Resting Heart Rate and the Risk of Microvascular Complications in Patients With Type 2 Diabetes Mellitus

Abstract

A higher resting heart rate is associated with an increased probability of cardiovascular complications and premature death in patients with type 2 diabetes mellitus. The impact of heart rate on the risk of developing microvascular complications, such as diabetic retinopathy and nephropathy, is, however, unknown. The present study tests the hypothesis that a higher resting heart rate is associated with an increased incidence and a greater progression of microvascular complications in patients with type 2 diabetes mellitus.
The relation between baseline resting heart rate and the development of a major microvascular event was examined in 11 140 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. Major microvascular events were defined as a composite of new or worsening nephropathy or new or worsening retinopathy. Patients with a higher baseline heart rate were at increased risk of a new major microvascular complication during follow-up (adjusted hazard ratio: 1.13 per 10 beats per minute; 95% confidence interval: 1.07-1.20; P<0.001). The excess hazard was evident for both nephropathy (adjusted hazard ratio: 1.16 per 10 beats per minute; 95% confidence interval: 1.08-1.25) and retinopathy (adjusted hazard ratio: 1.11 per 10 beats per minute; 95% confidence interval: 1.02-1.21).
Patients with type 2 diabetes mellitus who have a higher resting heart rate experience a greater incidence of new-onset or progressive nephropathy and retinopathy.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00145925. http://www.advance-trial.com/static/html/prehome/prehome.asp.

Full text

Resting Heart Rate and the Risk of Microvascular Complications in
Patients With Type 2 Diabetes Mellitus
Graham S. Hillis, MBChB, PhD; Jun Hata, MD, PhD; Mark Woodward, PhD; Vlado Perkovic, MBBS, PhD; Hisatomi Arima, MD, PhD;
Clara K. Chow, MD, PhD; Sophia Zoungas, MBBS, PhD; Anushka Patel, MBBS, PhD; Neil R. Poulter, MD; Giuseppe Mancia, MD, PhD;
Bryan Williams, MD; John Chalmers, MD, PhD
Background-—A higher resting heart rate is associated with an increased probability of cardiovascular complications and
premature death in patients with type 2 diabetes mellitus. The impact of heart rate on the risk of developing microvascular
complications, such as diabetic retinopathy and nephropathy, is, however, unknown. The present study tests the hypothesis that a
higher resting heart rate is associated with an increased incidence and a greater progression of microvascular complications in
patients with type 2 diabetes mellitus.
Methods and Results-—The relation between baseline resting heart rate and the development of a major microvascul ar event was
examined in 11 140 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified
Release Controlled Evaluation (ADVANCE) study. Major microvascular events were defined as a composite of new or worsening
nephropathy or new or worsening retinopathy. Patients with a higher baseline heart rate were at increased risk of a new major
microvascular complication during follow-up (adjusted hazard ratio: 1.13 per 10 beats per minute; 95% confiden ce interval: 1.07–
1.20; P<0.001). The exce ss hazard was evident for both nephropathy (adjusted hazard ratio: 1.16 per 10 beats per minute; 95%
confidence interval: 1.08–1.25) and retinopathy (adjusted hazard ratio: 1.11 per 10 beats per minute; 95% confidence interval:
1.02–1.21).
Conclusion-—Patients with type 2 diabetes mellitus who have a higher resting heart rate experience a greater incidence of new-
onset or progressive nephropathy and retinopathy.
Clinical Trial Registration-—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00145925. http://www.advance-trial.com/
static/html/prehome/prehome.asp ( J Am Heart Assoc. 2012;1:e002832 doi: 10.1161/JAHA.112.002832)
Key Words: diabetes mellitus, type 2 • heart rate • microcirculation
M
icroalbuminuria and retinopathy are indicators of
microvascular dysfunction, and both predict a poorer
outcome in patients with diabetes
1–3
and in individuals with
normal glycemic control.
4,5
In particular, even mild degrees of
microalbuminuria are a strong and independent predictor of
major cardiac events in the general population
6,7
and among
patients with diabetes
4
and hypertension.
8
Likewise, several
studies have reported an association between a higher resting
heart rate and an increased risk of cardiovascular complica-
tions in unselected populations and in patients with cardiac
disease.
9,10
Recently, we reported a similar relation between
resting heart rate and all-cause death, cardiovascular death,
and major cardiovascular events in patients with type 2
diabetes mellitus.
11
This was not attenuated after adjustment
for other factors that influence heart rate and outcome.
11
Although a growing volume of data supports an association
between higher resting heart rate and a greater risk of
macrovascular events in patients with type 2 diabetes, the
impact of heart rate on the risk of developing microvascular
complications, such as diabetic retinopathy and nephropathy,
is unknown. There are, however, reasons to suspect that an
elevated resting heart rate might predict microvascular
outcomes in this setting. In patients with hypertension, a
higher resting heart rate has been associated with a greater
prevalence of microalbuminuria,
12,13
a relation that was
From The George Institute for Global Health, University of Sydney, Australia
(G.S.H., J.H., M.W., V.P., H.A., C.K.C., S.Z., A.P., J.C.); Imperial College (N.R.P.)
and University College London (B.W.), London, United Kingdom; and University
of Milano-Bicocca, Milano, Italy (G.M.).
Correspondence to: Graham Hillis, MBChB, PhD, The George Institute for
Global Health, King George V Building, Royal Prince Alfred Hospital, Sydney,
NSW 2050, Australia. E-mail ghillis@georgeinstitute.org.au
Received April 25, 2012; accepted July 27, 2012.
ª 2012 The Authors. Published on behalf of the American Heart Association,
Inc., by Wiley-Blackwell. This is an Open Access article under the terms of the
Creative Commons Attribution Noncommercial License, which permits use,
distribution, and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 1
ORIGINAL RESEARCH

maintained after correction for a variety of potential
confounding factors. Similarly, a weak, but significant and
independent, association between baseline resting heart rate
and urinary albumin:creatinine ratio (ACR) was recently
reported in the Randomised Olmesartan and Diabetes Micro-
albuminuria Prevention study.
14
However, not all existing data
support an association between prevalent heart rate and
albuminuria,
15
and the cross-sectional results that are
currently available cannot address the relation between heart
rate and incident or progressive microa lbuminuria.
