Curr Heart Fail Rep (2013) 10:46–53 DOI 10.1007/s11897-012-0118-4
PHARMACOLOGIC THERAPY (WHW TANG, SECTION EDITOR)
Micronutrients in Chronic Heart Failure Selim R. Krim & Patrick Campbell & Carl J. Lavie & Hector Ventura
Published online: 16 October 2012 # Springer Science+Business Media New York 2012
Abstract Heart failure (HF)-associated mortality remains high, despite guideline-recommended medical therapies. Poor nutritional status and unintentional cachexia have been shown to have a strong association with worse survival in HF patients. Importantly, micronutrient deficiencies are potential contributing factors to the progression of HF. This review aims to summarize contemporary evidence on the role of micronutrients in the pathophysiology and outcome of HF patients. Emphasis will be given to the most wellstudied micronutrients, specifically, vitamin D, vitamin B complex, coenzyme Q10 and L-carnitine. S. R. Krim : P. Campbell : C. J. Lavie : H. Ventura (*) Department of Cardiology, John Ochsner Heart and Vascular Institute, Ochsner Clinical School - The University of Queensland School of Medicine, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA e-mail:
[email protected] S. R. Krim e-mail:
[email protected] P. Campbell e-mail:
[email protected] C. J. Lavie e-mail:
[email protected] C. J. Lavie Pennington Biomedical Research Center, Baton Rouge, LA, USA S. R. Krim : P. Campbell : C. J. Lavie Department of Cardiology, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70001, USA C. J. Lavie Department of Preventive Medicine, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA
Keywords Micronutrients . Vitamins . Coenzyme Q10 . L-carnitine . Heart failure
Introduction With over 5.5 million people affected in the US and an estimated health care-related cost amounting to nearly $28 billion [1], heart failure (HF) and its consequences are expected to continue to increase with the aging of our population. While improving implementation of guidelinerecommended pharmacologic and non-pharmacologic therapies has improved outcomes in HF patients [2], mortality remains significantly high [3, 4]. Poor nutritional status and unintentional weight loss have been identified as independent predictors of mortality in HF patients [5, 6]. Malnutrition and micronutrient deficiencies due to reduced intake, increased wasting, and diuretic therapy are potential contributing factors to the progression of HF. This review aims to underscore the importance and the role of micronutrients in the pathophysiology and outcome of HF patients. We will focus on micronutrients with the largest available data and potential for benefit, namely, vitamin D, vitamin B complex, coenzyme Q10 (CoQ10) and L-carnitine.
Methods We used Medline to search for recently published articles containing the key words “micronutrients”, “vitamins”, “nutrition”, “L-carnitine”, “coenzyme Q10” and “heart failure”. Available data from both observational and recent intervention studies will be presented for each micronutrient. Strengths and limitations of each study will be discussed. Table 1 highlights important studies on micronutrient
Curr Heart Fail Rep (2013) 10:46–53
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Table 1 2012 published studies on micronutrients in heart failure HF heart failure, LVEF left ventricular ejection fraction Micronutrient
Study Author
Study Population
Results
Limitations/strengths
Vitamin D
Gotsman I et al. [18]
25(OH) vitamin D levels were measured in 3,009 HF patients from a health maintenance organization (HMO) and compared to 46,825 non-HF patients
Large study
Thiamine
Schoenenberger AW et al. [30••]
Coenzyme Q10 and selenium
Alehagen U et al. [78]
L-carnitine
Ueland T et al. [67•]
Nine patients with symptomatic systolic HF (LVEF) < 40% were randomized to receive thiamine (300 mg/day) or placebo for 28 days. A 5-year prospective random ized double-blind placebocontrolled trial among Swedish citizens aged 70 to 88 was performed in 443 participants given combined supplementation of selenium and coenzyme Q10 or a placebo Plasma levels of free Lcarnitine as well as several of its precursors and derivates in HF patients (n 0 183) and matched healthy controls (n 0 111) were measured
