Gómez-Marcos et al. BMC Public Health 2010, 10:143
http://www.biomedcentral.com/1471-2458/10/143
STUDY PROTOCOL
Open Access
Central blood pressure and pulse wave velocity:
relationship to target organ damage and
cardiovascular morbidity-mortality in diabetic
patients or metabolic syndrome. An observational
prospective study. LOD-DIABETES study protocol
Manuel A Gómez-Marcos, José I Recio-Rodríguez, Emiliano Rodríguez-Sánchez, Yolanda Castaño-Sánchez,
Angela de Cabo-Laso, Benigna Sánchez-Salgado, Carmela Rodríguez-Martín, Carmen Castaño-Sánchez,
Leticia Gómez-Sánchez, Luis García-Ortiz*
Abstract
Background: Diabetic patients show an increased prevalence of non-dipping arterial pressure pattern, target organ
damage and elevated arterial stiffness. These alterations are associated with increased cardiovascular risk.
The objectives of this study are the following: to evaluate the prognostic value of central arterial pressure and
pulse wave velocity in relation to the incidence and outcome of target organ damage and the appearance of cardiovascular episodes (cardiovascular mortality, myocardial infarction, chest pain and stroke) in patients with type 2
diabetes mellitus or metabolic syndrome.
Methods/Design: Design: This is an observational prospective study with 5 years duration, of which the first year
corresponds to patient inclusion and initial evaluation, and the remaining four years to follow-up.
Setting: The study will be carried out in the urban primary care setting.
Study population: Consecutive sampling will be used to include patients diagnosed with type 2 diabetes
between 20-80 years of age. A total of 110 patients meeting all the inclusion criteria and none of the exclusion criteria will be included.
Measurements: Patient age and sex, family and personal history of cardiovascular disease, and cardiovascular risk
factors. Height, weight, heart rate and abdominal circumference. Laboratory tests: hemoglobin, lipid profile, creatinine, microalbuminuria, glomerular filtration rate, blood glucose, glycosylated hemoglobin, blood insulin, fibrinogen
and high sensitivity C-reactive protein. Clinical and 24-hour ambulatory (home) blood pressure monitoring and selfmeasured blood pressure. Common carotid artery ultrasound for the determination of mean carotid intima-media
thickness. Electrocardiogram for assessing left ventricular hypertrophy. Ankle-brachial index. Retinal vascular study
based on funduscopy with non-mydriatic retinography and evaluation of pulse wave morphology and pulse wave
velocity using the SphygmoCor system. The medication used for diabetes, arterial hypertension and hyperlipidemia
will be registered, together with antiplatelet drugs.
Discussion: The results of this study will help to know and quantify the prognostic value of central arterial
pressure and pulse wave velocity in relation to the evolution of the subclinical target organ damage markers and
the possible incidence of cardiovascular events in patients with type 2 diabetes mellitus.
Trial Registration: ClinicalTrials.gov Identifier: NCT01065155
* Correspondence: Lgarciao@usal.es
La Alamedilla Health Centre, Primary Care Research Unit, Castilla y León
Health Service - SACYL, Salamanca, Spain
© 2010 Gómez-Marcos et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Gómez-Marcos et al. BMC Public Health 2010, 10:143
http://www.biomedcentral.com/1471-2458/10/143
Background
The estimated prevalence of type 2 diabetes mellitus
(DM2) in the industrialized world is 6-8% [1]. The prevalence of the disease is expected to increase in the
coming years as a result of the increase in life expectancy in developed countries, and as a consequence of
changes in life style in the developing world. It has been
estimated that the number of diabetics will double over
the next 25 years. As a result, by the year 2030, Spain
can be expected to have over three million diabetic
patients [1,2]. Cardiovascular diseases are the main
causes of mortality among diabetic patients [3]. The
incidence of coronary mortality in DM2 patients is four
times greater than in the general population [4,5]. On
the other hand, the prevalence of arterial hypertension
(AHT) in DM2 is practically twice as high as in the
non-diabetic population. Thus, 50-60% of all DM2
patients are hypertensive, and this percentage increases
with age and the presence of nephropathy [6-8]. AHT in
the diabetic patient is usually systolic [9-12], its control
poses greater difficulties [13,14], and the nocturnal dip
in pressure is smaller [15]. Moreover, the concomitant
presence of both conditions (AHT and DM2) increases
cardiovascular morbidity-mortality - with an increased
incidence of coronary, cerebrovascular, and peripheral
vascular disease, renal failure, heart failure and diabetic
retinopathy, and a greater risk of death due to cardiovascular disease [16].
Clinical blood pressure (CBP) measurement remains
the standard of reference, and has been a key element in
predicting cardiovascular disease, but there is increasing
evidence that home blood pressure (HBP) measurement
by the patient, and particularly ambulatory blood pressure monitoring (ABPM), shows a stronger correlation
to target organ damage and cardiovascular events
[17-20]. The prognostic value of nocturnal blood pressure (BP), and particularly of the nocturnal decrease or
dip in systolic blood pressure (SBP), seems to be greater
than that of diurnal BP. Individuals with a lower nocturnal fall in BP have a greater prevalence of target organ
damage and a less favorable outcome [21,22].
