Progression Of Heart Failure Research Articles

Myocardial strain and work parameter changes predict long term mortality and rehospitalization in an acute heart failure patient population after levosimendan use

Abstract Introduction Decompensated acute heart failure (HF) in patients with reduced ejection fraction (HFrEF) signifies a pivotal stage in the progression of chronic HF. This condition is closely linked to increased rates of rehospitalization and a higher risk of mortality and morbidity due to inadequate decongestion. Recently, the field of quantitative echocardiography has experienced significant advancements, particularly in myocardial work analysis (MWA), which measures the energy the heart uses during each cardiac cycle. Purpose This study aimed to investigate the immediate effects of levosimendan on myocardial mechanics and to determine if these effects can predict the composite endpoint of HF-related rehospitalization and cardiovascular mortality. Methods 60 patients with HFrEF have been enrolled in the present study (age: 63.8±14.1, 46 males, 25 ischemic HFrEF, 35 non-ischemic HFrEF). or all patients, detailed baseline echocardiography, including strain imaging and myocardial work analysis (MWA), was conducted. Follow-up echocardiography was performed an average of 13.1±12.5 days after levosimendan administration. The clinical follow-up period lasted 496±191 days. Results Before levosimendan administration there was no significant difference in baseline echocardiographic, strain imaging and MWA parameters between ischemic and non-ischemic HFrEF groups. After the drug administration, left ventricular global wasted work (179±89 Hgmm% vs. 319±220 Hgmm%, p <0.05) was higher in the ischemic HFrEF group compared to non-ischemic HFrEF group. Among advanced echocardiographic parameters, global longitudinal strain (GLS) showed no significant improvement, however out of the MWA parameters, global work index (376±215 Hgmm% vs. 460±272 Hgmm%, p <0.05) improved significantly. The prognostic role of hemodynamic and novel echocardiographic parameters has been also assessed. Kaplan-Meier analysis revealed that LV stroke volume index improvement of 0.145 ml/m2 (p=0.01), LVEF improvement of at least 10% or more (p=0.032), LV GLS improvement of 0.85% (p=0.018) and lastly global constructive work improvement of 100 Hgmm% or more (p=0.021) resulted in significantly better event-free survival during the follow up period. Conclusion Levosimendan administration produces substantial immediate effects on hemodynamic parameters, myocardial deformation, and MWA metrics. These alterations appear to hold significant long-term prognostic value for predicting the composite endpoint and event-free survival.

The role of cardiovascular aging in heart failure

Cardiovascular aging represents a critical factor contributing to the rising prevalence of heart failure in aging populations, as structural and functional changes occurring in the heart and vasculature during aging result in an increased susceptibility to heart failure. Different aging-related molecular mechanisms contribute to these cardiovascular changes. Among these molecular mechanisms are epigenetic modifications, including altered DNA methylation, loss of histone and decline in sirtuins, which disrupt genomic stability and cellular metabolism. In addition, aging-related telomere shortening and mitochondrial dysfunction exacerbate oxidative stress and compromise energy homeostasis, promoting cardiac remodeling and functional impairment. Moreover, the aging myocardium also exhibits dysregulated autophagy, impaired angiogenesis, and poor extracellular matrix remodeling, all of which contribute to diminished cardiac resilience. Furthermore, clonal hematopoiesis of indeterminate potential and dysregulated inflammatory pathways intensify systemic and local inflammation, aggravating heart failure progression. On top of that, immune cell infiltration and the senescence-associated secretory phenotype exacerbate inflammatory responses, fostering maladaptive cardiac remodeling. Lastly, poor regenerative capacity, driven by reduced cardiomyocyte turnover and polyploidy, further limits the heart's ability to recover from injury. This review explores the multifaceted nature of cardiovascular aging and its contribution to heart failure by discussing the molecular mechanisms involved therein, elucidating which offers novel therapeutic avenues and potential for targeted and personalized interventions that address specific molecular dysfunctions to mitigate heart failure in elderly populations. Integrating research efforts to translate these molecular insights into clinical interventions will be beneficial in addressing the global burden of heart failure in the context of an aging population.

