Left ventricular oxygen utilization efficiency is impaired in chronic streptozotocin-diabetic sheep

Ramanathan, Tharumenthiran; Shirota, Kazuaki; Morita, Shin; Nishimura, Takashi; Huang, Yifei; Zheng, Xiaojiao; Hunyor, Stephen N.

doi:10.1016/s0008-6363(02)00497-2

Cited by 15 publications

(11 citation statements)

References 36 publications

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“…The decreased cardiac efficiency in hearts from STZadministered db/ϩ mice, manifested by an increase in unloaded MVO 2 , contrasts with data obtained with diabetic hearts from STZ-administered sheep (24), in which decreased cardiac efficiency was the result of impaired contractile efficiency with no change in unloaded MVO 2 . In fact, the slope of the PVA-MVO 2 relationship for STZadministered mouse hearts was the lowest (Table 3).…”

Section: Discussioncontrasting

confidence: 86%

Increased Myocardial Oxygen Consumption Reduces Cardiac Efficiency in Diabetic Mice

et al. 2006

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1Altered cardiac metabolism and function (diabetic cardiomyopathy) has been observed in diabetes. We hypothesize that cardiac efficiency, the ratio of cardiac work (pressurevolume area [PVA]) and myocardial oxygen consumption (MVO 2 ), is reduced in diabetic hearts. Experiments used ex vivo working hearts from control db/؉, db/db (type 2 diabetes), and db/؉ mice given streptozotocin (STZ; type 1 diabetes). PVA and ventricular function were assessed with a 1.4-F pressure-volume catheter at low (0.3 mmol/l) and high (1.4 mmol/l) fatty acid concentrations with simultaneous measurements of MVO 2 . Substrate oxidation and mitochondrial respiration were measured in separate experiments. Diabetic hearts showed decreased cardiac efficiency, revealed as an 86 and 57% increase in unloaded MVO 2 in db/db and STZ-administered hearts, respectively. The slope of the PVA-MVO 2 regression line was increased for db/db hearts after elevation of fatty acids, suggesting that contractile inefficiency could also contribute to the overall reduction in cardiac efficiency. The end-diastolic and end-systolic pressure-volume relationships in db/db hearts were shifted to the left with elevated end-diastolic pressure, suggesting left ventricular remodeling and/or myocardial stiffness. Thus, by means of pressure-volume technology, we have for the first time documented decreased cardiac efficiency in diabetic hearts caused by oxygen waste for noncontractile purposes. Diabetes 55: 466 -473, 2006 C ardiac efficiency is the ratio between energy output (work) and energy input (myocardial oxygen consumption [MVO 2 ]) for the heart. Currently, the most accepted definition of total cardiac work is pressure-volume area (PVA), the sum of external mechanical work and the potential energy triangle (1). Importantly, MVO 2 is linearly related to PVA. Extrapolation of this linear relationship to 0 work gives unloaded (PVA independent) MVO 2 , the oxygen cost of excitation-contraction coupling and basal metabolism.Furthermore, the inverse slope of the MVO 2 -PVA relationship defines the contractile efficiency.Recently, How et al. (2) demonstrated that pressurevolume loops and resulting determinations of PVA can be obtained with ex vivo perfused working mouse hearts, using a combined micromanometer (pressure)-conductance (volume) catheter. A fiber-optic oxygen probe gave simultaneous measurements of MVO 2 . An elevation in perfusate fatty acid concentration resulted in augmented fatty acid oxidation and reduced cardiac efficiency (increased MVO 2 with no change in work), manifested as increased unloaded MVO 2 (2).Perfused hearts from db/db mice, a monogenic model of type 2 diabetes with obesity and insulin resistance, have been characterized as having an early increase in fatty acid oxidation that precedes the onset of contractile dysfunction (3). Because elevated rates of fatty acid oxidation produce a decrease in cardiac efficiency in control hearts (2), the objective of the current investigation was to test the hypothesis that cardiac efficiency will be r...

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Section: Discussioncontrasting

confidence: 86%

Increased Myocardial Oxygen Consumption Reduces Cardiac Efficiency in Diabetic Mice

et al. 2006

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“…We observed reduced myocardial work efficiency in T2DM compared with lean controls. This observation is in line with data from animal models (50,61) and from obese humans (49,56,58) and augments the sparse human data evaluating this feature of myocardial function in human diabetes.…”

Section: E455 Myocardial Metabolic Flexibility In Type 2 Diabetessupporting

confidence: 84%

Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[¹⁸F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer

Mather

Hutchins

Perry

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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-Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[ 18 F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([ 11 C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin ϩ glucose euglycemic clamp conditions (120 mU·m Ϫ2 ·min Ϫ1 ) to 3-h saline infusion. Lean controls (n ϭ 10) were compared with glycemically controlled volunteers with T2DM (n ϭ 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P Ͻ 0.01) and significantly increased myocardial oxygen consumption (P ϭ 0.04) and perfusion (P ϭ 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P Ͻ 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P Ͻ 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P Ͻ 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P ϭ 0.003). Myocardial work efficiency was lower in T2DM (P ϭ 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P ϭ 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM. myocardial; heart; diabetes; metabolism; metabolic flexibility; positron emission tomography ALTERATIONS IN METABOLIC SUBSTRATE uptake and metabolism are part of the phenotype that defines type 2 diabetes mellitus (T2DM) (3,4,33,39,74). The phenomenon of "metabolic flexibility" is the capacity of an organism, a tissue bed, or a cell system to switch readily among fuel types. Impaired metabolic flexibility is another phenotypic feature of T2DM (33, 66).Impaired metabolic flexibility has been demonstrated in skeletal muscle in human diabetes (32,66). This whole body effect likely arises due to effects of impaired insulin-stimulated glucose uptake, together with abnormalities in availability, uptake, and metabolism of fatty acid fuels (33,66,75).The myocardium is also affected by T2DM. The fuel needs of the heart are dramatically different than those of skeletal muscle, supporting continuous work even under resting conditions. Abnormalities in myocardial fuel selection in animal models of diabetes have been described (42,54,75), including impairments in insulin-stimulated glucose uptake and impaired suppression of myocardial fatty acid u...

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“…However, there are also studies showing no effect of STZ on LV systolic pressure [1,2,19,20]. Nevertheless, it is striking that the clear difference in maximum LV pressure development between STZ and SHAM hearts in vitro (Figure 3) stands in contrast to the absence of any differences among systolic, mean or diastolic pressures measured in vivo (Table 1).…”

Section: Discussionmentioning

confidence: 94%

“…In many studies of the energetics of the diabetic heart, the deterioration of cardiac performance has been linked to a reduction of cardiac efficiency [1-5]. But, some studies have reported an unchanged value in diabetic animals [6-9].…”

Section: Introductionmentioning

confidence: 99%

“…For the first case (Figure 1A), compared with the control heart, the diabetic heart has a lower value of peak efficiency, but the same optimal afterload and the same peak afterload. Adoption of the same peak afterload is based on experimental results showing no difference in the left-ventricular systolic pressure [1,2,19,20]. But, there exists evidence that the left-ventricular systolic pressure is lower in the diabetic heart [4,9,21-25], which leads us to consider two other cases, in which the diabetic heart has a lower peak afterload and a lower optimal afterload, but its peak efficiency can be either lower than (the second case; Figure 1B), or the same as (the third case; Figure 1C), that of the control heart.…”

Section: Introductionmentioning

confidence: 99%

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The afterload-dependent peak efficiency of the isolated working rat heart is unaffected by streptozotocin-induced diabetes

Han

Goo

Barrett

et al. 2014

Cardiovasc Diabetol

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BackgroundDiabetes is known to alter the energy metabolism of the heart. Thus, it may be expected to affect the efficiency of contraction (i.e., the ratio of mechanical work output to metabolic energy input). The literature on the subject is conflicting. The majority of studies have reported a reduction of myocardial efficiency of the diabetic heart, yet a number of studies have returned a null effect. We propose that these discrepant findings can be reconciled by examining the dependence of myocardial efficiency on afterload.MethodsWe performed experiments on streptozotocin (STZ)-induced diabetic rats (7-8 weeks post-induction), subjecting their (isolated) hearts to a wide range of afterloads (40 mmHg to maximal, where aortic flow approached zero). We measured work output and oxygen consumption, and their suitably scaled ratio (i.e., myocardial efficiency).ResultsWe found that myocardial efficiency is a complex function of afterload: its value peaks in the mid-range and decreases on either side. Diabetes reduced the maximal afterload to which the hearts could pump (105 mmHg versus 150 mmHg). Thus, at high afterloads (for example, 90 mmHg), the efficiency of the STZ heart was lower than that of the healthy heart (10.4% versus 14.5%) due to its decreased work output. Diabetes also reduced the afterload at which peak efficiency occurred (optimal afterload: 63 mmHg versus 83 mmHg). Despite these negative effects, the peak value of myocardial efficiency (14.7%) was unaffected by diabetes.ConclusionsDiabetes reduces the ability of the heart to pump at high afterloads and, consequently, reduces the afterload at which peak efficiency occurs. However, the peak efficiency of the isolated working rat heart remains unaffected by STZ-induced diabetes.

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Left ventricular oxygen utilization efficiency is impaired in chronic streptozotocin-diabetic sheep

Cited by 15 publications

References 36 publications

Increased Myocardial Oxygen Consumption Reduces Cardiac Efficiency in Diabetic Mice

Increased Myocardial Oxygen Consumption Reduces Cardiac Efficiency in Diabetic Mice

Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[¹⁸F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer

The afterload-dependent peak efficiency of the isolated working rat heart is unaffected by streptozotocin-induced diabetes

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Left ventricular oxygen utilization efficiency is impaired in chronic streptozotocin-diabetic sheep

Cited by 15 publications

References 36 publications

Increased Myocardial Oxygen Consumption Reduces Cardiac Efficiency in Diabetic Mice

Increased Myocardial Oxygen Consumption Reduces Cardiac Efficiency in Diabetic Mice

Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer

The afterload-dependent peak efficiency of the isolated working rat heart is unaffected by streptozotocin-induced diabetes

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Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[¹⁸F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer