[Quantitative analysis of the left main coronary artery by 3D echocardiography. Role, possibilities and limitations of noninvasive imaging of the left coronary artery]. / Quantitative Analyse des Hauptstammes der linken Koronararterie durch 3D-Echokardiographie. Stellenwert, Möglichkeiten und Grenzen der nicht-invasiven Darstellung der linken Koronararterie.

The left main coronary artery was investigated in 30 patients using a transesophageal approach, and a 3D reconstruction of the 2D databases was performed. Two groups of patients were analyzed. First, patients with calcified aortic stenosis were investigated and the reconstructed data obtained were compared to the left ventricular angiogram of the left coronary artery. Second, the 2D databases of patients with non-calcified aortic valve and aortic anulus were reconstructed using the 3D technique. In group 1 the estimate in size of the left ventricular coronary artery was closely related to the diameter of the left coronary artery as obtained by the coronary angiogram (mean difference 0.08 mm, interval of confidence at 95%, -0.48 and +0.32 mm). In both groups a substantial increase in imaging of the left coronary artery was obtained compared to the standard 2D echocardiographic view (% in group 1, and % in group 2, respectively). Independent of the 3D reconstruction of the left coronary artery in the any-plane mode, an orthogonal imaging of the artery could be obtained in only 15% of patients in group 1 but in 40% of patients in group 2. We conclude that 3D reconstruction of the left coronary artery (LAD) is superior to 2D echocardiography in echo-imaging of the proximal part of the LAD and correlates strongly to the diameters measured in the left coronary angiogram. In patients with major calcification of the aortic anulus and/or a calcified native aortic valve this approach is associated with multiple artifacts in imaging. The rapid technical evolution in this technique including improvement in computer technology and appropriate software may ensure a further important role of 3D echo imaging in noninvasive visualization of the normal and diseased left main coronary artery.

Correlation between lung fibrosis and radiation therapy dose after concurrent radiation therapy and chemotherapy for limited small cell lung cancer.

PURPOSE: To evaluate the relationship between physician-identified radiographic fibrosis, lung tissue physical density change, and radiation dose after concurrent radiation therapy and chemotherapy for limited small cell lung cancer. MATERIALS AND METHODS: Fibrosis volumes of different severity levels were delineated on computed tomography (CT) images obtained at 1-year follow-up of 21 patients with complete response to concurrent radiation therapy and chemotherapy for limited small cell lung carcinoma. Delivered treatments were reconstructed with a three-dimensional treatment planning system and geometrically registered to the follow-up CT images. Tissue physical density change and radiation dose were computed for each voxel within each fibrosis volume and within normal lung. Patient responses were grouped per radiation and chemotherapy protocol. RESULTS: A significant correlation was noted between fibrosis grade and tissue physical density change and fibrosis grade. For doses less than 30 Gy, the probability of observing fibrosis was less than 2% with conventional fractionation and less than 4% with accelerated fractionation. Physical lung density change also showed a threshold of 30-35 Gy. For doses of 30-55 Gy and cisplatin and etoposide (PE) chemotherapy, fibrosis probability was 2.0 times greater for accelerated fractionation compared with conventional fractionation (P < .005) and was correlated to increasing dose for both fractionation schedules. CONCLUSION: Lung tissue physical density changes correlated well with fibrosis incidence, and both increased with increasing dose greater than a threshold of 30-35 Gy. With concurrent PE chemotherapy, fibrosis probability was twice as great with accelerated fractionation as with once-daily fractionation.

Activation of cardiac c-Jun NH(2)-terminal kinases and p38-mitogen-activated protein kinases with abrupt changes in hemodynamic load.

