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In the globalized western thinking, the accelerated techno-scientific-communicational progress generated a widespread critique toward ambiguity, promoting the notion that true knowledge must adhere to scientific paradigms, based on either true or false. As a reaction, this trend is adding to the social reality an increasing need of a tool that allows emancipation from the deterministic cage of scientific rationality. This need can be satisfied by ambiguity, as typical of crea-tive and receptive figurative arts. Their phenomenology, originating from an im-pulse, takes shape in its development, following free not decided ex-ante by a form, but being realized ex-post as acting-form (literally formativity) pathways. Thus created, figurative arts is ‘open’ to the free interpretation of spectator. Thus becoming conform, figurative art extend their cultural influence to the society, pre-ferring freedom around the polar couple of freedom and order.

Sudden death represents a common event in the natural history of patients affected by chronic heart failure. Such an outcome also has been shown to characterize the follow-up of the cardiomyoplasty procedure. We report two cases of patients who had cardiomyoplasty and experienced witnessed episodes of ventricular arrhythmia at variable times after surgery (2 years and 2 months, respectively). In the first case, an implantable cardioverter defibrillator (ICD) was implanted subsequent to the arrhythmic episode, whereas the second patient had a combined cardiomyoplasty and ICD implantation procedure. In particular, this patient underwent a modified wrapping technique, herein described, because of a large left ventricular dilatation. In both cases, ventricular defibrillation did not affect the correct functioning of the implanted cardiomyostimulator. Our article confirms that ventricular arrhythmia is common in cardiomyoplasty patients. The combined use of a skeletal muscle stimulator and implantable defibrillator may therefore be effective in preventing arrhythmia-related sudden death without any concurrent effect on the correct functioning of the wrapped muscle/heart circuit, with likely benefit on long-term cardiomyoplasty patient survival.

OBJECTIVE To determine the best test(s) for predicting functional recovery of hibernating myocardium after reperfusion. METHODS A prospective study to compare echocardiographic left ventricular diastolic wall thickness (> or =5 mm), low-dose dobutamine echocardiography and rest-redistribution thallium-201 scintigraphy, alone and in combination, for predicting recovery of left ventricular akinesis after surgical revascularization. RESULTS Twenty-eight consecutive patients aged 58+/-9 years were studied. Of the 448 left ventricular segments, 263 were akinetic at rest; 230/263 (87%) had wall thickness > or =5 mm, 135 (51%) had a positive response and 175 (66.5%) were graded viable on thallium. Of akinetic segments 61% improved after surgery. Left ventricular score decreased from 2.3+/-0.4 to 1.8+/-0.4 (P

The term myocardial ischemia describes a condition that exists when fractional uptake of oxygen in the heart is not sufficient to maintain the rate of cellular oxidation. This leads to extremely complex situations that have been extensively studied in recent years. Experimental research has been directed toward establishing the precise sequence of biochemical events leading to myocyte necrosis, as such knowledge could lead to rational treatments designed to delay myocardial cell death. At the present time, there is no simple answer to the question of what determines cell death and the failure to recover cell function after reperfusion. Problems arise because: (1) ischemic damage is not homogeneous and many factors may combine to cause cell death; (2) severity of biochemical changes and development of necrosis are usually linked (both the processes being dependent on the duration of ischemia) and it is impossible to establish a causal relation; and (3) the inevitability of necrosis can only be assessed by reperfusion of the ischemic myocardium. Restoration of flow, however, might result in numerous other negative consequences, thus directly influencing the degree of recovery. From the clinical point of view, we have recently learned that there are several potential manifestations and outcomes associated with myocardial ischemia and reperfusion. Without a doubt, ventricular dysfunction (either systolic or diastolic) of the ischemic zone is the most reliable clinical sign of ischemia, since electrocardiographic changes and symptoms are often absent. The ischemia-induced ventricular dysfunction, at least initially, is reversible, as early reperfusion of the myocardium results in restoration of normal metabolism and contraction. In the ischemic zone, recovery of contraction may occur instantaneously or, more frequently, with a considerable delay, thus yielding the condition recently recognized as the "stunned" myocardium. On the other hand, when ischemia is severe and prolonged, cell death may occur. Reperfusion at this stage is associated with the release of intracellular enzymes, damage of cell membranes, influx of calcium, persistent reduction of contractility, and eventual necrosis of at least a portion of the tissue. This entity has been called "reperfusion damage" by those who believe that much of the injury is the consequence of events occurring at the moment of reperfusion rather than a result of changes occurring during the period of ischemia. The existence of reperfusion damage, however, has been questioned, and it has been argued that, with the exception of induction of arrhythmias, it is difficult to be certain that reperfusion causes further injury. The existence of such an entity has clinical relevance, as it would imply the possibility of improving recovery with specific interventions applied at the time of reperfusion. In 1985, Rahimtoola described another possible outcome of myocardial ischemia. He demonstrated that late reperfusion (after months or even years) of an ischemic area showing ventricular wall-motion abnormalities might restore normal metabolism and function. He was the first to introduce the term "hibernating myocardium," referring to ischemic myocardium wherein the myocytes remain viable but in which contraction is chronically depressed. In this article we review our data on metabolic changes occurring during ischemia followed by reperfusion, obtained either in the isolated and perfused rabbit hearts or in ischemic heart disease patients undergoing intracoronary thrombolysis or aortocoronary bypass grafting.

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.

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.

Background Tumor necrosis factor alpha (TNF-α) increases in patients with severe congestive heart failure (CHF) and cachexia. Two naturally occurring modulators of TNF-α activity have been identified in human serum. These two soluble proteins are the extracellular domains of the TNF receptors (sTNF-RI and sTNF-RII, respectively). The determination of circulating sTNF-Rs could provide us with some additional information about the activation of this cytokine in CHF. Methods and Results This study was undertaken to examine the concentration of sTNF-Rs and of bioactive and antigenic TNF-α in 37 consecutive patients with various degrees of CHF compared with that of 26 age-matched healthy subjects. Antigenic TNF-α increased (from 14.3±7.08 to 33.5±13.1 pg/mL, P P P P P Conclusions Measurement of sTNF-Rs, in addition to antigenic and bioactive TNF-α, is essential for evaluation of the activation of this cytokine in CHF. Both sTNF-Rs increase in preterminal patients with severe CHF and might inhibit the in vitro cytotoxicity of TNF-α. Antigenic TNF-α also increases in severe CHF. The increased levels of sTNF-RII independently correlate with poor short-term prognosis.

