Search Results (24)

Background/Objectives: Left ventricular (LV) pseudoaneurysm is a rare but life-threatening complication after acute myocardial infarction, often resulting from inadequate excision of damaged myocardium and use of only a xenopericardial patch during primary LV free wall rupture repair. Methods: A 62-year-old female developed a giant LV pseudoaneurysm one year after initial surgical repair of a free wall rupture with a xenopericardial patch. Imaging confirmed a large pseudoaneurysm with a broad neck and mural thrombus. She underwent pseudoaneurysmectomy, LV reconstruction with a Dacron patch overlaid by a xenopericardial patch, and concomitant mitral and tricuspid valve repair. Results: Surgical exploration revealed a broad-necked pseudoaneurysm and dehisced patch material. The aneurysm was resected, and the LV was reconstructed, resulting in the exclusion of the pseudoaneurysm and improvement of the shape and function. The patient recovered uneventfully and was discharged in good clinical condition with restored LV function. Conclusions: Pseudoaneurysm formation after LV free wall rupture repair is often due to insufficient resection and the use of only a xenopericardial patch. Surgical management with complete excision, Dacron patch reconstruction, and xenopericardial reinforcement facilitates the favorable remodeling of LV geometry and function, and reduces the risk of recurrence. Full article

Background/Objectives: Aortic pulse wave velocity (aPWV) is a well-established surrogate marker of arterial stiffness. The Antares algorithm offers a method for determining aPWV from oscillometric blood pressure waveforms without requiring additional inputs. This prospective study aimed to evaluate the association and prognostic value of aPWV, determined by Antares, in predicting major adverse cardiovascular events (MACE). Methods: In total, 240 patients (median age 69, 25.4% female) underwent oscillometric blood pressure measurements, from which aPWV was calculated using the Antares algorithm. MACE, comprising myocardial infarction, stroke, or all-cause mortality, occurred in 19.2% of patients during a median follow-up of 43 months. Survival analyses were performed using continuous aPWV values, a 10 m/s threshold, and aPWV quartiles. Kaplan–Meier curves and log-rank tests were used to compare survival across aPWV groups. Cox proportional hazards models were applied to assess the independent predictive value of aPWV. Results: Patients with aPWV < 10 m/s showed significantly higher event-free survival compared to those with aPWV ≥ 10 m/s (log-rank p = 0.044). Quartile analysis reinforced this, with the highest event rate in the highest aPWV quartile (log-rank p < 0.01). Multivariable analysis confirmed aPWV as an independent predictor of MACE (HR per 1 m/s: 1.24, 95% CI: 1.08–1.41; HR per 1 SD: 1.53, 95% CI: 1.17–2.00, p = 0.002). Adding aPWV to a risk model improved predictive accuracy (C-index 0.68 to 0.71). Conclusions: In the investigated cohort, aPWV derived using the Antares algorithm is an independent predictor of cardiovascular events. This non-invasive approach is promising for improving simple outpatient risk stratification and targeting preventive measures. Full article

There is evidence to support a link between abnormal lipid metabolism and Alzheimer’s disease (AD) risk. Similarly, observational studies suggest a comorbid relationship between AD and coronary artery disease (CAD). However, the intricate biological mechanisms of AD are poorly understood, and its relationship with lipids and CAD traits remains unresolved. Conflicting evidence further underscores the ongoing investigation into this research area. Here, we systematically assess the cross-trait genetic overlap of AD with 13 representative lipids (from eight classes) and seven CAD traits, leveraging robust analytical methods, well-powered large-scale genetic data, and rigorous replication testing. Our main analysis demonstrates a significant positive global genetic correlation of AD with triglycerides and all seven CAD traits assessed—angina pectoris, cardiac dysrhythmias, coronary arteriosclerosis, ischemic heart disease, myocardial infarction, non-specific chest pain, and coronary artery disease. Gene-level analyses largely reinforce these findings and highlight the genetic overlap between AD and three additional lipids: high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), and total cholesterol. Moreover, we identify genome-wide significant genes (Fisher’s combined p value [FCP_gene] < 2.60 × 10⁻⁶) shared across AD, several lipids, and CAD traits, including WDR12, BAG6, HLA-DRA, PHB, ZNF652, APOE, APOC4, PVRL2, and TOMM40. Mendelian randomisation analysis found no evidence of a significant causal relationship between AD, lipids, and CAD traits. However, local genetic correlation analysis identifies several local pleiotropic hotspots contributing to the relationship of AD with lipids and CAD traits across chromosomes 6, 8, 17, and 19. Completing a three-way analysis, we confirm a strong genetic correlation between lipids and CAD traits—HDL and sphingomyelin demonstrate negative correlations, while LDL, triglycerides, and total cholesterol show positive correlations. These findings support genetic overlap between AD, specific lipids, and CAD traits, implicating shared but non-causal genetic susceptibility. The identified shared genes and pleiotropic hotspots are valuable targets for further investigation into AD and, potentially, its comorbidity with CAD traits. Full article

