Nephrol Dial Transplant (1996) 11: Editorial Comments
1514
Mortality in diabetic nephropathy: the importance of the QT interval
P. T. Sawicki
Medical Department of Metabolic Diseases and Nutrition (WHO Collaborating Centre for Diabetes), Heinrich-Heine
University of Dusseldorf, Germany
Key words: diabetic nephropathy; autonomic neuropathy; QT interval; hypertension; mortality
who died did so due to cardio- or cerebrovascular
causes, including sudden or unexpected death, see
Table 1.
Mortality in diabetic nephropathy
Predictors of mortality in diabetic nephropathy
The dramatic decrease in life expectancy in type 1
diabetes mellitus occurs only if the patients develop
diabetic nephropathy [1]. Borch-Johnsen followed
nearly 3000 type 1 diabetic patients diagnosed between
1930 and 1970 and found that relative mortality was
increased nearly 100-fold, but only in those patients
who developed an elevated urinary albumin excretion.
On the other hand this means that type 1 diabetic
patients who will not develop an elevated urinary
albumin excretion because of either a good metabolic
control or a yet unknown renal protective factor, have
a life expectancy very much comparable to the general
population. In this study [1] most patients died due to
cerebro- and cardiovascular causes, but also about
30-40% died of renal failure. However, during the
recent years after renal replacement therapy became
available, not only has the nearly 80% 10-year mortality decreased [2] but the causes of death have also
changed. We have looked on the causes of death in 85
type 1 diabetic patients with hypertension and diabetic
nephropathy who were followed for a mean of 9 years
until 1994 [3]. The total mortality was nearly 40%;
there were no renal deaths, but over 60% of the patients
In this study [3] we have also tried to identify prognostic markers for mortality in diabetic nephropathy
[3]. The following baseline parameters were included
in a stepwise regression analysis (backward selection):
age, gender, diabetes duration, presence of severe retinopathy, mean blood pressure, heart rate, RR variation,
the linear and the quadratic term for RR interval,
smoking, any neuropathy, autonomic neuropathy and
the maximal QTc interval in the ECG. In the final
model independent predictors were age, the length of
the maximum QTc period, autonomic neuropathy,
diabetes duration and RR variation, Table 2. This
result indicates that a prolongation the QT interval
represent an important risk marker for mortality not
only in patients after myocardial infarction and congestive heart failure but also in patients with diabetic
nephropathy. Of the patients with a baseline maximum
QTc above/equal the arbitrary cut off point of 450 ms*
45% died during the follow-up as compared to 32% of
those with a lower maximum QTc period, Table 1. The
main causes of death were cardiac. Sudden and unexpected deaths occurred only in patients with a maximal
QTc period above/equal the median of 450 ms*,
Table 2. In the life table analyses the group of patients
with the longest maximal QTc period, which was
arbitrary denned as >470 ms* (« = 9), had a considerably higher mortality risk (P = 0.0004) [3]. However,
the risk of death increased proportionally to the prolongation of the maximum QTc interval without an
apparent threshold effect.
Table 1. During a 5-13 years follow-up of 85 patients with diabetic
nephropathy 33 patients died. Causes of death are given for patients
with an initial maximal QTc period above or below 450 ms1'2
Causes of death
(ICD-9 code)
QTc-max
< 450 ms1'2
n = 38
QTc-max
> 450 ms1'2
«=47
Total mortality
Cardiac
(410; 411; 428)
Unexpected and sudden
death (427; 798)
Cerebrovascular
(431; 433)
Hypoglycaemia
(251)
Other
(038; 154; 162; E950)
12
5
21
0
7
4
2
0
2
3
5
5
Correspondence and offprint requests to: Peter T. Sawicki MD, Dept.
of Metabolic Diseases and Nutrition, Heinrich-Heine University,
PO Box 10 10 07, D-40001 Dusseldorf, Germany.
Reasons for prolongation of the QT interval in
diabetic nephropathy
Most patients with diabetic nephropathy exhibit some
degree of autonomic neuropathy [4] resulting in a
reduced vagal activity and increased sympathetic activity which can lead to alteration on the QT interval and
increase the risk of sudden death. However, QT prolongation may not only result from increased sympathetic cardiac nerve activity but may be directly due to
myocardial cell defects [5] which lead to a reduced
electrical stability and also predispose to ventricular
arrhythmia. Such cell defects may be for example
1515
Nephrol Dial Transplant (1996) 11: Editorial Comments
Table 2. Results of the Cox proportional hazards model, including the significant independent predictors of death in patients with diabetic
nephropathy
Variable
P-value
Difference
for risk
ratio
Risk ratio
95% CI
for risk
ratio
Age
Maximum QTc interval
Presence of autonomic neuropathy
Diabetes duration
RR variation = RR m a x /RR m l n
0.0007
0.0049
0.0068
0.0163
0.0359
5 years
10 ms 1 ' 2
yes/no
5 years
0.01
1.47
1.34
2.91
0.74
0.94
1.18;
1.09;
1.34;
0.58;
0.89;
caused by (silent) ischaemia and/or myocardial fibrosis
in patients with coronary artery disease, which is
frequently present in patients with diabetic nephropathy. In addition, volume overload and/or hypertension can reduce the threshold for arrhythmia through
an increased ventricular wall stress. Also, renal failure
and/or diuretic treatment can induce electrolyte imbalances leading to reduced myocardial refractoriness.
