[Methods for organisational health services research]. / Methoden für die organisationsbezogene Versorgungsforschung.

On 1 July 2009, the German Network for Health Services Research [Deutsches Netzwerk Versorgungsforschung e. V. (DNVF e. V.)] approved the Memorandum III "Methods for Health Services Research", supported by the member societies mentioned below and published in this journal (Gesundheitswesen 2009; 71: 505-510). The focus of this part of the Memorandum III "Methods for health services research" is on the questions and methods of organisational health services research. In a first step, we describe the central questions which are at the core of organisational health services research. In a second step, we describe the methodological standards and requirements with regard to a) sampling, b) measurement and c) research design. We present a phase model for complex intervention trials. This model allows to conduct high quality organisational health services research, to integrate different methods of social research and to show in which phase they are of special importance.

Intensive treatment of coronary artery disease in diabetic patients in clinical practice: results of the MITRA study.

Patients with diabetes are at high risk for the development of coronary artery disease and have a significantly impaired prognosis after ST-elevation myocardial infarction (STEMI) as compared with non-diabetic patients. The beneficial effect of pharmaceutical treatment for secondary prevention after STEMI is proven also for diabetics, but little is known about its use in clinical practice. Between June 1994 and December 2000, consecutive patients with STEMI, admitted to hospital within 24 h of symptoms onset, were enrolled into the multicenter MITRA registry in 61 hospitals in Germany. We examined whether there were differences in the frequencies of pharmaceutical secondary prevention after STEMI and in long-term outcomes between diabetics and nondiabetics in 8206 patients who had been discharged alive and followed for a mean period of 17 months. The prevalence of diabetes in 8206 patients discharged alive after acute STEMI was 18%. Diabetics were older and more often female, and more often already had prior myocardial infarction (MI) and stroke than non-diabetics. As chronic discharge medication, diabetics received aspirin and betablockers less often, but more often ACE inhibitors than non-diabetics. The mortality rate 17 months after STEMI was nearly twice as high in diabetics than in non-diabetics (19.1% vs. 10.4%, p<0.01 at univariate analysis; OR=1.50 and 95% CI 1.27-1.77 at multivariate analysis). The combined endpoint of death, MI and stroke occurred in 25.8% of diabetics, but only in 15.8% of non-diabetics ( p<0.01). Long-term treatment with aspirin, betablockers and ACE inhibitors in diabetics was associated with a significant reduction of mortality. Diabetics received intensive pharmaceutical therapy for secondary prevention significantly less often than non-diabetics, although the beneficial effects of this treatment were similar or even more pronounced as compared with non-diabetics. Diabetes was an independent predictor of increased mortality in follow-up after acute STEMI. Intensifying secondary prevention by a more frequent use of established pharmaceutical regimes might improve the prognosis of diabetics after STEMI and prevent cardiovascular and cerebrovascular events.

[Double nuclide myocardial scintigraphy with thallium 201 and iodine 123-heptadecanoic acid--the possibilities in cardiological diagnosis]. / Doppelnuklidmyokardszintigraphie mit Thallium 201 und Jod 123-Heptadekansäure--Möglichkeiten in der kardiologischen Diagnostik.

UNLABELLED: We studied in 11 patients the individual variable pattern of coronary blood supply after the end of diagnostic coronary catheterisation by intracoronary injection of T1201 into the left and J 123-heptadeconic acid into the right coronary artery. In 4 static views computer aided quantitative analysis of circumferential profiles was performed. Based on Schlesinger's criteria three types of coronary arterial patterns were defined (right, left preponderant, balanced) after the presentation in the angiographic projections. CONCLUSIONS: Sharp boders between different perfusion areas could be detected by the gamma camera. If patients with right preponderant circulation are compared with balanced circulation, the perfusion areas of the left coronary artery are greater in all cases with balanced circulation than expected. More important for the indication of coronary artery surgery is that a considerable area of the left ventricular myocardium is perfused by the right coronary artery independent of the anatomical perfusion pattern with the exception of the left preponderant type.

[Comparison of T1201 stress scintigraphy and rest and stress ventriculography with respect to the degree of stenosis and collateral findings]. / Vergleich von T1 201 Belastungsszintigraphie, Ruhe- und Belastungsventrikulographie unter Berücksichtigung von Stenosegrad und Kollateralbefund.

The influence of coronary obstructions and collaterals on the results of T1 201 myocardial scans and regional wall motion on ventriculography at rest and after pacing was examined with digital observer-independent methods, whereby criteria for positive and negative findings were defined in advance. The results indicate the high accuracy of 201-thallium scans in the detection of coronary artery disease in symptomatic single vessel disease, when the lesions obstruct greater than 60% of the vascular diameter. Cineventriculography at rest is inefficient as a test for this purpose. Ventriculography after pacing produced regional dysfunction in most of the patients and was comparable in its accuracy to T1 201 scans. A correlation of severity of stenoses and regional wall motion was not possible in the presented population. Collateral function is able to provide O2 supplies for normal myocardial function at rest and becomes insufficient during exercise and pacing. These results of T1201 stress scintigraphy correspond with results of stress ventriculography.

