Regenerative heart failure therapy headed for optimization.
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ABSTRACT:
SUBMITTER: Terzic A
PROVIDER: S-EPMC4019913 | biostudies-literature | 2014 May
REPOSITORIES: biostudies-literature
Publications
Regenerative heart failure therapy headed for optimization.
European heart journal 20140326 19
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Project description:Patient-derived stem cells enable promising regenerative strategies, but display heterogenous cardiac reparative proficiency, leading to unpredictable therapeutic outcomes impeding practice adoption. Means to establish and certify the regenerative potency of emerging biotherapies are thus warranted. In this era of clinomics, deconvolution of variant cytoreparative performance in clinical trials offers an unprecedented opportunity to map pathways that segregate regenerative from non-regenerative states informing the evolution of cardio-regenerative quality systems. A maiden example of this approach is cardiopoiesis-mediated lineage specification developed to ensure regenerative performance. Successfully tested in pre-clinical and early clinical studies, the safety and efficacy of the cardiopoietic stem cell phenotype is undergoing validation in pivotal trials for chronic ischemic cardiomyopathy offering the prospect of a next-generation regenerative solution for heart failure.
| S-EPMC4912443 | biostudies-literature
Project description:AimsCardiopoiesis is a conditioning programme that aims to upgrade the cardioregenerative aptitude of patient-derived stem cells through lineage specification. Cardiopoietic stem cells tested initially for feasibility and safety exhibited signs of clinical benefit in patients with ischaemic heart failure (HF) warranting definitive evaluation. Accordingly, CHART-1 is designed as a large randomized, sham-controlled multicentre study aimed to validate cardiopoietic stem cell therapy.MethodsPatients (n = 240) with chronic HF secondary to ischaemic heart disease, reduced LVEF (<35%), and at high risk for recurrent HF-related events, despite optimal medical therapy, will be randomized 1:1 to receive 600 × 10(6) bone marrow-derived and lineage-directed autologous cardiopoietic stem cells administered via a retention-enhanced intramyocardial injection catheter or a sham procedure. The primary efficacy endpoint is a hierarchical composite of mortality, worsening HF, Minnesota Living with Heart Failure Questionnaire score, 6 min walk test, LV end-systolic volume, and LVEF at 9 months. The secondary efficacy endpoint is the time to cardiovascular death or worsening HF at 12 months. Safety endpoints include mortality, readmissions, aborted sudden deaths, and serious adverse events at 12 and 24 months.ConclusionThe CHART-1 clinical trial is powered to examine the therapeutic impact of lineage-directed stem cells as a strategy to achieve cardiac regeneration in HF populations. On completion, CHART-1 will offer a definitive evaluation of the efficacy and safety of cardiopoietic stem cells in the treatment of chronic ischaemic HF.Trial registrationNCT01768702.
| S-EPMC5064644 | biostudies-literature
Project description:Cardiac resynchronization therapy using bi-ventricular pacing is proven effective in the management of heart failure (HF) with a wide QRS-complex. In the absence of QRS prolongation, however, device-based resynchronization is reported unsuitable. As an alternative, the present study tests a regenerative cell-based approach in the setting of narrow QRS-complex HF. Progressive cardiac dyssynchrony was provoked in a chronic transgenic model of stress-triggered dilated cardiomyopathy. In contrast to rampant end-stage disease afflicting untreated cohorts, stem cell intervention early in disease, characterized by mechanical dyssynchrony and a narrow QRS-complex, aborted progressive dyssynchronous HF and prevented QRS widening. Stem cell-treated hearts acquired coordinated ventricular contraction and relaxation supporting systolic and diastolic performance. Rescue of contractile dynamics was underpinned by a halted left ventricular dilatation, limited hypertrophy, and reduced fibrosis. Reverse remodeling reflected a restored cardiomyopathic proteome, enforced at systems level through correction of the pathological molecular landscape and nullified adverse cardiac outcomes. Cell therapy of a dyssynchrony-prone cardiomyopathic cohort translated prospectively into improved exercise capacity and prolonged survivorship. In narrow QRS HF, a regenerative approach demonstrated functional and structural benefit, introducing the prospect of device-autonomous resynchronization therapy for refractory disease.
