Tumour necrosis factor-α and the failing heart

Abstract. Immune activation plays a signicant role in the development and progression of chronic heart failure (CHF). Indeed, pro-inammatory cytokines, especially tumour necrosis factor- (TNF) are activated in this condition and exert direct detrimental actions on the myocardium. Physiological dampeners of TNF production, such as interleukin-10, catecholamines, cortisol, and others fail in the course of the disease. However, the outcomes of two large-scale clinical trials with etanercept and iniximab, which directly antagonise TNF have been rather disappointing. Nevertheless, TNF antagonism remains a major target of CHF therapy, although counterbalancing this cytokine alone may not be sufcient.     

Static exercise in anesthetized dogs,a cause of reflex alpha-adrenergic coronary vasoconstriction

Summary The coronary blood flow and vascular resistance responses to static hindlimb exercise were studied in 11 anesthetized dogs after - and combined - and -adrenergic blockade to determine if this stress causes coronary vasoconstriction. After -blockade static exercise increased the blood pressure and double product, but decreased the right and left ventricular (LV) coronary blood flow and increased the coronary vascular resistance. These vascular changes primarily occurred in the epicardial and mid-myocardial but not the endocardial layers of the LV. Following combined - and -adrenergic blockade, the systemic hemodynamic and coronary flow and resistance changes were abolished. These data suggest that -adrenergic mediated coronary vasoconstriction occurs during static hindlimb exercise in dogs.Dr. Longhurst is partially supported by an NIH Young Investigator Award, #HL-22667. Dr. Aung-Din is presently a resident in Neurosurgery at the University of Florida, Gainesville, Florida.     

TNFα in ischemia/reperfusion injury and heart failure

Abstract. During myocardial ischemia, both the myocardial and serum TNF concentrations are rapidly increased within the area at risk. With prolongation of ischemia and development of cardiomyocyte necrosis, the TNF concentration increases also in the surrounding viable portions of the myocardium. Indeed, in the scenario of myocardial ischemia/reperfusion, treatment with TNF antibodies reduced the extent of myocardial infarction in rabbits and attenuated the contractile dysfunction following microembolization in dogs. In the latter studies, the serum TNF concentration remained unaltered thereby supporting the notion of a direct action of TNF at the level of cardiomyocytes during ischemia/reperfusion.In heart failure, the serum TNF concentration is also increased, and in patients with advanced heart failure the serum TNF concentration is an independent predictor of mortality. The origin of the increased serum TNF concentration is not clearly identied yet, but TNF derived from the heart and peripheral organs contributes to the increased serum TNF concentration. Treatment with TNF antibodies in the clinical scenario, however, did not improve the prognosis of heart failure patients.     

Alterations in Adrenergic Receptor Signaling in Heart Failure

In the failing heart, several changes occur in cardiac adrenergic receptor-signal transduction pathways. The most striking of these changes occur in -ARs, and of the changes in -adrenergic receptors, 1-receptor down-regulation is the most prominent. Other changes include uncoupling of 2-adrenergic receptors and increased activity of the inhibitory G-protein, Gi. Most of these changes appear to be related to increased activity of the adrenergic nervous system, i.e. increased exposure to norepinephrine. Antagonists of the adrenergic nervous system improve left ventricular function and outcome in patients with heart failure. This fact supports the notion that activation of these neurohormonal systems exerts a net long-term detrimental effect on the natural history of chronic heart failure and that myocardial adrenergic desensitization phenomena are at least partially adaptive in the setting of left ventricular dysfunction.     

The treatment of hypertension: New lamps for old?

Summary Meta-analysis of clinical trials does not help the clinician to treat individual patients. A general conclusion that the reduction of high blood pressure is beneficial has to be matched by specific information about the level of blood pressure that is acceptable and about the effect of particular doses of specific drugs. Results obtained from trials of old-fashioned antihypertensive drugs cannot confidently be extrapolated to modern agents. Sufficient data do not exist to encourage universal drug treatment for patients with mild hypertension.     

