Cardiovascular Journal of Africa: Vol 31 No 3 (May/June 2020)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 31, No 3, May/June 2020

160

AFRICA

Consequences of elevated blood glucose

levels

ACS-induced hyperglycaemia is associated with increased risk

for in-hospital deaths, congestive heart failure and cardiogenic

shock.

The relative risk of in-hospital deaths for non-diabetic

ACS hyperglycaemic patients [admission blood glucose

≥

110

mg/dl (6.11 mmol/l)] is several fold higher versus matched

normoglycaemic counterparts.

This hyperglycaemia in

non-diabetic individuals is likely a combination of three factors:

previously undiagnosed diabetes, impaired glucose tolerance and

the acute stress response.

Whether elevated glucose levels are markers or direct

mediators of damaging outcomes following an acute myocardial

infarction (AMI) remains unresolved, although pre-clinical and

clinical data suggest harmful effects. For example, clinical trials

and epidemiological studies support a causative role because

intensive glycaemic control with insulin lowers the incidence of

cardiovascular complications.

High blood glucose availability

may also lead to ‘glucotoxic’ effects in cardiac endothelial cells,

to a much greater extent than in cardiomyocytes where increased

uptake is more dependent on the insulin-responsive glucose

transporter, GLUT-4. However, enhanced glycolytic flux also

has potential benefits: first, the membrane protection afforded

by increased flux and production of glycolytic ATP, and, second,

the enhanced oxidation of pyruvate with a decreased production

of harmful protons.

Here we propose that glucose–fatty acid interactions in the

ischaemic heart (FFA-induced lowering of glucose metabolism)

would not be restricted to only cardiomyocytes in this instance.

In support of this hypothesis, hyperglycaemia is associated with

impaired microvascular function, leukocyte capillary plugging,

enhanced platelet activation, larger infarct sizes and worse

functional recovery in AMI patients.

Key molecular mechanisms

whereby hyperglycaemia exerts such toxic effects include

higher intracellular oxidative stress, downstream metabolic

perturbations and activation of inflammatory pathways.

Clinical management

It is our viewpoint that one should routinely determine the

metabolic status (FFA, glucose, insulin) of suspected and

confirmedAMI patients (non-diabetic and diabetic) at the time of

admission, and thereafter monitor this in the ICU (for example,

to check for persistent hyperglycaemia). Which easily available

metabolic therapeutic options would be most appropriate under

such circumstances? The selection of a metabolically favourable

-blocker may be useful as in conjunction to its well-known

effects on haemodynamic parameters,

-blockers also inhibit

adipose lipolysis and limit subsequent FFA-mediated damaging

effects.

Modulating blood glucose levels is another therapeutic

option by employing the glucose–insulin–potassium (GIK)

cocktail originally proposed by Sodi-Pallares in 1969.

Indeed,

pharmacodynamic doses of insulin improve cardiac pump

function without increasing myocardial oxygen consumption

in acute ischaemic heart failure.

Lastly, FFA reduction and

stimulation of glucose metabolism in the ischaemic myocardium

by GIK treatment is able to blunt metabolic derangements.

However, such treatment must be initiated early, within the first

hours of symptom onset, because the relatively weak benefit of

most prior GIK studies is attributed to delayed infusion when

the ischaemic heart has already undergone substantial damage.

The major protective component of this cocktail is likely

to be insulin, which is known to lower FFA mobilisation,

to decrease circulating FFA levels and to promote glucose

uptake, thereby alternating dangerously high circulating blood

glucose levels. Insulin administration is also linked to additional

cardioprotective actions, independent of its ability to lower

systemic blood glucose levels.

Interestingly, when insulin was

infused at doses high enough to overcome stress-induced insulin

resistance, the subsequent lowering of FFA levels and restoration

of normoglycaemia were associated with cardioprotection in

patients undergoing coronary bypass grafting.

However, among

patients with suspected ACS, out-of-hospital administration

of intravenous GIK did not reduce progression to myocardial

infarction.

This study requires independent confirmation.

We agree with the American Heart Association (AHA) that

insulin treatment be initiated for ACS patients as soon as blood

glucose levels exceed 180 mg/dl (10 mmol/l), regardless of prior

diabetes history.

This option may easily be overlooked in ACS

patients with no history of diabetes in the ICU. The AHA

also recommends that ACS patients without diabetes should

be further evaluated at the time of hospitalisation (fasting

blood glucose and HbA

levels) to assess a persistent severity

of metabolic derangements. However, clinicians must also be

mindful of hypoglycaemia and the associated adverse prognosis

with intensive insulin treatment, and frequent blood sugar

testing is required.

Conclusion

Metabolic dysregulation is a frequent and actionable event in

ACS. Modulation of hyperglycaemia and increased circulatory

FFA levels call for diverse pharmacological interventions.

Additional studies and further refinement of current guidelines

are needed.

We thank Dr Heinrich Taegtmeyer, McGovern Medical School at UTHealth

Houston, TX for helpful discussions.

References

Opie LH. Effect of fatty acids on contractility and rhythm of the heart.

Nature

1970;

227

: 1055–1056.

Essop MF, Opie LH. Metabolic therapy for heart failure

. Eur Heart J

2004;

: 1765–1768.

Borst P, Loos JA, Christ EJ, Slater EC. Uncoupling activity of long-

chain fatty acids.

Biochim Biophys Acta

1962;

: 509–518.

Mjos OD. Effect of free fatty acids on myocardial function and oxygen

consumption in intact dogs.

J Clin Invest

1971;

: 1386–1389.

De Leiris J, Opie LH, Lubbe WF. Effects of free fatty acid and enzyme

release in experimental glucose on myocardial infarction.

Nature

1975;

253

: 746–747.

Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia

and increased risk of death after myocardial infarction in patients with

and without diabetes: a systematic overview.

Lancet

2000;

355

(9206):

773–778.

Zarich SW, Nesto RW. Implications and treatment of acute hypergly-

cemia in the setting of acute myocardial infarction.

Circulation

2007;

115

: e436–e439.