Decrease In Ejection Fraction Research Articles

EFFECTS OF PTEROSTILBENE ON HEART AND LUNG OXIDATIVE STRESS PARAMETERS IN TWO EXPERIMENTAL MODELS OF CARDIOVASCULAR DISEASE: MYOCARDIAL INFARCTION AND PULMONARY ARTERIAL HYPERTENSION.

Myocardial infarction (MI) and pulmonary artery hypertension (PAH) are two prevalent cardiovascular diseases. In both conditions, oxidative stress is associated with a worse prognosis. Pterostilbene (PTE), an antioxidant compound, has been studied as a possible therapy for cardiovascular diseases. This study aims to evaluate the effect of PTE on oxidative stress in the hearts of animals with myocardial infarction and in the lungs of animals with PAH. Male Wistar rats were used in both models. In the MI model, the experimental groups were sham, MI, and MI+PTE. In PAH model, the experimental groups were control, PAH, and PAH+PTE. Animals were exposed to MI through surgical ligation of the left coronary artery, or to PAH, by administration of monocrotaline (60 mg/kg). Seven days after undergoing cardiac injury, the MI+PTE animals were treated with PTE (100 mg/kg day) for 8 days. After this, the heart was collected for molecular analysis. The PAH+PTE animals were treated with PTE (100 mg/kg day) for 14 days, beginning 7 days after PAH induction. After this, the lungs were collected for biochemical evaluation. We found that PTE administration attenuated the decrease in ejection fraction and improved LV end-systolic volume in infarcted animals. In the PAH model, PTE improved pulmonary artery flow and decreased ROS levels in the lung. PTE administration promoted protective effects in terms of oxidative stress in two experimental models of cardiac diseases: MI and PAH. PTE also improved cardiac function in infarcted rats and pulmonary artery flow in animals with PAH.

Abstract PO4-17-02: A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND

Abstract Background: Approximately 20% of breast cancer (BC) cases are human epidermal growth factor receptor 2-positive (HER2+; immunohistochemistry [IHC] 3+, IHC 2+/in-situ hybridization [ISH]+), and up to ~50% of patients with primary or metastatic BC (mBC) have HER2-low tumors (IHC 1+, IHC 2+/ISH−), a new therapeutically targetable subset of BC. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved in the USA, EU, and other countries for the treatment of adult patients with unresectable or metastatic HER2+ BC who have received a prior anti-HER2-based regimen, or with unresectable or metastatic HER2-low BC who have received a prior chemotherapy (CTx) in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant CTx. Approvals followed positive results from the DESTINY-Breast03 and DESTINY-Breast04 clinical trials. In DESTINY-Breast03, T-DXd improved median progression-free survival (mPFS) compared with trastuzumab emtansine (28.8 vs 6.8 months, respectively; P< 0.0001) in previously treated (prior trastuzumab and taxane) patients with HER2+ mBC. In DESTINY-Breast04, T-DXd significantly improved mPFS vs physician’s choice of CTx (9.9 vs 5.1 months, respectively; P< 0.001) in all randomized patients with HER2-low mBC who were previously treated with one or two lines of CTx. Alongside these efficacy benefits, T-DXd has demonstrated an acceptable and generally manageable safety profile. To optimize care and maximize treatment benefit, insights into real-world T-DXd use and safety events of interest, including patient management and experience, are needed. This study aims to describe the effectiveness and tolerability of T-DXd in patients with HER2+ or HER2-low unresectable and/or mBC in a real-world setting. Trial design: DESTINY-Breast-RESPOND (NCT05592483) is a multicenter (120 sites planned as of June 2023), multi-country (HER2+ cohort: several regions globally; HER2-low cohort: North America only), prospective, observational study characterizing real-world clinical use, effectiveness, tolerability, and patient experience among adults who initiated T-DXd monotherapy, per standard of care, for HER2+ (second line or earlier) and HER2-low unresectable and/or mBC (T-DXd not provided by study sponsor). The decision to initiate T-DXd will be made by the physician prior to, and independent from, participation in this study. Approximately 750 patients with HER2+ and 250 patients with HER2-low disease will be enrolled. Patients must have received prior treatment with a trastuzumab-containing regimen in the metastatic setting or have evidence of disease progression within 6 months of neoadjuvant or adjuvant treatment (HER2+ cohort), or prior CTx in the metastatic setting or have evidence of disease progression within 6 months of adjuvant CTx (HER2-low cohort). Data will be collected via chart abstraction, patient-reported outcome questionnaires on tolerability and safety (PGI-TT, NCI PRO-CTCAE, and EORTC IL19), and a daily patient nausea/vomiting symptom diary. Endpoints will be analyzed separately for HER2+ and HER2-low cohorts. The primary endpoint of interest is time to next treatment from T-DXd initiation, a measure of real-world effectiveness. Other important endpoints include treatment patterns, safety events of interest (nausea/vomiting, fatigue, alopecia, interstitial lung disease/pneumonitis, left ventricular ejection fraction decrease) and their management, time to T-DXd discontinuation, and patient-reported tolerability. Patients will be observed until end of study (~60% of patients receive subsequent treatment or have died), withdrawal from study, or loss to follow up, whichever occurs first. Citation Format: Joyce O'Shaughnessy, Reva Basho, Maryam Lustberg, Gary H Lyman, Manoj Prahladan, Gareth D. James, Della Varghese, Flavia Lujan, Hans Tesch. A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-02.