Active ingredients of traditional Chinese medicine inhibit NOD-like receptor protein 3 inflammasome: a novel strategy for preventing and treating heart failure

Heart failure (HF) has emerged as a significant global public health challenge owing to its high rates of morbidity and mortality. Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is regarded as a pivotal factor in the onset and progression of HF. Therefore, inhibiting the activation of the NLRP3 inflammasome may represent a promising therapeutic approach for preventing and treating HF. The active ingredients serve as the foundation for the therapeutic effects of traditional Chinese medicine (TCM). Recent research has revealed significant advantages of TCM active ingredients in inhibiting the activation of the NLRP3 inflammasome and enhancing cardiac structure and function in HF. The study aimed to explore the impact of NLRP3 inflammasome activation on the onset and progression of HF, and to review the current advancements in utilizing TCM active ingredients to inhibit the NLRP3 inflammasome for preventing and treating HF. This provides a novel perspective for the future development of precise intervention strategies targeting the NLRP3 inflammasome to prevent and treat HF.

Optimization of treatment of endothelial dysfunction and arterial stiffness in patients with arterial hypertension and ischemic heart disease

The relevance of complex correction of endothelial dysfunction and arterial stiffness in patients with arterial hypertension and coronary heart disease is associated with their leading role in the development of cardiovascular diseases. Endothelial dysfunction, characterized by a deficiency of vasodilators, such as nitric oxide, and an increase in vasoconstrictor mediators, contributes to atherogenesis and thrombosis. At the same time, an increase in arterial stiffness leads to an increase in systolic pressure and impaired diastolic filling of the myocardium, which aggravates myocardial ischemia and contributes to the progression of heart failure. The introduction of an integrative approach to optimizing endothelial function and reducing arterial stiffness into clinical practice can significantly improve the prognosis and quality of life of patients, reducing the risk of serious cardiovascular events, including myocardial infarction and stroke. Results from randomized clinical trials support the efficacy of such a strategy, demonstrating that normalization of endothelial function and reduction in arterial stiffness are achievable with modern antihypertensive and lipidlowering drugs, including polypills. These drugs improve treatment adherence through simplified dosing regimens and provide effective management of multifactorial risks in patients. In addition, ongoing research and development of new therapeutics and treatments continue to highlight the need for early detection and targeted therapy in this patient population. Such strategies not only address the underlying pathophysiological changes but also aim to prevent long-term complications associated with these cardiovascular risk factors. By focusing on an individualized treatment protocol that includes both pharmacologic interventions and lifestyle changes, healthcare providers can offer a more dynamic and effective treatment plan that meets each patient’s individual needs, thereby optimizing therapeutic outcomes and improving patient compliance.Background. Cardiovascular diseases are the leading cause of death in Russia, with hypertension, coronary heart disease, and cerebrovascular disease predominating. The prevalence of hypertension is 53.9 %, but disease control remains poor, with less than 30 % of patients achieving target blood pressure levels. Therapy often includes combinations of medications, such as ACE inhibitors and angiotensin receptor blockers, which demonstrate advantages over monotherapy. Approximately 70.7 % of patients require combination therapy to effectively manage their condition.Objective. Comparison of the effects of fixed combinations of amlodipine, atorvastatin and perindopril (Lipertance® 10/20/10 mg) with a combination of amlodipine, lisinopril and rosuvastatin (Equamer® 5/10/20 mg) on the clinical progression of grade 2 and 3 arterial hypertension and functional class II and III coronary heart disease. Also study the effect on arterial stiffness, endothelial function, ankle-brachial index, vascular age.Materials and methods. The study included 65 patients with uncontrolled hypertension with systolic blood pressure (BP) ≥160 mmHg and/or diastolic BP ≥90 mmHg in combination with stable angina, taking two antihypertensive drugs at the beginning of the study. Depending on the therapy, the participants were divided into II groups: I – 30 people receiving a fixed combination of Lipertance; II group – 35 people taking a fixed combination of Equamer. All patients also received bisoprolol at a dosage of 5–10 mg and an antiplatelet agent at a dosage of 75–100 mg.Conclusions. Fixed combinations of Lipertance® and Equamer® drugs were highly effective in controlling blood pressure in patients with hypertension and coronary heart disease, achieving target systolic and diastolic levels in more than 85 % of patients. Both groups showed significant improvements in arterial stiffness and endothelial function, demonstrating their potential to reduce cardiovascular complications. Thus, these combinations can be recommended for routine use in clinical practice to improve prognosis and quality of life in patients.

