Publications by authors named "Mark T Kearney"

142 Publications

Pericyte insulin receptors modulate retinal vascular remodeling and endothelial angiopoietin signaling.

Endocrinology 2021 Aug 30. Epub 2021 Aug 30.

Leeds Institute of Cardiovascular and Metabolic Medicine, The University of Leeds, Leeds, United Kingdom.

Pericytes regulate vascular development, stability and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFR β-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited peri-venous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers. Pericyte coverage of capillaries was unaltered in peri-venous and peri-arterial plexi and no differences in vascular regression or endothelial proliferation were apparent. Isolated brain pericytes from PIRKO had decreased angiopoietin-1 mRNA, whereas retinal and lung angiopoietin-2 mRNA was increased. Endothelial phospho-Tie2 staining was diminished and FoxO1 was more frequently nuclear localized in the peri-venous plexus of PIRKO, in keeping with reduced angiopoietin-Tie2 signaling. Silencing of Insr in human brain pericytes led to reduced insulin-stimulated angiopoietin-1 secretion, and conditioned media from these cells was less able to induce Tie2 phosphorylation in human endothelial cells. Hence, insulin signaling in pericytes promotes angiopoietin-1 secretion and endothelial Tie2 signaling and perturbation of this leads to excessive vascular sprouting and venous plexus abnormalities. This phenotype mimics elements of diabetic retinopathy, and future work should evaluate pericyte insulin signaling in this disease.
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http://dx.doi.org/10.1210/endocr/bqab182DOI Listing
August 2021

Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat.

Circ Res 2021 Sep 21;129(7):720-734. Epub 2021 Aug 21.

Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., H.I., K.B., N.J.H., A.S., K.E.H., E.R.C., V.K.G., P.C., K.J.S., N.M., Y.A., N.E., J.B., A.M.N.W., S.T.F., K.E.P., R.M.C., K.N., D.J.B., S.B.W., M.T.K., P.S.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448413PMC
September 2021

Suboptimal Dosing of β-Blockers in Chronic Heart Failure: A Missed Opportunity?

J Cardiovasc Nurs 2021 Jul 26. Epub 2021 Jul 26.

Melanie McGinlay, RN Heart Failure Nurse Specialist, Leeds Teaching Hospitals NHS Trust, United Kingdom. Sam Straw, MBChB BHF Clinical Research Fellow, Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds, United Kingdom. Rowenna Byrom-Goulthorp, RN Research Nurse, Leeds Teaching Hospitals NHS Trust, United Kingdom. Samuel D. Relton, PhD Senior Research Fellow, Leeds Institute of Health Sciences, University of Leeds, United Kingdom. John Gierula, PhD NIHR Post-Doctoral Research Fellow, Leeds Institute of Cardiovascular and Metabolic Medicine. Richard M. Cubbon, PhD Associate Professor and Consultant Cardiologist, Leeds Institute of Cardiovascular and Metabolic Medicine. Mark T. Kearney, MD Professor and Consultant Cardiologist, Leeds Institute of Cardiovascular and Metabolic Medicine. Klaus K. Witte, MD Associate Professor and Consultant Cardiologist, Leeds Institute of Cardiovascular and Metabolic Medicine.

Background: The evidence base for the benefits of β-blockers in heart failure with reduced ejection fraction (HFrEF) suggests that higher doses are associated with better outcomes.

Objectives: The aim of this study was to report the proportion of patients receiving optimized doses of β-blockers, outcomes, and factors associated with suboptimal dosing.

Methods: This was a prospective cohort study of 390 patients with HFrEF undergoing clinical and echocardiography assessment at baseline and at 1 year.

Results: Two hundred thirty-seven patients (61%) were receiving optimized doses (≥5-mg/d bisoprolol equivalent), 72 (18%) could not be up-titrated (because of heart rate < 60 beats/min or systolic blood pressure <100 mm Hg), and the remaining 81 (21%) should have been. Survival was similarly reduced in those who could not and should have been receiving 5 mg/d or greater, and patient factors did not explain the failure to attain optimized dosing.

Conclusions: Many patients with HFrEF are not receiving optimal dosing of β-blockers, and in around half, there was no clear contraindication in terms of heart rate or blood pressure.
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http://dx.doi.org/10.1097/JCN.0000000000000847DOI Listing
July 2021

Impact of QRS duration on left ventricular remodelling and survival in patients with heart failure.

J Cardiovasc Med (Hagerstown) 2021 Jul 22. Epub 2021 Jul 22.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds Department of Cardiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK Department of Cardiology, Ziekenhuis Oost-Limburg, University Hasselt, Genk, Belgium.

Aims: In patients with chronic heart failure, QRS duration is a consistent predictor of poor outcomes. It has been suggested that for indicated patients, cardiac resynchronization therapy (CRT) could come sooner in the treatment algorithm, perhaps in parallel with the attainment of optimal guideline-directed medical therapy (GDMT). We aimed to investigate differences in left ventricular (LV) remodelling in those with narrow QRS (NQRS) compared with wide QRS (WQRS) in the absence of CRT, whether an early CRT strategy resulted in unnecessary implants and the effect of early CRT on outcomes.

Methods: Our cohort consisted of 214 consecutive patients with LV ejection fraction (LVEF) of 35% or less who underwent repeat echocardiography 1 year after enrolment. Of these, 116 patients had NQRS, and 98 had WQRS of whom 40 received CRT within 1 year and 58 did not.

Results: In the absence of CRT, patients with WQRS had less LV reverse remodelling compared with those with NQRS, with differences in ΔLVEF (+2 vs. +9%, P < 0.001) ΔLV end-diastolic diameter (-1 vs. -2 mm, P = 0.095), ΔLV end-systolic diameter (-2 vs. -4.5 mm, P = 0.038), LV end-systolic volume (-12.6 vs. -25.0 ml, P = 0.054) and LV end-diastolic volume (-7.3 vs. -12.2 ml, P = 0.071). LVEF was more likely to improve by at least 10% if patients had NQRS or received CRT (P = 0.08). Thirteen (24%) patients with WQRS achieved an LVEF greater than 35% in the absence of CRT; however, none achieved greater than 50%.

Conclusion: A strictly linear approach to heart failure therapy might lead to delays to optimal treatment in those patients with the most to gain from CRT and the least to gain from GDMT.
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http://dx.doi.org/10.2459/JCM.0000000000001231DOI Listing
July 2021

Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis.

Endocrinology 2021 Aug;162(8)

Leeds Institute of Cardiovascular and Metabolic Medicine, The University of Leeds, Leeds LS2 9JT, UK.

