American Heart Journal
Volume 147, Issue 6 , Pages 942-944, June 2004

Is there something special about ischemic heart disease in patients undergoing dialysis?

  • Charles A Herzog, MD

      Affiliations

    • Department of Medicine, Hennepin County Medical Center, University of Minnesota, Minneapolis, Minn, USA
    • Corresponding Author InformationReprint requests: Charles A. Herzog, MD, Hennepin County Medical Center, Department of Medicine, 701 Park Ave—Mail Code 865A, Minneapolis, MN 55415-1829, USA.

Article Outline

 

See related article on page 1017.

The management of ischemic heart disease in patients with end-stage renal disease (ESRD) is a daunting challenge for clinicians. Patients receiving renal replacement therapy with dialysis are at extraordinarily high risk for death (236/1000 patient-years in all US dialysis patients, 1998–2000). Cardiac disease accounts for 45% of all-cause mortality; 20% of cardiac deaths are attributed to acute myocardial infarction (AMI), and sudden cardiac death may be implicated in 60% of cardiac deaths.1 The burden of cardiac disease in the United States ESRD population is certain to increase, because the greatest increase in treated ESRD has occurred in patients with the highest risk for cardiovascular disease, older patients and patients with diabetic nephropathy. There were approximately 406,000 prevalent patients with ESRD in the United States in 2001 (292,000 patients undergoing dialysis and 114,000 patients with renal transplantations).2 The population of patients with diabetic ESRD tripled from 1990 to 2000 and is projected to increase another 10-fold by the year 2030. Current projections forecast 2.24 million patients with ESRD (and 1.3 million patients with ESRD caused by diabetes mellitus) in the year 2030.2

Generalized vasculopathy characterizes chronic renal failure.3 An assortment of risk factors implicated in accelerated cardiovascular disease in patients with ESRD include hypertension, dyslipidemia, hyperglycemia, smoking, physical inactivity, enhanced thrombogenicity, hyperparathyroidism, hyperhomocystinemia, increased sympathetic tone (including sleep apnea), and elevated levels of asymmetric dimethyl arginine (ADMA). The development of left ventricular hypertrophy (LVH) may be promoted by anemia and vascular noncompliance. Aortic stiffness (as assessed with aortic pulse wave velocity) is an independent predictor of death in patients undergoing dialysis.4 Premature coronary artery calcification can occur in young patients undergoing dialysis, and the metabolic abnormalities of ESRD, including elevated calcium-phosphate product5 and the synergistic interaction of hyperparathyroidism and inflammation (reflected by levels of C-reactive protein)6 may be implicated. Vascular endothelial dysfunction likely contributes to the expression of atherosclerotic disease; a single hemodialysis run may adversely affect endothelial function,7 and hyperglycemia can markedly reduce coronary vasodilator function even in patients with diabetes mellitus who do not have ESRD.8

The detection of coronary artery disease in patients with ESRD has typically focused on high-risk (predominantly diabetic) renal transplant candidates, yet only a minority of patients with ESRD are eligible for renal transplantation. Current practice guidelines address screening for coronary artery disease (CAD) in high-risk renal transplant candidates9 and patients who are on a waiting list for transplantation,10 but they do not include the patients at highest risk for cardiac death: dialysis patients who are not being considered for transplantation.

There are 2 reasons to screen for CAD in patients with ESRD. The first is risk stratification (usually before renal transplantation) for future adverse cardiac events (and optimization of medical therapy). The second distinct (and highly controversial) reason is to identify “obstructive” CAD for “prophylactic” revascularization before renal transplantation. In patients awaiting cadaveric renal transplants, the waiting list time now typically exceeds 3 years, which also means multiple “surveillance” stress imaging tests in patients on the waiting list, on the basis of current guidelines.10 In the dialysis population, the occurrence of angina is not a reliable surrogate for either restenosis after percutaneous coronary intervention (PCI) or progression of disease—silent ischemia is common, and volume status obfuscates the detection of myocardial ischemia. (Eating 5 bags of potato chips and obstructive CAD can both cause dyspnea, angina, or both in a patient undergoing dialysis, but the treatment is decidedly different.)

The strategy of prophylactic coronary revascularization before renal transplantation was studied by Manske et al.11 A total of 26 angina-free diabetic renal transplant candidates (with left ventricular ejection fraction >35%, and at least 1 coronary artery stenosis in the proximal two thirds of the vessel with a visually estimated diameter stenosis >75% and a translesional pressure gradient of at least 15 mm Hg) were randomized to undergo either medical therapy with nifedipine and aspirin or prophylactic coronary revascularization with percutaneous transluminal coronary angioplasty (PTCA; when judged technically feasible) or coronary artery bypass graft surgery (CABG). Ten of 13 patients who were medically treated versus 2 (both PTCA) of 13 patients who underwent revascularization had a pre-specified cardiac end point (unstable angina, myocardial infarction [MI], or cardiac death) at a median time of 8.4 months after randomization (P = .002), and the trial was prematurely terminated. In retrospect, the medical arm used questionable treatment, because β-blockers were not used, and the revascularization arm of the study treated the 8 patients who underwent PTCA and 5 patients who underwent CABG as receiving equivalent therapies (also problematic). Noninvasive screening was not performed, despite only a minority (25%–40%) of renal transplant candidates actually having obstructive CAD severe enough to “trigger” consideration for prophylactic revascularization.11, 12 Nevertheless, US renal transplant centers rely on noninvasive cardiac testing. For patients in the United States who are undergoing cadaveric renal transplantation in 1999, coronary angiography was performed in approximately 10% of patients in the year before transplantation, as compared with 29% of patients who had some type of stress test; 19% of living-related donor recipients had coronary angiography, and 42% had at least 1 stress test.2.

