What is the clinical evidence from this study?

Study design: Other. Population: Hypertension and concomitant cardiomyopathy (n=40). Intervention: Angiotensin II infusion vs. Baseline / Saline placebo. Primary outcome: Left ventricular ejection fraction (LVEF) at 6 weeks (p=<0.001).

January 1, 2020Open Access

Progression and regression of left ventricular hypertrophy and myocardial fibrosis in a mouse model of hypertension and concomitant cardiomyopathy

Q: What are the key findings of this study?

Angiotensin II-induced systemic hypertension significantly reduced left ventricular ejection fraction from 59.3% to 46.9% and increased myocardial fibrosis, which only partially reversed after blood pressure normalization.

Key Result

Angiotensin II-induced systemic hypertension significantly reduced left ventricular ejection fraction from 59.3% to 46.9% and increased myocardial fibrosis, which only partially reversed after blood pressure normalization.

Structured PICO

Does continuous angiotensin II infusion induce reversible left ventricular hypertrophy and myocardial fibrosis in a mouse model?

Population

40 male C57BL/6 J mice (14 ± 2 weeks old) subjected to angiotensin II-induced hypertension for up to 6 weeks, with a subset followed for 4 weeks post-infusion to assess reverse remodeling.

Intervention

Continuous angiotensin II infusion at 480 ± 34 ng/kg/min via subcutaneously implanted osmotic minipumps for up to 6 weeks.

Comparator

Placebo infusion of saline (0.9% NaCl) via subcutaneously implanted osmotic minipumps.

Outcome

Development and regression of left ventricular hypertrophy and myocardial fibrosis measured by serial cardiovascular magnetic resonance (CMR) imaging.surrogate

In a mouse model of hypertension, myocardial fibrosis and left ventricular systolic dysfunction are only partially reversible following the normalization of blood pressure.

Main Result

Absolute Event Rate: 46.9% vs 59.3%

p-value: p=<0.001

Limitations

The model is not a pure model for either hypertension or aortic stenosis.
Angiotensin II might have triggered diffuse fibrosis irrespective of the elevated blood pressure.
For T1-mapping, data was only acquired from the mid-ventricle short axis slice, potentially introducing a sampling error.
Blood pressure measurements were performed immediately after imaging sessions while animals were recovering from anaesthesia.
Reverse remodelling was only assessed at 4 weeks post cessation of the angiotensin II infusion, so longer follow-up might show further normalization.

Abstract

BACKGROUND: Myocardial fibrosis is observed in multiple cardiac conditions including hypertension and aortic stenosis. Excessive fibrosis is associated with adverse clinical outcomes, but longitudinal human data regarding changes in left ventricular remodelling and fibrosis over time are sparse because of the slow progression, thereby making longitudinal studies challenging. The purpose of this study was to establish and characterize a mouse model to study the development and regression of left ventricular hypertrophy and myocardial fibrosis in response to increased blood pressure and to understand how these processes reverse remodel following normalisation of blood pressure. METHODS: We performed a longitudinal study with serial cardiovascular magnetic resonance (CMR) imaging every 2 weeks in mice (n = 31) subjected to angiotensin II-induced hypertension for 6 weeks and investigated reverse remodelling following normalisation of afterload beyond 6 weeks (n = 9). Left ventricular (LV) volumes, mass, and function as well as myocardial fibrosis were measured using cine CMR and the extracellular volume fraction (ECV) s. RESULTS: Increased blood pressure (65 ± 12 vs 85 ± 9 mmHg; p < 0.001) resulted in higher indices of LV hypertrophy (0.09 0.08, 0.10 vs 0.12 0.11, 0.14 g; p < 0.001) and myocardial fibrosis (ECV: 0.24 ± 0.03 vs 0.30 ± 0.02; p < 0.001) whilst LV ejection fraction fell (LVEF, 59.3 57.6, 59.9 vs 46.9 38.5, 49.6 %; p < 0.001). We found a strong correlation between ECV and histological myocardial fibrosis (r = 0.89, p < 0.001). Following cessation of angiotensin II and normalisation of blood pressure (69 ± 5 vs baseline 65 ± 12 mmHg; p = 0.42), LV mass (0.11 0.10, 0.12 vs 0.09 0.08, 0.11 g), ECV (0.30 ± 0.02 vs 0.27 ± 0.02) and LVEF (51.1 42.9, 52.8 vs 59.3 57.6, 59.9 %) improved but remained impaired compared to baseline (p < 0.05 for all). There was a strong inverse correlation between LVEF and %ECV during both systemic hypertension (r = - 0.88, p < 0.001) and the increases in ECV observed in the first two weeks of increased blood pressure predicted the reduction in LVEF after 6 weeks (r = - 0.77, p < 0.001). CONCLUSIONS: We have established and characterized angiotensin II infusion and repeated CMR imaging as a model of LV hypertrophy and reverse remodelling in response to systemic hypertension. Changes in myocardial fibrosis and alterations in cardiac function are only partially reversible following relief of hypertension.

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