[Show abstract][Hide abstract] ABSTRACT: In the past decade, novel cell-based products have been studied in patients with acute and chronic cardiac disease to assess whether these therapies are efficacious in improving heart function and preventing the development of end-stage heart failure. Cardiac indications studied include acute myocardial infarction (AMI), refractory angina, and chronic heart failure (CHF). Increased clinical activity, experience, and multiple challenges faced by developers have been recognized at the regulatory level. In May 2014, the Committee for Advanced Therapies (CAT) discussed in an expert meeting various cell-based medicinal products developed for cardiac repair, with a focus on non-manipulated bone marrow cells, sorted bone marrow or apheresis, and expanded cells, applied to patients with AMI or CHF. The intention was to share information, both scientific and regulatory, and to examine the challenges and opportunities in this field. These aspects were considered from the quality, and non-clinical and clinical perspectives, including current imaging techniques, with a focus on AMI and CHF. The scope of this overview is to present the European regulatory viewpoint on cell-based therapies for cardiac repair in the context of scientific observations.
European Journal of Heart Failure 10/2015; DOI:10.1002/ejhf.422 · 6.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The goal of this paper is to provide an updated review for scientists and clinicians on the major areas in cardiovascular medicine published in the Journal. Leading topics in regenerative and personalized medicine are presented along with a critical overview of the field. New standards in large preclinical animal models of pulmonary hypertension and left bundle branch block are highlighted. Finally, clinical care in the areas of atherosclerosis, the aortic valve, platelet biology, and myocarditis is discussed as well as autonomic modulation therapies.
Journal of Cardiovascular Translational Research 10/2015; 8(8). DOI:10.1007/s12265-015-9657-x · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The traditional cardiac regenerative paradigm using non-modified adult stem cells with various routes of delivery into the myocardial target has thus far yielded unconvincing clinical outcomes. Besides factors related to heterogeneity in trial methodology, inter-patient variability and the rare incidence of adult stem cells with intrinsic repair potency underscore the importance of further optimization and standardization of regenerative platforms. Cardiac tissue engineering seizing upon the advances of cellular, molecular, and biomaterial development is shaping the next generation of the regenerative paradigm and thereby fostering disruptive curative treatments in heart failure.
[Show abstract][Hide abstract] ABSTRACT: Despite multimodal regimens and diverse treatment options alleviating disease symptoms, morbidity and mortality associated with advanced ischemic heart failure remain high. Recently, technological innovation has led to the development of regenerative therapeutic interventions aimed at halting or reversing the vicious cycle of heart failure progression. Driven by the unmet patient need and fueled by encouraging experimental studies, stem cell-based clinical trials have been launched over the past decade. Collectively, these trials have enrolled several thousand patients and demonstrated the clinical feasibility and safety of cell-based interventions. However, the totality of evidence supporting their efficacy in ischemic heart failure remains limited. Experience from the early randomized stem cell clinical trials underscores the key points in trial design ranging from adequate hypothesis formulation to selection of the optimal patient population, cell type and delivery route. Importantly, to translate the unprecedented promise of regenerative biotherapies into clinical benefit, it is crucial to ensure the appropriate choice of endpoints along the regulatory path. Accordingly, we here provide considerations relevant to the choice of endpoints for regenerative clinical trials in the ischemic heart failure setting.
Stem Cell Research & Therapy 08/2015; Stem Cell Res Ther(6(1)):159. DOI:10.1186/s13287-015-0143-9 · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: -Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the ARISTOTLE trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves.
-We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18,201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or prior valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR] 0.70, 95% CI 0.51-0.97 and HR 0.84, 95% CI 0.67-1.04; interaction p=0.38), causing less major bleeding (HR 0.79, 95% CI 0.61-1.04 and HR 0.65, 95% CI 0.55-0.77; interaction p=0.23), and reducing mortality (HR 1.01, 95% CI 0.84-1.22 and HR 0.84, 95% CI 0.73-0.96; interaction p=0.10).
-More than a quarter of the patients in ARISTOTLE with "nonvalvular" atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. Clinical Trial Registration Information-clinicaltrials.gov. Identifier: NCT00412984.
[Show abstract][Hide abstract] ABSTRACT: Stem cell therapy shows promise for regeneration in heart disease, yet interpatient variability challenges implementation into practice.
To establish a biomarker profile, predictive of reparative potential in patient-derived progenitors, human mesenchymal stem cells were isolated from patients undergoing coronary artery bypass grafting.
Stem cell delivery postinfarction translated into divergent benefit, distinguishing reparative from nonreparative populations.
