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From: Rich Murray on 17 Sep 2008 00:29
Overlooked aspartame-induced hypertension, HJ Roberts, Southern
Medical J, 2008 Sept.: Murray 2008.09.16
http://rmforall.blogspot.com/2008_09_01_archive.htm
Tuesday, September 16, 2008
http://groups.yahoo.com/group/aspartameNM/message/1556

South Med J. 2008 Sep; 101(9):969.
Overlooked aspartame-induced hypertension.
Roberts HJ.
PMID: 18708962

Overlooked Aspartame-Induced Hypertension

To the Editor: As a constructive comment on the excellent article by
Trewet, C. L. and Ernst, 1 on "resistant hypertension", allow me to
mention an important factor contributing to hypertension that
continues to be overlooked: "diet" products containing aspartame
which are being consumed by an estimated two-thirds of the population.

I reported earlier on hypertension in 64 aspartame reactors who were
not known to have had an elevated blood pressure prior to using this
chemical. 2

Its severity was impressive -- e.g., a registered nurse
with readings as high as 280/160.

The blood pressure in another nurse rose to 240/150.

Several patients were studies to rule out pheochromocytoma.

The causative role of aspartame products was indicted by
1) the striking improvement or normalization of blood pressure
after stopping aspartame, and
2) the prompt recurrence of hypertension following aspartame
resumption.

The association of hypertension with the consumption of cola
beverages (Diet Coke (TM)) has been confirmed by
Winkelmayer et al in a large prospective study of female nurses --
but NOT with caffeine consumption. They speculated that
"perhaps some other compound contained in soda-type soft drinks ....
may be responsible for the increased risk of hypertension."

I have reviewed the likely pharmacologic basis, especially the
conversion of phenylalanine (comprising half of the aspartame
molecule) to dopamine, epinephrine, and norepinephrine ... all
pressor substances. 2

Other aspartame reactors have evidenced peripheral vasomotor
features (including the Raynaud phenomenon, 2
and probable pulmonary hypertension. 4

At the very least, persons with hypertension that resist
conventional therapy ought to avoid aspartame products.

H. J. Roberts, MD, FACP, FCCP
Palm Beach Institute for Medical Research, Inc.
West Palm Beach, Florida

References

1. Trewet CL, Ernest ME.
Resistant hypertension; identifying causes and optimizing treatment
regimens.
South Med J 2008; 101: 166-173.

2. Robert HJ.
Aspartame Disease: An Ignored Epidemic
West Palm Beach, Sunshine Sentinel Press, 2001.

3. Winkelmayer WC, Stampfer MJ, Willett WC, et al.
Habitual caffeine intake and the risk of hypertension in women.
JAMA 2005; 294: 2330-2335.

4. Roberts HJ.
Aspartame induced dyspnea and pulmonary hypertension.
Townsend Letter for Doctors and Patients 2003: 54-55.
____________________________________________________


Aspartame Induced Arrhythmias and Sudden Death, HJ Roberts 2004:
Murray 2008.06.26
http://rmforall.blogspot.com/2008_06_01_archive.htm
Thursday, June 26, 2008
http://groups.yahoo.com/group/aspartameNM/message/1544

Aspartame Induced Arrhythmias and Sudden Death

By H. J. Roberts, M.D., F.A.C.P., F.C.C.P.
E-Mail: HJrobertsmd(a)aol.com
(c)2004 by H. J. Roberts, M.D.

A recent extensive review of sudden death in young athletes (1)
made no mention of aspartame as a primary cause or suspected
contributory factor, especially when demonstrable pathology was
absent.

This issue has assumed great public health importance because
"diet" products containing this chemical are being consumed by
over two-thirds of the population -- especially weight-conscious
persons.

I have repeatedly reported the serious cardiovascular,
'neuropsychiatric, metabolic and other adverse effects of
aspartame products. (2-4)

Among the first 1200 aspartame reactors in my data base,
193 (16%) had symptomatic arrhythmia,
85 (7%) atypical chest pain, and
64 (5%) recent or aggravated hypertension.

One hypertensive patient developed complete heart block within
hours after consuming his first diet cola.

Another had undergone unsuccessful radio frequency ablations in the
heart before awareness of having aspartame disease.

Pheochromocytoma was suspected in several aspartame reactors.

The issue of sudden death related to aspartame and its breakdown
products has been raised a number of times, particularly among
previously well individuals using such products... including pilots
and drivers, (3,4,6) and athletes.

I have detailed the release of norepinephrine, epinephrine, dopamine
and free methanol by aspartame; a host of pertinent-related
pathophysiologic conditions,
(e.g., cumulative formaldehyde adducts derived from aspartame in
tissue proteins and nucleic acids; excessive insulin release);
direct oropharyngeal absorption from gum, breath fresheners and
other products; and the increasing problem of aspartame addiction.
(4-7)

The likelihood of pulmonary hypertension induced by the
vasoconstrictive effects of aspartame products also has been
considered. (5)

It is relevant that unexplained dyspnea was experienced by 110
aspartame reactors, usually with prompt improvement after
abstinence.

Moreover, primary pulmonary hypertension was found at autopsy
in a 27 year old female aspartame reactor.

The lack of familiarity of most physicians and medical examiners
with the foregoing considerations can have serious legal
consequences.

A case in point is that of a young woman (also a Sunday School
teacher) who has been sentenced to serve 50 years in a Virginia
prison for allegedly poisoning her husband with methyl alcohol.
[ Diane and Charles Fleming ]

Elevated methanol blood concentrations were found postmortem in
this body builder/basketball player who drank ten diet drinks and
other aspartame products daily.

She remains incarcerated despite affidavits indicating that 10% of
aspartame becomes free methyl alcohol after consumption.

The need for clinicians and corporate-neutral investigators to
evaluate the contributory role of aspartame in cardiopulmonary
disorders and sudden death, and drug interactions with aspartame,
is underscored by the frequency of persons dying unexpectedly
being categorized as "death due to causes yet to be determined."

One interested resident of Orange county (California) found 192
persons listed in this category between July 11 and November 15,
2003 according to the Orange county Register.

References:

Maron BJ,
Sudden death in young athletes,
N Engl J Med 2003; 349: 1064-1075.

Roberts HJ,
Reactions to aspartame containing products: 551 cases,
J Appl Nutr l988; 40: 86-94.

Roberts HJ, Aspartame (NutraSweet): Is It Safe?
Philadelphia, The Charles Press, 1989.

Roberts HJ,
Aspartame Disease: An Ignored Epidemic.
West Palm Beach, Sunshine Sentinel Press, 2001.

Roberts HJ,
Aspartame-induced dyspnea and pulmonary hypertension,
Townsend Letter for Doctors & Patients 2003; 237 (January): 64-65.

Roberts HJ,
Ignored Health Hazards for Pilots and Drivers.
West Palm Beach, Sunshine Sentinel Press, 1998.

Roberts HJ, Aspartame (NutraSweet) addiction,
Townsend Letter for Doctors & Patients, 2000; 198 (January): 52-57.

H. J. Roberts, MD, FACP, FCCP
Palm Beach Institute for Medical Research
P. O. Box 17799
West Palm Beach, Florida 33416 USA
____________________________________________________


http://www.dorway.com/tldaddic.html 5-page review
Roberts HJ Aspartame (NutraSweet) addiction.
Townsend Letter 2000 Jan; HJRobertsMD(a)aol.com
http://www.sunsentpress.com/ sunsentpress(a)aol.com
Sunshine Sentinel Press P.O.Box 17799 West Palm Beach, FL 33416
800-814-9800 561-588-7628 561-547-8008 fax

http://groups.yahoo.com/group/aspartameNM/message/669
1038-page medical text "Aspartame Disease: An Ignored Epidemic"
published May 30 2001 $ 60.00 postpaid data from 1200 cases
available at http://www.amazon.com
over 600 references from standard medical research

http://groups.yahoo.com/group/aspartameNM/message/790
Moseley: review Roberts "Aspartame Disease: An Ignored Epidemic":
Murray 2002.02.07

Roberts, Hyman J., 1924- ,
Useful insights for diagnosis, treatment and public heath: an updated
anthology of original research, 2002, 798 pages,
aspartame disease, pages 627-685, 778-780

http://groups.yahoo.com/group/aspartameNM/message/859
Roberts: the life work of a brilliant clinician: aspartame toxicity:
Murray 2002.08.02
____________________________________________________


re "A Few too Many", Joan Acocella, The New Yorker, long review of
hangover
research 2008.05.26 -- same levels of formaldehyde and formic acid in
FEMA
trailers and other sources (aspartame, dark wines and liquors, tobacco
smoke): Murray 2008.06.05
http://rmforall.blogspot.com/2008_06_01_archive.htm
Thursday, June 5, 2008
http://groups.yahoo.com/group/aspartameNM/message/1541


formaldehyde and formic acid in FEMA trailers and other sources
(aspartame,
dark wines and liquors, tobacco smoke): Murray 2008.01.30
http://rmforall.blogspot.com/2008_01_01_archive.htm
Wednesday, January 30, 2008
http://groups.yahoo.com/group/aspartameNM/message/1508

The FEMA trailers give about the same amount of formaldehyde and
formic acid
daily as from a quart of dark wine or liquor, or two quarts (6 12-oz
cans)
of aspartame diet soda, from their over 1 tenth gram methanol impurity
(one
part in 10,000), which the body quickly makes into formaldehyde and
then
formic acid -- enough to be the major cause of "morning after" alcohol
hangovers.

