ORCID Profile
0000-0002-6258-1299
Current Organisations
University of Oxford, Wadham College
,
Aarhus University
,
University of Oxford
,
Aarhus Universitet
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Publisher: Wiley
Date: 24-07-2018
DOI: 10.1002/NBM.3992
Publisher: Elsevier BV
Date: 11-2021
Publisher: Springer Science and Business Media LLC
Date: 08-06-2021
DOI: 10.1038/S41467-021-23660-5
Abstract: Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene–environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-05-2023
DOI: 10.1161/CIRCULATIONAHA.122.062021
Abstract: Sodium–glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness. EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF n=36 left ventricular ejection fraction ≤40% New York Heart Association class ≥II NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF n=36 left ventricular ejection fraction ≥50% New York Heart Association class ≥II NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr/ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated. Empagliflozin treatment did not change cardiac energetics (ie, PCr/ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin – placebo], –0.25 [95% CI, –0.58 to 0.09] P =0.14) or HFpEF (adjusted mean treatment difference, –0.16 [95% CI, –0.60 to 0.29] P =0.47]. Likewise, there were no changes in PCr/ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, –0.13 [95% CI, –0.35 to 0.09] P =0.23) or HFpEF (adjusted mean treatment difference, –0.22 [95% CI, –0.66 to 0.23] P =0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed. In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF. URL: www.clinicaltrials.gov Unique identifier: NCT03332212.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-11-2021
DOI: 10.1161/CIRCULATIONAHA.121.054858
Abstract: Transient pulmonary congestion during exercise is emerging as an important determinant of reduced exercise capacity in heart failure with preserved ejection fraction (HFpEF). We sought to determine whether an abnormal cardiac energetic state underpins this process. We recruited patients across the spectrum of diastolic dysfunction and HFpEF (controls, n=11 type 2 diabetes, n=9 HFpEF, n=14 and severe diastolic dysfunction attributable to cardiac amyloidosis, n=9). Cardiac energetics were measured using phosphorus spectroscopy to define the myocardial phosphocreatine to ATP ratio. Cardiac function was assessed by cardiovascular magnetic resonance cine imaging and echocardiography and lung water using magnetic resonance proton density mapping. Studies were performed at rest and during submaximal exercise using a magnetic resonance imaging ergometer. Paralleling the stepwise decline in diastolic function across the groups (E/e′ ratio P .001) was an increase in NT-proBNP (N-terminal pro-brain natriuretic peptide P .001) and a reduction in phosphocreatine/ATP ratio (control, 2.15 [2.09, 2.29] type 2 diabetes, 1.71 [1.61, 1.91] HFpEF, 1.66 [1.44, 1.89] cardiac amyloidosis, 1.30 [1.16, 1.53] P .001). During 20-W exercise, lower left ventricular diastolic filling rates (r=0.58 P .001), lower left ventricular diastolic reserve (r=0.55 P .001), left atrial dilatation (r=–0.52 P .001), lower right ventricular contractile reserve (right ventricular ejection fraction change, r=0.57 P .001), and right atrial dilation (r=–0.71 P .001) were all linked to lower phosphocreatine/ATP ratio. Along with these changes, pulmonary proton density mapping revealed transient pulmonary congestion in patients with HFpEF (+4.4% [0.5, 6.4] P =0.002) and cardiac amyloidosis (+6.4% [3.3, 10.0] P =0.004), which was not seen in healthy controls (–0.1% [–1.9, 2.1] P =0.89) or type 2 diabetes without HFpEF (+0.8% [–1.7, 1.9] P =0.82). The development of exercise-induced pulmonary congestion was associated with lower phosphocreatine/ATP ratio (r=–0.43 P =0.004). A gradient of myocardial energetic deficit exists across the spectrum of HFpEF. Even at low workload, this energetic deficit is related to markedly abnormal exercise responses in all 4 cardiac chambers, which is associated with detectable pulmonary congestion. The findings support an energetic basis for transient pulmonary congestion in HFpEF.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jack Miller.