Diabetes and the QT Interval: Time for Debate

British Journal of Diabetes and Vascular Disease. 2004;4(3)

The electrocardiographic QT interval has been extensively studied in ischaemic heart

disease. Recently, there has been increasing interest in the relationship between
diabetes and QT abnormalities. QT prolongation and increased QTd have been shown
to predict cardiac death in both type 1 and type 2 diabetes mellitus. Although there is
general agreement that QT interval is affected by cardiac ischaemia, the effect of
hyperglycaemia on QT measures is controversial. There are also problems surrounding
QTd. First, there is controversy as to whether the measure has any physiological
meaning; secondly, there is no universally accepted method of measurement and hence
no consensus about the upper limit of normal. Nevertheless, several studies have
shown increased QTd in diabetic patients suggesting that assessment of the QT interval
could be a cost effective way of stratifying such patients according to cardiovascular risk
so that aggressive treatment could be directed appropriately to improve outcome.
Patients with diabetes mellitus are at an increased risk of dying from cardiovascular
diseases, the reason for which is not completely understood. Excess cardiovascular risk
in this population persists even after normalisation for other conventional cardiovascular
risk factors (hypertension, dyslipidaemia, physical inactivity, smoking) suggesting that
there are other incompletely understood mechanisms which increase cardiovascular
risk in diabetic patients. Ventricular instability, as manifested in QT abnormalities, might
be an important additional mechanism.
The QT interval, which is easily obtained from a standard resting ECG, reflects the total
duration of ventricular myocardial depolarisation and repolarisation. It can be corrected
for heart rate by using a variety of formulae. The QTc effectively is the QT interval
estimated at a rate of 60/minute. A commonly used correction formula is that of
Bazett[1]where QTc = QT RR interval. The Bazett formula, which has been heavily
criticised, in fact gives a slight over correction of QT interval at higher heart rates while
the formula of Hodges et al.[2] (QTc = QT + 1.75 [rate - 60]) has been shown to perform
much better and is gradually gaining more widespread acceptance. [3] There are,
however, very many QT correction formulae, a detailed discussion of which is beyond
the scope of this article. QTc prolongation is a risk factor for sudden death independent
of age.[4] The relationship between prolonged QT interval and an increased risk of
sudden death has been extensively studied in ischaemic heart disease [5] and a relative

risk of 2-5 has been reported. The long QT syndrome is associated with a very high risk
of ventricular fibrillation[6] and drugs such as quinidine that prolong the QT interval may
also cause sudden arrhythmic death.
QTd is defined as the difference between the maximum and minimum QT interval on
the 12 lead ECG (QTd = QT max - QT min). A single QT interval on the surface ECG
does not give any information on dispersion of recovery time (i.e. repolarisation) but
QTd is said to reflect spatial differences in myocardial recovery time. [7] Healthy subjects
exhibit a small degree of QTd.[8] Increased QTd has been observed in chronic heart
failure,[9] peripheral
vascular
disease,[10] hypertension,[11] hypertrophic
cardiomyopathy[12] and in CHD,[13] and has been correlated with increased risk of
cardiovascular death in these conditions and in healthy subjects. [14] Increased QTd after
acute MI is a risk factor for sudden death and QTd has been shown to decrease after
successful thrombolytic therapy.[15] It is, therefore, believed that QTd following an acute
MI depends not only on infarct site and size but also on reperfusion status.
Increased QTd may indicate non-uniform ventricular repolarisation, thus possibly
providing a substrate for the development of malignant ventricular arrhythmias.
Endocardial monophasic action potential studies have demonstrated that there are
regional differences in the duration of myocardial repolarisation that may be reflected in
the surface ECG.[16] Homogeneity of ventricular recovery time is believed to protect
against arrhythmias.
QTd can be corrected for heart rate but it has been argued that this should not be
done.[17] In any event, with a linear correction formula, e.g. the Hodges et al., 1983
formula,[2] there is no need for QTd rate correction, i.e. QTd is the same before and after
correcting for rate with this formula.[8]
QTc > 440 ms (0.44s) is universally considered as prolonged, although there are small
gender based differences. There is still some confusion about the upper limit of normal
QTd. QTd > 80 ms (0.08s) is usually considered as abnormally
prolonged.[18,19] However, on the basis of a study of over 3,000 neonates, children and
adults, an upper limit for normal QTd of 50 ms was suggested by Macfarlane et al.[8]
The main problem with QT interval assessment is that there is no universally recognised
standard method of analysis or of lead selection. It may not be possible to measure QT
interval in every lead, and measurement may be less than precise. QT interval can be
measured erroneously by misinterpreting either the beginning of the QRS complex or

the end of the T wave. Methodology for determining QTd varies between studies. It can
be measured manually, by digitisers, photocopy enlargement of an ECG, and by special
computer software. There is an urgent need for standardisation of lead selection and
method of measurement. The intra- and inter-observer reproducibility of QTd is low (and
significantly lower than that of QT interval) and has been shown to vary[20] and the
results, therefore, may not be fully comparable between studies. Some authors have
raised doubts about the meaning of QTd. It has been suggested that QTd is unlikely to
reflect any aspect of myocardial repolarisation and that it results mainly from the
variations in T loop morphology and QT measurement error.[21,22]

