Effect of 17 beta-oestradiol on contraction, Ca2+ current and intracellular free Ca2+ in guinea-pig isolated cardiac myocytes.

1. The effect of 17 beta-oestradiol on cardiac cell contraction, inward Ca2+ current and intracellular free Ca2+ ([free Ca2+]i) was investigated in guinea-pig single, isolated ventricular myocytes. The changes of cell length were measured by use of a photodiode array, the voltage-clamp experiments were performed with a switch clamp system and [free Ca2+]i was measured with the Ca2+ indicator, Fura-2. 2. 17 beta-Oestradiol (10, 30 microM) caused a decrease in cell shortening at both 22 and 35 degrees C. This negative inotropic effect was accompanied by a decrease in action potential duration mainly brought about by a shortening of the plateau region of the action potential. 17 beta-Oestradiol (10, 30 microM) induced a similar decrease in cell shortening in voltage-clamped and current-clamped cells. 3. In Fura-2 loaded cells, 17 beta-oestradiol (10 and 30 microM) decreased systolic Fura-2 fluorescence to 72 +/- 7% and 47 +/- 4% (n = 6, P less than 0.001) of control respectively. 17 beta-Oestradiol (10 microM) had no significant effect on diastolic Fura-2 fluorescence, but at higher concentration (30 microM) induced a slight decrease in resting Fura-2 fluorescence. The effect of 17 beta-oestradiol was reversible after 1-2 min of washout of the steroid. 4. 17 beta-Oestradiol (10 and 30 microM) decreased the peak inward Ca2+ current (ICa), which was sensitive to [Ca2+]o, dihydropyridines and isoprenaline, to 59 +/- 3% and 39 +/- 5% (n = 7 approximately 9, P less than 0.01) respectively, without producing any significant change in the shape of the current-voltage relationship.(ABSTRACT TRUNCATED AT 250 WORDS)     

Potassium exchange in the human heart during atrial pacing and myocardial ischaemia

Potassium homoeostasis in the heart was studied during atrial pacing in 20 patients undergoing diagnostic coronary angiography. The potassium concentrations in the coronary sinus and a systemic artery were recorded continuously by means of catheter tip potassium electrodes. Ten patients with coronary artery disease and a positive exercise test developed chest pain and ST segment depression on the electrocardiogram during atrial pacing. Potassium concentrations in the coronary sinus rose initially and increased further when myocardial ischaemia developed. Ten patients including five with normal coronary arteries remained symptom free during atrial pacing with no electrocardiographic changes. In these patients coronary sinus potassium concentration increased at the onset of pacing, but returned to near control values despite continued pacing. In both groups arterial potassium concentration remained constant. Immediately after the end of pacing there was an abrupt transient fall in potassium concentrations in the coronary sinus to below control values. These results indicate that in man, as in other species, an increase in heart rate causes the transient movement of potassium out of the cell into the extracellular space. The onset of myocardial ischaemia is associated with a further loss of potassium from the cell. The end of pacing or ischaemia is accompanied by a re-uptake of potassium by heart muscle.     

Potassium exchange in the human heart during atrial pacing and myocardial ischaemia.

Potassium homoeostasis in the heart was studied during atrial pacing in 20 patients undergoing diagnostic coronary angiography. The potassium concentrations in the coronary sinus and a systemic artery were recorded continuously by means of catheter tip potassium electrodes. Ten patients with coronary artery disease and a positive exercise test developed chest pain and ST segment depression on the electrocardiogram during atrial pacing. Potassium concentrations in the coronary sinus rose initially and increased further when myocardial ischaemia developed. Ten patients including five with normal coronary arteries remained symptom free during atrial pacing with no electrocardiographic changes. In these patients coronary sinus potassium concentration increased at the onset of pacing, but returned to near control values despite continued pacing. In both groups arterial potassium concentration remained constant. Immediately after the end of pacing there was an abrupt transient fall in potassium concentrations in the coronary sinus to below control values. These results indicate that in man, as in other species, an increase in heart rate causes the transient movement of potassium out of the cell into the extracellular space. The onset of myocardial ischaemia is associated with a further loss of potassium from the cell. The end of pacing or ischaemia is accompanied by a re-uptake of potassium by heart muscle.     

