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Biomedical subjects

R Ferrari

Publications and source records attributed to R Ferrari.

At least 181 records · Page 10Linked to original sources
PubMed1998

Metabolic disarrangement in ischemic heart disease and its therapeutic control.

The term myocardial ischaemia describes a condition which 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 which have been extensively studied in recent years. A large amount of experimental research has been directed to establish 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 no recovery on reperfusion. Problems arise because: (1) ischaemic damage is not homogeneous and many factors may combine to cause cell death; (2) severity of biochemical changes and development of necrosis are usually associated (both processes being dependent on the duration of the ischaemia) and it is impossible to establish a causal relationship; (3) the inevitability of necrosis can only be assessed by reperfusion of the ischaemic myocardium. Restoration of flow, however, might result in numerous further negative consequences, thus directly influencing the degree of recovery. From the clinical point of view, I have recently learned that there are several potential manifestations and outcomes associated with myocardial ischaemia and reperfusion. Without doubt ventricular dysfunction (either systolic or diastolic) of the ischaemic zone is the most reliable clinical sign of ischaemia, since ECG changes and symptoms are often absent. The ischaemia-induced ventricular dysfunction, at least initially, is reversible, as early reperfusion of the myocardium results in restoration of normal metabolism and contraction. In the ischaemic zone, recovery of contraction might occur instantaneously or, more frequently, with a considerable delay, thus yielding the condition recently recognized as the stunned myocardium. On the other hand, when ischaemia is severe and prolonged, cell death might occur. Reperfusion at this stage is associated with the release of intracellular enzymes, disruption 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 as result of changes occurring during the period of ischaemia. The existence of reperfusion damage, however, has been questioned, and it has been argued that, with the exception of the 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 out-come of myocardial ischaemia. He demonstrated that late reperfusion (after months or even years) of an ischaemic area showing ventricular wall-motion abnormalities might restore normal metabolism and function. He was the first to introduce the term hibernating myocardium, referring to ischaemic myocardium in which the myocytes remain viable but in which contraction is chronically depressed. Our data on metabolic changes occurring during ischaemia followed by reperfusion obtained either in the isolated and perfused rabbit hearts or in CAD patients undergoing intracoronary thrombolysis or aortocoronary by-pass grafting will be reviewed.

Animals↗
PubMed1998

Recognized molecular mechanisms of heart failure: approaches to treatment.

Abnormalities of cytosolic calcium handling and myocyte energetics appear to play an important role in mediating contractile dysfunction in heart failure. Systolic and diastolic dysfunction in the failing heart are related to abnormalities of the excitation-contraction mechanism as well as myofilament calcium sensitivity. These abnormalities can be viewed as a compensatory mechanism as the myocytes by down regulating its function and metabolic activity preserve energy consumption and allow better maintenance of basal cellular homeostasis. The end point of myocyte dysfunction, however, is a reduced contraction, which, in turn, might cause a reduced cardiac output and a threatening of arterial pressure. This causes a second level of adaptation, which implies a neuroendocrine response of the whole organism. Consequently, the syndrome of congestive heart failure is characterized not only by impaired ventricular function, but also by an increase in some endogenous substances leading to vasoconstriction and water and salt retention. Although activation of the systems that release these substances is presumed to be compensatory, the sympathetic nervous system and renin-angiotensin-aldosterone system as well as the endothelins may contribute to the pathogenesis of the syndrome. Opposite to the effects of these systems are those evoked by the release of atrial natriuretic peptides. The peptides exert a potent direct vasodilatation and natriuresis. In addition, atrial natriuretic peptides inhibit the release of norepinephrine from nerve terminals and suppress the formation of renin. However, the natriuretic and vasodilator effects of these peptides in patients with congestive heart failure are outweighed by the sodium retention and vasoconstriction caused by sympathetic stimulation and activation of the renin-angiotensin-aldosterone system. The reasons for this are not entirely known. The atrial stretch receptors that are responsible for the release of the atrial peptides become impaired, and it has been suggested that patient with heart failure may adapt to the physiologic effects of atrial natriuretic peptides. The possibility that congestive heart failure is in part a humoral disease is reviewed here and consequently pharmacologic treatment aimed at reducing the effects of the neuroendocrine response as to be advantageous for patients with heart failure.

Animals↗
PubMed1998

Protective effects of delapril, indapamide and their combination on stroke occurrence and lifespan in salt-loaded stroke-prone spontaneously hypertensive rats.

The effects of long-term oral administration of delapril (CAS 83435-67-0), indapamide (CAS 26807-65-8) and their combination on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp) for 31 weeks of treatment (8th-39th week of age) and up to 8 weeks thereafter. Body weight and saline consumption were investigated at regular intervals and cerebrovascular lesions, renal and heart weight were assessed after sacrifice. Untreated SHRsp served as controls. About 50% of control animals died within 6 weeks of saline administration and in 56% of surviving animals cerebral lesions were present at sacrifice, while no death and no cerebral lesions were observed in animals drinking saline, to which delapril, indapamide and their combination had been added, up to the end of treatment. This protective effect was maintained even in the withdrawal period. All treatments induced a highly significant (p < 0.001) reduction of heart weight/body weight and kidney weight/body weight ratios.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Acute increase of myocardial workload, hemodynamic instability, and myocardial histological changes induced by brain death in the cat.

