exercise tc - sestamibi myocardial perfusion single - photon emission computed tomography ( spect ) provides clinically useful information for diagnosis and risk stratification of patients with known or suspected coronary artery disease ( cad ) . a recent meta - analysis of the literature demonstrated that normal myocardial perfusion spect has a high negative predictive value for cardiac events.1,2 patients with normal myocardial perfusion spect are considered at low risk of cardiac events , the annualized event rate is generally < 1% during the first few years after testing . accordingly , in these low - risk patients , further ( invasive ) diagnostic and therapeutic strategies and associated medical care costs can be avoided.1 - 3 however , over time , a significant change in risk may occur after a normal myocardial perfusion spect . the underlying clinical risk and history of cad significantly influence the event rate after a normal myocardial perfusion spect . moreover , a temporal component of risk has been identified , which may increase the annualized cardiac event rate to 2% , even in the presence of a normal myocardial perfusion spect.4 these observations have led to the perception that a  warranty period  exists after a normal myocardial perfusion spect . in the currently available literature , mean follow - up after myocardial perfusion spect was approximately 3  years.1 - 3 data of very long - term outcome after normal myocardial perfusion spect are lacking , and consequently , the duration of the low - risk status after a normal test is not clear . the goals of the current study were as follows : ( 1 ) to assess very long - term outcome after normal myocardial perfusion spect . ( 2 ) to define a low - risk period after normal myocardial perfusion spect . ( 3 ) to identify predictors of increased risk . the study population consisted of 242 consecutive patients with known or suspected cad who underwent exercise tc - sestamibi myocardial perfusion spect and had normal myocardial perfusion at exercise and at stress . the majority of the study population has been described in a previous study from our center.5 the local medical ethics committee approved the protocol , and all the patients gave informed consent . a structured interview and clinical history were obtained , including assessment of cardiac risk factors , and the symptoms before the exercise test . all the patients performed a symptom - limited upright bicycle ergometry test with stepwise increment of 20  w every minute . cuff blood pressure measurement and standard 12-lead surface electrocardiograms were obtained at rest and every minute during exercise , until the end of the recovery phase . test endpoints included the following : severe angina , decrease in systolic blood pressure fall > 40  mm  hg , blood pressure > 240/120  mm  hg , or significant cardiac arrhythmia . an ischemic response was defined as 1  mm horizontal or downsloping st - segment depression at 80  ms after the j point . approximately 1  minute before the termination of the exercise test , an intravenous dose of 370  mbq of tc - sestamibi was administered as previously described.5 for resting studies , 370  mbq of the same tracer was administered at least 24  h after the exercise test . image acquisition was performed using a spect camera system ( orbiter camera ; siemens , iselin , nj ; or picker prism 3000xp camera ; picker , cleveland , oh ) . thirty - two projections were obtained , from the left posterior oblique to the right anterior oblique over 180. the semiquantitative interpretation of the scan was performed by visual analysis assisted by the circumferential profiles analysis . stress and rest tomographic views were reviewed side - by - side by two experienced observers who were unaware of the patients clinical data . in case of disagreement , follow - up data were collected in the year 2011 and were completed in respect of 233 patients ( 96% ) . outcome data were obtained by evaluation of hospital records , contacting the patient s general practitioner , and/or review of civil registries . the date of the last review or consultation was used to calculate follow - up time . endpoints were all - cause mortality , cardiac death , nonfatal myocardial infarction , and coronary revascularization . nonfatal myocardial infarction was defined as new symptoms of ischemia , and/or ecg changes indicative of new ischemia , and/or imaging evidence of myocardial infarction , accompanied