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In Reply—Serum Calcium and Risk of Sudden Cardiac Arrest in the General Population

      We appreciate the interest from Husain and colleagues in our recent article, in which we reported an association between lower levels of serum calcium and increased risk of sudden cardiac arrest (SCA). We will respond to each of their comments and also refer readers to the editorial by Lee
      • Lee H.C.
      Serum calcium: a sudden cardiac arrest risk factor [editorial].
      in the same issue, which we believe provides a balanced perspective on our findings.
      To our knowledge, our work remains the first community-based study to report the association of lower serum calcium level with SCA. It is also important to recognize that measurement of serum calcium within 90 days of the SCA event is a unique aspect of our study. All of the previously published associations between serum electrolytes were performed using measurements in samples collected at baseline, ranging between approximately 5 and 15 years in advance of the SCA event.
      • Chiuve S.E.
      • Korngold E.C.
      • Januzzi Jr., J.L.
      • Gantzer M.L.
      • Albert C.M.
      Plasma and dietary magnesium and risk of sudden cardiac death in women.
      • Kieboom B.C.
      • Niemeijer M.N.
      • Leening M.J.
      • et al.
      Serum magnesium and the risk of death from coronary heart disease and sudden cardiac death.
      • Peacock J.M.
      • Ohira T.
      • Post W.
      • Sotoodehnia N.
      • Rosamond W.
      • Folsom A.R.
      Serum magnesium and risk of sudden cardiac death in the Atherosclerosis Risk in Communities (ARIC) study.
      It is difficult to know how relevant these remote measurements may have been to the distant SCA event. Because our case-control study design does not allow for direct causal inferences, we were careful not to make any. Given the complexity of the SCA phenotype, we agree that prolongation of the QTc is likely to be multifactorial and is a consistent finding in multiple populations including ours. However, 10% higher values of the QTc in cases are well beyond what could be ascribed to measurement error. In fact, to illustrate this point, there are clinically established 2.5% higher values of the QTc in women compared with men (upper limits of normal, 450 ms in women vs 440 ms in men).
      • Rautaharju P.M.
      • Mason J.W.
      • Akiyama T.
      New age- and sex-specific criteria for QT prolongation based on rate correction formulas that minimize bias at the upper normal limits.
      We agree that potential mechanisms by which serum calcium levels may affect SCA risk are poorly understood, but our findings should serve as an impetus for efforts to improve the understanding of this phenomenon. In this context, it is important to recognize that differences in serum calcium values in the “clinically normal” range could still have implications for pathophysiology. Today, the general consensus in the field for mechanisms of the SCA complex trait is that there are likely to exist multiple overlapping substrates, risk factors, and triggers. How can we exclude the possibility that moderately lower serum calcium could be a risk modifier? In fact, one of the reported associations between low magnesium levels and SCA that Husain et al refer to was also in the “clinically normal” range.
      • Peacock J.M.
      • Ohira T.
      • Post W.
      • Sotoodehnia N.
      • Rosamond W.
      • Folsom A.R.
      Serum magnesium and risk of sudden cardiac death in the Atherosclerosis Risk in Communities (ARIC) study.
      Moreover, none of these previous studies were able to adjust for serum calcium values. We could not adjust for magnesium levels but did account for other potential confounders including potassium levels, hypothyroidism, diabetes, creatinine clearance, use of diuretics, and left ventricular ejection fraction, and the association between serum calcium level and SCA remained robust.
      We remain excited about the potential mechanistic and risk stratification implications of reporting this new association but certainly do not advocate for acting on these findings in terms of health promotion or SCA prevention without considerable further investigation.

      References

        • Lee H.C.
        Serum calcium: a sudden cardiac arrest risk factor [editorial].
        Mayo Clin Proc. 2017; 92: 1466-1468
        • Chiuve S.E.
        • Korngold E.C.
        • Januzzi Jr., J.L.
        • Gantzer M.L.
        • Albert C.M.
        Plasma and dietary magnesium and risk of sudden cardiac death in women.
        Am J Clin Nutr. 2011; 93: 253-260
        • Kieboom B.C.
        • Niemeijer M.N.
        • Leening M.J.
        • et al.
        Serum magnesium and the risk of death from coronary heart disease and sudden cardiac death.
        J Am Heart Assoc. 2016; 5: e002707
        • Peacock J.M.
        • Ohira T.
        • Post W.
        • Sotoodehnia N.
        • Rosamond W.
        • Folsom A.R.
        Serum magnesium and risk of sudden cardiac death in the Atherosclerosis Risk in Communities (ARIC) study.
        Am Heart J. 2010; 160: 464-470
        • Rautaharju P.M.
        • Mason J.W.
        • Akiyama T.
        New age- and sex-specific criteria for QT prolongation based on rate correction formulas that minimize bias at the upper normal limits.
        Int J Cardiol. 2014; 174: 535-540

      Linked Article

      • Serum Calcium and Risk of Sudden Cardiac Arrest in the General Population
        Mayo Clinic ProceedingsVol. 93Issue 3
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          We were pleased to read the article by Yarmohammadi et al1 in the October 2017 issue of Mayo Clinic Proceedings, in which they reported an independent association between low calcium levels and an increased risk of sudden cardiac arrest (SCA). We applaud their methodology and focused exploration of possible causal mechanisms of cardiac arrest. However, we are concerned about the weak physiologic basis for their findings, the range of calcium values discussed in the article, and the potential harm to the general population if calcium levels become a target for intervention.
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