Improvement In Cardiac Function Research Articles

Ultrasound-driven piezoelectret-based nanogenerator stimulates vagus nerve for myocardial infarction treatment

Myocardial infarction (MI) stands as the predominant cause of morbidity and mortality within the spectrum of cardiovascular diseases, with an unfavorable long-term prognosis. Vagus nerve stimulation (VNS) emerges as a potential clinically significant intervention for alleviating myocardial remodeling after MI, offering promise as a therapeutic approach. However, challenges persist in addressing the fundamental issues of flexibility, miniaturization, and the long-term use of VNS devices. Here, we devised an implantable ultrasound-driven piezoelectret-based nanogenerator (UPN) as a wireless-powered and battery-free vagus nerve stimulator. The UPN with the features of flexibility and lightweight exhibited a maximum output of 10.68 V and 261 μA (peak to peak) under an ultrasonic probe setup at 700 mW cm−2. In the in vivo efficacy study, VNS therapy resulted in a notable improvement in cardiac function with the treatment of UPN, a 20.42 % enhancement in left ventricular ejection fraction and an 11.76 % increase in fractional shortening on the 28th day were realized. Concomitantly, inflammatory responses, myocardial fibrosis, and sympathetic nerve remodeling witnessed a significant reduction. Particularly noteworthy is the observed therapeutic effect linked to the inhibition of the IL-17 and TNF signaling pathways. In summary, this study introduces a novel strategy for nerve stimulation, offering a potential avenue for treating chronic inflammatory diseases.

Left Atrial Strain for Prediction of Left Ventricular Reverse Remodeling After ST-segment Elevation Myocardial Infarction by Cardiac Magnetic Resonance Feature Tracking

Purpose: The study aimed to investigate the potential utility of left atrial (LA) strain by using cardiac magnetic resonance feature-tracking (CMR-FT) to predict left ventricular reverse remodeling (LVRR) following ST-segment elevation myocardial infarction (STEMI). Materials and Methods: Patients with a first STEMI treated by primary percutaneous coronary intervention were consecutively enrolled in the prospective study and underwent CMR scans at 5 days and 4 months. LA global longitudinal strain (reservoir strain [εs], conduit strain [εe], booster strain [εa]) and corresponding strain rate were assessed by CMR-FT using cine images. LVRR was defined as a reduction in the LV end-systolic volume index of >10% from baseline to follow-up. Logistic regression analyses were performed to determine the predictors of LVRR. Results: Of 90 patients analyzed, patients with LVRR (n=35, 39%) showed higher values of LA strain and strain rate and less extensive infarct size (IS) compared with patients without LVRR (n=55, 61%) at initial and second CMR. The LVRR group demonstrated significant improvements in LV and LA cardiac function over time, especially the obvious increase in LA strain and strain rate. In multivariate logistic regression analyses, εs and εe, together with IS, were independent predictors of LVRR. The combination of εs and IS could optimally predict the LVRR with the highest area under the curve of 0.743. Conclusions: Post-STEMI patients with LVRR presented better recovery from cardiac function and LA deformation compared with patients without LVRR. Assessment of εs and εe by using CMR-FT after STEMI enabled prediction of LVRR.

Medication reconciliation to minimise medication errors: Iatrogenic hypercalcaemia as a case report

Hypercalcaemia is a relatively less common yet life-threatening electrolyte disorder and is caused by parathyroid-dependent and independent factors. This case report describes an elderly lady, a known patient of stable hypothyroidism, hypertension, type 2 diabetes mellitus and non-oliguric chronic kidney disease-IV who presented with complaints of gradually worsening drowsiness. Investigations revealed a hypercalcemic crisis; all other contributory investigations were unremarkable. She was put on intravenous saline rehydration, furosemide, pamidronate, and calcitonin. However, due to new-onset haemodynamic instability, cardiomyopathy, and worsening renal parameters, haemodialysis was initiated to reduce the serum calcium levels rapidly. The patient remained asymptomatic after that, and her renal parameters improved to near baseline levels, though cardiac function improvement was not obtained at the end of one month. History elicited from the patient after her neurological improvement revealed that failing to interpret the prescription of three orthopaedics she had visited lately, she followed all simultaneously and had thus consumed toxic levels of calcium and Vitamin D. Medication reconciliatory measures such as e-prescribing, computerised drug dispensing system, automated patient drug dispensing boxes and ‘brown-bagging’ all ongoing medications during the physician visits would ensure reduction in medication errors, thus avoiding adverse events, reducing uncalled for mortalities and morbidities and healthcare cost.

