Inflammatory and Cardiovascular Biomarkers to Monitor Fabry Disease Progression.

Fabry disease is an invalidating multisystemic disorder affecting α-Galactosidase, a rate-limiting hydrolase dedicated to lipid catabolism. Non-metabolized substrates, such as Globotriaosylceramide and its derivatives trigger the direct or indirect activation of inflammatory events and endothelial dysfunction. In spite of the efficacy demonstrated by enzyme replacement therapy or pharmacological chaperones in delaying disease progression, few studies have analyzed whether these treatments can improve the pro-inflammatory state of FD patients. Therefore, the aim of this work was to assess cytokines and cardiovascular risk-related proteins detectable in plasma from FD patients, whether treated or not with ERT, to evaluate the reliability of these markers in monitoring disease stage and treatment effects. We identified inflammatory and endothelial dysfunction markers (ADAMTS-13, TNF-α, GDF-15, MIP-1ß, VEGFA, MPO, and MIC-1) that cooperate in a common pathway and are increased in FD patients' plasma samples. As shown by the assessment of these proteins over time, they can help to evaluate the risk of higher severity in FD, as well as ERT effects. Even though the analyzed proteins cannot be considered as proper biomarkers due to their non-specificity to FD, taken together they can provide a signature of reference molecules with prognostic value for early diagnosis, and evaluation of disease progression and treatment efficacy, using blood samples.

Genomic Factors and Therapeutic Approaches in HIV-Associated Neurocognitive Disorders: A Comprehensive Review.

HIV-associated neurocognitive disorders (HANDs) still persist despite improved life expectancy, reduced viral loads, and decreased infection severity. The number of patients affected by HANDs ranges from (30 to 50) % of HIV-infected individuals. The pathological mechanisms contributing to HANDs and the most serious manifestation of the disease, HIV-associated dementia (HAD), are not yet well understood. Evidence suggests that these mechanisms are likely multifactorial, producing neurocognitive complications involving disorders such as neurogenesis, autophagy, neuroinflammation, and mitochondrial dysfunction. Over the years, multiple pharmacological approaches with specific mechanisms of action acting upon distinct targets have been approved. Although these therapies are effective in reducing viral loading to undetectable levels, they also present some disadvantages such as common side effects, the need for administration with a very high frequency, and the possibility of drug resistance. Genetic studies on HANDs provide insights into the biological pathways and mechanisms that contribute to cognitive impairment in people living with HIV-1. Furthermore, they also help identify genetic variants that increase susceptibility to HANDs and can be used to tailor treatment approaches for HIV-1 patients. Identification of the genetic markers associated with disease progression can help clinicians predict which individuals require more aggressive management and by understanding the genetic basis of the disorder, it will be possible to develop targeted therapies to mitigate cognitive impairment. The main goal of this review is to provide details on the epidemiological data currently available and to summarise the genetic (specifically, the genetic makeup of the immune system), transcriptomic, and epigenetic studies available on HANDs to date. In addition, we address the potential pharmacological therapeutic strategies currently being investigated. This will provide valuable information that can guide clinical care, drug development, and our overall understanding of these diseases.

Protein Plasma Levels of the IGF Signalling System Are Altered in Major Depressive Disorder.

The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a peripheral biomarker has not been evaluated in depression. To do this, we measured plasma IGF-2 and other members of the IGF family such as Binding Proteins (IGFBP-1, IGFBP-3, IGFBP-5 and IGFBP-7) in a depressed group of patients (n = 51) and in a healthy control group (n = 48). In some of these patients (n = 15), we measured these proteins after a period (19 ± 6 days) of treatment with antidepressants. The Hamilton Depressive Rating Scale (HDRS) and the Self-Assessment Anhedonia Scale (SAAS) were used to measure depression severity and anhedonia, respectively. The general cognition state was assessed by the Mini-Mental State Examination (MMSE) test and memory with the Free and Cued Selective Reminding Test (FCSRT). The levels of both IGF-2 and IGFBP-7 were found to be significantly increased in the depressed group; however, only IGF-2 remained significantly elevated after correction by age and sex. On the other hand, the levels of IGF-2, IGFBP-3 and IGFBP-5 were significantly decreased after treatment, whereas only IGFBP-7 was significantly increased. Therefore, peripheral changes in the IGF family and their response to antidepressants might represent alterations at the brain level in depression.

