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Reducing coronary artery disease events in liver transplant patients: Moving toward identifying the vulnerable patient

2008; Lippincott Williams & Wilkins; Volume: 14; Issue: 12 Linguagem: Inglês

10.1002/lt.21660

1527-6473

Christopher P. Appleton, R. Todd Hurst,

Organ Transplantation Techniques and Outcomes

Liver TransplantationVolume 14, Issue 12 p. 1691-1693 EditorialFree Access Reducing coronary artery disease events in liver transplant patients: Moving toward identifying the vulnerable patient† Christopher P. Appleton, Corresponding Author Christopher P. Appleton [email protected] Division of Cardiovascular Diseases, Mayo Clinic Arizona, Scottsdale, AZDivision of Cardiovascular Diseases, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259Search for more papers by this authorR. Todd Hurst, R. Todd Hurst Division of Cardiovascular Diseases, Mayo Clinic Arizona, Scottsdale, AZSearch for more papers by this author Christopher P. Appleton, Corresponding Author Christopher P. Appleton [email protected] Division of Cardiovascular Diseases, Mayo Clinic Arizona, Scottsdale, AZDivision of Cardiovascular Diseases, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259Search for more papers by this authorR. Todd Hurst, R. Todd Hurst Division of Cardiovascular Diseases, Mayo Clinic Arizona, Scottsdale, AZSearch for more papers by this author First published: 24 November 2008 https://doi.org/10.1002/lt.21660Citations: 17 † See Article on Page 1725 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Cardiovascular disease (CVD) is a major cause of mortality in the modernized Western world. In the United States alone, CVD mortality accounts for approximately 800,000 deaths a year, a total greater than the number of deaths caused by cancer, obstructive pulmonary disease, and diabetes combined.1 Although the incidence of CVD has declined in recent years, this trend may be reversing. Age is the most predictive risk factor for CVD, and by 2000, nearly 20% of the population of the United States will be greater than 65 years old.2 The aging demographics of our population, combined with the epidemic of obesity, have led experts to predict that the incidence of CVD will increase despite improved therapies.3 Abbreviations CAC, coronary artery calcium; CAD, coronary artery disease; CT, computed tomography; CV, cardiovascular; CVD, cardiovascular disease; ESLD, end-stage liver disease; OLT, orthotopic liver transplant. Unfortunately, it is now clear that end-stage liver disease (ESLD) patients and orthotopic liver transplant (OLT) recipients are included in this epidemic of coronary artery disease (CAD). In fact, it may be that ESLD patients have accelerated coronary atherosclerosis. These emerging ideas are new. Less than 20 years ago, it was believed that the prevalence of CAD was lower in patients with cirrhosis than in healthy individuals.4 This theory came from autopsy studies that seemed to show less post-mortem evidence of CAD and the putative protective effects on the cardiovascular (CV) system of ESLD, including low blood pressure, low cholesterol levels, and increased estrogen levels. In the mid 1990s, this fallacy was debunked by angiographic evidence that showed at least moderate CAD in 5 to 30% of ESLD patients.4-6 Current evidence indicates that the incidence of CAD in ESLD patients6, 7 and OLT recipients8-10 is at least equal to that seen in an age-matched general population and may even be higher. In a recent single-center retrospective review of 303 OLT patients with a 10-year follow-up, 24 myocardial infarctions were observed in patients with an average age of 52 (range, 35-66 years), suggesting that premature CAD is frequent in this population.10 When recurrent disease and de novo malignancies are excluded, CAD represents the most common cause of death in long-term OLT survivors,11, 12 accounting for 10% to 25% of total mortality.10, 13 Should we be surprised at the prevalence of CAD and adverse CVD events in ESLD patients and OLT recipients? We do not think so. It is now widely recognized that atherosclerosis is an inflammatory process with complex interactions between a genetic predisposition and a multitude of risk factors. Inflammation is chronic in patients who have ongoing liver damage and liver failure. In addition, there is an increased prevalence of smoking in the ESLD population,14 and diabetes is common, occurring in 20% to 35% of this group.5, 14 After liver transplantation, immunosuppressive medications contribute to the development of hypertension (15%), obesity (body mass index > 30 kg/m2), diabetes (13%-25%),15 and increased cholesterol and triglyceride levels. Which risk factors best predict the presence of CAD in ESLD has not been completely elucidated,4, 10-12, 15 although older age is a constant in every study and preexisting diabetes appears to also increase risk,5 whereas the severity of liver disease at the time of OLT has generally been unrelated to long-term adverse CV events.10 CAD often remains asymptomatic until plaque rupture, an acute coronary syndrome, and, in up to 20% of patients, ventricular electrical instability and sudden death.17, 18 As a result, identifying and treating patients with subclinical atherosclerosis is an important goal in both ESLD and OLT patients. The real surprise has been the modest achievement toward this goal. Happily, this situation appears ready for a change through the direct measurement of subclinical atherosclerotic burden by newer technologies. In this issue, McAvoy et al.19 report the results of a prospective observational study on coronary artery calcium (CAC) in 101 patients undergoing assessment for OLT transplantation at their institution. Eight individuals were known to have CAD, whereas the remaining 93 patients were asymptomatic. By multiple linear regression analysis, the presence of CAC was most strongly associated with fasting glucose, with weaker correlations with age, higher systolic blood pressure, and a number of features of metabolic syndrome. There was no relationship with severity of liver disease, current or former smoking, gender, family history of CAD, or the Framingham