Crosstalk between microRNA and Oxidative Stress in Heart Failure: A Systematic Review.

Heart failure is defined as a clinical syndrome consisting of key symptoms and is due to a structural and/or functional alteration of the heart that results in increased intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. One of the key mechanisms determining myocardial dysfunction in heart failure is oxidative stress. MicroRNAs (miRNAs, miRs) are short, endogenous, conserved, single-stranded non-coding RNAs of around 21-25 nucleotides in length that act as regulators of multiple processes. A systematic review following the PRISMA guidelines was performed on the evidence on the interplay between microRNA and oxidative stress in heart failure. A search of Pubmed, Embase, Scopus, and Scopus direct databases using the following search terms: 'heart failure' AND 'oxidative stress' AND 'microRNA' or 'heart failure' AND 'oxidative stress' AND 'miRNA' was conducted and resulted in 464 articles. Out of them, 15 full text articles were eligible for inclusion in the qualitative analysis. Multiple microRNAs are involved in the processes associated with oxidative stress leading to heart failure development including mitochondrial integrity and function, antioxidant defense, iron overload, ferroptosis, and survival pathways.

Long COVID and its cardiovascular consequences: What is known?

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused high morbidity and mortality and has been a source of substantial challenges for healthcare systems globally. Despite a full recovery, a significant proportion of patients demonstrate a broad spectrum of cardiovascular, pulmonary and neurological symptoms that are believed to be caused by long-term tissue damage and pathological inflammation, which play a vital role in disease development. Microvascular dysfunction also causes significant health problems. This review aimed to critically appraise the current data on the long-term cardiovascular sequelae of coronavirus disease 2019 (COVID-19), with a primary focus on cardiovascular symptoms such as chest pain, fatigue, palpitations, and breathlessness, and more significant disease entities including myocarditis, pericarditis and postural tachycardia syndrome. Potential risk factors identified in recent studies that contribute towards the development of long COVID are also included alongside a summary of recent advances in diagnostics and putative treatment options.

An update on cardiovascular disorders in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a complex multifactorial etiology that develops as a result of autoimmune processes, leading to widespread inflammation and malfunction of multiple tissues and organs, and, as a consequence, triggers arterial hypertension, conduction disorders, valvular heart disease, pulmonary hypertension (PH), and venous thromboembolism events (VTE), contributing to increased mortality. Moreover, autoimmune abnormalities can accelerate atherogenesis and lead to many SLE manifestations, including coronary artery disease (CAD) and cerebrovascular events. The current review aimed to systematize existing data from the latest works and summarize published guidelines and recommendations. In particular, the prevalence of cardiovascular disorders in SLE patients, advances in diagnostics (including imaging methods and biomarker laboratory testing), the possible future direction of therapy, and the latest European Alliance of Associations for Rheumatology (EULAR) guidelines for optimal management of cardiovascular risk in SLE were overviewed.

Prognostic Implications of Immature Platelet Fraction at 5-Year Follow-up Among ACS Patients Treated With Dual Antiplatelet Therapy.

Objective: Platelets are strongly associated with cardiovascular events due to their role in thrombotic processes. Reticulated platelets have higher prothrombotic potential. The aim of the study was to evaluate the effectiveness of immature platelet fraction (IPF) in predicting long-term clinical outcomes in patients with acute coronary syndrome (ACS). Methods: This prospective, observational study enrolled patients with ACS treated with dual antiplatelet therapy comprising acetylsalicylic acid and clopidogrel or ticagrelor. The primary outcome was a composite endpoint defined as major adverse cardiovascular events (MACE): all-cause death, myocardial infarction (MI), ischemic stroke, or unplanned revascularization. IPF was determined using flow cytometry in the first 24 h of hospitalization. MACE were evaluated by 2 physicians based on electronic databases and source documentation including discharge letters received from patients upon telephone contact. Results: Overall, there were 140 ACS patients (mean age 65.1 ± 11.7, 37 females [26.4%]) included in this study. Of them, 22.9% had diabetes mellitus, 69.3% hyperlipidemia, 25% had a history of MI. The median IPF values were 2.85 [1.8-4.2] %. Clinical follow-up (median time: 57 months [interquartile range 55-59 months]) was available for 130 patients (92.9%). MACE occurred in 27 patients (20.8%). There were higher rates of MACE at higher IPF tertiles (3rd vs 1st tertile: HR = 5.341 95% CI: 1.546-18.454, P = .008). Cox regression analyses showed that IPF level was independently associated with MACE. Time-dependent receiver-operating characteristic curve analysis revealed area under the curve of 0.656 for 5-year outcome with an IPF cutoff point of 3.45% being 63.0% sensitive and 65.0% specific for MACE. Conclusions: The study showed IPF may be an independent predictor of long-term mortality and MACE (ClinicalTrials.gov number, NCT06177587).

