Jean-Christian Roussel

First clinical use of a bioprosthetic total artificial heart: report of two cases

BACKGROUND The development of artificial hearts in patients with end-stage heart disease have been confronted with the major issues of thromboembolism or haemorrhage. Since valvular bioprostheses are associated with a low incidence of these complications, we decided to use bioprosthetic materials in the construction of a novel artificial heart (C-TAH). We report here the device characteristics and its first clinical applications in two patients with end-stage dilated cardiomyopathy. The aim of the study was to evaluate safety and feasibility of the CARMAT TAH for patients at imminent risk of death from biventricular heart failure and not eligible for transplant. METHODS The C-TAH is an implantable electro-hydraulically actuated pulsatile biventricular pump. All components, batteries excepted, are embodied in a single device positioned in the pericardial sac after excision of the native ventricles. We selected patients admitted to hospital who were at imminent risk of death, having irreversible biventricular failure, and not eligible for heart transplantation, from three cardiac surgery centres in France. FINDINGS The C-TAH was implanted in two male patients. Patient 1, aged 76 years, had the C-TAH implantation on Dec 18, 2013; patient 2, aged 68 years, had the implantation on Aug 5, 2014. The cardiopulmonary bypass times for C-TAH implantation were 170 min for patient 1 and 157 min for patient 2. Both patients were extubated within the first 12 postoperative hours and had a rapid recovery of their respiratory and circulatory functions as well as a normal mental status. Patient 1 presented with a tamponade on day 23 requiring re-intervention. Postoperative bleeding disorders prompted anticoagulant discontinuation. The C-TAH functioned well with a cardiac output of 4·8-5·8 L/min. On day 74, the patient died due to a device failure. Autopsy did not detect any relevant thrombus formation within the bioprosthesis nor the different organs, despite a 50-day anticoagulant-free period. Patient 2 experienced a transient period of renal failure and a pericardial effusion requiring drainage, but otherwise uneventful postoperative course. He was discharged from the hospital on day 150 after surgery with a wearable system without technical assistance. After 4 months at home, the patient suffered low cardiac output. A change of C-TAH was attempted but the patient died of multiorgan failure. INTERPRETATION This preliminary experience could represent an important contribution to the development of total artificial hearts using bioprosthetic materials. FUNDING CARMAT SA.

Molecular risk stratification in advanced heart failure patients

Risk stratification in advanced heart failure (HF) is crucial for the individualization of therapeutic strategy, in particular for heart transplantation and ventricular assist device implantation. We tested the hypothesis that cardiac gene expression profiling can distinguish between HF patients with different disease severity. We obtained tissue samples from both left (LV) and right (RV) ventricle of explanted hearts of 44 patients undergoing cardiac transplantation or ventricular assist device placement. Gene expression profiles were obtained using an in‐house microarray containing 4217 muscular organ‐relevant genes. Based on their clinical status, patients were classified into three HF‐severity groups: deteriorating (n= 12), intermediate (n= 19) and stable (n= 13). Two‐class statistical analysis of gene expression profiles of deteriorating and stable patients identified a 170‐gene and a 129‐gene predictor for LV and RV samples, respectively. The LV molecular predictor identified patients with stable and deteriorating status with a sensitivity of 88% and 92%, and a specificity of 100% and 96%, respectively. The RV molecular predictor identified patients with stable and deteriorating status with a sensitivity of 100% and 96%, and a specificity of 100% and 100%, respectively. The molecular prediction was reproducible across biological replicates in LV and RV samples. Gene expression profiling has the potential to reproducibly detect HF patients with highest HF severity with high sensitivity and specificity. In addition, not only LV but also RV samples could be used for molecular risk stratification with similar predictive power.

New insights into mitral valve dystrophy: A Filamin-A genotype-phenotype and outcome study

Aims Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis. Methods and results We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring three different FLNA mutations. Phenotype was characterized by a comprehensive echocardiography focusing on mitral valve apparatus in comparison with control relatives. In this X-linked disease valves lesions were severe in men and moderate in women. Most men had classical features of mitral valve prolapse (MVP), but without chordal rupture. By contrast to regular MVP, mitral leaflet motion was clearly restricted in diastole and papillary muscles position was closer to mitral annulus. Valvular abnormalities were similar in the four families, in adults and young patients from early childhood suggestive of a developmental disease. In addition, mitral valve lesions worsened over time as encountered in degenerative conditions. Polyvalvular involvement was frequent in males and non-diagnostic forms frequent in females. Overall survival was moderately impaired in men (P = 0.011). Cardiac surgery rate (mainly valvular) was increased (33.3 ± 9.8 vs. 5.0 ± 4.9%, P < 0.0001; hazard ratio 10.5 [95% confidence interval: 2.9-37.9]) owing mainly to a lifetime increased risk in men (76.8 ± 14.1 vs. 9.1 ± 8.7%, P < 0.0001). Conclusion FLNA-MVD is a developmental and degenerative disease with complex phenotypic expression which can influence patient management. FLNA-MVD has unique features with both MVP and paradoxical restricted motion in diastole, sub-valvular mitral apparatus impairment and polyvalvular lesions in males. FLNA-MVD conveys a substantial lifetime risk of valve surgery in men.