| S-EPMC4599402 | biostudies-literature
Project description:Although evidence based guidelines recommend optimal use of beta blockers in all patients with chronic heart failure unless contraindicated, they are often underutilized and/or prescribed below the recommended dosage in the majority of patients with heart failure. To our knowledge, however, the optimal use of beta-blockers in chronic heart failure is not investigated in Ethiopia. Therefore, the aim of our study was to investigate the utilization and optimization of beta blockers in the management of patients with chronic heart failure in Ethiopia. A prospective observational study was conducted among ambulatory patients with chronic heart failure in Ethiopia. We included adult patients with a diagnosis of heart failure with a baseline left ventricular ejection fraction?<?40% who had been on follow-up for at least 6 months. Patients were recruited into the study during their appointment for medication refilling using simple random sampling technique. All patients were followed for at least 6 months to determine the optimal use of beta blockers. The optimal use of beta blockers was determined according to evidence based guidelines. After explaining the purpose of the study, we obtained written informed consent from all participants. Data were collected through patient interview and review of patients' medical records. Binary logistic regression analysis was performed to identify factors associated with utilization of beta blockers. A total of 288 patients were included in the study. Out of the total, 67% of the patients were receiving beta blockers. Among the patients who received beta blockers, 34.2% were taking guideline recommended beta blockers while 65.8% were taking atenolol, which is not guideline recommended beta blocker. Among the patients who received guideline recommended beta blockers, only 3% were taking optimal dose. Prior hospitalization [Adjusted Odds ratio (AOR) 0.38, 95% confidence interval (CI) 0.19-0.76], dose of furosemide?>?40 mg (AOR 0.39, 95% CI 0.20-0.76), ischemic heart disease (AOR 3.27, 95% CI 1.66-6.45), atrial fibrillation (AOR 4.41, 95% CI 1.38-14.13) were significantly associated with the utilization of beta-blockers. Despite proven benefit, beta blockers were not optimally used in most of the participants in this study. The presence of ischemic heart disease and atrial fibrillation were positively associated with the utilization of beta blockers while hospitalization and higher diuretic dose were negatively associated with the utilization of beta blockers. Clinicians should attempt to use evidence based beta blockers at guideline recommended target doses that have been shown to have morbidity and mortality benefit in chronic heart failure. Moreover, more effort needs to be done to minimize the potentially modifiable risk factors for underutilization of beta blocker in chronic heart failure therapy.
| S-EPMC7522285 | biostudies-literature
Project description:Background and aimsIn patients with de novo heart failure with reduced ejection fraction (HFrEF), improvement of left ventricular ejection fraction (LVEF) is expected to occur when started on guideline-recommended medical therapy. However, improvement may not be completed within 90 days.MethodsPatients with HFrEF and LVEF ≤ 35% prescribed a wearable cardioverter-defibrillator between 2017 and 2022 from 68 sites were enrolled, starting with a registry phase for 3 months and followed by a study phase up to 1 year. The primary endpoints were LVEF improvement > 35% between Days 90 and 180 following guideline-recommended medical therapy initiation and the percentage of target dose reached at Days 90 and 180.ResultsA total of 598 patients with de novo HFrEF [59 years (interquartile range 51-68), 27% female] entered the study phase. During the first 180 days, a significant increase in dosage of beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists was observed (P < .001). At Day 90, 46% [95% confidence interval (CI) 41%-50%] of study phase patients had LVEF improvement > 35%; 46% (95% CI 40%-52%) of those with persistently low LVEF at Day 90 had LVEF improvement > 35% by Day 180, increasing the total rate of improvement > 35% to 68% (95% CI 63%-72%). In 392 patients followed for 360 days, improvement > 35% was observed in 77% (95% CI 72%-81%) of the patients. Until Day 90, sustained ventricular tachyarrhythmias were observed in 24 wearable cardioverter-defibrillator carriers (1.8%). After 90 days, no sustained ventricular tachyarrhythmia occurred in wearable cardioverter-defibrillator carriers.ConclusionsContinuous optimization of guideline-recommended medical therapy for at least 180 days in HFrEF is associated with additional LVEF improvement > 35%, allowing for better decision-making regarding preventive implantable cardioverter-defibrillator therapy.
| S-EPMC11313580 | biostudies-literature
Project description:It has now been almost 20 years since first clinical trials of stem cell therapy for heart repair were initiated. While initial preclinical data were promising and suggested that stem cells may be able to directly restore a diseased myocardium, this was never unequivocally confirmed in the clinical setting. Clinical trials of cell therapy did show the process to be feasible and safe. However, the clinical benefits of this treatment modality in patients with ischemic and non-ischemic heart failure have not been consistently confirmed. What is more, in the rapidly developing field of stem cell therapy in patients with heart failure, relevant questions regarding clinical trials' protocol streamlining, optimal patient selection, stem cell type and dose, and the mode of cell delivery remain largely unanswered. Recently, novel approaches to myocardial regeneration, including the use of pluripotent and allogeneic stem cells and cell-free therapeutic approaches, have been proposed. Thus, in this review, we aim to outline current knowledge and highlight contemporary challenges and dilemmas in clinical aspects of stem cell and regenerative therapy in patients with chronic ischemic and non-ischemic heart failure.
