Paolo Raggi

Cardiac calcification in adult hemodialysis patients: A link between end-stage renal disease and cardiovascular disease?

OBJECTIVES We sought to determine clinical and laboratory correlates of calcification of the coronary arteries (CAs), aorta and mitral and aortic valves in adult subjects with end-stage renal disease (ESRD) receiving hemodialysis. BACKGROUND Vascular calcification is known to be a risk factor for ischemic heart disease in non-uremic individuals. Patients with ESRD experience accelerated vascular calcification, due at least in part to dysregulation of mineral metabolism. Clinical correlates of the extent of calcification in ESRD have not been identified. Moreover, the clinical relevance of calcification as measured by electron-beam tomography (EBT) has not been determined in the ESRD population. METHODS We conducted a cross-sectional analysis of 205 maintenance hemodialysis patients who received baseline EBT for evaluation of vascular and valvular calcification. We compared subjects with and without clinical evidence of atherosclerotic vascular disease and determined correlates of the extent of vascular and valvular calcification using multivariable linear regression and proportional odds logistic regression analyses. RESULTS The median coronary artery calcium score was 595 (interquartile range, 76 to 1,600), values consistent with a high risk of obstructive coronary artery disease in the general population. The CA calcium scores were directly related to the prevalence of myocardial infarction (p < 0.0001) and angina (p < 0.0001), and the aortic calcium scores were directly related to the prevalence of claudication (p = 0.001) and aortic aneurysm (p = 0.02). The extent of coronary calcification was more pronounced with older age, male gender, white race, diabetes, longer dialysis vintage and higher serum concentrations of calcium and phosphorus. Total cholesterol (and high-density lipoprotein and low-density lipoprotein subfractions), triglycerides, hemoglobin and albumin were not significantly related to the extent of CA calcification. Only dialysis vintage was significantly associated with the prevalence of valvular calcification. CONCLUSIONS Coronary artery calcification is common, severe and significantly associated with ischemic cardiovascular disease in adult ESRD patients. The dysregulation of mineral metabolism in ESRD may influence vascular calcification risk.

High coronary artery calcium scores pose an extremely elevated risk for hard events

OBJECTIVES We sought to assess the natural history of a cohort of asymptomatic individuals with very high (> or = 1,000) calcium scores (CSs) on a screening electron beam tomography (EBT) not submitted to further testing after the initial scan. We also compared the outcome of our prospective cohort with that of historical controls with severe abnormalities on myocardial perfusion imaging (MPI). BACKGROUND Coronary calcium detected on EBT imaging has been shown to correlate with the total plaque burden. However, there is still controversy as to the prognostic significance of calcium, as some investigators believe that the presence of coronary calcification may stabilize the atherosclerotic plaque. METHODS Ninety-eight asymptomatic subjects (mean age: 62 +/- 10) were followed for an average of 17 +/- 11 months (range: 4 to 36 months) after undergoing EBT screening for the occurrence of hard coronary events (HCEs), defined as myocardial infarction or coronary death. All patients had an initial CS > or = 1,000, and in none did the results of the EBT screening lead to further invasive or non-invasive testing. RESULTS During the follow-up period, 35 patients (36%) suffered an HCE. All events were recorded in the first 28 months of follow-up. Subjects with HCEs had higher initial CSs than subjects not suffering HCEs (1,561 +/- 270 vs. 1,199 +/- 200, p < 0.001). The annualized event rate in subjects with a CS > or = 1,000 was significantly greater than that of historical controls with severe perfusion abnormalities on MPI (25% vs. 7.4%, respectively; p < 0.0001). CONCLUSIONS A high CS (> or = 1,000) on a screening EBT in an asymptomatic person portends a very high risk of an HCE in the short term. This risk appears to be greater than the risk associated with a severe perfusion abnormality on MPI.

Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis.

