Doxorubicin-induced acute cardiotoxicity is associated with increased oxidative stress, autophagy, and inflammation in a murine model.

Drug-induced cardiotoxicity is a life-threatening side effect of doxorubicin (DOX) treatment that impacts patient prognosis and survival. In the majority of cases, the acute clinical form often remains asymptomatic, with few patients presenting rather nonspecific electrocardiographic abnormalities. While chronic toxicity has been more widely studied, the alterations appearing in acute cardiotoxicity are much less investigated. Thus, our in vivo study aimed to evaluate the process of DOX-induced acute myocardial toxicity by investigating oxidative stress and autophagy markers as mechanisms of myocardial toxicity in correlation with echocardiography and electrocardiography findings. Our results show that both autophagy and oxidative homeostasis were disrupted as soon as 7 days after DOX treatment, alterations that occurred even before the significant increase of NT-proBNP, a clinical marker for cardiac suffering. Moreover, we found a large number of alterations in the electrocardiography and echocardiography of treated rats. These findings suggest that DOX-induced myocardial toxicity started early after treatment initiation, possibly marking the initial phase of the unfolding process of cardiac damage. Further studies are required to completely decipher the mechanisms of DOX-induced cardiotoxicity.

Case Report: Acute Splenic Artery Thrombosis in a COVID 19, Postpartum Patient.

The incidence of thromboembolic disease is reported to be high in SARS-CoV2 disease. Pregnancy, an already physiologically hypercoagulable state, associated to COVID 19, generates even more concern regarding the potentially increased risk of thrombotic events. The exact incidence of such complications is yet unknown, but there is data suggesting that coagulopathy and thromboembolism are both increased in pregnancies affected by COVID-19. Since the outbreak of the COVID 19 pandemics, the most common described thrombotic events associated with SARS-COV2 infection have been venous thromboembolism and disseminated intravascular coagulation, while arterial thrombotic events are less commonly described. Splenic infarction is a rare disorder that can be secondary to a hypercoagulable state. There are only few cases of splenic infraction described, but none with splenic artery thrombosis, in a post-partum patient, on therapeutic anticoagulation regimen. We present the case of a 31-year-old Caucasian, 26 weeks pregnant woman, with no prior medical history, admitted to the hospital with a severe form of COVID 19 pneumonia and who, during the course of the disease, developed a massive splenic infarction with splenic artery thrombosis.

Immune Checkpoint Inhibitors and the Heart.

Immune checkpoint inhibitors (ICIs) represent a break-through treatment for a large number of cancer types. This treatment is increasingly being recommended. ICIs are prescribed for primary tumours and for metastases, adjuvant/neo-adjuvant therapy. Thus, there is an increased need for expertise in the field, including the ways of response and toxicities related to them. ICIs become toxic because of the removal of self-tolerance, which in turn induces autoimmune processes that affect every organ. However, when relating to the heart, it has been noticed to be leading to acute heart failure and even death caused by various mechanisms, such as: myocarditis, pericarditis, arrhythmia, and Takotsubo cardiomyopathy. This review aims to address the above issues by focusing on the latest findings on the topic, by adding some insights on the mechanism of action of ICIs with a special focus on the myocardial tissue, by providing information on clinical manifestations, diagnosis and (wherever possible) treatment of the cardiotoxic events related to this therapy. The information is expanding and in many cases, the articles we found refer mainly to case-presentations and studies conducted on small populations. However, we consider that it is worthwhile to raise awareness of this new treatment, especially since it is widely now and it provides a significant increase in the survival rate in patients who receive it.

Arguments for Using Direct Oral Anticoagulants in Cancer-Related Venous Thromboembolism.

(1) Background: Patients with cancer with a hypercoagulable state present an increased incidence of venous thromboembolism (VTE). Neoplastic patients with concurrent VTE undergoing anticoagulant treatment face a series of issues. (2) The aim of the present paper is to systematically summarize current VTE management in patients with neoplasia and to review the current clinical evidence from meta-analyses of randomized controlled trials and guidelines regarding the administration of direct oral anticoagulants (DOACs) for cancer-associated VTE. (3) Search Strategy: We performed a review on meta-analyses of randomized controlled trials and guidelines in favor of the administration of DOACs in patients with cancer-associated VTE published in the last 6 years in the Medline (PubMed) and Embase databases. (4) Results: 21 meta-analyses, 14 randomized controlled studies comparing DOACs to VKAs and LMWH, and 7 national and international guidelines were identified. We identified five studies that show the antineoplastic effect of DOAC on experimental models. (5) Conclusions: DOACs can be seen as the first choice for VTE treatment in neoplastic patients who have a low risk of bleeding, who do not have severe renal impairment, and who are not undergoing treatments that could interact with DOAC's mechanism of action.

Modern markers for evaluating bone disease in multiple myeloma (Review).

Multiple myeloma (MM) is a bone marrow neoplasia with increasing incidence compared to previous years. Although new therapeutic molecules have been introduced, it remains an incurable disease with severe repercussions to patients. For many patients, bone disease represents a severe problem often causing pain, pathological bone fractures, and spinal cord compression, which affects the quality of life. This article analyzes the main markers of bone destruction in MM as well as risk factors for severe bone damage. Bone complications have a negative impact on the quality of life of patients with MM, along with other associated complications (renal failure, hypogammaglobulinemia, osteolytic bone disease, hypercalcemia, anemia). The markers of bone destruction described in this article include: interleukin (IL)-6, tumor necrosis factor (TNF)-α, receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX, CTX), human bone sialoprotein (BSP) and dickkopf-1 secreted glycoprotein (DKK1). The future practical applicability of this literature review would be the large-scale determination of markers of bone destruction that correlate with the negative evolution to complications of bone disease or the implications that these markers have in regards to treatment.

Macrophage activation syndrome: A diagnostic challenge (Review).

Macrophage activation syndrome (MAS) represents an acute and severe inflammatory syndrome, idiopathic (primary) or secondary to infections, rheumatic diseases, malignancies, or drugs. MAS is underdiagnosed, being confused with sepsis, adverse effects of anti-arthritic drugs or exacerbated symptoms of evolving rheumatologic or infectious diseases. Because of the late diagnosis, most patients do not benefit from effective therapy, leading to death. Elucidation of valid early diagnostic criteria of MAS would be a particularly important step in reducing the mortality due to this pathology. Thus, the purpose of this review based on 40 studies centered on the diagnostic criteria of MAS. We detailed the main diagnostic criteria and the few diagnostic scores or sets of criteria that have been recently published. The criteria most frequently encountered in the literature include: Fever, hepatosplenomegaly, hyperferritinemia, hepatopathy, coagulopathy, thrombocytopenia, hypertriglyceridemia, decrease in erythrocyte sedimentation rate and bone marrow hemophagocytosis. The most elaborate diagnostic score will result following an ongoing international project and consensus, the Delphi International Survey.

ACE2 and Apelin-13: Biomarkers with a Prognostic Value in Congestive Heart Failure.