Insulin-like Growth Factor 2 (IGF-2) and Insulin-like Growth Factor Binding Protein 7 (IGFBP-7) Are Upregulated after Atypical Antipsychotics in Spanish Schizophrenia Patients.

Insulin-like growth factor 2 (IGF-2) and IGF binding protein 7 (IGFBP-7) have been related to schizophrenia (SZ) due to their implication in neurodevelopment. The purpose of this study was to assess whether the alterations in IGF-2 and IGFBP-7 in SZ patients are intrinsically related to the psychiatric disorder itself or are a secondary phenomenon due to antipsychotic treatment. In order to test this hypothesis, we measured plasma IGF-2 and IGFBP-7 in drug-naïve first episode (FE) and multiple episodes or chronic (ME) SZ Caucasian patients who have been following treatment for years. A total of 55 SZ patients (FE = 15, ME = 40) and 45 healthy controls were recruited. The Positive and Negative Syndrome Scale (PANSS) and the Self-Assessment Anhedonia Scale (SAAS) were employed to check schizophrenic symptomatology and anhedonia, respectively. Plasma IGF-2 and IGFBP-7 levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). The FE SZ patients had much lower IGF-2, but not IGFBP-7, than controls. Moreover, both IGF-2 and IGFBP-7 significantly increased after atypical antipsychotic treatment (aripiprazole, olanzapine, or risperidone) in these patients. On the other hand, chronic patients showed higher levels of both proteins when compared to controls. Our study suggests that circulatory IGF-2 and IGFBP-7 increase after antipsychotic treatment, regardless of long-term conditions and being lower in drug-naïve FE patients.

Second vs. First generation drug eluting stents in multiple vessel disease and left main stenosis: Two-year follow-up of the observational, prospective, controlled, and multicenter ERACI IV registry.

OBJECTIVE: To compare second generation drug eluting stents (2DES) with first generation (1DES) for the treatment of patients (pts) with multiple coronary vessel disease (MVD). BACKGROUND: Although 2DES improved safety and efficacy compared to 1DES, MVD remains a challenge for percutaneous coronary interventions. METHODS: ERACI IV was a prospective, observational, and controlled study in pts with MVD including left main and treated with 2DES (Firebird 2, Microport). We included 225 pts in 15 sites from Argentina. Primary endpoint was the incidence of major adverse cardiovascular events (MACCE) defined as death, myocardial infarction (MI), cerebrovascular accident (CVA) and unplanned revascularization; and to compare with 225 pts from ERACI III study (1DES). PCI strategy was planned to treat lesions ≥70% in vessels ≥ 2.00 mm, introducing a modified Syntax score (SS) where severe lesions in vessels < 2.0 mm and intermediate lesions were not scored. RESULTS: Baseline characteristics showed that compared to ERACI III, ERACI IV pts had higher number of diabetics (P = 0.02), previous revascularization (P = 0.007), unstable angina IIb/IIIc (P < 0.001) and three vessels/left main disease (P = 0.003). Modified SS was 22.2 ± 11. At 2 years of follow-up ERACI IV group had significantly lower incidence of death+ MI + CVA, (P = 0.01) and MACCE (P = 0.001). MACCE rate was similar in diabetics, (5.8%) and nondiabetics (7.0%). After performing a matched propensity score, MACCE remain significantly lower in ERACI IV (P = 0.005). CONCLUSION: This registry showed that 2DES in MVD has a remarkable low incidence of MACCE in unadjusted and adjusted analysis. © 2016 Wiley Periodicals, Inc.

Can We Improve the Outcomes of Multivessel Disease Using Modified SYNTAX and Residual SYNTAX Scores?