While the nonreparative subtype was characterized by low expression of cardiac transcription factors, reparative human mesenchymal stem cells demonstrated high expression of cardiac transcription factors.
This index of factors (cardiopoietic index) was found sensitive and specific in predicting impact of stem cell benefit on left ventricular function. The cardiopoietic index thus offers a tool to screen stem cell fitness for heart repair prior to intervention.
Biomarkers in Medicine 05/2015; 9(7):1-11. DOI:10.2217/bmm.15.31 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rationale: The ACCRUE (Meta-Analysis of Cell-based CaRdiac stUdiEs) is the first prospectively declared collaborative multinational database including individual data of patients (IPD) with ischemic heart disease treated with cell therapy. Objective: We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI) including IPDs from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). Methods and Results: The primary endpoint was freedom from combined major adverse cardiac and cerebrovascular events (MACCE; including all-cause death, re-AMI, stroke, and target vessel revascularization). The secondary endpoint was freedom from hard clinical endpoints (death, re-AMI, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy endpoints included changes in end-diastolic volume (ΔEDV), end-systolic volume (ΔESV), and ejection fraction (ΔEF), analyzed with random-effects meta-analyses and analysis of covariance. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on MACCE (14.0% vs. 16.3%, hazard ratio 0.86, 95%CI: 0.63;1.18) or death (1.4% vs 2.1%) or death/re-AMI/stroke (2.9% vs 4.7%) was identified in comparison to controls. No change in ΔEF (mean difference: 0.96%, 95%CI: -0.2;2.1), ΔEDV, or ΔESV was observed compared to controls. These results were not influenced by anterior AMI location, reduced baseline EF, or the use of MRI for assessing left ventricular parameters. Conclusions: This meta-analysis of IPD from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function.
Circulation Research 02/2015; 116(8). DOI:10.1161/CIRCRESAHA.116.304346 · 11.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Extended anterior myocardial infarction (MI) is frequently followed by left ventricular (LV) remodeling ensuing in heart failure and aneurysmatic transformation of the infarcted myocardial segment. Therapies that attenuate or reverse pathological LV remodeling have been shown to improve functional status and outcomes. This case reports our recent experience with a catheter based technique for ventricular restoration.
[Show abstract][Hide abstract] ABSTRACT: We investigated the effect of β- and α-adrenergic blockers on fractional flow reserve (FFR) and index of microvascular resistance (IMR). In 43 patients (pts) with intermediate stenoses, we measured FFR and IMR before and after nonselective β-blocker propranolol (30 μg/kg, n = 20) and selective β1-blocker metoprolol (40 μg/kg, n = 23) IC; (b) In additional 21 pts after percutaneous coronary intervention (PCI), FFR and IMR were measured before and after α-blocker phentolamine (3 mg) IC. Neither propranolol nor metoprolol changed values of FFR and IMR. Phentolamine slightly decreased FFR (from 0.88 ± 0.05 to 0.87 ± 0.06, p = 0.025) but did not change IMR. FFR decreased from >0.80 to ≤0.80 in 3 pts (14 %), but in none, the value decreased to <0.75. β-blockers do not affect FFR and IMR in intermediate stenoses. After PCI, a mild decrease in FFR occurs after α-blockers, though of limited clinical impact.
Journal of Cardiovascular Translational Research 11/2014; 7(9). DOI:10.1007/s12265-014-9599-8 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
This study assessed the independent significance of color Doppler 3-D vena contracta area (VCA) at rest and during exercise as a predictor of clinical outcome in mild-moderate functional mitral regurgitation (FMR). METHODS AND RESULTS: The subjects consisted of 62 patients (age, 68±11 years; 76% male) with chronic systolic heart failure and mild-moderate FMR (<2+/4) at rest. All patients underwent VCA assessment at rest and during semi-supine bicycle exercise. During median follow-up of 17 months (IQR, 13-20 months), 15 patients (24%) had composite endpoint of all-cause death (n=3), heart failure admission (n=11), and heart transplantation (n=1). At baseline, patients with vs. without endpoint had significantly larger VCA at rest (17±6 mm(2)vs. 13±7 mm(2), P=0.002) and at peak exercise (35±16 mm(2)vs. 21±12 mm(2), P<0.001). On Cox regression analysis, large (≥15-mm(2)) resting VCA (HR, 7.6; 95% CI: 1.93-13.02; P=0.004) and large (≥20-mm(2)) exercise-induced increase of VCA (HR, 5.1; 95% CI: 1.39-15.21; P=0.014) were independently associated with composite endpoint. Concomitant presence of large VCA at rest and its large increase during exercise occurred in 53% of patients with, vs. in only 8% without, endpoint (negative predictive value, 86%).
