Search Results (237)

Background/Objectives: Real-world evidence shows alarmingly suboptimal utilization of guideline directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). One of the barriers of GDMT implementation appears to be concerns about the potential development of drug-related adverse events (AEs), particularly in high-risk patients. This study aimed to evaluate whether advanced HFrEF (AHF) patients can be up-titrated safely and whether AHF predisposes individuals to the occurrence of putatively drug-related AEs. Methods: A total of 373 HFrEF patients with documented baseline, 2 months, and 12 months visits were analyzed for utilization and target dosages (TDs) of HF drugs. Successful up-titration and AEs were evaluated for different stages of HF reflected by N-terminal pro-B type natriuretic peptide (NT-proBNP) (<1000 pg/mL, 1000–2000 pg/mL, >2000 pg/mL). Results: A stepwise increase in HF medications was observed for all drug classes during follow-up. At 12 months, 73%, 75%, 62%, 86%, and 45% of patients received ≥90% of TDs of beta-blockers (BBs), renin–angiotensin system inhibitors (RASis), mineralocorticoid receptor antagonists (MRAs), sodium–glucose cotransporter-2 inhibitors (SGLT2 i), and triple-therapy, respectively. Predictors of successful up-titration in logistic regression were baseline HF drug TDs, estimated glomerular filtration rate (eGFR), and potassium, but not NT-proBNP or age. The development of AEs was rare, with hyperkalemia as the most common event (34% at 12 months). AEs were comparable in all stages of HF. However, the development of hyperkalemia was more frequent in patients with higher NT-proBNP and also accounted for most cases of incomplete up-titration. Conclusions: This study suggests that with dedicated protocols and frequent visits, GDMT can be successfully implemented across all stages of HFrEF, including patients with AHF. Full article

Background: This study presents an innovative approach to cardiovascular disease (CVD) risk prediction based on a comprehensive analysis of clinical, immunological and biochemical markers using mathematical modelling and machine learning methods. Baseline data include indices of humoral and cellular immunity (CD59, CD16, IL-10, CD14, CD19, CD8, CD4, etc.), cytokines and markers of cardiovascular disease, inflammatory markers (TNF, GM-CSF, CRP), growth and angiogenesis factors (VEGF, PGF), proteins involved in apoptosis and cytotoxicity (perforin, CD95), as well as indices of liver function, kidney function, oxidative stress and heart failure (albumin, cystatin C, N-terminal pro B-type natriuretic peptide (NT-proBNP), superoxide dismutase (SOD), C-reactive protein (CRP), cholinesterase (ChE), cholesterol, and glomerular filtration rate (GFR)). Clinical and behavioural risk factors were also considered: arterial hypertension (AH), previous myocardial infarction (PICS), aortocoronary bypass surgery (CABG) and/or stenting, coronary heart disease (CHD), atrial fibrillation (AF), atrioventricular block (AB block), and diabetes mellitus (DM), as well as lifestyle (smoking, alcohol consumption, physical activity level), education, and body mass index (BMI). Methods: The study included 52 patients aged 65 years and older. Based on the clinical, biochemical and immunological data obtained, a model for predicting the risk of premature cardiovascular aging was developed using mathematical modelling and machine learning methods. The aim of the study was to develop a predictive model allowing for the early detection of predisposition to the development of CVDs and their complications. Numerical methods of mathematical modelling, including Runge–Kutta, Adams–Bashforth and backward-directed Euler methods, were used to solve the prediction problem, which made it possible to describe the dynamics of changes in biomarkers and patients’ condition over time with high accuracy. Results: HLA-DR (50%), CD14 (41%) and CD16 (38%) showed the highest association with aging processes. BMI was correlated with placental growth factor (37%). The glomerular filtration rate was positively associated with physical activity (47%), whereas SOD activity was negatively correlated with it (48%), reflecting a decline in antioxidant defence. Conclusions: The obtained results allow for improving the accuracy of cardiovascular risk prediction, and form personalised recommendations for the prevention and correction of its development. Full article

