Less Known but Clinically Relevant Comorbidities of Atrial Fibrillation: A Narrative Review.

BACKGROUND: The important risk factors for atrial fibrillation (AF) in the general population are not always equally important in specific and relatively prevalent diseases. OBJECTIVE: The main goal of this narrative review is to focus attention on the presence and the relationship of AF with several important diseases, such as cancer or sepsis, in order to: 1) stimulate further research in the field, and 2) draw attention to this relationship and search for AF in clinical practice. METHODS: We searched PubMed, SCOPUS, Elsevier, Wiley, Springer, Oxford Journals, Cambridge, SAGE, and Google Scholar for less-known comorbidities of AF. The search was limited to publications in English. No time limits were applied. RESULTS: AF is widely represented in cardiovascular and other important diseases, even in those in which AF is rarely mentioned. In some specific clinical subsets of AF patients (e.g., patients with sepsis or cancer), the general risk factors for AF may not be so important. Patients with new-onset AF have a several-fold increase in relative risk of cancer, deep vein thrombosis, and pulmonary thromboembolism (PTE) during the follow-up. CONCLUSION: AF presence, prognosis, and optimal therapeutic approach are insufficiently recognised in several prevalent diseases, including life-threatening ones. There is a need for a better search for AF in PTE, pulmonary oedema, aortic dissection, sepsis, cancer and several gastrointestinal diseases. Improved AF detection would influence treatment and improve outcomes.

Pulmonary embolism bleeding score index (PEBSI): A new tool for the detection of patients with low risk for major bleeding on thrombolytic therapy.

BACKGROUND: Estimation of bleeding risk is an unmet need for individualized therapy in acute pulmonary embolism (PE) patients with increased mortality risk. METHODS: We analyzed the association between various patients' characteristics and occurrence of major bleeding (MB) according to the modified International Society of Thrombosis and Hemostasis (ISTH) criteria ("overt" bleeding is the only modification from the original criteria) at 7 days from admission to the hospital and thrombolytic therapy with a tissue-plasminogen activator (tPA). Pulmonary embolism bleeding score index (PEBSI) was created using multivariate regression analyses, and finely, dichotomous index was used for the discrimination of patients with low risk for MB from those with high risk. RESULTS: During the 6-year period (2015-2021) 367 PE patients were treated with tPA and included in the Regional PE registry. Among them, 29 (7.9%) fulfilled the criteria for MB. Five factors were identified as significantly associated with MB and were used to build the PEBSI score: previous bleeding, recent surgery, diabetes, the use of drugs that could be associated with bleeding, and anemia. PEBSI score showed c-index for 7-day MB 0.794 (95CI% 0.698-0.889). Patients with PEBSI scores of 0 or 1 had a low risk for MB (2.8%) and those with scores>1 had a high risk for MB (18.6%) (p < 0.001). Internal validation of PEBSI score using a randomly, equally split method confirmed the discriminative value of the PEBSI score. CONCLUSION: Novel PEBSI score has significant power to discriminate patients with low risk for MB on thrombolytic therapy from those with high risk.

Impact of ellagic acid application on doxorubicin-induced cardiovascular toxicity model.

Doxorubicin is an anticancer agent that is commonly used to treat a number of tumors and is associated with acute and chronic changes of the cardiovascular system. Ellagic acid has strong free radical scavenging capacity, neuroprotective and hepatoprotective effects, and is known to protect against changes occurring due to diabetes, cardiovascular diseases, and cancer. Twenty-four Wistar rats were divided in four groups: control group received saline, doxorubicin group received doxorubicin in a single dose of 20 mg/kg, ellagic acid group received ellagic acid in a dose of 4 mg/kg, and doxorubicin + ellagic acid group received doxorubicin and ellagic acid in same doses as in previous groups. The effect of ellagic acid treatment, alone or in combination with doxorubicin, was studied on isolated heart frequency and strength of the contraction, and on thoracic aorta contractile responses. Application of ellagic acid to rats pre-treated with doxorubicin significantly prevented functional changes occurring in the heart, but not in the thoracic aorta tissue. Ellagic acid statistically significantly (p < 0.001) prevented doxorubicin-induced increase in heart rate, while at the same time increased single contraction force (p < 0.001) and attenuated morphological changes on heart tissue induced by doxorubicin. We can conclude that ellagic acid has potential to prevent doxorubicin-induced changes of the cardiovascular system.

Effects of oleuropein on rat's atria and thoracic aorta: a study of antihypertensive mechanisms.

