Dose-dependent effects of acetaminophen and ibuprofen on mitochondrial respiration of human platelets.

Acetaminophen and ibuprofen are widely used over-the-counter medications to reduce fever, pain, and inflammation. Although both drugs are safe in therapeutic concentrations, self-medication is practiced by millions of aged patients with comorbidities that decrease drug metabolism and/or excretion, thus raising the risk of overdosage. Mitochondrial dysfunction has emerged as an important pathomechanism underlying the organ toxicity of both drugs. Assessment of mitochondrial oxygen consumption in peripheral blood cells is a novel research field Cu several applications, including characterization of drug toxicity. The present study, conducted in human platelets isolated from blood donor-derived buffy coat, was aimed at assessing the acute, concentration-dependent effects of each drug on mitochondrial respiration. Using the high-resolution respirometry technique, a concentration-dependent decrease of oxygen consumption in both intact and permeabilized platelets was found for either drug, mainly by inhibiting complex I-supported active respiration. Moreover, ibuprofen significantly decreased the maximal capacity of the electron transport system already from the lowest concentration. In conclusion, platelets from healthy donors represents a population of cells easily available, which can be routinely used in studies assessing mitochondrial drug toxicity. Whether these results can be recapitulated in patients treated with these medications is worth further investigation as potential peripheral biomarker of drug overdose.

Monoamine oxidase is a source of cardiac oxidative stress in obese rats: the beneficial role of metformin.

Diet-induced metabolic diseases, such as obesity, metabolic syndrome, and type 2 diabetes (T2DM) are the global threatening epidemics that share cardiovascular oxidative stress as common denominator. Monoamine oxidase (MAO) has recently emerged as a constant source of reactive oxygen species (ROS) in DM. Metformin, the first-line drug in T2DM, elicits cardiovascular protection via pleiotropic effects. The present study was aimed to assess the contribution of MAO to the early cardiac oxidative stress in a rat model of high-calorie junk food (HCJF) diet-induced obesity and prediabetes and whether metformin can alleviate it. After 6 months of HCJF, rats developed obesity and hyperglycemia. Hearts were isolated and used for the evaluation of MAO expression and ROS production. Experiments were performed in the presence vs absence of metformin (10 µM) and MAO-A and B inhibitors (clorgyline and selegiline, 10 µM), respectively. Both MAO isoforms were overexpressed and led to increased ROS generation in cardiac samples harvested from the obese animals. Acute treatment with metformin and MAO inhibitors was able to mitigate oxidative stress. More important, metformin downregulated MAO expression in the diseased samples. In conclusion, MAO contributes to oxidative stress in experimental obesity and can be targeted with metformin.

Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed.

Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature.

Monoamine Oxidase (MAO) Is Expressed at the Level of Mitral Valve with Severe Regurgitation in Hypertrophic Obstructive Cardiomyopathy: A Case Report.

Hypertrophic obstructive cardiomyopathy (HOCM) is one of the most common hereditary heart diseases. The severely hypertrophied interventricular septum combined with the systolic anterior movement (SAM) of the mitral valve (MV) frequently cause a significant pressure gradient in the left ventricular outflow tract associated with varying degrees of mitral regurgitation (MR). We present the case of a 64-year-old female patient who was diagnosed with HOCM two years ago and was admitted to the Institute of Cardiovascular Disease with exertion dyspnea and fatigue. Transthoracic echocardiography revealed concentric, asymmetrical left ventricular hypertrophy, an elongated anterior mitral leaflet (AML) and a significant SAM causing severe regurgitation, with indication for valvular replacement Monoamine oxidase (MAO), a mitochondrial enzyme, with 2 isoforms, MAO-A and B, has emerged as an important source of reactive oxygen species (ROS) in the cardiovascular system, but literature data on its expression in valvular tissue is scarce. Therefore, we assessed MAO-A and B gene (qPCR) and protein (immune fluorescence) expression as well as ROS production (spectrophotometry and confocal microscopy) and in the explanted MV harvested during replacement surgery. MAO expression and ROS production (assessed by both methods) were further augmented following ex vivo incubation with angiotensin II, an effect that was reversed in the presence of either MAO-A (clorgyline) or B (selegiline) inhibitor, respectively. In conclusion, MAO isoforms are expressed at the level of severely impaired mitral valve in the setting of HOCM and can be induced in conditions that mimic the activation of renin-angiotensin-aldosterone system. The observation that the enzyme can be modulated by MAO inhibitors warrants further investigation in a patient cohort.

Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity.

Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in humans. It has previously been demonstrated that amiodarone and its metabolite (desethylamiodarone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the electron transport system in various animal tissues and cell types. The present study, performed in human peripheral blood cells, and one liver-derived human cell line, is primarily aimed at assessing the concentration-dependent effects of these drugs on mitochondrial function (respiration and cellular ATP levels). Furthermore, we explore the efficacy of a novel cell-permeable succinate prodrug in alleviating the drug-induced acute mitochondrial dysfunction. Amiodarone and DEA elicit a concentration-dependent impairment of mitochondrial respiration in both intact and permeabilized platelets via the inhibition of both CI- and CII-supported respiration. The inhibitory effect seen in human platelets is also confirmed in mononuclear cells (PBMCs) and HepG2 cells. Additionally, amiodarone elicits a severe concentration-dependent ATP depletion in PBMCs, which cannot be explained solely by mitochondrial inhibition. The succinate prodrug NV118 alleviates the respiratory deficit in platelets and HepG2 cells acutely exposed to amiodarone. In conclusion, amiodarone severely inhibits metabolism in primary human mitochondria, which can be counteracted by increasing mitochondrial function using intracellular delivery of succinate.

Therapeutic Advances in Emergency Cardiology: A Focus on Acute Myocarditis.

BACKGROUND: Myocarditis, defined as an inflammation of the myocardium, is an important cause of dilated cardiomyopathy and congestive heart failure. Unfortunately, its diagnosis and etiology is often challenging in clinical practice, and thus, improving diagnosis and therapeutic approach of this cardiac pathology is a matter of great interest. AREAS OF UNCERTAINTY: The etiology of the disease may be represented by not only infectious agents, usually with viral determination, but also autoimmune and systemic diseases or drugs. Regarding diagnostic techniques, endomyocardial biopsy remains the gold standard; but beyond histological findings, an important step in achieving an accurate diagnosis was represented by the use immunohistochemical criteria and noninvasive diagnostic tests such as cardiac magnetic resonance imaging. DATA SOURCES: We reviewed current data on the current diagnosis and therapeutic approach of acute myocarditis. THERAPEUTIC ADVANCES: In addition to the standard heart failure therapy, some specific therapeutic options are available in selected cases. Viral myocarditis with persistent inflammation and viral clearance may be responsive to immunosuppressive therapy with azathioprine and cortisone or to immunoadsorption technique. Also, some chronic viral myocardial infections may benefit from 6 months of interferon-ß therapy. CONCLUSIONS: The diagnosis of acute myocarditis still remains a great challenge, despite advances related to new diagnostic procedures. Endomyocardial biopsy, an invasive diagnostic tool that is not always usually available in clinical practice, still remains the standard diagnostic technique. Due to the potential evolution of acute myocarditis, identifying new parameters that may allow an early selection of patients with great risk of evolution toward myocardial fibrosis and dilated cardiomyopathy may be a field of great interest for future studies.

Current Perspectives in Facilitated Angioplasty.

BACKGROUND: Ischemic heart disease represents the most important cause of mortality worldwide, and the management of patients with ST-elevation myocardial infarction (STEMI) still remains a great challenge. For a great number of patients who do not have immediate access to primary percutaneous coronary intervention (PCI), facilitated angioplasty may be a reasonable therapeutic option. AREAS OF UNCERTAINTY: The goal of reperfusion therapy is achieving repermeabilization of the infarct-related artery. However, the restoration of normal epicardial flow is not always followed by microvascular tissue perfusion and the presence of myocardial blush. Early studies assessing the benefits of facilitated angioplasty over primary PCI encountered disappointing results, with an increased number of bleeding complications. The invasive strategy following fibrinolysis mainly consists in angiography and PCI of the infarct-related artery between 2 and 24 hours after successful fibrinolysis or rescue PCI in failed fibrinolysis, hemodynamic, electrical instability, or worsening ischemia. Currently, a strategy of routine early angiography after fibrinolysis is recommended, taking into account studies that have demonstrated a reduced rate of reinfarction and recurrent ischemia, without an increased risk of stroke or major bleeding complications. THERAPEUTIC ADVANCES: After evaluating 1892 patients with STEMI within 3 hours after the onset of symptoms and revealing, beyond clear benefit of fibrinolysis, an increased risk of bleeding complications, the STREAM trial was the one that led to halving the tenecteplase dose for patients aged >75 years. A safety profile of adjusted-dose fibrinolytic therapy in elderly patients with STEMI will be further investigated by the ongoing STREAM-2 trial. CONCLUSIONS: With the current increased burden of acute coronary syndromes and the lack of immediate primary PCI facilities for all patients with STEMI, facilitated angioplasty seems a feasible therapeutic option. Another benefit of facilitated angioplasty may be represented by a major contribution of thrombolytic therapy in re-establishing microvascular myocardial blood flow.

