Cardiac Effects Research Articles

Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling.

Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.

Early myocardial injury in children on doxorubicin for cancer chemotherapy: a cross-sectional study in a tertiary referral centre in Kenya

IntroductionUse of doxorubicin, an anthracycline chemotherapeutic agent has been associated with late-occurring cardiac toxicities. Detection of early-occurring cardiac effects of cancer chemotherapy is essential to prevent occurrence of adverse events including toxicity, myocardial dysfunction, and death.ObjectiveTo investigate the prevalence of elevated cardiac troponin T (cTnT) and associated factors of myocardial injury in children on doxorubicin cancer chemotherapy.MethodsDesign: A cross-sectional study.Setting and subjects: A hospital-based study conducted on children aged 1-month to 12.4-years who had a diagnosis of cancer and were admitted at Kenyatta National Hospital (KNH).Interventions and outcomes: The patients underwent Echocardiography (ECHO) before their scheduled chemotherapy infusion. Twenty-four (24) hours after the chemotherapy infusion the patients had an evaluation of the serum cardiac troponin T (cTnT) and a repeat ECHO. Myocardial injury was defined as cTnT level > 0.014 ng/ml or a Fractional Shortening (FS) of < 29% on ECHO.ResultsOne hundred (100) children were included in the final analysis. Thirty-two percent (32%) of the study population had an elevated cTnT. A cumulative doxorubicin dose of > 175 mg/m2 was significantly associated with and elevated cTnT (OR, 10.76; 95% CI, 1.18–97.92; p = 0.035). Diagnosis of nephroblastoma was also associated with an elevated cTnT (OR, 3.0; 95% CI, 1.23–7.26) but not statistically significant (p = 0.105). Nine percent (9%) of the participants had echocardiographic evidence of myocardial injury.ConclusionWhen compared to echocardiography, elevated levels of cTnT showed a higher association with early-occurring chemotherapy-induced myocardial injury among children on cancer treatment at a tertiary teaching and referral hospital in Kenya.

Canonical and noncanonical contribution of thyroid hormone receptor isoforms alpha and beta to cardiac hypertrophy and heart rate in male mice.

Stimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). Aim of this study was to determine in vivo which TH receptor (TR), α or β, and which mode of TR action, canonical gene expression or DNA binding independent noncanonical action, mediate these effects. We compared global TRα and TRβ knockout mice (TRαKO; TRβKO) with wild-type (WT) mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRαGS; TRβGS). Hearts were studied with echocardiography at baseline and after seven weeks T3 treatment. Gene expression was measured with real-time PCR. Heart rate was recorded with radiotelemetry transmitters for seven weeks in untreated, hypothyroid and T3-treated mice. T3 induced ventricular hypertrophy in WT and TRβKO mice, but not in TRαKO mice. Hypertrophy was also induced in TRαGS mice. Thus, hypertrophy is mostly mediated by noncanonical TRα action. Similarly, repression of Mhy7 occurred in WT and TRαGS mice. Basal heart rate was largely dependent on canonical TRα action. But responsiveness to hypothyroidism and T3 treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRαKO mice, demonstrating that TRβ could compensate for absence of TRα. T3-induced cardiac hypertrophy could be attributed to noncanonical TRα action, whereas heart rate regulation was mediated by canonical TRα action. TRβ could substitute for canonical, but not noncanonical TRα action.

Cardiovascular health in pediatric patients with X-linked hypophosphatemia under two years of burosumab therapy

