Augustin Coisne

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.

Mitochondrial dysfunction as an arrhythmogenic substrate: a translational proof-of-concept study in patients with metabolic syndrome in whom post-operative atrial fibrillation develops.

OBJECTIVES This study sought to provide bedside evidence of the potential link between cardiac mitochondrial dysfunction and arrhythmia as reported in bench studies. BACKGROUND Atrial fibrillation (AF) is a frequent complication of cardiac surgery. Underlying mechanisms of post-operative atrial fibrillation (POAF) remain largely unknown. Because cardiac mitochondrial dysfunction has been reported in clinical conditions with a high risk of POAF, we investigated whether a causal link exists between POAF onset and pre-operative function of cardiac mitochondria. METHODS Pre-operative mitochondrial respiration and calcium retention capacity, respiratory complex activity, and myocardial oxidative stress were quantified in right atrial tissue from 104 consecutive patients with metabolic syndrome, in sinus rhythm, and undergoing coronary artery bypass graft surgery. RESULTS In this high-risk population, POAF occurred in 44% of patients. Decreased pre-operative mitochondrial respiration and increased sensitivity to calcium-induced mitochondrial permeability transition pore opening were significantly associated with POAF. Adenosine diphosphate-stimulated mitochondrial respiration supported by palmitoyl-l-carnitine was significantly lower in POAF patients and remained independently associated with AF onset after adjustment for age, body mass index, heart rate, beta-blocker use, and statin medication (multivariate logistic regression coefficient per unit = -0.314 ± 0.144; p = 0.028). Gene expression profile analysis identified a general downregulation of the mitochondria/oxidative phosphorylation gene cluster in pre-operative atrial tissue of patients in whom AF developed. CONCLUSIONS Our prospective study identifies an association between pre-operative mitochondrial dysfunction of the atrial myocardium and AF occurrence after cardiac surgery in patients with metabolic disease, providing novel insights into the link between mitochondria and arrhythmias in patients.

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.

Contrasting effects of diabetes and metabolic syndrome on post-operative atrial fibrillation and in-hospital outcome after cardiac surgery

population. The relationship between OSA and hypertension has been clearlydemonstrated [4]. BP should thenbemeasured systematically in all apneic patients when OSA has been diagnosed. As for the general population, the reference method for BP testing is office measurement. However, this diagnosticmethod is defective in this population due to the specific characteristics of OSA-related hypertension, in particular the fact that it is predominantly nocturnal. ABPM therefore is recognized as the most informative BP measurement method in apneic patients [5]. Until now, SBPM has not been assessed in an OSA population where its reliability was questionable owing to the nocturnal predominance of hypertension in these patients. The new findings of the current study are the direct comparison of clinic, SBPM and ABPM techniques in terms of diagnosis accuracy in OSA patients. Whereas about 75% of our patients were classified as hypertensive using ABPM, only one third and 25% were identified as hypertensive by clinic measurement and SBPM, respectively. This was explained by the large predominance of nocturnal hypertension in this group of patients since most of them exhibited elevated nocturnal BP. Our study demonstrated that in apneic patients, SBPM not only compared unfavorably with ABPM, but also demonstrated no significant advantage compared to clinic BP measurements for diagnosing hypertension. With the repetitive occurrence throughout the night of apneas and hypopneas, it was expected that morningmeasurements of SBPM could be sensitive enough to identify the during the night increase in sympathetic tone and BP [6]. We did not found such a result in our study. In a case–control studyof 24-hour ABPM inpatientswithOSA and matched controls, Davies et al. found clear differences at night with a reduced nocturnal fall in BP but only a short persistence of the systolic differences into the early morning [7]. Further studies assessing the interest of measuring SBPM immediately after awakening, in comparison to ABPM, are desirable in the specific situation of OSA.

