Erik Engblom

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.

Infective endocarditis in a Finnish teaching hospital: a study on 326 episodes treated during 1980–2004

Objectives: To evaluate potential changes of infective endocarditis (IE) in patients treated in a Finnish teaching hospital during the past 25 years. Patients: 326 episodes of IE in 303 patients treated during 1980–2004 were evaluated for clinical characteristics and their changes over time. Results: The mean age of the patients increased with time (from 47.2 to 54.5 years, p  =  0.003). Twenty-five (7.7%) episodes were associated with intravenous drug use (IVDU), with a significant increase of these episodes after 1996 (from 0 to 19 (20%), p < 0.001). Viridans streptococci were the most common causative agents of IE during 1980–1994, but after that Staphylococcus aureus was the most common pathogen (p  =  0.015). The proportion of IE of the aortic valve decreased during the study (from 30 (49%) to 26 (27%), whereas the proportions of mitral (11 (18%) to 33 (35%) and tricuspid valve IE (0 to 13 (14%) increased correspondingly (p  =  0.001). This was mainly due to more patients with IVDU. Chronic dialysis for renal failure as an underlying condition increased over time (from 0 to 7 (7.4%), p  =  0.015) but no other predisposing conditions changed. Complications such as neurological manifestations and heart failure did not change in frequency, but the incidence of lung emboli increased (from 0% to 10.5%, p < 0.001); 83% of these emboli occurred in patients with IVDU. The proportion of patients requiring surgical treatment and mortality due to IE did not change. Conclusions: During these 25 years, the causative agents, affected valves and complications of IE changed to some degree. These changes were mainly attributed to the increase of IVDU-associated IE. Except for the increase in age, the clinical presentation and outcome in non-addicts remained substantially unchanged.

The effect of 12-month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease.

SummaryFabry disease (McKusick 301500) is an X-linked lysosomal storage disorder secondary to deficient α-galactosidase A activity which leads to the widespread accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. We have recently shown that the myocardial perfusion reserve of Fabry patients is significantly decreased. Thus, in the present study we investigated, whether it can be improved with enzyme replacement therapy (ERT). Ten patients (7 male, 3 female; mean age 34, range 19–49 years) with confirmed Fabry disease were approved for this uncontrolled, open-label study. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and radiowater. Myocardial perfusion reserve was calculated as the ratio between maximal and resting perfusion. Perfusion measurements were performed before and after 6 and 12 months of ERT by recombinant human α-galactosidase A (Fabrazyme, Genzyme). Plasma Gb3 concentration decreased significantly and the patients reported that they felt better and suffered less pain after the ERT. However, neither resting or dipyridamole-stimulated myocardial perfusion nor myocardial perfusion reserve changed during the ERT. Pretreatment relative wall thickness correlated negatively with posttreatment changes in flow reserve (r = −0.76, p = 0.05) and positively with posttreatment changes in minimal coronary resistance (r = 0.80, p = 0.03). This study shows that 12 months of ERT does not improve myocardial perfusion reserve, although the plasma Gb3 concentration decreases. However, individual variation in the response to therapy was large and the results suggest that the success of the therapy may depend on the degree of cardiac hypertrophy.

Impaired myocardial perfusion reserve but preserved peripheral endothelial function in patients with Fabry disease

SummaryFabry disease (McKusick 301500) is an X-linked lysosomal storage disorder due to deficient α-galactosidase A activity, which leads to accumulation of glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. The effect of this accumulation on peripheral and cardiac vascular function is poorly known. We studied 15 Fabry patients (mean age 35 years and mean BMI 24.8 kg/m2) and 30 age- and BMI-matched healthy controls to examine whether myocardial perfusion reserve and peripheral artery endothelial function are altered. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and H215O. Myocardial blood flow reserve was calculated as the ratio between the dipyridamole-induced maximal blood flow and resting blood flow. Peripheral artery endothelial function was assessed by measuring the brachial artery flow-mediated dilatation using ultrasound at rest and during reactive hyperaemia. The myocardial perfusion reserve was significantly lower in Fabry patients than in controls (3.3 ± 1.2 vs 4.4 ± 1.6, p = 0.02), while the brachial artery flow-mediated dilatation was similar (5.9% ± 3.9%vs 4.5% ± 3.6%, p = 0.27). Thus, inFabry disease, myocardial perfusion reserve is reduced while the peripheral artery endothelial function is preserved.

Eikenella corrodens Prosthetic Valve Endocarditis in a Patient with Ulcerative Colitis

A 33-y-old male with ulcerative colitis developed prosthetic valve endocarditis (PVE) caused by Eikenella corrodens. The outcome of conservative treatment was successful. Only 2 cases of E. corrodens PVE were found in a survey of the English-language medical literature. In contrast to previous data indicating that eikenella infections usually derive from the oral cavity, our patient most likely acquired the infection by colonoscopy and mucosal biopsies, which were performed a few days before onset of the disease.A 33-y-old male with ulcerative colitis developed prosthetic valve endocarditis (PVE) caused by Eikenella corrodens. The outcome of conservative treatment was successful. Only 2 cases of E. corrodens PVE were found in a survey of the English-language medical literature. In contrast to previous data indicating that eikenella infections usually derive from the oral cavity, our patient most likely acquired the infection by colonoscopy and mucosal biopsies, which were performed a few days before onset of the disease.

Early impairment of coronary flow reserve is not associated with Chlamydia pneumoniae antibodies

BACKGROUND: Chlamydia pneumoniae infection has been associated with atherosclerosis by sero-epidemiological, histopathological and interventional studies, and animal experiments. We hypothesized that if chlamydial infection is causative of atherosclerosis, the occurrence of antibodies against C. pneumoniae should be associated with coronary vasomotor dysfunction - an early sign of atherosclerosis. AIM: To study the association between C. pneumoniae infection and coronary vasomotor function in young men without signs of ischemic heart disease. METHODS: Serum IgG and IgA antibody concentrations against C. pneumoniae were determined in 125 clinically healthy subjects undergoing positron emission tomography (PET) studies. Myocardial blood flow was measured at rest and during pharmacologically induced hyperemia using [ 15 O]H 2 O. Coronary flow reserve was calculated as the ratio of hyperemic blood flow to resting blood flow. RESULTS: No association was found between serum C. pneumoniae antibody concentrations and myocardial blood flow parameters. In contrast, more conventional risk factors for coronary artery disease, such as total cholesterol and apolipoprotein B, were inversely associated with hyperemic flow and flow reserve. CONCLUSIONS: We found no association between C. pneumoniae antibodies and coronary vasomotor function in subjects without ischemic heart disease. Thus, these results do not support the role of C. pneumoniae infection as an early phase risk factor for coronary artery disease.

Increased B-type natriuretic Peptide concentration is associated with reduced coronary vasoreactivity in patients with dilated cardiomyopathy but not in healthy young subjects.

Background/Aims. Natriuretic peptides are associated with the cardiovascular disease risk under a range of different circumstances. However, less is known about whether this association is found also in young healthy subjects. Methods. 9 patients with dilated cardiomyopathy and 26 healthy young subjects were studied. The myocardial blood flow measurements were performed basally and during adenosine infusion using PET. Results. S-proBNP concentrations were significantly higher (2153 ± 1964 versus 28 ± 17 ng/L, P = .000002) and adenosine-stimulated flow lower (1.6 ± 0.8 versus 3.6 ± 1.1 mL·g−1·min−1, P = .00001) in patients with dilated cardiomyopathy when compared to healthy subjects. S-proBNP concentration was inversely associated with adenosine stimulated flow in patients with dilated cardiomyopathy (r = −0.75, P = .019) but not in healthy subjects (r = −0.06, P = .84). Conclusions. Natriuretic peptides are inversely associated with coronary vasoreactivity in patients with dilated cardiomyopathy but not in healthy young subjects. Since reduced coronary vasoreactivity seems to be one of the earliest abnormalities in the development of coronary artery disease, this might indicate that natriuretic peptides are not predictor of cardiovascular disease risk in healthy young subjects.

Response to Letters Regarding Article, “Free Fatty Acid Depletion Acutely Decreases Cardiac Work and Efficiency in Cardiomyopathic Heart Failure”

We appreciate the opportunity of answering the points raised in the Letters to the Editor by Fragasso et al and Wiggers et al. Unfortunately, our results have been misinterpreted. The main purpose of our study was not to study the effect of acipimox on cardiac contractile function but to compare the responses in patients with heart failure with those in healthy volunteers.1 Therefore, a placebo group was not necessary. Our initial hypothesis was “that acute FFA depletion would result in …