Post-myocardial Infarction Heart Research Articles

Macrophage-mediated heart repair and remodeling: A promising therapeutic target for post-myocardial infarction heart failure.

Heart failure (HF) remains prevalent in patients who survived myocardial infarction (MI). Despite the accessibility of the primary percutaneous coronary intervention and medications that alleviate ventricular remodeling with functional improvement, there is an urgent need for clinicians and basic scientists to further reveal the mechanisms behind post-MI HF as well as investigate earlier and more efficient treatment after MI. Growing numbers of studies have highlighted the crucial role of macrophages in cardiac repair and remodeling following MI, and timely intervention targeting the immune response via macrophages may represent a promising therapeutic avenue. Recently, technology such as single-cell sequencing has provided us with an updated and in-depth understanding of the role of macrophages in MI. Meanwhile, the development of biomaterials has made it possible for macrophage-targeted therapy. Thus, an overall and thorough understanding of the role of macrophages in post-MI HF and the current development status of macrophage-based therapy will assist in the further study and development of macrophage-targeted treatment for post-infarction cardiac remodeling. This review synthesizes the spatiotemporal dynamics, function, mechanism and signaling of macrophages in the process of HF after MI, as well as discusses the emerging bio-materials and possible therapeutic agents targeting macrophages for post-MI HF.

Subclinical congestion in patients presenting with acute coronary syndrome

Abstract Funding Acknowledgements None. Introduction Patients admitted due to acute coronary syndrome (ACS) are stratified using Killip class for the severity of the post myocardial infarction (MI) heart failure (HF). Killip class classification is mainly based on clinical examination and overt signs and symptoms are usually needed to be present. Purpose To evaluate subclinical congestion with lung ultrasound (LUS) in patients presenting with acute coronary syndrome. Methods For a period of 4 years, we recorded the patients presented to the emergency department of our hospital due to acute coronary syndrome (HF) and no symptoms or signs of heart failure (Killip class I). LUS was performed on admission and patients were classified as having either "wet lung" (>3 b-lines in at least 3 lung fields) or "dry lung". Baseline characteristcs, laboratory findings as well as the result of the coronary angiogram were alse recorded. Results 286 patients were recorded, with mean age 71,2 years, 43,35% were female and 56,6% male. 36.01% of the patients presented with ST elevation MI (STEMI) and 63.98% with non ST elevation MI (NSTEMI). 34.2% of patients were classified as having "wet lung". Of them, 63.98% were STEMI patients and 36.1% NSTEMI. 27.2% were males and 72.8% females and 64.6% older than 60 years old. 10.7% had on admission left ventricular ejection fraction (LVEF) >50% whereas 89.3 % had LVEF <50%.Finally, 12,7% were found to have 1 vessel disease, 23.4% 2 vessel disease and 63.9% 3 vessel disease. Compared to patients classified as having "dry lung", patients with "wet lung" stayed in the hospital 74 days (vs 3.2, p<0.01), and their mean troponin levels were 10721 pg/ml (vs 3254 pg/ml, p<0.01). "Wet lung" patients were found to have mean GFR 56,2 mL/min/1.73 m² (vs 86.7 mL/min/1.73 m² , p<0.05). Conclusion 34.2% of the patients admitted due to ACS Killip 1, were classified as having "wet lung" when examined with LUS, suggesting a status of subclinical congestion. These patients were most often STEMI patients, female and of older age and were found to have reduced LVEF. Compared to the "dry lung" patients had higher troponin levels and most oftenly impaired renal function. LUS could help identify these patients, that although they seem to be asymptomatic in terms of HF, they probably need closer monitoring.

FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation

Abnormal cardiac fibrosis is the main pathological change of post-myocardial infarction (MI) heart failure. Although the E3 ubiquitin ligase FBXL8 is a key regulator in the cell cycle, cell proliferation, and inflammation, its role in post-MI ventricular fibrosis and heart failure remains unknown. FBXL8 was primarily expressed in cardiac fibroblasts (CFs) and remarkably decreased in CFs treated by TGFβ and heart subjected to MI. The echocardiography and histology data suggested that adeno-associated viruses (AAV9)-mediated FBXL8 overexpression had improved cardiac function and ameliorated post-MI cardiac fibrosis. In vitro, FBXL8 overexpression prevented TGFβ-induced proliferation, migration, contraction, and collagen secretion in CFs, while knockdown of FBXL8 demonstrated opposite effects. Mechanistically, FBXL8 interacted with Snail1 to promote Snail1 degradation through the ubiquitin–proteasome system and decreased the activation of RhoA. Moreover, the FBXL8ΔC3 binding domain was indispensable for Snail1 interaction and degradation. Ectopic Snail1 expression partly abolished the effects mediated by FBXL8 overexpression in CFs treated by TGFβ. These results characterized the role of FBXL8 in regulating the ubiquitin-mediated degradation of Snail1 and revealed the underlying molecular mechanism of how MI up-regulated the myofibroblasts differentiation-inducer Snail1 and suggested that FBXL8 may be a potential curative target for improving post-MI cardiac function.

Reticulon 3 deficiency ameliorates post-myocardial infarction heart failure by alleviating mitochondrial dysfunction and inflammation.

Multiple molecular mechanisms are involved in the development of heart failure (HF) after myocardial infarction (MI). However, interventions targeting these pathological processes alone remain clinically ineffective. Therefore, it is essential to identify new therapeutic targets for alleviating cardiac dysfunction after MI. Here, gain- and loss-of-function approaches were used to investigate the role of reticulon 3 (RTN3) in HF after MI. We found that RTN3 was elevated in the myocardium of patients with HF and mice with MI. Cardiomyocyte-specific RTN3 overexpression decreased systolic function in mice under physiological conditions and exacerbated the development of HF induced by MI. Conversely, RTN3 knockout alleviated cardiac dysfunction after MI. Mechanistically, RTN3 bound and mediated heat shock protein beta-1 (HSPB1) translocation from the cytosol to the endoplasmic reticulum. The reduction of cytosolic HSPB1 was responsible for the elevation of TLR4, which impaired mitochondrial function and promoted inflammation through toll-like receptor 4 (TLR4)/peroxisome proliferator-activated receptor gamma coactivator-1 alpha(PGC-1α) and TLR4/Nuclear factor-kappa B(NFκB) pathways, respectively. Furthermore, the HSPB1 inhibitor reversed the protective effect of RTN3 knockout on MI. Additionally, elevated plasma RTN3 level is associated with decreased cardiac function in patients with acute MI. This study identified RTN3 as a critical driver of HF after MI and suggests targeting RTN3 as a promising therapeutic strategy for MI and related cardiovascular diseases.

A Personalized Cell-Based Therapy for Ischemic Heart Failure With Reduced Ejection Fraction: Safety and Feasibility Outcomes of the Roll-In Cohort of the CardiAMP Cell Therapy Trial and Review of Similar Trials.

CardiAMP Cell Therapy for Heart Failure trial is a prospective, multicenter, randomized, controlled, double-blinded trial that has been granted breakthrough designation by the United States Food and Drug Administration. This trial evaluates clinical outcomes of intramyocardial delivery of a high dose of autologous bone marrow mononuclear cells in chronic postmyocardial infarction heart failure patients. This trial represents the first attempt to personalize marrow-derived cell-based therapy for the treatment of ischemic heart failure with reduced ejection fraction. The roll-in cohort of 10 patients demonstrated improvements in 6-minute walk distance at 6 months (+47.8 m, P = 0.01), 12 months (+46.4 m, P = 0.06), and 24 months (+31 m), and improvements in New York Heart Association class at 3 months (P = 0.015) and 6 months (P = 0.037). Four patients were reduced to New York Heart Association class I at 24 months and Minnesota Living with Heart Failure Questionnaire score was improved in 6 of 10 patients at 24 months. The improved clinical outcomes demonstrated in CardiAMP are consistent with previous clinical trials including the Transendocardial Autologous Cells in Ischemic Heart Failure (TAC-HFT) trial, Prospective Randomized Trial of Direct Endomyocardial Implantation of Bone Marrow Cells for Treatment of Severe Coronary Artery Diseases (PROTECT-CAD), and REGENERATE-Ischemic Heart Disease trial.

Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction.

Post-myocardial infarction heart failure (HF) is a major public health concern. Previous studies have reported the critical role of immune response in HF pathogenesis. However, limited studies have reported predictive immune-associated biomarkers for HF. So we attempted to identify potential immune-related indicators for HF early diagnosis and therapy guidance. This study identified two potential immune-related hub genes (IRHGs), namely CXCR5 and FOS, using bioinformatic approaches. The expression levels of CXCR5 and FOS and their ability to predict long-term HF were analyzed. Functional enrichment analysis revealed that the hub genes were enriched in immune system processes, including the interleukin-17 and nuclear factor-kappa B signaling pathways, which are involved in the pathogenesis of HF. Quantitative real-time polymerase chain reaction revealed that the Fos mRNA levels, but not the Cxcr5 mRNA levels, were downregulated in the mice of the HF group. This study successfully identified two IRHGs that were significantly and differentially expressed in the HF group and could predict long-term HF, providing novel insights for future studies on HF and developing novel therapeutic targets for HF.

Abstract 16391: Pro-Neoplastic Properties of Small Extracellular Vesicles From Failing Hearts

Background: Heart diseases are associated with an increased incidence of cancer independently of shared risk factors. The mechanism beyond this link is complex, unclear and limits our ability to develop effective therapies. We aimed to test the hypothesis that small cardiac extracellular vesicles (sEVs) contribute to the link between HF and cancer. Methods & Results: We used mouse models of heterotopic and orthotopic lung cancer and post-myocardial infarction (MI) heart failure (HF). sEVs were isolated by size exclusion chromatography. To determine the role of cardiac EVs in tumor growth, we focused on sEVs from cardiac mesenchymal stromal cells (cMSCs). cMSCs after MI secreted twice more sEVs, characterized with a unique proteome, compared with cMSCs from sham-MI ( Fig 1A ). cMSC-sEVs from post-MI HF harbored more tumor-promoting cytokines and microRNA (miR), such as periostin, osteopontin, IL-6, TNFα, galectin-3, and miR's 221 and 21. The pro-neoplastic effects of cMSC-sEVs on cancer cells were depended on cancer type, with a marked increase in proliferation and migration of lung and colon cancer cells but only a modest increase with more malignant triple-negative breast and melanoma cancer cells. Next, we inoculated lung cancer cells into mice and found that post-MI HF accelerated tumor growth. Furthermore, adoptive transfer of cMSC-sEVs from failing hearts accelerated tumor growth with and without systemic EV depletion ( Fig 1B ). Finally, we found that spironolactone mitigated the neoplastic effects of HF, attenuated tumor growth ( Fig 1C ), and reduced the number of cMSC-sEVs by 26%. Conclusions: We show, for the first time, that cardiac extracellular vesicles from post-MI failing heart harbor pro-neoplastic properties and promote tumor growth independently of other secreted factors. Spironolactone reduces the number of cardiac extracellular vesicles and the pro-neoplastic effects of post-MI heart failure.

Potent inhibition of MMP-9 by a novel sustained-release platform attenuates left ventricular remodeling following myocardial infarction

Sustained drug-release systems prolong the retention of therapeutic drugs within target tissues to alleviate the need for repeated drug administration. Two major caveats of the current systems are that the release rate and the timing cannot be predicted or fine-tuned because they rely on uncontrolled environmental conditions and that the system must be redesigned for each drug and treatment regime because the drug is bound via interactions that are specific to its structure and composition. We present a controlled and universal sustained drug-release system, which comprises minute spherical particles in which a therapeutic protein is affinity-bound to alginate sulfate (AlgS) through one or more short heparin-binding peptide (HBP) sequence repeats. Employing post-myocardial infarction (MI) heart remodeling as a case study, we show that the release of C9—a matrix metalloproteinase-9 (MMP-9) inhibitor protein that we easily bound to AlgS by adding one, two, or three HBP repeats to its sequence—can be directly controlled by modifying the number of HBP repeats. In an in vivo study, we directly injected AlgS particles, which were bound to C9 through three HBP repeats, into the left ventricular myocardium of mice following MI. We found that the particles substantially reduced post-MI remodeling, attesting to the sustained, local release of the drug within the tissue. As the number of HBP repeats controls the rate of drug release from the AlgS particles, and since C9 can be easily replaced with almost any protein, our tunable sustained-release system can readily accommodate a wide range of protein-based treatments.

