1.1 (cont.) Studies reporting cardiovascular outcomes or mortality by serum phosphate concentrations within the normal range. Adjusted Risk Increase (95% CI) HR 1.10 (1.02-1.18) per 0.32mM Pi increase HR 1.29 (1.07-1.55) for Pi quartile 4 vs. 1 HR 1.38 (1.09-1.73) for Pi vs. 1.00-1.25mM HR 1.74 (1.17-2.59) per 0.32mM Pi increase HR for Pi quartile 4 vs. 2 1.75 (1.27–2.40) 1.73 (1.22–2.45) OR 1.61 (1.20-2.14) per 0.32mM Pi increase CI, confidence interval; HR, hazard ratio; OR, odds ratio; Pi, phosphate; SD, standard deviation; MI, myocardial infarction; TIA, transient ischaemic attack. Outcome Cardiovascular mortality Mortality Composite outcome; mortality, incident stroke, myocardial infarction, TIA, cardiac failure, coronary revascularisation procedure Clinical heart failure Mortality failure/MI/stroke Coronary calcification F/U 30y 7y 2.5y 17y 4y 6y N 2,176 10,743 24,184 3,300 1,663 883 Population Community cohort; males only Medical outpatients with measures of creatinine, Pi and alkaline phosphatase Nationally representative community population. Normal renal function. Healthy community population without kidney disease, heart failure or myocardial infarction Post myocardial infarction Healthy adults, mean age 49 Author year Larsson 2010 Abramowitz 2010 McGovern 2013 Dhingra 2009 Aronson 2013 Tuttle 2009
Figure 1.3 Summary of possible pathways underlying the association between FGF-23 and cardiovascular events. CV, cardiovascular; VSMC, vascular smooth muscle cell; LVH, left ventricular hypertrophy. Vitamin D and cardiovascular disease Summary of vitamin D physiology Vitamin D (specifically vitamin D3, cholecalciferol) is synthesized in the skin through the action of ultraviolet-B light on to yield precholecalciferol, which spontaneously isomerises to cholecalciferol. Ingestion of vitamin D3 or vitamin D2 (ergocalciferol), found in dairy products, oily fish and eggs, is an additional source of circulating vitamin D. Hepatic hydroxylation of vitamin D3 and D2 yields vitamin D3 and D2 respectively, referred to collectively as 25(OH) vitamin D (25(OH)D). This circulating form of vitamin D is readily measured and is considered to reflect the body’s vitamin D status (). However, 25(OH)D must undergo further hydroxylation to 1,25-dihydroxyvitamin D (calcitriol) for biological activity. This hydroxylation takes place primarily in cells of the renal proximal tubule, catalysed by the mitochondrial enzyme 1-alpha hydroxylase. Calcitriol acts on the nuclear vitamin D receptor (VDR) to stimulate intestinal calcium and phosphate absorption, osteoclast activity, renal tubular phosphate reabsorption and to inhibit PTH synthesis. Together these actions maintain adequate blood levels of calcium and phosphate for bone formation. Regulation of circulating calcitriol concentrations occurs at the level of renal hydroxylase, the expression of which is inhibited by calcitriol and FGF-23, and
ratio (ACR), in a population without excretory kidney impairment (). However, since higher serum phosphate concentration is itself associated with lower urine creatinine excretion (), this association might not actually reflect a difference in albumin leak. A reduction in 24h urine phosphate, considered a reflection of lower dietary phosphate intake, was an independent predictor of albuminuria reduction in the PREMIER study of lifestyle interventions in obese subjects with preserved kidney function (though this study did not report serum phosphate data)(). Lower 25(OH)D concentrations have been associated with higher ACR (), but this may reflect confounding by muscle mass as the determinant of creatinine excretion rate; as might be expected, lower 25(OH)D is associated with sarcopaenia (). Whether higher-normal PTH and FGF-23 are associated with higher urine albumin excretion has not been reported. Summary of evidence and unanswered questions In summary, in general population samples without recognised metabolic bone pathology, variations in bone mineral axis parameters predict substantial increases in CVD and mortality. Although some bone mineral parameters are associated with traditional cardiovascular risk factors, adjusting for traditional risk factors does not abolish the prediction of adverse cardiovascular outcomes; higher phosphate predicts cardiovascular events despite being inversely associated with likelihood of metabolic syndrome components. Plausible pathophysiological mechanisms involving endothelium and other cardiovascular tissues have been proposed, but causal relationships have not been proven to underlie the clinical observations. If causal relationships exist this would have public health implications for cardiovascular disease prevention. The important unanswered questions in this field are therefore: Do the observed associations between bone mineral axis parameters and CVD reflect pathological effects of bone mineral axis disturbance? What is the most important parameter to optimise and how should this be done? What are the mechanisms by which bone mineral axis disturbance causes cardiovascular disease? How do these pathways interact with traditional paradigms of cardiovascular disease pathogenesis?