Methanol and formaldehyde and formic acid also result from many fruits
and
vegetables, tobacco and wood smoke, heater and vehicle exhaust,
household
chemicals and cleaners, cosmetics, and new cars, drapes, carpets,
furniture,
particleboard, mobile homes, buildings, leather... so all these
sources add
up and interact with many other toxic chemicals.

methanol impurity in alcohol drinks [ and aspartame ] is turned into
neurotoxic formic acid, prevented by folic acid, re Fetal Alcohol
Syndrome,
BM Kapur, DC Lehotay, PL Carlen at U. Toronto, Alc Clin Exp Res 2007
Dec.
plain text: detailed biochemistry, CL Nie et al. 2007.07.18: Murray
2008.02.24
http://rmforall.blogspot.com/2008_02_01_archive.htm
Sunday, February 24, 2008
http://groups.yahoo.com/group/aspartameNM/message/1524

"Of course, everyone chooses, as a natural priority, to enjoy peace,
joy,
and love by helping to find, quickly share, and positively act upon
evidence
about healthy and safe food, drink, and environment."

Rich Murray, MA Room For All rmforall(a)comcast.net
505-501-2298 1943 Otowi Road, Santa Fe, New Mexico 87505

http://RMForAll.blogspot.com new primary archive

http://groups.yahoo.com/group/aspartameNM/messages
group with 133 members, 1,556 posts in a public archive

http://groups.yahoo.com/group/aspartame/messages
group with 1,132 members, 22,932 posts in public archive
____________________________________________________


details on 6 epidemiological studies since 2004 on diet soda (mainly
aspartame) correlations, as well as 13 other mainstream studies on
aspartame toxicity since summer 2005: Murray 2007.11.14
http://rmforall.blogspot.com/2007_11_01_archive.htm
Wednesday, November 14, 2007
http://groups.yahoo.com/group/aspartameNM/message/1490
[ Selection ]

" When studying individual classes of caffeinated beverages, habitual
coffee consumption was not associated with increased risk of
hypertension.

By contrast, consumption of cola beverages was associated with an
increased risk of hypertension, independent of whether it was sugared
or
diet cola (P for trend <.001).

Conclusion
No linear association between caffeine consumption and incident
hypertension was found.

Even though habitual coffee consumption was not associated with an
increased risk of hypertension, consumption of sugared or diet cola
was
associated with it.

Further research to elucidate the role of cola beverages in
hypertension
is warranted. "

" The findings were consistent between the cohorts and were present
across types of soda beverages:
both sugared cola and diet cola beverages were associated with an
increased risk of hypertension (Table 5 and Table 6).

Hence, we speculate that it is not caffeine but perhaps some other
compound contained in soda-type soft drinks that may be responsible
for
the increased risk in hypertension.

If these associations are causal, they may have considerable impact on
public health. "

" Finally, an examination of the possible associations between
caffeinated cola beverages and the risk of hypertension
showed that
sugared caffeinated cola (NHS I, P for trend = .03; NHS II, P for
trend
<.001) (Table 5)
and diet caffeinated cola (NHS I, P for trend = .02; NHS II, P for
trend <.001) (Table 6)
were positively associated with hypertension in both cohorts. "

" Table 6. Age-Adjusted and Multivariate Relative Risks for Incident
Hypertension According to Frequency of Diet Cola Intake

Glasses or Cans of Diet Cola per Day
under 1 ------- 1 ----------- 2-3 ------- 4 and more --- P for Trend

Nurses’ Health Study I (1990-2002) 53,175 nurses, ages 44-69 in 1990

No. of cases of Incident Hypertension
17,268 ------- 1,154 ---------- 662 --------- 130
% 100 ---------- 6.7 ---------- 3.8 -------- 0.75
#% 32.5 -------- 2.2 ---------- 1.3 -------- 0.25 #% of 53,175

Person-years
479,890 ----- 30,579 --------17,316 ------- 3,173
% 100 -----------6.4 ---------- 3.6 -------- 0.66

Age-adjusted relative risk (95% CI)
1.00 -- 1.16(1.10-1.24)-- 1.23(1.13-1.33)-- 1.37(1.15-1.62)-- under .
001

Multivariate relative risk (95% CI)*
1.00 -- 1.07(1.00-1.13) -- 1.06(0.98-1.15) -- 1.16(0.97-1.37)------ .
02

Nurses’ Health Study II (1991-2003) 87,369 nurses, ages 27-44 in 1991

No. of cases of Incident Hypertension
10,192 -------- 1,452 ---------- 1,358 -------- 449
% 100 ---------- 14.3 ----------- 13.3 --------- 4.4
#% 11.7 --------- 1.7 ------------ 1.6 --------- 0.51 #% of 87,369

Person-years
713,971 ----- 91,144 ------- 77,398 ------- 21,265
% 100 --------- 12.8 --------- 10.8 ---------- 3.0


Age-adjusted relative risk (95% CI)
1.00 -- 1.16(1.10-1.23) -- 1.33(1.26-1.41) -- 1.63(1.49-1.80) under .
001