Myocardial protection by collateral vessels during experimental coronary ligation: a prospective study in a canine two-infarction model.

Previous work of this laboratory has shown that collateral flow can be increased over six weeks by a subcritical external constriction of the circumflex artery causing a 50 +/- 10% reduction of postocclusive reactive hyperemia. To investigate collateral function in acute myocardial infarction, the model was used to ligate two distant coronary branches on the ventricle simultaneously in order to compare in 8 dogs infarct size and perfusion area of the ligated vessels in control and collateralized sections. The acute collateral flow measured 7.2 +/- 2.5 ml/100 g/min-1 and increased to 17.3 +/- 6.7 (p less than 0.001) over 6 weeks. Separate analysis revealed a predominant increase of collateral flow in the epicardial layers 23.1 +/- 7.5 (p less than 0.01) versus 6.9 +/- 2.8 (p less than 0.01) in the subendocardium. Infarct size in the control area was 52.0 +/- 14.7% of the perfusion area, in the collateralized zone 19.0 +/- 14.2% (p less than 0.001). Infarct size expressed as per cent of perfusion area and collateral flow in the area at risk expressed as per cent of flow of normal sections correlated: (r = 0.76; p less than 0.05). Therefore, infarct size after a 6 hour coronary occlusion can be considered a function of the collateral flow over normal perfusion ratio. Localized induction of collaterals in this model caused a significant reduction of infarct size in relation to the perfusion area at risk.

[Hemodynamics of coronary stenoses]. / Hämodynamik von Koronarstenosen.

Under physiological conditions the resistance component of large epicardial coronary branches is very small in relation to total coronary resistance and can be neglected. The pressure losses across minor stenoses can be compensated by a decrease of resistance in the more peripheral coronary bed (autoregulation). This compensatory mechanism is limited to luminal obstructions less than 85%. Above this limit, when collateral vessels are not available, perfusion of the periphery becomes a function of the flow across the stenosis. As a consequence coronary reserve becomes abolished with an increasing obstruction. Coronary reserve describes an increase of coronary flow up to a factor of five, which, under normal conditions, is induced by dilation of resistors (arterioles) in the coronary bed. After exhaustion of coronary reserve the hemodynamic impact of a vascular narrowing can be expressed as the pressure loss across a coronary lesion (delta p). delta p is composed of viscous losses (AV) that are in linear relation to flow and inertial components that are related to the square of flow (B). Accordingly pressure loss across a stenosis can be expressed in a general form as delta p = AV X Q + B X Q2. In vitro data show that an approximation of delta p can be calculated on the basis of stenosis geometry including normal and minimal diameter, length, angle of entrance and exit, velocity of flow, viscosity and density of blood. Pressure losses across a stenosis can be divided in three components: the entrance, the narrow part, and the exit. Turbulence arises at the exit. This fact leads to a variable interaction of consecutive vascular lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative angiographic assessment of coronary stenoses: problems and pitfalls.

A precondition for quantitative angiography is strict standardization of all geometric parameters, i.e., position of the patient and radiation-source-object-image geometry. Correction for respiratory and cardiac cycles is equally important. When all these variables are controlled, the absolute size of a vessel can be a major source of error, since border recognition becomes progressively difficult with decreasing vascular diameter. Finally, contrast density, independent of vascular geometry, will induce errors by virtual magnification of minimal diameters. The results in this paper show the influences of image intensifier position, angulation of the imaging device, and contrast concentration on the geometry of model coronary stenoses when evaluated with computer-assisted quantitative methods. Increase of object-image intensifier distance led to an underestimation of size which increased with decreasing vascular diameter. Decrease in contrast concentration led to a significant overestimation of actual size, up to 20% (p less than 0.05). This effect could be confirmed in human coronary arteriograms (n = 11, p less than 0.05). In conclusion, realistic contrast-perfused calibration devices will have to be developed to replace wire or plaster models in order to control systemic errors that may impede the measurement of absolute vascular size.

Effect of myocardial oxygen consumption on infarct size in experimental coronary artery occlusion.