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.

Does Cardiac Function Improvement With Coronary Artery Bypass Grafting Reduce All-cause Mortality?

BackgroundThe effect of coronary artery bypass grafting (CABG) on cardiac function improvement remains controversial. Furthermore, recent evidence suggests that improvement in cardiac function after CABG does not improve life expectancy. This study aimed to examine whether CABG improved cardiac function and how this improvement influenced all-cause mortality and to compare patient prognosis according to preoperative cardiac function. MethodsThis retrospective study included patients with a left ventricular ejection fraction (LVEF) of ≤35% who underwent CABG between January 1994 and December 2022. We compared patients with and without cardiac function improvement, defined as an increase in LVEF of ≥10%, to identify associated factors and assess the impact on all-cause mortality. We also compared outcomes according to the degree of preoperative LV dysfunction. ResultsAmong the 166 patients included, 102 and 64 had a preoperative LVEF of 25%-35% and ≤25%, respectively. The mean follow-up duration was 79.9 ± 72.3 months. We observed significant LVEF improvement, from 28% (range, 23.3%-35%) preoperatively to 39% (range, 31%-46%) at 13.1 months postoperatively. The 7-year survival rates were similar in the ejection fraction ≤25% and 25%-35% groups (80.2% vs 73.8%, P = .11). However, patients with an LVEF improvement of ≥10% exhibited a markedly better prognosis than those without LVEF improvement at 7 years (85.9% vs 63.5%, P=.001). ConclusionsOur findings suggest that CABG may enhance cardiac function in more than half of patients with ischemic cardiomyopathy, with a correlation to improved all-cause mortality. Moreover, LVEF improvement after CABG is associated with an improved prognosis.

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

Surgical Treatment Strategy of Functional Tricuspid Regurgitation.

Functional tricuspid regurgitation (FTR) is a common type of tricuspid regurgitation (TR), particularly in cases of left heart valve disease. Historically, cardiac surgeons have not placed much emphasis on FTR and instead focused primarily on managing left heart valve disease. However, as research has progressed, it has become evident that severe TR significantly impacts the prognosis of heart valve surgery. Furthermore, significant improvements in postoperative cardiac function and quality of life have been observed when addressing the tricuspid valve alongside left heart disease management. This article aims to review current approaches for and timing of the surgical management of FTR while also analyzing the limitations of existing tricuspid surgical strategies.

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.

Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER

PurposeEvaluate long-term efficacy and safety of elamipretide during the open-label extension (OLE) of the TAZPOWER trial in individuals with Barth syndrome (BTHS). MethodsTAZPOWER was a 28-week randomized, double-blind, and placebo-controlled trial followed by a 168-week OLE. Patients entering the OLE continued elamipretide 40 mg subcutaneous daily. OLE primary endpoints were safety and tolerability; secondary endpoints included change from baseline in the 6-minute walk test (6MWT) and BarTH Syndrome Symptom Assessment (BTHS-SA) Total Fatigue score. Muscle strength, physician- and patient-assessed outcomes, echocardiographic parameters, and biomarkers, including cardiolipin (CL) and monolysocardiolipin (MLCL), were assessed. ResultsTen patients entered the OLE; 8 reached the week 168 visit. Elamipretide was well tolerated, with injection-site reactions being the most common adverse events. Significant improvements from OLE baseline on 6MWT occurred at all OLE time points (cumulative 96.1 m of improvement [week 168, P = .003]). Mean BTHS-SA Total Fatigue scores were below baseline (improved) at all OLE time points. Three-dimensional (3D) left ventricular stroke, end-diastolic, and end-systolic volumes improved, showing significant trends for improvement from baseline to week 168. MLCL/CL values showed improvement, correlating to important clinical outcomes. ConclusionElamipretide was associated with sustained long-term tolerability and efficacy, with improvements in functional assessments and cardiac function in BTHS.

(155) - Defining Optimal Criteria for LVAD Weaning in HF Patients with an Improvement in Cardiac Structure and Function: A VAD Wean Registry Analysis

(155) - Defining Optimal Criteria for LVAD Weaning in HF Patients with an Improvement in Cardiac Structure and Function: A VAD Wean Registry Analysis