Meteorin-like protein plasma levels are associated with worse outcomes in de novo heart failure.

Meteorin-like protein (Metrnl) has been recently suggested as a new adipokine with protective cardiovascular effects. Its circulating levels in patients seem to be associated with heart failure (HF), although with contradictory results. Our aim was to ascertain whether this adipokine could estimate the prognosis of HF in de novo HF (DNHF) patients. Metrnl plasma levels of 400 patients hospitalized with DNHF (55% of patients with HF with reduced ejection fraction, 17.3% HF with mid-range ejection fraction, 27.8% HF with preserved ejection fraction) were measured by enzyme-linked immunosorbent assay. We performed both sex-pooled and sex-specific analyses. A 12-month follow-up was conducted, during which clinical outcomes such as all-cause mortality, cardiovascular death and re-hospitalization due to HF were collected. After a 12-month follow up, higher plasma Metrnl levels were associated with an increased risk for all-cause death and cardiovascular death after adjusting by sex, age, LVEF, hypertension, diabetes, ischemic aetiology, chronic renal failure, NT-proBNP and troponin (hazard ratio [HR] = 1.003, 95% confidence interval [CI] = 1.000-1.005; p-value<.05 and HR = 1.004, 95% CI = 1.001-1.007, p-value<.05, respectively). In line with this, DNHF patients with increased levels of circulating Metrnl had a higher number of occurrences of cardiovascular events. Regarding Metrnl associations with parameters implicated in the development and progression of HF, we found that Metrnl circulating levels were positively correlated with age (r = .322, p-value<.0001), NT-proBNP (r = .281, p-value<.0001) and with the renal dysfunction markers urea (r = .322, p-value<.0001) and creatinine (r = .353, p-value<.0001) and higher in women than men (473.7 [385.9-594.0] pg/mL vs. 428.7 [349.1-561.3] pg/mL, p-value<.006). Finally, concerning the subtype of HF, Metrnl plasma levels were higher in HF with preserved ejection fraction. Patients with higher Metrnl levels have a worse prognosis in DNHF. Our results reinforce the association of Metrnl plasma levels with HF progression and outcomes.

Serial changes of systemic ventricular function and atrioventricular valve function in patients with failing Fontan.

This study investigated the longitudinal changes in ventricular function and atrioventricular valve function to clarify the timing and the mechanisms of failing Fontan. Patients who underwent total cavopulmonary connection between 1994 and 2023 were reviewed, and longitudinal echocardiographic examinations of ventricular function and atrioventricular valve regurgitation were analyzed. A total of 650 patients were included. The most frequent primary diagnosis was hypoplastic left heart syndrome in 175. Dominant right ventricle was observed in 337 (51.8%). The median age at total cavopulmonary connection was 2.3 (1.8-3.3) years. Failing Fontan was observed in 78 patients (12%) during the median follow-up of 6.2 years. Among them, dominant right ventricle was observed in 51 patients (65.4%). Patients with protein-losing enteropathy or plastic bronchitis (n = 37) developed Fontan failure early (median 2.6 years post-total cavopulmonary connection). Still, patients maintained ventricular function (93.1% normal at 5 years) and atrioventricular valve competence (no case of moderate/severe regurgitation at 5 years) over time. Patients who developed failing Fontan associated with progression of heart failure (n = 41) had later onset (median 8.3 years post-total cavopulmonary connection) but indicated progressive ventricular dysfunction (68.3% normal at 5 years, 53.8% normal at 10 years) and atrioventricular valve regurgitation (12.3% moderate/severe at 5 years, 15.3% moderate/severe at 10 years). Patients with failing Fontan indicated different serial ventricular and atrioventricular valve function profiles. Ventricular function was preserved in failing Fontan patients with protein-losing enteropathy or plastic bronchitis, whereas progressive ventricular dysfunction was observed in failing Fontan patients with heart failure.

Hypertrophic Cardiomyopathy: New Clinical and Therapeutic Perspectives of an "Old" Genetic Myocardial Disease.