An explorative study was conducted to evaluate the efficacy and safety of 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (SPP-004) in 10 pediatric patients with Leigh syndrome (LS) aged 3–24 months in 10 institutions between December 2014 and July 2019. The patients were randomized and allocated to the SPP-004 or placebo group for a 12-week double-blind period, followed by a 12-week open-label period with SPP-004 and then a long-term study of up to 180 weeks. The efficacy and safety were evaluated using the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) and adverse events (AEs), respectively. No significant differences were found between groups in NPMDS scores, but prolonged SPP-004 treatment stabilized or improved scores. During the initial double-blind phase, the serum lactate levels increased in the placebo group but not in the SPP-004 group. Over the period of prolonged treatment with SPP-004, the average serum lactate level gradually decreased to a normal level. One patient died due to heart failure, presumably due to an underlying disease. Overall, 7 out of 10 patients received SPP-004 without developing severe AEs until the termination of the long-term study. Given the severe symptoms and poor prognosis of pediatric LS, NPMDS scores were indicative of stabilization in pediatric LS patients treated with SPP-004. Full article

Background/Objectives: Organ transplantation is a life-saving intervention for patients with terminal organ failure, but long-term success is hindered by graft rejection and dependence on lifelong immunosuppressants. These drugs pose risks such as opportunistic infections and malignancies. Chimeric antigen receptor (CAR) technology, originally developed for cancer immunotherapy, has been adapted to regulatory T cells (Tregs) to enhance their antigen-specific immunosuppressive function. This systematic review evaluates the preclinical development of CAR-Tregs in promoting graft tolerance and suppressing graft-versus-host disease (GvHD). Methods: A systematic review following PROSPERO guidelines (CRD420251073207) was conducted across PubMed, Scopus, and Web of Science for studies published from 2015 to 2024. After screening 105 articles, 17 studies involving CAR-Tregs in preclinical or in vivo transplant or GvHD models were included. Results: CAR-Tregs exhibited superior graft-protective properties compared to unmodified or polyclonal Tregs. HLA-A2-specific CAR-Tregs consistently improved graft survival, reduced inflammatory cytokines, and suppressed immune cell infiltration across skin, heart, and pancreatic islet transplant models. The inclusion of CD28 as a co-stimulatory domain enhanced Treg function and FOXP3 expression. However, challenges such as Treg exhaustion, tonic signaling, and reduced in vivo persistence were noted. Some studies reported synergistic effects when CAR-Tregs were combined with immunosuppressants like rapamycin or tacrolimus. Conclusions: CAR-Tregs offer a promising strategy for inducing targeted immunosuppression in allogeneic transplantation. While preclinical findings are encouraging, further work is needed to optimize CAR design, ensure in vivo stability, and establish clinical-scale manufacturing before translation to human trials. Full article

Background/Objectives: We aimed to identify the factors associated with clinically important changes in quality of life (QoL) of real-world heart failure (HF) patients. Methods: This is a single-centre, prospective cohort study including 419 patients at an HF clinic between January 2013 and February 2020. QoL was assessed regularly using Minnesota Living with Heart Failure Questionnaire (MLHFQ). We used five nested linear mixed-effects models to account for QoL measurements between patients and within-patient. Models were adjusted for time, sociodemographic factors, comorbidities, self-care adherence, and HF severity factors. Results: Median age was 78 years, 54.4% of patients were female, and 49.6% had left ventricle ejection fraction ≥ 50%. At baseline, 62.5% of patients were New York Heart Association (NYHA) class II. Median N-terminal-pro-B type natriuretic peptide level was 1454 pg/mL. Mean MLHFQ total score at baseline was 25 points (95%CI: 22.97–27.60). Having an implanted cardiac resynchronization therapy-pacemaker (CRT-P) was associated with moderate to large improvement in QoL (−13.55 points, 95%CI: −22.45–−4.65). NYHA class II and estimated glomerular filtration rate < 30 mL/min/1.73 m² were associated with small to moderate QoL deterioration (9.74 points, 95%CI: 6.74–12.75 and 5.82 points, 95%CI: 1.17–10.47, respectively). NYHA classes III or IV and a recent HF hospitalization were associated with large to very large QoL deterioration (28.39 points, 95%CI: 23.82–32.96; 60.59 points, 95%CI: 34.46–86.72; and 26.91 points, 95%CI: 21.80–32.03, respectively). Conclusions: CRT-P implantation, NYHA class and HF hospitalization are associated with the most clinically important QoL changes. Full article