by detection of a rise and fall of cardiac biomarkers.6 major adverse cardiac events ( mace ) were defined as the occurrence of cardiac death , nonfatal myocardial infarction , or revascularization . values were expressed as mean    sd or number , and compared using the student s t test or chi - squared test . univariate and multivariate cox proportional hazard regression models ( spss statistical software version 15.0 , spss , chicago , il ) were used to identify independent predictors of outcome.7 variables were selected in a stepwise forward selection manner with entry and retention set at a significance level of .05 . the risk of a variable was expressed as a hazard ratio with a corresponding 95% confidence interval . the probability of survival was calculated using the kaplan - meier method , and survival curves were compared using the log - rank test . the study population consisted of 242 consecutive patients with known or suspected cad who underwent exercise tc - sestamibi myocardial perfusion spect and had normal myocardial perfusion at exercise and at stress . the majority of the study population has been described in a previous study from our center.5 the local medical ethics committee approved the protocol , and all the patients gave informed consent . a structured interview and clinical history were obtained , including assessment of cardiac risk factors , and the symptoms before the exercise test . all the patients performed a symptom - limited upright bicycle ergometry test with stepwise increment of 20  w every minute . cuff blood pressure measurement and standard 12-lead surface electrocardiograms were obtained at rest and every minute during exercise , until the end of the recovery phase . test endpoints included the following : severe angina , decrease in systolic blood pressure fall > 40  mm  hg , blood pressure > 240/120  mm  hg , or significant cardiac arrhythmia . an ischemic response was defined as 1  mm horizontal or downsloping st - segment depression at 80  ms after the j point . approximately 1  minute before the termination of the exercise test , an intravenous dose of 370  mbq of tc - sestamibi was administered as previously described.5 for resting studies , 370  mbq of the same tracer was administered at least 24  h after the exercise test . image acquisition was performed using a spect camera system ( orbiter camera ; siemens , iselin , nj ; or picker prism 3000xp camera ; picker , cleveland , oh ) . thirty - two projections were obtained , from the left posterior oblique to the right anterior oblique over 180. the semiquantitative interpretation of the scan was performed by visual analysis assisted by the circumferential profiles analysis . stress and rest tomographic views were reviewed side - by - side by two experienced observers who were unaware of the patients clinical data . in case of disagreement , follow - up data were collected in the year 2011 and were completed in respect of 233 patients ( 96% ) . outcome data were obtained by evaluation of hospital records , contacting the patient s general practitioner , and/or review of civil registries . the date of the last review or consultation was used to calculate follow - up time . endpoints were all - cause mortality , cardiac death , nonfatal myocardial infarction , and coronary revascularization . nonfatal myocardial infarction was defined as new symptoms of ischemia , and/or ecg changes indicative of new ischemia , and/or imaging evidence of myocardial infarction , accompanied by detection of a rise and fall of cardiac biomarkers.6 major adverse cardiac events ( mace ) were defined as the occurrence of cardiac death , nonfatal myocardial infarction , or revascularization . values were expressed as mean    sd or number , and compared using the student s t test or chi - squared test . univariate and multivariate cox proportional hazard regression models ( spss statistical software version 15.0 , spss , chicago , il ) were used to identify independent predictors of outcome.7 variables were selected in a stepwise forward selection manner with entry and retention set at a significance level of .05 . the risk of a variable was expressed as a hazard ratio with a corresponding 95% confidence interval . the probability of survival was calculated using the kaplan - meier method , and survival curves were compared using the log - rank test . there was a significant increase in heart rate ( 78    15 to 147    24 beats / minute , p  <  .001 ) , and systolic blood pressure ( 138    22 to 188    25  mm  hg , p  <  .001 from rest to peak exercise . the mean workload was 143    43  w , corresponding with an exercise duration of 7  minutes . the target heart rate ( 85% of the maximal predicted heart rate ) was reached in 173 patients ( 74% ) . exercise - induced angina occurred in 29 ( 12% ) patients , and 19 ( 8% ) had st segment depression during the exercise test.table  1patient characteristicsage ( years)54    12men122 ( 52%)height ( cm)170    10weight ( kg)74    13hypertension78 ( 33%)smoking61 ( 26%)hypercholesterolemia63 ( 27%)diabetes mellitus16 ( 7%)ace - inhibitor29 ( 12%)beta - blocker78 ( 33%)known coronary artery disease57 ( 24%)prior coronary revascularization55 ( 24%)prior myocardial infarction19 ( 8%)typical angina58 ( 25%)atypical angina120 ( 52%)nonspecific symptoms14 ( 6%)no symptoms41 ( 18% ) patient characteristics kaplan - meier survival curves and cumulative event rate are presented in figures  1 , 2 , 3 , 4 , and 5 . during a mean follow - up of 15.5    4.9  years , seventeen patients ( 7% ) underwent coronary artery bypass surgery , and 30 ( 13% ) underwent percutaneous coronary intervention . the annualized event rates for all - cause mortality , cardiac mortality , cardiac mortality / nonfatal infarction , and major adverse cardiac events were respectively 1.1% , 0.3% , 0.7% , and 1.8% . all - cause mortality was significantly higher in patients with known cad ( figure  5).figure  1kaplan - meier event - free survival for the endpoint of all - cause mortality in patients with normal exercise tc - sestamibi myocardial perfusion spectfigure  2kaplan - meier event - free survival for the endpoint of cardiac mortality in patients with normal exercise tc - sestamibi myocardial perfusion spectfigure  3kaplan - meier event - free survival for the endpoint of cardiac mortality and nonfatal myocardial infarction in patients with normal exercise tc - sestamibi myocardial perfusion spectfigure  4kaplan - meier event - free survival for the endpoint of major adverse cardiac events in patients with normal exercise tc - sestamibi myocardial perfusion spectfigure  5kaplan - meier event - free survival for the endpoint of all - cause mortality in patients with normal exercise tc - sestamibi myocardial perfusion spect , with or without a history of cad kaplan - meier event - free survival for the endpoint of all - cause mortality in patients with normal exercise tc - sestamibi myocardial perfusion spect kaplan - meier event - free survival for the endpoint of cardiac mortality in patients with normal exercise tc - sestamibi myocardial perfusion spect kaplan - meier event - free survival for the endpoint of cardiac mortality and nonfatal myocardial infarction in patients with normal exercise tc - sestamibi myocardial perfusion spect kaplan - meier event - free survival for the endpoint of major adverse cardiac events in patients with normal exercise tc - sestamibi myocardial perfusion spect kaplan - meier event - free survival for the endpoint of all - cause mortality in patients with normal exercise tc - sestamibi myocardial perfusion spect , with or without a history of cad univariate analysis demonstrated that age , diabetes mellitus , diastolic blood pressure at rest , and heart rate during exercise was predictors of all - cause mortality ( table  2 ) . diastolic blood pressures at rest and peak exercise heart rate were predictors of cardiac mortality . beta - blocker use , and peak exercise heart rate were predictors of cardiac mortality / nonfatal infarction . age , male gender , diastolic blood pressure at rest and peak exercise heart rate were predictors of major adverse cardiac events.table  2univariate predictors of outcomeall - cause mortalitycardiac mortalitycardiac mortality / nonfatal infarctionmajor adverse cardiac eventsclinical features  age > 70  years7.46 ( 2.8419.51)2.52 ( 0.5112.56)1.39 ( 0.385.10)3.59 ( 1.379.38 )  male gender1.53 ( 0.773.05)2.53 ( 0.659.78)1.96 ( 0.844.57)2.44 ( 1.414.24 )  hypertension0.79 ( 0.381.65)0.43 ( 0.092.03)1.43 ( 0.633.24)1.43 ( 0.822.49 )  smoking0.76 ( 0.341.69)1.06 ( 0.274.13)0.78 ( 0.302.05)0.65 ( 0.341.21 )  hypercholesterolemia0.60 ( 0.261.39)0.26 ( 0.032.06)1.16 ( 0.482.79)1.19 ( 0.662.15 )  diabetes mellitus3.12 ( 1.079.14)1.38 ( 0.1711.52)2.81 ( 0.849.44)2.35 ( 0.846.57 )  ace  inhibitor1.97 ( 0.814.84)0.69 ( 0.095.62)0.53 ( 0.122.37)1.25 ( 0.572.76 )  beta - blocker0.91 ( 0.441.87)1.70 ( 0.505.76)2.39 ( 1.065.38)1.62 ( 0.932.83)prior myocardial infarction1.77 ( 0.605.21)1.13 ( 0.149.37)2.21 ( 0.687.24)2.57 ( 0.996.66)stress test results  heart rate at rest0.99 ( 0.891.18)0.92 ( 0.611.40)0.84 ( 0.641.11)0.91 ( 0.791.04 )  peak exercise heart rate0.80 ( 0.710.90)0.60 ( 0.460.86)0.72 ( 0.600.86)0.82 ( 0.750.90 )  diastolic blood pressure rest0.75 ( 0.580.97)0.55 ( 0.310.98)0.70 ( 0.461.05)0.77 ( 0.630.95 )  rate pressure product at rest1.03 ( 0.931.14)0.96 ( 0.751.22)0.94 ( 0.801.10)0.97 ( 0.901.05 )  typical angina0.72 ( 0.242.20)0.69 ( 0.095.62)1.26 ( 0.403.94)2.02 ( 0.924.43 )  st segment changes0.53 ( 0.122.38)0.00 ( 0.004.18)0.89 ( 0.194.08)1.28 ( 0.493.31)values are expressed as cox proportional hazard ratio and 95% confidence interval . univariate predictors of outcome values are expressed as cox proportional hazard ratio and 95% confidence interval . multivariate models demonstrated that age , male gender , diabetes , heart rate at rest and peak exercise heart rate were independent predictors of all - cause mortality ( table  3 ) . heart rate at rest and peak exercise heart rate were predictors of cardiac mortality ( table  4 ) . male gender , diabetes , and peak exercise heart rate were predictors of cardiac mortality / nonfatal infarction ( table  5 ) . age , male gender , diabetes , diastolic blood pressure at rest , rate pressure product at rest , peak exercise heart rate , and st segment changes were independent predictors of major adverse cardiac events ( table  6).table  3multivariate predictors of all - cause mortalityhr ( 95% ci)p valueage*1.06 ( 1.041.09)<.001male gender2.70 ( 1.455.03).002diabetes3.06 ( 1.227.65).02heart rate at rest1.30 ( 1.071.58).01peak exercise heart rate0.80 ( 0.690.92).03values are expressed as cox proportional hazard ratio and 95% confidence interval . *  per 1 unit increment.table  4multivariate predictors of cardiac mortalityhr ( 95% ci)p valueheart rate at rest1.73 ( 1.022.94).04peak exercise heart rate0.50 ( 0.350.69)<.001values are expressed as cox proportional hazard ratio and 95% confidence interval.table  5multivariate predictors of cardiac mortality / nonfatal myocardial infarctionhr ( 95% ci)p valuemale gender2.61 ( 1.116.14).03diabetes6.93 ( 2.1822.04).01peak exercise heart rate0.70 ( 0.580.84)<.001values are expressed as cox proportional hazard ratio and 95% confidence interval.table  6multivariate predictors of major adverse cardiac eventshr ( 95% ci)p valueage*1.03 ( 1.01 - 1.06).01male gender2.82 ( 1.75 - 4.53)<.001diabetes3.95 ( 1.88 - 8.30)<.001diastolic blood pressure at rest0.79 ( 0.64 - 0.97).03rate - pressure product at rest1.14 ( 1.04 - 1.25).01peak exercise heart rate0.80 ( 0.71 - 0.89)<.001st segment changes2.94 ( 1.44 - 5.99).01values are expressed as cox proportional hazard ratio and 95% confidence interval . *  per 1 unit increment . multivariate predictors of all - cause mortality values are expressed as cox proportional hazard ratio and 95% confidence interval . multivariate predictors of cardiac mortality values are expressed as cox proportional hazard ratio and 95% confidence interval . multivariate predictors of cardiac mortality / nonfatal myocardial infarction values are expressed as cox proportional hazard ratio and 95% confidence interval . multivariate predictors of major adverse cardiac events values are expressed as cox proportional hazard ratio and 95% confidence interval . *  per 1 unit increment . there was a significant increase in heart rate ( 78    15 to 147    24 beats / minute , p  <  .001 ) , and systolic blood pressure ( 138    22 to 188    25  mm  hg , p  <  .001 from rest to peak exercise . the mean workload was 143    43  w , corresponding with an exercise duration of 7  minutes . the target heart rate ( 85% of the maximal predicted heart rate ) was reached in 173 patients ( 74% ) . exercise - induced angina occurred in 29 ( 12% ) patients , and 19 ( 8% ) had st segment depression during the exercise test.table  1patient characteristicsage ( years)54    12men122 ( 52%)height ( cm)170    10weight ( kg)74    13hypertension78 ( 33%)smoking61 ( 26%)hypercholesterolemia63 ( 27%)diabetes mellitus16 ( 7%)ace - inhibitor29 ( 12%)beta - blocker78 ( 33%)known coronary artery disease57 ( 24%)prior coronary revascularization55 ( 24%)prior myocardial infarction19 ( 8%)typical angina58 ( 25%)atypical angina120 ( 52%)nonspecific symptoms14 ( 6%)no symptoms41 ( 18% ) patient characteristics kaplan - meier survival curves and