Helena Tuunanen

Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy

Background— The anti-ischemic agent trimetazidine improves ejection fraction in heart failure that is hypothetically linked to inhibitory effects on cardiac free fatty acid (FFA) oxidation. However, FFA oxidation remains unmeasured in humans. We investigated the effects of trimetazidine on cardiac perfusion, efficiency of work, and FFA oxidation in idiopathic dilated cardiomyopathy. Methods and Results— Nineteen nondiabetic patients with idiopathic dilated cardiomyopathy on standard medication were randomized to single-blind trimetazidine (n=12) or placebo (n=7) for 3 months. Myocardial perfusion, FFA, and total oxidative metabolism were measured using positron emission tomography with [15O]H2O, [11C]acetate, and [11C]palmitate. Cardiac function was assessed echocardiographically; insulin sensitivity was assessed by the homeostasis model assessment index. Trimetazidine increased ejection fraction from 30.9±8.5% to 34.8±12% (P=0.027 versus placebo). Myocardial FFA uptake was unchanged, and &bgr;-oxidation rate constant decreased only 10%. Myocardial perfusion, oxidative metabolism, and work efficiency remained unchanged. Trimetazidine decreased insulin resistance (glucose: 5.9±0.7 versus 5.5±0.6 mmol/L, P=0.047; insulin: 10±6.9 versus 7.6±3.6 mU/L, P=0.031; homeostasis model assessment index: 2.75±2.28 versus 1.89±1.06, P=0.027). The degree of &bgr;-blockade and trimetazidine interacted positively on ejection fraction. Plasma high-density lipoprotein concentrations increased 11% (P<0.001). Conclusions— In idiopathic dilated cardiomyopathy with heart failure, trimetazidine increased cardiac function and had both cardiac and extracardiac metabolic effects. Cardiac FFA oxidation modestly decreased and myocardial oxidative rate was unchanged, implying increased oxidation of glucose. Trimetazidine improved whole-body insulin sensitivity and glucose control in these insulin-resistant idiopathic dilated cardiomyopathy patients, thus hypothetically countering the myocardial damage of insulin resistance. Additionally, the trimetazidine-induced increase in ejection fraction was associated with greater &bgr;1-adrenoceptor occupancy, suggesting a synergistic mechanism.

Free Fatty Acid Depletion Acutely Decreases Cardiac Work and Efficiency in Cardiomyopathic Heart Failure

Background— Metabolic modulators that enhance myocardial glucose metabolism by inhibiting free fatty acid (FFA) metabolism may improve cardiac function in heart failure patients. We studied the effect of acute FFA withdrawal on cardiac function in patients with heart failure caused by idiopathic dilated cardiomyopathy (IDCM). Methods and Results— Eighteen fasting nondiabetic patients with IDCM (14 men, 4 women, aged 58.8±8.0 years, ejection fraction 33±8.8%) and 8 matched healthy controls underwent examination of myocardial perfusion and oxidative and FFA metabolism, before and after acute reduction of serum FFA concentrations by acipimox, an inhibitor of lipolysis. Metabolism was monitored by positron emission tomography and [15O]H2O, [11C]acetate, and [11C]palmitate. Left ventricular function and myocardial work were echocardiographically measured, and efficiency of forward work was calculated. Acipimox decreased myocardial FFA uptake by >80% in both groups. Rate–pressure product and myocardial perfusion remained unchanged, whereas stroke volume decreased similarly in both groups. In the healthy controls, reduced cardiac work was accompanied by decreased oxidative metabolism (from 0.071±0.019 to 0.055±0.016 min−1, P<0.01). In IDCM patients, cardiac work fell, whereas oxidative metabolism remained unchanged and efficiency fell (from 35.4±12.6 to 31.6±13.3 mm Hg · L · g−1, P<0.05). Conclusions— Acutely decreased serum FFA depresses cardiac work. In healthy hearts, this is accompanied by parallel decrease in oxidative metabolism, and myocardial efficiency is preserved. In failing hearts, FFA depletion did not downregulate oxidative metabolism, and myocardial efficiency deteriorated. Thus, failing hearts are unexpectedly more dependent than healthy hearts on FFA availability. We propose that both glucose and fatty acid oxidation are required for optimal function of the failing heart.