The progression of heart failure is the result of the interaction of several pathogenetic processes that involve the activation of biomarkers belonging to the renin angiotensin aldosterone system (RAAS), to its counterregulatory mechanisms, to the sympathetic nervous system and inflammation, and to oxidative stress. This study is aimed at determining the prognostic role of biomarkers in the evolution of patients with heart failure. These biomarkers are representative of different pathogenetic pathways involved in the progression of heart failure and the possible interrelationships between them and heart remodelling. Method. This is a progressive observational study on 53 hospitalized patients with low ejection fraction heart failure, who were followed up for 12 months. The aetiology of heart failure was ischemic heart disease and dilated cardiomyopathy. The patients were clinically and biochemically evaluated by EKG (echocardiography) on admission and at 6 and 12 months. The biomarkers included in the present study were angiotensin-converting enzyme type 2 (ACE2), apelin-13, NT-proBNP (biomarkers involved in the counterregulation of RAAS), interleukin 17 (IL-17), hsCRP (inflammatory biomarkers), and urinary 8-iso-PGF2α (oxidative stress biomarker). The evolution was considered unfavourable if the patients presented complications during hospitalization, were readmitted for decompensated heart failure, or died. Results. From the study group, 14 patients (24.52%) presented an unfavourable clinical evolution. The biomarkers that were associated with the evolution of patients during hospitalization were ACE2, apelin-13, NT-proBNP, and hsCRP. Multivariate logistic regression analysis identified ACE2 and apelin-13 as independent, predictive biomarkers for the unfavourable evolution of patients over the study period. Values of ACE2 above 4000.75 pg/mL and of apelin-13 less than 402.5 pg/mL were associated with an unfavourable evolution (poor clinical outcomes). Conclusion. The serum values of ACE2 and apelin-13 correlate with the unfavourable evolution of patients with reduced ejection fraction heart failure.

Validation of Normal P-Wave Parameters in a Large Unselected Pediatric Population of North-Western Romania: Results of the CARDIOPED Project.

AIMS: Reference values of the P-wave on 12 lead electrocardiograms are lacking for children and adolescents in Eastern Europe. Hence, the present study is aimed at determining the standard values of the P-wave in children and adolescents based on ECG data from the CARDIOPED project, a large-scale general population of children who participated in a screening program in Transylvania, Romania. METHODS AND RESULTS: A total of 22,411 ECGs of participants aged 6 to 18 years old from a school-based ECG screening were obtained between February 2015 and December 2015 in Transylvania, Romania. Three pediatric cardiologists manually reviewed each ECG. P-wave duration, voltage, axis, and correlation with gender and age were analyzed. The mean P-wave duration was 88 ± 10.7 ms, with a maximum duration of 128 ms. P-wave showed a positive correlation with age but did not differ between sexes. There was a positive correlation between the P-wave duration and the heart rate, but not with the body max index. The mean P-wave axis was 40.4 ± 31.1, and the mean P-wave amplitude was 0.12 ± 0.03 mV. CONCLUSION: In this study on many pediatric subjects, we have provided normal limits for the P-wave in Romanian children aged 6-18 years. Our findings are useful for creating interpretation guidelines for pediatric ECG.

Short-Term Prognosis Value of sST2 for an Unfavorable Outcome in Hypertensive Patients.

BACKGROUND: sST2 represents a useful biomarker for the diagnosis and prognosis of patients with heart failure, but limited data is available on its role in patients with hypertension. The aim of this study is to evaluate the short-term prognosis value of sST2 for an unfavorable outcome in hypertensive patients. METHODS: This was a prospective observational study which enrolled 80 patients with hypertension, who were followed for one year. All patients underwent clinical, laboratory (including sST2), and echocardiographic assessment at baseline. The patients were grouped according to the cardiovascular (CV) events reported during the follow-up: group A (with CV events) and group B (without CV events). RESULTS: Overall, 59 CV events were reported during the follow-up period. Compared to group B, the patients in group A had significantly higher sST2 levels, a higher number of CV risk factors, and a higher left ventricle mass. Except for the diastolic dysfunction parameters, the echocardiographic findings were similar in the two groups. Patients in group A had a lower E/A ratio, larger deceleration time, and increased telediastolic pressure as quantified by the E/E/p = 0.006, Kaplan-Meier analysis). CONCLUSIONS: sST2 levels were correlated with the risk of adverse CV outcomes in hypertensive patients and may represent a useful prognostic marker in these patients.

Oral Anticoagulant Therapy-When Art Meets Science.

Anticoagulant treatment is extremely important and frequently encountered in the therapy of various cardiovascular diseases. Vitamin K antagonists (VKA) are in use for the prevention and treatment of arterial and venous thromboembolism, despite the introduction of new direct-acting oral anticoagulants (NOAC). The VKA still have the clear recommendation in patients with a mechanical prosthetic heart valve replacement or moderate to severe mitral stenosis of the rheumatic origin, in deep vein thrombosis associated with congenital thrombophilia, and in cases where NOAC are prohibited by social condition (financial reason) or by comorbidities (extreme weight, severe renal or liver disease). VKA dosing required to reach the targeted therapeutic range varies largely between patients (inter-individual variability). This inter-individual variability depends on multiple environmental factors such as age, mass, diet, etc. but it is also influenced by genetic determinism. About 30 genes implicated in the metabolism coumarins derivatives were identified, the most important being CYP2C9 and VKORC, each with several polymorphisms. Herein, we review the data regarding genetic alterations in general and specific populations, highlight the diagnosis options in particular cases presenting with genetic alteration causing higher sensitivity and/or resistance to VKA therapy and underline the utility of NOAC in solving such rare and difficult problems.

Biomarkers of Inflammation in Left Ventricular Diastolic Dysfunction.

Left ventricular diastolic dysfunction (LVDD) is an important precursor to many different cardiovascular diseases. Diastolic abnormalities have been studied extensively in the past decade, and it has been confirmed that one of the mechanisms leading to heart failure is a chronic, low-grade inflammatory reaction. The triggers are classical cardiovascular risk factors, grouped under the name of metabolic syndrome (MetS), or other systemic diseases that have an inflammatory substrate such as chronic obstructive pulmonary disease. The triggers could induce myocardial apoptosis and reduce ventricular wall compliance through the release of cytokines by multiple pathways such as (1) immune reaction, (2) prolonged cell hypoxemia, or (3) excessive activation of neuroendocrine and autonomic nerve function disorder. The systemic proinflammatory state causes coronary microvascular endothelial inflammation which reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes favoring hypertrophy development and increases resting tension. So far, it has been found that inflammatory cytokines associated with the heart failure mechanism include TNF-α, IL-6, IL-8, IL-10, IL-1α, IL-1ß, IL-2, TGF-ß, and IFN-γ. Some of them could be used as diagnosis biomarkers. The present review aims at discussing the inflammatory mechanisms behind diastolic dysfunction and their triggering conditions, cytokines, and possible future inflammatory biomarkers useful for diagnosis.

Hemodynamic monitoring using thoracic bioimpedance - an optimal solution for the treatment of hypertension.

Hypertension is a major issue of public health because of its increasing prevalence and multiple complications caused by failing to achieve an efficient blood pressure control. Considering hypertension as a hemodynamic disorder allows to prescribe a tailored therapy guided by individual hemodynamic parameters, therefore leading to an increased rate of control. We present the case of a 59 years old diabetic, dyslipidemic and obese male who, although treated with 5 classes of antihypertensive drugs had uncontrolled hypertension that caused left ventricular failure. Using the HOTMAN system of hemodynamic monitoring using thoracic electrical bioimpedance allowed a quick identification of the cause and guided the therapy, achieving blood pressure control after 5 days of treatment. Treating hypertension by identifying the underlying hemodynamic imbalance allows prescribing a tailored therapy and shortens the initiation and stabilization phases of treatment.

Usefulness of the Adipokines as Biomarkers of Ischemic Cardiac Dysfunction.

Cardiovascular disease is the leading cause of death among both women and men, but there is still a great percentage of misdiagnosis and lack of clearly defined criteria. Advances in biomolecular science have proven the crucial role of inflammation and, more importantly, the role of adipokines in mediating all stages of coronary artery disease. It has also been suggested that regional fat deposits, more precisely from thoracic region, have a major influence on the development of coronary artery disease by creating a local proatherogenic environment. The immune system closely interacts with metabolic risk factors to initiate, promote, and further aggravate the atherosclerotic lesions on the arterial wall all with the "help" of adipokines. So nowadays, research extensively focuses on uncovering biomarkers that would provide an increased chance of detecting subclinical cardiac distress and also add a consistent value to current guideline-imposed risk criteria.

