Publications by authors named "David Montaigne"

85 Publications

PPAR control of metabolism and cardiovascular functions.

Nat Rev Cardiol 2021 Jun 14. Epub 2021 Jun 14.

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.

Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.
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http://dx.doi.org/10.1038/s41569-021-00569-6DOI Listing
June 2021

Day-Time Declamping Is Associated with Better Outcomes in Kidney Transplantation: The Circarein Study.

J Clin Med 2021 May 26;10(11). Epub 2021 May 26.

CHU Lille, 59000 Lille, France.

Despite improvements in organ preservation techniques and efforts to minimize the duration of cold ischemia, ischemia-reperfusion (IR) injury remains associated with poor graft function and long-term survival in kidney transplantation. We recently demonstrated a clinically significant day-time variation in myocardial tolerance to IR, transcriptionally orchestrated by the circadian clock. Patient and graft post-transplant survival were studied in a cohort of 10,291 patients first transplanted between 2006 and 2017 to test whether kidney graft tolerance to IR depends on the time-of-the-day of clamping/declamping, and thus impacts graft and patient survival. Post-transplant 1- and 3-year survival decreased with increasing ischemia duration. Time-of-the-day of clamping did not influence outcomes. However, night-time (vs. day-time) declamping was associated with a significantly worse post-transplant survival. After adjustment for other predictors, night-time (vs. day-time) declamping remained associated with a worse 1-year (HR = 1.26 (1.08-1.47), = 0.0028 by Cox multivariable analysis) and 3-year (HR = 1.14 (1.02-1.27), = 0.021) outcome. Interestingly, the deleterious impact of prolonged ischemia time (>15 h) was partially compensated by day-time (vs. night-time) declamping. Compared to night-time declamping, day-time declamping was associated with a better prognosis of kidney transplantation despite a longer duration of cold ischemia.
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http://dx.doi.org/10.3390/jcm10112322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198093PMC
May 2021

60-S Retrogated Compressed Sensing 2D Cine of the Heart: Sharper Borders and Accurate Quantification.

J Clin Med 2021 May 29;10(11). Epub 2021 May 29.

University of Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-European Genomic Institute for Diabetes (EGID), F-59000 Lille, France.

Background And Objective: Real-time compressed sensing cine (CS) provides reliable quantification for both ventricles but may alter image quality. The aim of this study was to assess image quality and the accuracy of left (LV) and right ventricular (RV) volumes, ejection fraction and mass quantifications based on a retrogated segmented compressed sensing 2D cine sequence (CS).

Methods: Thirty patients were enrolled. Each patient underwent the reference retrogated segmented steady-state free precession cine sequence (SSFP), the real-time CS cine and the segmented retrogated prototype CS sequence providing the same slices. Functional parameters quantification and image quality rating were performed on SSFP and CS images sets. The edge sharpness, which is an estimate of the edge spread function, was assessed for the three sequences.

Results: The mean scan time was: SSFP = 485.4 ± 83.3 (SD) s (95% CI: 454.3-516.5) and CS = 58.3 ± 15.1 (SD) s (95% CI: 53.7-64.2) ( < 0.0001). CS subjective image quality score (median: 4; range: 2-4) was higher than the one provided by CS (median: 3; range: 2-4; = 0.0008) and not different from SSFP overall quality score (median: 4; range: 2-4; = 0.31). CS provided similar LV and RV functional parameters to those assessed with SSFP ( > 0.05). Edge sharpness was significantly better with CS (0.083 ± 0.013 (SD) pixel; 95% CI: 0.078-0.087) than with CS (0.070 ± 0.011 (SD) pixel; 95% CI: 0.066-0.074; = 0.0004) and not different from the reference technique (0.075 ± 0.016 (SD) pixel; 95% CI: 0.069-0.081; = 0.0516).

Conclusions: CS cine provides in one minute an accurate quantification of LV and RV functional parameters without compromising subjective and objective image quality.
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http://dx.doi.org/10.3390/jcm10112417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199407PMC
May 2021

Right Ventricular Volume and Function Assessment in Congenital Heart Disease Using CMR Compressed-Sensing Real-Time Cine Imaging.

J Clin Med 2021 Apr 29;10(9). Epub 2021 Apr 29.

University of Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-European Genomic Institute for Diabetes (EGID), F-59000 Lille, France.

Background And Objective: To evaluate the reliability of compressed-sensing (CS) real-time single-breath-hold cine imaging for quantification of right ventricular (RV) function and volumes in congenital heart disease (CHD) patients in comparison with the standard multi-breath-hold technique.

Methods: Sixty-one consecutive CHD patients (mean age = 22.2 ± 9.0 (SD) years) were prospectively evaluated during either the initial work-up or after repair. For each patient, two series of cine images were acquired: first, the reference segmented multi-breath-hold steady-state free-precession sequence (SSFP), including a short-axis stack, one four-chamber slice, and one long-axis slice; then, an additional real-time compressed-sensing single-breath-hold sequence (CS) providing the same slices. Two radiologists independently assessed the image quality and RV volumes for both techniques, which were compared using the Wilcoxon test and paired Student's test, Bland-Altman, and linear regression analyses. The visualization of wall-motion disorders and tricuspid-regurgitation-related signal voids were also analyzed.

Results: The mean acquisition time for CS was 22.4 ± 6.2 (SD) s (95% CI: 20.8-23.9 s) versus 442.2 ± 89.9 (SD) s (95% CI: 419.2-465.2 s) for SSFP ( < 0.001). The image quality of CS was diagnostic in all examinations and was mostly rated as good ( = 49/61; 80.3%). There was a high correlation between SSFP and CS images regarding RV ejection fraction (49.8 ± 7.8 (SD)% (95% CI: 47.8-51.8%) versus 48.7 ± 8.6 (SD)% (95% CI: 46.5-50.9%), respectively; = 0.94) and RV end-diastolic volume (192.9 ± 60.1 (SD) mL (95% CI: 177.5-208.3 mL) versus 194.9 ± 62.1 (SD) mL (95% CI: 179.0-210.8 mL), respectively; = 0.98). In CS images, tricuspid-regurgitation and wall-motion disorder visualization was good (area under receiver operating characteristic curve (AUC) = 0.87) and excellent (AUC = 1), respectively.