Temporal evolution of liver function parameters predicts clinical outcome in chronic heart failure patients (Bio-SHiFT study).

BACKGROUND: Liver dysfunction contributes to worse clinical outcomes in heart failure (HF) patients. However, studies exploring temporal evolutions of liver function parameters in chronic HF (CHF) pa- tients, and their associations with clinical outcome, are scarce. Detailed temporal patterns of alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGTP), total bilirubin (TBIL) and albumin (ALB) were investigated, and their relation with clinical outcome, in patients with stable CHF with reduced ejection fraction. METHODS: Tri-monthly plasma samples were collected from 250 patients during 2.2 (1.4-2.5) years of follow-up. ALP, GGTP, ALB, and TBIL were measured in 749 selected samples and the relationship between repeatedly measured biomarker levels and the primary endpoint (PEP; composite of cardiovas- cular death, heart transplantation, left ventricular assist device implantation, and hospitalization for worsened HF) was evaluated by joint models. RESULTS: Mean age was 66 ± 13 years; 74% were men, 25% in New York Heart Association class III-IV. 66 (26%) patients reached the PEP. Repeatedly measured levels of TBIL, ALP, GGTP, and ALB were associated with the PEP after adjustment for N-terminal prohormone B-type natriuretic peptide and high sensitivity troponin T (hazard ratio [95% confidence interval] per doubling of biomarker level: 1.98 [1.32; 2.95], p = 0.002; 1.84 [1.09; 3.05], p = 0.018, 1.33 [1.08; 1.63], p = 0.006 and 1.14 [1.09; 1.20], p < 0.001, respectively). Serial levels of ALP and GGTP, and slopes of the temporal evolutions of ALB and TBIL, adjusted for clinical variables, were also significantly associated with the PEP. CONCLUSIONS: Changes in serum levels of TBIL, ALP, GGTP, and ALB precede adverse cardiovascular events in patients with CHF. These routine liver function parameters may provide additional prognostic information in heart failure with reduced ejection fraction patients in clinical practice.

The cytokine trio - visfatin, placental growth factor and fractalkine - and their role in myocardial infarction with non-obstructive coronary arteries (MINOCA).

Myocardial infarction with nonobstructive coronary arteries (MINOCA) remains a puzzling clinical entity. It is characterized by clinical evidence of myocardial infarction (MI) with normal or near-normal coronary arteries in angiography. Given the complex etiology including multiple possible scenarios with varied pathogenetic mechanisms, profound investigation of the plausible biomarkers of MINOCA may bring further pathophysiological insights and novel diagnostic opportunities. Cytokines have a great diagnostic potential and are used as biomarkers for many diseases. An unusual trio of visfatin, placental growth factor (PlGF) and fractalkine (CX3CL1) can directly promote vascular dysfunction, inflammation and angiogenesis through the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. They are redundant in physiological processes and become overexpressed in the pathomechanisms underlying MINOCA. The knowledge about their concentration might serve as a valuable diagnostic and/or therapeutic tool for assessing vascular endothelial function. Here we analyze the current knowledge on visfatin, PlGF and CX3CL1 in the context of MINOCA and present the novel clinical implications of their combined expression as predictors or indicators of this condition.

Identification of cardiac-related serum miRNA in patients with type 2 diabetes mellitus and heart failure: Preliminary report.

BACKGROUND: Diabetic patients present an increased risk for heart failure (HF) independently of the presence of coronary artery disease (CAD) and hypertension. However, little is known about circulatory microRNA (miRNA), an important regulatory RNA in this population. OBJECTIVES: To evaluate serum miRNA profile of patients with diabetes mellitus (DM) and HF and analyze its relationship with pathophysiological pathways involved. MATERIAL AND METHODS: The accumulation of 179 miRNAs was measured in serum of diabetic patients with HF and compared to the same measurements in healthy control subjects. The miRNAs were assayed using quantitative polymerase chain reaction (qPCR) on the Serum/Plasma Focus microRNA PCR panel (Qiagen) with LightCycler® 96 Real-Time PCR System (Roche). A pairwise comparison of mean relative miRNA accumulation levels was performed to establish those miRNAs that are differently expressed in patients with: 1) HF; 2) HF and chronic coronary syndrome (HF-CAD); and 3) HF without chronic coronary syndrome (HF-nonCAD) compared to healthy controls. To gain insight into these functions of miRNAs, we applied Gene Ontology (GO) enrichment analysis of Biological Processes and Molecular Functions of their predicted targets. RESULTS: The pairwise comparison revealed that 12 miRNAs were significantly downregulated in HF-CAD patients compared to controls, whereas 4 miRNAs were considerably deregulated in HF-nonCAD patients, with miRNA-15b-5p being downregulated in both groups. The GO analysis revealed that differentially accumulated targets of miRNAs include genes involved in potassium channel function, MAPK kinase activity and DNA transcription regulation, with similar alterations observed in the whole HF group and HF-CAD subgroup as well as a response to stress and apoptosis (in HF group), and genes involved in the development (in HF-CAD group). No oriented specialization of deregulated miRNA targets was observed in the HF-nonCAD subgroup. CONCLUSION: We observed a significant downregulation of 13 miRNAs in diabetic HF patients, which was not reported previously either in HF or diabetic patients. Downregulated miRNAs regulate angiogenesis and apoptosis.

Dietary supplements, nutraceuticals and functional foods use after myocardial infarction depend on the age, sex, BMI and professional activity - a pilot study.

OBJECTIVES: To assess dietary supplements, functional foods and nutraceuticals use among the patients after myocardial infarction (MI). MATERIAL AND METHODS: The authors prospectively enrolled 100 consecutive patients hospitalized due to MI and remaining under coordinated outpatient care after MI in the authors' cardiology department. RESULTS: The authors showed that patients within median (interquartile range) 12.30 (10.18-14.57) months after MI use dietary supplements, nutraceuticals and functional foods in their everyday diet. Vitamins (53% patients), especially vitamin D (35%), were the most frequently used dietary supplements. In contrary to common usage of dietary supplements (59%), smaller proportion of patients use functional foods (21%) and nutraceuticals (5%), especially phytosterols. The authors found that the use of over-the-counter (OTC) drugs and dietary supplements is associated with age (participants <60 years old vs. participants ≥60 years old: OTC drugs: N = 8 [20.0%] vs. N = 32 [53.3%], p < 0.001; herbals: N = 3 [7.5%] vs. N = 16 [26.7%], p = 0.019), sex of the patients following MI (females vs. males: vitamins: N = 17 [70.8%] vs. N = 36 [47,4%], p = 0.045; vitamin D: N = 13 [54.2%] vs. N = 22 [28.9%], p = 0.024; omega-3 fatty acids: N = 3 [12.5%] vs. N = 1 [1.3%], p = 0.042; herbals: N = 8 [33.3%] vs. N = 11[14.5%], p = 0.040), as well as the BMI of the participants (BMI < 24.9 vs. BMI ≥ 25.0: multivitamin/ multimineral dietary supplements: N = 3 [15.0%] vs. N = 31 [42.5%], p = 0.035; vitamin B6: N = 1 [5.0%] vs. N = 21 [28.8%], p = 0.035). In the study group all participants with the age above retirement age have already withdrawn from professional activity and they more often used OTC drugs (N = 14 [25.9%] before retirement age vs. N = 26 [56.5%] above retirement age, p = 0.002). CONCLUSIONS: The patients following MI use supplements, functional foods and nutraceuticals. Their use depends on sex, age, BMI and professional activity. The authors believe that their potential beneficial effects require further evaluation in clinical longitudinal studies. Int J Occup Med Environ Health. 2023;36(6):732-43.

Platelet microRNAs as Potential Novel Biomarkers for Antiplatelet Therapy with P2Y12 Inhibitors and Their Association with Platelet Function.

INTRODUCTION: Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) require dual antiplatelet therapy (DAPT). However, the response to treatment can vary considerably. Certain platelet microRNAs (miRs) are suspected to predict DAPT response and influence platelet function. This study aimed to analyze selected miRs' expressions and compare them among patients treated with different P2Y12 inhibitors while assessing their association with platelet activity and turnover parameters. MATERIALS AND METHODS: We recruited 79 ACS patients post-PCI treated with clopidogrel, ticagrelor, or prasugrel, along with 18 healthy volunteers. Expression levels of miR-126-3p, miR223-3p, miR-21-5p, miR-197-3p, and miR-24-3p, as well as immature platelet fraction (IPF) and ADP-induced platelet reactivity, were measured and compared between groups. RESULTS: Analyses revealed significantly lower expressions of miR-126-3p, miR-223-3p, miR-21-5p, and miR-197-3p in patients treated with ticagrelor, compared to clopidogrel (fold changes from -1.43 to -1.27, p-values from 0.028 to 0.048). Positive correlations were observed between platelet function and the expressions of miR-223-3p (r = 0.400, p = 0.019) and miR-21-5p (r = 0.423, p = 0.013) in patients treated with potent drugs. Additionally, miR-24-3p (r = 0.411, p = 0.012) and miR-197-3p (r = 0.333, p = 0.044) showed correlations with IPF. CONCLUSIONS: The identified platelet miRs hold potential as biomarkers for antiplatelet therapy. (ClinicalTrials.gov number, NCT06177587).

Immature platelet fraction and immature platelet count as novel biomarkers of elevated platelet reactivity in NSTE-ACS patients receiving dual antiplatelet therapy.

BACKGROUND: Antiplatelet therapy is the cornerstone of treatment for patients presenting with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). Some patients may not respond to such therapy adequately, which is associated with a greater risk of ischemic events. Reticulated platelets are the youngest, largest, and most active platelet subtype. They have been initially shown to be associated with an increased risk of cardiovascular (CV) events and increased platelet activity. OBJECTIVES: The aim of the presented study was to evaluate whether the immature platelet fraction (IPF) reflects the response to antiplatelet treatment in invasively managed ACS patients. MATERIAL AND METHODS: This prospective study enrolled ACS patients treated with PCI and dual antiplatelet therapy (DAPT) comprising acetylsalicylic acid (ASA) and clopidogrel or ticagrelor. In all patients, venous blood was collected within 24 h after the procedure. Platelet parameters were measured, including IPF using the Sysmex hematological analyzer and adenosine diphosphate (ADP)-induced platelet reactivity using the Multiplate® Analyzer. RESULTS: A total of 108 patients were enrolled, including 62 with ST-segment elevation ACS (STE-ACS) and 46 with non-ST-segment elevation ACS (NSTE-ACS). Of them, 20.4% had diabetes mellitus, 26.9% had a history of MI and 59.2% of smoking. Spearman's correlation analysis demonstrated that higher IPF and immature platelet count (IPC) values are associated with increased ADP-induced platelet reactivity (respectively: rho = 0.387, 95% confidence interval (95% CI): 0.101-0.615, p = 0.008; and rho = 0.458, 95% CI: 0.185-0.666, p = 0.001) in NSTE-ACS but not in STE-ACS patients. CONCLUSION: Immature platelet count and IPF may be valuable markers of platelet activity in patients with NSTE-ACS treated invasively and receiving DAPT (ClinicalTrials.gov No. NCT06177587).

Immature platelet fraction in cardiovascular diagnostics and antiplatelet therapy monitoring.

Immature platelet fraction (IPF), circulating platelets still containing RNA, can be easily calculated by automated flow cytometry, this makes them an accessible biomarker. Higher IPF concentrations were reported in patients with thrombocytopenia, patients who were smokers, and also those who were diabetics. Several studies have reported their diagnostic and prognostic importance in patients presenting with acute coronary syndromes, especially ST-segment elevation myocardial infarction, where increased IPF level is an independent predictor of cardiovascular death. In addition, higher IPF were reported in patients with inadequate response to either clopidogrel or prasugrel, suggesting their potential role in antiplatelet therapy monitoring. Their prognostic significance was also observed in both coronary artery disease and postcardiac surgery status, where their higher levels correlated with the risk of major adverse cardiac events. The current review aims to present the current evidence on diagnostic, prognostic and potentially therapeutic roles of IPF in cardiovascular medicine.

