In this community-based study of ambulatory older adults without known cardiovascular disease, the combination of low vitamin D and high PTH concentrations identified a group of participants at a 2.5-fold risk for SCD compared to the group with normal levels of both markers. As individual risk factors, neither low vitamin D nor high PTH concentrations were associated with SCD events. These findings thus validate only part of our original hypothesis describing a link between the mineral metabolism pathway and SCD.
Participants with both low vitamin D and high PTH concentrations may have a greater degree of mineral metabolism dysregulation and a greater risk for SCD. Since these hormones are inter-related and represent markers of the same pathway, we had hypothesized that a simultaneous assessment may identify a higher risk subgroup at risk for SCD. This combined abnormality likely identifies a subset of participants with decreased vitamin D substrate and inadequate stimulation of the vitamin D receptor. Physiologically, secondary hyperparathyroidism is expected among people with vitamin D deficiency. Our analysis, however, demonstrates that the extent of PTH elevation may vary in the setting of 25-OHD deficiency. Participants with either a low concentration of vitamin D or high concentration of PTH only did not have an increased SCD risk. Characterization of the mineral metabolism pathway with one marker alone does not appear to identify the extent of subclinical cardiovascular disease that predisposes these participants to lethal arrhythmias including ventricular tachycardia or ventricular fibrillation and subsequent SCD.
Important strengths of this study include its focus on individuals who were free of clinical cardiovascular disease at baseline and the evaluation of adjudicated SCD events during long-term follow-up. Although this cohort was comprised of the elderly, the multivariate analyses adjusted for many traditional cardiovascular risk factors including age, hypertension, smoking and diabetes. The sudden nature of these out-of-hospital events distinguishes them from the other cardiovascular deaths that are typically precipitated by hospitalization for heart failure, myocardial infarction or stroke. Baseline assessments of vitamin D and PTH have identified a group of elderly people without prevalent cardiovascular disease, 12% of our sample, who are at an increased risk of SCD. These metabolic disturbances are likely contributing to subclinical disease including both electrophysiologic and structural remodeling of the heart. Although the QT interval was not significantly different across the various mineral metabolism groups at baseline, this baseline measure does not represent longitudinal changes in the repolarization interval. In addition, the ECG does not capture repolarization reserve and subsequent susceptibility to arrhythmias. Finally, these findings complement recent studies which have reported an independent association between these markers of mineral metabolism and SCD in high risk populations including those with end stage renal disease22
and coronary artery disease.23, 24
These associations serve to generate hypothesis regarding the potential impact of mineral metabolism disturbances on SCD; replication of our findings in other population-based cohorts is necessary to prove their validity.
Experimental evidence suggests that dysregulation in vitamin D and PTH synthesis results in structural and ionic channel remodeling that may increase the susceptibility to cardiac arrhythmias. Specifically, changes in these mineral metabolism measures are known to induce renin expression and subsequent activation of the renin-angiotensin-aldosterone system (RAAS).5
Activation of the mineralocorticoid receptor has been shown to cause an increase in the inward calcium channel current and a decrease in the transient outward potassium current.25
These changes can prolong the repolarization interval and cardiac action potential over time and increase the susceptibility to fatal ventricular arrhythmias.26,27
In addition, vitamin D appears to have a direct effect on cardiac repolarization as its administration in hemodialysis patients is associated with a reduction in QTc dispersion.28
Finally, dysregulation in vitamin D and PTH also induce cardiac hypertrophy6, 11–13
which are known risk factors for SCD.29, 30
In addition, our findings may help provide greater insight for the circannual variation in sudden cardiac death rates with peak incidences occurring during the winter months and the lowest in the summer.31–33
Various mechanisms related to daylight exposure have been implicated as a potential explanation for these observations. Prior studies have demonstrated seasonal variation in autonomic tone that may be induced by daylight exposure.34
Further, circannual variations in vitamin D and PTH levels may also contribute toward these differences in SCD rates. The photosynthesis of vitamin D is dependent on the intensity of ultraviolet radiation with peak values in the summer and lowest values in the winter.35, 36
Parathyroid hormone (PTH) also demonstrates an inverse seasonal relationship with 25-hydroxyvitamin D (25-OHD).37, 38
Although our analyses adjusted for both the site and season in which samples were collected, residual confounding may be present.
Our findings suggest that the combined assessment of vitamin D and PTH dysregulation is a stronger risk factor for SCD than non sudden-cardiac death. Future studies will need to validate these findings in other cohorts with more events and evaluate specific mechanisms that link the mineral metabolism pathways to cardiac arrhythmias.
Several limitations of the current study should be considered. The relatively small number of definitive SCD cases in our analyses reduced the power necessary to detect moderate sized effects; this may have limited our ability to find independent associations between either vitamin D or PTH with SCD in isolation. The limited number of SCD events also raises the possibility of model overfitting. In addition, the lack of interaction between vitamin D and PTH is most likely a consequence of low statistical power. However, the magnitude of the point estimates of the adjusted analyses and the findings combining both vitamin D deficiency and elevated PTH, our apriori hypothesis, suggest that these metabolic measures are likely associated with SCD risk. In addition, CHS consisted solely of elderly persons. The described associations of vitamin D and PTH with SCD cannot necessarily be extrapolated to younger populations. Further, given the low prevalence of cardioprotective medications in this cohort, our study cannot evaluate whether pharmacologic agents such as angiotensin converting enzyme inhibitors, statins, or beta blockers alter SCD risk in participants with mineral metabolism dysregulation. In addition, as with any observational study, there is likely to be residual confounding in the association of vitamin D or PTH with SCD.