Ultrasound­targeted microbubble destruction technology delivering ß­klotho to the heart enhances FGF21 sensitivity and attenuates heart remodeling post­myocardial infarction.

Fibroblast growth factor (FGF)21 is a peptide hormone that improves mitochondrial function and energy metabolism, and the deficiency of its co­receptor ß­klotho (KLB) causes decreased FGF21 sensitivity. The present study examined whether the cardiac delivery of plasmids containing the KLB gene via ultrasound­targeted microbubble destruction (UTMD) enhances the efficacy of FGF21 against heart failure post­acute myocardial infarction (AMI). For this purpose, the levels of FGF21 in patients and rats with heart dysfunction post­infarction were determined using ELISA. Sprague­Dawley rats received the 3X UTMD­mediated delivery of KLB@cationic microbubbles (KLB@CMBs) 1 week following the induction of AMI. Echocardiography, histopathology and biochemical analysis were performed at 4 weeks following the induction of AMI. The results revealed that patients with heart failure post­infarction had higher serum FGF21 levels than the healthy controls. However, the downstream signal, KLB, but not α­klotho, was reduced in the heart tissues of rats with AMI. As was expected, treatment with FGF21 did not substantially attenuate heart remodeling post­infarction. It was found that decreased receptors KLB in the heart may result in the insensitivity to FGF21 treatment. In vivo, the UTMD technology­mediated delivery of KLB@CMBs to the heart significantly enhanced the effects of FGF21 administration on cardiac remodeling and mitochondrial dysfunction in the rats following infarction. The delivery of KLB to the heart by UTMD and the administration of FGF21 attenuated mitochondrial impairment and oxidative stress by activating nuclear factor erythroid 2­related factor 2 signals. On the whole, the present study demonstrates that the cardiac delivery of KLB significantly optimizes the cardioprotective effects of FGF21 therapy on adverse heart remodeling. UTMD appears a promising interdisciplinary approach with which to improve heart failure post­myocardial infarction.

Gender Differences in Cardiac Organ Damage in Arterial Hypertension: Assessing the Role of Drug Nonadherence.

INTRODUCTION: Cardiac organ damage like left ventricular (LV) hypertrophy and left atrial (LA) enlargement is more prevalent in women than men with hypertension, but the mechanisms underlying this gender difference remain unclear. METHODS: We tested the association of drug nonadherence with the presence of LV hypertrophy and LA enlargement by echocardiography in 186 women and 337 men with uncontrolled hypertension defined as daytime systolic blood pressure (BP) ≥ 135mmHg despite the prescription of at least two antihypertensive drugs. Drug adherence was assessed by measurements of serum drug concentrations interpreted by an experienced pharmacologist. Aldosterone-renin-ratio (ARR) was measured on actual medication. RESULTS: Women had a higher prevalence of LV hypertrophy (46% vs. 33%) and LA enlargement (79% vs 65%, both p < 0.05) than men, while drug nonadherence (8% vs. 9%, p > 0.514) did not differ. Women were older and had lower serum renin concentration and higher ARR than men, while 24-h systolic BP (141 ± 9 mmHg vs. 142 ± 9 mmHg), and the prevalences of obesity (43% vs. 50%) did not differ (all p > 0.10). In multivariable analyses, female gender was independently associated with a two-fold increased risk of LV hypertrophy (OR 2.01[95% CI 1.30-3.10], p = 0.002) and LA enlargement (OR 1.90 [95% CI 1.17-3.10], p = 0.010), while no association with drug nonadherence was found. Higher ARR was independently associated with LV hypertrophy in men only (OR 2.12 [95% CI 1.12-4.00] p = 0.02). CONCLUSIONS: Among patients with uncontrolled hypertension, the higher prevalence of LV hypertrophy and LA enlargement in women was not explained by differences in drug nonadherence. REGISTRATION: URL:  https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03209154.

Platelet Membrane Nanocarriers Cascade Targeting Delivery System to Improve Myocardial Remodeling Post Myocardial Ischemia-Reperfusion Injury.