Numerous natural antioxidants commonly found in our daily diet have demonstrated significant benefits for human health and various diseases by counteracting the impact of reactive oxygen and nitrogen species. Their chemical properties enable a range of biological actions, including antihypertensive, antimicrobial, anti-inflammatory, anti-fibrotic, and anticancer effects. Despite promising outcomes from preclinical studies, ongoing debate persists regarding their reproducibility in human clinical models. This controversy largely stems from a lack of understanding of the pharmacokinetic properties of these compounds, coupled with the predominant focus on monotherapies in research, neglecting potential synergistic effects arising from combining different antioxidants. This study aims to provide an updated overview of natural antioxidants, operating under the hypothesis that a multitherapeutic approach surpasses monotherapy in efficacy. Additionally, this study underscores the importance of integrating these antioxidants into the daily diet, as they have the potential to prevent the onset and progression of various diseases. To reinforce this perspective, clinical findings pertaining to the treatment and prevention of non-alcoholic fatty liver disease and conditions associated with ischemia and reperfusion phenomena, including myocardial infarction, postoperative atrial fibrillation, and stroke, are presented as key references. Full article

This study aimed to investigate the impact of various vasculopathies alongside left ventricular hypertrophy (LVH) on cardiovascular risk in the elderly. This prospective cohort study included 3339 older adults from the Northern Shanghai Study, classified into four mutually exclusive left ventricular (LV) geometry groups based on echocardiographic data: normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Vasculopathy was categorized into three primary types: arteriosclerosis, atherosclerosis, and renal senescence. Major adverse cardiovascular events (MACEs) were defined as non-fatal acute myocardial infarction, non-fatal stroke, and cardiovascular deaths according to ICD-10 codes. Over a median follow-up period of 5.7 years, 221 incident cases of MACEs were identified. Concentric hypertrophy exhibited the highest prevalence of hypertension, the most significant increase in vascular stiffness, and the highest rate of MACEs. The adjusted Cox regression analysis showed that eccentric hypertrophy is associated with an increased risk of MACEs (HR: 1.638 [95% CI: 1.151–2.331], p = 0.006), while concentric hypertrophy shows an even higher risk (HR: 1.751 [95% CI: 1.127–2.721], p = 0.013). Conversely, concentric remodeling was not significantly associated with an increased risk of MACEs. Renal senescence presents a moderate but significant risk for MACEs, with an HR of 1.361 (95% CI: 1.019–1.819; p = 0.037) when adjusted for LVH. The Kaplan–Meier analysis showed that patients with LVH and multiple vasculopathies experience the most significant decrease in survival probability (log-rank p < 0.001). The subgroup analysis revealed that LVH significantly raises the risk of MACEs, especially in older males with hypertension, diabetes, or vasculopathy. This study reinforces the importance of LVH as a predictor of adverse cardiovascular outcomes and underscores the compounded risk associated with the presence of multiple vasculopathies. Additionally, it highlights renal senescence as a distinct and independent risk factor for MACEs, separate from LVH. Full article

Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s⁻¹) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s⁻¹) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine. Full article

One of the main aims of the Italian National Healthcare Outcomes Program (Programma Nazionale Esiti, PNE) is the identification of the hospitals with the lowest performance, leading them to improve their quality. In order to evaluate PNE impact for a subset of outcome indicators, we evaluated whether the performance of the hospitals with the lowest scores in 2016 had significantly improved after five years. The eight indicators measured the risk-adjusted likelihood of the death of each patient (adjusted relative risk—RR) 30 days after the admission for acute myocardial infarction, congestive heart failure, stroke, chronic obstructive pulmonary disease, chronic kidney disease, femur fracture or lung and colon cancer. In 2016, the PNE identified 288 hospitals with a very low performance in at least one of the selected indicators. Overall, 51.0% (n = 147) of these hospitals showed some degree of improvement in 2021, and 27.4% of them improved so much that the death risk of their patients fell below the national mean value. In 34.7% of the hospitals, however, the patients still carried a mean risk of death >30% higher than the average Italian patient with the same disease. Only 38.5% of the hospitals in Southern Italy improved the scores of the selected indicators, versus 68.0% in Northern and Central Italy. Multivariate analyses, adjusting for the baseline performance in 2016, confirmed univariate results and showed a significantly lower likelihood of improvement with increasing hospital volume. Despite the overall methodological validity of the PNE system, current Italian policies and actions aimed at translating hospital quality scores into effective organizational changes need to be reinforced with a special focus on larger southern regions. Full article

