Diet-induced obese mouse hearts tolerate an acute high-fatty acid exposure that also increases ischemic tolerance.

An ischemic insult is accompanied by an acute increase in circulating fatty acid (FA) levels, which can induce adverse changes related to cardiac metabolism/energetics. Although chronic hyperlipidemia contributes to the pathogenesis of obesity-/diabetes-related cardiomyopathy, it is unclear how these hearts are affected by an acute high FA-load. We hypothesize that adaptation to chronic FA exposure enhances the obese hearts' ability to handle an acute high FA-load. Diet-induced obese (DIO) and age-matched control (CON) mouse hearts were perfused in the presence of low- or high FA-load (0.4 and 1.8 mM, respectively). Left ventricular (LV) function, FA oxidation rate, myocardial oxygen consumption, and mechanical efficiency were assessed, followed by analysis of myocardial oxidative stress, mitochondrial respiration, protein acetylation, and gene expression. Finally, ischemic tolerance was determined by examining LV functional recovery and infarct size. Under low-FA conditions, DIO hearts showed mild LV dysfunction, oxygen wasting, mechanical inefficiency, and reduced mitochondrial OxPhos. High FA-load increased FA oxidation rates in both groups, but this did not alter any of the above parameters in DIO hearts. In contrast, CON hearts showed FA-induced mechanical inefficiency, oxidative stress, and reduced OxPhos, as well as enhanced acetylation and activation of PPARα-dependent gene expression. While high FA-load did not alter functional recovery and infarct size in CON hearts, it increased ischemic tolerance in DIO hearts. Thus, this study demonstrates that acute FA-load affects normal and obese hearts differently and that chronically elevated circulating FA levels render the DIO heart less vulnerable to the disadvantageous effects of an acute FA-load.NEW & NOTEWORTHY An acute myocardial fat-load leads to oxidative stress, oxygen wasting, mechanical inefficiency, hyperacetylation, and impaired mitochondrial function, which can contribute to reduced ischemic tolerance. Following obesity/insulin resistance, hearts were less affected by a high fat-load, which subsequently also improved ischemic tolerance. This study highlights that an acute fat-load affects normal and obese hearts differently and that obesity renders hearts less vulnerable to the disadvantageous effects of an acute fat-load.

Pulmonary arterial hypertension reduces energy efficiency of right, but not left, rat ventricular trabeculae.

KEY POINTS: Pulmonary arterial hypertension (PAH) triggers right ventricle (RV) hypertrophy and left ventricle (LV) atrophy, which progressively leads to heart failure. We designed experiments under conditions mimicking those encountered by the heart in vivo that allowed us to investigate whether consequent structural and functional remodelling of the ventricles affects their respective energy efficiencies. We found that peak work output was lower in RV trabeculae from PAH rats due to reduced extent and velocity of shortening. However, their suprabasal enthalpy was unaffected due to increased activation heat, resulting in reduced suprabasal efficiency. There was no effect of PAH on LV suprabasal efficiency. We conclude that the mechanism underlying the reduced energy efficiency of hypertrophied RV tissues is attributable to the increased energy cost of Ca2+ cycling, whereas atrophied LV tissues still maintain normal mechano-energetic performance. ABSTRACT: Pulmonary arterial hypertension (PAH) greatly increases the afterload on the right ventricle (RV), triggering RV hypertrophy, which progressively leads to RV failure. In contrast, the disease reduces the passive filling pressure of the left ventricle (LV), resulting in LV atrophy. We investigated whether these distinct structural and functional consequences to the ventricles affect their respective energy efficiencies. We studied trabeculae isolated from both ventricles of Wistar rats with monocrotaline-induced PAH and their respective Control groups. Trabeculae were mounted in a calorimeter at 37°C. While contracting at 5 Hz, they were subjected to stress-length work-loops over a wide range of afterloads. They were subsequently required to undergo a series of isometric contractions at various muscle lengths. In both protocols, stress production, length change and suprabasal heat output were simultaneously measured. We found that RV trabeculae from PAH rats generated higher activation heat, but developed normal active stress. Their peak external work output was lower due to reduced extent and velocity of shortening. Despite lower peak work output, suprabasal enthalpy was unaffected, thereby rendering suprabasal efficiency lower. Crossbridge efficiency, however, was unaffected. In contrast, LV trabeculae from PAH rats maintained normal mechano-energetic performance. Pulmonary arterial hypertension reduces the suprabasal energy efficiency of hypertrophied right ventricular tissues as a consequence of the increased energy cost of Ca2+ cycling.

