Myocardial Structure and Function in Heart Failure with Preserved Ejection Fraction: Molecular Insights and Therapeutic Strategies Targeting Transforming Growth Factor Beta Signaling
Bibliographic record
Abstract
Myocardial fibrosis has long been implicated in the pathophysiology of heart failure with preserved ejection fraction (HFPEF)—increasing myocardial stiffness and contributing to diastolic dysfunction. However, despite multiple therapeutic strategies to reduce myocardial fibrosis, clinically effective anti-fibrotic therapies remain sparse. At issue is that current HFPEF therapeutic strategies often target pro-fibrotic pathways indirectly or rely on associative evidence derived from animal models that do not faithfully recapitulate human HFPEF. In this thesis, the canonical signaling pathway of transforming growth factor beta (TGF-β), a master regulator of fibrosis, is directly targeted in three clinically relevant animal models of HFPEF—streptozotocin-diabetic (mRen-2)27 rats, 5/6 subtotal nephrectomy rats, and transverse aortic constriction-induced pressure overload mice. Blockade of the acetylation of Smad2/3—key intracellular signal transducers of TGF-β signaling—in cell culture and the three animal models of HFPEF reduced the expression of several pro-inflammatory and pro-fibrotic markers and also abrogated the reactivation of the fetal gene program. In the animal models, echocardiographic and invasive hemodynamic measurements revealed a reduction in interstitial cardiac fibrosis and an improvement in diastolic filling and relaxation with the inhibition of Smad2/3 acetylation. The approach of targeting fibrosis—a central pathology in HFPEF irrespective of the inciting stimuli—by selectively inhibiting a single post translational modification critical in the TGF-β signaling pathway, is a promising therapeutic approach that could be further developed to slow, or perhaps reverse, cardiac fibrosis in HFPEF.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".