Brain death-related hemodynamic instability may preclude donor heart procurement. The relationships between the initial changes of myocardial workload, hemodynamic deterioration, and myocardial histological changes caused by acute induction of brain death are unclear. Cats (n = 15) were submitted to brain death by rapid inflation of an intracranial balloon. A further 12 cats served as a sham-operated control group. The changes in heart rate, mean arterial blood pressure, systolic and diastolic arterial blood pressure, left ventricular developed pressure, LV dP/dtmax, rate-pressure product (RPP), and circulating noradrenaline and adrenaline were studied during 240 min after the induction of brain death. Central venous pressure was kept constant. The hearts were histologically examined afterward. Electrocerebral activity disappeared within 30 sec after balloon inflation. At 3 min, noradrenaline and adrenaline levels had increased 75- and 40-fold, respectively, compared to pre-induction levels. The hemodynamic response was characterized by an early and rapid increase of hemodynamic variables at 2.9 +/- 0.2 min. This was followed by a second phase of normalization or deterioration. Two distinct subgroups (n = 9) became hemodynamically unstable (HDU), characterized by a systolic arterial blood pressure < 90 mm Hg, at 108 +/- 29 min, and progressively deteriorated to 67 +/- 8 mm Hg at 240 min after inflation of the balloon. The hemodynamic variables of the other, hemodynamically stable (HDS), subgroup (n = 6) normalized at 60 min after inflation. Hemodynamic deterioration of the HDU subgroup compared to the HDS subgroup was significant at 10 min after induction of brain death. The maximum values of RPP were similar in the two subgroups. Respiratory and metabolic variables at the end of the experiment were not different in both subgroups. Histological evidence of myocardial damage was present in 73% (11/15) of the brain dead cats and absent in the control group. The histological changes were identified both in hearts of HDU (6/9) and HDS (5/6) cats. In the cat, no relationships were demonstrated between the acute increase of myocardial workload, the occurrence of hemodynamic deterioration, and myocardial histological changes after rapid induction of brain death. These results may contribute to the discussion whether hemodynamic instability of the donor is an appropriate exclusion criterion for heart transplantation.

Animals↗
PubMed1997

Apolipoprotein AI isoforms in serum determined by isoelectric focusing and immunoblotting.

Quantitative evaluation of serum apolipoprotein AI (apo AI) isoforms through densitometric analysis following isoelectric focusing (IEF) is described. The apo AI isoforms were identified by immunoblotting. By combining these techniques, a qualitatively invariant pattern was observed in 54 serum samples, obtained from 27 men and 27 women. Peak 1 (proapo AI, pI 5.75) accounts for about 8% of the total densitometric area, peak 3 (apo AIzero, pI 5.59) for about 74%, peak 4 (apo AI-1, pI 5.42) for about 13%, and peak 5 (apo AI-2, pI 5.37) for about 5%. In some subjects, the proportion of proapo AI was increased. Variations of the ratio of the different apo AI isoforms may be due to modification of the fractional catabolic rate of this apolipoprotein. The procedure proposed in this study may be useful for the evaluation of quantitative abnormalities in apo AI isoforms involved in the development of coronary heart diseases (CHD).

Adult↗
PubMed1997

The propionyl-L-carnitine hypothesis: an alternative approach to treating heart failure.

Propionyl-L-carnitine (PLC) is a naturally occurring compound that has been considered for the treatment of congestive heart failure (CHF). The rationale for its use in this pathology is related to its effects on cardiac and skeletal muscle. Chronic treatment with PLC improves the contraction of isolated and aerobic perfused rabbit hearts. The compound improves energy metabolism and myocardial contractility in different experimental models of heart failure, such as pressure-overloaded rats, infarct model of heart failure, and rabbit with streptozotocin-induced diabetes. In general, the effect of PLC is apparent in situations of high energy demand such as those induced by increased workload. It therefore seems likely that PLC is able to correct some metabolic steps of the process that leads to heart failure. In addition, PLC may be helpful in heart failure because of its specific action on peripheral skeletal muscle. Administration of PLC in patients with CHF improves skeletal muscle metabolism by increasing pyruvate flux into the Krebs cycle and by decreasing lactate production. These effects occur in the absence of major hemodynamic and neuroendocrinologic changes and may underlie the ability of PLC to increase exercise performance in patients with heart failure. In a randomized study of 50 patients with mild CHF, PLC increased the maximal exercise time, reduced lactate production, and improved left ventricular ejection fraction. There have been two large-scale trials on the effects of PLC on both cardiac and peripheral muscle function in CHF. One is ongoing; the other one, which just ended, failed to show an improvement in exercise capacity in the population studied. A benefit was evident only in a subgroup of patients with preserved ejection fraction and impaired baseline exercise duration.

Animals↗
PubMed1997

Reperfusion Injury: Does It Exist and Does It Have Clinical Relevance?

Although reperfusion is an absolute prerequisite for the survival of ischemic tissue, it is not necessarily without hazard. Many (but not all) cardiologists are of the opinion that some components of reperfusion may be detrimental and able to inflict injury over and above that attributable to the ischemia. In this article we define four sequelae of reperfusion that might be designated as "reperfusion injury." We identify possible underlying mechanisms and consider whether any of these forms of reperfusion injury are of clinical relevance.

Journal Article↗
PubMed1997

How European cardiologists perceive the role of calcium antagonists in the treatment of stable angina.

Some 100 European cardiologists discussed calcium antagonists' role in the management of stable angina. Sixty-two percent of those involved used calcium antagonists rather than beta-blockers as first line therapy; 46% were prepared to use calcium antagonists in patients who had had a myocardial infarction more than 6 months previously. Only one tenth would use calcium antagonists in angina patients with left ventricular dysfunction. There was a broad preference for the use of heart rate-moderating calcium antagonists in most forms of stable angina. The discussions also underlined the diagnostic importance of angiography, exercise testing and lipid profile analysis.

Adrenergic beta-Antagonists↗
PubMed1997

How european cardiologists perceive the role of calcium antagonists in the treatment of unstable angina.

Physicians in the United States have recently published a guide to the definition and management of unstable angina pectoris. The guideline divides this condition into three main groups: 'rest', 'new onset' and 'increasing' angina. For the great majority of patients, medication involves heparin, acetylsalicylic acid, nitrates and beta-blockers. In some patient groups, calcium antagonists are appropriate treatment. These recommendations seem to be broadly supported by European cardiologists. Study of individual cases, however, reveals a continuing diversity of opinion.

Angina, Unstable↗
PubMed1997

How European cardiologists perceive the role of calcium antagonists in follow-up after myocardial infarction.

About one hundred European cardiologists discussed the role of calcium antagonists in the follow-up management of myocardial infarction. beta-blockers are the treatment of choice. Where these are contra-indicated or otherwise unsuitable, many clinicians would use a non-dihydropyridine calcium antagonist alone or in combination with an ACE inhibitor. There is broad agreement that calcium antagonists should not be used in patients with concomitant left ventricular failure. Cholesterol estimation in post-infarction patients is essential.

Adrenergic beta-Antagonists↗
PubMed1997

Major differences among the three classes of calcium antagonists.

The safety of calcium antagonists has recently become a controversial issue among cardiologists. Thus, the role of calcium antagonists in the treatment of myocardial infarction and in secondary cardiovascular prevention is under review. As a consequence, the concept that the words 'calcium antagonists' comprise various drug classes has re-emerged. These differ in basic pharmacological properties, tissue selectivity, pharmacokinetics, and final haemodynamic effect. Obviously, such differences alter their therapeutic effect. In this article, the major differences among the three classes of calcium antagonists, phenylalkylamines, dihydropyridines and benzothiazepines, are discussed and reviewed. A comparative analysis of available clinical trials focusing on the usefulness of each drug class is provided for the reader's interest. Some particularly relevant pathological conditions are considered: chronic stable angina pectoris, vasospastic angina, unstable angina pectoris with threatened myocardial infarction, myocardial infarction, and congestive heart failure.

Aniline Compounds↗
PubMed1997

Skeletal muscle function at low work level as a model for daily activities in patients with chronic heart failure.

AIM: Metabolic exercise abnormalities have been reported in chronic heart failure patients. This study sought to evaluate whether these abnormalities affected daily activity. METHODS AND RESULTS: In 16 patients with moderate-to-severe chronic heart failure and in eight controls we measured femoral flow (thermodilution) and metabolism (glucose, lactate, free fatty acids, blood gas values) at rest and during a constant load of 20 W, which may mimic a daily activity. At rest, chronic heart failure patients had a leg flow similar to controls, but showed a higher leg oxygen consumption (4.6 +/- 0.6 vs 2.6 +/- 0.4 ml.min-1; P < 0.05), a higher arteriovenous oxygen difference (7.2 +/- 0.5 vs 5.4 +/- 0.7 ml.dl-1; P < 0.05), and a lower femoral vein pH (7.37 +/- 5.03 vs 7.42 +/- 0.01; P = 0.01). At 20 W, chronic heart failure patients had a leg flow similar to controls, but showed increased lactate release (from resting 11.7 +/- 33 to 142 +/- 125 micrograms.min-1 P < 0.0001 vs controls, from resting 5.7 +/- 15.4 to 50 +/- 149 micrograms.min-1 ns), higher arterial concentration of free fatty acids (781 +/- 69 vs 481 +/- 85 mumol.l-1; P < 0.01), lower femoral vein HCO3 (24.1 +/- 2.6 vs 26.3 +/- 1.7 mmol.l-1; P < 0.05) and base excess (-2.3 +/- 2.3 vs -0.24 +/- 1.7 mmol.l-1; P = 0.01). CONCLUSION: In chronic heart failure patients, the important cellular metabolic alterations already present at rest partially affect daily activities, owing to a further decrease in the efficiency of muscle metabolic processes, and may preclude tolerance of heavier activities. Such alterations appear, at least in part, independent of peripheral haemodynamic responses to exercise.

Activities of Daily Living↗