Low levels of vitamin D and coronary artery disease: Is it time for therapy?

The association between vitamin D and the prevalence and severity of coronary artery disease (CAD), major established cardiovascular risk factors, and acute ischemic events has been consistently demonstrated in large-scale observational studies and meta-analyses, with relevant prognostic implications. The rise in prevalence of hypovitaminosis D in recent years, reaching pandemic pro-portions, has pointed to the importance of the identification and optimization of the indications and strategies for the therapeutic use of vitamin D, with particular relevance for cardiovascular health. However, vitamin D supplementation has provided so far inconsistent results in primary prevention, with even fewer data reported in patients with established CAD. The present review aims to provide an updated overview of the available evidence and potential therapeutic applications of vitaminD in patients with CAD.

Prognostic impact of Vitamin D deficiency in patients with coronary artery disease undergoing percutaneous coronary intervention.

BACKGROUND: Whether Vitamin D deficiency represents an independent predictor of mortality and major cardiovascular events or rather the mirror of a more advanced clinical condition with increased comorbidities is still debated. We aimed at assessing the impact of vitamin D levels on the long-term outcomes among patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention. METHODS: Consecutive patients from a single centre were included. Vitamin D levels were measured at admission by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc). Severe deficiency was defined for 25(OH)D < 10 ng/ml. The primary study endpoint was overall mortality. Secondary endpoints were cardiovascular mortality, recurrent acute coronary syndrome or major cardiovascular events (a composite of death, recurrent MI and target vessel revascularization) at the longest available follow-up. RESULTS: We included a total of 705 patients, that were divided according to vitamin D tertiles (<12.7; 12.7-21.59; ≥21.6 ng/ml). Lower levels of Vitamin D were associated with renal failure (p=0.03), more severe coronary disease (p=0.001), diabetes mellitus and previous CABG (p<0.001), lower ejection fraction (p=0.02), acute presentation (p=0.04), use of statins (p=0.02), diuretics, nitrates and clopidogrel (p<0.001) and RASI (p=0.008). An inverse association was documented with BMI, glycemia, total cholesterol (p<0.001), creatinine and WBC (p=0.001). At a median follow-up of 996.5 [377-1552] days, 3.8% of the patients died. Vitamin D deficiency was significantly associated with overall mortality (7.6% vs 2.9% vs 0.4%, adjusted HR[95%CI]=3.6[1.43-8.9], p=0.006), MACE (adjusted HR[95%CI]=1.32[1.07-1.63], p=0.01) and the composite of death and MI (adjusted HR[95%CI]=1.3[1.03-1.65], p=0.03). A similarly increased risk was confirmed for all major higher-risk subsets of patients, with no significant interaction according to age, gender, diabetes mellitus or chronic kidney disease. CONCLUSION: Among patients undergoing percutaneous coronary interventions, lower levels of vitamin D are associated with an over 3-fold increased risk of mortality and major cardiovascular events. Future larger studies are certainly warranted in order to define the prognostic implications of cholecalciferol supplementation among high-risk patients with established coronary artery disease.

Cholecalciferol levels, inflammation and leukocytes parameters: Results from a large single-centre cohort of patients.