score. At first impression, this study suffers from the problems inherent in a retrospective analysis. In this case, there are incomplete data on key variables, computed tomography (CT) scanning technology that was variable (both electron-beam CT and spiral CT), and a Framingham risk score for predicting 10-year future CV event rates that could be calculated in only 81% of the patients. Yet this study, which would be rejected as deficient in methodology in almost any other group being studied by the CAC technique,20 is likely groundbreaking in the ESLD and OLT population. The reason is simple: it is not the associations between variables in the current study that are important (even if valid); rather, it is the direct evidence of advanced CAD by CAC, which confirms the high prevalence of disease in an ESLD population that has been suggested by long-term outcome studies. When the 8 patients with known CAD were excluded, a positive CAC score was seen in 74% of asymptomatic patients, with 16% having moderate plaque burden (CAC score, 101-400) and therefore moderate risk for an adverse acute coronary syndrome and with another 16% being at very high risk for an acute event with a CAC score of >400. These numbers exceed the prevalence and severity in a population of 50- to 55-year-old matched asymptomatic controls,21, 22 suggesting that the CAD process is accelerated and premature in many ESLD patients. This is exciting news for all solid organ transplant investigators who literally have a new window into the heart. CAC scoring by electron-beam CT or axial or spiral CT scanning is an established and robust clinical method for CV risk assessment20 and is performed without contrast agents and with only small doses of radiation. An official statement from the American Heart Association on the pathophysiology, imaging methods, and clinical implications for CAC testing and interpretation were initially published in 199623 and have been recently updated.20 To summarize the most recent evidence: (1) a positive test (CAC > 0) confirms that atherosclerotic plaque is present, and the greater the CAC score is, the greater the plaque burden and risk are, regardless of age, gender, or ethnicity20, 24; (2) a high CAC score (>100) is consistent with a high risk of an acute cardiac event within 2 to 5 years (>2% annual risk), with scores > 400 showing even higher event rates20; and (3) CAC provides an additive benefit to the assessment of traditional risk scoring algorithms, and this is important because these traditional methods perform very poorly for assessing CV risk in the ESLD patient population.10, 25 How to best use direct evidence of CAD by CAC now needs to be investigated. The issue of preventing acute CAD syndromes in ESLD patients undergoing OLT is divided into (1) the time of liver transplantation and the perioperative and postoperative periods up to 6 months after surgery and (2) the period after 6 months when the patient is usually more stable and on a reduced immunosuppression regimen. In both cases, the vulnerable patient needs to be identified. Advanced CAD in the form of detectable CAC may indicate vulnerability in both time periods, although data on an increased risk during the initial transplantation period are lacking.11 At present, it remains controversial what kind of preoperative test or stress test, if any, actually predicts adverse CV events during transplantation and in the immediate months that follow.26-29 At our institution, an aggressive dobutamine echo stress test protocol that is negative and achieves at least 85% of the maximal predicted heart rate is associated with a low risk of recognizable ischemic syndromes during and up to 4 months after transplantation.26 The most serious events that we and others observe seem to be from unstable arrhythmias at the time of donor liver reperfusion.11, 26 These, of course, could occur without ischemia in patients who have intraoperative acidosis, hypoxia, hypotension, or electrolyte and electrocardiogram abnormalities such as a prolonged QT interval. Of the long-term (>6 months) post-OLT survivor, we have no studies that address the issue of reducing acute cardiac events. Until these are available, it is logical to believe that traditional risk factor reduction will reduce the number of unexpected CVD events. A CAC score of >100 in general population patients is consistent with a >2% annual risk of a cardiac event within 2 to 5 years20 and thus may identify OLT recipients who need more aggressive risk factor reduction targets. This would include the use of 3-hydroxy-3-methyl-glutaryl–coenzyme A reductase inhibitors (statins), which have been historically avoided in this population because of possible adverse interactions with immunosuppressive drugs or increases in serum liver transaminase levels. In summary, by identifying advanced coronary atherosclerosis in the three-quarters of ESLD patients by CT CAC scanning, including 30% that appear to be in a high-risk group, the study by McAvoy and colleagues represents a major breakthrough in the way in which ESLD and OLT patients might be stratified for CVD risk. While prospective studies are being organized, OLT candidates identified as having a positive CAC score and, in particular, a high-risk CAC score of >100 should undergo cardiac stress testing and have CAD risk factors aggressively treated in an attempt to reduce acute coronary events during and after liver transplantation. For liver transplant investigators interested in improving outcomes, it is now time to start your engines: a new and potentially powerful CAD risk stratification tool is available for test driving. REFERENCES 1 Kung HC, Hoyert DL, Xu J, Murphy SL. Deaths: final data for 2005. Natl Vital Stat Rep 2008; 56: 1– 120. 2 US Census Bureau. 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Am Heart J 1996; 132: 536– 541. 29 Plotkin JS, Benitez RM, Kuo PC, Njoku MJ, Ridge LA, Lim JW, et al. Dobutamine stress echocardiography for preoperative cardiac risk stratification in patients undergoing orthotopic liver transplantation. Liver Transpl Surg 1998; 4: 253– 257. Citing Literature Volume14, Issue12December 2008Pages 1691-1693 ReferencesRelatedInformation