Multivariate relative risk (95% CI)*
1.00 -- 1.05(0.99-1.11) -- 1.09(1.03-1.15) -- 1.19(1.08-1.32) under .
001

Abbreviation: CI, confidence interval.
*Adjusted for age, body mass index, intake of alcohol, family history
of
hypertension, oral contraceptive use (in Nurses’Health Study II only),
physical activity, and smoking status, as well as the other classes of
beverage. "

http://jama.ama-assn.org/cgi/reprint/294/18/2330?ijkey=ff7fa86b688f2c2e23d9b6185\
19b890439fefb9e

full text pdf

http://jama.ama-assn.org/cgi/content/abstract/294/18/2330?ijkey=ff7fa86b688f2c2e\
23d9b618519b890439fefb9e&keytype2=tf_ipsecsha
full text html

JAMA Vol. 294 No. 18, November 9, 2005

Online Features
Original Contribution

Habitual Caffeine Intake and the Risk of Hypertension in Women
Wolfgang C. Winkelmayer, MD, ScD; wwinkelmayer(a)partners.org,
Meir J. Stampfer, MD, DrPH; stampfer(a)hsph.harvard.edu,
Walter C. Willett, MD, DrPH; walter.willett(a)channing.harvard.edu,
Gary C. Curhan, MD, ScD gary.curhan(a)channing.harvard.edu,
JAMA. 2005; 294: 2330-2335.

Context
Caffeine acutely increases blood pressure, but the association between
habitual consumption of caffeinated beverages and incident
hypertension
is uncertain.

Objective
To examine the association between caffeine intake and incident
hypertension in women.

Design, Setting, and Participants
Prospective cohort study conducted in the Nurses’ Health Studies
(NHSs) I and II of 155,594 US women free from physician-diagnosed
hypertension followed up over 12 years
(1990-1991 to 2002-2003 questionnaires).

Caffeine intake and possible confounders were ascertained from
regularly
administered questionnaires.

We also tested the associations with types of caffeinated beverages.

Main Outcome Measure
Incident physician-diagnosed hypertension.

Results
During follow-up, 19.541 incident cases of physician-diagnosed
hypertension were reported in NHS I and 13,536 in NHS II.

In both cohorts, no linear association between caffeine consumption
and
risk of incident hypertension was observed after multivariate
adjustment
(NHS I, P for trend = .29; NHS II, P for trend = .53).

Using categorical analysis, an inverse U-shaped association between
caffeine consumption and incident hypertension was found.

Compared with participants in the lowest quintile of caffeine
consumption, those in the third quintile had a 13 % and 12 % increased
risk of hypertension, respectively (95 % confidence interval in NHS I,
8
% - 18 %; in NHS II, 6 % - 18 %).

When studying individual classes of caffeinated beverages, habitual
coffee consumption was not associated with increased risk of
hypertension.

By contrast, consumption of cola beverages was associated with an
increased risk of hypertension, independent of whether it was sugared
or
diet cola (P for trend <.001).

Conclusion
No linear association between caffeine consumption and incident
hypertension was found.

Even though habitual coffee consumption was not associated with an
increased risk of hypertension, consumption of sugared or diet cola
was
associated with it.

Further research to elucidate the role of cola beverages in
hypertension
is warranted.

Author Affiliations:
Division of Pharmacoepidemiology and Pharmacoeconomics (Dr
Winkelmayer),
Renal Division (Drs Winkelmayer and Curhan),
and Channing Laboratory (Drs Stampfer, Willett, and Curhan),
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical
School,
and Departments of Epidemiology (Drs Stampfer, Willett, and Curhan)
and
Nutrition (Drs Stampfer and Willett), Harvard School of Public Health,
Boston, Mass.

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JAMA. 2006;295:2135.

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What's new in the other general journals
Tonks
BMJ 2005;331:1165-1166.

INTRODUCTION

Approximately 50 million people in the United States have
hypertension,
and the prevalence is increasing. 1

Hypertension is a major risk factor for coronary heart disease,
stroke,
and congestive heart failure. 2-3

Therefore, even small reductions in the prevalence of hypertension
could
have a potentially large public health and financial impact.

Much clinical lore about the possible association between caffeine
intake and the risk of hypertension is available.

Short-term studies have demonstrated that caffeine intake acutely
increases blood pressure, but over time, attenuation of this effect
does
occur. 4

Experimental studies have shown that caffeine can raise plasma levels
of
several stress hormones, such as epinephrine, norepinephrine, 5-6 and
cortisol, all of which can lead to an increase in blood pressure. 6-7

However, these experiments have been limited to relatively short
periods of observation, typically less than 1 week; information on a
more sustained neuroendocrine response to regular exposure to caffeine
is not available.

A long-term effect of caffeine intake on the risk of developing
hypertension would be of substantial public health importance given
the
widespread consumption of beverages containing caffeine, but
currently,
studies of this association are scarce.