Catheter ablation reduces ventricular tachycardia burden in patients with arrhythmogenic right ventricular cardiomyopathy: insights from a north-western French multicentre registry

Aims Studies assessing radiofrequency ablation (RFA) of ventricular tachycardia (VT) in arrhythmogenic right ventricular cardiomyopathy (ARVC) report VT recurrences, but have not evaluated the impact of RFA on relevant clinical events during follow-up. We aimed to investigate relevant RFA outcomes in a multicentric registry. Methods and results This study included 49 patients with ARVC (46 with definite diagnosis, 3 with borderline diagnosis according to revised Task Force Criteria) who underwent 92 RFA procedures (83 endocardial, 9 combined endo-epicardial) between 1999-2015. Ventricular tachycardia recurrences and VT burden were assessed after each procedure or after the last RFA. Over a mean follow-up of 64 ± 51 months, VT-free survival was 37% at 1 year, 19% at 5 years, and 14% at 10 years. Ventricular tachycardia burden was significantly reduced after one procedure (23 vs. 11 VT episodes/year, P < 0.01) and after the last RFA (14 vs. 2 VT episodes/year, P < 0.01). Over a mean follow-up of 49 ± 52 months, clinical response after the last RFA (freedom from sudden cardiac death, VT requiring hospitalization, or heart transplantation) was 86% at 1 year, 69% at 5 years, and 60% at 10 years. Clinical response was associated with right ventricular dysfunction (RVD) and low numbers of mappable VT before the first RFA. Conclusion RFA was predominantly targeted at the endocardial surface. Ventricular tachycardia recurrences were common, but few ARVC patients experienced major clinical events during follow-up. Further studies should investigate the benefit of extensive substrate ablation combined with endo-epicardial strategies.

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.

Electrical atrial vulnerability and renal complications in type 2 diabetes

To the Editor: We read with interest the recently published article by Zethelius and colleagues in Diabetologia, which studied characteristics of type 2 diabetes patients contributing to atrial fibrillation (AF) risk in a very large observational cohort [1]. The modifiable risk factor, albuminuria, was found to be strongly associated with AF in type 2 diabetes. Zethelius et al claim that microalbuminuria and macroalbuminuria, as risk factors for AF in diabetes, have not been described previously in the literature; this is incorrect, in our opinion. AF is the most common sustained cardiac arrhythmia. Diabetes contributes to an increased risk for AF, which has been estimated to be from 26 to over 100% higher in patients with diabetes than in non-diabetic people [2]. The mechanisms underlying this association remain largely unknown. Interestingly, prolonged P-wave duration on the ECG, considered to be an intermediate indicator of the accumulation of insults that ultimately leads to AF, has also been reported to be increased in patients with diabetes, even in those without ischaemia, hypertension or left ventricular hypertrophy [3]. Reduced kidney function and the presence of albuminuria were found to be predictive of AF in Atherosclerosis Risk in Communities (ARIC) study participants [4]. Microalbuminuria has also been linked to AF in a population of more than 20,000 hypertensive patients [5]. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, which included more than 11,000 patients with type 2 diabetes, Du et al showed that patients with AF had higher levels of blood pressure and albuminuria [6]. Finally, studying 2,671 type 2 diabetes patients originating from the SURDIAGENE (Survie, Diabete de type 2 et Genetique) and DIAB2NEPHROGENE (Diabete de type 2, Nephropathie et Genetique) cohorts, our group

Modified David Operation: A New Simple Method Using a Single Inflow Suture Line

The reimplantation technique for valve sparing aortic root replacement is increasingly used to treat aortic root enlargement. The systematic approach described by El Khoury in 2009 and modified in 2011 using the valsava graft (Gelweave valsalva, Sultzer, Vaskutek, renfrewshire, Scotland) is simple and reproducible. However, in-conduit suturing of the aortic valve annulus and small rim of sinus remnant to the graft sinuses is time consuming and may lead to bleeding, or distorsion of the native valve in the prosthetic root. We describe a simple technique to facilitate the native valve reimplantation. A reproducible, easy to achieve single inflow suture line is used allowing avoiding the continuous suture of the native valve used in all valve sparing surgical techniques.

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

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

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.