Endothelial insulin receptors (Insr) promote sprouting angiogenesis, although the underpinning cellular and molecular mechanisms are unknown. Comparing mice with whole-body insulin receptor haploinsufficiency (Insr+/-) against littermate controls, we found impaired limb perfusion and muscle capillary density after inducing hind-limb ischemia; this was in spite of increased expression of the proangiogenic growth factor Vegfa. Insr+/- neonatal retinas exhibited reduced tip cell number and branching complexity during developmental angiogenesis, which was also found in separate studies of mice with endothelium-restricted Insr haploinsufficiency. Functional responses to vascular endothelial growth factor A (VEGF-A), including in vitro angiogenesis, were also impaired in aortic rings and pulmonary endothelial cells from Insr+/- mice. Human umbilical vein endothelial cells with shRNA-mediated knockdown of Insr also demonstrated impaired functional angiogenic responses to VEGF-A. VEGF-A signaling to Akt and endothelial nitric oxide synthase was intact, but downstream signaling to extracellular signal-reduced kinase 1/2 (ERK1/2) was impaired, as was VEGF receptor-2 (VEGFR-2) internalization, which is required specifically for signaling to ERK1/2. Hence, endothelial insulin receptors facilitate the functional response to VEGF-A during angiogenic sprouting and are required for appropriate signal transduction from VEGFR-2 to ERK1/2.
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http://dx.doi.org/10.1210/endocr/bqab104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223729PMC
August 2021

Endothelial IGF-1 receptor mediates crosstalk with the gut wall to regulate microbiota in obesity.

EMBO Rep 2021 05 2;22(5):e50767. Epub 2021 May 2.

Faculty of Medicine and Health, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Changes in composition of the intestinal microbiota are linked to the development of obesity and can lead to endothelial cell (EC) dysfunction. It is unknown whether EC can directly influence the microbiota. Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are critical for coupling nutritional status and cellular growth; IGF-1R is expressed in multiple cell types including EC. The role of ECIGF-1R in the response to nutritional obesity is unexplored. To examine this, we use gene-modified mice with EC-specific overexpression of human IGF-1R (hIGFREO) and their wild-type littermates. After high-fat feeding, hIGFREO weigh less, have reduced adiposity and have improved glucose tolerance. hIGFREO show an altered gene expression and altered microbial diversity in the gut, including a relative increase in the beneficial genus Akkermansia. The depletion of gut microbiota with broad-spectrum antibiotics induces a loss of the favourable metabolic differences seen in hIGFREO mice. We show that IGF-1R facilitates crosstalk between the EC and the gut wall; this crosstalk protects against diet-induced obesity, as a result of an altered gut microbiota.
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http://dx.doi.org/10.15252/embr.202050767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097321PMC
May 2021

Non-communicable disease, sociodemographic factors, and risk of death from infection: a UK Biobank observational cohort study.

Lancet Infect Dis 2021 08 1;21(8):1184-1191. Epub 2021 Mar 1.

Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, UK. Electronic address:

Background: Non-communicable diseases (NCDs) have been highlighted as important risk factors for COVID-19 mortality. However, insufficient data exist on the wider context of infectious diseases in people with NCDs. We aimed to investigate the association between NCDs and the risk of death from any infection before the COVID-19 pandemic (up to Dec 31, 2019).

Methods: For this observational study, we used data from the UK Biobank observational cohort study to explore factors associated with infection death. We excluded participants if data were missing for comorbidities, body-mass index, smoking status, ethnicity, and socioeconomic deprivation, and if they were lost to follow-up or withdrew consent. Deaths were censored up to Dec 31, 2019. We used Poisson regression models including NCDs present at recruitment to the UK Biobank (obesity [defined by use of body-mass index] and self-reported hypertension, chronic heart disease, chronic respiratory disease, diabetes, cancer, chronic liver disease, chronic kidney disease, previous stroke or transient ischaemic attack, other neurological disease, psychiatric disorder, and chronic inflammatory and autoimmune rheumatological disease), age, sex, ethnicity, smoking status, and socioeconomic deprivation. Separate models were constructed with individual NCDs replaced by the total number of prevalent NCDs to define associations with multimorbidity. All analyses were repeated with non-infection-related death as an alternate outcome measure to establish differential associations of infection death and non-infection death. Associations are reported as incidence rate ratios (IRR) accompanied by 95% CIs.

Findings: After exclusion of 9210 (1·8%) of the 502 505 participants in the UK Biobank cohort, our study sample comprised 493 295 individuals. During 5 273 731 person-years of follow-up (median 10·9 years [IQR 10·1-11·6] per participant), 27 729 deaths occurred, of which 1385 (5%) were related to infection. Advancing age, male sex, smoking, socioeconomic deprivation, and all studied NCDs were independently associated with the rate of both infection death and non-infection death. Compared with White ethnicity, a pooled Black, Asian, and minority ethnicity group was associated with a reduced risk of infection death (IRR 0·64, 95% CI 0·46-0·87) and non-infection death (0·80, 0·75-0·86). Stronger associations with infection death than with non-infection death were observed for advancing age (age 65 years vs 45 years: 7·59, 95% CI 5·92-9·73, for infection death vs 5·21, 4·97-5·48, for non-infection death), current smoking (vs never smoking: 3·69, 3·19-4·26, vs 2·52, 2·44-2·61), socioeconomic deprivation (most vs least deprived quintile: 2·13, 1·78-2·56, vs 1·38, 1·33-1·43), class 3 obesity (vs non-obese: 2·21, 1·74-2·82, vs 1·55, 1·44-1·66), hypertension (1·36, 1·22-1·53, vs 1·15, 1·12-1·18), respiratory disease (2·21, 1·96-2·50, vs 1·28, 1·24-1·32), chronic kidney disease (5·04, 4·28-7·31, vs 2·50, 2·20-2·84), psychiatric disease (1·56, 1·30-1·86, vs 1·23, 1·18-1·29), and chronic inflammatory and autoimmune rheumatological disease (2·45, 1·99-3·02, vs 1·41, 1·32-1·51). Accrual of multimorbidity was also more strongly associated with risk of infection death (five or more comorbidities vs none: 9·53, 6·97-13·03) than of non-infection death (5·26, 4·84-5·72).

Interpretation: Several NCDs are associated with an increased risk of infection death, suggesting that some of the reported associations with COVID-19 mortality might be non-specific. Only a subset of NCDs, together with the accrual of multimorbidity, advancing age, smoking, and socioeconomic deprivation, were associated with a greater IRR for infection death than for other causes of death. Further research is needed to define why these risk factors are more strongly associated with infection death, so that more effective preventive strategies can be targeted to high-risk groups.