IntroductionX-linked hypophosphatemia (XLH) is caused by an inactivating mutation in the phosphate-regulating endopeptidase X-linked (PHEX) gene whose defective product fails to control phosphatonin fibroblast growth factor 23 (FGF23) serum levels. Although elevated FGF23 levels have been linked with detrimental cardiac effects, the cardiologic outcomes in XLH patients have been subject to debate. Our study aimed to evaluate the prevalence and severity of cardiovascular morbidity in pediatric XLH patients before, during, and after a 2-year treatment period with burosumab, a recombinant anti-FGF23 antibodyMethodsThis prospective observational study was conducted in a tertiary medical center, and included 13 individuals with XLH (age range 0.6–16.2 years) who received burosumab every 2 weeks. Clinical assessment at treatment initiation and after .5, 1, and 2 years of uninterrupted treatment included anthropometric measurements and cardiologic evaluations (blood pressure [BP], electrocardiogram, conventional echocardiography, and myocardial strain imaging).ResultsThe linear growth of all patients improved significantly (mean height z-score: from -1.70 ± 0.80 to -0.96 ± 1.08, P=0.03). Other favorable effects were decline in overweight/obesity rates (from 46.2% to 23.1%) and decreased rates of elevated BP (systolic BP from 38.5% to 15.4%; diastolic BP from 38.5% to 23.1%). Electrocardiograms revealed no significant abnormality throughout the study period. Cardiac dimensions and myocardial strain parameters were within the normative range for age at baseline and remained unchanged during the study period.ConclusionCardiologic evaluations provided reassurance that 2 years of burosumab therapy did not cause cardiac morbidity. The beneficial effect of this treatment was a reduction in cardiovascular risk factors, as evidenced by the lower prevalence of both overweight/obesity and elevated BP.

Anthracycline-induced cardiotoxicity – primary preventive options. An overview

Anthracycline-induced cardiotoxicity (AIC) has been known since the 1970s but remains relevant, mainly due to the widespread use of anthracyclines in oncological practice. Currently, AIC is viewed as a prolonged and continuous process that starts with the initial dose at molecular and cellular levels and advances, ultimately resulting in cardiomyopathy and heart failure. Many contemporary studies aim to discover methods for early detection of anthracycline-related myocardial injury. Additionally, ongoing research focuses on agents for primary prevention of AIC, examining their effectiveness, place, and timing of administration. This review aims to present the available preventive options, interconnecting them with their mechanisms of action and the mechanisms of AIC. According to current recommendations, primary prevention is indicated for high- and very high-risk patients and includes general measures to lower cardiovascular risk, neurohormonal therapy, and statins. Regular cardiology assessments are a crucial component of heart damage prevention. Evidence of mild myocardial injury (deteriorated Global Longitudinal Strain and troponin release) justi&amp;#64257; es cardioprotective measures. Some aspects remain unanswered, including whether early cardioprotection is required, as well as the role and ef&amp;#64257; cacy of sacubitril/valsartan and sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) for AIC prevention. Physical activity is a promising method to reduce the cardiac damaging effects of anthracyclines.&amp;nbsp;

Assessment of cardiac adverse events following COVID-19 vaccination by speckle tracking echocardiography

Cardiac discomfort has been reported periodically in COVID-19-vaccinated individuals. Thus, this study aimed to evaluate the role of myocardial strains in the early assessment of the clinical presentations after COVID-19 vaccination. Totally, 121 subjects who received at least one dose of vaccine within 6 weeks underwent laboratory tests, electrocardiogram (ECG), and echocardiogram. Two-dimensional speckle tracking echocardiography (2D-STE) was implemented to analyze changes in the left ventricular myocardium. After vaccination, 66 individuals (55.4 ± 17.4 years) developed cardiac discomforts, such as chest tightness, palpitations, dyspnea, and chest pain. The ECG readings exhibited both premature ventricular contractions and premature atrial contractions (n = 24, 36.4%), while none of the individuals in the control group manifested signs of cardiac arrhythmia. All had normal serum levels of creatine phosphokinase, creatine kinase myocardial band, troponin, N-terminal pro b-type natriuretic peptide, platelets, and D-dimer. Left ventricular ejection fraction in the symptomatic group (71.41% ± 7.12%) and the control group (72.18% ± 5.11%) (p = 0.492) were normal. Use of 2D-STE presented global longitudinal strain (GLS) and global circumferential strain (GCS) was reduced in the symptomatic group (17.86% ± 3.22% and 18.37% ± 5.22%) compared to the control group (19.54% ± 2.18% and 20.73% ± 4.09%) (p = 0.001 and p = 0.028). COVID-19 vaccine-related cardiac adverse effects can be assessed early by 2D-STE. The prognostic implications of GLS and GCS enable the evaluation of subtle changes in myocardial function after vaccination.