Effects of Low and High Plasma Concentrations of Dexmedetomidine on Myocardial Perfusion and Cardiac Function in Healthy Male Subjects

Background:Dexmedetomidine, a selective &agr;2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating &agr;2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic &agr;2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects. Methods:The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine. Results:The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, −27% from baseline [95% confidence interval, −31 to −23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate–pressure product (−23% [−28 to −18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (−3% [−12 to +6%] from low dexmedetomidine, P > 0.05; −29% [−39 to −18%] from baseline, P < 0.001) or statistically significantly affect the rate–pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate. Conclusions:In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.

Metabolic remodelling in human heart failure

In addition to the typical abnormalities in myocardial structure and function, it is well established that the cardiac metabolism is abnormal in patients with heart failure (HF). Insulin resistance is a common co-morbidity in HF patients and also modulates cardiac metabolism in HF. The notion that an altered myocardial metabolism may contribute to the disease pathogenesis and optimizing it may serve therapeutic purposes underscores the importance of identifying the metabolic characteristics of HF patients. In this paper, the literature on the metabolic changes in human HF is reviewed, and the effects of metabolic modulators on patients with HF are discussed.

Trimetazidine reduces endogenous free fatty acid oxidation and improves myocardial efficiency in obese humans.

INTRODUCTION The metabolic modulator trimetazidine (TMZ) has been suggested to induce a metabolic shift from myocardial fatty acid oxidation (FAO) to glucose utilization, but this mechanism remains unproven in humans. The oxidation of plasma derived FA is commonly measured in humans, whereas the contribution of FA from triglycerides stored in the myocardium has been poorly characterized. AIMS To verify the hypothesis that TMZ induces a metabolic shift, we combined positron emission tomography (PET) and magnetic resonance spectroscopy ((1)H-MRS) to measure myocardial FAO from plasma and intracellular lipids, and myocardial glucose metabolism. Nine obese subjects were studied before and after 1 month of TMZ treatment. Myocardial glucose and FA metabolism were assessed by PET with (18)F-fluorodeoxyglucose and (11)C-palmitate. (1)H-MRS was used to measure myocardial lipids, the latter being integrated into the PET data analysis to quantify myocardial triglyceride turnover. RESULTS Myocardial FAO derived from intracellular lipids was at least equal to that of plasma FAs (P = NS). BMI and cardiac work were positively associated with the oxidation of plasma derived FA (P ≤ 0.01). TMZ halved total and triglyceride-derived myocardial FAO (32.7 ± 8.0 to 19.6 ± 4.0 μmol/min and 23.7 ± 7.5 to 10.3 ± 2.7 μmol/min, respectively; P ≤ 0.05). These changes were accompanied by increased cardiac efficiency since unchanged LV work (1.6 ± 0.2 to 1.6 ± 0.1 Watt/g × 10(2), NS) was associated with decreased work energy from the intramyocardial triglyceride oxidation (1.6 ± 0.5 to 0.4 ± 0.1 Watt/g × 10(2), P = 0.036). CONCLUSIONS In obese subjects, we demonstrate that myocardial intracellular triglyceride oxidation significantly provides FA-derived energy for mechanical work. TMZ reduced the oxidation of triglyceride-derived myocardial FAs improving myocardial efficiency.

The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans

Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated whether 1) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo and 2) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content. Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo positron emission tomography with [(11)C]acetate and [(11)C]palmitate to quantify liver FFA metabolism (n = 8), or magnetic resonance spectroscopy (MRS) to measure hepatic fat content (n = 8), before and after the acute lowering of circulating FFAs by using the antilipolytic agent acipimox. MRS was again repeated after a 1-wk treatment period. Acipimox suppressed FFA levels while stimulating hepatic fractional extraction of FFAs (P < 0.05). As a result, fasting liver FFA uptake was decreased by 79% (P = 0.0002) in tight association with lipolysis (r = 0.996, P < 0.0001). The 1-wk treatment induced a significant improvement in systemic (+30%) and liver (+70%) insulin sensitivity (P < 0.05) and decreased circulating triglycerides (-20%, P = 0.06) and liver enzymes (ALT -20%, P = 0.03). No change in liver fat content was observed after either acute or sustained FFA suppression. We conclude that acute and sustained inhibitions of lipolysis and liver FFA uptake fail to deplete liver fat in healthy human subjects. Liver FFA uptake was decreased in proportion to FFA delivery. As a consequence, liver and systemic insulin sensitivity were improved, together with liver function, independently of changes in hepatic triglyceride accumulation.