Conclusions: Compressed-sensing real-time cine imaging enables, in one breath hold, an accurate assessment of RV function and volumes in CHD patients in comparison with standard SSFP, allowing a substantial improvement in time efficiency.
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http://dx.doi.org/10.3390/jcm10091930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125206PMC
April 2021

Prognostic value of aerobic capacity and exercise oxygen pulse in postaortic dissection patients.

Clin Cardiol 2021 Feb 31;44(2):252-260. Epub 2020 Dec 31.

CHU Lille, Department of Clinical Physiology & echocardiography, Univ. Lille, Inserm U1011-EGID, Lille, France.

Background: Although recommendations encourage daily moderate activities in post aortic dissection, very little data exists regarding cardiopulmonary exercise testing (CPET) to personalize those patient's physical rehabilitation and assess their cardiovascular prognosis.

Design: We aimed at testing the prognostic insight of CPET regarding aortic and cardiovascular events by exploring a prospective cohort of patients followed-up after acute aortic dissection.

Methods: Patients referred to our department after an acute (type A or B) aortic dissection were prospectively included in a cohort between September 2012 and October 2017. CPET was performed once optimal blood pressure control was obtained. Clinical follow-up was done after CPET for new aortic event and major cardio-vascular events (MCE) not directly related to the aorta.

Results: Among the 165 patients who underwent CPET, no adverse event was observed during exercise testing. Peak oxygen pulse was 1.46(1.22-1.84) mlO2/beat, that is, 97 (83-113) % of its predicted value, suggesting cardiac exercise limitation in a population under beta blockers (92% of the population). During a follow-up of 39(20-51) months from CPET, 42 aortic event recurrences and 22 MCE not related to aorta occurred. Low peak oxygen pulse (<85% of predicted value) was independently predictive of aortic event recurrence, while low peak oxygen uptake (<70% of predicted value) was an independent predictor of MCE occurrence.

Conclusion: CPET is safe in postaortic dissection patients should be used to not only to personalize exercise rehabilitation, but also to identify those patients with the highest risk for new aortic events and MCE not directly related to aorta.
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http://dx.doi.org/10.1002/clc.23537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852169PMC
February 2021

Severe SARS-CoV-2 patients develop a higher specific T-cell response.

Clin Transl Immunology 2020 23;9(12):e1217. Epub 2020 Dec 23.

Service de Biochimie automatisée Protéines CHU de Lille Lille France.

Objectives: Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for studying long-term immunity and vaccine strategies. We quantified IFNγ-secreting T cells reactive against the main viral SARS-CoV-2 antigens using a standardised enzyme-linked immunospot assay (ELISpot).

Methods: Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens. Using IFNγ T-CoV-Spot assay, we assessed T-cell and antibody responses in mild, moderate and severe SARS-CoV-2 patients and in control samples collected before the outbreak.

Results: Specific T cells were assessed in 60 consecutive patients (mild,  = 26; moderate,  = 10; and severe patients,  = 24) during their follow-up (median time from symptom onset [interquartile range]: 36 days [28;53]). T cells against M, N and S peptide pools were detected in  = 60 (100%),  = 56 (93.3%),  = 55 patients (91.7%), respectively. Using the MNS mix, IFNγ T-CoV-Spot assay showed a specificity of 96.7% (95% CI, 88.5-99.6%) and a specificity of 90.3% (75.2-98.0%). The frequency of reactive T cells observed with M, S and MNS mix pools correlated with severity and with levels of anti-S1 and anti-RBD serum antibodies.

Conclusion: IFNγ T-CoV-Spot assay is a reliable method to explore specific T cells in large cohorts of patients. This test may become a useful tool to assess the long-lived memory T-cell response after vaccination. Our study demonstrates that SARS-CoV-2 patients developing a severe disease achieve a higher adaptive immune response.
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http://dx.doi.org/10.1002/cti2.1217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757425PMC
December 2020

Single breath-hold compressed sensing real-time cine imaging to assess left ventricular motion in myocardial infarction.

Diagn Interv Imaging 2021 May 8;102(5):297-303. Epub 2020 Dec 8.

Department of Cardiovascular Radiology, Institut Cœur-Poumon, CHU de Lille, Boulevard du Pr Jules Leclercq, 59037 Lille Cedex, France; INSERM UMR 1011, Institut Pasteur de Lille, EGID (European Genomic Institute for Diabetes), FR3508, Univ. Lille, 59000 Lille, France. Electronic address:

Purpose: To evaluate the reliability of a real-time compressed sensing (CS) cine sequence for the detection of left ventricular wall motion disorders after myocardial infarction in comparison with the reference steady-state free precession cine sequence.

Materials And Methods: One hundred consecutive adult patients referred for either initial work-up or follow-up by cardiac magnetic resonance (CMR) in the context of myocardial infarction were prospectively included. There were 77 men and 23 women with a mean age of 63.12±11.3 (SD) years (range: 29-89 years). Each patient underwent the reference segmented multi-breath-hold steady-state free precession cine sequence including one short-axis stack and both vertical and horizontal long-axis slices (SSFP) and the CS real-time single-breath-hold evaluated sequence (CS) providing the same slices. Wall motion disorders were independently and blindly assessed with both sequences by two radiologists, using the American Heart Association left ventricle segmentation. Paired Wilcoxon signed-rank test was used to search for differences in wall motion disorders conspicuity between both sequences and receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosis performance of CS sequence using SSFP as the reference method.

Results: Each patient had at least one cardiac segment with wall motion abnormality on SSFP and CS images. The 1700 segments analyzed with SSFP were classified as normokinetic (360/1700; 21.2%), hypokinetic (783/1700; 46.1%), akinetic (526/1700; 30.9%) or dyskinetic (31/1700; 1.8%). Sensitivity and specificity of the CS sequence were 99.6% (95% CI: 99.1-99.9%) and 99.7% (95% CI: 98.5-100%), respectively. Area under ROC of CS diagnosis performance was 0.997 (95% CI: 0.993-0.999).