The role of mitogen-activated protein kinase (MAPK) pathways as signal transduction intermediates of hemodynamic stress leading to cardiac hypertrophy in the adult heart is not fully established. In a rat model of pressure-overload hypertrophy, we examined whether activation of MAPK pathways, namely, the extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and the p38-MAPK pathways, occurs during rapid changes in hemodynamic load in vivo. A slight activation of ERK2 and marked increases in JNK1 and p38-MAPK activities were observed 30 minutes after aortic banding. The increase in p38-MAPK activity was accompanied by an increase in the phosphorylation of the p38 substrate MAPK-activated protein kinases 2 and 3. Activation of these kinases was coincident with an increase in phosphorylation of c-Jun and activating transcription factor-2 (ATF-2) and enhanced DNA binding of activator protein-1 factors. Thus, hemodynamic stress of the adult rat heart in vivo results in rapid activation of several parallel MAPK kinase cascades, particularly stress-activated MAPK and p38-MAPK and their target transcription factors c-Jun and ATF-2.

Activation of cGMP-dependent protein kinase Ibeta inhibits interleukin 2 release and proliferation of T cell receptor-stimulated human peripheral T cells.

Several major functions of type I cGMP-dependent protein kinase (cGK I) have been established in smooth muscle cells, platelets, endothelial cells, and cardiac myocytes. Here we demonstrate that cGK Ibeta is endogenously expressed in freshly purified human peripheral blood T lymphocytes and inhibits their proliferation and interleukin 2 release. Incubation of human T cells with the NO donor, sodium nitroprusside, or the membrane-permeant cGMP analogs PET-cGMP and 8-pCPT-cGMP, activated cGK I and produced (i) a distinct pattern of phosphorylation of vasodilator-stimulated phosphoprotein, (ii) stimulation of the mitogen-activated protein kinases ERK1/2 and p38 kinase, and, upon anti-CD3 stimulation, (iii) inhibition of interleukin 2 release and (iv) inhibition of cell proliferation. cGK I was lost during in vitro culturing of primary T cells and was not detectable in transformed T cell lines. The proliferation of these cGK I-deficient cells was not inhibited by even high cGMP concentrations indicating that cGK I, but not cGMP-regulated phosphodiesterases or channels, cAMP-dependent protein kinase, or other potential cGMP mediators, was responsible for inhibition of T cell proliferation. Consistent with this, overexpression of cGK Ibeta, but not an inactive cGK Ibeta mutant, restored cGMP-dependent inhibition of cell proliferation of Jurkat cells. Thus, the NO/cGMP/cGK signaling system is a negative regulator of T cell activation and proliferation and of potential significance for counteracting inflammatory or lymphoproliferative processes.

Combined aortic and mitral stenosis in mucopolysaccharidosis type I-S (Ullrich-Scheie syndrome).

The genetic mucopolysaccharidosis syndromes (MPS) are autosomal recessive inborn errors of metabolism. Heart valve involvement in MPS is not uncommon but only a few case reports of successful cardiac surgery are available. In particular, reports of combined aortic and mitral stenosis associated with MPS type I-S are very rare. Both type I and type VI MPS are associated with significant left sided valvar heart disease that requires surgical valve replacement because of irregular valve thickening, fibrosis, and calcification. A 35 year old man had severe mitral valve stenosis after successful surgical replacement of a stenotic aortic valve. Valvar heart disease was investigated by cardiac ultrasound and left heart catheterisation. Histomorphological characterisation of the affected mitral valve was performed. The case illustrates typically associated clinical features of cardiac and extracardiac abnormalities found in MPS type I-S.

Role of AT1 and AT2 receptors in regulation of MAPKs and MKP-1 by ANG II in adult cardiac myocytes.

ANG II has been implicated in the hypertrophic response in ventricular myocytes by acting at the angiotensin type 1 (AT1) receptor. However, the role of the angiotensin type 2 (AT2) receptor in the adult heart is not as clearly understood. In adult rat ventricular myocytes (ARVM) and cardiac microvascular endothelial cells (CMEC), we examined the role of ANG II signaling, via AT1 and AT2 receptors, on the activation of the extracellular signal-regulated protein kinases (ERKs) and on the expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1. ANG II caused no detectable increase in ERK activity or in c-fos mRNA abundance in ARVM but increased ERK activity within 5 min in CMEC and increased c-fos mRNA levels. However, in the presence of the selective phosphoprotein phosphatase (PP-2A/PP-1) inhibitor okadaic acid (OA), a sustained increase in ERK activity, as well as in c-jun NH2-terminal protein kinase activity, in ARVM was observed. ANG II increased MKP-1 mRNA levels within 15 min in ARVM and CMEC. In contrast to the response in endothelial cells, however, ANG II activation of MKP-1 in ARVM was mediated by AT2-receptor activation. Thus there is constitutive as well as inducible suppression of ERKs and c-jun NH2-terminal protein kinases by MKP and PP-2A/PP-1 in the adult cardiac myocyte phenotype.

