SPECT in Asymptomatic Patients with Cardiovascular Risk Factors
Fernando Fabián Faccio, Bruno Nicolás Strada
Departamento de Imágenes, Sanatorio Privado San Gerónimo, Santa Fe.
(3000) Santa Fe, Santa Fe, Argentina. E-mail
Recibido 19-MAR-2014 – ACEPTADO despues de revision el 15 ABRIL-2014. The authors declare not having conflicts of interest
Rev Fed Arg Cardiol. 2014; 43(3): 116-120
Myocardial reperfusion studies have provided a significant contribution in patients known to be carriers or with symptoms suggesting CAD; however, the use of functional tests in asymptomatic patients has not been defined with accuracy.
In the light of the available epidemiological data in ischemic heart disease, in previously asymptomatic patients, the strategies and algorithms proposed should be reviewed to try to prevent major cardiac events in patients who were previously considered healthy.
A proper use of radioisotope imaging may offer significant documentation and help in screening asymptomatic patients.
The goal is to select subsets of asymptomatic patients in whom performing a functional myocardial perfusion SPECT test would be useful, and in turn to identify who between these patients would not benefit, having to undergo functional tests that has them even exposed to radiation unnecessarily.
INTRODUCTION It is known that myocardial perfusion (MP) studies have provided a significant contribution in patients known or with symptoms suggesting coronary artery disease (CAD); however, the use of functional tests has not been defined with accuracy in asymptomatic patients.
There are multiple forms of presentation of ischemic heart disease in patients that were previously asymptomatic; but undoubtedly the most dreaded one is still sudden cardiac death (SCD). As it was described in the Framingham epidemiological study, in the basal registry with a 26-year follow-up, in individuals between 30 and 59 years old, with no cardiac disease, SCD was the final outcome in 46% of the deaths by CAD in males and 34% in females . For this reason, strategies and algorithms should be given a new value, to prevent such dreaded event in patients that were previously considered healthy.
In patients with precordial pain or with equivalent symptoms such as dyspnea or syncope, it is mandatory to rule out CAD by different methods, since these symptoms may have atypical presentations of high risk of CAD, even more so in the presence of anomalies of the ischemic type in the electrocardiogram (ECG), which have proven to be associated to a greater risk of cardiac events.
The criteria about a proper use of radioisotope imaging may document and differentiate asymptomatic patients, and even those with equivalent symptoms of ischemia, including atypical precordial pain, angina equivalents or abnormal ECG .
The objective is to select subsets of totally asymptomatic patients in whom performing a functional myocardial perfusion SPECT test would be useful, and in turn to identify who between these patients would not benefit, having to undergo functional tests that may even expose them unnecessarily to radiation.
ASSESSMENT OF CLINICAL RISK
In asymptomatic patients, the way to assess the clinical risk of presenting events is based on the stratification and the performance of a proper medical treatment [3-4]. The cardiovascular events in the future may be estimated based on a global risk score, which is composed by traditional and new or emerging risk factors (RF), to thus estimate the major adverse cardiovascular events [5-6].
In the United States, the Framingham risk score (FRS) is the most widespread one and allows to estimate a cardiovascular death or non-fatal myocardial infarction (MI) . Thus, an individual may have a low FRS to present MI or death by cardiovascular disease (CVD), lower than 6% at 10 years, an intermediate risk that covers values of 6-20%, or high risk for those patients with a probability greater than 20% to present major cardiac events at 10 years. For asymptomatic patients, the FRS would include other variables as obesity, metabolic syndrome or family history of early CAD. Other factors that are not included in the FRS, are for example the incapacity by the patient to develop routine activities that would allow them to change their lifestyles.
The limitations of the FRS with the mismatch existing before the estimation that this score provides and the total load of the atheromatous plaque, become evident in the prospective study by Pen et al, who assessed the risk stratification by the Framingham score in comparison to the atherosclerotic plaque load measured by computed tomography angiography. From 1173 patients characterized as in low to intermediate risk by the FRS, the atherosclerotic plaque was present in 47.6-72.7% respectively . This study ratifies the mismatch between the clinical risk stratification and that derived from supplementary methods, which suggests the need to identify subsets in greater risk for the assessment of patients without known CAD.
