Marija Stojanović

The heart and liver are closely interconnected through complex hemodynamic, neurohumoral, inflammatory, and metabolic mechanisms. Dysfunction of either organ may adversely affect the other, giving rise to a broad spectrum of cardiohepatic disorders with important diagnostic and prognostic implications. This narrative review is based on a literature search strategy of PubMed and the Web of Science Core Collection covering publications from January 2000 through June 2026, with a focus on hypoxic hepatitis, congestive hepatopathy, and cirrhotic cardiomyopathy. Cardiac diseases may induce liver injury through acute hypoperfusion or chronic venous congestion, resulting in distinct clinical entities characterized by different pathophysiological mechanisms, laboratory findings, imaging features, and therapeutic approaches. Conversely, advanced liver disease may be associated with impaired cardiovascular function, including cirrhotic cardiomyopathy, a condition that frequently remains clinically silent until physiological or therapeutic stress unmasks impaired cardiac reserve. Recent advances in multimodal imaging, including echocardiography with myocardial deformation analysis, abdominal ultrasonography with Doppler evaluation, elastography, computed tomography, and cardiac magnetic resonance, together with emerging biomarkers, have provided additional tools for the recognition and characterization of these disorders, although the clinical value of some newer techniques and biomarkers remains under investigation. Nevertheless, differentiating congestion-related liver injury from progressive fibrosis and identifying subclinical cardiac dysfunction remain important clinical challenges. A comprehensive understanding of the bidirectional interactions between the heart and liver is important for timely diagnosis, accurate risk stratification, and appropriate management. Future studies should focus on standardized diagnostic pathways, validation of novel imaging techniques and biomarkers, and multidisciplinary strategies that may improve outcomes in patients with complex cardiohepatic disease.

Background/Objectives: Elevated homocysteine (Hcy) levels are associated with endothelial dysfunction, oxidative stress, and inflammation, contributing to cardiovascular disease development. The aim of this study was to examine the effects of vitamin B6 and folic acid on cardiometabolic biomarkers, cardiac oxidative stress, metabolic enzyme activities and cardiovascular histomorphometric parameters in homocysteine-loaded rats. Methods: Male Wistar albino rats were divided into four groups (n = 10, per group): C—saline 0.2 mL/day s.c. + saline 0.5 mL i.p; H: Hcy 0.45 µmol/g b.w./day s.c. + saline 0.5 mL i.p; C-B6+FA—saline 0.2 mL/day s.c. + vitamin B6 (7 mg/kg b.w. i.p./day) and folic acid (FA) (5 mg/kg b.w. i.p./day); and H-B6+FA—Hcy (0.45 µmol/g b.w./day s.c.) + vitamin B6 (7 mg/kg b.w. i.p./day) and FA (5 mg/kg b.w. i.p./day). Substances were applied s.c. for 2 weeks and i.p for 4 weeks. Results: B6+FA supplementation significantly reduced serum Hcy and LDL concentrations and attenuated Hcy-associated increases in cardiac SOD activity and right ventricular wall thickness. However, B6+FA was associated with increased cardiac MDA levels. MDH activity increased mainly in non-Hcy-loaded supplemented rats, whereas LDH activity, the cardio-somatic index, and aortic histomorphometric parameters remained unchanged. Conclusions: Combined B6+FA supplementation may improve Hcy metabolism, the LDL profile, and selected cardiac structural/oxidative alterations, but its association with increased lipid peroxidation suggests complex redox effects requiring cautious interpretation.

Translocator protein (TSPO) regulates mitochondrial function, inflammation, and oxidative stress; however, its role in acute myocardial injury (MI) remains incompletely understood. While previous studies have examined TSPO ligands in cardiac injury, the interplay between TSPO modulation and nitric oxide (NO) signaling in AMI has not been systematically investigated. The aim of this study was to investigate the effects of TSPO modulation by PK11195, alone or in combination with nitric oxide synthase (NOS) inhibition by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME), on cardiometabolic, inflammatory, oxidative stress, and histopathological parameters in an experimental model of isoprenaline-induced MI in rats. Male Wistar albino rats were divided into four groups: control (C); isoprenaline + saline-treated (ISO); isoprenaline + PK11195-treated (IP); and isoprenaline + PK11195 + L-NAME-treated (IPLN) groups. Isoprenaline administration induced MI, evidenced by elevated cardiac biomarkers, electrocardiographic (ECG) alterations, and histopathological damage. PK11195 treatment significantly attenuated MI and reduced pro-inflammatory cytokine levels while increasing anti-inflammatory cytokine levels, indicating protective effects. Nevertheless, TSPO modulation was associated with adverse metabolic effects, notably elevated fibrinogen and plasma homocysteine levels. Co-administration of L-NAME mechanistically demonstrated that NO availability is essential for PK11195 cardioprotective effects, as NOS inhibition partially abolished cardioprotection and modified oxidative stress parameters. Overall, TSPO modulation exerts complex actions in acute MI through regulating mitochondrial function, inflammatory signaling, and NO pathways, suggesting that TSPO is a potential, multifaceted therapeutic target.

