Reversal of contractile defects by mediating calcium homeostasis in human mini-heart models of heart failure with preserved ejection fraction (HFpEF) leads to first-in-human gene therapy clinical trial
Open accessAbstract
Abstract Aims Heart failure with preserved ejection fraction (HFpEF), is a global health problem lacking disease-modifying therapeutic options, reflecting a lack of predictive models for preclinical drug testing. Aligned with FDA Modernization Act 2.0, we aimed to create the first in vitro human-specific mini-heart models of HFpEF, and to test the efficacy of a candidate gene therapy to improve cardiac kinetics and correct the disease phenotype. Methods and Results Healthy human pluripotent stem cell-derived ventricular cardiomyocytes were used to bioengineer beating cardiac tissue strips and pumping cardiac chambers. When conditioned with transforming growth factor-β1 and endothelin-1, these mini-heart models exhibited signature disease phenotypes of significantly elevated diastolic force and tissue stiffness, and slowed contraction and relaxation kinetics, with no significant deficit in systolic force or ejection fraction versus unconditioned controls. Bioinformatic analysis of bulk RNA sequencing data from HFpEF mini-heart models and patient ventricular samples identified downregulation of SERCA2a of the calcium signalling pathway as a key differentially expressed gene. After dosage optimization, AAV-mediated expression of SERCA2a abrogated the disease phenotype and improved the cardiac kinetics in HFpEF mini-Hearts. Conclusions These findings contributed to FDA approval of an ongoing first-in-human gene therapy clinical trial for HFpEF, with Fast Track designation. We conclude that such human-based disease-specific mini-heart platforms are relevant for target discovery and validation that can facilitate clinical translation of novel cardiac therapies. Translational Perspective Heart failure with preserved ejection fraction (HFpEF) is a significant and growing global health concern lacking disease-modifying therapeutic options, reflecting inadequate preclinical models of the disease. Aligned with FDA Modernization Act 2.0, we created the first in vitro human-specific mini-heart models of HFpEF, demonstrated phenotypic disease characteristics of elevated stiffness and slowed kinetics, showed transcriptomic consistency with HFpEF patient data, identified SERCA2a as a key downregulated gene, performed dosing titration of SERCA2a gene therapy, and showed improvement of cardiac kinetics post-treatment. The findings contributed to FDA approval of an ongoing first-in-human gene therapy clinical trial for HFpEF.
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22 of 47 cited sources checked · 6 supported · 1 flagged · accuracy not yet measured
- Interpretationcitation
This study demonstrates the use of biologics for induction of disease without requiring patient-specific human induced pluripotent stem cells.
“In contrast to prior cardiac disease modeling approaches focused on genetic mutations, 20,42,43 this study demonstrates the use of biologics for induction of disease without requiring patient-specific human induced pluripotent stem cells.”
Quote in the paperSubstantial claim3 of 3 sources checked - Premisecitation
In mammalian hearts, HFpEF is associated with impaired cardiac relaxation, or lusitropy, which is evident both at rest and during exercise in the majority of HFpEF patients.
“In mammalian hearts, HFpEF is associated with impaired cardiac relaxation, or lusitropy, which is evident both at rest and during exercise in the majority of HFpEF patients.6,44”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [6] source
The Results (Study population and Baseline hemodynamics; page unavailable) report prolonged relaxation at rest in 50% of the 20 subjects, not a majority. The Discussion (Diastolic Relaxation Reserve; page unavailable) reports inadequate enhancement of relaxation during exercise, but does not establish that a majority had impaired relaxation both at rest and during exercise. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [44] source
In “HFpEF and Exercise Intolerance” (page unavailable), the paper describes slower relaxation and abnormal diastolic properties at rest as a generally accepted theory, but says what happens during exercise remains unsettled. Its “Baseline Characteristics” section also reports that other diastolic-function measures were similarly abnormal in HFpEF patients and controls. It does not establish impaired relaxation both at rest and during exercise in a majority of HFpEF patients. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Cardiac myocyte hypertrophy and cardiac fibrosis are markedly prevalent in patients with HFpEF, as confirmed in a large, prospective analysis of HFpEF myocardial tissue.
“Two pathological characteristics markedly prevalent in patients with HFpEF are cardiac myocyte hypertrophy and cardiac fibrosis, as confirmed in a large, prospective analysis of HFpEF myocardial tissue.8,9”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [8] source
The Methods (Myocardial Tissue Procurement and Processing; page unavailable) describe biopsies from 63 HFpEF patients and histological assessment of myocyte hypertrophy and fibrosis. The Discussion (HFpEF transcriptomic signatures and the role of co-morbidities; page unavailable) says related pathways were more engaged than in controls. These passages support the study’s relevance, but do not establish that both pathological findings were markedly prevalent in the patients’ tissue. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [9] source
The Myocardial Abnormalities section reports increased collagen in HFpEF endomyocardial biopsy tissue, supporting the fibrosis finding. The Epidemiology section describes hypertrophied hearts, but the copy does not establish that cardiac myocyte hypertrophy and fibrosis were both confirmed in a large, prospective analysis of HFpEF myocardial tissue. Page numbers are unavailable in the indexed copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Findingown data
SERCA2a (ATP2A2) is downregulated in HFpEF patients and in engineered HFpEF-hvCTS and HFpEF-hvCOC mini-heart models compared to respective controls.
“The SERCA2a (ATP2A2) DEG was downregulated in HFpEF patients and in engineered HFpEF-hvCTS and HFpEF-hvCOC mini-heart models compared to respective controls.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] source
The Results section reports many genes downregulated in HFpEF patients versus controls, but the passages in our copy do not identify SERCA2a (ATP2A2) as one of them. Searches for SERCA2a, ATP2A2, HFpEF-hvCTS, and HFpEF-hvCOC found no passage establishing the gene’s expression in patients or the engineered models; the paper’s Methods describe patient biopsies rather than those models. No page numbers were available for these passages. (LLM, conf=0.73)
Experimental — accuracy not yet measured
- Interpretationcitation
The human mini-heart models provide a relevant platform for dosage optimization, considering that results from animal experiments regarding effectiveness of cardiac gene transfer do not predict human myocardial transduction efficiency.