[Status of digitalis in therapy of acute and chronic heart failure]. / Stellenwert von Digitalis in der Therapie der akuten und chronischen Herzinsuffizienz.

Although supported by more than 200 years of experience and anecdotal clinical evidence, the efficacy of digitalis in the management of heart failure has been questioned until the past decade. The idea to improve contractility of the diseased myocardium with an inotropic agent is fundamental in the management of left ventricular dysfunction. The majority of clinical trials published since 1980, most of which examined patients with mild to moderate heart failure, indicate that digitalis alone or in combination with vasodilators may improve the clinical outcome particular in those patients with more advanced symptoms and poorer left ventricular function. Aside from its action as an inotropic drug the pharmacology and the mechanisms by which digitalis influence the diseased myocardium and peripheral circulation in heart failure has gained more complexity within the last years, raising the idea of other mechanisms that might be involved in its action. Particular for ACE inhibition multiple clinical trials have conclusively demonstrated its impact on survival and morbidity in congestive heart failure. Improvement of clinical outcome as measured in terms of fewer hospitalizations and improvement of symptoms in patients receiving digitalis seems to be comparable to patients receiving beta-blockers additional to diuretics and ACE inhibitors, an entirely different approach to the treatment of heart failure. Despite initial improvement of hemodynamics it now appears that there is no survival benefit found for digitalis in the management of heart failure.

Cardiac myocyte membrane wounding in the abruptly pressure-overloaded rat heart under high wall stress.

The potential role of transient sarcolemmal membrane wounding as a signal transduction event for cardiomyocyte hypertrophy was evaluated in rats with short-term pressure overload caused by banding of the proximal aorta. This procedure resulted in significant increases in left ventricular systolic (1.5-fold) and end-diastolic (2.6-fold) pressures and wall stresses that were associated with significant wall thinning and cavitary enlargement. Quantitative image analysis of frozen sections of the stressed ventricles obtained 60 minutes after banding demonstrated a 6- to 10-fold increase in cytosolic staining with a horseradish peroxidase-labeled anti-albumin antibody compared with sham-operated controls, indicating that an increase in transient sarcolemmal membrane permeability (wounding) is an early response to an abrupt increase in hemodynamic load in vivo. We conclude that an intense hemodynamic stress in vivo can result in histologically detectable cardiomyocyte wounding.

Regulation of bFGF expression and ANG II secretion in cardiac myocytes and microvascular endothelial cells.

Basic fibroblast growth factor (bFGF; fibroblast growth factor-2) and angiotensin II (ANG II), among other peptide signaling autacoids (cytokines), are known to regulate the phenotypic adaptation of cardiac muscle to physiological stress. The cell type(s) in cardiac muscle responsible for ANG II synthesis and secretion and the role of endogenous cytokines in the regulation of bFGF induction remain unclear. With the use of confluent, serum-starved, low-passage cultures of cardiac microvascular endothelial cells (CMEC), ANG II could be detected in cellular lysates and in medium conditioned by these cells with the use of high-performance liquid chromatography followed by radioimmunoassay. The secretion of angiotensins by individual CMEC could be detected with a cell-blot assay technique. ANG II secretion was decreased by brefeldin A, an agent that interrupts constitutive and regulated secretory pathways for peptide autacoid/ hormone synthesis, suggesting de novo synthesis, activation, and secretion of angiotensins by CMEC. In primary isolates of adult rat ventricular myocytes (ARVM) and CMEC, ANG II, acting at ANG II type 1 receptors in both cell types, was found to increase bFGF mRNA levels measured by ribonuclease protection assay. Endothelin-1 (ET-1), which is known to be synthesized by CMEC, and bFGF itself, which has been detected in both ARVM and CMEC, increased bFGF transcript levels in both cell types. Interleukin-1beta (IL-1beta), which like ANG II and ET-1 is known to activate mitogen-activated protein kinases in both ARVM and CMEC, increased bFGF mRNA levels only in cardiac myocytes. Thus cytokines such as ANG II, ET-1, bFGF, and IL-1beta locally generated by cellular constituents of cardiac muscle, including CMEC, regulate bFGF mRNA levels in a cell type-specific manner.

