Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure.
To compare the safety and efficacy of 2 doses of allogeneic bone marrow-derived human ...mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy.
Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval CI, 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (
=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (
=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by -6.4 g (interquartile range, -13.5 to -3.4 g;
=0.001) and 100 million by -6.1 g (interquartile range, -8.1 to -4.6 g;
=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1;
=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62;
=0.039), but not in 100 million (-0.07 log pg/mL; 95% CI, -0.36 to 0.23;
=0.65; between group
=0.07).
Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.
The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas ...allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT).
This study sought to test the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions.
Göttingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of allo-MSCs + allo-CSCs (ACCT: 200 million MSCs/1 million CSCs, n = 7), 200 million allo-MSCs (n = 8), 1 million allo-CSCs (n = 4), or placebo (Plasma-Lyte A, n = 6). Swine were assessed by cardiac magnetic resonance imaging and pressure volume catheterization. Immune response was tested by histologic analyses.
Both ACCT and allo-MSCs reduced scar size by −11.1 ± 4.8% (p = 0.012) and −9.5 ± 4.8% (p = 0.047), respectively. Only ACCT, but not MSCs or CSCs, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure-volume relation (+0.98 ± 0.41 mm Hg/ml; p = 0.016). The ACCT group had more phospho-histone H3+ (a marker of mitosis) cardiomyocytes (p = 0.04), and noncardiomyocytes (p = 0.0002) than did the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC-treated swine contained immunotolerant CD3+/CD25+/FoxP3+ regulatory T cells (p < 0.0001). Histologic analysis showed absent to low-grade inflammatory infiltrates without cardiomyocyte necrosis.
ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunologic reaction. Clinical translation to humans is warranted.
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Managing right-sided chronic heart failure (CHF) due to tricuspid regurgitation (TR) remains a clinical challenge. Tolvaptan (TLV), a vasopressin V2 receptor inhibitor, is effective in controlling ...decompensated HF. However, its effects on right-sided CHF caused by TR are unclear. We sought to clarify the effects of TLV in CHF patients complicated with TR. The cohort consisted of 33 CHF patients with moderate or severe TR and permanent atrial fibrillation, who required hospitalization for HF. We observed 19 patients treated with TLV plus conventional therapies (TLV group) and 14 patients with conventional therapies alone (conventional group). Clinical characteristics, echocardiographic parameters, and laboratory data were investigated. Baseline characteristics were similar between groups. In the TLV group, the severity of TR at admission was 73.7% moderate and 26.3% severe. In the conventional group, these percentages were 85.7% and 14.3%, respectively. During the follow-up, the severity of TR improved in the TLV group (trivial–mild: 52.6%; moderate: 36.8%; severe: 10.5%) (
p
< 0.01). However, it did not improve in the conventional group (trivial–mild: 21.4%; moderate: 50.0%; severe: 28.6%) (
p
= 0.08). The diameter of the tricuspid annulus (
p
< 0.01), basal (
p
= 0.02), and mid right ventricle (
p
= 0.04) was reduced at follow-up in the TLV group. Nevertheless, these parameters did not change in the conventional group. Serum creatinine levels were maintained (
p
= 0.74) in the TLV group, but deteriorated in the conventional group (
p
= 0.03). TLV reduced right ventricular dimensions and improved TR without deterioration of renal function. Thus, TLV may be a new drug for the treatment of CHF patients with TR.
Background Dialysis is an independent risk factor for in-stent restenosis (ISR) after stent implantation in coronary arteries. However, the characteristics of ISR in patients undergoing dialysis ...remain unclear, as there are no histological studies evaluating the causes of this condition. The aim of the present study was to investigate the causes of ISR between patients who are undergoing dialysis and those who are not by evaluating tissues obtained from ISR lesions using directional coronary atherectomy. Methods and Results A total of 29 ISR lesions from 29 patients included in a multicenter directional coronary atherectomy registry of 128 patients were selected for analysis and divided into a dialysis group (n=8) and a nondialysis group (n=21). Histopathological evaluation demonstrated that an in-stent calcified nodule was a major histological characteristic of ISR lesions in the dialysis group and the prevalence of an in-stent calcified nodule was significantly higher in the dialysis group compared with the nondialysis group (75% versus 5%, respectively;
<0.01). On the other hand, the prevalence of an in-stent lipid-rich plaque was significantly lower in the dialysis group compared with the nondialysis group (0% versus 43%, respectively;
=0.03). In all cases with an in-stent calcified nodule, the underlying calcification before stent implantation was moderate to severe. When tissue characteristics were stratified according to duration post-stent implantation, an in-stent calcified nodule in the dialysis group was mainly observed within 1 year after stent implantation. Conclusions In-stent calcified nodules are a common cause of ISR in patients undergoing dialysis and are observed within 1 year after stent implantation, suggesting different causes of ISR between patients undergoing dialysis and those who are not.
Background:Percutaneous coronary intervention (PCI) guided with fractional flow reserve (FFR) has been shown to improve clinical outcome. Although coronary angiography is the standard method for PCI ...guidance, the visual severity of stenosis is not always correlated with functional severity, suggesting that there are additional angiographic factors that affect functional ischemia.Methods and Results:To evaluate angiographic predictors of positive FFR in stenotic lesions, angiographic characteristics of 260 consecutive patients (362 lesions) who underwent FFR testing from April 2009 to September 2012 were analyzed. A scoring system (STABLED score) using these predictors was developed and compared with quantitative coronary angiography (QCA). %Diameter stenosis >50% (OR, 8.43; P<0.0001), tandem lesion (OR, 4.00; P<0.0001), true bifurcation (OR, 2.42; P=0.028), lesion length >20 mm (OR, 5.40; P=0.0002), and distance from ostium <20 mm (OR, 1.94; P=0.028) were determined as independent predictors of positive FFR. Area under the ROC curve for probability of positive FFR using the STABLED score (Stenosis 2 points, TAndem lesion 1 point, Bifurcation 1 point, LEsion length 1 point, Distance from ostium 1 point) was 0.85, higher than that for QCA stenosis alone (0.76). STABLED score ≥3 had 72.3% sensitivity and 83.6% specificity for predicting positive FFR, and PPV was 76.7%.Conclusions:Specific angiographic features are applicable for predicting functional ischemia. STABLED score correlates well with FFR. (Circ J 2015; 79: 802–807)
Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) differ in histopathology and prognosis. Although transendocardial delivery of mesenchymal stem cells is safe and provides cardiovascular ...benefits in both, a comparison of mesenchymal stem cell efficacy in ICM versus DCM has not been done.
We conducted a subanalysis of 3 single-center, randomized, and blinded clinical trials: (1) TAC-HFT (Transendocardial Autologous Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells in Ischemic Heart Failure Trial); (2) POSEIDON (A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction); and (3) POSEIDON-DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy). Baseline and 1-year cardiac structure and function and quality-of-life data were compared in a post hoc pooled analysis including ICM (n=46) and DCM (n=33) patients who received autologous or allogeneic mesenchymal stem cells. Ejection fraction improved in DCM by 7% (within-group,
=0.002) compared to ICM (1.5%; within-group,
=0.14; between-group,
=0.003). Similarly, stroke volume increased in DCM by 10.59 mL (
=0.046) versus ICM (-0.2 mL;
=0.73; between-group,
=0.02). End-diastolic volume improved only in ICM (10.6 mL;
=0.04) and end-systolic volume improved only in DCM (17.8 mL;
=0.049). The sphericity index decreased only in ICM (-0.04;
=0.0002). End-diastolic mass increased in ICM (23.1 g;
<0.0001) versus DCM (-4.1 g;
=0.34; between-group,
=0.007). The 6-minute walk test improved in DCM (31.1 m;
=0.009) and ICM (36.3 m;
=0.006) with no between-group difference (
=0.79). The New York Heart Association class improved in DCM (
=0.005) and ICM (
=0.02; between-group
=0.20). The Minnesota Living with Heart Failure Questionnaire improved in DCM (-19.5;
=0.002) and ICM (-6.4;
=0.03; δ between-group difference
=0.042) patients.
Mesenchymal stem cell therapy is beneficial in DCM and ICM patients, despite variable effects on cardiac phenotypic outcomes. Whereas cardiac function improved preferentially in DCM patients, ICM patients experienced reverse remodeling. Mesenchymal stem cell therapy enhanced quality of life and functional capacity in both etiologies.
URL: http://www.clinicaltrials.gov. Unique identifiers: TAC-HFT: NCT00768066, POSEIDON: NCT01087996, POSEIDON-DCM: NCT01392625.
Background The prognostic impact of optical coherence tomography-diagnosed culprit lesion morphology in acute coronary syndrome (ACS) has not been systematically examined in real-world settings. ...Methods and Results This investigator-initiated, prospective, multicenter, observational study was conducted at 22 Japanese hospitals to identify the prevalence of underlying ACS causes (plaque rupture PR, plaque erosion PE, and calcified nodules CN) and their impact on clinical outcomes. Patients with ACS diagnosed within 24 hours of symptom onset undergoing emergency percutaneous coronary intervention were enrolled. Optical coherence tomography-guided percutaneous coronary intervention recipients were assessed for underlying ACS causes and followed up for major adverse cardiac events (cardiovascular death, myocardial infarction, heart failure, or ischemia-driven revascularization) at 1 year. Of 1702 patients with ACS, 702 (40.7%) underwent optical coherence tomography-guided percutaneous coronary intervention for analysis. PR, PE, and CN prevalence was 59.1%, 25.6%, and 4.0%, respectively. One-year major adverse cardiac events occurred most frequently in patients with CN (32.1%), followed by PR (12.4%) and PE (6.2%) (log-rank
<0.0001), primarily driven by increased cardiovascular death (CN, 25.0%; PR, 0.7%; PE, 1.1%; log-rank
<0.0001) and heart failure trend (CN, 7.1%; PR, 6.8%; PE, 2.2%; log-rank
<0.075). On multivariate Cox regression analysis, the underlying ACS cause was associated with 1-year major adverse cardiac events (CN hazard ratio (HR), 4.49 95% CI, 1.35-14.89,
=0.014; PR (HR, 2.18 95% CI, 1.05-4.53,
=0.036; PE as reference). Conclusions Despite being the least common, CN was a clinically significant underlying ACS cause, associated with the highest future major adverse cardiac events risk, followed by PR and PE. Future studies should evaluate the possibility of ACS underlying cause-based optical coherence tomography-guided optimization.
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