Anticoagulation therapy in non-valvular atrial fibrillation after intracerebral hemorrhage: A propensity score–matched study

BackgroundThe effect of antithrombotic therapy on patients with atrial fibrillation who sustained previous intracerebral hemorrhage (ICH) remains uncertain. Data regarding antithrombotic therapy use in these patients are limited. This study aims to compare the clinical and overall outcomes of antithrombotic therapy and usual care in patients with atrial fibrillation who sustained ICH. MethodsWe assembled consecutive patients with atrial fibrillation sustaining an ICH from our institution. Multivariable regression analysis and propensity-matched analysis were applied to assess associations of different antithrombotic therapies and outcomes. The primary outcome was mortality within the longest follow-up. Kaplan-Meier curves and log-rank tests of the time-to-event data were used to assess differences in survival. ResultsIn total, 296 consecutive patients with atrial fibrillation who survived an ICH were included in this study. Our analysis demonstrated that antithrombotic therapy was associated with reduced mortality up to a 4-year duration of follow-up (OR, 0.49, 95 % CI 0.30–0.81). Similar results were obtained from the propensity-matched analysis (OR, 0.58, 95 % CI 0.34–0.98). Subgroup analysis showed that compared with usual care, direct oral anticoagulant (DOAC) with or without antiplatelet was associated with a lower risk of long-term mortality (OR, 0.34, 95 % CI 0.17–0.69). In addition, our analysis observed a significant interaction between cardiac insufficiency and treatment effect (P = 0.04). ConclusionsIn patients with atrial fibrillation who have a history of ICH, administration of antithrombotic therapy, especially DOAC, was associated with lower mortality. Future randomized trials are warranted to test the positive net clinical benefit of DOAC therapy.

Understanding Cardiomyopathy Induced by Doxorubicin Therapy: Mechanisms, Diagnosis, and Management Strategies

Doxorubicin-induced cardiomyopathy (DIC) is a significant complication of cancer treatment, characterized by irreversible cardiac damage and adverse effects on patient outcomes. Despite extensive research into its mechanisms and risk factors, effective prevention and management strategies still need to be discovered. This review summarizes the current understanding of DIC, including its epidemiology, mechanisms, clinical presentation, diagnosis, and prevention strategies. Emphasis is placed on the challenges in managing DIC, highlighting the need for novel therapeutic approaches targeting mitochondrial dysfunction, oxidative stress, and myocardial injury. Future research directions and advances in biomarker discovery are discussed, offering potential avenues for improving early detection and personalized management of DIC in cancer patients.

Abstract PO5-12-06: Minimization of treatment toxicity/side effects and their impact on quality of life (QoL) in patients (pts) with ER+/HER2- metastatic breast cancer (mBC)