A higher resting heart rate has been reported in patients
with diabetic retinopathy
16
and could be due to the relation
between retinopathy and autonomic dysfunction. Once again,
however, the importance of heart rate in the developme nt or
progression of diabetic eye disease remains unclear. Using
data from the Action in Diabetes and Vascular Disease:
Preterax and Diamicron Modified Release Controlled Evalua-
tion (ADVANCE) study (ClinicalTrials.gov No. NCT00145925),
we tested the hypothesis that a higher resting heart rate
would be associated with both an increased incidence and a
greater progression of microvascular complications in
patients with type 2 diabetes mellitus.
Methods
The ADVANCE study recruited 11 140 patients with type 2
diabetes mellitus from 215 centers in 20 countries between
June 2001 and March 2003.
17,18
The study made 2 random-
ized comparisons: (1) a double-blind assessment of the
efficacy of a fixed-combination perindopril–indapamide (2
mg/0.625 mg for 3 months, increasing, if tolerated, to 4 mg/
1.25 mg) versus placebo and (2) an open-label evaluation of an
intensive glucose-lowering regimen with modified-release
gliclazide, with a target hemoglobin A1c of ≤6.5%, versus
standard guideline-based glycemic control. The study was
approved by the local ethics committee for each participating
center, and all participants provided written informed consent.
Participants were ≥55 years of age and had been diagnosed
with type 2 diabetes mellitus after the age of 30 years. In
addition, they were required to have a history of cardiovas-
cular disease or ≥1 additional cardiovascular risk factor.
19
Detailed study methods
19
and the main results
17,18
of the
ADVANCE study have been reported previously.
Heart rate was measured at the same time as blood
pressure with a digital monitor (Omron HEM-705CP, Omron
Healthcare Inc, Lake Forest, IL). Recordings were made after
the patient had been resting in a seated position for a
minimum of 5 minutes. Three readings were taken, and the
mean of the latter 2 was used. Weight, height, urinary ACR,
serum creatinine, fasting lipid levels, and glyco sylated hemo-
globin also were measured at baseline.
The present study assesses the relation between resting
heart rate and the development of a major microvascular event
(a coprimary endpoint of the ADVANCE study) over the length of
the trial (median follow-up of 4.4 years). Major microvascular
events were defined, a priori, as a composite of new or
worsening nep hropathy or retinopathy. The former was defined
as ≥1 of the following: the development of macroalbuminuria,
defined as a urinary ACR of >300 lg albumin per milligram of
creatinine (confirmed by 2 positive results); doubling of the
serum creatinine level to ≥200 lmol/L (unless in the context of
acute illness, with subsequent recovery of renal function, or in
the context of the terminal phase of illness); the need for renal
replacement therapy due to diabetic kidney disease, in the
absence of another acute medic al cause that could require
transient dialysis; or death due to renal disease. Participants
had their crea tinine levels me asured as part of the study
protocol at baseline, 4 months, and 1 year and annually
thereafter until completion of the study. Renal function was
checked out with these time points at the discretion of their
treating clinicians. Urinary ACR was measured locally as part of
the study protocol at baseline, 2 years, 4 years, and completion
of the study. New or worsening retinopathy was defined as ≥1of
the following: the development of proliferative retinopathy
(identified by the incidence of new blood vessels on the disc or
elsewhere, vitreous hemorrhage, preretinal hemorrhage,
fibrous proliferations on the disc or elsewhere in a participant
known not to have this condition at entry); macular edema
(characterized by a retinal thickening within 1 disc diameter of
the macular center, in a participant known not to have this
condition at entry); diabetes-related blindness (corrected visual
acuity 3/60 or worse, persisting for ≥3 months and known to
not be due to nondiabetic causes, in a participant known not to
have this condition at entry); or the use of retinal photocoag-
ulation therapy. Particip ants underwent formal eye examination
and visual acuity testing at baseline, 2 years, 4 years, and
completion of the study.
Secondary endpoints were the individual components of
the primary outcome (new or worsening nephropathy and new
or worsening retinopathy). An Endpoint Adjudication Commit-
tee, unaware of treatment allocation, reviewed source docu-
mentation for all individuals who had a suspected primary
endpoint of the ADVANCE study. This included all the
microvascular endpoints considered in the present analyses.
Statistical Analyses
Baseline resting heart rate was considered both as a continuous
variable and after grouping into approximately equal fifths
according to its quintiles. Trends in baseline characteristics
across the fifths of heart rate were compared with linear and
logistic regression. Cox regression analyses were used to
calculate hazard ratios with 95% confidence intervals. These
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 2
Heart Rate and Microvascular Complications Hillis et al
ORIGINAL RESEARCH

were performed in models adjusted for age, sex, ADVANCE
study blood pressure treatment arm, and ADVANCE study
glycemic control arm and in models adjusted for multiple
baseline covariates (age, sex, ADVANCE study randomized
treatment, body mass index, duration of diabetes, glycosylated
hemoglobin, estimated glomerular filtration rate, urinary ACR,
systolic blood pressure, diastolic blood pressure, history of a
prior macrovascular complication of diabetes [myocardial
infarction, stroke, hospital admission for a transient ischemic
attack, hospital admission for unstable angina, coronary revas-
cularization, peripheral revascularization or amputation second-
ary to peripheral vascular disease], history of hospitalization for
heart failure, participation in moderate or vigorous exercise for
>15 minutes at least once weekly, current cigarette smoking,
total cholesterol, triglycerides, atrial fibrillation, treatment with
calcium channel blockers, and treatment with b-blockers).
Interactions were tested by adding appropriate terms to Cox
models. Linearity was assessed by comparing the categorical
model with the linear trend model.
20
It is possible that death
during follow-up might affect the association between heart rate
and the outcomes of interest. Therefore, we estimated subdis-
tribution hazard ratios after correcting for the competing risk of
death according to the methods of Fine and Gray.
21
Odds ratios
and 95% confidence intervals for albuminuria at baseline and
microvascular diabetic eye disease at baseline among the fifths
of heart rate were estimated by logistic regression. Analyses
were performed in SAS v9.2 (SAS Institute, Cary, NC), SPSS v18
(SPSS Inc., Chicago, IL), and Stata 11 (Statacorp LP, College
Station, TX), and all reported P values are 2 sided, with the 5%
threshold used to determine significance.
Results
Of the 11 140 patients randomized into the ADVANCE study,
2 individuals did not have their baseline resting heart rate
recorded. The remaining 11 138 patients are included in the
present analyses. Participants had a mean age of 66 years,
and 58% were male. The mean heart rate in the study
population, ± standard deviation, was 74±12 beats per
minute, with a range of 33 to 140 beats per minute. The
characteristics of the study population according to baseline
resting heart rate are shown in Table 1.
