Albert Hagège

Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction

OBJECTIVES This phase I trial was designed to assess the feasibility and safety of autologous skeletal myoblast transplantation in patients with severe ischemic cardiomyopathy. BACKGROUND Experimentally, myoblast grafting into postinfarction myocardial scars improves left ventricular function. METHODS Ten patients were included on the basis of the following criteria: 1) severe left ventricular dysfunction (ejection fraction < or = 35%); 2) the presence of a postinfarction akinetic and nonviable scar, as assessed by dobutamine echocardiography and 18-fluorodeoxyglucose positron emission tomography; and 3) an indication of coronary bypass in remote areas. Skeletal myoblasts were grown from a biopsy taken at the thigh. RESULTS An average of 871 x 10(6) cells (86% of myoblasts) were obtained after a mean period of 16 days and implanted uneventfully across the scar at the time of bypass. Except for one patient whose early death was unrelated to the cell transplantation, all patients had an uncomplicated postoperative course. Four patients showed delayed episodes of sustained ventricular tachycardia and were implanted with an internal defibrillator. At an average follow-up of 10.9 months, the mean New York Heart Association functional class improved from 2.7 +/- 0.2 preoperatively to 1.6 +/- 0.1 postoperatively (p < 0.0001), and the ejection fraction increased from 24 +/- 1% to 32 +/- 1% (p < 0.02). A blinded echocardiographic analysis showed that 63% of the cell-implanted scars (14 of 22) demonstrated improved systolic thickening. One noncardiac death occurred 17.5 months after transplantation. CONCLUSIONS These preliminary data suggest the feasibility and safety of autologous skeletal myoblast transplantation in severe ischemic cardiomyopathy, with the caveat of an arrhythmogenic potential. New-onset contraction of akinetic and nonviable segments suggests a functional efficacy that requires confirmation by randomized studies.

2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC)