PURPOSE OF REVIEW: In spite of the benefits of drug eluting (DES), these advantages were not translated to better outcome when percutaneous coronary interventions (PCI) were compared with coronary artery bypass surgery. PCI strategy allowing stent deployment in all intermediate lesions including small vessels together with DES design may be the reasons of these findings. RECENT FINDINGS: Recently randomized and observational studies demonstrated using functional flow reserve analysis, residual Syntax score risk, or residual ERACI score after PCI that a reasonably incomplete revascularization was associated with good long-term outcome and low events rate at follow-up. In the ERACI IV study, which included patients with multiple vessel disease and left main, all intermediate lesions and severe lesions in small vessels were excluded from the revascularization strategy, and the 3-year follow-up results showed a remarkable low incidence of death/MI and stroke. Intermediate stenosis or severe lesions in small vessels should not be incorporated in the PCI strategy in order to define patient clinical cardiac prognosis or completeness of revascularization.

Trends in primary percutaneous coronary intervention for the treatment of acute coronary ST-elevation myocardial infarction in Latin American countries: insights from the CECI consortium.

Background: ST-elevation myocardial infarction (STEMI) requires revascularization treatment, preferably via primary percutaneous coronary interventions (pPCI). There is a lack of data about contemporary management of STEMI in Latin America. Methods: This was a multicenter, multinational, prospective, and dynamic registry of patients undergoing pPCI in Latin America for STEMI (STEMI/LATAMI Registry) that was carried out in nine centers from five countries (Argentina, Ecuador, Venezuela, Bolivia, and the Dominican Republic) between June 2021 and June 2023. All interventionalists involved in the study were originally trained at the same institution (Centro de Estudios en Cardiología Intervencionista, Buenos Aires, Argentina). The primary objective was to evaluate procedural and in-hospital outcomes of pPCI in STEMI and in-hospital outcome in the Latin America (LATAM) region; as secondary endpoints, we analyzed the following subgroups: differences between pPCI vs. pharmaco-invasive or late presenters, gender, elderly and very elderly patients, cardiogenic shock outcomes, and causes of STEMI. Results: In total, 744 STEMI patients who underwent PCI between June 2021 and June 2023 in five countries (nine centers) in our continent were included; 76.3% had a pPCI, 8.1% pharmaco-invasive PCI, and 15.6% had late STEMI PCI. There were no differences in region or center when we evaluated in-hospital and 30 days of death. The rate of procedural success was 96.2%, and the overall in-hospital mortality rate was 2.2%. In the subgroup of pPCI, mean symptom onset-to-balloon time was 295.3 ± 246 min, and mean door-to-balloon time was 55.8 ± 49.9 min. The femoral approach was chosen in 60.5%. In 3.0% of patients, the left main disease was the culprit artery, with 1.63 ± 1.00 stents per patient (564 drug-eluting stents and 652 bare metal stents), with 34 patients receiving only plain optimal balloon angioplasty. Definitive stent thrombosis was related to the infarct artery as the primary cause of STEMI in 7.5% of patients. The use of assistant mechanical devices was low, at 2.1% in the pPCI group. Women were older, with large numbers in very elderly age (≥90 years), greater mortality, and incidence of spontaneous coronary dissection as a cause of STEMI (p < 0.001, p < 0.001, p < 0.001, and p < 0.003, respectively). Conclusion: In suitable LATAM Centers from low/medium-income countries, this prospective registry in patients with STEMI, PCI performed by well-trained operators has comparable results to those reported in well-developed countries.

Plasma IGFBP-3 and IGFBP-5 levels are decreased during acute manic episodes in bipolar disorder patients.