Exercise of obese mice induces cardioprotection and oxygen sparing in hearts exposed to high-fat load.

Exercise training is a potent therapeutic approach in obesity and diabetes that exerts protective effects against the development of diabetic cardiomyopathy and ischemic injury. Acute increases in circulating fatty acids (FAs) during an ischemic insult can challenge the heart, since high FA load is considered to have adverse cardiac effects. In the present study, we tested the hypothesis that exercise-induced cardiac effects in diet-induced obese mice are abrogated by an acute high FA load. Diet-induced obese mice were fed a high-fat diet (HFD) for 20 wk. They were exercised using moderate- and/or high-intensity exercise training (MIT and HIT, respectively) for 10 or 3 wk, and isolated perfused hearts from these mice were exposed to a high FA load. Sedentary HFD mice served as controls. Ventricular function and myocardial O2 consumption were assessed after 10 wk of HIT and MIT, and postischemic functional recovery and infarct size were examined after 3 wk of HIT. In addition to improving aerobic capacity and reducing obesity and insulin resistance, long-term exercise ameliorated the development of diet-induced cardiac dysfunction. This was associated with improved mechanical efficiency because of reduced myocardial oxygen consumption. Although to a lesser extent, 3-wk HIT also increased aerobic capacity and decreased obesity and insulin resistance. HIT also improved postischemic functional recovery and reduced infarct size. Event upon the exposure to a high FA load, short-term exercise induced an oxygen-sparing effect. This study therefore shows that exercise-induced cardioprotective effects are present under hyperlipidemic conditions and highlights the important role of myocardial energetics during ischemic stress.NEW & NOTEWORTHY The exercise-induced cardioprotective effects in obese hearts are present under hyperlipidemic conditions, comparable to circulating levels of FA occurring with an ischemic insult. Myocardial oxygen sparing is associated with this effect, despite the general notion that high fat can decrease cardiac efficiency. This highlights the role of myocardial energetics during ischemic stress.

Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice.

Although exercise training has been demonstrated to have beneficial cardiovascular effects in diabetes, the effect of exercise training on hearts from obese/diabetic models is unclear. In the present study, mice were fed a high-fat diet, which led to obesity, reduced aerobic capacity, development of mild diastolic dysfunction, and impaired glucose tolerance. Following 8 wk on high-fat diet, mice were assigned to 5 weekly high-intensity interval training (HIT) sessions (10 × 4 min at 85-90% of maximum oxygen uptake) or remained sedentary for the next 10 constitutive weeks. HIT increased maximum oxygen uptake by 13%, reduced body weight by 16%, and improved systemic glucose homeostasis. Exercise training was found to normalize diastolic function, attenuate diet-induced changes in myocardial substrate utilization, and dampen cardiac reactive oxygen species content and fibrosis. These changes were accompanied by normalization of obesity-related impairment of mechanical efficiency due to a decrease in work-independent myocardial oxygen consumption. Finally, we found HIT to reduce infarct size by 47% in ex vivo hearts subjected to ischemia-reperfusion. This study therefore demonstrated for the first time that exercise training mediates cardioprotection following ischemia in diet-induced obese mice and that this was associated with oxygen-sparing effects. These findings highlight the importance of optimal myocardial energetics during ischemic stress.

Effects of exercise on postexercise ventricular-arterial coupling and pulsatile efficiency in patients with systolic dysfunction.