Acute heart failure (AHF) is a clinical syndrome characterized by the sudden onset or rapid worsening of heart failure signs and symptoms, frequently triggered by myocardial ischemia, pressure overload, or cardiotoxic injury. A central component of its pathophysiology is the activation of intracellular signal transduction cascades that translate extracellular stress into cellular responses. Among these, the mitogen-activated protein kinase (MAPK) pathways have received considerable attention due to their roles in mediating inflammation, apoptosis, hypertrophy, and adverse cardiac remodeling. The canonical MAPK cascades—including extracellular signal-regulated kinases (ERK1/2), p38 MAPK, and c-Jun N-terminal kinases (JNK)—are activated by upstream stimuli such as angiotensin II (Ang II), aldosterone, endothelin-1 (ET-1), and sustained catecholamine release. Additionally, emerging evidence highlights the role of receptor-mediated signaling, cellular stress, and myeloid cell-driven coagulation events in linking MAPK activation to fibrotic remodeling following myocardial infarction. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade plays a central role in regulating cardiomyocyte survival, hypertrophy, energy metabolism, and inflammation. Activation of the PI3K/Akt pathway has been shown to confer cardioprotective effects by enhancing anti-apoptotic and pro-survival signaling; however, aberrant or sustained activation may contribute to maladaptive remodeling and progressive cardiac dysfunction. In the context of AHF, understanding the dual role of this pathway is crucial, as it functions both as a marker of compensatory adaptation and as a potential therapeutic target. Recent reviews and preclinical studies have linked PI3K/Akt activation with reduced myocardial apoptosis and attenuation of pro-inflammatory cascades that exacerbate heart failure. Among the multiple signaling pathways involved, glycogen synthase kinase-3β (GSK-3β) has emerged as a key regulator of apoptosis, inflammation, metabolic homeostasis, and cardiac remodeling. Recent studies underscore its dual function as both a negative regulator of pathological hypertrophy and a modulator of cell survival, making it a compelling therapeutic candidate in acute cardiac settings. While earlier investigations focused primarily on chronic heart failure and long-term remodeling, growing evidence now supports a critical role for GSK-3β dysregulation in acute myocardial stress and injury. This comprehensive review discusses recent advances in our understanding of the MAPK signaling pathway, the PI3K/Akt cascade, and GSK-3β activity in AHF, with a particular emphasis on mechanistic insights, preclinical models, and emerging therapeutic targets. Full article

Background: Left ventricular filling pressure (LVFP) is pivotal in heart failure management, yet non-invasive assessment remains challenging. While echocardiography is the first line, cardiovascular magnetic resonance (CMR) offers enhanced accuracy. This study evaluates the interplay between CMR-derived LVFP and echocardiography, focusing on sex differences and correlations with N-terminal pro-brain natriuretic peptide (NT-proBNP). Methods: In this prospective study, 222 patients with CMR-derived LVFP > 14 mmHg underwent transthoracic echocardiography (TTE) and CMR. Sex-specific CMR equations (incorporating left atrial volume and ventricular mass) were used to estimate pulmonary capillary wedge pressure (PCWP). Correlations between imaging parameters and NT-proBNP were assessed. Results: CMR-derived LVFP showed no sex-based differences (p = 0.3143), unlike echocardiographic indices: women had higher E/e′ (p < 0.0001) and lower lateral mitral annular velocities (p = 0.0159). CMR-derived LVFP correlated strongly with NT-proBNP (r = 0.47, p < 0.0001), outperforming E/e′ (r = 0.41). Stratification by CMR PCWP tertiles revealed higher NT-proBNP (p = 0.0003), left atrial volumes (p < 0.0001), and septal thickness (p < 0.0001) in the highest tertiles. CMR-derived LVFP demonstrated superior diagnostic accuracy (AUC = 0.754 vs. 0.740 for E/e′) in identifying elevated NT-proBNP (>400 pg/mL). Sex-independent CMR measures contrasted with echocardiography, where parameters like left atrial volume varied by sex (p = 0.012). Conclusions: CMR-derived LVFP is a robust, sex-independent biomarker strongly linked to NT-proBNP, offering superior diagnostic performance over echocardiography. Its integration with echocardiographic indices enhances the non-invasive assessment of cardiac filling pressures, advocating a synergistic imaging approach to refine heart failure management. Full article

Objective: We aimed to investigate the association between the pan-immune-inflammation value (PIV) and mortality in patients with heart failure with a reduced ejection fraction (HFrEF), along with clinical and biochemical parameters. Methods: In this retrospective cohort study, 419 patients diagnosed with HFrEF between January 2014 and December 2023 were analyzed. Data on demographic features, comorbidities, cardiac parameters [New York Heart Association (NYHA) classification, left ventricular ejection fraction (LVEF), ventricular dimensions], medication use, and laboratory findings (PIV, N-terminal pro-B-type natriuretic peptide [NT-proBNP], electrolytes, and complete blood count) were collected from institutional and national records. Results: Mortality occurred in 22.91% of patients. PIV > 696 was significantly associated with mortality (sensitivity: 37.5%, specificity: 78.64%, p = 0.006), but it was not an independent predictor in multivariate analysis. Instead, low body mass index (BMI), increased end-systolic diameter, reduced LVEF, advanced NYHA class (III/IV), elevated NT-proBNP, hyponatremia, and lymphopenia were identified as independent predictors (all p < 0.001). Conclusions: Although PIV was associated with mortality in patients with HFrEF, it did not independently predict outcomes beyond established risk factors. These results suggest that while inflammation may contribute to HFrEF pathophysiology, traditional clinical and biochemical markers remain more reliable for prognostication. Full article

As part of the “2nd Training Conference on Heart Failure and Atrial Fibrillation for Residents”, held in Madrid in November 2024, a collaborative initiative was launched to address the most common practical challenges in the management of heart failure (HF) in daily practice. This document is the result of the joint efforts of residents from various hospitals nationwide, in collaboration with senior physicians with extensive HF expertise and members of the Working Group of the Spanish Society of Internal Medicine. Our aim is to provide a useful tool that promotes learning and collaboration among professionals interested in this field. The structure of this document is based on a compilation of the most interesting and challenging questions raised during the conference. Each question is addressed with a concise and practical response, supported by updated references to ensure scientific rigor and facilitate consultation. Full article

Heart failure represents the terminal stage in the development of many cardiovascular diseases, and its pathological mechanisms are closely related to disturbances in energy metabolism and mitochondrial dysfunction in cardiomyocytes. In recent years, nicotinamide adenine dinucleotide (NAD⁺), a core coenzyme involved in cellular energy metabolism and redox homeostasis, has been shown to potentially ameliorate heart failure through the regulation of mitochondrial function. This review systematically investigates four core mechanisms of mitochondrial dysfunction in heart failure: imbalance of mitochondrial dynamics, excessive accumulation of reactive oxygen species (ROS) leading to oxidative stress injury, dysfunction of mitochondrial autophagy, and disturbance of Ca²⁺ homeostasis. These abnormalities collectively exacerbate the progression of heart failure by disrupting ATP production and inducing apoptosis and myocardial fibrosis. NAD⁺ has been shown to regulate mitochondrial biosynthesis and antioxidant defences through the activation of the deacetylase family (e.g., silent information regulator 2 homolog 1 (SIRT1) and SIRT3) and to increase mitochondrial autophagy to remove damaged mitochondria, thus restoring energy metabolism and redox balance in cardiomyocytes. In addition, the inhibition of NAD⁺-degrading enzymes (e.g., poly ADP-ribose polymerase (PARP), cluster of differentiation 38 (CD38), and selective androgen receptor modulators (SARMs)) increases the tissue intracellular NAD⁺ content, and supplementation with NAD⁺ precursors (e.g., β-nicotinamide mononucleotide (NMN), nicotinamide riboside, etc.) also significantly elevates myocardial NAD⁺ levels to ameliorate heart failure. This study provides a theoretical basis for understanding the central role of NAD⁺ in mitochondrial homeostasis and for the development of targeted therapies for heart failure. Full article