Distribution of β-Adrenoceptor Subtypes in Gastrointestinal Tract of Nondiabetic and Diabetic BB Rats A Longitudinal Study

The effects of aging and diabetes on thedistribution of -adrenoceptor subtypes in the gutwere investigated in the BB rat.[¹²⁵I]Cyanopindolol binding to 10-msections was evaluated using film autoradiography. Cyanopindolol binding to -,₁-, and₂-adrenoceptors was displaced by 1M propranolol, 50 nM ICI-89-406, and 100 nMICI-118-551, respectively. -Adrenoceptor bindingwas highest in the circular muscle of proximal colon and lowest in thepylorus of 4- to 5-month-old rats. Aging (8- to10-month-old vs. 4- to 5-month-old rats) was associatedwith increased -adrenoceptor binding in thepylorus and reduced binding in the proximal colon.Diabetes had a time-dependent effect on the level of-adrenoceptor binding. It was increased in theantral and pyloric stomach but longer periods ofdiabetes caused a reduction in -adrenoceptorbinding in the pylorus. Those in the intestine werereduced time-dependently and involved₁- or ₂-adrenoceptorsor both.     

Intermittent infusion of dobutamine in the therapy of severe congestive heart failure-long-term effects and lack of tolerance

Summary Twenty patients with refractory heart failure NYHA class IV were randomly assigned to infusion therapy with 9.25 g/kg/min dobutamine over 24 hours or placebo. Eight infusions over a 4-week period were performed in the hospital; between infusions breaks of 3 days were scheduled. A dose titration was performed before study during which dobutamine was infused at 2.5 g/kg/min and increased by 2.5 g/kg/min steps every 15 minutes up to a maximum dosage of 10 g/kg/min. After dobutamine, exercise duration on the treadmill stress test increased from 177±110 seconds to 251 ±120 seconds (p<0.05). The heart-rate response to exercise increased (91±20 to 116±26 beats/min at baseline, 88±17 to 132±26 beats/min after therapy). Body weight decreased from 70.9±15.5 to 68.9±14.2 kg (p<0.03). On placebo, no significant changes were evident. Systolic time intervals and hemodynamic parameters showed only minor and not significant changes in both groups. No excess mortality emerged during intermittent dobutamine therapy. No clinical or hemodynamic signs of tolerance development were evident during control assessment 3 days after the last infusion. Intermittent therapy with dobutamine seems to be a promising concept in the management of refractory severe heart failure.     

β-adrenoceptor Modulation and Heart Rate Variability—The Value of Scatterplot Measures of Compactness

This article compares different methods of scatterplot analysis to assess the optimal methodology. The scatterplot (Poincaré plot) is a nonlinear heart rate variability method where a return map is constructed by plotting each current cycle against the previous beat (RR vs. RR_n–1). Geometric analysis of the scatterplot allows short-term and long-term heart rate variability (HRV) to be assessed. A three-dimensional construct is also possible, where the third axis represents the density of values, at any given RR vs. RR_n–1 intersection. Topological methods of analysis can compute the density distribution function or compactness of a dataset. Scatterplots that otherwise appear very similar in the two-dimensional plot may be clearly differentiated using this approach. Correct characterization may improve the ability of scatterplot analysis to predict outcomes in cardiovascular disease.We have assessed two computational approaches that take account of scatterplot density, namely, the heart rate variability fraction and the compactness measure. Scatterplots were constructed from three double-blind and randomized placebo controlled studies conducted in a total of 49 healthy subjects. Single oral doses of antagonists (atenolol 50 mg [-1, propranolol 160 mg [-1 and -2], and ICI 118,551 25 mg [-2]) or agonists (xamoterol 200 mg [-1], salbutamol 8 mg [-2], prenalterol 50 mg [-1 and -2], and pindolol 10 mg [mainly -2] of the cardiac -adrenoceptor were studied.Salbutamol, pindolol, and xamoterol increased compactness and reduced HRV fraction significantly compared with placebo. However, when compared with the more conventional scatterplot parameters, these newer density methods were found to be less discriminating. An alternative approach to improve scatterplot discrimination, using the combination of several scatterplot features, is under investigation.     

