Introduction
Left ventricular hypertrophy (LVH) is a relatively
common cardiomyopathy. The prevalence of LVH in the general
population has been estimated at 12.9–16% for males and 9.1–19% for
females (1,2). The prevalence increases markedly with
age (1), the diagnosis of
hypertension (3) and the diagnosis
of diabetes (4). LVH and increased
left ventricular mass (LVM) is furthermore a known predictor of
poor cardiovascular outcomes, including sudden cardiac death
(5), ventricular arrhythmias
(6), and heart failure (7). However, LVH appears to be somewhat
reversible, with studies demonstrating a decreased left ventricular
myocardial mass (LVM) with a reduction in blood pressure (8), as well as exercise and weight loss
(9). Importantly, reductions in LVM
appear to reduce risk of poor cardiovascular outcomes in several
studies (10).
Aged garlic extract (AGE) is a supplement with
several known medicinal qualities. As regards cardiovascular
health, garlic supplementation has been shown to lower total
cholesterol levels (11), blood
pressure (12) and to prevent
oxidative DNA damage in essential hypertension (13). AGE has also been shown to attenuate
the progression of coronary atherosclerosis, improve vascular
function and exert favorable effects on oxidative biomarkers
(14,15). However, to the best of our knowledge,
no studies available to date have examined the effects of AGE on
LVM. Thus, the present placebo-controlled randomized double blinded
study, examined the effects of AGE on LVM in subjects with diabetes
mellitus (DM) using serial contrasted coronary CT scans.
Subjects and methods
Study design
The present study is a single center randomized,
placebo-controlled, double-blind comparison of AGE (2,400 mg daily)
compared to matching placebo capsules (ClinicalTrials.gov ID: NCT01534910). As previously
described (15), AGE (Kyolic),
provided by Wakunaga of America, was formulated by soaking sliced
raw garlic in aqueous ethanol for up to 20 months at room
temperature. The extract was then filtered and concentrated at a
low temperature. The AGE used in this trial contained 305 g
extracted solids/L. The finished product used in this clinical
study was commercially available. The participants were assigned to
AGE or placebo in a double-blinded manner, using numbered
containers assigned to a computer-generated randomization chart by
a nurse coordinator. The subjects were observed on therapy for 52
weeks. The subjects had study-related visits quarterly (at 13, 26,
29 and 52 weeks) where they were assessed for compliance and
adverse events.
Imaging and laboratory data
Laboratory data, including complete blood count,
chemistry panel, hemoglobin A1c levels and inflammatory biomarkers
were collected at weeks 1, 26 and 52. At baseline and week 52, the
subjects underwent non-contrast CT and coronary CT angiography
using a 64-slice multi-detector scanner. Sublingual nitroglycerin
or nitroglycerin spray 0.4 mg was administered prior to the scan.
Prescan beta-blockers were also administered to achieve a resting
heart rate of <60 beats/min. Quantitative data analyses were
performed using automated methods on a workstation and software (AW
4.6; GE Medical Systems) that used a Hounsfield unit-based
endocardial border detection technique. Images were reconstructed
with a slice thickness of 1.25 mm. LVM was also simultaneously
calculated automatically. The mid-diastolic phases were chosen for
measurement of LVM. The user acquiring the measurements was blind
to participant characteristics and randomization status of each
subject. The use of contrast CT for the measurement of chamber size
and LVM has been validated in previous studies (16,17).
Patient population
The patients were males and females aged 30–75 years
with known DM (defined as hemoglobin A1c levels, >6.5%; fasting
blood sugar levels, >125 mg/dl; and/or taking anti-diabetes
medications) with a coronary calcium score of >20 at baseline
and who consented to the study design. This study was approved by
the local IRB (Los Angeles Biomedical research Center). Notable
exclusion criteria included a known allergy to AGE, a body weight
>350 pounds, bleeding disorders, a history of known coronary
artery disease (CAD), any malignancy within the past 5 years and
serum creatinine levels >1.4 mg/dl.
Statistical analysis
Demographic and clinical characteristics were
determined at the baseline time point and compared by randomization
status. A Student's t-test or Chi-square test was used to assess
the differences in all baseline parameters. Continuous variables
are expressed as the means ± SD, while categorical variables are
stated as counts and percentages. For the primary outcome (change
in left ventricular mass over time), an analysis of variance
(ANOVA) model with Tukey's post hoc test was used to compare the
treatment arm versus placebo. Analyses was performed on an
intention-to-treat basis. SAS software (version 9.4; SAS Institute,
Inc.) was used to carry out all statistical analyses.
Results
A total of 65 diabetic patients successfully
completed the 1-year study and received a baseline and follow-up
CT, including 29 patients in the placebo arm and 36 patients in the
active treatment (AGE) arm. The baseline characteristics were
similar between the 2 groups (Table
I). The average age in the placebo group was 58.7 years and
59.4 years in treatment group (P=0.808). A higher number of
subjects in the placebo group were male (72% of patients vs. 50% in
the treatment arm), although this was not statistically significant
(P=0.067). Body mass index (BMI) was similar between the groups
(30.8 vs. 30.0 kg/m2, P=0.567). The subjects in both groups were
generally at a high cardiovascular risk with hypertension being 52%
in the placebo arm and 64% in the treatment arm (P=0.323); and
hyperlipidemia being 83% in the placebo arm vs. 92% in the
treatment arm (P=0.277). The cholesterol levels and inflammatory
marker levels measured were similar between groups. All patients
were diabetic as per the study protocol. All the patient baseline
characteristics are presented in Table
I.
 | Table I.Baseline characteristics of the study
subjects by treatment arm. |
Table I.
Baseline characteristics of the study
subjects by treatment arm.
| Characteristic | Placebo (n=29) | Active (n=36) | P-value |
|---|
| Age, (mean ± SD),
years |
58.7±11.4 |
59.4±11.2 | 0.808 |
| BMI (mean ± SD),
kg/m2 | 30.8±6.0 | 30.0±5.6 | 0.567 |
| Sex, male, n (%) | 21 (72) | 18 (50) | 0.067 |
| Race, Hispanic, n
(%) | 9
(31) | 14 (39) | 0.284 |
| Hypertension, n
(%) | 15 (52) | 23 (64) | 0.323 |
| Taking
anti-hypertensive medication, n (%) | 15 (52) | 23 (64) | 0.323 |
| Hyperlipidemia, n
(%) | 24
(83%) | 33
(92%) | 0.277 |
| Taking
anti-hyperlipidemia medication, n (%) | 24
(83%) | 33
(92%) | 0.277 |
| Family history of
heart disease, n (%) | 14
(48%) | 11
(31%) | 0.144 |
| Post-menopausal, n
(%) | 7
(24%) | 13
(36%) | 0.299 |
| Previous smoker, n
(%) | 11
(38%) | 15
(42%) | 0.760 |
| Present smoker, n
(%) | 5
(17%) | 2
(6%) | 0.131 |
| Taking aspirin, n
(%) | 21
(72%) | 21
(58%) | 0.238 |
| SBP (mean ± SD),
mmHg | 126.59±15.55 |
131.0±18.35 | 0.307 |
| DBP (mean ± SD),
mmHg | 76.86±9.57 | 79.11±9.59 | 0.350 |
| Heart rate (mean ±
SD), mmHg |
71.07±12.91 | 69.11±9.09 | 0.493 |
| Adiponectin (mean ±
SD), μg/dl |
10.01±11.01 |
9.22±5.75 | 0.872 |
| HDL cholesterol (mean
± SD), mg/dl |
40.10±12.56 |
40.11±11.14 | 0.293 |
| LDL cholesterol
calculated (mean ± SD), mg/dl |
72.55±33.10 |
66.56±27.34 | 0.695 |
| non-LDL cholesterol
(mean ± SD), mg/dl | 100.17±42.76 |
89.97±29.31 | 0.757 |
| Total cholesterol
(mean ± SD), mg/dl | 140.28±45.35 | 130.08±29.75 | 0.872 |
| hsCRP (mean ± SD),
mg/l |
3.47±3.90 |
2.26±2.15 | 0.933 |
| Interleukin 6 (mean ±
SD), ng/ml |
2.37±1.89 |
2.60±4.52 | 0.504 |
| Lp-PLA2 (mean ± SD),
ng/ml |
41.17±15.04 |
36.47±13.14 | 0.695 |
| Oxidized LDL (mean ±
SD), U/l |
28.69±10.60 | 24.97±8.07 | 0.923 |
| Triglycerides (mean ±
SD), mg/dl | 138.76±79.38 | 116.92±54.47 | 0.807 |
The baseline mean LVM was similar between groups
(121.0 g in treatment arm vs. 124.0 g in the placebo arm, P=0.69).
