Enhanced Mitochondrial Calcium Uptake Suppresses Atrial Fibrillation Associated With Metabolic Syndrome.

BACKGROUND: Patients with metabolic syndrome (MetS) have an increased risk of atrial fibrillation (AF). Impaired Ca2+ homeostasis and mitochondrial dysfunction have emerged as an arrhythmogenic substrate in both patients and animal models of MetS. Whether impaired mitochondrial Ca2+ handling underlies AF associated with MetS remains poorly explored. OBJECTIVES: The aim of this study was to determine the initial mechanisms related to AF susceptibility and mitochondrial dysfunction encountered in metabolic cardiomyopathy. METHODS: A total of 161 mice and 34 patients were studied. Mitochondrial Ca2+ and mitochondrial Ca2+ uniporter complex (MCUC) were investigated in right atrial tissue of patients with (n = 18) or without (n = 16) MetS and of C57Bl/6J mice fed with a high-fat sucrose diet (HFS) for 2 (n = 42) or 12 (n = 39) weeks. Susceptibility to AF was evaluated in isolated sinoatrial tissue and in vivo in mice. RESULTS: Increased expression of the MICUs subunits of the MCUC (1.00 ± 0.33 AU vs 1.29 ± 0.23 AU; P = 0.034) was associated with impaired mitochondrial Ca2+ uptake in patients (168.7 ± 31.3 nmol/min/mg vs 127.3 ± 18.4 nmol/min/mg; P = 0.026) and HFS mice (0.10 ± 0.04 ΔF/F0 × ms-1 vs 0.06 ± 0.03 ΔF/F0 × ms-1; P = 0.0086, and 0.15 ± 0.07 ΔF/F0 × ms-1 vs 0.046 ± 0.03 ΔF/F0 × ms-1; P = 0.0076 in 2- and 12-week HFS mice, respectively). HFS mice elicited a 70% increased susceptibility to AF. The MCUC agonist kaempferol restored MCUC activity in vitro and abolished the occurrence of AF in HFS mice. CONCLUSIONS: Impaired MCUC activity and mitochondrial Ca2+ homeostasis from the early stage of metabolic cardiomyopathy in mice lead to AF. Given that similar defects in cardiac mitochondrial Ca2+ handling are present in MetS patients, the modulation of the MCUC activity represents an attractive antiarrhythmic strategy.

High liver fibrosis scores in metabolic dysfunction-associated fatty liver disease patients are associated with adverse atrial remodeling and atrial fibrillation recurrence following catheter ablation.

Background: A number of epidemiological studies have suggested an association between metabolic dysfunction-associated fatty liver disease (MAFLD) and the incidence of atrial fibrillation (AF). However, the pathogenesis leading to AF in the context of MAFLD remains unclear. We therefore aimed at assessing the impact of MAFLD and liver fibrosis status on left atrium (LA) structure and function. Methods: Patients with a Fatty Liver Index (FLI) >60 and the presence of metabolic comorbidities were classified as MAFLD+. In MAFLD+ patients, liver fibrosis severity was defined using the non-alcoholic fatty liver disease (NAFLD) Fibrosis Score (NFS), as follows: MAFLD w/o fibrosis (NFS ≦ -1.455), MAFLD w/indeterminate fibrosis (-1.455 < NFS < 0.675), and MAFLD w/fibrosis (NFS ≧ 0.675). In the first cohort of patients undergoing AF ablation, the structural and functional impact on LA of MAFLD was assessed by LA strain analysis and endocardial voltage mapping. Histopathological assessment of atrial fibrosis was performed in the second cohort of patients undergoing cardiac surgery. Finally, the impact of MAFLD on AF recurrence following catheter ablation was assessed. Results: In the AF ablation cohort (NoMAFLD n = 123; MAFLD w/o fibrosis n = 37; MAFLD indeterm. fibrosis n = 75; MAFLD w/severe fibrosis n = 10), MAFLD patients with high risk of F3-F4 liver fibrosis presented more LA low-voltage areas as compared to patients without MAFLD (16.5 [10.25; 28] vs 5.0 [1; 11] low-voltage areas p = 0.0115), impaired LA reservoir function assessed by peak left atrial longitudinal strain (19.7% ± 8% vs 8.9% ± 0.89% p = 0.0268), and increased LA volume (52.9 ± 11.7 vs 43.5 ± 18.0 ml/m2 p = 0.0168). Accordingly, among the MAFLD patients, those with a high risk of F3-F4 liver fibrosis presented a higher rate of AF recurrence during follow-up (p = 0.0179). In the cardiac surgery cohort (NoMAFLD n = 12; MAFLD w/o fibrosis n = 5; MAFLD w/fibrosis n = 3), an increase in histopathological atrial fibrosis was observed in MAFLD patients with a high risk of F3-F4 liver fibrosis (p = 0.0206 vs NoMAFLD; p = 0.0595 vs MAFLD w/o fibrosis). Conclusion: In conclusion, we found that liver fibrosis scoring in MAFLD patients is associated with adverse atrial remodeling and AF recurrences following catheter ablation. The impact of the management of MAFLD on LA remodeling and AF ablation outcomes should be assessed in dedicated studies.

Heat-based transdermal delivery of a ramipril loaded cream for treating hypertension.

