Parathyroid Hormone and Cardiovascular Disease Events
Our study provides the first systematic review and meta-analysis of prospective studies of PTH and total CVD events, fatal and non-fatal CVD events, and intermediate outcomes in populations without chronic kidney disease. The meta-analysis indicates a significant increased risk for PTH excess and CVD events that ranges between 45% to 50%. The intermediate outcomes suggest that PTH is associated with higher systolic blood pressure in men and a trend was observed for an increased risk of incident hypertension in men and women. Furthermore, higher PTH was significantly associated with higher LV mass in both genders. The limited number of prospective studies precludes firm conclusions and we did not conduct a meta-analysis for the different intermediate outcomes.
Our systematic review and subsequent meta-analysis has several strengths. This first systematic review gives a broad overview of all prospective studies on PTH in relation to CVD events, and intermediate outcomes, and provides insight in its associated risks. The systematic review and meta-analysis were performed according to the PRISMA Statement and the MOOSE guideline and included a quality assessment—an important component to evaluate the methodological quality. The quality assessment allowed us to distinguish between poor, moderate and good quality studies and to the selection of only moderate and good quality studies. This resulted in studies with multivariable adjusted risk estimates and a large number of included CVD cases >3000. Moreover, the present analysis included only prospective cohort studies and most follow-ups lasted more than 6 year, which limits the problem of reverse causation bias.
The meta-analysis of observational studies might be influenced by heterogeneity. The variance between the included studies could partly be due to differences in study populations, PTH assays, outcome definitions, and adjustment for confounders. The use of random-effects models in our analyses adjusts in part for these variances between studies.
PTH can be assessed as the intact peptide of 1–84-amino-acid residues and as fragments. The type of assay depends on the research question and the study population. In participants with normal kidney function, the second-generation assay (2-site immunoassay) performs at least as well as the third-generation assay, which measures different PTH terminals and represent a larger proportion of the circulating PTH immune-reactivity in the assay. All included studies were performed in general populations, and were not primarily affected by chronic kidney disease, and measured intact (2-site immunoassay) PTH. Thus, variance between studies cannot be caused by use of different assays.
Furthermore, the majority of the studies adjusted for kidney function. Results of studies that performed sensitivity analyses for participants with high PTH and high calcium concentrations—indicative for hyperparathyroidism—did not show different results as compared with the main analyses. This suggests that the associations were not driven by participants with primary parathyroid disorders.
Subgroup analyses were performed to test the stability of the pooled estimates. The exclusion of studies with cardiac diseases at baseline resulted in a lower HR, which might indicate that cardiac patients are more prone to PTH excess and thereby have a higher risk of developing a secondary CVD event. The positive association between higher PTH concentrations and CVD events was consistent given the similar pooled risk estimates for total, fatal and non-fatal CVD events in both fixed and random models. This suggests that PTH excess might be involved in pathological processes that lead to CVD. However, it should be noted that the results of our meta-analysis could not identify whether PTH is a causal factor for CVD or whether PTH excess reflects disturbances in the mineral metabolism that predispose to higher CVD risk.
The studies in the meta-analysis used different approaches to define PTH categories. This might have affected our results, although we took into account the result of quartile 4 versus quartile 1 when available and used this approach consistently for all included studies. Sensitivity analyses for PTH and total CVD events based on PTH quartiles resulted in a greater estimate and lower heterogeneity than studies that used dichotomous cut-off values: pooled HR 1.71 (1.43–2.03). The estimate was especially stronger for fatal CVD events when PTH was divided in quartiles: HR 1.89 (1.54–2.32). PTH cut-off values reflect a smaller difference in PTH concentration between PTH groups compared with PTH quartiles. However, pooling studies that reported cut-off values still showed a significant HR 1.27 (1.06–1.53; I = 45%), which suggests that moderate elevations in PTH concentrations could play a role in the development of CVD events.