Conclusion: CS real-time cine imaging significantly reduces acquisition time without compromising the conspicuity of left ventricular -wall motion disorders in the context of myocardial infarction.
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http://dx.doi.org/10.1016/j.diii.2020.11.012DOI Listing
May 2021

Reproducibility of reading echocardiographic parameters to assess severity of mitral regurgitation. Insights from a French multicentre study.

Arch Cardiovasc Dis 2020 Oct 29;113(10):599-606. Epub 2020 Sep 29.

Department of Cardiology and Heart Valve Center, University Hospital of Rangueil, Toulouse 31400, France.

Background: Poor reproducibility in assessment of mitral regurgitation (MR) has been reported.

Aim: To investigate the robustness of echocardiographic MR assessment in 2019, based on improvements in technology and the skill of echocardiographists regarding MR quantification.

Methods: Reproducibility in parameters of MR severity and global rating were tested using transthoracic echocardiography in 25 consecutive patients independently analysed by 16 junior and senior cardiologists specialized in echocardiography (400 analyses per parameter).

Results: Overall interobserver agreement for mechanism definition, effective regurgitant orifice area (EROA) and regurgitant volume (RVol) was moderate, and was lower in secondary MR. Interobserver agreement was substantial for EROA [0.61, 95% confidence interval (CI) 0.45-0.75] and moderate for RVol with the PISA method (0.50, 95% CI 0.33-0.56) in senior physicians and was fair in junior physicians (0.33, 95% CI 0.19-0.51 and 0.36, 95% CI 0.36-0.43, respectively). Using a multiparametric approach, overall interobserver agreement for grading MR severity was fair (0.30), was slightly better in senior than in junior physicians (0.31 vs. 0.28, respectively) with substantial or almost perfect agreement more frequently observed in senior versus junior physicians (52% vs. 36%, respectively).

Conclusion: Reproducible transthoracic echocardiography MR quantification remains challenging in 2019, despite the expected high skills of echocardiographers regarding MR at the time of dedicated percutaneous intervention. The multiparametric approach does not entirely alleviate the substantial dispersion in measurement of MR severity parameters, whereas reader experience seems to partially address the issue. Our study emphasizes the continuing need for multimodality imaging and education in the evaluation of MR among cardiologists.
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http://dx.doi.org/10.1016/j.acvd.2020.02.004DOI Listing
October 2020

Utility of Three-Dimensional Transesophageal Echocardiography for Mitral Annular Sizing in Transcatheter Mitral Valve Replacement Procedures: A Cardiac Computed Tomographic Comparative Study.

J Am Soc Echocardiogr 2020 10 25;33(10):1245-1252.e2. Epub 2020 Jul 25.

Department of Clinical Physiology and Echocardiography - Heart Valve Center, CHU Lille, Lille, France; Université de Lille, U1011 - EGID, Lille, France; Inserm, U1011, Lille, France; Institut Pasteur de Lille, Lille, France.

Background: Three-dimensional (3D) transesophageal echocardiographic (TEE) imaging is frequently used as an initial screening tool in the evaluation of patients who are candidates for transcatheter mitral valve replacement (TMVR). However, little is known about the imaging correlation with the gold standard, computed tomographic (CT) imaging. The aims of this study were to test the quantitative differences between these two modalities and to determine the best 3D TEE parameters for TMVR screening.

Methods: Fifty-seven patients referred to the heart valve clinic for TMVR with prostheses specifically designed for the mitral valve were included. Mitral annular (MA) analyses were performed using commercially available software on 3D TEE and CT imaging.

Results: Three-dimensional TEE imaging was feasible in 52 patients (91%). Although 3D TEE measurements were slightly lower than those obtained on CT imaging, measurements of both projected MA area and perimeter showed excellent correlations, with small differences between the two modalities (r = 0.88 and r = 0.92, respectively, P < .0001). Correlations were significant but lower for MA diameters (r = 0.68-0.72, P < .0001) and mitroaortic angle (r = 0.53, P = .0001). Receiver operating characteristic curve analyses showed that 3D TEE imaging had a good ability to predict TMVR screening success, defined by constructors on the basis of CT measurements, with ranges of 12.9 to 15 cm for MA area (area under the curve [AUC] = 0.88-0.91, P < .0001), 128 to 139 mm for MA perimeter (AUC = 0.85-0.91, P < .0001), 35 to 39 mm for anteroposterior diameter (AUC = 0.79-0.84, P < .0001), and 37 to 42 mm for posteromedial-anterolateral diameter (AUC = 0.81-0.89, P < .0001).

Conclusions: Three-dimensional TEE measurements of MA dimensions display strong correlations with CT measurements in patients undergoing TMVR screening. Three-dimensional TEE imaging should be proposed as a reasonable alternative to CT imaging in this vulnerable population.
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http://dx.doi.org/10.1016/j.echo.2020.04.030DOI Listing
October 2020

Plasma Trimethylamine N-Oxide and Risk of Cardiovascular Events in Patients With Type 2 Diabetes.

J Clin Endocrinol Metab 2020 07;105(7)

CRNH-O, Plateforme Spectrométrie de Masse (PFSM, Mass Spectrometry Core Facility), Nantes, France.

Objective: Even though trimethylamine N-oxide (TMAO) has been demonstrated to interfere with atherosclerosis and diabetes pathophysiology, the association between TMAO and major adverse cardiovascular events (MACE) has not been specifically established in type 2 diabetes (T2D).

Research Design And Methods: We examined the association of plasma TMAO concentrations with MACE and all-cause mortality in a single-center prospective cohort of consecutively recruited patients with T2D.

Results: The study population consisted in 1463 SURDIENE participants (58% men), aged 65 ± 10 years. TMAO concentrations were significantly associated with diabetes duration, renal function, high-density lipoprotein cholesterol, soluble tumor necrosis factor receptor 1 (sTNFR1) concentrations (R2 = 0.27) and were significantly higher in patients on metformin, even after adjustment for estimated glomerular filtration rate (eGFR): 6.7 (8.5) vs 8.5 (13.6) µmol/L, respectively (PeGFR-adjusted = 0.0207). During follow-up (median duration [interquartile range], 85 [75] months), 403 MACE and 538 deaths were registered. MACE-free survival and all-cause mortality were significantly associated with the quartile distribution of TMAO concentrations, patients with the highest TMAO levels displaying the greatest risk of outcomes (P < 0.0001). In multivariate Cox models, compared with patients from the first 3 quartiles, those from the fourth quartile of TMAO concentration had an independently increased risk for MACE: adjusted hazard ratio (adjHR) 1.32 (1.02-1.70); P = 0.0325. Similarly, TMAO was significantly associated with mortality in multivariate analysis: adjHR 1.75 (1.17-2.09); P = 0.0124, but not when sTNFR1 and angiopoietin like 2 were considered: adjHR 1.16 (0.95-1.42); P = 0.1514.