Dapagliflozin Alleviates Myocardial Ischaemia Reperfusion Injury by Activating Mitophagy via the AMPK-PINK1/Parkin Signalling Pathway.

Myocardial ischaemia reperfusion injury (MIRI) determines infarct size and long-term outcomes after acute myocardial infarction (AMI). Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, alleviates MIRI in animal models. We investigated the potential mechanisms underlying the cardioprotective effect of dapagliflozin against MIRI, focusing on mitochondrial injury and mitophagy. MIRI mouse and H9C2 cell models were established. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed a significant alleviation of MIRI after pre-treatment of dapagliflozin compared to the model group (14.91±1.76 vs. 40.47±3.69%). Data from the pre-treatment dapagliflozin group showed a significant decrease in left ventricular ejection fraction (LVEF) (44.8±2.7 vs. 28.5±5.3%, P<0.01), left ventricular end-diastolic volume (LVEDV) (70.6±9.5 vs. 93.5±13.8 ul, P<0.05), and left ventricular end-systolic volume (LVESV) (39.0± 8.3 vs. 67.9±13.7 ul, P<0.05) compared to the model group. Dapagliflozin also reduced the levels of reactive oxygen species (ROS) and fragmented mitochondrial DNA, reversed the decrease in mitochondrial membrane potential, and suppressed apoptosis. Further study showed that dapagliflozin could protect against mitochondrial injury by rapidly clearing damaged mitochondria via mitophagy in a phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/parkindependent manner. Dapagliflozin regulated mitophagy in cardiomyocytes by suppressing the adenosine 5'monophosphate-activated protein kinase (AMPK)-PINK1/parkin signalling pathway, resulting in attenuated MIRI. Dapagliflozin alleviated MIRI by activating mitophagy via the AMPK-PINK1/parkin signalling pathway.

Baicalin alleviates angiotensin II-induced cardiomyocyte apoptosis and autophagy and modulates the AMPK/mTOR pathway.

As a main extraction compound from Scutellaria baicalensis Georgi, Baicalin exhibits various biological activities. However, the underlying mechanism of Baicalin on hypertension-induced heart injury remains unclear. Invivo, mice were infused with angiotensin II (Ang II; 500 ng/kg/min) or saline using osmotic pumps, followed by intragastrically administrated with Baicalin (5 mg/kg/day) for 4 weeks. Invitro, H9C2 cells were stimulated with Ang II (1 μM) and treated with Baicalin (12.5, 25 and 50 μM). Baicalin treatment significantly attenuated the decrease in left ventricular ejection fraction and left ventricular fractional shortening, increase in left ventricular mass, left ventricular systolic volume and left ventricular diastolic volume of Ang II infused mice. Moreover, Baicalin treatment reversed 314 differentially expressed transcripts in the cardiac tissues of Ang II infused mice, and enriched multiple enriched signalling pathways (including apoptosis, autophagy, AMPK/mTOR signalling pathway). Consistently, Baicalin treatment significantly alleviated Ang II-induced cell apoptosis invivo and invitro. Baicalin treatment reversed the up-regulation of Bax, cleaved-caspase 3, cleaved-caspase 9, and the down-regulation of Bcl-2. Meanwhile, Baicalin treatment alleviated Ang II-induced increase of autophagosomes, restored autophagic flux, and down-regulated LC3II, Beclin 1, as well as up-regulated SQSTM1/p62 expression. Furthermore, autophagy inhibitor 3-methyladenine treatment alleviated the increase of autophagosomes and the up-regulation of Beclin 1, LC3II, Bax, cleaved-caspase 3, cleaved-caspase 9, down-regulation of SQSTM1/p62 and Bcl-2 expression after Ang II treated, which similar to co-treatment with Baicalin. Baicalin treatment reduced the ratio of p-AMPK/AMPK, while increased the ratio of p-mTOR/mTOR. Baicalin alleviated Ang II-induced cardiomyocyte apoptosis and autophagy, which might be related to the inhibition of the AMPK/mTOR pathway.

Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study

BackgroundVariants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking.MethodsWe retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography). Genetic testing was performed for 59 established cardiomyopathy genes. Only variants of uncertain significance and (likely) pathogenic variants were included. Diagnostic yield of genetic testing was compared with a matched cohort of patients with dilated cardiomyopathy (DCM, n = 46) and a matched cohort of patients without cardiac disease (n = 111).ResultsAverage LVEF at time of CTRCD diagnosis was 30.1 ± 11.0%. Patients were 52.9 ± 14.6 years old at time of diagnosis and 30 (65.2%) were female. Most patients were treated for breast cancer or lymphoma, with a median doxorubicin equivalent dose of 300 mg/m2 [112.5-540.0]. A genetic variant, either pathogenic, likely pathogenic or of uncertain significance, was identified in 29/46 (63.0%) of patients with CTRCD, which is similar to the DCM cohort (34/46, 73.9%, p = 0.262), but significantly higher than in the negative control cohort (47/111, 39.6%, p = 0.018). Variants in TTN were the most prevalent in the CTRCD cohort (43% of all variants). All (likely) pathogenic variants identified in the CTRCD cohort were truncating variants in TTN.There were no significant differences in severity of CTRCD and in recovery rate in variant-harbouring individuals versus non-variant harbouring individuals.ConclusionsIn this case-control study, cancer patients with anthracycline-induced CTRCD have an increased burden of genetic variants in cardiomyopathy genes, similar to a DCM cohort. If validated in larger prospective studies, integration of genetic data in risk prediction models for CTRCD may guide cancer treatment. Moreover, genetic results have important clinical impact, both for the patient in the setting of precision medicine, as for the family members that will receive genetic counselling.

Post-COVID-19 myocardium and coronary involvement in a young patient: differential diagnosis and comprehensive treatment

The state of the heart after a coronavirus disease 2019 (COVID-19, coronavirus disease 2019) is very diverse and in some cases requires a complex differential diagnosis. We described a 35-year-old smoking male patient who, by the end of the first month after COVID-19, developed left ventricular dysfunction with decrease in ejection fraction to 25-30% and persistent left bundle branch block (LBBB). Echocardiography also detected local contractility disorders. A significant increase in blood anticardiac antibody titers was noted. Myocardial biopsy revealed active lymphocytic myocarditis, coronavirus ribonucleic acid, while coronary angiography revealed extensive stenosis of the anterior interventricular artery. On the first day after balloon angioplasty and stenting, the disappearance of LBBB block was noted with the appearance of deep negative T waves in the precordial leads, which did not allow ruling out a previous myocardial infarction. As a result of treatment of heart failure and steroid therapy, the structural and functional cardiac parameters and the electrocardiography were completely normalized by the end of the second year of treatment. Only a transient LBBB remained at high loads. Cardiac computed tomography after 2 years showed no delayed contrast agent accumulation in the myocardium, and coronary stenosis up to 30%.The mechanisms of complex myocardial and coronary damage (including the role of coronaritis in the atherosclerosis progression) after COVID-19 are discussed.

Abstract LB277: Exposure response and safety analysis of osimertinib in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC patients with EGFRm (FLAURA2)

