Improvement In Cardiac Function Research Articles

Hyperpolarized 13C and 31P MRS detects differences in cardiac energetics, metabolism, and function in obesity, and responses following treatment.

Obesity is associated with important changes in cardiac energetics and function, and an increased risk of adverse cardiovascular outcomes. Multi-nuclear MRS and MRI techniques have the potential to provide a comprehensive non-invasive assessment of cardiac metabolic perturbation in obesity. A rat model of obesity was created by high-fat diet feeding. This model was characterized using in vivo hyperpolarized [1-13C]pyruvate and [2-13C]pyruvate MRS, echocardiography and perfused heart 31P MRS. Two groups of obese rats were subsequently treated with either caloric restriction or the glucagon-like peptide-1 analogue/agonist liraglutide, prior to reassessment. The model recapitulated cardiovascular consequences of human obesity, including mild left ventricular hypertrophy, and diastolic, but not systolic, dysfunction. Hyperpolarized 13C and 31P MRS demonstrated that obesity was associated with reduced myocardial pyruvate dehydrogenase flux, altered cardiac tricarboxylic acid (TCA) cycle metabolism, and impaired myocardial energetic status (lower phosphocreatine to adenosine triphosphate ratio and impaired cardiac ΔG~ATP). Both caloric restriction and liraglutide treatment were associated with normalization of metabolic changes, alongside improvement in cardiac diastolic function. In this model of obesity, hyperpolarized 13C and 31P MRS demonstrated abnormalities in cardiac metabolism at multiple levels, including myocardial substrate selection, TCA cycle, and high-energy phosphorus metabolism. Metabolic changes were linked with impairment of diastolic function and were reversed in concert following either caloric restriction or liraglutide treatment. With hyperpolarized 13C and 31P techniques now available for human use, the findings support a role for multi-nuclear MRS in the development of new therapies for obesity.

Improvement of Cardiac Function and Subcellular Defects Due to Chronic Diabetes upon Treatment with Sarpogrelate

In order to investigate the subcellular mechanisms underlying the beneficial effects of sarpogrelate—a 5-HT2A receptor antagonist—on diabetic cardiomyopathy, diabetes was induced in rats by injecting streptozotocin (65 mg/kg). Diabetic animals were treated with or without sarpogrelate (5 mg/kg daily) for 6 weeks; diabetic animals were also treated with insulin (10 units/kg daily) for comparison. Elevated plasma levels of glucose and lipids, depressed insulin levels, hemodynamic alterations and cardiac dysfunction in diabetic animals were partially or fully attenuated by sarpogrelate or insulin treatment. Diabetes-induced changes in myocardial high-energy phosphate stores, as well as depressed mitochondrial oxidative phosphorylation and Ca2+-uptake activities, were significantly prevented by these treatments. Reductions in sarcolemma Na+-K+ ATPase, Na+-Ca2+ exchange, Ca2+-channel density and Ca2+-uptake activities were also attenuated by treatments with sarpogrelate and insulin. In addition, decreases in diabetes-induced sarcoplasmic reticulum Ca2+-uptake, Ca2+-release and Ca2+-stimulated ATPase activities, myofibrillar Mg2+-ATPase and Ca2+-stimulated ATPase activities, and myosin Mg2+-ATPase and Ca2+-ATPase activities were fully or partially prevented by sarpogrelate and insulin treatments. Marked alterations in different biomarkers of oxidative stress, such as malondialdehyde, superoxide dismutase and glutathione peroxidase, in diabetic hearts were also attenuated by treating the animals with sarpogrelate or insulin. These observations suggest that therapy with sarpogrelate, like that with insulin, may improve cardiac function by preventing subcellular and metabolic defects as a consequence of a reduction in oxidative stress.

Improvement of Cardiac Function and Subcellular Defects Due to Chronic Diabetes upon Treatment with Sarpogrelate

In order to investigate the subcellular mechanisms underlying the beneficial effects of sarpogrelate—a 5-HT2A receptor antagonist—on diabetic cardiomyopathy, diabetes was induced in rats by injecting streptozotocin (65 mg/kg). Diabetic animals were treated with or without sarpogrelate (5 mg/kg daily) for 6 weeks; diabetic animals were also treated with insulin (10 units/kg daily) for comparison. Elevated plasma levels of glucose and lipids, depressed insulin levels, hemodynamic alterations and cardiac dysfunction in diabetic animals were partially or fully attenuated by sarpogrelate or insulin treatment. Diabetes-induced changes in myocardial high-energy phosphate stores, as well as depressed mitochondrial oxidative phosphorylation and Ca2+-uptake activities, were significantly prevented by these treatments. Reductions in sarcolemma Na+-K+ ATPase, Na+-Ca2+ exchange, Ca2+-channel density and Ca2+-uptake activities were also attenuated by treatments with sarpogrelate and insulin. In addition, decreases in diabetes-induced sarcoplasmic reticulum Ca2+-uptake, Ca2+-release and Ca2+-stimulated ATPase activities, myofibrillar Mg2+-ATPase and Ca2+-stimulated ATPase activities, and myosin Mg2+-ATPase and Ca2+-ATPase activities were fully or partially prevented by sarpogrelate and insulin treatments. Marked alterations in different biomarkers of oxidative stress, such as malondialdehyde, superoxide dismutase and glutathione peroxidase, in diabetic hearts were also attenuated by treating the animals with sarpogrelate or insulin. These observations suggest that therapy with sarpogrelate, like that with insulin, may improve cardiac function by preventing subcellular and metabolic defects as a consequence of a reduction in oxidative stress.

Bone marrow cells contribute to seven different endothelial cell populations in the heart.

Understanding the mechanisms underlying vascular regeneration in the heart is crucial for developing novel therapeutic strategies for myocardial ischemia. This study investigates the contribution of bone marrow-derived cells to endothelial cell populations in the heart, and their role in cardiac function and coronary circulation following repetitive ischemia (RI). Chimeric rats were created by transplanting BM cells from GFP female rats into irradiated male recipients. After engraftment chimeras were subjected to RI for 17days. Vascular growth was assessed from recovery of cardiac function and increases in myocardial blood flow during LAD occlusion. After sorting GFP+ BM cells from heart and bone of Control and RI rats, single-cell RNA sequencing was implemented to determine the fate of BM cells. Our in vivo RI model demonstrated an improvement in cardiac function and myocardial blood flow after 17days of RI with increased capillary density in the rats subjected to RI compared to Controls. Single-cell RNA sequencing of bone marrow cells isolated from rats' hearts identified distinct endothelial cell (EC) subpopulations. These ECs exhibited heterogeneous gene expression profiles and were enriched for markers of capillary, artery, lymphatic, venous, and immune ECs. Furthermore, BM-derived ECs in the RI group showed an angiogenic profile, characterized by upregulated genes associated with blood vessel development and angiogenesis. This study elucidates the heterogeneity of bone marrow-derived endothelial cells in the heart and their response to repetitive ischemia, laying the groundwork for targeting specific subpopulations for therapeutic angiogenesis in myocardial ischemia.

Impact of baseline ECG characteristics on changes in cardiac biomarkers and echocardiographic metrices after acute myocardial infarction treated with Empagliflozin

The EMMY trial was a multicentre, investigator-initiated, placebo-controlled, double-blind trial, which enrolled 476 patients immediately following AMI and the first study demonstrating a significant reduction in NT-proBNP-levels as well as significant improvements in cardiac structure and function in patients after acute myocardial infarction treated with empagliflozin vs. placebo. However, hardly any data are available investigating the prognostic role of baseline electrocardiogram metrics in SGLT2-inhibitor-treated patients. This post-hoc analysis investigated the association of baseline ECG metrics collected in one centre of the trial (181 patients) with changes in structural and functional cardiac parameters as well as cardiac biomarkers in response to Empagliflozin treatment. A total of 181 patients (146 men; mean age 58 ± 14 years) were included. Median PQ-interval was 156 (IQR 144–174) milliseconds (ms), QRS width 92 (84–98) ms, QTc interval 453 (428–478) ms, Q-wave duration 45 (40–60) ms, Q-wave amplitude 0.40 (0.30–0.70) millivolt (mV), and heart rate was 71 (64–85) bpm. For functional cardiac parameters (LVEF and E/eʹ) of the entire cohort, a greater decrease of E/eʹ from baseline to week 26 was observed in shorter QRS width (P = 0.005).Structural cardiac endpoints were only found to have a significant positive correlation between LVEDD and Q wave duration (P = 0.037). Higher heart rate was significantly correlated with better response in LVEF (P = 0.001), E/eʹ (P = 0.021), and NT-proBNP (P = 0.005). Empagliflozin-treatment showed no interaction with the results. Baseline ECG characteristics post AMI are neither predictive for beneficial NTproBNP effects of Empagliflozin post AMI, nor for functional or structural changes within 26 weeks post AMI.

Neonatal Cardiac Mesenchymal Stromal Cells Promote Recovery of Infarcted Myocardium through CD44 Mediated FoxP3+ T-Regulatory Cells after Vascular Infusion.