Heart Rate and Microvascular Disease at Baseline
At baseline, 793 patients (7.1%) had microvascular diabetic eye
disease (proliferative retinopathy, retinal photocoagulation
therapy, macular edema, or blindness in at least one eye
thought to be due to diabetes). These individuals had a mean
resting heart rate of 76±12 beats per minute, compared to
74±12 beats per minute in patients without microvascular eye
disease at baseline (P<0.001). At the time of randomization,
7376 participants (66.2%) had normal urinary albumin levels
(urinary ACR <3.4 mg/mmol [<30 lg/mg]), 2861 (25.7%) had
microalbuminura (urinary ACR 3.4–33.9 mg/mmol [30–300
lg/mg]), and 401 (3.6%) had macroalbuminuria (urinary ACR
>33.9 mg/mmol [>300 lg/m g]). Five hundred patients (4.5%)
had missing ACR data. Figure 1 shows the prevalence of
albuminuria according to baseline resting heart rate (P for trend
<0.001). The age- and sex-adjusted and multivariable-adjusted
odds ratios for (a) albuminuria and (b) microvascular diabetic
eye disease at baseline according to fifth of resting heart rate
(with the lowest fifth as the reference) are shown in Tables 2
and 3. These data confirm a cross-sectional association
between baseline heart rate and both complications.
Heart Rate and Microvascular Complications
During a median follow-up of 4.4 years, 916 patients (8.2%)
experienced a major microvascular event. Three hundred and
ninety-seven patients (3.6%) developed new or worsening
nephropathy, and 575 (5.2%) developed new or worsening
retinopathy. Fifteen patients were lost to follow-up (vital status
unknown) at the end of follow-up and were censored at the last
follow-up assessment. In addition, 879 patients (7.9%) died
during follow-up. Patients who died before the occurrence of
each outcome were censored at the time of death (786 patients
for major microvascular events, 840 for retinopathy, and 817
for nephropathy were censored at the date of death).
A higher baseline resting heart rate was associated with a
greater risk of developing a major microvascular complication
during follow-up (Table 4). After adjustment for age, sex, and
randomized treatment, a 10-beats-per-minute increase in base-
line resting heart rate was associated with an 18% increase in the
observed hazard. This remained after adjustment for potential
confounders. The excess hazard was apparent for both compo-
nents of the primary outcome (nephropathy and retinopathy) but
was greater for the development of new or worsening diabetic
eye disease (Table 4), where a clear linear relation is apparent. In
contrast, the relation between heart rate and nephropathy is
nonlinear, with the excess hazard, relative to the lowest fifth,
only seen clearly in patients with a heart rate in the upper fifth
(Table 4). The risk estimates were essentially unchanged even
after correction for the competing risk of death (data not shown).
The increased risk of microvascular complications associ-
ated with a higher heart rate was observed in both sexes, in
patients who had suffered a prior major macrovascular compli-
cation (myocardial infarction, stroke, hospital admission for a
transient ischemic attack, hospital admission for angina,
coronary revascularization, peripheral revascularization, or
amputation secondary to peripheral vascular disease) and in
those who had not (Figure 2). Similarly, an excess hazard was
seen in patients both with and without preexisting microvascular
disease (Figure 2). It also was observed in patients who were not
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 3
Heart Rate and Microvascular Complications Hillis et al
ORIGINAL RESEARCH

Table 1. Baseline Characteristics by Baseline Fifths of Heart Rate
Total
(n=11 138)
Lowest Fifth
(n=2066)
2nd Fifth
(n=2393)
3rd Fifth
(n=2178)
4th Fifth
(n=2195)
Highest Fifth
(n=2306) P for Trend
Heart rate, bpm,
mean (range)
74 (33–140) 57 (33–63) 67 (64–70) 74 (71–76) 80 (77–83) 91 (84–140) …
Age, y, mean±SD 65.8±6.4 67.1±6.3 65.9±6.4 65.5±6.5 65.5±6.4 65.1±6.2 <0.001
Female, n (%) 4733 (42) 664 (32) 989 (41) 973 (45) 1050 (48) 1057 (46) <0.001
Active treatment arm for
blood pressure, n (%)
5568 (50) 1024 (50) 1195 (50) 1072 (49) 1127 (51) 1150 (50) 0.56
Active treatment arm for
glycemic control, n (%)
5570 (50) 1007 (49) 1216 (51) 1050 (48) 1098 (50) 1199 (52) 0.09
Systolic blood pressure, mm
Hg, mean±SD
145±22 147±22 144±21 143±21 145±21 146±21 0.18
Diastolic blood pressure, mm
Hg, mean±SD
81±11 79±11 80±11 81±11 81±11 82±11 <0.001
Body mass index,
kg/m
2
, mean±SD
28.3±5.2 28.8±5.0 28.5±5.0 28.2±5.3 28.2±5.2 28.2±5.3 <0.001
Current cigarette
smoker, n (%)
1550 (14) 234 (11) 314 (13) 333 (15) 324 (15) 345 (15) <0.001
Regular exercise, n (%) 5112 (46) 1029 (50) 1149 (48) 994 (46) 970 (44) 970 (42) <0.001
History of myocardial
infarction, n (%)
1334 (12) 392 (19) 316 (13) 251 (12) 205 (9) 170 (7) <0.001
History of stroke, n (%) 1022 (9) 168 (8) 197 (8) 198 (9) 217 (10) 242 (10) <0.001
History of hospitalization for
heart failure, n (%)
356 (3) 66 (3) 71 (3) 66 (3) 71 (3) 82 (4) 0.38
Previous or current
atrial fibrillation, n (%)
846 (8) 199 (10) 154 (6) 128 (6) 173 (8) 192 (8) 0.68
Prior macrovascular
disease, n (%)
3589 (32) 843 (41) 806 (34) 677 (31) 630 (29) 633 (27) <0.001
Prior microvascular
disease, n (%)
1152 (10) 179 (9) 249 (10) 206 (9) 242 (11) 276 (12) <0.001
Serum total cholesterol,
mmol/L, mean±SD
5.20±1.19 4.94±1.08 5.14±1.17 5.21±1.20 5.30±1.18 5.37±1.27 <0.001
Serum triglycerides,
mmol/L, mean±SD
1.96±1.29 1.84±1.14 1.88±1.15 1.91±1.21 2.04±1.35 2.11±1.52 <0.001
Duration of diabetes,
y, mean±SD
7.9±6.4 7.7±6.6 7.6±6.3 8.0
±6.5 8.2±6.2 8.2±6.2 <0.001
Continued
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 4
Heart Rate and Microvascular Complications Hillis et al
ORIGINAL RESEARCH

on a b-blocker but not in those who were on a b-blocker
(Figure 2), although there was no statistical evidence of an
interaction. A higher heart rate was associated with a greater
risk of a microvascular complication both in patients who were in
sinus rhythm and those with atrial fibrillation (on an electrocar-
diogram performed either at baseline or previously
22
).