BACKGROUND: Vitamin D deficiency represents a pandemic health problem with a broad spectrum of clinical implications. Several studies have involved lower levels of vitamin D with inflammatory disorders including cardiovascular, autoimmune and infectious disease. Indeed, the pathophysiological mechanisms are still poorly ascertained. We aimed at evaluating the impact of cholecalciferol (25(OH)D) levels on the biomarkers of acute-phase response and inflammation in a large cohort of patients with cardiovascular disease. METHODS: Consecutive patients undergoing coronary angiography were included. Main clinical features and chemistry parameters were assessed at admission. 25(OH)D levels were measured by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc, Stillwater, US). Hypovitaminosis D was defined for 25(OH)D < 10 ng/ml. RESULTS: A total of 3974 patients were included, of whom 29.4% had hypovitaminosis D. 25(OH)D deficiency was associated to age, female gender, diabetes mellitus, renal failure, previous percutaneous coronary intervention and smoke, acute presentation, severe coronary disease, higher glycemia and cholesterol and lower hemoglobin and ejection fraction (p < 0.001), higher platelet count (p = 0.004) and BMI (p = 0.05). 25(OH)D significantly directly related with white blood cells count and the different components of leukocytes formula, Neutrophils-to-Lymphocytes Ratio, Monocytes-to-Lymphocytes Ratio and C-reactive protein, but not with lymphocytes levels. In fact, hypovitaminosis D predicted levels above the median for both Neutrophils-to-Lymphocytes Ratio (≥2.56; 57.3% vs. 47.6%; p < 0.001; adjusted OR[95%CI] = 1.28[1.07-1.52; p = 0.007) and Monocytes -to-Lymphocytes Ratio (≥0.33; 59.1% vs. 49.8%; p < 0.001; adjusted OR[95%CI] = 1.3[1.1-1.54; p = 0.002), results were confirmed in major subgroups of patients. CONCLUSION: The present study demonstrates that, among patients with cardiovascular disease, 25(OH)D deficiency is associated with a higher metabolic and clinical risk profile and with an elevation of cellular and humoral inflammatory parameters. Future dedicated studies should be, therefore, advocated in order to define whether 25(OH)D supplementation can modulate the mediators of the acute phase response and therefore potentially offer clinical and prognostic advantages on a broad spectrum of inflammatory disease.

Vitamin D levels condition the outcome benefits of renin-angiotensin system inhibitors (RASI) among patients undergoing percutaneous coronary intervention.

BACKGROUND: Vitamin D deficiency is estimated as the most common medical condition worldwide, with severe implications on survival and on several inflammatory, immune-mediated and thrombotic disorders, and especially for cardiovascular disease. Recent studies have suggested that vitamin D could directly regulate the Renin-Angiotensin System (RAS) activity, therefore potentially interfering with the pharmacological effects of RAS Inhibitors (RASI), an issue that has seldom been explored. Therefore, the aim of the present study was to evaluate the prognostic impact of the use of RASI according to vitamin D levels among patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). METHODS: Consecutive patients undergoing PCI were included. Main clinical features and chemistry parameters were assessed at admission. Vitamin D levels were measured by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc). Severe deficiency was defined for 25(OH)D < 10 ng/mL. The primary study endpoint was defined as the occurrence of major cardiovascular events (MACE, a composite of death, recurrent Myocardial Infarction (MI) and target vessel revascularization) at the longest available follow-up. RESULTS: We included a total of 705 patients, that were divided according to vitamin D tertiles (< 12.7 ng/mL; 12.7-21.59 ng/mL; ≥21.6 ng/mL) and use of RASI. RASI therapy was significantly associated to arterial hypertension, creatinine, lower 25(OH)D, use of statins, diuretics, ASA and ticagrelor across vitamin D tertiles. At a median follow-up of 996 [377-1552] days, MACE occurred in 174 (24.7 %) patients. Severe hypovitaminosis D was significantly associated with a higher rate of MACE (HR[95 %CI] = 0.75[0.62-0.91], p = 0.004). The use of RASI significantly lowered the rate of MACE in patients with lower vitamin D (I tertile: 41.3 % vs 25.9 %, adjusted HR[95 %CI] = 0.43[0.26-0.73], p = 0.002); whilst a non-significant effect was observed for II and III tertiles values (18.6 %vs 29.5 %, adjusted HR[95 %CI] = 1.16[0.57-2.34], p = 0.69, and 21.2 % vs 12.6 %, adjusted HR[95 %CI] = 1.1[0.46-2.62], p = 0.83) (p int = 0.04). A similar prognostic interaction for RASI and vitamin D was observed for cardiovascular mortality and MI (p int = 0.03). CONCLUSION: Among patients undergoing PCI, the use of RASI was associated with lower risk of MACE only among patients with lower levels of vitamin D. Future larger studies are certainly warranted in order to define the prognostic implications of vitamin D supplementation on the RAS system modulation, especially among patients treated with RASI.

Low vitamin D levels affect left ventricular wall thickness in severe aortic stenosis.