Risk stratification in patients with heart failure: the value of considering both global longitudinal left ventricular strain and mechanical dispersion.

In previous studies, mechanical dispersion (MD) predicted ventricular arrhythmias independently of left ventricular ejection fraction (LVEF). Moreover, the combination of MD and global longitudinal strain (GLS) increased the prediction of arrhythmic events. We investigated the prognostic value of a new 2-dimensional strain index, GLS/MD, in patients with heart failure (HF). We analyzed 340 consecutive HF outpatients in sinus rhythm. Echocardiography was performed at 1.6 ± 0.4 months after hospital discharge. The end point included sudden cardiac death, ventricular fibrillation, and sustained ventricular tachycardia (SCD/VA). During the follow-up period (36 ± 9 months), SCD/VA occurred in 48 patients (14.1%). A multivariate Cox regression analysis, which included LVEF, early diastolic transmitral / mitral annular velocity ratio (E/E'), GLS, MD, and GLS/MD in the model, revealed that GLS/MD was the best independent predictor of SCD/VA (HR = 3.22, 95% confidence interval = 1.72-6.15, p = 0.03). Separate inclusion of LVEF, systolic mitral annular velocity, E/E', GLS, and MD together with GLS/MD showed that GLS/MD remained the best predictor of SCD/VA (each p < 0.05). The optimal GLS/MD cutoff value to predict SCA/VA was -0.20%/ms (80% sensitivity, 76% specificity). Irrespective of LVEF, free survival was significantly better in patients with GLS/MD ≤ -0.2%/ms (log-rank test, p < 0.001). In conclusion, GLS/MD may improve cardiovascular risk stratification in subjects with HF.

Perindopril Induces TSP-1 Expression in Hypertensive Patients with Endothelial Dysfunction in Chronic Treatment.

Thrombospondin-1 (TSP-1) is a potent endogenous inhibitor of both physiological and pathological angiogenesis, widely studied as a target in drug development for treating cancer. Several studies performed in the cardiovascular field on TSP-1 are contradictory, the role of TSP-1 in the physiopathology of cardiovascular disorders (CVDs) being, for the moment, incompletely understood and may be due to the presence of several domains in its structure which can stimulate many cellular receptors. It has been reported to inhibit NO-mediated signaling and to act on the angiogenesis, tissue perfusion, endothelial cell proliferation, and homeostasis, so we aimed to quantify the effect Perindopril has on TSP-1 plasma levels in hypertensive patients with endothelial dysfunction in comparison with other antihypertensive drugs, such as beta blockers, calcium channel blockers, and diuretics, in a chronic treatment. As a conclusion, patients under treatment with Perindopril had increased plasma levels of TSP-1 compared with other hypertensive patients and with the control group. The results of this study confirms the pleiotropic properties of Perindopril: anti-proliferative, anti-inflammatory, with effects showed by quantifying a single biomarker: TSP-1.

Prognosis and treatment of atrial fibrillation patients by European cardiologists: one year follow-up of the EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase (EORP-AF Pilot registry).

