Odoardo Visioli

Echocardiography during infusion of dobutamine for identification of reversible dyfunction in patients with chronic coronary artery disease

OBJECTIVES 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. BACKGROUND 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. METHODS 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. RESULTS 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 (p < 0.001) after dobutamine infusion, 1.51 +/- 0.38 (p < 0.001) immediately after and 1.51 +/- 0.38 (p < 0.001) 2 weeks after coronary artery bypass and 1.55 +/- 0.37 (p < 0.001) at 3-month follow-up. CONCLUSIONS 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.

Myocardial recovery during post-ischaemic reperfusion: Effects of nifedipine, calcium and magnesium

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.

Effect of α-tocopherol on hypoxic-perfused and reoxygenated rabbit heart muscle ☆

Abstract Experiments were undertaken to determine if α-tocopherol has a protective effect on heart muscle that is perfused under hypoxic (pO2 Although α-tocopherol had no effect on the isolated aerobically perfused heart, it attenuated the hypoxic-induced rise in resting tension, the depletion of the ATP and CP reserves, the deterioration of mitochondrial function (RCI and QO2), the release of LDH and CPK into the coronary effluent and the release of lactate. This protective effect of α-tocopherol persisted during reoxygenation.

Experimental cardiac hypertrophy: A quantitative ultrastructural study in the compensatory stage

Abstract An ultrastructural study of the rabbit myocardium with experimental advanced left ventricular hypertrophy was undertaken to determine the volumetric density, surface density and surface-to-volume ratio of the contractile material, mitochondria and T-system and to describe changes in the ultrastructure of the myocardium in this condition. Biometric data demonstrated a significant increase in the contractile mass which maintained its normal space arrangement. The mitochondria had a normal structure but biometric investigations confirmed a statistically significant decrease in the relative volume and the mitochondria/myofibril ratio. The T-system was dilated and seemed to have adapted itself to a larger contractile mass mainly by swelling. Finally, the structure of the sarcomere was analysed on the basis of the length/passive filling pressure curve. This curve showed that the passive lengthening of sarcomeres in the hypertrophic myocardium was less than in the normal heart.

The effects of ruthenium red on mitochondrial function during post-ischaemic reperfusion

Abstract Recently several attempts have been made to reduce reperfusion-induced calcium accumulation in the myocardium and in the mitochondria by using inhibitors of slow channel calcium transport such as verapamil, nifedipine and diltiazem. When these substances were given to the animals before death, or at the onset of ischaemia, they have been shown to prevent calcium accumulation in whole tissue and in isolated mitochondria [7–9, 15], while when added at the time of reperfusion, they failed to prevent myocardial calcium overloading [3, 15]. This supports the view that reperfusion-induced tissue calcium accumulation does not necessarily occur through the slow calcium channels and, at the present, the cause and the way in which this phenomenon can be modified by pharma-cological or other interventions remains unclear. For this reason, in this present study, we used ruthenium red in an attempt to reduce directly the reperfusion-induced mitochondrial calcium accumulation. Ruthenium is a polysaccaride dye which specifically inhibits calcium transport and binding by liver and heart mitochondria [7, 11].

Left ventricular hypertrophy: A cytometric study on 42 human hearts

A histocytometric study of 42 left ventricles was carried out. The cases consisted of normal hearts as well as a number of hypertrophic hearts which were progressively heavier in weight. The results of this study were analyzed by computer. We found an increase in myocardial cell size correlated with an increase in the ventricular free wall weight, up to a critical weight of 250 g. Beyond that critical weight, cellular hyperplasia was evident, followed by the further development of hypertrophy, in relation to the increase of ventricular weight. At the “critical weight” the progressive increase of cellular diameter, which is less than the theoretical value, abruptly ends and then decreases considerably. In contrast, this same phenomena is not seen for the cell length. The myocardial cell length shows a constant gradual increase always greater than the theoretical value regardless of ventricular weight. For this reason the cellular hyperplasia specifically presents an increase in cellular length beyond the increase in cellular diameter, which is reduced. A multiplication of myocardial nuclei beyond the critical weight was also observed. The results obtained are of physiopathological significance owing to modifications of the capillary network and the interstitial tissues.

Mitochondrial energy production and cation control in myocardial ischaemia and reperfusion.

SummaryIn 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 (ΔμH) 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 μmolars 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 ΔμH 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.

Right ventricular hypertrophy—A cytometric study on 55 human hearts

A histocytometric study of 42 left ventricles was carried out. The cases consisted of normal hearts as well as a number of hypertrophic hearts which were progressively heavier in weight. The results of this study were analyzed by computer. We found an increase in myocardial cell size correlated with an increase in the ventricular free wall weight, up to a critical weight of 250 g. Beyond that critical weight, cellular hyperplasia was evident, followed by the further development of hypertrophy, in relation to the increase of ventricular weight. At the “critical weight” the progressive increase of cellular diameter, which is less than the theoretical value, abruptly ends and then decreases considerably. In contrast, this same phenomena is not seen for the cell length. The myocardial cell length shows a constant gradual increase always greater than the theoretical value regardless of ventricular weight. For this reason the cellular hyperplasia specifically presents an increase in cellular length beyond the increase in cellular diameter, which is reduced. A multiplication of myocardial nuclei beyond the critical weight was also observed. The results obtained are of physiopathological significance owing to modifications of the capillary network and the interstitial tissues.

The occurrence of oxidative stress during reperfusion in experimental animals and men.

SummaryReperfusion 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.

Polyamines and noradrenaline following myocardial hypertrophy

Abstract The aliphatic amines, spermine and spermidine, and amino-oxidase activity were evaluated in hypertrophic rabbit heart obtained following aortic arch constriction. The polyamines were determined early after surgery (at 1, 2, 4, 8 h), during the first 10 days (at 1, 2, 5, 6, 10 days) and during the following 6 months (at 1, 2, 4, 6 months) after surgery. The pattern showed a rapid increase of spermine that reached a peak at 5 days after surgery (+146%). The changes of the enzymic activity are in accordance with the behaviour of polyamines. Under the same experimental conditions the myocardial concentrations of noradrenaline were evaluated. This chemical mediator rapidly increased 1 h after aortic stenosis. The results suggest that biogenic amines are related to the metabolic phenomena at the early stages of cardiac hypertrophy, and in particular to protein synthesis.