J. J. Schipperheyn

Combining salicylate and enalapril in patients with coronary artery disease and heart failure.

OBJECTIVE--To study the effects of adding a salicylate to the angiotensin converting enzyme inhibitor enalapril in patients with heart failure due to coronary artery disease. DESIGN--Double blind, crossover study for three days in hospital followed by an extended similar study outside hospital over two months of once daily enalapril plus salicylate and enalapril plus placebo. SETTING--Tertiary referral centre. PATIENTS--20 patients with heart failure due to myocardial infarction (New York Heart Association class II or III) and an ejection fraction less than 0.40. Twelve patients completed the two parts of the study. MAIN OUTCOME MEASURES--Blood pressure, plasma converting enzyme activity; plasma angiotensin II and noradrenaline concentrations; excretion of metabolites of renal and systemic prostanoids. RESULTS--The unloading effect of first and second dose of enalapril in the morning lasted only during the day; in the extended study it lasted 24 hours because of the drugs accumulation. Converting enzyme inhibitors attenuate the breakdown of bradykinin and therefore enhance prostaglandin E2 synthesis mediated by bradykinin. Evidence was found of such a prostaglandin E2 mediated contribution to ventricular unloading by enalapril, which was blocked by salicylate. The contribution, however, was small and variable, and salicylate addition had on average no significant de-unloading effect during the day. Unloading was abolished in only three of the 20 patients in the short term study and in one of the 12 in the extended study. At night, when other effects of enalapril on blood pressure had waned and the bradykinin induced effect persisted, salicylate significantly reduced the remaining small unloading effect. No effect was seen of salicylate addition on reversal of remodelling. Enalapril reduced angiotensin II induced synthesis of systemic and renal prostaglandin I2 and thromboxane A2, initially only during the day, but later also at night. It thereby masked suppression of thromboxane A2 synthesis by salicylate, which is the effect to which reinfarct prevention by salicylate is attributed. CONCLUSION--The risk is low that salicylate will substantially reduce the benefit of enalapril in patients with heart failure by de-unloading the ventricle. Like other effects induced by bradykinin significant de-unloading occurs in only a minority of the patients. In the presence of enalapril, however, salicylate will probably not be as effective as expected in reducing reinfarction risk, because enalapril already reduces thromboxane A2 synthesis effectively in patients with heart failure and no further reduction by salicylate was found.

Reproducibility of left ventricular size, shape and mass with echocardiography, magnetic resonance imaging and radionuclide angiography in patients with anterior wall infarction : A plea for core laboratories

After myocardial infarction, left ventricular volume and ejection fraction can be assessed by echocardiography, magnetic resonance imaging and radionuclide angiography to guide therapy and determine prognosis. Whether a measured parameter gives the same results irrespective of the method used and the observer who performs the analysis is only partly known. Intra-observer and inter-observer variability were determined for echo and magnetic resonance imaging. Left ventricular ejection fraction measured by these techniques was related to radionuclide angiograms performed in the same period. Intra-observer variability for both echo and MRI was low and in most instances below 5%. Inter-observer variability for the echo and MRI measurements were substantially higher than intra-observer variability. Comparison of the three imaging modalities revealed systematic differences. Therefore, in clinical studies, left ventricular volume and function parameters have to be measured with the same technique and by the same observer in qualified core laboratories.

Influence of angiotensin converting enzyme inhibition on pump function and cardiac contractility in patients with chronic congestive heart failure.

Eleven patients with coronary artery disease and chronic heart failure were studied before and three months after the angiotensin converting enzyme inhibitor enalapril was added to their frusemide medication. The following were measured: left ventricular pressure and volume with transient occlusion of the inferior vena cava, radionuclide angiography, and hormone concentrations in plasma. As in other reported studies, the clinical condition of the patients improved and their exercise tolerance increased moderately. Addition of enalapril reduced end diastolic and systolic pressure, reduced ventricular volume, and concomitantly increased the ejection fraction. The end systolic pressure-volume relation shifted to the left as it did in a similar animal study. In the animal study unloading by a vasodilator did not induce a leftward shift, so it can be inferred that in the present study unloading combined with a decrease in the angiotensin concentration was instrumental in remodelling the heart. Though unloading was expected to have a beneficial effect on the oxygen supply/demand ratio of the heart, the patients still showed the same drop in the ejection fraction during exercise as they did before treatment with enalapril, and early diastolic filling did not improve. Normally, regression of cardiac dilatation is only found if pump function improves; the present study showed that unloading in combination with angiotensin converting enzyme inhibition reshapes the ventricle without improving intrinsic pump function.

