Changes in the cardiovascular risk profile in children approaching kidney replacement therapy.

Background: Despite significant cardiovascular (CV) morbidity in children on dialysis and after kidney transplantation, data on the evolution of CV damage in children with chronic kidney disease (CKD) approaching kidney replacement therapy (KRT) is unknown. Methods: The burden, progression, and predictors of CV damage before KRT onset were explored in two prospective multicenter cohorts from Europe and Canada: Cardiovascular Comorbidity in Children with CKD (4C) and Haemodiafiltration, Heart and Height (3H) studies, conducted from 2009-19 and 2013-16, respectively. CV damage and risk factors were evaluated (i) cross sectionally at KRT-start (n = 248), and (ii) longitudinally over the 2-years preceding KRT start (n = 157; 331 patient-visits). Longitudinal analyses with mixed-effects models estimated associations of modifiable CV risk factors with change in carotid intima-media thickness (cIMT) standard deviation score (SDS), pulse wave velocity (PWV-SDS), left ventricular (LV) mass and systolic dysfunction. Findings: 248 patients, age 14.3 (12.2, 16.2) years were evaluated at median 35 (28-114) days before KRT start. Elevated cIMT-SDS and PWV-SDS were present in 43% and 25%, and LV hypertrophy and systolic dysfunction in 49% and 33%. Aortic stiffness and LV hypertrophy significantly increased, especially in the year before KRT start (adjusted odds ratio, OR 0.33, P = 0.002 and OR 0.54, P = 0.01, respectively). 79% of children had >3 modifiable CV risk factors at KRT onset. Diastolic BP and BMI were strongly associated with a linear increase in all CV measures. After controlling for CV risk factors, the time to KRT onset no longer predicted the burden of CV damage. Interpretation: This comprehensive CV evaluation shows the progressive accrual of modifiable risk factors and a high burden of CV damage in the years preceding KRT onset. CV damage in the pre-KRT period is preventable. Funding: Supported by EU4Health Programme (101085068) and Kidney Research UK (RP39/2013).

Multimodal Imaging Reveals that Sustained Inhibition of HIF-Prolyl Hydroxylases Induces Opposing Effects on Right and Left Ventricular Function in Healthy Rats.

PURPOSE: Hypoxia-inducible factor (HIF) drives transcription of critical hypoxia response genes, increasing the production of red blood cells in low oxygen conditions. In the absence of hypoxia, HIF is degraded by prolyl hydroxylases (HIF-PHs). Pharmacological HIF-PH inhibition stabilizes HIF and is being studied as a treatment for anemia. However, like sustained hypoxia, HIF-PH inhibition may increase pulmonary arterial pressure leading to right ventricular hypertrophy. The aim of this study was to assess the cardiac effects of sustained pharmacological HIF-PH inhibition using multimodal imaging, blood analysis, and histology. METHODS: Rats were dosed daily with a pan HIF-PH inhibitor or vehicle for 4 weeks followed by a 2-week washout period and underwent longitudinal magnetic resonance imaging (MRI) and echocardiography to simultaneously assess RV and LV function. Blood samples from weeks four and six were analyzed to determine red blood cell composition. Histology was performed on the cardiac tissue from a subset of rats at weeks four and six to assess structural effects. RESULTS: Imaging revealed that RV ejection fraction was reduced in animals receiving HIF-PH inhibitor and resulted in RV hypertrophy. Interestingly, HIF-PH inhibition had the opposite effect on the left ventricle (LV), increasing contractility measured by LV ejection fraction. LV effects were reversed by week six, while RV effects (functional and structural) were sustained. CONCLUSION: These opposing cardiac effects of HIF-PH inhibition warrant further study to both understand the potential negative effects on RV structure and function and investigate the therapeutic potential of increased LV contractility for conditions like heart failure.

Effect of ovariohysterectomy on queen myocardial function: echocardiographic evidence.

