Abnormal myocardial fatty acid metabolism in dilated cardiomyopathy detected by iodine-123 phenylpentadecanoic acid and tomographic imaging

The radioidinated synthetic fatty acid iodine-123 phenylpentadecanoic acid (IPPA) has proven useful in the identification of regional abnormalities of cardiac metabolism in patients with myocardial ischemia. The present study was performed to test the hypothesis that the myocardial distribution and turnover of fatty acids, assessed noninvasively with IPPA, are altered in patients with cardiomyopathy. Nine normal volunteers and 19 patients with dilated cardiomyopathy of various etiologies underwent cardiac imaging with single-photon emission computed tomography (SPECT) after intravenous injection of IPPA. Apical short-axis and basal short-axis sections were reconstructed and quantitatively analyzed for relative IPPA activity distribution and washout. Patients with congestive cardiomyopathy demonstrated significantly greater heterogeneity of IPPA uptake than normal subjects (maximal percent variation of activity 27 +/- 11 vs 18 +/- 4, p less than 0.01). They also demonstrated a more rapid percent washout rate than control subjects (24 +/- 8 vs 17 +/- 6 for the apical short-axis section, p less than 0.05; 26 +/- 7 vs 18 +/- 5 for the basal short-axis section, p less than 0.01). These abnormalities of fatty acid distribution and turnover were independent of the etiology of the cardiomyopathy. The degree of heterogeneity of IPPA uptake was significantly related to the patients' New York Heart Association functional class (r = 0.64, p less than 0.01). Thus, compared with normal myocardium, the myocardium of patients with congestive cardiomyopathy demonstrates a more heterogeneous distribution of fatty acid uptake, which parallels the clinical severity of the disease. Furthermore, patients with congestive cardiomyopathy demonstrate a more rapid myocardial clearance of the labeled fatty acid, as assessed with SPECT imaging.     

Coronary circulation and myocardial metabolism in dilated cardiomyopathy

Chest pain is a frequent complaint in patients with dilated cardiomyopathy (DCMP). Myocardial blood flow, coronary circulation parameters and coronary sinus lactate content were measured in 14 patients with DCMP and 10 healthy subjects. Myocardial blood flow in DCMP was 53.1 +/- 3.3 vs. 66.3 +/- 4.9 ml/min/100 g in the control group (p less than 0.05), coronary driving pressure was 59.1 +/- 4.6 vs. 72.8 +/- 8.8 mmHg (p less than 0.01). Subendocardial flow index (DPTI/TTI) in DCMP was 0.76 +/- 0.12 vs. 1.15 +/- 0.19 (p less than 0.01). The lactate content in coronary sinus blood was greater (1.93 +/- 0.45 mmol/l) than in the control group (1.43 +/- 0.48) (p less than 0.05). These results suggest that in DCMP myocardial blood flow is decreased, and in the majority of patients lactate is produced. Thus, it is possible that pain in DCMP is of anginal origin.     

Elevated left ventricular myocardial dopamine in preterminal idiopathic dilated cardiomyopathy

The adrenergic nervous system is chronically activated in patients with congestive heart failure (CHF). One consequence of this is depletion of the normally high levels of myocardial norepinephrine. In this study, myocardial norepinephrine and dopamine concentrations from the left ventricular walls of 3 patients undergoing cardiac transplantation for severe refractory CHF are reported. The dopamine/norepinephrine ratios were high in all 3 patients (29, 58 and 26%). This finding supports data from animal studies suggesting a change in the rate-limiting step for myocardial norepinephrine synthesis in CHF. Conversion of tyrosine to dopa by tyrosine hydroxylase is replaced as the rate-limiting step by inability to hydroxylate dopamine to norepinephrine. Thus, dopamine accumulates while norepinephrine is depleted.     