[Reversibility of changes in left and right ventricular geometry and hemodynamics in pulmonary hypertension. Echocardiographic characteristics before and after pulmonary thromboendarterectomy]. / Reversibilität von Veränderungen der links- und rechtsventrikulären Geometrie und Hämodynamik bei pulmonaler Hypertonie. Echokardiographische Charakterisierung bei Patienten vor und nach pulmonaler Thrombendarteriektomie.

Pulmonary thromboendarterectomy (PTE) leads to an acute decrease of right ventricular (RV) afterload in patients with chronic thromboembolic pulmonary hypertension. We investigated the changes in right and left ventricular (LV) geometry and hemodynamics by means of transthoracic echocardiography. The prospective study was performed in 14 patients (8 female, 6 male; age 55 +/- 20 years) before and 18 +/- 12 days after PTE. Total pulmonary vascular resistance and systolic pulmonary artery pressure were significantly decreased (PVR: preoperative 986 +/- 318, postoperative 323 +/- 280 dyn x s/cm5, p < 0.05; PAP preoperative 71 +/- 40, postoperative 41 +/- 40 mm Hg + right atrial pressure, p < 0.05). End diastolic and end systolic RV area decreased from 33 +/- 12 to 23 +/- 8 cm2, respectively, from 26 +/- 10 to 16 +/- 6 cm2, p < 0.05. There was an increase in systolic RV fractional area change from 20 +/- 12 to 30 +/- 16%, p < 0.05. RV systolic pressure rise remained unchanged (516 +/- 166 vs. 556 +/- 128 mm Hg/sec). LV ejection fraction remained within normal ranges (64 +/- 16 vs. 62 +/- 12%). Echocardiographically determined cardiac index increased from 2.8 +/- 0.74 to 4.1 +/- 1.74 l/min/m2. A decrease in LV excentricity indices (end diastolic: 1.9 +/- 1 vs. 1.1 +/- 0.3, end systolic: 1.7 +/- 0.6 vs. 1.1 +/- 0.4, p < 0.05) proved a normalization of preoperatively altered septum motion. LV diastolic filling returned to normal limits: (E/A ratio: 0.62 +/- 0.34 vs. 1.3 +/- 0.8; p < 0.05); Peak E velocity: 0.51 +/- 0.34 vs. 0.88 +/- 0.28 m/sec, p < 0.05; Peak A velocity: 0.81 +/- 0.36 vs. 0.72 +/- 0.42 m/sec, ns; E deceleration velocity: 299 +/- 328 vs. 582 +/- 294 cm/sec2, p < 0.05; Isovolumic relaxation time: 134 +/- 40 vs. 83 +/- 38 m/sec, p < 0.05). We could show a marked decrease in RV afterload shortly after PTE with a profound recovery of right ventricular systolic function--even in case of severe pulmonary hypertension. A decrease in paradoxic motion of the interventricular septum and normalization of LV diastolic filling pattern resulted in a significant increase of cardiac index.

Regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvascular endothelial cells. Role of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT1 alpha.

