Quantitative PET Imaging Detects Early Metabolic Remodeling in a Mouse Model of Pressure-Overload Left Ventricular Hypertrophy In Vivo

Background Sustained pressure overload leads to changes in cardiac metabolism, function, and structure. Both time course and causal relationships between these changes are not fully understood. Therefore, we studied spontaneously hypertensive rats (SHR) during early hypertension development and compared them to control Wistar Kyoto rats. Methods and Results We serially evaluated myocardial glucose uptake rates (Ki) with dynamic 2‐[ 18 F] fluoro‐2‐deoxy‐D‐glucose positron emission tomography, and ejection fraction and left ventricular mass to body weight ratios with cardiac magnetic resonance imaging in vivo, determined glucose uptake and oxidation rates in isolated perfused hearts, and analyzed metabolites, mammalian target of rapamycin activity and endoplasmic reticulum stress in dissected hearts. When compared with Wistar Kyoto rats, SHR demonstrated increased glucose uptake rates (Ki) in vivo, and reduced ejection fraction as early as 2 months of age when hypertension was established. Isolated perfused SHR hearts showed increased glucose uptake and oxidation rates starting at 1 month. Cardiac metabolite analysis at 2 months of age revealed elevated pyruvate, fatty acyl‐ and branched chain amino acid‐derived carnitines, oxidative stress, and inflammation. Mammalian target of rapamycin activity increased in SHR beginning at 2 months. Left ventricular mass to body weight ratios and endoplasmic reticulum stress were elevated in 5 month‐old SHR. Conclusions Thus, in a genetic hypertension model, chronic cardiac pressure overload promptly leads to increased myocardial glucose uptake and oxidation, and to metabolite abnormalities. These coincide with, or precede, cardiac dysfunction while left ventricular hypertrophy develops only later. Myocardial metabolic changes may thus serve as early diagnostic markers for hypertension‐induced left ventricular hypertrophy.

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Abstract 260: Time Course Observation of Left Ventricular Hypertrophy and Regression Induced by an Improved Technique

Circulation Research ◽

10.1161/res.111.suppl_1.a260 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Xiu Zhang ◽

Ling Li ◽

Amanda Szucsik ◽

Hadi Javan ◽

Yubin Deng ◽

...

Keyword(s):

Left Ventricular Hypertrophy ◽

Mouse Model ◽

Ventricular Hypertrophy ◽

Time Course ◽

Heart Function ◽

Systolic Pressure ◽

Weight Ratio ◽

Pressure Overload ◽

Left Ventricular ◽

Cardiac Wall

In order to study the left ventricular hypertrophy (LVH) and its regression, we improved the surgical technique for producing LV pressure overload and its reversing mouse model using the titanium clip placement for transverse aortic banding (AB) and removal for debanding (DB). A time course study on heart function and histology proved the importance of the regression time. Materials and methods: The technique was applying titanium clip for AB and removing for DB with minimal invasion. A total of 95 male C57BL6 mice weighing 20-30 g were used in this study. Experimental groups included: control (n=11), AB 3 (11), 4 (12), and 6 (12) wks, DB at 3 (12), 4 (11), and 6 (12) wks of AB for 1 wk. Carotid arteries velocity were measured to evaluate the constrictive level. Heart/body weight ratio, cardiac wall thickness from echocardiography, LV pressure from catheterization and heart histology studies were used to evaluate the pressure overload and hypertrophy. Results: The echocardiographic and histology results indicated that AB induce significent LVH which was a concentric hypertrophy at AB 3 wks and then progressively become a dilated hypertrophy at AB 6 wks. The cardiac function also indicated a stable ejection fraction before 3 wks of AB and then gradually declined at AB 6 wks. After 6 wks AB, the enlargement in LV dimensions becomes significant. When deband at 3 and 4 wks for one week, there were significant regression of hypertrophy but the regression is limited after AB 6 wks and the evidences of lung congestion were apparent. In catheterizaiton, the LV systolic pressure were markedly elevated in AB mice but these pressure elevations became less at AB 6 wks and the LV end-diastolic pressure (LVEDP) at AB 6 wks was elevated significantly. After DB at AB 3 and 4 wks, the pressure parameters retriced close to normal but LVEPD elevation retreat is limited in the DB 6 wks group. Conclusion: With applying and removing titanium clip to induce pressure overload and reversing can provide a relatively simple, effecive, consistent and minimal invasive methods to establish the mouse model for studying LVH and its regression. Our data indicate that AB induced mouse LVH could be retriced close to normal when remove the constriction at the concentric LVH phase but the regression is limited in dilated LVH.

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Remodeling of Glucose Metabolism Precedes Pressure Overload-Induced Left Ventricular Hypertrophy: Review of a Hypothesis

Cardiology ◽

10.1159/000369782 ◽

2015 ◽

Vol 130 (4) ◽

pp. 211-220 ◽

Cited By ~ 49

Author(s):

Bijoy K. Kundu ◽

Min Zhong ◽

Shiraj Sen ◽

Giovanni Davogustto ◽

Susanna R. Keller ◽

...

