IJCS | Volume 31, Nº4, July / August 2018

427 Jorge et al. Vitamin D and cardiovascular disease Int J Cardiovasc Sci. 2018;31(4)422-432 Review Article The Health Professionals Follow-up Study followed up 18,225 men during 10 years and observed an association between low vitamin D levels and increased AMI risk, even after adjustment for other risk factors. 45 Prospective studies have also found a high prevalence of vitamin D deficiency in patients hospitalized with AMI. A multicenter study carried out with 239 patients with acute coronary syndrome (ACS) showed that 96% of the individuals had low vitamin D levels at hospital admission. 46 Some studies show a potential independent association between severe vitamin D deficiency and intrahospital mortality in patients with ACS. Correia et al. 47 studied 206 patients with ACS and found that individuals with serum vitamin D levels lower than 10 ng/mL had a 24% rate of intrahospital cardiovascular mortality, which was significantly higher than that observed in the remaining patients (4.9%). 47 Heart failure HF has been associated with vitamin D deficiency. Shane et al. demonstrated a high prevalence of vitamin D deficiency in patients with HF, as well as an inverse correlation between serum levels of vitamin D with left ventricular function and disease severity. 48 Vitamin D deficiency has been associated with severe adverse events, such as hospitalization due to HF and mortality. Liu et al. 49 reported in a study with 548 patients that low levels of 25-hydroxyvitamin D were associated with higher BNP levels, as well as a higher rate of hospitalization due to HF and increasedmortality rate from all causes. 49 In the LURIC study, a prospective cohort study with 3,299 patients undergoing coronary angiography, the levels of N-terminal (NT)-proBNP related inversely to the levels of vitamin D. 50 In regards toHFwith normal ejection fraction (HFNEF), studies have shown conflicting results in terms of its association with vitamin D deficiency. In 2013, Lagoeiro et al. studied 85 outpatients with suspected HFNEF, of whom32 had confirmedHFNEF, and observed a negative correlation between vitaminDdeficiency and E/E’ ratio. 51 On the other hand, Pandit et al. 52 , in 2014, conducted a retrospective study with 1,011 patients and found no significant association between vitamin D levels and left ventricular diastolic performance. 52 Despite evidence demonstrating an association between vitamin D and HF, the exact mechanism by which this vitamin’s deficiency leads to worse clinical outcomes in patients with HF has not been clearly established yet. A potential mechanism could be through the occurrence of cardiorenal syndrome or worsening of renal function. 53 It is well known that the cardiovascular and renal systems are interrelated and that a decline in one of them could influence the other. Progression of cardiorenal syndrome involves hyperactivation of RAAS and sympathetic nervous system, as well as systemic inflammation, whichmay lead to electrolyte disturbances and disorders in fluid regulation, causing endothelial dysfunction, potentially leading to left ventricular remodeling and myocardial fibrosis. These changes generate a vicious cycle in which a decline in a system’s function contributes to its further deterioration. 54 Evidence supports vitamin D as an important regulator in the progression of cardiorenal syndrome. Deregulations in vitamin D metabolism due to reduced activity of the enzyme 1 α -hydroxylase and depletion of VDBPs due to proteinuria are responsible for vitamin D deficiency in chronic renal patients; given the high prevalence of chronic renal insufficiency in patients with HF, such changes can be prevalent in these patients. 55 Other evidence supporting the role of vitamin D deficiency in the pathogenesis of cardiorenal syndrome relates to the involvement of RAAS and inflammatory cytokines. Vitamin D deficiency leads to RAAS hyperactivation, contributing to left ventricular remodeling and emergence or worsening of HF. 56 Vitamin Ddeficiency can lead to increased production and release of inflammatory cytokines, which may have a direct or indirect negative effect in the myocardium, contributing to cell apoptosis, hypertrophy, fibrosis, ventricular remodeling, and negative inotropic effects, in addition to increased renal fibrosis and renal insufficiency. 57 VitaminDdeficiency andmyalgia induced by statins Statins are very effective agents in primary and secondary cardiovascular prevention in high-risk patients. 58 However, the side effects most frequently observed in the musculoskeletal system, such as myalgia, have been commonly observed in patients treated with statins, and these effects directly affect the adherence to treatment using these medications. Observational studies show that myalgia may occur in approximately 15 to 20% of the individuals treated with statins. 59 However, evidence from daily clinical practice shows that this prevalence is even greater. VDRs are present in muscle cells, and low vitamin D levels are