The challenge of rapidly diagnosing myocardial ischemia in unstable angina (UA) patients presenting to the Emergency Department (ED) is due to a lack of sensitive blood biomarkers. This has prompted an investigation into microRNAs (miRNAs) related to cardiac-derived Nourin for potential diagnostic application. The Nourin protein is rapidly expressed in patients with acute coronary syndrome (ACS) (UA and acute myocardial infarction (AMI)). MicroRNAs regulate gene expression through mRNA binding and, thus, may represent potential biomarkers. We initially identified miR-137 and miR-106b and conducted a clinical validation, which demonstrated that they were highly upregulated in ACS patients, but not in healthy subjects and non-ACS controls. Using integrated comprehensive bioinformatics analysis, the present study confirms that the Nourin protein targets miR-137 and miR-106b, which are linked to myocardial ischemia and inflammation associated with ACS. Molecular docking demonstrated robust interactions between the Nourin protein and miR137/hsa-miR-106b, involving hydrogen bonds and hydrophobic interactions, with −10 kcal/mol binding energy. I-TASSER generated Nourin analogs, with the top 10 chosen for structural insights. Antigenic regions and MHCII epitopes within the Nourin SPGADGNGGEAMPGG sequence showed strong binding to HLA-DR/DQ alleles. The Cytoscape network revealed interactions of -miR137/hsa-miR--106b and Phosphatase and tensin homolog (PTEN) in myocardial ischemia. RNA Composer predicted the secondary structure of miR-106b. Schrödinger software identified key Nourin-RNA interactions critical for complex stability. The study identifies miR-137 and miR-106b as potential ACS diagnostic and therapeutic targets. This research underscores the potential of miRNAs targeting Nourin for precision ACS intervention. The analysis leverages RNA Composer, Schrödinger, and I-TASSER tools to explore interactions and structural insights. Robust Nourin-miRNA interactions are established, bolstering the case for miRNA-based interventions in ischemic injury. In conclusion, the study contributes to UA and AMI diagnosis strategies through bioinformatics-guided exploration of Nourin-targeting miRNAs. Supported by comprehensive molecular analysis, the hypoxia-induced miR-137 for cell apoptosis (a marker of cell damage) and the inflammation-induced miR-106b (a marker of inflammation) confirmed their potential clinical use as diagnostic biomarkers. This research reinforces the growing role of miR-137/hsa-miR-106b in the early diagnosis of myocardial ischemia in unstable angina patients. Full article

Extracellular collagen remodeling is one of the central mechanisms responsible for the structural and compositional coherence of myocardium in patients undergoing myocardial infarction (MI). Activated primary cardiac fibroblasts following myocardial infarction are extensively investigated to establish anti-fibrotic therapies to improve left ventricular remodeling. To systematically assess vitamin C functions as a potential modulator involved in collagen fibrillogenesis in an in vitro model mimicking heart tissue healing after MI. Mouse primary cardiac fibroblasts were isolated from wild-type C57BL/6 mice and cultured under normal and profibrotic (hypoxic + transforming growth factor beta 1) conditions on freshly prepared coatings mimicking extracellular matrix (ECM) remodeling during healing after an MI. At 10 μg/mL, vitamin C reprogramed the respiratory mitochondrial metabolism, which is effectively associated with a more increased accumulation of intracellular reactive oxygen species (iROS) than the number of those generated by mitochondrial reactive oxygen species (mROS). The mRNA/protein expression of subtypes I, III collagen, and fibroblasts differentiations markers were upregulated over time, particularly in the presence of vitamin C. The collagen substrate potentiated the modulator role of vitamin C in reinforcing the structure of types I and III collagen synthesis by reducing collagen V expression in a timely manner, which is important in the initiation of fibrillogenesis. Altogether, our study evidenced the synergistic function of vitamin C at an optimum dose on maintaining the equilibrium functionality of radical scavenger and gene transcription, which are important in the initial phases after healing after an MI, while modulating the synthesis of de novo collagen fibrils, which is important in the final stage of tissue healing. Full article