Discussion
The present study demonstrates that a higher resting heart rate
predicts a greater risk of future microvascular complications in
patients with type 2 diabetes mellitus. As far as we are aware, this
has not been shown previously. The excess hazard associated
with a higher heart rate is independent of many other factors that
can influence heart rate and affect outcome in this setting. The
association is particularly apparent for the occurrence or
worsening of diabetic eye disease but is also evident for the
occurrence or worsening of diabetic nephropathy.
Heart Rate and Microvascular Events
The relation between higher heart rates and major adverse
cardiac events, such as myocardial infarction, cardiac death,
and hospitalization with heart failure, is now well recognized.
23
Indeed, we recently reported in ADVANCE that a higher heart
rate was a strong and independent predictor of all-cause death
and major cardiovascular complications, including cardiovas-
cular death, myocardial infarction, and stroke.
11
In contrast,
there are limited prior data, almost entirely cross sectional,
assessing the relation between heart rate and microvascular
disease. In patients with hypertension, Bohm and colleagues
12
reported that a higher heart rate is associated with increased
Table 1. Continued
Total
(n=11 138)
Lowest Fifth
(n=2066)
2nd Fifth
(n=2393)
3rd Fifth
(n=2178)
4th Fifth
(n=2195)
Highest Fifth
(n=2306) P for Trend
Hemoglobin A1c, %,
mean±SD
7.5±1.6 7.2±1.3 7.3±1.4 7.5±1.6 7.7±1.6 7.8±1.8 <0.001
Serum creatinine,
lmol/L, mean±SD
87±25 91±23 87±24 85±24 84±27 86±28 <0.001
Estimated GFR, mL/min
per 1.73m
2
, mean±SD
78±25 75±20 78±22 79±27 80±28 79±26 <0.001
Urinary ACR, mg/mmol,
mean (IQR)
1.7 (0.8–4.5) 1.4 (0.7–3.6) 1.6 (0.7–4.1) 1.6 (0.8–3.9) 1.9 (0.9–5.2) 2.0 (0.9–5.5) <0.001
b-Blocker, n (%) 2729 (25) 938 (45) 682 (28) 439 (20) 365 (17) 305 (13) <0.001
Calcium channel
antagonist, n (%)
3426 (31) 666 (32) 706 (30) 638 (29) 647 (29) 769 (33) 0.38
Categorical data are presented as numbers and percentages and compared with logistic regression models. Normally distributed continuous data are presented as mean ± standard deviation (SD) and are compared with a general linear
model. Skewed data are presented as median and interquartile range (IQR) and are compared with a linear model after log-transformation. ACR indicates albumin:creatinine ratio; GFR, glomerular filtration rate (estimated by the Modification
of Diet in Renal Disease formula). Regular exercise was defined as moderate or vigorous exercise for >15 minutes at least once per week.
Figure 1. Prevalence of albuminuria according to fifths of heart
rate at baseline.
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 5
Heart Rate and Microvascular Complications Hillis et al
ORIGINAL RESEARCH

prevalence and severity of microalbuminuria. This relation was
observed regardless of treatment with b-blockers
12
and
irrespective of whether the patient had a history of atrial
fibrillation.
13
However, in a recently reported analysis of The
PROspective pioglitAzone Clinical Trial In macroVascular
Events, a multicenter double-blind assessment of the effects
of pioglitazone versus placebo on major cardiovascular events
in patients with type 2 diabetes and a history of macrovascular
disease, no association was observed between resting heart
rate and microalbuminuria.
15
Despite this, heart rate and
microalbuminuria were each independently predictive of the
composite endpoint of all-cause death, myocardial infarction,
and stroke in this study.
15
Neither of the aforementioned studies
13,15
assessed the
relation between heart rate and incident albuminuria. Two
recent prospective studies have, however, identified a higher
heart rate as a pred ictor of renal dysfunction in the general
population.
24,25
In the Atherosclerosis Risk in Communities
(ARIC) Study, the haz ard of developing end-stage renal disease
was almost doubled among patients with a resting heart rate in
the upper quarter, when compared to the remaining subjects,
during a median of 16 years’ follow-up.
24
Similarly, in a cohort of
subjects participating in a Japanese health screening program,
a higher heart rate was associated with a greater risk of
declining estimated glomerular filtration rate and of developing
dipstick proteinuria (≥1) during 5 years of follow-up.
25
An association between a higher resting heart rate and
prevalent retinopathy in patients with diabetes has been
reported previously,
16
although not consistently.
26,27
In the
Wisconsin Epidemiological Study of Diabetic Retinopathy,
although patients with a higher resting heart rate had a
greater risk of incident macular edema and progressive
diabetic retinopathy over a 4-year period, this was attenuated
and was nonsignificant after correction for other factors,
including age, duration of diabetes, glycosylated hemoglobin,
and blood pressure.
28
In contrast, in our much larger cohort,
followed up for 4.4 years, we have observed strong and
independent associations between resting heart rate and
incident and progressive diabetic eye disease, even after
correction for a wide range of potential confounding factors
(including all of those mentioned above). Apart from differ-
ences in power, the discrepant results could reflect variances
in the study populations and protocols. The Wisconsin
Epidemiological Study of Diabetic Retinopathy recruited a
community-based cohort with a high prevalence of younger,
insulin-requiring patients, and the incidence and progression
of retinopathy was determined with fundus photography.
Potential Mechanisms
Although a higher re sting heart rate predicts a greater
prevalence of albuminuria and diabetic eye disease at
Table 2. Albuminuria at Baseline According to Fifth of Resting Heart Rate
Adjusted for Age and Sex Fully Adjusted*
Odds Ratio 95% Confidence Interval P Odds Ratio 95% Confidence Interval P
Lowest fifth 1 Reference … 1 Reference …
2nd fifth 1.10 0.96–1.26 0.17 1.13 0.98–1.30 0.10
3rd fifth 1.09 0.95–1.25 0.24 1.08 0.93–1.25 0.33
4th fifth 1.34 1.17–1.54 <0.001 1.27 1.10–1.47 0.001
Highest fifth 1.50 1.31–1.71 <0.001 1.35 1.17–1.56 <0.001
*Adjusted for age, sex, body mass index, duration of diabetes, glycosylated hemoglobin, estimated glomerular filtration rate, systolic blood pressure, diastolic blood pressure, history of
hospitalization for heart failure, prior macrovascular disease (see text), current cigarette smoking, participation in moderate or vigorous exercise for >15 minutes at least once weekly, total
cholesterol, triglyceride level, atrial fibrillation, use of calcium channel blockers, and use of b-blockers.