The presence of target organ damage increases the
risk of clinical cardiovascular complications in DM2. In
this context, left ventricular hypertrophy (LVH),
assessed according to electrocardiographic criteria,
increases the risk of coronary complications and stroke
[23]. Silent worsening of renal function, reflected by
increased creatinine levels, a drop in glomerular filtration rate (GFR), or an increase in protein excretion in
urine, increase the risk of cardiovascular diseases
[24,25]. Pathological ankle-brachial index (ABI) values
show very good correlation to the development of coronary complications, the incidence of stroke, and cardio-
Page 2 of 8
vascular mortality [26]. In addition, a number of
prospective studies have shown carotid artery intimamedia thickness (IMT) to be an independent risk factor
for both coronary disease and stroke [27]. An increased
IMT and/or the detection of atheroma plaques are associated with an up to four-fold increase in the relative
risk of clinical complications of arteriosclerosis [28].
On the other hand, the evaluation of major artery
stiffness is gaining importance as an indicator, since it is
one of the main determining factors of the general condition of blood circulation [29,30]. Arterial stiffness is
determined via two systems: pulse wave velocity (PWV)
(time from arrival of the pulse wave to the carotid artery
and femoral artery) and applanation radial tonometric
pulse wave analysis for calculating aortic pressure, as
well as the relationships between the latter and the peripheral pressure values [31-33]. Increased arterial stiffness or diminished arterial distensibility determined by
pulse pressure implies increased cardiovascular risk. On
the other hand, there is evidence that diabetes predisposes to premature vascular aging.
Considering the need in diabetic patients to better
establish the prognostic value of central arterial pressure
and pulse wave velocity in relation to the evolution of
the target organ damage markers (left ventricle growth
indicators, renal damage markers (microalbuminuria
and diminished glomerular filtration), retinal damage
and vascular markers (IMT of the carotid artery and
ABI)) and the possible incidence of cardiovascular
events in DM2 patients, an observational prospective
study involving annual follow-up over at least four years
is contemplated.
The following objectives have been established
To evaluate the prognostic value of central arterial pressure and pulse wave velocity in relation to the incidence
and outcome of renal (microalbuminuria, diminished glomerular filtration and the appearance of terminal renal
failure), cardiac (LVH) and vascular damage (IMT and
ABI), retinal vascular impairment, and the appearance of
cardiovascular episodes (cardiovascular mortality,
ischemic heart disease and stroke) in patients with DM2.
Methods/Design
Study design
An observational prospective study with a duration of 5
years, of which the first year corresponds to patient
inclusion, and the remaining four years to follow-up.
A minimum of 5 visits are contemplated, comprising a
baseline visit at the time of patient inclusion in the
study, and annual follow-up visits.
The study was approved by an independent ethics
committee from the University Hospital of Salamanca
Gómez-Marcos et al. BMC Public Health 2010, 10:143
http://www.biomedcentral.com/1471-2458/10/143
Page 3 of 8
(Spain), and all participants signed an informed consent
document.
heart failure. Symptomatic peripheral arterial disease:
Claudication over a distance of less than 100 m, resting
pain, amputation. Heart failure. Atrial fibrillation.
Setting
Treatment variables
The study will be carried out in the rural primary care
setting, in the research unit of La Alamedilla primary
care center, to which the general practitioners from two
primary care centers serving a population of 46,000
inhabitants send patients for the evaluation of possible
target organ damage and vascular risk.
Treatment for diabetes. Antihypertensive treatment.
Lipid-lowering treatment. Antiplatelet treatment.
Study subjects
Consecutive inclusion will be made of the patients
referred to the research unit and who meet the corresponding inclusion criteria, i.e., patients diagnosed with
DM2 and aged 20-80 years, with none of the following
exclusion criteria: patients unable to comply with the
protocol requirements (psychological and/or cognitive
disorders, failure to cooperate, educational limitations
and problems for understanding written language, failure to sign the informed consent document), patients
participating or who will participate in a clinical trial
during the study, and patients with serious comorbidities representing a threat to life over the subsequent 12
months.
The sample size has been calculated to determine the
time the patients take in suffering an event - the latter
being interpreted as morbidity-mortality or the appearance of new target organ damage. To this effect, two
groups will be considered, classified according to the
median central arterial pressure value. The study accepts
an alpha risk of 0.05 and a beta risk of 0.30 in two-sided
contrasting for the detection of a minimum difference in
relative risk between the two groups of ≥ 2.5 points, and
considering an events rate within the high central arterial pressure group (values above the median) of 35% at
the end of the study period. A total of 52 patients are
required in each group, estimating a loss to follow-up of
10%. A final total of 110 patients therefore will be
included.