Conclusions: We revealed an association between higher TMAO concentrations and increased risk of MACE and all-cause mortality, thereby opening some avenues on the role of dysbiosis in cardiovascular risk, in T2D patients.
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http://dx.doi.org/10.1210/clinem/dgaa188DOI Listing
July 2020

Clinical Characteristics and Outcome of Patients with Infective Endocarditis Diagnosed in a Department of Internal Medicine.

J Clin Med 2020 Mar 21;9(3). Epub 2020 Mar 21.

CHU Lille, Département de médecine interne et immunologie clinique, F-59000 Lille, France.

Clinical manifestations of infective endocarditis (IE) can be highly non-specific. Our objective was to describe the clinical characteristics of patients initially referred to a department of internal medicine for a diagnostic work-up, and eventually diagnosed with IE. We retrospectively retrieved adult patients admitted to the department of internal medicine at Lille University Hospital between 2004 and 2015 who fulfilled Duke Classification criteria for definite IE. Thirty-five patients were included. The most frequently involved bacteria were non-hemolytic streptococci. Most patients presented with various systemic, cardiac, embolic, rheumatic, and immunological findings, with no sign or symptom displaying high sensitivity. The first transthoracic echocardiogram was negative in 42% of patients. Furthermore, definite diagnosis required performing at least 2 transesophageal examinations in 24% of patients. We observed a trend towards decreased survival in the subgroup of patients in whom the delay between onset of symptoms and diagnosis was >30 days. In conclusion, patients who are initially referred to internal medicine for a diagnosis work-up and who are ultimately diagnosed with IE have non-specific symptoms and a high percentage of initial normal echocardiography. Those patients require prolonged echocardiographic monitoring as a prolonged delay in diagnosis is associated with poorer outcomes such as death.
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http://dx.doi.org/10.3390/jcm9030864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141516PMC
March 2020

Clinical significance of electrocardiographic markers of myocardial damage prior to aortic valve replacement.

Int J Cardiol 2020 May 29;307:130-135. Epub 2020 Jan 29.

CHU Lille, Department of Clinical Physiology and Echocardiography, France; Univ. Lille, U1011 - EGID, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, France.

Background: Pre-operative myocardial fibrosis and remodeling impact on outcomes after aortic valve replacement (AVR). We aimed at investigating the prognostic impact of preoperative electrocardiographic (ECG) markers of left ventricular (LV) myocardial damage, i.e. bundle branch block (BBB) and ECG strain pattern after (surgical or transcatheter) AVR for severe aortic stenosis (AS).

Methods: Between April 2008 and October 2017, we explored consecutive patients referred to our Heart Valve Clinic for first AVR for severe AS. Detailed pre-operative phenotyping and ECG analysis were performed. Patients were followed-up after AVR for major cardiac events (ME), i.e. cardiovascular death, cardiac hospitalization for acute heart failure and stroke.

Results: BBB and ECG strain were respectively observed in 13.5 and 21% of the 1122 patients included. These ECG markers identified a subgroup of older patients, with higher NYHA class and more advanced myocardial disease as detected by echocardiography, i.e. higher LV mass and lower LV ejection fraction, global longitudinal strain and integrated backscatter, than patients without ECG strain or BBB. ME occurred in 212 (18.6%) patients during a mean follow-up of 4.4 ± 1.5 years with higher incidence in case of ECG strain or BBB (HR 1.56, 95%CI 1.13-2.14, p = 0.006; HR 1.47, 95%CI 1.02-2.13, p = 0.04 respectively). The prognostic value of ECG strain remained significant after adjustment for age, diabetes and pre-operative LVEF.

Conclusions: Pre-operative ECG markers of myocardial damage identify a subgroup of AS patients at high risk of post-AVR cardiovascular complications irrespective of other prognostic factors and should help the multiparametric staging of cardiac damage to guide AVR.
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http://dx.doi.org/10.1016/j.ijcard.2020.01.073DOI Listing
May 2020

Serum tenascin-C is independently associated with increased major adverse cardiovascular events and death in individuals with type 2 diabetes: a French prospective cohort.

Diabetologia 2020 05 10;63(5):915-923. Epub 2020 Feb 10.

INSERM, Centre d'Investigation Clinique CIC1402, Université de Poitiers, CHU de Poitiers, Poitiers, France.

Aims/hypothesis: Tenascin-C (TN-C) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) diseases. Serum TN-C has not yet been specifically studied in individuals with type 2 diabetes, a condition associated with chronic low-grade inflammation and increased CV disease risk. In this study, we hypothesised that elevated serum TN-C at enrolment in participants with type 2 diabetes would be associated with increased risk of death and major adverse CV events (MACE) during follow-up.

Methods: We used a prospective, monocentric cohort of consecutive type 2 diabetes participants (the SURDIAGENE [SUivi Rénal, DIAbète de type 2 et GENEtique] cohort) with all-cause death as a primary endpoint and MACE (CV death, non-fatal myocardial infarction or stroke) as a secondary endpoint. We used a proportional hazard model after adjustment for traditional risk factors and the relative integrated discrimination improvement (rIDI) to assess the incremental predictive value of TN-C for these risk factors.

Results: We monitored 1321 individuals (58% men, mean age 64 ± 11 years) for a median of 89 months. During follow-up, 442 individuals died and 497 had MACE. Multivariate Cox analysis showed that serum TN-C concentrations were associated with an increased risk of death (HR per 1 SD: 1.27 [95% CI 1.17, 1.38]; p < 0.0001) and MACE (HR per 1 SD: 1.23 [95% CI 1.13, 1.34]; p < 0.0001). Using TN-C concentrations on top of traditional risk factors, prediction of the risk of all-cause death (rIDI: 8.2%; p = 0.0006) and MACE (rIDI: 6.7%; p = 0.0014) improved significantly, but modestly.