Despite the fact that in our study the mortality risk
associated with a prolongation of the QTc interval was
independent of other known risk factors and markers,
we think that a prolonged QTc interval indicates a
cluster or a focus of several detrimental conditions
frequently present in patients with diabetic nephropathy and we propose the use of the QT interval as a
sum indicator of the total mortality risk. Whatever the
reasons for the QT interval prolongation might be, the
major task is to improve the very poor prognosis in
these patients.
Possible therapeutic implications
During the past two decades, antihypertensive treatment has markedly improved the prognosis of type 1
diabetic patients with nephropathy. This treatment
reduced progression of diabetic nephropathy and
resulted in longer patient survival. It is of note that in
all studies which reported a significant reduction of
mortality under antihypertensive medication, treatment included beta-blocking agents [2,6,7]. The specific
benefit of beta-blocker treatment in patients with idiopathic QT interval prolongation has been well recognized [8]. This might, at least in part, have influenced
the beneficial outcome of antihypertensive therapy,
including these agents, by improving the myocardial
electrophysiological stability, possibly through a direct
reduction of vulnerability to sympathetic overactivity
and/or through an increase of vagal tone, which has
been shown to be associated with beta-blocker treatment [9], and result in a reduction of the susceptibility
to arrhythmia [10]. In addition, beta-blocking agents
have been shown to have cardioprotective properties
in silent myocardial ischaemia [11], which is particu-
1.84
1.64
6.32
0.95
0.99
larly often present in diabetic patients. In this context
it appears of interest that the beneficial effect of betablocker treatment following myocardial infarction was
particularly impressive in patients with diabetes mellitus [12]. However, because of the lack of controlled
randomized intervention studies the possible benefit
from treatment with beta-blocking agents in diabetic
nephropathy remains speculative. Intervention studies
including different therapeutic approaches and aiming
at decreasing this high mortality risk are urgently
needed in these patients.
References
1. Borch-Johnsen K, Kreiner S, Deckert T. Mortality of Type 1
(insulin dependent) diabetes mellitus in Denmark. Diabetologia
1986; 29: 767-772
2. Parving HH, Hommel E. Prognosis in diabetic nephropathy. Br
MedJ 1989; 299: 230-233
3. Sawicki PT, Dahne R, Bender R, Berger M. Prolonged QT
interval as a predictor of mortality in diabetic nephropathy.
Diabetologia 1996; 39: 77-81
4. Molgaard H, Christensen PD, Hermansen K, Sorensen KE,
Christensen CK, Mogensen CE. Early recognition of autonomic
dysfunction in microalbuminuria: significance for cardiovascular
mortality in diabetes mellitus? Diabetologia 1994; 37: 788-796
5. Towbin JA. New revelations about the long-QT syndrome. N
Engl J Med 1995; 333: 384-385
6. Mathiesen ER, Borch-Johnsen K, Jensen DV, Deckert T.
Improved survival in patients with diabetic nephropathy.
Diabetologia 1989; 32: 884-886
7. Sawicki PT, Muhlhauser I, Didjurgeit U, Baumgartner A,
Bender R, Berger M. Intensified antihypertensive therapy is
associated with improved survival in type 1 diabetic patients
with nephropathy. J Hypertens 1995; 13: 933-938
8. Schwarz PJ. Idiopathic long QT syndrome. Progress and questions. Am Heart J 1985; 2: 399-411
9. Melgaard H, Mickley H, Pless P, Bjerregaard P, Moller M.
Effects of metoprolol on heart rate variability in survivors of
acute myocardial infarction. Am J Cardiol 1993; 71: 1357-1359
10. Kennedy HL, Brooks MM, Barker AH et al. for the CAST
Investigators. Beta-blocker therapy in the cardiac arrhythmia
suppression trial. Am J Cardiol 1994; 74: 674-680
11. Pepine CJ, Cohn PF, Deedwania PC et al. for the ASIST Study
Group. Effects of treatment on outcome in mildly symptomatic
patients with ischemia during daily life. The Atenolol Silent
Ischemia Study (ASIST). Circulation 1994; 90: 762-768
12. Kjekshus J, Glipin E, Cali G, Blackey AR, Henning H, Ross
Jr J. Diabetic patients and beta-blockers after myocardial infarction. Eur Heart J 1990; 11: 43-50