Shanat Baig

Obesity represents a major global healthcare crisis, with childhood obesity rising at an alarming rate. Children with obesity are highly likely to carry it into adulthood, bringing numerous associated health risks. Even more troubling is the emerging understanding of “obesity memory”, which contributes to the frequent issue of weight regain. Here, we show that obesity imprints CD4 T cells through DNA methylation, leading to a long-time lag, spanning years, before adaptive immune homeostasis is restored after weight loss. Differential DNA methylation analysis highlights autophagy and immune senescence as potential key mechanisms underpinning this memory of obesity in CD4 T cells. In addition, particularly palmitate could be a key saturated fatty acid that can contribute to epigenetic alterations in CD4 T cells, potentially perpetuating this altered state. We identify molecular candidates (i.e., Stk26 and Cdkn1c) underpinning key cell functions (autophagy and immune senescence) that could be targeted to promote a return to immune homeostasis alongside weight loss. These findings raise the possibility that targeting such pathways could support the restoration of immune homeostasis alongside weight loss therapies.

Kidney donation reduces renal function by ≈30% allowing study of the cardiovascular effects of a reduced estimated glomerular filtration rate without comorbidities. We report 5-year results of a longitudinal, parallel-group, blinded end-point study of living kidney donors (n=50) and healthy controls (n=45). The primary end point, left ventricular mass, was measured using cardiac magnetic resonance. Secondary end points, 24-hour ambulatory blood pressure, and pulse wave velocity were measured using validated blood pressure monitors and the SphygmoCor device. Effect sizes were calculated as differences between change from baseline in the donor and control groups. In donors, estimated glomerular filtration rate was 95±15 mL/min per 1.73 m2 at baseline (predonation) and 67±14 mL/min per 1.73 m2 at 5 years. In controls, there was a −1±2 mL/min per 1.73 m2 decline per annum. Change in left ventricular mass at 5 years was not significantly different between donors and controls (mean difference, +0.40 g [95% CI, −4.68 to 5.49] P =0.876), despite an initial increase in mass in donors compared with controls at 12 months. Pulse wave velocity, which increased in donors at 12 months, returned to levels not different from controls at 5 years (mean difference, −0.24 m/s [95% CI, −0.69 to 0.21]). Change in ambulatory systolic blood pressure was not different in donors compared with controls (mean difference, +1.91 mm Hg [95% CI, −2.72 to 6.54]). We found no evidence that the reduction in estimated glomerular filtration rate after kidney donation was associated with a change in left ventricular mass detectable by magnetic resonance imaging at 5 years.

Background: Alström syndrome (ALMS) is a rare ciliopathy characterised by early onset insulin resistance, obesity, and dyslipidaemia and is a model for diseases that have huge social, health and economic impact. Cardiomyopathy develops in the majority, with high rates of morbidity and mortality, the definitive features of which are coarse replacement fibrosis and diffuse myocardial fibrosis (DIF). The pathogenesis of heart failure is thought to involve fibroblast accumulation and expansion of the extracellular matrix with excess protein deposition, leading to distorted organ architecture and impaired contractile function. Consecutive adults with genetically proven ALMS attending the National Centre for Rare Disease in Birmingham, England were studied. All patients underwent serial CMR, echocardiography and venous blood sampling, with computed tomography coronary angiography (CTCA) performed to assess severity of CAD. The aims of this study were: 1) to evaluate changes over time in DIF by cardiovascular magnetic resonance tissue characterization in ALMS; 2) to examine whether changes in DIF are associated with alteration in systolic or diastolic function; and 3) to evaluate the frequency and severity of coronary artery disease as a confounder for progression of ischaemic versus non-ischaemic fibrosis. Results: In total, 30/32 adults (63% male; 67% White British) participated. The median age at first scan was 21.3 years (interquartile range: 19.0–32.6) and participants were followed for a maximum of 67 months. Only 4 patients had significant coronary artery stenosis on post-mortem, invasive coronary angiography or CTCA. Mid short axis myocardial T1 times, myocardial extracellular volume, and left ventricular mass increased significantly over time, by an average of 21.8 ms (95% CI 17.4–26.1; p < 0.001), 1.1 percentage points (0.6–1.6, p < 0.001), and 2.8 g/m² (1.9–3.7; p < 0.001) per year, respectively. These changes were not associated with significant deterioration in myocardial structure or function. Conclusions: This is the first comprehensive prospective study demonstrating progression of DIF in ALMS over time, although no structural or functional consequences were noted within a median three and a half years’ follow up. Further study is warranted to define whether DIF is a by-stander or the driver to impaired contractile function, heart failure and death.

Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti-inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS. This is a Phase 2, single-centre, single-arm, open-label trial. A total of 18 patients with ALMS will be enrolled to receive PBI-4050 at a total daily oral dose of 800 mg for an initial 24 weeks with continuation for an additional 36 or 48 weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests. This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality. The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217 , February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015–001625-16, Sept 2015).

Background Fabry disease (FD) is an X-linked lysosomal storage disorder leading to intracellular accumulation of glycosphingolipid affecting multiple organs including the heart. Cardiac involvement is characterised by progressive left ventricular hypertrophy (LVH), fibrosis and heart failure. Progressive impairment of global longitudinal strain by speckle tracking echocardiography has been extensively described, with its use as a marker of systolic dysfunction validated in patients with advanced FD cardiomyopathy. CMR imaging is now at the forefront in the assessment of cardiovascular complications of FD and is the gold standard for measurement of cardiac volumes, ejection fraction (EF) and mass. Additionally, it allows detection of sphingolipid storage by T1 mapping and functional evaluation using feature tracking. We aim to characterise the relationship between systolic strain and myocardial deposition of sphingolipid across the spectrum of Fabry cardiomyopathy. Methods This is a cross-sectional, international multicentre study of 166 patients with genetically confirmed FD. All participants underwent CMR (1.5T, Avanto (UK) and Aera (Australia)) using a standardised clinical protocol with late gadolinium enhancement imaging. T1 mapping was performed on basal LV short axis slices using a Modified Look-Locker Inversion recovery (MOLLI) sequence, with region of interest values taken from basal septum. LVH was defined as elevated LV mass indexed for body surface area (LVMi) and low native T1 was defined from normalised reference ranges using healthy volunteers from individual centres (mean±2 SD). Systolic strain parameters (3D peak global longitudinal, GLS; circumferential, GCS; and radial, GRS) were obtained using CVI42 software. Results The mean age of patients was 44±15.16 years, with 63.9% female (n=106) and 36.1% male (n=60). In those with LVH (LVH+, n=72) low T1 reflecting storage was common (94%), whereas in those without LVH (LVH-, n=94) storage was present in less than half (41.5% low T1 vs 58.5% normal T1). There was no significant correlation between LVEF and LVMi (r=−0.38, p=0.625) but LVMi correlated with impairment of all systolic strain parameters (GLS: r=0.556, pConclusion Increasing LV mass is a marker of progressive FD cardiomyopathy and although not associated with impaired LVEF, is associated with impaired contractility measured by reduced myocardial strain. In early cardiac involvement with sphingolipid storage but no LVH, there is no change in contractility. In summary, impaired myocardial function in FD is a product both of storage and structural change with LVH.