic until adulthood. It still remains unclear whether large ASD closure in senior people should be performed or not. Temporary ASD balloon occlusion test has been suggested as a tool to assess the risk of acute left ventricular heart failure post-ASD closure, and it allows to better distinguish responders from non-responders. CASE PRESENTATION: An 83-year-old man with a long-standing uncorrected secundum ASD was admitted for recently decompensated right-sided heart failure. During hospitalization, this patient was studied with trans-esophageal echocardiography, cardiac magnetic resonance imaging, and right heart catheterization, showing high Qp:Qs ratio and favorable anatomical conditions for percutaneous closure. Because of patient's increasing need for intravenous diuretics and worsening renal function, it was considered that transcatheter ASD closure could improve symptoms, hence it was performed an attempt of percutaneous closure of the ASD with a fenestrated device. Unfortunately, irrespective of ASD being hemodynamically significant, it was found a very significant increase in pulmonary capillary wedge pressure during the temporary balloon occlusion test, supporting the existence of concealed left ventricular diastolic dysfunction. As a result, it was decided to abandon the procedure and not to close the ASD. CONCLUSION: This clinical case illustrates the value of temporary balloon occlusion test before permanent percutaneous closure of ASD in elderly patients, regardless of left ventricular (systolic or diastolic) dysfunction.

Cell Uptake of Steroid-BODIPY Conjugates and Their Internalization Mechanisms: Cancer Theranostic Dyes.

Estradiol-BODIPY linked via an 8-carbon spacer chain and 19-nortestosterone- and testosterone-BODIPY linked via an ethynyl spacer group were evaluated for cell uptake in the breast cancer cell lines MCF-7 and MDA-MB-231 and prostate cancer cell lines PC-3 and LNCaP, as well as in normal dermal fibroblasts, using fluorescence microscopy. The highest level of internalization was observed with 11ß-OMe-estradiol-BODIPY 2 and 7α-Me-19-nortestosterone-BODIPY 4 towards cells expressing their specific receptors. Blocking experiments showed changes in non-specific cell uptake in the cancer and normal cells, which likely reflect differences in the lipophilicity of the conjugates. The internalization of the conjugates was shown to be an energy-dependent process that is likely mediated by clathrin- and caveolae-endocytosis. Studies using 2D co-cultures of cancer cells and normal fibroblasts showed that the conjugates are more selective towards cancer cells. Cell viability assays showed that the conjugates are non-toxic for cancer and/or normal cells. Visible light irradiation of cells incubated with estradiol-BODIPYs 1 and 2 and 7α-Me-19-nortestosterone-BODIPY 4 induced cell death, suggesting their potential for use as PDT agents.

Platypnoea Orthodeoxia Syndrome and Patent Foramen Ovale Closure: Single-Centre Experience and Long-Term Follow-Up.

INTRODUCTION: Platypnoea orthodeoxia syndrome (POS) is an uncommon condition characterised by dyspnoea and arterial desaturation induced by an upright position and relieved in the supine position, usually due to a patent foramen ovale (PFO). Percutaneous closure of a PFO is the preferred treatment to cure POS. This study aimed to evaluate the clinical and gasometrical characteristics and to describe the long-term outcomes of percutaneous PFO closure in a group of patients with POS. METHODS: Patients with POS and a PFO treated by percutaneous intervention from 2010-2020 were reviewed. The primary efficacy outcome was the arterial oxygen pressure to fraction of inspired oxygen (PaO2/FiO2) ratio before and 24 hours after the procedure. Total clinical success was considered if the arterial oxygen saturation measured by pulse oximetry (SpO2) improved to >94% in the supine and sitting positions without supplemental oxygen, while partial success was considered if SpO2 improved from baseline but still required oxygen to achieve >94%. Secondary outcomes were an absolute improvement in SpO2 and sense of dyspnoea, without significant residual shunt on transthoracic echocardiography (TTE) at follow-up. RESULTS: Of 168 patients undergoing PFO or atrial septal defect closure, 14 had POS (8.3%). Percutaneous PFO closure was successfully performed in all patients with a single device. Twelve of 14 patients had total clinical success (86%) and one patient had partial success. The PaO2/FiO2 ratio increased from 155.9±50.6 to 318.3±73.4 after PFO closure (p=0.002). All patients with total clinical success had a successful secondary efficacy outcome with an absolute improvement in SpO2 and complete resolution of dyspnoea, which was maintained at follow-up (37±20 months; range, 11 months to 6 years). None had a significant residual shunt between 12 and 24 months of follow-up. CONCLUSION: The PFO percutaneous closure was a successful, durable and safe method for patients presenting with POS; it achieved major improvements in both gasometrical parameters and quality of life.