Although treatments for myocardial infarction have advanced significantly, the global mortality due to ischemia and subsequent reperfusion injury remains high. Here, a platelet (PLT) membrane nanocarrier (PL720) that encapsulates L-arginine and FTY720 to facilitate the cascade-targeted delivery of these substances to the myocardial injury site and enable the controlled release of L-arginine and FTY720 is developed. Such an innovative approach shows enhanced cardioprotection through multiple target strategies involved in ischemia-reperfusion injury and late reperfusion inflammation. During the ischemia-reperfusion phase, PL720 targets and accumulates in damaged coronary arteries. PL720 rapidly releases L-arginine, stimulating endothelial cells to produce NO, thereby dilating blood vessels and promoting blood flow recovery, while FTY720's sustained release exerts anti-apoptotic effects. During the late reperfusion inflammatory phase, PL720 is captured by circulating inflammatory monocytes and transported into a deeper ischemic myocardial lesion. PL720 promotes macrophage polarization and accelerates the inflammatory repair. Furthermore, the issue of bradycardia associated with the clinical use of FTY720 is innovatively relieved. Therefore, PL720 is a vascular injury and inflammation dual targeting strategy, exhibiting significant potential for multi-targeted therapy and clinical translation for cardiac injury.

Punicalagin attenuates ventricular remodeling after acute myocardial infarction via regulating the NLRP3/caspase-1 pathway.

CONTEXT: Punicalagin has myocardial protection; the mechanism of punicalagin on ventricular remodeling (VR) after acute myocardial infarction (AMI) remains unclear. OBJECTIVE: These studies explore the role and mechanism of punicalagin in preventing and treating VR after AMI. MATERIALS AND METHODS: Molecular docking was used to predict the targets of punicalagin. After 2 weeks of AMI model, the SD rats were randomly divided into model, and punicalagin (200, 400 mg/kg, gavage) groups for 4 weeks. Thoracotomy with perforation but no ligature was performed on rats in control group. The protein expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis speck-like protein (ASC), caspase-1, gasdermin D (GSDMD), and GSDMD-N, the mRNA expression of NLRP3, caspase-1, GSDMD, interleukin-1ß (IL-1ß) and IL-18 were evaluated. RESULTS: Punicalagin had binding activities with NLRP3 (Vina score, -5.8), caspase-1 (Vina score, -6.7), and GSDMD (Vina score, -6.7). Punicalagin could improve cardiac function, alleviate cardiac pathological changes, minimize the excessive accumulation of collagen in the left ventricular myocardium (p < 0.01), and inhibit cardiomyocyte apoptosis (p < 0.01). Furthermore, punicalagin could inhibit the overexpression of NLRP3, caspase-1, and GSDMD via immunohistochemistry (p < 0.01). Punicalagin inhibited the protein levels of NLRP3, caspase-1, ASC, GSDMD, and GSDMD-N (p < 0.05, p < 0.01). Punicalagin reduced the mRNA expression of NLRP3, caspase-1, GSDMD, IL-1ß and IL-18 (p < 0.05, p < 0.01). CONCLUSIONS: Punicalagin may provide a useful treatment for the future myocardial protection.

[Fuyu Decoction improves ventricular remodeling in rats with heart failure by inhibiting AMPK/mTOR pathway-mediated autophagy].

OBJECTIVE: To investigate the effect of Fuyu Decoction on ventricular remodeling and its association with AMPK/mTOR pathway-mediated autophagy in rats with heart failure. METHODS: Thirty male Wistar rat models of heart failure induced by ligation of the left anterior descending coronary artery were divided into model group, Fuyu Decoction treatment group, Fuyu Decoction treatment +AMPK agonist group (n=10), with another 10 rats receiving sham operation as the Sham group. After 8 weeks of drug intervention, the changes of ventricular function and ventricular remodeling indexs of the rats were assessed. TTC staining was used to detect the myocardial infarction area, and HE and Masson staining were used to observe the pathological changes in the myocardial tissue. Western blotting was performed to detect the protein expressions of p-AMPK, p-mTOR, LC3-II, Beclin1 and p62 in the myocardial tissue. RESULTS: Compared with the sham-operated rats, the rat models of heart failure showed significantly increased left ventricular end-diastolic volume (LVEDV), left ventricular endsystolic volume (LVESV), and left ventricular mass index (LVMI) (P < 0.01), reduced left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and decreased spherical index (SI) were (P < 0.01). The rat models also showed increased myocardial infarction area, obvious myocardial pathologies and fibrosis, increased apoptosis rate of the cardiomyocytes, enhanced myocardial expressions of p-AMPK, LC3-II/LC3-I and Beclin1 (P < 0.01), and reduced expressions of p-mTOR and p62 (P < 0.01). Fuyu Decoction treatment significantly ameliorated these changes in the rat models (all P < 0.01), but its effects were obviously blocked by treatment with EX229. CONCLUSION: Fuyu Decoction can improve ventricular remodeling in rats with heart failure by inhibiting AMPK/mTOR signaling-mediated autophagy in the cardiomyocytes.

