Pre-Clinical Investigation
Application of Speckle-Tracking Echocardiography in an Experimental Model of Isolated Subendocardial Damage

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Highlights

  • STE was performed in an experimental model of isolated subendocardial fibrosis, and comprehensive morphologic-functional correlation analyses were performed.

  • Functional impairment was present only in decreased global LS and global LSR values, whereas global systolic function and other strain parameters remained unaffected.

  • Global LS was associated with subendocardial collagen content and serum level of TIMP-1.

  • Global LS was identified as a superior predictor for the presence of subendocardial damage.

Background

The subendocardium is highly vulnerable to damage and is thus affected even in subclinical disease stages. Therefore, methods reflecting subendocardial status are of great clinical relevance for the early detection of cardiac damage and the prevention of functional impairment. The aim of this study was to investigate the potential ability of myocardial strain parameters to evaluate changes within the subendocardium.

Methods

Male 129/Sv mice were injected with isoproterenol (ISO; n = 32) to induce isolated subendocardial fibrotic lesions or saline as appropriate control (n = 15). Transthoracic echocardiography was performed using a 30-MHz linear-frequency transducer coupled to a high-resolution imaging system, and acquired images were analyzed for conventional and strain parameters. The degree of collagen content within the different cardiac layers was quantified by histologic analysis and serum levels of tissue inhibitor of metalloproteinase–1, a biomarker for fibrosis, were assessed.

Results

ISO treatment induced a marked increase in subendocardial collagen content in response to cell loss (control vs ISO, 0.6 ± 0.3% vs 5.8 ± 0.9%; P < .001) and resulted in a moderate increase in left ventricular wall thickness with preserved systolic function. Global longitudinal peak strain (LS) and longitudinal strain rate were significantly decreased in ISO-treated animals (LS, −15.49% vs −11.49% [P = .001]; longitudinal strain rate, −4.81 vs −3.88 sec−1 [P < .05]), whereas radial and circumferential strain values remained unchanged. Global LS was associated with subendocardial collagen content (r = 0.46, P = .01) and tissue inhibitor of metalloproteinase–1 serum level (r = 0.52, P < .05). Further statistical analyses identified global LS as a superior predictor for the presence of subendocardial fibrosis (sensitivity, 84%; specificity, 80%; cutoff value, −14.4%).

Conclusion

Assessment of LS may provide a noninvasive method for the detection of subendocardial damage and may consequently improve early diagnosis of cardiac diseases.

Section snippets

Methods

All animal procedures were performed in accordance with the guidelines of the German Law on the Protection of Animals. The experimental protocols (Figures 1C and 1D) were reviewed and approved by the authorities (Landesamt für Gesundheit und Soziales, Berlin, Germany). Animals used in this study served as placebo-treated control groups in ongoing projects and were kept under identical housing conditions (12-hour light/dark cycle, standard diet ad libitum). Data sets, histologic sections, and

Study Population

Animals were randomly assigned to both study protocol and treatment regime. Exclusively males were used in this study, aiming for better comparability and exclusion of hormonal fluctuation as a possible confounder.

Four animals (n = 3 in the first cohort, n = 1 in the second cohort) died in the course of ISO injections for reasons not further investigated (overall mortality under ISO treatment 12.5%; Supplemental Figure 1, available at www.onlinejase.com). Data from these animals were excluded

Discussion

In this experimental study we showed that pathologic changes within the subendocardium can be evaluated by assessment of LS using STE.

We demonstrated that in a small animal model of isolated subendocardial fibrosis, only LS and LSR allowed the assessment of functional impairment, while other strain values, as well as conventional parameters of LV systolic function, remained unaffected. Furthermore, global LS was found to be a superior predictor for the presence of subendocardial fibrotic

Conclusions

Our findings confirm the current concept that longitudinal mechanics of the left ventricle are determined mainly by subendocardial status. Consequently, longitudinal strain parameters are able to reflect subendocardial function and may contribute to assessment of early cardiac impairment, even in subclinical disease stages. Elevated TIMP-1 serum levels in combination with assessment of reduced longitudinal strain parameters might be a promising surrogate for subendocardial fibrosis.

Acknowledgments

We thank Dr. Franziska Schwarz (scivisto.com) for the scientific figure illustrations and Annelie Blumrich for proofreading. We are grateful to Dr. Dieter Fuchs and Dr. Magdalena Steiner (FUJIFILM VisualSonics) for providing insightful background information about the used software tools and excellent technical support. We further thank Beata Höft, Christiane Sprang, and Manuela Sommerfeld for their excellent technical assistance.

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    This work was supported by Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK; BER 5.4 PR). Ms. Brix was supported by Deutsche Stiftung für Herzforschung. Ms. Betz was supported by Deutsche Gesellschaft für Kardiologie and DZHK. Dr. Foryst-Ludwig was supported by Deutsche Forschungsgemeinschaft (KFO 218/2), Deutsche Stiftung für Herzforschung, and DZHK (BER 5.4 PR). Dr. Grune was supported by DynAge, FU Berlin. Dr. Kintscher was supported by DFG (KFO 218/2), Else Kröner-Fresenius Stiftung (2014_A100), and DZHK (BER 5.4 PR).

    Drs. Grune and Kintscher contributed equally to this work. Parts of this work will be used in the doctoral theses of Mr. Beyhoff and Ms. Betz.

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