Significance of an Increase in Diastolic Blood Pressure During a Stress Test in Terms of Comorbidities and Long-Term Total and CV Mortality

Abstract

Background:
A decrease in diastolic blood pressure (DBP) with exercise is considered normal, but the significance of an increase in DBP has not been validated. Our aim was to determine the relationship of DBP increasing on a stress test regarding comorbidities and mortality.

Methods:
Our database was reviewed from 1993-2010 using the first stress test of a patient. Non-Minnesota residence, baseline CV disease, rest DBP <60 or >100 mmHg, and age <30 or ≥80 were exclusion criteria. DBP response was classified Normal if peak DBP-rest DBP <0, Borderline 0-9, Abnormal ≥10mmHg. Mortality was determined from Mayo Clinic records and Minnesota Death Index. Logistic regression was used to determine the relationship of DBP response to presence of comorbidities. Cox regression was used to determine total and CV mortality risk by DBP response. All analyses were adjusted for age, sex and resting DBP.

Results:
20760 patients were included (51±11 years, female n=7314). Rest/peak averaged DBP 82±8/69 ±15 mmHg in normal vs 79±9/82±9 mmHg in borderline vs 76±9/92±11 mmHg in abnormal DBP response. There were 1582 deaths (8%) with 557 (3%) CV deaths over 12±5 years of follow-up. In patients with borderline and abnormal DBP response, odds ratios for obesity, hypertension, diabetes and current smoking were significant, while hazard ratios for total and CV death were not significant compared to patients with normal DBP response.

Conclusions:
DBP response to exercise is significantly associated with important comorbidities at the time of the stress test but does not add to the prognostic yield of stress test.

Full text

976 American Journal of Hypertension 31(9) September 2018
Brief communication
It is important for both good patient care and health care
economics to gain the most information possible from each
test performed. is is true for the exercise test which pro-
vides both diagnostic and prognostic information.1 is
means not only looking at the ST segment response but also
accurately reporting and identifying the signicance of other
exercise parameters including blood pressure(BP).
A gradual decrease in diastolic blood pressure (DBP)
with exercise has long been considered a normal response.2,3
While various studies have shown that hypertensive BP
response to exercise may be an independent predictor of le
ventricular hypertrophy,4 development of hypertension,5,6
and total and cardiovascular (CV) mortality in a low-risk
population,7,8 these studies were focused on systolic blood
pressure (SBP) responses to exercise.9,10 e signicance of
an increase in DBP with exercise in a low-risk population
has not been validated yet, either in terms of association
with comorbidities such as diabetes, hypertension, obesity,
and smoking that increase CV risk or in terms of the hard
endpoints of death and CVdeath.
Our aim was to determine the signicance of an increase
in DBP on an exercise test in terms of comorbidities and
long-term total and CV mortality.
METHODS
is was a retrospective study approved by Mayo Clinic
Rochester IRB. Patients not consenting to have their data
used in this research under Minnesota Statute (§144.335)
were excluded.11 e Mayo Integrated Stress Center data-
base was reviewed between 21 September 1993 and 20
December2010.
Study population
In this study, we included Minnesota residents who had
nonimaging, symptom-limited treadmill exercise tests on
the Bruce protocol between ages 30 and 79years. Where mul-
tiple qualifying tests were available for a given patient, the
Signicance of an Increase in Diastolic Blood Pressure
During a Stress Test in Terms of Comorbidities and
Long-Term Total and CV Mortality
NóraSydó,1,2,* TiborSydó,3,* Karina A.Gonzalez Carta,1 NasirHussain,1 BélaMerkely,2
Joseph G.Murphy,1 Ray W.Squires,1 FranciscoLopez-Jimenez,1 and Thomas G.Allison1
BACKGROUND
A decrease in diastolic blood pressure (DBP) with exercise is considered
normal, but the signicance of an increase in DBP has not been vali-
dated. Our aim was to determine the relationship of DBP increasing on
a stress test regarding comorbidities and mortality.