Rhein attenuates angiotensin II-induced cardiac remodeling by modulating AMPK-FGF23 signaling.

BACKGROUND: Increasing evidence indicates that myocardial oxidative injury plays a crucial role in the pathophysiology of cardiac hypertrophy (CH) and heart failure (HF). The active component of rhubarb, rhein exerts significant actions on oxidative stress and inflammation. Nonetheless, its role in cardiac remodeling remains unclear. METHODS: CH was induced by angiotensin II (Ang II, 1.4 mg/kg/d for 4 weeks) in male C57BL/6 J mice. Then, rhein (50 and 100 mg/kg) was injected intraperitoneally for 28 days. CH, fibrosis, oxidative stress, and cardiac function in the mice were examined. In vitro, neonatal rat cardiomyocytes (CMs) and cardiac fibroblasts (CFs) pre-treated with rhein (5 and 25 µM) were challenged with Ang II. We performed RNA sequencing to determine the mechanistic role of rhein in the heart. RESULTS: Rhein significantly suppressed Ang II-induced CH, fibrosis, and reactive oxygen species production and improved cardiac systolic dysfunction in vivo. In vitro, rhein significantly attenuated Ang II-induced CM hypertrophy and CF collagen expression. In addition, rhein obviously alleviated the increased production of superoxide induced by Ang II. Mechanistically, rhein inhibited FGF23 expression significantly. Furthermore, FGF23 overexpression abolished the protective effects of rhein on CMs, CFs, and cardiac remodeling. Rhein reduced FGF23 expression, mostly through the activation of AMPK (AMP-activated protein kinase). AMPK activity inhibition suppressed Ang II-induced CM hypertrophy and CF phenotypic transformation. CONCLUSION: Rhein inhibited Ang II-induced CH, fibrosis, and oxidative stress during cardiac remodeling through the AMPK-FGF23 axis. These findings suggested that rhein could serve as a potential therapy in cardiac remodeling and HF.

Up-regulation of Nrf2/HO-1 and inhibition of TGF-ß1/Smad2/3 signaling axis by daphnetin alleviates transverse aortic constriction-induced cardiac remodeling in mice.

Oxidative damage and accumulation of extracellular matrix (ECM) components play a crucial role in the adverse outcome of cardiac hypertrophy. Evidence suggests that nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) can modulate oxidative damage and adverse myocardial remodeling. Daphnetin (Daph) is a coumarin obtained from the plant genus Daphne species that exerts anti-oxidative and anti-inflammatory properties. Herein, we investigated the roles of Daph in transverse aortic constriction (TAC)-induced cardiac hypertrophy and fibrosis in mice. TAC-induced alterations in cardiac hypertrophy markers, histopathological changes, and cardiac function were markedly ameliorated by oral administration of Daph in mice. We found that Daph significantly reduced the reactive oxygen species (ROS) generation, increased the nuclear translocation of Nrf2, and consequently, reinstated the protein levels of NAD(P)H quinone dehydrogenase1 (NQO1), heme oxygenase-1 (HO-1), and other antioxidants in the heart. Besides, Daph significantly inhibited the TAC-induced accumulation of ECM components, including α-smooth muscle actin (α-SMA), collagen I, collagen III, and fibronectin, and interfered with the TGF-ß1/Smad2/3 signaling axis. Further studies revealed that TAC-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei and the protein levels of Bax/Bcl2 ratio and cleaved caspase 3 were substantially decreased by Daph treatment. We further characterized the effect of Daph on angiotensin II (Ang-II)-stimulated H9c2 cardiomyoblast cells and observed that Daph markedly decreased the Ang-II induced increase in cell size, production of ROS, and proteins associated with apoptosis and fibrosis. Mechanistically, Daph alone treatment enhanced the protein levels of Nrf2, NQO1, and HO-1 in H9c2 cells. The inhibition of this axis by Si-Nrf2 transfection abolished the protective effect of Daph in H9c2 cells. Taken together, Daph effectively counteracted the TAC-induced cardiac hypertrophy and fibrosis by improving the Nrf2/HO-1 axis and inhibiting the TGF-ß1/Smad2/3 signaling axis.

LongShengZhi alleviated cardiac remodeling via upregulation microRNA-150-5p with matrix metalloproteinase 14 as the target.

ETHNOPHARMACOLOGICAL RELEVANCE: LongShengZhi capsule (LSZ), a traditional Chinese medicine, is used for treatment of patients with vascular diseases. LSZ reduced doxorubicin-induced heart failure by reducing production of reactive oxygen species and inhibiting inflammation and apoptosis. AIM OF THE STUDY: This study was to explore whether LSZ could alleviate cardiac remodeling via upregulation of microRNA (miR)-150-5p and the downstream target. Cardiac remodeling was induced by Ang II in vivo and in vitro. RESULTS: LSZ attenuated Ang II-induced cardiac hypertrophy and fibrosis in rats, and in primary cardiomyocytes (CMs) and primary cardiac fibroblasts (CFs). MiR-150-5p was downregulated in Ang II-induced rat heart, CMs and CFs, and these decreases were reserved by LSZ. In vivo overexpression of miR-150-5p by transfection of miR-150-5p agomiR protected Ang II-induced cardiac hypertrophy and fibrosis in rats. Meanwhile, its overexpression also reversed Ang II-induced upregulation of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ß-myosin heavy chain (ß-MHC) in rat hearts and primary CMs, as well as upregulation of collagen I, collagen III and transforming growth factor-ß (TGF-ß) in rat hearts and primary CFs. Matrix metalloproteinase 14 (MMP14) was validated as the target gene of miR-150-5p, which was overexpressed in Ang II-induced rat heart, rat primary CMs and primary CFs. Notably, overexpression of MMP14 induced cardiac remodeling, and reversed the protective role of miR-150-5p in downregulating Ang II-induced upregulation of hypertrophy and fibrosis markers in vitro. CONCLUSION: Collectively, LSZ protects Ang II-induced cardiac dysfunction and remodeling via upregulation of miR-150-5p to target MMP14. Administration of LSZ, upregulation of miR-150-5p or targeting of MMP14 may be strategies for cardiac remodeling therapy.

Attenuation of ischemia-reperfusion injury by intracoronary chelating agent administration.

Ischemia-reperfusion (IR) injury accelerates myocardial injury sustained during the myocardial ischemic period and thus abrogates the benefit of reperfusion therapy in patients with acute myocardial infarction. We investigated the efficacy of intracoronary ethylenediaminetetraacetic acid (EDTA) administration as an adjunctive treatment to coronary intervention to reduce IR injury in a swine model. We occluded the left anterior descending artery for 1 h. From the time of reperfusion, we infused 50 mL of EDTA-based chelating agent via the coronary artery in the EDTA group and normal saline in the control group. IR injury was identified by myocardial edema on echocardiography. Tetrazolium chloride assay revealed that the infarct size was significantly lower in the EDTA group than in the control group, and the salvage percentage was higher. Electron microscopy demonstrated that the mitochondrial loss in the cardiomyocytes of the infarcted area was significantly lower in the EDTA group than in the control group. Echocardiography after 4 weeks showed that the remodeling of the left ventricle was significantly less in the EDTA group than in the control group: end-diastolic dimension 38.8 ± 3.3 mm vs. 43.9 ± 3.7 mm (n = 10, p = 0.0089). Left ventricular ejection fraction was higher in the EDTA group (45.3 ± 10.3 vs. 34.4 ± 11.8, n = 10, respectively, p = 0.031). In a swine model, intracoronary administration of an EDTA chelating agent reduced infarct size, mitochondrial damage, and post-infarct remodeling. This result warrants further clinical study evaluating the efficacy of the EDTA chelating agent in patients with ST-segment elevation myocardial infarction.

Heart Failure Subtypes and Cardiomyopathies in Women.

