Methotrexate & rheumatoid arthritis associated atherosclerosis: A narrative review of multidisciplinary approach for risk modification by the international board of experts.

Rheumatoid arthritis (RA) is an idiopathic, autoimmune connective tissue disorder that primarily affects the synovial joints, causing symmetric, erosive-deforming polyarthritis. It is also associated with extra-articular manifestations, particularly cardiovascular (CV) diseases (CVD). CV risk modification in RA remains unsolved despite recent advances in the management of RA. RA is an independent risk factor for atherosclerosis. RA and atherosclerosis share similar pathophysiological features (such as the pro-inflammatory cascade activation including interleukin-6) and risk factors (such as microflora dysbacteriosis and smoking). Patients with RA experience an exacerbation of atherogenesis, with atheromas destabilization, endothelial dysfunction, vasculitis, and hypercytokinemia. Consequently, the inflammatory response associated with RA is the basis for CVD development. The treat-to-target strategy not only improved RA control but also had a favorable effect on the morpho-functional state of the CV system in patients living with RA. Thus, disease-modifying antirheumatic drugs (DMARDs) - in particular methotrexate - may have a beneficial effect on the prevention of CV events in RA. It must be mentioned that RA is a serious multi-system disease, not only because of a window period during which the course of RA can be reversed, but also due to early damage to the heart and blood vessels. For this reason, a thorough cardiological assessment must be performed for all patients with RA, regardless of sex, age, disease stage, and disease activity score.

Diabetic Cardiomyopathy: 2023 Update by the International Multidisciplinary Board of Experts.

Diabetes mellitus (DM) is considered by many the pandemic of the 21st century and is associated with multiple organ damages. Among these, cardiovascular complications are responsible for an incredible burden of mortality and morbidity in Western Countries. The study of the pathological mechanisms responsible for the cardiovascular complications in DM patients is key for the development of new therapeutic strategies. The metabolic disorders caused by hyperglycemia, insulin resistance, and dyslipidemia, results in a cascade of pathomorphological changes favoring the atherosclerotic process and leading to myocardial remodeling. Parallel to this, oxidative stress, calcium overload, mitochondrial dysfunction, activation of protein kinase C signaling pathways, myocardial lipomatosis, and low-grade inflammation of the myocardium - are the main pathways responsible for the diabetic cardiomyopathy development. This review aims to appraise and discuss the pathogenetic mechanisms behind the diabetic cardiomyopathy development.

HIV-Related Atherosclerosis: State-of-the-Art-Review.

The infection caused by the Human Immunodeficiency Virus (HIV) has spread rapidly across the globe, assuming the characteristics of an epidemic in some regions. Thanks to the introduction of antiretroviral therapy into routine clinical practice, there was a considerable breakthrough in the treatment of HIV, that is now HIV is potentially well-controlled even in low-income countries. To date, HIV infection has moved from the group of life-threatening conditions to the group of chronic and well controlled ones and the quality of life and life expectancy of HIV+ people, with an undetectable viral load is closer to that of an HIV- people. However, unsolved issues still persist. For example: people living with HIV are more prone to the age-related diseases, especially atherosclerosis. For this reason, a better understanding of the mechanisms of HIV-associated destabilization of vascular homeostasis seems to be an urgent duty, that may lead to the development of new protocols, bringing the possibilities of pathogenetic therapies to a new level. The purpose of the article was to evaluate the pathological aspects of HIV-induced atherosclerosis.

AC-Mode of Chemotherapy as a Trigger of Cardiac Syndrome X: A Case Study.

In the period of dynamic development of pharmacological possibilities in the modern oncology, unfortunately, the issue of cardiotoxicity of chemotherapy did not lost its urgent value. Cardiotoxicity implies structural and functional myocardial alteration, together with an increase in the concentration of highly sensitive markers of myocardial necrosis, in particular T and I troponins, and N-terminal pro-BNP, as well as with a subclinical or clinical decrease in the LVEF. It is noteworthy that cardiotoxicity is manifested not only by the development of anthracycline cardiomyopathy with a high risk of convention into heart failure. It also can cause various cardiovascular pathologies, in particular cardiac syndrome X. This study described chemotherapy-induced microvascular angina in 23-year-old otherwise heathy woman. The diagnosis is challenging for doctors, since microvascular flow may be only detected by using functional test.

