ORIGINAL CONTRIBUTION. Risk of Developing Coronary Artery Disease Following a Normal Coronary Angiogram in Middle-Aged Adults

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1 ORIGINAL CONTRIBUTION Risk of Developing Coronary Artery Disease Following a Normal Coronary Angiogram in Middle-Aged Adults Maheswara S.G. Rao Golla, MBBS 1 ; Timir Paul, MD 2 ; Siddhartha Rao, MD 1 ; Chris Wiesen, PhD 3 ; Michael Yeung, MD 1 ; George A. Stouffer, MD 1 ABSTRACT: Atherosclerosis begins in the teenage years and progresses over time in susceptible individuals. It is unknown, however, whether coronary angiography in middle-aged adults showing no evidence of atherosclerosis identifies individuals at low risk for subsequent development of coronary artery disease (CAD). We identified 4068 patients 40 years of age who had at least two coronary angiograms between January 1, 1990 and March 31, Of these, 227 patients (5.8%) had no CAD and 251 patients (6.4%) had mild atherosclerotic disease (stenosis <30%) on the initial angiogram. Patients in the normal-angiogram group were younger, more often female, and less likely to use tobacco than patients in the mild-atherosclerosis group, while rates of diabetes and hypertension were the same. Angiographic evidence of any CAD and obstructive CAD was apparent in 26% and 4.8%, respectively of the normal-angiogram group on subsequent angiography performed 75 ± 46 months later. Myocardial infarction and revascularization occurred in 4.8% and 3.5%, respectively. Progression of CAD (odds ratio = 10.2), development of obstructive CAD (odds ratio = 8.9), myocardial infarction (odds ratio = 2.7), and revascularization (odds ratio = 8.4) were more frequent in the mild-atherosclerosis group. In summary, 26% of middle-aged adults with a normal coronary angiogram who had subsequent angiography for clinical reasons developed CAD, although the annual rates of myocardial infarction or revascularization were very low. Even mild atherosclerosis on the initial angiogram increased the rate of progression of CAD by 10-fold and the rate of revascularization by 8-fold. J INVASIVE CARDIOL 2014;26(12): KEY WORDS: coronary angiogram, atherosclerosis, myocardial infarction, coronary artery disease, revascularization The current paradigm is that coronary artery disease (CAD) starts at an early age as a fatty streak and progresses over time in response to various risk factors. 1,2 The first demonstrations of atherosclerotic CAD in young individuals were in American soldiers with a mean age of 21 years who died in the Korean and Vietnam Wars. 3-5 Similar results were found in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) 6 study of the right coronary artery in more than 3000 individuals aged years who died of external causes (primarily accidents or homicide) and the Bogalusa Heart Study 7 of 204 persons 2-39 years old who died from various causes, principally trauma. An intravascular ultrasound (IVUS) study performed in 262 donated hearts from individuals 33 ± 13 years old found atherosclerotic lesions in 52% of donated hearts, with the prevalence varying from 17% in individuals <20 years old to 85% in subjects 50 years old. 8 There are individuals in whom CAD progresses very slowly, if at all. Studies have generally shown that the lack of risk factors and/or the absence of subclinical CAD in middle-aged adults portends an excellent cardiovascular prognosis. Framingham Heart Study participants who were free of clinical cardiovascular disease and major risk factors at 50 years old had substantially lower risk of CAD and longer median survival time than participants who had two or more major risk factors. 9 Similarly, a study of 25,253 consecutive asymptomatic adults with a mean age of 56 years showed that the lack of coronary artery calcium by electron-beam tomography (EBT) was associated with an excellent prognosis. However, this study also found that the presence of even small amounts of coronary calcium, indicative of subclinical atherosclerotic disease, increased the risk of death during a mean follow-up of 6.8 ± 3 years. 10 The importance of understanding the natural history of individuals with normal or near-normal coronary angiograms was highlighted by a study of 398,978 patients undergoing elective coronary angiography at 663 hospitals from the American College of Cardiology National Cardiovascular Disease Registry (ACC-NCDR), a large national registry of diagnostic cardiac catheterization in the United States. This study found that 39.2% of the patients had absent or mild CAD (defined as <20% stenosis in all vessels). 11 The rate of subsequent development of atherosclerotic CAD in individuals with angiographically normal coronary arteries is not well studied and the natural history of the atherosclerotic process in older individuals without apparent disease is unknown. Identification of patients who have a very low lifetime risk of developing CAD would have wide-ranging 624 The Journal of Invasive Cardiology