Adult rat ventricular myocytes and cardiac microvascular endothelial cells (CMEC) both express an inducible nitric oxide synthase (iNOS or NOS2) following exposure to soluble inflammatory mediators. However, NOS2 gene expression is regulated differently in response to specific cytokines in each cell type. Interleukin-1 beta (IL-1 beta) induces NOS2 in both, whereas interferon gamma (IFN gamma) induces NOS2 expression in myocytes but not in CMEC. Therefore, we examined the specific signal transduction pathways that could regulate NOS2 mRNA levels, including activation of 44- and 42-kDa mitogenactivated protein kinases (MAPKs; ERK1/ERK2) and STAT1 alpha, a transcriptional regulatory protein linked to cell membrane receptors. Although IL-1 beta treatment increased ERK1/ERK2 activities in both cell types, IFN gamma activated these MAPKs only in myocytes. STAT1 alpha phosphorylation, consistent with IFN gamma-induced signaling, was readily apparent in both cell types, and binding of activated STAT1 alpha from cytoplasmic or nuclear fractions from IFN gamma-treated adult myocytes to a sis-inducible element could be demonstrated by gel-shift assay. The farnesyl transferase inhibitor BZA-5B blocked activation of ERK1/ERK2 and induction of NOS2 by IFN gamma and IL-1 beta in myocytes. IL-1 beta and IFN gamma-induced NOS2 gene expression in myocytes was also down-regulated by both protein kinase C (PKC) desensitization and by the PKC inhibitor bisindolylmaleimide, implicating PKC-linked activation of Ras or Raf in the induction of NOS2 by IL-1 beta and IFN gamma in cardiac muscle cells. In CMEC, the MAPK kinase inhibitor PD 98059 blocked activation of ERK1/ERK2 and down-regulated IL-1 beta-mediated NOS2 induction, whereas activation of ERK2 in the absence of cytokines by okadaic acid, an inhibitor of phosphoserine protein phosphatases, also induced NOS2 mRNA. These data demonstrate that ERK1/ERK2 activation appears to be necessary for the induction of NOS2 by IL-1 beta and IFN gamma in cardiac myocytes and CMEC. In the absence of ERK1/ERK2 activation by IFN gamma in CMEC, phosphorylation of STAT1 alpha is not sufficient for NOS2 gene expression. These overlapping yet distinct cellular responses to specific cytokines may serve to target NOS2 gene expression to specific cells or regions within the heart and also provide for rapid escalation of NO production if required for host defense.

Glucocorticoids increase osteopontin expression in cardiac myocytes and microvascular endothelial cells. Role in regulation of inducible nitric oxide synthase.

In heart muscle, the cytokine-inducible isoform of nitric oxide synthase (NOS2) is expressed in both cardiac myocytes and microvascular endothelial cells (CMEC). mRNA levels for both NOS2 and for osteopontin, a multifunctional extracellular matrix phosphoprotein containing and RGD integrin binding domain, are increased in cardiac muscle following intraperitoneal injection of adult rats with lipopolysaccharide. In vitro, interleukin-1 beta and interferon-gamma increased osteopontin mRNA levels in CMEC as well as NOS2 expression in both CMEC and cardiac myocytes. However, osteopontin mRNA levels in heart muscle in vivo, and in cardiac myocytes and CMEC in vitro, also are increased 10-30-fold by the synthetic glucocorticoid dexamethasone, an agent that suppresses cytokine induction of NOS2 in both cell types. The hexapeptide GRGDSP, which interrupts binding of RGD-containing proteins to cell surface integrins, increased NOS2 mRNA, while a synthetic osteopontin peptide analogue decreased NOS2 mRNA and protein levels in both cytokine-pretreated cardiac myocytes and CMEC cultures. Also, transfection with a full-length antisense-osteopontin cDNA in cytokine-pretreated CMEC decreased endogenous osteopontin mRNA and increased NOS2 mRNA levels. These results suggest that osteopontin could regulate the location and extent of NOS2 induction in the heart. Increased expression of osteopontin also may be one mechanism by which glucocorticoids suppress NOS2 activity in cardiac myocytes and microvascular endothelial cells.

Current status of phosphodiesterase inhibitors in the treatment of congestive heart failure.

The phosphodiesterase inhibitors have been recognised as potent inotropic and vasodilating drugs. In acute congestive heart failure they increase cardiac output, decrease left pulmonary capillary wedge pressure, and reduce total peripheral resistance with an improvement in loading conditions of the failing heart. Their potency in reversal of symptoms of acute congestive heart failure is quite similar to, or even better than, treatment with intravenous catecholamines and sodium nitroprusside. In chronic congestive heart failure, however, these agents increase mortality and have deleterious effects in the outcome of patients with severe left ventricular dysfunction.