Abstract Introduction: Treatment toxicity and side effects may be underreported (Basu Roy. J Thorac Oncol 2018:13:1815-17) and can negatively impact QoL. As such toxicities can influence pts’ treatment decisions, we surveyed pts with ER+/HER2- mBC to better understand the impact and patient reporting accuracy of treatment toxicities/side effects. Methods: The EQUALS 3 (ESR1 QUAlity of Life Survey 3), 55-question survey was designed by the EQUALS Steering Committee, trialed by pt advocates, emailed to US subjects (Cure Media Group and authors’ contacts), and posted to private BC Facebook and Twitter groups for 2 wks in June 2023. Eligible pts had ER+/HER2- mBC and treatment changes due to disease progression. Pts received a $10 gift card at survey completion. Survey answers were descriptively summarized. Results: 213 pts completed the survey. Most were &amp;lt; 60 yrs of age (77%), White (44%) or Hispanic/Latino (48%), peri-/postmenopausal (54%), and college-educated (71%); had income &amp;gt;$50,000 (66%); lived in urban (51%)/rural areas (22%); and had therapy lines of 1st (8%), 2nd (36%), or 3rd+ (51%). Current mBC treatments were endocrine therapy (ET) ± targeted therapies (70%), antibody drug conjugate (8%), chemotherapy (11%), and other (10%). Most pts had a female oncologist (65%) who worked in an academic hospital (61%); 68% had &amp;gt;1 oncologist. Surveyed pts reported toxicity concerns for side effects ranging from serious to nuisance. Side effects most frequently reported as extremely/moderately concerning were respiratory symptoms (51%), blood clots in lungs (49%) or heart/brain (47%), cognitive dysfunction (47%), infections (46%), nausea/vomiting (44%), cardiac adverse effects (44%), diarrhea (42%), gait instability (41%), fatigue (39%), joint pain (39%), hair loss (33%), or sexual dysfunction (27%). Although 49% of pts felt comfortable speaking to their medical team (MT) about side effects, 62% reported having minimized side effects to their MT due to fears/concerns of being seen as a complainer (70%), dose reduction (66%), being taken off drug (65%), not accessing other drugs with similar toxicities (61%), reduced efficacy with lower dose (59%), or coming off trial (47%). Almost half (47%) did not report treatment side effects, mostly due to fear of being seen as a complainer (63%), being taken off drug (57%), reduced efficacy with lower dose (51%), dose reduction (50%), not accessing other drugs (50%), or coming off trial (41%). QoL was poor/very poor in 20% of pts and QoL was the most common (68%) important/very important factor for making a treatment decision based on risks. Most common side effects that negatively impacted QoL were sexual dysfunction (45%), joint pain (38%), vaginal atrophy/dryness (36%), fatigue (33%), bone pain (31%), and hair loss (26%). Toxicities/side effects also impacted pts’ anxiety (49%), career (46%), marriage (42%), finances (32%), housework (30%), and relationships (19%). Regret after taking a cancer medication due to side effects was reported by 46% of pts. Conclusion: In this survey of pts with ER+/HER2- mBC on ET predominantly, many treatment side effects caused concern, not necessarily related to their seriousness, and most pts had minimized or hid side effects at some point due to fear of negative perceptions from their MT, reduced treatment efficacy, or clinical trial changes. Although QoL was overall good for most, 20% had poor QoL (largely impacted by sexual dysfunction, joint pain, and vaginal issues). Regret about toxicities was also common and should be explored. Provider awareness of pts’ toxicity experience, fears, and impacts on daily lives opens the door for educational tools to improve MT communications for treatment decisions, informed consent, and more accurate toxicity reporting in clinical trials. Citation Format: Sarah Sammons, Jane Meisel, Kelly Shanahan, Timothy Pluard, Fumiko Chino, Dario Trapani, Dominic Carroll, Monica Kozlowski, Elizabeth Attias, Nicole Kuderer. Minimization of treatment toxicity/side effects and their impact on quality of life (QoL) in patients (pts) with ER+/HER2- metastatic breast cancer (mBC) [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 PO5-12-06.

Electroacupuncture pre-treatment exerts a protective effect on LPS-induced cardiomyopathy in mice through the delivery of miR-381 via exosomes

ObjectiveThis study aims to investigate the cardiac protective effects and molecular mechanisms of electroacupuncture (EA) pre-treatment in lipopolysaccharide (LPS)-Induced Cardiomyopathy. Methods and resultsPre-treatment with EA was performed 30 min before intraperitoneal injection of LPS. Cardiac function changes in mice of the EA + LPS group were observed using electrocardiography, echocardiography, and enzyme linked immunosorbent assay (ELISA) and compared with the LPS group. The results demonstrated that EA pre-treatment significantly improved the survival rate of septic mice, alleviated the severity of endotoxemia, and exhibited notable cardiac protective effects. These effects were characterized by a reduction in ST-segment elevation on electrocardiography, an increase in ejection fraction (EF) and fraction shortening (FS) on echocardiography and a decrease in the expression of serum cardiac troponin I (cTn-I) levels. Serum exosomes obtained after EA pre-treatment were extracted and administered to septic mice, revealing significant cardiac protective effects of EA-derived exosomes. Furthermore, the antagonism of circulating exosomes in mice markedly suppressed the cardiac protective effects conferred by EA pre-treatment. Analysis of serum exosomes using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed a significant upregulation of miR-381 expression after EA pre-treatment. Inhibition or overexpression of miR-381 through serotype 9 adeno-associated virus (AAV9)-mediated gene delivery demonstrated that overexpression of miR-381 exerted a cardiac protective effect, while inhibition of miR-381 significantly attenuated the cardiac protective effects conferred by EA pre-treatment. ConclusionsOur research findings have revealed a novel endogenous cardiac protection mechanism, wherein circulating exosomes derived from EA pre-treatment mitigate LPS-induced cardiac dysfunction via miR-381.