Oleuropein (OLE) is the main bioactive ingredient in the leaves of the olive plant Olea europaea L. (Oleaceae), which has proven beneficial due to the antiinflammatory, antiatherogenic, anticancer, antimicrobial, and antiviral effects. This study aimed to investigate the antihypertensive and vasodilator potential of OLE by analyzing its acute effects on spontaneous atrial contractions and vasomotor responses of the isolated thoracic aorta in rats. We showed that the application of OLE induces negative chronotropic and inotropic effects on the heart. OLE also causes mild aortic vasodilation given that the maximal reduction in tension of intact aortic rings precontracted with phenylephrine was approximately 30%. This vasodilation is likely dependent on the nitric oxide released from the endothelium based on the effect obtained on denuded and phenylephrine precontracted aortic rings and responses reordered following vasoconstriction induced by high concentrations of K+ and heparin. Our findings provide a basis for further testing of OLE cardiovascular effects, which may lead to subsequent clinical research for its application in the treatment of hypertension and heart disease.

Prognostic Value and Immunohistochemical Analysis of Mismatch Repair Deficiency in Patients with Stage II and III Colorectal Carcinoma-A Single-Center Study.

Background and objectives: Deficient mismatch repair (MMR) status is associated with good prognosis but poor therapeutic response to adjuvant chemotherapy in patients with colorectal cancer. However, there are some opposed arguments considering therapeutic outcomes in patients with evidenced MMR deficiency in colorectal cancer. The aim of the study was the investigation of prognostic value and immunohistochemical analysis of the MMR-deficiency tumors. Materials and Methods: The study enrolled 104 patients with resected stage II and III colorectal cancer samples from the period 2018-2019. Results: The tumors with deficient MMR status were significantly associated with age up to 50 years and right-sided localization (p < 0.001). During the follow-up period of 22.43 ± 6.66 months, 21 patients (20.2%) died, whereas 14 patients (13.5%) had relapses. The loss of mutL homologue 1/postmeiotic segregation increased 2 (MLH1/PMS2) expression, compared to proficient MMR tumors, was associated with shorter disease-free survival in patients with lymphovascular invasion (p < 0.05), perineural invasion (p < 0.01), stage III (p < 0.05) and high-grade tumor (p < 0.05). Conclusions: This retrospective pilot study of a single-center cohort of patients with stage II and III colorectal cancer highlights the clinical importance of using immunohistochemistry (IHC) analysis as a guide for diagnostic algorithm in a country with limited resources, but with a high prevalence of colorectal carcinoma in the young patients. MMR-deficiency tumors compared with proficient MMR colorectal cancer was not shown to be a significant predictor of disease-free and overall survival.

Renal dysfunction as intrahospital prognostic indicator in acute pulmonary embolism.

BACKGROUND: Acute pulmonary embolism (PE), due to hemodynamic disturbances, may lead to multi-organ damage, including acute renal dysfunction. The aim of our study was to investigate the predictive role of renal dysfunction at admission regarding the short-term mortality and bleeding risk in hospitalized PE patients. METHODS: The retrospective cohort study included 1330 consecutive patients with PE. The glomerular filtration rate (GFR) was calculated using the serum creatinine value and Cocroft-Gault formula, at hospital admission. Primary outcomes were all-cause mortality and PE-related mortality in the 30 days following admission, as well as major bleeding events. RESULTS: Based on the estimated GFR, patients were divided into three groups: the first with GFR < 30 mL/min, the second with GFR 30-60 mL/min, and the third group with GFR > 60 mL/min. A multivariable analysis showed that GFR at admission was strongly associated with all-cause death, as well as with death due to PE. Patients in the first and second group had a significantly higher risk of 30-day all-cause mortality (HR 7.109, 95% CI 4.243-11.911, p < 0.001; HR 2.554, 95% CI 1.598-4.081, p < 0.001). Fatal bleeding was recorded in 1.6%, 0.5% and 0.8% of patients in the first, second and in the third group (p < 0.05). There were no significant differences regarding major bleeding rates among the groups. CONCLUSION: Renal dysfunction at admission in patients with acute pulmonary embolism is strongly associated with overall PE mortality.

Development and design of novel cardiovascular therapeutics based on Rho kinase inhibition-In silico approach.

Rho kinases, one of the best-known members of the serine/threonine (Ser/Thr) protein kinase family, can be used as target enzymes for the treatment of many diseases such as cancer or multiple sclerosis, and especially for the treatment of cardiovascular diseases. This study presents QSAR modeling for a series of 41 chemical compounds as Rho kinase inhibitors based on the Monte Carlo method. QSAR models were developed for three random splits into the training and test set. Molecular descriptors used for QSAR modeling were based on the SMILES notation and local invariants of the molecular graph. The statistical quality of the developed model, including robustness and predictability, was tested with different statistical approaches and satisfying results were obtained. The best calculated QSAR model had the following statistical parameters: r2 = 0.8825 and q2 = 0.8626 for the training set and r2 = 0.9377 and q2 = 0.9124 for the test set. Novel statistical metric entitled as the index of ideality of correlation was used for the final model assessment, and the obtained results were 0.6631 for the training and 0.9683 for the test set. Molecular fragments responsible for the increases and decreases of the studied activity were defined and they were further used for the computer-aided design of new compounds as potential Rho kinase inhibitors. The final assessment of the developed QSAR model and designed inhibitors was achieved with the application of molecular docking. An excellent correlation between the results from QSAR and molecular docking studies was obtained.

