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Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Disclosures:
  8. References

Stress dipyridamole technetium-99m sestamibi single photon emission computed tomographic imaging was used to study myocardial perfusion in 1116 hypertensive patients without known coronary artery disease (CAD). The test confirmed the presence of CAD in 28.9% of patients. As expected, patients with diabetes mellitus (DM) had a significantly higher prevalence of myocardial perfusion abnormalities (35.9% vs 23.9%; odds ratio, 1.79; 95% confidence interval [CI], 1.38–2.33; P<.0001) and high-risk myocardial imaging (16.4% vs 10.6%; odds ratio, 1.67; 95% CI, 1.18–2.37; P=.004) than those without DM. Odd ratios further increased, again as expected, with dyslipidemia (2.19; 95% CI, 1.54–3.12; P<.0001), peripheral arterial disease (2.61; 95% CI, 1.77–3.85; P<.0001), microalbuminuria (3.03; 95% CI, 1.91–4.82; P<.0001), and abnormal electrocardiographic findings (3.06; 1.68; 95% CI, 2.08–4.48; P<.0001). This large cohort study showed that more than 1 of 4 treated hypertensive patients have subclinical CAD. These study data should be clinically helpful in selecting hypertensive patients who are the most suitable candidates to screen for the presence of CAD.

Essential hypertension (EH) is a major risk factor for coronary artery disease (CAD), and it is associated with an increased risk of cardiovascular mortality and morbidity.1,2 In addition, the concomitant presence of hypertension and other atherogenic risk factors (ARFs) such as diabetes mellitus (DM) and dyslipidemia increases the risk of CAD.3 Myocardial ischemia has been reported to be associated with an increased risk of myocardial infarction (MI) and sudden death in a wide range of patient groups.4 Identification of patients at high risk is thus important for the selection of optimal management strategy in these patients.5 Myocardial perfusion imaging (MPI) is an established method for diagnosing and assessing the risk and prognosis of patients with suspected or known CAD mostly in DM.6–8 In a pooled analysis of 39,173 patients with a normal perfusion scan obtained by single photon emission computed tomography (SPECT) MPI, the annual event rate of cardiac death or MI was 0.6%. In contrast, in studies including 65,655 patients with abnormal results on MPI, the annual event rate was 5.9% per year. Studies on the prevalence and severity of abnormal MPI findings in treated hypertensive patients are lacking.

The aims of the present cross-sectional study were 3-fold: (1) to provide data on the prevalence and severity of CAD in EH; (2) to study the impact of other ARFs on the prevalence and severity of abnormal MPI in treated hypertensives; and (3) to identify which treated hypertensive patients should be screened for the presence of CAD.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Disclosures:
  8. References

Study Patients

Participants included in the present cross-sectional analysis were treated hypertensive patients undergoing dipyridamole stress technetium (Tc99m) sestamibi SPECT MPI at the nuclear medicine units of 2 university hospitals in Québec City, Canada, between June 2003 and November 2005. Patients were recruited from the hypertension clinic and from endocrinology, vascular medicine, and cardiology units. In 430 (38.3%) patients, stress SPECT MPI was performed as part of preoperative assessment of peripheral artery disease (PAD). All patients provided informed consent for MPI. Each hospital institutional review board approved the study.