Effects of Acute and One-Week Fatty Acid Lowering on Cardiac Function and Insulin Sensitivity in Relation with Myocardial and Muscle Fat and Adiponectin Levels

BACKGROUND/AIM We tested the hypothesis that a persistent reduction in free fatty acid (FFA) levels improves cardiac function and systemic insulin sensitivity via a reduction in the myocardial and skeletal muscle adiposities and a modulation in adipokine release. METHODS Study subjects (body mass index 22-30 kg/m(2), 57 ± 3 yr old) underwent magnetic resonance imaging and spectroscopy to measure the cardiac function and the amounts of fat inside and around the myocardium and skeletal muscle, before (n = 10) and after acute (n = 8) and 1 wk (n = 7, one excluded from analysis) lowering of circulating FFA by acipimox. Circulating adipokines (leptin, adiponectin, resistin, TNFα, IL-6, IL-8, plasminogen activator inhibitor-I, macrophage chemoattractant protein-1) were measured. RESULTS The ejection fraction (62 ± 2 vs. 56 ± 1%, P = 0.0035), cardiac output (6.6 ± 0.3 vs. 5.5 ± 0.2 liters/min, P = 0.0018), and forward work (708 ± 49 vs. 539 ± 44 mm Hg × liters/min, P = 0.018) were significantly lower after 1 wk of FFA lowering. In the six subjects undergoing all sessions, the stroke and end-diastolic volumes were also reduced, insulin sensitivity was increased by 33%, and adiponectinemia was decreased (-26%, P = 0.03). No change in intracellular cardiac and skeletal muscle triglyceride levels was observed. Metabolic changes correlated with the lowering of FFA. The reduction in cardiac function was related with changes in glycemia and insulin sensitivity, whereas the deflection in left ventricular work was correlated with the decline in FFA, lipid, and blood pressure levels. CONCLUSIONS A 1-wk FFA depletion suppressed cardiac function and improved insulin sensitivity. Intracellular triglyceride deposits in the heart and skeletal muscle played no role in the observed changes. Our data show that FFA participate in the physiological regulation of adipokine levels.

Human obesity is characterized by defective fat storage and enhanced muscle fatty acid oxidation, and trimetazidine gradually counteracts these abnormalities

An impaired ability to store fatty acids (FA) in subcutaneous adipose tissue (SAT) may be implicated in the pathogenesis of obesity-related diseases via overexposure of lean tissues and production of free radicals from FA oxidation (FAO). We studied regional FA metabolism in skeletal muscle and adipose tissue in humans and investigated the long-term effects of the FAO inhibitor trimetazidine on glucose and FA metabolism. Positron emission tomography (PET) and [(11)C]palmitate were used to compare FA metabolism in SAT and skeletal muscle between eight obese and eight nonobese subjects (BMI ≥/< 30 kg/m(2)). A subgroup of nine subjects underwent a 1-mo trimetazidine administration. PET with [(11)C]palmitate and [(18)F]fluorodeoxyglucose, indirect calorimetry, and MRI before and after this period were performed to characterize glucose and FA metabolism, fat masses, skeletal muscle triglyceride, and creatine contents. Obesity was characterized by a 100% elevation in FAO and a defect in the FA esterification rate constant (P < 0.05) in skeletal muscle. FA esterification was reduced by ~70% in SAT (P < 0.001) in obese vs. control subjects. The degrees of obesity and insulin resistance were both negatively associated with esterification-related parameters and positively with FAO (P < 0.05). Trimetazidine increased skeletal muscle FA esterification (P < 0.01) and mildly upregulated glucose phosphorylation (P = 0.066). Our data suggest that human obesity is characterized by a defect in tissue FA storage capability, which is accompanied by a (potentially compensatory) elevation in skeletal muscle FAO; trimetazidine diverted FA from oxidative to nonoxidative pathways and provoked an initial activation of glucose metabolism in skeletal muscle.

Motion detection and correction for dynamic 15O-water myocardial perfusion PET studies

PurposePatient motion during dynamic PET studies is a well-documented source of errors. The purpose of this study was to investigate the incidence of frame-to-frame motion in dynamic 15O-water myocardial perfusion PET studies, to test the efficacy of motion correction methods and to study whether implementation of motion correction would have an impact on the perfusion results.MethodsWe developed a motion detection procedure using external radioactive skin markers and frame-to-frame alignment. To evaluate motion, marker coordinates inside the field of view were determined in each frame for each study. The highest number of frames with identical spatial coordinates during the study were defined as “non-moved”. Movement was considered present if even one marker changed position, by one pixel/frame compared with reference, in one axis, and such frames were defined as “moved”. We tested manual, in-house-developed motion correction software and an automatic motion correction using a rigid body point model implemented in MIPAV (Medical Image Processing, Analysis and Visualisation) software. After motion correction, remaining motion was re-analysed. Myocardial blood flow (MBF) values were calculated for both non-corrected and motion-corrected datasets.ResultsAt rest, patient motion was found in 18% of the frames, but during pharmacological stress the fraction increased to 45% and during physical exercise it rose to 80%. Both motion correction algorithms significantly decreased (p<0.006) the number of moved frames and the amplitude of motion (p<0.04). Motion correction significantly increased MBF results during bicycle exercise (p<0.02). At rest or during adenosine infusion, the motion correction had no significant effects on MBF values.ConclusionSignificant motion is a common phenomenon in dynamic cardiac studies during adenosine infusion but especially during exercise. Applying motion correction for the data acquired during exercise clearly changed the MBF results, indicating that motion correction is required for these studies.

Cardiac function, perfusion, metabolism, and innervation following autologous stem cell therapy for acute ST-elevation myocardial infarction. A FINCELL-INSIGHT sub-study with PET and MRI

Purpose: Beneficial mechanisms of bone marrow cell (BMC) therapy for acute ST-segment elevation myocardial infarct (STEMI) are largely unknown in humans. Therefore, we evaluated the feasibility of serial positron emission tomography (PET) and MRI studies to provide insight into the effects of BMCs on the healing process of ischemic myocardial damage. Methods: Nineteen patients with successful primary reteplase thrombolysis (mean 2.4 h after symptoms) for STEMI were randomized for BMC therapy (2.9 × 106 CD34+ cells) or placebo after bone marrow aspiration in a double-blind, multi-center study. Three days post-MI, coronary angioplasty, and paclitaxel eluting stent implantation preceded either BMC or placebo therapy. Cardiac PET and MRI studies were performed 7–12 days after therapies and repeated after 6 months, and images were analyzed at a central core laboratory. Results: In BMC-treated patients, there was a decrease in [11C]-HED defect size (−4.9 ± 4.0 vs. −1.6 ± 2.2%, p = 0.08) and an increase in [18F]-FDG uptake in the infarct area at risk (0.06 ± 0.09 vs. −0.05 ± 0.16, p = 0.07) compared to controls, as well as less left ventricular dilatation (−4.4 ± 13.3 vs. 8.0 ± 16.7 mL/m2, p = 0.12) at 6 months follow-up. However, BMC treatment was inferior to placebo in terms of changes in rest perfusion in the area at risk (−0.09 ± 0.17 vs. 0.10 ± 0.17, p = 0.03) and infarct size (0.4 ± 4.2 vs. −5.1 ± 5.9 g, p = 0.047), and no effect was observed on ejection fraction (p = 0.37). Conclusion: After the acute phase of STEMI, BMC therapy showed only minor trends of long-term benefit in patients with rapid successful thrombolysis. There was a trend of more decrease in innervation defect size and enhanced glucose metabolism in the infarct-related myocardium and also a trend of less ventricular dilatation in the BMC-treated group compared to placebo. However, no consistently better outcome was observed in the BMC-treated group compared to placebo.