Table 3. Microvascular Diabetic Eye Disease at Baseline According to Fift h of Resting Heart Rate
Adjusted for Age and Sex Fully Adjusted*
Odds Ratio 95% Confidence Interval P Odds Ratio 95% Confidence Interval P
Lowest fifth 1 Reference … 1 Reference …
2nd fifth 1.27 0.99–1.62 0.06 1.29 0.99–1.67 0.06
3rd fifth 1.22 0.95–1.57 0.13 1.19 0.91–1.57 0.21
4th fifth 1.38 1.08–1.77 0.01 1.38 1.06–1.81 0.02
Highest fifth 1.62 1.28–2.06 <0.001 1.59 1.22–2.07 <0.001
*Adjusted for variables listed in footnote to Table 2, plus urinary albumin:creatinine ratio.
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 6
Heart Rate and Microvascular Complications Hillis et al
ORIGINAL RESEARCH

baseline and higher risk of subsequent microvascular events,
the results could reflect an association between heart rate
and other factors that might mediate microvascular disease.
There are, however, several plausible mechanisms by which
an elevated heart rate might predispose to such complica-
tions.
It has been suggested that a higher heart rate might
promote microalbuminuria because of increased exp osure of
the glomerulus to arterial pressure waves.
12
A similar mech-
anism also might explain the relation between more rapid
heart rates and ocular disease. An increased heart rate also
has a variety of direct detrimental cardiovasc ular conse-
quences. These include unfavorable effects on endothelial
function and proatherosclerotic activity,
29
which are important
factors in the progression of nephropathy and retinopathy.
30–32
A higher heart rate also is associated with factors such as
Table 4. Effects of Heart Rate on Major Microvascular Outcomes
No. Events/No. at Risk
Adjusted for Age, Sex, and Randomized
Treatment Fully Adjusted*
HR (95% CI) P HR (95% CI) P
Major microvascular events
Heart rate per 10 bpm 916/11 138 1.18 (1.12–1.24) <0.001 1.13 (1.07–1.20) <0.001
Heart rate fifths
Lowest fifth (33–63 bpm) 132/2066 1.00 (reference) 1.00 (reference)
2nd fifth (64 –70 bpm) 184/2393 1.23 (0.99–1.54) 0.07 1.27 (1.00–1.61) 0.047
3rd fifth (71–76 bpm) 161/2178 1.19 (0.94–1.49) 0.15 1.15 (0.90–1.47) 0.27
4th fifth (77 –83 bpm) 194/2195 1.45 (1.16–1.81) 0.001 1.39 (1.09–1.76) 0.008
Highest fifth (84–140 bpm) 245/2306 1.78 (1.44–2.20) <0.001 1.63 (1.29–2.06) <0.001
P
for trend <0.001 <0.001
P
for nonlinearity 0.37 0.27
New or worsening retinopathy
Heart rate per 10 bpm 575/11 138 1.22 (1.14–1.30) <0.001 1.16 (1.08–1.25) <0.001
Heart rate fifths
Lowest fifth (33–63 bpm) 71/2066 1.00 (reference) 1.00 (reference)
2nd fifth (64 –70 bpm) 96/2393 1.15 (0.84–1.56) 0.38 1.13 (0.82–1.57) 0.46
3rd fifth (71–76 bpm) 115/2178 1.51 (1.12–2.03) 0.007 1.44 (1.05–1.98) 0.02
4th fifth (77 –83 bpm) 139/2195 1.82 (1.36–2.43) <0.001 1.67 (1.23–2.28) 0.001
Highest fifth (84–140 bpm) 154/2306 1.94 (1.46–2.57) <0.001 1.72 (1.26–2.34) <0.001
P
for trend <0.001 <0.001
P
for nonlinearity 0.70 0.69
New or worsening nephropathy
Heart rate per 10 bpm 397/11 138 1.13 (1.04–1.22) 0.003 1.11 (1.02–1.21) 0.01
Heart rate fifths
Lowest fifth (33–63 bpm) 69/2066 1.00 (reference) 1.00 (reference)
2nd fifth (64 –70 bpm) 93/2393 1.24 (0.91–1.70) 0.18 1.45 (1.04–2.02) 0.03
3rd fifth (71–76 bpm) 58/2178 0.86 (0.60–1.21) 0.38 0.90 (0.61–1.31) 0.57
4th fifth (77 –83 bpm) 69/2195 1.05 (0.75–1.47) 0.78 1.10 (0.76–1.58) 0.61
Highest fifth (84–140 bpm) 108/2306 1.60 (1.18–2.17) 0.003 1.61 (1.15–2.26) 0.006
P
for trend 0.02 0.05
P
for nonlinearity 0.005 0.003
HR indicates hazard ratio; CI, confidence interval.
*Adjusted for age, sex, randomized treatment for blood pressure, randomized treatment for glucose, body mass index, duration of diabetes, glycosylated hemoglobin, prior macrovascular
complication of diabetes (see text), estimated glomerular filtration rate, urinary albumin:creatinine ratio, systolic blood pressure, diastolic blood pressure, history of hospitalization for heart
failure, regular exercise (see text), current cigarette smoking, total cholesterol, triglycerides, atrial fibrillation, use of calcium channel antagonists, and use of b-blockers.
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 7
Heart Rate and Microvascular Complications Hillis et al
ORIGINAL RESEARCH

Hazard
(a)
(b)
raƟo
for
10bpm increase
in
heart
rate
Sex
HR (95%
CI) P
P
for
interacƟon
Men 1 1
6(108
to
124)
<0 001
083
Prior
macrovascular
disease
Men 1.1
6(1.
08
to
1
.
24)
<0
.
001 0.
83
1
1.1nem
o
W (1.01 to 1.22) 0.03
31.1
oN
(1.06
to 1.21) <0.001 0.85
Yes
114
(1 03
to
125)
001
Treatment
with beta
blocker
Prior
microvascular
disease
Yes
1.14
(1.03 to
1
.25) 0
.
