Manuscript submitted to International Journal of Cardiology
1 Vitamin D, precocious acute myocardial infarction, and exceptional longevity
Running title: 25(OH)D in centenarians
Authors: Helios Pareja-Galeano, PhD1,2, Rafael Alis, MSc3,4, Fabian Sanchis-Gomar,
MD, PhD2, Alejandro Lucia, MD, PhD1,2, Enzo Emanuele, MD, PhD5
1
European University of Madrid, Spain
2
3
, Catholic
University of Valencia San Vicente Mártir, Valencia, Spain
4
School of Medicine, Catholic University of Valencia San Vicente Mártir, Valencia,
Spain
5
2E Science, Robbio, Pavia, Italy
Type of contribution: Letter to the Editor
Word count: 948
Corresponding author:
Fabian Sanchis-Gomar, MD, PhD
Research Institute of
Avda. de Córdoba s/n
28041 Madrid, Spain.
Phone: +34 91 779 2784; Fax: +34 91 390 8544
2 Recent studies have reported low circulating levels of 25-hydroxyvitamin D
(25(OH)D), the biologically active form of vitamin D, in patients with cardiovascular
disease (CVD) [1], hypertension [2], carotid atherosclerosis [3], atrial fibrillation [4],
and heart failure [5]. Moreover, vitamin D deficiency has been associated with all-cause
mortality [6,7] and predicts adverse cardiac events in patients with established CVD [8]
or after acute myocardial infarction (AMI) [9]. In turn, vitamin D supplementation
improves the modulation of autonomic tone [10].
Although centenarians (ie + years more than the average life
expectancy in the Western world) represent the paradigm for exceptional longevity
(EL), they are usually an heterogenous group of subjects who can either delay
, survive and even escape ) common age-related
diseases [11]. In contrast, precocious AMI is commonly considered a good
pathophysiological model of poor human healthy status, being associated with early
mortality [12-14]. Higher concentrations of 25(OH)D predict subsequent lower 13-year
total mortality and incident CVD [15]. Low levels of 25(OH)D have also been
associated with poor physical function (notably with poor grip strength) in people aged
98+ years [16]. This is an important consideration because preservation of muscle
strength late in life is a key issue in the functional capacity and health status of
long-lived individuals [16].
In the current study, we sought to investigate whether serum 25(OH)D levels can
be associated with healthy EL. To achieve this goal, three groups of subjects were
enrolled: i) centenarians free of age-related illnesses, ie, ( 104
years, 49% males), ii) patients with precocious AMI (ie, occurring before 40 years of
age; n=178, 27 39 years, 57% males), iii) and apparently healthy adults who were
3 were Caucasian whites ascertained to be of Italian descent. The main clinical
characteristics of the study participants have been previously reported [12,13]. Briefy,
all of the centenarians were free of hypertension, obesity, hypercholesterolemia, and
hypertriglyceridemia. All patients with precocious AMI were free of diabetes but some
had hypertension (36%), obesity (21%), hypercholesterolemia (54%), or
hypertriglyceridemia (22%) [12,13]. The study complied with the tenets of the
Declaration of Helsinki and was approved by the local ethics committee. Written
informed consent was obtained from all participants.
Blood samples were obtained under fasting consitions by venipuncture in an
antecubital vein and collected in plain tubes. After clotting, tubes were centrifuged and
sera were kept at -80 ºC until assayed. We measured serum 25(OH)D using the
ARCHITECT 25-OH vitamin D chemiluminescent microparticle immunoassay (Abbott
Diagnostics, Wiesbaden, Germany) [17]. Parathyroid hormone (PTH) was assayed with
a chemiluminescent assay (PTH LIAISON N-TACT; DiaSorin, Saluggia, Italy). Serum
calcium (Ca2+) and phosphorus (P) levels were measured using a BM-Hitachi 747-200
autoanalyzer (Hitachi-Roche, Tokyo, Japan). Comparisons of biochemical parameters
between the three subject groups were performed using ANOVA or Kruskal-Wallis
tests, as appropriate. Serum concentrations of 25(OH)D were also dichotomized into
25(OH)D < 20 or 20 ng/mL, respectively, because this value has been previously
shown to be a reliable cutoff for identifying subjects with greater disease risk [18].