The influence of myocardial oxygen consumption (MVO2) at the moment of coronary occlusion on the size of the ensuing necrosis was investigated in 12 anaesthetised dogs. A two-infarction model was used with a sequential occlusion of two distant coronary branches in the same heart, however under different levels of MVO2. One group of occlusions was produced at a high MVO2 of 21.6 +/- 3.0 ml O2 . min-1 . 100 g-1. This group was compared with a second in which necrosis proceeded at a low MVO2 estimated to be 5.9 +/- 1.5 ml O2 . min-1 . 100 g-1 averaged over a 90-min occlusion period. Infarct size expressed as percentage of perfusion area was 43 +/- 28% in group 1 and 11 +/- 11% in group 2 (p less than 0.005). The mass of the perfusion area was equal in both groups (17 +/- 4 g, 19 +/- 6 g). The amount of myocardial necrosis, which after a 90-min occlusion depends on the acute collateral blood flow, was in every case greater under high MVO2. Thus a low MVO2 at the moment of occlusion can postpone myocardial necrosis.

Comparison of Björk-Shiley ABP and St. Jude Medical Prostheses in a newly developed pulse duplicator.

Pre-clinical and clinical testing of artificial heart-valves has not been standardized. Therefore different centers have been using individual procedures. As a consequence, the results from different laboratories on different valves can be compared only after certain assumptions. In order to compare different valves under identical conditions, a pulse duplicator was developed and the Björk-Shiley and St. Jude Medical valves were studied in the aortic position under pulsatile flow, at stroke volumes ranging from 40 to 90 ml and frequencies from 40 to 130 cpm. Linear relationships were observed between the gradients as measured across the artificial valves and both, stroke volume and frequency. Loss of pressure divided by stroke volume, expressed as a function of frequency, was found to be a simple parameter to describe the fluid mechanical properties of an artificial valve under pulsatile flow and to compare different types of devices. The comparison of BS ABP and SJM aortic prostheses of equal diameter revealed the fluid mechanical properties of the SJM valve to be superior to those of the BS prosthesis under identical testing conditions.

Echocardiographic identification and analysis of function of the St. Jude medical heart valve prosthesis.

The St. Jude medical (SJM) heart valve prosthesis presents a new bi-leaflet design which in preclinical evaluation exhibited favourable haemodynamic characteristics. Therefore clinical trials started in February 1978. The entire valve is made of pyrolytic carbon which has a poor X-ray visibility and therefore an alternative for the noninvasive routine control of valvular function and postoperative follow-up had to be found. Experimental studies in a left heart simulator provided adequate echovisualisation of both leaflets, however, depending on the direction of their motion in relation to the echobeam. Identification of both leaflets and an analysis of their motion was possible with a transducer at right angles to the leaflet axis. The experimental data were confirmed by clinical observations after implantation of the SJM prosthesis in patients. Based on the information obtained, we are providing recommendations for the implantation of the SJM prosthesis in order to achieve optimal echocardiographic visualisation of the valve and its moving parts in the postoperative follow-up.

Heart valve replacement with the St. Jude medical prosthesis -- first clinical results --.

Starting in February 1978 52 St. Jude Medical Prostheses have been implanted in 47 patients (age 13--73 years) in aortic, mitral and tricuspid positions. Perioperative death occurred in 3 cases. Post mortem examination of these patients showed unimpaired valvular function. There were no other complications in an accumulated total valve time of approximately 300 months. Prior to surgery and post-operatively, several hemolytic parameters were analyzed. There was only a mild elevation in Serum LDH (285 +/- 10 iV/L). Fifteen patients underwent recatheterization 3 months postoperatively. The mitral valves did not reveal an enddiastolic gradient at rest, while the aortic valves had a peak to peak gradient of 8 +/- 2.1 mmHg. A standardized stress consisting of an infusion of isoproterenol was used. The results were compared to results obtained in patients with Björk-Shiley prostheses under identical conditions and did not show a significant difference. The preliminary hemodynamic findings correlate with preceding in vitro results and preclinical data, and the first clinical experience is promising.

Release of lysosomal enzymes during ischemic injury of canine myocardium.

The pathobiology of the process of myocardial injury during ischemia comprises a series of events that results in the release of lysosomal enzymes from their subcellular locations within the myocardium. We have developed a canine model of acute myocardial ischemia in which the anterior descending coronary artery is ligated, myocardial blood flow is measured using radioactive microspheres, and tissues from subendocardium and subepicardium are assayed for activity of lysosomal hydrolases:N-acetyl-beta-glucosaminidase (NAG), beta-glucuronidase (beta-gluc), and acid phosphatase (AP). Particulate fractions of subendocardium revealed significant depletion of of total acid hydrolases (NAG, beta-gluc, and AP) after one and two hours of ischemia. In addition, after two hours of ischemia, the total activity of these three hydrolases in the subendocardial supernatant was decreased, correlating significantly with diminished myocardial blood flow (NAG: r =0.96; beta-gluc: r = 0.95; AP: r = 0.75). The diminished enzymatic levels in thesupernatant suggested "washout" of the hydrolases that was more efficient in those ischemic areas that had higher myocardial flow (greater than 20% of control). These changes in distribution of lysosomal hydrolases indicate early involvement of these enzymes in the pathobiology of myocardial injury and demonstrate the dynamic relationship of "washout" of acid hydrolases with the degree of diminished blood flow.