Background/Objectives: Cognitive impairment is a frequent and underrecognized comorbidity in elderly patients with heart failure with preserved ejection fraction (HFpEF), contributing to poor outcomes and complicating disease management. This study aimed to identify risk factors associated with cognitive impairment in elderly HFpEF patients from Western Romania and to develop a point-based risk score for clinical use. Methods: We conducted a cross-sectional analysis of HFpEF patients aged ≥65 years. Cognitive status was assessed using the Mini-Mental State Examination-2 (MMSE-2), with significant impairment defined as a score <24. Multivariable logistic regression analysis was performed to identify independent predictors of cognitive dysfunction. Results: A total of 326 HFpEF patients were included. Diabetes mellitus, prior stroke or transient ischemic attack (TIA), carotid artery disease, elevated N-terminal pro–B-type natriuretic peptide (NT-proBNP), and reduced estimated glomerular filtration rate (eGFR) were independently associated with cognitive impairment. Higher Kansas City Cardiomyopathy Questionnaire (12-KCCQ) scores and anticoagulant therapy for atrial fibrillation were associated with a lower risk. Based on these variables, a simple point-based cognitive risk score was developed, demonstrating strong discriminatory ability (area under the curve = 0.84). A threshold of ≥2 points identified cognitive impairment with 75% sensitivity and 83% specificity. Conclusions: Our findings underscore the importance of integrated cardiovascular and cognitive assessment in elderly HFpEF patients. The developed risk score offers a pragmatic tool for the early identification of cognitive dysfunction, potentially informing timely interventions and preventive strategies. Full article

Background: As the terminal stage of cardiovascular disease, heart failure (HF) has garnered significant attention due to its recurrent nature, high mortality rates, and substantial medical burden. Shared decision-making (SDM) is an innovative strategy to improve medication adherence. From positive psychology insights, the effects on spirituality, benefit-finding (BF), decision self-efficacy, and patient engagement in SDM remain unexplored. Methods: This quantitative cross-sectional study was conducted from January 2023 to September 2024 at a hospital in Jiangsu. Data on general information, spirituality, BF, decision self-efficacy, and SDM were collected from 387 patients with chronic heart failure. Results: Spirituality was significantly associated with SDM (β = 0.8839, p < 0.001). BF played a mediating role in the relationship between spirituality and SDM (β = 0.2020, 95% CI: 0.0058–0.0261), accounting for 22.9% of the total effect. Decision self-efficacy was identified as a mediator in this relationship (β = 0.2636, 95% CI: 0.0120–0.0284), accounting for 29.8%. In addition, both BF and decision self-efficacy exhibited a chain mediation effect on the association between spirituality and SDM (β = 0.1451, 95% CI: 0.0061–0.0162), and the total indirect effect accounted for 69.1%. Conclusions: This study is the first to demonstrate that spirituality has significant direct and indirect effects on SDM, and it also reveals the underlying psychological mechanisms. Spiritual support services, BF intervention, and enhancing patients’ decision self-efficacy can promote their participation in SDM. These findings highlight the role of positive psychology in promoting SDM, showing potential contribution to promoting medication adherence in HF patients. Full article

Background and Objectives: Despite the latest advancements in interventional procedures and pharmacological therapy, the incidence of heart failure and death rate following an acute myocardial remain unacceptably high. This study was designed in response to the limited and conflicting literature data regarding the diagnostic and prognostic role of modern inflammatory biomarkers in patients with coronary artery disease. Materials and Methods: We conducted a case–control, prospective observational study. A total of 145 patients were analyzed, of whom 105 patients had an acute coronary syndrome diagnosis and represented the study group, while 40 patients with a chronic coronary syndrome diagnosis represented the control group. This study investigates the diagnostic and prognostic role of the interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), Growth differentiation factor 15 (GDF-15), and classic biomarkers in patients with ischemic coronary heart disease. Results: IL-1β exhibited a prognostic role, being significantly correlated with a left ventricular ejection fraction below 30%. GDF-15 plays a dual role, as a cardio-inflammatory biomarker, being significantly correlated with both N-terminal pro-brain natriuretic peptide (NT-proBNP), and IL-1β, IL-6, and CRP. At the same time, GDF-15 represents a surrogate marker for renal dysfunction. According to the ROC analysis, patients at high mortality risk can be identified with adequate accuracy by cardiac troponin, GDF-15, and IL-10, in addition to NT-proBNP. Logistic regression models confirmed NT-proBNP and IL-10 as mortality predictors. Conclusions: IL-1β stands out for its significant prognostic role, while IL-6 did not demonstrate a diagnostic or prognostic role in acute myocardial infarction patients. IL-10 demonstrated superior predictive value in terms of fatal prognosis compared with the other modern biomarkers. GDF-15 is representative of a multivalent biomarker involved in inflammation, heart failure, and renal dysfunction. Full article