“Our human mini-heart models also provide a relevant platform for dosage optimization, considering that results from animal experiments regarding effectiveness of cardiac gene transfer do not predict human myocardial transduction efficiency.77”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [77] source
The “Gene delivery: Critical step” section reports that human hearts in the CUPID IIb trial had much lower vector uptake than animal models that had shown therapeutic efficacy. This supports caution in extrapolating animal results, but the paper documents that discrepancy for a particular trial rather than establishing that animal experiments generally cannot predict human myocardial transduction efficiency. The human mini-heart platform is the citing authors’ own proposal, not a finding attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
33% (446/1351) of DEGs from the HFpEF-hvCOC model overlapped with DEGs from HFpEF patients.
“Venn diagrams showed that 29% (501/1748) of DEGs from the HFpEF-hvCTS model, and 33% (446/1351) of DEGs from the HFpEF-hvCOC model, overlapped with DEGs from HFpEF patients (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
29% (501/1748) of DEGs from the HFpEF-hvCTS model overlapped with DEGs from HFpEF patients.
“Venn diagrams showed that 29% (501/1748) of DEGs from the HFpEF-hvCTS model, and 33% (446/1351) of DEGs from the HFpEF-hvCOC model, overlapped with DEGs from HFpEF patients (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
TGF-β1/ET-1-treated hvCTS showed no significant reduction in systolic or developed force compared to controls.
“Measurements of passive stiffness, developed force, maximum +dF/dt and maximum -dF/dt versus percent strain (Fig. 1D) collectively showed that TGF-β1/ET-1-treated hvCTS displayed significantly increased passive stiffness along with slowed contraction and relaxation kinetics compared to Controls, with no significant reduction in systolic or developed force, which are key characteristics observed in”
Quote in the paperSubstantial claim - Findingown data
TGF-β1/ET-1-treated hvCTS displayed significantly increased passive stiffness compared to time-matched controls.
“Measurements of passive stiffness, developed force, maximum +dF/dt and maximum -dF/dt versus percent strain (Fig. 1D) collectively showed that TGF-β1/ET-1-treated hvCTS displayed significantly increased passive stiffness along with slowed contraction and relaxation kinetics compared to Controls, with no significant reduction in systolic or developed force, which are key characteristics observed in”
Quote in the paperSubstantial claim - Findingown data
TGF-β1/ET-1-treated hvCOC exhibited significantly higher passive chamber stiffness than control hvCOC.
“Figures 2B and C show a leftward-shifted diastolic pressure-area relationship, and significantly higher passive chamber stiffness in TGF-β1/ET-1-treated versus control hvCOCs, respectively (n=8-13, *p<0.05).”
Quote in the paperSubstantial claim - Findingown data
TGF-β1/ET-1-treated hvCTS displayed significantly slowed contraction and relaxation kinetics compared to time-matched controls.
“Consistently, the TGF-β1/ET-1-treated group displayed significantly slower contraction and relaxation kinetics compared to Control (Fig. 1B,C; n = 4-20, **p<0.01 and ***p<0.001).”
Quote in the paperSubstantial claim - Findingown data
In HFpEF hvCOC, developed pressure, stroke area, stroke work, and ejection fraction of AAV1-GFP- and AAV1-SERCA2a-treated mini-hearts were not significantly affected.
“As anticipated from our HFpEF hvCTS experiments, the related measures of pump function including developed pressure, stroke area, stroke work, and ejection fraction of AAV1-GFP-and AAV1-SERCA2atreated HFpEF hvCOC mini-hearts were not significantly affected (Fig. 6D-E).”
Quote in the paperNot a substantial claim - Findingown data
Single-factor treatments of hvCTS with either TGF-β1 or ET-1 individually did not elicit the characteristic combination of elevated stiffness and depressed kinetics achieved with the combination treatment.
“We note that single-factor treatments of hvCTS with either TGF-β1 or ET-1 individually did not elicit the characteristic combination of elevated stiffness and depressed kinetics achieved with the combination treatment (Supplemental Figs. 1 and 2).”
Quote in the paperNot a substantial claim - Findingown data
AAV1-SERCA2a transduction hastened the slowed contraction and relaxation kinetics compared to AAV1-GFP control in HFpEF hvCTS.
“Figure 5B shows that in representative HFpEF hvCTS tracings, AAV1-SERCA2a transduction hastened the slowed contraction and relaxation kinetics compared to the AAV1-GFP control.”
Quote in the paperSubstantial claim - Findingown data
Diastolic area was not significantly different in HFpEF hvCOC versus control.
“Figure 2A shows representative images of time-matched control and TGF-β1/ET-1-treated hvCOCs, in which the diastolic area was not significantly different in HFpEF versus Control (p = 0.244, not shown).”
Quote in the paperSubstantial claim - Findingown data
TGF-β1/ET-1-treated hvCOC showed no significant changes in developed pressure, stroke area, stroke work or ejection fraction compared to controls.
“Despite the increased stiffness, pressure-area tracings were similar (Fig. 2D, E), with no significant changes in developed pressure, stroke area, stroke work or ejection fraction observed between Control and TGF-β1/ET-1-treated hvCOCs (Fig. 2 E-F).”
Quote in the paperSubstantial claim - Findingown data
AAV1-SERCA2a treatment increased active and passive force in HFpEF hvCTS.
“This is corroborated in Figure 5C, where AAV1-SERCA2a treatment improved the abnormal kinetics of the HFpEF hvCTS by significantly shortening the diseased contraction and relaxation times toward non-transduced (NT) Control tissue values (n=5-8, p<0.05), while active and passive force were increased.”
Quote in the paperSubstantial claim - Findingown data
The HFpEF-hvCOC mini-ventricle model was more similar to human HFpEF patients than the HFpEF-hvCTS tissue strip model based on hierarchical clustering of enriched canonical pathways, disease and biofunctions, and cardiotoxicity functions.
“Ingenuity Pathway Analysis further revealed that the HFpEF-hvCOC mini-ventricle model was more similar to human HFpEF patients than the HFpEF-hvCTS tissue strip model based on hierarchical clustering of enriched canonical pathways, disease and biofunctions, and cardiotoxicity functions (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Data for AAV1-GFP and NT HFpEF hvCTS were very similar.