Cardiac safety of ozanimod, a novel sphingosine-1-phosphate receptor ligand, in COVID-19 patients requiring oxygen

BackgroundOzanimod is a novel immune modulator that could be useful in viral pulmonary infections by reducing lung inflammation. It’s an S1P receptor ligand known to induce bradycardia and more serious adverse cardiac effects such as atrioventricular block (AVB) and QT prolongation. We present a sub-study of the COZI trial where ozanimod was administered in acute pulmonary infection patients, to assess cardiac safety. MethodsIn this pilot randomized open label trial, COVID-19 patients requiring oxygen support were randomized in 2 groups: standard of care + ozanimod (OZA) versus standard of care alone (SOC). All patients were monitored with a 14-day ECG monitor (CardioSTAT®) during their hospitalization. We evaluated the cardiac effects of ozanimod on heart rate (HR), PR length, and QT duration. ResultsA total of 42 patients were analyzed: 23 in SOC and 19 in OZA. Mean hourly HR over the first 10 days of treatment decrease in OZA compared with SOC (p<0.0001). The maximum decrease in HR occurred on day 3, The maximum decrease in heart rate occurred on day 3, without significant difference between groups: 49 bpm (42-59) in OZA and 54 bpm (48-60) in SOC, p=0.45. No high degree atrioventricular block was recorded. QT and PR median values were within normal in both groups without significant difference. ConclusionThe maximal reduction in HR occurred 3 days after the onset of ozanimod treatment in patients hospitalized for COVID-19 but it did not remain significant over the 10-day treatment. No relevant cardiac adverse event was observed.

Evaluation of the vascular and cardiac effects of treatment with copaiba oil and white pitch: a perspective for reducing oxidative stress and improving cardiac microstructure

Autism is a neuropsychiatric disorder that develops in childhood and may have associated comorbidities, such as heart disease. As a treatment, alternative therapy means are being sought to conventional methods. For study purposes, autism has been induced through gestational exposure to valproic acid. With the aim of evaluating the vascular and cardiac effects of treatment with copaiba essential oil and white pitch caused by gestational exposure to valproic acid, on the 13th day of pregnancy, the rats in the negative control group received water and those in the experimental groups received valproic acid (600 mg/kg), intraperitoneally, once. The male puppies were divided into six groups: negative and positive controls; vehicle; treated with copaiba oil; with white pitch oil and copaiba oil associated with white pitch. TERRA® oils were administered via gavage for 30 consecutive days. As a result, a reduction in superoxide dismutase, catalase and creatine kinase and an increase in total antioxidant activity and malondialdehyde were verified. Presence of myocarditis, vacuolation and necrosis of cardiomyocytes. There was no significant change in area and diameter, but there was an increase in the volume density and length of cardiomyocytes and a decrease in the volume density of blood vessels and interstices and the length density of blood vessels. Thus, exposure to valproic acid during the intrauterine period caused changes in the cardiac microstructure. However, the use of copaíba and white pitch essential oils led to oxidative and nitrosative stress, and the combination of the two oils has promising results in reversing this condition.

Examination of cardiac functions during acute attack and remission period in children with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterized by recurring serosal inflammation. Cardiac involvement in FMF commonly manifests as pericarditis and pericardial effusion; however, there is limited research on myocardial function. This study aimed to assess cardiac functions during active inflammation and remission periods of FMF patients and investigate the cardiac effects of inflammation during the attack period. Thirty-eight FMF patients without additional cardiac diseases were included in the study. Demographic characteristics, clinical symptoms, family history, and MEFV gene analysis results were obtained retrospectively. Blood tests, blood pressure measurements, electrocardiogram evaluations, conventional echocardiography, and speckle tracking echocardiography were performed during the attack and remission periods. Disease severity was assessed using the Pras scoring system. During the attack period, FMF patients exhibited significantly higher leukocyte count, neutrophil count, C-reactive protein, and erythrocyte sedimentation rate compared to the remission period (p < 0.005). Speckle tracking echocardiography revealed decreased function in the inferior segments of the left ventricle during the attack period (p < 0.005). Right ventricular function was more affected in the moderate disease group. FMF patients with lymphopenia during the attack demonstrated more impaired right ventricular function compared to those with normal lymphocyte count. Conclusions: FMF patients experience cardiac abnormalities during active inflammation, highlighting the importance of monitoring cardiac functions in these patients. Speckle tracking echocardiography can provide valuable insights into cardiac involvement in FMF. These findings emphasize the cardiac impact of FMF inflammation and the significance of long-term cardiac function monitoring in the management of FMF patients. What is Known: • The current literature lacks studies investigating myocardial function in the pediatric population during the attack period of this particular disease. • Our objective was to assess the alterations in cardiac function during the attack and remission periods, considering clinical manifestations, disease severity, acute phase reactant levels, and mutation type. We also evaluated the pattern of cardiac involvement and the affected cardiac areas by comparing remission and attack periods. What is New: • Several studies have demonstrated a rise in the prevalence of ischemic cardiac disease and mortality among individuals with FMF. • Investigating cardiac involvement during the attack period in FMF patients can provide valuable insights for the prevention of long-term complications.

Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failuremodel.

MiR-181c-5p overexpression associates with heart failure (HF) and cardiac damage, but the underlying pathophysiology remains unclear. This study investigated the effect of miR-181c-5p inhibition on cardiac function and fibrosis in a rodent model of diastolic dysfunction, and evaluated additional effects on kidney as relevant comorbid organ. Diastolic dysfunction was induced in male C57/BL6J mice (n = 20) by combining high-fat diet, L-NG-nitroarginine methyl ester, and angiotensin II administration, and was compared to sham controls (n = 18). Mice were randomized to subcutaneous miR-181c-5p antagomiR (INH) or scrambled antagomiR injections (40 mg/kg/week). HF mice demonstrated diastolic dysfunction and increased fibrosis, which was attenuated by INH treatment. Remarkably, HF + INH animals had a threefold higher mortality rate (60%) compared to HF controls (20%). Histological examination revealed increased glomerular damage in all INH treated mice, and signs of thrombotic microangiopathy (TMA) in mice who died prematurely. Quantitative polymerase chain reaction demonstrated a miR-181c-5p-related downregulation of cardiac but not renal Tgfbr1 in HF + INH mice, while INH treatment reduced renal but not cardiac Vegfa expression in all mice. This study demonstrates cardiac anti-fibrotic effects of miR-181c-5p inhibition in a rodent HF model through targeting of Tgfbr1 in the heart. Despite improved diastolic function, HF + INH mice had higher mortality due to increased predisposition for TMA, increased renal fibrosis and glomerular damage, associated with Vegfa downregulation in kidneys.

Voluntary wheel running reduces tumor growth and increases capillarity in the heart during doxorubicin chemotherapy in a murine model of breast cancer.

Introduction: The possible beneficial effects of physical activity during doxorubicin treatment of breast cancer need further investigation as many of the existing studies have been done on non-tumor-bearing models. Therefore, in this study, we aim to assess whether short-term voluntary wheel-running exercise during doxorubicin treatment of breast cancer-bearing mice could induce beneficial cardiac effects and enhance chemotherapy efficacy. Methods: Murine breast cancer I3TC cells were inoculated subcutaneously to the flank of female FVB mice (n = 16) that were divided into exercised and non-exercised groups. Two weeks later, doxorubicin treatment was started via intraperitoneal administration (5mg/kg weekly for 3weeks). Organs were harvested a day after the last dose. Results: The tumor volume over time was significantly different between the groups, with the exercising group having lower tumor volumes. The exercised group had increased body weight gain, tumor apoptosis, capillaries per cardiomyocytes, and cardiac lactate dehydrogenase activity compared to the unexercised group, but tumor blood vessel density and maturation and tumor and cardiac HIF1-α and VEGF-A levels did not differ from those of the non-exercised group. Discussion: We conclude that even short-term light exercise such as voluntary wheel running exercise can decrease the subcutaneous mammary tumor growth, possibly via increased tumor apoptosis. The increase in cardiac capillaries per cardiomyocytes may also have positive effects on cancer treatment outcomes.

Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy.

