Clinical Relevance of Computed Tomography Pulmonary Venography.

BACKGROUND: In clinical routine, the pulmonary contrast-enhanced chest computer tomography (CT) is usually focussed on the pulmonary arteries. The purpose of this pictorial essay is to raise the clinicians' awareness for the clinical relevance of CT pulmonary venography. CASE PRESENTATION: A pictorial case series illustrates the clinical consequences of different pulmonary venous pathologies on systemic, pulmonary and bronchial circulation. CONCLUSION: Computed tomography pulmonary venography must be considered before atrial septal defect (ASD) closure and pulmonary lobectomy. Computed tomography pulmonary venography should be considered for patients with right ventricular overload and pulmonary hypertension, as well as for patients with unclear recurrent pulmonary infections, progressive dyspnoea, pleural effusions, haemoptysis, and for patients with respiratory distress after lung-transplantation.

Increased gene expression of the cardiac endothelin system in obese mice.

Obesity is a well-known risk factor of atherosclerosis and heart failure. In the human heart, a local endothelin system containing prepro-endothelin-1, endothelin-converting enzyme-1, and endothelin receptors A and B has been described. The endothelin system is activated in heart failure; however, the impact of obesity on the cardiac endothelin system is unknown. In this study, 18-week-old male C57BL/6 mice fed either a control diet or a high-fat diet for 10 weeks were analyzed. High-fat diet significantly increased the body weight of the animals and augmented low-density lipoprotein, high-density lipoprotein, and cholesterol plasma levels, compared to control. The animal groups showed no significant differences in left ventricular size or function (heart rate, ejection fraction, fractional shortening, left ventricular posterior wall thickness, cardiac output) after control or high-fat diet. We did not observe signs of cardiac hypertrophy or changes in markers of cardiac fibrosis in these heart samples. The cardiac expression of prepro-endothelin-1 mRNA, endothelin-converting enzyme-1 mRNA, and protein and endothelin receptors A and B mRNA was increased in 18-week-old obese C57BL/6 mice compared to animals with normal weight (p<0.05 vs. control). Furthermore, endothelin-1 plasma levels showed an increasing trend. In conclusion, an increased expression of genes of the endothelin system was observed in the hearts of 18-week-old mice after high-fat diet, possibly contributing to later cardiovascular complications of obesity.

Elevated cardiac troponin T indicating myocardial infarction or myocarditis-urgent cardiac catheter examination-or do we have to consider other reasons?

Alveolar rhabdomyosarcoma is an aggressive tumour in adulthood, in which cardiac troponin T seems to be a tumour marker and course parameter. We present the clinical course of a young man suffering from this rare disease and the development of troponin T during therapy. Noninvasive cardiac imaging was used to exclude cardiac involvement, myocardial infarction or inflammation processes.

Intra-aortic balloon pump (IABP) counterpulsation improves cerebral perfusion in patients with decreased left ventricular function.

BACKGROUND: The current goal of treatment after acute ischemic stroke is the increase of cerebral blood flow (CBF) in ischemic brain tissue. Intra-aortic balloon pump (IABP) counterpulsation in the setting of cardiogenic shock is able to reduce left ventricular afterload and increase coronary blood flow. The effects of an IABP on CBF have not been sufficiently examined. We hypothesize that the use of an IABP especially enhances cerebral blood flow in patients with pre-existing heart failure. METHODS: In this pilot study, 36 subjects were examined to investigate the effect of an IABP on middle cerebral artery (MCA) transcranial Doppler (TCD) flow velocity change and relative CBF augmentation by determining velocity time integral changes (ΔVTI) in a constant caliber of the MCA compared to a baseline measurement without an IABP. Subjects were divided into two groups according to their left ventricular ejection fraction (LVEF): Group 1 LVEF >30% and Group 2 LVEF ≤30%. RESULTS: Both groups showed an increase in CBF using an IABP. Patients with a LVEF ≤30% showed a significantly higher increase of ΔVTI in the MCA under IABP augmentation compared to patients with a LVEF >30% (20.9% ± 3.9% Group 2 vs.10.5% ± 2.2% Group 1, p<0,05). The mean arterial pressure (MAP) increased only marginally in both groups under IABP augmentation. CONCLUSIONS: IABP improves cerebral blood flow, particularly in patients with pre-existing heart failure and highly impaired LVEF. Hence, an IABP might be a treatment option to improve cerebral perfusion in selected patients with cerebral misperfusion and simultaneously existing severe heart failure.