“On average, the data for AAV1-GFP and NT HFpEF hvCTS were very similar.”
Quote in the paperNot a substantial claim - Findingown data
AAV1-SERCA2a treatment significantly shortened the diseased contraction and relaxation times toward non-transduced Control tissue values in HFpEF hvCTS.
“This is corroborated in Figure 5C, where AAV1-SERCA2a treatment improved the abnormal kinetics of the HFpEF hvCTS by significantly shortening the diseased contraction and relaxation times toward non-transduced (NT) Control tissue values (n=5-8, p<0.05), while active and passive force were increased.”
Quote in the paperSubstantial claim - Findingown data
AAV1-SERCA2a treatment significantly shortened area and pressure contraction times in HFpEF hvCOC.
“By contrast, AAV1-SERCA2a treatment significantly shortened area and pressure contraction times (Fig. 6E).”
Quote in the paperSubstantial claim - Findingown data
Dose response testing identified optimized concentrations of 1 ng/mL TGF-β1 and 100 nM ET-1 for effective combined induction of HFpEF models.
“Dose response effects for separate treatments of TGF-β1 (0-30 ng/mL) or ET-1 (0-100 nM) were also tested to identify the concentrations that could elicit a significant change in stiffness without compromising the integrity and success rate of the treated tissues, yielding optimized concentrations (1 ng/mL TGF-β1 and 100 nM ET-1) for effective combined induction of HFpEF models.”
Quote in the paperSubstantial claim - Findingown data
AAV1-SERCA2a improves the HFpEF phenotype in human ventricular cardiac tissue strips (hvCTS).
“Figure 5. AAV1-SERCA2a improves HFpEF phenotype in hvCTS.”
Quote in the paperSubstantial claim - Findingown data
AAV1-SERCA2a improves the HFpEF phenotype in human ventricular cardiac organoid chambers (hvCOC).
“Figure 6.AAV1-SERCA2a improves HFpEF phenotype in hvCOC.”
Quote in the paperSubstantial claim - Findingown data
Combined TGF-β1/ET-1 treatment confers an HFpEF phenotype in human engineered cardiac tissue models (hvCTS and hvCOC).
“Figure 2. Combined TGF-β1/ET-1 treatment conferred HFpEF phenotypic”
Quote in the paperSubstantial claim - Findingown data
The human mini-heart models of HFpEF described herein demonstrate improvements in myocardial kinetics with AAV1-SERCA2a treatment.
“Indeed, the human miniheart models of HFpEF described herein demonstrate improvements in myocardial kinetics with AAV1-SERCA2a treatment.”
Quote in the paperSubstantial claim - Findingown data
Combined TGF-β1/ET-1 treatment causes slower contraction and relaxation kinetics in human ventricular cardiac tissue strips (hvCTS) compared to control conditions.
“Representative normalized single-twitch force tracings at 1.0-Hz pacing show slower contraction and relaxation kinetics in the TGF-β1/ET-1-treated group (red) than the control group (black).”
Quote in the paperSubstantial claim - Interpretationown data
Restoration of SERCA2a is a target candidate for mitigating the HFpEF disease traits.
“These transcriptomic and bioinformatic results were consistent with the phenotypes observed in HFpEF patients, thereby identifying restoration of SERCA2a as a target candidate for mitigating the HFpEF disease traits.”
Quote in the paperSubstantial claim - Study design and conductown data
The percentage of cells expressing cardiac troponin T was verified to be between 65% and 85% using flow cytometry on differentiation day 15.
“The percentage of cells expressing cardiac troponin T was verified to be between 65% and 85% using flow cytometry on differentiation day 15, with the remainder being cardiac fibroblast-like stromal cells.”
Quote in the paperNot a substantial claim - Interpretationown data
Human-based disease-specific mini-heart platforms are relevant for target discovery and validation that can facilitate clinical translation of novel cardiac therapies.
“We conclude that such human-based disease-specific mini-heart platforms are relevant for target discovery and validation that can facilitate clinical translation of novel cardiac therapies.”
Quote in the paperSubstantial claim- Rests on an assumption: The human mini-heart models are predictive of human clinical outcomes.
- Interpretationcitation
Challenges persist for in vitro model systems to reproduce complex comorbidities such as diabetes and obesity that often accompany patients with HFpEF.
“Challenges persist for in vitro model systems to reproduce complex comorbidities such as diabetes and obesity that often accompany patients with HFpEF, 7 yet salient features of the cardiac phenotype may be adequately represented in engineered mini-heart models.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] source
- Interpretationown data
The results supported SERCA2a as a human-relevant therapeutic target for HFpEF.
“The results supported SERCA2a as a human-relevant therapeutic target for HFpEF, and further demonstrated the improvement of characteristic HFpEF phenotypes by AAV1-SERCA2a treatment in human mini-hearts, which contributed to an ongoing first-in-human gene therapy clinical trial for HFpEF (Modulation of SERCA2a of Intra-myocytic Calcium Trafficking in Heart Failure with Preserved Ejection Fraction”
Quote in the paperSubstantial claim - Interpretationreasoning
Considering there are 2 to 3 billion cardiomyocytes in the adult human heart, the optimized viral titer of 1x10^4 vg/cell used in the hvCOC mini-heart model of HFpEF translates to a dosage of 2-3x10^13 vg per patient heart.
“Considering there are 2 to 3 billion cardiomyocytes in the adult human heart, the optimized viral titer of 1x10 4 vg/cell used in the hvCOC mini-heart model of HFpEF translates to a dosage of 2-3x10 13 vg per patient heart; this informed the approved dosage of 3 x10 13 vg/patient to be delivered via intracoronary injection of HFpEF subjects in the MUSIC-HFpEF trial.”
Quote in the paperSubstantial claim- Rests on an assumption: There are 2 to 3 billion cardiomyocytes in the adult human heart.
- Rests on an assumption: The optimized viral titer of 1x10^4 vg/cell in the hvCOC mini-heart model translates to a dosage of 2-3x10^13 vg per patient heart.
- Interpretationown data
The preclinical human HFpEF models described are useful for investigating disease mechanisms.