Blood pressure reduction in stable angina by nifedipine was related to stroke and heart failure reduction but not to coronary interventions

BACKGROUND AND OBJECTIVE: Whether blood pressure (BP) reduction is a necessary prerequisite for cardiovascular risk reduction or an epiphenomenon has not been definitively established. We used an innovative analytic method to address this question. METHODS: For 7,287 participants in a stable angina trial comparing long-acting nifedipine to placebo, we estimated the BP response after 2 weeks of treatment corrected for regression-to-the mean, and then related the latter and assigned treatment to subsequent cardiovascular outcomes. RESULTS: Subsequent stroke and heart failure was strongly related to 2-week corrected systolic BP response, but coronary angiography and bypass surgery was not. Adjustment for the 2-week corrected systolic BP response changed nifedipine effect estimates (relative to placebo) for subsequent stroke from 28% (P=0.04) to 21% (P=0.13) risk reduction, and for heart failure from 30% (P=0.02) to 21% (P=0.11) risk reduction; but did not alter the effect estimates for coronary angiography (27% reduction, P<0.001), and coronary bypass surgery (22% reduction, P=0.002). CONCLUSION: The stroke and heart failure risk reduction by nifedipine GITS in patients with stable angina can be attributed partly to its BP lowering effect, whereas effects on coronary procedures are likely to be related almost entirely to its antianginal effects.     

An inhibitor of nitric oxide synthase does not increase contraction or beta-adrenoceptor sensitivity of ventricular myocytes from failing human heart

OBJECTIVE: Nitric oxide (NO) has been implicated in the depression of cardiac function in human heart failure. Some reports have identified iNOS (inducible nitric oxide synthase) within the myocyte component of the failing human heart, and NO is known to decrease the contraction amplitude of isolated ventricular myocytes. We have treated myocytes from failing human ventricle with a NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA), in an attempt to restore contractile function. METHODS AND RESULTS: Myocytes were isolated from failing and non-failing human ventricles and their contraction amplitude was measured during superfusion (32 degrees C, 1-2 mmol/l Ca2+) and electrical stimulation (0.1-2 Hz). The contraction amplitude of myocytes from failing hearts was depressed in a frequency-dependent manner. At 1 Hz, the contraction amplitude of cells from non-failing heart was 4.70 +/- 0.53% cell shortening (mean +/- SEM, n = 13 subjects), compared with 2.18 +/- 0.27% (P < 0.01, 11 patients) from patients with ischaemic heart disease (IHD) or 2.56 +/- 0.74% (P < 0.02, six patients) with dilated cardiomyopathy (DCM). Superfusion with 0.1 mmol/l L-NMMA did not increase contraction amplitude in myocytes from failing heart at either 0.2 Hz (n = 11) or 1 Hz (n = 7). Responses to beta-adrenoceptor stimulation were reduced in myocytes from failing human heart, with contraction amplitude in maximum isoprenaline 0.47 +/- 0.11 of that in high Ca2+ in the same cell (n = 6), compared to 0.99 +/- 0.07 in non-failing heart (n = 14, P < 0.01). The presence of 0.1 mmol/l L-NMMA did not increase the isoprenaline/Ca2+ ratio in myocytes from failing heart (0.40 +/- 0.09, P = NS). CONCLUSION: These results do not suggest a functional role for tonic NO production in the frequency-dependent depression of contraction or beta-adrenoceptor desensitisation in myocytes from failing human ventricle.     

Coronary flow reserve in patients with chest pain and normal coronary arteries.

BACKGROUND--Many studies have shown that coronary flow reserve is reduced in patients with chest pain and angiographically normal coronary arteries. The methods used to assess coronary blood flow have varied, but in nearly all reports dipyridamole has been used to bring about vasodilatation. This study was designed to assess whether the apparent impairment of coronary flow reserve seen with dipyridamole could be reproduced with either papaverine or adenosine, which induce maximum coronary blood flow by different mechanisms. METHODS--25 patients with chest pain and angiographically normal coronary arteries were studied with an intracoronary Doppler flow probe and quantitative angiography to determine epicardial coronary artery area, coronary blood flow velocity, coronary flow reserve, and coronary vascular resistance index (CVRI, the ratio of resistance after intervention to basal resistance). All patients received papaverine 8 mg. Eight patients with positive exercise tests received intracoronary papaverine (8 and 10 mg), intracoronary adenosine (6, 20, 60 micrograms), and high-dose intravenous dipyridamole (0.84 mg/kg). RESULTS--The velocity ratio (peak after intervention: baseline) (mean (SEM)) after 8 mg papaverine was 3.3 (0.2) (n = 25) and the coronary flow reserve was 4.1 (0.3) (n = 25). There were no differences between patients with a positive (n = 16) or negative (n = 9) exercise test. In eight patients coronary flow reserve was measured after increasing doses of papaverine, adenosine, and dipyridamole. Coronary flow reserve was 4.5 (0.3) with papaverine, 4.8 (0.3) with adenosine, and 3.5 (0.4) with dipyridamole (p = 0.08 v papaverine and adenosine). CVRI was 0.22 (0.01) with papaverine, 0.21 (0.02) with adenosine, and 0.29 (0.03) with dipyridamole (p < 0.05 v papaverine, p = 0.09 v adenosine). CONCLUSIONS--These results indicate that measurement of coronary flow reserve and CVRI in patients with chest pain and normal coronary arteries depends on the pharmacological stimulus. Normal values were obtained with papaverine in all patients, irrespective of the exercise test response. In patients with a positive exercise test significantly lower values were obtained with dipyridamole than with papaverine, or adenosine. The reported impairment of coronary flow reserve in patients with angina and normal coronary arteries may reflect the variability in response to different pharmacological agents. The mechanism underlying this variability is unknown, but may involve an abnormality of adenosine metabolism in the myocardium.     

