Expression of Circulating miR-21 and -29 and their Association with Myocardial Fibrosis in Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic Cardiomyopathy (HCM) is characterized by myocardial hypertrophy, fibrosis, and sarcomeric disarray. OBJECTIVE: To evaluate the expression levels of circulating miR-21 and -29 in patients with HCM and their association with clinical characteristics and myocardial fibrosis. METHODS: In this case-control study, 27 subjects with HCM, 13 subjects with hypertensive cardiomyopathy, and 10 control subjects were enrolled. Evaluation of patients' functional capacity was made by the six-minute walk test. Echocardiographic measurements of left ventricle systolic and diastolic function were conducted. Cardiac magnetic resonance late gadolinium enhancement (LGE) -through a semiquantitative evaluation- was used in the assessment of myocardial fibrosis extent in HCM patients. The expression of miR-21 and -29 in peripheral blood samples of all patients was measured via the method of quantitative reverse transcription polymerase chain reaction. RESULTS: Circulating levels of miR-21 were higher in both hypertensive and HCM (p<0.001) compared to controls, while expression of miR-29 did not differ between the three studied groups. In patients with HCM and LGE-detected myocardial fibrosis in more than 4 out of 17 myocardial segments, delta CT miR-21 values were lower than in patients with myocardial LGE in 3 or fewer myocardial segments (2.71 ± 1.06 deltaCT vs. 3.50 ± 0.55 deltaCT, p=0.04), indicating the higher expression of circulating miR-21 in patients with more extensive myocardial fibrosis. CONCLUSION: MiR-21 was overexpressed in patients with HCM and hypertensive cardiomyopathy. Importantly, in patients with HCM, more extensive myocardial fibrosis was associated with higher levels of miR-21.

The Role of Right Ventriculo-Arterial Coupling in Symptoms Presentation of Patients with Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. The hallmark of HCM is myocardial fibrosis which contributes to heart failure, arrhythmias, and sudden cardiac death (SCD). OBJECTIVE: To identify the factors implicated in heart failure symptoms and functional capacity of patients with HCM. METHODS: In this cohort study, 43 patients with HCM were recruited. According to functional capacity and symptoms presentation, patients were categorized according to New York Heart Association (NYHA) classification, and echocardiographic measurements of left ventricle systolic and diastolic function were conducted. The echocardiographic assessment of right ventriculo-arterial coupling (RVAC) was made by calculating the tricuspid annular peak systolic tissue Doppler velocity (TASV)/estimated RV systolic pressure (RVSP) ratio. RESULTS: Almost half (51%) of our study population present symptoms of heart failure and were categorized as the symptomatic group-NYHA 2 or higher. Maximum LVOT gradient, RVSP, and the ratio of E/e' were higher in the symptomatic group compared with the asymptomatic group. TASV was lower in the symptomatic group compared with the asymptomatic group (11 ± 1 cm/s vs. 13 ± 2 cm/s, p = 0.04). However, there was no difference in other potentially influential factors, such as heart rate or systemic blood pressure. The SCD risk score does not differ between the two studied groups. The RVAC (estimated with the TASV/RVSP ratio) was lower in the symptomatic group compared with the asymptomatic group (0.32 ± 0.09 vs. 0.46 ± 0.11, p < 0.001). CONCLUSION: A low RVAC (as estimated with TASV/RVSP ratio) value could represent an echocardiographic marker of right ventricular-arterial uncoupling in patients with HCM and impaired functional status.

The role of anti-eosinophilic therapies in eosinophilic granulomatosis with polyangiitis: a systematic review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, mostly affecting small-sized arteries and usually occurring in patients with an allergic background. Eosinophils seem to play a significant role in the pathogenesis of the disease and, therefore, biologics targeting interleukin 5 (IL5), a cytokine tightly linked to eosinophils, have emerged as a promising therapeutic tool. A systematic review of Medline was conducted from 2007 to 2022 to search for data regarding the use of anti-IL5 therapies in patients with EGPA. Ongoing or unpublished trials were also searched in ClinicalTrials.gov and the World Health Organization trials portal. The efficacy and safety of mepolizumab, an anti-IL5 monoclonal antibody (mAb), was confirmed by a randomized controlled trial (RCT), although a significant proportion of patients did not respond to this treatment. Other studies showed that both doses of 100 mg and 300 mg of mepolizumab are almost equally effective in EGPA. Benralizumab, an anti-IL5 receptor mAb has preliminary promising results and an RCT is planned to be conducted. Apart from their clinical efficacy in EGPA, anti-IL5 therapies may have steroid-sparing properties. Anti-IL5 therapies seem to be effective and safe in patients with refractory/relapsing EGPA and can be used as a steroid-sparing treatment. Nevertheless, more research is needed to clarify the pathophysiology of the disease; this may potentially lead to the identification of biomarkers to pinpoint patients most likely to respond to anti-IL5-blockade.