BACKGROUND Phosphate binders (calcium-based and calcium-free) are recommended to lower serum phosphate and prevent hyperphosphataemia in patients with chronic kidney disease, but their effects on mortality and cardiovascular outcomes are unknown. We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease. METHODS We did a systematic review of articles published in any language after Aug 1, 2008, up until Oct 22, 2012, by searching Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature. We included all randomised and non-randomised trials that compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders with those taking non-calcium-based binders. Eligible studies, determined by consensus with predefined criteria, were reviewed, and data were extracted onto a standard form. We combined data from randomised trials to assess the primary outcome of all-cause mortality using the DerSimonian and Laird random effects model. FINDINGS Our search identified 847 reports, of which eight new studies (five randomised trials) met our inclusion criteria and were added to the ten (nine randomised trials) included in our previous meta-analysis. Analysis of the 11 randomised trials (4622 patients) that reported an outcome of mortality showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders (risk ratio 0·78, 95% CI 0·61-0·98). INTERPRETATION Non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease. Further studies are needed to identify causes of mortality and to assess whether mortality differs by type of non-calcium-based phosphate binder. FUNDING None.

Progression of coronary calcium on serial electron beam tomographic scanning is greater in patients with future myocardial infarction

We conducted an observational study relating the occurrence of acute myocardial infarction (MI) to coronary artery calcium progression in 817 asymptomatic subjects referred for sequential electron beam tomographic imaging (average interval 2.2 +/- 1.3 years). A calcium volume score (CVS) was used for plaque quantification. The yearly mean absolute and percent CVS changes in the 45 patients who had a MI were 147 +/- 152 and 47 +/- 50%, respectively, compared with 63 +/- 128 and 26 +/- 32%, respectively (p <0.001, p = 0.01), in patients without events.

Decrease in Thoracic Vertebral Bone Attenuation With Calcium-Based Phosphate Binders in Hemodialysis

We performed a posthoc analysis of a 52‐week randomized trial conducted in adult hemodialysis patients that compared the effects of calcium‐based phosphate binders and sevelamer, a nonabsorbable polymer, on parameters of mineral metabolism and vascular calcification by electron beam tomography. In this analysis, we evaluated the relative effects of calcium and sevelamer on thoracic vertebral attenuation by CT and markers of bone turnover. Subjects randomized to calcium salts experienced a significant reduction in trabecular bone attenuation and a trend toward reduction in cortical bone attenuation, in association with higher concentrations of serum calcium, lower concentrations of PTH, and reduced total and bone‐specific alkaline phosphatase.

The Effects of Sevelamer and Calcium Acetate on Proxies of Atherosclerotic and Arteriosclerotic Vascular Disease in Hemodialysis Patients

Background: We recently determined that in hemodialysis patients, the use of calcium salts to correct hyperphosphatemia led to progressive coronary artery and aortic calcification as determined by sequential electron beam tomography (EBT) while the use of the non-calcium-containing binder sevelamer did not. Whether the specific calcium preparation (acetate vs. carbonate) might influence the likelihood of progressive calcification was debated. Methods: To determine whether treatment with calcium acetate was specifically associated with hypercalcemia and progressive vascular calcification, we conducted an analysis restricted to 108 hemodialysis patients randomized to calcium acetate or sevelamer and followed for one year. Results: The reduction in serum phosphorus was roughly equivalent with both agents (calcium acetate –2.5 ± 1.8 mg/dl vs. sevelamer –2.8 ± 2.0 mg/dl, p = 0.53). Subjects given calcium acetate were more likely to develop hypercalcemia (defined as an albumin-corrected serum calcium ≧10.5 mg/dl) (36 vs. 13%, p = 0.015). Treatment with calcium acetate (mean 4.6 ± 2.1 g/day – equivalent to 1.2 ± 0.5 g of elemental calcium) led to a significant increase in EBT-determined calcification of the coronary arteries (mean change 182 ± 350, median change +20, p = 0.002) and aorta (mean change 181 ± 855, median change +73, p < 0.0001). These changes were similar in magnitude to those seen with calcium carbonate. There were no significant changes in calcification among sevelamer-treated subjects. Conclusion: Despite purported differences in safety and efficacy relative to calcium carbonate, calcium acetate led to hypercalcemia and progressive vascular calcification in hemodialysis patients.

Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis

The current epidemic of obesity with the associated increasing incidence of insulin resistance, diabetes mellitus and atherosclerosis affecting a large proportion of the North American and Western populations, has generated a strong interest in the potential role of visceral adipose tissue in the development of atherosclerosis and its complications. The intra-abdominal and epicardial space are two compartments that contain visceral adipose tissue with a similar embryological origin. These visceral fats are highly inflamed in obese patients, patients with the metabolic syndrome and in those with established coronary artery disease; additionally they are capable of secreting large quantities of pro-inflammatory cytokines and free fatty acids. There is accumulating evidence to support a direct involvement of these regional adipose tissue deposits in the development of atherosclerosis and its complicating events, as will be reviewed in this article.

Coronary artery disease progression assessed by electron-beam computed tomography

The ability to observe changes in atherosclerotic plaque burden over time should provide an accurate measure of efficacy for different cardiovascular therapies. Electron-beam computed tomography (EBCT), by quantification of coronary artery calcification, is a noninvasive measure of atherosclerosis burden. This article summarizes data from abstracts and publications related to coronary artery calcium measurement and its use in progression studies. The issues related to interscan variability and reproducibility of this measure are detailed. The limitations of multidetector spiral computed tomography (high radiation dose and poor reproducibility) are also addressed. Several studies of progression using 2 scans, administered > or =1 year apart, demonstrate significant annual progression (22% to 52% per year). All studies demonstrate that therapy with cholesterol-lowering agents slows the atherosclerotic process, and that it may lead to regression of coronary calcium over time. There are 2 small prognostic studies that demonstrate that coronary events predominantly occur in those patients who exhibit significant progression of coronary artery calcium. Large multicenter trials are underway to evaluate the prognostic significance of coronary artery calcium progression. The progression of coronary artery atherosclerosis can be observed noninvasively by monitoring the progression of coronary calcification with EBCT. With annual progression rates of 22% to 52% and a median interscan variability of only 5% to 8%, this technology provides an opportunity to noninvasively monitor patients to assess the clinical efficacy of medical therapies in studies as short as 1 year.

Coronary Calcium on Electron Beam Tomography Imaging as a Surrogate Marker of Coronary Artery Disease

Although currently recognized risk factors for coronary artery disease are helpful to predict the development of atherosclerosis, their ability to identify individual patients at risk of events is limited. Therefore, surrogate markers are being investigated to identify disease in its early phases in an attempt to decrease cardiovascular morbidity and mortality. Coronary artery calcification is a useful surrogate marker of coronary artery disease, and it can be visualized and measured noninvasively by means of electron beam tomography (EBT) imaging. Atherosclerosis starts to infiltrate the arterial intima layer much before luminal stenosis develops. Calcium is present in the large majority of mature atherosclerotic plaques, although, in rare cases, it may be absent. Recent research indicates that in selected patient subsets, coronary calcium may add incremental prognostic value to conventional risk factors for coronary artery disease and should therefore be used in association with such factors. EBT imaging for detection of arterial calcification is best employed in asymptomatic individuals at intermediate risk of coronary artery disease, symptomatic patients at low risk of coronary artery disease, and to track disease progression.

Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is the most common genetic disorder causing premature cardiovascular disease and death. Heterozygous FH conservatively affects approximately 1:500 Canadians, and the more serious homozygous form affects approximately 1:1,000,000 Canadians, although these numbers might be underestimated. Of approximately 83,500 Canadians estimated to have FH, most are undiagnosed, which represents a simultaneous public health deficit and opportunity, because early treatment of heterozygous FH can normalize life expectancy. Diagnostic algorithms for FH incorporate increased plasma low-density lipoprotein cholesterol, pathognomonic clinical features, and family history of early cardiovascular disease and hyperlipidemia. DNA-based detection of causative mutations in FH-related genes can help with diagnosis. Maximizing diagnosis and treatment of FH in Canada will involve a multipronged approach, including: (1) increasing awareness of FH among health care providers and patients; (2) creating a national registry for FH individuals; (3) setting standards for screening, including cascade screening in affected families; (4) ensuring availability of standard-of-care therapies, in particular optimization of plasma low-density lipoprotein cholesterol levels and timely access to future validated therapies; (5) promoting patient-based support and advocacy groups; and (6) forming alliances with international colleagues, resources, and initiatives that focus on FH. This document aims to raise awareness of FH nationally, and to mobilize knowledge translation, patient support, and availability of treatment and health care resources for this underrecognized, but important medical condition.