Implantable cardioverter defibrillator lead implantation in patients with a persistent left superior vena cava--feasibility, chances, and limitations: representative cases in adults.

AIMS: Device implantation may be challenging in patients with venous abnormalities. The most common congenital variation--frequently associated with other congenital abnormalities--is described as persistent left superior vena cava (PLSVC). METHODS AND RESULTS: The present case series demonstrates successful implantable cardioverter defibrillator (ICD) lead implantation in the most common anatomic variations of PLSVC. All types of current ICD models (single and dual chamber, VDD, and cardiac resynchronization therapy devices) were used. Angiographic findings and implantation techniques (e.g. guiding and diagnostic catheters, wires, occlusion balloons, and rotation sequences) are presented in images and movie sequences. CONCLUSION: Device implantation in patients with PLSVC may be complex but a successful transvenous approach is possible in most of the cases. Careful imaging prior to implantation procedure is essential for understanding the individual anatomy and in order to choose adequate material and implantation strategy.

Latent pulmonary hypertension in atrial septal defect: Dynamic stress echocardiography reveals unapparent pulmonary hypertension and confirms rapid normalisation after ASD closure.

OBJECTIVE: Closure of atrial septal defects (ASD) prevents pulmonary hypertension, right heart failure and thromboembolic stroke. The exact timing for ASD closure is controversial. METHODS: In a prospective study to address the question whether unapparent pulmonary hypertension can be revealed prior to right ventricular (RV) remodelling, patients were investigated before and 6, 12, and 24 months after ASD closure using exercise stress echocardiography (ESE) and ergospirometry (n = 24). RESULTS: At rest, RV systolic pressure (RVSP) was normal in 58.8 %, slightly elevated in 26.5 %, and moderately elevated in 11.8 %. One patient showed severe pulmonary hypertension. During ESE, all patients with normal RVSP at rest exhibited an increase (25.7 ± 1.2 mmHg vs. 45.3 ± 2.3 mmHg, p < 0.001). After closure the RVSP was lower, both at rest and ESE. RV diameters decreased too. Tricuspid annulus plane systolic excursion (TAPSE) at rest remained lower after closure (24.0 ± 0.9 vs. 22.0 ± 0.9 mm, p < 0.05). TAPSE in ESE was elevated, and stayed stable after closure (30.1 ± 1.8 mm vs. 29.3 ± 1.6 mm). Before closure, RV systolic tissue velocities (s(a)) at rest were normal and decreased after closure (14.0 ± 1.0 cm/s vs. 11.5 ± 0.7 (6 month) vs. 10.6 ± 0.5 cm/s (12 month), p < 0.05). During ESE, s(a) velocity was similar before and after closure (23.0 ± 1.3 cm/s vs. 23.3 ± 1.9 cm/s). Maximal oxygen uptake (VO2/kg) did not differ between baseline and follow-ups. CONCLUSION: Latent pulmonary hypertension may become apparent in ESE. ASD closure leads to a significant reduction in this stress-induced pulmonary hypertension and to a decrease in the right heart diameters indicating reverse RV remodelling. RV functional parameters at rest did not improve. The VO2/kg did not change after ASD closure.

Pre-hospital discharge testing after implantable cardioverter defibrillator implantation: a measure of safety or out of date? A retrospective analysis of 975 patients.