Abstract Osimertinib (Osi) is a potent, CNS-active irreversible inhibitor of epidermal growth factor receptor-mutate (EGFRm) and T790M mutations. It is currently approved as the standard of care in patients with locally advanced (Stage IIIB or IIIC) or metastatic (Stage IV) EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR-TKI therapy and as the first-line agent in patients with locally advanced or metastatic EGFRm NSCLC. FLAURA2 is a global, randomized, open-label, multi-center phase III clinical study to investigate the safety and efficacy of Osi 80 mg once daily in combination with platinum-pemetrexed chemotherapy compared to Osi monotherapy, as a first-line treatment in patients with locally advanced or metastatic EGFRm NSCLC. This study is ongoing and an sNDA has been submitted for approval. The objectives of this current analyses were to 1) assess the exposure-efficacy relationship between population PK model-derived Osi exposure metrics (AUCss, Cmaxss, Cminss), and PFS in patients from the investigational arm (Osi + chemotherapy arm, n=244) of FLAURA2 study and 2) assess the relationship between Osi exposure metrics and key safety endpoints. The exposure response (ER) relationship between Osi and progression free survival (PFS) in patients enrolled in the investigational arm of FLAURA2 was assessed. Kaplan Meier plots with patients stratified by quartile exposure of Osi in the investigational arm indicated no clear ER relationship, though there appears to be a trend of lower PFS with highest AUCss quartile. A stepwise Cox proportional hazard analysis indicated that the effect of Osi exposure metrics were not statistically significant associated with PFS; however, the number of pemetrexed cycles appeared to be a significant covariate on PFS. The relationship between Osi exposure metrics and AEs CTCAE Grade 3 and above causally related to Osi, as well as AESIs from the investigational arm of FLAURA2 study were explored. The graphical exploration and logistic regression analysis did not identify statistically significant relationship of Osi exposures on CTCAE ≥ Grade 3 adverse events (AEs) causally related to Osi, AEs leading to Osi dose interruptions/reductions/discontinuations, and AESIs including ≥ Grade 3 haematological AEs, cardiac effects, left ventricular ejection fraction decrease and ≥ Grade 1 interstitial lung disease causally related to Osi. In conclusions, no statistically significant relationships between exposure of Osi and response were observed, supporting the recommended dose of Osi of 80 mg daily in the FLAURA2 patient population. Overall, the recommended dose of Osi as monotherapy or in combination with chemotherapy is 80 mg once daily, with a dose reduction to 40 mg daily if unacceptable toxicity is observed. Citation Format: Jincheng Yang, Damilola Olabode, Aarti Sawant, Karthick Vishwanathan, Srinivas Bachina, Alexandar Todd, Dana Ghiorghiu, Yuri Rukazenkov, Alex Phipps, Diansong Zhou, Azar Shahraz. Exposure response and safety analysis of osimertinib in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC patients with EGFRm (FLAURA2) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB277.

May high blood viscosity predict cardiac involvement in COVID-19 patients?

Aims: Assessing the effects of whole blood viscosity (WBV) on prognosis and deterioration in cardiac parameters in COVID-19 patients after recovery using cardiac magnetic resonance imaging (CMRI) and echocardiography is the purpose of this study. Methods: The study involved 70 patients. Patients who had COVID-19 pneumonia were admitted to the hospital. All patients met the eligibility criteria if they remained symptom-free of respiratory and cardiac symptoms and had negative swab test results at the end of the isolation period, for at least two weeks following the positive swab test result. Transthoracic echocardiography was performed within 24 hours prior to CMRI. WBV was measured in centipoises (cP) at 208 seconds-1 shear rate. The median value of WBV was calculated for the entire study population, which was subsequently utilized to divide the population into two subgroups. These were designated as high WBV and low WBV subgroups. Results: Elevated levels of hemoglobin, hematocrit, total protein, C-reactive protein, D-dimer, and fibrinogen were observed in individuals with high WBV. Conversely, TAPSE, S, and FAC were notably reduced in those with high WBV. Notably, CMRI revealed significant increases in native T1, native T2 mapping signal, and extracellular volume among patients with high WBV. Furthermore, in individuals with high WBV, there was a significant decrease in right ventricle stroke volume and right ventricle ejection fraction, accompanied by a notable increase in right ventricle end-systolic volume. Conclusion: WBV values measured during hospital admission may have early and late prognostic importance for COVID-19 infection.

Abstract 7187: Entresto protects against doxorubicin-induced cardiotoxicity in mice model of breast cancer

Abstract Doxorubicin (Dox) is a potent chemotherapeutic agent with high efficacy; however, dose-dependent cardiotoxicity undermines its effectiveness in cancer therapies. Entresto, a combination of sacubitril and valsartan (Sac/Val), offers a multi-modal approach. It enhances the beneficial response of the neurohormonal system of the heart while curbing the detrimental effects of the renin-angiotensin-aldosterone system and mitigating further cardiac damage by decreasing sensitivity to natriuretic peptides. The objective of this study is to assess the potential cardioprotective effects of Entresto on doxorubicin-induced cardiotoxicity (DIC) in a mouse model of breast cancer. To achieve this, a syngeneic tumor model of breast cancer was employed. Twenty-five 10-week-old female Balb/c mice were randomly divided into 5 groups: control, Tumor, Tumor + entresto, Tumor + Dox, and Tumor + entresto + Dox. Tumor groups were injected with 4T1 wild-type cells into the mammary fat pad via intraperitoneal injection. Subsequently, after a week, Dox groups were treated with Dox at 8 mg/kg body weight/week for 3 weeks, while control and tumor + entresto received saline. Following Dox treatment, control, and tumor + Dox animals were gavaged daily with saline, while Entresto groups were gavaged with entresto (60 mg/kg) for 3 weeks. Echocardiography assessed cardiac function at baseline and 3 weeks post-DOX treatment. All mice were euthanized at 4 weeks. Our results demonstrated that entresto treatment significantly ameliorated Dox-induced decreases in ejection fraction and fractional shortening while maintaining improved cardiac functions. Entresto also reversed Dox-induced altered levels of cardiac biomarkers (ANP and BNP). Gene and protein expression analyses in heart tissues revealed that entresto modulated the levels of autophagy-related (Beclin-1 and p62), apoptosis-associated (caspase 3 and Bcl-2) and antioxidant-related (Nrf2 and Keap1): genes and proteins expression altered by Dox treatment. Additionally, Entresto attenuated histological evidence of cellular toxicity, apoptosis, and fibrosis in Dox-treated animals with breast cancer. These findings suggest that Entresto confers cardiac protection against DIC in a mouse model of breast cancer without interfering with the antineoplastic effects of Dox. It underscores the potential clinical relevance of Entresto to enhance the safety and efficacy of doxorubicin-based cancer therapies. Citation Format: Abhishek Pandit, Alanna Costas, Biplov Sapkota, Shilpa Thota, Rizwana Begum, Naveen Chintalaramulu, Henry W. Green, Joseph Francis. Entresto protects against doxorubicin-induced cardiotoxicity in mice model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7187.