BACKGROUND: A suboptimal ventricular-arterial (VA) interaction may have a prolonged depressing effect on the failing heart after functional reserves forced to their limits under stress conditions such as exercise. The continuation of excessive load in the postexercise period may be more important than the load during exercise, because the sum of postexercise periods generally exceeds exercise time itself. We sought that exercise-induced changes in postexercise VA coupling and pulsatile efficiency in patients with heart failure (HF). METHODS: Thirty consecutive HF with reduced ejection fraction (EF) and thirty age-, sex- and peak VO2 -matched subjects with preserved EF were enrolled. Pre- and postexercise echocardiographic and tonometric measurements were taken to calculate left ventricular and arterial elastances, arterial compliance and wave reflections, and steady and pulsatile power. RESULTS: VA coupling significantly deteriorated in HF group (from 1·50 ± 0·47 to 2·00 ± 0·75 mmHg/mL, P < 0·01), but control group maintained basal favourable coupling status after exercise (from 1·04 ± 0·29 to 1·03 ± 0·24 mmHg/mL, P = 0·77). Pulsatile percentage of total power significantly increased with exercise in HF group, whereas it showed a significant decrease in control group. The change in pulsatile power fraction was correlated with the change in augmentation pressure (r = 0·41, ß = 3·00, P < 0·01) and inversely correlated with the change in total arterial compliance (r = -0·29, ß = -8·52, P = 0·02). CONCLUSION: Our data indicate that exercise-induced VA decoupling and pulsatile inefficiency extend into postexercise phase in patients with systolic dysfunction. The exact duration of these derangements requires further studies.

Biventricular performance in adults with a systemic right ventricle: new insights from myocardial work analysis.

To evaluate biventricular mechanics by means of echo-derived myocardial work (MW) analysis in patients with a systemic right ventricle (sRV). Comprehensive echo data were collected in all patients with a sRV who underwent transthoracic echocardiography at our tertiary centre between 2020 and 2021 including sRV function indices, global longitudinal strain (GLS) of right and left ventricle (RV/LV), biventricular MW, and atrial strain in those with congenitally corrected transposition of the great arteries (ccTGA). Fifty-six patients (37 [30.97-45.87]years, 59% male) and 49 healthy individuals matched per age and sex were included for comparison. Global work index (GWI:1106 [869.80-1293.10] Vs 314.2 [281.5-358.2]mmHg%, p < 0.0001) and global constructive work(GCW: 1542.50 [1338.9-1718.50] Vs 416.4 [365.70-464]mmHg%, p < 0.0001) were both increased for sRV compared to normal RV, reflecting exposition to a systemic afterload, with a contemporary raise in wasted work (GWW:197 [138.50-322.20] Vs 26.09 [17.80-43.48]mmHg%, p < 0.0001) and impaired efficiency (GWE:89 [83-93.54] Vs 93.67 [91.67-96] %, p < 0.0001). Conversely, sRV showed reduced MW indices in comparison to normal LV(p < 0.0001 for all). Non-systemic LV demonstrated normal GLS values (19.51 ± 3.9%), but reduced GWI (479 [368-665] Vs 2172 [1978-2386]mmHg%, p < 0.0001) and GCW (708 [490-815]mmHg% Vs 86.5 [59.25-118], p < 0.0001). Nevertherless, non-systemic LV showed also impaired efficiency (91 [88-94] Vs 95 [94-97]%, p < 0.0001). LVGLS values were related to RVGLS (R = 0.5, p = 0.00019), suggesting a consistent interventricular dependency. Atrial strain could be assessed in 16 out of 20 (80%) patients with ccTGA: both atria had reduced strain values compared to their normal counterparts. Moreover, pulmonary atrial strain during the reservoir phase was related to LVGWE (R = 0.58, p = 0.047) and inversely related to LVGLS (R = - 0.71, p = 0.0043). MW analysis is feasible in sRV and may provide additional clinical data. In our cohort MW revealed biventricular impairment, in particular for non-systemic LV, in spite of normal GLS values.

The evaluation of cardiac functions in deep Trendelenburg position during robotic-assisted laparoscopic prostatectomy.

Objective: This study aimed to demonstrate the reliability of the cardiac cycle efficiency value through its correlation with longitudinal strain by observing the effect of the deep Trendelenburg position. Design: A prospective, observational study. Setting: Single center. Participants: Between May and September 2022, the hemodynamic parameters of 30 patients who underwent robotic assisted laparoscopic prostatectomy under general anesthesia were prospectively evaluated. Measurements and main results: All invasive cardiac monitoring parameters and longitudinal strain achieved transesophageal echocardiography were recorded in pre-deep Trendelenburg position (T3) and 10th minute of deep Trendelenburg position (T4). Delta values were calculated for the cardiac cycle efficiency and longitudinal strain (values at T4 minus values at T3). The estimated power was calculated as 0.99 in accordance with the cardiac cycle efficiency values at T3 and T4 (effect size: 0.85 standard deviations of the mean difference: 0.22, alpha: 0.05). At T4, heart rate, pulse pressure variation, cardiac cycle efficiency, dP/dt and longitudinal strain were significantly lower than those at T3 (p = 0.009, p < 0.001, p < 0.001, and p < 0.001, respectively). There was a positive correlation between the delta-cardiac cycle efficiency and delta-longitudinal strain (R2 = 0.36, p < 0.001). Conclusion: Although the absence of significant changes in mean arterial pressure and cardiac index after Trendelenburg position suggests that cardiac workload has not changed, changes in cardiac cycle efficiency and longitudinal strain indicate increased cardiac workload due to increased ventriculo-arterial coupling.

Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling.

The present study aimed to examine the effects of low doses of angiotensin II (AngII) on cardiac function, myocardial substrate utilization, energetics, and mitochondrial function in C57Bl/6J mice and in a transgenic mouse model with cardiomyocyte specific upregulation of NOX2 (csNOX2 TG). Mice were treated with saline (sham), 50 or 400 ng/kg/min of AngII (AngII50 and AngII400) for two weeks. In vivo blood pressure and cardiac function were measured using plethysmography and echocardiography, respectively. Ex vivo cardiac function, mechanical efficiency, and myocardial substrate utilization were assessed in isolated perfused working hearts, and mitochondrial function was measured in left ventricular homogenates. AngII50 caused reduced mechanical efficiency despite having no effect on cardiac hypertrophy, function, or substrate utilization. AngII400 slightly increased systemic blood pressure and induced cardiac hypertrophy with no effect on cardiac function, efficiency, or substrate utilization. In csNOX2 TG mice, AngII400 induced cardiac hypertrophy and in vivo cardiac dysfunction. This was associated with a switch towards increased myocardial glucose oxidation and impaired mitochondrial oxygen consumption rates. Low doses of AngII may transiently impair cardiac efficiency, preceding the development of hypertrophy induced at higher doses. NOX2 overexpression exacerbates the AngII -induced pathology, with cardiac dysfunction and myocardial metabolic remodelling.

Measurements of cardiac efficiency and internal work of the left ventricle via reconstructed impedance cardiography.

Objective. The aim of this study was to investigate methods for measuring the cardiac efficiency (CE) and internal work (IW) of the left ventricle via reconstructed impedance cardiography (RICG).Approach.On the basis of the physiological context and Bernoulli's equation in physics, methods of measuring the CE and IW were proposed. The CE, IW, internal work index (IWI), and other data from 180 healthy adults and 144 patients with cardiovascular disease were measured.Main results. The CE of 180 healthy adults was 22.5 ± 2.2%, and the IWI was 22.3 ± 5.2 J l-1m-2. CE decreased with age, and the CE of the younger group (23.5 ± 1.9%) was larger than that of the older group (21.5 ± 1.9%),P < 0.01. The IWI increased with age, and the IWI of the younger group (19.0 ± 3.8 J l-1m-2) was smaller than that of the older group (24.8 ± 4.3 J l-1m-2),P < 0.01. There were no significant difference in CE (22.4 ± 2.2% and 22.6 ± 2.2%) or in the IWI (21.9 ± 5.1 J l-1m-2and 22.6 ± 5.2 J l-1m-2) between the male and female groups. The CEs and IWIs of patients with hypertension, coronary heart disease, and heart failure were 17.4 ± 2.4% and 41.8 ± 15.6 J l-1m-2, 17.6 ± 3.0% and 35.1 ± 10.4 J l-1m-2, and 15.8 ± 3.5% and 42.1 ± 15.6 J l-1m-2, respectively. These CEs were all smaller than that (21.6 ± 2.0%) of the healthy contrast groupP < 0.01, while the IWIs were all larger than that (24.6 ± 4.8 J l-1m-2) of the healthy contrast group,P < 0.01.Significance.The CEs and IWIs measured in this study may reflect physiological changes in healthy humans and pathogenic conditions in patients with cardiovascular disease.

Effect of norepinephrine challenge on cardiovascular determinants assessed using a mathematical model in septic shock: a physiological study.

