Versatile human cardiac tissues engineered with perfusable heart extracellular microenvironment for biomedical applications.

Engineered human cardiac tissues have been utilized for various biomedical applications, including drug testing, disease modeling, and regenerative medicine. However, the applications of cardiac tissues derived from human pluripotent stem cells are often limited due to their immaturity and lack of functionality. Therefore, in this study, we establish a perfusable culture system based on in vivo-like heart microenvironments to improve human cardiac tissue fabrication. The integrated culture platform of a microfluidic chip and a three-dimensional heart extracellular matrix enhances human cardiac tissue development and their structural and functional maturation. These tissues are comprised of cardiovascular lineage cells, including cardiomyocytes and cardiac fibroblasts derived from human induced pluripotent stem cells, as well as vascular endothelial cells. The resultant macroscale human cardiac tissues exhibit improved efficacy in drug testing (small molecules with various levels of arrhythmia risk), disease modeling (Long QT Syndrome and cardiac fibrosis), and regenerative therapy (myocardial infarction treatment). Therefore, our culture system can serve as a highly effective tissue-engineering platform to provide human cardiac tissues for versatile biomedical applications.

Are There Hopeful Therapeutic Strategies to Regenerate the Infarcted Hearts?

Ischemic heart disease remains the primary cause of morbidity and mortality worldwide. Despite significant advancements in pharmacological and revascularization techniques in the late 20th century, heart failure prevalence after myocardial infarction has gradually increased over the last 2 decades. After ischemic injury, pathological remodeling results in cardiomyocytes (CMs) loss and fibrosis, which leads to impaired heart function. Unfortunately, there are no clinical therapies to regenerate CMs to date, and the adult heart's limited turnover rate of CMs hinders its ability to self-regenerate. In this review, we present novel therapeutic strategies to regenerate injured myocardium, including (1) reconstruction of cardiac niche microenvironment, (2) recruitment of functional CMs by promoting their proliferation or differentiation, and (3) organizing 3-dimensional tissue construct beyond the CMs. Additionally, we highlight recent mechanistic insights that govern these strategies and identify current challenges in translating these approaches to human patients.

The Gut-Heart Axis: Updated Review for The Roles of Microbiome in Cardiovascular Health.

Cardiovascular diseases (CVDs), including coronary artery disease, stroke, heart failure, and hypertension, are the global leading causes of death, accounting for more than 30% of deaths worldwide. Although the risk factors of CVDs have been well understood and various treatment and preventive measures have been established, the mortality rate and the financial burden of CVDs are expected to grow exponentially over time due to the changes in lifestyles and increasing life expectancies of the present generation. Recent advancements in metagenomics and metabolomics analysis have identified gut microbiome and its associated metabolites as potential risk factors for CVDs, suggesting the possibility of developing more effective novel therapeutic strategies against CVD. In addition, increasing evidence has demonstrated the alterations in the ratio of Firmicutes to Bacteroidetes and the imbalance of microbial-dependent metabolites, including short-chain fatty acids and trimethylamine N-oxide, play a crucial role in the pathogenesis of CVD. However, the exact mechanism of action remains undefined to this day. In this review, we focus on the compositional changes in the gut microbiome and its related metabolites in various CVDs. Moreover, the potential treatment and preventive strategies targeting the gut microbiome and its metabolites are discussed.

Sodium-Glucose Cotransporter-2 Inhibitors After Acute Myocardial Infarction in Patients With Type 2 Diabetes: A Population-Based Investigation.