Funding: British Heart Foundation.
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http://dx.doi.org/10.1016/S1473-3099(20)30978-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323124PMC
August 2021

Diabetes, gender and deterioration in estimated glomerular filtration rate in patients with chronic heart failure: Ten-year prospective cohort study.

Diab Vasc Dis Res 2021 Jan-Feb;18(1):1479164120984433

Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Introduction: We aimed to evaluate the relationship between temporal changes in renal function and long-term mortality in patients with heart failure with reduced ejection fraction (HFrEF) and identify correlates of deteriorating renal function.

Methods: A total of 381 patients with HFrEF enrolled in a prospective cohort study between 2006-2014 had eGFR measured at initial visit and at 1 year. Baseline characteristics were used in a multivariate analysis to establish variables that predict deterioration in eGFR. Follow-up data were used to assess whether declining eGFR was related to outcomes.

Results: Patients were grouped into tertiles based on percentage change in eGFR. In a multivariate logistic regression analysis, male sex was associated with a 1.77-fold ([95% CI 1.01-2.89];  = 0.045) and diabetes a 1.66-fold ([95% CI 1.02-2.70];  = 0.041) greater risk of a decline in eGFR compared to those with stable/improving eGFR. Declining eGFR was associated with a 1.4-fold greater risk of death over 10 years ([95% CI 1.08-1.86];  = 0.01) and a 3.12-fold ([1.44-6.75];  = 0.004) greater risk of death at 1 year from second eGFR measurement.

Conclusions: In patients with HFrEF diabetes and male sex are independent predictors of a decline in eGFR at 1 year. A decline eGFR over 1 year is associated with higher long-term all-cause mortality.
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http://dx.doi.org/10.1177/1479164120984433DOI Listing
September 2021

Advanced care planning during the COVID-19 pandemic: ceiling of care decisions and their implications for observational data.

BMC Palliat Care 2021 Jan 11;20(1):10. Epub 2021 Jan 11.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Background: Observational studies investigating risk factors in coronavirus disease 2019 (COVID-19) have not considered the confounding effects of advanced care planning, such that a valid picture of risk for elderly, frail and multi-morbid patients is unknown. We aimed to report ceiling of care and cardiopulmonary resuscitation (CPR) decisions and their association with demographic and clinical characteristics as well as outcomes during the COVID-19 pandemic.

Methods: Retrospective, observational study conducted between 5th March and 7th May 2020 of all hospitalised patients with COVID-19. Ceiling of care and CPR decisions were documented using the Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) process. Unadjusted and multivariable regression analyses were used to determine factors associated with ceiling of care decisions and death during hospitalisation.

Results: A total of 485 patients were included, of whom 409 (84·3%) had a documented ceiling of care; level one for 208 (50·9%), level two for 75 (18·3%) and level three for 126 (30·8%). CPR decisions were documented for 451 (93·0%) of whom 336 (74·5%) were 'not for resuscitation'. Advanced age, frailty, White-European ethnicity, a diagnosis of any co-morbidity and receipt of cardiovascular medications were associated with ceiling of care decisions. In a multivariable model only advanced age (odds 0·89, 0·86-0·93 p < 0·001), frailty (odds 0·48, 0·38-0·60, p < 0·001) and the cumulative number of co-morbidities (odds 0·72, 0·52-1·0, p = 0·048) were independently associated. Death during hospitalisation was independently associated with age, frailty and requirement for level two or three care.

Conclusion: Ceiling of care decisions were made for the majority of patients during the COVID-19 pandemic, broadly in line with known predictors of poor outcomes in COVID-19, but with a focus on co-morbidities suggesting ICU admission might not be a reliable end-point for observational studies where advanced care planning is routine.
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http://dx.doi.org/10.1186/s12904-021-00711-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797882PMC
January 2021

Association of heart failure and its comorbidities with loss of life expectancy.

Heart 2021 Sep 5;107(17):1417-1421. Epub 2020 Nov 5.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK

Objective: Estimating survival can aid care planning, but the use of absolute survival projections can be challenging for patients and clinicians to contextualise. We aimed to define how heart failure and its major comorbidities contribute to loss of actuarially predicted life expectancy.

Methods: We conducted an observational cohort study of 1794 adults with stable chronic heart failure and reduced left ventricular ejection fraction, recruited from cardiology outpatient departments of four UK hospitals. Data from an 11-year maximum (5-year median) follow-up period (999 deaths) were used to define how heart failure and its major comorbidities impact on survival, relative to an age-sex matched control UK population, using a relative survival framework.

Results: After 10 years, mortality in the reference control population was 29%. In people with heart failure, this increased by an additional 37% (95% CI 34% to 40%), equating to an additional 2.2 years of lost life or a 2.4-fold (2.2-2.5) excess loss of life. This excess was greater in men than women (2.4 years (2.2-2.7) vs 1.6 years (1.2-2.0); p<0.001). In patients without major comorbidity, men still experienced excess loss of life, while women experienced less and were non-significantly different from the reference population (1 year (0.6-1.5) vs 0.4 years (-0.3 to 1); p<0.001). Accrual of comorbidity was associated with substantial increases in excess lost life, particularly for diabetes, chronic kidney and lung disease.

Conclusions: Comorbidity accounts for the majority of lost life expectancy in people with heart failure. Women, but not men, without comorbidity experience survival close to reference controls.
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http://dx.doi.org/10.1136/heartjnl-2020-317833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372397PMC
September 2021

Effect of disease-modifying agents and their association with mortality in multi-morbid patients with heart failure with reduced ejection fraction.

ESC Heart Fail 2020 Sep 13. Epub 2020 Sep 13.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Aims: An increasing proportion of patients with heart failure with reduced ejection fraction (HFrEF) have co-morbidities. The effect of these co-morbidities on modes of death and the effect of disease-modifying agents in multi-morbid patients is unknown.