BACKGROUND: The present study investigated the cardiovascular determinants of cardiac output (CO), mean systemic filling pressure analogue (Pmsa) derived by Geoffrey Parkin, efficiency of heart (Eh) and related parameters to a norepinephrine (NE) challenge [an increase of 10 mmHg mean arterial pressure (MAP) by NE] in septic shock patients using of a mathematical model. METHODS: Twenty-seven septic shock patients with pulse index continuous cardiac output (PiCCO) monitoring were enrolled. These patients required NE to maintain an individualized MAP for organ perfusion after early fluid resuscitation based on their clinical condition. NE was decreased to obtain a decrease of 10 mmHg from base MAP (MAP-10mmHg), and the NE doses were adjusted to return MAP to baseline (MAPbase) and produce an increase of 10 mmHg from MAPbase (MAP+10mmHg). Two NE challenge episodes were analyzed for each patient: from MAP-10mmHg to MAPbase and from MAPbase to MAP+10mmHg. The Pmsa, pressure gradient for venous return (PGvr), and Eh (PGvr relative to Pmsa) were estimated using a mathematical model for the three MAP levels (MAP-10mmHg, MAPbase and MAP+10mmHg). RESULTS: A total of 54 episodes of NE challenges were obtained in 27 patients. Significant and consistent increases were observed in the central venous pressure (CVP), Pmsa, and PGvr in response during the NE titration. ΔCO negatively and significantly correlated with ΔCVP (r=-0.722, P<0.0001), ΔPmsa (r=-0.549, P<0.0001), ΔResistance of venous return (Rvr) (r=-0.597, P<0.0001), and ΔResistance of systemic vascular beds (Rsys) (r=-0.597, P<0.0001). Episodes of decreasing CO/Eh were associated with a higher ΔCVP than the CO/Eh-increasing episodes. The area under the curve (AUC) of ΔCVP to predict decreased CO by the incremental NE was 0.86, and the AUC of ΔCVP to predict decreased Eh was 0.94. A cutoff of ΔCVP >1.5 mmHg for detecting decreased CO resulted in a sensitivity of 75% and a specificity of 94.1%. A cutoff of ΔCVP >1.5 mmHg for detecting decreased Eh resulted in a sensitivity of 64.3% and a specificity of 100%. CONCLUSIONS: There were a highly divergent response in Eh and CO to afterload challenge episodes of an NE-induced 10mmHg increase in MAP. An increase in CVP may be an early alarm to identify the reduction in CO/Eh during an NE-induced increase of MAP.

The ß3 Adrenergic Receptor Antagonist L-748,337 Attenuates Dobutamine-Induced Cardiac Inefficiency While Preserving Inotropy in Anesthetized Pigs.

Excessive myocardial oxygen consumption (MVO2) is considered a limitation for catecholamines, termed oxygen cost of contractility. We hypothesize that increased MVO2 induced by dobutamine is not directly related to contractility but linked to intermediary myocardial metabolism. Furthermore, we hypothesize that selective ß3 adrenergic receptor (ß3AR) antagonism using L-748,337 prevents this. In an open-chest pig model, using general anesthesia, we assessed cardiac energetics, hemodynamics and arterial metabolic substrate levels at baseline, ½ hour and 6 hours after onset of drug infusion. Cardiac efficiency was assessed by relating MVO2 to left ventricular work (PVA; pressure-volume area). Three groups received dobutamine (5 µg/kg/min), dobutamine + L-748,337 (bolus 50 µg/kg), or saline for time-matched controls. Cardiac efficiency was impaired over time with dobutamine infusion, displayed by persistently increased unloaded MVO2 from ½ hour and 47% increase in the slope of the PVA-MVO2 relation after 6 hours. Contractility increased immediately with dobutamine infusion (dP/dtmax; 1636 ± 478 vs 2888 ± 818 mmHg/s, P < 0.05) and persisted throughout the protocol (2864 ± 1055 mmHg/s, P < 0.05). Arterial free fatty acid increased gradually (0.22 ± 0.13 vs 0.39 ± 0.30 mM, P < 0.05) with peak levels after 6 hours (1.1 ± 0.4 mM, P < 0.05). By combining dobutamine with L-748,337 the progressive impairment in cardiac efficiency was attenuated. Interestingly, this combined treatment effect occurred despite similar alterations in cardiac inotropy and substrate supply. We conclude that the extent of cardiac inefficiency following adrenergic stimulation is dependent on the duration of drug infusion, and ß3AR blockade may attenuate this effect.

