Improving Cardiac Function in Ischaemic Heart Disease
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Ischaemic heart disease

Ischaemic heart disease (also called coronary heart disease) occurs when the blood supply to the heart is reduced and this vital muscle does not receive sufficient oxygen and nutrients. It typically arises when arteries are narrowed, commonly as the result of wall thickness where fatty deposits build up on the artery walls (atherosclerosis). If the wall thickness causes arteries supplying the heart to become completely blocked, this causes myocardial infarction (a heart attack), which can permanently damage the heart muscle or be fatal.

Ischaemic heart disease is the most common cause of death in most western countries and a leading cause of morbidity and mortality worldwide1.

A variety of risk factors contribute to ischaemic heart disease developing into heart failure. Cardiac fibrosis is known to be a key event in the progression from ischaemic heart disease to heart failure. The stiff fibrotic cardiac tissue affects the transmission of electrical impulses through the heart muscle causing it to beat irregularly and can this lead to left ventricular dysfunction. Although the precise mechanisms giving rise to cardiac fibrosis are not fully understood, correction of cardiac fibrosis has become an important therapeutic target in ischaemic heart disease research2.

Treatment of ischaemic heart disease

Once cardiac ischaemia has occurred, it is important to resume blood flow to the affected area of the heart as soon as possible in order to protect the muscle from damage and reduce the risk of heart attack. Current treatment strategies typically used to achieve this include revascularization procedures such as coronary bypass grafting, percutaneous coronary intervention, and transmyocardial revascularization.

A variety of treatments are commonly prescribed to reduce the risk of heart failure by reducing blood pressure (eg, diuretics, angiotensin-converting enzyme inhibitors), lowering the likelihood of blood clots developing (eg, antiplatelet agents) or reducing cholesterol levels (statins). However, currently there are no medical therapies that can be used to increase blood flow to chronically ischemic heart muscle. Such treatments are highly desirable since invasive procedures can be challenging or too risky to perform in many patients with acute disease. There has consequently been much research into novel pharmacological treatment strategies to improve cardiac function in patients with ischaemic heart disease.

One such line of research is the injection of human mesenchymal cell–derived extracellular vesicles into the heart muscle. A recent study in a pig model reported that this therapy increased vessel density and blood flow to ischemic myocardial tissue, resulting in increased cardiac output and stroke volume3.

Growth hormone secretagogues have also been shown to improve cardiac function in models of ischaemic heart disease4.

Cardiovascular effects of growth hormone secretagogues

Growth hormone secretagogues were initially developed as a means of correcting deficits in the level of circulating growth hormone. However, more recently it has become apparent that they also affect the cardiovascular system4. The reported cardiovascular effects of growth hormone secretagogues include reduction of peripheral resistance, improvement of contractility and cardioprotection4,5. Furthermore, studies have shown them to preserve normal electrical transmission in ischaemic mouse heart muscle cells and protect them from reperfusion injury6,7. This may be a function of their action to reduce cardiac fibrosis8.

Hexarelin is a stable growth hormone secretagogue reported to possess potent cardiovascular activity9,10.

Hexarelin and cardiac function

Hexarelin is a synthetic peptide growth hormone secretagogue that is a highly selective agonist of the growth hormone secretagogue receptor. It potently stimulates the release of growth hormone without interfering with natural growth hormone production. It was initially developed as a treatment for growth hormone deficiency, but was never marketed for this indication. During its development, it was observed that hexarelin also possesses cardiotropic effects, which were not a result of its effect on circulating growth hormone levels. Instead, it appears that hexarelin also activates specific cardiovascular growth hormone secretagogue receptors.

Acute administration of hexarelin to patients with coronary artery disease has been shown to improve cardiovascular function, including left ventricular ejection fraction11. The latest research in a mouse model indicates that hexarelin may preserve ventricular function, reduce inflammation and favourably remodel the process of fibrotic healing12.

Myocardial infarction was induced in 21 2-week-old mice by ligation of the left descending coronary artery. The mice were subsequently administered either hexarelin or control for 21 days. Magnetic resonance imaging (MRI) using a Bruker Biospec 9.4 Tesla (T) small animal MRI scanner was used to evaluate left ventricular function, mass and infarct size after the myocardial infarction. 

Left ventricular function was significantly better among the mice receiving hexarelin compared with those in the control group12. Hexarelin also restored parasympathetic tone by modulating the autonomic nervous system to enhance activity in the parasympathetic nervous system whilst reducing activity in the parasympathetic nervous system. In addition, hexarelin treatment was found to decrease troponin, interleukin and TNFa levels, which indicates that is may reduce inflammation and cardiomyocyte injury12.

Therefore in this study, MRI was able to identify that Hexarelin represents a promising candidate for pharmacological protection of cardiac function after a cardiac ischaemic event. The modulation of both fibrotic and inflammatory pathways in heart muscle raise hopes that hexarelin could provide a complete cardioprotective treatment.

References

1.       Hausenloy DJ and Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J. Clin. Invest. 2013;123:92–100.

2.       Segura AM, et al. Fibrosis and heart failure. Heart Fail. Rev 2014;19:173–185.

3.       Potz BA, et al. Extracellular Vesicle Injection Improves Myocardial Function and Increases Angiogenesis in a Swine Model of Chronic Ischemia. J Am Heart Assoc. 2018;7(12): e008344. Available at jaha.ahajournals.org/content/7/12/e008344.

4.       Isgaard J et al. Cardiovascular effects of ghrelin and growth hormone secretagogues. Cardiovasc Hematol Disord Drug Targets 2008;8(2):133–137.

5.       Kishimoto, I., et al. Therapeutic potential of ghrelin in cardiac diseases. Expert Rev. Endocrinol. Metab. 2009;4:283–289.

6.       Ma Y, et al. Growth hormone secretagogues protect mouse cardiomyocytes from in vitro ischemia/reperfusion injury through regulation of intracellular calcium. PLoS One. 2012;7(4):e35265. doi: 10.1371/journal.pone.0035265. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3320867/pdf/pone.0035265.pdf

7.       Granata R, et al. Cardiovascular actions of the ghrelin gene-derived peptides and growth hormone-releasing hormone. Exp Biol Med (Maywood). 2011;236(5):505–514.

8.       Angelino E, et al. Antifibrotic activity of acylated and unacylated ghrelin. Int. J. Endocrinol. 2015:385682.

9.       Mao Y, et al. Hexarelin treatment in male ghrelin knockout mice after myocardial infarction. Endocrinology 2013;154:3847–3854.

10.   Mao Y, et al The cardiovascular action of hexarelin. J. Geriatr. Cardiol. 2014;11:253–258.

11.   Broglio F, et al. Effects of acute hexarelin administration on cardiac performance in patients with coronary artery disease during by-pass surgery. Eur J Pharmacol. 2002 Jul 19;448(2-3):193–200.

12.   McDonald H, et al. Hexarelin treatment preserves myocardial function and reduces cardiac fibrosis in a mouse model of acute myocardial infarction. Physiol Rep 2018;6(9). Epub ahead of print. Available at doi.org/10.14814/phy2.13699.