Additional value of thallium-201 SPECT to a conventional exercise test for the identification of severe coronary lesions after an episode of unstable coronary artery disease

The additional value of thallium-201 SPECT to a conventional exercise test for the identification of patients with severe coronary lesions was evaluated in 170 men, one month after an episode of unstable coronary artery disease. Severe coronary lesions at coronary angiography — defined as three vessel disease, left main stenosis or proximal left anterior descending artery stenosis as part of two vessel disease — were observed in 45.9%. In the SPECT image, the left ventricular myocardium was divided into nine segments and each segment was classified as either normal (=0), reduced uptake (=1) or uptake defect (=2). The sum of gradings in all segments post-exercise was denoted SPECT score. The patients were divided into nine different groups regarding ST-depression during exercise (no ST-depression, ST-depression in 1–2 leads or 3 leads) and SPECT score (no SPECT score, 1–3 scores or 4 scores). Severe coronary lesions were, in 68% identified by SPECT score 4 and in 65% by ST-depression in 1 lead at exercise test. The specificity for identification of severe coronary lesions was, for both tests, 65%. SPECT score 4 and/or ST-depression in 3 leads identified 82% of the patients with severe coronary lesions with a specificity of 63%. Furthermore, SPECT score 3 identified more patients with isolated proximal left anterior descending artery stenosis than ST-depression alone at exercise test.     

Beta-blocker therapy combined with low-dose pimobendan in patients with idiopathic dilated cardiomyopathy and chronic obstructive pulmonary disease: report on two cases

Pimobendan is an inotropic and vasodilating drug with phosphodiesterase (PDE) III-inhibiting and calcium-sensitizing effects. It may also have a bronchodilatory effect by inhibiting PDE III in airway smooth muscle.We tried a -blocker combined with low-dose pimobendan in 2 patients who had refractory heart failure of NYHA functional class III or IV with idiopathic dilated cardiomyopathy (DCM) and chronic obstructive pulmonary disease (COPD). Both of them had previously failed to tolerate -blocking drugs because of the exacerbation of bronchospasm. After pimobendan was administered at 1.25 to 2.5 mg daily, metoprolol could be successfully introduced from a low dose of 1.25 mg daily without decreasing the peak expiratory flow rate. Over the next 1 to 2 years, they have continued -blocker therapy. One is currently receiving 10 mg daily of bisoprolol and another is taking 15 mg daily of metoprolol, and both are in NYHA functional class II without worsening heart failure or COPD. The combination of -blocker with low-dose pimobendan may be helpful for patients with DCM and COPD, but further clinical investigation is required.     

Mechanisms Involved in the Cardiac Protection Efficacy of Carvedilol

Beta-adrenergic receptor (-AR) blockers are proven therapeutic agents in diverse cardiovascular diseases including hypertension, angina, myocardial infarction and arrhythmias. Recent trials in heart failure patients (MOCHA, PRECISE, ANZ-carvedilol trial, CIBIS I/II, MERIT) have demonstrated the efficacy of -AR blockers to reduce morbidity and mortality in all grades of heart failure patients, leading to approval of at least one agent, carvedilol, for treatment of this progressive and malignant disease. In this review, the pharmacology of carvedilol is summarised and analysed with particular reference to the mechanism of cardiac protection. Such analysis is critical for understanding the complex mechanisms of carvedilol actions consisting of: 1. non-selective -AR blocking action; 2. ₁-AR blocking action; 3. antioxidant action; 4. prevention of organ remodeling via modulation of gene expression, including apoptosis. The overall combination of carvedilol pharmacology differentiates this drug from any other -AR blocking agent. In this brief review the pre-clinical pharmacology of carvedilol pertaining to cardioprotection is presented in the context of its potent anti-ischemic properties, its capacity to prevent cardiac remodeling and its potential role in prevention of apoptosis.     

Properties of labetalol,a combined α-and β-blocking agent,relevant to the treatment of myocardial ischemia

Summary Labetalol, a combined --adrenergic antagonist, is one of the new group of -adrenergic blockers reduces peripheral and coronary vascular resistances while preserving cardiac output. Unlike -adrenergic blockers, labetalol tends to reduce heart rate during rest and exercise. The drug is a potent antihypertensive agent which has been used by mouth and by vein to treat mild, moderate, and severe hypertension, including hypertensive emergencies. Labetalol has a hemodynamic profile which makes it an attractive agent for treating myocardial ischemia. The drug reduces blood pressure, left ventricular wall tension, heart rate, and contractility while preserving or even augmenting coronary blood flow. Studies with labetalol in hypertensive patients with angina have shown it to be more effective than placebo in reducing angina attacks and blood pressure while improving exercise tolerance. The drug appears to have antianginal and antihypertensive effects comparable to atenolol and propranolol. Side effects of treatment are observed and most are related to - and -adrenergic blockade. Labetalol also appears to be effective for treatment of normotensive patients with angina and for silent myocardial ischemia. It has no apparent effects on serum lipids and lipoproteins. Labetalol appears to be a useful drug for treating the hypertensive heart and its many complications.     