BACKGROUND: Vitamin D [25(OH)D] deficiency and degenerative aortic stenosis represent emerging conditions, linked to a progressive ageing of the population and increased frailty. Previous studies have associated lower levels of 25 (OH)D to the pathogenesis of atherosclerosis and vascular calcifications. However, few studies have evaluated, so far, the impact of vitamin D deficiency in patients with aortic stenosis, which was therefore the aim of present study. METHODS: Consecutive patients with severe degenerative aortic stenosis undergoing nonurgent coronary angiography were included. Aortic stenosis was defined as aortic valve area (AVA) less than 1 cm and/or mean gradient more than 40 mmHg. Indexed area and stroke volume or dobutamine stress evaluation were performed when indicated. Fasting samples were collected at admission for 25 (OH)D levels assessment. RESULTS: We included 137 patients with severe degenerative aortic stenosis (48.9% men, mean age 78.4 ±â€Š6.4 years) who were divided according to vitamin D median values (≥12.4 ng/ml). Patients with lower vitamin D had a more frequent history of coronary artery bypass graft (P = 0.02) and received more often angiotensin-converting enzyme-inhibitors (P = 0.03). Among them, 38.7% had vitamin D levels less than 10 ng/ml and only five patients were in therapy with vitamin D supplementation. We observed no significant relationship between vitamin D levels and echocardiographic parameters for the severity of aortic stenosis (AVA, peak and mean gradients, volumes, ejection fraction) except for a greater wall thickness in patients with lower vitamin D levels (r = -0.34, P = 0.03). Results did not change when excluding patients with renal failure or treated with vitamin D supplementation. CONCLUSION: Among patients with severe degenerative aortic stenosis, vitamin D deficiency is common. We found a significant association between left ventricular wall thickness and vitamin D levels, suggesting a potential role of this hormone in modulating hypertrophic remodelling in these patients. However, future larger studies are certainly needed to confirm our findings and to define their prognostic implications.

Vitamin D levels and platelet reactivity in diabetic patients receiving dual antiplatelet therapy.

BACKGROUND: Hypovitaminosis D represents an emerging cardiovascular risk factor, and especially among higher-risk subsets of patients, such as in those with diabetes mellitus. The anti-inflammatory and anti-thrombotic properties of vitamin D, in fact, could be even more beneficial among diabetics, where platelet hyperreactivity and suboptimal response to antiplatelet drugs has been associated with poorer outcomes. However, no study has so far evaluated the impact of vitamin D levels on platelet reactivity and high-on treatment platelet reactivity (HRPR) among diabetic patients receiving dial antiplatelet therapy (DAPT). METHODS: Our population is represented by a consecutive cohort ofdiabetic patients treated with DAPT (ASA + clopidogrel or ticagrelor or dose-adjusted prasugrel) for an acute coronary syndrome or elective PCI, undergoing platelet reactivity assessment at 30-90 days post-discharge. Aggregation was assessed by multiple-electrode aggregometry. HRPR was defined for values above the lower limit of normality (in non-treated patients). RESULTS: We included 440 patients, that were divided according to quartiles values of vitamin D (< 9.4; 9.4-15.59; 15.6-21.64; ≥ 21.65 ng/ml). Among them, 31 were excluded as chronically treated with vitamin D supplementation. Lower vitamin D quartiles were associated with more advanced age (p = 0.01), female gender (p = 0.04), renal failure (p = 0.005), history of previous MI (p = 0.01), CABG and use of diuretics (p = 0.003), severe coronary disease (p = 0.002), but lower ejection fraction (p = 0.001), treatment with statins (p = 0.04) and new ADP-antagonists (p = 0.002). Vitamin D levels related with higher HbA1c (p = 0.001), cholesterol (p = 0.02) and creatinine (p = 0.004) and lower hemoglobin (p = 0.004). The prevalence of HRPR with ASA was low and not related to vitamin D quartiles (3.4% vs 2.7% vs 1.8% vs 2.1%, p = 0.44; adjusted OR[95%CI] = 1.16[0.60-2.26], p = 0.67). The prevalence of HRPR for ADP antagonists was associated to hypovitaminosis D (40.2% vs 29.1% vs 29.4% vs 25.5%, p = 0.03; (adjusted OR[95%CI] = 1.76[1.04-2.98], p = 0.036for I vs II-IV quartile). The impact of vitamin D quartiles, was significant only in patients on new ADP antagonists (n = 225, of whom 81 on prasugrel 5 mg; p = 0.03; adjusted OR[95%CI] = 3.12[1.34-7.49], p = 0.009) but not with clopidogrel (p = 0.85, adjusted OR[95%CI] = 1.05[0.49-2.24], p = 0.89). CONCLUSIONS: Among diabetic patients receiving dual antiplatelet therapy for an acute coronary syndrome or elective percutaneous coronary intervention, severe vitamin D deficiency is associated with a higher ADP-mediated platelet reactivity and rate of HRPR, and especially for new ADP-antagonists over clopidogrel.