Ovariohysterectomy (OHE) is one of the most common surgeries in veterinary medicine. Although this surgical method has several advantages, it can alter the function of various organs such as heart. The present study investigated the effect of OHE on cardiac functions using M-mode echocardiography. A total of 10 healthy adult domestic short-haired cats were enrolled in the current study. Fractional shortening (FS) and ejection fraction (EF) percentages along with cardiac output (CO) were measured through the right parasternal approach in papillary muscle level view. Moreover, the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured by enzyme-linked immunosorbent assay before OHE (D0) as well as 10 (D10), 20 (D20) and 30 (D30) days after OHE. The results of this study showed that the mean FS and EF decreased on all days of the study. The FS reduction was significant between D10 and D30 and EF changes were significant between D10 and D20. The means of CO increased significantly on D0 compared to the D10. After D20, CO reduced until the end of the study. Mean concentrations of LH and FSH increased on all research days; but, the changes were significant until D20. Despite the negative effects of OHE on myocardial function, there was no significant correlation between hormonal levels and echocardiographic findings after OHE in this study.

Acyl ghrelin improves cardiac function in heart failure and increases fractional shortening in cardiomyocytes without calcium mobilization.

BACKGROUND AND AIMS: Ghrelin is an endogenous appetite-stimulating peptide hormone with potential cardiovascular benefits. Effects of acylated (activated) ghrelin were assessed in patients with heart failure and reduced ejection fraction (HFrEF) and in ex vivo mouse cardiomyocytes. METHODS AND RESULTS: In a randomized placebo-controlled double-blind trial, 31 patients with chronic HFrEF were randomized to synthetic human acyl ghrelin (0.1 µg/kg/min) or placebo intravenously over 120 min. The primary outcome was change in cardiac output (CO). Isolated mouse cardiomyocytes were treated with acyl ghrelin and fractional shortening and calcium transients were assessed. Acyl ghrelin but not placebo increased cardiac output (acyl ghrelin: 4.08 ± 1.15 to 5.23 ± 1.98 L/min; placebo: 4.26 ± 1.23 to 4.11 ± 1.99 L/min, P < 0.001). Acyl ghrelin caused a significant increase in stroke volume and nominal increases in left ventricular ejection fraction and segmental longitudinal strain and tricuspid annular plane systolic excursion. There were no effects on blood pressure, arrhythmias, or ischaemia. Heart rate decreased nominally (acyl ghrelin: 71 ± 11 to 67 ± 11 b.p.m.; placebo 69 ± 8 to 68 ± 10 b.p.m.). In cardiomyocytes, acyl ghrelin increased fractional shortening, did not affect cellular Ca2+ transients, and reduced troponin I phosphorylation. The increase in fractional shortening and reduction in troponin I phosphorylation was blocked by the acyl ghrelin antagonist D-Lys 3. CONCLUSION: In patients with HFrEF, acyl ghrelin increased cardiac output without causing hypotension, tachycardia, arrhythmia, or ischaemia. In isolated cardiomyocytes, acyl ghrelin increased contractility independently of preload and afterload and without Ca2+ mobilization, which may explain the lack of clinical side effects. Ghrelin treatment should be explored in additional randomized trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05277415.

Left ventricular dysfunction in the immediate post-natal period.

Background: Our objective was to examine the clinical presentation, echocardiographic findings, and outcomes of newborns presenting with left ventricle (LV) dysfunction in the first 48 hours of life without perinatal asphyxia or structural heart disease. We hypothesize that LV dysfunction may occur due to maladaptation to extrauterine life. Methods: This is a retrospective cohort analysis including infants born in a quaternary perinatal centre. Late preterm and term neonates who were diagnosed with left ventricular dysfunction at less than 48 hours of life were identified using an echocardiography clinical laboratory's database and extracorporeal life support database. LV dysfunction was defined as m-mode fractional shortening (FS) <28% or ejection fraction (EF) <50% on echocardiography or reduced function reported by a cardiologist. Data extracted included patient & maternal demographics, echocardiogram parameters, clinical status, and medications. The primary outcome measure was time to recovery of LV function based on echocardiography. Results: Of the 69 patients identified, 19 patients were included in the final analysis. The mean gestational age was 38 weeks. Thirteen (68%) infants did not have an underlying cause identified despite extensive work-up. Four (21%) infants had exposure to maternal illicit drug use during pregnancy. Three infants died, and all infants without identifiable etiologies had recovery of LV function within 14 days of life. Conclusions: LV dysfunction can occur during the abrupt transition from fetal to neonatal circulation and can be associated with maternal illicit drug use.