Intravenous infusion has been used as the method of cell delivery in many preclinical studies as well as in some early clinical trials. Among its advantages are broad distribution, ability to handle a large-volume infusion, and ease of access. Progenitor cells used in cell-based therapy act through their secretomes, rather than their ability to differentiate into lineage-specific cell type. Since not all progenitor cells have similar secretome potency, the innate abilities of the secretome of cells used in clinical trials will obviously dictate their effectiveness. We previously found that cardiac neonatal mesenchymal stromal cells (nMSCs) are more effective in repairing the infarcted myocardium compared to adult mesenchymal stromal cells (aMSCs) due to their robust secretome (Sharma et al Circulation Research 120:816-834, 2017). In this study, we explored the efficacy of intravenous (IV) delivery of nMSCs for myocardial recovery. Six-week-old male Brown Norway rats underwent acute MI by ligation of the left anterior descending artery, followed by IV infusion of cell dose 5 × 106 nMSCs/rat body weight (kg) or saline on days 0 and 5. We found that cardiac parameters in the rodent ischemia model improved 1month after nMSCs infusion, and the result is comparable with the intramyocardial injection of nMSCs. Tracking the infused cells in target organ revealed that their movement after IV delivery was mediated by the cell surface receptor CD44. Systemic injection of nMSCs stimulated immunomodulatory responses specifically by increasing FoxP3+ T-regulatory cell influenced anti-inflammatory macrophages (M2) in heart. These data demonstrate that nMSCs promote immunogenic tolerance via CD44-driven T-reg/M2 stimulation that helps nMSCs for longer viability in the injured myocardium for better functional recovery. Our data also demonstrate a rationale for a clinical trial of IV infusion of nMSCs to promote cardiac function improvement in the ischemic patients.

Aberrant left coronary artery from the pulmonary artery with patent ductus arteriosus - a case report and review of the literature

BackgroundAberrant left coronary artery from pulmonary artery (ALCAPA) is a very rare congenital heart defect. Its coexistence with patent ductus arteriosus (PDA) is extremely rare. The high pressures created by the left-to-right shunt in the pulmonary arteries can delay symptoms and create a real challenge in diagnosing ALCAPA. Missing this diagnosis can have severe results, including extensive ischemia and sudden death.Case presentationWe present a case of an infant born with a large PDA. Initially treated conservatively, however, due to congestive heart failure and lack of weight gain, she underwent surgical ligation of the PDA at the age of four and a half months. Following surgery, she developed pulmonary edema. Echocardiography revealed decreased ventricular function. ECG revealed ST elevations on lateral leads, and serum troponin was significantly increased. The patient underwent cardiac magnetic resonance imaging (MRI), which revealed signs of wall ischemia and decreased function of the left ventricle (LV) with unclear coronary anatomy. Diagnostic catheterization revealed an ALCAPA. She underwent surgical intervention, and the left coronary artery was re-implanted in the aortic sinus. Follow-up revealed slow improvement of cardiac function.Discussion and literature reviewThe coexistence of PDA and ALCAPA is a very rare occurrence. We found at least 10 reported cases in the literature. Delayed diagnosis might be detrimental. The prognosis of these patients is variable.ConclusionAn unusual post-surgical course following PDA repair requires a high index of suspicion and appropriate evaluation for ALCAPA, preferably with angiography.

Mechanisms of myocardial reverse remodelling and its clinical significance: A scientific statement of the ESC Working Group on Myocardial Function.

Cardiovascular disease (CVD) is the leading cause of morbimortality in Europe and worldwide. CVD imposes a heterogeneous spectrum of cardiac remodelling, depending on the insult nature, that is, pressure or volume overload, ischaemia, arrhythmias, infection, pathogenic gene variant, or cardiotoxicity. Moreover, the progression of CVD-induced remodelling is influenced by sex, age, genetic background and comorbidities, impacting patients' outcomes and prognosis. Cardiac reverse remodelling (RR) is defined as any normative improvement in cardiac geometry and function, driven by therapeutic interventions and rarely occurring spontaneously. While RR is the outcome desired for most CVD treatments, they often only slow/halt its progression or modify risk factors, calling for novel and more timely RR approaches. Interventions triggering RR depend on the myocardial insult and include drugs (renin-angiotensin-aldosterone system inhibitors, beta-blockers, diuretics and sodium-glucose cotransporter 2 inhibitors), devices (cardiac resynchronization therapy, ventricular assist devices), surgeries (valve replacement, coronary artery bypass graft), or physiological responses (deconditioning, postpartum). Subsequently, cardiac RR is inferred from the degree of normalization of left ventricular mass, ejection fraction and end-diastolic/end-systolic volumes, whose extent often correlates with patients' prognosis. However, strategies aimed at achieving sustained cardiac improvement, predictive models assessing the extent of RR, or even clinical endpoints that allow for distinguishing complete from incomplete RR or adverse remodelling objectively, remain limited and controversial. This scientific statement aims to define RR, clarify its underlying (patho)physiologic mechanisms and address (non)pharmacological options and promising strategies to promote RR, focusing on the left heart. We highlight the predictors of the extent of RR and review the prognostic significance/impact of incomplete RR/adverse remodelling. Lastly, we present an overview of RR animal models and potential future strategies under pre-clinical evaluation.

Tachycardia-Induced Cardiomyopathy in an Infant with Atrial Flutter and Prolonged Recovery of Cardiac Function.