Characteristics and Risk Factors of Yemeni Patients Presenting with Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA).

Background: Myocardial infarction with non-obstructive coronary artery (MINOCA) is a syndrome, which requires both clinical documentation of ST-elevation myocardial infarction (STEMI) (abnormal cardiac biomarker, ischemic symptoms, and electrocardiography changes) and detection of nonobstructive coronary arteries. The purpose of this study is to determine the incidence of and characteristics of patients with MINOCA in the Yemeni population. Methods: Consecutive patients admitted between January and June 2019 at Al-Thawra Hospital, Sana'a (Yemen), with STEMI diagnosis were enrolled in this study. Demographic, clinical, echocardiographic, and coronary angiography characteristics of patients were noted. Results: MINOCA was identified in 63 patients (25%) out of 249 admitted with STEMI diagnosis at Al-Thawra Hospital. The mean age of MINOCA patients was similar to obstructive coronary group; however, they were more often females and less frequently with diabetes and family history of coronary artery disease. Other risk factors like smoking, arterial hypertension, dyslipidemia, and oral tobacco were similar. Conversely, the percentage of Khat chewers was significantly higher in the MINOCA patients (P < 0.01) as compared to obstructive group. Conclusions: The relatively high incidence of MINOCA in our country and the long list of multiple potential causes of MINOCA should open further working diagnosis after coronary angiography and further efforts for defining the cause of myocardial infarction in each individual patient in Middle East countries.

Myocarditis and intramural coronary vasculitis in polyarteritis nodosa: an unusual treatable form of heart failure.

We describe an uncommon cardiac presentation of polyarteritis nodosa. A 68-year-old woman, with a history of fatigue, weight loss, and myalgia of the lower extremities, was admitted for congestive heart failure. Coronary arteries were normal. Endomyocardial biopsy showed active lymphocytic myocarditis with associated intramural small vessels necrotizing vasculitis. The overexpression of TLR-4 and the negativity for myocardial viruses suggested an immune mediated mechanism of cardiac damage. These histologic findings associated to weight loss >4 kg not due to dieting or other factors, myalgias, and polyneuropathy, were consistent with the diagnosis of polyarteritis nodosa. Immunosuppressive treatment, consisting of cyclophosphamide and prednisolone, led to a significant improvement of cardiac function. Polyarteritis nodosa can be the cause of unexplained heart failure due to myocarditis and intramural vessels vasculitis. Its recognition is crucial to obtain a cardiac recovery with a tailored immunosuppressive treatment.

An exploratory cross-sectional study of subclinical vascular damage in patients with polymyalgia rheumatica.

The aim of the study was to investigate the presence of subclinical vascular damage in polymyalgia rheumatica (PMR). We enrolled PMR patients having major cardiovascular risk factors (MCVRF) and, as controls, patients with MCVRF. All underwent: color Doppler ultrasound to evaluate the common carotid intima-media thickness (IMT), the anterior-posterior abdominal aortic diameter (APAD), and the prevalence of carotid artery stenosis; the cardio-ankle vascular index (CAVI) to measure arterial stiffness together with the ankle-brachial index (ABI) to investigate the presence of lower-extremity peripheral arterial disease. Finally, we measured the serum levels of adipocytokines implicated in vascular dysfunction. As a result, 48 PMR and 56 MCVRF patients were included. An increase of IMT (1.07/0.8-1.2 vs 0.8/0.8-1.05; p = 0.0001), CAVI (8.7/7.8-9.3 vs 7.6/6.9-7.8; p < 0.0001) and APAD values (21.15/18.1-25.6 vs 18/16-22; p = 0.0013) was found in PMR patients with respect to controls. No differences were reported in the prevalence of carotid artery stenosis or ABI values between the two groups. A significant correlation between IMT and CAVI in PMR and MCVRF subjects (r2 = 0.845 and r2 = 0.556, respectively; p < 0.01) was found. Leptin levels (pg/mL; median/25th-75th percentile) were higher in PMR than in MCVRF subjects (145.1/67-398.6 vs 59.5/39.3-194.3; p = 0.04). Serum levels of adiponectin (ng/mL) were higher in PMR patients (15.9/10.65-24.1 vs 6.1/2.8-22.7; p = 0.01), while no difference in serum levels of resistin (ng/mL) was found between PMR and MCVRF subjects (0.37/0.16-0.66 vs 0.26/0.14-1.24). Our study shows an increased subclinical vascular damage in PMR patients compared to those with MCVRF, paving the way for further studies aimed at planning primary cardiovascular prevention in this population.