Methods And Results: We performed a prospective cohort study of ambulatory patients with HFrEF to assess predictors of outcomes. We identified four key co-morbidities-ischaemic aetiology of heart failure, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and chronic kidney disease (CKD)-that were highly prevalent and associated with an increased risk of all-cause mortality. We used these data to explore modes of death and the utilization of disease-modifying agents in patients with and without these co-morbidities. The cohort included 1789 consecutively recruited patients who had an average age of 69.6 ± 12.5 years, and 1307 (73%) were male. Ischaemic aetiology of heart failure was the most common co-morbidity, occurring in 1061 (59%) patients; 503 (28%) patients had diabetes mellitus, 283 (16%) had COPD, and 140 (8%) had CKD stage IV/V. During mean follow-up of 3.8 ± 1.6 years, 737 (41.5%) patients died, classified as progressive heart failure (n = 227, 32%), sudden (n = 112, 16%), and non-cardiovascular deaths (n = 314, 44%). Multi-morbid patients were older (P < 0.001), more likely to be male (P < 0.001), and had higher New York Heart Association class (P < 0.001), despite having higher left ventricular (LV) ejection fraction (P = 0.001) and lower LV end-diastolic diameter (P = 0.001). Multi-morbid patients were prescribed lower doses of disease-modifying agents, especially patients with COPD who received lower doses of beta-adrenoceptor antagonists (2.7 ± 3.0 vs. 4.1 ± 3.4 mg, P < 0.001) and were less likely to be implanted with internal cardioverter defibrillators (7% vs. 13%, P < 0.001). In multivariate analysis, COPD and diabetes mellitus conferred a >2.5-fold and 1.5-fold increased risk of sudden death, whilst higher doses of beta-adrenoceptor antagonists were protective (hazard ratio per milligram 0.92, 95% confidence interval 0.86-0.98, P = 0.009). Each milligram of bisoprolol-equivalent beta-adrenoceptor antagonist was associated with 9% (P = 0.001) and 11% (P = 0.023) reduction of sudden deaths in patients with <2 and ≥2 co-morbidities, respectively.

Conclusions: Higher doses of beta-adrenoceptor antagonist are associated with greater protection from sudden death, most evident in multi-morbid patients. Patients with COPD who appear to be at the highest risk of sudden death are prescribed the lowest doses and less likely to be implanted with implantable cardioverter defibrillators, which might represent a missed opportunity to optimize safe and proven therapies for these patients.
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http://dx.doi.org/10.1002/ehf2.12978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754757PMC
September 2020

Unique Transcriptome Signature Distinguishes Patients With Heart Failure With Myopathy.

J Am Heart Assoc 2020 09 5;9(18):e017091. Epub 2020 Sep 5.

School of Biomedical Sciences Faculty of Biological Sciences University of Leeds United Kingdom.

Background People with chronic heart failure (CHF) experience severe skeletal muscle dysfunction, characterized by mitochondrial abnormalities, which exacerbates the primary symptom of exercise intolerance. However, the molecular triggers and characteristics underlying mitochondrial abnormalities caused by CHF remain poorly understood. Methods and Results We recruited 28 patients with CHF caused by reduced ejection fraction and 9 controls. We simultaneously biopsied skeletal muscle from the pectoralis major in the upper limb and from the vastus lateralis in the lower limb. We phenotyped mitochondrial function in permeabilized myofibers from both sites and followed this by complete RNA sequencing to identify novel molecular abnormalities in CHF skeletal muscle. Patients with CHF presented with upper and lower limb skeletal muscle impairments to mitochondrial function that were of a similar deficit and indicative of a myopathy. Mitochondrial abnormalities were strongly correlated to symptoms. Further RNA sequencing revealed a unique transcriptome signature in CHF skeletal muscle characterized by a novel triad of differentially expressed genes related to deficits in energy metabolism including adenosine monophosphate deaminase 3, pyridine nucleotide-disulphide oxidoreductase domain 2, and lactate dehydrogenase C. Conclusions Our data suggest an upper and lower limb metabolic myopathy that is characterized by a unique transcriptome signature in skeletal muscle of humans with CHF.
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http://dx.doi.org/10.1161/JAHA.120.017091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727001PMC
September 2020

Long-term performance of left ventricular leads in cardiac resynchronisation therapy.

Pacing Clin Electrophysiol 2020 12 28;43(12):1501-1507. Epub 2020 Aug 28.

Department of Cardiology, Leeds General Infirmary, Leeds, UK.

Background: Cardiac resynchronisation therapy (CRT) confers symptomatic and survival benefits in chronic heart failure with reduced ejection fraction (HFrEF). There remains a paucity of data on long-term performance of left ventricular (LV) leads, particularly with newer quadripolar lead designs.

Methods: This single-centre study utilised an electronic, outpatient HFrEF database to identify CRT recipients (2008-2014). The primary endpoint was temporal trend in LV pacing thresholds during follow-up. Secondary outcomes were complications relating to acute or chronic lead failure and device-related infections.

Results: Two hundred eighty patients were included, with mean (±SD) age of 74.2 years (±9.0) and median follow-up of 7.6 years (interquartile range 4-9). Mean LV threshold was 1.37 V (±0.73) at implant and remained stable over the study period. No differences were observed based upon lead manufacturer. Compared to non-quadripolar leads (n = 216), those of quadripolar designs (n = 64) had a lower threshold at 6 months (1.20 vs 1.37 V; P = .04) and at the end of the study period (1.32 vs 1.46 V; P = .04). Patients with HFrEF of ischaemic aetiology had higher thresholds at implant (1.46 vs 1.34 V; P = .05), and this persisted until the end of follow-up (1.49 vs 1.34 V; P = .03). There was low incidence of acute (0.71%; 2/280) and chronic lead failure (1.79%; 5/280), with four cases (1.43%) of device infection.

Conclusions: LV leads in the context of CRT have excellent chronic stability and low rates of adverse events. Those with newer quadripolar lead designs have lower thresholds at initial follow-up and in the longer term.
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http://dx.doi.org/10.1111/pace.14034DOI Listing
December 2020

Prioritizing symptom management in the treatment of chronic heart failure.

ESC Heart Fail 2020 10 5;7(5):2193-2207. Epub 2020 Aug 5.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Clarendon Way, Leeds, LS2 9NL, UK.

Chronic heart failure (CHF) is a chronic, progressive disease that has detrimental consequences on a patient's quality of life (QoL). In part due to requirements for market access and licensing, the assessment of current and future treatments focuses on reducing mortality and hospitalizations. Few drugs are available principally for their symptomatic effect despite the fact that most patients' symptoms persist or worsen over time and an acceptance that the survival gains of modern therapies are mitigated by poorly controlled symptoms. Additional contributors to the failure to focus on symptoms could be the result of under-reporting of symptoms by patients and carers and a reliance on insensitive symptomatic categories in which patients frequently remain despite additional therapies. Hence, formal symptom assessment tools, such as questionnaires, can be useful prompts to encourage more fidelity and reproducibility in the assessment of symptoms. This scoping review explores for the first time the assessment options and management of common symptoms in CHF with a focus on patient-reported outcome tools. The integration of patient-reported outcomes for symptom assessment into the routine of a CHF clinic could improve the monitoring of disease progression and QoL, especially following changes in treatment or intervention with a targeted symptom approach expected to improve QoL and patient outcomes.
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http://dx.doi.org/10.1002/ehf2.12875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524132PMC
October 2020

Divergent effects of genetic and pharmacological inhibition of Nox2 NADPH oxidase on insulin resistance-related vascular damage.