Background: Tachycardia-induced cardiomyopathy (TIC) is caused by prolonged tachycardia, leading to left ventricular dilatation and systolic dysfunction with heart failure. Although TIC is more common in adults, it is rare in early infancy. Methods: Clinical testing was performed as part of medical evaluation and management. Next-generation sequencing (NGS) was conducted for a patient with TIC. A literature review on TIC was also conducted. Results: The case involved a 5-month-old infant referred to the hospital due to symptoms of heart failure lasting at least two months. The infant's heart rate was 200 beats per minute, the left ventricular ejection fraction fell below 14%, and electrocardiograms showed atrial flutter, suggesting TIC. After cardioversion, there was no recurrence of atrial flutter, and cardiac function improved 98 days after tachycardia arrest. The NGS did not identify any pathogenic variants. The literature review identified eight early infantile cases of TIC. However, no previous reports described a case with such a prolonged duration of TIC as ours. Conclusions: This is the first report of a case of prolonged TIC in a child with the documented time to recover normal cardiac function. The improvement of cardiac function depends on the duration of TIC. Early recognition and intervention in TIC are essential to improve outcomes for infantile patients, as timely treatment offers the potential for recovery.

The Effects of Obstructive Sleep Apnea on the Cardiovascular System: A Comprehensive Review.

Obstructive sleep apnea (OSA) is an increasingly relevant cause of cardiovascular morbidity worldwide. Although the association between OSA and the cardiovascular system is well-known, the extent of its effects is still a topic of interest, including pathophysiologic mechanisms, cardiovascular sequelae, and OSA therapies and their effects. Commonly described mechanisms of cardiovascular etiologies revolve around sympathetic activation, inflammation, and intermittent hypoxia resulting from OSA. Ultimately, these effects lead to manifestations in the cardiovascular system, such as arrhythmias, hypertension, and heart failure, among others. The resulting sequelae of OSA may also have differential effects based on gender and age; several studies suggest female gender to have more susceptibility to cardiovascular mortality, as well as an increase in age. Furthermore, several therapies for OSA, both established and emerging, show a reduction in cardiovascular morbidity and may even reduce cardiovascular burden. Namely, the establishment of CPAP has led to improvement in hypertension and cardiac function in patients with heart failure and even reduced the progression of early stages of atherosclerosis. Effective management of OSA decreases abnormal neural sympathetic activity, which results in better rhythm control and blood pressure control, both in waking and sleep cycles. With newer therapies for OSA, its effects on the cardiovascular system may be significantly reduced or even reversed after long-term management. The vast extent of OSA on the cardiovascular system, as well as current and future therapeutic strategies, will be described in detail in this review.

#1677 Initiation of Vericiguat and short-term cardiovascular function improvement in heart failure patients with worsened renal function

Abstract Background and Aims Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, is approved for treating heart failure (HF) with reduced ejection fraction (HFrEF). This study aims to assess the short-term improvement in cardio-function resulting from in-hospital initiation of Vericiguat among patients with chronic kidney dysfunction (CKD), utilizing real-world data from a single-center experience in western China. Method Data were obtained from the Biobank of the First Affiliated Hospital of Xi'an Jiaotong University, spanning from January 2023 to December 2023. A total of 213 HF patients with Vericiguat initiation were screened for eligibility. Echocardiography was employed to evaluate cardio-function after 1- and 3-month short-term follow-up in each patient. Statistical analyses were conducted using one-way ANOVA (followed by Geisser-Greenhouse correction and Tukey's multiple comparison) to assess significance between different timepoints. Results Among the 213 patients randomized in this study, baseline characteristics were compared based on estimated glomerular filtration rate (eGFR) ≤ 30 (worsened renal function group, WRF, n = 20) and >30 mL/min/1.73 m2 (n = 193). No significant differences were observed in age, gender, and other biochemical parameters expect hemoglobin and creatine between the two groups (Table 1). Analysis of cardiac function after 1- and 3-month follow-up revealed a promising increase in left ventricular ejection fraction (EF) (37.2% vs. 43.9%, Mean diff −6.7, 95% CI −12.78 to −0.62, p = 0.03), fractional shortening (FS) (20.9% vs. 25.3%, Mean diff −4.42, 95% CI −8.57 to −0.27, p = 0.04), and a significant decrease in left ventricular end-diastolic dimension (LVEDD) (65.0 mm vs. 60.6 mm, Mean diff 4.35, 95% CI 0.33 to 8.38, p = 0.03) after 3-month follow-up compared to Vericiguat initiation in WRF patients. However, no significant changes were observed between the beginning and 1-month follow-up in echocardiographic measurements (Fig. 1). Conclusion In this real-world single-center study, Vericiguat demonstrated effectiveness in short-term improvement of cardiac function among HF patients with worsened renal function. The long-term efficacy in reducing major cardiovascular events in this subgroup, based on real-world experience, warrants further exploration.

