Cardiovascular Disease in Primary Hyperparathyroidism

Shonni J. Silverberg;

Department of Medicine College of Physicians and Surgeons New York, New York 10032

Address all correspondence and requests for reprints to: Shonni J. Silverberg, M.D., Department of Medicine, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032.


    Introduction
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 Introduction
 References
 
Our understanding of the cardiovascular manifestations of primary hyperparathyroidism (PHPT) remains incomplete, with conflicting data concerning their extent and clinical significance. Seeming discrepancies may be related to the fact that the clinical picture of PHPT has evolved. Once a symptomatic disorder characterized by significant hypercalcemia, PHPT today is most commonly seen in asymptomatic individuals with serum calcium levels within 1 mg/dL of the upper limits of normal (1). It should not, thus, be surprising that the cardiovascular manifestations of PHPT have changed as well.

The hyperparathyroid state, by its very nature, has the potential to affect the cardiovascular system. Alterations in either of the cardinal biochemical indices of PHPT, serum calcium, and PTH are known to affect cardiovascular function. Hypercalcemia has been associated with hypertension, left ventricular hypertrophy, and arrhythmias, as well as calcification of the myocardium, heart valves, and coronary arteries. PTH itself has direct positive chronotropic and mediated inotropic effects on the heart (2), and increased PTH levels have been associated with the development of left ventricular hypertrophy.

For many years, it was considered axiomatic that patients with PHPT were at an increased risk of death due to cardiovascular disease (3, 4, 5, 6). Increased mortality rates were reported in those with PHPT, particularly in several large studies from Sweden. The increase in the cardiovascular death rate persisted long after surgical cure. Several other studies found that the rates of premature death due to cardiovascular disease were less pronounced in those with more modest elevations in the serum calcium concentration. In 1998, Wermers et al. (7) reported mortality figures in PHPT patients diagnosed in Rochester, Minnesota, between 1965 and 1992. Overall mortality was lower than expected in patients with PHPT, and cardiovascular death rates, in particular, were markedly reduced (relative risk, 0.6). The authors, however, did find that higher maximal serum calcium levels were an independent predictor of mortality, especially those in the upper quartile of serum calcium concentrations. This is consistent with the findings of the Swedish studies of PHPT and at least one other study in which risk of premature cardiovascular death seemed to increase with higher serum calcium levels (8). The time period of the Scandinavian studies (reporting on patients from the 1950s through 1970s) mostly predated the introduction of the multichannel autoanalyzer. Thus, patients in these studies were more likely to have had symptomatic disease, with higher serum calcium concentrations. In contrast, the Mayo Clinic study described a largely asymptomatic population, suggesting that one explanation for the discrepant results is the change in disease severity.

There are limited data on the incidence of cardiovascular abnormalities in the mild PHPT seen commonly today. Hypertension is frequently seen in association with PHPT. Studies to investigate the mechanism of this association have variously (but inconsistently) invoked alterations in PRA and serum magnesium levels (9, 10). The nature of the association between hypertension and PHPT is in question, however, because cure of the hyperarathyoid process does not lead to improvement in blood pressure (10, 11, 12, 13). Stefenelli et al. (14) reported increased frequency of left ventricular hypertrophy (patients, 68%; controls, 28%), aortic valve calcification (patients, 63%; controls, 13%), mitral valve calcification (patients, 49%; controls, 15%), and myocardial calcification (patients, 69%; controls, 17%). The population they described was more severely affected (mean serum calcium, 12 mg/dL) than the typical patient seen in the United States. Studies in patients with more modest increases in serum calcium (11.1–11.3 mg/dL) showed an increased incidence of left ventricular hypertrophy (15), but no increase in valvular or myocardial calcifications (16). Left ventricular hypertrophy, felt to be the strongest predictor of cardiovascular morbidity, was found to regress after surgery in two studies (15, 17).

As the clinical findings in PHPT have become more subtle over time, the investigation of cardiovascular manifestations of the disease has turned to less clinically overt abnormalities. In view of the fact that PTH has many effects on the heart; to alter heart rate, coronary blood flow, peak pressure, and rate of rise of left ventricular pressure, it is reasonable to hypothesize that PHPT could be associated with abnormalities in vascular function, even in the absence of overt cardiovascular disease. Studies assessing the nature of vascular function in PHPT have focused on vascular reactivity, which measures small vessel or endothelial function, and vascular compliance, a measure of large vessel function.