Regional myocardial shape alterations in patients with anterior myocardial infarction

Objective: To assess the impact of regional left ventricular curvature in patients with an acute anterior myocardial infarction on ventricular volume.Methods: Left ventricular curvature was calculated at 100 points from apical four chamber echocardiograms of 68 patients with an acute anterior wall infarction. Curvature at any point of the contour was defined as the reciprocal of the radius of the circle that intersects that point tangentially and was independent of volume and geometric assumptions. Curvature, volume and shape of the patient group was compared with these measurements in 20 normal volunteers.Results: Diastolic curvature differed at the borderzone of the infarct and the apical area. In the basal septal area (point 9–18) mean curvature was lower in the patient group (0.1±2.7 versus 2.1±0.7; p<0.0001) as compared to the normal individuals. In the mid-septal area (point 22 to 27), mean curvature was more concave (− 0.1±2.6) in the patient group corresponding to in the normal population (− 0.4±1.3) p<0.005. In the apex point 52 and 53 diverged with a curvature of 9.9±1.9 in patients versus 9.4±2.9 p<0.005 in normal individuals. Systolic curvature diverged at the basal septum (point 1–4) with a mean curvature of 1.4±1.1 in patients compared to 3.5±2.5 in normal individuals p<0.01. Curvature differed also in the mid-septal region (point 9–29) with a curvature of − 1.7±1.2 in patients versus 0.4±0.9 (p<0.01) in normal individuals and in the apical septum (point 48–52) with a curvature of 16.6±5.2 in patients and 13.9±2.6 (p<0.0001) in healthy individuals. Separation of patients with the greatest curvature alteration to those with minor curvature change revealed, that baseline curvature analysis can discriminate patients at risk for left ventricular remodelling.Conclusion: Regional curvature analysis correctly identifies the geometric changes induced by myocardial infarction. Apical systolic curvature can distinguish those patients that are at risk for left ventricular remodelling from those who are not at risk.

Cold Ischemic Arrest: Comparison of Calcium-Free and Calcium-Containing Solutions

Isolated pumping rat hearts, perfused with reconstituted blood, were studied to compare the effects of 30 minutes of ischemic arrest following calcium-free or normal, calcium-containing cold cardioplegia on recovery of mechanical function, lactate production, myocardial adenosine triphosphate concentration, and release of creatine kinase (CK). As in clinical situations, the volume of the infusate was only three to four times the intracavitary blood volume. Hearts arrested with calcium-free solution showed incomplete recovery of mechanical function, whereas hearts arrested with calcium-containing solution recovered completely. After calcium-free arrest, stroke volume recovered to 76 +/- 29% (standard deviation [SD]) of its prearrest value. Enzyme release (CK) was significantly higher after calcium-free cardioplegia (7.7 +/- 4.6 units [SD]) than after cardioplegia with normal calcium (2.1 +/- 1.6 units [SD]). Since the addition of only 0.025 mmol calcium ions to a liter of calcium-free solution completely prevented its negative effect, it was concluded that calcium-free cardioplegia may cause limited but pronounced damage to myocardial cells, presumably because it removes calcium from the cellular membranes--the so-called calcium paradox. Probably due to residual calcium in blood and extracellular fluid, the damage is not so extensive after calcium-free cardioplegia as to be noticeable in clinical surgical situations. Residual calcium in the heart does not exclude the possibility, however, that a calcium paradox occurs in small scattered areas of the heart.

Calcium metabolism and depressed contractility in isolated human and porcine heart muscle

SummaryContractility is often depressed in isolated heart muscle. To analyze this phenomenon, we measured the derivative of left ventricular pressure (dP/dt) in intact and in isolated, blood perfused pig hearts, and peak force (F) or stress (F/mm2) in ventricular trabeculae of man and pig. When the heart was in the steady state at a priming frequency of 2 Hz an extrasystolic interval of 0.3 s was interposed, followed by four postextrasystolic intervals of 0.8 s. In the case of isolated trabeculae the priming frequency was 0.2 Hz, the extra interval 0.4 s, and the post-extrasystolic intervals were 5 s. The exponential decay of potentiation is characterized by the constant D: a low value of D indicates a rapid decay of potentiation. DP/dt was about 1000 mm Hg/s in the intact hearts, but within 1 h after isolation dP/dt decreased to about 700 mm Hg/s, and this was associated with a decrease in D from 0.63 to 0.40. Developed stress in the isolated trabeculac was about 2 mN/mm2 and D was about 0.20 under standard, in vitro conditions (a.o. 1.5 mM Ca2+, 0.2 Hz stimulus frequency). This stress is only 10% of the calculated stress in the intact heart. An increase of priming frequency, or of [Ca2+], or addition of 30 nM isoproterenol to the perfusate caused a marked increase in F and D. Properties of human and porcine trabeculae were quantitatively similar. The strong correlation between dP/dt, or F, and D suggests a causal relationship. This is consistent with the current model of e-c coupling in heart muscle, in which the activity of the Ca2+ pump of the sarcoplasmic reticulum determines the decay of potentiation and the amount of releasable Ca2+ in the reticulum determines force of contraction. Since isoproterenol stimulates the Ca2+ pump in the reticulum, the increase in D and F induced by this drug is consistent with the model. We conclude, that the decreased dP/dt, F, and D in isolated preparations was due to impaired sarcoplasmic reticulum function. The role of this phenomenon in the stunned heart syndrome, species differences and possible causes are discussed.