AIMS: The present study evaluates the relevance and additional safety value of pre-hospital discharge (PHD) testing in patients with implantable cardioverter defibrillator (ICD) therapy. METHODS: From June 1998 to May 2009, 975 patients (830 male, 145 female) with ICD were screened retrospectively for failed PHD and analysed for its consequences, risk factors, and patient characteristics after successful intra-operative testing in the implantation procedure. RESULTS: Pre-hospital discharge testing procedure was performed in 809 cases. No serious adverse events (e.g. death, persistant ventricular fibrillation or ventricular tachycardia, stroke) occurred. The overall incidence of failed PHD was 1.4% (n = 11). The underlying mechanisms were defibrillation threshold failure in 9/11 cases and sensing failure in 2/11 cases. CONCLUSIONS: In this study predictors for PHD-failure are: (i) cardiomyopathy other than ischaemic or dilative, (ii) young age, and (iii) small or very large left ventricular end-diastolic diameter ( < 40 or > 65 mm). Particularly, (i) manufacture of device or leads, (ii) lead design, (iii) medical treatment, or (iv) gender have no significant influence on PHD failure.

[19-year-old asthma patient with pronounced eosinophilia and acute coronary syndrome]. / 19-jähriger Asthmatiker mit ausgeprägter Eosinophilie und akutem Koronarsyndrom.

Diagnosis of Churg-Strauss syndrome should be considered in young asthmatics with fatigue and eosinophilia. On the base of the etiopathology of a 19-year old man, who was initially admitted because of dyspnoea, fever and acute chest pain, we show that eosinophilia gives an important hint for further diagnostic and is the key trend parameter. Histologically an eosinophilic myocarditis could be shown in the myocardial biopsy. High dose prednisolone induced a clear improvement in symptoms, with decrease of the inflammatory signs and the eosinophilia and a clear improvement of the left ventricular function.

Increased P2X7R expression in atrial cardiomyocytes of caveolin-1 deficient mice.

It has recently been shown in epithelial cells that the ATP-gated ion channel P2X7R is in part, associated with caveolae and colocalized with caveolin-1. In the present study of the mouse heart, we show for the first time, using immunohistochemistry and cryoimmunoelectron microscopy, that P2X7R is expressed in atrial cardiomyocytes and in cardiac microvascular endothelial cells, but not in the ventricle cardiomyocytes. Furthermore, biochemical data indicate the presence of two forms of P2X7R, the classical glycosylated 80 kDa isoform and a protein with the molecular weight of 56 kDa, in both cardiomyocytes and endothelial cells of the mouse heart. The functionality of both proteins in heart cells is still unclear. In cardiac tissue homogenates derived from caveolin-1 deficient mice (cav-1(-/-)), an increase of the P2Xrx7 mRNA and P2X7R protein (80 kDa) was found, particularly in atrial samples. In addition, P2rx7(-/-) mice showed enhanced protein levels of caveolin-1 in their atrial tissues. Although the details of cellular mechanisms that underlie the relationship between caveolin-1 and P2X7R in atrial cardiomyocytes and the electrophysiological consequences of the increased P2X7R expression in atrial cells of cav-1(-/-) mice remain to be elucidated, the cardiomyopathy detectable in cav-1(-/-) mice is possibly related to a disturbed crosstalk between P2X7R and caveolin-1 in different heart cell populations.

Receptor-independent sensitization of the adenylyl cylase after chronic treatment with cyclosporine A.

Chronic treatment with cyclosporine A (CyA) is often complicated by severe hypertension. If activation of the beta-adrenergic-receptor-linked adenylyl cyclase (AC) system contributes to hypertension is unresolved. Rats were treated with CyA (20 mg kg(-1) day(-1)) for 7 days. beta-adrenergic, muscarinic, and alpha-adrenergic receptors, G-proteins, and the activity of AC were determined in cardiac and pulmonary plasma membranes. The density of cardiac beta-adrenergic receptors, muscarinic receptors, alpha-adrenergic receptors, G(alphas) and, G(alphai) remained unchanged after treatment with CyA. However, CyA increased the responsiveness of AC to different stimulators. The responsiveness of AC was even more pronounced after solubilization and partial purification, suggesting a direct modulation of the enzyme. These data suggest that CyA modulates the activity of the sympathoadrenergic system by a direct, receptor-independent sensitization of AC, suggesting that this pathway contributes to hypertension in patients treated with CyA.

NT-proBNP correlates with right heart haemodynamic parameters and volumes in patients with atrial septal defects.

BACKGROUND: To investigate the role of N-terminal pro-BNP (NT-proBNP) for the estimation of right heart failure and pulmonary pressure in patients with atrial septal defects (ASD) before and after percutaneous defect closure. METHODS: We performed correlation analysis for NT-proBNP and right ventricular systolic pressure (RVSP) as well as right ventricular enddiastolic and endsystolic volume (RVEDV, RVESV) determined by cardiac magnetic resonance imaging (MRI) before and up to one year following ASD closure. Additionally NT-proBNP concentrations were correlated with right atrial (RA) and RV enddiastolic pressure (RVEDP), ASD size and interatrial left-to-right shunt. RESULTS: Baseline RVSP was 33+/-8 mmHg, which decreased significantly during follow-up. Initially, NT-proBNP levels were 240+/-93 pg/ml. After closure, a reduction to 116+/-62 pg/ml was obvious (p<0.01). Baseline MRI showed enlarged RV volumes in all individuals. At six and twelve months follow-up a significant reduction of RVEDV and RVESV was apparent. A positive correlation was noted between RV volumes and NT-proBNP (r=0.65, p<0.05). Furthermore RA pressure, RVEDP, RVSP and left-to-right shunt significantly correlated to peptide levels. No correlation was seen between ASD size and NT-proBNP. CONCLUSION: NT-proBNP correlates to right ventricular dilatation, pulmonary pressure and left-to-right shunt in volume load of the right heart caused by an underlying ASD.

A comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertension.

Patients with severe hypertension (>180/110 mm Hg) require large blood pressure (BP) reductions to reach recommended treatment goals (<140/90 mm Hg) and usually require combination therapy to do so. This 8-week, multicenter, randomized, double-blind, parallel-group study compared the tolerability and antihypertensive efficacy of the novel direct renin inhibitor aliskiren with the angiotensin converting enzyme inhibitor lisinopril in patients with severe hypertension (mean sitting diastolic blood pressure (msDBP)>or=105 mm Hg and <120 mm Hg). In all, 183 patients were randomized (2:1) to aliskiren 150 mg (n=125) or lisinopril 20 mg (n=58) with dose titration (to aliskiren 300 mg or lisinopril 40 mg) and subsequent addition of hydrochlorothiazide (HCTZ) if additional BP control was required. Aliskiren-based treatment (ALI) was similar to lisinopril-based treatment (LIS) with respect to the proportion of patients reporting an adverse event (AE; ALI 32.8%; LIS 29.3%) or discontinuing treatment due to AEs (ALI 3.2%; LIS 3.4%). The most frequently reported AEs in both groups were headache, nasopharyngitis and dizziness. At end point, ALI showed similar mean reductions from baseline to LIS in msDBP (ALI -18.5 mm Hg vs LIS -20.1 mm Hg; mean treatment difference 1.7 mm Hg (95% confidence interval (CI) -1.0, 4.4)) and mean sitting systolic blood pressure (ALI -20.0 mm Hg vs LIS -22.3 mm Hg; mean treatment difference 2.8 mm Hg (95% CI -1.7, 7.4)). Responder rates (msDBP<90 mm Hg and/or reduction from baseline>or=10 mm Hg) were 81.5% with ALI and 87.9% with LIS. Approximately half of patients required the addition of HCTZ to achieve BP control (ALI 53.6%; LIS 44.8%). In conclusion, ALI alone, or in combination with HCTZ, exhibits similar tolerability and antihypertensive efficacy to LIS alone, or in combination with HCTZ, in patients with severe hypertension.

Ventricular oversensing in 518 patients with implanted cardiac defibrillators: incidence, complications, and solutions.