METHODS
Our database was reviewed from 1993 to 2010 using the rst stress test
of a patient. Non-Minnesota residence, baseline cardiovascular (CV) dis-
ease, rest DBP <60 or >100mm Hg, and age <30 or ≥80 were exclusion
criteria. DBP response was classied: normal if peak DBP–rest DBP < 0,
borderline 0–9, and abnormal ≥10mm Hg. Mortality was determined
from Mayo Clinic records and Minnesota Death Index. Logistic regres-
sion was used to determine the relationship of DBP response to the
presence of comorbidities. Cox regression was used to determine total
and CV mortality risk by DBP response. All analyses were adjusted for
age, sex, and resting DBP.
RESULTS
Twenty thousand seven hundred sixty patients were included (51±11years,
female n=7,314). Rest/peak averaged DBP 82±8/69±15mm Hg in normal
vs. 79±9/82±9mm Hg in borderline vs. 76±9/92±11mm Hg in abnor-
mal DBP response. There were 1,582 deaths (8%) with 557 (3%) CV deaths
over 12± 5 years of follow-up. In patients with borderline and abnormal
DBP response, odds ratios for obesity, hypertension, diabetes, and current
smoking were signicant, while hazard ratios for total and CV death were
not signicant compared with patients with normal DBP response.
CONCLUSIONS
DBP response to exercise is signicantly associated with important
comorbidities at the time of the stress test but does not add to the
prognostic yield of stress test.
Keywords: blood pressure; exercise; hypertension; mortality.
doi:10.1093/ajh/hpy080
Correspondence: Thomas G.Allison (allison.thomas@mayo.edu).
Initially submitted February 1, 2018; date of rst revision April 2, 2018;
accepted for publication May 11, 2018; online publication May 15, 2018.
© American Journal of Hypertension, Ltd 2018. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
1Department of Cardiovascular Medicine, Mayo Clinic, Rochester,
Minnesota, USA; 2Heart and Vascular Center, Semmelweis University,
Budapest, Hungary; 3Csolnoky Ferenc Hospital, Veszprém, Hungary.
*These authors contributed equally to this work.
2018
September
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American Journal of Hypertension 31(9) September 2018 977
Diastolic Blood Pressure Response to Exercise
rst test chronologically was chosen to maximize follow-up.
Patients were excluded if they1 had documented history of
CV disease—including ischemic heart diseases, heart failure,
cardiac surgery, structural or valvular heart diseases, major
arrhythmias, debrillator or pacemaker, congenital heart
diseases, cerebrovascular diseases, and peripheral vascular
diseases2; pre-exercise DBP was <60 or >100mm Hg.
Clinicaldata
We collected demographic and clinical data prospect-
ively at the time of the exercise test. Heart rate (HR), BP,
and other exercise parameters were uploaded electronic-
ally to our database from the GE CASE stress testing sys-
tems (Milwaukee, WI). Patient characteristics—including
age, sex, and anthropometric data—and comorbidities were
collected at the time of the stress test from patient medical
charts and patient interview. We specically looked comor-
bidities including diabetes and hypertension (dened by the
previous diagnosis or receiving antihypertension medica-
tion), obesity (dened as body mass index ≥ 30kg/m2), cur-
rent smoking, and use of an HR-lowering drug (beta-blocker
or nondihydropyridine calcium channel blocker).
Exercise test protocol and variables
Symptom-limited treadmill exercise testing was per-
formed on usual medications using the standard Bruce
protocol according to ACC/AHA guidelines.12,13 Patients
were not allowed to grip the treadmill handrails tightly.
Resting HR and BP measurements were obtained in the
standing position immediately before the test. BP was meas-
ured by auscultation with a stethoscope placed over the bra-
chial artery while the cu was inated and deated manually
according to standard methods. DBP was taken as the h
Korotko phase (disappearance of all sound).14 Symptoms,
BP, HR, rating of perceived exertion, and workload were
electronically entered into the database during the nal
minute of each stage of exercise, peak exercise, 1 and 3 min-
utes of active recovery at 1.7 MPH/0% grade, and 6 minutes
postpeak exercise in seated recovery.