Familial dilated cardiomyopathy in patients transplanted for idiopathic dilated cardiomyopathy

OBJECTIVE: To evaluate the prevalence, clinical features, and pattern of inheritance of familial dilated cardiomyopathy (DCM) in heart transplant patients. PATIENTS AND METHOD: Patients with idiopathic DCM who had undergone heart transplantation were invited to participate. Patients with alcohol abuse were excluded. A clinical evaluation, 12-lead ECG, echocardiogram, blood tests, and DNA extraction were performed in patients and relatives. Familial DCM was defined as the presence of at least one relative with idiopathic DCM. Possible familial DCM was considered when at least one relative had left ventricular enlargement (LVE) (> 112% predicted LVEDD). RESULTS: One hundred and ninety-nine relatives of 43 families were studied. DCM was familial in 11 probands (25.6%) and possibly familial in 11 (25.6%). Fifteen relatives had DCM (7.5%), 26 (13.1%) LVE, and 5 (2.5%) hypertrophic cardiomyopathy. The pattern of inheritance was autosomal dominant in most families. Five probands (3 with familial DCM) had antecedents of consanguinity and possible recessive inheritance. Six probands (14%, 1 with familial DCM) had relatives with conduction system defects. Creatine kinase was moderately increased in 9 relatives (4.5%), 3 of them with LVE. Fifteen patients had at least moderate alcohol intake. Three of them had familial DCM (relatives without alcohol abuse) and 6 had possible familial DCM. CONCLUSIONS: The prevalence of familial DCM is high in patients who undergo heart transplant. Left ventricular enlargement, conduction system abnormalities, and elevated creatine kinase may be early markers of familial disease. Hypertrophic cardiomyopathy is present in some relatives of patients with idiopathic DCM. Familial DCM is present in patients with a previous diagnosis of alcoholic DCM.     

Characterization of altered myocardial fatty acid metabolism in patients with inherited cardiomyopathy

Inherited defects in myocardial long-chain fatty acid metabolism are increasingly recognized as a cause of cardiomyopathy and sudden death in children. To evaluate whether the phenotypic expression of these genetic diseases could be delineated using positron emission tomography (PET), 11 patients with inherited defects in fatty acid metabolism were evaluated and results were compared with those of 6 nonaffected siblings. Myocardial perfusion, myocardial oxygen consumption (MVO₂), and long-chain fatty acid metabolism were determined noninvasively with PET using quantitative mathematical models. There were no differences in haemodynamics, perfusion, MVO₂ or plasma substrate levels between groups. Patients with defects in enzymes of fatty acid -oxidation (acyl-CoA dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase deficiencies) n = 5 had diminished myocardial palmitate oxidation compared with healthy siblings (3.2 ± 3.0 vs 13.0 ± 5.6 nmol/g per min, p < 0.03) and a decrease in the percentage of MVO₂ accounted for by palmitate (2% ± 3% vs 9% ± 5%), p > 0.04). In these patients, extracted palmitate was shunted into a slow-turnover compartment (predominantly reflecting esterification to triglycerides) with expansion of palmitate in that pool (185 ± 246 compared with 27 ± 67 nmol/g in healthy siblings, p < 0.02). In contrast, myocardium of patients with carnitine deficiency (n = 6 (all on oral carnitine therapy) had normal palmitate extraction but expansion of the interstitial/cytosolic fatty acid pool (617 ± 399 vs 261 ± 73 nmol/g in healthy siblings, p < 0.04), suggesting different mechanisms for handling upstream fatty acyl intermediates. Thus, PET can be used to noninvasively assess abnormal myocardial handling of fatty acids in patients with inherited defects of metabolism. This approach should be useful in the assessment of altered myocardial fatty acid metabolism associated with cardiomyopathy as well as for evaluating the efficacy of therapeutic interventions in affected patients.     