The presence of relatively large VCA at rest and its significant increase during exercise is independently associated with adverse clinical outcome in patients with mild-moderate FMR at rest.
[Show abstract][Hide abstract] ABSTRACT: Background:
The presence of ergoreflex activity and its current relationship to hyperventilation and prognosis in cardiac patients is unclear. Therefore, we evaluated ergoreflex activity in cardiac patients with and without heart failure (CHF) as well as in healthy subjects, and we examined how ergoreceptor activity was related to a mortality risk score in CHF (MAGGIC).
Methods and results:
Twenty-five healthy subjects and 76 patients were included, among whom were 25 with ischemic heart disease (IHD), 24 with stable CHF, and 27 with unstable CHF. Ergoreflex activity was measured with a dynamic handgrip exercise, followed by post-handgrip regional circulatory occlusion (PH-RCO). Ergoreflex activity contributed significantly to ventilation (median [interquartile range] %V) in unstable CHF (81 [73-91] %V without PH-RCO, 92 [82-107] %V with PH-RCO, and 11 [6-20] difference in %V; P < .001) and was positively correlated with the MAGGIC risk score (Spearman ρ = 0.431; P = .002). No ergoreflex activity was observed in healthy subjects (-4 [-10 to 5] difference in %V), IHD (0 [-8 to 3] Diff in %V) and stable CHF (-3 [-11 to 6] difference in %V).
Ergoreflex activity contributes to hyperventilation, but only in CHF patients with persistent symptoms, and is closely related to the MAGGIC risk score. Ergoreflex activity was not present in patients with IHD or stable CHF, suggesting other reasons for the increased ventilatory drive in those patients.
[Show abstract][Hide abstract] ABSTRACT: Aims:
Treatment with percutaneous edge-to-edge mitral valve repair (Mitraclip) has recently been recommended as an alternative to conventional mitral valve repair for high surgical risk patients with symptomatic severe mitral regurgitation (MR). In this study, we report the first use of Mitraclip therapy in Belgium.
Methods and results:
This prospective registry includes 41 consecutive patients treated with the Mitraclip in two Belgian centres from October 2010 to June 2013. Acute procedural success, in-hospital safety end points and clinical status were analysed on an intention-to-treat basis up to one year after the procedure. In addition, determinants of major adverse cardiac events (MACE, death, surgical mitral valve intervention, and rehospitalization for heart failure) were analysed. Acute procedural success (successful clip placement and reduction of colour Doppler flow MR to < or = 2) was obtained in 32 patients (78%) and 18 of these patients received two clips. The primary safety end point was reached in 36 pts (88%): one patient died due to intracranial bleeding, there were three urgent surgical interventions and one severe access site bleeding. The MACE rate after one year was 41% (17 patients). There were 11 deaths (27%), six surgical interventions (15%) and 10 rehospitalizations for heart failure (24%). Additional subgroup analysis revealed that the one-year MACE rate was particularly high in patients with left ventricular ejection fraction (LVEF) < 25%: 62% vs. 36% in patients with LVEF > or = 5% (P = 0.05). At one year, MR < or = 2+ and NYHA class < or = 2 was present in 83% of the surviving patients
In high-risk patients with functional MR, treatment with the Mitraclip-device is a feasible and safe option resulting in improvement of MR severity and clinical symptoms. However, as MACE is high in some subgroups (e.g. LVEF < 25%), careful patient selection is crucial to ensure the maximum benefit from this new technique.
[Show abstract][Hide abstract] ABSTRACT: Platelet α2A-adrenergic receptors (ARs) mediate platelet aggregation in response to sympathetic stimulation. The 6.3-kb variant of α2A-AR gene is associated with increased epinephrine-induced platelet aggregation in healthy volunteers. The cytochrome P450 2C19*2 (CYP2C19*2) loss-of-function allele influences P2Y12-mediated platelet inhibition and hence the rate of major adverse cardiovascular events. We assessed the influence of 6.3-kb α2A-AR gene variant on platelet aggregation and its interaction with CYP2C19*2 loss-of-function allele in patients with stable angina on aspirin and clopidogrel (dual antiplatelet therapy).