BACKGROUND: The EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase (EORP-AF Pilot) provides systematic collection of contemporary data regarding the management and treatment of 3119 subjects with AF from 9 member European Society of Cardiology (ESC) countries. In this analysis, we report the development of symptoms, use of antithrombotic therapy and rate vs. rhythm strategies, as well as determinants of mortality and/or stroke/transient ischaemic attack (TIA)/peripheral embolism during 1-year follow-up in this contemporary European registry of AF patients. METHODS: The registry population comprised consecutive in- and out-patients with AF presenting to cardiologists in participating ESC countries. Consecutive patients with AF documented by ECG were enrolled. Follow-up was performed by the local investigator, initially at 1 year, as part of a long-term cohort study. RESULTS: At the follow-up, patients were frequently asymptomatic (76.8%), but symptoms are nevertheless common among paroxysmal and persistent AF patients, especially palpitations, fatigue, and shortness of breath. Oral anticoagulant (OAC) use remains high, ∼78% overall at follow-up, and of those on vitamin K antagonist (VKA), 84% remained on VKA during the follow-up, while of those on non-VKA oral anticoagulant (NOAC) at baseline, 86% remained on NOAC, and 11.8% had changed to a VKA and 1.1% to antiplatelet therapy. Digitalis was commonly used in paroxysmal AF patients. Of rhythm control interventions, electrical cardioversion was performed in 9.7%, pharmacological cardioversion in 5.1%, and catheter ablation in 4.4%. Despite good adherence to anticoagulation, 1-year mortality was high (5.7%), with most deaths were cardiovascular (70%). Hospital readmissions were common, especially for atrial tachyarrhythmias and heart failure. On multivariate analysis, independent baseline predictors for mortality and/or stroke/TIA/peripheral embolism were age, AF as primary presentation, previous TIA, chronic kidney disease, chronic heart failure, malignancy, and minor bleeding. Independent predictors of mortality were age, chronic kidney disease, AF as primary presentation, prior TIA, chronic obstructive pulmonary disease, malignancy, minor bleeding, and diuretic use. Statin use was predictive of lower mortality. CONCLUSION: In this 1-year follow-up analysis of the EORP-AF pilot general registry, we provide data on the first contemporary registry focused on management practices among European cardiologists, conducted since the publication of the new ESC guidelines. Overall OAC use remains high, although persistence with therapy may be problematic. Nonetheless, continued OAC use was more common than in prior reports. Despite the high prescription of OAC, 1-year mortality and morbidity remain high in AF patients, particularly from heart failure and hospitalizations.

The Significance of Inflammation in Atrial Fibrillation.

AIM: The aim of the study was to assess the inflammatory status in individuals diagnosed with atrial fibrillation (Afi) and establish an association between this status and the clinicopathological features. MATERIAL AND METHODS: Our study was conducted retrospectively and initially involved 278 patients. However, after excluding 27 patients, we ultimately ended up with 167 patients who had an inflammatory status and 84 patients who did not have an inflammatory status. These patients were then analyzed. RESULTS: Patients who had inflammation showed higher values for the CHA2DS2-VASc and HAS-BLED scores (P= 0.0132 for CHA2DS2-VASc and P= 0.0024 for HAS-BLED). Also, it was observed that patients with associated inflammation exhibited an increase in both the volume and the area of the left atrium. Patients with hypertension had a higher prevalence of inflammation, with heart failure and with ischemic heart disease. It is worth noting that patients with atrial fibrillation and increased inflammatory status exhibited higher rates of stroke (22.75% vs 10.71% in patients without inflammation, odds ratio = 2.455, 95% confidence interval 1.161 to 5.425, p = 0.0253). CONCLUSIONS: Our research has demonstrated that patients diagnosed with atrial fibrillation and exhibiting a heightened inflammatory status also present association with other comorbidities, including hypertension, heart failure, ischemic heart disease, and stroke.

Early detection of anthracycline-mediated cardiotoxicity: the value of considering both global longitudinal left ventricular strain and twist.

Anthracyclines are important anticancer drugs, but their use is limited by cardiotoxicity. Left ventricular ejection fraction (LVEF) is often inadequate to detect myocardial disease induced by chemotherapy. Tissue Doppler and bidimensional-strain imaging could detect LV myocardial dysfunction earlier than LVEF. In drug-induced cardiotoxicity, torsional and longitudinal LV deformations [LV twist (LVtw), radial strain (GRS), global longitudinal strain (GLS)] are damaged. We assessed whether a new index, GLS×LVtw, could predict future anthracycline-induced cardiomyopathy. Echocardiography, troponin, and natriuretic peptide determination were prospectively performed in 74 patients before and after 6, 12, 24, and 52 weeks of anthracycline treatment. These patients were treated for breast cancer, Hodgkin's or non-Hodgkin's lymphoma, acute lymphoblastic or myeloblastic leukaemia, or osteosarcoma. At 6 weeks after initiation of chemotherapy, isovolumic relaxation time, systolic mitral annular velocity, LVGLS, LVGRS, LV apical rotation, LVtw, and GLS×LVtw deteriorated, and troponin levels became elevated (all p < 0.05 by ANOVA) before LVEF decreased. The receiver operating characteristic curves identified early deterioration of GLS×LVtw as the best predictor of later cardiotoxicity (area under curve = 0.93), followed by GLS (0.84) and LV apical rotation (0.81) deterioration. In conclusion, early change in the GLS×LVtw index seems to be a good predictor of future development of anthracycline-induced cardiotoxicity.

