Effects of excess calcium load on the cardiovascular system measured with electron beam tomography in end-stage renal disease

Paolo Raggi

Cardiology and Non-Invasive Imaging, Tulane University, New Orleans, LA, USA

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality in dialysis patients and current research indicates that it might be linked to high serum phosphorus levels and calcium–phosphorus product. The severe osteopathy known to exist in end-stage renal disease (ESRD) patients is often coupled with an inability of bone to handle excess calcium loads. This might predispose to overflow and deposition of calcium and phosphate crystals in various soft tissues and in particular the cardiovascular apparatus. Atherosclerosis is a slow process that expands in the context of the arterial intimal layer and it is for the most part associated with extracellular calcification. Electron beam tomography (EBT) is a radiological technique utilized to non-invasively visualize this silent marker of atherosclerosis: vascular calcification. Several investigations conducted in non-ESRD patients have conclusively demonstrated that coronary calcification indicates a high risk for cardiac events. As EBT allows precise estimates of the extent of vascular and valvular calcification, it might become an important clinical tool in ESRD patients to assess the effect of excess calcium and phosphate load in soft tissues, estimate the cardiovascular risk of events and gauge the effectiveness of therapy.

Keywords: calcification; calcium; cardiovascular disease; chronic renal failure; coronary artery disease; phosphorus; EBCT; haemodialysis; phosphate binders

Atherosclerosis, cardiac calcifications and imaging with electron beam tomography

Atherosclerotic lesions form in the context of the intimal layer of the arterial wall and are composed of variable amounts of cholesterol debris, inflammatory, smooth muscle and foam cells, fibrotic tissue, and calcium according to their degree of development [1]. Calcium accumulates steadily in the plaque and its presence is verifiable via microscopic examination from the very early stages of disease formation. It is not until the more mature developmental phases of the plaque, however, that this marker of atherosclerosis can be identified non-invasively via external body imaging. Calcification of atherosclerotic lesions is due to a process of active deposition of calcium in the atherosclerotic plaque that utilizes metabolic pathways similar to those found in normal human bone [2,3]. Indeed, several anabolic and catabolic bone enzymes can be found in the plaque milieu [2], and vascular cells of different origin may develop osteoblastic and osteoclastic phenotypes when exposed to appropriate stimuli [3]. Of note, the nucleating factor for calcified foci both in cardiac valves and atherosclerotic plaques often consists of cholesterol crystals [4]. Therefore, lipids may constitute a common link to several forms of cardiovascular diseases that evolve into calcified lesions. Patients undergoing haemodialysis are known to suffer high cardiac morbidity and mortality and frequently show extensive cardiovascular calcifications [5,6]. As a result of treatment with large oral doses of calcium-based phosphate binders and the utilization of high concentrations of calcium salts in the dialysate, these patients are often in positive calcium balance. Further, several ESRD patients demonstrate adynamic bone disease features with the inability to buffer excess calcium [7,8]. Therefore, it could be argued that the overflow of calcium due to excess mineral load may predispose to the development of soft-tissue calcification. The composition of atherosclerotic plaques does not qualitatively differ in patients undergoing chronic dialysis and patients with coronary artery disease without ESRD. However, Schwarz et al. showed in pathological studies that the atherosclerotic lesions found in the intimal layer of the arteries of patients with ESRD, contain more extensive calcium deposits than those of patients with and without established coronary artery disease of similar age [9]. They also found that although the thickness of the media layer was increased, no calcification could be detected in its context.

Electron beam tomography (EBT) is a high-speed radiological technique, which enables the imaging specialist to obtain accurate and detailed pictures of cardiac valves, coronary arteries, and other cardiovascular and chest structures [10]. It employs a fourth generation computed tomography (CT) device with a design substantially different from that of spiral CT technology. In fact, in the EBT design a fan of X-ray is rotated around the stationary human body, while in the conventional spiral CT's a mechanical pair—consisting of an X-ray source and detector—is revolved around the human body while this is slowly advanced through the CT gantry (Figure 1Go). The attendant mechanical inertia slows the imaging process with frequent blurring of the cardiac images. EBT is highly sensitive for the detection of cardiovascular calcifications (Figure 2Go) and the calcium scores calculated from the ensuing tomographic images provide an accurate quantification of the extent of calcium deposition [1113]. As the calcified portion of an atherosclerotic plaque represents only 15–20% of the total plaque volume, calcium is considered a marker of atherosclerosis and not the expression of the entire disease.



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Fig. 1. Schematic representation of an EBT scanner. A fan of X-ray, generated during the impact of an electron beam against a series of tungsten rings, is swept along an arch of 210°. The high imaging speed due to absence of mechanical inertia, typical of conventional helical CTs, prevents image blurring.

 


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Fig. 2. Example of EBT image showing a moderate of calcium deposited in the middle portion of the left anterior descending coronary artery (arrow).