Background Whether the early use of sodium-glucose cotransporter-2 (SGLT2) inhibitors have cardioprotective effects following acute myocardial infarction is unknown. Thus, we aimed to evaluate the association between the early initiation of SGLT2 inhibitors and cardiac event rates in patients with diabetes with acute myocardial infarction undergoing percutaneous coronary intervention. Methods and Results Based on the National Health Insurance claims data in South Korea, patients who received percutaneous coronary intervention for acute myocardial infarction between 2014 and 2018 were analyzed. Patients given SGLT2 inhibitors or other glucose-lowering drugs were matched based on a propensity score. The primary end point was a composite of all-cause mortality and hospitalizations for heart failure. Major adverse cardiac events (a composite of all-cause death, nonfatal myocardial infarction, and ischemic stroke) were compared as the secondary end point. After 1:2 propensity score matching, the SGLT2 inhibitors group (938 patients) and the no use of SGLT2 inhibitors group (1876 patients) were compared. During a median follow-up of 2.1 years, the early use of SGLT2 inhibitors was associated with lower risks of both the primary end point (9.8% versus 13.9%; adjusted hazard ratio [HR], 0.68 [95% CI, 0.54-0.87]; P=0.002) and secondary end point (9.1% versus 11.6%; adjusted HR, 0.77 [95% CI, 0.60-0.99]; P=0.04). All-cause mortality and hospitalizations for heart failure were also significantly lower in early users of SGLT2 inhibitors. Conclusions The early use of SGLT2 inhibitors in patients with diabetes treated with percutaneous coronary intervention for acute myocardial infarction was associated with a significantly lower risk of cardiovascular events, including all-cause mortality, hospitalizations for heart failure, and major adverse cardiac events.

Vascular regeneration and skeletal muscle repair induced by long-term exposure to SDF-1α derived from engineered mesenchymal stem cells after hindlimb ischemia.

Despite recent progress in medical and endovascular therapy, the prognosis for patients with critical limb ischemia (CLI) remains poor. In response, various stem cells and growth factors have been assessed for use in therapeutic neovascularization and limb salvage in CLI patients. However, the clinical outcomes of cell-based therapeutic angiogenesis have not provided the promised benefits, reinforcing the need for novel cell-based therapeutic angiogenic strategies to cure untreatable CLI. In the present study, we investigated genetically engineered mesenchymal stem cells (MSCs) derived from human bone marrow that continuously secrete stromal-derived factor-1α (SDF1α-eMSCs) and demonstrated that intramuscular injection of SDF1α-eMSCs can provide long-term paracrine effects in limb ischemia and effectively contribute to vascular regeneration as well as skeletal muscle repair through increased phosphorylation of ERK and Akt within the SDF1α/CXCR4 axis. These results provide compelling evidence that genetically engineered MSCs with SDF-1α can be an effective strategy for successful limb salvage in limb ischemia.

Core-Shell Droplet-Based Angiogenic Patches for the Treatment of Ischemic Diseases: Ultrafast Processability, Physical Tunability, and Controlled Delivery of an Angiogenic Cocktail.

The patch-based delivery system has been a promising therapeutic approach for treating various vascular diseases. However, conventional methods face several challenges, including labor-intensive and time-consuming processes associated with patch fabrication or factor incorporation, inadequate physical properties, and uncontrolled release of factors. These limitations restrict the potential applications in clinical settings. To overcome these issues, we propose a novel core-shell-shaped droplet patch system called an angiogenic patch (AP). Our system offers several distinct advantages over conventional patches. It enables a rapid and straightforward fabrication process utilizing only two biodegradable ingredients [alginate and ε-poly(l-lysine)], ensuring minimal toxicity. Moreover, the AP exhibits excellent physical integrity to match and withstand physiological mechanics and allows for customizable patch dimensions tailored to individual patients' pathological conditions. Notably, the AP enables facile loading of angiogenic cytokines during patch fabrication, allowing sustained release at a controlled rate through tunable network cross-linking. Subsequently, the AP, delivering a precisely formulated cocktail of angiogenic cytokines (VEGF, bFGF, EGF, and IGF), demonstrated significant effects on endothelial cell functions (migration and tubule formation) and survival under pathological conditions simulating ischemic injury. Likewise, in in vivo experiments using a mouse model of hindlimb ischemia, the AP encapsulating the angiogenic cocktail effectively restored blood flow following an ischemic insult, promoting muscle regeneration and preventing limb loss. With its simplicity and rapid processability, user-friendly applicability, physical tunability, and the ability to efficiently load and control the delivery of angiogenic factors, the AP holds great promise as a therapeutic means for treating patients with ischemic diseases.