Echocardiography and Correction of Mitral Regurgitation: An Unbreakable Link.

BACKGROUND: Degenerative mitral valve (MV) disease causing mitral regurgitation (MR) is the most common organic valve pathology and is classified based on leaflet motion. MV repair is indicated as the preferred technique (Class I indication) when the results are expected to be durable. Therefore, a detailed and systematic evaluation of MV apparatus is pivotal in allowing the proper surgical planning, as well as the screening for trans catheter-based treatment when surgery is not indicated. AIM: The aim of the present review is to describe the crucial role of both Transthoracic Echocardiography (TTE) and Transesophageal Echocardiography (TEE) in the decisional process and the guidance of MV repair procedures. TTE is the main investigation and the first approach used to make diagnosis of MR, to assess the severity and to describe the underlying mechanism, while TEE, especially with 3D echocardiography, has been shown to be useful for clarifying complicated valvular anatomy, assessing the surgical result and detecting complications. The surgical treatment of MR takes advantage of ultrasound evaluation of MV apparatus at any stage of the process, thus making the link between surgery and echocardiography unbreakable throughout the perioperative phase.

2D/3D echocardiographic determinants of left ventricular reverse remodelling after MitraClip implantation.

AIMS: The aim of this study was to describe incidence and determinants of left ventricular reverse remodelling (r-LVR) at 6 months follow-up after MitraClip implantation in patients with secondary severe mitral regurgitation (MR) and reduced left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Forty-five patients, undergoing MitralClip implantation with low ejection fraction and high surgical risk were enrolled in this study. Three of them died before the scheduled 6 months follow-up period and one patient had cardiac surgery due to MitraClip detachment. All patients underwent transthoracic 2D and 3D echocardiography before and 6 months after the procedure. A significant MR severity reduction and an improvement in New York Heart Association (NYHA) class were detected in all patients. The study population was divided in two groups according to the presence of r-LVR (51%, n = 23 patients) or not (non-rLVR group, 18 patients). Non-significant differences in MR aetiology and number of clips implanted were found. Left ventricular reverse remodelling patients showed significant lower values of logistic EuroSCORE and STS score, left ventricular end-diastolic volume index (LVEDV/i), right ventricular end systolic area, and pulmonary artery systolic pressure (PASp) at baseline evaluation. At multivariable analysis, baseline PASp value resulted to be the only independent predictor of r-LVR [odds ratio 95% confidence interval 0.94 (0.89-0.99), P = 0.021]. In r-LVR patients, a significant improvement in LVEF and global longitudinal strain and a reduction in left atrial volume index were detected after 6 months, whereas in non-rLVR subgroup a significant increase in both LVEDV/i and left ventricular end-systolic volume index was observed at follow-up. CONCLUSION: Even if a reduction of MR was detected in all patients after MitralClip implant, our findings suggest that end-stage patients presenting with higher left ventricular volumes, logistic scores, and PASp may not benefit from the procedure at longer follow-up in terms of left ventricular function.

Mediterranean diet adherence and synergy with acute myocardial infarction and its determinants: A multicenter case-control study in Italy.