“Overall, the preclinical human HFpEF models described herein are shown to be useful in investigating disease mechanisms, and for facilitating the identification of novel druggable targets and screening of therapeutics by enabling species-specific predictions of the clinical effectiveness and safety of new medicines in advance of human trials.”
Quote in the paperSubstantial claim - Interpretationnone given
Inclusion of data from this study using the same GMP-grade viral vector contributed to successful Investigational New Drug (IND) and Fast Track Designation (FTD) applications to the U.S. FDA.
“Indeed, our new MUSIC-HFpEF trial using AAV1-SERCA2a gene therapy is the only current human clinical trial targeting relaxation in HFpEF, and inclusion of data from this study using the same GMP-grade viral vector contributed to our successful Investigational New Drug (IND) and Fast Track Designation (FTD) applications to the U.S. FDA.”
Quote in the paperSubstantial claim- Rests on an assumption: The MUSIC-HFpEF trial using AAV1-SERCA2a gene therapy is the only current human clinical trial targeting relaxation in HFpEF.
- Interpretationreasoning
This informed the approved dosage of 3x10^13 vg/patient to be delivered via intracoronary injection of HFpEF subjects in the MUSIC-HFpEF trial.
“Considering there are 2 to 3 billion cardiomyocytes in the adult human heart, the optimized viral titer of 1x10 4 vg/cell used in the hvCOC mini-heart model of HFpEF translates to a dosage of 2-3x10 13 vg per patient heart; this informed the approved dosage of 3 x10 13 vg/patient to be delivered via intracoronary injection of HFpEF subjects in the MUSIC-HFpEF trial.”
Quote in the paperSubstantial claim - Interpretationown data
The current study data clearly indicate that SERCA2a represents a relevant target for human HFpEF.
“However, the current study data clearly indicate that SERCA2a represents a relevant target for human HFpEF.”
Quote in the paperSubstantial claim - Premisecitation
Viral delivery of SERCA2a in HFpEF hearts can improve relaxation parameters.
“These results establish that viral delivery of SERCA2a in HFpEF hearts can improve relaxation parameters.13”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] source
- Premisecitation
In the Otsuka-Long-Evans Tokushima Fatty rat model of spontaneous non-insulin-dependent type II diabetes mellitus, short-term expression of SERCA2a restored oxygen consumption and relaxation parameters to normal levels.
“In multiple studies using short-term expression of SERCA2a, oxygen consumption and relaxation parameters were restored to normal levels in these HFpEF models.12,47,48”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [12] source
- cites [47] 2007, . Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins. J Mol Cell Cardiol
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48] 2007, Transcoronary gene transfer of SERCA2a increases coronary blood flow and decreases cardiomyocyte size in a type 2 diabetic rat model, Am J Physiol Heart Circ Physiol
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationnone given
The experiments reported herein establish the hvCTS and hvCOC mini-heart models of HFpEF in human species-specific diseased heart tissues.
“The experiments reported herein establish the hvCTS and hvCOC mini-heart models of HFpEF in human species-specific diseased heart tissues.”
Quote in the paperSubstantial claim - Interpretationreasoning
The preclinical human HFpEF models described are useful for facilitating the identification of novel druggable targets.
“Overall, the preclinical human HFpEF models described herein are shown to be useful in investigating disease mechanisms, and for facilitating the identification of novel druggable targets and screening of therapeutics by enabling species-specific predictions of the clinical effectiveness and safety of new medicines in advance of human trials.”
Quote in the paperSubstantial claim - Premisecitation
Without positive transduction, gene therapy cannot be effective.
“Without positive transduction, gene therapy cannot be effective; the above data strongly indicated that optimal titers are critical for the success of cardiac gene therapies in humans, in addition to other considerations such as delivery method, vector serotype and tropism, and potential side effects.78”
Quote in the paperSubstantial claim - Premisecitation
We have previously shown that in HFpEF animal models characterized by abnormal lusitropy and a decrease in SERCA2a, delivery of SERCA2a by gene transfer restored relaxation parameters such as -dP/dt, the left ventricular time constant of isovolumic relaxation, tau, and the passive stiffness of the left ventricle to normal levels.
“We have previously shown that in HFpEF animal models characterized by abnormal lusitropy and a decrease in SERCA2a, delivery of SERCA2a by gene transfer restored relaxation parameters such as -dP/dt, the left ventricular time constant of isovolumic relaxation, tau, and the passive stiffness of the left ventricle to normal levels.12,13,[47][48][49]”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [12] source
- cites [13] source
- cites [47] 2007, . Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins. J Mol Cell Cardiol
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48] 2007, Transcoronary gene transfer of SERCA2a increases coronary blood flow and decreases cardiomyocyte size in a type 2 diabetic rat model, Am J Physiol Heart Circ Physiol
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [49] source
- Premisecitation
In CUPID-1, HFrEF patients randomized to the highest dose of a single intra-coronary infusion of AAV1-SERCA2a showed less deterioration in 6-minute walk distance, peak VO2 and NT-proBNP levels after 6 months.
“In Phase 1 (CUPID-1), HFrEF patients randomized to the highest dose of a single intra-coronary infusion of AAV1-SERCA2a showed less deterioration in 6-minute walk distance, peak VO2 and NT-proBNP levels after 6 months.[58][59][60]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58][59][60]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The preclinical human HFpEF models described are useful for screening therapeutics by enabling species-specific predictions of the clinical effectiveness and safety of new medicines in advance of human trials.
“Overall, the preclinical human HFpEF models described herein are shown to be useful in investigating disease mechanisms, and for facilitating the identification of novel druggable targets and screening of therapeutics by enabling species-specific predictions of the clinical effectiveness and safety of new medicines in advance of human trials.”
Quote in the paperSubstantial claim
- May combine two claims. 26
- Classified as probably not a substantial claim. 12
May combine two claims.
PremisecitationSERCA2a protein levels were found to be significantly decreased in senescent human myocardium that is characterized by HFpEF, which was associated with myocardial function impairment at baseline that was exacerbated by hypoxic conditions and higher heart rates.
“Furthermore, SERCA2a protein levels were found to be significantly decreased in senescent human myocardium that is characterized by HFpEF, 50 which was associated with myocardial function impairment at baseline that was exacerbated by hypoxic conditions and higher heart rates.[51][52][53]”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [50] source
Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [51][52][53]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
InterpretationcitationThe hvCTS and hvCOC human mini-heart models have proven effective for modeling different cardiovascular disease states and testing of drugs and biologics.