Impact of high-dose statins on vitamin D levels and platelet function in patients with coronary artery disease.

BACKGROUND: Statins represent a pivotal treatment in coronary artery disease, offering a reduction in cardiovascular risk even beyond their lipid-lowering action. However, the mechanism of these "pleiotropic" benefits of statins is poorly understood. Vitamin D has been suggested as a potential mediator of the anti-inflammatory, anti-thrombotic and vascular protecting effects of statins. Aim of present study was to assess the impact of a high-intensity statin therapy on vitamin D levels and platelet function in patients with coronary artery disease. METHODS: Patients discharged on dual antiplatelet therapy and high-intensity statins after an ACS or elective PCI were scheduled for main chemistry and vitamin D levels assessment at 30-90days post-discharge. Vitamin D (25-OHD) dosing was performed by chemiluminescence method through the LIAISON® Vitamin D assay (Diasorin Inc). Platelet function was assessed by Multiplate® (multiple platelet function analyser; Roche Diagnostics AG). RESULTS: Among 246 patients included, 142 were discharged on a new statin therapy or with an increase in previous dose (Inc-S), while 104 were already receiving a high-dose statin at admission, that remained unchanged (Eq-S). Median follow-up was 75.5days. Patients in the Inc-S group were younger (p=0.01), smokers (p<0.001), with a less frequent history of hypercholesterolemia (p=0.05), diabetes (p=0.03), hypertension (p=0.02), or previous cardiovascular events (p<0.001). They were more often admitted for an acute coronary syndrome (p<0.001) and used less anti-hypertensive drugs or nitrates. Higher total circulating calcium was observed in the Inc-S group (p=0.004), while baseline vitamin D levels were similar in the 2 groups (p=0.30). A significant reduction in the circulating low-density lipoprotein (LDL) cholesterol was observed in the Inc-S group. Vitamin D levels increased in the Inc-S patients but not in the Eq-S group (delta-25OHD: 23.2±20.5% vs 3.1±4.7%, p=0.003), with a linear relationship between the magnitude of vitamin D elevation and the reduction of LDL cholesterol (r=-0.17, p=0.01). Platelet reactivity was significantly lower in the Inc-S patients, when evaluating aggregation with different platelet activating stimuli (arachidonic acid, p=0.02, collagen, p=0.004, thrombin-activating peptide, p=0.07, ADP, p=0.002). CONCLUSIONS: In patients with coronary artery disease, the addition of a high-intensity statin treatment, besides the lipid-lowering effects, is associated to a significant increase in vitamin D levels and lower platelet reactivity, potentially providing explanation of the "pleiotropic" benefits of statins therapy in cardiovascular disease.

Vitamin D levels and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor.