The present study evaluates the incidence of various complications in implanted cardiac defibrillators (ICD) therapy due to ventricular oversensing (VO) and its complications. From June 1998 to May 2005, we retrospectively screened 518 patients (1085.6 patient years) for the occurrence of VO episodes (441 male, 77 female). The overall incidence was 7.3% (n = 38) with inappropriate shock deliveries accounting for 2.3% (n = 12). All VO episodes were caused by either T-wave oversensing (n = 10), myopotentials (n = 8), electrode failure (n = 5), interference with electromagnetic fields (n = 3), double-counting (n = 4), pacemaker interactions (n = 2), or others (n = 2). There were five life-threatening events due to inappropriate ICD reaction. In eight (22%) cases, ICD reprogramming was able to avoid further oversensing episodes (e.g. adaptation of sensitivity, T-wave suppression feature), 13 (35%) patients had to undergo invasive procedures (e.g. electrode replacing) to suppress VO, 16 (43%) were told to avoid the trigger situation, and one demanded to deactivate all ICD therapies because of inappropriate shock delivery. Our data demonstrate that VO is a rare complication, but might lead to life-threatening events. In most cases, VO episodes could be prevented by appropriate ICD reprogramming or avoidance of the initiating trigger.

Failure of ascorbic acid to prevent contrast-media induced nephropathy in patients with renal dysfunction.

AIMS: Contrast-media induced nephropathy (CIN) remains a common complication after contrast dye exposure especially in patients with chronic renal impairment (CRI). We sought to evaluate the efficacy of the antioxidant ascorbic acid as an adjunct to hydration in limiting the incidence of contrast induced nephrotoxicity after coronary procedures. MATERIALS AND METHODS: In a randomized, double-blind, prospective, single center-study, 143 consecutive patients with CRI (creatinine level > 120 micromol/l) referred to coronary angiography/intervention were randomly assigned to receive 1 g ascorbic acid or placebo in adjunct to saline hydration prior to and after angiography. Creatinine and urea nitrogen levels were measured prior to and up to 6 days after exposure to contrast agent. RESULTS: The development of CIN occurred totally in 8/143 (5.6%) patients. Between the two groups no significant difference was detected (Vitamin C 5/74 (6.8%) patients; placebo 3/69 (4.3%) patients). After adjusting for the amount of contrast dye, drug treatment, cardiovascular risk factors, ejection fraction, or sex, again no differences were detected. No patient required dialysis. More patients with diabetes had development of CIN (7/85; 8.2%) compared with nondiabetic patients (1/58; 1.7%), although not significant (p = 0.14). The incidence of CIN was elevated in patients with high amounts (> 140 ml) of contrast volume used (6/8). CONCLUSIONS: Our study does not support the prophylactic use of ascorbic acid in patients with renal dysfunction exposed to contrast dye.

Apoptosis of human macrophages by Flt-4 signaling: implications for atherosclerotic plaque pathology.

BACKGROUND: Neointimal inflammation and angiogenesis are important contributors of progression and destabilization of the atherosclerotic plaque. While the role of vascular endothelial growth factor (VEGF) and its receptors VEGF-R1 (Flt-1) and VEGF-R2 (Flk-1) in this process has clearly been defined, expression of the VEGF-R3 (Flt-4) has only been documented on lymphatic and tumor endothelium. This study examined Flt-4 expression in human atherosclerotic plaque and explored its implications for atherosclerotic disease. METHODS AND RESULTS: Carotid artery thrombendartherectomy specimens from 10 patients with unstable plaque were stained for Flt-4 and its specific growth factors VEGF-C and VEGF-D. Microvascular endothelial cells (MVEC) stained positive for VEGF-C and -D, but not for Flt-4. Interestingly, macrophages within inflammatory perivascular regions coexpressed Flt-4, VEGF-C and VEGF-D. In vitro studies confirmed the expression of Flt-4, VEGF-C and VEGF-D in human monocytes and cultured macrophages. Treatment of macrophages with VEGF-D induced apoptosis as determined by annexin V staining, by immunoblotting of activated caspase 3, and by the ratio of Bcl-2/Bax as well as by DNA fragmentation. Immunohistochemical studies of advanced human carotid atherosclerotic plaque confirmed the coexpression of Flt-4 with activated caspase 3 and TUNEL staining in macrophages, indicating an ongoing apoptotic process. CONCLUSION: Human monocytes/macrophages express VEGF-C and -D and their receptor Flt-4 in vitro and in vivo within advanced atherosclerotic lesions. Flt-4, in turn, mediates monocyte/macrophage apoptosis and may this way alter plaque stability.