Disruptions in homocysteine (Hcy) metabolism may increase the liver’s susceptibility to developing conditions such as alcoholic liver disease, viral hepatitis, hepatocellular carcinoma (HCC), and cirrhosis. The aim of this study was to examine effects of aerobic treadmill training on hepatic injury biomarkers in sera, oxidative stress parameters, the activity of metabolic enzymes, and histological characteristics in the liver tissue of rats with experimentally induced hyperhomocysteinemia. Male Wistar albino rats were divided into four groups (N = 10, per group): C—saline 0.2 mL/day sc. 2×/day for 14 days + saline 0.5 mL ip.1×/day for 28 days; H—homocysteine 0.45 µmol/g b.w. 2×/day for 14 days + saline 0.5 mL ip.1×/day for 28 days; CPA—saline 0.2 mL/day sc. 2×/day for 14 days + aerobic treadmill training for 28 days; and HPA—homocysteine 0.45 µmol/g b.w. 2×/day for 14 days + aerobic treadmill training for 28 days. The serum albumin concentration was decreased in both physically active (PA) groups compared to sedentary groups. Concentration of malondialdehyde in liver tissue homogenates was lower in both PA groups compared to the H group. The total lactate dehydrogenase and malate dehydrogenase activities were significantly elevated in the HPA group compared to the C and H groups. Activities of aminotransferases in sera samples, and activities of catalase and superoxide dismutase in liver tissue did not significantly differ between groups. No significant histological changes were found in liver tissue in groups. This study demonstrated that aerobic treadmill training can reduce lipid peroxidation in liver tissue under hyperhomocysteinemic conditions, providing a protective effect. However, hyperhomocysteinemia can alter energy metabolism during aerobic exercise, shifting it toward anaerobic pathways and leading to elevated lactate dehydrogenase activity in the liver. Given that conditions like hyperhomocysteinemia are associated with an increased risk of cardiovascular diseases and liver damage, understanding how exercise influences these dynamics could guide therapeutic approaches.

The aim of this study was to investigate the effects of aerobic treadmill training regimen of four weeks duration on oxidative stress parameters, metabolic enzymes, and histomorphometric changes in the colon of hyperhomocysteinemic rats. Male Wistar albino rats were divided into four groups (n = 10, per group): C, 0.9% NaCl 0.2 mL/day subcutaneous injection (s.c.) 2x/day; H, homocysteine 0.45 µmol/g b.w./day s.c. 2x/day; CPA, saline (0.9% NaCl 0.2 mL/day s.c. 2x/day) and an aerobic treadmill training program; and HPA, homocysteine (0.45 µmol/g b.w./day s.c. 2x/day) and an aerobic treadmill training program. The HPA group had an increased level of malondialdehyde (5.568 ± 0.872 μmol/mg protein, p = 0.0128 vs. CPA (3.080 ± 0.887 μmol/mg protein)), catalase activity (3.195 ± 0.533 U/mg protein, p < 0.0001 vs. C (1.467 ± 0.501 U/mg protein), p = 0.0012 vs. H (1.955 ± 0.293 U/mg protein), and p = 0.0003 vs. CPA (1.789 ± 0.256 U/mg protein)), and total superoxide dismutase activity (9.857 ± 1.566 U/mg protein, p < 0.0001 vs. C (6.738 ± 0.339 U/mg protein), p < 0.0001 vs. H (6.015 ± 0.424 U/mg protein), and p < 0.0001 vs. CPA (5.172 ± 0.284 U/mg protein)) were detected in the rat colon. In the HPA group, higher activities of lactate dehydrogenase (2.675 ± 1.364 mU/mg protein) were detected in comparison to the CPA group (1.198 ± 0.217 mU/mg protein, p = 0.0234) and higher activities of malate dehydrogenase (9.962 (5.752–10.220) mU/mg protein) were detected in comparison to the CPA group (4.727 (4.562–5.299) mU/mg protein, p = 0.0385). Subchronic treadmill training in the rats with hyperhomocysteinemia triggers the colon tissue antioxidant response (by increasing the activities of superoxide dismutase and catalase) and elicits an increase in metabolic enzyme activities (lactate dehydrogenase and malate dehydrogenase). This study offers a comprehensive assessment of the effects of aerobic exercise on colonic tissues in a rat model of hyperhomocysteinemia, evaluating a range of biological indicators including antioxidant enzyme activity, metabolic enzyme activity, and morphometric parameters, which suggested that exercise may confer protective effects at both the physiological and morphological levels.