Vitamin D levels and left ventricular function in beta-thalassemia major with iron overload.

Heart disease is the primary cause of death in patients with beta-thalassemia major. The study aimed to determine the association between vitamin D and left ventricular function in patients with beta-thalassemia major with iron overload. A cross-sectional hospital-based study was conducted, where the vitamin D and ferritin levels of children living with beta-thalassemia major were measured, and left ventricular function was assessed utilizing ejection fraction (EF) and fractional shortening (FS) using 2D echocardiography. The mean serum ferritin was 4622 ± 2289 ng/ml, and the mean serum vitamin D levels were 22 ± 7.7 ng/ml. The mean values of EF were 62.30 ± 6.9%, and FS was 31.21 ± 4.8%. Statistically significant negative correlation (r = -0.447, p < 0.001) was found between vitamin D and serum ferritin values, and a significant positive association was found between vitamin D levels concerning EF and FS with a p-value of 0.034 and 0.014, respectively.Conclusion: It was observed  that increasing ferritin was associated with lower vitamin D levels which in turn influenced fractional shortening /cardiac function in these patients.  What is Known: • Patients with Beta Thalassemia major on long term transfusion are prone to develop heart disease / cardiac failure due to chronic iron overload. What is New: • Patients with beta thalassemia major on long term term transfusions with iron overload who are vitamin D deficient are more prone to the cardiac complications which inturn can be prevented by vitamin D supplementation.

A detailed echocardiographic evaluation of ventricular functions in stable full term small for gestational age babies.

PURPOSE: SGA infants with fetal growth restriction have reduced ability to adapt themselves to the postnatal life because of certain epigenetic changes in cardiac function. The aim of the present study is to assess and compare the cardiac functions of fetal growth restricted SGA newborns to the term stable AGA newborns, and evaluate any differences in the cardiac functions during the postnatal transitional circulation. METHOD: This observational study was conducted at a multispecialty tertiary care hospital in Western India from June to November 2021. The newborns were evaluated using bedside echocardiography at 24-48 h and repeat screening after 48 h. The echocardiographic assessment of the systolic function was done using EF, FS, FAC and TAPSE; diastolic function using E/A wave ratio and global functioning using LV MPI. RESULT: Twnety-four babies were included in cases and 30 in the control arm of the study. Maternal and newborn characteristics were comparable between the two groups. FS, EF for left ventricle and TAPSE, FAC for right ventricular systolic function were significantly lower in SGA group (p = 0.02, 0.02, 0.00 and 0.01; respectively). The current study revealed a lower tricuspid E/A ratio and higher mitral E/A ratio with a significant difference beyond 48 h in the first week of life (p value 0.00). Left ventricular MPI was significantly higher in SGA infants compared to AGA infants during two subsequent readings in immediate newborn period with p values 0.01 and 0.02 respectively. The subgroup analysis revealed that fetal growth-restricted neonates with absent end-diastolic flow had a greater impact on ventricular functions. CONCLUSION: Present study showed a significant systolic and diastolic dysfunction during initial newborn period in growth restricted SGA infants.

Natural history of hypertrophic cardiomyopathy in cats from rehoming centers: The CatScan II study.