Lipoprotein apheresis influences monocyte subpopulations.

BACKGROUND: Monocytes can be differentiated into subpopulations depending on their expression profile of CD14 and CD16. CD16-positive monocytes are associated with coronary artery disease. Up to now, no data exist about the effect of lipoprotein apheresis (LA) on the distribution of monocyte subpopulations. METHODS: 80 patients who underwent LA at the University Hospital Dresden were included in the study. 8 out of the 80 LA patients received LA for the first time at the time point of blood analysis. Six different methods of LA were used (H.E.L.P. n = 8; Liposorber D n = 10; LF n = 14; DALI n = 17; MONET n = 11; Therasorb® LDL n = 12). Blood samples were taken immediately before and after LA and analyzed for CD14 and CD16 expression on monocytes. A total of 42 patients with cardiovascular risk factors but no indication for LA served as control group. RESULTS: The composition of monocyte-population was analyzed in regard to the 3 subpopulations. After LA, an increase in classical monocytes (CD14++CD16-) (93.3% vs. 93.9%, p < 0.01) and a decrease in non-classical monocytes (CD14+CD16+) (1.5% vs 1.0%; p < 0.001) were observed. LA did not change the amount of intermediate monocytes (CD14++CD16+) (5.3% vs. 5.1%). Two methods (MONET and Therasorb® LDL) did not influence the distribution of monocyte subpopulations. Interestingly, patients with LDL-C above 2.5 mmol/l prior LA showed increased amounts of intermediate monocytes. CONCLUSION: The distribution of monocyte populations is influenced by LA but depends on the distinct method of LA. Influences of LA were mainly observed in the content of classical and non-classical monocytes, whereas the intermediate monocyte population remained unaltered by LA.

Two distinct mechanisms mediate a differential regulation of protein kinase C isozymes in acute and prolonged myocardial ischemia.

An activation of protein kinase C (PKC) in acute myocardial ischemia has been shown previously using its translocation to the plasma membrane as an indirect parameter. However, whether PKC remains activated or whether other mechanisms such as altered gene expression may mediate an isozyme-specific regulation in prolonged ischemia have not been investigated. In isolated perfused rat hearts, PKC activity and the expression of PKC cardiac isozymes were determined on the protein level using enzyme activities and Western blot analyses and on the mRNA level using reverse transcriptase-polymerase chain reaction after various periods of global ischemia (1 to 60 minutes). As early as 1 minute after the onset of ischemia, PKC activity is translocated from the cytosol to the particulate fraction without change in total cardiac enzyme activity. This translocation involves all major cardiac isozymes of PKC (ie, PKCalpha, PKCdelta, PKCepsilon, and PKCzeta). This rapid, nonselective activation of PKCs is only transient. In contrast, prolonged ischemia (>/=15 minutes) leads to an increased cardiac PKC activity (119+/-7 versus 190+/-8 pmol/min per mg protein) residing in the cytosol. This is associated with an augmented, subtype-selective isozyme expression of PKCdelta and PKCvarepsilon (163% and 199%, respectively). The specific mRNAs for PKCdelta (948+/-83 versus 1501+/-138 ag/ng total RNA, 30 minutes of ischemia) and PKCepsilon (1597+/-166 versus 2611+/-252 ag/ng total RNA) are selectively increased. PKCalpha and PKCzeta remain unaltered. In conclusion, two distinct activation and regulation processes of PKC are characterized in acute myocardial ischemia. The early, but transient, translocation involves all constitutively expressed cardiac isozymes of PKC, whereas in prolonged ischemia an increased total PKC activity is associated with an isozyme-selective induction of PKCepsilon and PKCdelta. Whether these fundamentally different activation processes interact remains to be elucidated.