Since its first pathological description over 65 years ago, hypertrophic cardiomyopathy (HCM), with a worldwide prevalence of 1:500, has emerged as the most common genetically determined cardiac disease. Diagnostic work-up has dramatically improved over the last decades, from clinical suspicion and abnormal electrocardiographic findings to hemodynamic studies, echocardiography, contrast-enhanced cardiac magnetic resonance, and genetic testing. The implementation of screening programs and the use of implantable cardioverter defibrillators (ICDs) for high-risk individuals have notably reduced arrhythmic sudden deaths, altering the disease's mortality profile. Therapeutic breakthroughs, including surgical myectomy, alcohol septal ablation, and the novel introduction of "myosin inhibitors", have revolutionized symptom management and reduced progression to advanced heart failure (HF) and death. Despite this progress, refractory HF-both with preserved and reduced systolic function-has become the predominant cause of HCM-related mortality. While most patients with HCM experience a favorable clinical course with low morbidity and mortality, timely identification and targeted treatment of high-risk subgroups progressing toward progressive HF remain a pressing challenge, even for expert clinicians.

NPA7: A Dual Receptor Activating Peptide That Inhibits Cardiac Oxidative Stress.

Cardiomyocyte oxidative stress significantly contributes to the progression of hypertension-induced heart failure, highlighting the need for targeted therapies. We developed a novel peptide, NPA7, that coactivates the GC-A (guanylyl cyclase A)/cGMP and MasR (Mas receptor)/cAMP pathway. This study aimed to test NPA7's ability to inhibit oxidative stress by modulating the p62-KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (nuclear factor erythroid 2-related factor 2) pathway in human cardiomyocytes (HCMs) and a rat model of hypertension. Oxidative stress was induced in HCMs using H2O2 with PBS or NPA7 treatment. Intracellular reactive oxygen species levels were assessed via dihydroethidium staining. Western blotting analysis measured p62, KEAP1, and NRF2 protein levels, while GSH/GSSG ratios and antioxidant gene expression were analyzed. HCMs were transfected with siRNA targeting GC-A, MasR, or p62 before NPA7 and H2O2 treatment. In vivo, spontaneously hypertensive rats received saline or NPA7, with normotensive WKY rats as control and cardiac oxidative stress, KEAP1 protein levels, NOX2, and p67 mRNA levels were measured. NPA7 reduced H2O2-induced reactive oxygen species levels and increased GSH/GSSG ratio in HCMs. Silencing GC-A and MasR reversed NPA7's effects. NPA7 activated the KEAP1-NRF2 pathway, enhancing NRF2's antioxidant target gene expression. In p62 knockdown HCMs, NPA7-induced KEAP1 degradation and NRF2 activation were diminished. Reactive oxygen species levels were elevated in spontaneously hypertensive rat versus WKY hearts however, NPA7 treatment reduced myocardial reactive oxygen species, suppressed KEAP1 protein, and decreased NOX2 and p67 mRNA levels. NPA7 exhibits antioxidant properties in HCMs and spontaneously hypertensive rat hearts by targeting GC-A and MasR through the p62-KEAP1-NRF2 pathway, supporting a novel therapeutic approach against cardiovascular disease-related oxidative stress.

Image-Based Estimation of Left Ventricular Myocardial Stiffness.

Elevation in left ventricular (LV) myocardial stiffness is a key remodeling-mediated change that underlies the development and progression of heart failure (HF). Despite the potential diagnostic value of quantifying this deterministic change, there is a lack of enabling techniques that can be readily incorporated into current clinical practice. To address this unmet clinical need, we propose a simple protocol for processing routine echocardiographic imaging data to provide an index of left ventricular myocardial stiffness, with protocol specification for patients at risk for heart failure with preserved ejection fraction. We demonstrate our protocol in both a preclinical and clinical setting, with representative findings that suggest sensitivity and translational feasibility of obtained estimates.

Downregulation of cardiac inflammation via the CaMKII δ/NF-κB pathway in heart failure by Lonicerae Japonicae Flos and Angelicae Sinensis Radix.