2 Table 1. Demographics and baseline characteristics of study participants. Normal Angiogram Mild Atherosclerosis Number Age at initial coronary angiogram (years) Time between angiograms (months) P-Value 54 ± 9 57 ± 10 < ± ± Female gender 141 (62.1%) 127 (50.6%).01 Male gender 86 (37.9%) 124 (49.4%).01 Hypertension 189 (83%) 219 (87%).21 Diabetes 98 (43%) 103 (41%).63 Family history of CAD 88 (38%) 82 (32%).16 History of tobacco use 92 (40.5%) 169 (67%) <.001 Body mass index 31.0 ± ± Hypercholesterolemia 103 (45.4%) 157 (62.5%) <.001 Creatinine (mg/dl) 1.6 ± ± Data presented as mean ± standard deviation or number (percentage). insulin or oral hypoglycemic agents. Hypercholesterolemia was defined as low-density lipoprotein (LDL) 130 mg/dl ( 3.3 mmol/l). Obesity was defined as body mass index of 30 kg/m 2. Diagnosis of MI was based on a review of the medical record. Statistical analysis. Statistical analyses were performed with SPSS system version 14.0 for Windows. Pearson Chi-square test was used to assess the differences in categorical variables between the two groups and odds ratios (ORs) were used to evaluate the strength of association between dependent and independent variables. Analysis of variance (ANOVA) was used to assess the differences in means of continuous variables between the two groups. Potential predictors of progression of CAD were identified by the univariate analysis. Multiple logistic regression was used to assess the independent relation between risk factors and outcomes of the study. SAS version 9.2 for Windows was used to generate Kaplan-Meier curves. All P-values were two-tailed and considered significant when.05. public health implications in regard to prevention strategies and evaluation of chest pain syndromes. Thus, the current study examined the hypothesis that the lack of angiographically apparent CAD after age 40 identifies individuals who had a very low risk of subsequent development of obstructive CAD. Methods All adult patients who had two or more coronary angiograms at the University of North Carolina between January 1, 1990 and March 1, 2011 were identified. Patients who were <40 years old, presented with acute myocardial infarction (MI), or had prior revascularization (percutaneous coronary intervention or coronary artery bypass grafting) at the time of initial angiogram were excluded. Patients with heart transplantation at any point during the study period were also excluded. Coronary angiography was performed in multiple views using standard techniques. The initial and subsequent coronary angiograms were reviewed by two experienced observers who were blinded to the patient and/or timing of the angiogram. Coronary angiograms were classified as normal if all epicardial arteries and major branches were free of atherosclerotic changes (defined as the presence of a discrete stenosis and/or intimal irregularities). Angiograms that were classified as normal were reviewed by two additional experienced observers. Mild atherosclerosis was defined as the presence of intimal irregularities and/or a discreet lesion that was < 30% stenotic. Coronary artery disease risk factor definitions. Hypertension was defined as ongoing treatment with antihypertensive medications and history of blood pressure 140/90 mm Hg. Diabetes was defined as ongoing treatment with Results A total of 4068 patients had two or more angiograms during the study period. Of these, 227 patients (5.8%) had no angiographic evidence of CAD on the initial angiogram (normal-angiogram group). The comparison group was 251 patients (6.4%) who had angiographic evidence of atherosclerotic disease, but no stenosis >30% by visual analysis (mild-atherosclerosis group). Patients in the normal-angiogram group were younger (54 ± 9 years vs 57 ± 10 years; P<.001), more often female (62% vs 