Stéphanie Mouton

Myocardial Contractile Dysfunction Is Associated With Impaired Mitochondrial Function and Dynamics in Type 2 Diabetic but Not in Obese Patients

Background— Obesity and diabetes mellitus are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance, and diabetes mellitus on the intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy. Methods and Results— Right atrial myocardium was obtained from 141 consecutive patients presenting no sign of cardiomyopathy. We investigated ex vivo isometric contraction, mitochondrial respiration and calcium retention capacity, and respiratory chain complex activities and oxidative stress status. Diabetes mellitus was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction, and increased myocardial oxidative stress, regardless of weight status. In contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated hemoglobin A1C, but neither body mass index nor the insulin resistance index (homeostasis model assessment–insulin resistance), was independently associated with cardiac mitochondrial function. Furthermore, diabetes mellitus was associated with cardiac mitochondrial network fragmentation and significantly decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to hemoglobin A1C. Conclusion— Worsening of intrinsic myocardial contraction in the transition from obesity to diabetes mellitus is likely related to worsening of cardiac mitochondrial function because impaired mitochondrial function and dynamics and contractile dysfunction are observed in diabetic patients but not in “metabolically healthy” obese patients at early stage in insulin resistance.

Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study

BACKGROUND On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia-reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. METHODS We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia-reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia-reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. FINDINGS In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32-0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68-0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning-afternoon variation in hypoxia-reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia-reoxygenation myocardial injury, Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia-reperfusion injury modulator CDKN1a/p21. INTERPRETATION Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery. FUNDING Fondation de France, Fédération Française de Cardiologie, EU-FP7-Eurhythdia, Agence Nationale pour la Recherche ANR-10-LABX-46, and CPER-Centre Transdisciplinaire de Recherche sur la Longévité.

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

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.

Obesity Paradox in the Clinical Significance of Effective Prosthetic Orifice Area after Aortic Valve Replacement

The definition of prosthesis–patient mismatch (PPM) remains to be refined to enhance its prognosis insight after surgical aortic valve replacement (SAVR) for severe aortic stenosis, especially in obese patients [(1)][1]. We aimed at investigating the respective prevalence and prognostic value of

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

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 (r2 = 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.

Clinical Significance of Right Ventricular Longitudinal Function Parameters After Aortic Valve Replacement

Changes in parameters of longitudinal systolic function after cardiac surgery (i.e., tricuspid annular plane systolic excursion [TAPSE] and peak systolic velocity [PSV] of tricuspid annulus obtained by M-mode or Doppler tissue imaging) have been described for many years, with almost no data on their