Recently, Malhotra et al, found that silent myocardial ischemia (SMI) shown by MP studies
in asymptomatic patients without known previous CAD, has a low prognostic significance.
When differentiating the patients by age, they saw that in those older than 74 years,
ischemia is not related to the number of RF for CAD, while in individuals younger than 74
years, the increase in coronary RF was associated to a greater prevalence in SMI [9-10].
The incidence of diabetes mellitus (DM) has increased in an alarming fashion in the last 2 decades. In year 2000, DM affected 17.7 million people in USA, and 171 million people in the world, with a projection estimated to double for year 2030 . Moreover, CAD is the cause of death in approximately 75% of the asymptomatic diabetic patients older than 65 years .
In diabetic, asymptomatic patients, the finding of abnormal MP studies ranged from 21% to 59% [13-15]. In turn, the events in asymptomatic diabetic patients are similar to those with angina. In spite of this evidence, the results from the DIAD study (Detection of Ischemia in Asymptomatic Diabetics)  indicated that a routine MP test in diabetic patients would not be justified. We should not neglect emphasizing the low rate of events occurring in the DIAD, the fact that the population after being admitted into the study optimized in a significant way the anti-ischemic treatment and the great adherence to the treatment in the follow-up of this study. These characteristics proper of this study, that do not reflect or resemble daily clinical practice, were perhaps a limitation to find significant results in a diabetic population that by being asymptomatic and without previous cardiovascular events, could be considered in low risk.
For some studies, the calcium score resulted the best predictor of all-cause mortality, in both diabetic and non-diabetic patients , and an independent predictor of coronary events and stroke in type 2 diabetic patients . The potential supplementary role between the calcium score and MP to stratify risk in asymptomatic diabetic patients resulted additive or by synergy . A good strategy could be to perform MP studies in those patients that present a calcium score greater than 100 .
The use of screening for CAD in asymptomatic diabetic patients is controversial. In 2006, the ADA (American Diabetes Association) suggested that the stress test with ergometer could be considered appropriate for these patients , and only in the presence of abnormal rest ECG a functional imaging test should be requested. Based on limited experiences, we could consider that MP would be recommended in asymptomatic diabetic patients with autonomic neuropathy or evidence of carotid, renal, femoral vascular disease, etc.
In an experience of our own on 104 asymptomatic diabetic patients, studied in a prospective way with stress/rest MP, 41 had abnormal MP (39.4%) (Figures 1, 2 and 3).
Figure 1. It shows a severe and extensive apical, infero-lateral-apical, inferior, and also antero-lateral and antero-lateral-apical ischemia. The value of SSS of 20, SDS 20, and SRS 0 are observed
Figure 2. Representation of the polar map of stress above, and in rest below
Figure 3. Deterioration of apico-lateral motility in post-stress
to the basal one,
with drop in EF from 59% in the basal one to 55% in the post-stress one.
The univariate and multivariate analysis of the variables that were taken into account (Tables 1 and 2), showed in the multivariate analysis that age >70 years and the male gender were associated to a greater frequency of abnormal MP. Also in another experience , in a population of asymptomatic patients, the presence of DM, advanced age and male gender were the variables with a greater statistical power to predict abnormal MP.
Family history of CAD
Peripheral vascular disease
The impact of chronic kidney disease (CKD) both for cardiovascular mortality and total mortality, is well established. In the recent guideline of the National Kidney Foundation and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, it is advised to consider the patients with CKD as a group in high risk of CAD [22-27].
The strong association between CKD and DM with cardiovascular mortality and the high prevalence that reaches ranges of epidemic, makes for the risk stratification effective in these patients to assume a relevant significance [28,29].