Patients were aged 45 years or older, without known CAD but with treated EH. Hypertension was defined by a history of systolic blood pressure (BP) ≥140 mm Hg and/or diastolic BP ≥90 mm Hg for nondiabetic patients and ≥130 mm Hg and/or ≥80 mm Hg for diabetic patients. Because there were no defined criteria for investigating CAD in hypertensive patients and because many of our patients had DM, as in many hypertension clinics,9 patients were included in the study if they fulfilled the American Diabetes Association (ADA) consensus guidelines3 adapted for our hypertensive population. These criteria included atypical chest pain, dyspnea or shortness of breath, resting electrocardiographic (ECG) abnormalities suggestive of ischemia or infarction, PAD, or ≥2 of the following risk factors in addition to EH (one for hypertensive diabetic patients): (1) type 2 DM defined as repeated fasting blood glucose ≥126 mg/dL (7 mmol/L) and treated either with oral antidiabetic agents or insulin; (2) dyslipidemia including total cholesterol ≥240 mg/dL (6.2 mmol/L), low-density lipoprotein cholesterol ≥160 mg/dL (4.1 mmol/L), or high-density lipoprotein cholesterol <35 mg/dL (0.9 mmol/L); (3) smoking; (4) microalbuminuria; (5) family history of CAD before age 55 years for men and 65 years for women; and (6) patients planning a vigorous exercise program. Several patients were referred because they were obese in addition to other ADA criteria or had PAD and therefore were unable to achieve a diagnostic level of exercise or because they had uninterpretable ECG results due to abnormal ST-segment changes or left bundle branch block. Many patients were also referred because physicians felt that exercise ECG was limited in its ability to determine the location and extent of silent ischemic myocardium and/or because they were convinced that a negative result did not exclude CAD.10 Exclusion criteria were history of typical angina, documented history of CAD including positive coronary angiography, previous abnormal MPI findings, clinical MI, previous revascularization, nitrate therapy, and active bronchospasm.

Pharmacologic Stress-Rest Protocol

All patients underwent a 1- or 2-day stress-rest protocol. β-Blockers as well as negative chronotropic calcium antagonists given for the treatment of EH were withheld for 48 hours before the test. Tc99m sestamibi (296 MBq to 1110 MBq) was injected at rest and during pharmacologic stress. Intravenous dipyridamole was administrated continuously at a dose of 0.142 mg/kg for a 4-minute period. Tc99m sestamibi was injected 4 minutes after the end of the infusion. Patients were instructed to avoid caffeine-containing beverages and xanthine-containing products for 24 hours before the test. The resting study was performed within 48 hours after the stress study. Three minutes before the rest injection of Tc99m sestamibi, sublingual nitroglycerin (0.4 mg) was given to the patient unless there were contraindications, hypotension, or very recent use of type 5 phosphodiesterase inhibitors.

Imaging Protocol and Interpretation

Dipyridamole stress Tc99m sestamibi and rest nitroglycerin Tc99m sestamibi SPECT imaging were performed in concordance with standards of the American Society of Nuclear Cardiology11 using Irix triple-head or Axis double-head cameras (Philips Medical Systems, Bothell, WA) equipped with high-resolution collimators. Semiquantitative visual interpretation of MPI involved tomograms divided into 20 segments for each patient.12 Each segment was scored by consensus of 2 experienced observers who were unaware of the clinical data using a 5-point scoring system (0=normal to 4=absence of segmental perfusion). Three global perfusion indexes were used to combine the assessments of deficit extent and severity. Summed stress scores (SSS) were obtained by adding the scores of the 20 segments of the stress images. A score <4 points was considered normal, 4 to 8 points slightly abnormal, 9 to 13 points moderately abnormal, and >13 points severely abnormal. Summed rest scores (SRS [extent of scar]) were obtained in a similar way by adding the scores of the 20 segments of the resting images. Subsequently, to assess the extent of reversible ischemia, summed difference scores were calculated by subtracting the SRS from the SSS.

Statistical Analysis

Data management and statistical analysis were conducted using SPSS for Windows version 11.0 (SPSS Inc, Chicago, IL). Baseline quantitative variables were described by arythmetic mean and standard deviation and analyzed using Student t test. For baseline categoric variables, absolute and relative frequencies were described and analyzed by chi-squared test for Fisher exact test, as required. The relative importance of the various predictors for CAD was determined using a logistic-regression model after accounting for the effect of covariables. Selection of covariables for entry consideration into the multivariate model was based on univariate statistical significance. The model included ARFs already described. The 95% confidence interval (CI) for the difference between proportions was provided. For all analyses, a P value <.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Disclosures:
  8. References

Baseline Characteristics

A total of 1116 treated hypertensive patients, referred for screening of silent CAD and fulfilling the ADA criteria, underwent Tc99m sestamibi dipyridamole stress and rest SPECT MPI. Clinical characteristics are shown in the Table. Nearly half of the patients were men. The mean age was 66.3±10.0 years. Additional ARFs were particularly prevalent in these patients, including DM in 41.4%, dyslipidemia in 62.0%, current smoking in 31.2%, and PAD in 38.5%. Microalbuminuria was present in 18.2% of hypertensive patients with DM and in only 0.3% of hypertensive patients without DM. Body mass index was significantly higher (P<.0001) in hypertensive patients with DM (30.6±5.0 kg/m2) than in patients with EH without DM (26.9±4.2 kg/m2).

