The development of protocols to cover clinical care in cardiology.

PROCAS (PRofiles Of CAre System) is one of the AIM projects whose objectives are to improve the quality and efficiency of medical treatment. These will be realised in establishing a methodology for defining and developing what are termed "Profiles of Care". These are sets of options for clinicians which are meant to create acceptable ways of managing patients with similar conditions and which represent good clinical practice. Moreover, a prototype system will be realised by the application of informatics and telematics, to enhance the provision of efficient and effective care in both hospitals and outpatient departments. Because of the retrospective nature of the ICD-9-CM system for the classification of cardiological patients, a draft for a Prospective Patient Data Model, which involves the assessment of somatic, psychosocial, environmental and demographic axes, is being presented. This multi-axial evaluation allows for the generation of the smallest unit of diagnostic-therapeutic procedures, based on the definition of the patient's health problem; that is: the patient-orientated diagnosis or the appropriate indication.

Clinical value of studies with radioiodinated heptadecanoic acid in patients with coronary artery disease.

The results described in the literature of myocardial scintigraphy with radioiodinated heptadecanoic acid (IHDA) to detect coronary stenoses are contradictory. In the present study, IHDA scintigraphy was performed in nine control subjects and 67 patients with coronary artery disease. The acquisition time was 75 min and background correction was not applied. The time-activity curves of regions of interest were analyzed by curve fitting with a monoexponential plus constant. Two parameters were used: the halftime value of the monoexponential (T1/2 in min) and the ratio of the amplitude (A) of the monoexponential and the total activity at time t = 0 (amplitude + constant = A + C): A/A + C as a percentage. Based on the control group, a region of normal T1/2 values and A/A + C ratios was defined, for each calculated T1/2-A/A + C pair the probability of originating from a normal region was calculated. The value of the IHDA test, using the index of merit (sensitivity + specificity-100%), increased in the patient group without MI with the severity of the stenosis (21%, 24% and 47% for stenoses greater than or equal to 75%, greater than or equal to 90% and greater than or equal to 99%). In patients with MI, only small positive values in regions of non-infarct-related vessels were found (-1%-16%). It is concluded that the value of the IHDA test to detect stenoses of coronary arteries is too low to apply this test in clinical practice. However, a new type of analysis is offered, based on curve fitting of individual pixels.(ABSTRACT TRUNCATED AT 250 WORDS)

The fate of 131I-17-iodoheptadecanoic acid during lactate loading: its oxidation is strongly inhibited in favor of its esterification. A radiochemical study in the canine heart.

The influence of lactate loading on fatty acid metabolism (pH = 7.4) by the normal canine heart was investigated radiochemically using the radioiodinated fatty acid 131I-17-iodoheptadecanoic acid (131I-17-HDA). Fatty acid metabolism was studied during control conditions (n = 8) and after lactate loading (n = 7). In the canine heart total myocardial 131I-17-HDA radioactivity (uptake) was not changed during the lactate intervention. The oxidation decreased fivefold (measured as free 131I-iodide ion) from 70% to 14% (p less than 0.0001, Student's t-test). Thin-layer chromatography of cardiac lipids demonstrated that the non-oxidized 131I-17-HDA was mainly stored in the triglycerides and phosphoglycerides. These results suggest that lactate inhibits cardiac 131I-HDA oxidation.

The influence of lactate and dipyridamole on myocardial fatty acid metabolism in man, traced with 123I-17-iodoheptadecanoic acid.

Changes in myocardial metabolism can be detected externally by registration of time-activity curves after administration of radioiodinated fatty acids. In this scintigraphic study the influence of lactate on fatty acid metabolism was investigated in the normal human myocardium, traced with 123I-17-iodoheptadecanoic acid (123I-17-HDA). In patients (paired, n = 7) lactate loading decreased the uptake of 123I-17-HDA significantly from 27 (control: 22-36) to 20 counts/min/pixel (16-31; p less than 0.05 Wilcoxon). The half-time value increased to more than 60 min (n = 5), oxidation decreased from 61 to 42%. Coronary vasodilatation, a well-known side effect of lactate loading, was studied separately in a dipyridamole study (paired, n = 6). Coronary vasodilatation did not influence the parameters of the time-activity curve. These results suggest that changes in plasma lactate level as occurring, among other effects, during exercise will influence the parameters of dynamic 123I-17-HDA scintigraphy of the heart.

