A porcine model of heart failure with preserved ejection fraction:magnetic resonance imaging and metabolic energetics

Aims A significant proportion of heart failure (HF) patients have HF preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF remains a critical unmet need. A key obstacle to therapeutic innovation in HFpEF is the paucity of pre-clinical models. Although several large animal models have been reported, few demonstrate progression to decompensated HF. We have established a model of HFpEF by enhancing a porcine model of progressive left ventricular (LV) pressure overload and characterized HF in this model including advanced cardiometabolic imaging using cardiac magnetic resonance imaging and hyperpolarized carbon-13 magnetic resonance spectroscopy. Methods and results Pigs underwent progressive LV pressure overload by means of an inflatable aortic cuff. Pigs developed LV hypertrophy (50% increase in wall thickness, P <0.001, and two-fold increase in mass compared to sham control, P <0.001) with no evidence of LV dilatation but a significant increase in left atrial volume (P = 0.013). Cardiac magnetic resonance imaging demonstrated T1 modified Look-Locker inversion recovery values increased in 16/17 segments compared to sham pigs (P <0.05-P <0.001) indicating global ventricular fibrosis. Mean LV end-diastolic (P = 0.047) and pulmonary capillary wedge pressures (P = 0.008) were elevated compared with sham control. One-third of the pigs demonstrated clinical signs of frank decompensated HF, and mean plasma BNP concentrations were raised compared with sham control (P = 0.008). Cardiometabolic imaging with hyperpolarized carbon-13 magnetic resonance spectroscopy agreed with known metabolic changes in the failing heart with a switch from fatty acid towards glucose substrate utilization. Conclusions Progressive aortic constriction in growing pigs induces significant LV hypertrophy with cardiac fibrosis associated with left atrial dilation, raised filling pressures, and an ability to transition to overt HF with raised BNP without reduction in LVEF. This model replicates many aspects of clinical HFpEF with a predominant background of hypertension and can be used to advance understanding of underlying pathology and for necessary pre-clinical testing of novel candidate therapies

Evaluation of cardiac energetics by non-invasive P-31 magnetic resonance spectroscopy

Alterations in myocardial energy metabolism have been implicated in the pathophysiology of cardiac diseases such as heart failure and diabetic cardiomyopathy. 31P magnetic resonance spectroscopy (MRS) is a powerful tool to investigate cardiac energetics non-invasively in vivo, by detecting phosphorus ( 31P)-containing metabolites involved in energy supply and buffering. In this article, we review the historical development of cardiac 31P MRS, the readouts used to assess cardiac energetics from 31P MRS, and how 31P MRS studies have contributed to the understanding of cardiac energy metabolism in heart failure and diabetes. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers

Evaluation of cardiac energetics by non-invasive 31P magnetic resonance spectroscopy

Alterations in myocardial energy metabolism have been implicated in the pathophysiology of cardiac diseases such as heart failure and diabetic cardiomyopathy. 31P magnetic resonance spectroscopy (MRS) is a powerful tool to investigate cardiac energetics non-invasively in vivo, by detecting phosphorus ( 31P)-containing metabolites involved in energy supply and buffering. In this article, we review the historical development of cardiac 31P MRS, the readouts used to assess cardiac energetics from 31P MRS, and how 31P MRS studies have contributed to the understanding of cardiac energy metabolism in heart failure and diabetes. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers

Evaluation of cardiac energetics by non-invasive \u3csup\u3e31\u3c/sup\u3eP magnetic resonance spectroscopy

\u3cp\u3eAlterations in myocardial energy metabolism have been implicated in the pathophysiology of cardiac diseases such as heart failure and diabetic cardiomyopathy. \u3csup\u3e31\u3c/sup\u3eP magnetic resonance spectroscopy (MRS) is a powerful tool to investigate cardiac energetics non-invasively in vivo, by detecting phosphorus ( \u3csup\u3e31\u3c/sup\u3eP)-containing metabolites involved in energy supply and buffering. In this article, we review the historical development of cardiac \u3csup\u3e31\u3c/sup\u3eP MRS, the readouts used to assess cardiac energetics from \u3csup\u3e31\u3c/sup\u3eP MRS, and how \u3csup\u3e31\u3c/sup\u3eP MRS studies have contributed to the understanding of cardiac energy metabolism in heart failure and diabetes. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. \u3c/p\u3

Single dose of empagliflozin increases in vivo cardiac energy status in diabetic db/db mice

In the EMPA-REG OUTCOME trial, empagliflozin, a potent and specific inhibitor of the sodium glucose co-transporter 2, showed impressive benefits on cardiovascular outcome in patients with Type 2 diabetes.1 Empagliflozin reduced three-point primary composite outcome (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, which was mainly attributed to a 38% relative risk reduction in cardiovascular death.1 A 35% relative risk reduction in hospitalization for heart failure and a 32% relative risk reduction in all-cause mortality was also reported.1 However, the underlying mechanisms explaining these beneficial outcomes are yet to be elucidated. Deprivation of cardiac energy, characterized by a decreased cardiac phosphocreatine-to-ATP ratio (PCr/ATP), has been proposed to play a major role in the development of heart failure.2 Empagliflozin increases plasma ketone body levels and it has therefore been hypothesized that a shift in energy substrate metabolism towards ketones or an increased availability of ketones as add-on fuel could explain the positive cardiovascular outcomes in the EMPA-REG study.3 To test the ‘fuel hypothesis’, we investigated whether an increase in plasma ketones by empagliflozin was accompanied by an increase in cardiac PCr/ATP. We administered a single dose of empagliflozin in fasting db/db mice, to simulate a situation in which plasma ketone levels are immediately increased. This acute experimental design allows investigating the effect of alterations in fuel availability on changes in cardiac PCr/ATP ratio without interference from other factors, such as cardiac remodelling after long-term treatment. Using 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), we measured in vivo cardiac PCr/ATP and function, respectively