Vanadium(IV) Complexes with Methyl-Substituted 8-Hydroxyquinolines: Catalytic Potential in the Oxidation of Hydrocarbons and Alcohols with Peroxides and Biological Activity.

Methyl-substituted 8-hydroxyquinolines (Hquin) were successfully used to synthetize five-coordinated oxovanadium(IV) complexes: [VO(2,6-(Me)2-quin)2] (1), [VO(2,5-(Me)2-quin)2] (2) and [VO(2-Me-quin)2] (3). Complexes 1-3 demonstrated high catalytic activity in the oxidation of hydrocarbons with H2O2 in acetonitrile at 50 °C, in the presence of 2-pyrazinecarboxylic acid (PCA) as a cocatalyst. The maximum yield of cyclohexane oxidation products attained was 48%, which is high in the case of the oxidation of saturated hydrocarbons. The reaction leads to the formation of a mixture of cyclohexyl hydroperoxide, cyclohexanol and cyclohexanone. When triphenylphosphine is added, cyclohexyl hydroperoxide is completely converted to cyclohexanol. Consideration of the regio- and bond-selectivity in the oxidation of n-heptane and methylcyclohexane, respectively, indicates that the oxidation proceeds with the participation of free hydroxyl radicals. The complexes show moderate activity in the oxidation of alcohols. Complexes 1 and 2 reduce the viability of colorectal (HCT116) and ovarian (A2780) carcinoma cell lines and of normal dermal fibroblasts without showing a specific selectivity for cancer cell lines. Complex 3 on the other hand, shows a higher cytotoxicity in a colorectal carcinoma cell line (HCT116), a lower cytotoxicity towards normal dermal fibroblasts and no effect in an ovarian carcinoma cell line (order of magnitude HCT116 > fibroblasts > A2780).

Translating phototherapeutic indices from in vitro to in vivo photodynamic therapy with bacteriochlorins.

OBJECTIVE: To compare hydrophilic and lipophilic bacteriochlorin photosensitizers in the photodynamic therapy of cancer, and relate their properties and in vitro phototoxicities to the efficacy of in vivo PDT treatments. MATERIALS AND METHODS: Photochemical characterization of a hydrophilic bacteriochlorin (F2 BOH) photosensitizer, and its use in PDT was compared with the performance of a closely related but water-insoluble bacteriochlorin (F2 BMet or redaporfin). Biodistribution, pharmacokinetics, skin photosensitivity, PDT efficacy and immune responses of two bacteriochlorins were compared. PDT in vitro employed CT26 colon carcinoma cells. BALB/c mice bearing CT26 cells were treated according to a protocol where the illumination of the subcutaneous tumor is performed 15 minute after intravenous administration of the photosensitizer, while it is in the vascular compartment (vascular-PDT). RESULTS: F2 BOH has photochemical properties comparable to redaporfin and both are promising photosensitizers for PDT. Although, F2 BOH is 10 times less phototoxic in vitro than redaporfin, the phototoxicity of F2 BOH in vascular-PDT is comparable to that of redaporfin. This is consistent with the fact that the vasculature is the main target of vascular-PDT. F2 BOH-PDT led to long-term cures and stimulation of the immune system. CONCLUSION: F2 BOH is soluble in aqueous media, photostable, has a convenient elimination half-life of 44 hours and leads to very low skin photosensitivity one week after administration. F2 BOH and redaporfin are both very phototoxic in vascular-PDT, but this could not be anticipated from their widely different phototherapeutic indices in vitro. PDT with F2 BOH enabled long-term cures of BALB/c mice with subcutaneously implanted CT26 tumors, and the cured mice rejected tumor re-inoculation one year after the treatment. Lasers Surg. Med. 50:451-459, 2018. © 2018 Wiley Periodicals, Inc.