Cardiac resynchronization therapy homogenizes myocardial glucose metabolism and perfusion in dilated cardiomyopathy and left bundle branch block

OBJECTIVES: We investigated whether cardiac resynchronization therapy (CRT) affects myocardial glucose metabolism and perfusion in dilated cardiomyopathy (DCM) and left bundle branch block (LBBB). BACKGROUND: Patients with DCM and LBBB present with asynchronous left ventricular (LV) activation, leading to reduced septal glucose metabolism. Cardiac resynchronization therapy recoordinates LV activation, but its effects on myocardial glucose metabolism and perfusion remain unknown. METHODS: In 15 patients (10 females; 61 +/- 13 years) with DCM and LBBB (QRS width 165 +/- 15 ms), gated (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and technetium-99m ((99m)Tc)-sestamibi single-photon emission computed tomography were performed before and after two weeks of CRT. Uptake of FDG and (99m)Tc-sestamibi was determined in four LV wall areas. Ejection fraction and volumes were calculated from gated PET. RESULTS: Baseline FDG uptake was heterogeneous (p < 0.0001), with lowest uptake in the septal region (56 +/- 12%) and highest uptake in the lateral region (89 +/- 6%). During CRT, septal and anterior increases (p < 0.01) and lateral decreases (p < 0.01) resulted in homogeneously distributed glucose metabolism. Baseline heterogeneity (p < 0.0001) in (99m)Tc-sestamibi uptake was modest (lowest septal 65 +/- 10%; maximum lateral 84 +/- 5%) and also reduced with CRT, although some heterogeneity (p < 0.05) remained. The septal-to-lateral ratio increased with CRT for FDG (0.62 +/- 0.12 to 0.91 +/- 0.26, p < 0.001) and (99m)Tc-sestamibi uptake (0.77 +/- 0.13 to 0.85 +/- 0.16, p < 0.01). The LV end-diastolic and end-systolic volumes decreased from 293 +/- 160 to 272 +/- 158 ml (p < 0.05) and from 244 +/- 164 to 220 +/- 160 ml (p < 0.01), respectively. Ejection fraction increased from 22 +/- 12% to 25 +/- 13% (p < 0.01). CONCLUSIONS: Glucose metabolism is reduced more than perfusion in the septal compared with LV lateral wall in patients with DCM and LBBB. Cardiac resynchronization therapy restores homogeneous myocardial glucose metabolism with less influence on perfusion.     

Prognostic implication of myocardial texture analysis in idiopathic dilated cardiomyopathy.

BACKGROUND AND AIM: Abnormal myocardial acoustic properties have been reported in patients with idiopathic dilated cardiomyopathy (IDC). The aim of this study was to investigate the relationship between quantitative ultrasonic textural alterations of myocardium and clinical outcome in IDC. METHODS: Baseline clinical and echocardiographic variables were obtained from 28 patients with IDC. By using a videodensitometric approach, quantitative myocardial texture analysis was performed on images obtained from septum and posterior wall (PW). Cyclic variation (CV) index of mean gray level (MGL) was calculated according to the formula: (MGLdiast-MGLsyst)/MGLdiastx100. All patients were followed for an average of 11+/-5 months for the occurrence of cardiac death or repeated hospitalization due to worsening of heart failure. RESULTS: During follow-up, 10 patients experienced cardiac events (6 cardiac deaths and 4 heart failure events). The CV indexes of both septum and PW were significantly lower in patients with cardiac events than those of event free patients (6.8+/-9.6% vs. 13.6+/-8.2%, P<0.05 and 5.3+/-6.4% vs.15.7+/-7.2% P<0.001, respectively). Univariate analysis defined the following variables as predictors of outcome: PW-CV index (chi2=13.0, P=0.0003), transmitral E/A ratio (chi2=12.5, P=0.0004), symptom status (chi2=8.7, P=0.003), and septum-CV index (chi2=4.7, P=0.03). Multivariate stepwise regression analysis showed that the PW-CV index (chi2=7.5, P=0.006) and E/A ratio (chi2=6.5, P=0.01) were the independent predictors of outcome. The event-free survival rate of patients with PW-CV index <11% was significantly lower than those with an index > or = 11 (35.7% vs. 92.8%, P=0,001). CONCLUSION: The assessment of severely depressed CV index provides valuable prognostic information in patients with IDC.     

Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction

BackgroundResults on myocardial substrate metabolism in the failing heart have been contradictory. Insulin resistance, a common comorbidity in heart failure patients, and medical therapy may modify myocardial metabolism in complex fashions. Therefore, we characterized myocardial oxidative and free fatty acid (FFA) metabolism in patients with idiopathic dilated cardiomyopathy (IDCM) and investigated the contributions of insulin resistance and β-blocker therapy.Methods and ResultsNineteen patients with IDCM (age 58 ± 8 years, ejection fraction 33 ± 8.8%) and 15 healthy controls underwent examination of myocardial blood perfusion, oxidative and FFA metabolism using positron emission tomography and [¹⁵O]H₂O, [¹¹C]acetate and [¹¹C]palmitate, respectively. Echocardiography was used to assess myocardial function, work, and efficiency of forward work. Insulin resistance was calculated using the homeostasis model assessment index (HOMA index) and the degree of β-blockade was estimated with a β-adrenoceptor occupancy test. IDCM patients were characterized by decreased cardiac efficiency (35 ± 2 versus 57 ± 12 mm Hg·L·g⁻¹, P < .0001) and reduced myocardial FFA uptake (5.5 ± 2.0 versus 6.4 ± 1.2 μmol·100 g⁻¹·min⁻¹, P < .05), but the FFA β-oxidation rate constant was not changed. In the patients, myocardial FFA uptake was inversely associated with left ventricular (LV) ejection fraction (r = −0.63, P < .01), indicating that further depression of LV function induces an opposite switch to greater FFA uptake. The FFA β-oxidation rate constant correlated positively with the HOMA index (r = 0.53, P < .05). In patients on β-1 selective β-blockers, β-1 adrenoceptor occupancy correlated inversely with LV work, oxidative metabolism, and FFA uptake; similar relationships were not found in patients on nonselective β-blocker.ConclusionsMyocardial FFA metabolism is reduced in patients with IDCM. However, when LV function is further depressed and insulin resistance manifested, myocardial FFA uptake and oxidation are, in turn, upregulated. These findings may partly explain the discrepancies between previous studies about cardiac metabolism in heart failure.     

HLA antigens in idiopathic dilated cardiomyopathy

Disturbances of humoral and cellular immunity are common in patients with idiopathic dilated cardiomyopathy and they may contribute to the initiation and maintenance of myocardial damage. HLA antigens were studied in 102 patients with dilated cardiomyopathy and a control hospital population. HLA-DR4 was significantly more common in patients with idiopathic cardiomyopathy (41 patients, 40%) than in the control group (123 patients, 24%). The distribution of other antigens was not significantly different in the two groups. The distribution of blood group antigens, immunoglobulin concentrations, and disease severity was similar in patients with the HLA-DR4 antigen and those without it. These results suggest that HLA-DR4 antigen may be a genetic marker for susceptibility to dilated cardiomyopathy.     

Late potentials in idiopathic dilated cardiomyopathy

Twenty-five patients with idiopathic dilated cardiomiopathy were investigated in order to evaluate the role of late ventricular potentials as possible markers of ventricular tachycardia or sudden cardiac death. Holter monitoring showed ventricular tachycardia in 9 patients (group A) all of whom had late ventricular potentials, (mean +/- SD length 37.22 +/- 15.83 ms and mean +/- SD voltage 5.62 +/- 2.78 microV). Mean +/- SD ejection fraction in this group was 20 +/- 9.39%. In 16 patients (group B), without ventricular tachycardia, means +/- SD ejection fraction 27.5 +/- 8.17%; late ventricular potentials were recorded in 2 patients. During the follow-up period (means +/- SD 11.53 +/- 7.19 months), 3 patients underwent heart transplantation, 2 patients underwent pace-maker implantation and 2 patients from the ventricular tachycardia group died one from sudden cardiac death and the other from progressive heart failure. No significant differences were found in the ejection fraction either between the ventricular tachycardia and the non-ventricular tachycardia group, or between the late ventricular potentials and the non-late ventricular potential groups. Negative data were also obtained when we tried to find a correlation between the ejection fraction and late ventricular potential length and/or voltage. Good results were observed with regard to sensitivity (100%), specificity (87%) and predictive accuracy (81%) but follow-up data did not specify a definite prognostic value for late ventricular potentials. The Authors conclude that late ventricular potentials are markers of patients with idiopathic dilated cardiomyopathy who are prone to ventricular tachycardia. However, the role of late ventricular potentials in sudden cardiac death is still uncertain.     