Hyperhomocysteinemia represents a pathological condition characterized by an increased concentration of homocysteine in the blood, exceeding the threshold of 15 µmol/L. Hyperhomocysteinemia can be caused by genetic defects in enzymes involved in the metabolism of homocysteine and inadequate intake of vitamin B6, folic acid, and/or vitamin B12, disturbances in kidney and thyroid function, malignant diseases, psoriasis, and diabetes, as well as the use of certain medications, alcohol, tobacco, and caffeine. Hyperhomocysteinemia leads to damage to blood vessels through the induction of the proliferation of vascular smooth muscle cells, disruption of physiological endothelial functions, accumulation of reactive oxygen and nitrogen species, i.e., induction of oxidative and nitrosative stress, increased production of collagen, and degradation of the elastic fibers of the arterial wall, disturbance in the production of nitric oxide, dysfunction in the H2S signaling pathway, cellular hypomethylation, homocysteinylation of proteins, and disturbances in lipid metabolism. These pathophysiological mechanisms lead to accelerated atherosclerosis, which ultimately results in diseases such as acute myocardial infarction, heart failure, stroke, and peripheral vascular disease. In patients with the aforementioned diseases, or with associated risk factors such as hypertension, diabetes, obesity, smoking, or a positive family history of coronary heart disease, it is of great importance to determine and monitor the concentration of homocysteine in the blood and to take measures in the form of lifestyle changes aimed at secondary prevention of the consequences that hyperhomocysteinemia brings with it.

Introduction/aim: Nitric oxide (NO) is a key mediator which, paradoxically, regulates sinusoidal (intrahepatic) and systemic/splanchnic circulation. The main goal of this study was to measure NO and compare serum values of NO with flow data in visceral blood vessels of the liver, spleen, kidney and intestine in patients with cirrhosis. Material and methods: This prospective study included 80 patients with cirrhosis of the liver. Doppler ultrasonography was used to assess flow velocity and resistive index (RI) in the hepatic (HA), right (RRA), and left renal (LRA), splenic (SA) and superior mesenteric artery (SMA). NO concentration was determined using the DetectX® Nitric Oxide colorimetric detection kit. Results: We found a statistically significant difference in the mean NO value in the group of patients without ascites compared to the ascites group, as well as in the group of patients with A stage in relation to C stage of cirrhosis (p <0.05). There is statistically significant negative correlation between NO and diameter, and maximal and minimal velocity in LRA. There is significant positive correlation between NO and minimal velocity in SMA. Conclusions: In this study, we found that patients with cirrhosis of the liver were exposed to significantly higher RI LRA, RRA, SA and HA. In patients with cirrhosis complicated by ascites and in those with end stage liver disease, the NO level was significantly higher. The concentration of NO had an effect on the diameter and flow rate in the LRA and flow rate in SMA.

Background and Objectives: Upper endoscopy is considered the gold standard for screening and diagnosis of esophageal varices (EV). Non-invasive methods for predicting EV have become a research hotspot in recent years. The aim of this study was to assess the role of non-invasive scores in predicting the presence of EV in patients with liver cirrhosis, and to determine the value of these scores in predicting the outcome of patients with cirrhosis presenting with acute variceal bleeding. Materials and Methods: A total of 386 patients with liver cirrhosis were included. The model for end-stage liver disease (MELD), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AST/ALT), AST to platelet ratio index (APRI), fibrosis-4-index (FIB-4), fibrosis index (FI), King’s Score, albumin-bilirubin (ALBI) score, and platelet-albumin-bilirubin (PALBI) score were calculated. The discriminatory capacities of the examined scores in predicting the presence of esophageal varices were tested using receiver operating characteristic (ROC) curves. Results: The ROC curve analysis showed (area under the curve) AUC values of ALBI and PALBI of 0.603, and 0.606, respectively, for the prediction of EV. APRI, MELD, PALBI, King’s, FIB-4, and ALBI scores showed statistically significant correlation with EV bleeding (p < 0.05). AUC of APRI and MELD for predicting EV bleeding were 0.662 and 0.637, respectively. The AUC value of MELD in short-term mortality was 0.761. Conclusions: ALBI and PALBI scores had modest diagnostic accuracy of EVs in liver cirrhosis. APRI and MELD can be used as a reference index for the EV bleeding, and MELD score is best associated with short-term outcome in cirrhotic patients.

The aim of this study was to investigate the effect of the application of homocysteine as well as its effect under the condition of aerobic physical activity on the activities of matrix metalloproteinases (MMP), lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) in cardiac tissue and on hepato-renal biochemical parameters in sera of rats. Male Wistar albino rats were divided into four groups (n = 10, per group): C: 0.9% NaCl 0.2 mL/day subcutaneous injection (s.c.); H: homocysteine 0.45 µmol/g b.w./day s.c.; CPA saline (0.9% NaCl 0.2 mL/day s.c.) and a program of physical activity on a treadmill; and HPA homocysteine (0.45 µmol/g b.w./day s.c.) and a program of physical activity on a treadmill. Subcutaneous injection of substances was applied 2 times a day at intervals of 8 h during the first two weeks of experimental protocol. Hcy level in serum was significantly higher in the HPA group compared to the CPA group (p < 0.05). Levels of glucose, proteins, albumin, and hepatorenal biomarkers were higher in active groups compared with the sedentary group. It was demonstrated that the increased activities of LDH (mainly caused by higher activity of isoform LDH2) and mMDH were found under the condition of homocysteine-treated rats plus aerobic physical activity. Independent application of homocysteine did not lead to these changes. Physical activity leads to activation of MMP-2 isoform and to increased activity of MMP-9 isoform in both homocysteine-treated and control rats.