Resting Cardiac Efficiency Affects Survival Following Transcatheter Aortic Valve Replacement.

OBJECTIVE: Cardiac power to left ventricular mass (LVM) ratio, also termed cardiac efficiency (CE), reflects the rate of cardiac work delivered to the potential energy stored in LVM. We sought to assess the association between baseline resting CE and survival post transcatheter aortic valve replacement (TAVR). METHODS: We retrospectively extracted data of patients who received TAVR in the Mayo Clinic Foundation with follow up data available at 1 year. Cardiac output was measured using Doppler echocardiography at baseline. CE was calculated using the formula, (cardiac output × mean arterial blood pressure)/(451 × LVM × 100) W/100 g. Survival score analysis was performed to identify cut off value for CE to identify the maximum difference in mortality in the study cohort. Patients were subsequently divided into 2 groups CE < 0.38 W/100 g and CE ≥ 0.38 W/100 g. Survival was determined using Kaplan-Meier method. RESULTS: We included 954 patients in the final analysis. CE in group1 vs group 2 was 0.31 ± 0.05 W/100 g vs 0.59 ± 0.18 W/100 g. Patients in group1 were more likely to be male, had a higher prevalence of atrial fibrillation, prior myocardial infarction, mitral and tricuspid regurgitation. They also had a higher STS risk score, NYHA functional class, and lower aortic valve area. The remainder of the baseline characteristics was similar in both groups. A lower CE was associated with higher 1-year mortality following TAVR based on multivariate analysis. (Group1: 22.18% vs Group 2: 9.89%, p < .0001). CONCLUSION: In our cohort, a low baseline CE (<0.38 W/100 g) conferred higher mortality risk following TAVR.

Increased Myocardial Oxygen Consumption Precedes Contractile Dysfunction in Hypertrophic Cardiomyopathy Caused by Pathogenic TNNT2 Gene Variants.

Background Hypertrophic cardiomyopathy is caused by pathogenic sarcomere gene variants. Individuals with a thin-filament variant present with milder hypertrophy than carriers of thick-filament variants, although prognosis is poorer. Herein, we defined if decreased energetic status of the heart is an early pathomechanism in TNNT2 (troponin T gene) variant carriers. Methods and Results Fourteen individuals with TNNT2 variants (genotype positive), without left ventricular hypertrophy (G+/LVH-; n=6) and with LVH (G+/LVH+; n=8) and 14 healthy controls were included. All participants underwent cardiac magnetic resonance and [11C]-acetate positron emission tomography imaging to assess LV myocardial oxygen consumption, contractile parameters and myocardial external efficiency. Cardiac efficiency was significantly reduced compared with controls in G+/LVH- and G+/LVH+. Lower myocardial external efficiency in G+/LVH- is explained by higher global and regional oxygen consumption compared with controls without changes in contractile parameters. Reduced myocardial external efficiency in G+/LVH+ is explained by the increase in LV mass and higher oxygen consumption. Septal oxygen consumption was significantly lower in G+/LVH+ compared with G+/LVH-. Although LV ejection fraction was higher in G+/LVH+, both systolic and diastolic strain parameters were lower compared with controls, which was most evident in the hypertrophied septal wall. Conclusions Using cardiac magnetic resonance and [11C]-acetate positron emission tomography imaging, we show that G+/LVH- have an initial increase in oxygen consumption preceding contractile dysfunction and cardiac hypertrophy, followed by a decline in oxygen consumption in G+/LVH+. This suggests that high oxygen consumption and reduced myocardial external efficiency characterize the early gene variant-mediated disease mechanisms that may be used for early diagnosis and development of preventive treatments.

Combined Therapy With Dobutamine and Omecamtiv Mecarbil in Pigs With Ischemic Acute Heart Failure Is Attributed to the Effect of Dobutamine.