51%; P=.01), less likely to use tobacco (41% vs 67%; P<.001), and less likely to be hypercholesterolemic (45.4% vs 62.5%; P<.001) than patients in the mild-atherosclerosis group (Table 1). There were no significant differences in the percentage of patients with diabetes, hypertension, or family history of CAD. Creatinine levels and body mass index were similar in the two groups (Table 1). During a mean follow-up of 75 ±46 months, 26% of patients in the normal-angiogram group developed angiographically apparent CAD and 4.8% developed obstructive CAD (defined as 70% stenosis in an epicardial coronary artery or major branch). Angiographic progression of CAD (78% vs 26%; OR = 10.2; P<.001) and the development of obstructive CAD (31% vs 4.8%; OR = 8.9; P<.001) were much more common in the mild-atherosclerosis group compared to the normal-angiogram group (Figure 1). There was a trend toward the likelihood of developing angiographically apparent CAD, but not the development of obstructive CAD, increasing with decile of age in the normal-angiogram group (Figure 1B). There was a weakly positive correlation between the time separating the angiograms and the most severe stenosis on Vol. 26, No. 12, December

3 FIGURE 1. Angiographic changes in coronary artery disease (CAD). Angiographic evidence of progression of CAD, development of obstructive CAD, need for revascularization or occurrence of myocardial infarction in the normal angiogram group and the mild atherosclerosis group (A: * P<.001). Risk of development of any CAD and progression to obstructive CAD by decile of age in the normal angiogram group (B: differences were not statistically significant). the subsequent angiogram in the mild-atherosclerosis group (r 2 = 0.284; P<.001), whereas there was no correlation in the normal-angiogram group (P=.11). Multivariate analysis showed that male gender (OR = 2.5; P<.001) and diabetes (OR = 2.1; P=.01) were associated with progression to obstructive CAD in the mild-atherosclerosis group. There were no traditional risk factors that identified progression of CAD in the normal-angiogram group, although there was a trend toward male gender being a risk (P=.07). Because of the retrospective nature of this study, we were unable to determine if non-traditional risk factors were associated with progression of disease. Revascularization (24% vs 3.5%; OR = 8.4; P<.001) and MI (12% vs 4.8%; OR = 2.7; P=.01) were much more common in the mild-atherosclerosis group than in the normal-angiogram group (Figure 1). Kaplan-Meier curves of MI and/or revascularization (Figure 2A) and MI, revascularization, and/or the development of obstructive CAD (Figure 2B) showed that these events were significantly less common over time in the normal-angiogram group than in the mild-atherosclerosis group. Within 2 years after a normal angiogram, none of the 227 patients had a clinical cardiovascular event. Over the course of the study, the clinical event rate was 1% per year in patients in the normal-angiogram group compared to 4.3% per year in the mild-atherosclerosis group (P<.001). Discussion This study examined the hypothesis that a normal coronary angiogram after the age of 40 years old would identify patients who were atherosclerosis-resistant and thus would not develop CAD during their lifetime. Our results were not consistent with this hypothesis, as we found that 26% of patients who initially had a normal coronary angiogram and then required a second angiogram for a clinical indication had evidence of CAD. This study only included patients who had a second angiogram and thus likely overestimates the risk of progression in patients with normal coronary angiograms. Importantly, however, a group of patients who developed CAD after a normal angiogram were identified, raising the question of the mechanism by which this occurs. It is possible that atherosclerotic changes can begin after the age of 40 years in some individuals or alternatively, early atherosclerotic changes, possibly present for decades but undetectable by angiography, can enter a phase of rapid progression in older individuals. Angiography is an insensitive technique for evaluating low levels of coronary atherosclerosis and the use of more sophisticated imaging would have identified earlier changes of atherosclerosis. A study of 44 patients with suspected CAD and normal coronary angiograms found atherosclerosis in 48% of patients when IVUS of the left anterior descending and left main coronary arteries was performed. 