Inflammation serves an essential function in the occurrence and progression of heart failure (HF), especially in the early stage. Lonicerae japonicae Flos (LJF), Angelicae sinensis Radix (ASR), and their compatibility (LJF+ASR) can inhibit excessive inflammation and have significant cardioprotective effects. However, the primary active ingredients and mechanism of LJF and ASR in anti-inflammatory and anti-HF effect remain to be elucidated. This study aimed to evaluate the influence of LJF, ASR, and LJF+ASR on early inflammation and subsequent cardiac function in HF mice and to identify the primary pharmacologically active components of these compounds. LJF, ASR, and LJF+ASR components entering the plasma and heart were identified via UPLC-LTQ-Orbitlaps-MSn. The cardioprotective effects of LJF, ASR, and LJF+ASR after 8 weeks of treatment were validated in transverse aortic constriction (TAC)-induced HF mice via echocardiography, HE staining, and cardiac indices. The anti-inflammatory effects of these treatments after 1 week of TAC induction, as well as the cardioprotective and anti-inflammatory effects of the primary component chlorogenic acid (CGA), were confirmed in H9c2 cardiomyocytes through flow cytometry, Western blot, and siRNA transfection. LJF, ASR and LJF+ASR enhanced cardiac contractile function and ameliorated cardiac pathological remodeling induced by TAC. Moreover, these compounds inhibited platelet-granulocyte aggregation, platelet-monocyte aggregation, the calmodulin-dependent protein kinase II delta (CaMKII δ)/nuclear factor-kappaB (NF-κB) signaling pathway and proinflammatory factor levels in early-stage HF to different extents. Moreover, 9 potentially effective components were identified in the aqueous extract and blood-absorbed components of LJF+ASR, and CGA inhibited the CaMKII δ/NF-κB signaling pathway and decreased proinflammatory factor levels in vitro. LJF, ASR, LJF+ASR and CGA inhibit the CaMKII δ/NF-κB signaling pathway and are potentially novel therapeutics for mitigating early inflammation and improving late cardiac function of HF.

Proteomic analysis reveals QiShenYiQi Pills ameliorates ischemia-induced heart failure through inhibition of mitochondrial fission.

QiShenYiQi Pills (QSYQ) has widely used in clinical treatment of cardiovascular diseases; however, the exact mechanism behind its effectiveness still requires further investigation. The purpose of the study was to explore the potential mechanism of QSYQ in the treatment of ischemic heart failure from the perspective of proteomics. In vivo, to observe QSYQ actions on the progression of ischemia-induced heart failure, cardiac function and remodeling was analyzed. The heart tissues of mice were used for Tandem Mass Tag (TMT)-based proteomic analysis. Cardiomyocytes were prepared and subjected to oxygen-glucose deprivation injury. QSYQ effects on differential proteins expressions, mitochondrial fission and mitochondrial function were assayed. QSYQ treatment preserved cardiac function, limited cardiac fibrosis and alleviated cardiomyocyte hypertrophy in post-myocardial ischemia mice. Proteomic analysis revealed that QSYQ-responsive proteins were mainly involved in mitochondrial fission, including mitochondrial calcium uniporter (MCU), membrane associated ring-CH-type finger 5 (MARCHF5), and mitochondrial fission process 1 (MTFP1). Protein-protein interaction analysis revealed that MCU, MARCHF5 and MTFP1 commonly interacted with dynamin-related protein 1 (DRP1). Knockdown of MCU, MARCHF5, or MTFP1 attenuated excessive mitochondrial fission in cardiomyocytes through regulating DRP1 phosphorylation and its mitochondrial translocation. QSYQ decreased the phosphorylation of DRP1 at Ser616 and enhanced its inhibitory phosphorylation at Ser637, as well as mitigating the mitochondrial recruitment and oligomerization of DRP1, through downregulation of these three differential proteins. As a result, QSYQ alleviated aberrant mitochondrial fission, ameliorated mitochondrial dysfunction, and protected cardiomyocytes from ischemic injury. The novelty lies in the proteomics-based investigation of the mechanism of QSYQ, uncovering that QSYQ mitigated ischemia-induced heart failure by suppressing MCU/MARCHF5/MTFP1-DRP1-driven mitochondrial fission.

Implementation of an Exercise Prescription SmartPhrase in the Electronic Health Record

BackgroundExercise can delay and improve heart failure (HF) progression. Health care providers may be aware of the exercise guidelines; however, implementation for HF patients has been difficult. ObjectiveTo implement a SmartPhrase in the electronic health record (EHR) to streamline prescription of exercise for HF patients. MethodsThis descriptive quality improvement project recruited 8 nurse practitioners (NPs) from HF clinics to test the methods and measures. ResultsSix (75%) NPs accessed the SmartPhrase during clinic visits and completed questionnaires. NPs rated the SmartPhrase high on acceptability and appropriateness. Feasibility responses varied. ConclusionsNPs indicated the Exercise Dose SmartPhrase may be more feasible if data to calculate the exercise dose was automatically drawn from the EHR. This is valuable feedback that will be instrumental in refining the SmartPhrase.