Heart failure affects over 2.6 million women and 3.4 million men in the United States with known sex differences in epidemiology, management, response to treatment, and outcomes across a wide spectrum of cardiomyopathies that include peripartum cardiomyopathy, hypertrophic cardiomyopathy, stress cardiomyopathy, cardiac amyloidosis, and sarcoidosis. Some of these sex-specific considerations are driven by the cellular effects of sex hormones on the renin-angiotensin-aldosterone system, endothelial response to injury, vascular aging, and left ventricular remodeling. Other sex differences are perpetuated by implicit bias leading to undertreatment and underrepresentation in clinical trials. The goal of this narrative review is to comprehensively examine the existing literature over the last decade regarding sex differences in various heart failure syndromes from pathophysiological insights to clinical practice.

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation.

Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced ß-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from ß-oxidation to glycolysis, may induce cardiac structural remodeling.

Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility.

BACKGROUND: Right ventricular dysfunction (RVD) is the leading cause of death in pulmonary arterial hypertension (PAH), but no RV-specific therapy exists. We showed microtubule-mediated junctophilin-2 dysregulation (MT-JPH2 pathway) causes t-tubule disruption and RVD in rodent PAH, but the druggable regulators of this critical pathway are unknown. GP130 (glycoprotein 130) activation induces cardiomyocyte microtubule remodeling in vitro; however, the effects of GP130 signaling on the MT-JPH2 pathway and RVD resulting from PAH are undefined. METHODS: Immunoblots quantified protein abundance, quantitative proteomics defined RV microtubule-interacting proteins (MT-interactome), metabolomics evaluated the RV metabolic signature, and transmission electron microscopy assessed RV cardiomyocyte mitochondrial morphology in control, monocrotaline, and monocrotaline-SC-144 (GP130 antagonist) rats. Echocardiography and pressure-volume loops defined the effects of SC-144 on RV-pulmonary artery coupling in monocrotaline rats (8-16 rats per group). In 73 patients with PAH, the relationship between interleukin-6, a GP130 ligand, and RVD was evaluated. RESULTS: SC-144 decreased GP130 activation, which normalized MT-JPH2 protein expression and t-tubule structure in the monocrotaline RV. Proteomics analysis revealed SC-144 restored RV MT-interactome regulation. Ingenuity pathway analysis of dysregulated MT-interacting proteins identified a link between microtubules and mitochondrial function. Specifically, SC-144 prevented dysregulation of electron transport chain, Krebs cycle, and the fatty acid oxidation pathway proteins. Metabolomics profiling suggested SC-144 reduced glycolytic dependence, glutaminolysis induction, and enhanced fatty acid metabolism. Transmission electron microscopy and immunoblots indicated increased mitochondrial fission in the monocrotaline RV, which SC-144 mitigated. GP130 antagonism reduced RV hypertrophy and fibrosis and augmented RV-pulmonary artery coupling without altering PAH severity. In patients with PAH, higher interleukin-6 levels were associated with more severe RVD (RV fractional area change 23±12% versus 30±10%, P=0.002). CONCLUSIONS: GP130 antagonism reduces MT-JPH2 dysregulation, corrects metabolic derangements in the RV, and improves RVD in monocrotaline rats.

Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival.

Doxorubicin (DOX) is an effective anticancer drug. However, its use is hampered by the development of very mortal cardiomyopathy. Here, we investigate whether the co-administration of the antidepressant paroxetine (P), known to exert beneficial cardiovascular effects, would provide effective cardioprotection. Experiments were performed in male Wistar rats randomly assigned to control group (0.5 mL/kg 0.9% NaCl, i.v., n = 7), DOX group (DOX 5 mg /kg i.v., n = 23) and DOX+P group (DOX 5 mg/kg, i.v. plus P 10 mg/kg p.o. daily, beginning five days before DOX administration and during the follow-up period, n = 11). Rats' body weight and echocardiography parameters were monitored before and after drug/vehicle administration. Cardiac histology was performed post-mortem, as well as beta1-adrenergic receptor (ß1-AR), beta2-adrenergic receptor (ß2-AR), G protein-coupled receptor kinases type 2 (GRK2), type 3 (GRK3), beta-arrestin 1, and beta-arrestin 2 gene expression using RT-qPCR. DOX-treated rats exhibited bad general condition, adynamia, loss of body weight, and low survival. Echocardiography revealed two phenotypes: cardiomyopathy with left ventricular (LV) hypertrophy (DOX-HCM) and cardiomyopathy with LV dilation (DOX-DCM). In DOX-HCM rats only, there was an increased GRK2 and GRK3 gene expression and synthesis. DOX+P co-treated rats exhibited good general condition, normal spontaneous behaviour, gained weight over time, had increased survival, and preserved LV morphology and contractility. In these rats, gene expression and synthesis of GRK2 and GRK3 were decreased, while ß1-AR and ß2-AR were increased. Present results show for the first time that P effectively reduces DOX-induced cardiotoxicity and enhances survival.