Anthropometric measurements
Body weight is to be determined on two occasions using
a homologated electronic scale (Seca 770) following due
calibration (precision ± 0.1 kg), with the patient wearing
light clothing and no shoes. These readings will be
rounded to 100 g. Height in turn will be measured with
a portable system (Seca 222), recording the average of
two readings, and with the patient shoeless in the standing position. The values will be rounded to the closest
centimeter. Body mass index (BMI)(kg/m2) will be calculated. Waist circumference will be measured using a
flexible graduated measuring tape with the patient in
the standing position without clothing. The upper border of the iliac crests are located, and the tape is
wrapped around above this point, parallel to the floor,
ensuring that it is adjusted without compressing the
skin. The reading is taken at the end of a normal breath
according to the recommendations of the 2007 SEEDO
Conference [34].
Laboratory parameters
Lipids, creatinine, glucose, high-sensitivity C-reactive
protein (CRP), fibrinogen and glycosylated hemoglobin
(HbA1c) in blood and microalbuminuria. The parameters will be measured on a blind basis in the reference laboratory after patient fasting for at least 8 hours.
Office or clinical blood pressure
Office blood pressure measurement involves three measurements of systolic (SBP) and diastolic blood pressure
(DBP), using the average of the last two, with a validated
OMRON model M7 sphygmomanometer (Omron
Health Care, Kyoto, Japan), by following the recommendations of the European Society of Hypertension [35].
Pulse pressure (PP) will be estimated with the mean
values of the second and third measurements.
Home blood pressure (HBP)
Measurements
Sociodemographic variables and cardiovascular risk factors
Patient age, sex, race, educational level and occupational status. Hypertension, dyslipidemia, alcohol
consumption, smoking, physical activity and a history
of premature cardiovascular disease (before 55 years of
age in males and before 65 in females) in first-degree
relatives.
Cardiovascular diseases
Coronary events: Myocardial infarction, unstable angina,
stable angina, coronary revascularization. Cerebrovascular events: Ischemic stroke, intracranial hemorrhage,
transient brain ischemia. Hospital admissions due to
This parameter will be measured using an OMROM
model M7 sphygmomanometer (Omron Health Care,
Kyoto, Japan). Three measurements will be made in the
morning (between 6:00 and 9:00 a.m.), and three in the
afternoon/evening (between 18:00 and 21:00 p.m.), over
a period of 7 days, with a minimum interval of one minute between measurements, and excluding the first measurement in each case and the values corresponding to
the first day of measurement [36]. The investigator will
instruct the patients on how to perform the blood pressure recordings at home. Written instructions will be
provided, as well as a self-registry sheet, to ensure correct pressure monitoring.
Gómez-Marcos et al. BMC Public Health 2010, 10:143
http://www.biomedcentral.com/1471-2458/10/143
Ambulatory blood pressure monitoring (ABPM)
The ABPM was performed on a day of standard activity,
with an adequate cuff for the size of the patient’s arm. A
control system, SpaceLabs 90207 model (Spacelabs
Healthcare, Issaquah, Washington, USA), validated
according to the protocol of the British Hypertension
Society, was used [37]. The records in which the percentage of valid readings was ≥66% of the total and with
valid readings at all times were considered to be valid.
Furthermore, for the records to be evaluable, at least 14
measurements were required during the daytime period,
or at least seven during the nightime or rest period. The
monitor was scheduled for obtaining blood pressure measurements every 20 min during the daytime period and
every 30 min during the rest period. The average and dispersión estimators of SBP and DBP were calculated during the 24-h, daytime and nightime periods, defined
based on the diary reported by the patient. The patient
completes a form specifying bedtime and wake-up time.
Assessment of carotid intima-media thickness
Carotid ultrasonography to assess IMT was performed by
two investigators specifically trained for this before starting the study. A Sonosite Micromax ultrasound (Sonosite
Inc., Bothell, Washington, USA) device paired with a
5-10 Mhz multifrequency high-resolution linear transducer with Sonocal software was used for performing
automatic measurements of IMT for optimising reproducibility. Measurements were made of the primitive carotid
after the examination of a longitudinal section of 10 mm
at a distance of 1 cm from the bifurcation, performing
measurements in the anterior or proximal wall, and in
the posterior or distal wall in the lateral, anterior and
posterior projections, following an axis perpendicular to
the artery to discriminate two lines, one for the intimablood interface and the other to the media-adventitious
interface. A total of 6 measurements were obtained of
the right carotid and other 6 of the left carotid, using
average values (average IMT) and maximum values (maximum IMT) calculated by the software automatically. The
measurements were obtained with the subject lying
down, with the head extended and slightly turned opposite to the carotid examined, following the recommendations of the Manheim Carotid Intima-Media Thickness
Consensus [38]. Finally, IMT image is frozen in telediastole by means of electrocardiogram triggering to avoid a
confounding effect of pulsatile deformation of wall thickness and transferred to a computer. The average IMT
was considered to be abnormal if it was above 0.9 mm,
or if there were atherosclerotic plaques with a diameter
over 1.5 mm, or a focal increase of 0.5 mm, or 50% of
the adjacent IMT [16].