Angiotensin-converting enzyme (ACE) inhibitors play an important role in the development of anti-hypertension approaches, with ramipril being one of the most widely used ACE inhibitor prodrugs orally administered once or twice a day. Due to its low bioavailability, large amounts have to be administered to obtain a therapeutic effect. In this work, we propose a ramipril loaded pharmaceutical formulation in contact with an electrothermal actuator based on a gold nanohole array as an efficient approach to increase the transdermal ramipril flux. Using rats as an in vivo model, the effect on the systolic and diastolic blood pressure is evaluated, showing that under optimized conditions the blood pressure could be regulated. Heat activation resulted in total drug delivery out of a bandage loaded with 1 mg ramipril, revealing a flux of 50.9 ± 2.8 µg cm-2 h-1. Importantly, heat-based transdermal dispensing allowed efficient and rapid delivery of ramipril in spontaneously hypertensive rats, with its active form (ramiprilat) detected in blood as early as 5 minutes after delivery onset, accompanied by significant decrease in blood pressure.

Diabetes mellitus and cardiovascular mortality across the spectrum of aortic stenosis.

OBJECTIVE: Current data regarding the impact of diabetes mellitus (DM) on cardiovascular mortality in patients with aortic stenosis (AS) are restricted to severe AS or aortic valve replacement (AVR) trials. We aimed to investigate cardiovascular mortality according to DM across the entire spectrum of outpatients with AS. METHODS: Between May 2016 and December 2017, patients with mild (peak aortic velocity=2.5-2.9 m/s), moderate (3-3.9 m/s) and severe (≥4 m/s) AS graded by echocardiography were included during outpatient cardiology visits in the Nord-Pas-de-Calais region in France and followed-up for modes of death between May 2018 and August 2020. RESULTS: Among 2703 patients, 820 (30.3%) had DM, mean age was 76±10.8 years with 46.6% of women and a relatively high prevalence of underlying cardiovascular diseases. There were 200 cardiovascular deaths prior to AVR during the 2.1 years (IQR 1.4-2.7) follow-up period. In adjusted analyses, DM was significantly associated with cardiovascular mortality (HR=1.40, 95% CI 1.04 to 1.89; p=0.029). In mild or moderate AS, the cardiovascular mortality of patients with diabetes was similar to that of patients without diabetes. In severe AS, DM was associated with higher cardiovascular mortality (HR=2.65, 95% CI 1.50 to 4.68; p=0.001). This was almost exclusively related to a higher risk of death from heart failure (HR=2.61, 95% CI 1.15 to 5.92; p=0.022) and sudden death (HR=3.33, 95% CI 1.28 to 8.67; p=0.014). CONCLUSION: The effect of DM on cardiovascular mortality varied across AS severity. Despite no association between DM and outcomes in patients with mild/moderate AS, DM was strongly associated with death from heart failure and sudden death in patients with severe AS.

Antioxidants other than vitamin C may be detected by glucose meters: Immediate relevance for patients with disorders targeted by antioxidant therapies.

Owing to their ease of use, glucose meters are frequently used in research and medicine. However, little is known of whether other non-glucose molecules, besides vitamin C, interfere with glucometry. Therefore, we sought to determine whether other antioxidants might behave like vitamin C in causing falsely elevated blood glucose levels, potentially exposing patients to glycemic mismanagement by being administered harmful doses of glucose-lowering drugs. To determine whether various antioxidants can be detected by seven commercial glucose meters, human blood samples were spiked with various antioxidants ex vivo and their effect on the glucose results were assessed by Parkes error grid analysis. Several of the glucose meters demonstrated a positive bias in the glucose measurement of blood samples spiked with vitamin C, N-acetylcysteine, and glutathione. With the most interference-sensitive glucose meter, non-blood solutions of 1 mmol/L N-acetylcysteine, glutathione, cysteine, vitamin C, dihydrolipoate, and dithiothreitol mimicked the results seen on that glucose meter for 0.7, 1.0, 1.2, 2.6, 3.7 and 5.5 mmol/L glucose solutions, respectively. Glucose meter users should be alerted that some of these devices might produce spurious glucose results not only in patients on vitamin C therapy but also in those being administered other antioxidants. As discussed herein, the clinical relevance of the data is immediate in view of the current use of antioxidant therapies for disorders such as the metabolic syndrome, diabetes, cardiovascular diseases, and coronavirus disease 2019.

Multiple Selection Criteria for Probiotic Strains with High Potential for Obesity Management.

Since alterations of the gut microbiota have been shown to play a major role in obesity, probiotics have attracted attention. Our aim was to identify probiotic candidates for the management of obesity using a combination of in vitro and in vivo approaches. We evaluated in vitro the ability of 23 strains to limit lipid accumulation in adipocytes and to enhance the secretion of satiety-promoting gut peptide in enteroendocrine cells. Following the in vitro screening, selected strains were further investigated in vivo, single, or as mixtures, using a murine model of diet-induced obesity. Strain Bifidobacterium longum PI10 administrated alone and the mixture of B. animalis subsp. lactis LA804 and Lactobacillus gasseri LA806 limited body weight gain and reduced obesity-associated metabolic dysfunction and inflammation. These protective effects were associated with changes in the hypothalamic gene expression of leptin and leptin receptor as well as with changes in the composition of gut microbiota and the profile of bile acids. This study provides crucial clues to identify new potential probiotics as effective therapeutic approaches in the management of obesity, while also providing some insights into their mechanisms of action.