Taking into account that DM and hypertension are the main causes of nephropathy, it would seem that the risk of suffering CKD could be due to associated RF, more than the disease proper. However, the study by Abdul Hakeem et al , showed that the presence and severity of abnormalities of MP was more relevant in patients that only had CKD, without DM. Moreover, in patients with normal MP, the yearly rate of cardiac death was 0.5% in diabetic patients and 2.35% in the presence of CKD. If both RF are added, this value increases to 2.9%, with no statistically significant differences in regard to just presenting CKD. As a conclusion, in spite of the MP studies being normal, just the presence of CKD is associated to a yearly death rate 3 times higher than the rest of the population, even in the group with the worse evolution, as those with DM.
The presence of greater activation of the renin-angiotensin-aldosterone system, volume overload, a difficulty to control blood pressure, and a lower possibility of using drugs effectively, are some of the conditions described to justify a worse prognosis in these patients, where MP could play an important role to detect silent myocardial ischemia, and thus to attempt differentiating the patients that could have adverse cardiovascular events. 28% of the patients that only present CKD have SSS (Summed Stress Score) >8 in MP and 1 in 5 of them have SRS (Summed Rest Score) >6 .
Metabolic syndrome (MBS) is defined in different ways according to the different associations. The concept of resistance to insulin, which originates pathophysiologically on an increase in abdominal fat, makes the definition of MBS proposed by the IDF (International Diabetes Federation) to be one of the most accepted ones . This includes inevitably, the presence of abdominal perimeter >94 cm in men or >80 cm in women, associated to at least 2 of the following criteria: triglycerides >150 mg/dl or specific treatment for it; HDL <50 mg/dl in men or <40 mg/dl in women, or specific treatment for it; blood pressure >135/85 mmHg or antihypertensive treatment; and basal glycemia >100 mg/dl or specific treatment.
The scientific community has not accepted unanimously that MBS is an entity, but rather a conjunction of risk factors.
Grundy states that abdominal obesity constitutes the basis of most cardiovascular risk that leads to a progressive increase in blood pressure and the modification of the lipid and glucidic metabolism . Individuals with abdominal obesity in early stages, already presented a greater risk of cardiovascular complications and in them, MBS can be diagnosed in patients that would not be categorized as hypertensive or diabetic. This concept plays a key role in the primary prevention of cardiovascular events, with a limited role in secondary prevention.
Taking into account these considerations, there is a need in the subset of asymptomatic patients to resort to some supplementary method that may predict cardiovascular events. This was evaluated in a Japanese population by Kenichi Nakajima et al , who unexpectedly showed that the presence of MBS was not associated to a significant increase in sudden cardiac death or acute coronary syndrome, in comparison to the subset of patients without MBS. Between multiple and different variables analyzed, only the presence of SSS (Summed Stress Score) >9 was a predictor of total cardiovascular events, including the need of percutaneous coronary intervention, CABG, new diagnosis of angina, severe heart failure, ischemic stroke and new diagnosis of peripheral vascular disease. From what was presented here, it arises that MP SPECT is a fundamental pillar when making decisions on this subset of patients that have a limited acknowledgement by the medical community.
Family history of early CAD
ATP III (Adult Treatment Panel) defines early cardiovascular disease as the presence of CAD in first-degree relatives <55 years in men and <65 years in women .
The publication of the Framingham Heart Study demonstrated that this subset of patients leads to a greater risk of cardiovascular events and they should be considered for a more aggressive prevention therapy. Nevertheless, the low incidence of events related to this single risk factor, originated the need to find a supplementary method that would select and/or stratify these patients better. The group of experts in cardiac computed tomography has suggested and published in 2010, the criteria for the proper use of it, agreeing that in patients in low risk of cardiovascular events, but with a family history of early CAD, the use of the calcium score would be appropriate, with the aim of documenting atherosclerosis and to reclassify these patients . Recently, a discordance in studies that pose the stratification of clinical risk through the Framinghan Risk Score (FRS) and computed tomography angiography (CTA) was published, warning that 47% of the patients classified as in low risk by FRS, had atherosclerotic plaques in CTA, and from them, 14.8% were non-calcified plaques, that were related to a greater vulnerability for thrombotic phenomena . Thus, Kral et al , when studying with MP Gated SPECT, patients with family history of early CAD, the presence of ischemia was associated to a greater rate of cardiovascular events, having a worse prognosis as SSS (Summed Stress Score) increased. However, patients with SSS, classified as in a minimal or mild degree, were associated to a greater incidence of acute coronary syndrome. The conclusions of the study were that the presence of ischemia is frequent in this population, and that adjusted to others RF, every 5% of increase in the severity of ischemia results in an increase of 77% in the rate of acute coronary events.
More than enough elements have been reported, to pay attention to this subset of patients and select them by a supplementary diagnostic method that may make evident the real risk they present, as considered by Hendel et al, in the documents reported by the American Society of Nuclear Cardiology for the role of MP in asymptomatic individuals, advising to perform a functional test in this subset of patients, even though there are still no consensus guidelines to support it .
Since there is a low prevalence of silent myocardial ischemia in asymptomatic patients without previously known CAD, and moreover, taking into account the low number of cardiac events that they present during their follow-up, a careful selection of a functional test for these patients could be considered, so we will surely have to add in the global assessment of the patient, some or several of the coronary RF such as diabetes mellitus, advanced age, sex, early family history and chronic kidney disease. Besides, the method that will provide the greatest additional and useful diagnostic and/or prognostic information should be defined accurately.
The detection of silent ischemia by a myocardial perfusion SPECT test in the subset of asymptomatic patients proved to relate in a consistent manner with major cardiovascular events during follow-up.
Kannel WB, Thomas HE. Sudden Coronary Death;The Framingham Study. Ann N Y AcadSci 1982; 382: 3-21.
Hendel RC, Berman DS, Di Carli MF et al. CCF / ASNC / ACR / AHA / ASE / SCCT / SCMR / SNM 2009 Appropriate use criteria for cardiac radionuclide imaging. J Am Coll Cardiol 2009; 53: 2201-29.
Bitton A, Gaziano TA. The Framingham Heart Study’s Impact on Global Risk Assessment. Prog Cardiovasc Dis 2010; 53 (1): 68-78.
Batsis JA, Lopez-Jimenez F. Cardiovascular risk assessment from individual risk prediction to estimation of global risk and change in risk in the population. BMC Med 2010; 8: 29.
Hemann BA, Bimson WF, Taylor AJ. The Framingham Risk Score: of appraisal of its benefits and limitations. Am Heart Hosp J 2007; 5: 91-6.
Wenger NK. The Reynolds risk score: Improved accuracy for cardiovascular risk in women: The Reynolds Risk Score. JAMA 2007; 297: 611-9.
Ruilope LM. The Framingham risk score is valuable in Europeans. Nat Rev Nephrol 2010; 6: 14-5.
Pen A, Yam Y, Chen L, et al. Discordance between Framingham Risk Score and atherosclerotic plaque burden. Eur Heart J 2013; 34: 1075-82.
Malhotra S, Sharma R, Kliner DE, et al. Relationship between silent myocardial ischemia and coronary artery disease risk factors. J Nucl Cardiol 2013; 20: 731-8.
Petretta M, Fiumara G, Petretta M, et al. Detection of silent myocardial ischemia: Is it clinically relevant? J Nucl Cardiol 2013; 20: 707-10.
Nild S, Roglic G, Green A, et al. Global prevalence of diabetes. Estimates for the year 2000 and projection for 2030. Diabetes Care 2004; 27: 1047-53.
Bonow RO, Bohannon N, Hazzard W. Risk stratification in coronary artery disease and special population. Am J Med 1996; 101: 175-225.
Bax JJ, Bonon RO, Tschope D, et al. Global dialogue group for the evaluation of cardiovascular risk in patients with diabetes: The potential myocardial perfusion scintigraphy for risk stratification of asymptomatic patients with type 2 diabetes. J Am Coll Cardiol 2006; 48: 754-60.