cumulative event rate are presented in figures  1 , 2 , 3 , 4 , and 5 . during a mean follow - up of 15.5    4.9  years , seventeen patients ( 7% ) underwent coronary artery bypass surgery , and 30 ( 13% ) underwent percutaneous coronary intervention . the annualized event rates for all - cause mortality , cardiac mortality , cardiac mortality / nonfatal infarction , and major adverse cardiac events were respectively 1.1% , 0.3% , 0.7% , and 1.8% . all - cause mortality was significantly higher in patients with known cad ( figure  5).figure  1kaplan - meier event - free survival for the endpoint of all - cause mortality in patients with normal exercise tc - sestamibi myocardial perfusion spectfigure  2kaplan - meier event - free survival for the endpoint of cardiac mortality in patients with normal exercise tc - sestamibi myocardial perfusion spectfigure  3kaplan - meier event - free survival for the endpoint of cardiac mortality and nonfatal myocardial infarction in patients with normal exercise tc - sestamibi myocardial perfusion spectfigure  4kaplan - meier event - free survival for the endpoint of major adverse cardiac events in patients with normal exercise tc - sestamibi myocardial perfusion spectfigure  5kaplan - meier event - free survival for the endpoint of all - cause mortality in patients with normal exercise tc - sestamibi myocardial perfusion spect , with or without a history of cad kaplan - meier event - free survival for the endpoint of all - cause mortality in patients with normal exercise tc - sestamibi myocardial perfusion spect kaplan - meier event - free survival for the endpoint of cardiac mortality in patients with normal exercise tc - sestamibi myocardial perfusion spect kaplan - meier event - free survival for the endpoint of cardiac mortality and nonfatal myocardial infarction in patients with normal exercise tc - sestamibi myocardial perfusion spect kaplan - meier event - free survival for the endpoint of major adverse cardiac events in patients with normal exercise tc - sestamibi myocardial perfusion spect kaplan - meier event - free survival for the endpoint of all - cause mortality in patients with normal exercise tc - sestamibi myocardial perfusion spect , with or without a history of cad univariate analysis demonstrated that age , diabetes mellitus , diastolic blood pressure at rest , and heart rate during exercise was predictors of all - cause mortality ( table  2 ) . diastolic blood pressures at rest and peak exercise heart rate were predictors of cardiac mortality . beta - blocker use , and peak exercise heart rate were predictors of cardiac mortality / nonfatal infarction . age , male gender , diastolic blood pressure at rest and peak exercise heart rate were predictors of major adverse cardiac events.table  2univariate predictors of outcomeall - cause mortalitycardiac mortalitycardiac mortality / nonfatal infarctionmajor adverse cardiac eventsclinical features  age > 70  years7.46 ( 2.8419.51)2.52 ( 0.5112.56)1.39 ( 0.385.10)3.59 ( 1.379.38 )  male gender1.53 ( 0.773.05)2.53 ( 0.659.78)1.96 ( 0.844.57)2.44 ( 1.414.24 )  hypertension0.79 ( 0.381.65)0.43 ( 0.092.03)1.43 ( 0.633.24)1.43 ( 0.822.49 )  smoking0.76 ( 0.341.69)1.06 ( 0.274.13)0.78 ( 0.302.05)0.65 ( 0.341.21 )  hypercholesterolemia0.60 ( 0.261.39)0.26 ( 0.032.06)1.16 ( 0.482.79)1.19 ( 0.662.15 )  diabetes mellitus3.12 ( 1.079.14)1.38 ( 0.1711.52)2.81 ( 0.849.44)2.35 ( 0.846.57 )  ace  inhibitor1.97 ( 0.814.84)0.69 ( 0.095.62)0.53 ( 0.122.37)1.25 ( 0.572.76 )  beta - blocker0.91 ( 0.441.87)1.70 ( 0.505.76)2.39 ( 1.065.38)1.62 ( 0.932.83)prior myocardial infarction1.77 ( 0.605.21)1.13 ( 0.149.37)2.21 ( 0.687.24)2.57 ( 0.996.66)stress test results  heart rate at rest0.99 ( 0.891.18)0.92 ( 0.611.40)0.84 ( 0.641.11)0.91 ( 0.791.04 )  peak exercise heart rate0.80 ( 0.710.90)0.60 ( 0.460.86)0.72 ( 0.600.86)0.82 ( 0.750.90 )  diastolic blood pressure rest0.75 ( 0.580.97)0.55 ( 0.310.98)0.70 ( 0.461.05)0.77 ( 0.630.95 )  rate pressure product at rest1.03 ( 0.931.14)0.96 ( 0.751.22)0.94 ( 0.801.10)0.97 ( 0.901.05 )  typical angina0.72 ( 0.242.20)0.69 ( 0.095.62)1.26 ( 0.403.94)2.02 ( 0.924.43 )  st segment changes0.53 ( 0.122.38)0.00 ( 0.004.18)0.89 ( 0.194.08)1.28 ( 0.493.31)values are expressed as cox proportional hazard ratio and 95% confidence interval . univariate predictors of outcome values are expressed as cox proportional hazard ratio and 95% confidence interval . multivariate models demonstrated that age , male gender , diabetes , heart rate at rest and peak exercise heart rate were independent predictors of all - cause mortality ( table  3 ) . heart rate at rest and peak exercise heart rate were predictors of cardiac mortality ( table  4 ) . male gender , diabetes , and peak exercise heart rate were predictors of cardiac mortality / nonfatal infarction ( table  5 ) . age , male gender , diabetes , diastolic blood pressure at rest , rate pressure product at rest , peak exercise heart rate , and st segment changes were independent predictors of major adverse cardiac events ( table  6).table  3multivariate predictors of all - cause mortalityhr ( 95% ci)p valueage*1.06 ( 1.041.09)<.001male gender2.70 ( 1.455.03).002diabetes3.06 ( 1.227.65).02heart rate at rest1.30 ( 1.071.58).01peak exercise heart rate0.80 ( 0.690.92).03values are expressed as cox proportional hazard ratio and 95% confidence interval . *  per 1 unit increment.table  4multivariate predictors of cardiac mortalityhr ( 95% ci)p valueheart rate at rest1.73 ( 1.022.94).04peak exercise heart rate0.50 ( 0.350.69)<.001values are expressed as cox proportional hazard ratio and 95% confidence interval.table  5multivariate predictors of cardiac mortality / nonfatal myocardial infarctionhr ( 95% ci)p valuemale gender2.61 ( 1.116.14).03diabetes6.93 ( 2.1822.04).01peak exercise heart rate0.70 ( 0.580.84)<.001values are expressed as cox proportional hazard ratio and 95% confidence interval.table  6multivariate predictors of major adverse cardiac eventshr ( 95% ci)p valueage*1.03 ( 1.01 - 1.06).01male gender2.82 ( 1.75 - 4.53)<.001diabetes3.95 ( 1.88 - 8.30)<.001diastolic blood pressure at rest0.79 ( 0.64 - 0.97).03rate - pressure product at rest1.14 ( 1.04 - 1.25).01peak exercise heart rate0.80 ( 0.71 - 0.89)<.001st segment changes2.94 ( 1.44 - 5.99).01values are expressed as cox proportional hazard ratio and 95% confidence interval . *  per 1 unit increment . multivariate predictors of all - cause mortality values are expressed as cox proportional hazard ratio and 95% confidence interval . *  per 1 unit increment . multivariate predictors of cardiac mortality values are expressed as cox proportional hazard ratio and 95% confidence interval . multivariate predictors of cardiac mortality / nonfatal myocardial infarction values are expressed as cox proportional hazard ratio and 95% confidence interval . multivariate predictors of major adverse cardiac events values are expressed as cox proportional hazard ratio and 95% confidence interval . *  per 1 unit increment . in this study , very long - term outcome after normal exercise tc - sestamibi myocardial perfusion spect was assessed in respect of 233 patients with known or suspected cad . the 15.5    4.9-year follow - up demonstrated that the overall outcome of these patients was favorable . particularly , in the first 5  years after normal exercise tc - sestamibi myocardial perfusion spect , annualized event rates were very low . predictors of increased risk were identified by multivariate analyses of clinical and exercise test data . exercise testing variables associated with an increased risk were heart rate at rest , peak exercise heart rate , diastolic blood pressure at rest , rate pressure product at rest , and st segment changes . currently , there are no studies providing very long - term outcome data , and consequently the duration of the low - risk status after a normal test is not clear.1 - 4 several previous studies have reported on the medium - term prognosis after a normal myocardial perfusion spect . in these previous studies , the number of included patients ranged from 88 to 273 , and mean follow - up ranged from 10  months to 7.4  years.1 - 3 in the available literature , mean follow - up after myocardial perfusion spect was approximately 3  years.1 - 3 the previous studies have demonstrated that the medium - term prognosis of patients with suspected or known cad and normal myocardial perfusion spect is favorable . moreover , several large observational series have studied medium - term prognosis in patients with normal or low - risk thallium-201 , tc - sestamibi , and tc - tetrofosmin . meta - analyses of these series revealed that the annualized cardiac mortality rate was approximately 0.5%.1,2 the dutch heart foundation data8 indicate that all - cause mortality in men aged 55 - 64 years , during the period 1986 - 1998 was ( min - max ) 2808 - 3175 , and cardiac mortality was 206 - 422/100.000 . in women aged 55 - 64 years , in the period 1985 - 1996 , all - cause mortality was ( min - max ) 476 - 771 , and cardiac mortality was 64.9 - 106/100.000 . hence , the event rates in the general population appear to be lower than in the study population . the study patients were referred to exercise myocardial perfusion spect by their treating physicians , and the risk profile of the patients was different from that of the general population . in the present study with 15-year follow - up the present study demonstrates that patients with a normal exercise tc - sestamibi myocardial perfusion spect have a favorable prognosis even at 15-year follow - up . in these patients a watchful waiting approach to care is justified , and additional diagnostic strategies including invasive coronary angiography can be avoided . previous studies have shown that this type of management strategy may be both clinically effective and cost - effective.9,10 clearly , clinical judgment remains important in deciding patient management decisions , also in patients with a normal exercise tc - sestamibi myocardial perfusion spect . the duration of the low - risk status depends on several factors that influence the natural progression of ( subclinical ) cad . the present study demonstrates that several clinical and exercise test parameters can be used to identify patients at increased risk for adverse outcome . prognosis was worse in patients with a history of cad . additionally multivariate analysis demonstrated that several clinical and exercise testing parameters influence very long - term outcome . therefore , follow - up should be closer in patients with known cad , and/or clinical and exercise parameters indicating higher risk status . repeated testing should be considered in patients with a change in symptoms or worsening clinical status . information on changes in medical therapy during follow - up was not available . during the period when the spect studies were performed , electrocardiogram gated acquisition was not routinely performed in our laboratory . gated spect provides information on regional and global left ventricular function , which is an important predictor of long - term prognosis . future studies are needed to clarify the value of gated spect for the assessment of very long - term prognosis in patients with normal myocardial perfusion . patients with suspected or known cad and normal exercise tc - sestamibi myocardial perfusion spect have a favorable 15-year prognosis . follow - up should be closer after this initial 5-year period and in patients with known cad , and/or having clinical and exercise parameters indicating higher risk status .
objectivethe goal of this study was to evaluate the very long - term outcome after normal exercise 99mtc - sestamibi myocardial perfusion single - photon emission computed tomography ( spect ) . 
 exercise 99mtc - sestamibi spect is widely used for risk stratification , but data on very long - term outcome after a normal test are scarce.methodsa consecutive group of 233 patients ( 122 men , mean age 54    12  years ) with known or suspected coronary artery disease ( cad ) underwent exercise 99mtc - sestamibi spect and had normal myocardial perfusion at exercise and at rest . 
 follow - up endpoints were all - cause mortality , cardiac mortality , nonfatal myocardial infarction , and coronary revascularization . 
 predictors of outcome were identified by cox proportional hazard regression models using clinical and exercise testing variables.resultsduring a mean follow - up of 15.5    4.9  years , 41 ( 18% ) patients died , of which 13 were cardiac deaths . 
 a total of 18 ( 8% ) patients had a nonfatal myocardial infarction , and 47 ( 20% ) had coronary revascularization . 
 the annualized event rates for all - cause mortality , cardiac mortality , cardiac mortality / nonfatal infarction , and major adverse cardiac events were , respectively , 1.1% , 0.3% , 0.7% , and 1.8% . 
 multivariate analysis demonstrated that the variables age , male gender , diabetes , diastolic blood pressure at rest , rate pressure product at rest , peak exercise heart rate , and st segment changes were independent predictors of major adverse cardiac events.conclusionpatients with suspected or known cad and normal exercise 99mtc - sestamibi myocardial perfusion spect have a favorable 15-year prognosis . 
 follow - up should be closer in patients with known cad , and/or having clinical and exercise parameters indicating higher risk status .