01
40.1(
11
.1oN
to 1.18) 0.002 0.36
80.1
(1
2
.1
se
Y
to 1.36) 0.001
Treatment with beta blocker
Atrial
fibrillaƟon
80
.
1
(
5
1.1
o
N
to 1.23) <0.001 0.23
4
9
.0(60.
1
s
e
Y to 1.20) 0.35
No 1.13 (1.06 to 1.19) <0.001 0.68
Randomised
treatment for blood pressure
No 1.13 (1.06 to 1.19) <0.001 0.68
42
.1
se
Y
(1.00
to 1.53) 0.048
40.1(21
.1
o
b
e
c
a
l
P to 1.22) 0.004 0.85
Perindopril/Indap
4
1.1edima (1.05 to 1.24) 0.001
Randomised treatment
for
glucose
p/ p ( )
60.1(51.1dradnatS to 1.24) <0.001 0.94
7
0
0.0
)2
2
.
1
ot30.
1
(2
1
.
1e
v
i
s
n
e
t
nI
Hazard raƟo
0.5 1.0 2.0
70.1(31.1llarevO to 1.20) <0.001
Hazard raƟo for highest vs.
lowest
fiŌh
of heart rate
Sex
HR (95% CI) P
P for
interacƟon
Men 1
80 (1
35
to
240)
<0 001
073
Prior
macrovascular
disease
Men 1
.
80 (1.
35 to
2
.
40)
<0
.
001
0.73
5
9.0
(
4
4
.1n
e
m
o
W
to 2.16) 0.08
7
1
.1(65.1oN
to 2.09) 0.003 0.28
Yes
169(
113to
254
)
001
Treatment with beta blocker
Prior
microvascular
disease
Yes
1
.
69 (
1
.13
to
2.54
)
0.01
91.1(
6
5
.
1oN
to 2.03) 0.001 0.86
92.1(0
1
.2s
e
Y to 3.43) 0.003
Treatment
with
beta blocker
Atrial
fibrillaƟon
53.1
(
97
.
1oN to 2.38) <0.001 0.11
56
.
0(11.1seY
to 1.90) 0.71
No 1.
60
(1.25 to 2.03) <0.001 0.60
Randomised treatment
for
blood
pressure
No 1.
60
(1.25 to 2.03) 0.001 0.60
98.0(81
.
2se
Y
to 5.34) 0.09
65.
1
ob
e
c
a
l
P
(1.14 to
2.15) 0.006 0.99
Perindo
pril/Indap 4
7.
1ed
im
a
(
1.23 to 2.45) 0.002
Randomised treatment for glucose
p/ p (
)
02.1
(
6
6
.
1
d
r
a
dna
t
S
to 2.30) 0.002 0.53
51
.1(1
6
.1ev
i
sn
e
tnI to 2.25) 0.006
Hazard raƟo
92.
1
(36.1l
l
arevO
to 2.06) <0.001
2.0
0
.4
0
.
15.0
Figure 2. Effects of baseline heart rate on major microvascular events in subgroups. Adjusted for age, sex, randomized treatment for blood
pressure, randomized treatment for glucose, body mass index, duration of diabetes, glycosylated hemoglobin, prior macrovascular complication of
diabetes (see text), estimated glomerular filtration rate, urinary albumin:creatinine ratio, systolic blood pressure, diastolic blood pressure, history
of hospitalization for heart failure, regular exercise (see text), current cigarette smoking, total cholesterol, triglycerides, atrial fibrillation, use of
calcium channel antagonists, and use of b-blockers. Where relevant, the variable used for subgrouping was excluded from the model. Centers of
boxes are placed at the estimates of adjusted hazard ratio (HR) for each subgroup. Areas of the boxes are proportional to the reciprocal of the
variance of the estimates. Horizontal lines represent 95% confidence intervals (CI). Vertical broken lines indicate the estimate of overall adjusted
hazard ratio. The widths of diamonds represent 95% CI. bpm indicates beats per minute.
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 8
Heart Rate and Microvascular Complications Hillis et al
ORIGINAL RESEARCH

obesity, higher blood pressure, a proatherosclerotic lipid
profile, and reduced physical activity,
10,33
all of which are
associated with an increased risk of microvascul ar complica-
tions and are targets for intervention to improve outcome in
patients with diabetes mellitus.
34
Finally, a faster resting heart
rate is a characteristic feature of autonomic neuropathy, which
is in turn associated with an increased prevalence of othe r
complications, such as nephropathy and retinopathy.
35
It is
possible, therefore, that the observed relation between heart
rate and microvascular events is mediated at least in part by
sympathetic overactivity, although correlations between heart
rate and measures of sympathetic tone are relatively weak.
36
When baroreflex control of heart rate is assessed by sensitive
methods, abnormalities are apparent at an early stage in
patients with diabetes. These changes predate obvious diabetic
complications and evidence of autonomic dysfunction that can
be detected by conventional methods.
37,38
Intriguingly, a higher
heart rate per se also has been shown to predict an increased
risk of developing incident diabetes.
39
This could reflect
physical deconditioning and other factors that predispose to
developing diabetes but reinforces the complex interrelations
among heart rate, neural mechanisms, and metabolic control.
It could be that the observed hazard associated with a
higher heart rate is due to a combination of mechanisms and
that the importance of each varies among individuals.
Likewise, the mechanisms could have synergistic effects.
For example, a higher heart rate might result in direct
microvascular damage, but this could be accentuated by the
presence of hypertension. In particular, elevated nocturnal
blood pressure in diabetes is associated with incident
microalbuminuria
40
and progressive nephropathy.
41
The risk
attributable to this “nondipping” pattern might not be
conveyed in the measured daytime blood pressure and might
be magnified by a higher resting heart rate, which increases
exposure of the microvasculature to the elevated pressures.
In summary, the mechanisms by which a higher resting
heart rate predicts an increased risk of microvascular
complications in type 2 diabetes mellitus are unclear, and it
could be that several interrelated processes are involved. One
potential method of assessing whether there might be a direct
relation would be to assess th e effects of a pure rate-limi ting
drug, such as ivabradine, on microvascular outcomes.
Differences in the Observed Relation Between
Heart Rate and Eye Disease and Nephrop athy
In this analysis, the relation between resting heart rate and
the risk of developing diabetic eye disease seems stronger
than the association with incident nephropathy. In addition, in
contrast to retinopathy, the data suggest that the relation
between heart rate and renal disease is nonlinear, with the
excess hazard clearly seen only in patients with a resting
heart rate in the upper fifth. Similarly, in the baseline, cross-
sectional data, the increased prevalence of microalbuminuria
is most obvious in patients with heart rates in the upper two
fifths. This raises the possibility that the relation between
heart rate and microvascular disease could vary in differing
vascular beds. This is not unexpected, given that the effects of
blood pressure–lowering treatment and more intensive
glycemic control in the ADVANCE study were more apparent
in the kidney than in the eye. Similar differential effects of
treatment on differing microvascular complications have been
observed in other large studies.