Plasma leptin, but not resistin, TNF-α and adiponectin, is associated with echocardiographic parameters of cardiac remodeling in patients with coronary artery disease.

The aim of this research was to assess the relationship between plasma adiponectin, leptin, resistin, tumor necrosis factor alpha (TNF-α) levels and echocardiographic parameters of ventricular remodeling in patients with coronary artery disease, without acute myocardial infarction. The study population consisted of 49 patients with echocardiographic measurements performed. After adjustment for age, gender, body mass index, systolic and diastolic blood pressure, and glycaemia, adiponectin was statistically significant associated with interventricular septum thickness (ß = -0.304), left ventricular posterior wall thickness (ß = -0.402), left ventricular end diastolic diameter (LVEDD; ß = 0.385) and left ventricular relative wall thickness (ß = -0.448, p < .05 for all). The associations were no longer significant when only patients without diabetes were included in the analysis. Leptin was associated with LVEDD (ß = -0.354) and left ventricular relative wall thickness (ß = 0.385, p < .05 for all). No associations between resistin, TNF-α and echocardiographic left ventricular parameters assessed were found in these patients. In conclusion, in patients with coronary artery disease and without acute myocardial infarction leptin may represent a potential mechanism of adverse cardiac remodeling. Resistin and TNF-α might not be involved in ventricular remodeling in these patients.

Non-alcoholic fatty liver disease, bulb carotid intima-media thickness and obesity phenotypes: results of a prospective observational study.

AIMS: The objective of this prospective study was to assess the correlation between carotid intima-media thickness at the common carotid (CIMTc) and carotid bifurcation (CIMTb) level, hepatic fat accumulation, and obesity phenotypes. MATERIAL AND METHODS: Two hundred obese adults, in which CIMTc and CIMTb thickness was determined, were included. According to body mass index (BMI) and presence of metabolic syndrome (MetS), patients were classified as metabolically healthy obese (MHO, obesity without MetS) and metabolically unhealthy obese (MUHO, obesity with MetS). MHO patients were further classified as MHO1 (obese with increased waist circumference) and MHO2 (obese with increased waist circumference plusone of the 4 criteria for MetS). Non-alcoholic fatty liver disease (NAFLD) presence was assessed by fatty liver index (FLI). RESULTS: CIMTc and CIMTb increased with obesity phenotypes from 0.74 mm and 1.04 mm in MHO1 to 0.84 mm and 1.23 mm in MHO2 and 0.88 mm and 1.74 mm in MUHO. Obesity phenotypes were significantly correlated with CIMTb. NAFLD frequency increased from 66.0% in the MHO1 to 73.0% in the MHO2 and 84.2% in the MUHO (p<0.05). Independent of age, BMI, total cholesterol, HbA1c, and HOMA-IR, the CIMTc was significantly associated with FLI in all obesity phenotypesand CIMTb only in MHO2 and MUHO. CONCLUSIONS: Our results suggest that subclinical atherosclerosis varies according to obesity phenotypes and is correlated with the hepatic fat accumulation.

Serum Soluble ST2 and Diastolic Dysfunction in Hypertensive Patients.