The Hemodynamic Profile and Intraoperative Bleeding Impact on Liver Transplant Patients.

Liver transplantation is the treatment of choice for end-stage liver disease and despite accumulated experience over the years, improved surgical techniques, better immunosuppression and adequate intensive care management, it still represents the greatest challenge for anesthesiologists. The aim of the study was the characterization of the hemodynamic profile of patients with liver cirrhosis undergoing liver transplantation with the help of the PiCCO system during the three surgical stages, the impact of bleeding on hemodynamic status and correlation between the amount of bleeding, lactate levels, severity scores and survival rate and complications. Another focus of this study was the amount of transfused blood products and their impact on postoperative complications. Our study included 70 patients who underwent liver transplantation in our center and were hemodynamically monitored with the PiCCO system. Data were processed using the Python 3.9 programming language. Results: The mean MELD severity score was 18 points. During surgery, significant variations in the hemodynamic parameters occurred. All patients had a decrease in cardiac output in the anhepatic phase, with 50% presenting a decrease of more than 40%. In total, 78% of patients showed a decrease in the global ejection fraction, with a median value of 30%.Overall, 75% of patients had a total blood loss of less than 6000 mL and 31 patients developed immediate postoperative complications with a 50% probability with blood loss exceeding 6500 mL. Seven patients (10%) did not survive after 30 days. An amount of 5 mmol/L of serum neohepatic lactate determines a 50% probability of complications. Conclusions: Surgical technique causes an important decrease in cardiac output. Intraoperative bleeding has a major impact on outcome and the first month represents a critical period after liver transplantation. Statistical tests describe the probability of 30/90-day survival and the occurrence of complications according to variables such as intraoperative bleeding and MELD severity score. Intraoperative transfusion correlates with the occurrence of postoperative complications.

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and -10.62 mL/m2, p = 0.008) with a recessive model. We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.

Vagus nerve stimulation alleviates cardiac dysfunction and inflammatory markers during heart failure in rats

Vagus nerve stimulation (VNS) is under clinical investigation as a therapy for heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate its therapeutic effects on three main components of heart failure: cardiac function, cardiac remodeling and central neuroinflammation using a pressure overload (PO) rat model. Male Sprague-Dawley rats were divided into four groups: PO, PO + VNS, PO + VNS sham, and controls. All rats, except controls, underwent a PO surgery to constrict the thoracic aorta (~50 %) to induce HFrEF. Open loop VNS therapy was continuously administered to PO + VNS rats at 20 Hz, 1.0 mA for 60 days. Evaluation of cardiac function and structure via echocardiograms showed decreases in stroke volume and relative ejection fraction and increases in the internal diameter of the left ventricle during systole and diastole in PO rats (p < 0.05). However, these PO-induced adverse changes were alleviated with VNS therapy. Additionally, PO rats exhibited significant increases in myocyte cross sectional areas indicating hypertrophy, along with significant increases in myocardial fibrosis and apoptosis, all of which were reversed by VNS therapy (p < 0.05). Furthermore, VNS mitigated microglial activation in two central autonomic nuclei: the paraventricular nucleus of the hypothalamus and locus coeruleus. These findings demonstrate that when VNS therapy is initiated at an early stage of HFrEF progression (<10 % reduction in relative ejection fraction), the supplementation of vagal activity is effective in restoring multi organ homeostasis in a PO model.

