Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy

Abstract

A, Stanley WC, Recchia FA. Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 293: H3270-H3278, 2007. First published October 5, 2007; doi:10.1152/ajpheart.00887.2007.-Under resting conditions, the failing heart shifts fuel use toward greater glucose and lower free fatty acid (FFA) oxidation. We hypothesized that chronic metabolic abnormalities in patients with dilated cardiomyopathy (DCM) are associated with the absence of the normal increase in myocardial glucose uptake and maintenance of cardiac mechanical efficiency in response to pacing stress. In 10 DCM patients and 6 control subjects, we measured coronary flow by intravascular ultrasonometry and sampled arterial and coronary sinus blood. Myocardial metabolism was determined at baseline, during atrial pacing at 130 beats/min, and at 15 min of recovery by infusion of [ 3 H]oleate and [ 13 C]lactate and measurement of transmyocardial arteriovenous differences of oxygen and metabolites. At baseline, DCM patients showed depressed coronary flow, reduced uptake and oxidation of FFA, and preferential utilization of carbohydrates. During pacing, glucose uptake increased by 106% in control subjects but did not change from baseline in DCM patients. Lactate release increased by 122% in DCM patients but not in control subjects. Cardiac mechanical efficiency in DCM patients was not different compared with control subjects at baseline but was 34% lower during stress. Fatty acid uptake and oxidation did not change with pacing in either group. Our results show that in DCM there is preferential utilization of carbohydrates, which is associated with reduced flow and oxygen consumption at rest and an impaired ability to increase glucose uptake during stress. These metabolic abnormalities might contribute to progressive cardiac deterioration and represent a target for therapeutic strategies aimed at modulating cardiac substrate utilization. microcirculation FATTY ACIDS provide 60 -90% of the energy necessary to sustain contractile function in the resting fasting state, with the remainder coming from glucose and lactate oxidation. During acute cardiac stress, such as pacing or exercise, the healthy human heart rapidly increases glucose and lactate uptake, with a relative decline in free fatty acid (FFA) uptake (1,3,4,9). Clinical and animal studies have suggested that this response is advantageous: it increases myocardial metabolic efficiency, since carbohydrates are a more efficient substrate than lipids, generating more contractile power for any given rate of myocardial oxygen consumption (MV O 2 ) (20,29,31).Dilated cardiomyopathy (DCM) is often characterized by reduced FFA uptake and oxidation and accelerated glycolysis and glucose oxidation under resting conditions (7,21,31). This metabolic shift may act to optimize the limited oxidative capacity of cardiomyopathic hearts resulting from impairment of mitochondrial function (28) and/or ATP transfer from ...

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“…There is direct evidence for a global chronic cardiac metabolic shift in DCM patients characterized by decreased free fatty acids (FFA) uptake and oxidation and increased carbohydrate utilization at rest as documented by measuring transmyocardial arteriovenous differences of oxygen and major metabolites. 11 Non-invasive PET studies in non-ischemic cardiomyopathy found similar results. 16,17 It is hypothesized that the shift in myocardial substrate utilization, partially resembling the neonatal metabolic phenotype, 18 is a compensatory response of the severely impaired and energy-depleted myocardium which optimizes energy metabolism, by using glucose as a more efficient fuel.…”

“…Myocardial metabolic changes at rest could be detrimental under stress conditions. At variance with normal hearts which shift their metabolism from preferential use of FFA to glucose under stress, cardiomyopathic hearts cannot further increase glucose uptake 11 and rely upon FFA utilization which is associated with a lower myocardial mechanical efficiency. This mechanism can involve not only the whole myocardium but also specific regions.…”

“…Among other mechanisms, variation in myocardial perfusion and metabolism may play a relevant role in causing progressive ventricular impairment and adverse prognosis. Coronary microvascular dysfunction 10 and myocardial metabolic shift toward preferential glucose utilization 11 are some of the recognized underlying pathophysiologic mechanisms. It is expected that the final outcome as well as the possible response to treatment will depend on the interaction of interventions with this complex individual functional myocardial substrate.…”

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“…Down‐regulation of enzymes for β‐oxidation occurs due to a decrease in activity of the PPARα pathway, which is a transcriptional regulator of FA use (Doenst et al ., 2013). Decreased FA uptake and oxidation (with preferential utilization of carbohydrates) have been observed in patients with dilated cardiomyopathy and symptoms of HF compared with healthy controls (Neglia et al ., 2007). In a further molecular study analysing human left ventricular biopsy tissue, total expression and mRNA levels of medium‐chain and long‐chain acyl CoA dehydrogenase (involved in FA β‐oxidation) were down‐regulated by >40% ( P  < 0.05) in patients with HF compared with age‐matched controls (Sack et al ., 1996).…”

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“…In the adult heart, ATP comes mainly from the -oxidation of fatty acids, an oxygen dependent process. The 10 -40% remaining come from glucose degradation through glycolysis, an oxygen independent process (Neglia et al, 2007;Stanley et al, 2005).…”