Metabolic remodelling of the failing heart: beneficial or detrimental?

Bilsen, Marc van; Nieuwenhoven, Frans A. van; Vusse, Ger J.

doi:10.1093/cvr/cvn282

Cited by 168 publications

(135 citation statements)

References 95 publications

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“…7 Cardiac energy metabolism mainly depends on fatty acids and glucose, and ketone bodies are normally a minor substrate for the intact myocardium. 8 In HF, however, energy metabolism is altered; the failing myocardium exhibits impaired fatty acid and glucose metabolism, resulting in increased transportation of ketone bodies from the liver. 9, 10 Additionally, ketone utilization by skeletal muscle is impaired in patients with HF as a clinical feature of a debilitating systemic condition.…”

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confidence: 99%

Exhaled Acetone Concentration Is Related to Hemodynamic Severity in Patients With Non-Ischemic Chronic Heart Failure

Yokokawa

Sugano

Shimouchi

et al. 2016

Circ J

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Background:We hypothesized that exhaled acetone concentration (EAC), reflecting altered blood ketone body metabolism and increased acetone exhaust because of pulmonary congestion in heart failure (HF), would correlate with hemodynamic parameters in patients with non-ischemic chronic HF. Methods and Results:We prospectively enrolled 102 non-ischemic HF patients with New York Heart Association (NYHA) class I-III. Exhaled breath was collected after an overnight fast. Echocardiography and cardiac catheterization were performed in all patients. We also enrolled 17 control patients without HF. EAC in the HF patients was significantly higher than that in the control patients (median EAC; 0.53 vs. 0.38 ppm, P=0.012). EAC positively correlated with blood total ketone bodies (r=0.454, P<0.001), NYHA class (r=0.489, P<0.001), and plasma B-type natriuretic peptide (r=0.316, P=0.001). Right heart catheterization revealed that EAC significantly correlated with pulmonary capillary wedge pressure (PCWP, r=0.377, P<0.001). Receiver-operating characteristic analysis revealed that EAC >1.05 ppm was associated with PCWP ≥18 mmHg (area under the curve [AUC] 0.726, sensitivity 50%, specificity 89%). EAC was shown to be a comparable diagnostic biomarker for HF to BNP (AUC 0.760, sensitivity 80%, specificity 70%).Conclusions: EAC may be a novel noninvasive biomarker that correlates hemodynamic severity in non-ischemic chronic HF. (Circ J 2016; 80: 1178 -1186

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confidence: 99%

Exhaled Acetone Concentration Is Related to Hemodynamic Severity in Patients With Non-Ischemic Chronic Heart Failure

Yokokawa

Sugano

Shimouchi

et al. 2016

Circ J

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“…Studies primarily concerned the FA oxidation pathway and presented the downregulation of genes involved in FA transport and oxidation in pathological hypertrophy, whereas upregulation of several of these genes was observed in adaptive hypertrophy (63). The decreased expression of genes involved in FA oxidation that is observed in pathological hypertrophy is believed to be due to a decline in the activity of peroxisome proliferatoractivated receptor-␣ (PPAR␣), the transcription factor that plays a crucial role in the transcriptional regulation of genes involved in FA metabolism (21,30,52,69). Moreover, expression of PPAR␣ and its downstream targets, i.e., medium-chain acyl-CoA dehydrogenase and carnitine palmitoyltransferase I (CPT I), was upregulated after endurance training (52).…”

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confidence: 99%

“…Conversely, the hypertrophy observed in different pathological settings is accompanied by cardiac dysfunction or increased morbidity (61). The failing heart is characterized by alterations in energy metabolism, including mitochondrial dysfunction and a reduction in the fatty acid (FA) oxidation rate, which is compensated partially by an increase in glucose utilization (52,69).…”

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Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy

Dobrzyń

Pyrkowska

Duda

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Dobrzyn P, Pyrkowska A, Duda MK, Bednarski T, Maczewski M, Langfort J, Dobrzyn A. Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy. Am J Physiol Endocrinol Metab 304: E1348 -E1358, 2013. First published April 30, 2013 doi:10.1152/ajpendo.00603.2012.-Cardiac hypertrophy is accompanied by molecular remodeling that affects different cellular pathways, including fatty acid (FA) utilization. In the present study, we show that cardiac lipid metabolism is differentially regulated in response to physiological (endurance training) and pathological [abdominal aortic banding (AAB)] hypertrophic stimuli. Physiological hypertrophy was accompanied by an increased expression of lipogenic genes and the activation of sterol regulatory element-binding protein-1c and Akt signaling. Additionally, FA oxidation pathways regulated by AMPactivated protein kinase (AMPK) and peroxisome proliferator activated receptor-␣ (PPAR␣) were induced in trained hearts. Cardiac lipid content was not changed by physiological stimulation, underlining balanced lipid utilization in the trained heart. Moreover, pathological hypertrophy induced the AMPK-regulated oxidative pathway, whereas PPAR␣ and expression of its downstream targets, i.e., acylCoA oxidase and carnitine palmitoyltransferase I, were not affected by AAB. In contrast, pathological hypertrophy leads to cardiac triglyceride (TG) and diacylglycerol (DAG) accumulation, although the expression of lipogenic genes and the levels of FA transport proteins (CD36 and FATP) were not changed or reduced compared with the sham group. A possible explanation for this phenomenon is a decrease in lipolysis, as evidenced by the increased content of adipose triglyceride lipase inhibitor G0S2, the increased phosphorylation of hormone-sensitive lipase at Ser 565 , and the decreased protein levels of DAG lipase that attenuate TG and DAG contents. The increased TG and DAG accumulation observed in AAB-induced hypertrophy might have lipotoxic effects, thereby predisposing to cardiomyopathy and heart failure in the future. lipogenesis; endurance training; sterol regulatory element-binding protein-1; adipose triglyceride lipase; hormone-sensitive lipase CARDIAC HYPERTROPHY IS ASSOCIATED with extensive remodeling, which in due course will affect cardiac function and ultimately contribute to the transition from compensatory hypertrophy to cardiac failure (70). Molecular remodeling in the heart caused by hypertrophy differs between physiological and pathological stimuli. The physiological cardiac hypertrophy caused by endurance training shows enhancement of cardiac function at rest and during exercise and is not a risk factor for heart failure (19, 29). The adaptations include increases in cardiac mass and dimension, maximum oxygen consumption, and coronary blood flow (35). Additionally, exercise results in a balanced growth of cardiomyocytes with a normal myofibril to mitochondrial ratio (52, 71). Conversely, the hype...

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“…Reduced expression of fatty acid oxidation enzymes has also been observed in failing human hearts (37,41). However, the role of reduction of fatty acid oxidation in the progression of left ventricular (LV) remodeling and heart failure remains controversial (43). Some authors consider reduction of fatty acid oxidation an adaptive response, which may protect the myocardium by potentially favorable effects of stimulation of glucose oxidation in stressed cardiac myocytes (45).…”

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confidence: 99%

Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice

Pellieux

Montessuit

Papageorgiou

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Normal myocardium adapts to increase of nutritional fatty acid supply by upregulation of regulatory proteins of the fatty acid oxidation pathway. Because advanced heart failure is associated with reduction of regulatory proteins of fatty acid oxidation, we hypothesized that failing myocardium may not be able to adapt to increased fatty acid intake and therefore undergo lipid accumulation, potentially aggravating myocardial dysfunction. We determined the effect of high-fat diet in transgenic mice with overexpression of angiotensinogen in the myocardium (TG1306/R1). TG1306/R1 mice develop ANG II-mediated left ventricular hypertrophy, and at one year of age approximately half of the mice present heart failure associated with reduced expression of regulatory proteins of fatty acid oxidation and reduced palmitate oxidation during ex vivo working heart perfusion. Hypertrophied hearts from TG1306/R1 mice without heart failure adapted to high-fat feeding, similarly to hearts from wild-type mice, with upregulation of regulatory proteins of fatty acid oxidation and enhancement of palmitate oxidation. There was no myocardial lipid accumulation or contractile dysfunction. In contrast, hearts from TG1306/R1 mice presenting heart failure were unable to respond to high-fat feeding by upregulation of fatty acid oxidation proteins and enhancement of palmitate oxidation. This resulted in accumulation of triglycerides and ceramide in the myocardium, and aggravation of contractile dysfunction. In conclusion, hearts with ANG II-induced contractile failure have lost the ability to enhance fatty acid oxidation in response to increased fatty acid supply. The ensuing accumulation of lipid compounds may play a role in the observed aggravation of contractile dysfunction

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Metabolic remodelling of the failing heart: beneficial or detrimental?

Cited by 168 publications

References 95 publications

Exhaled Acetone Concentration Is Related to Hemodynamic Severity in Patients With Non-Ischemic Chronic Heart Failure

Exhaled Acetone Concentration Is Related to Hemodynamic Severity in Patients With Non-Ischemic Chronic Heart Failure

Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy

Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice

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