Exercise test interpretation data including the reason
for termination, symptoms, abnormal signs, and exercise
electrocardiographic (ECG) analysis were added to the
database immediately aer the test. DBP response was clas-
sied as normal if peak DBP–rest DBP was <0, borderline if
0–9, and abnormal if ≥10mm Hg. Functional aerobic cap-
acity was expressed as 100% × actual performance time/
predicted performance time based on previous publica-
tions from our laboratory.10 Peak HR was also expressed as
percent predicted peak HR.15 HR recovery was calculated
as peak exercise HR minus HR at 1 minute of active re-
covery at 1.7 MPH/0% grade. An abnormal exercise ECG
was dened as any ST depression or elevation >1.0mm ir-
respective of the resting ECG, while an abnormal exercise
ECG was considered positive only if the resting ECG did
not present with signicant ST-T abnormalities, the patient
was not taking digitalis, and rate-related le bundle branch
block did not occur.
Mortality outcomes
Outcomes were taken from Mayo Clinic patient records
and the Minnesota Death Index which was reviewed in
March 2016. Adeath was considered to be CV-related if a CV
condition was included among the rst three listed causes in
the Minnesota Death Index. Mortality data were classied
using ICD 9 (391, 391.9, 394–398, 402, 404, 410–414, 415–
417, 420–429, 430–438, 440–448, 451–454, 456–459) and
ICD 10 (I101, I05–I09, I11, I13, I20–I25, I26–I28, I30–I52,
I60–I69, I70–I79, I80–I89) codes.
Statistical analysis
Statistical analyses were performed using SAS 9.4
(Raleigh, NC). Patient characteristics, outcomes, and exer-
cise data were analyzed by BP groups. Logistic regression
was used to determine the relationship of DBP response to
the presence of obesity (body mass index ≥ 30kg/m2), cur-
rent smoking, hypertension, and diabetes. Cox regression
was used to determine long-term total and CV mortality risk
according to DBP response. All analyses were adjusted for
age, sex, and resting DBP. We also performed fully adjusted
Cox regression analyses using hypertension, diabetes, cur-
rent smoking, and use of an HR-lowering drug as covariates,
along with other exercise variables including low functional
aerobic capacity (<80% predicted), abnormal HR recovery,
and abnormal exercise ECG. P<0.05 was considered signi-
cant for all analyses.
RESULTS
Study population
A total of 20,760 patients (age 51±11years) were avail-
able for analysis. ere were 7,314 females (35%). eir
demographic and clinical data stratied by DBP response,
along with the long-term outcome data are shown in
Table1.
Exercise test results
Exercise test data by DBP response are provided in part
A of the Table 1. Because of the large sample size, even
minor dierences, such as in resting HR or highest rating
of perceived exertion reached statistical signicance, though
some age trends were pronounced. In general, patients with
normal DBP response (N= 11,254, 54%) have the overall
best results, though dierences among the groups are gen-
erally small. Functional aerobic capacity was the same in
normal and borderline DBP groups, but lower in patients
with abnormal DBP response. Rest DBP/peak DBP averaged
82±8/69±15mm Hg in normal vs. 79±9/82±9mm Hg
in borderline vs. 76± 9/92±11mm Hg in abnormal DBP
response. Resting DBP was lower in patients with abnormal
DBP response, while their peak DBP was higher. Resting
SBP was not dierent between borderline and abnormal
DBP groups, but the SBP of abnormal response group was
higher with a lower peak HR.
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978 American Journal of Hypertension 31(9) September 2018
Sydó etal.
Comorbidities
Table 1 part B shows the rates of obesity, hypertension,
diabetes, and current smoking along with odds ratios (95%
condence intervals) for borderline and abnormal vs. normal
DBP response. Patients with borderline and abnormal DBP
response had more obesity, hypertension, diabetes and were
more likely to be current smokers compared with patients
with normal DBP response.