Background/Objectives: Low-grade systemic inflammation, characteristic of heart failure (HF), is a nonspecific inflammatory syndrome that affects the entire body. Macrophage migration inhibitory factor 1 (MIF-1) is a pro-inflammatory cytokine, a key mediator of the innate immune response, and may serve as a potential biomarker of monocyte homing and activation in HF with reduced and mildly reduced ejection fraction (HFrEF, HFmrEF). Methods: We evaluated 70 hemodynamically stable patients with left ventricular EF (LVEF) < 50% by means of echocardiography and blood sampling. Results: We report significant correlations between MIF-1, LVEF (r = −0.33, p = 0.005), LV global longitudinal strain (LVGLS, r = 0.41, p = 0.0004), and tricuspid annular plane systolic excursion (TAPSE, r = −0.37, p = 0.001). MIF-1 levels in HFrEF patients were relatively higher, but not significantly different from those observed in HFmrEF. MIF-1 showed significant associations with TAPSE to systolic pulmonary artery pressure ratio (TAPSE/sPAP, p < 0.0001). Also, patients with TAPSE/sPAP < 0.40 mm/mmHg had significantly higher levels of MIF-1 (p = 0.009). Moreover, ischemic cardiomyopathy (ICM) was more frequent in patients with MIF-1 concentrations above 520 pg/mL (57.1% MIF-1^hi vs. 28.6% MIF-1^lo, p = 0.029). In terms of congestion, MIF-1 showed significant associations with the presence of peripheral edema (p = 0.007), but none was found with self-reported dyspnea (p = 0.307) and New York Heart Association (NYHA) class (p = 0.486). Also, no relationship was reported with N-terminal pro-B-type natriuretic peptide concentrations (NT-proBNP, r = 0.14, p = 0.263). However, the six-minute walk distance was greater in individuals in the MIF-1^lo group when compared to those in the MIF-1^hi group (404.0 ± 127.4 vs. 324.8 ± 124.1 m, p = 0.010). Conclusions: Beyond identifying inflammatory biomarkers related to disease severity, linking MIF-1 to various pathophysiological mechanisms may highlight the active involvement of the monocyte-macrophage system in HF. This system holds notable significance in congestion-related conditions, acting as a major source of reactive oxygen species that perpetuate inflammation. Full article

Background: Suppression of Tumorigenicity 2 (ST2), a member of the interleukin-1 receptor family, plays a crucial role in immune regulation. Elevated sST2 levels are associated with poor prognosis in various inflammatory and cardiovascular diseases, including acute heart failure (AHF), sepsis and transplant rejection. Objectives and methods: This study aimed to evaluate the diagnostic and prognostic accuracy of sST2, along with other biomarkers, such as high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), procalcitonin (PCT) and mid-regional pro-adrenomedullin (MR-proADM), in patients with AHF, sepsis and AHF/sepsis overlap. Results: A cohort of 74 patients was analyzed, and comparison statistics revealed that sST2 levels were significantly higher in the AHF/sepsis group (113.88 ng/mL) compared to the AHF group (42.24 ng/mL, p = 0.024), while no significant difference was observed between sepsis and AHF groups (p = 0.10). Other biomarkers, including hs-CRP and PCT, showed significant differences between the AHF and AHF/sepsis groups. ROC curve analysis identified sST2 as a strong predictor of mortality and readmission, with high AUC values for 30-day readmission (0.821) and mortality (0.87). Conclusions: These findings suggest that combining biomarkers, including sST2, could improve the early diagnosis, risk stratification and management of critically ill patients with overlapping AHF and sepsis. Further studies with larger populations are needed to validate these findings and explore the potential of integrating these biomarkers into clinical practice. Full article