Effect of Wire Jailing at Side Branch in 1-Stent Strategy for Coronary Bifurcation Lesions.

OBJECTIVES: This study aimed to determine whether side branch (SB) wire jailing before main vessel (MV) stenting could prevent SB occlusion after the 1-stent strategy for bifurcation percutaneous coronary intervention. BACKGROUND: The benefits of SB wire jailing in the 1-stent strategy remain unclear. METHODS: From the COBIS (Coronary Bifurcation Stenting) III registry, 1,890 patients with bifurcation lesions who underwent the 1-stent strategy using second-generation drug-eluting stents were identified and classified into 2 groups according to the use of SB wire jailing: wire jailing (n = 819) and non-wire jailing (n = 1,071). The incidence of SB occlusion (Thrombolysis In Myocardial Infarction flow grade <3) and target lesion failure (cardiac death, myocardial infarction, or target lesion revascularization) was compared. RESULTS: The incidence of final SB occlusion was not significantly different between wire jailing (1.8%) vs non-wire jailing (2.9%; P = 0.182). However, wire jailing at the SB was a significant protective factor for SB occlusion after MV stenting on multivariate analysis and was significantly associated with a lower incidence of SB occlusion in patients with significant stenoses (≥60%) at the SB (5.1% vs 11.3%; odds ratio: 0.42; 95% CI: 0.19-0.89; P = 0.028) or MV (3.1% vs 6.2%; odds ratio: 0.49; 95% CI: 0.24-0.95; P = 0.039). During follow-up (median 52 months), the incidence of target lesion failure was not significantly different between wire jailing and non-wire jailing (7.6% vs 6.3%; P = 0.343). CONCLUSIONS: During bifurcation percutaneous coronary intervention with the 1-stent strategy, wire jailing at the SB was associated with a lower rate of final SB occlusion following MV stenting in patients with severe stenoses at the SB or MV but not with overall bifurcation lesions. Long-term clinical outcomes were comparable between the 2 groups.

Comparison of risk profiles for new-onset atrial fibrillation between patients aged <60 and ≥60 years.

BACKGROUND: Atrial fibrillation (AF) has a heterogeneous pathophysiology according to individual patient characteristics. This study aimed to identify the effects of widely known risk factors on AF incidence according to age and to elucidate the clinical implications of these effects. METHODS AND RESULTS: We analyzed data from 501,668 subjects (≥18years old) without AF and valvular heart disease from the Korean National Health Insurance Service-National Sample Cohort. The total population was divided into two groups according to age, <60years and ≥60years. AF occurred in 0.7% of the overall population (3,416 of 501,668) during the follow-up period (mean 47.6 months). In Cox regression analysis, age, male sex, previous ischemic stroke, heart failure, and hypertension were related to increased risk of new-onset AF in both age groups. Especially in the <60years age group, risk of new-onset AF was increased by relatively modifiable risk factors: obesity (body mass index ≥25kg/m2; hazard ratio[HR] 1.37 [1.22-1.55], p<0.001, interaction p<0.001), and hypertension (HR 1.93[1.69-2.22], p<0.001, interaction p<0.001). Although interactions were not significant, chronic obstructive pulmonary disease (HR 1.41[1.24-1.60], p<0.001) and chronic kidney disease (HR 1.28[1.15-1.41], p<0.001) showed increased trends of the risk of new-onset AF in the ≥60years age group. CONCLUSION: The risk profile for new-onset AF was somewhat different between the <60years and the ≥60years age groups. Compared to the ≥60years group, relatively modifiable risk factors (such as obesity and hypertension) had a greater impact on AF incidence in the <60years age group. Different management strategies to prevent AF development according to age may be needed.