The effects of acute and chronic ibopamine treatment on resting and exercise hemodynamics, exercise capacity and plasma catecholamines were evaluated in 25 patients with chronic heart failure, using a double-blind, parallel, placebo-controlled design. During 2 months of therapy with either placebo or ibopamine (100 mg, 3 times daily), 1 patient was withdrawn from each group for worsening heart failure, New York Heart Association functional class improved in 4 patients on ibopamine and in 1 on placebo, and furosemide dose could be decreased in 4 on ibopamine and in no patient on placebo. Acute ibopamine administration induced, in comparison with placebo, a significant increase of cardiac and stroke volume indexes both at rest and peak exercise, with a reduction of systemic vascular resistance. These hemodynamic changes were maintained also after chronic therapy, with no evidence of tolerance development. Exercise capacity (evaluated as peak exercise duration and oxygen consumption, and ventilatory threshold) did not significantly change. Resting and peak exercise norepinephrine plasma levels were significantly reduced after both acute and chronic ibopamine administration. Thus, the hemodynamic and neurohumoral effects of ibopamine make this drug potentially useful for the chronic treatment of congestive heart failure.

Background.The effect of alteplase versus heparin in pulmonary embolism has not been studied extensively with serial pulmonary angiograms. Objectives.The aim of this randomized, open trial was to evaluate the efficacy and safety of alteplase followed by heparin, versus heparin alone, in 30 patients with angiographically documented pulmonary embolism. Methods.Twenty patients were allocated randomly to a 2-h infusion of alteplase (10 mg bolus, then 90 mg over 2 h) followed by heparin; the other 16 patients were given intravenous heparin at a continuous infusion rate of 1,750 IU/h. Results.The vascular obstruction, assessed by the Miller index at pulmonary angiography, decreased significantly in alteplasetreated patients (p < 0.01) from a baseline of 28.3 ± 2.9 to a value of 24.8 ± 5.2 2 h after the start of infusion; in the heparin group there was no change (from 25.3 ± 5.3 to 25.2 ± 5.4). Mean pulmonary artery pressure decreased significantly from a baseline of 30.2 ± 7.8 mm Hg to 21.4 ± 6.7 in the alteplase group and increased in the heparin group (from 22.3 ± 10.5 to 24.8 ± 11.2 mm Hg). For a subset of patients, lung scans were performed at baseline and on days 7 and 30. There were no differences between the two groups in the follow-up lung scans, but there were significant decreases from the baseline values. Bleeding occurred in 14 of 20 alteplase-treated patients and in 6 of 16 in the heparin group (p = NS). There were three major bleeding episodes in the alteplase group and two in the heparin group. Two patients died after fibrinolysis (one of acute renal failure after cardiac tamponade and one of cardiac arrest after cerebral hemorrhage) and one patient in the heparin group died of recurrent pulmonary embolism. Conclusions.Alteplase resulted in a greater and faster improvement of the angiographic and hemodynamic variables compared with heparin. However, the high frequency of bleeding observed with alteplase in this trial suggests that patients should be carefully selected before thrombolytic therapy is given.

There are several potential outcomes of myocardial ischemia. When ischemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. Interventions aimed at reducing mechanical activity and oxygen demand, either before ischemia or during reperfusion, have been shown to delay the onset of ischemic damage and to improve recovery on reperfusion. When myocardial ischemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function. Under these conditions, reperfusion restores complete contractile performance. This type of ischemia, leading to a reversible, chronic left ventricular dysfunction, has been termed hibernating myocardium. Depression of mechanical activity is, actually, a protective mechanism whereby the hibernating cells reduce their oxygen demands in the setting of reduced oxygen supply. A third possible outcome after a short period of myocardial ischemia is a transient postischemic ventricular dysfunction, a situation termed stunned myocardium. As in the case of hibernating myocardium, the depressed contractile function occurring during stunning could be a protective mechanism, allowing the reperfused cells to gradually recover their metabolism and function.

Recent reports suggested that a complex alteration in beta-receptor function occurs in failing human myocardium. We evaluated beta-receptor-subtype activity in an experimental model of monocrotaline (MCT)-induced cardiomyopathy in the rat. Through pulmonary hypertension, MCT causes right ventricular hypertrophy (RVH), either associated with heart failure or not, beta-Receptor function was evaluated in both failing-hypertrophic and hypertrophic hearts in binding studies with [125I]iodocyanopindolol (ICYP) and by measuring adenylate cyclase (AC) activity. In the right failing ventricle, beta 1- but not beta 2-receptor density was decreased. Lesion-associated modifications in the adenylate cyclase system were also observed: isoproterenol- and guanosine 5' [beta, gamma-imido]triphosphate [Gpp(NH)p]-stimulated cyclic AMP formation was reduced in the right failing ventricle, while the cyclic AMP responses to NaF and forskolin were unchanged. On the other hand, no changes in either beta-receptor density or function were found in hypertrophic ventricles. MCT-induced heart failure in the rat is thus associated with a selective decrease of beta 1-receptor density and function. These results suggest that MCT-induced cardiac failure may be an appropriate model in which to investigate heart insufficiency further.

The current evolution of University is examined in parallel with the evolution of society. Society of uncertainty, crisis of the social actor, selective mechanisms of the elite, fundamental role of technical predominance and of economical processes are analyzed based on the "tradition" concept. The possibility of an authoritative comeback of the role of University is found in an active and articulated intervention of integration and cultural mediation, substantiating the bridge of tradition.

Although a close relationship between haemorrheological disorders and thrombogenesis has been known for a long time, only the recent introduction of newly developed analytical techniques has allowed a precise assessment of the main haemorrheological parameters. The employment of these techniques in routine clinical practice has enabled, for instance, a more accurate investigation of the pathogenetic triggers underlying numerous thrombotic disorders affecting the cardiovascular system. A survey of the most exhaustive prospective studies shows that some haemorrheological parameters (e.g. plasma and blood viscosity) as well as their main determining factors (e.g. haematocrit and fibrinogen) are well defined independent cardiovascular risk factors. Nonetheless, further large scale studies are required to adequately dissect the relative contribution of both haemorrheological alterations and other thrombophilic factors in the pathogenesis of different cardiovascular diseases related to thrombotic disorders.