Vascular Forum: collective intelligence in the resolution of vascular clinical cases.

BACKGROUND: Collective intelligence is extremely important in collective groups that discuss clinical medical cases, assisting professionals in their decision-making processes, and consequently, helping their patients. OBJECTIVES: To evaluate the rate of resolution and characteristics of the clinical discussions carried out in a private instant messaging group and its clinical applicability. METHODS: Retrospective analysis of clinical discussions and events on the Vascular Forum, an open group for specialists accessed with mobile devices. RESULTS: From July 2015 to July 2017, 1013 subjects were discussed among 680 members. Twenty-six (2.57%) of these subjects were curiosities, 101 (9.97%) related to diagnostic doubts, 492 (48.57%) to treatment doubts, and 205 (20.24%) to general doubts, while 189 (17.5%) were case reports. The mean number of interactions per event was 16.599 (±1.366). The mean time from posting of a new subject to the first reply was 42.14 (±7.55) min. The subject discussed was miscellaneous in 358 cases, venous in 336 cases, lymphatic in 15 cases, and arterial in 304 cases and the total number of replies was 15985. CONCLUSIONS: Interaction between experts using instant messaging technology proved capable of raising subjects for discussion and eliciting management approaches quickly. The rate of resolution, defined as the time taken for the first correct answer to be posted, was also high. The Vascular Forum proved to be a tool of great clinical value for its participants, confirming the importance of collective intelligence in medicine.

Manual thrombectomy efficiency in relationship to the area at risk in patients with myocardial infarction with TIMI 0-1 coronary flow: Insights from an all comers registry.

OBJECTIVES: To review the effectiveness of manual thrombectomy (MT) in a series of patients with ST-elevation myocardial infarction (STEMI) exclusively presenting with TIMI 0-1 flow undergoing percutaneous coronary intervention (PCI), in accordance to the angiographically estimated area at risk (AAR). Second, to assess major in-hospital clinical events, emphasizing neurological outcomes. BACKGROUND: The routine utilization of MT in STEMI is not recommended. However, in recent trials, a significant proportion of patients had neither large thrombus burden nor a totally occluded coronary segment, neutralizing the expected benefits of MT. In addition, the efficiency of MT to remove thrombus has rarely been addressed. Finally, MT diminished distal embolization, which has been related to mortality. RESULTS: In 850 consecutive STEMI-patients, MT was utilized in 525 (62%) and it was considered efficient (TIMI 2-3 flow after MT) in 445 (85%). We found a significant interaction between the AAR and the effectiveness of MT to reduce infarct size (P-interaction = 0.014). In patients having AAR ≥ 28% (n = 184), efficient MT conferred lesser infarct size compared to inefficient MT (Ln-transformed peak CK): 7.87 ± 0.86 versus 8.36 ± 0.41 IU/L, P = 0.005, with no impact for AAR <28%. Clinical outcomes including stroke between MT and PCI-only groups were not different. CONCLUSION: In comparison with the group where MT was inefficient, efficient MT may modestly reduce final infarct size without a significant clinical benefit. In comparison with PCI-only, no difference was found regarding stroke. © 2017 Wiley Periodicals, Inc.

Soluble TNF-related apoptosis induced ligand (sTRAIL) is augmented by Post-Conditioning and correlates to infarct size and left ventricle dysfunction in STEMI patients: a substudy from a randomized clinical trial.