“Despite the sub-physiologic levels of function typical of engineered tissue constructs for in vitro studies, the hvCTS and hvCOC human mini-heart models used in this study have proven effective for modeling different cardiovascular disease states and testing of drugs and biologics.17,18,22,23”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [17] 2019, Human Cardiac Ventricular-Like Organoid Chambers and Tissue Strips From Pluripotent Stem Cells as a Two-Tiered Assay for Inotropic Responses, Clin Pharmacol Ther source
- cites [18] 2021, Adverse effects of hydroxychloroquine and azithromycin on contractility and arrhythmogenicity revealed by human engineered cardiac tissues, J Mol Cell Cardiol source
The Introduction identifies hvCTS as a human engineered tissue used to investigate drug effects, and the Conclusion says the constructs provide a platform for screening cardiac safety and efficacy. But this paper studies hvCTS and hvCAS, not hvCOC; it does not establish that the named pair has proven effective across different cardiovascular disease states or for testing biologics. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [22] 2018, Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells, Biomaterials source
The Results section on pump performance reports that hvCOC responded to several drugs, and the Discussion says it distinguished dose responses to positive and negative inotropes. The paper compares hvCOC with hvCTS and describes disease modeling as a potential application, but it does not establish that both models have proven effective for modeling different cardiovascular disease states or for testing biologics. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [23] Cashman TJ , Josowitz R , Gelb BD , Li RA , Dubois NC and Costa KD . Construction of Defined Human Engineered Cardiac Tissues to Study Mechanisms of Cardiac Cell Therapy. J Vis Exp. 2016:e53447. source
May combine two claims.
PremisecitationThe fundamental structural and functional characteristics of the HFpEF heart include delayed and incomplete LV relaxation and reduced LV compliance.
“The fundamental structural and functional characteristics of the HFpEF heart include delayed and incomplete LV relaxation and reduced LV compliance.6,7”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [6] source
The Results (Study population and Baseline hemodynamics) report prolonged LV relaxation in 50% of subjects. The Results (LV Diastolic Reserve with exercise) and Discussion describe less complete relaxation and increased chamber stiffness during exercise. These findings support the functional abnormalities, but not the unqualified claim that delayed relaxation and reduced compliance are fundamental characteristics of every HFpEF heart. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [7] source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe FDA Modernization Act 2.0 ends the long-standing animal mandate and promotes the use of validated in vitro human alternatives for next-generation drug development.
“Indeed, the recently passed FDA Modernization Act 2.0 ends the long-standing animal mandate and promotes the use of validated in vitro human alternatives for next-generation drug development.21”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [21] 2023, FDA Modernization Act 2.0 Paves the Way to Computational Biology and Clinical Trials in a Dish, Circulation source
In the paper’s discussion of the FDA Modernization Act 2.0 (page not specified), the authors say the act updates the animal-testing mandate by allowing regulators to consider alternatives, including human cell-based methods. The passage supports the shift toward in vitro methods for drug development, but does not say those alternatives have been validated. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationBioengineered cardiac tissues, created from human pluripotent stem cell (hPSC)-derived cardiomyocytes, have successfully modeled aspects of native human heart structure and function, including cardiotoxic and therapeutic responses, and phenotypic characteristics of genetic and acquired cardiomyopathies.
“Bioengineered cardiac tissues, created from human pluripotent stem cell (hPSC)derived cardiomyocytes, have successfully modeled aspects of native human heart structure and function, 16 including cardiotoxic and therapeutic responses, 17,18 and phenotypic characteristics of genetic and acquired cardiomyopathies.19,20”
Quote in the paperSubstantial claim4 of 5 sources checked- cites [16] source
- cites [17] 2019, Human Cardiac Ventricular-Like Organoid Chambers and Tissue Strips From Pluripotent Stem Cells as a Two-Tiered Assay for Inotropic Responses, Clin Pharmacol Ther source
- cites [18] 2021, Adverse effects of hydroxychloroquine and azithromycin on contractility and arrhythmogenicity revealed by human engineered cardiac tissues, J Mol Cell Cardiol source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [19] 2018, Cardiac Tissue Engineering Models of Inherited and Acquired Cardiomyopathies, Methods Mol Biol source
- cites [20] 2019, Correlation between frataxin expression and contractility revealed by in vitro Friedreich’s ataxia cardiac tissue models engineered from human pluripotent stem cells, Stem Cell Res Ther source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationCardiac myocytes isolated from HFpEF patients and experimental models exhibit prolonged relaxation, diminished contraction velocity, a decrease in β-adrenergic response, and increased myocardial stiffness.
“Cardiac myocytes isolated from HFpEF patients and experimental models exhibit prolonged relaxation, diminished contraction velocity, a decrease in β-adrenergic response, and increased myocardial stiffness.45,46”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [45] source
The Introduction reports slowed or incomplete left-ventricular relaxation in HFpEF, and the Discussion reports increased passive myocardial stiffness in patient tissue and cites earlier findings of increased stiffness in isolated cardiomyocytes. It does not establish prolonged relaxation in isolated myocytes, diminished contraction velocity, or a decreased β-adrenergic response. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [46] source
The Function section (p. 6) reports impaired relaxation in 29% of patients and an abnormal ventricular shortening velocity in 14%. These are echocardiographic findings, not measurements from isolated cardiac myocytes. The paper does not establish the claimed β-adrenergic response, increased myocardial stiffness, or findings in experimental models. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationCUPID-2 confirmed the safety of AAV1-SERCA2a but showed no effect on the primary outcome of HF hospitalization or decompensated HF.
“A larger Phase 2 study (CUPID-2), testing a higher dose (10 13 viral genome particles of AAV1-SERCA2a per patient), confirmed the safety of this approach, 61,62 but showed no effect on the primary outcome of HF hospitalization or decompensated HF.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [61] source
The Discussion (page unavailable) says AAV1/SERCA2a caused no untoward effects in AGENT-HF and that this was consistent with the CUPID studies. The Introduction and Results describe CUPID-2 as having no clinical benefit or neutral results, but our copy does not identify HF hospitalization or decompensated HF as its primary outcome. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [62] source
May combine two claims.