Bioprosthetic Total Artificial Heart Induces a Profile of Acquired Hemocompatibility With Membranes Recellularization

The Carmat total artificial heart (C-TAH) (Velizy-Villacoublay, France) is an implantable electro-hydraulically actuated biventricular pump that has been developed to minimize mechanical assist device-related morbidities [(1)][1]. Its blood-contacting surfaces consist of expanded

A bioprosthetic total artificial heart for end-stage heart failure: Results from a pilot study.

BACKGROUND The electro-hydraulically actuated Carmat total artificial heart (C-TAH) is designed to replace the heart in patients with end-stage heart failure, either as bridge to transplant or destination therapy. It provides pulsatile flow and contains bio-prosthetic blood contacting materials. A clinical feasibility study was conducted to evaluate the C-TAH safety and performance. METHODS Hospitalized patients, at imminent risk of death from irreversible biventricular failure despite optimal medical management, and not eligible for transplant or eligible but on extracorporeal life support, were enrolled. The primary endpoint was 30-days survival. RESULTS Four patients were implanted with the C-TAH, three as destination therapy (ages 76, 68, 74) and one as bridge to transplant (age 58). They had implant times of 74, 270, 254 and 20 days respectively. All patients were free from hemolysis, clinical neurologic events, clinical evidence of thrombus and device-related infections. Hemodynamic and physical recovery allowed two patients to be discharged home for a cumulative duration of 7 months. The anticoagulation management strategy comprised initial unfractionated heparin, from postoperative day 2, followed by low molecular weight heparin and aspirin. An increased D-dimer level was observed in all patients during months 1 to 4. Temporary suspension of heparin anticoagulation resulted in thrombocytopenia and increased fibrin monomer, reversed by resuming anticoagulation with heparin. Causes of death were device-related (2 cases), respiratory failure and multi-organ failure. CONCLUSIONS Preliminary clinical results with the C-TAH demonstrated good safety and performance profiles in patients suffering from biventricular failure, which need to be confirmed in a pivotal study.

Prospective clinical and biological comparison of three blood cardioplegia techniques in low-risk CABG patients: better is worse than good enough

OBJECTIVE Three myocardial protection techniques were evaluated in a prospective, randomised trial during coronary artery bypass grafts in 69 patients. MATERIAL AND METHOD Twenty seven patients received intermittent hyperkalaemic undiluted warm blood anterograde cardioplegia (AC), 21 received continuous hyperkalaemic undiluted warm blood retrograde cardioplegia (RC) and 21 received intermittent, hyperkalaemic, diluted cold blood (15 degrees C), anterograde cardioplegia (CC). Assessment criteria were clinical, laboratory and haemodynamic. RESULTS Groups were homogeneous in terms of age, sex, cardiovascular risk factors, severity of coronary disease, preoperative ejection fraction, and number of bypass grafts performed. The oxygen extraction coefficient, and lactate and troponin production in the coronary sinus on aortic unclamping was not significantly different between the three groups. The base excess was -0.19+/-0.13 in the RC group, -0.18+/-0.52 in the AC group and -2.67+/-0.59 in the CC group (P<0.01 CC vs. AC and CC vs. RC). The priming volume was 1485+/-64 ml (CC), 1317+/-44 ml (RC) and 1318+/-30 ml (AC) (P<0.05 CC vs. AC and CC vs. RC). The haematocrit during CPB was 28.9+/-0.9 (CC), 32.5+/-0.8 (RC) and 32+/-0.7 (AC) (P<0.05 CC vs. AC and CC vs. RC). The volume of crystalloid delivered was 735+/-85 ml (CC), 362+/-67 ml (RC) and 357+/-105 ml (AC) (P<0.05 CC vs. AC and CC vs. RC). The incidence of ventricular fibrillation on aortic unclamping was 61.9% (CC), 9.5% (RC) and 0% (AC) (P<0.01 CC vs. AC and CC vs. RC). The transfusion rate, duration of intubation, postoperative troponin level, complication rate and mortality were not significantly different between the three groups. Haemodynamic parameters at H2, H4, H8 did not vary significantly between the three groups. CONCLUSION These three techniques appear to be comparable in terms of myocardial protection. Anterograde cardioplegia ensures an identical degree of security to retrograde cardioplegia regardless of the coronary lesions, apart from redo lesions. CC requires greater haemodilution of the patients during CPB.

