Research Spotlight

Pannia, E., R. Hammoud, R. Kubant, J. Sa, N. Yang, M. Ho, D. Chatterjee, Z. Pausova, E. Arning, T. Bottiglieri and G. H. Anderson (2019). “5-Methyltetrahydrofolate in Maternal Diets Alters DNA Methylation Potential and Increases Later Life Weight Gain and Food Intake in Wistar Rat Dams and Female Offspring (P11-022-19).” Curr Dev Nutr Volume 3, Issue Supplement 1, June 2019. [Epub ahead of print].

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Objectives: Diet during pregnancy programs the mother and offspring post-weaning (PW). Folic acid (FA, synthetic folate) mediates DNA methylation (DNAm) reactions and high intakes, simulating those consumed by American women, lead to epigenetic dysregulation of energy metabolic pathways. 5-methyltetrahydrofolate (5MTHF), the bioactive folate form, has gained popularity as a supplement due to direct cellular uptake and utilization and does not increase unmetabolized FA (UMFA). However, a comparison of folate forms on in utero programming of offspring or maternal health has not been reported. Our objectives were to compare the effects of folate dose (low vs high) and form (FA vs 5MTHF) during pregnancy on DNAm potential, and the early and later PW phenotype of Wistar rat mothers and female offspring (mothers-to-be). Methods: Pregnant Wistar rats (n = 22/group) were fed an AIN93G diet with recommended FA (1X, 2mg/kg diet), 5X-FA or equimolar 5MTHF. Dams were fed 1X-FA during lactation and then dams and female pups were fed a high fat diet for 19 weeks. Weight gain (WG), food intake (FI), energy expenditure (EE), insulin resistance (IR), plasma 5MTHF, UMFA, homocysteine (tHcy), and hepatic S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and DNA methyltransferases (DNMT) activity at birth and PW were measured. Results: Dams fed 5MTHF diets had lower DNMT activity at birth and female pups had higher SAM: SAH ratios (P < 0.05) indicative of altered DNAm potential compared to FA diets. Plasma 5MTHF at birth was dose dependent with 5X diets leading to higher levels than 1X diets (P < 0.001) in dams and pups. In contrast, UMFA was only higher in 5X-FA dams. 5MTHF dams had higher tHcy at birth and were more IR at 1 week PW than FA fed dams (P < 0.05). In both dams and offspring, high 5MTHF also led to higher WG (> 15%, P < 0.001) and FI (> 5%, P < 0.001) compared to high FA diets up to 19 weeks. EE (P < 0.05) was higher suggesting a compensatory response to WG. 5X-MTHF dams, but not offspring, also had greater hepatic lipids (P < 0.05) than other groups. Conclusions: Folate dose and form during pregnancy affects DNAm potential at birth and early and later phenotype of dams and female offspring. High 5MTHF increases WG, FI and hepatic lipids PW suggesting it may not be the preferred form for prenatal supplements or additions to the food supply. Funding Sources: Supported by CIHR-INMD; EP supported by NSERC-CGS D.

Packer, M. (2019). “Is Long-Standing Atrial Fibrillation a Biomarker of or Contributor to the Symptoms or Progression of Chronic Heart Failure?” Am J Med Jun 17. [Epub ahead of print].

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There is consensus that atrial fibrillation is a biomarker of the disease process in heart failure. Prolonged atrial distension due to chronic increases in left ventricular filling pressures contributes to the genesis of the arrhythmia. The disease process in the ventricles can also affect the atrial myocardium. Additionally, the atria are susceptible to fibrosis that results from the inflammation of epicardial adipose tissue that is seen in obesity or diabetes. The degree of atrial fibrosis is particularly marked in patients with persistent and long-standing atrial fibrillation. When the left atrium is severely fibrotic, restoration of sinus rhythm does not fully restore force transmission to the left ventricle. Patients with heart failure are at increased risk of stroke and systemic thromboembolism, whether in sinus rhythm or atrial fibrillation. The risk of stroke is higher in those with atrial fibrillation, perhaps because their atrial disease is more severe. Unless contraindicated, patients with atrial fibrillation should receive non–vitamin K-dependent oral anticoagulants, which have been shown to be noninferior or superior to warfarin in preventing stroke, but carry a lower risk of intracranial bleeding, particularly in patients with heart failure. However, even in sinus rhythm, the use of these drugs (e.g., rivaroxaban) in chronic heart failure appears to reduce the risk of stroke. Does atrial fibrillation itself contribute to the progression of heart failure? Atrial tachyarrhythmias can lead to cardiomyopathy, but if high ventricular rates can be minimized, irregularity of the ventricular response does not adversely affect cardiac performance. In patients whose rate is < 100 per minute, the outcomes of patients with atrial fibrillation are not influenced by the rapidity of the ventricular response. Additionally, although it is commonly believed that patients with heart failure with atrial fibrillation fare worse than those in sinus rhythm, this risk is confined to those with paroxysmal or recent-onset arrhythmias. Longstanding atrial fibrillation is not associated with an increased risk of death or hospitalization for heart failure, as compared with sinus rhythm. (Excerpt from article in press, unpaginated; no abstract available.)