A recent longitudinal study in 1,017 men found a positive association
between coffee consumption and blood pressure and incident
hypertension
in unadjusted analyses. 8

Although the association with blood pressure level was significant in
multivariate analyses, a nonsignificant 40 % increase in the risk of
incident diagnosis of hypertension (95 % confidence interval [CI], –6
%
to 109 %) for 3 to 4 cups per day and a 43 % increase (95% CI, –6 % to
118 %) for 5 or more cups per day vs no coffee consumption was found.

No published studies to date of the association between caffeine
intake
and the risk of hypertension in women are available.

To prospectively elucidate whether caffeine intake or consumption of
certain caffeine-containing beverages is associated with the risk of
incident hypertension in women, we examined these questions in 2 large
cohort studies of women, the Nurses’ Health Studies (NHSs) I and II.

METHODS

Study Populations

The NHS I cohort was assembled in 1976 when 121,700 female registered
nurses, aged 30 to 55 years, completed and returned a mailed
questionnaire. 9

Follow-up questionnaires have been mailed every 2 years to update
information on health-related behaviors and medical events.

The NHS II began in 1989, when 116,671 female registered nurses, aged
25
to 42 years, completed and returned a mailed questionnaire.

Questionnaires have been mailed every 2 years to update exposure
information and diagnosis of new diseases.

The follow-up for both cohorts exceeds 90 %.

In this analysis, all participants who had not been diagnosed with
hypertension before the return of the 1990 NHS I or 1991 NHS II
questionnaires were included.

This study was approved by the institutional review board at Brigham
and
Women’s Hospital, Boston, Mass.

Receipt of each questionnaire implies participant’s consent.

Dietary Assessment

Food frequency questionnaires were used to measure dietary intake and
were completed in 1990, 1994, and 1998 for NHS I and 1991, 1995, and
1999 for NHS II.

Participants were asked about their usual intake of foods and
beverages
during the past year.

The response options for specified serving sizes were the following:
never or less than once per month;
1 to 3 times per month;
1 per week;
2 to 4 per week;
5 to 6 per week;
1 per day;
2 to 3 per day;
4 to 5 per day;
and 6 or more per day.

The relevant beverages included on the questionnaire were the
following:
low-calorie cola (eg, Diet Coke or Diet Pepsi with caffeine),
regular cola (eg, Coke, Pepsi,
or other cola beverages with sugar),
tea with caffeine, tea without caffeine,
coffee with caffeine, and decaffeinated coffee.

Total caffeine intake was calculated primarily using US Department of
Agriculture food composition sources.

In these calculations, it was assumed that the content of caffeine was
137 mg per cup of coffee, 47 mg per cup of tea, 46 mg per can or
bottle
of cola beverage, and 7 mg per serving of chocolate candy. 10

This method of measuring coffee intake was shown to be valid in both
the
NHS I cohort and a similar cohort study of male health professionals.
11-13

Assessment of Other Variables

Data on height and family history of hypertension were collected at
baseline in both cohorts.

Information on weight was updated every 4 years.

Using each participant’s updated weight, body mass index was
calculated
by dividing the weight in kilograms by height in meters squared.

Also, an updated variable for weight difference between baseline and
the
time of respective follow-up questionnaire was generated.

Information on oral contraceptive use in the NHS II cohort also was
updated every 4 years.

The same semiquantitative food frequency questionnaires were used to
determine intake of alcohol, sodium, potassium, magnesium, calcium,
and
phosphorus. 14

Physical activity was assessed in NHS I (1988, 1992, and 1996) and NHS
II (1989, 1993, and 1997) cohorts; energy expenditure was expressed in
metabolic equivalent tasks. 15

In addition, the frequency of analgesic drug use (aspirin,
nonsteroidal
anti-inflammatory drugs, and acetaminophen) was ascertained. 16-17

Outcome Definition

The baseline and biennial follow-up questionnaires inquired about
physician-diagnosed hypertension and the year of diagnosis.

Self-reported diagnosis of hypertension was found to be reliable in
the
NHS I cohort. 18

In a subset of women who reported hypertension, review of medical
records confirmed a documented systolic and diastolic blood pressure,
respectively, higher than 140 mm Hg and 90 mm Hg in 100 % and higher
than 160 mm Hg and 95 mm Hg in 77 % of participants.

Additionally, self-reported hypertension was predictive of subsequent
cardiovascular events. 18

A study participant was considered to have a history of hypertension
if
she reported a diagnosis of high blood pressure on any questionnaire
up
to and including the 1990 questionnaire in NHS I and the 1991
questionnaire in NHS II, and therefore was excluded from the study.

Among the remaining women in each cohort, incident cases were included
as those who first reported hypertension on any of the subsequent
biennial questionnaires and whose date of diagnosis was after the
return
of the 1990 NHS I or the 1991 NHS II questionnaire.