Am J Physiol Cell Physiol 2020 07 13;319(1):C64-C74. Epub 2020 May 13.

Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.

Insulin resistance leads to excessive endothelial cell (EC) superoxide generation and accelerated atherosclerosis. The principal source of superoxide from the insulin-resistant endothelium is the Nox2 isoform of NADPH oxidase. Here we examine the therapeutic potential of Nox2 inhibition on superoxide generation in saphenous vein ECs (SVECs) from patients with advanced atherosclerosis and type 2 diabetes and on vascular function, vascular damage, and lipid deposition in apolipoprotein E-deficient (ApoE) mice with EC-specific insulin resistance (ESMIRO). To examine the effect of genetic inhibition of Nox2, ESMIRO mice deficient in ApoE and Nox2 (ESMIRO/ApoE/Nox2) were generated and compared with ESMIRO/ApoE/Nox2 littermates. To examine the effect of pharmacological inhibition of Nox2, we administered gp91dstat or scrambled peptide to ESMIRO/ApoE mice. SVECs from diabetic patients had increased expression of Nox2 protein with concomitant increase in superoxide generation, which could be reduced by the Nox2 inhibitor gp91dstat. After 12 wk Western diet, ESMIRO/ApoE/Nox2 mice had reduced EC superoxide generation and greater aortic relaxation to acetylcholine. ESMIRO/ApoE/Nox2 mice developed more lipid deposition in the thoraco-abdominal aorta with multiple foci of elastin fragmentation at the level of the aortic sinus and greater expression of intercellular adhesion molecule-1 (ICAM-1). Gp91dstat reduced EC superoxide and lipid deposition in the thoraco-abdominal aorta of ESMIRO/ApoE mice without causing elastin fragmentation or increased ICAM-1 expression. These results demonstrate that insulin resistance is characterized by increased Nox2-derived vascular superoxide. Complete deletion of Nox2 in mice with EC insulin resistance exacerbates, whereas partial pharmacological Nox2 inhibition protects against, insulin resistance-induced vascular damage.
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http://dx.doi.org/10.1152/ajpcell.00389.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468885PMC
July 2020

Infection-Related Hospitalization in Heart Failure With Reduced Ejection Fraction: A Prospective Observational Cohort Study.

Circ Heart Fail 2020 05 1;13(5):e006746. Epub 2020 May 1.

Leeds Institute of Cardiovascular and Metabolic Medicine, The University of Leeds, Clarendon Way, Leeds, United Kingdom (M.D., E.G., A.M.N.W., T.A.S., A.K., S.S., J.G., M.P., J.L., K.K.W., M.T.K., R.M.C.).

Background: Hospitalization is a common adverse event in people with heart failure and reduced ejection fraction, yet is often not primarily due to decompensated heart failure (HF). We investigated the long-term prognosis following infection-related hospitalization.

Methods: We conducted a prospective observational cohort study of 711 people with heart failure and reduced ejection fraction recruited from 4 specialist HF clinics in the United Kingdom. All hospitalization episodes (n=1568) were recorded and categorized as primarily due to decompensated HF, other cardiovascular disease, infection-related, or other noncardiovascular disease. Survival was determined after the first hospitalization.

Results: During 2900 patient-years of follow-up, there were a total of 14 686 hospital days. At least one hospitalization occurred in 467 people (66%); 25% of first hospitalizations were primarily due to infection and these were not associated with typical signs including tachycardia and pyrexia. Compared with other categories of hospitalization, infection-related was associated with older age, lower serum albumin, higher blood neutrophil counts, and greater prevalence of chronic obstructive pulmonary disease at recruitment. Median survival after first infection-related hospitalization was 18.6 months, comparable to that after first decompensated HF hospitalization, even after age-sex adjustment. The burden of all-cause rehospitalization was comparable irrespective of the category of first hospitalization, but infection more commonly caused re-hospitalization after index infection hospitalization.

Conclusions: Infection is a common driver of hospitalization in heart failure and reduced ejection fraction and often presents without classical signs. It is associated with high mortality rates, comparable to decompensated HF, and a major burden of rehospitalization caused by recurrent episodes of infection.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006746DOI Listing
May 2020

Personalized Rate-Response Programming Improves Exercise Tolerance After 6 Months in People With Cardiac Implantable Electronic Devices and Heart Failure: A Phase II Study.

Circulation 2020 05 17;141(21):1693-1703. Epub 2020 Apr 17.

Leeds Institute of Cardiovascular and Metabolic Medicine (J.G., J.E.L., M.F.P., C.A.C., R.B., A.O.K., H.C., L.C.K., S.S., R.M.C., M.T.K., K.K.W.), University of Leeds, United Kingdom.

Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by blunting of the positive relationship between heart rate and left ventricular (LV) contractility known as the force-frequency relationship (FFR). We have previously described that tailoring the rate-response programming of cardiac implantable electronic devices in patients with HFrEF on the basis of individual noninvasive FFR data acutely improves exercise capacity. We aimed to examine whether using FFR data to tailor heart rate response in patients with HFrEF with cardiac implantable electronic devices favorably influences exercise capacity and LV function 6 months later.

Methods: We conducted a single-center, double-blind, randomized, parallel-group trial in patients with stable symptomatic HFrEF taking optimal guideline-directed medical therapy and with a cardiac implantable electronic device (cardiac resynchronization therapy or implantable cardioverter-defibrillator). Participants were randomized on a 1:1 basis between tailored rate-response programming on the basis of individual FFR data and conventional age-guided rate-response programming. The primary outcome measure was change in walk time on a treadmill walk test. Secondary outcomes included changes in LV systolic function, peak oxygen consumption, and quality of life.

Results: We randomized 83 patients with a mean±SD age 74.6±8.7 years and LV ejection fraction 35.2±10.5. Mean change in exercise time at 6 months was 75.4 (95% CI, 23.4 to 127.5) seconds for FFR-guided rate-adaptive pacing and 3.1 (95% CI, -44.1 to 50.3) seconds for conventional settings (analysis of covariance; =0.044 between groups) despite lower peak mean±SD heart rates (98.6±19.4 versus 112.0±20.3 beats per minute). FFR-guided heart rate settings had no adverse effect on LV structure or function, whereas conventional settings were associated with a reduction in LV ejection fraction.