Conclusions/interpretation: In individuals with type 2 diabetes, increased serum TN-C concentrations were independently associated with death and MACE. Therefore, including TN-C as a prognostic biomarker could improve risk stratification in these individuals.
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http://dx.doi.org/10.1007/s00125-020-05108-5DOI Listing
May 2020

Prognostic significance of the renal resistive index in the primary prevention of type II diabetes.

J Clin Hypertens (Greenwich) 2020 02 31;22(2):223-230. Epub 2020 Jan 31.

Institut Cœur Poumon, CHU Lille, Lille, France.

The renal resistive index has been demonstrated to predict the progression of renal disease and recurrence of major cardiac events in high-risk cardiovascular patients, in addition to other comorbidities. We aimed to assess the prognostic significance of the renal resistive index in type 2 diabetic patients for primary prevention. From 2008 to 2011, patients with type 2 diabetes underwent cardiovascular evaluation, including renal resistive index assessment by renal Doppler ultrasound. The incidence of all-cause death, cardiovascular events, dialysis requirement or a twofold increase in creatinine was recorded. Survival curves were estimated by the Kaplan-Meier method. Two hundred sixty-six patients were included; 50% of the patients were men, an HbA1C level of 8.1 ± 1.7% (65 ± 13.6 mmol/mol) and a serum creatinine level of 8 [7-9] mg/L. The mean 24-hour systolic blood pressure, 24-hour diastolic blood pressure, and 24-hour pulse pressure were 133.4 ± 16.7, 76.5 ± 9.4, and 56.9 ± 12.4 mm Hg, respectively. The median renal resistive index was 0.7 [0.6-0.7] with a threshold of 0.7 predictive of monitored events. After adjustment of the 24-hour pulse pressure, age and 24-hour heart rate, a renal resistive index ≥0.70 remained associated with all-cause death (hazard ratio: 3.23 (1.16-8.98); P = .025) and the composite endpoint of major clinical events (hazard ratio: 2.37 (1.34-4.18); P = .003). An elevated renal resistive index with a threshold of 0.7 is an independent predictor of a first cardiovascular or renal event in type 2 diabetic patients. This simple index should be implemented in the multiparametric staging of diabetes.
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http://dx.doi.org/10.1111/jch.13819DOI Listing
February 2020

First-in-Human Implant of the Cephea Transseptal Mitral Valve Replacement System.

Circ Cardiovasc Interv 2019 09 12;12(9):e008003. Epub 2019 Sep 12.

CRFSkirball Center for Innovation, Orangeburg, New York (T.V., O.K.K., J.F.G.).

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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.008003DOI Listing
September 2019

Transcatheter mitral valve replacement: factors associated with screening success and failure.

EuroIntervention 2019 Dec 6;15(11):e983-e989. Epub 2019 Dec 6.

CHU Lille, Heart Valve Clinic, Lille, France.

Aims: Transcatheter mitral valve replacement (TMVR) is a promising therapeutic solution to treat high-risk patients with severe mitral regurgitation (MR) contraindicated to surgery. Optimal selection of patients who will benefit from the procedure is of paramount importance. We aimed to investigate factors associated with TMVR screening.

Methods And Results: From November 2016 to July 2018, we examined conditions associated with TMVR screening success in patients referred to the two French heart valve clinics with the greatest TMVR experience. Among a total of 40 consecutively screened patients, 16 (40%) were selected for TMVR (8 Twelve Intrepid, 7 Tendyne and 1 HighLife), while 24 patients (60%) were refused for TMVR mainly because of a too large mitral annulus (MA) (n=15, 62% of those refused), or too small anatomy and risk of neo-left ventricular outflow tract (LVOT) obstruction (n=6, 25% of those refused). Patients with suitable anatomy for TMVR were more often male and more frequently suffered from secondary MR (p=0.01) associated with previous myocardial infarction and presented a commissure-to-commissure diameter less than 39 mm (AUC=0.72, p=0.0085) and LVESD greater than 32 mm (AUC=0.83, p<0.0001) on transthoracic echocardiography, and an MA area less than 17.6 cm² (AUC=0.95, p<0.0001) and anteroposterior diameter greater than 41.6 mm (AUC=0.87, p<0.001) on CT scan.

Conclusions: Despite several prostheses being available, most patients referred to heart valve clinics who are good candidates with regard to their clinical profile cannot have TMVR because of mismatch between their anatomy and prosthesis characteristics. Our findings suggest the need to develop new prostheses adapted to larger mitral annuli but with a lower impact on the LVOT.
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http://dx.doi.org/10.4244/EIJ-D-19-00444DOI Listing
December 2019

Compressed sensing real-time cine imaging for assessment of ventricular function, volumes and mass in clinical practice.

Eur Radiol 2020 Jan 1;30(1):609-619. Epub 2019 Aug 1.

Department of Cardiovascular Radiology, Institut Cœur-Poumon, CHU Lille, Boulevard du Pr Jules Leclercq, 59037, Lille Cedex, France.

Objectives: This study was conducted in order to evaluate the accuracy of a compressed sensing (CS) real-time single-breath-hold cine sequence for the assessment of left and right ventricular functional parameters in daily practice.

Methods: Cardiac magnetic resonance (CMR) cine images were acquired from 100 consecutive patients using both the reference segmented multi-breath-hold steady-state free precession (SSFP) acquisition and a prototype single-breath-hold real-time CS sequence, providing the same slice number, position, and thickness. For both sequences, the left (LV) and right ventricular (RV) ejection fractions (EF) and end-diastolic volumes (EDV) were assessed as well as LV mass (LVM). The visualization of wall-motion disorders (WMD) and signal void related to mitral or tricuspid regurgitation was also analyzed.

Results: The CS sequence mean scan time was 23 ± 6 versus 510 ± 109 s for the multi-breath-hold SSFP sequence (p < 0.001). There was an excellent correlation between the two sequences regarding mean LVEF (r = 0.995), LVEDV (r = 0.997), LVM (r = 0.981), RVEF (r = 0.979), and RVEDV (r = 0.983). Moreover, inter- and intraobserver agreements were very strong with intraclass correlations of 0.96 and 0.99, respectively. On CS images, mitral or tricuspid regurgitation visualization was good (AUC = 0.85 and 0.81, respectively; ROC curve analysis) and wall-motion disorder visualization was excellent (AUC ≥ 0.97).

Conclusion: CS real-time single-breath-hold cine imaging reduces CMR scan duration by almost 20 times in daily practice while providing reliable measurements of both left and right ventricles. There was no clinically relevant information loss regarding valve regurgitation and wall-motion disorder depiction.

Key Points: • Compressed sensing single-breath-hold real-time cine imaging is a reliable sequence in daily practice. • Fast CS real-time imaging reduces CMR scan time and improves patient workflow. • There is no clinically relevant information loss with CS regarding heart valve regurgitation or wall-motion disorders.
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http://dx.doi.org/10.1007/s00330-019-06341-2DOI Listing
January 2020

Left atrial epicardial adipose tissue radiodensity is associated with electrophysiological properties of atrial myocardium in patients with atrial fibrillation.

Eur Radiol 2019 Jun 6;29(6):3027-3035. Epub 2018 Nov 6.

Univ Lille, F-59000, Lille, France.

Objective: To evaluate whether the epicardial adipose tissue (EAT) phenotype is associated with the electrophysiological properties of adjacent atrial myocardium in patients with atrial fibrillation (AF).

Methods: Between January and May 2017, 30 consecutive patients referred for a first AF catheter ablation were prospectively included. For each patient, a pre-procedural computed tomography scan was performed to assess total and left atrial (LA) EAT amount and radiodensity. A detailed point-by-point voltage mapping using an electroanatomic mapping system was realized to assess the presence of LA low-voltage zone (LVZ).

Results: Ten patients (33.3%) presented at least one LVZ. Older age (65 ± 7 vs. 58 ± 10 years, p = 0.05) was the only clinical parameter associated with LVZ. Despite no greater LA-EAT thickness by CT scan (3.0 [2.6-3.5] mm vs. 2.8 [2.2-3.1] mm, p = 0.354), patients with LA-LVZ presented significantly lower LA-EAT radiodensity than patients with no LA-LVZ (- 101.8 ± 12.5 HU vs. - 90.4 ± 6.3 HU, p = 0.004). No difference between total-EAT volume (131 ± 61 cm vs.107 ± 58 cm, p = 0.361) and total-EAT radiodensity (- 106.8 ± 4.3 HU vs. - 102.4 ± 6.9 HU, p = 0.119) was found.

Conclusion: Low LA-EAT radiodensity is associated with the presence of LVZ in patients with medical history of AF.

Key Points: • Cardiovascular risk factors are associated with low adipose tissue computed tomography attenuation. • Epicardial adipose tissue (EAT) has emerged as an important factor in the pathogenesis of metabolic-related cardiac diseases such as atrial fibrillation. • We showed that low left atrial EAT attenuation is associated with the presence of low-voltage zone, a surrogate for atrial fibrosis, within the adjacent myocardium.
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http://dx.doi.org/10.1007/s00330-018-5793-4DOI Listing
June 2019

Time to Check the Clock in Cardiovascular Research and Medicine.

Circ Res 2018 08;123(6):648-650

From the European Genomic Institute for Diabetes, University of Lille, France (D.M., B.S.).

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http://dx.doi.org/10.1161/CIRCRESAHA.118.313543DOI Listing
August 2018

Epicardial fat amount is associated with the magnitude of left ventricular remodeling in aortic stenosis.

Int J Cardiovasc Imaging 2019 Feb 17;35(2):267-273. Epub 2018 Oct 17.

European Genomic Institute for Diabetes (E.G.I.D), FR 3508, 59000, Lille, France.

Both genetic and environmental factors interact to control left ventricular (LV) remodeling in the context of aortic stenosis (AS). Epicardial adipose tissue (EAT) is a specific visceral adipose tissue with paracrine properties in close contact with the myocardium. We sought to assess determinants of EAT amount and its association with the magnitude and pattern of LV remodeling in patients suffering from severe AS. Between January 2014 and September 2017, we prospectively explored consecutive patients referred to our Heart Valve Center for SAVR presenting with severe AS and normal left ventricular ejection fraction (> 50%). Comprehensive transthoracic echocardiography (TTE) including assessment of LV remodeling and EAT amount were performed. 202 patients were included. EAT was significantly larger in elderly, diabetic and obese patients. EAT thickness was correlated positively with indexed LV mass in AS (r = 0.21; p < 0.0001) as well as severe LV remodeling pattern. Importantly, this observation persisted after adjustment for other factors associated with LV remodeling (β ± SE = 1.74 ± 0.34; p < 0.0001). Large amounts of EAT are positively and independently associated with more pronounced and severe LV remodeling in severe AS. Further exploration regarding the impact of functional properties of EAT on LV remodeling is required.
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http://dx.doi.org/10.1007/s10554-018-1477-zDOI Listing
February 2019

Outcomes of Patients With Asymptomatic Aortic Stenosis Followed Up in Heart Valve Clinics.

JAMA Cardiol 2018 11;3(11):1060-1068

Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.

Importance: The natural history and the management of patients with asymptomatic aortic stenosis (AS) have not been fully examined in the current era.

Objective: To determine the clinical outcomes of patients with asymptomatic AS using data from the Heart Valve Clinic International Database.

Design, Setting, And Participants: This registry was assembled by merging data from prospectively gathered institutional databases from 10 heart valve clinics in Europe, Canada, and the United States. Asymptomatic patients with an aortic valve area of 1.5 cm2 or less and preserved left ventricular ejection fraction (LVEF) greater than 50% at entry were considered for the present analysis. Data were collected from January 2001 to December 2014, and data were analyzed from January 2017 to July 2018.

Main Outcomes And Measures: Natural history, need for aortic valve replacement (AVR), and survival of asymptomatic patients with moderate or severe AS at entry followed up in a heart valve clinic. Indications for AVR were based on current guideline recommendations.