High-Sensitivity Troponin (hs-Tn) for Cardiovascular Risk Prognostication: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic low-grade inflammation is involved in coronary atherosclerosis progression whereas recent research efforts suggest that preventative methods should be tailored to the "residual inflammatory risk". As such, modalities for the early identification of the risk have to be investigated. METHODS: We performed a systematic review and meta-analysis according to the PRISMA guidelines. Any study that presented the prognostic value of high sensitivity troponin (hs-cTn) of vascular inflammation in stable patients without known cardiac heart disease was considered to be potentially eligible. The Medline (PubMed) database was searched up to April 22, 2021. The main endpoint was the difference in c-index (Δ[c-index]) with the use of hs-cTn for major adverse cardiovascular events (MACEs), cardiovascular and all-cause mortality. We calculated I² to test heterogeneity. RESULTS: In total, 44 studies and 112,288 stable patients without known coronary heart disease were included in this meta-analysis. The mean follow-up duration of the whole cohort was 6.8 ± 1.1 years. 77,004 (68.5%) of the patients presented with low cardiovascular risk while 35,284 (31.5%) in high. The overall pooled estimate of Δ[c-index] for MACE was 1.4% (95%CI: 0.7-2.1, I2=0%) and for cardiovascular death 1.3% (95%CI: 0.3-2.3, I2=0%). Finally, the overall pooled estimate of Δ[c-index] for all-cause mortality was 3% (95%CI: 1.9-3.9, I2=86%), while high heterogeneity was observed between the studies. CONCLUSION: The predictive usefulness of changes in hs-cTn measures in stable individuals with either high or low cardiovascular risk, demonstrates that assessing vascular inflammation in addition to clinical risk factors enhances risk prediction for cardiovascular events and all-cause mortality. Further prospective studies are necessary to confirm these findings and assist clinical decision-making regarding the most optimal prevention strategy.

Is there a Role for Anti-IL-5 Therapies in Eosinophilic Fasciitis?

Introduction: Eosinophilic Fasciitis (EF) is a rare disease, originally proposed as "diffuse fasciitis with eosinophilia" by Shulman in 1974. Symptoms of EF include peripheral eosinophilia accompanied by symmetrical inflammation of the subcutaneous fascia and muscle, usually locating in the upper arms or thighs. There is no approved standard of care treatment. Methods: Taking into account that eosinophils may be pathogenetically involved in EF, we performed a review on Medline focusing on anti-Interleukin-5 (IL-5) therapies in EF. Results: Only one case of a patient with EF has been reported who was successfully treated with reslizumab, an anti-IL-5 therapy. The patient had EF refractory to the commonly used immunosuppressive treatment but when reslizumab was added, the patient experienced remission of her symptoms. Discussion: The exact aetiology of EF is still unclear, and many therapeutic approaches have been tested. Commonly used immunosuppressive agents, such as corticosteroids are not always effective and associate with significant side effects. Eosinophils seem to have a role in the pathogenesis of the disease; anti-eosinophilic therapies targeting IL-5/IL-5 Receptor could be an attractive alternative for the treatment of the disease.

Cardiovascular risk stratification by coronary computed tomography angiography imaging: current state-of-the-art.