Packer, M. (2019). “Effect of catheter ablation on pre-existing abnormalities of left atrial systolic, diastolic, and neurohormonal functions in patients with chronic heart failure and atrial fibrillation.” Eur Heart J 40(23): 1873-1879.

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The critical role of the left atrium (LA) in cardiovascular homoeostasis is mediated by its reservoir, conduit, systolic, and neurohormonal functions. Atrial fibrillation is generally a reflection of underlying disease of the LA, especially in patients with heart failure. Disease-related LA remodelling leads to a decline in both atrial contractility and distensibility along with an impairment in the control of neurohormonal systems that regulate intravascular volume. Catheter ablation can lead to further injury to the atrial myocardium, as evidenced by post-procedural troponin release and tissue oedema. The cardiomyocyte loss leads to replacement fibrosis, which may affect up to 30-35% of the LA wall. These alterations further impair atrial force generation and neurohormonal functions; the additional loss of atrial distensibility can lead to a ‘stiff LA syndrome’, and the fibrotic response predisposes to recurrence of the atrial arrhythmia. Although it intends to restore LA systole, catheter ablation often decreases the chamber’s transport functions. This is particularly likely in patients with long-standing atrial fibrillation and pre-existing LA fibrosis, especially those with increased epicardial adipose tissue (e.g. patients with obesity, diabetes and/or heart failure with a preserved ejection fraction). Although the fibrotic LA in these individuals is an ideal substrate for the development of atrial fibrillation, it may be a suboptimal substrate for catheter ablation. Such patients are not likely to experience long-term restoration of sinus rhythm, and catheter ablation has the potential to worsen their haemodynamic and clinical status. Further studies in this vulnerable group of patients are needed.

Osoegawa, K., K. C. Mallempati, S. Gangavarapu, A. Oki, K. Gendzekhadze, S. R. Marino, N. K. Brown, M. P. Bettinotti, E. T. Weimer, G. Montero-Martin, L. E. Creary, T. A. Vayntrub, C. J. Chang, M. Askar, S. J. Mack and M. A. Fernandez-Vina (2019). “HLA alleles and haplotypes observed in 263 US families.” Hum Immunol Jun 27. [Epub ahead of print].

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The 17th International HLA and Immunogenetics Workshop (IHIW) conducted a project entitled “The Study of Haplotypes in Families by NGS HLA”. We investigated the HLA haplotypes of 1017 subjects in 263 nuclear families sourced from five US clinical immunogenetics laboratories, primarily as part of the evaluation of related donor candidates for hematopoietic stem cell and solid organ transplantation. The parents in these families belonged to five broad groups – African (72 parents), Asian (115), European (210), Hispanic (118) and “Other” (11). High-resolution HLA genotypes were generated for each subject using next-generation sequencing (NGS) HLA typing systems. We identified the HLA haplotypes in each family using HaplObserve, software that builds haplotypes in families by reviewing HLA allele segregation from parents to children. We calculated haplotype frequencies within each broad group, by treating the parents in each family as unrelated individuals. We also calculated standard measures of global linkage disequilibrium (LD) and conditional asymmetric LD for each ethnic group, and used untruncated and two-field allele names to investigate LD patterns. Finally we demonstrated the utility of consensus DNA sequences in identifying novel variants, confirming them using HLA allele segregation at the DNA sequence level.

Obelenis Ryan, D. P., J. Bianchi, J. Ignacio, L. M. Wolford and J. R. Goncalves (2019). “Cone-beam computed tomography airway measurements: Can we trust them?” Am J Orthod Dentofacial Orthop 156(1): 53-60.

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INTRODUCTION: Pharyngeal airway space (PAS) assessment has been used in the past for a better understanding of orthodontic and surgical outcomes; however, this analysis could be unreliable. Our objective was to evaluate possible changes in the PAS reading in the same patient from their consecutive cone-beam computed tomography (CBCT) scans. METHODS: We evaluated a total of 27 patients’ CBCT scans obtained at 2 time points with the use of a standardized acquisition protocol. The mean age at T0 was 31 years (range 17-62 years) and the follow-up records (T1) were taken after 4-6 months. Dolphin Imaging software was used to measure the volumes of the nasopharynx, oropharynx, and hypopharynx. We also evaluated the craniocervical position with the use of a lateral cephalogram. RESULTS: The variables exhibited high intraclass correlation coefficients (ICCs) when measuring the same CBCT scan twice (T0 and T0). However, The ICC between the measurements performed on the first and second CBCT scans (T0 and T1) showed that the only variable with high reproducibility between the 2 scans was cranial base, with an ICC >0.97. Average differences of 682.1 mm(3), 2255.3 mm(3), and 517.4 mm(3) were found for the nasopharynx, oropharynx, and hypopharynx, respectively. Regarding the cephalometric angles, average differences between T0 and T1 scans were 0.6 degrees , 2.7 degrees , and 0.4 degrees for OPT.CVT, OPT.SN, and cranial base, respectively. CONCLUSIONS: Different CBCT exams with equal scanning and patient positioning protocols can result in different 3D PAS readings. A more careful interpretation of CBCT volumetric data to achieve adequate conclusions of the clinical outcomes is necessary.