Evaluation of peripheral artery involvement
This was evaluated using the ankle-brachial index (ABI),
performed in the morning without having consumed
Page 4 of 8
coffee or tobacco for at least 8 hours prior to measuring
and an ambient temperature of 22-24°C. With the feet
uncovered, in a supine decubitus position after 20 minutes of rest, the pressure in the lower extremities was
measured using a portable Doppler system Minidop Es100Vx (Hadeco, Inc. Arima, Miyamae-ku, Kawasaki,
Japan) applying the probe at the anterior or posterior
tibial artery at an angle of approximately 60° to the
direction of blood flow. The transducer’s cuff was
quickly inflated in each ankle about 30 mmHg above
the systolic pressure and the pressure was allowed to
descend (by about 2 mmHg per second) until the first
sound corresponding to the systolic pressure was heard.
The blood pressure was also measured in both arms
(measured twice at 3-5 minute intervals). The ABI was
calculated separately for each foot by dividing the higher
of the two systolic pressures in the ankle by the highest
of the two systolic pressures in the arm [39]. It is considered subclinical organ damage if it is lower than 0.9
[16].
Cardiac assessment
The electrocardiographic examination was performed with
a General Electric MAC 3.500 ECG System (Niskayuna,
New York, USA), that measures automatically the voltage
and duration of waves and estimates the criteria of the
Cornell voltage-duration product (Cornell VDP) [40] to
assess the LVH by the following equation: Men ((RaVL +
SV3) * QRS) and women ((RaVL + SV3) * QRS + 6). LVH
is defined as the voltage-duration product > 2,440 mm/ms
(16). We will estimate left ventricular mass index (LVMI)
by Novacode equation [41].
Renal assessment
The kidney damage was assessed by measuring creatinine plasma concentration, the glomerular filtration rate
was estimated by CKD-EPI (Chronic Kidney Disease
Epidemiology Collaboration) [42] and the MDRD-IDMS
(Modification of Diet in Renal Disease-Isotopic Dilution
Mass Spectrometry) [43] equation and proteinuria were
assessed by the albumin/creatinine ratio following the
2007 European Society of Hypertension/European
Society of Cardiology Guidelines criteria [16]. Subclinical organ damage was defined as plasma creatinine
between 1.3 - 1.5 mg/dl in men and 1.2 - 1.4 mg/dl in
women, glomerular filtration rate below 60 ml/min or
albumin/creatinine ratio > 22 mg/gr in men and 31 mg/
gr in women. Renal disease was defined as plasma creatinine of 1.5 mg/dl or higher in men and 1.4 mg/l in
women or albumin/creatinine ratio > 300 mg/24 h.
Evaluation of retinal involvement
Retinography was performed with a Topcon TRC NW
200 non-mydriatic retinal camera (Topcon Europe B.C.
Capelle a/d IJssel The Netherlands), obtaining images
centered on the papilla. Once the images were captured,
two independent observers classified them according to
Gómez-Marcos et al. BMC Public Health 2010, 10:143
http://www.biomedcentral.com/1471-2458/10/143
the Keith-Wagener classification for hypertensive retinopathy [44], with a third reading being performed in
cases where there were discrepancies. Grades III or IV
(hemorrhages or exudates, papillary edema) are considered to be associated with cardiovascular disease [16].
Evaluation of pulse wave velocity and central blood
pressure
The pulse wave velocity (PWV) was calculated using the
SphygmoCor System (Vx Pulse Wave Velocity), (AtCor
Medical Pty Ltd Head Office, West Ryde, Australia)
with the patient in the supine decubitus position. The
carotid and femoral pulse wave was analyzed, estimating
the delay in the electrocardiograma (ECG) wave and calculating the PWV. The space measurements were taken
with a measuring tape from the suprasternal notch to
the carotid and femoral arteries at the sensor location.
A measurement of greater than 12 m/s is considered
subclinical organ damage [16].
Using the SphygmoCor system (Px Pulse Wave Analysis)(Atcor Medical, Australia), with the patient in the sitting position and resting the arm on a rigid surface,
pulse wave analysis will be made with a sensor in the
radial artery - using mathematical transformation to
estimate the aortic pulse wave. From the aortic wave
morphology, central (aortic) arterial pressure will be
estimated, along with central ventricular load, diastolic
perfusion pressure, the subendocardial viability index,
the pressure increment, central pulse pressure and the
augmentation index (PWA), defined as the percentage
increase in central pulse pressure: AIx = pressure
increase/pulse pressure * 100 [33].
All explorations will be carried out on a yearly basis,
and due registry will be made of any changes in the
sociodemographic variables or cardiovascular risk factors, and of the appearance of events.