Syphilitic bi-valvular endocarditis and myocarditis: modern tools applied to long-forgotten complications of a re-emerging disease.

The incidence of syphilis has increased steadily over the past 25 years. Undiagnosed cases have presumably increased in the same proportions, and rare complications are at particularly high risk of being unrecognised. A previously healthy 60-year-old man presented with rapidly progressive heart failure and severe aortic and mitral valve insufficiency, with direct valvular destruction and preservation of the aortic valve annulus and aortic root. Treponemal serology was reactive, with rapid plasma reagin titre of 1:128. The patient also had classic manifestations of tertiary syphilis: fusiform aneurysm of the aorta and meningovascular syphilis. He underwent bi-valvular and ascending aorta replacement, and the presence of Treponema pallidum was confirmed by specific immunohistochemistry and PCR in all tissues, including aortic and mitral valves, myocardium, and aorta. This case links T pallidum to infectious endocarditis with severe damage to both aortic and mitral valves, in addition to confirmed syphilitic myocarditis, a long-forgotten complication. It occurred 4 years after probable infection, long before what would be expected according to current understanding of its natural history. Syphilis serology should be considered in patients with culture-negative endocarditis as well as in those with heart failure or arrhythmias of unclear cause, especially in the presence of risk factors for syphilis. Syphilitic endocarditis and myocarditis are potentially lethal but treatable conditions.

Diastolic Dysfunction and Cardiac Energy Deficit: Understanding Progressive Heart Failure in the Light of SGLT2 Inhibitors

Diastolic Dysfunction and Cardiac Energy Deficit: Understanding Progressive Heart Failure in the Light of SGLT2 Inhibitors

CMR phenotyping of asymptomatic hypertrophic cardiomyopathy at increased risk for heart failure progression

CMR phenotyping of asymptomatic hypertrophic cardiomyopathy at increased risk for heart failure progression

Atractylenolide-III restrains cardiac fibrosis after myocardial infarction via suppression of the RhoA/ROCK1 and ERK1/2 pathway.

Cardiac fibrosis, a critical factor in myocardial remodeling post-myocardial infarction (MI), can advance heart failure progression. Atractylenolide III (ATL-III), derived from Atractylodes lancea, has recognized antioxidant and anti-inflammatory effects; however, its influence on cardiac fibrosis remains unclear. MI was induced in mice by permanent ligation of the left anterior descending (LAD) coronary artery, followed by 2weeks of ATL-III or dimethyl sulfoxide (DMSO) treatment. Cardiac fibrosis was assessed by echocardiography, tissue histology, and serum biomarkers of myocardial injury. In vitro, the effects of ATL-III on cardiac fibroblast (CF) proliferation and collagen deposition were evaluated using immunofluorescence, 5-Ethynyl-2'-deoxyuridine (EdU), and western blot techniques. Network pharmacology and molecular docking identified potential ATL-III targets. ATL-III treatment significantly improved cardiac function, as evidenced by increased ejection fraction (EF) and fractional shortening (FS) and reduced left ventricular dilation. Histological analysis revealed decreased fibrotic areas in ATL-III-treated mice, along with reduced expression of fibrosis markers α-SMA and Collagen I. ATL-III also alleviated oxidative stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels while increasing superoxide dismutase (SOD) activity. Furthermore, ATL-III suppressed inflammation, decreasing TNF-α, IL-6, and IL-1β protein and mRNA levels. In vitro, ATL-III inhibited TGF-β1-induced CF proliferation, migration, and differentiation, reducing the expression of fibrotic markers. Mechanistically, ATL-III suppressed the RhoA/ROCK1 and ERK1/2 signaling pathways, as confirmed by molecular docking and pathway analysis. ATL-III demonstrates therapeutic potential in mitigating post-MI cardiac fibrosis by reducing oxidative stress, inflammation, and CF activation. These findings highlight ATL-III as a promising candidate for the treatment of cardiac fibrosis and associated heart failure.