Interpretationown dataThe above data strongly indicated that optimal titers are critical for the success of cardiac gene therapies in humans, in addition to other considerations such as delivery method, vector serotype and tropism, and potential side effects.
“Without positive transduction, gene therapy cannot be effective; the above data strongly indicated that optimal titers are critical for the success of cardiac gene therapies in humans, in addition to other considerations such as delivery method, vector serotype and tropism, and potential side effects.78”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [78] 2020, Consideration of clinical translation of cardiac AAV gene therapy, Cell Gene Ther Insights source
May combine two claims.
Findingown dataSimilar results were obtained using hvCOC mini-hearts created from a second independent hPSC cell line, supporting the robustness of the HFpEF model.
“Similar results were obtained using hvCOC mini-hearts created from a second independent hPSC cell line, supporting the robustness of our HFpEF model (Supplemental Fig. 3).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe percentage of GFP-positive hvCMs gradually increased over time after AAV1-GFP transduction, reaching a plateau that was dependent on the viral titer.
“The percentage of GFP-positive hvCMs also gradually increased over time after AAV1-GFP transduction (Fig. 4B), reaching a plateau that was dependent on the viral titer (i.e., viral genomes per cell, vg/cell).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe Calcium Signaling pathway was differentially activated in both human HFpEF patients and in the HFpEF-hvCOC model, but not in the HFpEF-hvCTS model, relative to their respective controls.
“Interestingly, the Calcium Signaling pathway was differentially activated in both human HFpEF patients and in the HFpEF-hvCOC model, but not in the HFpEF-hvCTS model, relative to their respective controls (Fisher's exact test P-values: human HFpEF; p=0.008, hvCOC; p=0.01 and hvCTS; p=0.10) (Fig. 3B).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationnone givenThe findings contributed to FDA approval of an ongoing first-in-human gene therapy clinical trial for HFpEF, with Fast Track designation.
“These findings contributed to FDA approval of an ongoing first-in-human gene therapy clinical trial for HFpEF, with Fast Track designation.”
Quote in the paperNot a substantial claim- Rests on an assumption: The human mini-heart models are predictive of human clinical outcomes.
May combine two claims.
Study design and conductnone givenThe in vitro human HFpEF heart models described herein have been constructed using multiple hPSC cell lines, and rigorously validated using a range of phenotypic assessments recapitulating key characteristics of the disease, including favorable comparison with HFpEF patient transcriptomic data.
“Toward this goal, the in vitro human HFpEF heart models described herein have been constructed using multiple hPSC cell lines, and rigorously validated using a range of phenotypic assessments recapitulating key characteristics of the disease, including favorable comparison with HFpEF patient transcriptomic data.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).
InterpretationreasoningThe new hvCTS and hvCOC models may represent a more specific patient subpopulation.
“Considering the diverse nature of HFpEF, the new hvCTS and hvCOC models here may represent a more specific patient subpopulation.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataFindings provide evidence of hastened contraction kinetics in the HFpEF-hvCOC mini-heart model treated with AAV1-SERCA2a, though the phenotype correction is clearer in the hvCTS model.
“Taken together, these findings provide evidence of hastened contraction kinetics in the HFpEF-hvCOC mini-heart model treated with AAV1-SERCA2a, though the phenotype correction is clearer in the hvCTS model.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHFpEF is becoming the most prevalent cause of heart failure, accounting for over 50% of all HF cases.
“Heart failure with preserved ejection fraction (HFpEF) is becoming the most prevalent cause of heart failure, [1][2][3] accounting for over 50% of all HF cases.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1][2][3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataAAV1-SERCA2a treatment improved characteristic HFpEF phenotypes in human mini-hearts, which contributed to an ongoing first-in-human gene therapy clinical trial for HFpEF.
“The results supported SERCA2a as a human-relevant therapeutic target for HFpEF, and further demonstrated the improvement of characteristic HFpEF phenotypes by AAV1-SERCA2a treatment in human mini-hearts, which contributed to an ongoing first-in-human gene therapy clinical trial for HFpEF (Modulation of SERCA2a of Intra-myocytic Calcium Trafficking in Heart Failure with Preserved Ejection Fraction”
Quote in the paperSubstantial claim- Rests on an assumption: The human mini-heart models are predictive of human clinical outcomes.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenData analysis was performed by research assistants blinded to the experimental group assignments.
“Data analysis was performed by research assistants blinded to the experimental group assignments.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataRandomly selected hvCTSs were treated with TGF-β1/ET-1, and time-matched hvCTS without TGF-β1/ET-1 treatment served as healthy controls.
“To induce the HFpEF phenotype, randomly selected hvCTSs were treated with TGF-β1 (1 ng/mL) for 4.5 days, followed by treatment with TGF-β1 (1 ng/mL) plus ET-1 (100 nM) for 1 additional day prior to contractile assessment.Time-matched hvCTS without TGF-β1/ET-1 treatment served as healthy controls.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAbnormalities in cardiac relaxation in experimental models of HFpEF have been attributed to deficiency in the content and activity of SERCA2a, which decreases the rate of Ca2+ uptake into the SR during relaxation, resulting in prolonged contraction.
“The abnormalities in cardiac relaxation in experimental models of HFpEF have been attributed to deficiency in the content and activity of SERCA2a, 12,[47][48][49] which decreases the rate of Ca 2+ uptake into the SR during relaxation, 12,13,47,48 resulting in prolonged contraction.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [12] source
- cites [47] 2007, . Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins. J Mol Cell Cardiol
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48] 2007, Transcoronary gene transfer of SERCA2a increases coronary blood flow and decreases cardiomyocyte size in a type 2 diabetic rat model, Am J Physiol Heart Circ Physiol
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [49] source
- cites [13] source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe differential expression analysis between HFpEF-hvCOC/hvCTS models and controls adjusted for percentage of cardiac troponin T-expressing cells before tissue fabrication and age of tissue at time of data collection as baseline covariates.
“Differential expression gene (DEG) analysis between HFpEF-hvCOC/hvCTS models (TGF-β1/ET-1-treated versus control) was performed using DESeq2 (v1.24.0), using percentage of cardiac troponin T-expressing cells before tissue fabrication and age of tissue at time of data collection as baseline covariates.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S4 (based).