BACKGROUND: The natural history of hypertrophic cardiomyopathy (HCM) in cats has been mainly studied in cats referred for suspected heart disease, which can skew the results towards cats with clinical signs. Few data are available on factors associated with development of HCM in cats. HYPOTHESES: (1) Clinical variables can predict which cats will develop HCM; (2) HCM in cats not referred for suspected heart disease is associated with a low rate of cardiovascular events. ANIMALS: One hundred seven cats from rehoming centers without a history of clinical signs of cardiac or systemic disease at the time of adoption. METHODS: Prospective longitudinal study. After rehoming, shelter cats were reexamined for serial echocardiograms. Cox regression analysis was used to identify predictors of development of HCM in cats that were normal at baseline. Adverse cardiovascular events including heart failure, thromboembolism, or sudden death were recorded. RESULTS: Cats were monitored for a median of 5.6 [1.2-9.2] years. At baseline, 68/107 cats were normal, 18/107 were equivocal and 21/107 had HCM. Nineteen cats developed HCM during the study period. The factors at baseline associated with increased hazard of developing HCM were lower left atrial fractional shortening, higher left ventricular fractional shortening, and higher body weight. Cardiovascular events were observed in 21% of cats with HCM. CONCLUSIONS AND CLINICAL IMPORTANCE: Cardiovascular events were common in cats with HCM from a rehoming center study sample. Lower left atrial systolic function appears to precede overt HCM.

The effect of placental transfusion on hemodynamics in premature newborns: a randomized controlled trial.

Despite of growing evidence of the beneficial effects of placental transfusion techniques, there is no available sufficient data about their effects on vulnerable hemodynamics and myocardium of premature infants. The purpose of this work is to study ventricular functions and hemodynamics after applying different placental transfusion techniques, delayed cord clamping (DCC), cut cord milking (C-UCM), and intact cord milking (I-UCM). Sixty-four infants delivered whether by C-section or vaginal delivery were randomly assigned to undergo C-UCM (20-30 cm), I-UCM (3-4 strippings), and DCC (30-60 s). Functional echocardiography was done on day 1 and day 3 of life for 57 infants. Primary outcome variable was superior vena cava flow measurement in infants having placental transfusion in the first 24 h of life and between 64 and 72 h. Secondary outcomes were other echocardiographic and clinical hemodynamic parameters, and biventricular functions in those infants. Of a total 196 preterm infants ≤ 32 weeks delivered in the study period, from January 2021 to August 2021, 57 infants were eligible and survived till the second examination. They were randomly assigned to the three groups. Neonates randomly assigned to DCC had significantly higher superior vena cava flow and lower right ventricular systolic function in the first 24 h of life. This finding vanished at day 3. Neonates undergone different methods of placental transfusions had similar hemoglobin, admission temperature, and mean blood pressure in the first 24 h of life. CONCLUSION: Despite their potential benefits, placental transfusions have shown to alter the hemodynamics and adversely affect myocardial function of premature neonates. TRIAL REGISTRATION: This trial was registered in the clinical trial gov NCT04811872. WHAT IS KNOWN: • Placental transfusion techniques might have benefits regarding prematurity- related morbidities and mortality. WHAT IS NEW: • Placental transfusion might adversely affect the myocardium and alter hemodynamics in premature infants.

Cardiac Function Assessment in Fetuses With Ductus Arteriosus Constriction: A Two-Dimensional Echocardiography and FetalHQ Study.