There are several potential outcomes of myocardial ischaemia. When ischaemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. Interventions aimed at reducing mechanical activity and oxygen demand either before ischaemia or during reperfusion have been shown to delay the onset of ischaemic damage and to improve recovery during reperfusion. When myocardial ischaemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function. Under these conditions, reperfusion restores complete contractile performance. This type of ischaemia leading to a reversible, chronic left ventricular dysfunction has been termed `hibernating myocardium'. It is important clinically recognize hibernation as reperfusion of hibernating myocardium by angioplasty or heart surgery restores contraction and this correlates with long term survival. A third possible outcome after a short period of myocardial ischaemia is a transient post-ischaemic ventricular dysfunction, a situation termed `stunned myocardium'.

Myocardial hibernation, as first defined by Rahimtoola, is a state of chronic contractile dysfunction in patients with coronary artery disease which is fully reversible upon reperfusion. Clinical conditions consistent with the existence of myocardial hibernation include unstable and stable angina, myocardial infarction heart failure, and anomalous origin of coronary arteries. The mechanisms of hibernation are not known. Morphological alterations have been described in the hibernating area of patients, but these information are strongly affected by the diagnostic criteria utilized to screen patients. It has been postulated that hibernation is an adaptive phenomenon occurring during ischemia. In this context, downregulation of contraction is not regarded as a consequence of energetic deficit, but as a regulatory event aimed at reducing energy expenditure, thereby maintaining integrity and viability. Thus, hibernation might bear a relationship to the phenomenon of low-flow perfusion-contraction matching, or repetitive stunning or preconditioning. Clear-cut evidence for the mechanism of hibernation in the clinical setting seems likely to remain elusive, because of the nature of the studies needed to document it. Current experimental evidence supports the view that hibernation, stunning, preconditioning, or their coexistence can be responsible for regional myocardial contractile dysfunction which is reversible upon reperfusion. These are all adaptive and protective phenomena independent of their terminology and strict definitions and do not always apply to the extremely complex situation of myocardial ischemia in man. (Mol Cell Biochem 186: 195–199, 1998)

We studied 21 patients undergoing valve replacement for severe aortic stenosis and marked left ventricular dysfunction (mean ejection fraction 27 +/- 7.9%) without significant coronary disease or other valve diseases. At 5-60 months (average 26 +/- 18) after surgery, the patients underwent a clinical history, physical examination and a complete M-mode, two-dimensional and Doppler transthoracic echocardiographic study. Thirteen patients were examined with cardiopulmonary exercise testing. Two patients with a low preoperative transvalvular pressure gradient (

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.

There are several potential outcomes of myocardial ischaemia. When ischaemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. When myocardial ischaemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function. Under these conditions, reperfusion restores complete contractile performance. This type of ischaemia, leading to a reversible, chronic left ventricular dysfunction, has been termed hibernating myocardium. The difference between this condition and that described before, i.e. prolonged ischaemia, which results in further damage on reperfusion, is, most likely, related to residual coronary flow. In the hibernating myocardium, which is supplied by a narrow coronary artery, blood flow is not low enough to cause progression toward tissue necrosis, but it is low enough to cause intracellular changes and adaptative mechanisms which, in turn, are responsible for the down-regulation of myocardial contractility and for the preservation of viability. The level of underperfusion is sufficient to maintain aerobic metabolism of the quiescent myocardium as demonstrated by the absence of lactate and creatine phosphokinase releases. There are no doubts that revascularization is essential for hibernating myocardium, and the clinical goal to achieve is the possibility of accurately distinguishing viable from infarcted tissue. A third possible outcome of myocardial ischaemia is a post-ischaemic ventricular dysfunction or myocardial stunning. This term describes a transient mechanical dysfunction that persists on reperfusion after a short period of ischaemia, despite the absence of irreversible damage.

The pharmacological activity of L-carnitine presents various aspects. The best known function of L-carnitine is the transport of long-chain fatty acids from cytosol across the inner mitochondrial membrane into the mitochondrial matrix, the site of jβ-oxidation [1]. Long-chain acyl-CoA cannot pass through the inner mitochondrial membrane, but their metabolic product, acylcarnitine, formed by the action of carnitine palmitoyltransferase I, an enzyme located on the outer surface of the inner mitochondrial membrane, can. Another enzyme, carnitine-acylcarnitine translocase exchanges carnitine (out) with acyl-carnitine (in) in a stoichiometric ratio of 1:1 and ensures the constancy of the intramitochondrial carnitine pool. The incoming acylcarnitine reacts with CoA. This reaction is catalyzed by the enzyme carnitine palmitoyltransferase II, which is attached to the inside of the inner membrane. Thus, acyl-CoA is reformed in the mitochondrial matrix, and carnitine is made available for exchange by the translocase [2, 3].

Carotid sinus hypersensitivity (CSH) has been studied in subjects in sinus rhythm, but it has never been studied in patients with chronic atrial fibrillation (AF). After a finding of CSH in a patient with chronic AF and syncope, we studied the effects of carotid sinus stimulation in a group of patients with AF. Ten patients with chronic AF and normal ventricular rates who complained of dizziness or loss of consciousness underwent right and left carotid sinus massage (CSM) during ECG monitoring. A control group of ten patients with AF but without neurological symptoms was likewise investigated. CSH was present in eight symptomatic patients (5 patients presented right CSH, 1 left and 2 bilateral CSH), but only in three of the control patients. The mean duration of asystole induced by right CSM was 5.94 ± 2.10 seconds; the mean asystolic interval induced by left CSM lasted 8.58 ± 1.42 seconds. Six patients in the symptomatic group had a recurrence of spontaneous symptomatology during CSM, so that a diagnosis of carotid sinus syndrome was established. All symptomatic patients (8 patients with CSH, 2 patients with ventricular standstills but without CSH) received a permanent ventricular pacemaker. Following pacing, all patients, except for one with a significant drop of systolic blood pressure during CSM. became completely asymptomatic. In elder patients with chronic AF, CSH can induce prolonged ventricular asystole, which may be responsible for neurological symptoms such as dizziness, presyncope, or syncope, as observed in patients in sinus rhythm with carotid sinus syndrome. Abnormal sensitivity of the carotid sinus could, therefore, be one of the causes of increased morbidity and mortality in patients with chronic AF. Permanent ventricular pacing may help reduce these complications.