#2770 Evaluation of the effect of IV iron therapy on eGFR and Pro-BNP in patients with chronic kidney disease and heart failure with preserved EF

Abstract Background and Aims Iron replacement in treating heart failure (HF) is an issue whose importance has been better understood in recent years. Although controversies exist, randomized controlled studies have shown that IV iron treatment reduces mortality and improves symptomatology in heart failure with low EF (HFrEF). IV iron has not dramatically affected survival in heart failure with preserved EF (HFpEF). However, there is data that it might reduce symptoms and hospitalizations. For patients with chronic kidney disease (CKD) and HF, around 60% of them have HFpEF. Major heart failure and iron studies have often been performed on patients with low EF. Furthermore, in some of these studies, GFR values were not reported, and in the others, GFR was often > 60 ml/minute. We planned this study to evaluate the effects of IV iron therapy on eGFR and Pro-BNP levels in non-dialysis CKD patients with HFpEF. Method This study was conducted between January 2022 and December 2023. Patients with iron deficiency anemia, stage 2-5ND chronic kidney disease, and those with Pro-BNP values of 1000 and above were selected. Two independent cardiologists evaluated them, and the diagnosis of heart failure was confirmed. Patients were given one dose of 500 or 1000 mg of FCM. Control values were obtained at the 1-month follow-up. Hospitalized or transfused patients, cases with primary hematological disease, and cases with conditions affecting ferritin levels were excluded. Patients whose RAAS blockade, SGLT-2 inhibitor, and diuretic doses were changed, were excluded from the analysis. No patients received ESA or HIF stabilizers. Demographic and clinical data of the patients were recorded. The patients' creatinine, eGFR, hemoglobin, ferritin, and pro-BNP levels were evaluated before and after iron treatment Results Seventy-four patients were recruited. Forty-seven patients were women. The average age was 68 ± 11 years. Forty-eight of the patients had diabetes (64.9%) and 47 (63.5%) had coronary artery disease. The etiology of HFpEF was diastolic heart failure in 45 patients (60%). Other patients had valve disease, HFmEF, HFimpEF, isolated right-sided HF, and mixed types of HFpEF. After IV iron treatment, an increase of 3 ± 1 ml/min in GFR and 1.1 ± 0.1 g/dL in hemoglobin was detected. ProBNP levels decreased by 46%. All findings were statistically significant. The findings are summarized in Table 1. Conclusion The decrease in ProBNP levels was similar to the HFrEF literature. No positive or negative effects of iron on GFR were observed in the REVOKE and FIND-CKD studies, which compared oral and IV iron in CKD patients. The small but significant increase in GFR in our study could be attributed to the improvement of cardiac function. However, the small number of patients and the short follow-up period make it difficult to reach a definitive conclusion on this issue. We have shown that IV iron treatment significantly reduces Pro-BNP levels in CKD patients with HFpEF. IV iron has no adverse effects on renal function in the short term, and there is little signal of potential positive effects. Longer-term studies, preferably randomized with oral iron, with appropriate sample size, are needed to evaluate how IV iron affects end-points such as HF symptom score, hospitalization, eGFR slope, need for renal replacement, and mortality in this patient group. Strengths Well-selected patient group, a high Pro-BNP cut-off point, re-evaluation of each patient by the cardiologists Limitations Relatively small cohort, short follow-up period

Gold nanoparticles-conjugation of irisin enhances therapeutic effect by improving cardiac function and attenuating inflammation in sepsis

Introduction: Irisin is considered to be a promising therapeutic approach for cardiac depression and inflammatory disorders. The short half-life of irisin impeded its use and drug effcacy in the treatment. Objective: This study aimed to examine if pegylated gold nanoparticles-conjugated to irisin would improve therapeutic effects in cecal ligation and puncture (CLP)-induced sepsis in mice. Method: Recombinant irisin were conjugated to a pegylated gold nanoparticle, which was given to mice exposed to CLP. The cecal ligation procedure and sham on mice were operated and assigned to one of following five groups: I) CLP group: The mouse models underwent the CLP surgical procedure and received only vehicle saline treatment (n= 5); II) CLP + soluble Irisin: The mouse underwent the CLP and received an i.m (TA) injection of 1 ug of soluble irisin into each leg (n= 5); III) CLP + Gold nanoparticle-conjugated to Irisin: The mouse models underwent the CLP and received an i.m (TA) injection of 1 μg of Gold nanoparticle-irisin via intramuscular injection (TA) into each leg w (n= 5); IV) CLP + Gold nanoparticles- conjugated to IgG: The mouse underwent the CLP and received an i.m (TA) injection of gold nanoparticles conjugated to IgG (n=5). V) Sham: The mouse underwent the surgical operation without conducting the CLP (n=10). The post-operated animals were observed for one week, and survival rates were estimated. Echocardiography was performed to measure cardiac function at 12 hours following CLP. TUNEL was employed to detect apoptosis in both cardiac and skeletal muscles; histology was conducted to assess tissue injury in muscles. Enzyme linked immunosorbent assay (ELISA) was conducted to examine release of interleukin 6 (IL6) and the tumor necrosis factor (TNF) alpha. Results: Compared to the CLP control, soluble irisin treatment improved cardiac function recovery, as indicated by the fractional shortening (FS) and ejection fraction (EF). Irisin treatment exhibited reduced IL6 and TNF-alpha release in association with less apoptosis, lower muscle injury index and improved survival post-CLP. However, compared to soluble irisin treatment, gold nanoparticles-conjugated to irisin showed a significant improvement in cardiac function, suppression of apoptosis, reduced IL6 and TNF-alpha releases, decreased muscle injury and an improved survival rate of post-CLP. Conclusion: This study reveals that gold nanoparticles-conjugated irisin can serve to improve irisin’s therapeutic effects over a longer course of treatment. National Institute of General MedicalSciences (R01GM 141339); National Heart, Lung, andBlood Institute Grants (R01 HL089405). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Reprogramming cardiac macrophages with circular RNAs to attenuate post-MI adverse remodeling