Single dose of empagliflozin increases in vivo cardiac energy status in diabetic db/db mice

In the EMPA-REG OUTCOME trial, empagliflozin, a potent and specific inhibitor of the sodium glucose co-transporter 2, showed impressive benefits on cardiovascular outcome in patients with Type 2 diabetes.1 Empagliflozin reduced three-point primary composite outcome (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, which was mainly attributed to a 38% relative risk reduction in cardiovascular death.1 A 35% relative risk reduction in hospitalization for heart failure and a 32% relative risk reduction in all-cause mortality was also reported.1 However, the underlying mechanisms explaining these beneficial outcomes are yet to be elucidated. Deprivation of cardiac energy, characterized by a decreased cardiac phosphocreatine-to-ATP ratio (PCr/ATP), has been proposed to play a major role in the development of heart failure.2 Empagliflozin increases plasma ketone body levels and it has therefore been hypothesized that a shift in energy substrate metabolism towards ketones or an increased availability of ketones as add-on fuel could explain the positive cardiovascular outcomes in the EMPA-REG study.3 To test the ‘fuel hypothesis’, we investigated whether an increase in plasma ketones by empagliflozin was accompanied by an increase in cardiac PCr/ATP. We administered a single dose of empagliflozin in fasting db/db mice, to simulate a situation in which plasma ketone levels are immediately increased. This acute experimental design allows investigating the effect of alterations in fuel availability on changes in cardiac PCr/ATP ratio without interference from other factors, such as cardiac remodelling after long-term treatment. Using 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), we measured in vivo cardiac PCr/ATP and function, respectively

Single dose of empagliflozin increases in vivo cardiac energy status in diabetic db/db mice

In the EMPA-REG OUTCOME trial, empagliflozin, a potent and specific inhibitor of the sodium glucose co-transporter 2, showed impressive benefits on cardiovascular outcome in patients with Type 2 diabetes.1 Empagliflozin reduced three-point primary composite outcome (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, which was mainly attributed to a 38% relative risk reduction in cardiovascular death.1 A 35% relative risk reduction in hospitalization for heart failure and a 32% relative risk reduction in all-cause mortality was also reported.1 However, the underlying mechanisms explaining these beneficial outcomes are yet to be elucidated. Deprivation of cardiac energy, characterized by a decreased cardiac phosphocreatine-to-ATP ratio (PCr/ATP), has been proposed to play a major role in the development of heart failure.2 Empagliflozin increases plasma ketone body levels and it has therefore been hypothesized that a shift in energy substrate metabolism towards ketones or an increased availability of ketones as add-on fuel could explain the positive cardiovascular outcomes in the EMPA-REG study.3\u3cbr/\u3e\u3cbr/\u3eTo test the ‘fuel hypothesis’, we investigated whether an increase in plasma ketones by empagliflozin was accompanied by an increase in cardiac PCr/ATP. We administered a single dose of empagliflozin in fasting db/db mice, to simulate a situation in which plasma ketone levels are immediately increased. This acute experimental design allows investigating the effect of alterations in fuel availability on changes in cardiac PCr/ATP ratio without interference from other factors, such as cardiac remodelling after long-term treatment. Using 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), we measured in vivo cardiac PCr/ATP and function, respectively

In vivo proton T-1 relaxation times of mouse myocardial metabolites at 9.4 T

PurposeProton magnetic resonance spectroscopy (H-1-MRS) for quantitative in vivo assessment of mouse myocardial metabolism requires accurate acquisition timing to minimize motion artifacts and corrections for T-1-dependent partial saturation effects. In this study, mouse myocardial water and metabolite T-1 relaxation time constants were quantified. MethodsCardiac-triggered and respiratory-gated PRESS-localized H-1-MRS was employed at 9.4 T to acquire signal from a 4-mu L voxel in the septum of healthy mice (n=10) while maintaining a steady state of magnetization using dummy scans during respiratory gates. Signal stability was assessed via standard deviations (SD) of zero-order phases and amplitudes of water spectra. Saturation-recovery experiments were performed to determine T-1 values. ResultsPhase SD did not vary for different repetition times (TR), and was 13.1 degrees 4.5 degrees. Maximal amplitude SD was 14.2%+/- 5.1% at TR=500 ms. Myocardial T-1 values (mean +/- SD) were quantified for water (1.71 +/- 0.25 s), taurine (2.18 +/- 0.62 s), trimethylamine from choline-containing compounds and carnitine (1.67 +/- 0.25 s), creatine-methyl (1.34 +/- 0.19 s), triglyceride-methylene (0.60 +/- 0.15 s), and triglyceride-methyl (0.90 +/- 0.17 s) protons. ConclusionThis work provides in vivo quantifications of proton T-1 values for mouse myocardial water and metabolites at 9.4 T. Magn Reson Med 73:2069-2074, 2015. (c) 2014 Wiley Periodicals, In