Outcomes
ere were a total of 1,582 deaths (7.6%) over an aver-
age follow-up of 12.4 ± 5.0 years. Consistent with the
exclusion of baseline CV disease and residence in a state
(Minnesota) with low CV mortality, the overall and CV
death rates (557, 2.7%) were low. In the Table 1 part C
hazard ratios (95% condence intervals) for death and CV
death are shown. Although there was a trend of increas-
ing total and CV death rates with borderline and abnor-
mal DBP response, hazard ratios were not signicant aer
minimal adjustment for age, sex, and pre-exercise DBP
or aer full adjustment for clinical risk factors and other
exercise test abnormalities. Substitution of peak DBP or
delta DBP as a continuous variable for the categorical vari-
ables normal, borderline, and abnormal DBP response did
not identify a signicant impact of DBP on CV or total
death (data not shown).
Table1. Results according to diastolic blood pressure response
A.Exercise test results by diastolic blood pressure response
Normal DBP response,
N=11,254 (54%)
Borderline DBP response,
N=6,042 (29%)
Abnormal DBP response,
N=3,463 (17%)
Mean ± SD Mean ± SD Mean ± SD
Age (years) 50.4±10.5 52.2±10.6a54.0±10.7a,b
Female (n, %) 3,978, 35.4% 2,159, 35.7% 1,177, 34.0%
FAC (%) 93.9±21.6 93.4±22.7 92.3±23.6a
Resting HR (bpm) 77.2±13.2 76.5±12.7a75.9±12.7a
Peak HR (bpm) 164.9±19.6 162.0±19.6a160.8±18.7a,b
HR-lowering drug 1,321 (11.7%) 823 (13.6%)a465 (13.4%)a
Resting SBP (mm Hg) 124.7±16.4 123.3±16.6a123.4±17.4a
Resting DBP (mm Hg) 82.5±8.8 79.2±8.5a76.1±8.8a,b
Peak SBP (mm Hg) 173.9±24.1 177.8±23.9a186.4±25.3a,b
Peak DBP (mm Hg) 68.8±15.1 82.4±8.7a91.5±10.5a,b
Delta DBP (mm Hg) −13.6±13.0 +3.1±2.9a+15.4±6.3a,b
B.Comorbidities by diastolic blood pressure response
Rate, Referent Rate, OR [95% CI] Rate, OR [95% CI]
Obesity 36%, Referent 39%, 1.33 [1.24–1.42]a41%, 1.63 [1.50–1.77]a
Hypertension 22%, Referent 24%, 1.20 [1.11–1.30]a27%, 1.48 [1.34–1.63]a
Diabetes 5%, Referent 7%, 1.19 [1.04–1.36]a8%, 1.33 [1.13–1.55]a
Current smoking 10%, Referent 12%, 1.30 [1.17–1.44]a13%, 1.42 [1.25–1.61]a
C. Mortality by diastolic blood pressure response
Rate, Referent Rate, HR [95% CI] Rate, HR [95% CI]
Age, sex, rest DBP adjusted model
Death 6%, Referent 9%, 1.01 [0.89–1.13] 11%, 1.07 [0.94–1.22]
CV death 2%, Referent 3%, 1.14 [0.94–1.39] 4%, 1.16 [0.93–1.45]
Fully adjusted model
Death 6%, Referent 9%, 1.01 [0.90–1.14] 11%, 1.07 [0.93–1.22]
CV death 2%, Referent 3%, 1.21 [0.99–1.49] 4%, 1.15 [0.91–1.45]
Continuous variables expressed as mean ± SD; discrete variables N (%). Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood
pressure; CV, cardiovascular; FAC, functional aerobic capacity; HR, heart rate; bpm, beats per minute; OR, odds ratio; CI, confidence interval;
HR, hazard ratio.
aDifferent than normal DBP at P < .05.
bBorderline DBP different than abnormal DBP at P < .05.
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American Journal of Hypertension 31(9) September 2018 979
Diastolic Blood Pressure Response to Exercise
DISCUSSION
We conrm that a decrease in DBP is the normal re-
sponse to exercise seen in more than 50% of exercise tests.
DBP response to exercise is signicantly associated with
the prevalence of obesity, hypertension, diabetes, and cur-
rent smoking at the time of the stress test, though the ac-
tual dierences in rates of these comorbidities among DBP
groups are small. Aborderline (increase of <10mm Hg) or
abnormal (increase of >10 mm Hg) was not signicantly
associated in an independent manner with long-term death
or CV death. DBP response to exercise is not strongly related
to functional aerobic capacity, which has been shown to be
the strongest prognostic factor on the exercise test.16
e physiological basis of the observed interaction between
resting DBP and change in DBP with exercise is not clear, but
resting DBP was not signicant in any of the Cox regression
models. is may represent simple regression to themean.