Organization of data collection
The patients referred to the research unit of La Alamedilla primary care center will be interviewed by a contracted nurse specifically trained for the project. A
history will be compiled and a basic exploration will be
carried out. A 24-hour ambulatory blood pressure monitoring (ABPM) device will be fitted, and the patients will
receive an OMRON M7 sphygmomanometer for selfmeasurement of blood pressure at home. Vascular
exploration will be made (pulse analysis with the SphygmoCor system, ABI and ECG), and an appointment will
be made for blood sampling. Posteriorly, carotid artery
ultrasound will be performed by two specifically trained
members of the research team. Data input will be made
using the Teleform system (Autonomy Cardiff Vista,
California, USA), with a questionnaire previously
designed for the project, and exporting the data to the
Page 5 of 8
SPSS version 15.0 statistical package (SPSS Inc., Chicago, Illinois, USA) for posterior analysis.
Statistics analysis
A first descriptive analysis will be made of the sociodemographic and clinical characteristics of the study
groups. The data will be presented with the mean and
95% confidence interval in the case of quantitative variables, and as frequency distributions for qualitative variables. The Pearson chi-squared test will be used to
analyze associations between qualitative variables. The
Student t-test for independent samples will be used to
compare the means for the two arterial pressure groups.
In turn, the analysis of repeated measures will be based
on the McNemar test for qualitative data and the Student
t-test for paired data in application to quantitative data.
Survival will be analyzed with the Kaplan-Meier and
actuarial methods on each visit and at the end of follow-up. The log-rank test will be used for comparing
survival in the two groups. Lastly, a Cox regression
model will be developed to estimate the event risk
between the groups, adjusting for the possible confounding variables analyzed in the study.
Hypothesis contrasting will establish an alpha risk factor of 0.05 as the limit of statistical significance. The
SPSS/PC+ version 15.0 statistical package will be used
(SPSS Inc., Chicago, Illinois, USA).
Quality control
Different processes will be carried out to guarantee
study data quality and thus maximize the validity and
reliability of the measurements of the results. To this
effect, field work operative manuals have been developed, specifying the correct technique for performing
each of the tests. Educative leaflets have also been developed to ensure that the patients correctly perform pressure measurement in the home - all these measures
confirming the correct practical application of each
technique. Meetings will be held on a weekly basis with
the principal investigator of the study in order to analyze the entire process, and an annual report on the
course of the study will be prepared.
Ethical and legal issues
In order to guarantee data confidentiality, all the electronic and paper copies of the protocol, signed informed
consent documents and results of the tests made in
each of the patients will be kept locked in a safe place,
and only the study investigators will have access to the
data on the subjects who agree to participate in the
study.
The study has been approved by the ethics committee
and complies with Spanish data protection law 15/1999
Gómez-Marcos et al. BMC Public Health 2010, 10:143
http://www.biomedcentral.com/1471-2458/10/143
and its recently developed specifications (Royal Decree
(RD) 1720/2007). Knowledge and agreement to cooperate has been established with the implicated services,
signed by the legal representative of the center.
Discussion
The results of this study will be of great scientific relevance, since they will allow us to quantify the degree to
which central arterial pressure and pulse wave velocity
are related to the different target organ lesions (carotid
IMT, peripheral arterial disease, kidney, retina and
heart), and to analyze their course over time. To our
knowledge, this is the first study to assess target organ
damage in diabetic patients and its relationship to central arterial pressure and pulse wave velocity over a follow-up period of at least four years.
Pulse wave velocity is the gold standard for assessing
the stiffness of the large arteries, and is an important
predictor of cardiovascular events [45]. A recent review
[46] has shown it to be correlated to patient age and
arterial pressure, though its association to diabetes is
not so clear. Discrepancies have been observed among
different studies, and the recorded associations are weak
[45]. Likewise, it is not certain that the different instruments used to assess arterial stiffness are equivalent. In
this sense, a study in diabetic patients has concluded
that pulse pressure and pulse wave velocity increase in
diabetic individuals, though this is not associated to the
augmentation index, and such parameters may not be
reliable as a measure of arterial stiffness in diabetics
[47]. In this same line, another study comparing different procedures for assessing arterial stiffness in diabetic
subjects has concluded that further research is needed
to clarify their usefulness in diabetic patients [48].
As regards the relationship between these arterial stiffness measures and target organ lesions and their course
over time in diabetic individuals, the existing evidence is
scarce and inconclusive. With the present study we
hope to contribute evidence to clarify some of these
issues.
Study limitations
The main limitation of this study is its small sample size
for assessing end events. However, this is remedied by
the fact that the analysis will be made with the data of a
multicenter study in which 800 patients will be included.
Abbreviations
DM2: Diabetes mellitus 2; AH: Arterial hypertension; BMI: Body mass index;
CBP: Clinical blood pressure; BP: Blood pressure; SBP: Systolic blood pressure;
DPB: Diastolic blood pressure; HBP: Home blood pressure; ABPM: Ambulatory
blood pressure monitoring; ABI: Ankle-brachial index; IMT: Intima-media
thickness; HbA1c: Glycated hemoglobin; LVH: Left ventricular hypertrophy;
PWV: Pulse wave velocity; ECG: Electrocardiographic; MDRD: Modification of
Diet in Renal Disease.
Page 6 of 8
Acknowledgements
This project was supported by the Regional Health Management of the
Castilla y León (SACYL) in the call march 26 of and resolved in July 7 of
2009 (GRS. 428 /A/09) and ISCIII (RD06/018/27).