The majority of calcium antagonists used clinically belong to three distinct chemical classes: the phenylalkylamines, the dihydropyridines, and the benzothiazepines. In recent years their mode of action has been unravelled, their limitations recognized, and their efficacy and use in the management of patients with a broad spectrum of cardiovascular and other disorders defined. It is clear, however, that these drugs are not all alike, providing an explanation for their differing effects. The final therapeutic effect in humans depends on the mechanisms of action at the molecular level, the tissue selectivity, and the hemodynamic changes of each agent. All these aspects are examined in detail in this article. Concepts that are highlighted are as follows: (a) Molecular biology has allowed recognition of the polypeptide components of the alpha 1 subunit of the L-type Ca2+ channel and the finding of peptide segments covalently labelled by all three classes of drugs. (b) The location of these segments within the peptides is different: Binding sites for dihydropyridines are located externally, whereas those for verapamil and diltiazem are located internally, in the cytosolic part of the membrane. (c) Dihydropyridine binding is voltage dependent. This explains the selectivity of this class of drugs for vascular smooth muscle, which is more depolarized than cardiac muscle. (d) Phenylalkylamines and benzothiazepines reach their receptors at the internal surface of the sarcolemma through the channel lumen. Their binding is facilitated by the repetitive depolarization of atrioventricular and cardiac tissue, a phenomenon described as use dependence. This explains why these drugs are not highly selective, but equipotent for the myocardium, the atrioventricular conducting tissue, and the vasculature. (e) Dihydropyridines act through selective vasodilatation and may increase heart rate and contractility via a reflex mechanism. On the contrary, phenylalkylamines and diltiazem act through a combination of effects, including reduction of afterload, heart rate, and contractility. When taken together, all these differences distinguish the preferential clinical utilization of one of these compounds for a given cardiovascular pathology.

Left ventricular dysfunction is in most cases the consequence of myocardial ischemia. It may occur transiently during an attack of angina and usually it is reversible. It may persist over hours or even days in patients after an episode of ischemia followed by reperfusion, leading to the so-called condition of stunning. In patients with persistent limitation of coronary flow, left ventricular dysfunction may be present over months and years, or indefinitely in subjects with fibrosis, scar formation, and remodeling after myocardial infarction. However, chronic left ventricular dysfunction does not mean permanent or irreversible cell damage. Hypoperfused myocytes can remain viable but akinetic. This type of dysfunction has been called hibernating myocardium. The dysfunction due to hibernation can be partially or completely restored to normal by reperfusion. It is, therefore, important to clinically recognize a hibernating myocardium. In the present article we evaluate stunning and hibernation with respect to clinical decision making and, when possible, we refer to our ongoing clinical experience.

The aim of this study was to test whether the contractile response of akinetic myocardium to low dose dobutamine is useful for detecting myocardial viability in patients with coronary artery disease and persistent left ventricular dysfunction.In some patients with chronic coronary artery disease, persistent abnormalities of left ventricular wall motion can be reversed by successful coronary artery bypass surgery. Thus, identification of potentially reversible dysfunction has important therapeutic and prognostic implications. Echocardiography during infusion of low dose dobutamine can detect viable myocardium in patients after thrombolytic therapy. However, there is no detailed information on the use of this method in patients with chronic left ventricular dysfunction without reperfusion.We studied 33 selected patients with angiographically proved coronary artery disease and persistent left ventricular dysfunction. The effect of dobutamine infusion (5 micrograms/kg body weight per min, followed by 10 micrograms/kg per min) on left ventricular wall motion was evaluated by transthoracic echocardiography before coronary artery bypass grafting and compared with that obtained immediately after the operation (evaluated by intraoperative epicardial echocardiography) and both 2 weeks and 3 months later. Left ventricular wall motion was analyzed qualitatively by dividing the left ventricle into 16 segments, and a score was assigned to each region.Before coronary artery bypass surgery, 314 segments were akinetic. Of these, 183 became normokinetic immediately after revascularization, and 15 became hypokinetic. Dobutamine infusion was able to predict improvement in 178 of the 205 segments that recovered function after revascularization (sensitivity 86.8%) and to identify 89 of the 109 segments that did not recover postoperatively (specificity 81.6%). Mean (+/- SD) segment scores were 2.24 +/- 0.35 at baseline, 1.49 +/- 0.34 (p0.001) after dobutamine infusion, 1.51 +/- 0.38 (p0.001) immediately after and 1.51 +/- 0.38 (p0.001) 2 weeks after coronary artery bypass and 1.55 +/- 0.37 (p0.001) at 3-month follow-up.Echocardiography during infusion of low dose dobutamine is a safe and accurate method for identifying reversible dysfunctioning myocardium and predicts early reversibility of wall motion after surgical revascularization in selected patients with coronary artery disease with chronic left ventricular dysfunction.

Reperfusion, without doubt, is the most effective way to treat the ischaemic myocardium. Late reperfusion may, however, cause further damage. We attempted to identify the nature and time-course of metabolic changes occurring during ischaemia followed by reperfusion either in isolated and perfused rabbit hearts or in coronary artery disease (CAD) patients undergoing intracoronary thrombolysis or aortocoronary bypass grafting. In isolated hearts, reperfusion after prolonged ischaemia causes exacerbation of cell damage, leading to a breakdown of the permeability barrier of ions as well as of larger molecules, such as creatine phosphokinase. As consequence, reperfusion results in a large increase in intracellular calcium, leading to mitochondrial calcium overload with subsequent damage to the mitochondrial structure and loss of the ability to produce adenosine triphosphate (ATP). The ultimate mediator of the membrane damage is not known. It has been suggested that myocardial production of oxygen free radicals above the neutralizing capacity of the myocytes is an important cause of reperfusion damage. There is evidence that prolonged ischaemia reduces the naturally occurring defence mechanisms of the heart against oxygen free radicals, particularly mitochondrial manganese superoxide dismutase, and the intracellular pool of reduced glutathione. Consequently, reperfusion results in severe oxidative damage, as evidenced by tissue accumulation and release of oxidized glutathione. An oxygen free radical-mediated impairment of mechanical function also occurs during reperfusion of the human heart. During surgical reperfusion of CAD patients, we observed a prolonged and sustained release of oxidized glutathione; the degree of oxidative stress can inversely correlated with recovery of mechanical and haemodynamic function.(ABSTRACT TRUNCATED AT 250 WORDS)