Effects of acetyl strophanthidin on duration of atrial fibrillation in the neurally-intact and blockaded dog

Summary Although the inotropic and dromotropic effects of cardiac glycosides in atrial fibrillation (AF) are well recognized, their action on AF itself is not clear. Accordingly, to determine whether cardiac glycosides prolong AF, the duration of electrically induced AF, atrioventricular conduction, and left ventricular function were assessed for 30 minutes before and for 30 minutes following intravenous administration of acetyl strophanthidin (AS), 20 g/kg, in neurally intact, -blocked, and -blocked and vagotomized dogs. In the intact dog, AS, 20 g/kg, increased peak dp/dt by 132±35 mmHg·sec^-1, p<0.05, and slowed ventricular response by 16±7 min^-1, p<0.05, but had a variable effect on Af duration. While the increased left ventricular peak dp/dt persisted for 15 minutes after AS, an increased duration of AF was evident only at 20 minutes, when the effects of AS on left ventricular (LV) inotropy were no longer apparent. Moreover, the subset of dogs that did not demonstrate prolongation of average duration of AF after AS had a greater increment of peak dp/dt than those that showed prolongation, 237±52 versus 53±31 mmHg·sec^-1, p<0.05. An additional 20 g/kg, which produced ventricular extrasystoles, prolonged AF duration when compared to both control and 30-minute measurements. Acetyl strophanthidin, 20 g/kg, had a variable effect on duration of AF with -blockde but prolonged duration by 114±34%, p<0.05, with both vagotomy and -blockade. Thus the conclusion is reached that, at a clinically relevant dosage, cardiac glycosides did not exert a statistically significant influence on duration of AF; at a toxic dosage, however, an AF-enhancing effect was apparent. The inotropic effects of cardiac glycosides appear to obscure this effect. An AF-enhancing action of cardiac glycosides in the presence of neurohumoral blockade suggests that the effects on AF may not only be vagally mediated.     

Platelet and Thrombin Activity Following Cardiac Catheterization Despite Treatment with Aspirin

Thromboembolic complications are reported to occur in up to 0.5–2% of left cardiac catheterizations and angiographies. Activation of the hemostatic system may contribute to their onset. To prevent platelet and thrombin activity during catheterization, aspirin or systemic heparin are often used in addition to heparinized flush solutions. We investigated whether aspirin alone can prevent platelet and thrombin activity induced by catheterization in ten consecutive patients (nine males, mean 50 ± 8 years) undergoing elective left cardiac catheterization after at least 5 days of oral aspirin (75–300 mg/d). Anticoagulant drugs were not given. Peripheral venous samples were drawn before, immediately after (time 0), and at 15, 60, and 180 minutes after the procedure for measurement of thrombin–antithrombin (TAT), prothrombin fragment 1.2 (F 1.2), fibrinopeptide A (FPA), and -thromboglobulin (-TG). TAT, F1.2, and FPA increased significantly at time 0 compared with both before and 180 minutes after the procedure (P < 0.04); -TG values were higher at time 0 compared with 180 minutes later (P = 0.01). TAT levels were related to those of FPA (r = 0.66; P = 0.0003), F1.2 (r = 0.35; P = 0.01), and -TG (r = 0.37; p = 0.04). Thus, routine left cardiac catheterization is associated with transient, systematically detectable, activation of coagulation and platelets, despite aspirin therapy. Newer antiplatelet agents may be more effective in preventing hemostatic activation induced by catheterization.     

