Diastolic Dysfunction is Generated in Mice with Knockout of Smoothelin‐like 1 Protein
Bibliographic record
Abstract
BACKGROUND Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Ultimately, heart failure (HF) is the common final outcome for most patients with CVD, and HF with preserved ejection fraction (HFpEF) has gained increasing prevalence. Clinical evidence associates HFpEF with microvascular dysfunction and endothelial inflammation, which in turn drive pathologic cardiac remodeling. No therapeutics are available for improving outcomes of HFpEF patients; thus, further research is required to better understand its etiology since the molecular pathways leading to HFpEF are not confined to one pathology. Of particular note, our recent experiments reveal a novel role for the smoothelin‐like 1 (SMTNL1) protein in the endothelium which when disturbed drives dramatic alterations in systemic inflammation, endothelial functional responses, and cardiovascular performance. OBJECTIVE The study examined the impact of SMTNL1 deficiency on cardiac function in male murine models. METHODS SMTNL1 global knockout (KO) mice (10‐week old, young male) were anesthetized by isoflurane and underwent M‐mode echocardiographic (ECG) imaging (Vevo770, Visual Sonics, Canada), followed by left ventricular (LV) catheterization (PVR 1045, Millar Instruments, Houston, TX) and pressure‐volume (PV) loop measurements to assess the systolic‐diastolic and hemodynamic parameters of cardiac function. The background strain 129S6 wildtype (WT) mice served as the control group. Mice were terminated at the end of PV loop procedures, and serum was collected for detection of circulating markers (Luminex array, EveTechnologies Inc.). RESULTS Gross dissection revealed distinct cardiac morphology; hearts from KO animals were significantly smaller than WT littermates (~12% smaller HM:TL ratios), but the proportion of heart mass taken up by LV was greater (~10% larger LV:HM ratios). The non‐invasive ECG analysis of KO mice showed normal ejection fraction (%EF: 54.5±3.3 vs 44.0±3.0) and fractional shortening (%FS: 28.2±2.2 vs 21.7±1.7) relative to the WT counterparts. However, PV loop analysis revealed diastolic dysfunction with significantly increased end diastolic pressure (EDP: 11.6±1.7 vs 4.9±1.8 mmHg, p<0.05) and LV relaxation time (Tau; 11.7±0.4 vs 7.0±0.4 ms, p<0.0001) along with a steeper end diastolic PV relationship (EDPVR: 0.55±0.14 vs 0.22±0.06, p<0.05) an indicator of stiffer heart, in KO group when compared to the WT group. Additionally, circulating serum markers such as sE‐selectin and pro‐MMP9 were elevated in the KO mice. CONCLUSION In the present study, we have identified intriguing linkages for SMTNL1 and pathophysiological definitions of diastolic dysfunction, and suggest SMTNL1 knockout animals represent a new pre‐clinical model to examine the development of HF‐pEF. However, the pathophysiological role of SMTNL1 protein in the regulation of cardiac hemodynamics, potentially through endothelial inflammation and microvascular dysfunction requires further study. Support or Funding Information ‐Libin Cardiovascular Institute of Alberta, University of Calgary ‐Achievers in Medicine Scholarship from Cumming School of Medicine, University of Calgary ‐CIHR Travel award This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".