2D : two-dimensional 99mTc-DPD : 99mTechnetium-3,3-diphosphono- 1,2-propanodi-carboxylic acid ACE : angiotensin-converting enzyme AF : atrial fibrillation AL : amyloid light chain AR : aortic regurgitation ARB : angiotensin receptor blocker ATTR : amyloidosis-transthyretin type AV : atrioventricular BiVAD : biventricular assist device BNP : brain natriuretic peptide BPM : Beats per minute CCS : Canadian Cardiovascular Society CFC : cardiofacialcutaneous CHA2DS2-VASc : Congestive Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65–74, and Sex (female) CMR : cardiac magnetic resonance CRT : cardiac resynchronization therapy CRT-D : cardiac resynchronization therapy-defibrillator CRT-P : Cardiac resynchronization therapy with a pacemaker CT : computed tomography DC : direct current DNA : deoxyribonucleic acid E/A : ratio of mitral peak velocity of early filling (E) to mitral peak velocity of late filling (A) E/e’ : ratio of early transmitral flow velocity (E) to early mitral annulus velocity (e’) EACTS : European Association for Cardio-Thoracic Surgery ECG : electrocardiogram EF : ejection fraction EPS : electrophysiological study ESC : European Society of Cardiology FDA : (US) Food and Drug Administration FHL1 : four and a half LIM domains 1 HAS-BLED : hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly (>65 years), drugs/alcohol concomitantly HCM : hypertrophic cardiomyopathy hs-cTnT : high sensitivity cardiac troponin T HTS : high throughput sequencing ICD : implantable cardioverter defibrillator ILR : implantable loop recorder INR : international normalized ratio IUD : intrauterine device LA : left atrium LAMP-2 : lysosome-associated membrane protein 2 LBBB : left bundle branch block LEOPARD : Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, and sensory-neural Deafness LGE : late gadolinium enhancement LV : left ventricular LVAD : left ventricular assist device LVH : left ventricular hypertrophy LVOTO : left ventricular outlow tract obstruction MADIT-RIT : Multicenter Automatic Defibrillator Implantation Trial—Reduce Inappropriate Therapy MAPK : mitogen activated protein kinase MELAS : mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes MERFF : myoclonic epilepsy with ragged red fibres MRA : mineralocorticoid receptor antagonist MYBPC3 : myosin-binding protein C, cardiac-type MYH7 : myosin-7 (s-myosin heavy chain) MYL3 : myosin light chain 3 NOAC : new oral anticoagulants NSVT : non-sustained ventricular tachycardia NT-proBNP : N-terminal pro brain natriuretic peptide NYHA : New York Heart Association OAC : oral anticoagulants o.d. : omni die (every day) PC-CMR : phase contrast cardiac magnetic resonance PDE5 : phosphodiesterase type 5 PET : positron emission tomography PRKAG2 : gamma-2 sub-unit of the adenosine monophosphate-activated protein kinase RAAS : renin angiotensin aldosterone system RV : right ventricular SAM : systolic anterior motion SCD : sudden cardiac death SAA : septal alcohol ablation S-ICD™ : Subcutaneous lead implantable cardioverter defibrillator SPECT : single photon emission computed tomography SSFP : steady-state free precession SVT : supraventricular tachycardia TOE : transoesophageal echocardiography TNNI3 : troponin I, cardiac muscle TNNT2 : troponin T, cardiac muscle TPM1 : tropomyosin alpha-1 chain TTE : transthoracic echocardiography TTR : transthyretin VF : ventricular fibrillation VKA : vitamin K antagonist VT : ventricular tachycardia WHO : World Health Organization Guidelines summarize and evaluate all available evidence at the time of the writing process, on a particular issue with the aim of assisting health professionals in selecting the best management strategies for an individual patient, with a given condition, taking into account the impact on outcome, as well as the risk-benefit-ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help the health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. A great number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organisations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated. Members of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management (including diagnosis, treatment, prevention and rehabilitation) of a given condition according to ESC Committee for Practice Guidelines (CPG) policy. A critical evaluation of diagnostic and therapeutic procedures was performed including assessment of the risk-benefit-ratio. Estimates of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength of recommendation of particular management options were weighed and graded according to predefined scales, as outlined in Tables 1 and 2 . The experts of …

Myoblast transplantation for heart failure.

Intramyocardial skeletal muscle transplantation has been shown experimentally to improve heart function after infarction. We report success with this procedure in a patient with severe ischaemic heart failure. We implanted autologous skeletal myoblasts into the postinfarction scar during coronary artery bypass grafting of remote myocardial areas. 5 months later, there was evidence of contraction and viability in the grafted scar on echocardiography and positron emission tomography. Although this result is encouraging, it requires validation by additional studies.

The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) Trial First Randomized Placebo-Controlled Study of Myoblast Transplantation

Background— Phase I clinical studies have demonstrated the feasibility of implanting autologous skeletal myoblasts in postinfarction scars. However, they have failed to determine whether this procedure was functionally effective and arrhythmogenic. Methods and Results— This multicenter, randomized, placebo-controlled, double-blind study included patients with left ventricular (LV) dysfunction (ejection fraction ≤35%), myocardial infarction, and indication for coronary surgery. Each patient received either cells grown from a skeletal muscle biopsy or a placebo solution injected in and around the scar. All patients received an implantable cardioverter-defibrillator. The primary efficacy end points were the 6-month changes in global and regional LV function assessed by echocardiography. The safety end points comprised a composite index of major cardiac adverse events and ventricular arrhythmias. Ninety-seven patients received myoblasts (400 or 800 million; n=33 and n=34, respectively) or the placebo (n=30). Myoblast transfer did not improve regional or global LV function beyond that seen in control patients. The absolute change in ejection fraction (median [interquartile range]) between 6 months and baseline was 4.4% (0.2; 7.3), 3.4% (−0.3; 12.4), and 5.2% (−4.4; 11.0) in the placebo, low-dose, and high-dose groups, respectively (P=0.95). However, the high-dose cell group demonstrated a significant decrease in LV volumes compared with the placebo group. Despite a higher number of arrhythmic events in the myoblast-treated patients, the 6-month rates of major cardiac adverse events and of ventricular arrhythmias did not differ significantly between the pooled treatment and placebo groups. Conclusions— Myoblast injections combined with coronary surgery in patients with depressed LV function failed to improve echocardiographic heart function. The increased number of early postoperative arrhythmic events after myoblast transplantation, as well as the capability of high-dose injections to revert LV remodeling, warrants further investigation.