Interpretationnone givenOur current work provides the first direct link to human relevance.
“Our current work provides the first direct link to human relevance.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe consequence of slowed calcium re-uptake has implications not only for myocardial relaxation but also contributes to the development of diastolic stiffness, key features in the pathophysiology of HFpEF.
“Thus, the consequence of slowed calcium re-uptake has implications not only for myocardial relaxation but also contributes to the development of diastolic stiffness, key features in the pathophysiology of HFpEF.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe reported HFpEF-hvCTS and HFpEF-hvCOC mini-heart models are uniquely of human origin in the disease setting (HFpEF), and amenable to sophisticated phenotypic measurements, demonstrating the ability to recapitulate characteristic phenotypes seen in HFpEF patients.
“In conclusion, the reported HFpEF-hvCTS and HFpEF-hvCOC mini-heart models are uniquely of human origin in the disease setting (HFpEF), and amenable to sophisticated phenotypic measurements, as in the above experiments, demonstrating the ability to recapitulate characteristic phenotypes seen in HFpEF patients.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataUsing the SERCA2a transgene as an example, we demonstrated how the human mini-Heart HFpEF models are used to identify novel druggable targets followed by therapeutic screening for cardiac functional improvements.
“Using the SERCA2a transgene as an example, we also demonstrated how the human mini-Heart HFpEF models are used to identify novel druggable targets followed by therapeutic screening for cardiac functional improvements.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe data suggest treatment methods for HFpEF involving increasing, or restoring, intracellular calcium homeostasis in cardiomyocytes by increasing or enhancing calcium uptake by SERCA to ameliorate or reverse the slowed contraction and relaxation kinetics in HFpEF, which is translatable to humans.
“The data further suggest treatment methods for HFpEF involving increasing, or restoring, intracellular calcium homeostasis in cardiomyocytes by increasing or enhancing calcium uptake by SERCA to ameliorate or reverse the slowed contraction and relaxation kinetics in HFpEF, which is translatable to humans.”
Quote in the paperSubstantial claim- Rests on an assumption: The human mini-heart models are predictive of human clinical outcomes.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.
InterpretationreasoningThe versatile HFpEF models can be further custom-tailored, as needed, for discovering additional novel targets and screening therapeutics; the human mini-heart model is also helpful for titrating dosages in human trials.
“The versatile HFpEF models can be further custom-tailored, as needed, for discovering additional novel targets and screening therapeutics; the human mini-heart model is also helpful for titrating dosages in human trials.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationDespite experimental evidence that SERCA2a gene transfer improves cardiac function in HFrEF, and functional deficiencies of SERCA2 have been well validated in the context of HFrEF, there are mixed reports regarding the protein levels of SERCA2a in humans.
“Despite experimental evidence that SERCA2a gene transfer improves cardiac function in HFrEF, and functional deficiencies of SERCA2 have been well validated in the context of HFrEF, there are mixed reports regarding the protein levels of SERCA2a in humans.[64][65][66][67][68][69][70][71][72][73][74][75][76]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [64][65][66][67][68][69][70][71][72][73][74][75][76]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationreasoningOur study underscores the value of looking for common patterns that may arise from diverse yet complementary experimental disease models that each have strengths and limitations.
“Our study also underscores the value of looking for common patterns that may arise from diverse yet complementary experimental disease models that each have strengths and limitations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningOur approach is aligned with guidelines of the recent FDA Modernization Act 2.0 in support of alternatives to animal testing.
“Therefore, our approach is aligned with guidelines of the recent FDA Modernization Act 2.0 in support of alternatives to animal testing.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationFollow-up analysis of available patient cardiac tissue revealed transduction efficiency far below doses that were effective in preclinical models, which likely explained the neutral outcome.
“Follow-up analysis of available patient cardiac tissue revealed transduction efficiency far below doses that were effective in preclinical models, which likely explained the neutral outcome.63”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [63] source
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenThe CUPID-2 trial's strategy was to increase SERCA2a activity as a means of improving contractile dysfunction characteristic of HFrEF; the effect on cardiac relaxation was never assessed.
“Also, the CUPID-2 trial's strategy was to increase SERCA2a activity as a means of improving contractile dysfunction characteristic of HFrEF; the effect on cardiac relaxation was never assessed.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
HFpEF lacks disease-modifying therapeutic options.
“Heart failure with preserved ejection fraction (HFpEF), is a global health problem lacking disease-modifying therapeutic options, reflecting a lack of predictive models for preclinical drug testing.”
The paper relies on this without support.
Many therapies that reduce mortality and morbidity in HFrEF have little benefit for HFpEF patients because the biology and clinical course for the two diseases are very different.
“Unfortunately, many therapies that reduce mortality and morbidity in HFrEF have little benefit for HFpEF patients because the biology and clinical course for the two diseases are very different.”
The paper relies on this without support.
There are 2 to 3 billion cardiomyocytes in the adult human heart.
“Considering there are 2 to 3 billion cardiomyocytes in the adult human heart, the optimized viral titer of 1x10 4 vg/cell used in the hvCOC mini-heart model of HFpEF translates to a dosage of 2-3x10 13 vg per patient heart; this informed the approved dosage of 3 x10 13 vg/patient to be delivered via intracoronary injection of HFpEF subjects in the MUSIC-HFpEF trial.”
The paper relies on this without support.
The optimized viral titer of 1x10^4 vg/cell in the hvCOC mini-heart model translates to a dosage of 2-3x10^13 vg per patient heart.
“Considering there are 2 to 3 billion cardiomyocytes in the adult human heart, the optimized viral titer of 1x10 4 vg/cell used in the hvCOC mini-heart model of HFpEF translates to a dosage of 2-3x10 13 vg per patient heart; this informed the approved dosage of 3 x10 13 vg/patient to be delivered via intracoronary injection of HFpEF subjects in the MUSIC-HFpEF trial.”
The paper relies on this without support.
The MUSIC-HFpEF trial using AAV1-SERCA2a gene therapy is the only current human clinical trial targeting relaxation in HFpEF.