This method recently has been used in a study of folate intake and the
risk of hypertension in women. 19

Statistical Methods

The time of observation was between return of the 1990 NHS I and 1991
NHS II and the 2002 NHS I and 2003 NHS II questionnaires.
Participants who did not return the baseline questionnaires for this
study were allowed to contribute person-time for later time intervals,
provided that they had not been diagnosed with hypertension prior to
return of the respective questionnaire.
Participants were censored after being diagnosed with hypertension or
at
the time of death.
Each cohort was analyzed separately.
Age-adjusted Cox proportional hazards regression models were used to
estimate relative risks and 95% CIs.
In addition, multivariate models were constructed that adjusted for
other known risk factors of the study outcome:
age (continuous), body mass index (continuous), alcohol use (6
categories), physical activity (quintiles of metabolic equivalent
tasks), smoking status (current, past, or never), family history of
hypertension (yes/no), and current oral contraceptive use (yes/no;
only
in NHS II).
In additional analyses, we ensured that sodium, magnesium, calcium,
potassium, and phosphorus intake (quintiles) did not confound the
estimates from these multivariate models.
All variables were updated to reflect the most recent value provided
by
the participants on the biennial questionnaires.
Participants with missing data were assigned to a missing category for
that specific time period.
We determined P values for trend for each of the exposures of interest
by using the median for each category.
Level of significance for P values for trend was <.05.
Also the interaction between caffeine intake and the other variables
was
tested.
We used SAS version 8.2 for UNIX statistical software package
(SAS Institute Inc, Cary, NC).

RESULTS

In NHS I, 53,175 women had not been diagnosed with hypertension at
baseline in 1990.

Another 7,916 participants who did not respond to the 1990
questionnaire
but who did respond to a later questionnaire disclosing that they
previously had not been diagnosed with hypertension allowed them to
contribute person-time from that point in time.

Over the 12 years (539,388 person-years of follow-up), 19,541 incident
cases of physician-diagnosed hypertension were reported.

In NHS II, 94,503 participants who were free of hypertension (87,369
in
1991 and an additional 7,134 at a later point in time) were included
in
the analyses of younger women.

During 909,199 person-years of observation, 13,536 participants
responded that they were diagnosed with hypertension by a physician.

Participant characteristics by quintile of caffeine intake are
presented
in Table 1.

In both cohorts, mean caffeine consumption ranged from less than 20 mg/
d
in the lowest quintile to approximately 600 mg/d in the highest
quintile.

Caffeine intake was correlated positively with alcohol consumption and
smoking status
r = 0.12, P < .001 for NHS I; r = 0.23, P < .001 for NHS II),
whereas all other relevant characteristics did not differ
materially across quintiles of caffeine consumption.


Table 1. Baseline Characteristics of Cohort by Quintile of Caffeine
Intake in Nurses’ Health Study I (N = 53,175)
and Nurses’ Health Study II (N = 87,369)*

Age-adjusted analyses demonstrated an inverse U-shaped relation
between
caffeine intake and the incidence of hypertension in both cohorts.

Compared with participants in the lowest quintile of caffeine
consumption, the risk of incident hypertension was increased by 14 %
(95
% CI, 9 % -19 % for NHS I) and 15 % (95 % CI, 9 % - 21 % for NHS II)
for
those in the third quintile, whereas those in the highest quintile
were
not at an increased risk of hypertension (Table 2).

Multivariate adjustment did not materially change these findings
(Table 2).

Table 2. Age-Adjusted and Multivariate Relative Risks for Incident
Hypertension According to Quintile of Caffeine Intake

To further examine this inverse U-shaped association, the frequency of
use of different caffeine-containing beverages in relation to the risk
of incident hypertension was evaluated.
In multivariate models including beverage type, rather than actual
caffeine intake, no association between frequency of intake of
caffeinated coffee and incident hypertension was observed in either
cohort.
Compared with NHS I participants drinking less than 1 cup per day of
caffeinated coffee, the relative risks were
1.06 (95% CI, 1.01-1.10) for those consuming 1 cup per day,
1.00 (95% CI, 0.97-1.04) for those drinking 2 to 3 cups per day,
0.93 (95% CI, 0.88-0.99) for those drinking 4 to 5 cups per day,
and 0.88 (95% CI, 0.80-0.98) for those drinking 6 or more cups per day
(Table 3).
The trend for the NHS I cohort was marginally significant for
an inverse association between coffee intake and the risk of
hypertension (Table 3; P for trend = .02).
The findings in the NHS II cohort were practically identical (P for
trend = .03).
The results for intake of decaffeinated coffee also were similar to
the
data for caffeinated coffee intake (data not shown);
the trend suggested an inverse association of risk of hypertension in
the NHS I cohort (P for trend = .08)
but not in the NHS II cohort (P for trend = .67).

Table 3. Age-Adjusted and Multivariate Relative Risks for Incident
Hypertension According to Frequency of Coffee Intake

An association between caffeinated tea intake and incident
hypertension
in the NHS I cohort (Table 4; P for trend = .79) was not found.
However, in the cohort of younger women in NHS II, a moderate increase
in risk of hypertension (P for trend = .01; Table 4) was detected.