Biochemistry of radioiodinated free fatty acids.

Radioiodinated free fatty acids have been developed to study myocardial metabolism non-invasively in man. In the present study the distribution of radiolabeled lipids in the myocardium and in arterial and coronary sinus blood was evaluated following injection of three commonly used iodinated fatty acids in fasted (n = 5) and lactate loaded (n = 3) dogs. Five minutes after simultaneous i.v. injection of radioiodinated 17-I-heptadecanoic acid (IHDA), 15-(p-I-phenyl) pentadecanoic acid (IPPA) and 15-(p-I-phenyl)-3,3-dimethyl-pentadecanoic acid (DMIPPA) a biopsy specimen and samples of arterial and coronary sinus blood were taken. After extraction and TLC the relative distribution of radioactivity in the aqueous phase (containing the oxidation products), pellet and organic phase was calculated. The organic phase was further divided into phospholipids, diglycerides, free fatty acids, triglycerides and cholesterol-esters. Seventy two percent of IHDA was oxidized, 36% of IPPA and 7% of DMIPPA. The organic phase consisted primarily of triglycerides and phospholipids. The ratios of triglycerides to phospholipids were about the same for IHDA, IPPA and DMIPPA (0.58, 0.65 and 0.50, respectively). Free IHDA in tissue samples was low (4%) and elevated for IPPA and DMIPPA, (17% and 37%). During lactate loading triglycerides were higher for all three fatty acids. For IHDA and IPPA this increase was paralleled by a decrease in the aqueous phase, in case of DMIPPA the aqueous phase remained the same. Five minutes after injection most of the organic phase of both arterial and coronary sinus blood consisted of the injected fatty acids, the aqueous phase contained oxidation products. There were only minor differences during lactate loading.(ABSTRACT TRUNCATED AT 250 WORDS)

Variables of myocardial backdiffusion, determined with 17-iodo-131 heptadecanoic acid in the normal dog heart.

Under normal and ischemic conditions backdiffusion of radiolabeled non-esterified fatty acids (NEFA) has been demonstrated. In the fasted normal canine heart the extraction fraction (EF) during interventions with glucose or lactate loading, vasodilation, and metabolic level augmentation was determined, and compared with the control EF. Backdiffusion alterations were deduced from the EF changes. After iv injection of 17-iodo-131 heptadecanoic acid (IHDA), 11 blood samples were drawn from aorta and coronary sinus in a time period of 60 minutes. In the control and vasodilation group the EF slowly decreased from 40 to 10%. In contrast, the EF in the noradrenaline group was constant. During glucose and lactate infusion the EF became negative within 10 min and remained negative. These results suggest that during physiological circumstances backdiffusion is determined by the metabolic level of the heart and its substrate availability.

Comparison of 17-iodine-131 heptadecanoic acid kinetics from externally measured time-activity curves and from serial myocardial biopsies in an open-chest canine model.

The relation between the externally measured myocardial time-activity curve and the radiochemically determined kinetics of iodine-131(131I) heptadecanoic acid was studied in an open-chest canine model under different metabolic interventions. Kinetics were assessed by analysis of 12 biopsies taken in an assay period of 90 min. Time-activity curves were fitted with a monoexponential plus constant. The halftime value of the exponential of the external curve corresponded well with the elimination rate of 131I from the myocardium: 14.6 +/- 4.5 min vs. 14.6 +/- 5.3 min. The constant was build up of three components: free 131I in cardiac tissue, the almost constant activity of the radiolabeled free fatty acid (FFA) in the myocardial lipid pool, and the radioactivity of blood and noncardiac tissues. The contribution of blood and noncardiac tissue to the constant amounted to a mean value of 77%. These findings support the analysis of externally measured time-activity curves with a monoexponential plus constant curve fit, in which background correction is not necessary. In cases where lipid storage is predominantly present, high T1/2 values, both internally and externally, were found, which were fitted with a monoexponential curve. It can be concluded that externally measured time-activity curves reflect satisfactorily the kinetics of radioiodinated heptadecanoic acid.