Three-dimensional echocardiographic reconstruction of the mitral valve, with implications for the diagnosis of mitral valve prolapse.

Mitral valve prolapse has been diagnosed by two-dimensional echocardiographic criteria with surprising frequency in the general population, even when preselected normal subjects are examined. In most of these individuals, however, prolapse appears in the apical four-chamber view and is absent in roughly orthogonal long-axis views. Previous studies of in vitro models with nonplanar rings have shown that systolic mitral annular nonplanarity can potentially produce this discrepancy. However, to prove directly that apparent leaflet displacement in a two-dimensional view does not constitute true displacement above the three-dimensional annulus requires reconstruction of the entire mitral valve, including leaflets and annulus. Such reconstruction would also be necessary to explore the complex geometry of the valve and to derive volumetric measures of superior leaflet displacement. A technique was therefore developed and validated in vitro for three-dimensional reconstruction of the entire mitral valve. In this technique, simultaneous real-time acquisition of images and their spatial locations permits reconstruction of a localized structure by minimizing the effects of patient motion and respiration. By applying this method to 15 normal subjects, a coherent mitral valve surface could be reconstructed from intersecting scans. The results confirm mitral annular nonplanarity in systole, with a maximum deviation of 1.4 +/- 0.3 cm from planarity. They directly show that leaflets can appear to ascend above the mitral annulus in the apical four-chamber view, as they did in at least one view in all subjects, without actual leaflet displacement above the entire mitral valve in three dimensions, thereby challenging the diagnosis of prolapse by isolated four-chamber view displacement in otherwise normal individuals. This technique allows us to address a uniquely three-dimensional problem with high resolution and provide new information previously unavailable from the two-dimensional images. This new appreciation should enhance our ability to ask appropriate clinical questions relating mitral valve shape and leaflet displacement to clinical and pathologic consequences.

Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study

BACKGROUND Heart failure develops after myocardial infarction and is a major cause of morbidity and mortality. The ability to direct differentiation of embryonic stem cells (ESC) towards a cardiomyogenic phenotype makes them an attractive therapeutic option for cardiac repair, but species-specific and individual-specific immunological imprinting remains a hurdle. Our aim was to ascertain whether the purported immune privilege of ESC allows for their cross-species engraftment in a clinically relevant large-animal model. METHODS We studied engraftment and differentiation of cardiac-committed mouse ESC in 18 sheep in which a myocardial infarction had been induced; nine controls received medium and nine sheep (five of which were immunosuppressed) received ESC. The gain in myocardial function was measured by echocardiography 1 month after cell transplantation. FINDINGS Cardiac-committed murine ESC engrafted in infarcted myocardium of immunosuppressed and immunocompetent sheep, and differentiated into mature cardiomyocytes that expressed connexins. Colonisation of the scar area by ESC was accompanied by a functional benefit of the damaged myocardium. Left-ventricular ejection fraction deteriorated in the control group by a median of 9.9% (range -20 to 0.3) relative to baseline (p=0.011) whereas in the treated group it improved by 6.6% (-5.7 to 50.8; comparison between groups p=0.002). INTERPRETATION These findings obtained in a clinically relevant large-animal model of heart failure strengthen the potential therapeutic use of ESC to regenerate the severely dysfunctional myocardium and bring additional evidence for an immune privilege of these cells.