Future Perspectives to Improve CHA2DS2VASc Score: The Role of Left Atrium Remodelling, Inflammation and Genetics in Anticoagulation of Atrial Fibrillation.

In 10% of ischemic strokes, non-valvular atrial fibrillation (NVAF) is detected retroactively. Milder, or even asymptomatic forms of NVAF have shown high mortality, thrombotic risk, and deterioration of cognitive function. The current guidelines for the diagnosis and treatment of AF contain "grey areas", such as the one related to anticoagulant treatment in men with CHA2DS2-VASc score 1 and women with score 2. Moreover, parameters such as renal function, patient weight or left atrium remodelling are missing from the recommended guidelines scores. Vulnerable categories of patients including the elderly population, high hemorrhagic risk patients or patients with newly diagnosed paroxysmal episodes of atrial high rate at device interrogation are at risk of underestimation of the thrombotic risk. This review presents a systematic exposure of the most important gaps in evaluation of thrombotic and hemorrhagic risk in patients with NVAF. The authors propose new algorithms and risk factors that should be taken into consideration for an accurate thrombotic and hemorrhagic risk estimation, especially in vulnerable categories of patients.

Considering Diastolic Dyssynchrony as a Predictor of Favorable Response in LV-Only Fusion Pacing Cardiac Resynchronization Therapy.

Background: CRT improves systolic and diastolic function, increasing cardiac output. Aim of the study: to assess the outcome of LV diastolic dyssynchrony in a population of fusion pacing CRT. Methods: Diastolic dyssynchrony was measured by offline speckle-tracking-derived TDI timing assessment of the simultaneity of E″ and A″ basal septal and lateral walls. New parameters introduced: E″ and, respectively, A″ time (E″T/A″T) as the time difference between E″ (respectively, A″) peak septal and lateral wall. Patients were divided into super-responders (SR), responders (R), and non-responders (NR). Results: Baseline characteristics: 62 pts (62 ± 11 y.o.) with idiopathic DCM, EF 27 ± 5.2%; 29% type III diastolic dysfunction (DD), 63% type II, 8% type I. Average follow-up 45 ± 19 months: LVEF 37 ± 7.9%, 34%SR, 61%R, 5%NR. The E″T decreased from 90 ± 20 ms to 25 ± 10 ms in SR with significant LV reverse remodeling (LV end-diastolic volume 193.7 ± 81 vs. 243.2 ± 82 mL at baseline, p < 0.0028) and lower LV filling pressures (E/E' 13.2 ± 4.6 vs. 11.4 ± 4.5, p = 0.0295). DD profile improved in 65% of R with a reduction in E/E' ratio (21 ± 9 vs. 14 ± 4 ms, p < 0.0001). Significant cut-off value calculated by ROC curve for LV diastolic dyssynchrony is E″T > 80 ms and A″T > 30 msec. Conclusions: The study identifies the cut-off values of diastolic dyssynchrony parameters as predictors of favorable outcomes in responders and super-responder patients with fusion CRT pacing. These findings may have important implications in patient selection and follow-up.

Remote Monitoring in Cardiac Resynchronization Therapy-First Experience in Romania with a CRT Virtual Ward.

