VOLUME 11 NUMBER 2 • JUNE 2014
89
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
coronary blood flow
30,31
and myocardial metabolism.
32,33
In long-term
type 1 diabetes, myocardial blood flow response to sympathetic
stimulation is significantly impaired.
Scintigraphically, cardiac sympathetic dysinnervation was
identified in 77% of newly diagnosed metabolically stabilised
type 1 diabetic patients.
27
The pattern of cardiac sympathetic
dysinnervation of newly diagnosed type 1 diabetic patients is
heterogeneous with a predominant affection of the posterior
myocardial region.
25,27
More recent publications, however, emphasise
that neither impairment of metabolic control nor the presence of
CV denervation may be a prerequisite for the development of
impaired vasodilatory reserve. Diastolic dysfunction occurring early
in the course of type 1 diabetes has been reported to be associated
with abnormal cardiac sympathetic function as assessed by cardiac
sympathetic imaging.
34,35
Neuronal abnormalities are reported to progress with duration
of diabetes.
36
In parallel, defects of cardiac sympathetic innervation
are more enhanced in long-term than in newly diagnosed type
1 diabetes patients.
25,27
In patients with a long diabetes history,
heterogeneity of cardiac sympathetic dysinnervation, characterised
by a more advanced affection of the posterior myocardium in
comparison to the anterior, lateral and septal myocardium has
been observed.
25
In studies on small groups of patients with type 1
diabetes, frequent sympathetic dysinnervation and a predominance
in the posterior myocardial region,
37
and proximal sympathetic
hyperinnervation of the heart
38
has been observed with PET.
Immunological factors against sympathetic ganglia have been
reported to be associated with cardiac sympathetic dysfunction.
39-45
Auto-antibodies against sympathetic ganglia have been found in
20–35% of type 1 diabetes patients.
39,41,42
The presence of auto-
antibodies against sympathetic ganglia has been shown to be
associated with scintigraphically assessed cardiac sympathetic
dysfunction
39,41
and electrocardiogram (ECG)-based abnormalities
of heart rate variation.
41
Auto-antibodies against sympathetic
ganglia seem to be rather specific for cardioneuropathy of type 1
diabetes patients.
41
Hypoglycaemia
Additional haemodynamic changes have been reported to be
associated with hypoglycaemia.
46
An increase in heart rate and
peripheral systolic blood pressure as well as a reduction in central
blood pressure and peripheral arterial resistance (causing a widening
of pulse pressure) has been described. Furthermore, an increase
in myocardial contractility, stroke volume and cardiac output has
been observed.
47
In healthy people, arteries have been reported
to become more elastic during hypoglycaemia, with a decline in
wall stiffness.
46
In people with a longer history of type 1 diabetes,
however, due to an enhanced arterial wall stiffness, hypoglycaemia
is followed by a less pronounced fall in central arterial pressure.
46,48
As a consequence, a temporary markedly increase in the workload
of the heart must be assumed.
46
On ECG, hypoglycaemia has been found to elicit ST-wave
changes with lengthening of the QT interval
49
and cardiac
repolarisation.
50
Therefor the risk for arrhythmia is assumed to be
increased.
46
Related to hypoglycaemia, various abnormal heart
rhythms, including ventricular tachycardia and atrial fibrillation,
have been observed.
In conclusion, hypoglycaemia has been found to potentially
cause abnormal electrical activity in the heart and is assumed to
provoke sudden death.
46
An association between hypoglycaemia
and sudden death has been detected by various investigators.
51-56
In line with the hypothesis, an autopsy study demonstrated that
sudden unexpected deaths were four times more frequent in type
1 diabetes patients than in non-diabetic people.
56
Cardiovascular risk
Risk factors for microvascular complications
The risk of microvascular complications is influenced by several
factors, such as puberty, blood pressure, dyslipidaemia, gender,
diabetes duration, smoking and lifestyle.
57-59
Poor metabolic
control has been identified as an important factor contributing
to microvascular complications.
60,61
In addition, familial risk factors
related to all microvascular complications of type 1 diabetes have
been reported.
62
A study performed in type 1 diabetes patients (onset age<30
years) among 6 707 families revealed a significantly increased risk
of retinopathy (odds ratio 9.9; CI 5.6–17.7,
p
<0.001), nephropathy
(6.2; CI 2.9–13.2,
p
<0.001) and neuropathy (2.2; CI 1.0–5.2;
p
<0.05) in type 1 diabetes siblings of patients diagnosed with
these complications.
62
In an analysis of 572 type 1 diabetes participants of the Pittsburgh
EDC study (mean follow up: 15 years), baseline HbA
1c
level was
an independent risk factor for fatal CAD, along with duration of
diabetes and albuminuria.
63
Lower baseline insulin dose, however,
was strongly predictive of non-fatal CAD, as was lower renal
function, and higher diastolic blood pressure and lipid levels.
63
In patients with diabetes onset at age 5–14 years, a higher risk
for complications (retinopathy, nephropathy and neuropathy) has
been found compared to patients diagnosed either at a very young
age or after puberty.
62
In adolescents with type 1 diabetes, an
elevated blood pressure or body mass index (BMI),
64-66
dyslipidaemia
and smoking
67-69
were associated with an elevated risk of incipient
nephropathy, early retinopathy and peripheral neuropathy.
With the onset of diabetic nephropathy, a dramatic increase in
the risk for CAD has to be assumed. After 20 years with diabetes,
up to 29% of patients with childhood-onset type 1 diabetes
and nephropathy will have CAD compared to only 2–3% in
similar patients without nephropathy.
70
In addition to traditional
cardiovascular disease risk factors, elevated mean HbA
1c
levels and
macroalbuminuria were significantly associated with alterations in
left ventricular structure and function evaluated by cardiac magnetic
resonance imaging (MRI).
71
In observational studies, the relationship between blood pressure
and the progression of chronic kidney disease (CKD) and incident
end-stage renal disease (ESRD) is direct and progressive in diabetes.
72
However, most of the evidence is in type 2 diabetes. High blood
pressure is a common feature of type 1 diabetes as well, and an
increase in blood pressure in type 1 diabetes increases the risk of
nephropathy.
73,74
Masked hypertension is not infrequent.
72
In people
with type 1diabetes an increase in systolic bloodpressure, particularly
at night, precedes the development of microalbiminuria.
75
It has
been argued that, unlike in type 2 diabetes, in people with type 1
diabetes, hypertension develops often after the establishment of
microalbuminuria. Hence, 24-hour blood pressure monitoring in
type 1 diabetes may be a useful diagnostic procedure.
In the DCCT/EDIC study, during a 15.8-year median follow
up, 630 of 1 441 participants developed hypertension.
76
Intensive
therapy during the DCCT reduced the risk of incident hypertension
by 24% during the EDIC study follow up. A higher HbA
1c
level,