In a meta-analysis which investigated exercise BP and
long-term CV events and mortality—including 12 longitu-
dinal studies with more than 46,000 patients and 15years
follow up—it was determined that hypertensive BP response
(systolic BP ≥210mm Hg for males and ≥190mm Hg for
females) at moderate exercise intensity during exercise stress
testing is an independent risk factor for CV events and mor-
tality, but they only examined the SBP response.8
One other large study of 12,000 patients investigated the
relationship of hemodynamic response and cardiometa-
bolic risk factors in patients—including patients with cor-
onary artery disease (CAD)—undergoing treadmill exercise
testing. Patients with obesity, hypertension, and smokers
showed higher values of peak SBP and DBP, while in diabetic
patients they did not nd any dierence in DBP. In contrast
to their ndings, we found more abnormal DBP response in
patients having these comorbidities. e dierence may be
explained by the dierent study populations.17
In Myers etal.18 study—which focused on exercise cap-
acity and mortality, both in healthy men and patients with
CAD—peak SBP was lower in those who died, while DBP
was not dierent. ey stated that exercise capacity is a
more powerful predictor of mortality than other exercise
test parameters or even risk factors for CV disease. We
would also like to emphasize that DBP responses—even
with the presence of comorbidities—are not associated with
long-term total or CV mortality; therefore focus should be
turned to other variables including exercise capacity and HR
recovery.19,20
In terms of potential mechanisms, an increase in DBP
with exercise may be a result of increased arterial stiness or
endothelial dysfunction, which are considered early signs of
atherosclerotic vascular disease.21,22 On the other hand, the
fact that coronary arteries ll during diastole might suggest
that an increase in DBP during exercise could be protective
in patients with coronary artery disease, and this has been at
least somewhat conrmed in the settling of myocardial per-
fusion imaging.23 High DBP during exercise may also cause
enhanced external counterpulsation, increasing the develop-
ment of collateral channels.24
us, although we can speculate that increased DBP with
exercise signals higher peripheral arteriolar resistance and
impaired exercise-induced vasodilation through various
mechanisms which increase myocardial oxygen demand
during exercise by increasing aerload, higher exercise DBP
conversely has the potential to decrease exercise-induced
myocardial ischemia by increasing of myocardial bloodow.
Strengths and limitations
e strengths of our study include a large consecutive cohort
with complete mortality follow-up over a long time period.
Exercise test data were robust and complete, and important
data on comorbidities and pharmacotherapies were available.
In terms of limitations, our study reected the limited racial
diversity seen in Minnesota, so our results may not be applic-
able to more diverse racial or ethnic groups, especially African
Americans who have high rates of hypertension in comparison
to white Americans. Overall mortality was low, reecting the
status of Minnesota as a state with low total and CV mortality.
Measuring BP on an exercise test is not always easy at a
high HR given noise of the treadmill and patient motion. We
relied solely on unconrmed DBP assessment by ausculta-
tion with a manually inated cu; invasive measures of BP
were not performed. Exercise tests were not systematically
repeated to determine if the response of DBP to exercise was
consistent.
Exercise tests were conducted in a clinical environment,
and patients were instructed to exercise to subjective fa-
tigue. Gas exchange was not measured to conrm the level
of metabolic eort by the respiratory exchangeratio.
For our nonimaging noncardiopulmonary stress tests,
we generally used the Bruce protocol (>90% of tests where
gas exchange is not measured), so we did not have a suf-
cient number of patients of cycle ergometer or treadmill
tests on other protocols to perform similar analyses of DBP
responses.
ACKNOWLEDGMENTS
e authors would like to acknowledge the critical assist-
ance of Laurie Barr for her help in extracting these data from
the Mayo Integrated Stress Center database. No specic
funding was required for this work.
DISCLOSURE
e authors declared no conict of interest.
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