Results: Of the 1375 patients included in this analysis, 834 (60.7%) were male, and the mean (SD) age was 71 (13) years. A total of 861 patients (62.6%) had severe AS (aortic valve area less than 1.0 cm2). The mean (SD) overall survival during medical management (mean [SD] follow up, 27 [24] months) was 93% (1%), 86% (2%), and 75% (4%) at 2, 4, and 8 years, respectively. A total of 104 patients (7.6%) died under observation, including 57 patients (54.8%) from cardiovascular causes. The crude rate of sudden death was 0.65% over the duration of the study. A total of 542 patients (39.4%) underwent AVR, including 388 patients (71.6%) with severe AS at study entry and 154 (28.4%) with moderate AS at entry who progressed to severe AS. Those with severe AS at entry who underwent AVR did so at a mean (SD) of 14.4 (16.6) months and a median of 8.7 months. The mean (SD) 2-year and 4-year AVR-free survival rates for asymptomatic patients with severe AS at baseline were 54% (2%) and 32% (3%), respectively. In those undergoing AVR, the 30-day postprocedural mortality was 0.9%. In patients with severe AS at entry, peak aortic jet velocity (greater than 5 m/s) and LVEF (less than 60%) were associated with all-cause and cardiovascular mortality without AVR; these factors were also associated with postprocedural mortality in those patients with severe AS at baseline who underwent AVR (surgical AVR in 310 patients; transcatheter AVR in 78 patients).

Conclusions And Relevance: In patients with asymptomatic AS followed up in heart valve centers, the risk of sudden death is low, and rates of overall survival are similar to those reported from previous series. Patients with severe AS at baseline and peak aortic jet velocity of 5.0 m/s or greater or LVEF less than 60% have increased risks of all-cause and cardiovascular mortality even after AVR. The potential benefit of early intervention should be considered in these high-risk patients.
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http://dx.doi.org/10.1001/jamacardio.2018.3152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583052PMC
November 2018

Prognostic value of plasma MR-proADM vs NT-proBNP for heart failure in people with type 2 diabetes: the SURDIAGENE prospective study.

Diabetologia 2018 12 19;61(12):2643-2653. Epub 2018 Sep 19.

Centre d'Investigation Clinique, CHU de Poitiers, Poitiers, France.

Aims/hypothesis: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the gold standard prognostic biomarker for diagnosis and occurrence of heart failure. Here, we compared its prognostic value for the occurrence of congestive heart failure with that of plasma mid-region pro-adrenomedullin (MR-proADM), a surrogate for adrenomedullin, a vasoactive peptide with vasodilator and natriuretic properties, in people with type 2 diabetes.

Methods: Plasma MR-proADM concentration was measured in baseline samples of a hospital-based cohort of consecutively recruited participants with type 2 diabetes. Our primary endpoint was heart failure requiring hospitalisation.

Results: We included 1438 participants (age 65 ± 11 years; 604 women and 834 men). Hospitalisation for heart failure occurred during follow-up (median 64 months) in 206 participants; the incidence rate of heart failure was 2.5 (95% CI 2.2, 2.9) per 100 person-years. Plasma concentrations of MR-proADM and NT-proBNP were significantly associated with heart failure in a Cox multivariable analysis model when adjusted for age, diabetes duration, history of coronary heart disease, proteinuria and baseline eGFR (HR [95%CI] 1.83 [1.51, 2.21] and 2.20 [1.86, 2.61], respectively, per 1 SD log increment, both p < 0.001). MR-proADM contributed significant supplementary information to the prognosis of heart failure when we considered the clinical risk factors (integrated discrimination improvement [IDI, mean ± SEM] 0.021 ± 0.007, p = 0.001) (Table 3). Inclusion of NT-proBNP in the multivariable model including MR-proADM contributed significant complementary information on prediction of heart failure (IDI [mean ± SEM] 0.028 ± 0.008, p < 0.001). By contrast, MR-proADM did not contribute supplementary information on prediction of heart failure in a model including NT-proBNP (IDI [mean ± SEM] 0.003 ± 0.003, p = 0.27), with similar results for heart failure with reduced ejection fraction and preserved ejection fraction.

Conclusions/interpretation: MR-proADM is a prognostic biomarker for heart failure in people with type 2 diabetes but gives no significant complementary information on prediction of heart failure compared with NT-proBNP.
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http://dx.doi.org/10.1007/s00125-018-4727-7DOI Listing
December 2018

Peri-operative acute kidney injury upon cardiac surgery time-of-day.

Int J Cardiol 2018 Dec 19;272:54-59. Epub 2018 Jul 19.

CHU Lille, Department of Clinical Physiology and Echocardiography, Heart Valve Clinic, F-59000 Lille, France; European Genomic Institute for Diabetes (E.G.I.D), Univ Lille, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France. Electronic address:

Background: A relevant morning-afternoon variation in ischemia-reperfusion (IR) insult after cardiac surgery has been demonstrated. We speculated that the biorhythm might also impact systemic reactions involved in acute kidney injury (AKI) following cardiac surgery. We aimed at investigating incidence, determinants and prognostic impact of AKI in a large cohort of patients referred for surgical aortic valve replacement (SAVR) according to surgery time-of-day.

Methods: Between 2009 and 2015, we explored consecutive patients referred to our Heart Valve Center (CHU Lille) for first SAVR. Patients undergoing morning and afternoon SAVR were matched into pairs by propensity score and followed for major events (ME) i.e. cardiovascular death, cardiac hospitalization for acute heart failure (HF) and post-operative myocardial infarction. AKI was defined using KDIGO classification.

Results: In the matched population (n = 596 patients), AKI occurred in 20% of patients. After multivariable adjustment, medical history of hypertension, pre-operative renal function impairment and cardio-pulmonary bypass duration were independent predictors of AKI onset. Post-operative AKI was significantly associated with increased occurrence of ME and specifically of cardiac hospitalization for HF (p = 0.0035 and p = 0.0071, respectively) during the 500 days following SAVR. Finally, AKI occurrence and severity were similar between morning and afternoon groups (p = 0.98 and p = 0.99, respectively).