BACKGROUND: Suboptimal platelet inhibition still represents an important challenge, especially for patients undergoing percutaneous coronary interventions (PCIs). However, very few are known so far on the predictors of high-residual platelet reactivity (HRPR) despite antiplatelet strategies. Increasing attention has been paid in the last years to the role of vitamin D in atherothrombosis. Therefore, the aim of our study was to evaluate the impact of vitamin D levels on platelet function in patients treated with dual antiplatelet therapy (DAPT). Patients treated with DAPT (ASA and clopidogrel or ticagrelor) after a recent acute coronary syndrome (ACS) or elective PCI were scheduled for platelet function assessment at 30-90 days post-discharge. Platelet function was assessed by whole blood impedance aggregometry (Multiplate®-Roche Diagnostics AG), HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values ≥417 AU*min (for ADP-antagonists). Fasting samples were obtained for main chemistry parameters and vitamin D level assessment. Our population is represented by 503 patients, who were divided according to vitamin D quartiles (≤9.1; 9.2-14.4; 14.5-21.7; >21.7 ng/ml). Lower vitamin D levels related with age (p = 0.04), diabetic status (p = 0.05), and previous coronary surgery (p = 0.007), therapy with beta-blockers and statins (p = 0.01 and p = 0.02). Vitamin D inversely related to the levels of total cholesterol (p = 0.01), triglycerides (p < 0.001), hemoglobin (p = 0.05), and HbA1c (p < 0.001). Significantly higher platelet reactivity was observed after platelet stimulation with ADP (p = 0.01), but not with other platelet activators. The prevalence of HRPR for ASA was low (1.2%) and not conditioned by Vitamin D levels (adjusted OR[95%CI] = 1.56[0.71-3.5], p = 0.27). HRPR with ADP-antagonists was observed in 26% of patients, and the rate increased with lower vitamin D quartiles (37.3% vs 22.2% vs 24.4% vs 20.2%, p = 0.005, adjusted OR[95%CI] = 1.23[1.02-1.49], p = 0.04). An absolute increase in HRPR with lower vitamin D levels was similarly observed among patients receiving ticagrelor (adjusted OR[95% CI] = 1.40[0.95-2.06], p = 0.08), and those on clopidogrel (adjusted OR[95%CI] = 1.31[0.99-1.75], p = 0.06). Thus, lower vitamin D levels are associated with higher platelet reactivity and impaired effectiveness of ADP-antagonists, while not influencing the effectiveness of ASA. Future studies will tell whether vitamin D supplementation can reduce platelet reactivity, overcoming the phenomenon of resistance to antiplatelet agents.

Vitamin D deficiency is independently associated with the extent of coronary artery disease.

BACKGROUND: Vitamin D (25-OH D3) deficiency represents a rising social and economic problem in Western countries. Vitamin D has been recently reported to modulate inflammatory processes, endothelium and smooth muscle cell proliferation and even platelet function, thus potentially modulating atherothrombosis. Great interest has been addressed on its impact on cardiovascular outcome, with contrasting results. The aim of current study was to evaluate the relationship between 25-OH D3 and the extent of coronary artery disease (CAD) in a consecutive cohort of patients undergoing coronary angiography. MATERIALS AND METHODS: Patients undergoing elective coronary angiography were included in a cross-sectional study. Fasting samples were collected for 25-OH D3 levels assessment. Significant CAD was defined as at least 1 vessel stenosis > 50%, while severe CAD as left main and/or trivessel disease, as evaluated by quantitative coronary angiography. RESULTS: Hypovitaminosis D was observed in 70·4% of 1484 patients. Patients were divided according to vitamin D tertiles (< 9·6; 9·6-18·4; ≥ 18·4). Lower vitamin D levels were associated with age, female gender (P < 0·001), renal failure (P = 0·05), active smoking (P = 0·001), acute coronary syndrome at presentation (P < 0·001), therapy with calcium antagonists (P = 0·02) and diuretics (P < 0·001), less beta-blockers (P = 0·02) and statins (P = 0·001) use. Vitamin D was directly related to haemoglobin (P < 0·001) and inversely with platelet count (P = 0·002), total and low-density-lipoprotein cholesterol (P = 0·002 and P < 0·001) and triglycerides (P = 0·01). Vitamin D did not influence angiographic features of coronary lesions, but was associated with higher prevalence of left main or right CAD (P = 0·03). Vitamin D deficiency was significantly associated with higher prevalence of CAD (adjusted OR [95%CI] = 1·32[1·1-1·6], P = 0·004) and severe CAD (adjusted OR [95%CI] = 1·18[1-1·39], P = 0·05). CONCLUSION: Hypovitaminosis D was observed in the vast majority of patients undergoing coronary angiography. Vitamin D deficiency is significantly associated with the prevalence and extent of CAD, especially for patients with values < 10 ng/mL. Therefore, future large studies are needed to evaluate whether vitamin D supplementation may prevent CAD and its progression.