Authors’ contributions
Conception of the idea for the study: MAGM and LGO. Development of the
protocol, organization and funding: MAGM, LGO, ERS, JIRR, YCS, AdCL, BSS,
CRM, CCS and LGS. Writing of the manuscript: MAGM. All the authors have
read the draft critically, to make contributions, and have approved the final
text.
Competing interests
The authors declare that they have no competing interests.
Received: 12 February 2010 Accepted: 18 March 2010
Published: 18 March 2010
References
1. King H, Aubert RE, Herman WH: Global burden of diabetes, 1995-2025:
prevalence, numerical estimates, and projections. Diabetes Care 1998,
21:1414-31.
2. Wild S, Roglic G, Green A, Sicree R, King H: Global prevalence of diabetes:
estimates for the year 2000 and projections for 2030. Diabetes Care 2004,
27:1047-53.
3. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from
coronary heart disease in subjects with type 2 diabetes and in
nondiabetic subjects with and without prior myocardial infarction. N
Engl J Med 1998, 339:229-34.
4. Stamler J, Vaccaro O, Neaton JD, Wentworth D: Diabetes, other risk
factors, and 12-yr cardiovascular mortality for men screened in the
Multiple Risk Factor Intervention Trial. Diabetes Care 1993, 16:434-44.
5. Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR,
Holman RR: Risk factors for coronary artery disease in non-insulin
dependent diabetes mellitus: United Kingdom Prospective Diabetes
Study (UKPDS: 23). Bmj 1998, 316:823-8.
6. Laakso M: Hypertension and macrovascular disease–the killing fields of
NIDDM. Diabetes Res Clin Pract 1998, 39(Suppl):S27-33.
7. Sowers JR, Epstein M: Diabetes mellitus and associated hypertension,
vascular disease, and nephropathy. An update. Hypertension 1995,
26:869-79.
8. Williams B: The Hypertension in Diabetes Study (HDS): a catalyst for
change. Diabet Med 2008, 25(Suppl 2):13-9.
9. Howard G, O’Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman R,
Selby JV, Saad MF, Savage P, Bergman R: Insulin sensitivity and
atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS)
Investigators. Circulation 1996, 93:1809-17.
10. Maceira B, Perez Tamajon L, Losada M: [Treatment of arterial hypertension
in the diabetic patient. From theory to hard reality]. Nefrologia 2001,
21(Suppl 3):39-45.
11. Tarnow L, Rossing P, Gall MA, Nielsen FS, Parving HH: Prevalence of arterial
hypertension in diabetic patients before and after the JNC-V. Diabetes
Care 1994, 17:1247-51.
12. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ,
Fletcher AE, Forette F, Goldhaber A, Palatini P, Sarti C, Fagard R: Effects of
calcium-channel blockade in older patients with diabetes and systolic
hypertension. Systolic Hypertension in Europe Trial Investigators. N Engl
J Med 1999, 340:677-84.
13. Brown MJ, Castaigne A, de Leeuw PW, Mancia G, Palmer CR, Rosenthal T,
Ruilope LM: Influence of diabetes and type of hypertension on response
to antihypertensive treatment. Hypertension 2000, 35:1038-42.
14. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G,
Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A, Rutan GH, Stamler J:
Effect of diuretic-based antihypertensive treatment on cardiovascular
disease risk in older diabetic patients with isolated systolic hypertension.
Systolic Hypertension in the Elderly Program Cooperative Research
Group. Jama 1996, 276:1886-92.
15. Bauduceau B, Mayaudon H, Dupuy O, Palou M, Czerniak E, Bredin C,
Belmejdoub G: [The impact of dipper and non-dipper characteristics in
the fluctuation of arterial blood pressure. A study of a population of 484
diabetic patients]. Arch Mal Coeur Vaiss 2000, 93:969-73.
Gómez-Marcos et al. BMC Public Health 2010, 10:143
http://www.biomedcentral.com/1471-2458/10/143
16. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G,
Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L,
Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A, Vahanian A, Camm J,
De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C,
Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M,
Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E,
Ambrosioni E, Lindholm LH, Viigimaa M, Adamopoulos S, Agabiti-Rosei E,
Ambrosioni E, Bertomeu V, Clement D, Erdine S, Farsang C, Gaita D, Lip G,
Mallion JM, Manolis AJ, Nilsson PM, O’Brien E, Ponikowski P, Redon J,
Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B: 2007
Guidelines for the Management of Arterial Hypertension: The Task Force
for the Management of Arterial Hypertension of the European Society of
Hypertension (ESH) and of the European Society of Cardiology (ESC). J
Hypertens 2007, 25:1105-87.
17. Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, Den Hond E,
McCormack P, Staessen JA, O’Brien E: Superiority of ambulatory over clinic
blood pressure measurement in predicting mortality: the Dublin
outcome study. Hypertension 2005, 46:156-61.