BACKGROUND: Cardiovascular diseases are the leading causes of mortality and morbidity in Western countries. The possible synergistic effect of poor adherence to a Mediterranean diet (MD) and other risk factors for acute myocardial infarction (AMI) such as hypertension, cholesterol, ever smoker, BMI> 25, diabetes, has not been deeply studied. DESIGN: Case-control study. METHODS: Patients with first AMI and controls from four tertiary referral Italian centers were screened for enrolment. Dietary information was collected through a questionnaire and a MD adherence score was calculated. Physical activity and smoking habits were also registered. The Synergy Index was calculated according to Rothman. RESULTS: 127 cases and 173 controls were enrolled. The analysis was conducted using a dichotomous variable for the MD score with values ≥7 representing good adherence. Multivariate analysis showed the following variables associated to AMI: ever smoker (OR = 2.08), diabetes (OR = 1.42), hypertension (OR = 2.08), hypercholesterolemia (OR = 2.47), BMI> 25 (OR = 1.99), while a protective effect emerged both in subjects scoring > 7 on the MD score (OR = 0.55) and in subjects resident of Southern Italy (OR = 0.38). A synergistic effect does exist between poor adherence to the MD and the following risk factors: hypertension, hypercholesterolemia, BMI >25, diabetes and being a resident in central and northern Italy. CONCLUSION: Synergy between heart disease risk factors and MD underlines the need to enlarge the list of known modifiable cardiovascular risk factors to include and promote adherence to Mediterranean dietary habits.

Impact of active smoking on myocardial infarction severity in reperfused ST-segment elevation myocardial infarction patients: the smoker's paradox revisited.

AIMS: To investigate the influence of cardiovascular risk factors (CV-RFs) on infarct severity and post-infarction left ventricular (LV) remodelling in acutely reperfused ST-segment elevation myocardial infarction (STEMI) patients studied with cardiovascular magnetic resonance (CMR). METHODS AND RESULTS: Four-hundred seventy-one patients were included in the study. Baseline CMR was performed at 4 ± 1 days after STEMI to assess area-at-risk, infarct size (IS), myocardial salvage index (MSI), microvascular obstruction (MVO), intramyocardial haemorrhage (IMH), LV volumes, and function. Cardiovascular magnetic resonance was repeated 4 months after STEMI (n = 383) to assess adverse LV remodelling (increase of LV end-diastolic volume >20% between baseline and follow-up). Smoking was associated with IMH at baseline even after correction for other factors associated with ischaemia-reperfusion injury including MVO, IS, and MSI (OR: 2.17, 95% CI: 1.17-4.00, P = 0.01). Unexpectedly, smoking was an independent protective predictor against adverse LV remodelling (OR: 0.43, 95% CI: 0.24-0.77, P = 0.005), consistent with the 'smoker's paradox'. However, the presence of IMH at baseline abolished the paradoxical, beneficial effects of smoking with respect to IS, baseline LV function, and post-infarction LV remodelling. No association between other CV-RFs, infarct severity, or post-infarction LV remodelling was observed. CONCLUSION: In patients with reperfused STEMI, smoking is strongly and independently associated with IMH at baseline. Nonetheless, consistent with the 'smoker's paradox', smoking was an independent predictor of more favourable post-infarction LV remodelling. However, the paradoxical beneficial effects of smoking were lost in patients with IMH.

Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis.

Chronic inflammatory diseases such as rheumatoid arthritis (RA) are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to the impairment of endothelial function, the earlier and reversible stage of atherosclerotic plaque formation. Since tumor necrosis factor (TNF) inhibits enzymatic degradation of ADMA, anti-TNF agents could restore its physiological level. The aim of this study was to investigate the effect of TNF inhibitors on ADMA serum levels in patients with RA. Our results suggest a possible effect of anti-TNF drugs on ADMA serum levels; longer studies would be necessary to confirm the role ADMA in assessing cardiovascular risk in RA.

Altered glucose homeostasis is associated with increased serum apelin levels in type 2 diabetes mellitus.