 

Use of EBT imaging in clinical practice

The extent of coronary calcification measured by means of the traditional calcium score shows a good correlation with the total plaque burden found at autopsy [14], and there is a fair relationship between calcium score and the probability of underlying obstructive coronary disease [15]. Further, the negative predictive value for coronary artery disease of a negative EBT scan (CS=0) is very high, as only 2–4% of obstructive coronary artery lesions show no calcification [16]. Conversely, the presence of coronary calcification in asymptomatic individuals is a strong predictor of cardiovascular morbidity and mortality. Arad et al. reported on the cardiovascular outcomes of a cohort of 1173 asymptomatic patients after an average follow-up of 19 months from the initial EBT screening [17]. The sensitivity, specificity, and negative predictive value of a calcium score >160 for the prediction of an event were 89, 82, and 99% respectively. The odds of suffering an event with a calcium score >160, were 35.4 times that of patients without calcium. Additionally, in this analysis the ability of coronary calcification to predict an event was greater than that of all traditional risk factors for coronary artery disease. Similar results were reported in a more recent study by Raggi et al. [18]. The authors showed that not only the absolute calcium score, but also a high score relative to the expected age and sex range for the patient under investigation indicated a severe risk of suffering a myocardial infarction and death in the short term. These observations may be very relevant for the care of ESRD patients. In fact, cardiovascular disease represents the leading cause of morbidity and mortality in these patients, accounting for nearly half of all deaths. As EBT can be used to assess the extent of cardiovascular calcification and to estimate the associated risk of cardiovascular events, it can be a very useful tool in the management of ESRD patients. Braun et al. [5] first employed this technology in a group of 49 patients undergoing regular dialysis. They demonstrated extensive calcific disease of both coronary arteries and cardiac valves and an accelerated rate of progression of calcification during a short follow-up period. Similarly, in an ongoing experience with a large cohort of haemodialysis patients, Raggi et al. found extensive calcification of the aorta, coronary arteries, mitral, and aortic valves [19]. In that study, >76% of the patients had coronary calcium scores exceeding the 75th percentile of age and sex matched controls, a level known to indicate a high risk for cardiac events [18]. In observational studies conducted in ESRD patients, the risk of suffering cardiovascular events has been related to the presence of elevated serum phosphorus levels and calcium–phosphate product [20]. Therefore, a strict control of these factors appears to be of utmost importance to limit soft-tissue calcification and potentially reduce cardiovascular risk. Another application of EBT that can potentially aid physicians involved with the treatment of dialysis patients is serial assessments of the calcification status of cardiovascular tissues. As reported above, Braun et al. showed that valvular calcifications progress very rapidly in chronic dialysis patients [5]. Callister et al. on the other hand, demonstrated that in non-ESRD patients progression of coronary calcification could be substantially reduced with the implementation of lipid-lowering therapy [21]. Accordingly, a prospective and randomized study with sequential EBT imaging is currently being conducted on haemodialysis patients treated with either conventional doses of oral calcium-based phosphate binders or Renagel® [19]. This synthetic polymer binds phosphate in the gut without exchanging calcium and helps to significantly reduce the serum calcium–phosphorus product [22]. Further, in long-term studies Renagel® has been shown to reduce LDL-cholesterol and increase HDL-cholesterol levels to an extent similar to those of statins [22]. Therefore, the hypothesis behind the current investigation is that Renagel® may slow the progression of cardiovascular calcifications in ESRD patients due to its multiple potentially beneficial mechanisms (Figure 3Go). It is further hoped that in the future the slowing of cardiovascular calcification processes may translate into reduction of cardiovascular events as it has already been shown in asymptomatic individuals [23].



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Fig. 3. Hypothetical mechanisms through which medical therapy might be able to slow progression of cardiovascular calcification. Oxidized LDL is accumulated in the intima as atherosclerosis progresses. LDL is ingested by macrophages, which transform into foam cells. Heavily laden macrophages eventually go through a process of programmed cell death (i.e. apoptosis) and release several mediators of inflammation in the plaque milieu. Both statin therapy and Renagel® lower oxidized LDL and raise HDL serum levels. The latter facilitate reverse transport of cholesterol debris outside of the plaque and slows the inflammatory processes initiated by LDL-ox. Renagel® couples an ability to lower the serum calcium–phosphorus product with a strong beneficial activity on the lipid status.

 
In summary, ESRD patients are at high risk of suffering serious cardiovascular events. The development of calcified atherosclerotic disease and the frequent occurrence of events are secondary to the high prevalence of risk factors for cardiovascular disease [24] and, probably, to the mismanagement of calcium and phosphorus balance [25,26]. EBT imaging can be utilized to non-invasively detect and quantitate cardiovascular calcification providing relevant prognostic information. Further, sequential EBT imaging can be employed to assess the effectiveness of medical therapy instituted to slow the progression of disease.