Keyword(s):

Glucose Metabolism ◽

Left Ventricular Hypertrophy ◽

Glucose Uptake ◽

Ventricular Hypertrophy ◽

Pressure Overload ◽

Left Ventricular ◽

Metabolic Imaging ◽

Mtor Inhibition ◽

Sequence Of Events ◽

Metabolic Remodeling

When subjected to pressure overload, the ventricular myocardium shifts from fatty acids to glucose as its main source for energy provision and frequently increases its mass. Here, we review the evidence in support of the concept that metabolic remodeling, measured as an increased myocardial glucose uptake using dynamic positron emission tomography (PET) with the glucose analogue 2-deoxy-2-[18F]fluoro-D-glucose (FDG), precedes the onset of left ventricular hypertrophy (LVH) and heart failure. Consistent with this, early intervention with propranolol, which attenuates glucose uptake, prevents the maladaptive metabolic response and preserves cardiac function in vivo. We also review ex vivo studies suggesting a link between dysregulated myocardial glucose metabolism, intracellular accumulation of glucose 6-phosphate (G6P) and contractile dysfunction of the heart. G6P levels correlate with activation of mTOR (mechanistic target of rapamycin) and endoplasmic reticulum stress. This sequence of events could be prevented by pretreatment with rapamycin (mTOR inhibition) or metformin (enzyme 5′-AMP-activated protein kinase activation). In conclusion, we propose that metabolic imaging with FDG PET may provide a novel approach to guide the treatment of patients with hypertension-induced LVH.

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The Dysregulation of Pro-angiogeneic Factors in Pressure-overload Left Ventricular Hypertrophy Results in Inadequate Myocardial Capillarization

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0035-1544334 ◽

2015 ◽

Vol 63 (S 01) ◽

Author(s):

K. Neef ◽

M. Zeriouh ◽

E. Kuhn ◽

A.-C. Deppe ◽

I. Slottosch ◽

...

Keyword(s):

Left Ventricular Hypertrophy ◽

Ventricular Hypertrophy ◽

Pressure Overload ◽

Left Ventricular

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Cardiomyocyte loss is not required for the progression of left ventricular hypertrophy induced by pressure overload in female mice

Journal of Anatomy ◽

10.1111/joa.12463 ◽

2016 ◽

Vol 229 (1) ◽

pp. 75-81 ◽

Cited By ~ 4

Author(s):

Julia Schipke ◽

Clara Grimm ◽

Georg Arnstein ◽

Jens Kockskämper ◽

Simon Sedej ◽

...

Keyword(s):

Left Ventricular Hypertrophy ◽

Ventricular Hypertrophy ◽

Pressure Overload ◽

Left Ventricular ◽

Female Mice

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Abstract 313: STIM1 Silencing Reverses Pressure-overload Induced Cardiac Hypertrophy In Mice

Circulation Research ◽

10.1161/res.113.suppl_1.a313 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Ludovic O Bénard ◽

Daniel S Matasic ◽

Mathilde Keck ◽

Anne-Marie Lompré ◽

Roger J Hajjar ◽

...

Keyword(s):

Ventricular Hypertrophy ◽

Contractile Function ◽

Pressure Overload ◽

Left Ventricular ◽

Aortic Banding ◽

Cross Section Area ◽

Abdominal Aortic ◽

Section Area

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We demonstrated that STIM1 silencing prevented the development of left ventricular hypertrophy (LVH) in rats after abdominal aortic banding. Our aim was to study the role of STIM1 during the transition from LVH to heart failure (HF). For experimental timeline, see figure. Transverse Aortic Constriction (TAC) was performed in C57Bl/6 mice. In vivo gene silencing was performed using recombinant Associated AdenoVirus 9 (AAV9). Mice were injected with saline or with AAV9 expressing shRNA control or against STIM1 (shSTIM1) (dose: 1e+11 viral genome), which decreased STIM1 cardiac expression by 70% compared to control. While cardiac parameters were similar between the TAC groups at weeks 3 and 6, shSTIM1 animals displayed a progressive and total reversion of LVH with LV walls thickness returning to values observed in sham mice at week 8. This reversion was associated with the development of significant LV dilation and severe contractile dysfunction, as assessed by echography. Hemodynamic analysis confirmed the altered contractile function and dilation of shSTIM1 animals. Immunohistochemistry showed a trend to more fibrosis. Despite hypertrophic stimuli, there was a significant reduction in cardiac myocytes cross-section area in shSTIM1-treated animals as compared to other TAC mice. This study showed that STIM1 is essential to maintain compensatory LVH and that its silencing accelerates the transition to HF.

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