Clinical manifestations and outcomes of coronavirus disease-19 in heart transplant recipients: a multicentre case series with a systematic review and meta-analysis.

Available data on clinical presentation and mortality of coronavirus disease-2019 (COVID-19) in heart transplant (HT) recipients remain limited. We report a case series of laboratory-confirmed COVID-19 in 39 HT recipients from 3 French heart transplant centres (mean age 54.4 ± 14.8 years; 66.7% males). Hospital admission was required for 35 (89.7%) cases including 14/39 (35.9%) cases being admitted in intensive care unit. Immunosuppressive medications were reduced or discontinued in 74.4% of the patients. After a median follow-up of 54 (19-80) days, death and death or need for mechanical ventilation occurred in 25.6% and 33.3% of patients, respectively. Elevated C-reactive protein and lung involvement ≥50% on chest computed tomography (CT) at admission were associated with an increased risk of death or need for mechanical ventilation. Mortality rate from March to June in the entire 3-centre HT recipient cohort was 56% higher in 2020 compared to the time-matched 2019 cohort (2% vs. 1.28%, P = 0.15). In a meta-analysis including 4 studies, pre-existing diabetes mellitus (OR 3.60, 95% CI 1.43-9.06, I2  = 0%, P = 0.006) and chronic kidney disease stage III or higher (OR 3.79, 95% CI 1.39-10.31, I2  = 0%, P = 0.009) were associated with increased mortality. These findings highlight the aggressive clinical course of COVID-19 in HT recipients.

Left atrial strain: A memory of the severity of atrial myocardial stress in atrial fibrillation.

BACKGROUND: Left atrial (LA) strain is a simple marker of LA function. The aim of the study was to evaluate the determinants of atrial cardiomyopathy in AF. METHODS: In this pilot study, we prospectively evaluated clinical, biological, metabolomic and echocardiographic parameters for 85 consecutive patients hospitalized for atrial fibrillation (AF) with restoration of sinus rhythm at 6 months. Eighty-one patients with an analysable LA strain at 6 months were divided into groups according to median reservoir strain:<23.3% (n=40) versus≥23.3% (n=41). RESULTS: Compared to patients with the highest LA strain, patients with lowest LA strain had multiple differences at admission: clinical (older age; more frequent history of AF; more patterns of persistent AF); biological (higher fasting blood glucose levels, glycated haemoglobin, high-sensitivity C-reactive protein, and urea; lower glomerular filtration rate); metabolomic (higher levels of kynurenine, kynurenine/tryptophan, and urea/creatinine; lower levels of arginine and methionine/methionine sulfoxide); and echocardiographic (higher two-dimensional end-systolic LA volume [LAV] indexes; higher three-dimensional end-systolic and end-diastolic LAV and right atrial volume indexes; lower LA and right atrial emptying fractions and three-dimensional right ventricular ejection fraction) (all P<0.05). Area under the receiver operating characteristic curve to predict LA strain alteration at 6 months was highest for a combined score including clinical, biological, metabolomic and echocardiographic variables at admission (area under the receiver operating characteristic curve 0.871; P<0.0001). CONCLUSIONS: LA reservoir strain could be a memory of initial atrial myocardial stress in AF. It can be predicted using a combination of clinical, biological, metabolomic and echocardiographic admission variables.

Restoring Sinus Rhythm Reverses Cardiac Remodeling and Reduces Valvular Regurgitation in Patients With Atrial Fibrillation.

BACKGROUND: Cardiac chamber remodeling in atrial fibrillation (AF) reflects the progression of cardiac rhythm and may affect functional regurgitation. OBJECTIVES: The purpose of this study was to explore the 3-dimensional echocardiographic variables of cardiac cavity remodeling and the impact on functional regurgitation in patients with AF with/without sinus rhythm restoration at 12 months. METHODS: A total of 117 consecutive patients hospitalized for AF were examined using serial 3-dimensional transthoracic echocardiography at admission, at 6 months, and at 12 months (337 examinations). RESULTS: During follow-up, 47 patients with active restoration of sinus rhythm (SR) (through cardioversion and/or ablation) had a decrease in all atrial indexed volumes (Vi), end-systolic (ES) right ventricular (RV) Vi, an increase in end-diastolic (ED) left ventricular Vi, and an improvement in 4-chambers function (P < 0.05). Patients with absence/failure of restoration of SR (n = 39) had an increase in ED left atrial Vi and ED/ES RV Vi without modification of 4-chambers function, except for a decrease in left atrial emptying fraction (P < 0.05). Patients with spontaneous restoration of SR (n = 31) had no changes in Vi or function. The authors found an improvement vs baseline in severity of functional regurgitation in patients with active restoration of SR (tricuspid and mitral regurgitation) and in spontaneous restoration of SR (tricuspid regurgitation) (P < 0.05). In multivariable analysis, right atrial and/or left atrial reverse remodeling exclusively correlated with intervention (cardioversion and/or ablation) during 12-month follow-up. CONCLUSIONS: Management of AF should focus on restoration of SR to induce anatomical (all atrial Vi, ES RV Vi) and/or functional (4 chambers) cardiac cavity reverse remodeling and reduce severity of functional regurgitation. (Thromboembolic and Bleeding Risk Stratification in Patients With Non-valvular Atrial Fibrillation [FASTRHAC]; NCT02741349).

Biochemical studies and molecular dynamics simulations of Smad3-Erbin interaction identify a non-classical Erbin PDZ binding.

In this work, we describe how the Erbin PDZ domain interacts with Smad3, a transductor of the Transforming Growth Factor-beta (TGFbeta) pathway, via its MH2 domain. This interaction was described as important for TGFbeta signaling as it could potentially repress the transcriptional activity of the growth factor. In order to clarify our preliminary experimental observations pointing this interaction, we built a 3D model of the Erbin PDZ/Smad3 MH2 complex and checked its stability using molecular dynamics simulations. This model pointed out charged residues in Smad3 and Erbin which could be important for the interaction. By introducing point mutations of these residues within the proposed binding domains, we experimentally confirmed that arginine 279, glutamic acid 246 in Smad3 and glutamic acid 1321 in Erbin are important for the binding. These data suggest a possible novel interface of binding in the Erbin PDZ domain and reveal an unconventional mode of interaction for a PDZ domain and its ligand.

MCC, a new interacting protein for Scrib, is required for cell migration in epithelial cells.

To further characterize the molecular events supporting the tumor suppressor activity of Scrib in mammals, we aim to identify new binding partners. We isolated MCC, a recently identified binding partner for beta-catenin, as a new interacting protein for Scrib. MCC interacts with both Scrib and the NHERF1/NHERF2/Ezrin complex in a PDZ-dependent manner. In T47D cells, MCC and Scrib proteins colocalize at the cell membrane and reduced expression of MCC results in impaired cell migration. By contrast to Scrib, MCC inhibits cell directed migration independently of Rac1, Cdc42 and PAK activation. Altogether, these results identify MCC as a potential scaffold protein regulating cell movement and able to bind Scrib, beta-catenin and NHERF1/2.