Heart transplantation in selected patients aged 60 years and older: a two-decade retrospective and multicentre analysis

OBJECTIVES This study analysed survival and long-term outcomes of heart transplantation in patients aged 60 years and older. We also analysed the impact of a national graft allocation priority [Super Emergency (SE)] and compared survival with younger patients in our centres and in France. METHODS We performed a multicentre (University Hospitals in Nantes, Rennes and Tours), 2-decade retrospective study between 1 January 1994 and 31 December 2013. Elderly recipients were placed on the same list as younger patients; the use of marginal donors remained occasional. RESULTS A total of 212 patients aged between 60 and 68 years were included. The 1-, 5-, and 10-year survival rates were 83.2%, 77.4% and 63.8%, respectively, which were significantly worse than those of recipients aged <60 years (1-, 5-, and 10-year survival rates of 87.3%, 80.4% and 68.0%, respectively). The postoperative course was acceptable. The main cause of death was malignancy (29.8% in our cohort). Survival was similar between the first and second decades and among the SE group. Our population exhibited better survival than patients <60 years transplanted in France during the same period with 1-, 5-, and 10-year survival rates of 76.8%, 68.0% and 56.3%, respectively. Predictors of survival in the multivariate analysis included ischaemic cardiomyopathy [hazard ratio (HR) 4.1] and postoperative complications, such as dialysis (HR 9.5) and mechanical circulatory support (HR 4.2). CONCLUSIONS We report positive postoperative course and long-term outcomes after heart transplantation in older recipients using conventional donors. Our satisfactory outcomes may be explained by the stringent selection of recipients combined with regular follow-up.

Ultrasound-guided transversus abdominis plane/genitofemoral blocks for a patient receiving extracorporeal life support.

Extracorporeal life support may be used in patients with refractory cardiogenic shock. The femoral venoarterial route can be used for implanting cannulae in patients who are hemodynamically unstable. Here we describe the use of an ultrasound-guided transversus abdominis plane block supplemented with the femoral component of the genitofemoral nerve as the anesthesia technique for peripheral cannulation of the femoral vessels in a patient with severe acute heart failure after myocardial infarction with ST-segment elevation. The procedure was performed using 40 mL of a 50:50 mixture of 0.5% levobupivacaine and 2% lidocaine (30 mL for transversus abdominis plane and 10 mL for genitofemoral block) associated with low-dose remifentanil infusion during spontaneous breathing. A left ventricular assist device was successfully implanted 4 days later.

Structural valve deterioration of biosprosthetic aortic valve: an underestimated complication

Objectives: Structural valve deterioration (SVD) remains a major bioprosthesis‐related complication, as recently described for the Mitroflow valve (models LX and 12A) (LivaNova, London, United Kingdom). The real incidence of the SVD risk remains unclear, often due to methodologic pitfalls by systematically using the Kaplan‐Meier estimator and/or the Cox model. In this report, we propose for the first time a precise statistical modeling of this issue. Methods: Five hundred sixty‐one patients who underwent aortic valve replacement with the aortic Mitroflow valve between 2002 and 2007 were included. We used an illness–death model for interval‐censored data. Median follow‐up was 6.6 years; 103 cases of SVD were diagnosed. Results: The 4‐year and 7‐year SVD cumulative incidences after the first anniversary of surgery were 15.2% (95% confidence interval, 11.9‐19.1) and 31.0% (95% confidence interval, 25.8‐37.2), respectively. Female gender, dyslipidemia, chronic obstructive pulmonary disease, and severe patient‐prosthesis mismatch were significant risk factors of SVD. The occurrence of SVD was associated with a 2‐fold increase in the risk of death. Conclusions: Appropriate statistical models should be used to avoid underestimating the SVD complication associated with worse long‐term survival.

Inverse probability weighting to control confounding in an illness‐death model for interval‐censored data

Multistate models with interval-censored data, such as the illness-death model, are still not used to any considerable extent in medical research regardless of the significant literature demonstrating their advantages compared to usual survival models. Possible explanations are their uncommon availability in classical statistical software or, when they are available, by the limitations related to multivariable modelling to take confounding into consideration. In this paper, we propose a strategy based on propensity scores that allows population causal effects to be estimated: the inverse probability weighting in the illness semi-Markov model with interval-censored data. Using simulated data, we validated the performances of the proposed approach. We also illustrated the usefulness of the method by an application aiming to evaluate the relationship between the inadequate size of an aortic bioprosthesis and its degeneration or/and patient death. We have updated the R package multistate to facilitate the future use of this method.