R wave amplitude during exercise. Relation to left ventricular function and coronary artery disease.

Change in R wave amplitude (mean delta R) was measured sequentially during and after 12 lead maximal treadmill exercise tests in 14 subjects with normal coronary arteries and 62 patients with coronary artery disease. In normal subjects mean delta R decreased maximally one minute after exercise and returned to control levels within three minutes. In contrast, mean delta R increased in patients with coronary artery disease, the greatest change occurring in patients with either triple vessel or left main disease or those with an akinetic region on the left ventriculogram. R wave amplitude returned to resting levels in five minutes. Increase in R wave amplitude was not directly related to changes in the ST segment. Changes in R wave amplitude during maximal treadmill exercise may improve the discrimination between patients with and without coronary artery disease and may help to identify those patients with abnormal left ventricular function.     

Predictors of prognosis in severe chronic heart failure.

A total of 127 patients with chronic heart failure referred to our exercise laboratory were studied retrospectively to identify parameters predictive of prognosis. Patients were followed for a mean of 14.6 months. The group as a whole had severe ventricular dysfunction with a median ejection fraction of 17% and a median peak rate of oxygen consumption of 13.7 ml/kg/min. During the follow-up period 23 patients (18%) died and 18 (14%) underwent cardiac transplantation. The effect of the following variables on outcome (death or transplantation) were examined: age, cause of heart failure, cardiothoracic ratio on chest radiography, left ventricular end-systolic dimension on echocardiography, left ventricular ejection fraction on radionuclide ventriculography, mean dose of diuretic, plasma sodium and urea concentrations, and peak oxygen consumption during exercise. Although all variables except cause of heart failure affected outcome on univariate analysis, multivariate analysis identified three variables that were statistically significant and independent predictors of outcome. In order of importance these were plasma sodium level, left ventricular ejection fraction and peak oxygen consumption. Even in this group of patients with severe heart failure, these variables were predictive of outcome.     

Assessment of regional left ventricular function by magnetic resonance

The ability of magnetic resonance to determine regional left ventricular function was investigated in 18 patients--13 with coronary artery disease (nine with previous infarction), one with congestive cardiomyopathy, one with mitral stenosis, one with an atrial septal defect, and two without detectable cardiac abnormality. Coronal magnetic resonance images were acquired through the aortic valve and sagittal images were acquired in the plane of widest diameter of the left ventricle seen in the coronal image, both at end diastole and end systole. Regional wall motion assessed by magnetic resonance was compared with the results of anteroposterior and left lateral x ray ventriculograms by two independent observers. The left ventricular wall was divided into three segments in each plane and the motion of the segments was classified as normal, hypokinetic, akinetic, or dyskinetic. Muscle thickness was measured in each segment of the magnetic resonance images and was considered to be abnormal if in the systolic images it was less than 75% of that in neighbouring segments or if it failed to increase by at least 25% between diastole and systole. Wall motion assessments by the two methods agreed in 68 of 105 segments analysed, but differed by one class in 32 segments and by two classes in five segments. The differences can be explained by the conditions under which the investigations were performed and by the disparity between a tomographic section and an x ray projection. Magnetic resonance showed 25 segments to have abnormal wall thickness. Only one patient with infarction did not have an area of wall thinning and no patient without infarction had an area of thinning. It is concluded that magnetic resonance allows an accurate non-invasive assessment of left ventricular wall motion and thickness.