Low levels of Soluble TNF-related apoptosis induced ligand (sTRAIL) seem to be related to worse prognosis after an acute coronary syndrome. PostConditioning (PostCond) may protect the heart from reperfusion injury. We sought to evaluate the impact of PostCond on sTRAIL in relationship to infarct size (area under the curve of Troponin T, AUCTnT) and left ventricle ejection fraction (LVEF) in a series of patients undergoing primary coronary intervention for ST-segment elevation myocardial infarction (STEMI). In a substudy of a randomized trial that tested the effects of PostCond in STEMI-patients, sTRAIL was measured 24 h after reperfusion (PostCond n = 39, Control n = 39). Correlations between sTRAIL and both AUCTnT and LVEF were studied for each study arm. At 24 h, sTRAIL was higher for PostCond vs Controls (46.4 ± 30.6 vs 32.9 ± 23.4, p = 0.031), was negatively related to AUCTnT [B = -0.09, 95 % CI (-0.15 to -0.30), p = 0.005] and was positively related to both in-hospital [B = 0.10, 95 % CI (0.02-0.17), p = 0.018], and follow-up LVEF [B = 0.21, 95 % (0.10-0.32), p = 0.001]. No significant relationship was found for Controls. On multivariate analysis, PostCond was an independent predictor for sTRAIL [B = 12.13 95 % CI (0.40-23.87), p = 0.043]. In conclusion, PostCond positively influenced sTRAIL, which was related to reduced infarct size and better LVEF. Further studies are needed to understand potential mechanisms elicited by PostCond in infarct size reduction.

Twelve-year trends in unprotected left main coronary artery occlusion: insights from a real-world multicentre study.

AIMS: Acute myocardial infarction (AMI) resulting from unprotected left main coronary artery (LMCA) occlusion and subtotal occlusion is a life-threatening condition. Although AMI management has improved in the past two decades, there is limited information on recent trends in patient characteristics, management, and outcomes for acute unprotected LMCA-related AMI. This study aims to assess such trends over a 12 year period. METHODS AND RESULTS: This retrospective multicentre study includes patients with unprotected LMCA occlusion/subtotal occlusion admitted to three tertiary hospitals between 2008 and 2020. The patients were divided into two groups based on the chronology of presentation: a 'past group' (January 2008 to December 2014) and a 'contemporary group' (January 2015 to December 2020). The study compares clinical characteristics, management approaches, and outcomes between the two groups. The study includes 128 patients, with 51 (40%) in the 'past group' and 77 (60%) in the 'contemporary group'. Baseline risk factors did not show statistically significant differences between the two groups, except for hypertension (49% vs. 74%; P = 0.005). Chest pain was more frequent in the 'past group' (98% vs. 89%; P = 0.014), and a trend towards more cardiac arrests was observed in the 'contemporary group' (18% vs. 31%; P = 0.087). Revascularization type did not differ significantly (P = 0.419), but manual thrombectomy was less frequently used (41% vs. 23%; P = 0.032) and stent implantation showed a trend towards higher rates (66% vs. 78%; P = 0.150) in the 'contemporary cohort'. There was a gradual shift from bare-metal to drug-eluting stents, with a significantly higher percentage of ticagrelor/prasugrel loading in the 'contemporary cohort' (5% vs. 79%; P < 0.001). The use of mechanical circulatory support (MCS), although not statistically significant, was higher among patients in the 'past group' (67% vs. 51%; P = 0.073). The type of MCS differed significantly between groups, with a decrease in intra-aortic balloon pump use (67% vs. 42%; P = 0.005) and an increase in veno-arterial extracorporeal membrane oxygenation (4% vs. 22%; P = 0.005) and Impella system (0% vs. 3%) over time. Survival analysis showed no significant differences (P = 0.599; log-rank test) in all-cause mortality between the different time groups, with the long-term survival rate being approximately 30%. CONCLUSIONS: In our real-world population, despite the progressive use of newer drugs and more advanced devices over time, patients with unprotected LMCA occlusion/subtotal occlusion remain a subpopulation with poor prognosis.