| S-EPMC9783726 | biostudies-literature
Project description: Not available
| S-EPMC8646349 | biostudies-literature
Project description:AimsThis study sought to describe and evaluate the impact of a routine in-hospital cardiac resynchronization therapy (CRT) programme, including comprehensive heart failure (HF) evaluation and systematic echo-guided CRT optimization.Methods and resultsCRT implanted patients were referred for optimization programme at 3 to 12 months from implantation. The program included clinical and biological status, standardized screening for potential cause of CRT non-response and systematic echo-guided atrioventricular and interventricular delays (AVd and VVd) optimization. Initial CRT-response and improvement at 6 months post-optimization were assessed with a clinical composite score (CCS). Major HF events were tracked during 1 year after optimization. A total of 227 patients were referred for CRT optimization and enrolled (71 ± 11 years old, 77% male, LVEF 30.6 ± 7.9%), of whom 111 (48.9%) were classified as initial non-responders. Left ventricular lead dislodgement was noted in 4 patients (1.8%), and loss or ≤90% biventricular capture in 22 (9.7%), mostly due to arrhythmias. Of the 196 patients (86%) who could undergo echo-guided CRT optimization, 71 (36.2%) required VVd modification and 50/144 (34.7%) AVd modification. At 6 months post-optimization, 34.3% of the initial non-responders were improved according to the CCS, but neither AVd nor VVd echo-guided modification was significantly associated with CCS-improvement. After one-year follow-up, initial non-responders maintained a higher rate of major HF events than initial responders, with no significant difference between AVd/VVd modified or not.ConclusionsOur study supports the necessity of a close, comprehensive and multidisciplinary follow-up of CRT patients, without arguing for routine use of echo-guided CRT optimization.
| S-EPMC9715781 | biostudies-literature
Project description:BackgroundFew data are available regarding changes in mitral regurgitation (MR) severity with guideline-recommended medical therapy (GRMT) in heart failure (HF). Our aim was to evaluate the evolution and impact of MR after GRMT in the Biology study to Tailored treatment in chronic heart failure (BIOSTAT-CHF).MethodsA retrospective post-hoc analysis was performed on HF patients from BIOSTAT-CHF with available data on MR status at baseline and at 9-month follow-up after GRMT optimization. The primary endpoint was a composite of all-cause death or HF hospitalization.ResultsAmong 1022 patients with data at both time-points, 462 (45.2%) had moderate-severe MR at baseline and 360 (35.2%) had it at 9-month follow-up. Regression of moderate-severe MR from baseline to 9 months occurred in 192/462 patients (41.6%) and worsening from baseline to moderate-severe MR at 9 months occurred in 90/560 patients (16.1%). The presence of moderate-severe MR at 9 months, independent from baseline severity, was associated with an increased risk of the primary endpoint (unadjusted hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.57-2.63; p < 0.001), also after adjusting for the BIOSTAT-CHF risk-prediction model (adjusted HR, 1.85; 95% CI 1.43-2.39; p < 0.001). Younger age, LVEF ≥ 50% and treatment with higher ACEi/ARB doses were associated with a lower likelihood of persistence of moderate-severe MR at 9 months, whereas older age was the only predictor of worsening MR.ConclusionsAmong patients with HF undergoing GRMT optimization, ACEi/ARB up-titration and HFpEF were associated with MR improvement, and the presence of moderate-severe MR after GRMT was associated with worse outcome.
| S-EPMC9334376 | biostudies-literature
Project description:Administration of bone marrow-derived mesenchymal stem cells (MSCs) is an innovative approach for the treatment of a range of diseases that are not curable by current therapies including heart failure. A number of clinical trials have been completed and many others are ongoing; more than 2,000 patients worldwide have been administered with culture-expanded allogeneic or autologous MSCs for the treatment of various diseases, showing feasibility and safety (and some efficacy) of this approach. However, protocols for isolation and expansion of donor MSCs vary widely between these trials, which could affect the efficacy of the therapy. It is therefore important to develop international standards of MSC production, which should be evidence-based, regulatory authority-compliant, of good medical practice grade, cost-effective, and clinically practical, so that this innovative approach becomes an established widely adopted treatment. This review article summarizes protocols to isolate and expand bone marrow-derived MSCs in 47 recent clinical trials of MSC-based therapy, which were published after 2007 onwards and provided sufficient methodological information. Identified issues and possible solutions associated with the MSC production methods, including materials and protocols for isolation and expansion, are discussed with reference to relevant experimental evidence with aim of future clinical success of MSC-based therapy.
| S-EPMC3912818 | biostudies-literature