Relationship of Neonatal Seizure Burden Before Treatment and Response to Initial Antiseizure Medication.

OBJECTIVE: To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pretreatment maximal hourly seizure burden and total seizure duration with successful response to initial antiseizure medication (ASM). STUDY DESIGN: This was a retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between January 25, 2017, and October 9, 2019. We evaluated a cohort of neonates born at ≥36 weeks of gestation with moderate-to-severe HIE who underwent continuous electroencephalogram monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1) pretreatment maximal hourly seizure burden, (2) pretreatment total seizure duration, (3) time from first seizure to initial ASM, and (4) successful response to initial ASM. RESULTS: Among 39 neonates meeting inclusion criteria, greater pretreatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pretreatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (relative risk 1.007, 95% CI 1.003-1.010). CONCLUSIONS: Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.

Evolution of the Sarnat exam and association with 2-year outcomes in infants with moderate or severe hypoxic-ischaemic encephalopathy: a secondary analysis of the HEAL Trial.

OBJECTIVE: To study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE). DESIGN: Secondary analysis of the High-dose Erythropoietin for Asphyxia and EncephaLopathy Trial. Adjusted ORs (aORs) for death or neurodevelopmental impairment (NDI) based on SE severity category and change in category were constructed, adjusting for sedation at time of exam. Absolute SE Score and its change were compared for association with risk for death or NDI using locally estimated scatterplot smoothing curves. SETTING: Randomised, double-blinded, placebo-controlled multicentre trial including 17 centres across the USA. PATIENTS: 479/500 enrolled neonates who had both a qualifying SE (qSE) before TH and a SE after rewarming (rSE). INTERVENTIONS: Standardised SE was used across sites before and after TH. All providers underwent standardised SE training. MAIN OUTCOME MEASURES: Primary outcome was defined as the composite outcome of death or any NDI at 22-36 months. RESULTS: Both qSE and rSE were associated with the primary outcome. Notably, an aOR for primary outcome of 6.2 (95% CI 3.1 to 12.6) and 50.3 (95% CI 13.3 to 190) was seen in those with moderate and severe encephalopathy on rSE, respectively. Persistent or worsened severity on rSE was associated with higher odds for primary outcome compared with those who improved, even when qSE was severe. CONCLUSION: Both rSE and change between qSE and rSE were strongly associated with the odds of death/NDI at 22-36 months in infants with moderate or severe HIE.

Association of EEG Background and Neurodevelopmental Outcome in Neonates With Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.

BACKGROUND AND OBJECTIVES: Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin or placebo for neonates with HIE treated with therapeutic hypothermia. METHODS: Participants had EEG recorded throughout hypothermia. EEG background was classified as normal, discontinuous, or severely abnormal (defined as burst suppression, low voltage suppressed, or status epilepticus) at 5 1-hour epochs: onset of recording, 24, 36, 48, and 72 hours after birth. The predominant background pattern during the entire continuous video EEG monitoring recording was calculated using the arithmetic mean of the 5 EEG background ratings (normal = 0; discontinuous = 1; severely abnormal = 2) as follows: "predominantly normal" (mean = 0), "normal/discontinuous" (0 < mean<1), "predominantly discontinuous" (mean = 1), "discontinuous/severely abnormal" (1 < mean<2), or "predominantly severely abnormal" (mean = 2). Primary outcome was death or neurodevelopmental impairment (NDI) defined as cerebral palsy, Gross Motor Function Classification Score ≥1, or cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition at age 2 years. Neurodevelopment was also categorized into a 5-level ordinal measure: no, mild, moderate, severe NDI, or death for secondary analysis. We used generalized linear regression models with robust standard errors to assess the relative risk of death or NDI by EEG background in both unadjusted and adjusted analyses controlling for the effects of treatment group, sex, HIE severity, and study recruitment site. RESULTS: Among 142 neonates, the predominant background EEG pattern was predominantly normal in 35 (25%), normal/discontinuous in 68 (48%), predominantly discontinuous in 11 (7.7%), discontinuous/severely abnormal in 16 (11%), and predominantly severely abnormal in 12 (8.5%). Increasing severity of background across monitoring epochs was associated with increasingly worse clinical outcomes. Children with severe EEG background abnormality at any time point (n = 36, 25%) were significantly more likely to die or have severe NDI at 2 years (adjusted relative risk: 7.95, 95% CI 3.49-18.12). DISCUSSION: EEG background is strongly associated with NDI at age 2 years. These results can be used to assist health care providers to plan follow-up care and counsel families for decision-making related to goals of care.