42,43
Whether this reflects
differing pathophysiological mechanisms, is a chance fi nding,
or is du e to the definitions used and the relatively short
duration of follow-up is not clear.
Strengths and Limitations
The present study explores the relation between heart rate
and future microvascular complications in patients with type 2
diabetes mellitus in a large population recruited from 20
countries and with diverse ethnic backgrounds, which was
well characterized and followed up closely. The primary
endpoint of this epidemiological evaluation was a coprimary
endpoint of the main ADVANCE study, and all components of
it were independently adjudicated according to predefined
criteria. Nevertheless, it has the limitations inherent in any
such post hoc analysis. Although the large study population
ensures considerable statistical power and allows reliable
correction for many potential confounding factors, it is not
possible to fully correct for all possible conf ounders. In
particular, autonomic function was not assessed at baseline.
Conclusion
Patients with type 2 diabetes mellitus who have a higher
resting heart rate have a greater prevalence of microalbu-
minuria and diabetic eye disease. They also experience a
greater inc idence of new-onset or progressive nephropathy
and retinopathy, which suggests that an increased heart rate
might be a potential mediator of these outcomes. Further
work is required to assess this and to determine whether
lifestyle measures or pharmacological therapies that can slow
heart rate might reduce the risk of microvascul ar complica-
tions. In particular, the benefits of heart rate reduction in the
prevention of progressive diabetic retinopathy deserve further
attention.
Sources of Funding
The ADVANCE study was funded by Servier and the National
Health and Medical Research Council of Australia (grant Nos.
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 9
Heart Rate and Microvascular Complications Hillis et al
ORIGINAL RESEARCH

211086 and 358395). Neither funding body had any input into
the analy sis or interpretation of the present data.
Disclosures
Drs Woodward, Zoungas, Patel, Poulter, Mancia, Williams, and
Chalmers have received lecture fees and/or travel expenses
from Servier. Drs Woodward, Zoungas, Patel, Poulter, and
Chalmers have also received grant support from Servier.
References
1. The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes mellitus.
The Diabetes Control and Complications Trial research group. N Engl J Med.
1993;329:977–986.
2. Rajala U, Pajunpaa H, Koskela P, Keinanen-Kiukaanniemi S. High cardiovas-
cular disease mortality in subjects with visual impairment caused by diabetic
retinopathy. Diabetes Care. 2000;23:957–961.
3. Klein R, Klein BE, Moss SE, Cruickshanks KJ. Association of ocular disease and
mortality in a diabetic population. Arch Ophthalmol. 1999;117:1487–1495.
4. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP,
Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S. Albuminuria and risk of
cardiovascular events, death, and heart failure in diabetic and nondiabetic
individuals. JAMA. 2001;286:421–426.
5. McClintic BR, McClintic JI, Bisognano JD, Block RC. The relationship between
retinal microvascular abnormalities and coronary heart disease: a review. Am
J Med. 2010;123:374.e1–374.e7.
6. Arnlov J, Evans JC, Meigs JB, Wang TJ, Fox CS, Levy D, Benjamin EJ, D’Agostino
RB, Vasan RS. Low-grade albuminuria and incidence of cardiovascular disease
events in nonhypertensive and nondiabetic individuals: the Framingham Heart
Study. Circulation. 2005;112:969–975.
7. Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen G, Clausen P,
Scharling H, Appleyard M, Jensen JS. Very low levels of microalbuminuria are
associated with increased risk of coronary heart disease and death
independently of renal function, hypertension, and diabetes. Circulation.
2004;110:32–35.
8. Romundstad S, Holmen J, Hallan H, Kvenild K, Ellekjaer H. Microalbuminuria
and all-cause mortality in treated hypertensive individuals: does sex matter?
The Nord-Trondelag Health Study (HUNT), Norway. Circulation. 2003;
108:2783–2789.
9. Fox K, Borer JS, Camm AJ, Danchin N, Ferrari R, Lopez Sendon JL, Steg PG,
Tardif JC, Tavazzi L, Tendera M. Resting heart rate in cardiovascular disease.
J Am Coll Cardiol. 2007;50:823–830.
10. Palatini P. Elevated heart rate in cardiovascular diseases: a target for
treatment? Prog Cardiovasc Dis. 2009;52:46–60.
11. Hillis GS, Woodward M, Rodgers A, Chow CK, Li Q, Zoungas S, Patel A,
Webster R, Batty GD, Ninomiya T, Mancia G, Poulter NR, Chalmers J. Resting
heart rate and the risk of death and cardiovascular complications in patients
with type 2 diabetes mellitus. Diabetologia. 2012;55:1283–1290.
12. Bohm M, Reil JC, Danchin N, Thoenes M, Bramlage P, Volpe M. Association of
heart rate with microalbuminuria in cardiovascular risk patients: data from i-
SEARCH. J Hypertens. 2008;26:18–25.
13. Bohm M, Thoenes M, Neuberger HR, Graber S, Reil JC, Bramlage P, Volpe M.
Atrial fibrillation and heart rate independently correlate to microalbuminuria in
hypertensive patients. Eur Heart J. 2009;30:1364–1371.
14. Ritz E, Viberti GC, Ruilope LM, Rabelink AJ, Izzo JL Jr, Katayama S, Ito S,
Mimran A, Menne J, Rump LC, Januszewicz A, Haller H. Determinants of urinary
albumin excretion within the normal range in patients with type 2 diabetes: the
Randomised Olmesartan And Diabetes MicroAlbuminuria Prevention (ROAD-
MAP) study.
Diabetologia. 2010;53:49–57.
15. P fister R, Erdmann E, Schneider CA. Association and prognostic impact of
heart rate and micro-albuminuria in patients with type 2 diabetes and
cardiovascular disease: results from the PROactive trial. J Atheroscler Thromb.
2011;18:65–71.
16. Imano E, Miyatsuka T, Motomura M, Kanda T, Matsuhisa M, Kajimoto Y,
Yamasaki Y, Hori M. Heart rate elevation and diabetic retinopathy in patients
with type 2 diabetes mellitus and normoalbuminuria. Diabetes Res Clin Pract.