Transcription, storage and release of atrial natriuretic factor in the failing human heart.

1. In this study the relationship between the synthesis of atrial natriuretic factor at the level of atrial natriuretic factor mRNA and the atrial storage and circulating plasma levels of atrial natriuretic factor were investigated in 15 patients with heart failure. The patients underwent right and left heart catheterization before cardiac surgery for valve replacement or coronary artery bypass grafting. 2. Plasma concentrations of atrial natriuretic factor were correlated to atrial levels of atrial natriuretic factor mRNA. Atrial levels of atrial natriuretic factor mRNA and plasma concentrations of atrial natriuretic factor exhibited a close correlation to both pulmonary artery pressure and left atrial pressure. No relationship, however, could be found between the right atrial content of atrial natriuretic factor and both the expression of atrial natriuretic factor mRNA in the atria and the plasma levels of atrial natriuretic factor. 3. From these data it may be concluded that increased plasma levels of atrial natriuretic factor in the pressure- and/or volume-overloaded heart are associated with an elevated level of atrial natriuretic factor mRNA. We suggest that not only plasma levels of atrial natriuretic factor but also the expression of atrial natriuretic factor in the atrial are related to left ventricular filling pressures in the failing human heart.

Atrial natriuretic peptide mRNA in patients with heart disease.

The regulation of atrial natriuretic peptide (ANP) synthesis within cardiac atrial myocytes was investigated in 8 patients undergoing cardiac surgery (valve replacement or coronary bypass graft). Hemodynamic data were obtained during cardiac catheterization and venous plasma samples for ANP were withdrawn prior to surgery. Probes for determination of tissue ANP levels and ANPmRNA concentrations were taken from the right atrium. Both plasma ANP (r = 0.75; P less than .05) and ANPmRNA (r = 0.86; P less than .01) were closely related to mean pulmonary artery pressure. ANPmRNA was also related to plasma ANP (r = 0.60; P less than .07). However, no significant relationships were obtained between either plasma ANP or ANPmRNA and right atrial ANP concentrations. These data suggest that right atrial ANP synthesis is regulated by cardiac filling pressures and possibly by plasma ANP levels, independent from corresponding ANP tissue concentrations.

Role of right and left atrial dimensions for release of atrial natriuretic peptide in left-sided valvular heart disease and idiopathic dilated cardiomyopathy.

To evaluate the role of atrial dimensions for release of atrial natriuretic peptide (ANP), right and left atrial dimensions (cross-sections) were determined by 2-dimensional echocardiography in 50 patients with left-sided valvular heart disease or idiopathic dilated cardiomyopathy. All patients underwent right- and left-sided heart catheterization with measurement of central hemodynamics. Plasma samples for ANP were withdrawn from femoral vein (ANPv) and ascending aorta. An estimate of right and left meridional atrial wall stress was derived by multiplying cross-sectional areas with pressures of the respective atria. As expected ANPv was closely related to mean right (r = 0.63; p less than 0.001; n = 50) and left atrial pressures (r = 0.61; p less than 0.001; n = 47). Furthermore, a positive correlation between ANPv and right (r = 0.56; p less than 0.001; n = 48) and left (r = 0.30; p less than 0.05; n = 48) atrial cross-sections was obtained. Finally, an excellent relation was found between ANPv and right (r = 0.73; p less than 0.001; n = 48) as well as left (r = 0.58; p less than 0.001; n = 44) meridional atrial wall stress, indicating that atrial wall stress rather than atrial pressures or dimensions alone determines plasma ANP concentrations. However, for identical right and left meridional atrial wall stress 3- to 4-times higher plasma ANPv levels were obtained in patients with idiopathic dilated cardiomyopathy than in patients with left-sided valvular heart disease. This indicates that release of ANP to the same stimulus may be modulated by the nature of the underlying heart disease.