Showing papers by "Philip A. Poole-Wilson published in 1989"

Regulation of intracellular pH in the myocardium; relevance to pathology.

Abstract: Intracellular pH affects the contractile function of the heart, metabolic reactions, ion exchange and calcium homoeostasis. Numerous studies have concluded that a fall of extracellular pH, by whatever mechanism, causes a fall of contractility by alteration of intracellular pH. Measurement of cytosolic intracellular pH using microelectrodes has confirmed that earlier deduction. Acidosis reduces the slow calcium current and the release of calcium from the sarcoplasmic reticumul but, because the cytosolic calcium does not fall, the major site of action of hydrogen ions appears to be on the calcium sensitivity of the contractile proteins. In man acidosis can be detected 15 s after the occlusion of a coronary artery and is a major mechanism for the simultaneous loss of contractility in ischaemia. A transient alkalosis is not detected in man but has been reported in isolated heart preparations where ATP consumption is low. An imposed mild respiratory acidosis during hypoxia increases the subsequent recovery of mechanical function on reoxygenation whereas a severe acidosis can be harmful. Acidosis in ischaemic may be advantageous due to a cardioplegic effect, inhibition of transsarcolemmal calcium fluxes or a reduction of mitochondrial calcium overload. Calcium uptake on reperfusion or reoxygenation has been linked to an inward movement of sodium in exchange for hydrogen ions on reperfusion and subsequent sodium-calcium exchange. Such a mechanism in its simplest form cannot account for the similar uptake of calcium on reoxygenation and reperfusion. Acidosis is a cause of early contractile failure in ischaemia but the role of acidosis in causing cell necrosis is not established.

Treatment of heart failure with diuretics: body compartments, renal function and plasma hormones.

Abstract: Body fluid compartments, renal function and plasma hormones were measured in 13 patients with severe chronic heart failure, when the referring physician considered the patient to be appropriately treated. Although renal function was substantially impaired and plasma noradrenaline, aldosterone and renin activity were elevated, fluid compartments were within the normal range. These results show that careful clinical assessment of patients by an experienced physician is a reliable method of assessing restoration of 'normal' body fluid volumes with diuretics.

Digoxin--a redundant drug in congestive cardiac failure.

Abstract: Controversy continues concerning the use of digoxin as a positive inotropic agent in the treatment of heart failure in patients in sinus rhythm. Digoxin is properly used to control the heart rate in patients in atrial fibrillation. The findings from 14 uncontrolled and 6 controlled clinical trials have been examined. Digoxin does exert a small chronic positive inotropic effect. Although some individual patients, particularly those with fluid overlond, appear to benefit from digoxin, controlled clinical trials in patients, most of whom have been treated with diuretics, have failed to demonstrate an Increase of exercise capacity. No mortality trial has been attempted. Digoxin has the potential to be harmful in patients with ischemic heart disease. Alternative and safer therapies have been shown to be equal or superior to digoxin.

Comparison between isomyosin pattern and contractility of right ventricular myocytes isolated from rats with right cardiac hypertrophy

Abstract: The contractile properties of single rat cardiac cells isolated from normal and hypertrophied right ventricles have been investigated. These have been correlated with the isoenzyme composition of the whole ventricle. Right cardiac hypertrophy was induced by injecting rats with monocrotaline, an alkaloid which induces severe pulmonary hypertension. Ca2+ ATPase activity and myosin alpha-chain percentage were decreased in the hypertrophied right ventricle as compared with that of control rats. The contraction amplitude and speed of shortening of the isolated cells were measured using an inverted microscope, video camera, and edge detection device. Cells from the hypertrophied ventricle showed a significantly decreased contraction amplitude and speed of shortening in maximally activating concentrations of isoprenaline. A statistically significant correlation existed between myosin alpha-chain percentage and both contraction amplitude and speed of shortening in maximum isoprenaline. This was truc when all cells studied were included, as well as within the hypertrophy group. A similar, although not always statistically significant, correlation was observed when cells were maximally activated with calcium. These results suggest that changes in isomyosin pattern that occur in cardiac hypertrophy produce alterations in contraction amplitude and speed of shortening which can be detected in single cells isolated from the hypertrophied ventricles. Isolated cells appear to give responses representative of the function of the whole heart.

A new exercise test for the assessment of heart failure: use of a self powered treadmill.

Abstract: Time limited exercise on a self powered treadmill was evaluated as a method of assessing functional capacity in patients with mild heart failure. The characteristics of the treadmill were established by exercising 11 controls at three speeds and two inclinations and comparing oxygen consumption with that on a motorised treadmill under the same conditions. Oxygen consumption on the self powered treadmill at an equivalent speed and inclination was significantly higher because of the work needed to overcome the friction of the belt. Unlike a conventional treadmill, increasing the gradient on the self powered treadmill did not increase oxygen consumption. The distance walked in 12 minutes on the self powered treadmill was measured in eight patients with mild heart failure and ten controls. Maximal oxygen consumption was measured in the same group on a conventional treadmill by a mass spectrometer. There was a significant correlation between the distance walked and maximum oxygen consumption. In patients with mild heart failure the distance travelled in 12 minutes on a self powered treadmill provides a practical, inexpensive, and sensitive method of assessing functional capacity.

Unpredictable zero drift in intravascular micromanometer tipped catheters during long term pulmonary artery pressure recording: implications for catheter design

Abstract: Zero drift may be a cause of imprecision when micromanometer tipped catheters are used for intravascular pressure measurement over long periods of time. Drift of only a few mm Hg may represent a significant error when accurate recording of low vascular pressures is required. To overcome this problem a micromanometer tipped catheter has been modified so that it can be calibrated easily while it is in the circulation. Laboratory testing has demonstrated that when zero drift occurs this intravascular “reference calibration” is a valid linear function of true zero (r = 0.999). As the sensitivity of the catheter is unaffected by zero drift, it is possible to measure pressure accurately by compensating for this zero drift. During dynamic testing of two catheters, there was a mean net drift over 24 h of −0.54 mm Hg. Clinical evaluation of the catheter was undertaken in the human pulmonary circulation in eight patients (two for 48 h, five for 24 h and one for 8 h). In contrast to the laboratory findings, over the first 4 h after catheterisation there was a phase of rapid zero drift: the net drift was −1.9 (SD 3.3) mm Hg with a range of drift of 5.5 (7.4) mm Hg. Subsequently there was gradual drift: the net drift between 4 and 24 h was −0.44 (2.1) mm Hg with a range of drift of 2.8(1.0)mm Hg; and the net drift between 24 and 48 h was 3.7(2.1) mm Hg with a range of drift of 4.1(1.9) mm Hg. During long term intravascular pressure measurement with micromanometer tipped catheters, zero drift may occur unpredictably and should be quantified.

Exercise as a means of assessing heart failure and its response to treatment.

Abstract: Exercise testing was originally applied to healthy subjects and to patients who had, or were suspected of having, ischemic heart disease. Its extension as a means to evaluate heart failure and the response to treatment was logical. Unfortunately, interpreting these tests when done on patients with heart failure is considerably more complicated, being greatly affected by the severity of heart failure, the exercise protocol employed and numerous other factors. An ideal exercise test for use in evaluating heart failure has not yet been designed. Expired gas analysis adds objectivity to the test, but interpretation is more complex than originally thought.

Morphological and functional characteristics of myocytes isolated from human left ventricular aneurysms.

Abstract: Isolated single myocytes were prepared from myocardium of developing ventricular aneurysms and from myocardium within the scar of chronic ventricular aneurysms. The morphology and function of the individual cells were compared. The cells from developing aneurysms were rod-shaped, with a distinct sarcomeric structure, but did not contract even in the presence of high calcium concentrations. The sarcomere length was significantly higher than that of cells from chronic aneurysms and approached the theoretical point at which no contraction can occur. Cells from chronic aneurysms were either rod-shaped and contractile, or rounded due to hypercontracture of the myofilaments. Electron microscopy of cells from developing aneurysms confirmed the presence of elongated sarcomeres, a loss of the actin-myosin interdigitation, and damage to the contractile proteins which was particularly evident in the thin filaments. Cells with similar characteristics have also been isolated from a ruptured, ischaemic papillary muscle. These changes, which are due either to ischaemia or to overstretching of cells, may account for the weakness of the wall of developing aneurysms and be a cause of rupture or enlargement.

Calcium and Reperfusion Damage in Heart Muscle

Abstract: The GISSI trial of streptokinase 1 in patients with myocardial infarction has established that thrombosis is an important process in the pathology of myocardial infarction, that reperfusion of the myocardium is advantageous, and that the duration of the ischaemic period is a critical determinant of the sequelae of infarction. The results have since been confirmed in four more recent trials (Table 1).2−5 The endpoint of the GISSI trial was death, an unquestionable endpoint Table 1 Thrombolysis in acute myocardial infarction: % mortality reduction Time to onset of pain, hrs Duration of admn. (min) Study Agent n 0-3/6 3/6-24 ISIS II Streptokinase+aspirin 8592 53% 32-38% 60 AIMS Apsac+heparin versus placebo+heparin 1004 47% 5 ASSET rt-PA+heparin versus placebo ?5000 24% 180 ISAM Streptokinase versus placebo 1741 20% 12% 60 GISSI Streptokinase versus placebo 11806 23% 6% 60 with immediate impact on clinician, patient and the public. Other studies have demonstrated reduction of infarct size and improved myocardial function after thrombolytic therapy. These clinical trials have confirmed what has been established over the last two decades by experimental scientists, namely that infarct size was determined by (1) the duration of the ischaemic period, (2) the amount Table 2 Further objectives after thrombolytic therapy 1. Prevent reperfusion damage 2. Maximise blood flow (patency is not reflow) 3. Prevent re-occlusion 4. Modify inflammatory response of muscle dependent for blood flow on the occluded artery, (3) the presence of residual blood flow through the native vessels, (4) the blood flow through collateral vessels, and (5) the oxygen consumption at the moment of occlusion.