Bringing Hope to Improve Treatment in Pancreatic Ductal Adenocarcinoma-A New Tool for Molecular Profiling of KRAS Mutations in Tumor and Plasma Samples.

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising, and prognosis remains poor due to late diagnosis and limited effective therapies. Currently, patients are treated based on TNM staging, without molecular tumor characterization. This study aimed to validate a technique that combines the amplification refractory mutation system (ARMS) with high-resolution melting analysis (HRMA) for detecting mutations in codon 12 of KRAS in tumor and plasma, and to assess its prognostic value. METHODS: Prospective study including patients with newly diagnosed PDAC with tumor and plasma samples collected before treatment. Mutations in codon 12 of KRAS (G12D, G12V, G12C, and G12R) were detected using ARMS-HRMA and compared to Sanger sequencing (SS). Univariate and multivariate analyses were used to evaluate the prognostic significance of these mutations. RESULTS: A total of 88 patients, 93% with ECOG-PS 0-1, 57% with resectable disease. ARMS-HRMA technique showed a higher sensitivity than SS, both in tumor and plasma (77% vs. 51%; 25 vs. 0%, respectively). The most frequent mutation was G12D (n = 32, 36%), followed by G12V (n = 22, 25%). On multivariate analysis, patients with G12D and/or G12C mutations, either in tumor or plasma, had lower PFS (HR 1.792, 95% CI 1.061-3.028, p = 0.029; HR 2.081, 95% CI 1.014-4.272, p = 0.046, respectively) and lower OS (HR 1.757, 95% CI 1.013-3.049, p = 0.045; HR 2.229, 95% CI 1.082-4.594, p = 0.030, respectively). CONCLUSIONS: ARMS-HRMA is a rapid and cost-effective method for detecting KRAS mutations in PDAC patients, offering the potential for stratifying prognosis and guiding treatment decisions. The presence of G12D and G12C mutations in both tumor and plasma is associated with a poorer prognosis.

Percutaneous Valvular and Structural Heart Disease Interventions. 2024 Core Curriculum of the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC.

The percutaneous treatment of structural, valvular, and non-valvular heart disease (SHD) is rapidly evolving. The Core Curriculum (CC) proposed by the EAPCI describes the knowledge, skills, and attitudes that define competency levels required by newly trained SHD interventional cardiologists (IC) and provides guidance for training centres. SHD ICs are cardiologists who have received complete interventional cardiology training. They are multidisciplinary team specialists who manage adult SHD patients from diagnosis to follow-up and perform percutaneous procedures in this area. They are competent in interpreting advanced imaging techniques and master planning software. The SHD ICs are expected to be proficient in the aortic, mitral, and tricuspid areas. They may have selective skills in either the aortic area or mitral/tricuspid areas. In this case, they must still have common transversal competencies in the aortic, mitral, and tricuspid areas. Additional SHD domain competencies are optional. Completing dedicated SHD training, aiming for full aortic, mitral, and tricuspid competencies, requires at least 18 months. For full training in the aortic area, with basic competencies in mitral/tricuspid areas, the training can be reduced to 1 year. The same is true for training in the mitral/tricuspid area, with competencies in the aortic area. The SHD IC CC promotes excellence and homogeneous training across Europe and is the cornerstone of future certifications and patient protection. It may be a reference for future CC for national associations and other SHD specialities, including imaging and cardiac surgery.

Percutaneous Valvular and Structural Heart Disease Interventions.2024 Core Curriculum of the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC in collaboration with the European Association of Cardiovascular Imaging (EACVI) and the Cardiovascular Surgery Working Group (WG CVS) of the European Society of Cardiology.

