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R Ferrari

Publications and source records attributed to R Ferrari.

At least 73 records · Page 4Linked to original sources
PubMed1996

Skeletal muscle metabolism in experimental heart failure.

We studied peripheral skeletal muscle metabolism in monocrotaline-treated rats. Two distinct groups emerged: a percentage of the animals developed ventricular hypertrophy, with no signs of heart failure (compensated group), whilst others, besides ventricular hypertrophy, developed the syndrome of congestive heart failure (CFH group). Oxidative metabolism and redox cellular state were expressed in terms of creatine phosphate, purine (ATP, ADP and AMP) and pyridine (NAD and NADH) nucleotides tissue content. Skeletal muscles with different metabolism were studied: (a) Soleus (oxidative), (b) extensor digitorium longus (glycolytic) and tibialis anterior (oxidative and glycolytic). The results showed that in CFH animals a decreased high-energy phosphates content occurs in the soleus and extensor digitorum longus, but not in the tibialis anterior. In the soleus. ATP declined from 20.31 +/- 2.5 of control group to 9.55 +/- 0.61 mumol/g dry wt. while in the extensor digitorum longus ATP declined from 30.92 +/- 2.68 to 22.7 +/- 1.54 mumol/g dry wt. In both these muscles, a shift of NAD/NADH couple towards oxidation was also observed (from 26.58 +/- 3.34 to 6.95 +/- 0.97 and from 18.88 +/- 3.43 to 10.57 +/- 1.61, respectively). These alterations were more evident in the aerobic soleus muscle. On the contrary, no major changes occurred in skeletal muscle metabolism of compensated animals. The results show that: (1) a decrease in muscle high-energy phosphates occurs in CFH; (2) this is accompanied by a decrease of NAD/NADH couple suggesting an impairment in oxygen utilization or availability.

Adenosine Diphosphate↗
PubMed1996

Is stunning an important component of preconditioning?

We tested the hypothesis that stunning following a brief period of ischaemia is a component of cardioprotection afforded by preconditioning in an in vitro model of global normothermic ischaemia. Isolated Langendorff-perfused rat hearts, after 120-150 min of aerobic perfusion, were divided into four groups. Groups 1 and 2 constituted the aerobic and ischaemic controls. The other hearts were preconditioned by two 2-min ischaemia/reperfusion cycles. Two ischaemic preconditioning protocols were used, the only difference being prolongation of the reperfusion cycle from 5 (group 3) to 20 min (group 4) before the onset of severe ischaemic insult. Mechanical function, energetic metabolism and the rate of enzyme release were followed throughout. In group 3, myocardial function remained significantly downregulated before the onset of severe ischaemia. This resulted in cardiac protection as evidenced by enhanced recovery of systolic pressure (37.7 +/- 3.6 v 61.9 +/- 5.7 mmHg for groups 2 and 3, respectively; P < 0.02), reduced rise in diastolic pressure (55.8 +/- 5.9 v 34.3 +/- 5.2 mmHg; P < 0.02), reduced creatine kinase (CK) release (957.3 +/- 175.7 v 541.5 +/- 85.9 mU/min/gww; P < 0.05) and higher contents of high-energy phosphate at the end of ischaemia [3.6 +/- 0.3 v 25.3 +/- 2.9 mumol/gdw for creatine phosphate (CP), P < 0.001] as well as after reperfusion (16.8 +/- 2.4 v 31.4 +/- 1.8 for CP, P < 0.01, and 3.9 +/- 0.5 v 6.2 +/- 0.8 mumol/gdw for ATP, P < 0.05). When severe ischaemia was started only after complete recovery of mechanical function (group 4), no protection was observed. Our data suggest that a decrease in mechanical function or stunning occurring after the short period of ischaemia causes ATP sparing and constitutes an additional mechanism of preconditioning cardioprotection in vitro.

Animals↗
PubMed1996

Metabolic and functional consequences of successive no-flow and sustained low-flow ischaemia; a 31P MRS study in rat hearts.