Alterations in cardiac oxygen consumption under chronic pressure overload

Summary Hypertension and resulting left ventricular hypertrophy was induced in young male Wistar rats (60 to 70 days old) by narrowing of one renal artery (Goldblatt II). 8 and 24 weeks after operation, myocrdial oxygen consumption was measured on a modified in situ heart-lung preparation with nearly isovolumetric left ventricular contractions. Measured myocardial oxygen consumption was related to left ventricular wall stress. The myosin isoenzyme pattern of each heart was determined with pyrophosphate gel electrophoresis.Oxygen consumption related to wall stress averaged over the entire heart cycle amounted to 15 moles O₂/g·min 8 weeks after operation, and 24.4 moles O₂/g·min in age-matched controls ( 38%, p<0.0005). When wall stress was averaged over systole, oxygen consumption of the hypertrophied hearts amounted to 0.112 moles O₂/g·beat, and 0.149 moles O₂/g·beat in the controls ( 25%, p<0.05). The proportion of VM-3 (the cardiac myosin isoenzyme of lowest ATPase activity) increased from 26.3% in the controls to 30.1% in the Goldblatt hearts ( 14%, n.s.).24 weeks after operation, oxygen consumption related to wall stress averaged over the entire heart cycle amounted to 16.1 moles O₂/g·min, in age-matched controls 20.5 moles O₂/g·min ( 21%, p<0.05). When wall stress was averaged over systole, oxygen consumption of the Goldblatt hearts amounted to 0.080 moles O₂/g·beat, and in the controls 0.107 moles O₂/g·beat ( 25%, p<0.005). The proportion of VM-3 increased from 33.5% in the controls to 43.2% in the hypertrophied hearts ( 29%, p<0.05).The present findings indicate that the reduced oxygen consumption of the pressure-loaded heart should be attributed to a redistribution of myosin isoenzymes. The transformation of myocardium into a slower, but more efficiently working muscle due to an increase in VM-3 can be interpreted as an adaptational process.Supported by the Deutsche Forschungsgemeinschaft     

Disassociation of muscle triglyceride content and insulin sensitivity after exercise training in patients with Type 2 diabetes

Aim/hypothesis We determined the effect of exercise training on insulin sensitivity and muscle lipids (triglyceride [TG_m] and long-chain fatty acyl CoA [LCACoA] concentration) in patients with Type 2 diabetes.Methods Seven patients with Type 2 diabetes and six healthy control subjects who were matched for age, BMI, % body fat and VO₂peak participated in a 3 days per week training program for 8 weeks. Insulin sensitivity was determined pre- and post-training during a 120 min euglycaemic-hyperinsulinaemic clamp and muscle biopsies were obtained before and after each clamp. Oxidative enzyme activities [citrate synthase (CS), -hydroxy-acyl-CoA (-HAD)] and TG_m were determined from basal muscle samples pre- and post training, while total LCACoA content was measured in samples obtained before and after insulin-stimulation, pre- and post training.Results The training-induced increase in VO₂peak (~20%, p<0.01) was similar in both groups. Compared with control subjects, insulin sensitivity was lower in the diabetic patients before and after training (~60%; p<0.05), but was increased to the same extent in both groups with training (~30%; p<0.01). TG_m was increased in patients with Type 2 diabetes (170%; p<0.05) before, but was normalized to levels observed in control subjects after training. Basal LCACoA content was similar between groups and was unaltered by training. Insulin-stimulation had no detectable effect on LCACoA content. CS and -HAD activity were increased to the same extent in both groups in response to training (p<0.001).Conclusion/interpretation We conclude that the enhanced insulin sensitivity observed after short-term exercise training was associated with a marked decrease in TG_m content in patients with Type 2 diabetes. However, despite the normalization of TG_m to levels observed in healthy individuals, insulin resistance was not completely reversed in the diabetic patients.Abbreviations -HAD -hydroxy-acyl-CoA - CS citrate synthase - DAG diacylglycerol - DEXA dual energy X-ray absorptiometry - LCACoA long-chain fatty acyl CoA - PI3-kinase phosphatidylinositol 3-kinase - TG_m muscle triacylglycerol     

A Three-dimensional Analysis of Blood Vessels in Bronchioloalveolar Carcinoma

The three-dimensional architecture of blood vessels within lung adenocarcinomas has not been well studied. In 19 cases with bronchioloalveolar carcinoma with central fibrosis, we three-dimensionally examined blood vessel architecture in 150 m thick sections stained with elastin staining and anti-CD34 antibody. We examined four regions: normal alveoli and three regions within the tumor including an area adjacent to the normal alveoli (external area), an area in which tumor cells were replacing epithelial cells (replacement area), and a central fibrotic area (fibrotic area). Elastin staining showed that elastic fibers formed the framework of the alveoli, and the alveolar structure shrank more strongly to the center of the tumor due to folding of alveolar walls invaded by adenocarcinoma cells. We also measured three vessel parameters in these four regions. The vessel diameters were 4.08±1.10 m, 3.95±1.02 m, 5.04±1.56 m, and 6.11±2.23 m, the circumferences of those vessels seen as complete circles were 43.11±12.78 m, 43.71±12.87 m, 95.21±39.32 m, and 126.77±54.65 m; the lengths between vessel bifurcations were 13.28±3.08 m, 13.47±4.58 m, 24.91±9.66 m, and 41.82±28.08 m in the normal alveoli, and the external, replacement, and fibrotic areas, respectively. Blood vessel architecture changed such that the vessels became larger and coarser towards the center of the tumor. Our three-dimensional analysis suggests continuous remodeling of alveolar capillaries rather than angiogenesis within bronchioloalveolar carcinoma.     

Clinical Trials of Carvedilol in Heart Failure

Carvedilol is a non-selective ₁ and -adrenergic antagonist with antioxidant properties. This novel, competitive antagonist has been studied in 8 placebo-controlled clinical trials involving over 1800 heart failure patients with systolic dysfunction in varying degrees of severity. Overall, carvedilol is well-tolerated in heart failure patients, with a predictable reduction in heart rate and favorable hemodynamic actions. The overall incidence of side effects including hypotension, dizziness, bradycardia and worsening heart failure are no worse than placebo, and can be minimized with careful titration. Improvement in left ventricular ejection fraction has been observed with carvedilol in all studies. A significant reduction in the risks of dying or being hospitalized has also been demonstrated. Some studies have demonstrated improvements in clinical parameters such as symptom status and exercise tolerance, but these benefits have been more difficult to demonstrate conclusively. These clinical trials have established an important role of carvedilol in the management of heart failure. The results from the recent survival trials of beta-adrenergic antagonists have confirmed the mortality benefit of this class of drug in the management of patients with heart failure.     

Oligosaccharides accumulated in the bovineβ-mannosidosis kidney

Summary The phenotype of bovine-mannosidosis (-mannosidase deficiency), recently identified in Salers cattle, is similar to the caprine form of the disease (Abbittet al., 1991). This investigation was designed to characterize accumulated kidney oligosaccharides in bovine-mannosidosis. Oligosaccharides were extracted from the kidney of an affected Salers calf and purified by chromatographic techniques. The amount of accumulating oligosaccharides in 1 g of wet tissue was about 21µmol. Structures of derivatized oligosaccharides were characterized by high-performance liquid chromatography, mass spectrometry, methylation analysis and sequential exoglycosidase digestions. The major accumulating oligosaccharides were Man1-4GlcNAc and Man1-4GlcNAc1-4GlcNAc. Oligosaccharides accumulating in minor amounts were Man1-4GlcNAc1-4Man1-4GlcNAc, Man1-6Man1-4GlcNAc1-4GlcNAc and Man1-4GlcNAc1-4Man1-4GlcNAc1-4GlcNAc. As in caprine-mannosidosis, oligosaccharides with terminal-mannose residues and cleaved as well as uncleaved chitobiose linkages were identified in bovine-mannosidosis kidney. The accumulating oligosaccharides in tissue were thus identical in bovine and caprine-mannosidosis; however, the source of the novel oligosaccharides remains to be determined.     

Endothelial Dysfunction in Congestive Heart Failure: Effects of Carvedilol

In this review, we have examined the role of oxidative stress and apoptosis in the continuum of molecular changes that accompanies congestive heart failure. Cytokine activation and tumor necrosis factor-, in particular, may play a role in this continuum, favouring both oxidative stress and apoptosis. Carvedilol, a non selective - and -blocker, exerts an anti-apoptotic effect on both the myocytes and the endothelial cells as a consequence of its antioxidant activity. The ability of carvedilol to inhibit apoptosis may have important clinical relevance in congestive heart failure. It is also important to emphasise that, in congestive heart failure, apoptosis occurs, not only in the heart, but also in the periphery. An increased rate of endothelial apoptosis may explain the occurrence of endothelial dysfunction in congestive heart failure.