Preclinical studies have shown the therapeutic potential of VEGF-B (vascular endothelial growth factor B) in revascularization of the ischemic myocardium, but the associated cardiac hypertrophy and adverse side effects remain a concern. To understand the importance of endothelial proliferation and migration for the beneficial versus adverse effects of VEGF-B in the heart, we explored the cardiac effects of autocrine versus paracrine VEGF-B expression in transgenic and gene-transduced mice. We used single-cell RNA sequencing to compare cardiac endothelial gene expression in VEGF-B transgenic mouse models. Lineage tracing was used to identify the origin of a VEGF-B-induced novel endothelial cell population and adeno-associated virus-mediated gene delivery to compare the effects of VEGF-B isoforms. Cardiac function was investigated using echocardiography, magnetic resonance imaging, and micro-computed tomography. Unlike in physiological cardiac hypertrophy driven by a cardiomyocyte-specific VEGF-B transgene (myosin heavy chain alpha-VEGF-B), autocrine VEGF-B expression in cardiac endothelium (aP2 [adipocyte protein 2]-VEGF-B) was associated with septal defects and failure to increase perfused subendocardial capillaries postnatally. Paracrine VEGF-B led to robust proliferation and myocardial migration of a novel cardiac endothelial cell lineage (VEGF-B-induced endothelial cells) of endocardial origin, whereas autocrine VEGF-B increased proliferation of VEGF-B-induced endothelial cells but failed to promote their migration and efficient contribution to myocardial capillaries. The surviving aP2-VEGF-B offspring showed an altered ratio of secreted VEGF-B isoforms and developed massive pathological cardiac hypertrophy with a distinct cardiac vessel pattern. In the normal heart, we found a small VEGF-B-induced endothelial cell population that was only minimally expanded during myocardial infarction but not during physiological cardiac hypertrophy associated with mouse pregnancy. Paracrine and autocrine secretions of VEGF-B induce expansion of a specific endocardium-derived endothelial cell population with distinct angiogenic markers. However, autocrine VEGF-B signaling fails to promote VEGF-B-induced endothelial cell migration and contribution to myocardial capillaries, predisposing to septal defects and inducing a mismatch between angiogenesis and myocardial growth, which results in pathological cardiac hypertrophy.

Eliciting the views of left breast cancer patients' receiving deep inspiration breath hold radiation therapy to inform the design of multimedia education and improve patient-centred care for prospective patients.

The currently accepted best practice radiation treatment for left breast cancer patients is Deep Inspiration Breath Hold (DIBH) where patients hold a deep breath to reduce late cardiac and pulmonary effects from treatment. DIBH can be challenging and induce or exacerbate anxiety in patients due to the perceived pressure to reduce radiation treatment side effects. This study explored the experiences of patients treated with Deep Inspiration Breath Hold Radiation Therapy (DIBH-RT) to improve patient-centred care and inform the design of multimedia educational tools for future patients undergoing DIBH. This descriptive qualitative study was underpinned by a social constructivist approach to create new educational and patient care approaches based on previous patients' experiences. Semi-structured interviews were conducted with patients who had completed DIBH-RT for breast cancer. Data was analysed with reflexive thematical analysis. Twenty-two patients were interviewed with five key themes identified: (1) informational needs, (2) care needs, (3) autonomy, (4) DIBH performance influencers and (5) other centredness. Recommendations were derived from these themes to improve future treatments of DIBH patients. These recommendations revolved around improvements to education, patient-centred care and strategies to improve self-efficacy with breath holding. Patients offer a wealth of knowledge regarding their lived experiences with treatment which can enhance future patients' experiences if incorporated into their education and care. Eliciting patients' views of their DIBH-RT treatment highlighted the need to improve patient self-efficacy with DIBH through familiarity with their planned treatment from new multimedia education, and foster patient care to enhance their experience.

Interferons and interferon-related pathways in heart disease.

Interferons (IFNs) and IFN-related pathways play key roles in the defence against microbial infection. However, these processes may also be activated during the pathogenesis of non-infectious diseases, where they may contribute to organ injury, or function in a compensatory manner. In this review, we explore the roles of IFNs and IFN-related pathways in heart disease. We consider the cardiac effects of type I IFNs and IFN-stimulated genes (ISGs); the emerging role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; the seemingly paradoxical effects of the type II IFN, IFN-γ; and the varied actions of the interferon regulatory factor (IRF) family of transcription factors. Recombinant IFNs and small molecule inhibitors of mediators of IFN receptor signaling are already employed in the clinic for the treatment of some autoimmune diseases, infections, and cancers. There has also been renewed interest in IFNs and IFN-related pathways because of their involvement in SARS-CoV-2 infection, and because of the relatively recent emergence of cGAS-STING as a pattern recognition receptor-activated pathway. Whether these advances will ultimately result in improvements in the care of those experiencing heart disease remains to be determined.