Brainstem C1 neurons mediate heart failure decompensation and mortality during acute salt loading.

Heart failure (HF) is an emerging epidemic worldwide. Despite advances in treatment, the morbidity and mortality rate of HF remain high, and the global prevalence continues to rise. Common clinical features of HF include cardiac sympathoexcitation, disordered breathing, and kidney dysfunction; kidney dysfunction strongly contributes to sodium retention and fluid overload, leading to poor outcomes of HF patients. We have previously shown that brainstem pre-sympathetic neurons (C1) from the rostral ventrolateral medulla (RVLM) play a key role in sympathetic regulation in experimental models of HF. However, the role of RVLM-C1 neurons during salt-loading in the context of HF is unknown. This study tests whether RVLM C1 neurons drive cardiorespiratory decompensation and ultimately lead to sudden death in HF rats. Adult male Sprague-Dawley rats underwent arteriovenous shunt to induce HF with preserved ejection fraction (HFpEF). Two weeks after HFpEF induction, bilateral selective ablation of RVLM C1 neurons was performed using anti-dopamine β-hydroxylase-saporin toxin. Animals were then fed a high Na+ diet (3% Na+ in food and 2% Na+ in water) for 3 weeks to induce compensated-to-decompensated HF state transition. Echocardiography, cardiac autonomic function, breathing function, and survival were assessed during the progression of HF. Salt loading resulted in marked decompensation in HF rats, as evidenced by a significant decrease in survival rates (survival: 10% vs. 100% HFpEF + Na+ vs. HFpEF). Furthermore, HFpEF + Na+ animals showed a further increase in cardiac sympathetic drive and more severe disordered breathing, including higher hypoxia-related epochs (i.e. apnoeas/hypopnoeas), compared with HF. Ablation of RVLM C1 neurons partly reduced the excessive cardiac sympathoexcitation during salt loading in HF, improved the exaggerated disordered breathing in HFpEF+ Na+ rats, and reduced decompensation-linked mortality. We found that hypoxia, but not high sodium, was the major contributor to impaired calcium handling in isolated adult cardiomyocytes. Our results strongly suggest that RVLM C1 neurons contribute to acute HF decompensation during salt loading by a mechanism encompassing further increases in sympathetic outflow and hypoxia-related breathing disorders. This mechanism may ultimately impact cardiac contractility through cardiomyocyte calcium mishandling, increasing morbidity and mortality.

A Podcast on Patient and Physician Perspectives in the Holistic Care of Heart-Related Challenges of Type 2 Diabetes.

Type 2 diabetes (T2D) frequently coexists with cardiorenal complications. Therefore, a holistic approach to patient management is required, with specialists such as primary care physicians, cardiologists, endocrinologists, and nephrologists working together to provide patient care. Although glycemic control is important in the management of T2D, patients with T2D and acceptable glycemic control are still at risk from cardiovascular (CV) events such as stroke, heart attack, and heart failure (HF). Therefore, management of other risk factors, such as high blood pressure, high cholesterol, smoking cessation, and excess bodyweight, are imperative for reducing the risk of CV disease and HF in patients with T2D. In addition to pharmacological interventions, patient self-care, including beneficial dietary changes, regular exercise, and smoking cessation are critical for improving heart health and reducing the risk of CV events and progression of HF. In this podcast, a patient with lived experience of the heart-related challenges of T2D and a cardiologist discuss the link between T2D and heart-related complications, the pharmacological interventions and lifestyle modifications that can be used to reduce the risk of CV events and prevent HF, and the complexities of engaging with the healthcare system when managing multiple comorbidities. The discussion highlights the importance of patient education and empowerment for the management of heart-related challenges of T2D, and the central role of collaborative care between physicians of multiple specialties to reduce CV risk for patients with T2D.