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

Background— Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results— We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74–0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52–0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro–B-type natriuretic peptide and troponin) versus enalapril. Conclusions— Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy

Autologous skeletal myoblast transplantation might improve postinfarction ventricular function, but graft viability and differentiation (ie, proof of concept) has not been shown. A 72-year-old man had autologous cultured myoblasts from his vastus lateralis injected to an area of transmural inferior myocardial infarction in non-reperfused scar tissue. He showed improvement in symptoms and left-ventricular ejection fraction. When he died 17.5 months after the procedure, the grafted post-infarction scar showed well developed skeletal myotubes with a preserved contractile apparatus. 65% of myotubes expressed the slow myosin isoform and 33% coexpressed the slow and fast isoforms (vs 44% and 0.6%, respectively, in skeletal muscle). Myoblast grafts can survive and show a switch to slow-twitch fibres, which might allow sustained improvement in cardiac function.

Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients.

Background— Skeletal myoblast (SM) transplantation (Tx) in a post-myocardial infarction (MI) scar experimentally improves left ventricular (LV) ejection fraction (EF). Short-term follow-up (FU) studies have suggested that a similar benefit could clinically occur despite an increased risk of LV arrhythmias. Methods and Results— We report the long-term FU of the first worldwide cohort of grafted patients (n =9, 61.8±11.6 years, previous MI, EF ≤35%) operated on (autologous SM Tx and bypass surgery) in 2000 to 2001 and evaluated before Tx, at 1 month (M1) and at a median FU of 52 (18 to 58) months after Tx (37 patient-years). NYHA class improved from 2.5±0.5 to 1.8±0.4 at M1 (P=0.004 versus baseline) and 1.7±0.5 at FU (P=not significant versus M1; P=0.0007 versus baseline). EF increased from 24.3±4% to 31±4.1% at M1 (+28%, P=0.001 versus baseline) and remained stable thereafter (28.7±8.1%, +18% versus baseline). There were 5 hospitalizations for heart failure in 3 patients at 28.6±9.9 months, allowing implant in 2 patients with a resynchronization pacemaker. An automatic cardiac defibrillator (ACD) was implanted in 5 patients for nonsustained (n =1) or sustained (n =4) ventricular tachycardia at 12.2±18.6 (1 to 45) months. Despite a beta-blocker/amiodarone combination therapy, there were 14 appropriate shocks for 3 arrhythmic storms in 3 patients at 6, 7, and 18 months after ACD implantation. Conclusions— In this cohort of severe heart failure patients both clinical status and EF stably improve over time with a strikingly low incidence of hospitalizations for heart failure (0.13/patient-years) and the arrhythmic risk can be controlled by medical therapy and/or on-request ACD implantation.

A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates

Cell therapy holds promise for tissue regeneration, including in individuals with advanced heart failure. However, treatment of heart disease with bone marrow cells and skeletal muscle progenitors has had only marginal positive benefits in clinical trials, perhaps because adult stem cells have limited plasticity. The identification, among human pluripotent stem cells, of early cardiovascular cell progenitors required for the development of the first cardiac lineage would shed light on human cardiogenesis and might pave the way for cell therapy for cardiac degenerative diseases. Here, we report the isolation of an early population of cardiovascular progenitors, characterized by expression of OCT4, stage-specific embryonic antigen 1 (SSEA-1), and mesoderm posterior 1 (MESP1), derived from human pluripotent stem cells treated with the cardiogenic morphogen BMP2. This progenitor population was multipotential and able to generate cardiomyocytes as well as smooth muscle and endothelial cells. When transplanted into the infarcted myocardium of immunosuppressed nonhuman primates, an SSEA-1+ progenitor population derived from Rhesus embryonic stem cells differentiated into ventricular myocytes and reconstituted 20% of the scar tissue. Notably, primates transplanted with an unpurified population of cardiac-committed cells, which included SSEA-1- cells, developed teratomas in the scar tissue, whereas those transplanted with purified SSEA-1+ cells did not. We therefore believe that the SSEA-1+ progenitors that we have described here have the potential to be used in cardiac regenerative medicine.