Augmented early aged neutrophil infiltration contributes to late remodeling post myocardial infarction.

Neutrophils oscillate in number and phenotype after being released from bone marrow. Myocardial infarction (MI) outcome is associated with the time-of-day of ischemia onset. However, the underlying contributive factors of neutrophils to cardiac remodeling post MI remain unknown. We examined neutrophil infiltration into the heart and cardiac function and remodeling in C57BL/6J MI model created by permanent coronary ligation at different zeitgeber times (ZT). We found that cell surface markers (CD62L, CXCR2, CXCR4) of neutrophils in peripheral blood lost diurnal oscillation 24 h post MI. Meanwhile, circadian gene Bmal1, Nr1d1, and Clock mRNA expression displayed disrupted diurnal patterns. Flow cytometry showed augmented aged neutrophil (CD11b+Ly6G+CD62Llow) infiltration into the heart along with increased circulating aged neutrophils in MI groups with more infiltration at ZT5 (p < 0.05), but no difference for aged neutrophil infiltration at different ZT points in late stage. Infiltrated neutrophils had significantly higher CXCL2 and CXCR2 but lower CXCR4 gene expression (p < 0.05). Mice that underwent ligation at ZT5 had high mortality rate and large infarct size. Echocardiography showed that those mice had significantly larger end diastolic and systolic volume and lower ejection fraction (p < 0.05). Immunohistology revealed that those mice displayed more fibrosis, cardiomyocyte hypertrophy, and less angiogenesis compared to ZT13 or ZT21 group (p < 0.05). However, treatment with anti-CXCL2 antibody significantly reduced LV dilatation, fibrosis, hypertrophy and improved cardiac function. These results indicate greater aged neutrophil infiltration into the heart contributes to cardiac hypertrophy, fibrosis, and dysfunction which suggests that blocking neutrophil aging may be a therapeutic alternative following acute myocardial infarction.

Açaí seed extract (ASE) rich in proanthocyanidins improves cardiovascular remodeling by increasing antioxidant response in obese high-fat diet-fed mice.

Obesity is recognized as an independent risk factor for cardiovascular diseases and is an important contributor to cardiac mortality. Açaí seed extract (ASE), rich in proanthocyanidins, has been shown to have potential anti-obesity effects. This study aimed to investigate the therapeutic effect of ASE in cardiovascular remodeling associated with obesity and compare it with that of rosuvastatin. Male C57BL/6 mice were fed a high-fat diet or a standard diet for 12 weeks. The ASE (300 mg/kg/day) and rosuvastatin (20 mg/kg/day) treatments started in the 8th week until the 12th week, totaling 4 weeks of treatment. Our data showed that treatment with ASE and rosuvastatin reduced body weight, ameliorated lipid profile, and improved cardiovascular remodeling. Treatment with ASE but not rosuvastatin reduced hyperglycemia and oxidative stress by reducing immunostaining of 8-isoprostane and increasing SOD-1 and GPx expression in HFD mice. ASE and rosuvastatin reduced NOX4 expression, increased SIRT-1 and Nrf2 expression and catalase and GPx activities, and improved vascular and cardiac remodeling in HFD mice. The therapeutic effect of ASE was similar to that of rosuvastatin in reducing dyslipidemia and cardiovascular remodeling but was superior in reducing oxidative damage and hyperglycemia, suggesting that ASE was a promising natural product for the treatment of cardiovascular alterations associated with obesity.

Systematic exploration of the potential material basis and molecular mechanism of the Mongolian medicine Nutmeg-5 in improving cardiac remodeling after myocardial infarction.

