The effect of insulin on the heart: Part 2: Effects on function during and post myocardial ischaemia.

Insulin infusion has been advocated in the treatment of myocardial ischaemia and myocardial infarction. There is evidence from experimental animal studies for a protective effect of high-dose insulin administration in myocardial ischaemia and myocardial infarction. In some relatively small study populations a reduction in mortality was reported in those patients who received glucose-insulin-potassium (GIK) during myocardial infarction, which was confirmed in two meta-analyses. However, it has not been possible to reproduce these positive results in large randomised clinical trials. (Neth Heart J 2010;18:255-9.).

Effects of high-dose insulin infusion on left ventricular function in normal subjects.

Background. Only a few studies have reported on the effect of high-dose insulin (HDI) infusion on cardiac function in healthy volunteers. Methods. We studied ten healthy volunteers with low-dose dobutamine (LDD, 10 mug/kg/min) echo-cardio-graphy and HDI echocardiography (insulin administration for one hour) by volume and Doppler analysis. Results. During LDD, cardiac output increased from 5.7+/-1.3 l/min to 9.0+/-2.1 l/min (p<0.001) and during HDI from 5.5+/-1.2 l/min to 6.2+/-1.1 l/min (p=0.048). Increase was not only due to increase in frequency, which was only present in the LDD study, but also due to increase in stroke volume (from 82+/-15 ml to 110+/-23 ml, p<0.001 during LDD and from 82+/-16 ml to 93+/-24 ml, p=0.014 during HDI). The increase in stroke volume was the result of a decrease in end-systolic volume with an unchanged end-diastolic volume. Conclusion. High-dose insulin infusion results in increased cardiac output by improving systolic myocardial function. (Neth Heart J 2010;18:183-9.).

The effect of insulin on the heart : Part 1: Effects on metabolism and function.

Positive inotropic effects of insulin were described early after the isolation of insulin from the pancreas but data on the effect of insulin on the heart are conflicting. Systemic insulin administration results in a reduction in circulating free fatty acids and an improvement in myocardial glucose uptake, which causes an efficiency improvement in the myocardial cell. There is strong evidence that insulin administration results in functional improvement in dysfunctional myocardium. (Neth Heart J 2010;18:197-201.).

Calcium sensitivity of force in human ventricular cardiomyocytes from donor and failing hearts.

In failing human myocardium changes occur, in particular, in isoform composition and phosphorylation level of the troponin T (TnT) and troponin I (TnI) subunits of the actin filament and the myosin light chains (MLC-1 and -2), but it is unclear to what extent they influence cardiac performance. This overview concentrates on the relation between contractile function, contractile protein composition and phosphorylation levels in small biopsies from control (donor) hearts, from biopsies obtained during open heart surgery (NYHA Class I-IV) and from end-stage failing (explanted, NYHA class IV) hearts. Furthermore, attention is paid to the effect of the catalytic subunit of protein kinase A on isometric force development in single Triton-skinned human cardiomyocytes isolated from donor and end-stage failing left ventricular myocardium at different resting sarcomere lengths. A reduction in sarcomere length from 2.2 to 1.8 microm caused reductions in maximum isometric force by approximately 35% both in donor and in failing cardiomyocytes. The midpoints of the calcium sensitivity curves (pCa50) of donor and end-stage failing hearts differed markedly at all sarcomere lengths (mean delta pCa50 = 0.22). Our findings indicate that 1) TnI phosphorylation contributes to the differences in calcium sensitivity between donor and end-stage failing hearts, 2) human ventricular myocardium is heterogeneous with respect of the phosphorylation of TnT, MLC-2 and the isoform distribution of MLC-1 and MLC-2, and 3) the Frank-Starling mechanism is preserved in end-stage failing myocardium.

Image-derived input functions for determination of MRGlu in cardiac (18)F-FDG PET scans.

UNLABELLED: Image-derived input functions (IDIF) are frequently used in cardiac (18)F-FDG PET studies for determination of the myocardial metabolic rate of glucose (MRGlu). The purpose of this study was to assess which vascular structure is most suited for defining the IDIF, using online arterial blood sampling (AS) as the gold standard. METHODS: In 18 patients with ischemic heart disease, 370 MBq FDG were injected during a hyperinsulinemic euglycemic clamp. Studies were performed with a Siemens/CTI HR+ PET scanner using a dynamic scanning protocol. A fully automated blood-sampling device was used for continuous AS. IDIF were obtained using regions of interest (ROIs) of 3 different sizes defined on the left ventricle (LV), left atrium (LA), ascending aorta (AA), and descending aorta (DA). MRGlu was calculated with all input functions. Ratios between MRGlu obtained with IDIF and AS were calculated for each patient. RESULTS: Time-activity curves from smaller ROIs suffered more from statistical noise with only a modest reduction of spillover effects, which led to more variation in calculated MRGlu. Mean ratios of MRGlu obtained with IDIF and AS were close to 1 when AA and DA (0.97 +/- 0.07 and 1.00 +/- 0.11, respectively) were used to define the input function. However, when LA and LV were used, mean ratios were 0.81 +/- 0.06 and 0.79 +/- 0.08, respectively, reflecting a significant underestimation of MRGlu. The use of AA for defining the input function resulted in the best agreement with AS and the smallest interobserver variation. CONCLUSION: The ascending aorta is the structure of choice for defining IDIF and a large ROI (diameter, approximately 15 mm) should be used to minimize the effects of statistical noise.