Current cardiovascular risk stratification by use of clinical risk score systems or plasma biomarkers is good but less than satisfactory in identifying patients at residual risk for coronary events. Recent clinical evidence puts now further emphasis on the role of coronary anatomy assessment by coronary computed tomography angiography (CCTA) for the management of patients with stable ischaemic heart disease. Available computed tomography (CT) technology allows the quantification of plaque burden, identification of high-risk plaques, or the functional assessment of coronary lesions for ischaemia detection and revascularization for refractory angina symptoms. The current CT armamentum is also further enhanced by perivascular Fat Attenuation Index (FAI), a non-invasive metric of coronary inflammation, which allows for the first time the direct quantification of the residual vascular inflammatory burden. Machine learning and radiomic features' extraction and spectral CT for tissue characterization are also expected to maximize the diagnostic and prognostic yield of CCTA. The combination of anatomical, functional, and biological information on coronary circulation by CCTA offers a unique toolkit for the risk stratification of patients, and patient selection for targeted aggressive prevention strategies. We hereby provide a review of the current state-of-the art in the field and discuss how integrating the full capacities of CCTA into clinical care pathways opens new opportunities for the tailored management of coronary artery disease.

Biomarkers of Vascular Inflammation for Cardiovascular Risk Prognostication: A Meta-Analysis.

OBJECTIVES: The purpose of this study was to systematically explore the added value of biomarkers of vascular inflammation for cardiovascular prognostication on top of clinical risk factors. BACKGROUND: Measurement of biomarkers of vascular inflammation is advocated for the risk stratification for coronary heart disease (CHD). METHODS: We systematically explored published reports in MEDLINE for cohort studies on the prognostic value of common biomarkers of vascular inflammation in stable patients without known CHD. These included common circulating inflammatory biomarkers (ie, C-reactive protein, interleukin-6 and tumor necrosis factor-a, arterial positron emission tomography/computed tomography and coronary computed tomography angiography-derived biomarkers of vascular inflammation, including anatomical high-risk plaque features and perivascular fat imaging. The main endpoint was the difference in c-index (Δ[c-index]) with the use of inflammatory biomarkers for major adverse cardiovascular events (MACEs) and mortality. We calculated I2 to test heterogeneity. This study is registered with PROSPERO (CRD42020181158). RESULTS: A total of 104,826 relevant studies were screened and a final of 39 independent studies (175,778 individuals) were included in the quantitative synthesis. Biomarkers of vascular inflammation provided added prognostic value for the composite endpoint and for MACEs only (pooled estimate for Δ[c-index]% 2.9, 95% CI: 1.7-4.1 and 3.1, 95% CI: 1.8-4.5, respectively). Coronary computed tomography angiography-related biomarkers were associated with the highest added prognostic value for MACEs: high-risk plaques 5.8%, 95% CI: 0.6 to 11.0, and perivascular adipose tissue (on top of coronary atherosclerosis extent and high-risk plaques): 8.2%, 95% CI: 4.0 to 12.5). In meta-regression analysis, the prognostic value of inflammatory biomarkers was independent of other confounders including study size, length of follow-up, population event incidence, the performance of the baseline model, and the level of statistical adjustment. Limitations in the published literature include the lack of reporting of other metrics of improvement of risk stratification, the net clinical benefit, or the cost-effectiveness of such biomarkers in clinical practice. CONCLUSIONS: The use of biomarkers of vascular inflammation enhances risk discrimination for cardiovascular events.

Machine learning of native T1 mapping radiomics for classification of hypertrophic cardiomyopathy phenotypes.

We explored whether radiomic features from T1 maps by cardiac magnetic resonance (CMR) could enhance the diagnostic value of T1 mapping in distinguishing health from disease and classifying cardiac disease phenotypes. A total of 149 patients (n = 30 with no heart disease, n = 30 with LVH, n = 61 with hypertrophic cardiomyopathy (HCM) and n = 28 with cardiac amyloidosis) undergoing a CMR scan were included in this study. We extracted a total of 850 radiomic features and explored their value in disease classification. We applied principal component analysis and unsupervised clustering in exploratory analysis, and then machine learning for feature selection of the best radiomic features that maximized the diagnostic value for cardiac disease classification. The first three principal components of the T1 radiomics were distinctively correlated with cardiac disease type. Unsupervised hierarchical clustering of the population by myocardial T1 radiomics was significantly associated with myocardial disease type (chi2 = 55.98, p < 0.0001). After feature selection, internal validation and external testing, a model of T1 radiomics had good diagnostic performance (AUC 0.753) for multinomial classification of disease phenotype (normal vs. LVH vs. HCM vs. cardiac amyloid). A subset of six radiomic features outperformed mean native T1 values for classification between myocardial health vs. disease and HCM phenocopies (AUC of T1 vs. radiomics model, for normal: 0.549 vs. 0.888; for LVH: 0.645 vs. 0.790; for HCM 0.541 vs. 0.638; and for cardiac amyloid 0.769 vs. 0.840). We show that myocardial texture assessed by native T1 maps is linked to features of cardiac disease. Myocardial radiomic phenotyping could enhance the diagnostic yield of T1 mapping for myocardial disease detection and classification.