Conclusion: We showed that despite current high-quality patient management during and following SAVR, peri-operative AKI remains frequent, developing in 20% of patients, and clearly worsens mid-term post-operative outcomes. AKI more often develops in patients with pre-operative chronic kidney disease and long duration of cardiac surgery but is not influenced by surgery time-of-day.
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http://dx.doi.org/10.1016/j.ijcard.2018.07.081DOI Listing
December 2018

Aortic root size is associated with nocturnal blood pressure in a population of hypertensive patients under treatment for obstructive sleep apnea.

Sleep Breath 2019 Jun 24;23(2):439-446. Epub 2018 Jul 24.

CHU Lille, Institut Cœur Poumon, Bd Pr Leclercq, F-59000, Lille, France.

Background: Obstructive sleep apnea (OSA) is associated with an increased aortic root size. This association has never been studied in patients with hypertension undergoing continuous positive airway pressure (CPAP) treatment for OSA.

Methods: The 24-h blood pressure (BP) monitoring of 142 hypertensive patients undergoing CPAP treatment for OSA was prospectively documented. Aortic root diameter was assessed by echocardiography.

Results: The population included 33.8% women, with an overall mean age of 60.7 ± 10.5 years. The median body mass index was 32.7 [29. 5-36.3] kg/m. The median treatment score was 3 [2-4] anti-hypertensive drugs per day. The median 24-h systolic and diastolic BP were 130 [120-144] and 74.5 [69-82] mmHg, respectively. The night-time systolic and diastolic BP were 119.5 [108-136] and 67 [61-74] mmHg, respectively. The mean diameter of the aorta at the level of the Valsalva sinuses was 34.9 ± 4.4 mm and 20.4 ± 2.3 mm/m when adjusted for height. Patients underwent ventilation for a median duration of 3.8 [1. 7-7.5] years, with a median night-time duration of 6.6 [5. 5-7.5] h per night. The median residual apnea-hypopnea index under ventilation was 2 [1-4] events per hour. A multivariate analysis showed that aortic root size was associated with male gender (p < 0.01) and nocturnal diastolic BP (p < 0.01). When normalized for height, aortic root diameter was positively associated with age (p < 0.01) and nocturnal diastolic BP (p < 0.01).

Conclusion: In OSA patients, the relationship between aortic root diameter and nocturnal BP persists on CPAP therapy. Further studies that evaluate the potential protective effect of OSA treatment on aortic root dilatation should monitor nocturnal diastolic BP.
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http://dx.doi.org/10.1007/s11325-018-1698-3DOI Listing
June 2019

Daytime variations in perioperative myocardial injury - Authors' reply.

Lancet 2018 05 24;391(10135):2106. Epub 2018 May 24.

University of Lille, EGID, F-59000 Lille, France; Inserm, U1011, F-Lille, France; University Hospital CHU Lille, Lille, France; Institut Pasteur de Lille, Lille, France.

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http://dx.doi.org/10.1016/S0140-6736(18)30758-XDOI Listing
May 2018

ATP-sensitive potassium channels in the sinoatrial node contribute to heart rate control and adaptation to hypoxia.

J Biol Chem 2018 06 17;293(23):8912-8921. Epub 2018 Apr 17.

From the Heart Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, EC1M 6BQ, United Kingdom,

ATP-sensitive potassium channels (K) contribute to membrane currents in many tissues, are responsive to intracellular metabolism, and open as ATP falls and ADP rises. K channels are widely distributed in tissues and are prominently expressed in the heart. They have generally been observed in ventricular tissue, but they are also expressed in the atria and conduction tissues. In this study, we focused on the contribution and role of the inwardly rectifying K channel subunit, Kir6.1, in the sinoatrial node (SAN). To develop a murine, conduction-specific Kir6.1 KO model, we selectively deleted Kir6.1 in the conduction system in adult mice (cKO). Electrophysiological data in single SAN cells indicated that Kir6.1 underlies a K current in a significant proportion of cells and influences early repolarization during pacemaking, resulting in prolonged cycle length. Implanted telemetry probes to measure heart rate and electrocardiographic characteristics revealed that the cKO mice have a slow heart rate, with episodes of sinus arrest in some mice. The PR interval (time between the onset of the P wave to the beginning of QRS complex) was increased, suggesting effects on the atrioventricular node. studies of whole heart or dissected heart regions disclosed impaired adaptive responses of the SAN to hypoxia, and this may have had long-term pathological consequences in the cKO mice. In conclusion, Kir6.1-containing K channels in the SAN have a role in excitability, heart rate control, and the electrophysiological adaptation of the SAN to hypoxia.
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http://dx.doi.org/10.1074/jbc.RA118.002775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995522PMC
June 2018

Differential effects of inhibitory G protein isoforms on G protein-gated inwardly rectifying K currents in adult murine atria.

Am J Physiol Cell Physiol 2018 05 17;314(5):C616-C626. Epub 2018 Jan 17.

The Heart Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry , London , United Kingdom.

G protein-gated inwardly rectifying K (GIRK) channels are the major inwardly rectifying K currents in cardiac atrial myocytes and an important determinant of atrial electrophysiology. Inhibitory G protein α-subunits can both mediate activation via acetylcholine but can also suppress basal currents in the absence of agonist. We studied this phenomenon using whole cell patch clamping in murine atria from mice with global genetic deletion of Gα, combined deletion of Gα/Gα, and littermate controls. We found that mice with deletion of Gα had increased basal and agonist-activated currents, particularly in the right atria while in contrast those with Gα/Gα deletion had reduced currents. Mice with global genetic deletion of Gα had decreased action potential duration. Tissue preparations of the left atria studied with a multielectrode array from Gα knockout mice showed a shorter effective refractory period, with no change in conduction velocity, than littermate controls. Transcriptional studies revealed increased expression of GIRK channel subunit genes in Gα knockout mice. Thus different G protein isoforms have differential effects on GIRK channel behavior and paradoxically Gα act to increase basal and agonist-activated GIRK currents. Deletion of Gα is potentially proarrhythmic in the atria.
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http://dx.doi.org/10.1152/ajpcell.00271.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008071PMC
May 2018
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