Inotropic support in ischemic acute heart failure (AHF) is controversial. We tested a therapeutic principle for AHF by combining a low dose of omecamtiv mecarbil (OM; 0.25 mg/kg bolus plus 0.25 mg/kg/h) with a low dose of dobutamine (Dobut; 1.25 µg/kg/min). In 10 pigs subjected to myocardial ischemia by left coronary microembolization, this cotreatment increased cardiac power (CP) from 0.48 ± 0.14 to 0.81 ± 0.22 W (P < .05). When the drugs were given as a monotherapy, CP increased from 0.57 ± 0.11 to 0.65 ± 0.15 W (OM; n = 5; not significant) and from 0.40 ± 0.07 to 0.70 ± 0.10 W (Dobut; n = 5; P < .05). Dobut counteracted OM-mediated impairments in early relaxation and diastolic shortening. In a second protocol using the same doses, we assessed cardiac efficiency in 5 healthy pigs by relating myocardial oxygen consumption (MVO2) to the pressure-volume area. Here, the increases in cardiac work and MVO2 were matched, leaving cardiac efficiency unaltered by this drug combination. Low-dose cotreatment with OM + Dobut produces an appropriate hemodynamic effect with improved CP at doses that do not affect cardiac efficiency. This outcome is mainly attributed to the inotropic effect of Dobut.

NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity.

Obesity and diabetes are independent risk factors for cardiovascular diseases, and they are associated with the development of a specific cardiomyopathy with elevated myocardial oxygen consumption (MVO2) and impaired cardiac efficiency. Although the pathophysiology of this cardiomyopathy is multifactorial and complex, reactive oxygen species (ROS) may play an important role. One of the major ROS-generating enzymes in the cardiomyocytes is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), and many potential systemic activators of NOX2 are elevated in obesity and diabetes. We hypothesized that NOX2 activity would influence cardiac energetics and/or the progression of ventricular dysfunction following obesity. Myocardial ROS content and mechanoenergetics were measured in the hearts from diet-induced-obese wild type (DIOWT) and global NOK2 knock-out mice (DIOKO) and in diet-induced obese C57BL/6J mice given normal water (DIO) or water supplemented with the NOX2-inhibitor apocynin (DIOAPO). Mitochondrial function and ROS production were also assessed in DIO and DIOAPO mice. This study demonstrated that ablation and pharmacological inhibition of NOX2 both improved mechanical efficiency and reduced MVO2 for non-mechanical cardiac work. Mitochondrial ROS production was also reduced following NOX2 inhibition, while cardiac mitochondrial function was not markedly altered by apocynin-treatment. Therefore, these results indicate a link between obesity-induced myocardial oxygen wasting, NOX2 activation, and mitochondrial ROS.

Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency.

BACKGROUND: Impaired cardiac insulin signalling and high cardiac fatty acid oxidation rates are characteristics of conditions of insulin resistance and diabetic cardiomyopathies. The potential role of liver-derived peptides such as adropin in mediating these changes in cardiac energy metabolism is unclear, despite the fact that in skeletal muscle adropin can preferentially promote glucose metabolism and improve insulin sensitivity. OBJECTIVES: To determine the influence of adropin on cardiac energy metabolism, insulin signalling and cardiac efficiency. METHODS: C57Bl/6 mice were injected with either vehicle or a secretable form of adropin (450 nmol/kg, i.p.) three times over a 24-h period. The mice were fasted to accentuate the differences between animals in adropin plasma levels before their hearts were isolated and perfused using a working heart system. In addition, direct addition of adropin to the perfusate of ex vivo hearts isolated from non-fasting mice was utilized to investigate the acute effects of the peptide on heart metabolism and ex vivo function. RESULTS: In contrast to the observed fasting-induced predominance of fatty acid oxidation as a source of ATP production in control hearts, insulin inhibition of fatty acid oxidation was preserved by adropin treatment. Adropin-treated mouse hearts also showed a higher cardiac work, which was accompanied by improved cardiac efficiency and enhanced insulin signalling compared to control hearts. Interestingly, acute adropin administration to isolated working hearts also resulted in an inhibition of fatty acid oxidation, accompanied by a robust stimulation of glucose oxidation compared to vehicle-treated hearts. Adropin also increased activation of downstream cardiac insulin signalling. Moreover, both in vivo and ex vivo treatment protocols induced a reduction in the inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the major enzyme of glucose oxidation, and the protein levels of the responsible kinase PDH kinase 4 and the insulin-signalling inhibitory phosphorylation of JNK (p-T183/Y185) and IRS-1 (p-S307), suggesting acute receptor- and/or post-translational modification-mediated mechanisms. CONCLUSIONS: These results demonstrate that adropin has important effects on energy metabolism in the heart and may be a putative candidate for the treatment of cardiac disease associated with impaired insulin sensitivity.