The percutaneous treatment of structural, valvular, and non-valvular heart disease (SHD) is rapidly evolving. The Core Curriculum (CC) proposed by the EAPCI describes the knowledge, skills, and attitudes that define competency levels required by newly trained SHD interventional cardiologists (IC) and provides guidance for training centres. SHD ICs are cardiologists who have received complete interventional cardiology training. They are multidisciplinary team specialists who manage adult SHD patients from diagnosis to follow-up and perform percutaneous procedures in this area. They are competent in interpreting advanced imaging techniques and master planning software. The SHD ICs are expected to be proficient in the aortic, mitral, and tricuspid areas. They may have selective skills in either the aortic area or mitral/tricuspid areas. In this case, they must still have common transversal competencies in the aortic, mitral, and tricuspid areas. Additional SHD domain competencies are optional. Completing dedicated SHD training, aiming for full aortic, mitral, and tricuspid competencies, requires at least 18 months. For full training in the aortic area, with basic competencies in mitral/tricuspid areas, the training can be reduced to 1 year. The same is true for training in the mitral/tricuspid area, with competencies in the aortic area. The SHD IC CC promotes excellence and homogeneous training across Europe and is the cornerstone of future certifications and patient protection. It may be a reference for future CC for national associations and other SHD specialities, including imaging and cardiac surgery.

Triple, simultaneous, very late coronary stent thrombosis.

Coronary artery stent thrombosis is an uncommon but potentially catastrophic complication. The risk of very late stent thrombosis (VLST) raises important safety issues regarding the first generation of drug-eluting stents (DES). Although several complex mechanisms for VLST have been suggested and various predictors have been described, its pathophysiology is not completely understood and it is not known whether longer-term dual antiplatelet therapy reduces the risk. We present a rare case of simultaneous very late DES thrombosis in the three vascular territories, following discontinuation of antiplatelet therapy seven years after stent placement, presenting as cardiogenic shock.

ST-Segment Elevation: An Unexpected Culprit.

The clinical presentation of pulmonary embolism (PE) and acute coronary syndrome can be similar. We report a case of a patient presenting with antero-septal ST-segment elevation after cardiac arrest, found to have acute-PE-mimicking ST-segment elevation myocardial infarction (STEMI), treated with aspiration thrombectomy and catheter-directed thrombolysis (CDT). A 78-year-old man was admitted with dyspnea, chest pain and tachycardia. During evaluation, cardiac arrest in pulseless electrical activity was documented. Advanced life support was started immediately. ECG post-ROSC revealed ST-segment elevation in V1-V4 and aVR. Echocardiography showed normal left ventricular function but right ventricular (RV) dilation and severe dysfunction. The patient was in shock and was promptly referred to cardiac catheterization that excluded significant CAD. Due to the discordant ECG and echocardiogram findings, acute PE was suspected, and immediate invasive pulmonary angiography revealed bilateral massive pulmonary embolism. Successful aspiration thrombectomy was performed followed by local alteplase infusion. At the end of the procedure, mPAP was reduced and blood pressure normalized allowing withdrawal of vasopressor support. Twenty-four-hour echocardiographic reassessment showed normal-sized cardiac chambers with preserved biventricular systolic function. Bedside echocardiography in patients with ST-segment elevation post-ROSC is instrumental in raising the suspicion of acute PE. In the absence of a culprit coronary lesion, prompt pulmonary angiography should be considered if immediately feasible. In these cases, CDT and aspiration in high-risk acute PE seem safe and effective in relieving obstructive shock and restoring hemodynamics.

Doxorubicin-sensitive and -resistant colorectal cancer spheroid models: assessing tumor microenvironment features for therapeutic modulation.