Acknowledgments

Supported by an unrestricted grant from Genzyme Corporation.

Notes

Correspondence and offprint requests to: Paolo Raggi, MD, FACP, FACC, Director of Preventive Cardiology and Non-Invasive Imaging, Tulane University, 1430 Tulane Avenue, SL-48, New Orleans, LA 70112, USA. Email: praggi{at}attglobal.net Back

References

  1. Stary HC. Natural history of calcium deposits in atherosclerosis progression and regression. Z Kardiol2000; 89 [Suppl 2]: 28–35
  2. Bostrom K, Watson KE, Horn S, Wortham C, Herman IM, Demer LL. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest1993; 91: 1800–1809[ISI][Medline]
  3. Bostrom KI. Cell differentiation in vascular calcification. Z Kardiol2000; 89 [Suppl 2]: 69–74[ISI][Medline]
  4. Demer LL. Lipid hypothesis on cardiovascular calcifications. Circulation1997; 95: 297–298[Free Full Text]
  5. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis1996; 27: 394–401[ISI][Medline]
  6. Bommer J, Strohbeck E, Goerich J, Bahner M, Zuna I. Arteriosclerosis in dialysis patients. Int J Artif Organs1996; 19: 638–644[ISI][Medline]
  7. Kurz P, Monier-Faugere MC, Bognar B et al. Evidence for abnormal calcium homeostasis in patients with adynamic bone disease. Kidney Int1994; 46: 855–861[ISI][Medline]
  8. Malluche HH, Sawaya BP, Faugere MC. Dialysis: current status, contemporary limitations and future challenges. Kidney Int1995; 50 [Suppl]: S37–S39[ISI]
  9. Schwarz U, Buzello M, Ritz E et al. Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant2000; 15: 218–223[Abstract/Free Full Text]
  10. Wexler L, Brundage B, Crouse J et al. Coronary artery calcification: pathophysiology, epidemiology, imaging methods and clinical implications. A statement for health professionals from the American Heart Association. Circulation1996; 94: 1175–1192[Free Full Text]
  11. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol1990; 15: 827–832[ISI][Medline]
  12. Callister TQ, Cooil B, Raya S, Lippolis NJ, Russo DJ, Raggi P. Coronary artery disease: Improved reproducibility of calcium scoring with an electron beam-CT volumetric method. Radiology1998; 208: 807–814[Abstract]
  13. Detrano R, Tang W, Kang X et al. Accurate coronary calcium phosphate mass measurements from electron beam computed tomograms. Am J Card Imaging1995; 9: 167–173[Medline]
  14. Sangiorgi G, Rumberger JA, Severson A et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol1998; 31: 126–133[ISI][Medline]
  15. Rumberger JA, Brundage BH, Rader DJ, Kondos G. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc1999; 74: 243–252[ISI][Medline]
  16. Rumberger JA, Sheedy PF, Breen JF, Fitzpatrick LA, Schwartz RS. Electron beam computed tomography and coronary artery disease: scanning for coronary artery calcium. Mayo Clin Proc1996; 71: 369–377[ISI][Medline]
  17. Arad Y, Spadaro LA, Goodman K et al. Predictive value of electron beam computed tomography of the coronary arteries. 19-month follow-up of 1173 asymptomatic subjects. Circulation 1996; 93: 1951–1953[Abstract/Free Full Text]
  18. Raggi P, Callister TQ, Cooil B et al. Identification of patients at increased risk of first unheralded acute myocardial infarction by electron-beam computed tomography. Circulation2000; 101: 850–855[Abstract/Free Full Text]
  19. Raggi, P, Reinmueller, Chertow et al. Cardiac calcification is prevalent and severe in a group of 203 ESRD patients as measured by electron beam CT scanning. J Am Soc Nephrol2000; 11 (Abstract A0405)
  20. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calciumxphosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis1998; 31: 607–617[ISI][Medline]
  21. Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron beam computed tomography. N Engl J Med1998; 339: 1972–1978[Abstract/Free Full Text]
  22. Chertow GM, Burke SK, Dillon MA, Slatopolsky E. Long-term effects of sevelamer hydrochloride on the calciumxphosphorus product and lipid profile of haemodialysis patients. Nephrol Dial Transplant1999; 14: 2907–2914[Abstract/Free Full Text]
  23. Raggi P, Callister TQ, Lippolis NJ, Russo DJ. Cardiac events in patients with progression of coronary calcification on electron beam computed tomography. Radiology1999; 213(P): 351(Abstract)
  24. Mailloux LU, Haley WE. Hypertension in the ESRD patient: pathophysiology, therapy, outcomes, and future directions. Am J Kidney Dis1998; 32: 705–719[ISI][Medline]
  25. Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis1997; 29: 641–649[ISI][Medline]
  26. Drüeke TB. A clinical approach to the uraemic patient with extraskeletal calcifications. Nephrol Dial Transplant1996; 11: 37–42