Population Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary Syndrome.

To date, many questions about the extent and cause of pharmacokinetic (PK) variability of even the most widely studied and prescribed ß1-adrenergic receptor blockers, such as metoprolol and bisoprolol, remain unanswered. Given that there are still no published population pharmacokinetic (PopPK) analyses of bisoprolol in routinely treated patients with acute coronary syndrome (ACS), the aim of this study was to determine its PK variability in 71 Serbian patients with ACS. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In each patient, the same formulation of bisoprolol was administered once or twice daily at a total daily dose of 0.625-7.5 mg. We separately assessed the effects of 31 covariates on the PKs of bisoprolol, and our results indicated that only 2 covariates could have possible influence on the variability of the clearance of bisoprolol: the mean daily dose of the drug and smoking habits of patients. These findings suggest that possible autoinduction of drug metabolism by higher total daily doses and induction of cytochrome P450 isoform 3A4 (CYP3A4) by cigarette smoke in liver could be the potential causes of increased total clearance of bisoprolol in patients with ACS.

A first-in-man clinical evaluation of Ultimaster, a new drug-eluting coronary stent system: CENTURY study.

AIMS: To report the six-month angiographic and two-year clinical outcome data from the first-in-man study with the Ultimaster DES, a thin-strut cobalt-chromium sirolimus-eluting stent (SES) with an innovative abluminal-gradient-coated bioresorbable polymer. METHODS AND RESULTS: CENTURY is a multicentre, single-arm, prospective study that enrolled 105 patients (113 lesions) with coronary artery disease. All patients were scheduled to have an angiographic follow-up at six months, while 45 and 20 patients respectively had IVUS and OCT assessments. The primary endpoint was six-month in-stent late lumen loss. Secondary endpoints included clinical, IVUS and OCT outcomes. Clinical follow-up is available up to two years and will continue up to five years. Procedural success was 97.1% and device success was 100%. Angiographic late loss at six months was 0.04±0.35 mm, also reflected in a low binary restenosis rate of 0.9% and confirmed by IVUS-assessed neointimal volume obstruction of 1.02±1.62%. The mean strut coverage assessed by OCT was 96.2% with 1.66±4.02 malapposed stent struts. There were no deaths in the study, three (2.9%) periprocedural and one (0.9%) spontaneous myocardial infarction, not related to the target vessel. At one and two years, the target lesion failure rate was 3.8% and 5.7%, while the TLR rate was 1.9% and 2.8%, respectively. There was one acute definite stent thrombosis. CONCLUSIONS: The Ultimaster™ novel bioresorbable polymer sirolimus-eluting stent demonstrated good performance, including high procedural success and strong suppression of neointimal proliferation at six months. Good safety and effectiveness were shown up to two years in the studied population.

Regional differences among female patients with heart failure from the Cardiac Insufficiency BIsoprolol Study in ELDerly (CIBIS-ELD).

BACKGROUND: The aim of our study was to examine regional differences in the demographics, etiology, risk factors, comorbidities and treatment of female patients with heart failure (HF) in the Cardiac Insufficiency BIsoprolol Study in ELDerly (CIBIS-ELD) clinical trial. METHODS AND RESULTS: One hundred and fifty-nine female patients from Germany and 169 from Southeastern (SE) Europe (Serbia, Slovenia and Montenegro) were included in this subanalysis of the CIBIS-ELD trial. Women comprised 54% of the study population in Germany and 29% in SE Europe. German patients were significantly older. The leading cause of HF was arterial hypertension in German patients, 71.7% of whom had a preserved ejection fraction. The leading etiology in SE Europe was the coronary artery disease; 67.6% of these patients had a reduced left ventricular ejection fraction (34.64 ± 7.75%). No significant differences were found in the prevalence of traditional cardiovascular risk factors between the two regions (hypertension, diabetes, hypercholesterolemia, smoking and family history of myocardial infarction). Depression, chronic obstructive pulmonary disease and malignancies were the comorbidities that were noted more frequently in the German patients, while the patients from SE Europe had a lower glomerular filtration rate. Compared with the German HF patients, the females in SE Europe received significantly more angiotensin converting enzyme inhibitors, loop diuretics and less frequently angiotensin receptor blockers and mineralocorticoid receptor antagonists. CONCLUSIONS: Significant regional differences were noted in the etiology, comorbidities and treatment of female patients with HF despite similar risk factors. Such differences should be considered in the design and implementation of future clinical trials, especially as women remain underrepresented in large trial populations.