Introduction: Bipolar disorder (BD) is a recurrent and disabling psychiatric disorder related to low-grade peripheral inflammation and altered levels of the members of the insulin-like growth factor (IGF) family. The aim of this study was to evaluate the plasma levels of IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, IGFBP-5, IGFBP-7, and inflammatory markers such as tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1ß (MIP-1ß). Methods: We used the Young Mania Rating Scale (YMRS) to determine the severity of the symptomatology, while proteins were measured by enzyme-linked immunosorbent assay (ELISA). We included 20 patients with BD who suffered a manic episode and 20 controls. Some BD patients (n = 10) were evaluated after a period (17 ± 8 days) of pharmacological treatment. Results: No statistical difference was found in IGF-2, IGFBP-1, IGFBP-7, TNF-α, and MIP-1ß levels. However, IGFBP-3 and IGFBP-5 levels were found to be statistically decreased in BD patients. Conversely, the MCP-1 level was significantly increased in BD patients, but their levels were normalized after treatment. Intriguingly, only IGFBP-1 levels were significantly decreased after treatment. No significant correlation was found between the YMRS and any of the proteins studied either before or after treatment or between IGF proteins and inflammatory markers. Discussion: To some extent, IGFBP-3 and IGFBP-5 might be further explored as potential indicators of treatment responsiveness or diagnosis biomarkers in BD.

High Non-Cardiac Death Incidence Should Be a Limitation of Drug-Eluting Stents Implantation? Insights from Recent Randomized Data.

Despite the introduction of drug-eluting stents (DES) significantly improved the efficacy and safety of percutaneous coronary interventions (PCI), particularly in a high-risk group of patients, the gap between PCI with his competitor's coronary artery bypass surgery (CABG) and/or optimal medical treatment alone was not reduced. In this revision, we highlighted the fact that in recent years landmark randomized studies reported at mid and long-term follow-ups a high incidence of non-cardiac death, cancer incidence, or both in the DES group of patients. The overall incidence of non-cardiac death was significantly higher in the DES vs. the comparator arm: 5.5% and 3.8%, respectively, p = 0.000018, and non-cardiac death appears to be more divergent between DES vs. the comparator at the extended follow-up to expenses of the last one. One of these trials reported five times greater cancer incidence in the DES arm at late follow-up, 5% vs. 0.7% p < 0.0018. We review the potential reason for these unexpected findings, although we can discard that DES biology could be involved in it. Until all these issues are resolved, we propose that DES implantation should be tailored accorded patient age, life expectancy, and lesion complexity.

Randomized comparison of cost-saving and effectiveness of oral rapamycin plus bare-metal stents with drug-eluting stents: three-year outcome from the randomized oral rapamycin in Argentina (ORAR) III trial.

OBJECTIVES: The Oral Rapamycin in ARgentina (ORAR) III trial is a randomized study comparing a strategy of oral rapamycin (OR) plus bare-metal stent (BMS) versus a strategy of drug-eluting stents (DES) in patients with de novo coronary lesions. The purpose of this study was to assess the 3 years cost-effectiveness outcome of each strategy. BACKGROUND: OR after BMS has been associated with reduction of target vessel revascularization (TVR) although its value in long-term efficacy in comparison with DES is unknown. METHODS: In three hospitals in Buenos Aires, Argentina, 200 patients were randomized to OR plus BMS (n = 100) or DES (n = 100). Primary objectives were costs and effectiveness. Cost analysis included in-hospital and follow-up costs. Safety was defined as the composite of death, myocardial infarction (MI), and stroke. Efficacy was defined as TVR. RESULTS: Baseline characteristics between groups were similar. The 3-year follow-up rate was 99%. Cardiac mortality was 2% and 5% in OR group and DES group, respectively (P = 0.44). The composite of death, MI and stroke rate was 11% in OR group and 20% in DES group (P = 0.078). TVR rate was 14.5% in OR group and 17.6% in DES group (P = 0.50), respectively. Three year cumulative costs were significantly lower in the OR arm as compared to the DES arm (P = 0.0001) and DES strategy did not result cost-effective according to the non-inferiority test. CONCLUSIONS: At 3 years follow-up, there were no differences in effectiveness between the two strategies, and DES strategy was not more cost-effective as compared to OR plus BMS.

Efficacy and safety of a double-coated paclitaxel-eluting coronary stent: the EUCATAX trial.