18. O’Brien E, Asmar R, Beilin L, Imai Y, Mallion JM, Mancia G, Mengden T,
Myers M, Padfield P, Palatini P, Parati G, Pickering T, Redon J, Staessen J,
Stergiou G, Verdecchia P: European Society of Hypertension
recommendations for conventional, ambulatory and home blood
pressure measurement. J Hypertens 2003, 21:821-48.
19. Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G:
Prognostic value of ambulatory and home blood pressures compared
with office blood pressure in the general population: follow-up results
from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA)
study. Circulation 2005, 111:1777-83.
20. Garcia-Ortiz L, Gomez-Marcos MA, Martin-Moreiras J, Gonzalez-Elena LJ,
Recio-Rodriguez JI, Castano-Sanchez Y, Grandes G, Martinez-Salgado C:
Pulse pressure and nocturnal fall in blood pressure are predictors of
vascular, cardiac and renal target organ damage in hypertensive
patients (LOD-RISK study). Blood Press Monit 2009, 14:145-51.
21. Hansen TW, Jeppesen J, Rasmussen S, Ibsen H, Torp-Pedersen C:
Ambulatory blood pressure and mortality: a population-based study.
Hypertension 2005, 45:499-504.
22. Kikuya M, Ohkubo T, Asayama K, Metoki H, Obara T, Saito S, Hashimoto J,
Totsune K, Hoshi H, Satoh H, Imai Y: Ambulatory blood pressure and 10year risk of cardiovascular and noncardiovascular mortality: the
Ohasama study. Hypertension 2005, 45:240-5.
23. Verdecchia P, Porcellati C, Reboldi G, Gattobigio R, Borgioni C, Pearson TA,
Ambrosio G: Left ventricular hypertrophy as an independent predictor of
acute cerebrovascular events in essential hypertension. Circulation 2001,
104:2039-44.
24. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL,
White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S,
Leimberger JD, Califf RM, Pfeffer MA: Relation between renal dysfunction
and cardiovascular outcomes after myocardial infarction. N Engl J Med
2004, 351:1285-95.
25. 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, 286:421-6.
26. Fowkes FG, Murray GD, Butcher I, Heald CL, Lee RJ, Chambless LE,
Folsom AR, Hirsch AT, Dramaix M, deBacker G, Wautrecht JC, Kornitzer M,
Newman AB, Cushman M, Sutton-Tyrrell K, Fowkes FG, Lee AJ, Price JF,
d’Agostino RB, Murabito JM, Norman PE, Jamrozik K, Curb JD, Masaki KH,
Rodriguez BL, Dekker JM, Bouter LM, Heine RJ, Nijpels G, Stehouwer CD,
Ferrucci L, McDermott MM, Stoffers HE, Hooi JD, Knottnerus JA, Ogren M,
Hedblad B, Witteman JC, Breteler MM, Hunink MG, Hofman A, Criqui MH,
Langer RD, Fronek A, Hiatt WR, Hamman R, Resnick HE, Guralnik J,
McDermott MM: Ankle brachial index combined with Framingham Risk
Score to predict cardiovascular events and mortality: a meta-analysis.
Jama 2008, 300:197-208.
27. Takiuchi S, Kamide K, Miwa Y, Tomiyama M, Yoshii M, Matayoshi T, Horio T,
Kawano Y: Diagnostic value of carotid intima-media thickness and
plaque score for predicting target organ damage in patients with
essential hypertension. J Hum Hypertens 2004, 18:17-23.
28. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr:
Carotid-artery intima and media thickness as a risk factor for myocardial
Page 7 of 8
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
infarction and stroke in older adults. Cardiovascular Health Study
Collaborative Research Group. N Engl J Med 1999, 340:14-22.
Agabiti-Rosei E, Mancia G, O’Rourke MF, Roman MJ, Safar ME, Smulyan H,
Wang JG, Wilkinson IB, Williams B, Vlachopoulos C: Central blood pressure
measurements and antihypertensive therapy: a consensus document.
Hypertension 2007, 50:154-60.
O’Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE: Clinical
applications of arterial stiffness; definitions and reference values. Am J
Hypertens 2002, 15:426-44.
Inoue N, Maeda R, Kawakami H, Shokawa T, Yamamoto H, Ito C, Sasaki H:
Aortic pulse wave velocity predicts cardiovascular mortality in middleaged and elderly Japanese men. Circ J 2009, 73:549-53.
McEniery CM, Yasmin , McDonnell B, Munnery M, Wallace SM, Rowe CV,
Cockcroft JR, Wilkinson IB: Central pressure: variability and impact of
cardiovascular risk factors: the Anglo-Cardiff Collaborative Trial II.
Hypertension 2008, 51:1476-82.
Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D,
Hughes AD, Thurston H, O’Rourke M: Differential impact of blood
pressure-lowering drugs on central aortic pressure and clinical
outcomes: principal results of the Conduit Artery Function Evaluation
(CAFE) study. Circulation 2006, 113:1213-25.
Salas-Salvado J, Rubio MA, Barbany M, Moreno B: [SEEDO 2007 Consensus
for the evaluation of overweight and obesity and the establishment of
therapeutic intervention criteria]. Med Clin (Barc) 2007, 128:184-96.