Table Table.  Clinical Characteristics of the Hypertensive Study Population (N=1116)
CharacteristicsValue
Age, y66.3±10.0
Male sex537 (48.1)
Body mass index, kg/m228.2±4.5
Duration of hypertension, y11.5±11.4
Type 2 diabetes mellitus462 (41.4)
Duration of type 2 diabetes mellitus, y13.8±10.3
Atypical chest pain601 (53.9)
Dyspnea341 (30.6)
Dyslipidemia692 (62.0)
Abnormal resting ECG results407 (43.6)
Family history of premature CAD208 (18.6)
Smoking348 (31.2)
Peripheral arterial disease430 (38.3)
Microalbuminuria88 (7.7)
Values are expressed as mean ± SD or No. (%). Abbreviations: CAD, coronary artery disease; ECG, electrocardiographic.

Results of Tc99m Sestamibi SPECT Imaging

Using SSS, CAD was present in 28.9% of the 1116 treated hypertensive patients studied. Overall, MPI abnormalities were significantly more prevalent in EH patients with DM, dyslipidemia, microalbuminuria, and abnormal resting ECG findings or in patients with PAD than in patients with EH without these risk factors (Figure 1). As seen in Figure 2A, a significantly higher percentage of hypertensive patients with DM had silent ischemia (35.9% vs 23.9% in hypertensives without DM; odds ratio [OR], 1.79; 95% CI, 1.38–2.33; P<.0001). As mentioned, MPI findings were categorized as normal, slightly abnormal, moderately abnormal, and severely abnormal based on SSS. High-risk scan results that include moderately and severely abnormal MPI results were significantly more frequent in hypertensive patients with DM than in patients without DM (16.4% vs 10.6%, respectively; OR, 1.67; 95% CI, 1.18–2.37; P=.004) (Figure 2B). With respect to SRS reflecting the extent of scar, the incidence of an abnormal scan result was also significantly higher in diabetic than in nondiabetic hypertensive patients (23.2% vs 15.0%; P=.001).

image

Figure 1. Frequency of type 2 diabetes mellitus (DM), dyslipidemia (DYSL), microalbuminuria (MICRO), smoking (SMK), abnormal resting electrocardiographic findings (ECG), and peripheral artery disease (PAD) in asymptomatic patients with a normal or an abnormal summed stress score (SSS).

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Figure 2. Frequency (A) of abnormal summed stress score (SSS) and (B) high-risk SSS in patients with hypertension (n=654) and in patients with essential hypertension (EH) and diabetes mellitus (DM) (n=462).

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Typical examples of Tc99m sestamibi SPECT imaging are illustrated in Figure 3. Indeed, Figure 3A illustrates the MPI scan of a 68-year-old woman with EH, DM, dyslipidemia, abnormal resting ECG findings, and a family history of early CAD who complained of dyspnea. MPI results were normal, with an SSS and an SRS of 0. In contrast, Figure 3B shows an MPI scan of a 72-year-old woman sent to the nuclear medicine department for a preoperative evaluation. She also had dyslipidemia, was a smoker, and had obstruction of carotid and femoral arteries but normal resting ECG results. MPI showed a severe but partially reversible ischemia in the anterior, apical, and septal walls with a high-risk SSS of 20. Coronary angiography showed obstruction of the interventricular artery (100%) and right proximal artery (80%); the patient was referred to cardiac surgery and underwent coronary artery bypass grafting.

image

Figure 3. (A) Dipyridamole technetium-99m sestamibi single photon emission computed tomographic study showing a normal myocardial perfusion image with normal summed stress score (SSS) and summed rest score (SRS). (B) An abnormal image showing ischemia (arrows) in the anterior, septal, and apical walls during stress that was partially reversible at rest with an SSS of 20, an SRS of 7, and a summed difference score of 13.