At follow-up scans, the mean LVM in the treatment arm decreased to
119 g (1.65% decrease) and the mean LVM in the placebo arm was
similar at 124.6 g (0.48% increase). The decrease in LVM in the
treatment arm trended towards statistical significance (P=0.059).
The change in LVM in the placebo arm was not statistically
significant (P=0.97). The mean difference in absolute change
between the groups was not statistically significant (−1.68 g in
the treatment arm vs. 0.04 g in the placebo arm, P=0.30) (Table II).
| Table II.Left ventricular mass by treatment
arm. |
Table II.
Left ventricular mass by treatment
arm.
|
| Baseline | Follow-up | Within group
change | Between group
change |
|---|
|
|
|
|
|
|
|---|
| Group | LVM (mean ± SD) | P-valuea | LVM (mean ± SD) | P-valueb | P-valuec | P-valued |
|---|
| Active (n=36) | 121.00±34.7 | 0.69 | 119.30±34.77 | 0.542 | 0.0593 | 0.300 |
| Placebo (n=29) |
124.60±37.33 | 124.60±35.13 | 0.9764 |
Discussion
In the present study, a trend towards a decreased
LVM was observed in patients undergoing 1 year of treatment with
AGE, with a reduction of mass of 1.65%. The same trend was not
observed in the placebo arm, in which the LVM was essentially
unaltered following 1 year of placebo therapy (increased by 0.48%).
These results suggest an effect of AGE in reducing LVM; however,
studies with larger sample sizes are warranted to confirm these
findings.
AGE is known to decrease blood pressure (12,18)
which in turn, is known to reduce left ventricular mass (8). A reduction in blood pressure may indeed
be the mechanism behind the observed effects. AGE may also have a
direct effect on cardiomyocytes that has yet to be determined. AGE
has also been demonstrated to improve endothelial function, which
may reduce afterload and stress on the myocardium (19). Finally, AGE reduces inflammation and
this in turn my improve myocardial mass and induce regression
(20).
This study has several limitations. Firstly, the
sample size was small, and may not have been powerful enough to
detect a statistically significant effect of AGE on LVM. Second, it
was only a 1-year study, and it may take a longer period of time to
observe the full effects of AGE on myocardial mass changes. Third,
the population cohort was predominantly male and Hispanic, which
limits generalizability. Future research is required in order to
include similar trials with larger sample sizes and longer duration
in order to better understand the trend observed in the current
study.
Acknowledgements
Not applicable.
Funding
This study was supported by a grant to Dr Budoff
from Wakunaga of America, the manufacturer of the AGE used in this
study.
Availability of data and materials
All data generated or analyzed during this study are
included in this published article or are available from the
corresponding author on reasonable request.
Authors' contributions
EH was invovled in the conception and design of the
study and in the writing of the manuscript. KS was invovled in the
design of the study, and in data collection and the editing of the
manuscript. AK was invovled in the design of the study, and in
stastical analysis and the editing of the manuscript. LC was
invovled in the conception and design of the study, and in data
collection, manuscript supervision, and in the editing of the
manuscript. DB was invovled in data collection and in the editing
of the manuscript. SSM was invovled in data collection and in the
editing of the manuscript. RN was invovled in the conception and
design of the study, data collection, manuscript supervision and in
the editing of the manuscript. SA was invovled in data collection
and in the editing of the manuscript. EJ was invovled in the
conception and design of the study, and in data collection,
manuscript supervision and in the editing of the manuscript. CS was
invovled in the design of the study, data collection and in the
editing of the manuscript. FF was invovled in the design of the
study, data collection, and in the editing of the manuscript. SH
was involved in the design of the study and in the editing of the
manuscript. SS was invovled in the design of the study, data
collection and in the editing of the manuscript. AJ was invovled in
the design of the study and in the editing of the manuscript. BC
was invovled in the design of the study and in the editing of the
manuscript. GT was invovled in the design of the study and in the
editing of the manuscript. MJB was involved in the conception and
design of the study, data collection, manuscript supervision and in
the editing of the manuscript.
Ethics approval and consent to
participate
This study was approved by the local IRB (Los
Angeles Biomedical research Center). All patients provided signed
and written informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests
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