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Cardiac magnetic resonance assessment of interstitial myocardial fibrosis and cardiomyocyte hypertrophy in hypertensive mice treated with spironolactone.

ABSTRACT: Nearly 50% of patients with heart failure (HF) have preserved LV ejection fraction, with interstitial fibrosis and cardiomyocyte hypertrophy as early manifestations of pressure overload. However, methods to assess both tissue characteristics dynamically and noninvasively with therapy are lacking. We measured the effects of mineralocorticoid receptor blockade on tissue phenotypes in LV pressure overload using cardiac magnetic resonance (CMR).Mice were randomized to l-nitro-?-methyl ester (l-NAME, 3 mg/mL in water; n=22), or l-NAME with spironolactone (50 mg/kg/day in subcutaneous pellets; n=21). Myocardial extracellular volume (ECV; marker of diffuse interstitial fibrosis) and the intracellular lifetime of water (?ic; marker of cardiomyocyte hypertrophy) were determined by CMR T1 imaging at baseline and after 7 weeks of therapy alongside histological assessments. Administration of l-NAME induced hypertensive heart disease in mice, with increases in mean arterial pressure, LV mass, ECV, and ?ic compared with placebo-treated controls, while LV ejection fraction was preserved (>50%). In comparison, animals receiving both spironolactone and l-NAME ("l-NAME+S") showed less concentric remodeling, and a lower myocardial ECV and ?ic, indicating decreased interstitial fibrosis and cardiomyocyte hypertrophy (ECV: 0.43 ± 0.09 for l-NAME versus 0.25 ± 0.03 for l-NAME+S, P<0.001; ?ic: 0.42 ± 0.11 for l-NAME groups versus 0.12 ± 0.05 for l-NAME+S group). Mice treated with a combination of l-NAME and spironolactone were similar to placebo-treated controls at 7 weeks.Spironolactone attenuates interstitial fibrosis and cardiomyocyte hypertrophy in hypertensive heart disease. CMR can phenotype myocardial tissue remodeling in pressure-overload, furthering our understanding of HF progression.

SUBMITTER: Coelho-Filho OR

PROVIDER: S-EPMC4309062 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Cardiac magnetic resonance assessment of interstitial myocardial fibrosis and cardiomyocyte hypertrophy in hypertensive mice treated with spironolactone.

Coelho-Filho Otavio R OR Shah Ravi V RV Neilan Tomas G TG Mitchell Richard R Moreno Heitor H Kwong Raymond R Jerosch-Herold Michael M

Journal of the American Heart Association 20140625 3

<h4>Background</h4>Nearly 50% of patients with heart failure (HF) have preserved LV ejection fraction, with interstitial fibrosis and cardiomyocyte hypertrophy as early manifestations of pressure overload. However, methods to assess both tissue characteristics dynamically and noninvasively with therapy are lacking. We measured the effects of mineralocorticoid receptor blockade on tissue phenotypes in LV pressure overload using cardiac magnetic resonance (CMR).<h4>Methods and results</h4>Mice wer ...[more]

PMID: 24965024

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Project description:BackgroundAortic stenosis is accompanied by progressive left ventricular hypertrophy and fibrosis. We investigated the natural history of these processes in asymptomatic patients and their potential reversal post-aortic valve replacement (AVR).MethodsAsymptomatic and symptomatic patients with aortic stenosis underwent repeat echocardiography and magnetic resonance imaging. Changes in peak aortic-jet velocity, left ventricular mass index, diffuse fibrosis (indexed extracellular volume), and replacement fibrosis (late gadolinium enhancement [LGE]) were quantified.ResultsIn 61 asymptomatic patients (43% mild, 34% moderate, and 23% severe aortic stenosis), significant increases in peak aortic-jet velocity, left ventricular mass index, indexed extracellular volume, and LGE mass were observed after 2.1±0.7 years, with the most rapid progression observed in patients with most severe stenosis. Patients with baseline midwall LGE (n=16 [26%]; LGE mass, 2.5 g [0.8-4.8 g]) demonstrated particularly rapid increases in scar burden (78% [50%-158%] increase in LGE mass per year). In 38 symptomatic patients (age, 66±8 years; 76% men) who underwent AVR, there was a 19% (11%-25%) reduction in left ventricular mass index (P<0.0001) and an 11% (4%-16%) reduction in indexed extracellular volume (P=0.003) 0.9±0.3 years after surgery. By contrast midwall LGE (n=10 [26%]; mass, 3.3 g [2.6-8.0 g]) did not change post-AVR (n=10; 3.5 g [2.1-8.0 g]; P=0.23), with no evidence of regression even out to 2 years.ConclusionsIn patients with aortic stenosis, cellular hypertrophy and diffuse fibrosis progress in a rapid and balanced manner but are reversible after AVR. Once established, midwall LGE also accumulates rapidly but is irreversible post valve replacement. Given its adverse long-term prognosis, prompt AVR when midwall LGE is first identified may improve clinical outcomes.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifiers: NCT01755936 and NCT01679431.