Astragaloside IV derivative HHQ16 ameliorates infarction-induced hypertrophy and heart failure through degradation of lncRNA4012/9456

Reversing ventricular remodeling represents a promising treatment for the post-myocardial infarction (MI) heart failure (HF). Here, we report a novel small molecule HHQ16, an optimized derivative of astragaloside IV, which effectively reversed infarction-induced myocardial remodeling and improved cardiac function by directly acting on the cardiomyocyte to reverse hypertrophy. The effect of HHQ16 was associated with a strong inhibition of a newly discovered Egr2-affiliated transcript lnc9456 in the heart. While minimally expressed in normal mouse heart, lnc9456 was dramatically upregulated in the heart subjected to left anterior descending coronary artery ligation (LADL) and in cardiomyocytes subjected to hypertrophic stimulation. The critical role of lnc9456 in cardiomyocyte hypertrophy was confirmed by specific overexpression and knockout in vitro. A physical interaction between lnc9456 and G3BP2 increased NF-κB nuclear translocation, triggering hypertrophy-related cascades. HHQ16 physically bound to lnc9456 with a high-affinity and induced its degradation. Cardiomyocyte-specific lnc9456 overexpression induced, but knockout prevented LADL-induced, cardiac hypertrophy and dysfunction. HHQ16 reversed the effect of lnc9456 overexpression while lost its protective role when lnc9456 was deleted, further confirming lnc9456 as the bona fide target of HHQ16. We further identified the human ortholog of lnc9456, also an Egr2-affiliated transcript, lnc4012. Similarly, lnc4012 was significantly upregulated in hypertrophied failing hearts of patients with dilated cardiomyopathy. HHQ16 also specifically bound to lnc4012 and caused its degradation and antagonized its hypertrophic effects. Targeted degradation of pathological increased lnc4012/lnc9456 by small molecules might serve as a novel promising strategy to regress infarction-induced cardiac hypertrophy and HF.

Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates.

Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs. We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated. We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion. These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.

Abstract P1068: Yap Induces A Neonatal Like Pro-renewal Niche In The Adult Heart

The heart is a poorly renewable organ, meaning that tissue architecture and the cardiac microenvironment are irreversibly disrupted after injury. This presents a major challenge in treatment of ischemic heart disease, the leading cause of death worldwide. To date, most studies have focused on cardiomyocytes (CMs). However, very few studies have examined CM-extrinsic mechanisms, such as innate immunity, that complement CM-intrinsic mechanisms in heart renewal. Inactivation of the Hippo signaling pathway can rebuild the post ischemic microenvironment and improve cardiac function. We investigated spatially resolved cellular relationships of neonatal and adult renewal-competent hearts to gain insight into inefficient mammalian heart renewal. Spatial transcriptomics and single-cell sequencing of adult control hearts and hearts expressing YAP5SA, an active version of the Hippo signaling pathway effector YAP, which models heart renewal, revealed a conserved, renewal-competent CM population in control hearts and amplified in YAP5SA hearts. This CM population was also found in the wildtype, renewal competent neonatal heart after myocardial infarction, as well as the adult human heart. In YAP5SA hearts and neonatal hearts post myocardial infarction, resident macrophages and cardiac fibroblasts expressing complement pathway genes colocalized with these CMs, creating a pro-renewal microenvironment. Complement loss-of-function in fibroblasts or macrophages suppressed cardiomyocyte proliferation in both neonatal injured hearts and adult YAP5SA hearts, indicating that the complement system plays a direct role in heart renewal.