Conclusions: In this phase II study, FFR-guided rate-response programming determined using a reproducible, noninvasive method appears to improve exercise time and limit changes to LV function in people with HFrEF and cardiac implantable electronic devices. Work is ongoing to confirm our findings in a multicenter setting and on longer-term clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02964650.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045066DOI Listing
May 2020

IGFBP-1 in Cardiometabolic Pathophysiology-Insights From Loss-of-Function and Gain-of-Function Studies in Male Mice.

J Endocr Soc 2020 Jan 4;4(1):bvz006. Epub 2019 Nov 4.

Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK.

We have previously reported that overexpression of human insulin-like growth factor binding protein (IGFBP)-1 in mice leads to vascular insulin sensitization, increased nitric oxide bioavailability, reduced atherosclerosis, and enhanced vascular repair, and in the setting of obesity improves glucose tolerance. Human studies suggest that low levels of IGFBP-1 are permissive for the development of diabetes and cardiovascular disease. Here we seek to determine whether loss of IGFBP-1 plays a causal role in the predisposition to cardiometabolic disease. Metabolic phenotyping was performed in transgenic mice with homozygous knockout of IGFBP-1. This included glucose, insulin, and insulin-like growth factor I tolerance testing under normal diet and high-fat feeding conditions. Vascular phenotyping was then performed in the same mice using vasomotor aortic ring studies, flow cytometry, vascular wire injury, and angiogenesis assays. These were complemented with vascular phenotyping of IGFBP-1 overexpressing mice. Metabolic phenotype was similar in IGFBP-1 knockout and wild-type mice subjected to obesity. Deletion of IGFBP-1 inhibited endothelial regeneration following injury, suggesting that IGFBP-1 is required for effective vascular repair. Developmental angiogenesis was unaltered by deletion or overexpression of IGFBP-1. Recovery of perfusion following hind limb ischemia was unchanged in mice lacking or overexpressing IGFBP-1; however, overexpression of IGFBP-1 stimulated hindlimb perfusion and angiogenesis in insulin-resistant mice. These findings provide new insights into the role of IGFBP-1 in metabolic and vascular pathophysiology. Irrespective of whether loss of IGFBP-1 plays a causal role in the development of cardiometabolic disorders, increasing IGFBP-1 levels appears effective in promoting neovascularization in response to ischemia.
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http://dx.doi.org/10.1210/jendso/bvz006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074193PMC
January 2020

Inorganic Nitrate Promotes Glucose Uptake and Oxidative Catabolism in White Adipose Tissue Through the XOR-Catalyzed Nitric Oxide Pathway.

Diabetes 2020 05 21;69(5):893-901. Epub 2020 Feb 21.

Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, U.K.

An aging global population combined with sedentary lifestyles and unhealthy diets has contributed to an increasing incidence of obesity and type 2 diabetes. These metabolic disorders are associated with perturbations to nitric oxide (NO) signaling and impaired glucose metabolism. Dietary inorganic nitrate, found in high concentration in green leafy vegetables, can be converted to NO in vivo and demonstrates antidiabetic and antiobesity properties in rodents. Alongside tissues including skeletal muscle and liver, white adipose tissue is also an important physiological site of glucose disposal. However, the distinct molecular mechanisms governing the effect of nitrate on adipose tissue glucose metabolism and the contribution of this tissue to the glucose-tolerant phenotype remain to be determined. Using a metabolomic and stable-isotope labeling approach, combined with transcriptional analysis, we found that nitrate increases glucose uptake and oxidative catabolism in primary adipocytes and white adipose tissue of nitrate-treated rats. Mechanistically, we determined that nitrate induces these phenotypic changes in primary adipocytes through the xanthine oxidoreductase-catalyzed reduction of nitrate to NO and independently of peroxisome proliferator-activated receptor-α. The nitrate-mediated enhancement of glucose uptake and catabolism in white adipose tissue may be a key contributor to the antidiabetic effects of this anion.
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http://dx.doi.org/10.2337/db19-0892DOI Listing
May 2020

Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca Handling After Pressure Overload.

Circulation 2020 01 7;141(3):199-216. Epub 2020 Jan 7.

Inserm, UMR-S 1180, Signalisation et Physiopathologie Cardiovasculaire, Université Paris-Saclay, Châtenay-Malabry, France (F.B., P.M., K.B., P.G., S.G., F.L., A.-M.G., J.P.B., J. Sabourin).

Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear.

Methods: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery.

Results: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca signaling alterations (increased SOCE, decreased [Ca] transients amplitude and decay rate, lower SR Ca load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult.

Conclusions: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970549PMC
January 2020

Chronic heart failure with diabetes mellitus is characterized by a severe skeletal muscle pathology.

J Cachexia Sarcopenia Muscle 2020 04 21;11(2):394-404. Epub 2019 Dec 21.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Background: Patients with coexistent chronic heart failure (CHF) and diabetes mellitus (DM) demonstrate greater exercise limitation and worse prognosis compared with CHF patients without DM, even when corrected for cardiac dysfunction. Understanding the origins of symptoms in this subgroup may facilitate development of targeted treatments. We therefore characterized the skeletal muscle phenotype and its relationship to exercise limitation in patients with diabetic heart failure (D-HF).

Methods: In one of the largest muscle sampling studies in a CHF population, pectoralis major biopsies were taken from age-matched controls (n = 25), DM (n = 10), CHF (n = 52), and D-HF (n = 28) patients. In situ mitochondrial function and reactive oxygen species, fibre morphology, capillarity, and gene expression analyses were performed and correlated to whole-body exercise capacity.

Results: Mitochondrial respiration, content, coupling efficiency, and intrinsic function were lower in D-HF patients compared with other groups (P < 0.05). A unique mitochondrial complex I dysfunction was present in D-HF patients only (P < 0.05), which strongly correlated to exercise capacity (R = 0.64; P < 0.001). Mitochondrial impairments in D-HF corresponded to higher levels of mitochondrial reactive oxygen species (P < 0.05) and lower gene expression of anti-oxidative enzyme superoxide dismutase 2 (P < 0.05) and complex I subunit NDUFS1 (P < 0.05). D-HF was also associated with severe fibre atrophy (P < 0.05) and reduced local fibre capillarity (P < 0.05).

Conclusions: Patients with D-HF develop a specific skeletal muscle pathology, characterized by mitochondrial impairments, fibre atrophy, and derangements in the capillary network that are linked to exercise intolerance. These novel preliminary data support skeletal muscle as a potential therapeutic target for treating patients with D-HF.
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http://dx.doi.org/10.1002/jcsm.12515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113493PMC
April 2020

Myocardial Effects of Aldosterone Antagonism in Heart Failure With Preserved Ejection Fraction.

