Myocardial High-Energy Phosphate and Substrate Metabolism in Swine With Moderate Left Ventricular Hypertrophy

Abstract

Background Although left ventricular hypertrophy (LVH) is frequently associated with impaired coronary vasodilator reserve, it is uncertain whether this leads to myocardial ischemia under physiological conditions. The goal of the present study was to determine whether swine with moderate LVH exhibit metabolic evidence of ischemia when myocardial oxygen requirements are increased. Methods and Results Myocardial metabolism was evaluated in an open-chest anesthetized preparation at baseline and during dobutamine infusion in 13 adolescent pigs with moderate LVH induced by supravalvular aortic banding and 12 age-matched control pigs. Transmural myocardial blood flow was quantified with radioactive microspheres; the ratio of phosphocreatine to ATP (PCr/ATP) in the anterior LV free wall was measured by 31 P–nuclear magnetic resonance; and anterior wall lactate release was quantified from the arterial-coronary venous difference in 14 C- or 13 C-labeled lactate. In a subset of 5 animals from each group, the metabolic fate of exogenous glucose was determined from the transmyocardial difference in 6- 14 C-glucose and its metabolites 14 C-lactate and 14 CO 2 . Coronary reserve, as assessed by the ratio of blood flow during adenosine infusion to baseline blood flow, was significantly lower in the LVH pigs compared with controls (3.5±0.4 versus 5.5±0.4 mL/g · min, P <.05); however, transmural myocardial blood flow was similar in both groups of pigs, both at baseline and with dobutamine stimulation, probably reflecting the higher coronary perfusion pressure in the LVH pigs. At baseline, PCr/ATP tended to be lower in the LVH pigs ( P =.09) but decreased similarly with dobutamine infusion in both groups. Isotopically measured anterior wall lactate release did not differ between the groups at baseline, nor did the increase in lactate release differ during dobutamine stimulation. The uptake of glucose, lactate, and free fatty acids did not differ between the groups in the basal state. However, during dobutamine stimulation, glucose uptake was greater in the LVH group (0.84±0.09 μmol/g · min versus 0.59±0.08 μmol/g · min, P <.05). In a subset of animals, 14 C-glucose was used to assess glucose oxidation. These data showed that the LVH animals had a greater rate of glucose oxidation (0.60±0.10 versus 0.28±0.08 μmol/g · min, P <.05) and a greater rate of glucose conversion to lactate (0.20±0.04 versus 0.09±0.02 μmol/g · min, P <.05) compared with the control pigs. Conclusions These results suggest that despite their reduced coronary vasodilator reserve and the absence of a greater rise in myocardial blood flow to compensate for a substantially higher LV double product, pigs with this model of moderate LVH do not exhibit a greater susceptibility to myocardial ischemia during dobutamine stress. However, LVH pigs exhibit significantly greater use of exogenous glucose during dobutamine stress, as evidenced by increases in both glucose oxidation and anaerobic glycolysis.

Oxidative capacity in failing hearts

“…Consistent with these observations, we (18,24) recently reported that ATP synthase and adenine nucleotide translocator (ANT) protein expression is decreased in animals with CHF secondary to postinfarction remodeling or pacinginduced heart failure. In swine with moderate pressure overload produced by ascending aortic constriction, Massie et al (19) found that basal PCr/ATP tended to be decreased in animals with LVH and that PCr/ATP decreased significantly and similarly in normal and LVH hearts during the increased cardiac work state produced by dobutamine infusion. They observed that animals with LVH had greater glucose uptake during dobutamine stimulation; however, a greater fraction of the glucose was oxidized in the LVH animals, indicated that the preference for glucose in the LVH hearts was not the result of ischemia.…”

“…Approximately 40% of the animals developed CHF as manifested by an increased LV end-diastolic pressure, exercise intolerance, and ascites; the increase in LV/body weight was twice as great in animals that developed CHF as in those with compensated LVH. With the use of a similar but milder degree of aortic constriction in swine, Massie et al (19) found that a stenosis that produced a 25-mmHg pressure gradient across the aortic narrowing resulted in a 38% increase of LV mass in 6 mo with no evidence of heart failure in any of the animals. The more severe aortic narrowing makes the present model useful for study of the response of physiological and metabolic variables to severe pressure overload and the evolution to overt CHF.…”

An isolated perfused pig heart model for the development, validation and translation of novel cardiovascular magnetic resonance techniques

“…Cardiac energetics have been studied in stunned, hibernating and hypertrophied myocardium [15-18]. Graded ischaemia [19], ischaemic preconditioning [20] and the coronary microcirculation [21] have all been studied in different porcine models.…”

Mitral Regurgitation

“…The measurements presented were adjusted for BSA, and confounding conditions were excluded during patient recruitment, thereby supporting the proposal that increased LVM is associated with an altered PCr/ATP, as has been shown with animal models. [33][34][35] Correlation of derived echocardiographic measurements such as FS% and LVM/BSA with PCr/ATP reflects the relationship with the measured echocardiographic parameters from which these are calculated. Our data show no correlation between the biochemical ratio and the calculated wall stress.…”

“…Recently, Massie et al 35 showed that the proportion of glucose that the heart oxidizes is higher in pigs with LV hypertrophy. They argued that a different substrate preference could offer a partial explanation for the lower PCr/ATP in LV hypertrophy because a low ratio has been observed when glucose is the sole substrate in perfused hearts.…”