Pacing and the non-invasive evaluation of myocardial fatty acid metabolism by means of 17-123I-heptadecanoic acid scintigraphy.

The extent of myocardial non-esterified fatty acid (NEFA) oxidation depends among other things on exogeneous NEFA supply and energy demand. In 6 patients with a multi-programmable pacemaker scintigraphy with 17-123Iodo-heptadecanoic acid (17-123I-HDA) was performed to investigate NEFA metabolism at two levels: at a control level (basal heart rate 69 +/- 6) and at increased pace frequency (104 +/- 5). In both situations the derived time-activity curves, measured during a period of 75 min, were fitted with a monoexponential plus a constant curve: A(t) = A(0).exp (-t In2/T1/2) + C. The half-time value, the uptake measured as the peak activity and the relative size of the oxidation pool were determined. The median of the half-time value did not change: 24 min (range 19-31) in the control heart rate study and 22 min (19-27) during the increased pace frequency study. The median of the uptake increased significantly from 33 cpm/pixel/2 mCi/100 kg (23-34) to 40 cpm/pixel/2 mCi/100 kg (35-42; p less than 0.05 Wilcoxon). The median of the relative size of the oxidation pool increased from 57% (52-62) to 69% (63-71; p less than 0.05). We conclude that during pacing the augmented need for NEFA resulted in a demonstrable increase in uptake and oxidation of 17-123I-HDA. This result suggests that radioiodinated NEFA may be a valuable tool to quantify noninvasively the level of the myocardial NEFA metabolism in the human heart.

Feline left ventricular oxygen consumption is not affected by volume expansion, ejection or redevelopment of pressure during relaxation.

We studied the dependency of myocardial oxygen consumption on the mechanical events during left ventricular relaxation in isolated supported cat hearts. The volume of the left ventricle was controlled by means of a balloon connected to a membrane pump. Oxygen consumption (MVO2 in cm3.min-1.100 g-1) for three protocols (PROT) performed at peak isovolumic pressure, was studied: (1) rapid ejection to zero pressure, (2) partial rapid ejection followed by redevelopment of pressure, (3) volume expansion during relaxation, and compared with oxygen consumption of isovolumic (ISOV) beats. We found (mean +/- SD): (table; see text) In the protocols 1 and 3 the differences were not significant (paired Student's t-test, p greater than 0.05). In protocols 1 and 2 left ventricular volume was decreased up to 2.15 cm3 (i.e. stroke volume, SV) during the pressure release. We studied the specific effect of ejection (i.e., wall muscle shortening) in a fourth protocol in which the ventricle ejected up to 2.7 cm3 under nearly zero pressure load (isobaric contraction). There was a small amount of oxygen consumption associable with this unloaded ejection i.e. MVO2 = 3.38 (+/- 0.47) + 0.30 (+/- 0.16) SV, but it was too small to compensate for a decrease in MVO2 expected from the pressure release according to the tension time index. These findings suggest that oxygen consumption does not depend on the mechanical events during ventricular relaxation.

Analysis of myocardial time-activity curves of 123I-heptadecanoic acid. I. Curve fitting.

Myocardial time-activity curves can be described by two or more parameters. To establish the optimal curve fitting method 33 myocardial time-activity curves were analyzed with different curve fitting methods: monoexponential, biexponential and monoexponential plus constant. A background correction was not applied. Biexponential curve fitting resulted in redundancy of parameters. Optimal curve fitting was obtained with monoexponential plus constant. The constant represents the background activity together with the stored radiolabelled lipids and the half-time value represents the wash-out of radioiodide from the myocardium. A strong relation was found between the constant and the half-time value: small errors in the determination of the constant (background activity) resulted in considerable errors of the half-time value. It is concluded that optimal analysis of a myocardial time-activity curve can be performed with a monoexponential plus constant without earlier correction for background activity.

Analysis of myocardial time-activity curves of 123I-heptadecanoic acid. II. The acquisition time.