Circulating and Platelet MicroRNAs in Cardiovascular Risk Assessment and Antiplatelet Therapy Monitoring.

Micro-ribonucleic acids (microRNAs) are small molecules that take part in the regulation of gene expression. Their function has been extensively investigated in cardiovascular diseases (CVD). Most recently, miRNA expression levels have been suggested as potential biomarkers of platelet reactivity or response to antiplatelet therapy and tools for risk stratification for recurrence of ischemic evens. Among these, miR-126 and miR-223 have been found to be of particular interest. Despite numerous studies aimed at understanding the prognostic value of miRNA levels, no final conclusions have been drawn thus far regarding their utility in clinical practice. The aim of this review is to critically appraise the evidence on the association between miRNA expression, cardiovascular risk and on-treatment platelet reactivity as well as provide insights on future developments in the field.

Dynamic personalized risk prediction in chronic heart failure patients: a longitudinal, clinical investigation of 92 biomarkers (Bio-SHiFT study).

The aim of our observational study was to derive a small set out of 92 repeatedly measured biomarkers with optimal predictive capacity for adverse clinical events in heart failure, which could be used for dynamic, individual risk assessment in clinical practice. In 250 chronic HFrEF (CHF) patients, we collected trimonthly blood samples during a median of 2.2 years. We selected 537 samples for repeated measurement of 92 biomarkers with the Cardiovascular Panel III (Olink Proteomics AB). We applied Least Absolute Shrinkage and Selection Operator (LASSO) penalization to select the optimal set of predictors of the primary endpoint (PE). The association between repeatedly measured levels of selected biomarkers and the PE was evaluated by multivariable joint models (mvJM) with stratified fivefold cross validation of the area under the curve (cvAUC). The PE occurred in 66(27%) patients. The optimal set of biomarkers selected by LASSO included 9 proteins: NT-proBNP, ST2, vWF, FABP4, IGFBP-1, PAI-1, PON-3, transferrin receptor protein-1, and chitotriosidase-1, that yielded a cvAUC of 0.88, outperforming the discriminative ability of models consisting of standard biomarkers (NT-proBNP, hs-TnT, eGFR clinically adjusted) - 0.82 and performing equally well as an extended literature-based set of acknowledged biomarkers (NT-proBNP, hs-TnT, hs-CRP, GDF-15, ST2, PAI-1, Galectin 3) - 0.88. Nine out of 92 serially measured circulating proteins provided a multivariable model for adverse clinical events in CHF patients with high discriminative ability. These proteins reflect wall stress, remodelling, endothelial dysfunction, iron deficiency, haemostasis/fibrinolysis and innate immunity activation. A panel containing these proteins could contribute to dynamic, personalized risk assessment.Clinical Trial Registration: 10/05/2013 https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 .

The influence of oxygen deprivation and donor age on the effect of statins on human mesenchymal stromal cells.

To date, no study evaluated the effect of oxygen deprivation together with statins pretreatment on human mesenchymal stromal cells (MSCs). The aim of our study was to establish the influence of atorvastatin and rosuvastatin on MSC proliferation and cytotoxicity in different oxygenic conditions. Human MSCs isolated from the bone marrow (n = 12) were incubated with statins. The proliferation rate and cytotoxic effect were evaluated in normoxic (21 %O2) and hypoxic (2%O2) conditions, also in relation to donor age. The treatment with atorvastatin was associated with significantly higher proliferation rate compared to control, both in hypoxic (19 % median increase) and normoxic conditions (20 %), p = 0.02 and p = 0.04, respectively. Atorvastatin had no significant cytotoxic effect on MSCs. Treatment with rosuvastatin in hypoxia resulted in significantly higher proliferation rate (15 %, p = 0.02) comparing to control with no significant cytotoxicity. In atmospheric oxygen concentration, rosuvastatin was associated with no significant change in proliferation and higher cytotoxicity compared to untreated control (p = 0.042 and p = 0.015, for 0.04 µM and 1 µM solutions respectively). There were no differences in the effect of statins on MSC from young donors vs. aged donors. These results suggest that statins could support MSC-based therapy of acute myocardial infarction.