O’Brien E, Asmar R, Beilin L, Imai Y, Mancia G, Mengden T, Myers M,
Padfield P, Palatini P, Parati G, Pickering T, Redon J, Staessen J, Stergiou G,
Verdecchia P: Practice guidelines of the European Society of
Hypertension for clinic, ambulatory and self blood pressure
measurement. J Hypertens 2005, 23:697-701.
Coca A, Bertomeu V, Dalfo A, Esmatjes E, Guillen F, Guerrero L, Llisterri JL,
Marin-Iranzo R, Megia C, Rodriguez-Manas L, Suarez C: [Blood pressure self
measurement: Spanish consensus document]. Nefrologia 2007, 27:139-53.
O’Brien E, Petrie J, Littler W, de Swiet M, Padfield PL, O’Malley K,
Jamieson M, Altman D, Bland M, Atkins N: The British Hypertension
Society protocol for the evaluation of automated and semi-automated
blood pressure measuring devices with special reference to ambulatory
systems. J Hypertens 1990, 8:607-19.
Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N,
Csiba L, Desvarieux M, Ebrahim S, Fatar M, Hernandez Hernandez R, Jaff M,
Kownator S, Prati P, Rundek T, Sitzer M, Schminke U, Tardif JC, Taylor A,
Vicaut E, Woo KS, Zannad F, Zureik M: Mannheim carotid intima-media
thickness consensus (2004-2006). An update on behalf of the Advisory
Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th
European Stroke Conferences, Mannheim, Germany, 2004, and Brussels,
Belgium, 2006. Cerebrovasc Dis 2007, 23:75-80.
Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL,
Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D,
Stanley JC, Taylor LM Jr, White CJ, White J, White RA, Antman EM, Smith SC
Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA,
Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B: ACC/AHA 2005
Practice Guidelines for the management of patients with peripheral
arterial disease (lower extremity, renal, mesenteric, and abdominal
aortic): a collaborative report from the American Association for Vascular
Surgery/Society for Vascular Surgery, Society for Cardiovascular
Angiography and Interventions, Society for Vascular Medicine and
Biology, Society of Interventional Radiology, and the ACC/AHA Task
Force on Practice Guidelines (Writing Committee to Develop Guidelines
for the Management of Patients With Peripheral Arterial Disease):
endorsed by the American Association of Cardiovascular and Pulmonary
Rehabilitation; National Heart, Lung, and Blood Institute; Society for
Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular
Disease Foundation. Circulation 2006, 113:e463-654.
Okin PM, Roman MJ, Devereux RB, Kligfield P: Electrocardiographic
identification of increased left ventricular mass by simple voltageduration products. J Am Coll Cardiol 1995, 25:417-23.
Havranek EP, Froshaug DB, Emserman CD, Hanratty R, Krantz MJ,
Masoudi FA, Dickinson LM, Steiner JF: Left ventricular hypertrophy and
cardiovascular mortality by race and ethnicity. Am J Med 2008, 121:870-5.
Gómez-Marcos et al. BMC Public Health 2010, 10:143
http://www.biomedcentral.com/1471-2458/10/143
Page 8 of 8
42. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI,
Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J: A new equation to
estimate glomerular filtration rate. Ann Intern Med 2009, 150:604-12.
43. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate
method to estimate glomerular filtration rate from serum creatinine: a
new prediction equation. Modification of Diet in Renal Disease Study
Group. Ann Intern Med 1999, 130:461-70.
44. Keith NM, Wagener HP, Barker NW: Some different types of essential
hypertension: their course and prognosis. Am J Med Sci 1974, 268:336-45.
45. Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG: Aortic
pulse-wave velocity and its relationship to mortality in diabetes and
glucose intolerance: an integrated index of vascular function? Circulation
2002, 106:2085-90.
46. Cecelja M, Chowienczyk P: Dissociation of aortic pulse wave velocity with
risk factors for cardiovascular disease other than hypertension: a
systematic review. Hypertension 2009, 54:1328-36.
47. Lacy PS, O’Brien DG, Stanley AG, Dewar MM, Swales PP, Williams B:
Increased pulse wave velocity is not associated with elevated
augmentation index in patients with diabetes. J Hypertens 2004,
22:1937-44.
48. Jerrard-Dunne P, Mahmud A, Feely J: Ambulatory arterial stiffness index,
pulse wave velocity and augmentation index–interchangeable or
mutually exclusive measures? J Hypertens 2008, 26:529-34.
Pre-publication history
The pre-publication history for this paper can be accessed here:http://www.
biomedcentral.com/1471-2458/10/143/prepub
doi:10.1186/1471-2458-10-143
Cite this article as: Gómez-Marcos et al.: Central blood pressure and
pulse wave velocity: relationship to target organ damage and
cardiovascular morbidity-mortality in diabetic patients or metabolic
syndrome. An observational prospective study. LOD-DIABETES study
protocol. BMC Public Health 2010 10:143.
Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submit