“Indeed, our new MUSIC-HFpEF trial using AAV1-SERCA2a gene therapy is the only current human clinical trial targeting relaxation in HFpEF, and inclusion of data from this study using the same GMP-grade viral vector contributed to our successful Investigational New Drug (IND) and Fast Track Designation (FTD) applications to the U.S. FDA.”
The paper relies on this without support.
The human mini-heart models are predictive of human clinical outcomes.
“We conclude that such human-based disease-specific mini-heart platforms are relevant for target discovery and validation that can facilitate clinical translation of novel cardiac therapies.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The HFpEF ECC model exhibited increased passive chamber stiffness and a leftward-shifted diastolic pressure-area relationship, while maintaining Ejection Fraction (EF), thus recapitulating hallmark features of the disease phenotype.
“The HFpEF ECC model exhibited increased passive chamber stiffness and a leftward-shifted diastolic pressure–area relationship, while maintaining Ejection Fraction (EF), thus recapitulating hallmark features of the disease phenotype.”
From Mini-hearts for disease modeling and drug testing – process optimization versus biological functionality (2026) · cites this paper as Costa et al., 2024
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Complete phenotype reversal conflicts with increased passive force
MajorThe abstract says treatment eliminated the disease phenotype, but the results say passive force increased after treatment. Elevated passive tension is one of the abnormalities used to define the model, so these statements do not support a complete reversal.
“AAV-mediated expression of SERCA2a abrogated the disease phenotype and improved the cardiac kinetics in HFpEF mini-Hearts.”
“AAV1-SERCA2a treatment improved the abnormal kinetics of the HFpEF hvCTS by significantly shortening the diseased contraction and relaxation times toward non-transduced (NT) Control tissue values (n=5-8, p<0.05), while active and passive force were increased.”
Chamber loading ranges differ between methods and figure
MinorThe methods list volumetric loading only through 100 μL, whereas the figure caption describes the chamber pressure-area measurements over 0-200 μL. The stated measurement protocol does not account for the plotted loading range.
“Chamber pressure and digital video were acquired simultaneously under spontaneously beating and electrically paced conditions (as above) at 0, 25, 50, and 100 μL of volumetric loading.”
“(B) Change in diastolic pressure versus change in diastolic area for control (black) and TGF-β1/ET-1-treated (red) hvCOC subject to 0-200 µL hydrostatic loading.”
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Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium
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Self-citationGene therapy for the treatment of heart failure: promise postponed
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Self-citationThe opposing effects of CCN2 and CCN5 on the development of cardiac hypertrophy and fibrosis
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Self-citationAnimal models of heart failure with preserved ejection fraction
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Human SERCA2a levels correlate inversely with age in senescent human myocardium
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Self-citationDiagnosis and Management of Heart Failure with Preserved Ejection Fraction: 10 Key Lessons
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CCN5, a Novel Transcriptional Repressor of the Transforming Growth Factor β Signaling Pathway
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Self-citationSERCA2a in Heart Failure: Role and Therapeutic Prospects
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Self-citationMyocyte-Depleted Engineered Cardiac Tissues Support Therapeutic Potential of Mesenchymal Stem Cells
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Self-citationCalcium sequestration by the sarcoplasmic reticulum in heart failure
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FDA Modernization Act 2.0 Paves the Way to Computational Biology and Clinical Trials in a Dish
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Self-citationIntroducing Genes to the Heart: All About Delivery
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Self-citationGene Remodeling in Type 2 Diabetic Cardiomyopathy and Its Phenotypic Rescue with SERCA2a
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Self-citationGene profiling during regression of pressure overload-induced cardiac hypertrophy
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Self-citationSERCA2a Protein Levels Are Unaltered in Human Heart Failure
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Self-citationCardiac Tissue Engineering Models of Inherited and Acquired Cardiomyopathies
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Self-citationConstruction of Defined Human Engineered Cardiac Tissues to Study Mechanisms of Cardiac Cell Therapy
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Self-citationConsideration of clinical translation of cardiac AAV gene therapy
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Construction of Defined Human Engineered Cardiac Tissues to Study Mechanisms of Cardiac Cell Therapy
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Self-citationP1509Empagliflozin directly improves diastolic function in human heart failure
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Self-citationDistinct Myocardial Gene Expression Signatures in Heart Failure with Preserved Ejection Fraction
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Self-citation
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Shooshtarian, A. K., O’Gallagher, K., Shah, A. M., & Zhang, M. (2025) · Heart Failure Reviews · doi:10.1007/s10741-025-10487-1 · Cited by 30 · see citing works
Viskupičová, J., & Espinoza-Fonseca, M. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169200 · Cited by 19 · see citing works
Fudim, M., Sarma, S., MacNamara, J. P., Ascheim, D. D., Kittipibul, V., Doukellis, K., Dhimitri, A., Fitzhugh, R., Kamat, N., Costa, K. D., et al. (2026) · Heart Failure Reviews · doi:10.1007/s10741-025-10589-w · Cited by 4 · see citing works
Self-citationCano-Jorge, M., Gómez, S., den Toonder, J. M. J., Wang, Y., & Passier, R. C. (2025) · Cardiovascular Research · doi:10.1093/cvr/cvaf247 · Cited by 6 · see citing works
Hecking, J., Cano-Jorge, M., Passier, R., & Rivera-Arbeláez, J. M. (2026) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2025.1719533
- Authors
- Costa, K. D., Wong, A. O. T., Mak, S. Y., Roberts, E. G., Keung, W., Correia, C., Walentinsson, A., Christoffersson, J., Cheung, A., Lieu, D. K., Jennbacken, K., Wang, Q.-D., Hajjar, R. J., & Li, R. A.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Costa, Kevin D.
- ORCID
- Venue
- bioRxiv
- Publisher
- openRxiv
- Published
- 2024-08-28
- OpenAlex
- W4401937167
- Cited by
- 5
- References
- 77
- Citations by year
- 2026: 2 · 2025: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- AstraZeneca
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- heart failure with preserved ejection fraction, human pluripotent stem cell-derived cardiomyocytes, AAV gene therapy, SERCA2a, calcium homeostasis, diastolic dysfunction, cardiac stiffness, disease-modifying therapy, preclinical drug testing, transcriptomics, endothelin-1, TGF-β1
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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