Recently, a model of acute hibernation, based on successive no-flow and low-flow ischaemia in the isolated rabbit heart has been described. In the present study this model was used in isolated rat hearts. 31P NMR was used to follow the time course of intracellular pH (pHi) and high-energy phosphates; mechanical activity of the heart was assessed simultaneously. Control hearts were subjected to 180 min of low-flow ischaemia and 60 min of reperfusion (group A). In the acute hibernation group, low-flow was preceded by 5 min of no-flow ischaemia (group B). In group A contracture developed during low-flow. The time to onset of contracture was 51 min (range: 28 to 123 min). In group B, contracture did not occur during low-flow ischaemia (P < 0.01): recovery of left ventricular developed pressure and end-diastolic pressure was significantly better during the first 15 min of reperfusion (P < 0.05). In group A pHi decreased from 7.06 +/- 0.04 to 6.64 +/- 0.14 during the first 30 min of low-flow. After contracture developed in this group two pHi values were measured amounting to 6.33 +/- 0.15 and 6.86 +/- 0.05 at the end of low-flow. At the end of reperfusion pHi was 6.29 +/- 0.05 and 7.09 +/- 0.06. In group B, pHi decreased from 7.08 +/- 0.03 to 6.55 +/- 0.03 during no-flow ischaemia. During low-flow ischaemia, pHi increased to 6.73 +/- 0.05 and remained constant. During reperfusion pHi recovered to 7.06 +/- 0.03. In group A and B phosphocreatine (PCr) levels at the end of low-flow ischaemia amounted to 13 +/- 8% and 26 +/- 6% of pre-ischaemic levels, respectively. During reperfusion, PCr recovery was better in group B: 67 +/- 12% v 23 +/- 11% (P < 0.05). In group A and B, ATP levels at the end of low-flow ischaemia were 5 +/- 10% and 19 +/- 9%, respectively. The rate of ATP depletion during low-flow ischaemia was initially similar in both groups, but between 45 and 90 min ATP depletion still continued in group A, while this had leveled off in group B (P < 0.01). During reperfusion no significant changes in ATP were observed. We propose that increased glucose transport and glycolytic flux are able to maintain ionic homeostasis and diastolic function when low-flow ischaemia is preceded by a short period of no-flow ischaemia.

Animals↗
PubMed1996

Heat shock protein changes in hibernation: a similarity with heart failure?

Myocardial hibernation is an adaptive phenomenon occurring during ischaemia. Patients with hibernating myocardium often have a history of an acute ischaemic insult, followed by prolonged hypoperfusion and symptoms of congestive heart failure (CHF), which is a complex syndrome involving several adaptational mechanisms. We tested the hypothesis that these two conditions evoke the myocardial expression of heat shock protein 72 (hsp72) as an adaptive response at the molecular level. Short-term acute hibernation was induced in isolated and perfused rat hearts subjected to 8 min total ischaemia followed by 292 min low-flow ischaemia (coronary flow: 1.0 ml/min), followed by 60 min of reperfusion. Total ischaemia caused quiescience. Subsequent low-flow resulted in a temporal early increase of lactate release, no re-establishment of developed pressure, no increase in diastolic pressure. Reperfusion resulted in 85.7 +/- 7.2% recovery of developed pressure, a small washout of lactate and CPK, no contracture, confirming that viability was maintained despite prolonged hypoperfusion. This sequence of events was linked to an increase in hsp72 content in the right (from 18.1 +/- 3.8% to 34.6 +/- 2.3%. P < 0.01) and left (from 19.7 +/- 2.6% to 37.6 +/- 3.3%, P < 0.01) ventricles. Three-hundred min of low-flow perfusion of the rat heart in absence of the short period of total ischaemia caused irreversible damage and failed to induced hsp72. CHF was induced in rats by intraperitoneal administration of monocrotaline. As a result, right ventricular weight increased from 171.3 +/- 7.2 to 412.3 +/- 18.7 mg. P < 0.001, peripheral and pleural effusion were evident and measurable, plasma arterial natriuretic peptide increased from 15.2 +/- 1.9 to 123.5 +/- 5.4 pg/ml, P < 0.001, confirming the occurrence of the syndrome of CHF. This was concomitant with significant expression of hsp72, more evident in the right (from 5.0 +/- 0.9% to 39.4 +/- 1.6%, P < 0.001) than in the left (from 3.5 +/- 0.6% to 13.0 +/- 1.2%, P < 0.001) ventricle. These data suggest that an adaptational process occurs at myocardial level during either hibernation or CHF. The expression of hsp72 could be viewed as a stereotyped adaptational reaction of the cardiac cell to stress conditions.

Animals↗
PubMed1996

Effects of felodipine on the ischemic heart: insight into the mechanism of cytoprotection.

To assess whether the administration of felodipine protects the myocardium in a dose-dependent manner against ischemia and reperfusion, isolated rabbit hearts were infused with three different concentrations of felodipine: 10(-10), 10(-9), and 10(-8) M. Diastolic and developed pressures were monitored; coronary effluent was collected and assayed for CPK activity and for noradrenaline concentration; mitochondria were harvested and assayed for respiratory activity; and ATP production and calcium content and tissue concentration of ATP, creatine phosphate (CP), and calcium were determined. The occurrence of oxidative stress during ischemia and reperfusion was also monitored in terms of tissue content and release of reduced (GSH) and oxidized (GSSG) glutathione. Treatment with felodipine at 10(-10) and 10(-9) M had no effect on the hearts when perfused under aerobic conditions, whilst the higher dose reduced developed pressure from 57.7 +/- 2.6 to 30.0 +/- 2.6 mmHg (p < 0.01). On reperfusion treated hearts recovered better than the untreated hearts with respect to left ventricular performance, replenishment of ATP and CP stores, and mitochondrial function. Recovery of developed pressure was 100% at 10(-8) M, 55% at 10(-9) M, and 46% at 10(-10) M. The reperfusion-induced tissue and mitochondrial calcium overload, release of CPK and noradrenaline, and oxidative stress were also significantly reduced. The effects of felodipine were dose dependent. Felodipine inhibited the initial rate of ATP-driven calcium uptake but failed to affect the initial rate of mitochondrial calcium transport. It is concluded that felodipine infusion provides dose-dependent protection of the heart against ischemia and reperfusion. Because this protection also occurred at 10(-9) M and 10(-10) M in the absence of a negative inotropic effect during normoxia and of a coronary dilatory effect during ischaemia, it cannot be attributed to an energy-sparing effect or to improvement in oxygen delivery. From our data we can envisage two other major mechanisms-(1) membrane protection and (2) reduction in oxygen toxicity. The ATP-sparing effect occurring at 10(-8) M is likely to be responsible for the further protection.

Adenosine Triphosphate↗
PubMed1996

Activation of the neuroendocrine response in heart failure: adaptive or maladaptive process?

Congestive heart failure is a clinical syndrome in which the capacity of the heart to maintain cardiac output is impaired. As a consequence, blood pressure is threatened and endocrine and paracrine mechanisms are activated to preserve circulatory homeostasis and to maintain blood pressure. At terminal stages, a complex multiorgan syndrome develops with severe pump failure, intense systemic vasoconstriction, and avid water and sodium retention. Increasing evidence points to humoral circulating or locally synthesized substances as one of the causes of the terminal consequences of heart failure. Therefore, the hypothesis that the syndrome of heart failure is, at least in part, a humoral disease has developed and is obtaining scientific credibility. Consequently, the neuroendocrine response to heart failure is no longer viewed as a compensatory beneficial mechanism. Instead, we have learned through the years that pharmacological treatment aimed at reducing the effect of the neuroendocrine response is indeed clinically and prognostically advantageous for the patient.

Adaptation, Physiological↗
PubMed1996

Cardioprotective effect of angiotensin-converting enzyme inhibitors in patients with coronary artery disease.

Clinical and experiments study with angiotensin-converting enzyme (ACE) inhibitors suggest that these agents may improve coronary artery disease by acting at multiple sites in the series of events leading to end-stage heart disease. These agents reduce blood pressure, improve prognosis and symptoms in patients with severe heart failure and in patients after acute myocardial infarction with left ventricular dysfunction. They are useful in the early, acute phase of myocardial infarction. More recently, ACE inhibitors have been shown to reduce in vitro vascular hypertrophy, to attenuate arteriosclerosis, and to maintain endothelium function. Whether these effects occur at clinical levels is still uncertain. The exciting clinical data have led to the proposal that alteration of ACE activity, particularly in tissue, is an important factor in development and progression of CAD. The ACE system is complex, with endocrine, paracrine, and autocrine effects. ACE is present in cardiac and vascular tissue. Therefore, the beneficial effects of ACE inhibitors can be classified as "cardio" and "vasculo" protective. This article summarizes a number of independent and complementary mechanisms pointing to a role of ACE and ACE inhibition in coronary artery disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Continuous versus intermittent warm blood cardioplegia: functional and energetics changes.

BACKGROUND: The aim of this study was to compare the protective effects of continuous warm blood cardioplegia (CWBC) and intermittent warm blood cardioplegia (IWBC) in an experimental model of blood-perfused, isolated rabbit heart. METHODS: In the CWBC group, cardiac arrest was induced by continuous infusion of blood cardioplegia (10 mEq/L KCl) followed by 30 minutes of reperfusion with blood. In the IWBC group, after 5 minutes of perfusion with blood cardioplegia (10 mEq/L KCl), coronary flow was abolished for 10 minutes, followed by reperfusion with blood cardioplegia for 5 minutes. This sequence was repeated three times for a total period of 45 minutes. Finally the hearts were reperfused for 30 minutes with blood. RESULTS: Infusion of potassium induced a marked increase in coronary perfusion pressure (from 50 +/- 3 to 98 +/- 1 mm Hg; p < 0.01), which remained elevated throughout in the CWBC group, whereas in the IWBC group, it dropped to 0 during each no-flow period. In both groups, cardioplegia resulted in a significant reduction in oxygen consumption (from 5.5 +/- 0.2 to 0.6 +/- 0.03 mL O2.min-1.100 g-1 wet wt; p < 0.01). During CWBC, glucose extraction was significantly reduced (from 152 +/- 10 to 64 +/- 18 micrograms.min-1.g-1 wet wt; p < 0.01). Free fatty acid uptake and creatine kinase and lactate release were not affected. During IWBC, in contrast, a transient but significant release of creatine kinase (from 643 +/- 254 to 2,234 +/- 296 mU.min-1.g-1 wet wt; p < 0.01) and lactate (from 63 +/- 22 to 374 +/- 32 micrograms.min-1.g-1 wet wt; p < 0.01) occurred after each period of ischemia. Despite these metabolic differences, both cardioplegic procedures allowed a prompt and complete recovery of mechanical function and tissue content of high-energy phosphates. CONCLUSIONS: Both CWBC and IWBC exert optimal protection in the isolated blood perfused rabbit heart. Thus, IWBC can be safely used to improve visualization of the surgical field.

Adenine Nucleotides↗
PubMed1996

Prevalence of celiac disease in patients with juvenile chronic arthritis.

We estimated the prevalence of celiac disease in children with juvenile chronic arthritis (JCA), using antiendomysium antibodies as the screening test to select patients for intestinal biopsy. We studied 119 children with JCA and found four patients with antiendomysium antibodies. In three of these patients (2.5%), intestinal biopsy revealed villous atrophy; in the fourth the intestinal mucosa was normal. We conclude that the prevalence of celiac disease is increased in patients with JCA.

Adolescent↗
PubMed1996

Biochemical analysis of muscle biopsy in overnight fasting patients with severe chronic heart failure.

To better characterize the role of skeletal muscle in chronic heart failure we studied energetic charge, metabolites and enzyme activity in the energy production pathway. We selected 15 males with severe chronic heart failure (NYHA class III, stable clinical conditions and in normal nutritional status) and seven controls. Controls and patients were submitted to biopsy of the vastus lateralis muscle in resting and fasting conditions. Hormone profiles were also evaluated. Our results showed near normal ATP, ADP and AMP concentrations, but there were substantially more reductions in glycogen (46 +/- 5 vs 77 +/- 6 mumoles glycosidic units.g-1 fresh tissue) and creatine phosphate (5 +/- 1 vs 13 +/- 1 mumoles.g-1 fresh tissue) in patients than in controls. We also found a reduction in glycolytic activity (pyruvate kinase 1009 +/- 79 vs 1625 +/- 26 nmoles. min-1.mg protein-1), despite normal tricarboxylic acid cycle velocity, an increase in alanine amino-transferase (964 +/- 79 vs 425 +/- 34 nmoles. min-1.mg protein-1) and in aspartate aminotransferase (515 +/- 44 vs 291 +/- 56 nmoles.min-1.mg protein-1). An increase was also observed in total NADH cytochrome c reductase (128 +/- 14 vs 68 +/- 5 nmoles.min-1.mg protein-1), while cytochrome oxidase activity was normal. The cortisol/insulin ratio was slightly elevated (77 +/- 4 vs 32 +/- 12). In conclusion, normonutritive patients with severe heart failure show an imbalance in the energy production/utilization ratio. The impairment is probably due both to a decrease in production and an increase in consumption of energy owing to greater cellular workload and/or a hypercatabolic state.

Adenine Nucleotides↗
PubMed1996

Sick euthyroid syndrome in patients with moderate-to-severe chronic heart failure.

BACKGROUND: Changes in peripheral thyroid hormone concentration and metabolism can occur in euthyroid patients suffering from severe non-thyroidal illnesses. Recently, sick euthyroid syndrome has been reported in patients suffering from advanced heart failure. AIM: This study was to evaluate prospectively the presence and pathophysiological implications of sick euthyroid syndrome in moderate-to-severe chronic heart failure patients. METHODS: The study population were 199 chronic heart failure patients admitted over a 2-year period to our heart failure unit for assessment of cardiac transplantation. They were closely followed up with clinical and instrumental examinations (including clinical, hormonal, nutritional and cardiac function evaluations). Sick euthyroid syndrome was defined as a serum total triiodothyronine value of less than the lowest normal limit (< 1.23 nmol.l-1) in the presence of a normal serum thyroid stimulating hormone concentration. RESULTS: Sick euthyroid syndrome was found in 36/199 patients (18%). According to the New York Heart Association (NYHA) classification of severity of heart failure, sick euthyroid syndrome patients appear in higher NYHA classes (31% of classes III and IV, vs 7% of class I and II). Such patients also weigh less and are more frequently malnourished. Alterations in cardiac index, ventricular filling pressures, functional impairment, and the liver function parameters, were more significant in sick euthyroid syndrome than in non-sick euthyroid syndrome patients. Serum norepinephrine and atrial natriuretic factor were significantly higher, and insulin significantly lower in the sick euthyroid syndrome group. During follow-up, deaths were significantly more frequent in sick euthyroid syndrome patients (13/27, 48%) than in non-sick euthyroid syndrome (30/141, 21%; P < 0.005). In six sick euthyroid syndrome patients who underwent heart transplantation, mean total triiodothyronine values increased from 0.9 +/- 0.1 before to 1.96 +/- 0.3 nmol.l(-1)post-transplantation (P < 0.05). CONCLUSIONS: In a large and representative population of patients with moderate-to-severe heart failure, sick euthyroid syndrome shows a prevalence of 18%. Its occurrence was related to the degree of functional cardiac impairment, but was not an independent negative prognostic factor. Preliminary results indicate that heart transplantation is associated with reversibility of sick euthyroid syndrome.

Adult↗
PubMed1996

The role of mitochondria in ischemic heart disease.

Mitochondria in the heart play two roles essential for cell survival: ATP synthesis and maintenance of Ca2+ homeostasis. These two processes are driven by the same energy source, the H+ electrochemical gradient (delta microH). Under aerobic physiologic conditions, mitochondria do not contribute to the beat-to-beat regulation of cytosolic Ca2+, although a Ca2+ transient in mitochondrial matrix has been described. Micromolar increases in mitochondrial Ca2+ concentration stimulate the Krebs cycle and the NADH redox potential and, therefore, ATP synthesis. Trimetazidine has been shown to improve the calcium transient and, in so doing, the overall myocardial energy production. Under pathologic conditions, mitochondrial Ca2+ overload causes a series of vicious cycles that lead to irreversible cell damage. During ischemia, an alteration in intracellular Ca2+ homeostasis occurs and mitochondria are able to buffer cytosolic Ca2+, suggesting that they retain the Ca(2+)-transporting capacity. Accordingly, once isolated, even after prolonged ischemia the majority of the mitochondria are able to use oxygen for ATP phosphorylation. When isolated after reperfusion, mitochondria are structurally altered, contain large quantities of Ca2+, and produce an excess of oxygen free radicals. Their membrane pores are stimulated and the capacity for oxidative phosphorylation is irreversibly disrupted. The role of mitochondrial DNA damage in progressive human diseases such as coronary atherosclerosis is receiving growing interest. The sequence of ischemia and reperfusion, through increased production of oxygen free radicals, causes mitochondrial deletions in several areas of the mitochondrial genome. This cumulative mitochondrial DNA damage is associated with induction of nuclear oxidative phosphorylation gene mRNA. These observations support the hypothesis that mitochondria and mitochondrial DNA damage play important roles in ischemic heart disease.

Adenosine Triphosphate↗
PubMed1996

Left ventricular dysfunction due to the new ischemic outcomes: stunning and hibernation.

Several potential manifestations and outcomes are associated with myocardial ischemia and reperfusion. When ischemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. When ischemia is less severe or shorter in duration, recovery of contraction may occur instantaneously or more commonly, after considerable delay, which is the condition recognized as "stunned myocardium." Stunning is defined as a transient left ventricular dysfunction that persists after reperfusion despite the absence of irreversible damage and restoration of normal or near-normal coronary flow. Oxidative stress and alteration of calcium homeostasis during reperfusion are the probable causes of stunning. Clinically, stunning may occur after acute infarction, successful thrombolysis, unstable angina, angioplasty, resolution of coronary spasm, open-heart surgery, or transplantation. It can be treated with interventions aimed at prevention or reversal. When ischemia is prolonged but less severe, myocytes may remain viable but exhibit depressed contraction. Under these conditions, reperfusion restores normal contractile performance. This type of ischemia, leading to a reversible, chronic left ventricular dysfunction, has been termed "hibernating myocardium." The intrinsic mechanisms of this condition are unknown. Clinically, it is very important to diagnose hibernation because reperfusion of the hibernating myocardium by angioplasty or heart surgery restores contraction, and this correlates with long-term survival. A number of methods are available to access the hibernating myocardium. These include cardiac imaging techniques that evaluate myocardial viability, such as positron emission tomography and thallium myocardial imaging, or methods that evaluate contractile reserve, such as low-dose dobutamine echocardiography. Interestingly, reperfusion of patients with end-stage ischemic cardiomyopathy and hibernating myocardium can be considered an alternative to transplantation.

Cardiomyopathies↗
PubMed1996

Neuroendocrine response to standing and mild exercise in patients with untreated severe congestive heart failure and chronic constrictive pericarditis.

OBJECTIVES: Plasma hormones at rest in patients with untreated severe congestive cardiac failure are similar to those occurring during heavy exercise in healthy people. This study examines the hypothesis that the neuroendocrine effects of exercise are modified in untreated congestive cardiac failure. DESIGN: The effect of lying, standing, upright exercise, and recovery on several plasma hormones was measured in healthy controls and 2 groups of patients with severe untreated heart failure. The level of exercise was the same in all groups and low enough to be within the capacity of patients with severe failure. PATIENTS: There were 12 healthy controls, 9 patients with untreated severe congestive cardiac failure caused by myocardial disease, and 12 patients with untreated constrictive pericarditis. SETTING: A tertiary referral centre in North India. RESULTS: Heart rate, noradrenaline, renin activity, aldosterone, cortisol, growth hormone and atrial natriuretic peptide (ANP) were higher in the 2 groups of patients than in the healthy controls during both rest and exercise (P < 0.01 for both comparisons). In general, the effects of this mild degree of exercise were no greater than those of standing. The increase in heart rate during exercise was greater in the group with constrictive pericarditis than in the controls (P = 0.04) and (non-significantly) in congestive heart failure. Apart from these differences the pattern of responses to standing and exercise was similar in the three groups. CONCLUSIONS: While there was evidence of a broad neuroendocrine activation in patients with congestive cardiac failure, the only abnormal increase during exercise (of marginal significance) was found for renin activity in those with myocardial disease. In patients with untreated congestive failure, a substantially normal endocrine response to exercise was superimposed on abnormal resting concentrations.

Adult↗
PubMed1996

[Activation and role of the tumor necrosis factor-alpha in congestive heart failure].

Recently, an activation of the immune system has been demonstrated in congestive heart failure (CHF). Aim of this study was to evaluate the effects of CHF on the activation of alpha tumor necrosis factor (TNF-alpha), a pleiotropic cytokine. Since the soluble forms of the TNF membrane receptors, sTNF-RI and sTNF-RII, have been shown to modulate TNF-alpha biological activity, we determined antigenic TNF-alpha, bioactive TNF-alpha, sTNF-RI and sTNF-RII in 52 patients with varying degrees of CHF (NYHA functional class II, III, IV). The etiology of CHF was coronary artery disease in 51% of the patients, idiopathic dilated cardiomyopathy in 38% and valvular disease in 11%. All patients were treated with ACE-inhibitors, digoxin and inotropic agents. Antigenic TNF-alpha was significantly increased in NYHA functional class IV patients (from 12.1 +/- 7.6 to 38.5 +/- 12.4 pg/ml, p < 0.001) whereas cytotoxic activity was always under the detection limit of the assay (100 pg/ml). Soluble TNF receptors were significantly elevated in NYHA functional class IV patients: sTNF-RI increased from 1.27 +/- 0.48 to 4.54 +/- 2.11 ng/ml (p < 0.001) and sTNF-RII from 2.25 +/- 0.55 to 7.78 +/- 2.13 ng/ml (p < 0.001). The possible modulation of TNF-alpha biological activity by the soluble receptors was investigated by means of spiking experiments after addition of 625 pg/ml human recombinant TNF-alpha to each serum sample. The biological activity of the added TNF-alpha was significantly inhibited by the high levels of soluble receptors present in the sera of NYHA functional class IV patients (from 625 to 249 +/- 176 pg/ml, p < 0.001). The results show that TNF-alpha and its soluble receptors are activated in severe CHF. The high concentration of soluble TNF receptors circulating in CHF patients are likely to play a protective role against TNF-alpha biological activity.

Aged↗
PubMed1996

Right heart failure chronically stimulates heat shock protein 72 in heart and liver but not in other tissues.

OBJECTIVES: During cardiac failure several ontogenically developed adaptional mechanisms are activated. Among these, heat-shock proteins (HSP) are expressed in response to stress. The aim of the present study was to investigate the HSP72 protein expression in lungs, liver, cardiac and skeletal muscles during congestive heart failure (CHF). METHODS: CHF was induced in Sprague-Dawley rats by a single intraperitoneal injection of monocrotaline (50 mg/kg). Two groups of animals emerged: a CHF group (n = 10) with right ventricular hypertrophy, pleural and peritoneal effusions, and an Hypertrophy group (n = 12) with right ventricular hypertrophy without CHF. The data for each group were compared with those of control (saline infused) age-matched rats. Lungs, liver, right and left ventricles, soleus, extensor digitorum longus and tibialis anterior muscles were excised and analyzed for HSP72 concentration by Western blot analysis using a specific monoclonal antibody. Noradrenaline levels in the heart were also measured using HPLC. RESULTS: The CHF group showed: (1) reduced right (0.460 +/- 0.090 vs 0.830 +/- 0.070 nmol/ventricle, P < 0.01) and left (1.10 +/- 0.09 vs 2.10 +/- 0.130 nmol/ventricle, P < 0.001) ventricular content of noradrenaline compared to the control; (2) significant activation of HSP72 concentration in right and left ventricles (39.4 +/- 1.6 vs 5 +/- 0.9% and 13 +/- 1.2 vs 3.5 +/- 0.6%, P < 0.001 both) and in the liver (39.8 +/- 11 vs 6 +/- 2%, P < 0.001); (3) no modification in HSP72 concentration in lungs and all of the peripheral muscles considered. The Hypertrophy group showed: (1) unchanged total noradrenaline tissue content as compared to the control; and (2) unmodified HSP72 concentration in all tissues analyzed. CONCLUSIONS: The present study demonstrates that CHF, but not compensatory hypertrophy, is a specific stimulus for chronic HSP72 induction in the heart and liver. On the contrary, CHF does not affect HSP in lungs and peripheral muscles. HSP 72 induction represents an intracellular marker of stress reaction which can persist chronically.

Animals↗