Table 4. Age-Adjusted and Multivariate Relative Risks for Incident
Hypertension According to Frequency of Caffeinated Tea Intake

Finally, an examination of the possible associations between
caffeinated
cola beverages and the risk of hypertension showed that
sugared caffeinated cola (NHS I, P for trend = .03; NHS II, P for
trend
<.001) (Table 5)
and diet caffeinated cola (NHS I, P for trend = .02; NHS II, P for
trend <.001) (Table 6)
were positively associated with hypertension in both cohorts.

Table 5. Age-Adjusted and Multivariate Relative Risks for Incident
Hypertension According to Frequency of Sugared Cola Intake

Table 6. Age-Adjusted and Multivariate Relative Risks for Incident
Hypertension According to Frequency of Diet Cola Intake

Glasses or Cans of Diet Cola per Day
under 1 ------- 1 ----------- 2-3 ------- 4 and more --- P for Trend

Nurses’ Health Study I (1990-2002) 53,175 nurses, ages 44-69 in 1990

No. of cases of Incident Hypertension
17,268 ------- 1,154 ---------- 662 -------- 130
% 100 ---------- 6.7 ---------- 3.8 -------- 0.75
#% 32.5 -------- 2.2 ---------- 1.3 -------- 0.25 #% of 53,175

Person-years
479,890 ----- 30,579 ------17,316 ------- 3,173
% 100 -----------6.4 ---------- 3.6 -------- 0.66

Age-adjusted relative risk (95% CI)
1.00 -- 1.16(1.10-1.24)-- 1.23(1.13-1.33)-- 1.37(1.15-1.62)-- under .
001

Multivariate relative risk (95% CI)*
1.00 -- 1.07(1.00-1.13) -- 1.06(0.98-1.15) -- 1.16(0.97-1.37)------ .
02

Nurses’ Health Study II (1991-2003) 87,369 nurses, ages 27-44 in 1991

No. of cases of Incident Hypertension
10,192 -------- 1,452 ---------- 1,358 -------- 449
% 100 ---------- 14.3 ----------- 13.3 --------- 4.4
#% 11.7 --------- 1.7 ------------ 1.6 --------- 0.51 #% of 87,369

Person-years
713,971 ----- 91,144 --------- 77,398 ----- 21,265
% 100 --------- 12.8 ------------ 10.8 --------- 3.0


Age-adjusted relative risk (95% CI)
1.00 -- 1.16(1.10-1.23) -- 1.33(1.26-1.41) -- 1.63(1.49-1.80) under .
001

Multivariate relative risk (95% CI)*
1.00 -- 1.05(0.99-1.11) -- 1.09(1.03-1.15) -- 1.19(1.08-1.32) under .
001

Abbreviation: CI, confidence interval.
*Adjusted for age, body mass index, intake of alcohol, family history
of
hypertension, oral contraceptive use (in Nurses’Health Study II only),
physical activity, and smoking status, as well as the other classes of
beverage.

Additional analyses adjusting for intake of sodium, magnesium,
potassium, phosphorus, and calcium or analgesic drug use did not
change
the results materially for the caffeine intake or specific beverage
intake analyses. When testing the robustness of the results, such as
by
limiting the analysis to those women who reported having had a routine
physical examination during the time interval or by using baseline
body
mass index and updated change in weight rather than updated body mass
index, the results were virtually unchanged (data not shown).

COMMENT

In this prospective study of the association between caffeine intake
and
the risk of physician-diagnosed hypertension in 2 large cohorts of
women, we found a modest inverse U-shaped association between caffeine
intake and hypertension in both cohorts.

The magnitude of the highest multivariate relative risk was 1.13 in
NHS
I and 1.12 in NHS II.

To better understand this nonlinear relation between caffeine intake
and
the risk of hypertension, we evaluated the individual associations of
several caffeine-containing beverages.

Neither caffeinated nor decaffeinated coffee demonstrated a positive
association with incident hypertension in either cohort.

The results for consumption of caffeinated tea were inconclusive:
although no association was observed in the NHS I cohort, a positive
trend was shown in the NHS II cohort.

By contrast, we found a highly significant association between cola
intake (sugared or low-calorie cola) and incident hypertension that
was
consistent across the cohorts.

To our knowledge, this study is the first to prospectively evaluate
the
putative effect of caffeine consumption on the long-term risk of
hypertension in women.

The speculation that coffee may cause hypertension was supported by
several small experiments over short periods of observation ( under 80
days). 20

If the short-term effects of caffeine on blood pressure persist, then
habitual coffee drinking might contribute to an excess risk of
hypertension.

Such an effect would be of great public health importance given the
widespread use of coffee and other caffeinated beverages.

In this study with more than 1.4 million person-years of follow-up,
the
relevant exposures and outcomes have been found valid and accurate,
11-13,18 and coffee intake was updated to reflect changes in
individual
behavior.