Prognostic significance of NT-proBNP and sST2 biomarkers in patients with post-myocardial infarction heart failure after a coronavirus infection

Aim. To determine the prognostic significance of N-terminal pro-brain natriuretic peptide (NT-proBNP) and soluble ST2 (sST2) in patients with post-myocardial infarction heart failure after a coronavirus disease 2019 (COVID-19)Material and methods. Three following groups were formed: in patients of group I (main), who underwent inpatient treatment for COVID-19, the cause of heart failure (HF) was prior Q-wave myocardial infarction; in patients of group II (comparison) without COVID-19, the cause of HF was prior Q-wave myocardial infarction; Group III (comparison) — patients with HF of ischemic origin without postinfarction cardiosclerosis and COVID-19. Statistical processing was carried out using the software package IBM SPSS Statistics Version 26.0.Results. The patients of all three groups included in the present study were comparable. After 6 months in group I, HF course worsening was recorded. In patients of groups I and II, an increase in NYHA HF class from 2 to 3 and 4 was recorded, in contrast to patients of group III, among whom the number of patients with class 3 HF decreased by 25% due to compensation to class 2. Patients of the studied groups, who had elevated serum levels of NT-proBNP and sST2, had more pronounced structural and functional myocardial disorders than patients with normal levels of these biomarkers. Using analysis of adverse cardiovascular events, such as recurrent myocardial infarction, cerebrovascular accident, hospitalization due to coronary artery disease, decompensated HF, which required hospitalization, a predictive model was developed using a neural network. There were following most important factors of the developed model: age, level of NT-proBNP and sST2, lung involvement according to computed tomography.Conclusion. Modern biomarkers NT-proBNP and sST2 have sufficient predictive value to determine the risk of adverse events in HF.

CTRP12 ameliorates post-myocardial infarction heart failure through down-regulation of cardiac apoptosis, oxidative stress and inflammation by influencing the TAK1-p38 MAPK/JNK pathway.

C1q/tumour necrosis factor-related protein 12 (CTRP12) is closely related to coronary artery disease and has an outstanding cardioprotective effect. However, whether CTRP12 participates in heart failure (HF) has not been well studied. This work aimed to explore the role and mechanism of CTRP12 in post-myocardial infarction (MI) HF. Rats were subjected to left anterior descending artery ligation and then raised for six weeks to establish post-MI HF. Recombinant adeno-associated virus-mediated gene transfer was applied to overexpress or silence CTRP12 in rat hearts. RT-qPCR, Immunoblot, Echocardiography, Haematoxylin-eosin (HE) staining, Masson's trichrome staining, TUNEL staining and ELISA were carried out. CTRP12 levels were decreased in the hearts of rats with post-MI HF. The overexpression of CTRP12 improved cardiac function and attenuated cardiac hypertrophy and fibrosis in rats with post-MI HF. CTRP12 silencing exacerbated cardiac dysfunction, hypertrophy and fibrosis in rats with post-MI HF. The cardiac apoptosis, oxidative stress and inflammatory response induced by post-MI HF were weakened by CTRP12 overexpression or aggravated by CTRP12 silencing. CTRP12 inhibited the activation of the transforming growth factor-β activated kinase 1 (TAK1)-p38 mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK) pathway in the hearts of rats with post-MI HF. Treatment with the TAK1 inhibitor reversed the adverse effects of CTRP12 silencing on post-MI HF. CTRP12 protects against post-MI HF by modulating the TAK1-p38 MAPK/JNK pathway. CTRP12 may be a therapeutic target for the treatment of post-MI HF.

IL-6 in the infarcted heart is preferentially formed by fibroblasts and is modulated by purinergic signaling.