Plasma microRNA-126-3p and neutrophil-to-lymphocyte ratio in patients with chronic kidney disease: relationships to ambulatory 24-h blood pressure.

Pro-inflammatory milieu of chronic kidney disease (CKD) results in endothelial damage and contributes to increased cardiovascular risk. The aim of the study was to evaluate association between neutrophil-to-lymphocyte ratio (NLR) and plasma relative expression of endothelially abundant miR-126-3p with circadian blood pressure (BP) pattern in CKD patients. This single-center observational study involved CKD stage 1-5 patients and healthy age- and sex-matched control subjects. All study participants had 24-h automatic blood pressure measurement (ABPM) performed. Plasma miRNA was quantified by qRT-PCR, in relation to endogenous U6 snRNA. In total, 90 CKD patients (60 ± 14 years, 52% males, 33 renal transplant recipients) and 25 healthy control subjects (55 ± 13 years, 48% males, p > 0.05) were enrolled in the study. We observed a positive correlation between miR-126-3p and average nighttime SBP (rho = 0.27, P = 0.02), average nighttime DBP (rho = 0.32, P = 0.003), night-day SBP ratio (ND-SBP), rho = 0.23, P = 0.03 and night-day DBP ratio (ND-DBP), rho = 0.26, P = 0.02. A positive association was found between NLR and average nighttime SBP (rho = 0.25, P = 0.01), ND-SBP (rho = 0.26, P = 0.006), and ND-DBP (rho = 0.28, P = 0.03). In the multiple regression model, NLR remained an independent predictor of average nighttime SBP (Beta per log change of NLR [95% CI]: 11.2 [1.8-10.6], P = 0.02), whereas miR-126-3p of nighttime DBP (1.88 [0.48; 3.28], p = 0.009), The results of our study point towards a link between both NLR and miR-126-3p and nighttime hypertension in CKD patients.

Temporal patterns of macrophage- and neutrophil-related markers are associated with clinical outcome in heart failure patients.

AIMS: Evidence on the association of macrophage- and neutrophil-related blood biomarkers with clinical outcome in heart failure patients is limited, and, with the exception of C-reactive protein, no data exist on their temporal evolution. We aimed to investigate whether temporal patterns of these biomarkers are related to clinical outcome in patients with stable chronic heart failure (CHF). METHODS AND RESULTS: In 263 patients with CHF, we performed serial plasma measurements of scavenger receptor cysteine-rich type 1 protein M130 (CD163), tartrate-resistant acid phosphatase type 5 (TRAP), granulins (GRN), spondin-1 (SPON1), peptidoglycan recognition protein 1 (PGLYRP1), and tissue factor pathway inhibitor (TFPI). The Cardiovascular Panel III (Olink Proteomics AB, Uppsala, Sweden) was used. During 2.2 years of follow-up, we collected 1984 samples before the occurrence of the composite primary endpoint (PE) or censoring. For efficiency, we selected 567 samples for the measurements (all baseline samples, the last two samples preceding the PE, and the last sample before censoring in event-free patients). The relationship between repeatedly measured biomarker levels and the PE was evaluated by joint models. Mean (±standard deviation) age was 67 ± 13 years; 189 (72%) were men; left ventricular ejection fraction (%) was 32 ± 11. During follow-up, 70 (27%) patients experienced the PE. Serially measured biomarkers predicted the PE in a multivariable model adjusted for baseline clinical characteristics [hazard ratio (95% confidence interval) per 1-standard deviation change in biomarker]: CD163 [2.07(1.47-2.98), P < 0.001], TRAP [0.62 (0.43-0.90), P = 0.009], GRN [2.46 (1.64-3.84), P < 0.001], SPON1 [3.94 (2.50-6.50), P < 0.001], and PGLYRP1 [1.62 (1.14-2.31), P = 0.006]. CONCLUSIONS: Changes in plasma levels of CD163, TRAP, GRN, SPON1, and PGLYRP1 precede adverse cardiovascular events in patients with CHF.