DEVELOPMENT AND VALIDATION OF A LIPOPOLYSACCHARIDE-INDUCED MYOCARDIAL INFLAMMATION MODEL IN MICE FOR PRECLINICAL RESEARCH ON STEM CELL-BASED THERAPY

One of the serious cardiovascular complications during the COVID-19 pandemic was myocardial inflammation, which often affected young patients but was particularly dangerous for the elderly. This condition, triggered by systemic inflammation in acute respiratory distress syndrome, contributed to the progression of heart failure. Due to the lack of effective treatment methods, this led to high mortality rates among affected patients. The lipopolysaccharide-induced model of myocardial injury can replicate the pathogenic myocardial changes characteristic of inflammation seen in COVID-19, providing a valuable tool for experimental studies of potential anti-inflammatory therapies, including stem cell treatments. Objective. This study aimed to develop and validate a lipopolysaccharide-induced model of inflammatory myocardial injury to investigate the regenerative potential of stem cells in myocarditis of various origins. Materials and methods. The study was conducted on female FVB «wild-type» mice aged 4–5 months. A single intraperitoneal injection of E. coli lipopolysaccharide was administered at doses of 1 mg/kg or 5 mg/kg to induce a systemic inflammatory response. Electrocardiographic assessments were performed before the injection and on days 7 and 14 post-injection. On these days, histological sections of the heart were prepared to analyze morphological markers of inflammatory myocardial injury, and immunohistochemical staining for the apoptosis marker CD95 was conducted. Results. One week after the administration of lipopolysaccharide, electrocardiographic studies in mice revealed an increase in heart rate compared to baseline, with increases of 19.6 % and 13.2 % following the administration of lipopolysaccharide (LPS) at doses of 1 mg/kg and 5 mg/kg, respectively. This response indicates a compensatory reaction to the impairment of the heart’s contractile function due to myocardial injury. Additionally, signs of intraventricular conduction disturbances were observed, including R wave deformation and ventricular extrasystoles, which persisted in the group receiving LPS at a dose of 5 mg/kg after two weeks. Histological sections in both animal subgroups, one week after LPS administration, revealed cytoplasmic swelling and eosinophilia resulting from myofibril contraction, along with significant vascular congestion characterized by stasis and aggregation of erythrocytes. These changes were more pronounced in the group receiving the 5 mg/kg LPS dose. Two weeks after administration of LPS at a dose of 1 mg/kg, significantly less severe manifestations of myocardial injury were observed, indicating partial recovery due to endogenous repair mechanisms. In contrast, the group receiving the 5 mg/kg dose exhibited morphological signs of persistent inflammation in the heart tissue. Immunohistochemical analysis revealed the expression of the apoptosis marker CD95 in cells throughout the entire section of myocardium in mice with LPS-induced inflammation. Conclusions. A model of lipopolysaccharide-induced inflammatory myocardial injury in mice has been developed and validated for investigating the regenerative potential of stem cells in inflammatory heart diseases. Electrophysiological and morphological studies indicate that a dose of 5 mg/kg of E. coli lipopolysaccharide is optimal for inducing more pronounced inflammatory changes in the myocardium of laboratory mice compared to a dose of 1 mg/kg.

The impact of shock therapy on depression development and remote prognosis in cardiac resynchronization therapy recipients.

The aim of this study was to assess the incidence and clinical significance of depression in patients with cardiac resynchronization therapy with an implantable cardioverter-defibrillator (CRT-D). The study was also to evaluate the impact of shock therapy on depression development and long-term prognosis. The prospective study encompassed 396 consecutive heart failure (HF) patients implanted with CRT-D. All patients completed the Beck Depression Inventory (BDI-II) and underwent a psychiatric examination at baseline. 221 patients free of depressive symptoms at baseline were included into the final analysis. The assessment of psychiatric status was routinely repeated every 6 months as well as after the shock delivery. The primary outcome was a composite endpoint of death or hospitalization for HF. During long-term observation (median 37.1 months) 52 (23.5%) patients suffered from an implantable cardioverter-defibrillator (ICD) shock, whereas 48 (21.8%) subjects developed depression. The incidence of new-onset depression was significantly higher in patients after shock delivery (Shock Group), CRT non-responders and subjects with atrial fibrillation. The risk for a composite endpoint was higher in the Shock Group than subjects without an ICD intervention: 57.7% vs. 25.4% and in patients with new-onset depression compared to the population free of this disorder: 62.5% vs. 24.9% (all p < 0.001). New-onset depression (HR 1.7) and an ICD shock (HR 2.1) were strong independent predictors of poor prognosis. Depression is a common mental disorder in CRT-D recipients, that adversely affects long-term prognosis. Subjects suffering from ICD shocks and those with HF progression are at higher risk of experiencing depressive symptoms.