Optimal fitting of a myocardial time-activity curve is accomplished with a monoexponential plus a constant, resulting in three parameters: amplitude and half-time of the monoexponential and the constant. The aim of this study was to estimate the precision of the calculated parameters. The variability of the parameter values as a function of the acquisition time was studied in 11 patients with cardiac complaints. Of the three parameters the half-time value varied most strongly with the acquisition time. An acquisition time of 80 min was needed to keep the standard deviation of the half-time value within +/- 10%. To estimate the standard deviation of the half-time value as a function of the parameter values, of the noise content of the time-activity curve and of the acquisition time, a model experiment was used. In most cases the SD decreased by 50% if the acquisition time was increased from 60 to 90 min. A low amplitude/constant ratio and a high half-time value result in a high SD of the half-time value. Tables are presented to estimate the SD in a particular case.

The influence of glucose on the myocardial time-activity curve during 17-iodo-123 heptadecanoic acid scintigraphy.

The lipid pools of the heart (i.e. the triglyceride and phospholipid pool) participate in the free fatty acid metabolism. The degree of involvement, for instance will be determined by the available substrate in the blood. Scintigraphy with 17-iodo-123 heptadecanoic acid was performed to study free fatty acid kinetics in the normal human myocardium during control and glucose infusion (n = 9). In both situations the derived time-activity curves, measured during a period of 75 min, obeyed a monoexponential plus a constant curve fitting [A(t) = A(o)exp(-tln2/T1/2)+C]. During glucose infusion the half-time values did not change but the lipid storage increased in favour of the oxidation pool. In the three protocols used, hypoglycaemic responses were observed, therefore these protocols cannot be advocated.

Mechanical determinants of myocardial energy turnover.

Energy turnover of the left ventricle does not differ in isovolumic contractions and contractions where pressure is released from peak to zero. This experimental result corresponds to predictions from a time varying elastance model of the mechanical and energetic properties of the left ventricle. To assess the validity of this model for cardiac muscle in general, experiments were designed to investigate whether mechanical and energetic behaviour of isolated cardiac muscle preparations could also be predicted from the time varying elastance model. The results obtained so far indicate, however, that not all experimental results can be accommodated by the model. This suggests that the value of the model may be limited.

Radioiodinated free fatty acids; can we measure myocardial metabolism?

To investigate the feasibility of radioiodinated free fatty acids for 'metabolic imaging', the kinetics and distribution pattern of metabolites of 131I-heptadecanoic acid were studied in canine myocardium throughout metabolic interventions. In control dogs and in dogs during glucose/insulin and sodium lactate infusion, biopsy specimens were taken during a 90-min period after 131I-HDA administration and analyzed. Clearly distinct patterns of distribution and elimination were seen during the metabolic interventions, indicating the usefulness of iodinated fatty acids for metabolic studies.

Metabolic fate of radioiodinated heptadecanoic acid in the normal canine heart.

To clarify the metabolic fate of radioiodinated heptadecanoic acid in myocardium, the time course and distribution of the radioactivity over 131I-heptadecanoic acid, free radioiodide, and various lipids (with incorporated iodoheptadecanoic acid) were determined in normal canine myocardium. In 10 dogs seven biopsy specimens were taken over 30 min after injection of 131I-heptadecanoic acid. The radioactivity in the specimens increased until the fifth minute and decreased thereafter, with a half-time of 36 min. In the fifth minute, 61% of the radioactivity was free iodide, and its curve paralleled the curve of the total radioactivity. As early as the first minute 131I-heptadecanoic acid activity was reduced to 14% and decreased further. Activity of radioiodinated phospholipids, (mono, di, tri)-glycerides, and cholesterol-esters remained constant after an initial increase. These results indicate that immediately after uptake, 131I-heptadecanoic acid is either metabolized, liberating the radioiodide, or stored in lipids. Because the activity of radiolabeled lipids remained constant during the study period and because iodide activity paralleled the total activity in biopsy specimens, it is concluded that in normal myocardium, washout of free radioiodide determines the elimination rate as observed during a scintigraphic study. Thus the elimination rate cannot be related to the beta-oxidation rate as previously supposed.