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Predictors of Myocardial Ischemia

The ORs and 95% CIs for the presence of myocardial ischemia in patients with hypertension and other significant ARFs are shown in Figure 4. Overall, the odds of an abnormal SSS in hypertensive patients are significantly increased when DM is present in those patients (OR, 1.79; 95% CI, 1.38–2.33; P<.0001). The addition of other ARFs to EH and DM produces a further increment in odds. Indeed, CAD in hypertensive patients appears to be best predicted by DM along with the presence of microalbuminuria or abnormal resting ECG findings. Individually, the incidence of an abnormal SSS is increased 47% by microalbuminuria (OR, 1.93; 95% CI, 1.20–3.11; P=.007) and 33% by abnormal resting ECG findings (OR, 1.57; 95% CI, 1.07–2.30; P=.021) in hypertensive patients with DM. The effect of dyslipidemia (OR, 1.71; 95% CI, 1.24–2.36; P<.001) or PAD (OR, 1.68; 95% CI, 1.12–2.52; P<.012) on the incidence of myocardial ischemia is significant in hypertensive patients with DM as compared with those with the same ARFs but not DM. As opposed to microalbuminuria and abnormal ECG findings, however, the additional contribution of dyslipidemia or PAD on the incidence of myocardial ischemia in nondiabetic patients is not as significant as it is for patients who have both hypertension and DM (Figure 4). Although those patients should be aggressively treated, MPI will still be helpful in many hypertensive patients with or without DM and in those with or without microalbuminuria who are asymptomatic or in whom dyspnea is not considered relevant by their physicians. On the other hand, a normal MPI result will obviate the need for more aggressive and costly testing such as coronary angiography.

image

Figure 4. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the presence of abnormal summed stress score (SSS) in patients with essential hypertension (EH) associated with other risk factors: dyslipidemia (DYSL), peripheral artery disease (PAD), abnormal resting electrocardiographic results (ECG), diabetes mellitus (DM), and microalbuminuria (MICRO). aOR associated with hypertensives without these risk factors, 1. + indicates presence; −, absence.

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Interestingly, a subanalysis confined to patients with a high-risk MPI result (Figure 5) showed consistency with what was found in patients with an abnormal SSS of any degree (Figure 5). An abnormal resting ECG result appears to be the best predictor of a high-risk SSS in hypertensives without DM (OR, 2.17; 95% CI, 1.31–3.62; P=.002) and in patients with both hypertension and DM (OR, 3.54; 95% CI, 2.11–5.92; P<.0001). It is noteworthy that the incidence of a high-risk MPI result is doubled in hypertensive patients with diabetes and microalbuminuria as compared with patients with hypertension without these risks (20.2% vs 10.6%) (OR, 2.14; 95% CI, 1.19–3.86; P=.010). The sample size (430 patients) was adequate to substantiate that the predictive value of PAD appears to be relevant mostly in diabetic patients for the detection of abnormal SSS (OR, 2.61; 95% CI, 1.77–3.85; P<.0001) and of high-risk MPI (OR, 1.96; 95% CI, 1.16–3.31; P=.010). The predictive value of DM duration as it has been reported in previous studies (mostly for type 1 DM)3 was not demonstrated in the present study.

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Figure 5. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the presence of high-risk summed stress score (SSS) in patients with hypertension associated with other risk factors: dyslipidemia (DYSL), peripheral artery disease (PAD), abnormal resting electrocardiographic results (ECG), diabetes mellitus (DM), and microalbuminuria (MICRO). aOR associated with hypertensives without these risk factors, 1. + indicates presence; −, absence.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Disclosures:
  8. References