Prognosis of idiopathic dilated cardiomyopathy

Previous reports in referral populations have emphasized the poor prognosis of dilated cardiomyopathy. This study evaluated mortality and morbidity in patients presenting at a referral center between 1989 and 1993. One hundred seventy-two consecutive patients were studied. At presentation, 82 were in New York Heart Association functional class III/IV. Mean (+/- SD) left ventricular end-diastolic dimension was 69 +/- 11 mm, ejection fraction was 25 +/- 10%, VO2 max was 21 +/- 9 mL/min/kg, and sodium was 136 +/- 9 mM. Treatments included vasodilators (n = 157, 92%), anticoagulation (n = 50, 29%), amiodarone (n = 52, 30%), and cardiac defibrillator (n = 5, 3%). During the follow-up period (mean, 26 +/- 29 months), 16 patients died and 60 developed progressive heart failure; 46 (27%) required cardiac transplantation. The majority of the patients (102, 59%) were stable or improved. Established prognostic determinants (left ventricular end-diastolic dimension, ejection fraction, sodium, and arrhythmia) were of low predictive value for the development of progressive heart failure or sudden death. The 1- and 2-year probabilities of death or transplantation was 16 and 21%, respectively (death only 6 and 7%, respectively). These observations are subject to referral bias, but suggest that the majority of patients can remain stable. Any improvement in survival compared to earlier experience can be due to earlier diagnosis, availability of transplantation, and new heart failure management strategies.     

T-lymphocyte subsets in idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) is a common clinical problem in Africa. To determine if there is a defect of immune regulation in patients with IDC, the percentage of total T-cells (OKT3 positive), helper/inducer cells (OKT4 positive) and suppressor/cytotoxic cells (OKT8 positive) were measured using monoclonal antibodies in 20 patients with IDC and in 20 age-matched normal control subjects. The percentage of helper/inducer cells was significantly higher in the IDC patients (45 +/- 2% mean +/- standard error) than in the normal subjects (33 +/- 2%) and 8 of the 20 IDC patients had a helper/suppressor cell ratio (OKT4/OKT8) higher than the normal range. Of the 8 patients with this abnormality, 7 were studied within 3 months of the onset of their illness. Results suggest that an excessive immune reaction is part of the pathogenesis of IDC in Africans.     

Ventricular arrhythmias in idiopathic dilated cardiomyopathy

Twenty four hour ambulatory electrocardiograms were recorded in 60 patients with idiopathic dilated cardiomyopathy. The diagnosis was based on clinical, laboratory, and cardiac catheterisation findings. All patients had a left ventricular ejection fraction less than 0.55; in 39 it was less than 0.40. Ventricular extrasystoles were evident in all patients: they were rare in 11 (18%), moderately frequent in 24 (40%), and frequent in 25 (42%). Multiform extrasystoles were recorded in 57 patients (95%), paired ventricular extrasystoles in 47 (78%), and non-sustained ventricular tachycardias consisting of three to 19 beats in 25 (42%) of the 60 patients studied. Eight patients had more than five episodes of ventricular tachycardia a day. Patients with atrial fibrillation had the same frequency and grade of ventricular arrhythmias as those with sinus rhythm. Patients with infrequent and frequent ventricular extrasystoles could not be differentiated on the basis of the clinical or haemodynamic findings. The mean values of NYHA functional class, cardiac index, left ventricular end diastolic pressure, and ejection fraction were, however, significantly different in patients with and without ventricular tachycardia. During follow up of 12 +/- 5 months seven patients died; all seven had an ejection fraction less than 0.40. In four patients who died of congestive heart failure, but in only one of the three patients who died a sudden cardiac death, ventricular tachycardia was recorded during ambulatory monitoring. High grade ventricular arrhythmias are often seen in patients with idiopathic dilated cardiomyopathy; patients with ventricular tachycardia have more impairment of left ventricular function than patients without ventricular tachycardia; and ambulatory monitoring may be of little help in identifying patients at increased risk of sudden cardiac death.     