Recently there has been growing interest in the relationship between diabetes and QTc
and QTd. Prevalence of prolonged QT interval and increased QTd is higher in people
with type 1 and type 2 diabetes as compared to non-diabetic subjects,[18,19,23] especially
in the presence of autonomic neuropathy.[24] The prevalence of QT prolongation has
been reported to be as high as 16% in type 1 diabetes (11% in males and 21% in
female patients)[23]and 26% in type 2 diabetes,[19] while that of increased QTd has been
reported as 7% in type 1 diabetes (8% in men and 5% in women)[18] and 33% in type 2
diabetes.[19] No association between QT abnormalities and gender has been observed
in type 2 diabetes.[19,25] Diabetic patients with more pronounced QT abnormalities tend
to have higher age and blood pressure and they tend to have cardiovascular
complications.[18,19] However, even patients with a recent diagnosis of diabetes and
without overt cardiac complications have been observed to have increased QTd
compared to non-diabetic subjects.[25] QT interval is affected by CHD and autonomic
neuropathy and it is possible that these new diabetic patients with prolonged QT interval
and increased QTd may have had undiagnosed neuropathy or CHD.
Prolonged QTc and increased QTd are independent markers for CHD in type 1 and type
2 diabetes[18,19] and have been demonstrated to be highly significant predictors of
cardiac death[26] even in newly diagnosed type 2 diabetes.[27] Comparison between QTd
and microalbuminuria suggests that increased QT dispersion is a better predictor of
cardiac death in patients with diabetes.[26] QTd > 78 ms after six years of diabetes
predicted cardiac death with 100% sensitivity and 90% specificity i.e. an odds ratio of
nine,[27] compared with an odds ratio of 1.8 for microalbuminuria (95% CI, 1.2-2.8) in an
overview.[28]

No association has
complications.[18,19,25]

been

found

between

QTd

and

microvascular

diabetic

Cardiac autonomic neuropathy is a well-recognised complication of diabetes and is

believed to be responsible for an increased risk of sudden death. Ewing's battery of
tests[29]remains too cumbersome for use in routine clinical practice. Consensus
statements released by the American Diabetic Association and the American Academy
of Neurology indicate that testing for prolongation of Bazett's heart rate-QTc is easy and
specific for diabetic cardiac autonomic failure.[30] QTc, however, is seldom used to
evaluate alteration in cardiac sympathetic innervation in the clinical setting because of
its insensitivity for autonomic failure. A meta-analysis recently concluded that
measurement of QTc is a more accurate test for autonomic failure in young men with
diabetes and that QTc rules out autonomic failure best among diabetic patients in whom
it is most sensitive (i.e. men and young people).[31] In a recent study among patients
with type 1 diabetes, QTc did not correlate with the severity of autonomic neuropathy as
indicated by other cardiovascular autonomic tests.[32] Thus, there is general agreement
that the presence of cardiac autonomic dysfunction increases the duration of the QT
interval but it is still controversial as to whether or not it influences QTd. Most studies
have failed to demonstrate any significant association between QTd and autonomic
dysfunction in multivariate analysis.[25
The reasons for QT abnormalities in diabetes are not completely understood. Does
uncontrolled hyperglycaemia per se contribute to QT prolongation and increased QTd?
In a study of healthy non-diabetic subjects, an independent association between high
plasma glucose concentration and increased QTc duration and QTd was reported. [33] It
was further shown in the same study that inhibition of glucose induced insulin release,
by octerotide infusion during a hyperglycaemic clamp, did not influence ECG changes,
suggesting that insulin does not play a major role in glucose induced ECG changes. A
similar relation was observed between QTc duration and fasting glucose in a large
population based study of more than 6,500 patients. [34] QT interval duration was found
to be independently associated with HbA1c in type 1 diabetes in the EURODIAB IDDM
Complication Study.[23]
In several studies in type 1 diabetes[18] and type 2 diabetes,[19,25] QT abnormalities were
not influenced by the level of metabolic control (HbA 1c) or duration of diabetes. In
another study, mean HbA1c was significantly greater for those with a QTc in the upper
tertile compared to the lower tertile among adults with diabetes (8.0% vs. 7.5%, p0.05)
and impaired fasting glucose (5.7% vs. 5.4%, p0.05), but there was no difference

among adults with normal glucose.[35] A possible influence of hyperglycaemia on QT

abnormalities can not be excluded and is worthy of further research.
It has been proposed that hyperglycaemia may produce ventricular instability by
increased sympathetic activity, increased cytosolic calcium content in myocytes or
both.[36]Insulin stimulates sympathetic activity and diabetes is known to be associated
with impaired parasympathetic cardiac control. This is reflected in a reduced ability to
regulate heart rate as well as a reduction in heart rate variability.[37]
In the United Kingdom Prospective Diabetes Study (UKPDS), which enrolled adults with
newly diagnosed type 2 diabetes, a significant reduction in all microvascular end points
was noted in the intensive treatment group compared to the standard treatment group
while a trend toward a reduction in cardiovascular outcomes was not statistically
significant (p=0.052).[38] However, it has been shown in an epidemiological analysis of a
UKPDS cohort that, for every 1% reduction in HbA 1c, there was an approximately 14%
reduction of all cause mortality and MI, an effect which was statistically significant. [39] A
systematic review after analysing data from six randomised controlled trials comparing
conventional treatment with intensive insulin therapy noted a moderate treatment effect
of glycaemic control on macrovascular events in type 1 diabetes.[40]Improving metabolic
control, including glycaemia substantially reduces the burden of cardiovascular disease
in diabetes.
The mechanism by which prolonged QT interval and increased QTd predict increased
cardiac mortality and morbidity in diabetes has been much debated. It appears that
these two parameters provide different information. QTd is believed to correlate to a
greater extent with the risk of ventricular arrhythmias than QT prolongation. Some
conditions associated with a prolonged QT interval, e.g. therapy with sotalol may
actually reduce the risk of sudden death in association with a reduction in QTd but an
increase in QTc.[41] It was initially thought that this is because QTd reflects electrical
heterogeneity, but this view has now been challenged and QTd has been proposed as a
non-invasive marker of potentially lethal underlying cardiac abnormalities - the most
important being ischaemia.[42] It is further supported by the observation that QTd is
prolonged immediately after an MI and tends to reduce after successful
thrombolysis.[15] Overall, increased QTd seems to represent the sum of several adverse
cardiac abnormalities such as fibrosis, hypertrophy, dilatation, ischaemia and probably,
autonomic dysfunction.[27,42] All these factors individually confer increased
cardiovascular risk and QTd, as a summation, could be a global prognostic marker for

cardiac mortality in patients with diabetes. The debate on what causes sudden death arrhythmia or ischaemia - continues. It has been suggested that a patient with QT
abnormalities should undergo tests for myocardial ischaemia (treadmill test) as well as
left ventricular abnormalities (echocardiogram).[42]
Most of the studies of QT abnormalities in diabetes are observational and there is a
marked paucity of interventional studies. There is a wealth of data to link QT
abnormalities with cardiac ischaemia, but these abnormalities have been found even in
newly diagnosed diabetic patients with no apparent cardiac disease. Despite an
extensive literature search, no study was found that has assessed the effect, if any, of
controlling hyperglycaemia on QTd and QT prolongation in patients with diabetes. It will
be of interest to know if these QT abnormalities can be ameliorated by successful
control of hyperglycaemia in diabetic patients without cardiovascular complications.
However, improved glycaemic control will need to be achieved by diet or by drugs that
do not by themselves affect QT interval (e.g. metformin, insulin). It has been recently
shown in a small study that glibenclamide, a commonly used second-generation
sulphonylurea, causes an increased QTc and QTd.[43] However, larger studies are
needed to clarify this further.
Increased QTd could possibly be used to identify a subgroup of diabetic patients which
is at a particularly high risk of adverse cardiovascular outcome. Patients with this QT
abnormality could be targeted for more detailed cardiac investigations, including a
treadmill test, echocardiogram and angiography. If other structural or functional cardiac
abnormalities are identified, specific therapeutic efforts, e.g. aggressive lowering of
blood pressure etc. may be undertaken in an attempt to alter the outcome favourably.
Despite the problems inherent in the accuracy and reproducibility of QT measurements,
the greatest advantage of using the QT interval as a screening test is that it does not
require patient compliance, is non-invasive, easily obtained and cost effective.
However, it remains to be seen if more aggressive control of hyperglycaemia in this
subgroup will help in improving QT abnormalities (i.e. ventricular instability) and,
therefore, cardiac outcome. More long-term interventional studies are needed to shed
light on this issue.

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