The usefulness of stress myocardial imaging studies for the prediction of MI and cardiac death in patients with ESRD who are evaluated for kidney or kidney-pancreas transplantation was recently reported in a meta-analysis by Rabbat et al.13 Because of the paucity of suitable primary data, the authors pooled 8 stress nuclear and 4 echocardiographic studies (therefore precluding a direct comparison of echocardiography and nuclear imaging). When compared with negative test results, positive test results (which include fixed defects indicative of previous MI, but not inducible ischemia), had an increased relative risk (RR) of future MI, (RR, 2.73; 95% CI, 1,25–5.97) and cardiac death (RR, 2.92; 95% CI, 1.66–5.12), with similar findings in patients with diabetes mellitus. A fixed defect (analyzed separately), however, was not predictive of MI, but it was strongly predictive of cardiac death (RR, 4.74; 95% CI, 2.26–7.94). From my perspective as the cardiology consultant to a renal transplant program, I'm left hanging by studies yielding fixed defects—is the adverse cardiac outcome solely caused by arrhythmia (and not ischemia), or is the imaging test misleading about the presence of undetected obstructive CAD in viable coronary artery vascular territories? If we really believed the noninvasive test results, we could dispense with coronary angiography in patients with fixed defects.

The accuracy of pharmacologic stress nuclear imaging (compared with coronary angiography) in renal transplant candidates has been disappointing in the few published series14, 15, 16 that actually compared stress nuclear imaging with coronary angiography, rather than prediction of future clinical events. In Marwick's14 prospective series on dipyridamole single photon emission computed tomography (SPECT), the authors reported a depressingly low 29% sensitivity rate for the detection of stenoses ≥70% in renal transplant candidates. In Vandenberg's15 retrospective series, the sensitivity and specificity rates were 62% and 76%, respectively, for a 75% stenosis. Boudreau et al16 reported a 86% sensitivity rate and 72% specificity rate of dipyridamole planar thallium imaging for the detection of stenoses >70% reduction in cross-sectional area. Using a novel stress protocol of combined dipyridamole-exercise thallium imaging in patients undergoing dialysis (but only 14% in patients with diabetes mellitus), Dahan et al17 reported a 92% sensitivity rate and 89% specificity rate (compared with coronary artery stenosis ≥70%). There are few publications on dobutamine stress echocardiography in patients with ESRD that use coronary angiography in the entire study population. We prospectively screened 50 renal transplant candidates (39 with diabetes mellitus) and performed dobutamine stress echocardiography and subsequent quantitative coronary angiography (QCA) in the entire cohort.12 The sensitivity and specificity rates of the stress echocardiogram were 75% and 71%, respectively, for QCA stenosis >70% and 75% and 76%, respectively, for visually estimated stenosis >75%.

The paper by Ragosta et al in this issue of the Journal provides a possible explanation for the poor sensitivity of vasodilator stress nuclear scintigraphy for the detection of obstructive CAD in patients with ESRD who have diabetes mellitus. Intravenous adenosine (at a dose used in stress imaging studies) was a suitable provocative agent for increasing coronary flow velocity in angiographically normal coronary arteries in nondiabetic patients and patients with diabetes mellitus without overt renal disease. In contrast, patients with diabetic ESRD had a markedly lower coronary velocity reserve, predominantly because of elevations in baseline flow. It is tempting to link these experimental findings to the clinical setting of CAD screening; the detection of CAD in part relies on differential perfusion in normal and obstructed vascular beds after vasodilator stress; when normal vessels have a blunted increase in flow, the sensitivity of the imaging test could be compromised. Although the authors attribute their findings to diabetic ESRD, it's not clear that this phenomenon is restricted to diabetes mellitus, because Ragosta et al did not study patients with ESRD who did not have diabetes mellitus. They may also have underestimated the impact of left ventricular hypertrophy (LVH), because only 43% of the patients with ESRD were identified with electrocardiography as having LVH; echocardiographic studies of patients with ESRD yield a LVH prevalence of approximately 75%. Anemia did not appear to be a contributor to the high resting basal coronary flow seen in the patients with ESRD.

All interesting studies (including the present one) pose additional research questions. Is the phenomenon of increased basal coronary flow present in patients with ESRD who do not have diabetic renal failure (and does it occur in patients without LVH)? Does the type of vasodilator matter (vis-à-vis stimulation of adenosine receptors)? It would be interesting to replicate this study comparing intracoronary adenosine with papaverine, to eliminate the possibility of relative adenosine resistance. Future studies targeting the special population of patients undergoing dialysis, an expanding group characterized by a large burden of cardiovascular disease, are warranted.

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References 

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PII: S0002-8703(04)00018-3

doi:10.1016/j.ahj.2003.12.025

American Heart Journal
Volume 147, Issue 6 , Pages 942-944, June 2004

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