EAL

HTN: Cocoa and Chocolate (2007)

Citation:

Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P, Desideri G, Blumberg JB, Ferri C. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension. 2005; 46 (2): 398-405.

PubMed ID: 16027246

Study Design:

Randomized Crossover Trial

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

To evaluate the effects of flavanol-rich dark chocolate on 24-hour ambulatory blood pressure monitoring, endothelium-dependent vasorelaxation, insulin sensitivity and vascular inflammation in patients with essential hypertension.

Inclusion Criteria:

Never-treated, grade I patients with essential hypertension, diagnosed according to European Societies of Hypertension and Cardiology criteria
25 to 60 years of age
No diabetes or impaired glucose tolerance
Systolic BP between 140mm Hg and 159mmHg or diastolic BP between 90mm Hg and 99mmHg
Absence of macroproteinuria
BMI between 18 and 27 for males, 18 and 26 for females
Total serum cholesterol under 6.1mmol per L
Serum triglyceride under 1.7 mmol per L.

Exclusion Criteria:

Pregnancy
Concomitant diseases
Use of medications including dietary supplements
Smokers
Consumers of wine and other alcoholic beverages
Patients with atherosclerotic lesions based on Echo-Doppler exam of limb and neck vessels
Patients with cardiac abnormalities based on M-mode and B-mode ECGs.

Description of Study Protocol:

Recruitment

Subjects referred to outpatient department. Controls recruited from medical staff.

Design

Randomized controlled crossover trial.

Blinding Used

Measurements made by blinded personnel.

Intervention

Subjects randomized to receive dark chocolate or white chocolate for 15 days.

Statistical Analysis

Differences in blood pressure and metabolic indices between hypertensives and normotensives analyzed by paired Student's T-test
Within each treatment group, changes in insulin sensitivity indices, blood pressure and biomarkers of vascular inflammation from baseline analyzed by one-factor ANOVA
For multiple comparisons, data were analyzed with a two-factor repeated-measures ANOVA with time and treatment as the two factors
Post-hoc comparisons were performed by Tukey's honestly significant difference test.

Data Collection Summary:

Timing of Measurements

After seven-day chocolate-free run-in phase, subjects assigned to either dark or white chocolate for 15 days, separated by a seven-day chocolate-free washout period and then other assigned treatment.

Dependent Variables

24-hour ambulatory blood pressure monitoring recorded by non-invasive oscillometric device
Endothelium-dependent vasorelaxation via flow-mediated dilation of the brachial artery
Insulin sensitivity via oral glucose tolerance tests after overnight fast
Serum biomarkers of vascular inflammation: High-sensitive C-reactive protein and intercellular adhesion molecule-1 assessed by enzyme-linked immunonephelometric and immunoassay kits
Routine hematological assessment with serum electrolytes and lipid profile, including total cholesterol, HDL and LDL-cholesterol and triglyceride
Homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI) and insulin sensitivity index (ISI) calculated from oral glucose tolerance test values
Body weight.

Independent Variables

Subjects received either 100g per day dark chocolate (480kcals, 88mg flavanols) or 90g per day white chocolate (480kcals, flavanol-free) for 15 days
Isocaloric diets
Seven-day chocolate-free run-in phase, treatments separated by seven-day chocolate-free washout period; subjects given lists of foods
Maintain usual diet and physical activity; compliance checked through daily food and exercise diaries.

Control Variables

Age
Gender.

Description of Actual Data Sample:

Initial N: 20 subjects with essential hypertension; 10 males, 10 females. 15 normotensive controls; seven males, eight females.
Age: Mean, 43.65±7.8 years for patients; mean, 33.9±7.6 years for controls
Anthropometrics: Compared with controls, hypertensives had higher blood pressure (P<0.0001) and HOMA-IR (P=0.005) and lower QUICKI (P=0.0007) and ISI (P=0.01)
Location: Italy.

Summary of Results:

	HTN: Dark Chocolate, Before	HTN: Dark Chocolate, After	Controls: Dark Chocolate, Before	Controls: Dark Chocolate, After
24-hour SBP ABPM	135.5±5.8	123.6±6.3, P<0.0001	109.3±8.4	102.7±6.4, P<0.0001
24-hour DBP ABPM	88.0±4.1	79.6±5.4, P<0.0001	71.6±5.1	67.5±4.2, P<0.0001
SBP daytime ABPM	141.3±4.8	129.3±5.7, P<0.0001	112.9±8.5	105.9±6.6, P<0.0001
SBP night ABPM	120.2±11.6	108.7±9.1, P<0.0001	99.8±8	94.5±6, P<0.0001
DBP daytime ABPM	92.4±3.8	84.6±5.6, P<0.0001	74±5.7	69.8±4.5, P<0.0001
DBP night ABPM	76.2±6.3	66±7, P<0.0001	64.7±3.9	61.5±4, P<0.0001

Other Findings

In hypertensives, dark chocolate reduced SBP (-11.0±6.3mm Hg, P<0.0001) and DBP (-6.2±4.2mm Hg, P<0.0001) and remained unchanged after white chocolate. Ambulatory blood pressure decreased after dark chocolate (24-hour systolic, -11.9±7.7mm Hg, P<0.0001; 24-hour diastolic, -8.5±5.0mm Hg, P<0.0001), but not white chocolate.
In hypertensives, dark chocolate but not white chocolate decreased the homeostasis model assessment of insulin resistance (HOMA-IR, F=16.57, P<0.0001), but it improved the quantitative insulin sensitivity check index (QUICKI, F=29.37, P<0.0001), insulin sensitivity index (ISI, F=39.62, P<0.0001) and flow-mediated dilation
In hypertensives, dark chocolate also decreased serum total cholesterol (from 5.4±0.6 to 5.0±0.7mmol per L, P=0.0003) and LDL-cholesterol (from 3.4±0.5 to 3.0±0.6mmol per L; P<0.05), but not triglycerides or HDL. White chocolate had no effect.
Age and gender did not influence the effect of chocolate on HOMA-IR, QUICKI, ISI, ABPM and FMD values in either group.

Author Conclusion:

Findings support a potentially beneficial action of chocolate flavanols on blood pressure, vasorelaxation and insulin sensitivity in essential hypertensives and suggest directions for further research in this area
Interestingly, consumers of chocolate and other candies appear to have a lower mortality rate, compared to those who do not eat candy
Nonetheless, it is important to note that the dark chocolate used in this and related studies differ markedly from the majority of the commercially available cocoa or chocolate confectionery with very low flavanol content
Caution is always warranted when considering dietary recommendations for foods high in fat and calories, especially for cardiovascular disease.

Funding Source:

University/Hospital:

University of L'Aquila, Tufts University

Reviewer Comments:

Compliance checked through food diaries.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes