Research Spotlight

Pannia, E., Hammoud, R., Simonian, R., Arning, E., Ashcraft, P., Wasek, B., Bottiglieri, T., Pausova, Z., Kubant, R. and Anderson, G.H. (2020). “[6S]-5-Methyltetrahydrofolic Acid and Folic Acid Pregnancy Diets Differentially Program Metabolic Phenotype and Hypothalamic Gene Expression of Wistar Rat Dams Post-Birth.” Nutrients 13(1).

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[6S]-5-methyltetrahydrofolic acid (MTHF) is a proposed replacement for folic acid (FA) in diets and prenatal supplements. This study compared the effects of these two forms on maternal metabolism and hypothalamic gene expression. Pregnant Wistar rats received an AIN-93G diet with recommended FA (1X, 2 mg/kg, control), 5X-FA or equimolar levels of MTHF. During lactation they received the control diet and then a high fat diet for 19-weeks post-weaning. Body weight, adiposity, food intake, energy expenditure, plasma hormones, folate, and 1-carbon metabolites were measured. RNA-sequencing of the hypothalamus was conducted at parturition. Weight-loss from weaning to 1-week post-weaning was less in dams fed either form of the 5X vs. 1X folate diets, but final weight-gain was higher in 5X-MTHF vs. 5X-FA dams. Both doses of the MTHF diets led to 8% higher food intake and associated with lower plasma leptin at parturition, but higher leptin at 19-weeks and insulin resistance at 1-week post-weaning. RNA-sequencing revealed 279 differentially expressed genes in the hypothalamus in 5X-MTHF vs. 5X-FA dams. These findings indicate that MTHF and FA differ in their programing effects on maternal phenotype, and a potential adverse role of either form when given at the higher doses.

Ong, G., Pibarot, P., Redfors, B., Weissman, N.J., Jaber, W.A., Makkar, R.R., Lerakis, S., Gopal, D., Khalique, O., Kodali, S.K., Thourani, V.H., Anwaruddin, S., McAndrew, T., Zhang, Y., Alu, M.C., Douglas, P.S. and Hahn, R.T. (2020). “Diastolic Function and Clinical Outcomes After Transcatheter Aortic Valve Replacement: PARTNER 2 SAPIEN 3 Registry.” J Am Coll Cardiol 76(25): 2940-2951.

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BACKGROUND: Few studies have evaluated if diastolic function could predict outcomes in patients with aortic stenosis. OBJECTIVES: The authors aimed to assess the association between diastolic dysfunction (DD) and outcomes in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR). METHODS: Baseline, 30-day, and 1- and 2-year transthoracic echocardiograms from the PARTNER (Placement of Aortic Transcatheter Valves) 2 SAPIEN 3 registry were analyzed by a consortium of core laboratories and divided into the American Society of Echocardiography DD groups. RESULTS: Among the 1,750 included, 682 (54.4%) had grade 1 DD, 352 (28.1%) had grade 2 DD, 168 (13.4%) had grade 3 DD, and 51 (4.1%) had indeterminate DD grade. Incremental baseline grades of DD were associated with an increase in combined 1- and 2-year cardiovascular (CV) death/rehospitalization (all p < 0.002) and all-cause death at 2 years (p = 0.01) but not at 1 year. Improvement in DD grade/grade 1 DD at 30 days post-TAVR was seen in 70.8% patients. Patients with improvement in ≥1 grade of DD/grade 1 DD had reduced 1-year CV death/rehospitalization (p < 0.001) and increased 2-year survival (p = 0.01). Baseline grade 3 DD was a predictor of 1-year CV death/rehospitalization (hazard ratio: 2.73; 95% confidence interval: 1.07 to 6.98; p = 0.04). Improvement in DD grade/grade 1 DD at 30 days was protective for 1-year CV death/rehospitalizations (hazard ratio: 0.39; 95% confidence interval: 0.19 to 0.83; p = 0.01). CONCLUSIONS: In the PARTNER 2 SAPIEN 3 registry, baseline DD was a predictor of up to 2 years clinical outcomes in patients who underwent TAVR. Improvement in DD grade at 30 days was associated with improvement in short-term clinical outcomes. (The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - PARTNER II - PARTNERII - S3 Intermediate [PARTNERII S3i]; NCT03222128; PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - High Risk and Nested Registry 7 [PII S3HR/NR7]; NCT03222141).

Nelson, M.R., Zhang, X., Pan, Z., Spechler, S.J. and Souza, R.F. (2020). “Mast Cell Effects on Esophageal Smooth Muscle and their Potential Role in Eosinophilic Esophagitis and Achalasia.” Am J Physiol Gastrointest Liver Physiol Dec 23. [Epub ahead of print].

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Mast cells and eosinophils are the key effector cells of allergic disorders. Although most studies on eosinophilic esophagitis (EoE), an allergic disorder of the esophagus, have focused on the role of eosinophils, recent studies suggest a major role for mast cells in causing the clinical manifestations of this disease. Cellular and animal studies have demonstrated that mast cells can cause esophageal muscle cells to proliferate and differentiate into a more contractile phenotype, and that mediators released by degranulating mast cells such as tryptase and histamine can activate smooth muscle contraction pathways. Thus, activated mast cells in the esophageal muscularis propria might cause esophageal motility abnormalities, including the failure of lower esophageal sphincter relaxation typical of achalasia. In addition, mast cells have been implicated in the pathogenesis of a number of neurodegenerative disorders of the central nervous system such as Alzheimer’s and Parkinson’s diseases, because degranulating mast cells release pro-inflammatory and cytotoxic mediators capable of damaging neurons. Such mast cell degranulation in the myenteric plexus of the esophagus could cause the loss of enteric neurons that characterizes achalasia. In this report, we review the molecular mechanisms of esophageal smooth muscle contraction, and how mast cells products might affect that muscle and cause neurodegeneration in the esophagus. Based on these data, we present our novel, conceptual model for an allergy-induced form of achalasia mediated by mast cell activation in the esophageal muscularis propria

Natale, A., Calkins, H., Osorio, J., Pollak, S.J., Melby, D., Marchlinski, F.E., Athill, C.A., Delaughter, C., Patel, A.M., Gentlesk, P.J., DeVille, B., Macle, L., Ellenbogen, K.A., Dukkipati, S.R., Reddy, V.Y. and Mansour, M. (2020). “Positive Clinical Benefit on Patient Care, Quality of Life and Symptoms After Contact-Force Guided Radiofrequency Ablation in Persistent Atrial Fibrillation: Analyses from PRECEPT Prospective Multicenter Study.” Circ Arrhythm Electrophysiol Dec 8. [Epub ahead of print].

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Background – There is limited evidence on the long-term clinical benefits of catheter ablation in patients with persistent atrial fibrillation (PsAF). Methods – PRECEPT was a prospective, multicenter, single-arm Food and Drug Administration-regulated Investigational Device Exemption clinical study. Patients were followed up to 15 months after ablation. Outcomes included use of antiarrhythmic drugs (AADs), rate of cardioversions and cardiovascular hospitalization, Atrial Fibrillation Effect on Quality-of-Life (AFEQT) score, and Canadian Cardiovascular Society Severity of Atrial Fibrillation (CCS-SAF) score. Results – A total of 333 enrolled PsAF patients underwent ablation. The cardioversion rate decreased by 83% at the 9-15 months follow-up. AAD utilization decreased by 69% at 12-15 months post-ablation. The Kaplan-Meier estimate of freedom from cardiovascular hospitalization was 84.2% [95% confidence interval: 80.2%, 88.2%] at 15 months. Consistent improvements in mean AFEQT composite (+50.0) were seen at 6 months, sustained at 15 months, and exceeded the minimum clinically important difference. Improvements in AFEQT scores were significantly better among participants without documented atrial arrhythmia recurrences. By CCS-SAF symptom classification, over 80% of patients were asymptomatic (Class 0) at 15 months post-ablation compared to only 0.7% at baseline. Conclusions – Contact force-guided radiofrequency ablation of PsAF was associated with a significant decrease in AAD use, cardioversion rate and hospitalization. Clinically meaningful improvements in quality of life were observed in all patients. Majority of the patients (>80%) were asymptomatic at 15 months post-ablation. The positive clinical impact of improved quality of life and reduced healthcare utilization may help with shared decision making in PsAF treatment.

Naik, C.A., Mathai, S.K., Sandkovsky, U.S., Ausloos, K.A., Guileyardo, J.M., Schwartz, G., Mason, D.P., Gottlieb, R. and Grazia, T.J. (2021). “Acute myocardial infarction secondary to mucormycosis after lung transplantation.” IDCases 23: e01019.

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We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.