18 Additional studies using more sophisticated imaging are needed to determine whether the absence of CAD after the age of 40 years would identify a group of patients who would never develop atherosclerotic CAD. In the current study, 76% of patients did not show evidence of CAD on repeat angiography, demonstrating that the majority of patients with normal coronary angiograms do not show progression over medium-term follow-up. Prior studies examining the likelihood of development of CAD in patients with normal coronary angiograms have been 626 The Journal of Invasive Cardiology

4 small and reported inconsistent results. Palmeri et al identified 46 patients with angiographically normal coronary arteries who had another coronary angiogram during a subsequent 15-year period. Progression of CAD was observed in 41% of patients at a mean follow-up of 110 ± 40 months. Five patients (11%) with angiographically normal coronary arteries developed an acute MI during the follow-up period. 13 A study of 22 patients with normal coronary angiograms found that none of the patients developed any CAD on a second angiogram at a mean interval between studies of 42 months. 14 Pitts et al reported that 2 of 17 subjects with a previously normal coronary angiogram developed angiographically apparent CAD during a follow-up period of almost 9 years. 15 These data and our study likely overestimate the risk of progression of CAD in patients with normal coronary angiograms, because only patients with a clinical condition that warranted a second angiogram were studied. A normal coronary angiogram at any point after 40 years of age, even in patients requiring a second coronary angiogram, portends an excellent prognosis. The annual risk of MI or revascularization was approximately 1% and there were no MIs or revascularization within 2 years of a normal angiogram. While this is the first study to report revascularization as an endpoint, numerous prior studies with varying follow-up have reported an annual rate of MI and/or cardiac death in the range of 0%-0.97% for patients with normal coronary angiograms Consistent results are also found when utilizing CT angiography. A study of 1234 patients undergoing angiography for clinical reasons found no incidences of cardiac death or MI in patients with normal coronary arteries who were followed for a mean of 52 ± 22 months (compared to a rate of 12% and 46% in patients with non-obstructive CAD and obstructive CAD, respectively). 17 In this study of patients who had subsequent coronary angiography, the annual rate of MI or revascularization was 4.3% in the mild-atherosclerosis group compared to 1% in the normal-angiogram group. Our results are consistent with prior studies, which have consistently shown higher event rates in patients with even mild disease. Proudfit et al followed 357 patients with normal coronary angiograms and 101 patients with <30% estimated narrowing of at least one coronary artery for approximately 10 years. Coronary events, defined as death from coronary disease, subsequent MI, or angiographic evidence of progression of coronary obstruction, occurred in 2.1% of those who had normal arteriograms vs 13.8% of the group with mild disease. 12 Increased risk of cardiac events in patients with mild disease compared to normal angiography was also found by Palmeri et al, 13 Marchandise et al, 14 and Pitts et al. 15 Lastly, the Coronary Artery Surgery Study (CASS) registry showed that mild atherosclerosis has a negative effect on prognosis compared to normal coronary angiograms. 16 Of 21,487 patients in the registry who had normal left ventricular function, 3136 coronary angiograms were normal and 915 had stenosis <50% in one or FIGURE 2. (A) Risk of adverse cardiovascular endpoints stratified by the results of the initial angiogram. Kaplan-Meier curves of the risk of myocardial infarction (MI) or revascularization or (B) the risk of MI, revascularization, or development of obstructive coronary artery disease (CAD). Vol. 26, No. 12, December

