Pre-Clinical Investigation
Left Ventricular Longitudinal Strain as a Marker for Point of No Return in Hypertensive Heart Failure Treatment

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Highlights

  • There is no medical treatment that benefits HFpEF outcomes.

  • Global longitudinal strain impairment with heart failure occurs in HFpEF model rats.

  • ACE-I is beneficial after longitudinal strain but before circumferential strain impairment.

  • Myocardial strain could be the marker for point of no return for HFpEF treatment.

Background

There are currently no therapies that can improve prognosis in cases of heart failure (HF) with preserved ejection fraction (EF). We hypothesized that there is a point of no return after which no response to treatment is noted and that for the prevention of hypertensive HF this point may be determined by left ventricle (LV) strain, in the prevention of hypertensive HF. Here an angiotensin-converting enzyme inhibitor (ACE-I) was initiated based on myocardial strain imaging and its effects were determined in an animal model.

Methods

Thirty-two male Dahl salt-sensitive rats, age 6 weeks, were divided into six experimental groups and compared with low-salt (n = 8) and high-salt control groups (n = 8). In the early treatment group, ACE-I was administered from the age of 6 weeks (n = 4); in the longitudinal strain (LS) group, at 10-12 weeks when LS impairment was >–21% (n = 4); in the circumferential strain (CS) group, at 16-18 weeks when CS impairment was >–18% (n = 4); and in the EF group, at 20 weeks when EF was <55% (n = 4). Subsequently, all rats were sacrificed at 23 weeks age, the LV and lung weight were measured, and pathologic analyses were performed.

Results

At 23 weeks of age, the lung and LV weights increased in the high-salt control, EF, and CS groups, whereas the lung and LV weights in the LS and early groups were similar to those in the low-salt control group. The percentage of area of subendocardial fibrosis was >6% in the high-salt control, EF, and CS groups and <3% in the LS, early, and low-salt groups. Serial echocardiography demonstrated LS improvement in the LS group; however, the CS and EF groups showed no differences.

Conclusions

Heart failure–related lung congestion was prevented when ACE-I was administered soon after LS impairment, accompanied by suppression of cardiac hypertrophy and fibrosis, thereby suggesting that the point of no return of myocardial remodeling due to hypertension was present after LS but before CS impairment.

Section snippets

Experimental Animals

Animal experiments were carried out humanely after obtaining approval for this study from the Institutional Animal Experiments Committee of the University of Tsukuba. Experimental protocols were in accordance with the Regulation for Animal Experiments in our university.

In this study, 32 male Dahl salt-sensitive (DSS) rats ages 6-23 weeks, a well-validated animal model of HFpEF due to hypertension (DIS/Eis; Eisai, Tokyo, Japan), were used. Rats were divided into six experimental groups (Figure 1

Results

Initial measurements were obtained from all 32 rats, and histologic measurements were performed in 28 rats. Four rats in the high-salt group died spontaneously. Among these, two rats in the control group died at 20 and 22 weeks and two rats in the ACE-I treated group died at 12 (early group) and 16 weeks (CS group).

Discussion

To the best of our knowledge, this is the first study to investigate the effect of myocardial strain to identify the optimal timing of ACE-I treatment initiation for preventing heart failure. This study demonstrated that if ACE-I administration was initiated just after the LS impairment, heart failure, which was characterized by an increase in lung weight, LV weight, and amount of subendocardial fibrosis, can be prevented. Although the CS group showed intermediate improvement in subendocardial

Conclusion

Myocardial strains by echocardiography may be able to guide the therapeutic timing in HFpEF. The PNR of HFpEF treatment may exist between just after LS impairment and before CS impairment.

Acknowledgments

We thank Emi Shiomitsu, BSc (Department of Medical Science, Faculty of Medicine, University of Tsukuba), for assistance with pathologic specimen measurements.

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    T.I. and Y.S. received grants from the Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (16K09416).

    Conflicts of Interest: None.

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