Aggregation to 5 increasing doses of epinephrine (from 0.156 to 10 μmol/L) was assessed in aggregation units by Multiplate Analyzer and platelet reactivity in P2Y12 reactivity units and % inhibition by VerifyNow P2Y12 assay before percutaneous revascularization. Gene polymorphisms were analyzed with TaqMan Drug Metabolism assay. Of 141 patients, aggregation was higher in 6.3-kb carriers (n=52) when compared with wild types (n=89) at all epinephrine doses (P<0.05) apart from 10 μmol/L (P=0.077). Percentage inhibition was lower (P=0.048) in 6.3-kb α2A-AR carriers. Percentage inhibition was lower (P=0.005) and P2Y12 reactivity units was higher (P=0.012) in CYP2C19*2 allele carriers. Higher P2Y12 reactivity units (P=0.037) and lower percentage inhibition (P=0.009) were observed in carriers of both 6.3-kb α2A-AR variant and CYP2C19*2 allele when compared with wild-type or with either mutation on its own.
The 6.3-kb α2A-AR variant is associated with increased platelet reactivity to epinephrine and has an additive effect along with CYP2C19*2 loss-of-function allele on P2Y12-mediated platelet responses in patients with stable angina on dual antiplatelet therapy.
[Show abstract][Hide abstract] ABSTRACT: The Journal provides the clinician and scientist with the latest advances in discovery research, emerging technologies, preclinical research design and testing, and clinical trials. We highlight advances in areas of induced pluripotent stem cells, genomics, biomarkers, multimodality imaging, and antiplatelet biology and therapy. The top publications are critically discussed and presented along with anatomical reviews and FDA insight to provide context.
Journal of Cardiovascular Translational Research 03/2014; 7(5). DOI:10.1007/s12265-014-9555-7 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present analysis addresses the potential clinical and physiologic significance of discordance in severity of coronary artery disease between the angiogram and fractional flow reserve (FFR) in a large and unselected patient population.
Between September 1999 and December 2011, FFR and percent diameter stenosis (DS) as assessed by quantitative coronary angiography were obtained in 2986 patients (n = 4086 coronary stenoses), in whom at least one stenosis was of intermediate angiographic severity. Fractional flow reserve correlated slightly but significantly with DS [-0.38 (95% CI: -0.41; -0.36); P < 0.001]. The sensitivity, specificity, and diagnostic accuracy of a ≥50% DS for predicting FFR ≤ 0.80 were 61% (95% CI: 59; 63), 67% (95% CI: 65; 69), and 0.64 (95% CI: 0.56; 0.72), respectively. In different anatomical settings, sensitivity and specificity showed marked variations between 35 to 74% and 58 to 76%, respectively, resulting in a discordance in 35% of all cases for these thresholds. For an angiographic threshold of 70% DS, the diagnostic performance by the Youden's index decreased from 0.28 to 0.11 for the overall population.
The data confirm that one-third of a large patient population shows discordance between angiogram ≥50%DS and FFR ≤0.8 thresholds of stenosis severity. Left main stenoses are often underestimated by the classical 50% DS cut-off compared with FFR. This discordance offers physiologic insights for future trials. It is hypothesized that the discordance between angiography and FFR is related to technical limitations, such as imprecise luminal border detection by angiography, as well as to physiologic factors, such as variable minimal microvascular resistance.
European Heart Journal 03/2014; 35(40). DOI:10.1093/eurheartj/ehu094 · 15.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Information on exercise capacity and training in patients who underwent valvular surgery is scarce. The aim of this study is to evaluate postoperative exercise capacity and functional improvement after exercise training according to the preoperative risk and type of surgery. In this prospective study, 145 patients who underwent aortic valve surgery (AVS) or mitral valve surgery (MVS) and who were referred for cardiac rehabilitation were stratified according to the preoperative risk (European System for Cardiac Operative Risk Evaluation [EuroSCORE]) and type of surgery (sternotomy vs ministernotomy or port access). Exercise capacity was evaluated at the start and end of cardiac rehabilitation. Postoperative exercise capacity and the benefit from exercise training were compared between the groups. Patients with a higher preoperative risk had a worse postoperative exercise capacity, with a lower load, peak VO2, anaerobic threshold and 6-minute walking distance (all p <0.001), and a higher VE/VCO2 slope (p = 0.01). In MVS, port access patients performed significantly better at baseline (all p <0.05), but in AVS, ministernotomy patients performed better than sternotomy patients with a concomitant coronary artery bypass graft (p <0.05). Training resulted in an improvement in exercise capacity in each risk group and each type of surgery (all p <0.05). This gain in exercise capacity was comparable for the EuroSCORE risk groups and for the types of surgery, for patients after AVS or MVS. In conclusion, exercise capacity after cardiac surgery is related to the preoperative risk and the type of surgery. Despite these differences in postoperative exercise capacity, a similar benefit from exercise training is obtained, regardless of their preoperative risk or type of surgery.
The American journal of cardiology 01/2014; 113(8). DOI:10.1016/j.amjcard.2014.01.413 · 3.28 Impact Factor