Multivariate logistic regression analysis was performed to test the association between
serum 25(OH)D < 20 ng/mL and EL and precocious AMI after adjustment for sex and
CVD risk factors. error was set at 0.05 (two-tailed).
We found significant differences in serum 25(OH)D levels among the three
4 followed by healthy young adults and AMI patients (Table 1 see also Figure 1 for a
box-and-whisker plots of serum 25(OH)D levels in the three study groups). All pairwise
comparisons between the three study groups were significant (all p<0.001). There were
no significant differences in PTH, Ca2+ or P concentrations among the groups. In
multivariable analysis, the odds ratios for having serum 25(OH)D levels < 20 ng/mL
was 0.31 (95% confidence interval (CI): 0.23, 0.77; p<0.001) in healthy centenarians
and 3.85 (95% CI: 2.12, 6.79, p<0.001) in patients with precocious AMI.
Although the influence of potential environmental confounders (particularly,
individual differences in sun exposure) cannot be ruled out, our data suggest that higher
serum 25(OH)D levels are associated with healthy EL. Bischoff-Ferrari et al. [18]
estimated the optimal serum concentrations of 25(OH)D in relation to bone mineral
density, lower-extremity function, dental health, risk of falls, fractures, cancer
prevention, incident hypertension and mortality. They concluded that 25(OH)D levels <
20 ng/mL are associated with adverse effects, while the concentrations
appeared to be close to 30 ng/mL. Of note, our centenarian dodgers showed mean serum
25(OH)D levels slightly higher than 30 mg/mL. In contrast, AMI patients
were ~14 ng/mL, which falls in the range associated with higher likelihood of disease
conditions. These authors also stated that an intake of vitamin D (cholecalciferol)
/day is needed to reach at least 50% of the aforementioned 25(OH)D optimal
concentrations [18]. Given the low incidence of malnutrition in Western countries, there
is a small possibility that diet deficiencies play a role in the 25(OH)D differences
observed in our study. Numerous risk factors have been associated with vitamin D
deficiency, which should be ideally controlled for in future research. These include
increased distance from the equator, shorter days related to non-summer seasons, indoor
5 clothing, air pollution, smoking, obesity, physical inactivity, genetic factors,
malabsorption, renal and liver disease, and certain medications such as glucocorticoids,
anti-rejection medications, human immunodeficiency virus medications, or some
antiepileptic drugs [19].
In conclusion, serum vitamin D levels seem to be associated with successful
aging, possibly reflecting, among other physiological advantages, a highly conserved
cardiovascular function. The latter could play a central role in the extended life span of
centenarians.
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9 Table 1. Serum levels of 25(OH)D, PTH, Ca2+ and P by group.
Healthy adults (n=180) 27-39 years
Centenarian dodgers
(n=79) 100-104 years
AMI patients
(n=178) 28-39 years 25(OH)D (ng/mL) 23.0 (13.3, 34.0) 32.1 (24.0, 34.2)* 14.4 (12.7, 23.1)*
PTH (pg/mL) 39.1±14.6 41.7±19.1 43.7±17.2
Ca2+ (mg/dL) 9.4±0.5 9.5±0.5 9.4±0.4
P (mg/dL) 3.3±0.6 3.2±0.5 3.3±0.4
Data are expressed as medians (interquartile ranges) for skewed variables or means ±
standard deviations for normally distributed data. Abbreviations: 25(OH)D,
25-hydroxyvitamin D; PTH, parathyroid hormone; Ca2+, calcium; P, phosphorus. Symbol:
10 Legend to Figure 1. Box-and-whisker plots of serum 25-hydroxyvitamin D (25(OH)D)
levels in the three study groups. The boxes represent the median (black middle line)