Effect of collateral flow on epicardial and endocardial lysosomal hydrolases in acute myocardial ischemia.

Early changes in lysosomal enzymes must occur if their role is significant in irreversible myocardial injury. Therefore, we ligated the anterior descending coronary artery in 14 dogs and after 60 min excised epicardial and endocardial samples from the ischemic and adjacent normal heart. The collateral flow measured with radioactive microspheres in the endocardial samples averaged 19% of control. The muscle was disrupted and fractionated by ultracentrifugation into nuclear pellet (NP), heavy lysosomal pellet (HL), light lysosomal pellet (LL), microsomal pellet (M) and supernate (S). Electron microscopy demonstrated changes characteristic of sichemia in whole tissues and sedimented fractions. Acid phosphatase reaction product was present in residual bodies in the HL fraction and membrane-bound vesicles in the LL fraction and in the intact tissue. Significant decreases in the specific activity of N-acetyl-beta-glucosaminidase and beta-glucuronidase occurred in the endocardial LL fraction, while significant increases in both were found in the ts fraction (P less than 0.05). Losses of acid phosphatase occurred in both LL and S fractions. Moreover, decreases of total N-acetyl-beta-glucosaminidase in the HL fraction and of total beta-glucuronidase and acid phosphatase in the LL fraction were positively correlated (P less than 0.01) with the degree of ischemia measured with radioactive microspheres. Only insignificant enzymatic changes were found when the collateral flow was greater than 40%, and the differences were less significant in epicardial samples where the flow averaged 29%. The early loss of enzymes from the lysosomal fractions in severe ischemia suggests a role for lysosomal hydrolases in the necrosis that follows coronary occlusion.

Phospholipase A and acid lipase activity during release of lysosomal hydrolases.

Hydrolysis of cardiac and hepatic lysosomal phospholipids by endogenous phospholipase A occurs during incubation at 37 degrees C at pH 5.0. Lysophospholipids and free fatty acids accumulate in association with release of hydrolases from the lysosomes into the supernatant. Acid-active neutral lipid lipases contribute to the release of free fatty acids. Albumin inhibits the production of these surface-active lipids as well as the release of hydrolases. The soluble phospholipase A is inhibited by albumin, soluble protein (cytoplasmic), heparin, and protamine sulfate. Thus, hydrolysis of lysosomal lipids, catalyzed by endogenous phospholipases, as well as acid-active neutral lipid lipases, may contribute significantly to the increased permeability, swelling, and subsequent lysis of lysosomes. Stabilization of the lysosomal membrane is associated with integrity of the structural lipids of the membrane.

Lysosomes of cardiac and skeletal muscle: resolution by zonal centrifugation.

The application of zonal centrifugation to the analysis of homogenates of cardiac and skeletal muscle permits selection of fractions that are enriched in markers for lysosomes, sarcolemma, sarcoplasmic reticulum, and mitochondria. The method of disruption of normal and pathological tissue alters significantly the distribution of total protein and peaks of enzymatic activity on the gradient. Total activities of cathepsin, N-acetyl-beta-glucosaminidase, beta-glucuronidase, and para-nitrophenylphosphatase are distributed at different concentrations of sucrose on the gradient. Beta-Glucuronidase appears to "mark" the sarcoplasmic reticulum, as well as lysosomes, of skeletal muscle, para-Nitrophenylphosphatase, a common marker of acid phosphatase of lysosomes, is enriched in those fractions of cardiac muscle containing the highest specific activity of ouabain-inhibited Na-K-ATPase. Thus, these two enzymes appear to have a localization in at least two separate organelles. On the other hand, these results may indicate the isolation of several "populations" of lysosomes that are associated constantly with distribution peaks of other organelles. In any event, attempts to correlate changes in structure of organelles of normal and pathological specimens of tissue with functional impairment, e.g., Ca2+ uptake, activity of Na-K-ATPase, etc., must include consideration of dual localization of enzymatic markers or cross contamination by populations of other organelles.

Structural and functional characteristics of membrane fractions from cardiomyopathic and dystrophic muscle.

Subcellular fractions from ventricular muscle of the cardiomyopathic Syrian hamster and breast muscle from the dystrophic chicken were prepared by zonal centrifugation in sucrose gradients. This tenchnique permitted the analysis of a wide spectrum of subcellular particles prior to sedimentation, thus avoiding loss of activity through particle clumping. Substantial differences in the distribution of beta-glucuronidase and p-nitrophenyl-phosphatase in zonal fractions from myopathic and control tissues provided evidence for contamination of fractions containing fragmented sarcoplasmic reticulum by lysosomes. This contamination may contribute signifantly to the altered lipid composition and Ca2+ transport function of the myopathic preparations.