Introduction: The research on tumor microenvironment (TME) has recently been gaining attention due to its important role in tumor growth, progression, and response to therapy. Because of this, the development of three-dimensional cancer models that mimic the interactions in the TME and the tumor structure and complexity is of great relevance to cancer research and drug development. Methods: This study aimed to characterize colorectal cancer spheroids overtime and assess how the susceptibility or resistance to doxorubicin (Dox) or the inclusion of fibroblasts in heterotypic spheroids influence and modulate their secretory activity, namely the release of extracellular vesicles (EVs), and the response to Dox-mediated chemotherapy. Different characteristics were assessed over time, namely spheroid growth, viability, presence of hypoxia, expression of hypoxia and inflammation-associated genes and proteins. Due to the importance of EVs in biomarker discovery with impact on early diagnostics, prognostics and response to treatment, proteomic profiling of the EVs released by the different 3D spheroid models was also assessed. Response to treatment was also monitored by assessing Dox internalization and its effects on the different 3D spheroid structures and on the cell viability. Results and Discussion: The results show that distinct features are affected by both Dox resistance and the presence of fibroblasts. Fibroblasts can stabilize spheroid models, through the modulation of their growth, viability, hypoxia and inflammation levels, as well as the expressions of its associated transcripts/proteins, and promotes alterations in the protein profile exhibit by EVs. Summarily, fibroblasts can increase cell-cell and cell-extracellular matrix interactions, making the heterotypic spheroids a great model to study TME and understand TME role in chemotherapies resistance. Dox resistance induction is shown to influence the internalization of Dox, especially in homotypic spheroids, and it is also shown to influence cell viability and consequently the chemoresistance of those spheroids when exposed to Dox. Taken together these results highlight the importance of finding and characterizing different 3D models resembling more closely the in vivo interactions of tumors with their microenvironment as well as modulating drug resistance.

Facile Access to Structurally Diverse Antimalarial Indoles Using a One-Pot A3 Coupling and Domino Cyclization Approach.

A multistep and diversity-oriented synthetic route aiming at the A3 coupling/domino cyclization of o-ethynyl anilines, aldehydes and s-amines is described. The preparation of the corresponding precursors included a series of transformations, such as haloperoxidation and Sonogashira cross-coupling reactions, amine protection, desilylation and amine reduction. Some products of the multicomponent reaction underwent further detosylation and Suzuki coupling. The resulting library of structurally diverse compounds was evaluated against blood and liver stage malaria parasites, which revealed a promising lead with sub-micromolar activity against intra-erythrocytic forms of Plasmodium falciparum. The results from this hit-to-lead optimization are hereby reported for the first time.

Ticagrelor Loading on ST-Elevation Myocardial Infarction: Interaction With Prodromal Angina on Infarct Size and Clinical Events.

INTRODUCTION: Ticagrelor might reduce infarct size by exerting a more potent antiplatelet effect or by promoting a potential conditioning stimulus in ST-elevation myocardial infarction (STEMI) patients. Pre-infarction angina (PIA) is an effective preconditioning stimulus that reduces ischemia-reperfusion injury. Because little is known on the interaction of PIA in STEMI-patients loaded with ticagrelor, we sought to determine if patients loaded with ticagrelor had improved clinical outcomes as compared to clopidogrel and to study if it is modulated by the presence of PIA. METHODS: From 1272 STEMI patients submitted to primary percutaneous coronary intervention and treated with clopidogrel or ticagrelor from January 2008 to December 2018, 826 were analyzed after propensity score matching. Infarct size was estimated using peak creatine kinase (CK) and troponin T (TnT), and clinical impact was evaluated through cumulative major cardiac and cerebrovascular events (MACCE) at 1-year follow-up. Matched patients and their interaction with PIA were analyzed. RESULTS: Patients loaded with ticagrelor had lower peak CK [1405.50 U/L (730.25-2491.00), P < .001] and TnT [3.58 ng/mL (1.73-6.59), P < .001)], regardless of PIA. The presence of PIA was associated with lower CK (P = .030), but not TnT (P = .097). There was no interaction between ticagrelor loading and PIA (P = .788 for TnT and P = .555 for CK). There was no difference in MACCE incidence between clopidogrel or ticagrelor loading (P = .129). Cumulative survival was also similar between clopidogrel or ticagrelor, regardless of PIA (P = .103). CONCLUSION: Ticagrelor reduced infarct sizes independently and without a synergic effect with PIA. Despite reducing infarct size, clinical outcomes were similar across both groups.