BACKGROUND: Apelin is an adipokine that plays a role in the regulation of glucose homeostasis and in obesity. The relationship between apelin serum concentration and dysmetabolic conditions such as type 2 diabetes (T2D) is still controversial. Aims of our study are: 1) determine the circulating levels of apelin in a large cohort of Italian subjects with T2D, T1D and in non-diabetic controls; 2) identify putative metabolic determinants of modified apelin concentrations, in order to search possible mechanism of apelin control; 3) investigate changes in apelin levels in response to sharp modifications of glucose/insulin metabolism in T2D obese subjects before and 3 days after bariatric surgery. METHODS: We recruited 369 subjects, 119 with T2D, 113 with T1D and 137 non-diabetic controls. All subjects underwent a complete clinical examination, including anthropometric and laboratory measurements. Serum apelin levels were determined by EIA (immunoenzyme assay). RESULTS: Patients with T2D had significantly higher serum apelin levels compared to controls (1.23 ± 1.1 ng/mL vs 0.91 ± 0.7 ng/mL, P<0.001) and to T1D subjects (0.73 ± 0.39 ng/mL, P<0.001). Controls and T1D subjects did not differ significantly in apelin levels. Apelin concentrations were directly associated with fasting blood glucose (FBG), body mass index (BMI), basal Disposition Index (DI-0), age, and diagnosis of T2D at bivariate correlation analysis. Multiple regression analysis confirmed that diagnosis of T2D, basal DI-0 and FBG were all determinants of serum apelin levels independently from age and BMI. Bariatric surgery performed in a subgroup of obese diabetic subjects (n = 12) resulted in a significant reduction of apelin concentrations compared to baseline levels (P = 0.01). CONCLUSIONS: Our study demonstrates that T2D, but not T1D, is associated with increased serum apelin levels compared to non-diabetic subjects. This association is dependent on impaired glucose homeostasis, and disappears after bariatric surgery, providing further evidence regarding the relationship between apelin and the regulation of glucose metabolism.

Correlation between coronary artery disease severity, left ventricular mass index and carotid intima media thickness, assessed by radio-frequency.

BACKGROUND: Intima-media thickness of the common carotid artery (CCA-IMT) is a validated marker of systemic atherosclerosis process. The aim of this study was to evaluate the association between coronary artery disease (CAD), left ventricular hypertrophy (LVH) and CCA-IMT, assessed by Radio Frequency-Quality Intima Media Thickness (RFQIMT) method, the next generation of IMT real-time measurement, based on the direct analysis of the radiofrequency signal and endowed with high accuracy and reproducibility in early detection of arterial wall thickness. METHODS: 115 patients (76 men, mean age: 65.1 ± 12 years) referred to our department and shown significant (≥ 70% luminal obstruction) stenosis at least in one major epicardial coronary artery were studied. Coronary angiograms were divided for severity and extent of the disease: 79 patients (69%) had one, 24 patients (21%) two, 12 patients (10%) three major epicardial coronary arteries with ≥ 70% stenosis. All patients underwent echocardiography and carotid ultrasound examination, assessed by RF. RESULTS: Dividing RFQIMT data in tertiles, dyslipidaemia (31 patients with IMT ≥ 1.20 mm vs 16 with IMT = 0.91-1.19 vs 25 with IMT ≤ 0.9, p = 0.004), LVMI (153.5 ± 20.6 g/m² in IMT ≥ 1.20 mm vs 131.2 ± 8.4 g/m² in IMT = 0.91-1.19 mm vs 114.3 ± 11.1 g/m² in IMT ≤ 0.9 mm, P < 0.001) and number of high stenosed coronary arteries (IMT ≥ 1.20 mm population more often showed three vessel diseases than IMT ≤ 0.90 mm one, P < 0.001) seemed to be significantly related to CCA-IMT increases. Furthermore, LVMI is positively related to IMT (r = 0.91; P < 0.001). In a multivariate regression model (R2 = 0.88), RFQIMT remained significantly associated with the dyslipidemia (regression coefficient ± standard error [SE]: 0.057 ± 0.023; p = 0.017), LVMI (regression coefficient ± SE: 0.01 ± 0.001; P < 0.0001) and number of damaged coronaries (regression coefficient ± SE: 0.0174 ± 0.028; P < 0.0001). CONCLUSIONS: RFQIMT is a sophisticated method for carotid ultrasound evaluation. Its evaluation in patients with at least one important major epicardial coronary vessel stenosis would help the accuracy in the general assessment of the number of coronary lesions in these patients.