J Am Heart Assoc 2020 01 19;9(1):e011521. Epub 2019 Dec 19.

Multidisciplinary Cardiovascular Research Centre and Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds United Kingdom.

Background Spironolactone may have prognostic benefit in selected patients with heart failure with preserved ejection fraction. This study assessed the myocardial tissue effects of spironolactone in heart failure with preserved ejection fraction. Methods and Results A 1:1 randomized controlled study of 6 months of spironolactone versus control in heart failure with preserved ejection fraction. The primary outcome was change in myocardial extracellular volume fraction by cardiovascular magnetic resonance as a surrogate of diffuse fibrosis. Of 55 randomized patients, 40 (20 women; age, 75.2±5.9 years) completed follow-up (19 treatment, 21 control). A significant change in extracellular volume over the study period was not seen (treatment, 28.7±3.7% versus 27.7±3.4% [=0.14]; controls, 27.6±3.4% versus 28.3±4.4% [=0.14]); however, the rate of extracellular volume expansion was decreased by spironolactone (-1.0±2.4% versus 0.8±2.2%). Indexed left ventricular mass decreased with treatment (104.4±26.6 versus 94.0±20.6 g/m; =0.001) but not in controls (101.4±29.4 versus 104.0±32.8 g/m; =0.111). Extracellular mass decreased by 13.8% (15.1±4.8 versus 13.0±3.4 g/m; =0.003), and cellular mass decreased by 8.3% (37.6±10.0 versus 34.3±7.9 g/m; =0.001) with spironolactone, but was static in controls. Conclusions Spironolactone did not lead to significant change in extracellular volume. However, spironolactone did decrease rate of extracellular expansion, with a decrease in the mass of both cellular and extracellular myocardial compartments. These data point to the mechanism of action of spironolactone in heart failure with preserved ejection fraction, including a direct tissue effect with a reduction in rate of myocardial fibrosis.
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http://dx.doi.org/10.1161/JAHA.118.011521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988171PMC
January 2020

Piezo1 channel activation mimics high glucose as a stimulator of insulin release.

Sci Rep 2019 11 14;9(1):16876. Epub 2019 Nov 14.

Leeds Institute for Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, United Kingdom.

Glucose and hypotonicity induced cell swelling stimulate insulin release from pancreatic β-cells but the mechanisms are poorly understood. Recently, Piezo1 was identified as a mechanically-activated nonselective Ca permeable cationic channel in a range of mammalian cells. As cell swelling induced insulin release could be through stimulation of Ca permeable stretch activated channels, we hypothesised a role for Piezo1 in cell swelling induced insulin release. Two rat β-cell lines (INS-1 and BRIN-BD11) and freshly-isolated mouse pancreatic islets were studied. Intracellular Ca measurements were performed using the fura-2 Ca indicator dye and ionic current was recorded by whole cell patch-clamp. Piezo1 agonist Yoda1, a competitive antagonist of Yoda1 (Dooku1) and an inactive analogue of Yoda1 (2e) were used as chemical probes. Piezo1 mRNA and insulin secretion were measured by RT-PCR and ELISA respectively. Piezo1 mRNA was detected in both β-cell lines and mouse islets. Yoda1 evoked Ca entry was inhibited by Yoda1 antagonist Dooku1 as well as other Piezo1 inhibitors gadolinium and ruthenium red, and not mimicked by 2e. Yoda1, but not 2e, stimulated Dooku1-sensitive insulin release from β-cells and pancreatic islets. Hypotonicity and high glucose increased intracellular Ca and enhanced Yoda1 Ca influx responses. Yoda1 and hypotonicity induced insulin release were significantly inhibited by Piezo1 specific siRNA. Pancreatic islets from mice with haploinsufficiency of Piezo1 released less insulin upon exposure to Yoda1. The data show that Piezo1 channel agonist induces insulin release from β-cell lines and mouse pancreatic islets suggesting a role for Piezo1 in cell swelling induced insulin release. Hence Piezo1 agonists have the potential to be used as enhancers of insulin release.
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http://dx.doi.org/10.1038/s41598-019-51518-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856185PMC
November 2019

Divergent skeletal muscle mitochondrial phenotype between male and female patients with chronic heart failure.

J Cachexia Sarcopenia Muscle 2020 02 20;11(1):79-88. Epub 2019 Aug 20.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Background: Previous studies in heart failure with reduced ejection fraction (HFrEF) suggest that skeletal muscle mitochondrial impairments are associated with exercise intolerance in men. However, the nature of this relationship in female patients remains to be elucidated. This study aimed to determine the relationship between skeletal muscle mitochondrial impairments and exercise intolerance in male and female patients with HFrEF.

Methods: Mitochondrial respiration, enzyme activity, and gene expression were examined in pectoralis major biopsies from age-matched male (n = 45) and female (n = 11) patients with HFrEF and healthy-matched male (n = 24) and female (n = 11) controls. Mitochondrial variables were compared between sex and related to peak exercise capacity.

Results: Compared with sex-matched controls, complex I mitochondrial oxygen flux was 17% (P = 0.030) and 29% (P = 0.013) lower in male and female patients with HFrEF, respectively, which correlated to exercise capacity (r = 0.71; P > 0.0001). Female HFrEF patients had a 32% (P = 0.023) lower mitochondrial content compared with controls. However, after adjusting for mitochondrial content, male patients demonstrated lower complex I function by 15% (P = 0.030). Expression of key mitochondrial genes regulating organelle dynamics and maintenance (i.e. optic atrophy 1, peroxisome proliferator-activated receptor γ coactivator-1α, NADH:ubiquinone oxidoreductase core subunit S1/S3, and superoxide dismutase 2) were selectively lower in female HFrEF patients.

Conclusions: These data provide novel evidence that HFrEF induces divergent sex-specific mitochondrial phenotypes in skeletal muscle that predispose towards exercise intolerance, impacting mitochondrial 'quantity' in female patients and mitochondrial 'quality' in male patients. Therapeutic strategies to improve exercise tolerance in HFrEF should consider targeting sex-specific mitochondrial abnormalities in skeletal muscle.
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http://dx.doi.org/10.1002/jcsm.12488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015245PMC
February 2020

Optimising pacemaker therapy and medical therapy in pacemaker patients for heart failure: protocol for the OPT-PACE randomised controlled trial.

BMJ Open 2019 07 17;9(7):e028613. Epub 2019 Jul 17.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Introduction: Permanent artificial pacemaker implantation is a safe and effective treatment for bradycardia and is associated with extended longevity and improved quality of life. However, the most common long-term complication of standard pacemaker therapy is pacemaker-associated heart failure. Pacemaker follow-up is potentially an opportunity to screen for heart failure to assess and optimise patient devices and medical therapy.