Diagnosis of Evans syndrome.

This manuscript concerns the case of a patient hospitalized and diagnosed with Evans syndrome. She was hospitalized with signs of thrombocytopenia induced purpura, petechiae, ecchymosis and anemia. She was successfully treated with corticoids and blood transfusions. Our purpose is to explain her clinical presentation and the exams, we used in order to make the diagnosis of Evans syndrome, which requires great suspicion. Moreover, other diseases causing hemolytic anemia and thrombocytopenia must be excluded. We used laboratory tests (blood samples, Coombs examination and virologic test). Bone marrow examination took place twice. Evans syndrome is an autoimmune disease which is characterized by the coexistence of hemolytic anemia and immune-mediated thrombocytopenia. There is no typical clinical presentation. Its etiology is unknown and its therapy is generally poor. Diagnosis of Evans syndrome is very difficult and requires the exclusion of other diseases causing anemia and thrombocytopenia.

MicroRNAs as Biomarkers in Hypertrophic Cardiomyopathy: Current State of the Art.

BACKGROUND: Hypertrophic Cardiomyopathy (HCM) is the most common inherited Cardiomyopathy. The hallmark of HCM is myocardial fibrosis that contributes to heart failure, arrhythmias and sudden cardiac death. OBJECTIVE: Currently, there are no reliable serum biomarkers for the detection of myocardial fibrosis, while cardiac magnetic resonance (CMR) is an imaging technique to detect myocardial fibrosis. MicroRNAs (miRNAs) have been increasingly suggested as biomarkers in cardiovascular diseases. However, in HCM there is as yet no identified and verified specific circulating miRNA signature. METHODS: We conducted a review of the literature to identify the studies that indicate the possible roles of miRNAs in HCM. RESULTS: From studies in transgenic mice with HCM, miR-1, -133 may identify HCM in the early asymptomatic phase. Human miR-29a could be used as a circulating biomarker for detection of both myocardial hypertrophy and fibrosis in HCM, while it could also have a possible additional role in discrimination of hypertrophic obstructive cardiomyopathy from non-obstructive HCM. Additionally, miR-29a-3p is associated with diffuse myocardial fibrosis in HCM, while miR-1-3p could discriminate end-stage HCM from dilated cardiomyopathy and left ventricle dilation. Another role of miRNAs could also be the contribution in the differential diagnosis between HCM and phenocopies. Moreover, miRNA- targeted therapy (miR-133 mimics) is promising in inhibiting cardiac hypertrophy, but this is still in the early stages. CONCLUSION: A more reliable and specific signature of miRNAs is expected with forthcoming studies in samples from HCM patients and correlation of miRNAs with CMR and serum markers of fibrosis may implicate novel diagnostic and therapeutic pathways.

Antithrombotic Therapy in Carotid Artery Disease.

The management of asymptomatic atherosclerotic carotid artery disease and the role of antithrombotic therapy is of increasing importance for stroke prevention. Non-invasive imaging of carotid plaques can identify high-risk plaque features that are associated with the risk of plaque rupture. Carotid plaque necrosis, hemorrhage, fibrous cap thinning, and the presence of foam cells have all been correlated with the risk of rupture and onset of neurological symptoms in patients with carotid stenosis. Antiplatelets are currently recommended for patients with a history of ischemic stroke and/or significant carotid artery stenosis, with aspirin and clopidogrel being the most widely used and studied agents. The role of dual antiplatelet therapy remains controversial. Moreover, there is scarce evidence on the role of newer anticoagulant agents in stable patients with carotid artery stenosis. In this review article, we discuss the pathophysiology of carotid atherosclerosis, the use of non-invasive imaging for detecting the vulnerable carotid plaque and summarize the existing clinical evidence on the use of antiplatelet and antithrombotic agents in carotid artery disease.