Cardiovascular Characteristics in Patients with Prader-Willi Syndrome

Abstract The most prevalent type of syndromic obesity is referred to as Prader-Willi Syndrome (PWS), being determined by the lack of expression of paternal genes on chromosome 15q11.2-q13 due to genomic or epigenetic variations, such as DNA and histone methylation or acetylation. The syndrome is frequently associated with behavioral disorders, intellectual deficiencies, short stature, polyphagia, hypogonadism and muscular hypotonia, all stemming from the multiple endocrine dysfunctions characterizing this condition. Cardiovascular (CV) anomalies can manifest even in the early stages of life, and those with PWS have an elevated risk of early onset cardiovascular diseases. The somatic and behavioral aspects of the syndrome interact intricately to cause this increased risk for CV pathologies. Changes in the GH-IGF axis are seen in most Prader-Willi Syndrome (PWS) patients, irrespective of obesity. Specific cardiovascular features of GHD in adult PWS patients include reduced cardiac mass, decreased ejection fraction, and diminished chronotropic response to dobutamine.

Biomarkers and subclinical left ventricular dysfunction in patients with type 2 diabetes without clinical manifestations of cardiovascular diseases

Aim. To study the relationship between the structural and functional left ventricular (LV) parameters and N-terminal pro-brain natriuretic peptide (NT-proBNP) and inflammatory markers in patients with type 2 diabetes (T2D) without clinical manifestations of cardiovascular diseases, as well as to evaluate the possibility of their use for early diagnosis of subclinical LV dysfunction.Material and methods. Data from 120 patients of both sexes aged 45-75 years (57,11±7,9 years) were analyzed. They were divided into three following groups: 1st — with T2D (n=47), 2nd — with prediabetes (n=20), 3rd — control (n=53). All participants underwent transthoracic echocardiography with assessment of the linear and volumetric heart dimensions, systolic and diastolic LV function. Speckle tracking echocardiography was analyzed with calculation of LV global longitudinal strain (GLS). The blood levels of NT-proBNP and inflammatory markers were determined (high-sensitivity C-reactive protein (hsCRP), fibrinogen, interleukin-6).Results. According to echocardiography, patients with carbohydrate metabolism disorders revealed significantly higher LV mass values, LV posterior wall thickness, and relative wall thickness in comparison with the control group. Transmitral flow parameters, as well as tissue Doppler sonography, in the T2D and prediabetes groups were significantly different from those in the control group. GLS in the groups of patients with carbohydrate metabolism disorders was lower than in the control group (p=0,001). The level of NT-proBNP was significantly higher in the T2D and prediabetes groups compared to the control group, while in all three groups it did not exceed normal values (p&lt;0,001). A higher level of NT-proBNP was associated with hypertension — odds ratio (OR) 3,64 [1,02-13,04] (p=0,005), a decrease in LV ejection fraction — OR 1,25 [1,06-1 ,47] (p=0,007), concentric hypertrophy — OR 4,84 [1,43-16,41] (p=0,011) and decreased GLS — OR 1,85 [1,62-2,06] (p=0,005), an increase in the ratio of early and late diastolic transmitral flow (E/A) — OR 0,01 [0,008-0,416] (p=0,024) and isovolumic relaxation time (IVRT) — OR 1,08 [1,03-1,14] (p=0,03). The sensitivity and specificity of NT-proBNP as a test for predicting GLS reduction &lt;-18% were 86 and 27%, respectively. The hsCRP level, within the reference values, was significantly higher in the T2D and prediabetes groups compared to the control group (p&lt;0,001) and demonstrated a direct linear relationship with E/A, IVRT, early diastolic deceleration time (p&lt;0,05). A higher level of hsCRP was significantly associated with diastolic dysfunction — OR 1,16 [1,02-1,32] (p=0,023), as well as with a GLS decrease &lt;-18% — OR 1,58 [1,12-4,65] (p=0,03).Conclusion. In patients with T2D without clinical manifestations of cardiovascular disease, the presence of concentric LV myocardial hypertrophy, LV diastolic dysfunction and decreased GLS (&lt;-18%) is associated with higher blood levels of NT-proBNP and hsCRP. However, in all cases, the levels of biomarkers do not exceed the reference values, which does not allow their use in the early diagnosis of subclinical LV dysfunction in T2D.

Cardiac magnetic resonance imaging in heart transplant recipients with biopsy-negative graft dysfunction.