OBJECTIVES: The aim of this study was the comparison of a new double-coated paclitaxel-eluting coronary stent with bare-metal stent (BMS) in patients undergoing percutaneous coronary intervention. BACKGROUND: Stent coating with biodegradable polymers as a platform for elution of drugs has the potential for complete elution of drugs and for decreasing the risk of late complications. METHODS: Multicenter randomized trial comparing a paclitaxel-eluting stent (PES) coated with a biodegradable polymer and glycocalyx with the equivalent BMS. We randomly assigned 422 patients with de novo coronary lesions to PES (211 patients) or to BMS (211 patients). Primary end point was target vessel failure (TVF) defined as cardiac death, myocardial infarction, and target vessel revascularization. Clinical secondary end points were target vessel revascularization, target lesion revascularization, stent thrombosis (ST), and major adverse cardiovascular events (MACE). Angiographic secondary end points were late loss and binary restenosis. RESULTS: At 1 year of follow-up, TVF rate was 9.5% in the PES group and 17.1% in the BMS group (P=0.02), and MACE rate was 10% in PES and 19% in BMS arm (P=0.009). All other secondary end points were reached but ST. ST rate was low and similar in both study arms. CONCLUSIONS: The study shows that patients treated with PES with dual coating technology had significantly lower incidence of TVF and MACE than those treated with BMS design; however, longer follow-up should be necessary to assess true advantages of this technology compared with the previous one.

Therapeutic Approaches in Lysosomal Storage Diseases.

Lysosomal Storage Diseases are multisystemic disorders determined by genetic variants, which affect the proteins involved in lysosomal function and cellular metabolism. Different therapeutic approaches, which are based on the physiologic mechanisms that regulate lysosomal function, have been proposed for these diseases. Currently, enzyme replacement therapy, gene therapy, or small molecules have been approved or are under clinical development to treat lysosomal storage disorders. The present article reviews the main therapeutic strategies that have been proposed so far, highlighting possible limitations and future perspectives.

Microglia: The Real Foe in HIV-1-Associated Neurocognitive Disorders?

The current use of combined antiretroviral therapy (cART) is leading to a significant decrease in deaths and comorbidities associated with human immunodeficiency virus type 1 (HIV-1) infection. Nonetheless, none of these therapies can extinguish the virus from the long-lived cellular reservoir, including microglia, thereby representing an important obstacle to curing HIV. Microglia are the foremost cells infected by HIV-1 in the central nervous system (CNS) and are believed to be involved in the development of HIV-1-associated neurocognitive disorder (HAND). At present, the pathological mechanisms contributing to HAND remain unclear, but evidence suggests that removing these infected cells from the brain, as well as obtaining a better understanding of the specific molecular mechanisms of HIV-1 latency in these cells, should help in the design of new strategies to prevent HAND and achieve a cure for these diseases. The goal of this review was to study the current state of knowledge of the neuropathology and research models of HAND containing virus susceptible target cells (microglial cells) and potential pharmacological treatment approaches under investigation.

Randomized comparison between bare-metal stent plus colchicine versus drug-eluting stent alone in prevention of clinical adverse events after percutaneous coronary intervention.

The use of colchicine is associated with a significant reduction of cardiac adverse events in patients with coronary artery disease. Past small randomized trials with oral immunosuppressive or anti-inflammatory therapies have demonstrated a reduction of adverse clinical events after bare metal stent implantation. The potential role of adjunctive colchicine after bare-metal stent implantation, compared with drug-eluting stent alone, is unknown. The primary end point of the study will be to compare cost-effectiveness at 1 year of follow-up of coronary intervention with bare-metal stent implantation plus 1 mg of colchicine during 3 months versus percutaneous coronary intervention with drug-eluting stent implantation alone. ClinicalTrials.gov identifier: NCT04382443.

Increased incidence of serious late adverse events with drug-eluting stents when compared with coronary artery bypass surgery: a cause of concern.

Percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) in pre-drug-eluting stents (DESs) era, randomized trials and meta-analysis showed that the extension of coronary artery disease was not associated with a better survival with CABG, and only diabetic patients had an inferior survival with PCI. After the introduction of DES, we would expect a substantial improvement in PCI results compared with CABG, narrowing the gap between both revascularization strategies, However, on the contrary, most randomized studies between DES and CABG showed that rate of recurrences remained and there is an unexpected increased of late serious adverse events including spontaneous myocardial infarction and death. In this review, we try to described each of these problems and find out explanations for these new findings searching for potential solutions.

Role of Iterative Reconstruction Algorithm for the Assessment of Myocardial Infarction with Dual Energy Computed Tomography.

RATIONALE AND OBJECTIVES: Low monochromatic energy levels (40 keV) derived from delayed enhancement dual energy cardiac computed tomography (DE-DECT) allow the evaluation of myocardial infarcts (MI) among stable patients, although at the expense of high image noise. We explored whether the application of adaptive statistical iterative reconstruction (ASIR) to 40-keV DE-DECT (unavailable with previous software versions) might improve image quality and detection of MI in stable patients. MATERIALS AND METHODS: We prospectively enrolled patients with a history of previous MI, and performed delayed-enhancement cardiac magnetic resonance (DE-CMR) and DE-DECT within the same week. DE-DECT images were reconstructed with 0% and 60% ASIR. RESULTS: MI was identified in 18 (80%) patients with both DE-CMR and DE-DECT. On a per segment basis, we did not identify significant differences regarding the diagnostic performance of DE-DECT with and without ASIR [area under receiver operating characteristic curve 0.86 vs. 0.83, p = 0.10]. The application of ASIR improved the signal-to-noise ratio of DE-DECT with 0% ASIR compared to DE-DECT with 60% ASIR (6.07 ± 2.1 vs. 11.1 ± 4.5, p < 0.0001). However, qualitative assessment of MI image quality (3.35 ± 1.2, vs. 3.55 ± 1.1, p = 0.10) and diagnostic confidence (4.40 ± 0.9 vs. 4.60 ± 0.8, p = 0.10) were not significantly improved. Using DE-DECT with 60% ASIR, a threshold over 199 HU showed a sensitivity of 67% and a specificity of 92% for the detection of segments with MI. CONCLUSION: In this study, DE-DECT allowed accurate detection of MI among stable patients compared with DE-CMR, and the application of ASIR improved signal-to-noise ratio of DE-DECT, although the diagnostic performance showed only non-significant improvements.

One-Year Follow-Up Results From the Observational, Multicenter, Prospective, and Controlled Registry: The WALTZ All-Comers Study.

The aim of this study was to evaluate 1-year follow-up results in an all "comers" population treated with a new cobalt chromium bare-metal stent (BMS) design. Since August 2016 to March 2017, 201 (9.7% of screening population) consecutive patients undergoing coronary stent implantation in 11 centers in Argentina were prospectively included in our registry. The inclusion criteria were multiple-vessel disease and/or unprotected left main disease, acute coronary syndromes (ACS) with at least one severe (⩾70%) stenosis in any of major epicardial vessel. In-stent restenosis, protected left main stenosis, or impossibility to receive dual-antiplatelet therapy was an exclusion criterion. Major adverse cardiac events (MACE) were the primary endpoint and included cardiac death, myocardial infarction (MI), and target lesion revascularization (TLR); also, all components of the primary endpoint were separately analyzed. Completeness of revascularization was analyzed as post hoc data using residual SYNTAX or ERACI risk scores. Demographic characteristics showed that 6.5% of patients were very elderly, 22.5% have diabetes, 47% have multiple-vessel disease, 67% have ACS, and 32% have ST elevation MI. At a mean of 376 ± 18.1 days of follow-up, MACE was observed in 10.4% of patients: death + MI + cardiovascular accident (CVA) in 3% (6 of 201) and cardiac death + MI + CVA in 1.5% (3 of 201). Residual ERACI score ⩽5 was associated with 98% of event-free survival (P < .04). In conclusion, this prospective, multicenter, and observational all-comers registry with this novel BMS design showed a low incidence of adverse events at 1 year mainly due to coronary restenosis.