Heart Failure Incidence Following ST-Elevation Myocardial Infarction.

ST-elevation myocardial infarction (STEMI) survivors have a heightened risk of developing heart failure (HF). The magnitude of this risk with the advent of primary percutaneous coronary intervention is less characterized. We aimed to examine the incidence and predictors of incident HF and all-cause mortality in a contemporary STEMI cohort. We performed a retrospective analysis of 700 consecutive patients with STEMI treated with primary percutaneous coronary intervention at a tertiary hospital. The primary outcome was the occurrence of HF during follow-up. HF was defined by HF hospitalization or the presence of congestion that led to de novo prescription or up-titration of diuretics in the outpatient clinic. The secondary outcome was defined by the occurrence of HF or all-cause mortality. During a median follow-up period of 43.6 months, HF events occurred in 110 patients (15.7%), 34 (4.8%) managed as outpatient and 76 (10.9%) requiring hospitalization. Left ventricular ejection fraction (LVEF) <50% was present in 76% of those who developed HF. Age (hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.01 to 1.06), diabetes (HR 1.85, 95% CI 1.12 to 3.05), door-to-balloon time (HR 1.002, 95% CI 1.000 to 1.003), Killip-Kimball class ≥II (HR 2.24, 95% CI 1.32 to 3.80) and LVEF <50% (HR 1.71, 95% CI 1.01 to 2.92) were independent predictors. All-cause mortality incidence was 8.7%. HF was independently associated with a threefold increased risk of dying (HR 3.52, 95% CI 1.85 to 6.69, p <0.001). In conclusion, a substantial proportion of contemporary patients with STEMI develop HF, which triplicates the risk of dying. Older age, diabetes and LVEF <50% independently predicted the development of HF and all-cause death.

Atmospheric features and risk of ST-elevation myocardial infarction in Porto (Portugal): A temperate Mediterranean (Csb) city.

INTRODUCTION AND OBJECTIVES: Some atmospheric features have been linked to the triggering of myocardial infarction. Because data from the Temperate-Mediterranean is scarce, we sought to study whether meteorological parameters influence the incidence of ST-elevation myocardial infarction (STEMI) as confirmed by primary percutaneous intervention in a city with temperate weather (Porto, Portugal). METHODS: Retrospective analysis of a series of STEMI-patients from January 2010 to December 2017. Temperature (T), relative humidity (RH), precipitation, and atmospheric pressure were obtained from a government-led institute. We utilized a generalized linear model (GLM) with a Poisson distribution, where a series of models with multivariable analysis were computed. The effects (GLM coefficients) are presented as excess relative risk (ERR). RESULTS: One thousand and four consecutive STEMI-patients were included. The most important predictors of STEMI were Tmin two days before (for 1°C drop ERR=1.9%, p=0.009) and a 1% increase in RH three days before (EER=0.7%, p=0.006). Conversely, the same increase in RH the day before reduced the relative risk (EER=-0.6%, p=0.023). Temperature range, atmospheric pressure and precipitation had no impact on STEMI incidence. CONCLUSION: In a Temperate-Mediterranean city hot or cold temperature extremes, temperature drop and relative humidity had a significant impact on the occurrence of STEMI.

Hyponatremia--an unusual trigger of Takotsubo cardiomyopathy.

Takotsubo cardiomyopathy is an acute cardiac entity with clinical manifestations similar to myocardial infarction, accounting for 1-2% of acute coronary syndrome admissions. Its underlying pathophysiology is not yet well established. It is usually associated with acute physical or emotional stress, but the list of potential triggers has grown as the condition attracts the attention of the medical community. In order to diagnose the condition correctly and to gain new insights into it, we need to know its potential triggers as well as its clinical presentation and diagnostic criteria. We report a case of takotsubo cardiomyopathy triggered by hyponatremia.