Voluntary Wheel Running Reduces Cardiometabolic Risks in Female Offspring Exposed to Lifelong High-Fat, High-Sucrose Diet.

Maternal and postnatal overnutrition has been linked to an increased risk of cardiometabolic diseases in offspring. This study investigated the impact of adult-onset voluntary wheel running to counteract cardiometabolic risks in female offspring exposed to a life-long high-fat, high-sucrose (HFHS) diet. Dams were fed either a HFHS or a low-fat, low-sucrose (LFLS) diet starting from 8 weeks prior to pregnancy and continuing throughout gestation and lactation. Offspring followed their mothers' diets. At 15 weeks of age, they were divided into sedentary (Sed) or voluntary wheel running (Ex) groups, resulting in four groups: LFLS/Sed (n = 10), LFLS/Ex (n = 5), HFHS/Sed (n = 6), HFHS/Ex (n = 5). Cardiac function was assessed at 25 weeks, with tissue collection at 26 weeks for mitochondrial respiratory function and protein analysis. Data were analyzed using two-way ANOVA. While maternal HFHS diet did not affect the offspring's body weight at weaning, continuous HFHS feeding post-weaning resulted in increased body weight and adiposity, irrespective of the exercise regimen. HFHS/Sed offspring showed increased left ventricular wall thickness and elevated expression of enzymes involved in fatty acid transport (CD36, FABP3), lipogenesis (DGAT), glucose transport (GLUT4), oxidative stress (protein carbonyls, nitrotyrosine), and early senescence markers (p16, p21). Their cardiac mitochondria displayed lower oxidative phosphorylation (OXPHOS) efficiency and reduced expression of OXPHOS complexes and fatty acid metabolism enzymes (ACSL5, CPT1B). However, HFHS/Ex offspring mitigated these effects, aligning more with LFLS/Sed offspring. Adult-onset voluntary wheel running effectively counteracts the detrimental cardiac effects of a lifelong HFHS diet, improving mitochondrial efficiency, reducing oxidative stress, and preventing early senescence. This underscores the significant role of physical activity in mitigating diet-induced cardiometabolic risks.

Helical tomotherapy craniospinal irradiation in primary brain tumours: Toxicities and outcomes in a peadiatric and adult population

ObjectiveAs craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our centre over an 11-year period. Methods and materialsOur study included all patients that underwent CSI by HT, between September 2009 and January 2020, in the Department of Radiation Oncology of the Toulouse Cancer Institute. Acute radiotherapy toxicities were reported and medium- to long-term outcomes analysed. ResultsAmong the 79 patients included, 70.9 % were younger than 18 years at diagnosis, the median age was 13 (range: 1–52) at the time of radiation therapy, 67.1 % of patients had medulloblastoma. Half of them (49.4 %) had a metastatic disease at diagnosis. The median dose of CSI was 36 Gy (range, 18–36). Seventy-seven patients received a radiation boost to the original location of the primary tumour (97.5 %), 32 patients also received a boost to their metastatic sites (40.5 %). Median follow-up was 55.5 months (95 %CI = [41.2; 71.8]). The 3-year event-free survival rate was 66.3 % (95 %CI = [54.2; 75.9]). Most patients presented with acute haematological toxicities during CSI (85.9 %), predominantly severe thrombocytopenia (39.7 %). Among the 64 patients assessed for medium- and long-term outcomes, 52 survived and 47 were alive and disease-free at the latest follow-up visit on record. There were 3.8 % secondary tumours: two meningiomas and one diffuse intrinsic pontine glioma. Adult and paediatric patients respectively presented with secondary cataract (4.3 % vs 22.0 %), persistent hearing disorders (26.1 % vs 29.3 %), pulmonary or cardiac late effects (4.3 % vs 2.4 %), hormonal pituitary gland deficiencies (30.0 % vs 56.8 %) and psycho-cognitive disorders (56.5 % vs 53.7 %). ConclusionCSI dispensed by HT, did not result in any additional acute or late toxicities when compared to 3D-CSI. There was no increase in the secondary tumour rate compared to that reported in the literature.