What is the clinical evidence from this study?

Study design: Other. Population: Hypertension (n=26). Intervention: Valsartan vs. Vehicle. Primary outcome: Left ventricular posterior wall thickness (mm) (p=0.0068).

What question did this study set out to answer?

To characterize the contribution of a non-renin-dependent enzymatic pathway for angiotensin II generation in the blood and cardiac tissue of transgenic rats expressing human angiotensinogen.

November 15, 2019Frontiers in Cardiovascular MedicineOpen Access

Activation of the Human Angiotensin-(1-12)-Chymase Pathway in Rats With Human Angiotensinogen Gene Transcripts

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Key result

Valsartan reduces LV posterior wall thickness ~12% and lowers daytime arterial pressure in transgenic rats.

P=0.0068
n=26

Why the study?

The discovery of Ang-(1-12) as an alternate substrate underscored the potential role of renin-independent pathways for Ang II generation, prompting characterization in a transgenic rat model expressing the human angiotensinogen gene.

Population

TGR(hAGT)L1623 rats expressing human angiotensinogen and SD control rats

Comparison

Oral valsartan vs vehicle

Design

Preclinical animal study

Follow-up

2 weeks

Authors

CFCarlos M. FerrarioPreventive Cardiology JVJessica L. VonCannonWake Forest University SASarfaraz AhmadSwami Keshwanand Rajasthan Agricultural University

Discussion

Member takes

Implication

Should not change hypertension practice; leaves open renin-independent cardiac Ang II pathways in humanized models.

Key Points

To characterize the contribution of a non-renin-dependent enzymatic pathway for angiotensin II generation in the blood and cardiac tissue of transgenic rats expressing human angiotensinogen.
TGR(hAGT)L1623 transgenic rats were treated orally with vehicle or the AT1 receptor blocker valsartan for 14 days.
Plasma renin activity, plasma and cardiac angiotensins, and cardiac enzymatic activities of chymase, ACE, and ACE2 were measured, with peptide identification verified by mass spectrometry.
Valsartan treatment augmented plasma angiotensin I and II concentrations and induced a 46% rise in left ventricular human Ang-(1-12) levels without altering rat cardiac Ang-(1-12).
Mass spectrometry confirmed a greater than 4-fold increase in cardiac Ang II content in transgenic rats compared with Sprague-Dawley control rats.
Cardiac chymase and ACE2 activities were significantly higher than ACE activity in transgenic rats and remained unaltered following AT1 receptor blockade.

Structured PICO

Population

TGR(hAGT)L1623 rats (transgenic model of hypertension due to insertion of the human angiotensinogen gene in Sprague Dawley rats) and Sprague Dawley control rats

Intervention

Valsartan orally for 2 weeks

Comparator

Vehicle

Outcome

Plasma and cardiac expression of angiotensins, plasma renin activity and cardiac enzymatic activities of chymase, angiotensin converting enzyme (ACE) and ACE2surrogate

Main Result

Absolute Event Rate: 2.14% vs 2.43%

p-value: p=0.0068

In a humanized rat model of hypertension, AT1-receptor blockade increases cardiac human Ang-(1-12) levels, highlighting a renin-independent mechanism for Ang II formation in the heart.

Limitations

The identity of the enzyme cleaving the human AGT sequence in these transgenic rats remains to be fully identified.
The study does not directly answer whether cardiac Ang II was formed intracellularly.

Cite This Study

Ferrario et al. (2019) studied Hypertension (n=26). Valsartan vs. Vehicle was evaluated on Left ventricular posterior wall thickness (mm) (p=0.0068). A 2-week treatment with valsartan in transgenic rats expressing the human angiotensinogen gene significantly reduced left ventricular posterior wall thickness and daytime arterial pressure.

synapsesocial.com/papers/6a0eeda453f874f2b222f561 https://doi.org/10.3389/fcvm.2019.00163

Topics

Hypertension management

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Activation of the Human Angiotensin-(1-12)-Chymase Pathway in Rats With Human Angiotensinogen Gene Transcripts

Discussion

Member takes

Implication

Key Points

Structured PICO

Main Result

Limitations

Cite This Study

Topics

Activation of the Human Angiotensin-(1-12)-Chymase Pathway in Rats With Human Angiotensinogen Gene Transcripts

Discussion

Member takes

Implication

Key Points

Structured PICO

Main Result

Limitations

Cite This Study

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Topics

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