Visual inspection of the funnel plot illustrates that studies with a smaller standard error at the top of the funnel plot were more symmetrically distributed than studies with a larger standard error at the bottom of the funnel plot. This suggests possible publication bias favoring smaller studies with significant results, which implies that the pooled estimate could be an overestimation of the true association; however, the power to detect publication bias is low given the limited number of studies. In addition, negative studies are less likely to be published and not all endpoints of the included studies were adjudicated and definitions of end points could be different between studies.
PTH might be directly related to CVD events via receptors in the myocardium or could be a marker for another factor that is the cause of the increased risk observed in our systematic review. Circulating PTH is part of a complex endocrine system that consists of multiple factors as 25-hydroxyvitamin D, phosphate, calcitonin, fibroblast growth factor-23 and kidney function. It could be that PTH excess reflects other disturbances along the same pathway that could that predispose to higher CVD risk. Also, other hormones released from the parathyroid gland, such as parathyroid hormone related peptide—which may cross-react with intact PTH—may be related to the pathogenesis of CVD events. In addition, high dietary sodium intake increases the urinary excretion of calcium, and a negative calcium balance could result in higher PTH concentrations. Furthermore, high blood pressure and LV hypertrophy are major risk factors for CVD events with established complications of stroke, myocardial infarction and heart failure. Thus, our findings for intermediate outcomes suggest that PTH could also contribute to cardiovascular risk via hypertension or via cardiac remodeling.
Based on the available prospective studies and the absence of randomized controlled trials, this meta-analysis highlights a risk factor for CVD in older populations. In patients with secondary hyperparathyroidism undergoing dialysis, treatment with the calcimimetic agent cinacalcet, which lowers serum parathyroid hormone calcium and phosphorus concentrations, did not reduce CVD risk, although the results showed a trend favoring the cinacalcet group. Randomized controlled trials in older persons are therefore warranted to determine whether PTH-modifying therapies could result in less CVD events. It should be noted that lack of a gold standard to measure PTH hampers clinical decision making and treatment for subjects with high PTH concentrations. Nonetheless, more awareness should be given to individuals with a high PTH concentration in general populations, in medical disciplines besides nephrology.
Discussion
Our study provides the first systematic review and meta-analysis of prospective studies of PTH and total CVD events, fatal and non-fatal CVD events, and intermediate outcomes in populations without chronic kidney disease. The meta-analysis indicates a significant increased risk for PTH excess and CVD events that ranges between 45% to 50%. The intermediate outcomes suggest that PTH is associated with higher systolic blood pressure in men and a trend was observed for an increased risk of incident hypertension in men and women. Furthermore, higher PTH was significantly associated with higher LV mass in both genders. The limited number of prospective studies precludes firm conclusions and we did not conduct a meta-analysis for the different intermediate outcomes.
Our systematic review and subsequent meta-analysis has several strengths. This first systematic review gives a broad overview of all prospective studies on PTH in relation to CVD events, and intermediate outcomes, and provides insight in its associated risks. The systematic review and meta-analysis were performed according to the PRISMA Statement and the MOOSE guideline and included a quality assessment—an important component to evaluate the methodological quality. The quality assessment allowed us to distinguish between poor, moderate and good quality studies and to the selection of only moderate and good quality studies. This resulted in studies with multivariable adjusted risk estimates and a large number of included CVD cases >3000. Moreover, the present analysis included only prospective cohort studies and most follow-ups lasted more than 6 year, which limits the problem of reverse causation bias.
The meta-analysis of observational studies might be influenced by heterogeneity. The variance between the included studies could partly be due to differences in study populations, PTH assays, outcome definitions, and adjustment for confounders. The use of random-effects models in our analyses adjusts in part for these variances between studies.
PTH can be assessed as the intact peptide of 1–84-amino-acid residues and as fragments. The type of assay depends on the research question and the study population. In participants with normal kidney function, the second-generation assay (2-site immunoassay) performs at least as well as the third-generation assay, which measures different PTH terminals and represent a larger proportion of the circulating PTH immune-reactivity in the assay. All included studies were performed in general populations, and were not primarily affected by chronic kidney disease, and measured intact (2-site immunoassay) PTH. Thus, variance between studies cannot be caused by use of different assays.