Graft dysfunction (GD) after heart transplantation (HTx) can develop without evidence of cell- or antibody-mediated rejection. Cardiac magnetic resonance imaging (CMR) has an evolving role in detecting rejection; however, its role in biopsy-negative GD has not been described. This study examines CMR findings, evaluates outcomes based on CMR results, and seeks to identify the possibility of rejection missed through endomyocardial biopsy by using CMR in HTx recipients with biopsy-negative GD. HTx recipients with GD [defined as a decrease in left ventricular ejection fraction (LVEF) by >5% and LVEF<50%] in the absence of rejection by biopsy or allograft vasculopathy and who underwent CMR were included in the study. The primary outcome was a composite of all-cause mortality, re-transplantation, or persistent LVEF<50%. Overall, 34 HTx recipients developed biopsy-negative GD and underwent CMR. Left ventricular late gadolinium enhancement (LGE) on CMR was observed in 16 patients with two distinct patterns: diffuse epicardial (n=13) and patchy (n=3) patterns. Patients with LGE developed GD later after HTx [4 (1.4-6.8) vs. 0.8 (0.3-1.2) years, P<0.001], were more often symptomatic (88% vs. 56%, P=0.06), and had greater haemodynamic derangement (pulmonary capillary wedge pressure: 19±7 vs. 13±3mmHg, P=0.002) as compared with those without LGE. No significant difference was observed in the primary composite outcome between patients with LGE and those without LGE (50% vs. 38% of patients with events, P=0.515). During a median follow-up of 3.8years, mean LVEF improved similarly in the LGE-negative (37-55%) and LGE-positive groups (32-55%) (P=0.16). Biopsy-negative GD occurs with and without LGE when assessed by CMR, indicative of possible rejection/inflammation occurring only in a subset of patients. Irrespective of LGE, LVEF improvement occurs in most GD patients, suggesting that other neurohormonal or immunomodulatory mechanisms may also contribute to GD development.

TIGAR Deficiency Blunts Angiotensin-II-Induced Cardiac Hypertrophy in Mice.

Hypertension is the key contributor to pathological cardiac hypertrophy. Growing evidence indicates that glucose metabolism plays an essential role in cardiac hypertrophy. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism in pressure overload-induced cardiac remodeling. In the present study, we investigated the role of TIGAR in cardiac remodeling during Angiotensin II (Ang-II)-induced hypertension. Wild-type (WT) and TIGAR knockout (KO) mice were infused with Angiotensin-II (Ang-II, 1 µg/kg/min) via mini-pump for four weeks. The blood pressure was similar between the WT and TIGAR KO mice. The Ang-II infusion resulted in a similar reduction of systolic function in both groups, as evidenced by the comparable decrease in LV ejection fraction and fractional shortening. The Ang-II infusion also increased the isovolumic relaxation time and myocardial performance index to the same extent in WT and TIGAR KO mice, suggesting the development of similar diastolic dysfunction. However, the knockout of TIGAR significantly attenuated hypertension-induced cardiac hypertrophy. This was associated with higher levels of fructose 2,6-bisphosphate, PFK-1, and Glut-4 in the TIGAR KO mice. Our present study suggests that TIGAR is involved in the control of glucose metabolism and glucose transporters by Ang-II and that knockout of TIGAR attenuates the development of maladaptive cardiac hypertrophy.

MSC exosomes attenuate sterile inflammation and necroptosis associated with TAK1-pJNK-NFKB mediated cardiomyopathy in diabetic ApoE KO mice.

Diabetes is a debilitating disease that leads to complications like cardiac dysfunction and heart failure. In this study, we investigated the pathophysiology of diabetes-induced cardiac dysfunction in mice with dyslipidemia. We hypothesize diabetes in ApoE knockout (ApoE-/-) mice induces cardiac dysfunction by increasing inflammation and necroptosis. ApoE-/- mice were divided into experimental groups: Control, Streptozotocin (STZ), STZ + MSC-Exo (mesenchymal stem cell-derived exosomes), and STZ+MEF-Exo (Mouse embryonic fibroblast derived exosomes). At Day 42, we assessed cardiac function, collected blood and heart tissues. Heart tissue samples were analyzed for inflammation, necroptosis, signaling mechanism, hypertrophy and adverse structural remodeling using histology, immunohistochemistry, western blotting, RT-PCR, cytokine array and TF array. STZ treated ApoE-/- mice developed diabetes, with significantly (p<0.05) increased blood glucose and body weight loss. These mice developed cardiac dysfunction with significantly (p<0.05) increased left ventricular internal diameter end diastole and end systole, and decreased ejection fraction, and fractional shortening. We found significant (p<0.05) increased expression of inflammatory cytokines TNF- a, IL-6, IL-1a, IL-33 and decreased IL-10 expression. Diabetic mice also exhibited significantly (p<0.05) increased necroptosis marker expression and infiltration of inflammatory monocytes and macrophages. MSC-Exos treated mice showed recovery of diabetes associated pathologies with significantly reduced blood glucose, recovered body weight, increased IL-10 secretion and M2 polarized macrophages in the heart. These mice showed reduced TAK1-pJNK-NFKB inflammation associated expression and improved cardiac function with significantly reduced cardiac hypertrophy and fibrosis compared to diabetic mice. Treatment with MEF-Exos did not play a significant role in attenuating diabetes-induced cardiomyopathy as these treatment mice presented with cardiac dysfunction and underlying pathologies observed in STZ mice. Thus, we conclude that cardiac dysfunction develops in diabetic ApoE-/- mice, arising from inflammation, necroptosis, and adverse tissue remodeling, which is ameliorated by MSC-Exos, a potential therapeutic for diabetes-induced cardiomyopathy.

CT Images in Follicular Lymphoma: Changes after Treatment Are Predictive of Cardiac Toxicity in Patients Treated with Anthracycline-Based or R-B Regimens

The aim of this study is to evaluate changes in epicardial adipose tissue (EAT) and cardiac extracellular volume (ECV) in patients with follicular lymphoma (FL) treated with R-CHOP-like regimens or R-bendamustine. We included 80 patients with FL between the ages of 60 and 80 and, using computed tomography (CT) performed at onset and at the end of treatment, we assessed changes in EAT by measuring tissue density at the level of the cardiac apex, anterior interventricular sulcus and posterior interventricular sulcus of the heart. EAT is known to be associated with metabolic syndrome, increased calcium in the coronary arteries and therefore increased risk of coronary artery disease. We also evaluated changes in ECV, which can be used as an early imaging marker of cardiac fibrosis and thus myocardial damage. The R-CHOP-like regimen was associated with lower EAT values (p &lt; 0.001), indicative of a less active metabolism and more adipose tissue, and an increase in ECV (p &lt; 0.001). Furthermore, in patients treated with anthracyclines and steroids (R-CHOP-like) there is a greater decrease in ejection fraction (EF p &lt; 0.001) than in the R-B group. EAT and ECV may represent early biomarkers of cardiological damage, and this may be considered, to our knowledge, the first study investigating radiological and cardiological parameters in patients with FL.

Distinguishing sterile inflammation from graft infection

We describe the case of a 68-year-old man who underwent ascending aortic replacement and thoracic endovascular aortic repair. Four years later, the patient developed neck pain on the right side and chest computed tomography showed expansion of fluid in the mediastinum which had extended to the neck. Echocardiography revealed advanced severity of aortic regurgitation and decreased ejection fraction. Given the progression of aortic regurgitation, decreased cardiac function, and rapidly expanding fluid accumulation causing neck pain, reoperation was indicated. All microbiological test including polymerase chain reaction were negative indicating absence of any infection. The patient is being followed-up without antibiotics and CT has not shown peri-graft fluid 2 years postoperatively. Since infection cannot be excluded completely, it is important to assess the condition with selective medium, extended culture periods, genetic testing, and consultations with microbiology laboratories when normal culture tests for general bacteria, and fungi are negative which can help avoid drug-resistant bacteria count, elevated medical costs, and drug side effects due to the improper use of antibiotics through proper diagnosis.

Lesions of the heart and parenchymatous organs in patients with COVID-19 and other acute respiratory infections

Based on available literature, this study aimed to critically assess the effect of SARS-CoV-2 and other respiratory viruses on the heart and parenchymatous internal organs, identify their common and distinctive features, assess the frequency of cytokine storm and “post-infection” syndrome, and identify risk factors for severe systemic reaction and damage to internal organs, particularly the heart.&#x0D; In the databases of MEDLINE/PubMed, eLibrary, Web of Science, CyberLeninka, and Openmedcom.ru, primary information (full-text and abstract databases) in English and Russian was searched using selected keywords from 2003 to 2023.&#x0D; Acute respiratory viral infection pathogens can cause not only respiratory but also cardinal, gastroenterological, neurological, and other complications.&#x0D; Acute respiratory viral infections have many similarities in their effects on parenchymal organs. The emergence of new viruses requires in-depth study, and it is important to consider both the distinctive features of the clinical picture of viral infections and the general patterns of influence on internal organs. In the medium term, patients who have COVID-19 may have complex heart damage in the form of a decrease in ventricular ejection fraction, appearance of pericardial effusion, and development of various types of focal myocardial lesions. The combined nature of damage to the heart and parenchymal organs is influenced by background diseases, nature of the course of viral infection, and features of therapy. The features of lesions of parenchymal organs and the heart after acute respiratory viral infection require further study, including their effect on the development of late complications.