Incidence of end-stage renal disease after heart transplantation and effect of its treatment on survival.

AIMS: Many heart transplant recipients will develop end-stage renal disease in the post-operative course. The aim of this study was to identify the long-term incidence of end-stage renal disease, determine its risk factors, and investigate what subsequent therapy was associated with the best survival. METHODS AND RESULTS: A retrospective, single-centre study was performed in all adult heart transplant patients from 1984 to 2016. Risk factors for end-stage renal disease were analysed by means of multivariable regression analysis and survival by means of Kaplan-Meier. Of 685 heart transplant recipients, 71 were excluded: 64 were under 18 years of age and seven were re-transplantations. During a median follow-up of 8.6 years, 121 (19.7%) patients developed end-stage renal disease: 22 received conservative therapy, 80 were treated with dialysis (46 haemodialysis and 34 peritoneal dialysis), and 19 received a kidney transplant. Development of end-stage renal disease (examined as a time-dependent variable) inferred a hazard ratio of 6.45 (95% confidence interval 4.87-8.54, P < 0.001) for mortality. Tacrolimus-based therapy decreased, and acute kidney injury requiring renal replacement therapy increased the risk for end-stage renal disease development (hazard ratio 0.40, 95% confidence interval 0.26-0.62, P < 0.001, and hazard ratio 4.18, 95% confidence interval 2.30-7.59, P < 0.001, respectively). Kidney transplantation was associated with the best median survival compared with dialysis or conservative therapy: 6.4 vs. 2.2 vs. 0.3 years (P < 0.0001), respectively, after end-stage renal disease development. CONCLUSIONS: End-stage renal disease is a frequent complication after heart transplant and is associated with poor survival. Kidney transplantation resulted in the longest survival of patients with end-stage renal disease.

Longitudinal patterns of N-terminal pro B-type natriuretic peptide, troponin T, and C-reactive protein in relation to the dynamics of echocardiographic parameters in heart failure patients.

AIMS: To further elucidate the nature of the association between N-terminal pro-B type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-TnT), C-reactive protein (CRP), and clinical outcome, we examined the relationship between serial simultaneous measurements of echocardiographic parameters and these biomarkers in chronic heart failure (CHF) patients. METHODS AND RESULTS: In 117 CHF patients with ejection fraction ≤50%, NT-proBNP, hs-TnT, and CRP were measured simultaneously with echocardiographic evaluation at 6-month intervals until the end of 30 months follow-up or until an adverse clinical event occurred. Linear mixed effects models were used for data-analysis. Median follow-up was 2.2 years (interquartile range 1.5-2.6). We performed up to six follow-up evaluations with 55% of patients having at least three evaluations performed. A model containing all three biomarkers revealed that doubling of NT-proBNP was associated with a decrease in left ventricular ejection fraction by 1.83 (95% confidence interval -2.63 to -1.03)%, P < 0.0001; relative increase in mitral E/e' ratio by 12 (6-18)%, P < 0.0001; relative increase in mitral E/A ratio by 16 (9-23)%, P < 0.0001; decrease in tricuspid annular plane systolic excursion by 0.66 (-1.27 to -0.05) mm, P = 0.03; rise in tricuspid regurgitation peak systolic gradient by 2.74 (1.43-4.05) mmHg, P = 0.001; and increase in left ventricular and atrial dimensions, P < 0.05. Hs-TnT and CRP showed significant associations with some echocardiographic parameters after adjustment for clinical covariates, but after adjustment for the other biomarkers the associations were not significant. CONCLUSION: Serum NT-proBNP independently reflects changes in echocardiographic parameters of systolic function, left ventricular filling pressures, estimated pulmonary pressure, and chamber dimensions. Our results support further studies on NT-proBNP as a surrogate marker for haemodynamic congestion and herewith support its potential value for therapy guidance.

The Association Between Cytomegalovirus Infection and Cardiac Allograft Vasculopathy in the Era of Antiviral Valganciclovir Prophylaxis.