Severe oligozoospermia in a young man with chronic myeloid leukemia on long-term treatment with imatinib started before puberty.

OBJECTIVE: To report the effect of long-term treatment with the tyrosine kinase inhibitor imatinib started before the onset of puberty on semen parameters, bone mineral density, and hormone values. DESIGN: Case report. SETTING: University hospital. PATIENT(S): An 18-year-old man given treatment with imatinib for chronic myeloid leukemia. INTERVENTION(S): Clinical, biochemical and dual-energy X-ray absorptiometry evaluations. MAIN OUTCOME MEASURE(S): Semen analysis, serum levels of gonadotropins, inhibin-B, and testosterone, bone mineral density, markers of skeletal homeostasis. RESULT(S): Semen analyses showed severe oligozoospermia after long-term administration of imatinib started before puberty. The inhibin-B/FSH ratio was reduced. A low bone mineral density for chronologic age was observed. CONCLUSION(S): This case study documents the potential risk of an impairment of semen parameters in patients undergoing a treatment with tyrosine kinase inhibitors before the complete maturation of the testis.

3D echocardiographic delineation of mitral-aortic intervalular fibrosa pseudoaneurysm caused by bicuspid aortic valve endocarditis.

Pseudoaneurysm of the mitral-aortic intervalvular fibrosa is a rare complication of infective endocarditis of the aortic valve eventually resulting in coronary artery compression, stroke or rupture into the left atrium, aorta or pericardial space. A prompt diagnosis by either transthoracic or transesophageal echocardiography is mandatory to address the patient to cardiac surgery. We report the clinical case of a 25-year-old white man who was admitted to the emergency department for dyspnoea and fever. Echocardiographic examination showed a bicuspid aortic valve with a huge sessile vegetation and a pseudaneurysm of the mitral-aortic intervalvular fibrosa. In addition to conventional two-dimensional examination, three-dimensional echocardiography provided additional information of this complication, precisely delineating the lesions and addressing the cardiac surgeon in choosing the most appropriate operating strategy. Patient underwent then aortic root replacement and the pseudoaneurysm was closed by means of a bovine pericardial patch.

Update on phase II studies of erythropoietin in acute myocardial infarction. Rationale and design of Exogenous erythroPoietin in Acute Myocardial Infarction: New Outlook aNd Dose Association Study (EPAMINONDAS).

Erythropoietin (Epo) is a hematopoietic hormone produced mainly by the kidneys in response to hypoxia. Recent acquisitions in the fields of hematology, neurology, cardiology, and experimental medicine show cytoprotective, angiogenetic and antiinflammatory effects of Epo. Exogenous erythroPoietin in Acute Myocardial Infarction: New Outlook aNd Dose Association Study (EPAMINONDAS, EudraCTno. 200500485386) is one of four ongoing randomized controlled trials, each testing the effects of Epo in >or=100 patients with STEMI. EPAMINONDAS is a multicenter, prospective, double-blind, placebo-controlled, dose-finding study assessing intravenous moderate doses of human recombinant Epo (epoietin-alpha, 100 or 200 IU/kg/die) versus placebo, given on the first 3 days, in 102 patients with first ST-segment elevation myocardial infarction. Initial dosing is within 12 h of primary percutaneous coronary revascularization. The primary endpoint is infarct size, quantified by CK-MB time-concentration curve, left ventricular wall motion score index, and pattern of contrast-enhanced magnetic resonance imaging. Secondary endpoints are ischemic recurrences, ventricular remodelling, and safety events, assessed in-hospital and at 12 months' follow-up. The results of current phase II studies will help define the safety/efficacy profile of Epo for patients with STEMI.