We found strong evidence to refute speculation that coffee consumption
is associated with an increased risk of hypertension in women.

The associations found between caffeinated tea consumption and the
risk
of hypertension differed between the 2 cohorts.

In the NHS I cohort, no association was found; however, in the NHS II
cohort, a significant positive trend was observed.

A recent study conducted among 711 men and 796 women in Taiwan found a
strong inverse association between both frequency and duration of tea
intake and hypertension. 21

Since the types of tea (green or oolong) consumed in that study are
likely different from those consumed in our study of US women, the
comparability of the findings from these 2 studies appears uncertain.

In both NHS cohorts we found a positive association between frequency
of
caffeinated soft drink consumption and the risk of hypertension.

The findings were consistent between the cohorts and were present
across
types of soda beverages: both sugared cola and diet cola beverages
were
associated with an increased risk of hypertension (Table 5 and Table
6).

Hence, we speculate that it is not caffeine but perhaps some other
compound contained in soda-type soft drinks that may be responsible
for
the increased risk in hypertension.

If these associations are causal, they may have considerable impact on
public health.

Recent studies have found an effect of the intake of cola beverages on
insulin resistance in a rat model 22; in humans, the intake of cola
beverages was associated with an increased risk of diabetes in the NHS
II cohort. 23

These studies have attributed these associations to the glycemic load
of
corn syrup, which is used as sweetener in these beverages, and the
caramel coloring, which is rich in advanced glycation end products.

Further studies on the possible mechanisms underlying these
associations
clearly are needed.

We acknowledge the limitations of this study.

We cannot rule out that individuals susceptible to adverse effects of
caffeinated coffee intake on their blood pressure in the past may have
reduced their consumption of beverages containing caffeine.

Patients were asked about the frequency of their food intake, but no
information was available on the daily timing of such ingestion.

We did not directly measure the participants’ blood pressure and the
diagnosis of hypertension was self-reported.

Nonetheless, self-reported blood pressure has been validated and
demonstrated to be a strong predictor of actual values. 18

Furthermore, we do not know whether these findings are generalizable
beyond populations of predominantly white women.

We also cannot exclude the possibility that the associations found are
residually confounded.

Lastly, no statement can be made on the effect of coffee intake on the
control of blood pressure among individuals already diagnosed with
hypertension.

In conclusion, consumption of coffee in women does not appear to
increase the risk of developing hypertension.

Whether caffeinated soft drinks are causally related to the risk of
hypertension and its underlying mechanism will require further study.

AUTHOR INFORMATION

Corresponding Author: Wolfgang C. Winkelmayer, MD, ScD, Division of
Pharmacoepidemiology and Pharmacoeconomics and Renal Division, Brigham
and Women’s Hospital, 1620 Tremont St, Suite 3030, Boston, MA 02120
wwinkelmayer(a)partners.org,

Author Contributions: Dr Winkelmayer had full access to all of the
data
in the study and takes responsibility for the integrity of the data
and
the accuracy of the data analysis.

Study concept and design: Winkelmayer, Willett, Curhan.

Acquisition of data: Stampfer, Willett, Curhan.

Analysis and interpretation of data: Winkelmayer, Stampfer, Willett,
Curhan.

Drafting of the manuscript: Winkelmayer.

Critical revision of the manuscript for important intellectual
content:
Winkelmayer, Stampfer, Willett, Curhan.

Statistical analysis: Winkelmayer, Willett, Curhan.

Obtained funding: Willett, Curhan.

Administrative, technical, or material support: Stampfer, Willett,
Curhan.

Study supervision: Curhan.

Financial Disclosures: None reported.

Funding/Support:
This study was funded by National Institutes of Health grants DK52866,
DK66574, CA87969, and CA050385.

Dr Winkelmayer is a 2004 T. Franklin Williams Scholar in Geriatric
Nephrology and a recipient of the American Society of
Nephrology-ASP-Junior Development Award in Geriatric Nephrology,
jointly
sponsored by the Atlantic Philanthropies, the American Society of
Nephrology, the John A. Hartford Foundation, and the Association of
Subspecialty Professors.
He is also supported by an American Heart Association Scientist
Development grant (0535232N).

Role of the Sponsors:
None of the funding organizations had any role in the design and
conduct
of the study; collection, management, analysis, and interpretation of
the data; or preparation, review, or approval of the manuscript.

Author Affiliations
Division of Pharmacoepidemiology and Pharmacoeconomics (Dr
Winkelmayer),
Renal Division (Drs Winkelmayer and Curhan), and Channing Laboratory
(Drs Stampfer, Willett, and Curhan), Department of Medicine, Brigham
and
Women’s Hospital, Harvard Medical School, and Departments of
Epidemiology (Drs Stampfer, Willett, and Curhan) and Nutrition (Drs
Stampfer and Willett), Harvard School of Public Health, Boston, Mass.

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