There are conflicting data on the nature of altered vascular reactivity in PHPT. Nilsson et al. (18) reported an abnormal endothelial vasodilatory response in PHPT, as demonstrated by the response to local infusion of metacholine and nitroprusside. This finding differed from that of Neunterfl et al. (19), who reported normal endothelial-dependent dilatation, but abnormal vascular smooth muscle reactivity (nitroglycerin induced changes in the arterial media).

Recent interest in the role of the endothelins may lead to an increased understanding of altered vascular reactivity in PHPT. Secretion of endothelin-1, a potent vasoconstrictor, is inhibited by PTH. Endothelin, in turn, may modulate PTH secretion as well. Several endothelin receptor subtypes have been identified in human parathyroid tissues. It is possible that PTH-mediated inhibition of endothelin could explain the vasodilatory properties of PTH. Preliminary data in a small group of patients with PHPT has shown increased levels of endothelin in patients with the disease (20).

Focusing instead on macrovascular changes, Smith et al. (21) report in this issue of the journal on vascular stiffness in patients with mild PHPT. Decreased vascular compliance is normally seen with advancing age, as well as in smokers, and in those with hypertension, diabetes, and lipoprotein abnormalities (22). The authors use pulse wave analysis to measure vessel stiffness. Comparing 21 patients with mild PHPT with a control population, the authors determined the augmentation of central pressure and calculated the augmentation index, a measure of vascular stiffness in large conduit arteries. They find that despite similar systolic brachial pressures, those with PHPT had significantly higher indices of vessel stiffness compared with age- and sex-matched control subjects.

These results, in a population fairly typical in severity of PHPT, are of considerable interest. The technique used is noninvasive, easy to perform, rapid, and highly reproducible. Although primarily a research technique at present, pulse wave analysis could well become a clinical tool. However, questions remain before we can be confident of results using this methodology in PHPT. Pulse wave analysis generates central arterial waveforms that are dependent on a number of factors that may confound the results of this interesting study. Among the many factors that regulate the arterial waveform are age, height, and obesity. Whereas in the study of Smith et al. (21) the mean age is similar in control and patient populations, the large SD of the former group raises the possibility that inclusion of young control subjects, whose augmentation is normally lower than in older individuals, could have confounded the results. It is also important to match other demographic features in patient and control groups, because height (and obesity) can alter augmentation index. Perhaps a case-control design study would allow a fuller interpretation of data.

It is also of interest, as well as a potential limitation of the study, that the patients investigated may not represent a typical cohort with PHPT. Although typical in severity of hypercalcemia, 24% (5 of 21) of patients had fasting glucose levels consistent with impaired glucose tolerance. Did the inclusion of these patients lead to the profile of PHPT patients as having increased fasting insulin and triglyceride levels? Vascular compliance is known to be decreased in diabetes, regardless of the presence of atherosclerosis. Among the causes are nonenzymatic glycosylation of proteins in the arterial walls and leakage of macromolecules into the vessel walls. Increased arterial stiffness has been reported in the prediabetic state as well as measured by indices of glucose tolerance and insulin levels (23). This could apply to the rather large subset of patients in this study. It is unclear whether the reported increase in vascular stiffness was present in the remaining cohort with normal carbohydrate metabolism.

Decreased vascular compliance is associated with increased cardiovascular risk. A myriad of techniques exist to measure different aspects of vascular compliance. It is important to confirm the findings of Smith et al. (21). If the findings are confirmed in a demographically matched population without possible confounding glucose/lipoprotein abnormalities, this technique could be a valuable addition to the evaluatory armamentarium in PHPT. As we extend our understanding of both vascular compliance and reactivity in PHPT, it is also important to determine the longitudinal course of such alterations. Are they progressive over time in untreated patients? And are these changes reversible following parathyroidectomy? With available data suggesting that many asymptomatic patients can be safely followed without parathyroidectomy (1), this information will be of key importance in the management of patients with asymptomatic PHPT.


    Acknowledgments
 
I thank Dr. Matthew Maurer for invaluable discussions.

Received August 9, 2000.

Accepted August 9, 2000.


    References
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 Introduction
 References
 

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