Effects of calcium, inorganic phosphate, and pH on isometric force in single skinned cardiomyocytes from donor and failing human hearts.

BACKGROUND: During ischemia, the intracellular calcium and inorganic phosphate (P(i)) concentrations rise and pH falls. We investigated the effects of these changes on force development in donor and failing human hearts to determine if altered contractile protein composition during heart failure changes the myocardial response to Ca(2+), P(i), and pH. METHODS AND RESULTS: Isometric force was studied in mechanically isolated Triton-skinned single myocytes from left ventricular myocardium. Force declined with added P(i) to 0.33+/-0.02 of the control force (pH 7.1, 0 mmol/L P(i)) at 30 mmol/L P(i) and increased with pH from 0.64+/-0.03 at pH 6.2 to 1.27+/-0.02 at pH 7.4. Force dependency on P(i) and pH did not differ between donor and failing hearts. Incubation of myocytes in a P(i)-containing activating solution caused a potentiation of force, which was larger at submaximal than at maximal [Ca(2+)]. Ca(2+) sensitivity of force was similar in donor hearts and hearts with moderate cardiac disease, but in end-stage failing myocardium it was significantly increased. The degree of myosin light chain 2 phosphorylation was significantly decreased in end-stage failing compared with donor myocardium, resulting in an inverse correlation between Ca(2+) responsiveness of force and myosin light chain 2 phosphorylation. CONCLUSIONS: Our results indicate that contractile protein alterations in human end-stage heart failure alter Ca(2+) responsiveness of force but do not affect the force-generating capacity of the cross-bridges or its P(i) and pH dependence. In end-stage failing myocardium, the reduction in force by changes in pH and [P(i)] at submaximal [Ca(2+)] may even be less than in donor hearts because of the increased Ca(2+) responsiveness.

Carbon-11 acetate as a tracer of myocardial oxygen consumption.

Estimation of myocardial oxygen consumption (MVO2) and myocardial blood flow (MBF) is important for the understanding of various (patho)physiological mechanisms and diseases. Clearance rates of carbon-11 labelled acetate, determined with positron emission tomography, allow estimation of MVO2 on a segmental level and non-invasively. In addition, MBF can be determined from uptake rates. In this review, the background to estimation of MVO2 and MBF is discussed, as well as the currently available literature that has used 11C-acetate to estimate MVO2 and MBF.

Feasibility of planar myocardial carbon 11-acetate imaging.

BACKGROUND: Myocardial oxygen consumption can be determined by using carbon 11-acetate (11C-acetate) and positron emission tomography (PET). The aim of this study was to validate planar 11C-acetate scintigraphy in healthy individuals by relating the myocardial clearance rate of dynamic 11C-acetate scintigraphy with the rate-pressure product, which is used as a measure of cardiac work. Also, the optimal curve-fitting procedure of the time-activity curve and the intraobserver and interobserver variation of determining the clearance rates were assessed. METHODS AND RESULTS: Six subjects were studied at rest, and seven subjects were studied during dobutamine stimulation. Imaging was performed with a planar camera equipped with high-energy collimators for 45 minutes after the injection of 185 MBq of 11C-acetate. Myocardial time-activity curves were corrected for decay. During the study, heart rates and blood pressures were measured to calculate the rate-pressure product. Myocardial time-activity curves showed a clear biphasic pattern. Clearance rates were expressed in k values. The best fitting procedure, as assessed by means of the lowest error of k and the best correlation with the rate-pressure product, proved to be a monoexponential fit on the first part of the time-activity curve (kmono). Subjects studied during dobutamine infusion had significantly higher rate-pressure product (15.0 +/- 2.1*10(3) vs 8.6 +/- 1.2*10(3), P < .001) and 11C-acetate clearance rates (kmono = 0.0657 +/- 0.0110 vs 0.0313 +/- 0.0056, P < .0001) than subjects studied at rest. There was low intraobserver and interobserver variation in determining kmono values. A significant correlation between the rate-pressure product and the monoexponential clearance rate was found (kmono = 5.11*10(-6)*RPP-0.012; r = 0.94, P < .001). CONCLUSIONS: The estimation of myocardial oxygen consumption is feasible with planar 11C-acetate scintigraphy. Clearance rates and the relation with the rate-pressure product are similar to those reported in PET studies. This technique may be used for the assessment and follow-up of global myocardial metabolic abnormalities, eg, in patients with hypertensive heart disease, cardiomyopathy, myocarditis, and valvular disease.