Acute myocardial infarction (AMI) is a leading cause of mortality and morbidity worldwide. This work aims to investigate the translational potential of a multi-omics study (comprising metabolomics, lipidomics, glycomics, and metallomics) in revealing biomechanistic insights into AMI. Following the N-glycomics and metallomics studies performed by our group previously, untargeted metabolomic and lipidomic profiles were generated and analysed in this work via the use of a simultaneous metabolite/lipid extraction and liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis workflow. The workflow was applied to blood plasma samples from AMI cases (n = 101) and age-matched healthy controls (n = 66). The annotated metabolomic (number of features, n = 27) and lipidomic (n = 48) profiles, along with the glycomic (n = 37) and metallomic (n = 30) profiles of the same set of AMI and healthy samples were integrated and analysed. The integration method used here works by identifying a linear combination of maximally correlated features across the four omics datasets, via utilising both block-partial least squares-discriminant analysis (block-PLS-DA) based on sparse generalised canonical correlation analysis. Based on the multi-omics mapping of biomolecular interconnections, several postulations were derived. These include the potential roles of glycerophospholipids in N-glycan-modulated immunoregulatory effects, as well as the augmentation of the importance of Ca–ATPases in cardiovascular conditions, while also suggesting contributions of phosphatidylethanolamine in their functions. Moreover, it was shown that combining the four omics datasets synergistically enhanced the classifier performance in discriminating between AMI and healthy subjects. Fresh and intriguing insights into AMI, otherwise undetected via single-omics analysis, were revealed in this multi-omics study. Taken together, we provide evidence that a multi-omics strategy may synergistically reinforce and enhance our understanding of diseases. Full article

Myocardial infarction is a leading cause of death worldwide and has severe consequences including irreversible damage to the myocardium, which can lead to heart failure. Cardiac tissue engineering aims to re-engineer the infarcted myocardium using tissues made from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to regenerate heart muscle and restore contractile function via an implantable epicardial patch. The current limitations of this technology include both biomanufacturing challenges in maintaining tissue integrity during implantation and biological challenges in inducing cell alignment, maturation, and coordinated electromechanical function, which, when overcome, may be able to prevent adverse cardiac remodeling through mechanical support in the injured heart to facilitate regeneration. Polymer scaffolds serve to mechanically reinforce both engineered and host tissues. Here, we introduce a novel biodegradable, customizable scaffold composed of wet-spun polycaprolactone (PCL) microfibers to strengthen engineered tissues and provide an anisotropic mechanical environment to promote engineered tissue formation. We developed a wet-spinning process to produce consistent fibers which are then collected on an automated mandrel that precisely controls the angle of intersection of fibers and their spacing to generate mechanically anisotropic scaffolds. Through optimization of the wet-spinning process, we tuned the fiber diameter to 339 ± 31 µm and 105 ± 9 µm and achieved a high degree of fidelity in the fiber structure within the scaffold (fiber angle within 1.8° of prediction). Through degradation and mechanical testing, we demonstrate the ability to maintain scaffold mechanical integrity as well as tune the mechanical environment of the scaffold through structure (Young’s modulus of 120.8 ± 1.90 MPa for 0° scaffolds, 60.34 ± 11.41 MPa for 30° scaffolds, 73.59 ± 3.167 MPa for 60° scaffolds, and 49.31 ± 6.90 MPa for 90° scaffolds), while observing decreased hysteresis in angled vs. parallel scaffolds. Further, we embedded the fibrous PCL scaffolds in a collagen hydrogel mixed with hiPSC-CMs to form engineered cardiac tissue with high cell survival, tissue compaction, and active contractility of the hiPSC-CMs. Through this work, we develop and optimize a versatile biomanufacturing process to generate customizable PCL fibrous scaffolds which can be readily utilized to guide engineered tissue formation and function. Full article

Long-term exercise-induced metabolic adaptations occupy a central position in exercise-afforded cardiac benefits. Emerging evidence suggests that branched-chain amino acid (BCAA) catabolic defect contributes to cardiac dysfunction in multiple cardiometabolic diseases. However, the role of BCAA catabolism in exercise-afforded cardiac benefits remains unknown. Here, we show that exercise improves BCAA catabolism and thus reduce cardiac vulnerability to myocardial ischemic injury. Exercise increased circulating BCAA levels in both humans (male adolescent athletes) and mice (following an 8-week swimming intervention). It increased the expression of mitochondrial localized 2C-type serine-threonine protein phosphatase (PP2Cm), a key enzyme in regulating BCAA catabolism, and decreased BCAA accumulation in mouse hearts, indicating an increase in BCAA catabolism. Pharmacological promotion of BCAA catabolism protected the mouse heart against myocardial infarction (MI) induced by permanent ligation of the left descending coronary artery. Although cardiac-specific PP2Cm knockout showed no significant effects on cardiac structural and functional adaptations to exercise, it blunted the cardioprotective effects of exercise against MI. Mechanistically, exercise alleviated BCAA accumulation and subsequently inactivated the mammalian target of rapamycin in MI hearts. These results showed that exercise elevated BCAA catabolism and protected the heart against myocardial ischemic injury, reinforcing the role of exercise in the promotion of cardiac health. Full article