5 more segments. The 7-year mortality rate was 4% for the patients with a normal angiogram and 8% with mild disease (P<.001). Study limitations. There are several limitations to this study. It was a retrospective cohort study. As noted above, coronary angiography is an insensitive method for determining the presence of atherosclerosis. The study cohort only included patients who had a second angiogram and thus the study likely overestimated the risk of progression of CAD. Only patients who had a second angiogram at our hospital were included and thus individuals who had additional angiograms at other hospitals were not included. Information on non-traditional risk factors was not available on most patients and thus it was not possible to determine if these influenced the risk of progression. Entry into the study was not limited to those patients undergoing coronary angiography for evaluation of CAD-related symptoms, as the design of the study was broad to include as many patients as possible. Conclusion In summary, we found that angiographically apparent CAD developed in 26% and obstructive CAD developed in 4.8% of patients over the age of 40 years with initially normal coronary angiograms who required a second coronary angiogram for clinical indications during a mean follow-up period of 75 ± 46 months. Despite having symptoms and/ or a clinical condition that necessitated a second angiogram, these patients had an excellent prognosis, with an annual rate of MI or revascularization of 1%. 9. Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006;113(6): Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol. 2007;49(18): Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med. 2010;362(10): Erratum in: N Engl J Med. 2010;363(5): Proudfit WL, Bruschke VG, Sones FM Jr. Clinical course of patients with normal or slightly or moderately abnormal coronary arteriograms: 10- year follow-up of 521 patients. Circulation. 1980;62(4): Palmeri ST, Akula DN, Agarwal S, Wilson AC, Casazza L, Moreyra AE. Late angiographic follow-up in adults with initial angiographic normal or minimally narrowed coronary arteries. Am J Cardiol. 2007;99(10): Epub 2007 Apr Marchandise B, Bourassa MG, Chaitman BR, Lesperance J. Angiographic evaluation of the natural history of normal coronary arteries and mild coronary atherosclerosis. Am J Cardiol. 1978;41(2): Pitts WR, Lange RA, Cigarroa JE, Hillis LD. Repeat coronary angiography in patients with chest pain and previously normal coronary angiogram. Am J Cardiol. 1997;80(8): Kemp HG, Kronmal RA, Vlietstra RE, Frye RL. Seven year survival of patients with normal or near normal coronary arteriograms: a CASS registry study. J Am Coll Cardiol. 1986;7(3): Andreini D, Pontone G, Mushtaq S, et al. A long-term prognostic value of coronary CT angiography in suspected coronary artery disease. JACC Cardiovasc Imaging. 2012;5(7): Erbel R, Ge J, Bockisch A, et al. Value of intracoronary ultrasound and Doppler in the differentiation of angiographically normal coronary arteries: a prospective study in patients with angina pectoris. Eur Heart J. 1996;17(6): References 1. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9): Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med. 2011;17(11): Enos WF Jr, Beyer JC, Holmes RH. Pathogenesis of coronary disease in American soldiers killed in Korea. J Am Med Assoc. 1955;158(11): Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea; preliminary report. J Am Med Assoc. 1953;152(12): McNamara JJ, Molot MA, Stremple JF, Cutting RT. Coronary artery disease in combat casualties in Vietnam. JAMA. 1971;216(7): Strong JP, Malcom GT, McMahan CA, et al. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. JAMA. 1999;281(8): Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med. 1998;338(23): Tuzcu EM, Kapadia SR, Tutar E, et al. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound. Circulation. 2001;103(22): From the 1 Division of Cardiology, University of North Carolina, Chapel Hill, North Carolina; 2 Division of Cardiology, East Tennessee State University, Johnson City, Tennessee; and 3 Howard W. Odum Institute for Social Science, University of North Carolina, Chapel Hill, North Carolina. Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein. Presented in abstract form to the American College of Cardiology Annual Scientific Sessions Manuscript submitted January 20, 2014, provisional acceptance given April 28, 2014, final version accepted June 30, Address for correspondence: George A. Stouffer, MD, Division of Cardiology, University of North Carolina, Chapel Hill, NC rstouff@med.unc.edu 628 The Journal of Invasive Cardiology

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