Early Glycemic State and Outcomes of Neonates With Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: In infants with hypoxic-ischemic encephalopathy (HIE), conflicting information on the association between early glucose homeostasis and outcome exists. We characterized glycemic profiles in the first 12 hours after birth and their association with death and neurodevelopmental impairment (NDI) in neonates with moderate or severe HIE undergoing therapeutic hypothermia. METHODS: This post hoc analysis of the High-dose Erythropoietin for Asphyxia and Encephalopathy trial included n = 491 neonates who had blood glucose (BG) values recorded within 12 hours of birth. Newborns were categorized based on their most extreme BG value. BG >200 mg/dL was defined as hyperglycemia, BG <50 mg/dL as hypoglycemia, and 50 to 200 mg/dL as euglycemia. Primary outcome was defined as death or any NDI at 22 to 36 months. We calculated odds ratios for death or NDI adjusted for factors influencing glycemic state (aOR). RESULTS: Euglycemia was more common in neonates with moderate compared with severe HIE (63.6% vs 36.6%; P < .001). Although hypoglycemia occurred at similar rates in severe and moderate HIE (21.4% vs 19.5%; P = .67), hyperglycemia was more common in severe HIE (42.3% vs 16.9%; P < .001). Compared with euglycemic neonates, both, hypo- and hyperglycemic neonates had an increased aOR (95% confidence interval) for death or NDI (2.62; 1.47-4.67 and 1.77; 1.03-3.03) compared to those with euglycemia. Hypoglycemic neonates had an increased aOR for both death (2.85; 1.09-7.43) and NDI (2.50; 1.09-7.43), whereas hyperglycemic neonates had increased aOR of 2.52 (1.10-5.77) for death, but not NDI. CONCLUSIONS: Glycemic profile differs between neonates with moderate and severe HIE, and initial glycemic state is associated death or NDI at 22 to 36 months.

Characteristics, Genetic Testing, and Diagnoses of Infants with Neonatal Encephalopathy Not Due to Hypoxic Ischemic Encephalopathy: A Cohort Study.

OBJECTIVE: To characterize the presentation and evaluation of infants with neonatal encephalopathy (NE) not due to hypoxic-ischemic encephalopathy (non-HIE NE) and to describe the genetic abnormalities identified. STUDY DESIGN: Retrospective cohort study of 193 non-HIE NE neonates admitted to a level IV NICU from 2015 through 2019. For changes in testing over time, Cochrane-Armitage test for trend was used with a Bonferroni-corrected P-value, and comparison between groups was performed using Fisher exact test. RESULT: The most common symptom of non-HIE NE was abnormal tone in 47% (90/193). Ten percent (19/193) died prior to discharge, and 48% of survivors (83/174) required medical equipment at discharge. Forty percent (77/193) underwent genetic testing as an inpatient. Of 52 chromosomal studies, 54 targeted tests, and 16 exome sequences, 10%, 41%, and 69% were diagnostic, respectively, with no difference in diagnostic rates between infants with and without an associated congenital anomaly and/or dysmorphic feature. Twenty-eight genetic diagnoses were identified. CONCLUSIONS: Neonates with non-HIE NE have high rates of morbidity and mortality and may benefit from early genetic testing, even in the absence of other exam findings. This study broadens our knowledge of genetic conditions underlying non-HIE NE, which may enable families and care teams to anticipate the needs of the individual, allow early initiation of targeted therapies, and facilitate decisions surrounding goals of care.

Preterm infants variability in cerebral near-infrared spectroscopy measurements in the first 72-h after birth.

BACKGROUND: Cerebral near-infrared spectroscopy is a non-invasive tool used to measure regional cerebral tissue oxygenation (rScO2) initially validated in adult and pediatric populations. Preterm neonates, vulnerable to neurologic injury, are attractive candidates for NIRS monitoring; however, normative data and the brain regions measured by the current technology have not yet been established for this population. METHODS: This study's aim was to analyze continuous rScO2 readings within the first 6-72 h after birth in 60 neonates without intracerebral hemorrhage born at ≤1250 g and/or ≤30 weeks' gestational age (GA) to better understand the role of head circumference (HC) and brain regions measured. RESULTS: Using a standardized brain MRI atlas, we determined that rScO2 in infants with smaller HCs likely measures the ventricular spaces. GA is linearly correlated, and HC is non-linearly correlated, with rScO2 readings. For HC, we infer that rScO2 is lower in infants with smaller HCs due to measuring the ventricular spaces, with values increasing in the smallest HCs as the deep cerebral structures are reached. CONCLUSION: Clinicians should be aware that in preterm infants with small HCs, rScO2 displayed may reflect readings from the ventricular spaces and deep cerebral tissue. IMPACT: Clinicians should be aware that in preterm infants with small head circumferences, cerebral near-infrared spectroscopy readings of rScO2 displayed may reflect readings from the ventricular spaces and deep cerebral tissue. This highlights the importance of rigorously re-validating technologies before extrapolating them to different populations. Standard rScO2 trajectories should only be established after determining whether the mathematical models used in NIRS equipment are appropriate in premature infants and the brain region(s) NIRS sensors captures in this population, including the influence of both gestational age and head circumference.

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo.

BACKGROUND: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. METHODS: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. RESULTS: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). CONCLUSION: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. IMPACT: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

Regulation of cardiovascular health and disease by visceral adipose tissue-derived metabolic hormones.

Visceral adipose tissue (VAT) is a metabolic organ known to regulate fat mass, and glucose and nutrient homeostasis. VAT is an active endocrine gland that synthesizes and secretes numerous bioactive mediators called 'adipocytokines/adipokines' into systemic circulation. These adipocytokines act on organs of metabolic importance like the liver and skeletal muscle. Multiple preclinical and in vitro studies showed strong evidence of the roles of adipocytokines in the regulation of metabolic disorders like diabetes, obesity and insulin resistance. Adipocytokines, such as adiponectin and omentin, are anti-inflammatory and have been shown to prevent atherogenesis by increasing nitric oxide (NO) production by the endothelium, suppressing endothelium-derived inflammation and decreasing foam cell formation. By inhibiting differentiation of vascular smooth muscle cells (VSMC) into osteoblasts, adiponectin and omentin prevent vascular calcification. On the other hand, adipocytokines like leptin and resistin induce inflammation and endothelial dysfunction that leads to vasoconstriction. By promoting VSMC migration and proliferation, extracellular matrix degradation and inflammatory polarization of macrophages, leptin and resistin increase the risk of atherosclerotic plaque vulnerability and rupture. Additionally, the plasma concentrations of these adipocytokines alter in ageing, rendering older humans vulnerable to cardiovascular disease. The disturbances in the normal physiological concentrations of these adipocytokines secreted by VAT under pathological conditions impede the normal functions of various organs and affect cardiovascular health. These adipokines could be used for both diagnostic and therapeutic purposes in cardiovascular disease.

Association Between Early EEG Background and Outcomes in Infants With Mild HIE Undergoing Therapeutic Hypothermia.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) occurs in 1-4:1000 live births. Although neonates with moderate-severe HIE have been studied over several decades, newborns with mild HIE remain understudied, including seizure occurrence, electroencephalography (EEG) characteristics, and outcome. METHODS: We conducted a retrospective cohort study of neonates ≥35 weeks of gestation with mild HIE who underwent therapeutic hypothermia to correlate the early EEG background pattern with clinical course and outcomes. RESULTS: Of the included 29 neonates, 10 infants had a moderately to severely abnormal EEG background and 19 had either a normal or a mildly abnormal background. Those with moderately to severely abnormal background also had more multiorgan dysfunction (90% vs 42%, P = 0.02) and a higher incidence of subdural and intraventricular hemorrhages (80% vs 26%, P = 0.02). The overall seizure incidence was 20.7% and was significantly higher in newborns with more severely abnormal background compared to neonates with less abnormal background (50% vs 5%; P = 0.01; relative risk, 9.5; 95% confidence interval, 1.28-70.6). Seizure onset was between 11 and 63 hours of life. Regardless of the EEG background pattern, seizures were brief with an overall low seizure burden. None of the newborns with normal or mildly abnormal background had a new onset of seizures after 24 hours of recording or developed epilepsy during infancy. CONCLUSIONS: In neonates with mild HIE, early moderately to severely abnormal EEG background is common and strongly associated with an increased risk for seizures.

Retrospective Evaluation of First-line Levetiracetam use for Neonatal Seizures after Congenital Heart Defect repair with or without Extracorporeal Membrane Oxygenation.

OBJECTIVE: Levetiracetam (LEV) efficacy for neonatal seizures is debated. We evaluated LEV as a first line anti-seizure medicine (ASM) in neonates following neonatal congenital heart defect (CHD) repair who did not require extracorporeal membrane oxygenation (ECMO) vs neonates who required ECMO. METHODS: A single center retrospective review of neonates with CHD from 2015 to 2020 was conducted. Neonates were included if seizures were present on continuous EEG after CHD repair either on or off ECMO, and they received LEV as a first line ASM. Primary outcomes were seizure resolution with LEV, adverse events and response to subsequent ASM. RESULTS: Eighteen total neonates were evaluated, 10 with seizures post-CHD repair who did not require ECMO and 8 who required ECMO. In the non-ECMO cohort, nine of ten were successfully treated with LEV monotherapy with no adverse events. In comparison, the eight neonates who required ECMO had a higher initial seizure burden (1.6% vs 17%, p=0.003), were more likely to have injury on neuroimaging (12.5 vs 75%, p= 0.04), and all neonates required multiple ASMs. Seizure burden did not decrease with LEV, but significantly decreased with phenobarbital and fosphenytoin (14.4% and 10.5%, p = 0.024). CONCLUSIONS: Neonates with CHD and seizures on and off ECMO demonstrated divergent seizure characteristics including seizure burden and response to LEV. LEV may reduce neonatal seizure burden after uncomplicated CHD repair. However, in neonates requiring ECMO, multiple ASMs were required. A prospective evaluation of ASM efficacy and safety in this high-risk population is urgently needed.

Topiramate Is Safe for Refractory Neonatal Seizures: A Multicenter Retrospective Cohort Study of Necrotizing Enterocolitis Risk.

BACKGROUND: A previously published, single-institution, case series suggested an association between topiramate administration in neonates and subsequent development of necrotizing enterocolitis (NEC). This contradicted our more extensive experiences using topiramate in this population. We therefore studied safety and tolerability of topiramate for treating refractory neonatal seizures, hypothesizing that the risk of developing NEC following topiramate exposure was low and that most infants tolerate topiramate. METHODS: This multicenter retrospective cohort study included seventy-five neonates who received topiramate to treat seizures from January 2011 to October 2019 at three geographically diverse level IV neonatal intensive care units affiliated with pediatric tertiary hospitals. Data included demographics, birth history, seizure etiology, treatment response, side effects, and occurrence and details of NEC. RESULTS: Three of seventy-five infants (4%) developed NEC following topiramate exposure. These infants did not differ in gestational age, birth weight, seizure etiology, postmenstrual age, weight when topiramate was initiated, or dosing of topiramate. Topiramate was well tolerated. Only three infants (4%) discontinued due to side effects. The most common side effect (20%) was weight loss (typically <5%). Topiramate was felt to be efficacious (61%). Most infants (72%) continued topiramate when discharged. CONCLUSIONS: Our multicenter, 75-infant study demonstrated that development of NEC after treatment with topiramate was rare (4%) and refutes prior literature suggesting an association. Topiramate was felt to be efficacious and was well tolerated. Although limited by retrospective design, study data are broadly applicable and support thoughtful use of topiramate as a safe, reasonable option for treating refractory neonatal seizures.

Treatment of Neonatal Seizures: Comparison of Treatment Pathways From 11 Neonatal Intensive Care Units.

OBJECTIVE: Seizures are a common neonatal neurologic emergency. Many centers have developed pathways to optimize management. We evaluated neonatal seizure management pathways at level IV neonatal intensive care units (NICUs) in the United States to highlight areas of consensus and describe aspects of variability. METHODS: We conducted a descriptive analysis of 11 neonatal seizure management pathways from level IV NICUs that specialize in neonatal neurocritical care including guidelines for electroencephalography (EEG) monitoring, antiseizure medication (ASM) choice, timing, and dose. RESULTS: Study center NICUs had a median of 70 beds (interquartile range: 52-96). All sites had 24/7 conventional EEG initiation, monitoring, and review capability. Management pathways uniformly included prompt EEG confirmation of seizures. Most pathways included a provision for intravenous benzodiazepine administration if either EEG or loading of ASM was delayed. Phenobarbital 20 mg/kg IV was the first-line ASM in all pathways. Pathways included either fosphenytoin or levetiracetam as the second-line ASM with variable dosing. Third-line ASMs were most commonly fosphenytoin or levetiracetam, with alternatives including topiramate or lacosamide. All pathways provided escalation to continuous midazolam infusion with variable dosing for seizures refractory to initial medication trials. Three pathways also included lidocaine infusion. Nine pathways discussed ASM discontinuation after resolution of acute symptomatic seizures with variable timing. CONCLUSIONS: Despite a paucity of data from controlled trials regarding optimal neonatal seizure management, there are areas of broad agreement among institutional pathways. Areas of substantial heterogeneity that require further research include optimal second-line ASM, dosage, and timing of ASM discontinuation.

Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study.

INTRODUCTION: The EMBRACE study (Clinical Trials No. NCT02462759) evaluated nusinersen in infants/children with infantile- or later-onset spinal muscular atrophy (SMA) who were ineligible for the ENDEAR and CHERISH studies. METHODS: Participants were randomized to intrathecal nusinersen (12-mg scaled equivalent dose; n = 14) or sham procedure (n = 7) in part 1 (~14 months) and subsequently received open-label nusinersen for ~24 months in part 2 of the study. RESULTS: Part 1 was stopped early after the demonstration of motor function benefit with nusinersen in ENDEAR. There were no nusinersen-related adverse events (AEs) and no study discontinuations due to nusinersen-related AEs. The most common AEs included pyrexia, cough, pneumonia, and upper respiratory tract infections. Motor milestone responder rates were higher in those receiving nusinersen at last available assessment (93%) than in those receiving sham procedure in part 1 (29%) or transitioned from sham to nusinersen in part 2 (83%). This functional improvement was observed despite the small sample size and shortened part 1 trial duration that undermined the power of the study to demonstrate such treatment effects at a significant level. DISCUSSION: Nusinersen demonstrated a favorable long-term benefit-risk profile in this broad population of individuals with infantile- or later-onset SMA.

Transforaminal intrathecal delivery of nusinersen for older children and adults with spinal muscular atrophy and complex spinal anatomy: an analysis of 200 consecutive injections.

BACKGROUND: Nusinersen is the only approved treatment for all spinal muscular atrophy (SMA) subtypes and is delivered intrathecally. Distorted spinal anatomy and instrumentation preclude standard approaches for intrathecal access, necessitating alternative techniques for delivery. The purpose of this study is to report technical success and adverse events of transforaminal intrathecal delivery of nusinersen. METHODS: 28 patients, mean age 24.1±9.8 years (range 10.0-51.0 years), with intermediate or late onset SMA, underwent a combined 200 transforaminal nusinersen injections. All patients had osseous fusion or spinal instrumentation precluding standard posterior access routes. Patients who underwent nusinersen injections using a technique other than transforaminal lumbar puncture (n=113) were excluded. Technical success, adverse events (AEs) and radiation exposure were recorded. RESULTS: 200 (100%) procedures were technically successful; 6 (3%) required a second level of attempt for access. 187 (93.5%) interventions were completed using cone beam computed tomography (CBCT) with two-axis fluoroscopic navigational overlay. 13 (6.5%) procedures were performed with fluoroscopic-guidance only at subsequent sessions. There were 8 (4.0%) mild AEs and 2 (0.5%) severe AEs; one patient received antibiotics for possible traversal of the large bowel but did not develop meningitis, and one patient developed aseptic meningitis. Mean air kerma was 74.5±161.3 mGy (range 5.2-1693.0 mGy). CONCLUSION: Transforaminal intrathecal delivery of nusinersen is feasible and safe for gaining access in patients with distorted spinal anatomy. The use of CBCT delineates anatomy and optimizes needle trajectory during the initial encounter, and may be used selectively for subsequent procedures.

Thioredoxin Interacting Protein Is Required for a Chronic Energy-Rich Diet to Promote Intestinal Fructose Absorption.

Increased consumption of fats and added sugars has been associated with an increase in metabolic syndromes. Here we show that mice chronically fed an energy-rich diet (ERD) with high fat and moderate sucrose have enhanced the absorption of a gastrointestinal fructose load, and this required expression of the arrestin domain protein Txnip in the intestinal epithelial cells. ERD feeding induced gene and protein expression of Glut5, and this required the expression of Txnip. Furthermore, Txnip interacted with Rab11a, a small GTPase that facilitates the apical localization of Glut5. We also demonstrate that ERD promoted Txnip/Glut5 complexes in the apical intestinal epithelial cell. Our findings demonstrate that ERD facilitates fructose absorption through a Txnip-dependent mechanism in the intestinal epithelial cell, suggesting that increased fructose absorption could potentially provide a mechanism for worsening of metabolic syndromes in the setting of a chronic ERD.

Molecular mechanisms of heart regeneration.

The adult mammalian heart is incapable of clinically relevant regeneration. The regenerative deficit in adult mammalian heart contrasts with the fetal and neonatal heart, which demonstrate substantial regenerative capacity after injury. This deficiency in adult mammals is attributable to the lack of resident stem cells after birth, combined with an inability of pre-existing cardiomyocytes to complete cytokinesis. Studies of neonatal heart regeneration in mammals suggest that latent regenerative potential can be re-activated. Dissecting the cellular and molecular mechanisms that promote cardiomyocyte proliferation is key to stimulating true regeneration in adult humans. Here, we review recent advances in our understanding of cardiomyocyte proliferation that suggest molecular approaches to heart regeneration.

Effect of dietary fat and sucrose consumption on cardiac fibrosis in mice and rhesus monkeys.

Calorie restriction (CR) improved health span in 2 longitudinal studies in nonhuman primates (NHPs), yet only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institute on Aging (NIA) study did not. Here, analysis of left ventricle samples showed that CR did not reduce cardiac fibrosis relative to controls. However, there was a 5.9-fold increase of total fibrosis in UW hearts, compared with NIA hearts. Diet composition was a prominent difference between the studies; therefore, we used the NHP diets to characterize diet-associated molecular and functional changes in the hearts of mice. Consistent with the findings from the NHP samples, mice fed a UW or a modified NIA diet with increased sucrose and fat developed greater cardiac fibrosis compared with mice fed the NIA diet, and transcriptomics analysis revealed diet-induced activation of myocardial oxidative phosphorylation and cardiac muscle contraction pathways.

Short-chain fatty acid delivery: assessing exogenous administration of the microbiome metabolite acetate in mice.

Short-chain fatty acids (SCFAs) are fermentation by-products of gut microbes which have been linked to positive effects on host physiology; the most abundant SCFA is acetate. Exogenous administration of acetate alters host metabolism, immune function, and blood pressure, making it a biologic of interest. The effects of acetate have been attributed to activation of G-protein-coupled receptors and other proteins (i.e., HDACs), often occurring at locations distant from the gut such as the pancreas or the kidney. However, due to technical difficulties and costs, studies have often delivered exogenous acetate without determining if systemic plasma acetate levels are altered. Thus, it is unclear to what extent each method of acetate delivery may alter systemic plasma acetate levels. In this study, we aimed to determine if acetate is elevated after exogenous administration by drinking water (DW), oral gavage (OG), or intraperitoneal (IP) injection, and if so, over what timecourse, to best inform future studies. Using a commercially available kit, we demonstrated that sodium acetate delivered over 21 days in DW does not elicit a measurable change in systemic acetate over baseline. However, when acetate is delivered by OG or IP injection, there are rapid, reproducible, and dose-dependent changes in plasma acetate. These studies report, for the first time, the timecourse of changes in plasma acetate following acetate administration by three common methods, and thus inform the best practices for exogenous acetate delivery.