Vitamin D status, left ventricular geometric abnormalities and cardiovascular disease

Authors

  • C. J. Lavie,

    Corresponding author
    1. Ochsner Heart and Vascular Institute, Ochsner Clinical School, University of Queensland, School of Medicine, New Orleans, LA, USA
    2. Pennington Biomedical Research Center, Baton Rouge, LA, USA
    • Correspondence: Carl Lavie MD, Ochsner Heart and Vascular Institute, 1514 Jefferson Hwy, New Orleans, Louisiana, LA 70121, USA.

      (fax: +504-842-5875; e-mail: clavie@ochsner.org).

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  • J. J. DiNicolantonio,

    1. Wegmans Pharmacy, Ithaca, NY, USA
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  • J. H. O'Keefe,

    1. Mid America Heart Institute at St. Luke's Hospital, University of Missouri, Kansas City, MO, USA
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  • R. V. Milani

    1. Ochsner Heart and Vascular Institute, Ochsner Clinical School, University of Queensland, School of Medicine, New Orleans, LA, USA
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Although cardiovascular disease (CVD) mortality in the USA has reached a plateau during the last four decades, indeed even declining slightly in the last 20 years, CVD remains the leading cause of morbidity and mortality in both men and women in the USA and most western societies [1]. The projected total cost of CVD in the USA for 2008 was more than $500 billion and is expected to be more than double during the next two decades, thus emphasizing the need for prevention and treatment of CVD [1]. Although much attention has focused on the leading CVD risk factors, namely obesity, type 2 diabetes mellitus (T2DM), hypertension, dyslipidaemia and smoking, other factors may also be involved in the pathogenesis and progression of CVD. In the current issue of the Journal of Internal Medicine, Ameri et al. [2] highlight the association in a healthy cohort from the Baltimore Longitudinal Study of Aging between vitamin D and left ventricular (LV) geometry, two potential risk factors for CVD that we have previously investigated [3-12].

An adverse impact of LV hypertrophy (LVH) on CVD morbidity and mortality has been indicated in many studies [7]. The major risk factors for LVH include hypertension, obesity and age, all of which are also known risk factors for CVD. However, data also suggest that LVH may be independently related to CVD, including both coronary heart disease and heart failure (HF). Many other cardiac abnormalities and risk factors, including LV systolic dysfunction, T2DM and valvular heart disease, lead to marked increases in the risk of LVH, and this may be partly related to the known association between LVH and CVD morbidity and mortality [7]. We have demonstrated the powerful prognostic impact of both eccentric and concentric LVH on subsequent mortality, even in large cohorts of patients without significant valvular heart disease and with preserved LV systolic function [7-10]. Moreover, we also demonstrated in these cohorts that the more subtle LV geometric abnormality of concentric remodelling, which represents an increase in relative wall thickness (i.e. thick ventricular walls relative to LV chamber size), without definite LVH (according to the recommended LV mass criteria), was associated with increases in subsequent mortality of more than twofold [7-10]. Furthermore, adverse changes in LV geometry over time have been associated with high rates of mortality, whereas favourable remodelling and regression of LVH have been associated with increased survival [8]. Finally, we recently demonstrated that 13% of patients with concentric LVH and preserved systolic function progressed to systolic dysfunction and HF during a 3-year follow-up [11]. Therefore, we have emphasized the potential value of reporting and recognizing the importance of LV geometric abnormalities, including both concentric remodelling and definite LVH, in CVD prevention.

Although the exact definition of vitamin D deficiency has been heavily debated [3-5], unequivocally low levels of vitamin D (<20 ng mL−1) are now recognized to be highly prevalent worldwide, particularly in elderly populations, and even more so in mainly house-bound and physically inactive elderly individuals. Likewise, the exact role of vitamin D in the pathogenesis of CVD is controversial, but low levels of vitamin D may adversely affect the cardiovascular system, including increasing levels of parathyroid hormone, activating the renin–angiotensin–aldosterone system (RAAS) and increasing insulin resistance, thus leading to hypertension and LVH, metabolic syndrome and T2DM, systemic inflammation and increased risk of atherosclerosis and CVD events (Fig. 1) [3].

Figure 1.

Potential mechanisms for CV effects of vitamin D deficiency. CV, cardiovascular; DM, diabetes mellitus; HTN, hypertension; LVH, left ventricular hypertrophy; MetS, metabolic syndrome; RAAS, renin–angiotensin–aldosterone system. Reproduced from Lavie et al. [3]

In the study conducted in an elderly cohort with low levels of vitamin D deficiency (<12%), Ameri et al. demonstrate an interesting interaction between vitamin D status, hypertension and abnormalities of LV geometry [2]. Very recently, Fall et al. reported that high circulating vitamin D concentrations were associated with improved LV geometry and function amongst elderly subjects from Sweden [13]; this finding was supported by the results of the many studies reviewed by these authors, but not by those of other studies [14, 15]. Certainly, it is reasonable that low levels of vitamin D may lead to activation of the RAAS and relative hyperparathyroidism, both of which may increase the risk of hypertension/LVH. However, many factors may be associated with vitamin D deficiency, which can confound the relationship between vitamin D deficiency and abnormal LV geometry, including obesity, T2DM, insulin resistance, race, age and a sedentary indoor lifestyle.

It should be noted that Ameri and co-workers did not assess some potentially important information, such as details regarding hypertension (duration and severity of hypertension and medication), alcohol consumption, 24-h urinary excretion of phosphate and calcium (which may better represent total body calcium and phosphate stores than serum levels) and, most importantly, dose and duration of vitamin D supplementation. In addition, the population studied was relatively healthy, with more than 60% use of vitamin D supplementation and a very low prevalence (7%) of LVH. The authors also did not assess levels of fibroblast growth factor-23 (FGF-23). Recent evidence has highlighted the role in CVD of FGF-23, a hormone secreted into the blood from osteocytes (which increase renal phosphorous excretion and inhibit vitamin D activation), suggesting that FGF-23 is independently associated with all-cause death and incident HF in the elderly, especially in those with chronic kidney disease [16]. It is possible that increased FGF-23, levels of which may rise in parallel with vitamin D concentration as Ameri et al. suggest, may at least in part underlie the abnormal LV geometry observed by the authors at raised vitamin D levels. Indeed, it has been shown that FGF-23 has a direct role in LVH and mortality in patients with chronic kidney disease [17]. Therefore, evaluation of FGF-23 levels, as well as parathyroid hormone and calcium/phosphate status, may be a useful addition in future studies of the impact of vitamin D on LV geometry.

In conclusion, substantial evidence supports a role of LV geometry in the pathogenesis of CVD. Vitamin D metabolism appears to be associated with the RAAS, hypertension and LV geometry/LVH, as well as with other aspects of CVD. The findings of this study, together with previous evidence, have raised concerns about a potential U-shaped relationship between vitamin D levels and CVD [3, 18]. Future, large randomized placebo-controlled trials, such as the VITAL (VITamin D and OmegA-3 TriaL), may increase understanding of the relationships between baseline and on-treatment vitamin D levels and subsequent CVD and cancer morbidity and mortality. In addition, these studies should not only provide insight into the role of vitamin D deficiency in CVD and cancer, but may also determine whether high levels of this vitamin/hormone are associated with clinical toxicity.

Conflict of interest statement

There is no conflict of interest to declare.

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