ETHNOPHARMACOLOGICAL RELEVANCE: Nutmeg-5, which consists of Myristica fragrans Houtt., Aucklandia lappa Decne., Inula helenium L., Fructus Choerospondiatis and Piper longum L., is an ancient and classic formula in traditional Mongolian medicine that is widely used in the treatment of ischemic heart disease. However, its material basis and pharmacological mechanisms remain to be fully elucidated. AIM OF THE STUDY: The aim of this study was to explore the potential material basis and molecular mechanism of Nutmeg-5 in improving cardiac remodeling after myocardial infarction (MI). MATERIALS AND METHODS: The constituents of Nutmeg-5 absorbed into the blood were identified by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). A mouse MI model was induced in male Kunming mice by permanent ligation of the left anterior descending coronary artery (LDA) ligation. Echocardiography was performed to assess cardiac function. The protective effect of Nutmeg-5 and compound Danshen dripping pills as positive control medicine on post-MI cardiac remodeling was evaluated by tissue histology and determination of the serum protein levels of biomarkers of myocardial injury. RNA sequencing analysis of mouse left ventricle tissue was performed to explore the molecular mechanism of Nutmeg-5 in cardiac remodeling after MI. RESULTS: A total of 27 constituents absorbed into blood were identified in rat plasma following gavage administration of Nutmeg-5 (0.54 g/kg) for 1 h. We found that ventricular remodeling after MI was significantly improved after Nutmeg-5 treatment in mice, which was demonstrated by decreased mortality, better cardiac function, decreased heart weight to body weight and heart weight to tibia length ratios, and attenuated cardiac fibrosis and myocardial injury. RNA sequencing revealed that the protective effect of Nutmeg-5 on cardiac remodeling after MI was associated with improved heart metabolism. Further study found that Nutmeg-5 treatment could preserve the ultrastructure of mitochondria and upregulate gene expression related to mitochondrial function and structure. HIF-1α (hypoxia inducible factor 1, alpha subunit) expression was significantly upregulated in the hearts of MI mice and significantly suppressed in the hearts of Nutmeg-5-treated mice. In addition, Nutmeg-5 treatment significantly activated the peroxisome proliferator-activated receptor alpha signaling pathway, which was inhibited in the hearts of MI mice. CONCLUSIONS: Nutmeg-5 attenuates cardiac remodeling after MI by improving heart metabolism and preserving mitochondrial dysfunction by inhibiting HIF-1α expression in the mouse heart after MI.

Heavy Burden of Toxic Dilated Cardiomyopathy Among Young Adults: A Retrospective Study and Review of the Literature.

BACKGROUND: Dilated cardiomyopathy (DCM) is a well described entity for heart failure (HF) with reduced left ventricular ejection fraction (LVEF). Recently, drugs and other substance of abuse have been recognised as potential triggers for DCM. The aim of this study was to assess the survival in patients ≤ 65 years of age with toxic cardiomyopathy (TCM). Left ventricular remodelling and the potential usefulness of left ventricular assist devices (LVADs) was also assessed. METHODS: This was a single-centre retrospective study from January 2003 to August 2019 of 553 patients ≤ 65 years old with LVEF < 40% at a tertiary-care cardiology centre. RESULTS: A total of 201 patients (36%) had a diagnosis of idiopathic DCM. Further analysis identified 38 patients (19%) for which a TCM was the most likely etiology (amphetamine [50%], cocaine [37%], anabolic steroids [8%], and energy drinks [5%]). Despite a mean LVEF of 17 ± 8% at presentation, most patients (n = 27; 71%) had event-free survival with guideline-directed medical therapy, and 61% (n = 23) recovered an LVEF ≥ 40% after a median follow-up of 21 ± 23 months. Seven patients (18%) required an LVAD and 1 patient (3%) a transplantation. All LVADs were explanted or decommissioned after partial or complete LVEF recovery after a median support time of 11 ± 4 months. CONCLUSIONS: TCM induced by substance abuse is a frequent cause of HF, accounting for almost 20% of patients ≤ 65 years of age with DCM of unknown etiology. Treatment must be tailored on an individual basis. Mechanical circulatory support demonstrated its usefulness in carefully selected patients.