Plasma IL-6 is elevated after myocardial infarction (MI) and is associated with increased morbidity and mortality. Which cardiac cell type preferentially contributes to IL-6 and how its production is regulated is largely unknown. Here, we studied the cellular source and purinergic regulation of IL-6 formation in a murine MI model. IL-6, measured in various cell types in post MI hearts by qPCR, RNAscope and at protein level, was preferentially formed by fibroblasts (CFs). scRNAseq in infarcted mouse and human hearts confirmed this finding. Adenosine stimulated fibroblast IL-6 formation via A2bR in a Gq-dependent manner. CFs highly expressed Adora2b, rapidly degraded extracellular ATP to AMP but lacked CD73. In mice and humans Adora2B was also mainly expressed by fibroblasts (scRNAseq). Global IL-6 formation was assessed in isolated hearts in mice lacking CD73 on T-cells (CD4CD73-/-) a condition known to be associated with adverse cardiac remodeling. The ischemia-induced release of IL-6 was strongly attenuated in CD4CD73-/- mice, suggesting adenosine-mediated modulation. Together this demonstrates that post-MI IL-6 is mainly derived from activated CFs and is controlled by T-cell derived adenosine. Purinergic metabolic cooperation between CFs and T-cells is a novel mechanism with therapeutic potential which modulates IL6 formation by the heart.

Risk prediction model construction for post myocardial infarction heart failure by blood immune B cells.

Myocardial infarction (MI) is a common cardiac condition with a high incidence of morbidity and mortality. Despite extensive medical treatment for MI, the development and outcomes of post-MI heart failure (HF) continue to be major factors contributing to poor post-MI prognosis. Currently, there are few predictors of post-MI heart failure. In this study, we re-examined single-cell RNA sequencing and bulk RNA sequencing datasets derived from the peripheral blood samples of patients with myocardial infarction, including patients who developed heart failure and those who did not develop heart failure after myocardial infarction. Using marker genes of the relevant cell subtypes, a signature was generated and validated using relevant bulk datasets and human blood samples. We identified a subtype of immune-activated B cells that distinguished post-MI HF patients from non-HF patients. Polymerase chain reaction was used to confirm these findings in independent cohorts. By combining the specific marker genes of B cell subtypes, we developed a prediction model of 13 markers that can predict the risk of HF in patients after myocardial infarction, providing new ideas and tools for clinical diagnosis and treatment. Sub-cluster B cells may play a significant role in post-MI HF. We found that the STING1, HSPB1, CCL5, ACTN1, and ITGB2 genes in patients with post-MI HF showed the same trend of increase as those without post-MI HF.

Inflammation-Responsive Micellar Nanoparticles from Degradable Polyphosphoramidates for Targeted Delivery to Myocardial Infarction.

Nanoparticles that undergo a localized morphology change to target areas of inflammation have been previously developed but are limited by their lack of biodegradability. In this paper, we describe a low-ring-strain cyclic olefin monomer, 1,3-dimethyl-2-phenoxy-1,3,4,7-tetrahydro-1,3,2-diazaphosphepine 2-oxide (MePTDO), that rapidly polymerizes via ring-opening metathesis polymerization at room temperature to generate well-defined degradable polyphosphoramidates with high monomer conversion (>84%). Efficient MePTDO copolymerizations with norbornene-based monomers are demonstrated, including a norbornenyl monomer functionalized with a peptide substrate for inflammation-associated matrix metalloproteinases (MMPs). The resulting amphiphilic peptide brush copolymers self-assembled in aqueous solution to generate micellar nanoparticles (30 nm in diameter) which exhibit excellent cyto- and hemocompatibility and undergo MMP-induced assembly into micron-scale aggregates. As MMPs are upregulated in the heart postmyocardial infarction (MI), the MMP-responsive micelles were applied to target and accumulate in the infarcted heart following intravenous administration in a rat model of MI. These particles displayed a distinct biodistribution and clearance pattern in comparison to nondegradable analogues. Specifically, accumulation at the site of MI competed with elimination predominantly through the kidney rather than the liver. Together, these results suggest this as a promising new biodegradable platform for inflammation targeted delivery.

Increased serum albumin corrected anion gap levels are associated with increased incidence of new-onset HF and poor prognosis in patients with acute myocardial infarction

BackgroundThere is scant evidence on a relationship between metabolic acid load and acute myocardial infarction (AMI). We evaluated the relationship between serum albumin corrected anion gap (ACAG), a metabolic acid load biomarker, and post-myocardial infarction heart failure (post-MI HF) in patients with AMI. MethodsThis prospective, single-center study enrolled 3,889 patients with AMI. The primary endpoint was the incidence of post-MI HF. Serum ACAG levels were calculated with the following formula: ACAG = AG + (40 - [albuminemia in g/l]) × 0.25. ResultsAfter correction for multiple confounding factors, patients in the fourth quartile of ACAG (highest serum ACAG levels) showed 33.5% higher risk of out-of-hospital HF [hazard ratio (HR) = 1.335, 95% CI = 1.034–1.724, p = 0.027], and 60% higher risk of in-hospital HF [odds ratio (OR) = 1.600, 95% CI = 1.269–2.017, p < 0.001] than those in the first quartile of ACAG (lowest serum ACAG levels). Altered levels of eGFR mediated 31.07% and 37.39% of the association between serum ACAG levels with out-of-hospital HF and in-hospital HF, respectively. Furthermore, altered levels of hs-CRP mediated 20.85% and 18.91% of the association between serum ACAG levels with out-of-hospital and in-hospital HF, respectively. ConclusionOur study showed that higher metabolic acid load was associated with increased incidences of post-MI HF in the AMI patients. Furthermore, deterioration of renal function and the hyperinflammatory state partially mediated the association between metabolic acid load and the incidence of post-MI HF.

Sonodynamic therapy reduces cardiomyocyte apoptosis through autophagy activated by reactive oxygen species in myocardial infarction.

Myocardial infarction (MI) is lethal to patients because of acute ischemia and hypoxia leading to cardiac tissue apoptosis. Autophagy played a key role in MI through affecting the survival of cardiomyocytes. LncRNA-MHRT (myosin heavy-chain-associated RNA transcripts) was specific to the heart and cardiomyocytes, and inhibition of lncRNA-MHRT transcription under pathological stimuli could cause cardiac hypertrophy and even heart failure (HF). Sonodynamic therapy (SDT) is a new and developing medical technique that utilizes low-intensity ultrasound to locally activate a preloaded sonosensitizer. Our group previously reported that SDT could regulate autophagy. In this study, we investigated whether SDT could reduce MI-induced cardiomyocyte apoptosis via activating autophagy pathway. SDT improved cardiac function and suppresses MI-induced cardiomyocyte apoptosis. SDT alleviated MI-induced cardiomyocyte apoptosis by improving autophagy. MHRT mediated the inhibiting effect of SDT on cardiomyocyte apoptosis via activating autophagy pathway. Our data reveal a novel effect that SDT protects against MI and confirm that SDT reduces MI-induced cardiomyocyte apoptosis via activating MHRT-mediated-autophagy. Thus, our findings also indicate that SDT may be used as a potential method for treatment of post-myocardial infarction heart failure.

Potential Neuromodulation of the Cardio-Renal Syndrome.

The cardio-renal syndrome (CRS) type 2 is defined as a progressive loss of renal function following a primary insult to the myocardium that may be either acute or chronic but is accompanied by a decline in myocardial pump performance. The treatment of patients with CRS is difficult, and the disease often progresses to end-stage renal disease that is refractory to conventional therapy. While a good deal of information is known concerning renal injury in the CRS, less is understood about how reflex control of renal sympathetic nerve activity affects this syndrome. In this review, we provide insight into the role of the renal nerves, both from the afferent or sensory side and from the efferent side, in mediating renal dysfunction in CRS. We discuss how interventions such as renal denervation and abrogation of systemic reflexes may be used to alleviate renal dysfunction in the setting of chronic heart failure. We specifically focus on a novel cardiac sensory reflex that is sensitized in heart failure and activates the sympathetic nervous system, especially outflow to the kidney. This so-called Cardiac Sympathetic Afferent Reflex (CSAR) can be ablated using the potent neurotoxin resinferitoxin due to the high expression of Transient Receptor Potential Vanilloid 1 (TRPV1) receptors. Following ablation of the CSAR, several markers of renal dysfunction are reversed in the post-myocardial infarction heart failure state. This review puts forth the novel idea of neuromodulation at the cardiac level in the treatment of CRS Type 2.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.