Cardiac macrophages (cMφ) play a critical role in cardiac remodeling following myocardial infarction (MI). Reprogramming cMφ towards a favorable wound-healing phenotype is emerging as a promising therapeutic strategy for MI patients. Circular RNAs (circRNAs) are a unique class of non-coding RNAs with high stability and abundance, making them attractive therapeutic targets. However, the role of circRNAs in cMφ physiology during heart failure (HF) progression is poorly understood. To identify circRNAs as key regulators of cMφ dynamics, we performed RNA sequencing and bioinformatics analysis on heart biopsies from healthy donors and patients with ischemic HF. We identified a promising circRNA, circMJ1, as a regulator of Mφ polarization and inflammatory response. CircMJ1 was highly expressed in cMφ and its expression was associated with cMφ polarization. Knockdown of circMJ1 significantly inhibited inflammatory signaling pathways in cMφ and reduced the secretion of pro-inflammatory cytokines. The secretome from circMJ1-silenced cMφ (circMJ1-KD cMφ) also significantly suppressed the migration of cardiac fibroblasts and apoptosis of cardiomyocytes. To further assess the therapeutic effcacy of circMJ1-KD Mφ in cardiac remodeling in the context of MI, we employed a novel multicellular 3D ex vivo model, called living myocardial slices (LMS). We applied circMJ1-KD Mφ to both rat LMS subjected to cryo-injury mimicking MI and HF patient-derived LMS. Interestingly, co-culture with circMJ1-KD Mφ demonstrated a remarkable reduction in inflammation and fibrosis, alongside notable improvement in cardiac function in both cryo-injured rat LMS and HF patient-derived LMS. Overall, our findings reveal circMJ1 as a crucial "switch" for Mφ dynamics and suggest the therapeutic potential of engineered circMJ1-silenced Mφ to improve post-MI healing. Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) –465131031. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Therapeutic potential of hiPSC-derived cardiomyocytes for Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) results in progressive and incurable cardiomyopathy, leading to significant morbidity and mortality due to heart failure. There is currently no effective cure for DMD that can correct the genetic defects and compensate for the lack of dystrophin. Therefore, the therapeutic strategies that focus on the transplantation of induced pluripotent stem cells (iPSCs) derived cardiomyocytes are promising options, and remain to be investigated to which extent they can restrain the cardiomyocyte loss phenotype and improve cardiac function. There has been significant progress in the differentiation of cardiomyocytes (CMs) from hiPSCs (human iPSCs). Three hiPSC lines: AICS-0011, 029 iPS clone 4-PCBC, and PCBC16iPS were investigated based on previously published culture and differentiation methods. We will inject differentiated CMs into the heart of Mdx mice that are mutated or deficient for NOD-scid, IL2Rg to allow for xenotransplantation engraftment. Having confirmed the effcient differentiation of CMs from all three hiPSC lines, the next step will be to transplant CMs. The engraftment rate after transplantation will be quantified by IHC staining for human lamin A/C and the relative level of genomic human DNA from isolated hearts. Correction of dystrophin expression will be measured via IHC for dystrophin. Echocardiography will be performed to measure improvement in cardiac systolic or diastolic function. If therapeutic transplantation of hiPSC-CMs is possible, it could improve the survival of DMD patients. This project was supported by RMM091621DS008, NIH155993, and NIH160665. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

COMPARISON OF CARDIAC STRUCTURAL AND FUNCTIONAL CHANGES BETWEEN SURGERY AND MEDICATION TREATMENT IN PATIENTS WITH PRIMARY ALDOSTERONISM BASED ON ECHOCARDIOGRAPHY