Higher prevalence of vitamin D deficiency in HF patients when compared to non-HF patients. Vitamin D deficiency was an inde pendent predictor of in creased mortality in patients with HF. Vitamin D supplemen tation was independent ly associated with re duced mortality in HF patients Improved LVEF in Thiamine treated group when compared to placebo
supplementation in HF that were published in 2012. As shown below, most studies have focused on a single micronutrient supplementation strategy. Vitamin D Vitamin D is produced mainly in the skin via the action of ultraviolet-B radiation, which converts 7-dehydrocholesterol into vitamin D3 (cholecalciferol). A smaller source of vitamin D comes from dietary intake (e.g. vitamin D3 from fish and dairy products, vitamin D2 (ergocalciferol) from plants) [7]. A number of studies have shown that vitamin D deficiency is more common among patients with HF compared with age- matched healthy control patients [8–10, 11•]. The mechanisms by which vitamin D deficiency impacts the pathophysiology of HF appears to be multifactorial, including adverse effects on the reninangiotensin system and resultant hypertension (HTN) and abnormal left ventricular (LV) geometry, endothelial function and systemic inflammation (i.e. upregulation of
Very small study
Improved mortality, significant decrease in NT-proBNP levels, and improved cardiac function in the treament group
Not an exclusive HF cohort, although 46 % of the study population were NYHA class II–IV.
High levels of the carnitine derivates acetyl-carnitine and, in particular palmitoyl-carnitine, correlated with the degree of HF, NYHA class. And all cause mortality
Cross sectional study. Control group not optimally matched to the HF patients and did not have hemodynamic data
cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-10) [12–14]. In the clinical setting, the association of low vitamin D levels in chronic HF has been suggested in a number of observational studies and case control studies [8, 10, 12, 15••]. Ameri et al. [16] showed that mean serum 25(OH) vitamin D levels were significantly lower in HF patients when compared to healthy controls. Moreover, among HF patients who underwent echocardiography, those with serum 25(OH) vitamin D levels < 10 ng/ml (< 25 mmol/L) had larger LV volumes and lower LV systolic function when compared to patients with serum 25(OH) vitamin D levels > 10 ng/ml. Another study by Pilz et al. [10] showed a significant negative correlation between serum 25(OH) vitamin D, New York Heart Association (NYHA) class and NTproBNP levels. Interestingly, a positive correlation was observed between mean serum 25(OH) vitamin D and LV function. Additionally, Shane et al. [8] measured 25(OH) vitamin D in 101 patients with severe HF who were undergoing evaluation for cardiac transplantation. In their study,
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UNOS status 1 patients (inotrope dependent patients/LV assist devices) had significantly lower serum 25(OH) vitamin D levels. Moreover, low serum 25(OH) vitamin D concentrations were associated with evidence of diminished exercise tolerance as measured by peak oxygen consumption (VO2.) Randomized controlled studies evaluating the effect of vitamin D replacement on HF outcomes have shown mixed results [12, 15••, 17]. In one study [12], 123 ambulatory HF patients with NYHA Class II–IV symptoms were randomized to receive either 50 μg of vitamin D3 plus 500 mg of calcium daily or placebo plus 500 mg of calcium daily for 9 months. The study group showed a higher increase in median 25(OH) vitamin D levels when compared to the control group. Although vitamin D supplementation was not associated with significantly favorable changes in natriuretic peptides levels, cardiac volumes or LV function, patients who received vitamin D showed higher increase serum concentrations of the anti-inflammatory cytokine IL-10 and lower levels of cytokine TNF-α. On the other hand, natriuretic peptides levels, LV ejection fraction (LVEF) and cardiac volumes did not significantly change between the two groups. Moreover, both groups showed similar survival rate after 15 months of follow-up. The suboptimal vitamin D levels in the control group, as well as the high number of dropouts, were an important limitation of the study and may have explained those findings. Another study [14] investigated the effects of vitamin D supplementation on function exercise capacity and quality of life (QoL) in older HF patients with known vitamin D deficiency (defined as 25 OH vitamin D level of
