Beta blockade during and after myocardial infarction: an overview of the randomized trials

BACKGROUNDTo delineate the mechanism(s) of catecholamine-mediated cardiac toxicity, we exposed cultures of adult cardiac muscle cells, or cardiocytes, to a broad range of norepinephrine concentrations.METHODS AND RESULTSNorepinephrine stimulation resulted in a concentration-dependent decrease in cardiocyte viability, as demonstrated by a significant decrease in viable rod-shaped cells and a significant release of creatine kinase from cells in norepinephrine-treated cultures. Norepinephrine-mediated cell toxicity was attenuated significantly by beta-adrenoceptor blockade and mimicked by selective stimulation of the beta-adrenoceptor, whereas the effects mediated by the alpha-adrenoceptor were relatively less apparent. When norepinephrine stimulation was examined in terms of cardiocyte anabolic activity, there was a concentration-dependent decrease in the incorporation of [3H]phenylalanine and [3H]uridine into cytoplasmic protein and nuclear RNA, respectively. The decrease in cytoplasmic labeling was largel...

Adrenergic effects on the biology of the adult mammalian cardiocyte.

The accumulation of endogenous catecholamines within the extracellular space of the ischemic myocardium has been studied in the isolated perfused (Langendorff) heart of the rat subjected to various periods of complete ischemia, with subsequent collection of the reperfusate. Catecholamines and deaminated metabolites were measured by radioenzymatic methods, or high pressure liquid chromatography. Ischemic periods of less than 10 minutes are not associated with an increased overflow of catecholamines or metabolites. Longer periods of ischemia are accompanied by the overflow of noradrenaline and its deaminated metabolite 3,4-dihydroxyphenylglycol. This overflow increases with lengthening of the preceding ischemic period (10 minutes: 2.5 +/- 0.6, 20 minutes: 209.8 +/- 17.2, 60 minutes: 1270.5 +/- 148.1 pmol noradrenaline/g heart). Noradrenaline concentration is highest during the first minute of reperfusion, suggesting that the noradrenaline detected during reperfusion is released into the extracellular space of the myocardium during ischemia and is subsequently eluted. Experiments with variation of extracellular calcium concentration and with neuronal uptake (uptake1) blocking agents suggest that different mechanisms of catecholamine release are acting during the course of ischemia. A calcium-independent carrier-mediated efflux of noradrenaline from the nerve terminals is of major importance, using the same carrier as is normally responsible for transporting noradrenaline from the synaptic clefts into the neuronal varicosities. Thus, various uptake1-blocking agents diminish the noradrenaline overflow following ischemic periods of between 10 and 40 minutes. The noradrenaline overflow following longer periods of ischemia is unaffected by uptake1-blocking agents, and additional noradrenaline release at this time is probably consequent upon dissolution of cell membranes. Overflow of adrenaline and dopamine occurs to a minor degree (less than 5% of the corresponding noradrenaline overflow), and only after ischemic periods of more than 15 minutes.

Release of endogenous catecholamines in the ischemic myocardium of the rat. Part A: Locally mediated release.

H89 is marketed as a selective and potent inhibitor of protein kinase A (PKA) Since its discovery, it has been used extensively for evaluation of the role of PKA in the heart, osteoblasts, hepatocytes, smooth muscle cells, neuronal tissue, epithelial cells, etc Despite the frequent use of H89, its mode of specific inhibition of PKA is still not completely understood It has also been shown that H89 inhibits at least 8 other kinases, while having a relatively large number of PKA-independent effects which may seriously compromise interpretation of data Thus, while recognizing its kinase inhibiting properties, it is advised that H89 should not be used as the single source of evidence of PKA involvement H-89 should be used in conjunction with other PKA inhibitors, such as Rp-cAMPS or PKA analogs

