Heikki Ukkonen

Cardiac Positron Emission Tomography/Computed Tomography Imaging Accurately Detects Anatomically and Functionally Significant Coronary Artery Disease

Background— Computed tomography (CT) is increasingly used to detect coronary artery disease, but the evaluation of stenoses is often uncertain. Perfusion imaging has an established role in detecting ischemia and guiding therapy. Hybrid positron emission tomography (PET)/CT allows combination angiography and perfusion imaging in short, quantitative, low-radiation-dose protocols. Methods and Results— We enrolled 107 patients with an intermediate (30% to 70%) pretest likelihood of coronary artery disease. All patients underwent PET/CT (quantitative PET with 15O-water and CT angiography), and the results were compared with the gold standard, invasive angiography, including measurement of fractional flow reserve when appropriate. Although PET and CT angiography alone both demonstrated 97% negative predictive value, CT angiography alone was suboptimal in assessing the severity of stenosis (positive predictive value, 81%). Perfusion imaging alone could not always separate microvascular disease from epicardial stenoses, but hybrid PET/CT significantly improved this accuracy to 98%. The radiation dose of the combined PET and CT protocols was 9.3 mSv (86 patients) with prospective triggering and 21.8 mSv (21 patients) with spiral CT. Conclusion— Cardiac hybrid PET/CT imaging allows accurate noninvasive detection of coronary artery disease in a symptomatic population. The method is feasible and can be performed routinely with <10 mSv in most patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00627172.

Effects of intracoronary injection of mononuclear bone marrow cells on left ventricular function, arrhythmia risk profile, and restenosis after thrombolytic therapy of acute myocardial infarction

AIMS To assess the efficacy and safety of bone marrow cell (BMC) therapy after thrombolytic therapy of an acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS Patients with STEMI treated with thrombolysis followed by percutaneous coronary intervention (PCI) 2-6 days after STEMI were randomly assigned to receive intracoronary BMCs (n = 40) or placebo medium (n = 40), collected and prepared 3-6 h prior PCI and injected into the infarct artery immediately after stenting. Efficacy was assessed by the measurement of global left ventricular ejection fraction (LVEF) by left ventricular angiography and 2-D echocardiography, and safety by measuring arrhythmia risk variables and restenosis of the stented vessel by intravascular ultrasound. At 6 months, BMC group had a greater absolute increase of global LVEF than placebo group, measured either by angiography (mean +/- SD increase 7.1 +/- 12.3 vs. 1.2 +/- 11.5%, P = 0.05) or by 2-D echocardiography (mean +/- SD increase 4.0 +/- 11.2 vs. -1.4 +/- 10.2%, P = 0.03). No differences were observed between the groups in the adverse clinical events, arrhythmia risk variables, or the minimal lumen diameter of the stented coronary lesion. CONCLUSION Intracoronary BMC therapy is associated with an improvement of global LVEF and neutral effects on arrhythmia risk profile and restenosis of the stented coronary lesions in patients after thrombolytic therapy of STEMI.

Myocardial efficiency during levosimendan infusion in congestive heart failure

Levosimendan, a novel calcium‐dependent calcium sensitizer of the myocardial contractile proteins, also enhances diastolic relaxation and induces peripheral vasodilation by opening potassium channels. To assess the combined energetical effects of levosimendan infusion in vivo, we performed positron emission tomography in patients with decompensated chronic heart failure.

Effect of Cardiac Resynchronization on Myocardial Efficiency and Regional Oxidative Metabolism

Background—Recent studies have demonstrated increased left ventricular contractility with cardiac resynchronization therapy (CRT) using atriobiventricular stimulation. This study evaluated the effect of CRT on myocardial oxidative metabolism and efficiency. Methods and Results—Eight patients with New York Heart Association functional class III-IV congestive heart failure were studied during atrial pacing (control) and atriobiventricular stimulation at the same rate. The monoexponential clearance rate of [11C]acetate (kmono) was measured with positron emission tomography to assess myocardial oxidative metabolism in the left and right ventricles (LV and RV, respectively). Myocardial efficiency was measured using the work metabolic index (WMI). Stroke volume index improved by 10% (P =0.011) with CRT, although both global LV and RV kmono were unchanged compared with control. Septal kmono increased by 15% (P =0.04), and the septal/lateral wall kmono ratio increased by 22% (P =0.01). WMI increased by 13% (P =0.024) with CRT. Conclusions—CRT improves LV function without increasing global LV oxidative metabolism, resulting in improved myocardial efficiency. Oxidative metabolism of the interventricular septum increases relative to the lateral wall, which suggests successful resynchronization.

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.

Clinical Value of Absolute Quantification of Myocardial Perfusion With 15O-Water in Coronary Artery Disease

Background— The standard interpretation of perfusion imaging is based on the assessment of relative perfusion distribution. The limitations of that approach have been recognized in patients with multivessel disease and endothelial dysfunction. To date, however, no large clinical studies have investigated the value of measuring quantitative blood flow and compared that with relative uptake. Methods and Results— One hundred four patients with moderate (30%–70%) pretest likelihood of coronary artery disease (CAD) underwent PET imaging during adenosine stress using 15O-water and dynamic imaging. Absolute myocardial blood flow was calculated from which both standard relative myocardial perfusion images and images scaled to a known absolute scale were produced. The patients and the regions then were classified as normal or abnormal and compared against the reference of conventional angiography with fractional flow reserve. In patient-based analysis, the positive predictive value, negative predictive value, and accuracy of absolute perfusion in the detection of any obstructive CAD were 86%, 97%, and 92%, respectively, with absolute quantification. The corresponding values with relative analysis were 61%, 83%, and 73%, respectively. In region-based analysis, the receiver operating characteristic curves confirmed that the absolute quantification was superior to relative assessment. In particular, the specificity and positive predictive value were low using just relative differences in flow. Only 9 of 24 patients with 3-vessel disease were correctly assessed using relative analysis. Conclusions— The measurement of myocardial blood flow in absolute terms has a significant impact on the interpretation of myocardial perfusion. As expected, multivessel disease is more accurately detected. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00627172.

Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy.

OBJECTIVES The aim of this study was to determine the effect of exercise training on myocardial oxidative metabolism and efficiency in patients with idiopathic dilated cardiomyopathy (DCM) and mild heart failure (HF). BACKGROUND Exercise training is known to improve exercise tolerance and quality of life in patients with chronic HF. However, little is known about how exercise training may influence myocardial energetics. METHODS Twenty clinically stable patients with DCM (New York Heart Association classes I through III) were prospectively separated into a training group (five-month training program; n = 9) and a non-trained control group (n = 11). Oxidative metabolism in both the right and left ventricles (RV and LV) was measured using [(11)C]acetate and positron emission tomography. Myocardial work power was measured using echocardiography. Myocardial efficiency for forward work was calculated as myocardial work power per mass/LV oxidative metabolism. RESULTS Significant improvements were noted in exercise capacity (VO(2)) and ejection fraction in the training group, whereas no changes were observed in the non-trained group. Exercise training reduced both RV and LV oxidative metabolism and elicited a significant increase in LV forward work efficiency, although no significant changes were observed in the non-trained group. CONCLUSIONS Exercise training improves exercise tolerance and LV function. This is accompanied by a decrease in biventricular oxidative metabolism and enhanced forward work efficiency. Therefore, exercise training elicits an energetically favorable improvement in myocardial function and exercise tolerance in patients with DCM.

Adolescence risk factors are predictive of coronary artery calcification at middle age: the Cardiovascular Risk in Young Finns Study

OBJECTIVES The purpose of this study was to examine the roles of adolescence risk factors in predicting coronary artery calcium (CAC). BACKGROUND Elevated coronary heart disease risk factor levels in adolescence may predict subsequent CAC independently of change in risk factor levels from adolescence to adulthood. METHODS CAC was assessed in 589 subjects 40 to 46 years of age from the Cardiovascular Risk in Young Finns Study. Risk factor levels were measured in 1980 (12 to 18 years) and in 2007. RESULTS The prevalence of any CAC was 19.2% (27.9% in men and 12.2% in women). Age, levels of systolic blood pressure (BP), total cholesterol, and low-density lipoprotein cholesterol (LDL-C) in adolescence, as well as systolic BP, total cholesterol, diastolic BP, and pack-years of smoking in adulthood were higher among subjects with CAC than those without CAC. Adolescence LDL-C and systolic BP levels predicted CAC in adulthood independently of 27-year changes in these risk factors. The multivariable odds ratios were 1.34 (95% confidence interval: 1.05 to 1.70; p=0.02) and 1.38 (95% confidence interval: 1.08 to 1.77; p=0.01), for 1-SD increase in adolescence LDL-C and systolic BP, respectively. Exposure to both of these risk factors in adolescence (defined as values at or above the age- and sex-specific 75th percentile) substantially increased the risk of CAC (multivariable odds ratio: 3.5 [95% confidence interval: 1.7 to 7.2; p=0.007]) between groups with no versus both risk factors. CONCLUSIONS Elevated adolescence LDL-C and systolic BP levels are independent predictors of adulthood CAC, indicating that adolescence risk factor levels play an important role in the pathogenesis of coronary heart disease.

Myocardial efficiency during calcium sensitization with levosimendan: A noninvasive study with positron emission tomography and echocardiography in healthy volunteers

Dynamic positron emission tomography (PET) with [11C]acetate allows noninvasive assessment of myocardial oxygen consumption. In combination with echocardiography, PET enables determination of cardiac efficiency (defined as useful cardiac work per unit of oxygen consumption). We used this approach to compare the effects of levosimendan, a Ca2+‐dependent calcium sensitizer, with dobutamine and sodium nitroprusside in healthy male volunteers. The effects of levosimendan on kmono, an index of oxygen consumption, and cardiac efficiency were neutral, whereas the hemodynamic profile was consistent with balanced inotropism and vasodilatation. Dobutamine enhanced cardiac efficiency at the expense of increased oxygen requirement, but the effects of nitroprusside on kmono and cardiac efficiency were neutral. This study shows the feasibility of PET in phase 1 pharmacodynamic studies and suggests potential energetical advantages of calcium sensitization with levosimendan.