Objective: Conducted a systematic meta-analysis on the changes in follow-up parameters of echocardiography in patients with primary aldosteronism after surgery and drug treatment, in order to explore their differences. Design and method: We conducted the PubMed, Embase, and Cochrane library databases for English full-text articles on the follow-up study of echocardiography parameters in PA patients before and after surgery and drug treatment published from its establishment until June 1, 2023,Perform meta-analysis on the included studies using RevMan software. Results: A total of 515 PA patients (>18 years old) were included in 4 studies, including the surgical group (n=303) and the medication group (n=212), 2 short-term follow-up studies (average follow-up time of 1 year), and 2 long-term follow-up studies (average follow-up time of 3.7 years). Surgery treatment had better performance in improving cardiac contractile function, The main manifestation is the reversal of left ventricular hypertrophy (LVMI: M=-2.6, p=0.047), while there is no significant improvement in cardiac diastolic function (E/A: M=+0.06, p=0.51); In long-term follow-up studies, surgery and medical treatment still showed significant benefits in reducing blood pressure (surgical group: -14 ± 6 mm Hg/-9 ± 10 mm Hg, p<0.001; drug group: -10 ± 12mmHg/-11 ± 9mmHg, p<0.001). Interestingly, the surgical group and drug group did not show better blood pressure control effects than short-term follow-up (p=0.56), Surgery (LVMI: M=-12.6, p=0.01)and medication (LVMI: M=-11.9, p=0.01])can significantly improve left ventricular hypertrophy in patients, with no significant difference (P=0.143). Although surgery (E/A: M=+0.14, p=0.125) and medication (E/A: M=+0.09, p=0.2) can numerically improve diastolic function, there is no statistically significant difference. Conclusions: Both medication and surgical treatment can reverse the damage to the heart structure and function in PA patients. In the short term, surgical treatment has a more significant reversal of cardiac function, especially in left ventricular hypertrophy, but in the long term, there is no significant difference between medication and surgical treatment.

Setmelanotide Administration Improves Cardiac Systolic Function in Sirtuin-3 Deficient Mice

We previously showed that activation of the brain leptin-melanocortin system, particularly melanocortin-4 receptors (MC4R), markedly improves cardiac function in experimental models of heart failure (HF) via mechanisms that are still poorly understood. Sirtuin 3 (Sirt3) is an important regulator of mitochondrial oxidative phosphorylation and deficiency of Sirt3 has been implicated in cardiovascular diseases. We recently found increased Sirt3 expression as well as increased levels of NAD+, the main Sirt3 activator, in cardiomyocytes of rats treated with chronic intracerebroventricular infusion of leptin at a dose that does not spill over into the systemic circulation. Therefore, we hypothesized that stimulation of Sirt3 activity is required for the improvement of cardiac function during activation of the brain leptin-MC4R axis. To test this hypothesis, we first examined if chronic MC4R activation, using an MC4R agonist, setmelanotide, improves cardiac function in naïve Sirt3-deficient (Sirt3-KO) mice. Baseline cardiac function was assessed by echocardiography (VisualSonics-VEVO3100®) in male and female Sirt3-KO and wild-type (WT) control mice (n=5/group) at 20 weeks of age, and then weekly during setmelanotide treatment (2 mg/kg/day — i.p. via osmotic minipump model 1002) for 3 weeks. Chronic MC4R activation with setmelanotide transiently reduced food intake in both groups and promoted weight loss in Sirt3-KO mice. Setmelanotide treatment improved systolic function in WT mice as evidenced by increases in ejection fraction and fractional shortening (EF: 52.8±4.4 vs. 72.4±4.4%; FS: 26.9±2.7 vs. 42.8±6.4%, for baseline vs. week 3, respectively) and other measures of systolic function including circumferential and longitudinal strains. Despite showing a tendency for reduced systolic function compared to WT controls at baseline, Sirt3-KO mice also exhibited improvement in systolic function with setmelanotide administration (EF: 44.1±1.8 vs. 65.3±2.9% and FS: 21.4±1.0 vs. 35.1±2.1%). No major changes were observed in measures of diastolic function. These results suggest that in a non-HF model, MC4R activation does not require stimulation of Sirt3 to improve indices of systolic function. (1R01HL163076, 1R01DK121411, P20GM104357, P30GM149404, U54GM115428, and AHA-835218). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

ITGAM: A Pivotal Regulator in Macrophage Dynamics and Cardiac Function During Sepsis-Induced Cardiomyopathy.

Sepsis-induced cardiomyopathy (SIC) is a critical complication arising from sepsis characterized by reversible myocardial dysfunction. Despite the increasing attention to SIC in research, the underlying molecular mechanisms remain poorly comprehended. In this study, we utilized bioinformatics to analyze RNA-sequencing (RNA-seq) and single-cell RNA-sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database to identify key immune cell populations and molecular markers associated with SIC. Our experimental approach combined in vitro and in vivo studies to investigate the roles of integrin alpha M(ITGAM) and intracellular adhesion molecule-1(ICAM-1) in macrophage recruitment and phenotypic polarization, as well as their impact on cardiac function during SIC. The bioinformatics analysis disclosed significant alterations in gene expression and immune cell composition within the cardiac tissue during SIC, where macrophages emerged as the predominant immune cell type. Notably, ITGAM was identified as a key regulatory molecule that modulates macrophage function, driving the pathogenesis of SIC through its influence on the recruitment and functional reprogramming of these cells. In vitro experiments revealed that lipopolysaccharide (LPS) stimulation triggered an upregulation of ITGAM in macrophages and ICAM-1 in endothelial cells, underscoring their critical roles in immune cell mobilization and intercellular communication. The strategic administration of ITGAM-neutralizing antibodies to SIC mice resulted in a marked decrease in macrophage infiltration within the cardiac tissue, which was initially associated with an improvement in cardiac function. However, this intervention paradoxically resulted in an increased mortality rate during the later phases of SIC, underscoring the complex and dualistic function of ITGAM. This study provides new insights into the complex dynamics of immune cells within the cardiac environment during SIC, with a particular emphasis on the modulatory role of ITGAM in shaping macrophage behavior. The findings shed light on the reversible nature of myocardial dysfunction in SIC and emphasize the importance of targeted therapeutic strategies for the effective management of SIC.

Exploring the Efficacy Enhancement Mechanism of Qixue Shuangbu prescription after TCM processing for treating chronic heart failure by regulating ERK/Bcl-2/Bax/Caspases-3 signaling pathway

Qixue Shuangbu prescription (QSP) has been used for the treatment of chronic heart failure (CHF) with remarkable curative effect. Processed QSP (PQSP) could significantly improve the treatment of CHF after traditional Chinese medicine (TCM) processing. This study elucidated the underlying efficacy enhancement mechanism of QSP after TCM processing for treating CHF in vitro and in vivo. The injury of rat cardiomyoblast H9c2 cells was induced by anoxia/reoxygenation to mimic CHF state in vitro. Sixty Sprague-Dawley rats were used to established CHF model by intraperitoneally injecting doxorubicin (the accumulative dose 15 mg/kg). Biochemical examinations were performed in serum and cellular supernatant, respectively. Cardiac functions and histopathological changes were evaluated in CHF model rats. The protein and mRNA levels of ERK1/2, Bcl-2, Bax and Caspase-3 were evaluated by Western blot and RT-PCR, respectively. All above results of low dose crude QSP-treated group (L-CQSP), high dose CQSP-treated group (H-CQSP), low dose PQSP-treated group (L-PQSP), high dose PQSP-treated group (H-PQSP) were compared to systematically explore correlations between TCM processing and the efficacy enhancement for treating CHF of PQSP. Compared with the model group, the L-CQSP group showed significant improvement in cardiac function at 8th weeks, while no significant improvement in cardiomyocyte apoptosis and fibrosis. Both H-CQSP, L-PQSP and H-PQSP exerted beneficial therapeutic effects in injured H9c2 cardiomyocytes and CHF model rats. L-PQSP and H-PQSP significantly increased cell viability and the activity of SOD, decreased the activities of LDH, MDA and NO, up-regulated the expression of ERK1/2 and Bcl-2, down-regulated the expression of Bax and Caspase-3 compared to the same dosage of CQSP. The efficacy enhancement mechanism of PQSP after TCM processing for treating CHF was directly related to the regulation of ERK/Bcl-2/Bax/Caspases-3 signaling pathway.

Cardioprotection and Suppression of Fibrosis by Diverse Cancer and Non-Cancer Cell Lines in a Murine Model of Duchenne Muscular Dystrophy.

The dynamic relationship between heart failure and cancer poses a dual challenge. While cardiac remodeling can promote cancer growth and metastasis, tumor development can ameliorate cardiac dysfunction and suppress fibrosis. However, the precise mechanism through which cancer influences the heart and fibrosis is yet to be uncovered. To further explore the interaction between heart failure and cancer, we used the MDX mouse model, which suffers from cardiac fibrosis and cardiac dysfunction. A previous study from our lab demonstrated that tumor growth improves cardiac dysfunction and dampens fibrosis in the heart and diaphragm muscles of MDX mice. We used breast Polyoma middle T (PyMT) and Lewis lung carcinoma (LLC) cancer cell lines that developed into large tumors. To explore whether the aggressiveness of the cancer cell line is crucial for the beneficial phenotype, we employed a PyMT breast cancer cell line lacking integrin β1, representing a less aggressive cell line compared to the original PyMT cells. In addition, we examined immortalized and primary MEF cells. The injection of integrin β1 KO PyMT cancer cells and Mouse Embryo Fibroblasts cells (MEF) resulted in the improvement of cardiac function and decreased fibrosis in the heart, diaphragm, and skeletal muscles of MDX mice. Collectively, our data demonstrate that the cancer line aggressiveness as well as primary MEF cells are sufficient to impose the beneficial phenotype. These discoveries present potential novel clinical therapeutic approaches with beneficial outcome for patients with fibrotic diseases and cardiac dysfunction that do not require tumor growth.