BACKGROUND: Remote monitoring (RM) is becoming a standard of care for patients with cardiac resynchronization therapy (CRT). This technology combines the use of pacemakers or implantable cardioverter-defibrillators (ICD) and wireless communication to provide physicians with continuous, real-time information on the patient's cardiac activity. The purpose of the study was to evaluate if the remote monitoring technology in the follow-up CRT patients is feasible and safe. METHODS: A total of nine patients were enrolled in the study, implanted with a CRT system with wireless transmission capabilities. Immediately after the procedure received the RM, were enrolled in the virtual clinic and instructed by the doctor how to use the device at home. Regular virtual transmissions were made automatically every 3 weeks, respecting optimal transmission conditions. The accumulation of fluid in the lungs, atrial or ventricular tachyarrhythmia together with system integrity automatically activate alerts. RESULTS: One hundred and one transmissions were collected and analyzed from the virtual ward. Average follow-up was 7.7±4.8 months, longest follow-up was 18 months. None of the patients experienced complications during the study period, with three of them being follow-up solely through telemetric means by implanting physician. Treatment optimization was successfully conducted via phone consultations, when necessary, without any adverse events. CONCLUSIONS: The results of our study suggest that RM could be integrated into routine CRT management protocols, enhancing patients care and resource utilization.

Update in LV Only Fusion CRT Pacing: Annals and Future Perspectives.

Triple-chamber cardiac devices are utilized for cardiac resynchronization therapy (CRT) and is the standard-of-care therapy for heart failure (HF) patients in the current guidelines. In the setting of biventricular (BIV) pacing it involves a mandatory implantation of right ventricular (RV) lead that allows simultaneous BIV pacing with 0 ms VV (ventricular to ventricular) interval. Nevertheless, it seems that response to CRT is not related to RV lead position. RV pacing is known for deleterious effects on RV/Left Ventricle (LV) function and should not be used in persons with normal atrioventricular conduction (AV) and sinus rhythm. As it compensates for the additional asynchrony induced by unnecessary stimulation of RV pacing, only pacing the left ventricle (LV) may result in improved cardiac resynchronization therapy (CRT) outcomes and a decrease in the number of individuals who do not respond to the procedure. Furthermore, leadless LV fusion CRT pacing without RV lead could be a potential CRT therapy alternative to BIV pacing in nonischemic heart failure patients with preserved AV conduction. The aim of our study is to made an update in cardiac resynchronization therapy with LV only fusion pacing.

Factors Associated with Stroke in Atrial Fibrillation. A Retrospective Study.

AIM: The aim of our study was to retrospectively evaluate known factors such as CHA2DS2-VASc, but, also, new factors (such as left atrial remodeling), associated with the development of stroke in patients with atrial fibrillation (AFi). MATERIAL AND METHODS: We performed a retrospective study in which 251 patients with AFi were included. 47 patients had an ischemic stroke before the diagnosis of AFi, at the time of diagnosis or after AFi was diagnosed. The CHA2DS2-VASc score was analyzed for all patients together with other left atrial remodeling parameters. RESULTS: We observed that among the patients with ischemic stroke approximately 61.70% were over 72.5 years old compared to those without stroke who presented this age in a proportion of only 44.61% (OR=2.001, P=0.0367). The CHA2DS2-VASc score had the greatest statistical impact for stroke, as expected. Patients with a CHA2DS2-VASc score >4.5 presented stroke in a proportion of 87.23% compared to CHA2DS2-VASc <4.5 who had stroke only in a proportion of 12.77% (OR=11.51, P=<0.0001). Regarding left atrial remodeling parameters, low LA ejection fraction was associated with a high percentage of stroke among patients (61.70%) compared to those with LA EF>34.5% who had stroke only in a percentage of 38.30% (OR= 2.124, P=0.0238). CONCLUSIONS: Although the CHA2DS2-VASc score remains a good factor for predicting the association of AFi with ischemic stroke, echocardiographic parameters for the evaluation of the left atrium can be used as new risk factors for predicting the occurrence of ischemic stroke in patients with AFi.

Reduced Left Ventricular Twist Early after Acute ST-Segment Elevation Myocardial Infarction as a Predictor of Left Ventricular Adverse Remodelling.