2001;52:185–191.
17. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S,
Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu
LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B. Effects of a fixed
combination of perindopril and indapamide on macrovascular and microvas-
cular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a
randomised controlled trial. Lancet. 2007;370:829–840.
18. Patel A, MacMahon S, Chalm ers J, Neal B, Billot L, Woodward M, Marre M, Cooper
M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G,
Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE,
Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in
patients with type 2 diabetes. N Engl J Med. 2008;358:2560–2572.
19. Study rationale and design of advance: Action in Diabetes and Vascular
Disease—Preterax and Diamicron MR Controlled Evaluation. Diabetologia.
2001;44:1118–1120.
20. Woodward M. Epidemiology: Study Design and Data Analysis. 2nd ed. Boca
Raton, FL: Chapman and Hall/CRC Press; 2005:554–557.
21. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a
competing risk. J Am Stat Assoc. 1999;94:496–509.
22. Du X, Ninomiya T, de Galan B, Abadir E, Chalmers J, Pillai A, Woodward M,
Cooper M, Harrap S, Hamet P, Poulter N, Lip GY, Patel A. Risks of
cardiovascular events and effects of routine blood pressure lowering among
patients with type 2 diabetes and atrial fibrillation: results of the ADVANCE
study. Eur Heart J. 2009;30:1128–1135.
23. Fox KM. Current status: heart rate as a treatable risk factor. Eur Heart J.
2011;13(suppl C):C30–C36
24. Brotman DJ, Bash LD, Qayyum R, Crews D, Whitsel EA, Astor BC, Coresh J.
Heart rate variability predicts ESRD and CKD-related hospitalization. J Am Soc
Nephrol. 2010;21:1560–1570.
25. Inoue T, Iseki K, Iseki C, Ohya Y, Kinjo K, Takishita S. Heart rate as a risk factor
for developing chronic kidney disease: longitudinal analysis of a screened
cohort. Clin Exp Nephrol. 2009;13:487–493.
26. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin
Epidemiologic Study of Diabetic Retinopathy, II. Prevalence and risk of
diabetic retinopathy when age at diagnosis is less than 30 years. Arch
Ophthalmol. 1984;102:520–526.
27. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin
Epidemiologic Study of Diabetic Retinopathy, III. Prevalence and risk of
diabetic retinopathy when age at diagnosis is 30 or more years. Arch
Ophthalmol.
1984;102:527–532.
28. Wong TY, Moss SE, Klein R, Klein BE. Is the pulse rate useful in assessing risk
of diabetic retinopathy and macular oedema? The Wisconsin Epidemiological
Study of Diabetic Retinopathy. Br J Ophthalmol. 2001;85:925–927.
29. Ceconi C, Guardigli G, Rizzo P, Francolini G, Ferrari R. The heart rate story. Eur
Heart J. 2011;13(suppl C):C4–C13.
30. Nakagaw a T, Tanabe K, Croker BP, Johnson RJ, Grant MB, Kosugi T, Li Q.
Endothelial dysfunction as a potential contributor in diabetic nephropathy. Nat
Rev Nephrol. 2011;7:36–44.
31. Stehouwer CD. Endothelial dysfunction in diabetic nephropathy: state of the
art and potential significance for non-diabetic renal disease. Nephrol Dial
Transplant. 2004;19:778–781.
32. Rosenson RS, Fioretto P, Dodson PM. Does microvascular disease predict
macrovascular events in type 2 diabetes? Atherosclerosis. 2011;218:13–
18.
33. Jurca R, Jackson AS, LaMonte MJ, Morrow JR Jr, Blair SN, Wareham NJ, Haskell
WL, van Mechelen W, Church TS, Jakicic JM, Laukkanen R. Assessing
cardiorespiratory fitness without performing exercise testing. Am J Prev Med.
2005;29:185–193.
34. Standards of medical care in diabetes—2008. Diabetes Care. 2008;31(suppl 1):
S12–S54.
35. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy.
Diabetes Care. 2003;26:1553–1579.
36. Grassi G, Vailati S, Bertinieri G, Seravalle G, Stella ML, Dell’Oro R, Mancia G.
Heart rate as marker of sympathetic activity. J Hypertens. 1998;16:1635–
1639.
37. Fratt ola A, Parati G, Gamba P, Paleari F, Mauri G, Di Rienzo M, Castiglioni P,
Mancia G. Time and frequency domain estimates of spontaneous baroreflex
sensitivity provide early detection of autonomic dysfunction in diabetes
mellitus. Diabetologia. 1997;40:1470–1475.
38. Weston PJ, James MA, Panerai R, McNally PG, Potter JF, Thurston H, Swales JD.
Abnormal baroreceptor-cardiac reflex sensitivity is not detected by conven-
tional tests of autonomic function in patients with insulin-dependent diabetes
mellitus. Clin Sci (Lond). 1996;91:59–64.
39. Carnethon MR, Golden SH, Folsom AR, Haskell W, Liao D. Prospective
investigation of autonomic nervous system function and the development of
type 2 diabetes: the Atherosclerosis Risk in Communities study, 1987–1998.
Circulation. 2003;107:2190–2195.
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 10
Heart Rate and Microvascular Complications Hillis et al
ORIGINAL RESEARCH

40. Lurbe E, Redon J, Kesani A, Pascual JM, Tacons J, Alvarez V, Batlle D. Increase
in nocturnal blood pressure and progression to microalbuminuria in type 1
diabetes. N Engl J Med. 2002;347:797–805.
41. Knudsen ST, Laugesen E, Hansen KW, Bek T, Mogensen CE, Poulsen PL.
Ambulatory pulse pressure, decreased nocturnal blood pressure reduction and
progression of nephropathy in type 2 diabetic patients. Diabetologia.
2009;52:698–704.
42. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve
FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M,
Vitek ME, Henderson WG, Huang GD. Glucose control and vascular
complications in veterans with type 2 diabetes. N Engl J Med.
2009;360:129–139.
43. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, Cuddihy R,
Cushman WC, Genuth S, Grimm RH Jr, Hamilton BP, Hoogwerf B, Karl D, Katz
L, Krikorian A, O’Connor P, Pop-Busui R, Schubart U, Simmons D, Taylor H,
Thomas A, Weiss D, Hramiak I. Effect of intensive treatment of hyperglycaemia
on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD
randomised trial. Lancet. 2010;376:419–430.
DOI: 10.1161/JAHA.112.002832 Journal of the American Heart Association 11
Heart Rate and Microvascular Complications Hillis et al
ORIGINAL RESEARCH