Background: Fetal ductal constriction (DC) is associated with excessive polyphenol-rich food (PRF) consumption during pregnancy. However, the effect of this hemodynamic change on fetal cardiac function still needs to be elucidated. Therefore, this study aimed to evaluate the cardiac function of fetuses with PRF-related DC and to describe serial observations of cardiac function changes. Methods: We compared the traditional echocardiographic indices, including morphological, hemodynamic, and functional parameters, between study fetuses and controls. For global and segmental deformation analysis of the left and right ventricles, fetalHQ with the speckle-tracking technique was used to calculate sphericity index (SI), global longitudinal strain (GLS), fractional shortening (FS), fractional area change (FAC), etc. In addition, follow-up data were compared with the generalized linear model. Results: A total of 60 DC fetuses and 60 gestational-matched controls were enrolled in our study, with 20 DC fetuses undertaking a follow-up echocardiogram after 2-3 weeks. Compared with controls, there was a distinct decrease in right ventricular GLS (RVGLS) (-13.39 ± 3.77 vs. -21.59 ± 2.51, p < 0.001), RVFAC (22.20 ± 9.56 vs. 36.01 ± 4.84, p < 0.001), left ventricular GLS (LVGLS) (-19.52 ± 3.24 vs. -23.81 ± 2.01 p < 0.001), and LVFAC (39.64 ± 7.32 vs. 44.89 ± 4.91, p = 0.004). For 24-segment FS analysis, DC fetuses showed lower FS in left ventricular (LV) segments 18-24, with no difference in LV segments 1-17. Right ventricular (RV) FS in segments 4-23 was also reduced in the DC group. The 24-segment SI analysis indicated significantly lower SI in DC than those in controls for LV segments 1-14 and RV segments 19-24. We found that the pulsatility index (PI) of ductus arteriosus (DA) was an independent variable for RVGLS (ß = -0.29, p = 0.04). In 20 DC fetuses with follow-up echocardiograms, no obvious difference in myocardial deformation was found between the initial examination and follow-up data. Conclusion: Left and right ventricular performances were both impaired in DC fetuses, along with a series of morphological and hemodynamic changes. Although the state of DA constriction improved on second examinations, cardiac function was not completely restored.

Cardiac Spinal Afferent Denervation Attenuates Renal Dysfunction in Rats With Cardiorenal Syndrome Type 2.

Cardiorenal syndrome type 2 (CRS2) is defined as a chronic cardiovascular disease, usually chronic heart failure (CHF), resulting in chronic kidney disease. We hypothesized that the cardiac spinal afferent reflex (CSAR) plays a critical role in the development of CRS2. Our data suggest that cardiac afferent ablation by resiniferatoxin not only improves cardiac function but also benefits the kidneys and increases long-term survival in the myocardial infarction model of CHF. We also found that renal denervation has a similar reno-protective effect in CHF rats. We believe this novel work contributes to the development of a unique neuromodulation therapy to treat CHF patients.

Cardiotoxicity of Chemical Substances: An Emerging Hazard Class.

(1) Background: Human health risks and hazards from chemical substances are well regulated internationally. However, cardiotoxicity, is not defined as a stand-alone hazard and therefore there are no defined criteria for the classification of substances as cardiotoxic. Identifying and regulating substances that cause cardiovascular adverse effects would undoubtedly strengthen the national health systems. (2) Methods: To overcome the aforementioned gap, a roadmap is proposed for identifying regulatory criteria from animal studies and endorse legislation in order to classify substances as cardiotoxic. The roadmap consists of: (i) the identification of the appropriate animal species and strains; (ii) the identification of the lines of scientific evidence (e.g., histopathological, biochemical and echocardiographic indices etc.) from animal studies with relevance to humans; (iii) the statistical analysis and meta-analysis for each line of scientific evidence after exposure to well-established cardiotoxicants to humans (e.g., anthracyclines) in order to identify threshold values or range of normal and/ or altered values due to exposure; (iv) validation of the above described lines of evidence in animals exposed to other alleged cardiotoxic substances (e.g., anabolic androgen steroids (AAS) and pesticides); (v) establishment of mechanisms of action based on information of either known or alleged cardiotoxicants; and (vi) introduction of novel indices and in silico methods. (3) Results: Preliminary results in rats indicate a clear distinction from normal values to values measured in rats exposed to anthracyclines regarding left ventricle (LV) fractional shortening (FS) and LV ejection fraction (EF). A distinctive pattern is similarly observed for Creatine Kinase-Myocardial Band isoenzyme (CK-MB) and cardiac tissue glutathione (GSH). These findings are encouraging and indicate that there is room for targeted research to this end, and that these specific indices and biochemical markers should be further investigated in order to be developed to regulatory criteria. (4) Conclusions: Further research should be conducted by both the scientific and regulatory community that aims to clearly define the cardiotoxicity hazard caused by chemicals and develop a full set of scientific criteria.