Endogenous proteinases modulate the function of the beta-adrenergic receptor-adenylate cyclase system.

Photoaffinity labeling techniques have recently demonstrated that mammalian beta 1- and beta 2-adrenergic receptors reside on peptides of Mr 62 000-64 000. These receptor peptides are susceptible to endogenous metalloproteinases which produce peptides of Mr 30 000-55 000. Several proteinase inhibitors markedly attenuate this process, specifically EDTA and EGTA. In this study we investigated the functional significance of this proteolysis (and its inhibition) in the beta 2-adrenergic receptor-adenylate cyclase system derived from rat lung membranes. Membrane preparations containing proteolytically derived fragments of the receptor of Mr 40 000-55 000 are fully functional with respect to their ability to bind beta-adrenergic antagonist radioligands such as [3H]dihydroalprenolol and beta-adrenergic antagonist photoaffinity reagents such as p-azido-m-[125I]iodobenzylcarazolol. They retain the ability to form a high-affinity, agonist-promoted, guanine nucleotide-sensitive complex thought to represent a ternary complex of agonist, receptor and guanine nucleotide regulatory protein. Nonetheless, after proteolysis, GTP is less able to revert this high-affinity receptor complex to one of lower affinity, and all aspects of adenylate cyclase stimulation are reduced. In addition, the functional integrity of the N protein in membranes prepared without proteinase inhibitors is reduced as assessed by reconstitution studies with the cyc- variant of S49 lymphoma cell membranes. These results suggest that endogenous proteolysis does not directly impair the ability of beta-adrenergic receptors to either bind ligands or interact with the guanine nucleotide regulatory protein. However, they imply that endogenous proteolysis likely impairs the functionality of other components of the adenylate cyclase system, such as the nucleotide regulatory protein.

Desensitization of the pulmonary adenylyl cyclase system: a cause of airway hyperresponsiveness in congestive heart failure?

OBJECTIVES: This study was designed to investigate whether the adrenergic signal transduction in the lung and the responsiveness of airway smooth muscle to adrenergic stimulation are modulated in congestive heart failure. BACKGROUND: Wheezing and airway hyperresponsiveness are often present in heart failure. In the failing heart, chronic adrenergic stimulation down-regulates beta-adrenergic receptors and adenylyl cyclase. We hypothesized that airway dysfunction in heart failure could be due to a similar modulation of pulmonary adrenergic signal transduction. METHODS: Heart failure was induced in rats by aortic banding, resulting in increases in plasma norepinephrine, lung wet weight indicating congestion and left ventricular end diastolic pressure after four weeks. Beta-receptor densities in pulmonary plasma membranes were measured by radioligand binding using [125I]iodocyanopindolol. The G protein levels were determined by Western blot. Adenylyl cyclase activities in lung membranes were quantified as [32P]cAMP (cyclic adenosine-5'-monophosphate) synthesis rate. To functionally assess airway smooth muscle relaxation, carbachol-precontracted isolated tracheal strips were used. RESULTS: Beta-receptor density was significantly decreased in heart failure from 771 +/- 89 to 539 +/- 44 fmol/mg protein without changes in receptor affinities. The beta1-/beta2-subtype ratio, however, remained constant. The G(i and alpha) and G(s alpha) protein expression was unchanged. Adenylyl cyclase activity stimulated directly with forskolin was decreased by 28%. Relaxation of tracheal strips in response to isoproterenol and forskolin, but not to papaverin, was diminished by 30%. CONCLUSIONS: In heart failure, the down-regulation of pulmonary beta-receptors and concomitant decrease in adenylyl cyclase activity result in a significant attenuation of cAMP-mediated airway relaxation. These mechanisms may play a pivotal role in the pathogenesis of"cardiac asthma."