Project description:Background: Diffuse myocardial fibrosis is a common pathological process in many cardiovascular diseases. In order to determine disease, we must have standard normal imaging values. We investigated myocardial interstitial fibrosis of the left ventricle (LV) in a healthy population of Chinese adults and explored the impact of gender, age, and other physiological factors using a T1 mapping technique of cardiac magnetic resonance imaging (CMR). Materials and Methods: We recruited 69 healthy adult Chinese subjects (35 males; age 18-76). LV function and global strain were obtained from functional imaging. T1 mapping was performed using a modified look-locker sequence. Global and segmental native T1 and extracellular volume (ECV) were calculated using dedicated software. Gender, age, and segmental variation of both native myocardial T1 and ECV of the LV were analyzed. Results: The global myocardial native T1 and ECV of the LV in this Chinese adult healthy population was 1,202 ± 45 ms and 27 ± 3% at 3T field strength, respectively. Females had a higher myocardial native T1 and ECV of the LV compared to males [1,210 (1,188-1,264) ms vs. 1,182 (1,150-1,211) ms, P < 0.001; 28 ± 3 vs. 26 ± 3%, P = 0.027, respectively]. ECV in older group was higher than younger group [27 (26-29)% vs. 25 (24-29), P = 0.019]. The multi-variate linear regression analysis showed that only gender (Beta = -0.512, P < 0.001) was independently related with global native T1 of LV while gender (Beta = -0.278, P = 0.017) and age (Beta = 0.303, P = 0.010) were independently related with global ECV of LV. From the base to apex of the LV, myocardial native T1 (P = 0.020) and ECV (P < 0.001) significantly increased. Within the same slice of the LV, there were significant segmental variations of both myocardial native T1 (P < 0.001) and ECV (P < 0.001) values. Conclusion: Gender and age have significant impacts on the imaging markers of myocardial interstitial fibrosis in healthy adult Chinese volunteers. Segmental variation of myocardial interstitial fibrosis was also observed.

Project description:BackgroundDuchenne muscular dystrophy (DMD) leads to progressive cardiomyopathy. Detection of myocardial fibrosis with late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) is critical for clinical management. Due to concerns of brain deposition of gadolinium, non-contrast methods for detecting and monitoring myocardial fibrosis would be beneficial.ObjectivesWe hypothesized that native T1 mapping and/or circumferential (εcc) and longitudinal (εls) strain can detect myocardial fibrosis.Methods156 CMRs with gadolinium were performed in 66 DMD boys and included: (1) left ventricular ejection fraction (LVEF), (2) LGE, (3) native T1 mapping and myocardial tagging (εcc-tag measured using harmonic phase analysis). LGE was graded as: (1) presence/absence by segment, slice, and globally; (2) global severity from 0 (no LGE) to 4 (severe); (3) percent LGE using full width half maximum (FWHM). εls and εcc measured using feature tracking. Regression models to predict LGE included native T1 and either εcc-tag or εls and εcc measured at each segment, slice, and globally.ResultsMean age and LVEF at first CMR were 14 years and 54%, respectively. Global εls and εcc strongly predicted presence or absence of LGE (OR 2.6 [1.1, 6.0], p = 0.029, and OR 2.3 [1.0, 5.1], p = 0.049, respectively) while global native T1 did not. Global εcc, εls, and native T1 predicted global severity score (OR 2.6 [1.4, 4.8], p = 0.002, OR 2.6 [1.4, 6.0], p = 0.002, and OR 1.8 [1.1, 3.1], p = 0.025, respectively). εls correlated with change in LGE by severity score (n = 33, 3.8 [1.0, 14.2], p = 0.048) and εcc-tag correlated with change in percent LGE by FWHM (n = 34, OR 0.2 [0.1, 0.9], p = 0.01).ConclusionsPre-contrast sequences predict presence and severity of LGE, with εls and εcc being more predictive in most models, but there was not an observable advantage over using LVEF as a predictor. Change in LGE was predicted by εls (global severity score) and εcc-tag (FWHM). While statistically significant, our results suggest these sequences are currently not a replacement for LGE and may only have utility in a very limited subset of DMD patients.

Dataset Information

Cardiac magnetic resonance assessment of interstitial myocardial fibrosis and cardiomyocyte hypertrophy in hypertensive mice treated with spironolactone.

Publications

Cardiac magnetic resonance assessment of interstitial myocardial fibrosis and cardiomyocyte hypertrophy in hypertensive mice treated with spironolactone.

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