MicroRNA-34c-5p provokes isoprenaline-induced cardiac hypertrophy by modulating autophagy via targeting ATG4B.

Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs (miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34c-5p on cardiac hypertrophy and the mechanism involved. The expression of miR-34c-5p was proved to be elevated in heart tissues from isoprenaline (ISO)-infused mice. ISO also promoted miR-34c-5p level in primary cultures of neonatal rat cardiomyocytes (NRCMs). Transfection with miR-34c-5p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor (Anf) and ß-myosin heavy chain (ß-Mhc) in NRCMs. In contrast, treatment with miR-34c-5p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34c-5p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34c-5p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34c-5p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4B (ATG4B) was identified as a direct target of miR-34c-5p, and miR-34c-5p was certified to interact with 3' untranslated region of Atg4b mRNA by dual-luciferase reporter assay. miR-34c-5p reduced the expression of ATG4B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34c-5p abolished the detrimental effects of ISO by restoring ATG4B and increasing autophagy. In conclusion, our findings illuminate that miR-34c-5p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4B and autophagy. It suggests that regulation of miR-34c-5p may offer a new way for handling hypertrophy-related cardiac dysfunction.

Nicotinamide Mononucleotide Alleviates Cardiomyopathy Phenotypes Caused by Short-Chain Enoyl-Coa Hydratase 1 Deficiency.

Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency plays a role in cardiomyopathy. Whether ECHS1 deficiency causes or is only associated with cardiomyopathy remains unclear. By using Echs1 heterogeneous knockout (Echs1 +/-) mice, we found that ECHS1 deficiency caused cardiac dysfunction, as evidenced by diffuse myocardial fibrosis and upregulated fibrosis-related genes. Mechanistically, ECHS1 interacts with the p300 nuclear localization sequence, preventing its nuclear translocation in fibroblasts. ECHS1 deficiency promotes p300 nuclear translocation, leading to increased H3K9 acetylation, a known risk factor for cardiomyopathy. Nicotinamide mononucleotide-mediated acetylation targeting suppressed ECHS1 deficiency-induced cardiomyopathy phenotypes in Echs1 +/- mice. Thus, enhancing p300-mediated H3K9ac is a potential interventional approach for preventing ECHS1 deficiency-induced cardiomyopathy.

Comparison of Intestinal Microbiota Between Healthy and MMVD Chihuahuas Using 16S rRNA Gene Amplicon Sequencing.

Myxomatous mitral valve disease (MMVD) is the most common cause of congestive heart failure in dogs, and although complications of MMVD to the lungs and kidneys have been identified, complications to the gut are less well understood. The intestinal microbiota is an important factor in the gut, and although the association between heart disease and the intestinal microbiota has been shown in human medicine, it is unknown in dogs. The study aimed to evaluate the relationship between MMVD and gut microbiota. A total of 69 healthy Chihuahuas and Chihuahuas with MMVD were evaluated for cardiac health by echocardiography and chest radiography and grouped according to ACVIM guidelines. Fecal samples were collected from all cases and 16S rRNA sequencing was used to reveal the intestinal microbiota. There were significant differences in LA/Ao, LVIDd, E vel, VHS, and VLAS with the severity of ACVIM. On the other hand, there were no significant differences in the diversity and composition of gut microbiota among the groups. The present study did not identify the effects of MMVD on the gut microbiota.

TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis.

Mitochondria are essential for cardiac myocyte function, but damaged mitochondria trigger cardiac myocyte death. Although mitophagy, a lysosomal degradative pathway to remove damaged mitochondria, is robustly active in cardiac myocytes in the unstressed heart, its mechanisms and physiological role remain poorly defined. We discovered a critical role for TRAF2, an innate immunity effector protein with E3 ubiquitin ligase activity, in facilitating physiological cardiac myocyte mitophagy in the adult heart, to prevent inflammation and cell death, and maintain myocardial homeostasis.