BACKGROUND: The left ventricular (LV) remodelling process represents the main cause of heart failure after a ST-segment elevation myocardial infarction (STEMI). Speckle-tracking echocardiography (STE) can detect early deformation impairment, while also predicting LV remodelling during follow-up. The aim of this study was to investigate the STE parameters in predicting cardiac remodelling following a percutaneous coronary intervention (PCI) in STEMI patients. METHODS: The study population consisted of 60 patients with acute STEMI and no history of prior myocardial infarction treated with PCI. The patients were assessed both by conventional transthoracic and ST echocardiography in the first 12 h after admission and 6 months after the acute phase. Adverse remodelling was defined as an increase in LVEDV and/or LVESV by 15%. RESULTS: Adverse remodelling occurred in 26 patients (43.33%). By multivariate regression equation, the risk of adverse remodelling increases with age (by 1.1-fold), triglyceride level (by 1.009-fold), and midmyocardial radial strain (mid-RS) (1.06-fold). Increased initial twist decreases the chances of adverse remodelling (0.847-fold). The LV twist presented the largest area under the receiver operating characteristic (ROC) curve to predict adverse remodelling (AUROC = 0.648; 95% CI [0.506;0.789], p = 0.04). A twist value higher than 11° has a 76.9% specificity and a 72.7% positive predictive value for reverse remodelling at 6 months.

Potential role for pentoxifylline as an anti-inflammatory drug for patients with acute coronary syndrome.

The link between inflammation and acute coronary syndrome (ACS) remains to be sufficiently elucidated. It has been previously suggested that there is an inflammatory process associated with ACS. Pentoxifylline, a methylxanthine derivate, is known to delay the progression of atherosclerosis and reduce the risk of vascular events, especially by modulating the systemic inflammatory response. The present study is a single-blind, randomized, prospective study of pentoxifylline 400 mg three times a day (TID) added to standard therapy vs. standard therapy plus placebo in ACS patients with non-ST elevation myocardial infarction (NSTEMI). Patients with ACS were randomized to receive standard therapy plus placebo in one arm (group A; aspirin, clopidogrel or ticagrelor, statin) and in the other arm (group B) pentoxifylline 400 mg TID was added to standard therapy. The primary outcome was the rate of major adverse cardiovascular events (MACEs) at 1 year. A total of 500 patients underwent randomization (with 250 assigned to group A and 250 to group B) and were followed-up for a median of 20 months. The mean age of the patients was 62.3±10.3 years, 80.4% were male, 20.8% had diabetes, 49.4% had hypertension, and 42% were currently smoking. The statistical analysis was performed for 209 patients in group A and 210 patients in group B (after dropouts due to study drug discontinuation). A primary endpoint occurred in 12.38% (n=26) of patients in group B, as compared with 15.78% (n=33) of those in group A [relative risk (RR), 0.78; 95% confidence interval (CI), 0.486-0.1.263; P=0.40], including cardiovascular death (RR, 0.93; 95% CI, 0.48-1.80, P=0.84), non-fatal myocardial infarction (RR, 1.1; 95% CI, 0.39-3.39, P=0.78), stroke (RR, 0.99; 95% CI, 0.14-6.99, P=0.99) and coronary revascularization (RR, 0.12; 95% CI, 0.015-0.985, P=0.048). Thus, adding pentoxifylline to standard treatment in patients with ACS did not improve MACE at 1 year but had some benefit on the need for coronary revascularization.

Metformin Acutely Mitigates Oxidative Stress in Human Atrial Tissue: A Pilot Study in Overweight Non-Diabetic Cardiac Patients.

Metformin, the first-line drug in type 2 diabetes mellitus, elicits cardiovascular protection also in obese patients via pleiotropic effects, among which the anti-oxidant is one of the most investigated. The aim of the present study was to assess whether metformin can acutely mitigate oxidative stress in atrial tissue harvested from overweight non-diabetic patients. Right atrial appendage samples were harvested during open-heart surgery and used for the evaluation of reactive oxygen species (ROS) production by means of confocal microscopy (superoxide anion) and spectrophotometry (hydrogen peroxide). Experiments were performed after acute incubation with metformin (10 µM) in the presence vs. absence of angiotensin II (AII, 100 nM), lipopolysaccharide (LPS, 1 µg/mL), and high glucose (Gluc, 400 mg/dL). Stimulation with AII, LPS, and high Gluc increased ROS production. The magnitude of oxidative stress correlated with several echocardiographic parameters. Metformin applied in the lowest therapeutic concentration (10 µM) was able to decrease ROS generation in stimulated but also non-stimulated atrial samples. In conclusion, in a pilot group of overweight non-diabetic cardiac patients, acute incubation with metformin at a clinically relevant dose alleviated oxidative stress both in basal conditions and conditions that mimicked the activation of the renin-angiotensin-aldosterone system, acute inflammation, and uncontrolled hyperglycemia.