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1527-3466.2006.00261.x

The Many Faces of H89: A Review

Twenty-eight patients with heart failure caused by congestive cardiomyopathy, which had been diagnosed according to the criteria of Goodwin and Oakley, were treated with beta-blocking agents for six to 62 months, except for four patients who died within two months. Repeated non-invasive investigations were performed before and during treatment as well as exercise tests and chest x-rays. The echocardiographic and pulse curve findings indicated an improvement in systolic and diastolic myocardial function. The ejection fraction increased from 0.32 +/- 0.02 to 0.42 +/- 0.04, and the third heart sound amplitude and rapid filling wave were significantly reduced. The functional classification improved in 15 patients while in 12 patients it remained unchanged and in one it deteriorated. During follow-up, 10 patients died, most of them suddenly. The mortality was lower than expected in this severely ill group of patients. The beneficial effect of chronic beta-blockade in patients with congestive cardiomyopathy suggests that catecholamines are involved in the pathogenesis of congestive cardiomyopathy, and that patients with congestive cardiomyopathy may have inappropriate sympathetic cardiac stimulation which can be reduced by chronic beta-blockade. It is suggested that beta-receptor blockade should be added to conventional treatment with digitalis and diuretics in all patients with severe myocardial failure caused by congestive cardiomyopathy.

https://heart.bmj.com/content/heartjnl/44/2/117.full.pdf

Beneficial effects of long-term beta-blockade in congestive cardiomyopathy.

A possible role of noradrenaline in the development of myocardial infarction: an experimental study in the isolated rat heart.

Effects of tumor-load and malnutrition on myocardial function in the isolated working rat heart

Cardiac sensitivity and responsiveness to β-adrenergic stimulation in experimental cancer and undernutrition

The extent of ischemic injury has been studied in the isolated working rat heart utilizing an aortic ball valve that reduces the coronary flow. A number of factors were tested including high heart rate, noradrenaline, acidosis, alkalosis, high afterload, beta-blockade, glucose-insulin-potassium (GIK), palmitate and methylprednisolone. Mechanical performance, myocardial contents of ATP, creatine phosphate, glycogen and lactate and the leakage of creatine phosphokinase (CK) from the myocardium to the perfusion buffer were measured and used for determination of the ischemic injury. Tachycardia, noradrenaline and palmitate are factors that markedly increase the ischemic injury in this preparation. GIK and probably metoprolol decrease the release of CK compared with the controls.

Factors Modifying Ischemic Injury in the Isolated Rat Heart

SUMMARY In585patients with a first acutemyocardial infarction themaximumactivity ofheat stable lactate dehydrogenase (EC11127) was correlated withmortality atthree monthsThe patients participated inadouble blind trial withmetoprolol inacutemyocardial infarction Inall patients nottaking abeta blocker ahighly significant correlation was found, butthis was notevident inthose whowereWhenpatients withanterior or inferior infarctions treated with a placebo were analysed separately thecorrelation remained, asitdidwhenthepatients whowere alive on the fourth dayafter theonsetofpain were analysed separately Nocorrelation was observed between enzyme activity andthree monthmortality inthese subgroups ifonlypatients treated withmetoprolol were included Inasubsample ofonly171patients it was found that themaximumactivity ofcreatine kinase (EC 2732) andcreatine kinase subunit Bdidnotcorrelate withthree monthmortality regardless of treatment Thusitisconcluded that whenasufficiently large numberofpatients areinvestigated there isahighly significant correlation between theenzymatic estimation ofinfarct size andearly mortality inacutemyocardial infarction Thisrelation didnotpersist whenpatients treated with betablockade were analysed Several studies havebeenperformed tocorrelate serumenzymeactivity withearly mortality inacute myocardial infarction Inmostreports thehospital mortality rate wasusedtoevaluate early mortality '-I Withafewexceptions, suchasthestudy ofHofvendahl,4 apositive correlation hasbeenfound between these twovariables Themaximumserumactivity of aspartate aminotransferase (EC2611), creatine kinase, lactate dehydrogenase, andcreatine kinase MB havebeenmeasured Oneofthedisadvantages of manyofthese studies wastheinclusion ofpatients withaprevious myocardial infarction Thepurpose ofthis studywastocorrelate the maximumactivity ofheatstable lactate dehydrogenase, creatine kinase, andcreatine kinase subunit Bin patients suffering afirst definite myocardial infarction withmortality atthree months Patients andmethods Allthe585patients fulfilled given criteria forafirst definite myocardial infarction Theywereadmitted to

A. Waldenström

Papers

A possible role of noradrenaline in the development of myocardial infarction: an experimental study in the isolated rat heart.

Effects of tumor-load and malnutrition on myocardial function in the isolated working rat heart

Cardiac sensitivity and responsiveness to β-adrenergic stimulation in experimental cancer and undernutrition

Factors Modifying Ischemic Injury in the Isolated Rat Heart

Correlation between enzymatic estimation ofinfarct size andearly mortality rate