Wackers FJT, Young LH, Inzucchi SE, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects. The DIAD study. Diabetes care 2004; 27: 1954-61.
Faccio F, Strada B, Carlessi A, et al. Variables predictoras de perfusión miocárdica anormal en pacientes diabéticos asintomáticos. XXXI Congreso FAC 2013. Rev Fed Arg Cardiol 2013; 42 (supl 1): 33. Abstract #100.
Raggi P, Shaw LJ, Berman DS, et al. Prognostic value of coronary artery calcium screening in subjects with and without diabetes. J Am Coll Cardiol 2004; 43: 1663-9.
Elkeles RS, Godsland IF, Feher MD. Coronary calcium measurement improves prediction of cardiovascular events in asymptomatic patients with type 2 diabetes: the PREDICT study. Eur Heart J 2008; 29 (18): 2244-51.
Anand VD, Lim E, Lahiri A, et al. The role of non-invasive imaging in the risk stratification of asymptomatic diabetic subjects. Eur Heart J 2006; 27: 905-12.
Scholte AJ, Bax JJ, Wackers FJ. Screening of asymptomatic patients with type 2 diabetes mellitus for silent coronary artery disease: Combined use of stress myocardial perfusion imaging and coronary calcium scoring. J Nucl Cardiol 2006; 13: 11-8.
American Diabetes Association. Standars of medical care in diabetes - 2010. Diabetes Care 2010; 33: S11-61.
Faccio F, Strada B, Carlessi A, et al. Predicting variables of abnormal myocardial perfusion in asymptomatic patients. IAEA International Conference on Integrated Medical Imaging in Cardiovascular Diseases. Poster IAEA-CN-202/192. Viena 2013; Sept 30
Meisinger C, Doring A, Lowel H, KORA Study Group. Chronic kidney disease and risk of incident myocardial infarction and all-cause and cardiovascular disease mortality in middle-aged men and women from the general population. Eur Heart J 2006; 27: 1245–50.
Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296-305.
Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003; 41: 47-55.
Weiner DE, Tighiouart H, Amin MG, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol 2004; 15: 1307-15.
Anavekar NS, McMurray JJ, Velázquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004; 351: 1285–95.
Muntner P, He J, Hamm L, et al. Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 2002; 13: 745-53.
Levey AS, Coresh J, Balk E, et al., National Kidney Foundation. National kidney foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003; 139: 137-47.
Chobanian AV, Bakris GL, Black HR, et al., National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003; 289: 2560-72.
Hakeem A, Bhatti S, Karmali K, et al. Renal function and risk stratification of diabetic and nondiabetic patients undergoing evaluation for coronary artery disease. J Am Coll Cardiol: cardiovascular imaging 2010; 3: 734-45.
Grundy SM. Metabolic Syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol 2006; 47: 1093-100.
Nakajima K, Takeishi Y, Matsuo S, et al. Metabolic syndrome is not a predictor for cardiovascular events in Japanese patients with diabetes mellitus asymptomatic for coronary artery disease: A retrospective analysis of the J-ACCESS-2 study. J Nucl Cardiol 2013; 20: 234-41.
Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-24.
Allen J. Taylor, Manuel Cerqueira, John McB. Hodgson. ACCF / SCCT / ACR / AHA / ASE / ASNC / NASCI / SCAI / SCMR 2010 Appropriate use criteria for cardiac computed tomography. Am Coll Cardiol 2010; 56 (22): 1864-94.
. Kral BG, Becker DM, Vaidya D, et al. Severity of inducible myocardial ischemia predicts incident acute coronary syndromes in asymptomatic individuals with a family history of premature coronary artery disease. J Nucl Cardiol 2012; 19: 28-36.
Hendel R, Abott B, Bateman T, et al; The role radionuclide myocardial perfusion imaging for asymptomatic individuals. J Nucl Cardiol 2011; 18: 3-15.