Long term beta adrenergic receptor blockade following myocardial infarction promotes myocardial angiogenesis
SummaryBeta blockers reduce heart rate and myocardial contractility thereby reducing myocardial work load. Diastolic perfusion time is also lengthened by beta blockers supporting the use of this drug class as acute and chronic treatment following myocardial infarction. Studies have demonstrated that beta blockers can reduce total mortality, nonfatal myocardial infarction and sudden death in patients who have already suffered a myocardial infarction by 20-30%. Despite the potential benefit of beta block
Beta blockers reduce heart rate and myocardial contractility thereby reducing myocardial work load. Diastolic perfusion time is also lengthened by beta blockers supporting the use of this drug class as acute and chronic treatment following myocardial infarction. Studies have demonstrated that beta blockers can reduce total mortality, nonfatal myocardial infarction and sudden death in patients who have already suffered a myocardial infarction by 20-30%. Despite the potential benefit of beta blockers following myocardial infarction, only 20-50% of eligible patients receive these agents in the US. Researchers from the University of Iowa now show that beta blockers are able to increase angiogenesis in infarcted hearts further strengthening the case for their use
Cardiovascular disease has been the leading therapeutic category for over two decades growing in value from $60 billion in 1997 to $351.8 billion in 2003, a trend that will continue (see our feature The cardiovascular report).
Coronary heart disease is by far the leading cause of deaths from cardiovascular disease. Of the 12 million or so Americans with coronary heart disease, some 1 million suffer new or recurrent coronary attacks each year.
The initial aims in treating myocardial infarction are to minimize ischemic damage. Hence emphasis is focused on breaking up existing thrombi (thrombolysis) and slowing formation of further thrombi (using antithrombotic anticoagulants or platelet inhibitors) as an immediate and long-term objective.
Myocardial infarction produces considerable cardiac myocytes death and consequently increased diastolic wall stress and chronic functional overload of the remaining myocardium. This is particularly the case following involvement of the left ventricle which undergoes progressive structural remodelling consisting of thinning and scarring of the infarcted region rendering it incapable of contraction. The surviving myocardium, which takes on the responsibility of maintaining cardiac function becomes hypertrophied and imposes an increased oxygen demand.
Beta blockers reduce heart rate and myocardial contractility via an inhibition of sympathetic stimulation reducing myocardial oxygen consumption. As well as reducing myocardial work load, blood flow is also increased due to a lengthened diastolic perfusion time. Beta blockers are therefore used both acutely and chronically following myocardial infarction. Administration of intravenous beta blockers within 12 to 24 hours of infarction, followed by oral therapy, has been found to reduce the mortality rate approximately 13% within the first week of infarction. Initiation of beta-blocker therapy within days to weeks after infarction and continuation of therapy for periods ranging from several months to three years has been found to reduce total mortality, nonfatal myocardial infarction and sudden death by 20-30%
In response to increased oxygen demand following myocardial infarction, existing resistance vessels supplying the myocardium vasodilate augmenting blood flow. In addition neovascularization takes place via angiogenesis.
Angiogenesis represents an emerging therapeutic target. Pharmaceutical and clinical interest in angiogenesis initially focused on the development of strategies to block the process of neovascularization as an approach to cancer. More recently however stimulators of angiogenesis have been sought for the treatment of ischemic diseases.
Bradycardia also stimulates angiogenesis. The mechanism underlying this phenomenon is suggested to involve increased myocardial stretching. When the heart is in diastole, the ventricle wall becomes stretched which in turn causes the release of vascular growth factors and increased expression of their receptors. Consequently the chronic use of beta blockers, especially beta 1-selective antagonist could improve vascularization as well reducing oxygen demand. In their recent AJP paper, Dedkov et al test the angiogenic properties of beta 1 blockers using atenolol which is already used in patients who have suffered a myocardial infarction.
In their study Dedkov et al investigate the effects of a 4-week atenolol treatment of rats previously subjected to experimental myocardial infarction. Drug treatment was found to have little effect on remodelling but minimized the decline in left ventricle performance. This was related to an increase in the myocardial hypertrophy observed after infarction as well as improved coronary perfusion reserve and myocardial perfusion. In other words atenolol-treated infarcted hearts are likely to be less susceptible to ischemia under conditions of high oxygen demand than their untreated counterparts. Histological assessment demonstrated that this reflected arteriolar growth.
In 2004 the beta-blocker market in the US stood at approximately $2.2 billion and grew approximately 21% in 2003 versus 2002. Despite the state of this market there remains considerable under-use of beta blockers following myocardial infarction, with only 20-50% of eligible patients receiving these agents in the US. This is reportedly due in part to physicians avoiding prescription of beta blockers in patients with co-morbid conditions viewed as contraindications for beta blocker use (such as diabetes and congestive heart failure). Unfortunately these patients as well as other high risk patients including the elderly are those most likely to benefit from beta blocker use. In addition it is commonly believed that beta blockers reduce the quality of life even though in reality beta blockers produce a lower incidence of adverse effects than calcium antagonists.
It is clear therefore that further education is required to highlight the potential advantages of using long-term beta blockers as a means of reducing secondary infarction. The present study demonstrates that beta blockers can improve post-infarct cardiac function by increasing vascularization as well as by reducing oxygen demand. This should help pharmaceutical companies and advisory bodies convey the potential advantages of beta adrenergic blockade. Furthermore companies involved in developing new therapeutic formulations or novel beta blockers may find it advantageous to evaluate the level of angiogenesis afforded to their products.