Currently, the clinical impact of cell therapy after a myocardial infarction (MI) is limited by low cell engraftment due to low cell retention, cell death in inflammatory and poor angiogenic infarcted areas, secondary migration. Cells interact with their microenvironment through integrin mechanoreceptors that control their survival/apoptosis/differentiation/migration and proliferation. The association of cells with a three-dimensional material may be a way to improve interactions with their integrins, and thus outcomes, especially if preparations are epicardially applied. In this review, we will focus on the rationale for using collagen as a polymer backbone for tissue engineering of a contractile tissue. Contractilities are reported for natural but not synthetic polymers and for naturals only for: collagen/gelatin/decellularized-tissue/fibrin/Matrigel™ and for different material states: hydrogels/gels/solids. To achieve a thick/long-term contractile tissue and for cell transfer, solid porous compliant scaffolds are superior to hydrogels or gels. Classical methods to produce solid scaffolds: electrospinning/freeze-drying/3D-printing/solvent-casting and methods to reinforce and/or maintain scaffold properties by reticulations are reported. We also highlight the possibility of improving integrin interaction between cells and their associated collagen by its functionalizing with the RGD-peptide. Using a contractile patch that can be applied epicardially may be a way of improving ventricular remodeling and limiting secondary cell migration. Full article

Autophagic/lysosomal dysfunction is a critical pathogenesis of neuronal injury after ischemic stroke. Trehalose has been validated to restore the impaired autophagy flux by boosting transcription factor EB (TFEB) nuclear translocation, but orally administrated trehalose can be greatly digested by intestinal trehalase before entering into brain. Melibiose (MEL), an analogue of trehalose, may thoroughly exert its pharmacological effects through oral administration due to absence of intestinal melibiase. The present study was to investigate whether melibiose could also confer a neuroprotection by the similar pharmacological mechanism as trehalose did after ischemic stroke. The rats were pretreated with melibiose for 7 days before middle cerebral artery occlusion (MCAO) surgery. Twenty-four hours following MCAO/reperfusion, the cytoplasmic and nuclear TFEB, and the proteins in autophagic/lysosomal pathway at the penumbra were detected by western blot and immunofluorescence, respectively. Meanwhile, the neurological deficit, neuron survival, and infarct volume were assessed to evaluate the therapeutic outcomes. The results showed that the neurological injury was significantly mitigated in MCAO+MEL group, compared with that in MCAO group. Meanwhile, nuclear TFEB expression in neurons at the penumbra was significantly promoted by melibiose. Moreover, melibiose treatment markedly enhanced autophagy flux, as reflected by the reinforced lysosomal capacity and reduced autophagic substrates. Furthermore, the melibiose-elicited neuroprotection was prominently counteracted by lysosomal inhibitor Bafilomycin A1 (Baf-A1). Contrarily, reinforcement of lysosomal capacity with EN6 further improved the neurological performance upon melibiose treatment. Our data suggests that melibiose-augmented neuroprotection may be achieved by ameliorating autophagy flux via facilitation of TFEB nuclear translocation in neurons after ischemic stroke. Full article

Due to the limited regenerative capabilities of cardiomyocytes, incidents of myocardial infarction can cause permanent damage to native myocardium through the formation of acellular, non-conductive scar tissue during wound repair. The generation of scar tissue in the myocardium compromises the biomechanical and electrical properties of the heart which can lead to further cardiac problems including heart failure. Currently, patients suffering from cardiac failure due to scarring undergo transplantation but limited donor availability and complications (i.e., rejection or infectious pathogens) exclude many individuals from successful transplant. Polymeric tissue engineering scaffolds provide an alternative approach to restore normal myocardium structure and function after damage by acting as a provisional matrix to support cell attachment, infiltration and stem cell delivery. However, issues associated with mechanical property mismatch and the limited electrical conductivity of these constructs when compared to native myocardium reduces their clinical applicability. Therefore, composite polymeric scaffolds with conductive reinforcement components (i.e., metal, carbon, or conductive polymers) provide tunable mechanical and electroactive properties to mimic the structure and function of natural myocardium in force transmission and electrical stimulation. This review summarizes recent advancements in the design, synthesis, and implementation of electroactive polymeric composites to better match the biomechanical and electrical properties of myocardial tissue. Full article