BACKGROUND: Echocardiographic evaluation of left ventricular (LV) structural and functional alterations in hypertension has some limitations, potentially overcome by using biomarkers. ST2, a prognostic biomarker for heart failure and myocardial infarction patients, was less studied in hypertension. AIM: To analyze the relationship between serum ST2 levels and diastolic dysfunction (DD) in hypertension. METHOD: We enrolled 88 hypertensive outpatients (average age 65 years, 69.3% females) in a prospective study, stratified for presence of LV hypertrophy (LVH). For each patient clinical examination, lab workup (routine and serum ST2 levels) and echocardiography were performed. RESULTS: Hypertensive patients with LVH had higher age, pulse pressure, mean arterial pressure, and serum ST2, while having lower serum albumin than those without LVH. Serum ST2 levels correlate with parameters of LV remodeling and DD. We found that 5.3% of ST2 level variability was caused by a 1-unit variation of cardiovascular risk. We identified cut-off values for discriminating hypertension with LVH versus that without LVH and grade 2 DD versus normal diastolic performance. CONCLUSION: ST2 could be used as diagnostic biomarker for cardiac remodeling and altered diastolic performance in hypertension, providing additional data to echocardiography. It could represent a milestone in early detection of cardiac performance alteration.

A rare case of pacemaker induced tachycardia in an elderly woman with cor triatriatum sinistrum.

Pacemaker induced tachycardia (PIT) is a rare iatrogenic rhythm disorder which tipically occurs in patients with dual-chamber pacemakers and has different causes, including oversensing of atrial tachyarrhythmia waves. Cor triatriatum sinistrum is a congenital abnormality infrequent in adults, associated with a high risk of atrial tachyarrhythmia. We present the case of a 80-year-old woman incidentally diagnosed with cor triatriatum sinistrum echocardiographycally, implanted with a DDD pacemaker for sinus node disease, who developed atrial tachyarrhythmia (paroxysmal atrial fibrillation and left atrial tachycardia), which triggered a PIT, successfully aborted by automatic mode switch. This is the first case in literature that associates cor triatriatum sinistrum and PIT.

Better prognosis in overweight/obese coronary heart disease patients with high plasma levels of leptin.

BACKGROUND AND AIM: The involvement of leptin in atherosclerosis is very complex, including inflammation, the oxidative stress and thrombosis. Leptin has atherogenic and also antiatherogenic actions. In obesity elevated leptin levels are not sufficient to prevent disturbances of energy balance, suggesting that obese people are leptin resistant. The aim of the study was to investigate the relationship between baseline plasma levels of leptin and the incidence of new ischemic events in patients with CHD. METHODS: Plasma levels of leptin in fifty nine consecutive patients (29 men and 30 women) with CHD hospitalized in the County Emergency Clinical Hospital of Cluj-Napoca were measured using commercially available ELISA at admission. Patients with active infectious disease, neoplasia, acute coronary syndrome, stroke, hepatic or renal failure and severe heart failure were excluded The relationship between leptin levels and incident cardiovascular events (angina, nonfatal myocardial infarction or heart failure) over two years follow-up was studied using MEDCALC version 9.6. RESULTS: 73.6% patients with CHD were overweight or suffered of obesity. There were no significant differences between women and men regarding the plasma levels of leptin, the body mass index (BMI), the number of rehospitalizations, rehospitalizations/patient, diabetes mellitus, hypertension or dyslipidemia. Only in women plasma levels of leptin are correlated with BMI. As compared with men with overweight and obesity (BMI≥25kg/m(2)), plasma levels of leptin were significantly higher in women with overweight and obesity (3905.97±463.91 pg/ml vs 1835.17±533.9 pg/ml) (p<0.002). Patient gender could not be demonstrated to influence prognosis. During the two years we recorded one or more readmissions in 26 patients (44%). The analysis of time till readmission using Kaplan-Meier curves, showed that leptin level (cut-off 2000 pg/ml, HR 0.38, 95% CI 0.17-0.83; p=0.01) and BMI (cut-off 28 kg/m(2), HR 0.3164, 95% CI 0.145-0.0689; p<0.01) were significantly associated with prognosis. CONCLUSION: Patients with plasma levels of leptin >2000 pg/ml and BMI >28kg/m(2) had a better prognosis, suggesting a protective role of leptin in overweight/mild obesity.