Heterogeneous electron-transfer rate constants for M2(O2CR)4(0)/+, where M = Mo, W, Ru, or Rh and R = alkyl or aryl.

By the use of Nicholson's method, the heterogeneous electron-transfer rate constants (ks) for the oxidation of a series of M2(O2CR)4 complexes have been determined in benzonitrile, where the metal M = Mo, W, Ru, or Rh and R = alkyl or aryl. For R = tBu, the values of ks follow the order M = Mo > W > Ru > Rh. No simple influence of R on ks was observed, although added ligands that are known to reversibly bind to the dinuclear center were shown to influence the E1/2 values in order of their basicity and to suppress the rate of electron transfer. The reported data are compared with those obtained for Cp2Fe0/+, Cp2*Fe0/+, and Ru(bpy)2(2)+/3+ and with earlier work on dirhenium multiply bonded compounds.

Isometric tension development and its calcium sensitivity in skinned myocyte-sized preparations from different regions of the human heart.

OBJECTIVE: In this study we investigated whether differences exist or develop in patients with aortic or mitral valve disease in myofibrillar contractile function and contractile protein composition between subendo- and subepicardial human ventricular tissue. Isometric tension, its calcium sensitivity and contractile protein composition were studied in left ventricular subendo- and subepicardial and in atrial biopsies obtained during open heart surgery from 24 patients with mitral or aortic valve disease. METHODS: Isometric tension was measured in mechanically isolated skinned myocyte-sized preparations at different free calcium concentrations at 15 degrees C. Protein composition was analysed by one-dimensional gel electrophoresis. A comparison was made between the results of subendo- and subepicardial ventricular tissue within each New York Heart Association class and within the different hemodynamically overloaded groups. RESULTS: Maximal isometric tension was significantly lower in atrial than in ventricular preparations. The concentration of calcium required for half-maximal activation was significantly higher in atrial than in ventricular preparations. Within the ventricle no differences were found in contractile protein composition, isometric tension and its calcium sensitivity between subendo- and subepicardial tissue when all patients were treated as one group or when patients were subdivided according to severity of heart disease or hemodynamic overload. CONCLUSIONS: In this group of patients with ventricular volume or pressure overload no regional differences exist or develop during cardiac disease in left ventricular myofibrillar protein composition and force production. Maximal isometric tension and its calcium sensitivity are smaller in atrial than in ventricular preparations.

Force production in mechanically isolated cardiac myocytes from human ventricular muscle tissue.

OBJECTIVE: The expression of contractile isoforms changes during various pathological conditions but little is known about the consequences of these changes for the mechanical properties in human ventricular muscle. We investigated the feasibility of simultaneous determination of protein composition and isometric force development in single cardiac myocytes from human ventricular muscle tissue obtained from small biopsies taken during open heart surgery. METHODS: Small biopsies of about 3 mg wet weight were taken during open heart surgery from patients with aortic valve stenosis. These biopsies were divided in two parts. One part (approximately 2 mg) was used for mechanical isolation of single myocytes and subsequent force measurement while the remaining part was used, in aliquots of 1 microgram dry weight, for protein analysis by polyacrylamide gel electrophoresis. The myocytes were attached with silicon glue to a sensitive force transducer and a piezoelectric motor, mounted on an inverted microscope and permeabilized by means of Triton X-100. Force development was studied at various free calcium concentrations. RESULTS: From all biopsies, myocytes could be obtained and the composition of contractile proteins could be determined. The average isometric force (+/- s.e.m.) at saturating calcium concentration obtained on 20 myocytes from 5 patients amounted to 51 +/- 8 kN/m2. Force was half maximal at a calcium concentration of 2.47 +/- 0.10 microM. CONCLUSION: These measurements indicate that it is possible to study the correlation between mechanical properties and protein composition in small biopsies from human ventricular muscle.

Model for laser damage dependence on thin-film morphology.

The high laser damage thresholds often reported for porous thin films are discussed in terms of point defects or small absorbing inclusions as sites of thin-film damage initiation. The model is based on the internal pressure built up upon laser heating at short times. The competing effects of short pressure relaxation distances and low thermal conductivity inherent in porous films are discussed. The model predicts that at thicknesses less than or equal to the neck or column diameter of a porous film, the effect of lower thermal conductivity should dominate and cause the films to exhibit lower laser damage thresholds than their denser counterparts.

Histologic atypia in clinically benign nevi. A prospective study.

Histologic features of dysplastic nevi include varying degrees of pattern atypia, cytologic atypia, and host response. The purpose of this prospective study was to determine the prevalence of these histologic features in benign acquired nevi. Fifty-eight junctional and compound nevi from 26 volunteer subjects were excised and examined. All nevi met each of the following criteria: 5 mm or less in diameter, symmetric, round or slightly oval, uniform pigmentation, distinct and regular margins, and no erythema. One or more of the histologic features associated with dysplastic nevi were present in 87.8% of the lesions; two or more were present in 69%; and all three histologic features were found in 29.3%. These results indicate that histologic features of dysplastic nevi occur in benign common acquired nevi.