Coronary endothelial dysfunction and myocardial cell damage in chronic stable idiopathic dilated cardiomyopathy

Impairment of endothelium-dependent vasodilatation in response to acetylcholine reflects an abnormal endothelial function. Labelled indium-111 monoclonal antimyosin antibodies enable detection of myocardial cell damage. We analysed whether endothelial dysfunction correlates with myocardial antimyosin uptake in a selected group of patients with idiopathic dilated cardiomyopathy. METHODS: Twenty-two consecutive patients with chronic stable idiopathic dilated cardiomyopathy (18 males and four females) were included. The duration of heart failure symptoms was 46+/-34 months. At inclusion, the functional class of New York Heart Association was 2.1+/-0.7. Endothelial function was evaluated using intracoronary graded concentrations of acetylcholine. Vasomotor responses of the left anterior descending coronary artery were measured by quantitative coronary analysis. Myocardial uptake of antimyosin antibodies was quantified by means of a heart-to-lung ratio (HLR). RESULTS: Eighteen patients showed endothelial dysfunction (82%) and the remaining four patients showed a normal endothelial function. There were no statistically significant differences between patients with and without endothelial dysfunction in relation to clinical, echocardiographic and hemodynamic parameters. In addition, these variables did not correlate with the magnitude of the vasomotor response to acetylcholine. Eighteen patients (82%) showed abnormal antimyosin uptake; 15 of them (83%) showed endothelial dysfunction. The global mean HLR of antimyosin uptake was 1.73+/-0.24. The coronary vasomotor response to acetylcholine correlated with the intensity of uptake of antimyosin antibodies (r=-0.45, P<0.04). CONCLUSIONS: Coronary endothelial dysfunction and myocardial antimyosin uptake was found in a high percentage of patients with chronic stable idiopathic dilated cardiomyopathy. The abnormal vasomotor response seems to be related to the degree of myocardial damage.     

Relation between ventriculoarterial coupling and myocardial energetics in patients with idiopathic dilated cardiomyopathy

Objectives. The purpose of this study was to evaluate left ventricular contractility, arterial loading conditions and the way their interaction affects myocardial energetics.Background. Ventriculoarterial coupling, defined as the ratio of effective arterial elastance to left ventricular end-systolic elastance, is known to reflect the mechanoenergetic performance of the heart. However, relations between the coupling and efficiencies of energy transfer from oxygen consumption to hydraulic energy have not been fully investigated in failing hearts.Methods. Pressure-volume data were measured in 23 patients with idiopathic dilated cardiomyopathy by using a conductance catheter, and myocardial oxygen consumption was obtained simultaneously in 16 patients by a double-thermistor coronary sinus catheter. End-systolic elastance was determined by transient inferior cava occlusion.Results. Data are reported as mean value ± SE. Ventriculoarterial coupling at baseline was 3.14 ± 0.28. It decreased from 3.12 ± 0.43 to 1.86 ± 0.15 (p < 0.05) for the group receiving dobutamine infusion and from 3.16 ± 0.45 to 1.78 ± 0.22 (p < 0.01) for the group receiving the oral phosphodiesterase inhibitor MS-857. The ratio of pressure-volume area to myocardial oxygen consumption had a positive correlation with ventriculoarterial coupling. The ratio of external work to pressure-volume area had a hyperbolic correlation with the coupling. The mechanical efficiency defined as the ratio of external work to myocardial oxygen consumption remained within a narrow range (16.4 ± 1.2%).Conclusions. The degree of ventriculoarterial coupling is far from optimal and the cardiovascular performance is severely depressed mechanically and energetically in patients with idiopathic dilated cardiomyopathy. Although inotropic agents improve the coupling, they have a minimal effect on mechanical efficiency.