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July 5, 2017JCI InsightOpen Access

Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction

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Key result

Patients with left ventricular diastolic dysfunction exhibited significantly higher leukocyte ROCK activity compared to age- and sex-matched controls (median 1.33 vs 0.61, P=0.05).

Population

Preclinical models including fibroblast-specific ROCK2-deficient mice, constitutively active ROCK knock-in…

Comparison

Fibroblast-specific deletion of ROCK2 or… vs Littermate control mice subjected to the same…

Design

Preclinical

Follow-up

4 weeks

Authors

TSToru ShimizuJikei University School of MedicineNNNikhil NarangAdvocate Lutheran General HospitalPCPhetcharat ChenUniversity of Arizona

Discussion

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Member takes

Overview

ROCK2 inhibition may merit testing for hypertensive diastolic dysfunction; leaves open translation from fibroblast-specific mouse models to patients.

Structured PICO

P
Population
20 older adults (mean age 66, 70% female), comprising 10 patients with left ventricular diastolic dysfunction and 10 age- and sex-matched controls.
E
Exposure
Fibroblast-specific deletion of ROCK2 (ROCK2Postn-/-) or constitutively active ROCK knock-in (caROCKPostn-/-) subjected to Angiotensin II infusion (1,000 ng/kg/min for 4 weeks).
C
Comparator
Littermate control mice (ROCK2flox/flox or caROCKflox/flox) subjected to the same Angiotensin II infusion or saline.
O
Outcome
Cardiac hypertrophy (left ventricular wall thickness, LV mass), interstitial fibrosis, and diastolic dysfunction (E/A ratio, isovolumetric relaxation time) at 4 weeks.surrogate

Main Result

Absolute Event Rate: 1.33% vs 0.61%

p-value: p=0.05

Fibroblast ROCK2 is a critical mediator of cardiac hypertrophy and fibrosis, suggesting it may be a novel therapeutic target for left ventricular diastolic dysfunction.

Limitations

  • It remains to be determined whether the mouse model used for diastolic dysfunction is generalizable to HFpEF in humans, where different etiologies may contribute.
  • It is unknown whether cardiac fibroblasts from patients with HFpEF and diastolic dysfunction have elevated ROCK2 expression and activity.

Cite This Study

Shimizu et al. (2017) studied Left ventricular diastolic dysfunction (n=20). Left ventricular diastolic dysfunction vs. Age- and sex-matched controls was evaluated on Leukocyte ROCK activity (p-MBS/t-MBS ratio) (p=0.05). Patients with left ventricular diastolic dysfunction exhibited significantly higher leukocyte ROCK activity compared to age- and sex-matched controls (median 1.33 vs 0.61, P=0.05).

synapsesocial.com/papers/6a93a8ef87f8000eec56ad39https://doi.org/10.1172/jci.insight.93187
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Also Consider

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