In the heart mitochondria exert two roles essential for cell survival: ATP synthesis and maintainance of Ca2+ homeostasis. These two processes are driven by the same energy source: the H+ electrochemical gradient (delta microH) which is generated by electron transport along the inner mitochondrial membrane. Under aerobic physiological condition mitochondria do not contribute to the beat to beat regulation of cytosolic Ca2+, although Ca2+ transient in mitochondrial matrix has been described. Increases in mitochondrial Ca2+ of mumolars concentration stimulate the Krebs cycle and NADH redox potential and, therefore, ATP synthesis. Under pathological conditions, however, mitochondrial Ca2+ transport and overload might cause a series of vicious cycles leading to irreversible cell damage. Mitochondrial Ca2+ accumulation causes profound alterations in permeability of the inner membrane to solutes, leading to severe mitochondrial swelling. In addition Ca2+ transport takes precedence over ATP synthesis and inhibits utilization of delta microH for energy production. These processes are important to understand the sequence of the molecular events occurring during myocardial reperfusion after prolonged ischaemia which lead to irreversible cell damage. During ischaemia an alteration of intracellular Ca2+ homeostasis occurs and mitochondria are able to buffer cytosolic Ca2+, suggesting that they retain the Ca2+ transporting capacity. Accordingly, once isolated, even after prolonged ischaemia, the majority of the mitochondria is able to use oxygen for ATP phosphorylation. When isolated after reperfusion, mitochondria are structurally altered, contain large quantities of Ca2+, produce excess of oxygen free radicals, their membrane pores are stimulated and the oxidative phosphorylation capacity is irreversibly disrupted. Most likely, reperfusion provides oxygen to reactivate mitochondrial respiration but also causes large influx of Ca2+ in the cytosol as result of sarcolemmal damage. Mitochondrial Ca2+ transport is therefore stimulated at maximal rates and, as consequence, the equilibrium between ATP synthesis and Ca2+ influx is shifted towards Ca2+ influx with loss of the ability of ATP synthesis.

1. Yanagisawa M, Masaki T. Molecular biology and biochemistry of the endothelins. Trends Pharmacol Sci 1989;10:374-8. 2. Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-74. 3. Ando K, Hirata Y, Schichiri M, Emori T, Marumo F. Presence of immunoreactive endothelin in human plasma. FEBS Lett 1989;245:164-6. 4. Marumo F, Sakamoto H, Ando K, Ishigami T, Kawakami M. A highly sensitive radioimmunoassay of atrial natriuretic peptide (ANP) in human plasma and urine. Biochem Biophys Res Commun 1986;137:231-6. 5. Lippton HL, Ohlstein EH, Summer WR, Hyman AL. Analysis of responses to endothelins in the rabbit pulmonary and systemic vascular beds. J Appl Physiol 1991;70:331-41. 6. Cody R J, Haas GJ, Binskley PF, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation 1992;85:504-9.

The acute and chronic effects of the dihydropyridine calcium antagonist nisoldipine were studied in patients with chronic heart failure (LV EF

As a general rule, calcium antagonist protection has usually been obtained in the experimental setting when the drugs were added before the onset of ischemia (1-15). This ability to protect applies to verapamil, nifedipine, diltiazem, as well as to their derivatives such as gallopamil (16) and anipamil (16-19).

Nisoldipine was administered at 10(-9) M, a dose lacking negative inotropism, to isolated and perfused rabbit hearts submitted to 60 min ischaemia (1 ml.min-1) followed by 30 min reperfusion. The drug was delivered either 30 min before ischaemia, at the onset and after 30 min of ischaemia and during reperfusion only. Cardiac protection was evaluated in terms of recovery of left ventricular pressure during reperfusion, release of creatine phosphokinase (CPK), mitochondrial function, tissue content of adenosine triphosphate (ATP) and creatine phosphate (CP), calcium homeostasis and the occurrence of oxidative stress, established measuring content and release of reduced and oxidized glutathione. The cytoprotective action of nisoldipine occurs in the absence of negative inotropism and is closely related to the time of administration. Optimal myocardial preservation is achieved when nisoldipine is given before or at the onset of ischaemia. Prophylactic administration of nisoldipine improved the recovery of the developed pressure from 15.9 +/- 1.0 (SE) mmHg to 47.8 +/- 1.9 mmHg, P0.01 and reduced the release of CPK from 830 +/- 29 to 229 +/- 27 mU.min-1 g-1 wet wt, P0.01. The accumulation of tissue and mitochondrial calcium was reduced from 58 +/- 11 and 49 +/- 9 to 14 +/- 6 and 10 +/- 4 mmol.kg-1 dry wt respectively, P0.01. This resulted in a significant (P0.01) preservation of all indices of mitochondrial function, allowing a higher recovery of ATP and CP after reperfusion (from 4.1 +/- 0.7 and 10.0 +/- 0.6 to 16.1 +/- 1.0 and 29.9 +/- 0.2 mumol.g-1 dry wt respectively, P0.001). Reperfusion-induced myocardial accumulation and release of oxidized glutathione were reduced from 0.493 +/- 0.07 nmol.mg-1 protein and 0.768 +/- 0.063 nmol.min-1 g-1 wet wt to 0.225 +/- 0.07 and 0.157 +/- 0.038 respectively, P0.01. Similar data were obtained when nisoldipine was given at the time of ischaemia, while administration 30 min after the onset of ischaemia showed only a trend towards protection. Nisoldipine lost its protective effect when given on reperfusion. A multifactorial analysis of the data suggest that the cardioprotective effect of nisoldipine is related to the maintenance of membrane integrity, possibly since nisoldipine is highly lipophilic.

Cicloprolol is a new beta-blocking agent with high selectivity for beta 1 receptors and high intrinsic sympathomimetic activity. We studied the acute hemodynamic effects of cicloprolol in nine subjects with no evidence of left ventricular dysfunction who underwent cardiac catheterization for the evaluation of chest pain. All patients had normal coronary angiography and left ventriculography. Left ventricular pressure was determined throughout the cardiac cycle using a Millar 8Fr Minotip catheter; an echocardiogram, phonocardiogram, and ECG were simultaneously recorded to obtain left ventricular pressure-diameter loops. All the measurements were repeated before and after the intravenous administration of cicloprolol. Cicloprolol was administered at increasing doses of 0.05, 0.10, and 0.25 mg/kg until a cardiac output increase of at least 15% over basal values was achieved. A decrease of mean arterial pressure or cardiac output after cicloprolol was not observed in any patient. Cicloprolol administration significantly increased cardiac output (24%), stroke volume (22%), and peak positive dP/dt (25%); no significant changes in heart rate, systemic blood pressure, right atrial pressure, or pulmonary artery pressures were observed. No significant change in the echocardiographic parameters occurred. Among the indices of left ventricular diastolic function, the time constant of isovolumetric relaxation was significantly decreased (-43%) after cicloprolol; moreover, the left ventricular pressure-diameter loop in the protodiastolic phase was shifted to the left following cicloprolol infusion. This study confirms that in subjects with normal left ventricular function cicloprolol can improve resting left ventricular systolic function, and it shows that this action can also be attended by a more rapid isovolumetric relaxation, similar to what has been observed with other sympathomimetic amines.

Reperfusion, without doubt, is the most effective way to treat the ischaemic myocardium. Late reperfusion may however cause further damage. Myocardial production of oxygen free radicals above the neutralizing capacity of the myocytes is an important cause of this reperfusion damage. There is evidence that prolonged ischaemia reduces the naturally occurring defence mechanisms of the heart against oxygen free radicals, particularly mitochondrial manganese superoxide dismutase, and intracellular pool of reduced glutathione. Consequently, reperfusion results in a severe oxidative damage, as evidenced by tissue accumulation and release of oxidized glutathione. An oxygen free radical-mediated impairment of mechanical function also occurs during reperfusion of human heart. In fact we observed during surgical reperfusion of coronary artery disease (CAD) patients, a prolonged and sustained release of oxidized glutathione; the degree of oxidative stress was inversely correlated with recovery of mechanical and haemodynamic function. These findings represent the rationale for therapeutic interventions which increase the cellular antioxidant capacities and improve the efficacy of myocardial reperfusion.

The ventilatory response to exercise was evaluated in 26 normal sedentary men and 68 patients with chronic heart failure using the slope of the relation between minute ventilation (VE) and carbon dioxide production (VCO2). All subjects underwent maximal upright bicycle cardiopulmonary exercise testing; 33 patients also underwent right-sided cardiac catheterization. The slope of VE/VCO2 was calculated by linear regression analysis using data from all the exercise tests and the first 60% of exercise duration; a high correlation was seen between these results (r = 0.83; p less than 0.001). The slope of VE/VCO2 was significantly, though weakly, related to peak exercise work load, oxygen consumption and ventilatory threshold (r = -0.49, -0.56 and -0.49, respectively), several peak exercise hemodynamic parameters and peak exercise dead space/tidal volume ratio (r = 0.70). With use of multivariate analysis, the only independent determinants of the slope were peak exercise dead space/tidal volume ratio and cardiac index. Thus, in patients with heart failure, exercise hyperventilation can contribute to the impairment of functional capacity and can be considered a compensatory response to abnormal hemodynamics and lung blood distribution in order to keep blood gas concentrations normal.

The term hibernating myocardium describes a particular outcome of myocardial ischemia in which myocytes show a chronically depressed contractile ability but remain viable. Revascularization of hibernating tissue causes a recovery of mechanical function that correlates with long-term survival. Therefore it is important clinically to distinguish hibernating from infarcted myocardium, since asynergies due to hibernation will improve on reperfusion, whilst those due to infarct will not. One suggested technique to identify hibernating myocardium is to stimulate the myocytes acutely, but briefly, by administration of inotropic agents while monitoring contractile function by echocardiography. We report our experience on the use of low dosages of dobutamine. Myocardial viability was validated by measuring the recovery in contraction of the akinetic areas after coroanry artery bypass surgery by means of intraoperative epicardial echocardiography. The test has a sensitivity of 93% and a specificity of 78%. It is useful for identification of viable myocardium and also for quantification of intraoperative risk in individual patients. Limitations of this test are related to the presence of downregulation of beta receptors and to the impossibility of differentiating hibernating from stunned myocardium. Another useful technique of identifying hibernating myocardium is the use of radionuclear markers for viability. In our experience the two most important tests are (1) rest-redistribution imaging of thallium 201 (which has a high sensitivity of 93% but a low specificity of 44%) and (2) 99mTe-Sestamibi imaging, which provides information on both perfusion and function with a single injection. This latter technique allows differentiation between stunning and hibernating on the basis of coronary flow, which is preserved in stunning and reduced in hibernation.

It has been suggested that the sudden presence of oxygen during reperfusion after a period of ischemia may be toxic for the myocardial cell. The oxygen molecule is capable of producing reactions in the cell, forming highly reactive free radicals, and inducing lipid peroxidation of membranes, altering their integrity and increasing their fluidity and permeability. The ischemic and reperfused cardiac cell is the prime candidate for this reaction sequence and may explain the molecular mechanism underlying the pathologic events related to membrane dysfunction and calcium homeostasis. However, the myocardium has a series of defense mechanisms including the enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase plus other endogenous antioxidants such as vitamin E, ascorbic acid, and cysteine to protect the cell against the cytotoxic oxygen metabolites. The prerequisite for oxygen free radical involvement in ischemia and reperfusion damage is that ischemia alters the defense mechanisms against oxygen toxicity. It is known that ischemia may impair mitochondrial SOD and, with reperfusion, oxidative stress may occur as shown by tissue accumulation and release of oxidized glutathione. This tripeptide molecule in the cofactor of glutathione peroxidase, the enzyme that removes hydrogen and lipid peroxides. Its formation and subsequent release is a reliable index of oxidative damage. In our study, we investigated the effects of N-acetylcysteine on oxidative damage in the isolated rabbit heart. N-acetylcysteine increases, in a dose-dependent manner (from 10(-7) to 10(-5) M), the myocardial glutathione content and provides an important degree of protection against ischemia and reperfusion. Oxidative stress does not occur, mitochondrial function is maintained, enzyme release is reduced, and contractile recovery is increased. Similarly, we administered N-acetylcysteine in the pulmonary artery of coronary artery disease patients undergoing coronary bypass grafting (150 mg/kg in 1 hour followed by 150 mg/kg in 4 hours). The degree of oxidative stress on reperfusion was reduced and recovery of cardiac function improved. In this article, we review the cardioprotective role of thiol-containing agents.

The effects of captopril and of other angiotensin-converting enzyme inhibitors (zofenopril, fosenopril and enalaprilic acid) were tested on the isolated rabbit heart and aorta. Captopril elicited an erratic negative inotropic effect and a reduction in basal coronary perfusion pressure (10(-5)-10(-4) M). The increase of coronary perfusion pressure induced by vasopressin, methoxamine, angiotensin II and Bay K 8644 was partially antagonized by captopril (10(-7)-10(-4) M) in a non-specific manner. These actions were not modified by saralasin or indomethacin and by ex vivo pretreatment with captopril itself. On the aortic strips, the contraction plateau induced by KCl and angiotensin II was partially inhibited (10(-6)-10(-4) M), while no effect was observed on those induced by noradrenaline, serotonin and PGF2 alpha. The Ca2+ concentration-response curve appeared shifted to the right in a non-competitive manner. The other angiotensin-converting enzyme inhibitors showed no effect up to 10(-4) M on isolated heart or aorta. Results obtained with captopril were consistent with vasorelaxant activity independent of the tissue renin-angiotensin system. Modulatory activity on the intracellular calcium movement may be involved.

To assess whether propionyl-L-carnitine protects rabbit heart against the deterioration caused by ischemia and reperfusion, isolated hearts were infused with a medium containing it in different concentrations. During control, normoxic perfusion, and 60 minutes of low-flow ischemia (37 degrees C) followed by 30 minutes of reperfusion, diastolic, and developed pressures were monitored; coronary effluent was collected and assayed for lactate and creatine phosphokinase (CPK); mitochondria were harvested and assayed for oxidative phosphorylation and calcium content; and tissues for concentration of adenosine triphosphate (ATP) and creatine phosphate. Propionyl-L-carnitine reduced the ischemic deterioration of mitochondrial function and the depletion of tissue stores of ATP. On reperfusion, hearts treated with it recovered better than the untreated hearts with respect to left ventricular performance, replenishment of ATP and CP stores, and mitochondrial function. The reperfusion-induced mitochondrial calcium overload and release of CPK were also reduced. The effect of propionyl-L-carnitine was dose dependent. At 10(-8) M it failed to modify ischemic and reperfusion damage but protected well at 10(-7) M. No further protection was obtained at 10(-6) M. Propionyl-L-carnitine thus protects the myocardium against some of the deleterious effects of ischemia and reperfusion. In particular it protects mitochondrial function, perhaps partly by preventing mitochondrial calcium overload. Because this protection occurs in the absence of a negative inotropic effect during normoxia or of a coronary dilatatory effect during ischemia, it cannot be attributed to an energy-sparing effect or to the improvement of oxygen delivery.

Reperfusion is the prerequisite for the ischemic myocardium to recover its metabolic and mechanical function. However, reperfusion after a prolonged period of ischemia in the experimental animal may exacerbate, or at least accelerate, the occurrence of ischemic injury, whilst in humans at the least it is not beneficial. This entity has been called reperfusion damage, since much of the damage is believed to be caused by events occurring at the moment of reperfusion rather than by changes occurring during ischemia. The existence of reperfusion damage, however, has been questioned, and evidence in favour of the concept is sparse. At the moment the molecular events occurring at the time of reperfusion are not completely understood, and the relative importance of several proposed deleterious mechanisms is not yet established. One of the most fashionable ideas for the cause of reperfusion damage is that the function of cell membrane is modified by oxygen radicals generated at the moment of reperfusion. Evidence in favour of and against this hypothesis is described in detail in the present article.

To clarify the role of chronic anaemia in the pathogenesis of the left ventricular hypertrophy (LVH) of chronic uraemia, nine normotensive dialysed patients were studied before and 3 and 6 months after start of intravenous treatment with recombinant human erythropoietin (rHuEpo). M-Mode echocardiographic estimations of left ventricular mass indices (LVMi) and plasma noradrenaline determinations were made at 3 and 6 months, and total blood volume (TBV) only at 6 months. Resting haemoglobin values were 5.9 +/- 1.3 (SD) g/dl, increased within 3 months to 10.2 +/- 1.2 (P less than 0.001), then remained unchanged. Baseline LVMi was 115 +/- 18 g/m2 body surface area (b.s.a.) and decreased significantly (P less than 0.0025) over the entire period to a final value of 78 +/- 13 g, which did not differ from the average value for 19 healthy controls. Resting plasma noradrenaline was 1.45 +/- 0.44 pmol/ml and did not change significantly, although values were reduced at the 3rd month, when decreased heart rates and slightly and non-significantly increased blood pressures were recorded. TBV did not vary because the increased erythrocyte mass was compensated for by parallel decreases in plasma volume. These data demonstrate the existence of a cause-effect relationship between uraemic anaemia and LVH, although the precise mechanism remains unknown. Amelioration of anaemia with rHuEpo, by allowing recovery from the attendant LVH, might improve long-term cardiovascular prognosis in some dialysed uraemic patients.

We have investigated the relation between occurrence of myocardial oxidative stress and functional recovery during postischemic reperfusion in 20 selected patients subjected to aortocoronary bypass grafting. Patients were selected for having normal percent ejection fraction and left ventricular end-diastolic pressure before the operation. Occurrence of oxidative stress was assessed by measuring the formation and release of oxidized glutathione (GSSG) in the coronary sinus immediately before aortic cross-clamp, 1, 5, 10, and 20 minutes after removal of aortic cross-clamp, and 10 and 20 minutes after the end of cardiopulmonary bypass. Reduced glutathione (GSH), lactate, and creatine phosphokinase release were also monitored with the same timing. Standard hemodynamic measurements were recorded by means of a triple-lumen thermodilution pulmonary artery catheter before sternotomy, 15 minutes after the end of cardiopulmonary bypass, and during the 24 hours after termination of cardiopulmonary bypass. Reperfusion in patients after a short period of ischemia (less than 30 minutes; group 1) resulted in a small and transient release in the coronary sinus of GSSG and GSH and in a progressive improvement of hemodynamic parameters reaching a stable state 4 hours after the operation. In patients with a period of ischemia longer than 30 minutes (group 2), reperfusion induced a marked and sustained release of lactate, GSH, and GSSG; the arteriocoronary sinus difference for GSSG was still negative after the end of cardiopulmonary bypass. The arteriocoronary sinus difference for creatine phosphokinase also remained negative for as long as 20 minutes after cardiopulmonary bypass, and the rate of functional recovery was significantly delayed, reaching the values of group 1 only 12 hours after the operation. In these patients there was a positive correlation (r = 0.88, p less than 0.01) between the duration of ischemia and the myocardial arteriovenous difference for GSSG. In addition, there was a negative correlation between the arteriocoronary sinus difference for GSSG and cardiac index measured 2, 4, and 6 hours after the operation. These data suggest for the first time that, depending on the severity of the ischemic period, oxidative stress occurs during reperfusion of patients with coronary artery disease who are subjected to heart surgery and that it may be linked with a delay in postoperative recovery of cardiac function.

Over the past 5 – 6 years there has been a growing interest in the concept that oxygen radicals play a role in the pathogenesis of myocardial ischemia and infarction (1–6). Up to 6 years ago it was generally believed that the degree of ischemic damage following a coronary occlusion was simply determined by the ratio of oxygen supply to the oxygen demand of the heart. Consequently, therapeutic interventions have been employed to reduce the demand or to increase the supply of oxygen to the myocardium. Only recently has the concept emerged that oxygen can be toxic and that oxygen free radicals could be the determinant of the degree of ischemic damage in the heart. Much of the work in the field has dealt with coronary reperfusion models as coronary reperfusion following myocardial ischemia is characterized by reintroduction of oxygen into the system.

To determine the clinical value of respiratory gas analysis during exercise, oxygen consumption (VO2) at peak exercise and at lactate and ventilatory threshold was assessed in 34 patients with chronic heart failure who underwent maximal exercise testing with expiratory gas monitoring and serial determinations of mixed venous lactate and hemodynamics by Swan-Ganz catheterization. A lactate threshold, defined as the point of abrupt increment of blood lactate, could be identified in every patient; the ventilatory threshold, detected on the basis of the respiratory changes, was found in 26 patients (77%). Lactate and ventilatory thresholds were significantly related to each other (r = 0.94; p less than 0.001) and to peak VO2 (r = 0.89; p less than 0.001 in both). Among the resting hemodynamic measurements, peak VO2 was significantly related only to total pulmonary resistances (r = -0.35). Among the parameters at maximal exercise, it was positively related to cardiac index, stroke work, stroke volume index and mean arterial pressure (r = 0.89, 0.74, 0.74 and 0.56, respectively) and inversely related to systemic vascular and total pulmonary resistances (r = -0.74 and -0.63). Using multivariate stepwise regression analysis only maximal cardiac index and, to a lesser degree, total pulmonary resistance were related to peak VO2. Similar correlations were found between the hemodynamics and the lactate and ventilatory threshold. Thus, peak VO2, lactate and ventilatory thresholds can be detected in most patients with chronic heart failure. These parameters are highly correlated to each other and bear similar relations to the hemodynamic response to exercise. The cardiac index is the main central hemodynamic determinant of exercise capacity.

The authors evaluated retrospectively sinoatrial conduction time (SACT), sinus node recovery time (SNRT), and corrected sinus node recovery time (CSNRT) in 272 patients with atrioventricular and/or intraventricular conduction defects without evidence of overt sinus node dysfunction. The study was designed to determine the prevalence of electrophysiologic sinus node abnormalities in patients with overt atrioventricular and/or intraventricular conduction defects. One or more sinus node electrophysiological abnormalities were observed in 133 cases (48.9%). There was a significant prevalence of electrophysiologic sinus node abnormalities only in patients older than 71 years of age. The data suggest that the involvement of the specialized conduction system is much more diffuse than one might expect simply observing the single recorded ECG defect and that the prevalence of associated defects of the conduction system increases with increasing age of patients.

In 30 patients undergoing coronary angiography the effects of lopamidol on sinus node activity, atrioventricular and intraventricular conduction were evaluated using His Bundle recordings, and compared to the effects produced by Diathzoate. Diatrizoate resulted in an increase in sinus cycle length and prolonged AV nodal conduction, resulting in second degree A V block in two patients, lopamidol had significantly less effect on sinus cycle (P

To assess whether pretreatment with the calcium antagonist anipamil protects the heart against ischemic and reperfusion damage and to establish how long the protection persists after cessation of the therapy, rabbits were injected subcutaneously twice daily for 5 days with 2 mg/kg body weight of this drug. The heart was then isolated 2, 6, or 12 hours after the last injection and was perfused by the Langendorff technique during a control period and 90 minutes of total ischemia (37 degrees C), followed by 30 minutes of reperfusion. Diastolic and developed pressure was monitored; coronary effluent was collected and assayed for creatine phosphokinase (CPK); mitochondria were harvested and assayed for respiratory activity, ATP production, and calcium content; and tissue concentration of adenosine triphosphate (ATP) and creatine phosphate were determined. The data obtained with anipamil were compared with those obtained with verapamil administered to the rabbit at the same dose and following the same procedure. Pretreatment with anipamil induced a negative inotropic effect under normoxic conditions; reduced the rate and extent of depletion of ATP and creatine phosphate during ischemia, with an incomplete restoration of the nucleotides after reperfusion; maintained mitochondrial function and calcium homeostasis during ischemia and reperfusion; reduced the rate of CPK release; and improved the recovery of ventricular function on reperfusion. The protective effects of anipamil persisted for as long as 12 hours after the last administration. In contrast, the protective and negative inotropic effects of verapamil were no longer apparent in heart isolated 6 or 12 hours after the last dose of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the effects of various interventions introduced at the time of post-ischaemic reperfusion on mechanical activity, tissue and mitochondrial calcium, mitochondrial function and tissue ATP and CP of isolated perfused rabbit hearts. These interventions were: nifedipine, low calcium (0.75 mM, 0.15 mM and 0.05 mM), high magnesium (15 mM) and high magnesium (15 mM) with low calcium (0.75 mM). Ischemia was induced by abolishing coronary flow for 60 min, followed by 30 min of reperfusion. The results indicate that nifedipine when given during reperfusion had no protective effect, whilst it was beneficial when administrated before ischaemia. Lowering calcium content of the perfusate during reperfusion may be advantageous, depending on the degree of calcium reduction. Reperfusion with high magnesium reduced the mitochondrial calcium overload and maintained the mitochondrial ATP-producing capacity but failed to modify the increase of tissue calcium and of diastolic pressure. Lowering calcium content in the presence of high magnesium resulted in better protection. These data suggest that the conditions of reperfusion may influence the capacity of myocardial recovery.