Pharmacogenomic study of anthracycline-induced cardiotoxicity in Mexican pediatric patients.

Background: The aim of this study was to evaluate the association between well-defined genetic risk variants in SLC28A3, RARG and UGT1A6 and anthracycline-induced cardiotoxicity in Mexican pediatric patients. Methods: We tested a cohort of 79 children treated with anthracyclines for the presence of SLC28A3-rs7853758, RARG-rs2229774 and UGT1A6-rs17863783. Results: The SLC28A3-rs7853758 variant was more frequent in this cohort, while the UGT1A6-rs17863783 and RARG-rs2229774 variants were present at lower frequencies. A clinically important decrease of fractional shortening was associated with SLC28A3-rs7853758 variant. Conclusion: In this cohort, 39.2% of patients carried the protective SLC28A3 variant. A small number of tested patients have the risk variants of UGT1A6 and RARG. None of the patients shared the two risk variants.

Role of Anti-Beta-1-Adrenergic Receptor Antibodies in Cardiac Dysfunction in Patients with Cirrhotic Cardiomyopathy.

Cirrhotic cardiomyopathy (CCM) is a recognized complication of cirrhosis and is associated with poor outcomes, especially under challenges such as surgery/liver transplantation. However, the mechanism is not clear, and the treatment is not specific. The present study aimed to evaluate the role of anti-ß1-adrenergic receptor antibodies (anti-ß1-AR) in CCM. We enrolled 3 groups: healthy controls, cirrhotic patients without CCM, and patients with CCM. We found that the anti-ß1-AR levels in the CCM group were significantly higher than that in the non-CCM group; anti-ß1-AR was positively correlated to NT-proBNP, negatively correlated to left ventricular ejection fraction, fractional shortening ((r = - 0.466, P < 0.05), and the ratio of peak early (E wave) and atrial (A wave) flow velocities (E/A (r = - 0.475, P < 0.05) in CCM patients. Anti-ß1-AR is a useful predictive biomarker for the presence of CCM and eventually may also have therapeutic implications. Clinical Trials Registration: Chinese Clinical Trials No. ChiCTR 2,000,037,730.

Doxorubicin-induced delayed-onset subclinical cardiotoxicity in mice.

Subclinical cardiotoxicity at low total cumulative doxorubicin (DOX) doses can manifest into cardiomyopathy in long-term cancer survivors. However, the underlying mechanisms are poorly understood. In male B6C3F1 mice, assessment of cardiac function by echocardiography was performed at 1, 4, 10, 17, and 24 weeks after exposure to 6, 9, 12, and 24 mg/kg total cumulative DOX doses or saline (SAL) to monitor development of delayed-onset cardiotoxicity. The 6- or 9-mg/kg total cumulative doses resulted in a significant time-dependent decline in systolic function (left ventricular ejection fraction (LVEF) and fractional shortening (FS)) during the 24-week recovery although there was not a significant alteration in % LVEF or % FS at any specific time point during the recovery. A significant decline in systolic function was elicited by the cardiotoxic cumulative DOX dose (24 mg/kg) during the 4- to 24-week period after treatment compared to SAL-treated counterparts. At 24 weeks after DOX treatment, a significant dose-related decrease in the expression of genes and proteins involved in sarcoplasmic reticulum (SR) calcium homeostasis (Ryr2 and Serca2) was associated with a dose-related increase in the transcript level of Casp12 (SR-specific apoptosis) in hearts. These mice also showed enhanced apoptotic activity in hearts indicated by a significant dose-related elevation in the number of apoptotic cardiomyocytes compared to SAL-treated counterparts. These findings collectively suggest that a steady decline in SR calcium handling and apoptosis might be involved in the development of subclinical cardiotoxicity that can evolve into irreversible cardiomyopathy later in life.