Methods And Analysis: The study is a multicentre, phase-3 randomised trial. The 1200 participants will be people who have a permanent pacemaker for bradycardia for at least 12 months, randomly assigned to undergo a transthoracic echocardiogram with their pacemaker check, thereby tailoring their management directed by left ventricular function or the pacemaker check alone, continuing with routine follow-up. The primary outcome measure is time to all-cause mortality or heart failure hospitalisation. Secondary outcomes include external validation of our risk stratification model to predict onset of heart failure and quality of life assessment.

Ethics And Dissemination: The trial design and protocol have received national ethical approval (12/YH/0487). The results of this randomised trial will be published in international peer-reviewed journals, communicated to healthcare professionals and patient involvement groups and highlighted using social media campaigns.

Trial Registration Number: NCT01819662.
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http://dx.doi.org/10.1136/bmjopen-2018-028613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661620PMC
July 2019

Heart failure: A preventable and treatable complication of type 2 diabetes.

J Diabetes 2019 07 29;11(7):613-616. Epub 2019 Apr 29.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

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http://dx.doi.org/10.1111/1753-0407.12930DOI Listing
July 2019

TRPC5 ion channel permeation promotes weight gain in hypercholesterolaemic mice.

Sci Rep 2019 01 28;9(1):773. Epub 2019 Jan 28.

School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.

Transient Receptor Potential Canonical 5 (TRPC5) is a subunit of a Ca-permeable non-selective cationic channel which negatively regulates adiponectin but not leptin in mice fed chow diet. Adiponectin is a major anti-inflammatory mediator and so we hypothesized an effect of TRPC5 on the inflammatory condition of atherosclerosis. Atherosclerosis was studied in aorta of ApoE mice fed western-style diet. Inhibition of TRPC5 ion permeation was achieved by conditional transgenic expression of a dominant negative ion pore mutant of TRPC5 (DNT5). Gene expression analysis in adipose tissue suggested that DNT5 increases transcript expression for adiponectin while decreasing transcript expression of the inflammatory mediator Tnfα and potentially decreasing Il6, Il1β and Ccl2. Despite these differences there was mild or no reduction in plaque coverage in the aorta. Unexpectedly DNT5 caused highly significant reduction in body weight gain and reduced adipocyte size after 6 and 12 weeks of western-style diet. Steatosis and circulating lipids were unaffected but mild effects on regulators of lipogenesis could not be excluded, as indicated by small reductions in the expression of Srebp1c, Acaca, Scd1. The data suggest that TRPC5 ion channel permeation has little or no effect on atherosclerosis or steatosis but an unexpected major effect on weight gain.
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http://dx.doi.org/10.1038/s41598-018-37299-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349875PMC
January 2019

Prognostic Significance of Incidental Nonsustained Ventricular Tachycardia Detected on Pacemaker Interrogation.

Am J Cardiol 2019 02 7;123(3):409-413. Epub 2018 Nov 7.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.

Symptomatic sustained ventricular tachycardia is a life threatening arrhythmia requiring prompt treatment. However, the risk associated with asymptomatic nonsustained ventricular tachycardia (NSVT) detected on routine permanent pacemaker (PPM) interrogation in patients with known cardiac conduction disease is unknown. Our aim is to determine if asymptomatic NSVT detected on PPM interrogation is associated with increased mortality. As part of a prospective observational cohort study, 582 patients with long-term pacemakers were recruited at a tertiary cardiac centre, and followed for 4 ± 1.96 years (mean ± standard deviation). At each subsequent pacemaker check, any symptoms and ventricular high-rate episodes were recorded. We excluded 17 patients due to incomplete data. In the remaining 565 patients (57% male, age 74.5 ± 19.2 years, left ventricular ejection fraction 50.0 ± 11.3%), NSVT was found in 125 (22.1%) patients with a higher prevalence in males (65% vs 54%; p = 0.033). Those with NSVT were more likely to have had coronary artery disease (p = 0) or previous myocardial infarction (p = 0.015). After correction for baseline variables, NSVT had no impact on survival (n = 52 [42%] vs n = 162 [37%]; log-rank p = 0.331, hazard ratio: 0.927, 95% confidence interval: 0.678 to 1.268, p = 0.697). In conclusion, asymptomatic NSVT identified on PPM interrogation does not appear to be associated with increased mortality, thus whether treatment to suppress this arrhythmia is of benefit remains unproven.
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http://dx.doi.org/10.1016/j.amjcard.2018.10.040DOI Listing
February 2019

Prospective evaluation and long-term follow-up of patients referred to secondary care based upon natriuretic peptide levels in primary care.

Eur Heart J Qual Care Clin Outcomes 2019 07;5(3):218-224

Leeds Institute of Cardiovascular and Metabolic Medicine, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Clarendon Way, Leeds, UK.

Aims: The UK National Institute for Health and Care Excellence (UK-NICE) and European Society of Cardiology (ESC) guidelines advise natriuretic peptide (NP) assessment in patients presenting to primary care with symptoms possibly due to chronic heart failure (HF), to determine need for specialist involvement. This prospective service evaluation aimed to describe the diagnostic and prognostic utility of these guidelines.

Methods And Results: We prospectively collected clinical, echocardiography and outcomes data (minimum 5 years) from all patients referred to the Leeds HF Service for 12 months of following the initiation of the NP-guideline-directed pathway. Between 1 May 2012 and 1 August 2013, 1020 people with symptoms possibly due to HF attended either with a raised NT-pro-BNP or a previous myocardial infarction (MI) with an overall rate of left ventricular systolic dysfunction (LVSD) of 33%. Of these, 991 satisfied the ESC criteria (NT-pro-BNP ≥125 pg/mL) in whom the rate of LVSD was 32%, and 821 the UK-NICE criteria in whom the rate of LVSD was 49% in those with a previous MI, 25% in those with NT-pro-BNP concentration 400-2000 pg/mL, and 54% in those with NT-pro-BNP concentration of >2000 pg/mL. An NT-pro-BNP concentration 125-400 pg/mL had a 12% risk of LVSD. Specificity was poor in women >70 years, who made up the largest proportion of attendees. Elevated NT-pro-BNP levels were associated with lower survival even in the absence of LVSD.

Conclusion: In people referred through the ESC and UK-NICE guidelines, elevated NT-pro-BNP is a marker of increased mortality risk, but there is wide variation in specificity for LVSD. Age- and sex-adjusted criteria might improve performance.
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http://dx.doi.org/10.1093/ehjqcco/qcy053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613597PMC
July 2019
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