BACKGROUND: Previous studies on the association between cytomegalovirus (CMV) infection and cardiac allograft vasculopathy (CAV) were conducted on patients transplanted in the prevalganciclovir prophylaxis era. The aim of our study is to evaluate this relation in heart transplantation (HTx) recipients treated according to current prophylactic and immunosuppressive regimens. METHODS: This single-center retrospective study included all consecutive adult patients that underwent HTx between January 1, 2000, and May 31, 2018. Clinically relevant CMV infection was defined as either plasma CMV DNAemia ≥ 1000 IU/mL with/without clinical symptoms or <1000 IU/mL with symptoms. The primary endpoint was first manifestation of CAV diagnosed by coronary angiography. For statistical analysis, the cause-specific hazard regression model was applied, with clinically relevant CMV infection and any CMV infection as time-dependent variables. RESULTS: In total, 260 patients were included in the analysis. The median (interquartile range) follow-up was 7.88 (4.21-12.04) years. During the follow-up, clinically relevant CMV infection was diagnosed in 96 (37%) patients and CAV in 149 (57%) patients. In the multivariate regression analysis, independent predictors of CAV were: number of rejection episodes (cause-specific hazard ratio [95% confidence interval]: 1.18 [1.04-1.34], P = 0.01), hypertension (1.61 [1.11-2.34], P = 0.01), treatment with mycophenolate mofetil (0.68 [0.47-0.97], P = 0.03). No significant association was observed between CMV infection and CAV, except for patients who experienced a breakthrough CMV infection (n = 24) during prophylaxis (1.94 [1.11-3.40], P = 0.02). CONCLUSIONS: In the era of contemporary immunosuppression and valganciclovir prophylaxis, a significant effect of CMV infection on the risk of CAV was seen only among HTx recipients with CMV breakthrough infection.

Impact of renal function on clinical outcomes after PCI in ACS and stable CAD patients treated with ticagrelor: a prespecified analysis of the GLOBAL LEADERS randomized clinical trial.

BACKGROUND: Impaired renal function (IRF) is associated with increased risks of both ischemic and bleeding events. Ticagrelor has been shown to provide greater absolute reduction in ischemic risk following acute coronary syndrome (ACS) in those with versus without IRF. METHODS: A pre-specified sub-analysis of the randomized GLOBAL LEADERS trial (n = 15,991) comparing the experimental strategy of 23-month ticagrelor monotherapy (after 1-month ticagrelor and aspirin dual anti-platelet therapy [DAPT]) with 12-month DAPT followed by 12-month aspirin after percutaneous coronary intervention (PCI) in ACS and stable coronary artery disease (CAD) patients stratified according to IRF (glomerular filtration rate < 60 ml/min/1.73 m2). RESULTS: At 2 years, patients with IRF (n = 2171) had a higher rate of the primary endpoint (all-cause mortality or centrally adjudicated, new Q-wave myocardial infarction [MI](hazard ratio [HR] 1.64, 95% confidence interval [CI] 1.35-1.98, padj = 0.001), all-cause death, site-reported MI, all revascularization and BARC 3 or 5 type bleeding, compared with patients without IRF. Among patients with IRF, there were similar rates of the primary endpoint (HR 0.82, 95% CI 0.61-1.11, p = 0.192, pint = 0.680) and BARC 3 or 5 type bleeding (HR 1.10, 95% CI 0.71-1.71, p = 0.656, pint = 0.506) in the experimental versus the reference group. No significant interactions were seen between IRF and treatment effect for any of the secondary outcome variables. Among ACS patients with IRF, there were no between-group differences in the rates of the primary endpoint or BARC 3 or 5 type bleeding; however, the rates of the patient-oriented composite endpoint (POCE) of all-cause death, any stroke, MI, or revascularization (pint = 0.028) and net adverse clinical events (POCE and BARC 3 or 5 type bleeding) (pint = 0.045), were lower in the experimental versus the reference group. No treatment effects were found in stable CAD patients categorized according to presence of IRF. CONCLUSIONS: IRF negatively impacted long-term prognosis after PCI. There were no differential treatment effects found with regard to all-cause death or new Q-wave MI after PCI in patients with IRF treated with ticagrelor monotherapy. CLINICAL TRIAL REGISTRATION: The trial has been registered with ClinicalTrials.gov, number NCT01813435.