Furthermore, the majority of the studies adjusted for kidney function. Results of studies that performed sensitivity analyses for participants with high PTH and high calcium concentrations—indicative for hyperparathyroidism—did not show different results as compared with the main analyses. This suggests that the associations were not driven by participants with primary parathyroid disorders.
Subgroup analyses were performed to test the stability of the pooled estimates. The exclusion of studies with cardiac diseases at baseline resulted in a lower HR, which might indicate that cardiac patients are more prone to PTH excess and thereby have a higher risk of developing a secondary CVD event. The positive association between higher PTH concentrations and CVD events was consistent given the similar pooled risk estimates for total, fatal and non-fatal CVD events in both fixed and random models. This suggests that PTH excess might be involved in pathological processes that lead to CVD. However, it should be noted that the results of our meta-analysis could not identify whether PTH is a causal factor for CVD or whether PTH excess reflects disturbances in the mineral metabolism that predispose to higher CVD risk.
The studies in the meta-analysis used different approaches to define PTH categories. This might have affected our results, although we took into account the result of quartile 4 versus quartile 1 when available and used this approach consistently for all included studies. Sensitivity analyses for PTH and total CVD events based on PTH quartiles resulted in a greater estimate and lower heterogeneity than studies that used dichotomous cut-off values: pooled HR 1.71 (1.43–2.03). The estimate was especially stronger for fatal CVD events when PTH was divided in quartiles: HR 1.89 (1.54–2.32). PTH cut-off values reflect a smaller difference in PTH concentration between PTH groups compared with PTH quartiles. However, pooling studies that reported cut-off values still showed a significant HR 1.27 (1.06–1.53; I = 45%), which suggests that moderate elevations in PTH concentrations could play a role in the development of CVD events.
Visual inspection of the funnel plot illustrates that studies with a smaller standard error at the top of the funnel plot were more symmetrically distributed than studies with a larger standard error at the bottom of the funnel plot. This suggests possible publication bias favoring smaller studies with significant results, which implies that the pooled estimate could be an overestimation of the true association; however, the power to detect publication bias is low given the limited number of studies. In addition, negative studies are less likely to be published and not all endpoints of the included studies were adjudicated and definitions of end points could be different between studies.
PTH might be directly related to CVD events via receptors in the myocardium or could be a marker for another factor that is the cause of the increased risk observed in our systematic review. Circulating PTH is part of a complex endocrine system that consists of multiple factors as 25-hydroxyvitamin D, phosphate, calcitonin, fibroblast growth factor-23 and kidney function. It could be that PTH excess reflects other disturbances along the same pathway that could that predispose to higher CVD risk. Also, other hormones released from the parathyroid gland, such as parathyroid hormone related peptide—which may cross-react with intact PTH—may be related to the pathogenesis of CVD events. In addition, high dietary sodium intake increases the urinary excretion of calcium, and a negative calcium balance could result in higher PTH concentrations. Furthermore, high blood pressure and LV hypertrophy are major risk factors for CVD events with established complications of stroke, myocardial infarction and heart failure. Thus, our findings for intermediate outcomes suggest that PTH could also contribute to cardiovascular risk via hypertension or via cardiac remodeling.
Based on the available prospective studies and the absence of randomized controlled trials, this meta-analysis highlights a risk factor for CVD in older populations. In patients with secondary hyperparathyroidism undergoing dialysis, treatment with the calcimimetic agent cinacalcet, which lowers serum parathyroid hormone calcium and phosphorus concentrations, did not reduce CVD risk, although the results showed a trend favoring the cinacalcet group. Randomized controlled trials in older persons are therefore warranted to determine whether PTH-modifying therapies could result in less CVD events. It should be noted that lack of a gold standard to measure PTH hampers clinical decision making and treatment for subjects with high PTH concentrations. Nonetheless, more awareness should be given to individuals with a high PTH concentration in general populations, in medical disciplines besides nephrology.
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