There are now many prospective studies with MPI on the prevalence and prospective value of detecting myocardial ischemia in diabetic patients and in patients with known or suspected ischemic heart disease.10–13 Cardiac event rates in diabetics with unknown CAD are significantly higher in those with abnormal MPI findings, resulting in a 3- to 8-fold increased risk compared with diabetic patients with normal MPI findings. In contrast, there is no study on the prevalence and severity of CAD using a standardized technique in treated hypertensive patients.14 Although data reported in the present cross-sectional study confirm and expand those of our preliminary work,15 the information provided herein may be clinically important because such a large sample size was not examined in previous studies. In our sample of treated hypertensive patients without known CAD, we observed that the overall prevalence of myocardial ischemia was 28.9% but, as expected, rose to 35.9% in hypertensive diabetics. Our findings of a risk of CAD nearly twice as high in hypertensive patients with DM (35.9%) than in hypertensive patients without diabetes (23.9%) are in accordance with those of other investigators.16 In contrast, the higher prevalence (35.9%) of CAD in diabetics we studied than that observed (22%) in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study17 probably reflects difference in patient selection. Indeed, in the DIAD study, patients were younger and had normal ECG findings and fewer ARFs. Based on SSS and SRS results, our study not only confirms a higher prevalence of ischemia but also suggests a higher prevalence of MI or a cardiomyopathic process in patients with DM.

Importantly, our study showed that abnormalities on MPI and severity were significantly more prevalent in patients with additional ARFs. The high prevalence of abnormal SSS and high-risk MPI results in hypertensive patients with or without DM but with abnormal resting ECG findings are in agreement with the findings of the Milan study,18 showing that ST-T abnormalities were the best predictor of myocardial ischemia on MPI in type 2 DM patients. A most important finding of the present study is that microalbuminuria was a significant predictor of myocardial ischemia in our diabetic population. Indeed, the presence of high-risk MPI results doubled in the presence of microalbuminuria. These findings are clinically relevant not only because they confirm previous works but because all studies have reported a significant association between microalbuminuria and total mortality or cardiovascular morbidity and mortality.19 Unfortunately, in the present study, microalbuminuria could not be viewed as a predictor of silent CAD on MPI in hypertensive patients without diabetes, as it was present in <1% of these patients at baseline. This low frequency may be in relation to more intensive and early aggressive treatment of hypertension. Peripheral artery disease was present with a similar prevalence in both hypertensive patients without (39.3%) and with DM (37.4%). The high prevalence of PAD is also clinically relevant as a retrospective cohort of 1427 patients with DM revealed that ST-T abnormalities on resting ECG and/or evidence of PAD identified the most suitable candidates for further screening.20

Study Limitations

The potential limitations of our data merit consideration. One of the limitations of this study is the absence of detailed information about modes of treatment of hypertension and/or diabetes or degree of diabetes and hypertension control. In addition, our study has insufficient information about secondary organ involvement and autonomic nervous system dysfunction, variables that have been shown to be associated with a higher rate of CAD in diabetic patients.17 However, the present study was planned to evaluate the presence and severity of unknown CAD, ARFs, and their relation to MPI findings rather than on degree of hypertension and/or diabetes control and their complications. Another limitation of our study is the fact that patients referred for MPI probably represent a group with an intermediate likelihood of CAD, as patients with a higher likelihood (such as those with typical angina pain or those who already had clear exercise-induced ECG changes) would most likely have been sent directly to coronary angiography while patients with a lower likelihood (those without ADA criteria) would not have been referred for MPI. This restricts the validity of our results to a similar clinical setting of selected hypertensive patients referred to a nuclear medicine unit for MPI.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Disclosures:
  8. References

The findings from this study suggest that there may be a need for evidence-based guidelines for screening treated hypertensive patients with atypical symptoms (eg, chest pain, dyspnea) to identify a subset of patients with silent ischemia or CAD who are at risk for adverse cardiac events. Our results suggest a possible role for stress MPI in selecting asymptomatic hypertensive patients unable to perform an exercise test and patients with other major ARFs such as DM, resting ECG abnormalities or evidence of PAD, and most importantly microalbuminuria. The total burden of risk factors in these patients substantially increases the possibility of identifying significant CAD that requires intervention.3 On the basis of other studies reported to date,11 it is now clear that normal or an equivocally (slightly) abnormal MPI is associated with a benign prognosis. Consequently, the patients with low-risk MPI results can most often be managed with medical therapy that includes intensive secondary prevention. In contrast, patients with moderately to severely abnormal results (high-risk MPI results) will most likely be referred for further coronary investigation and treatment. More important, it might be anticipated that early identification of CAD will be associated with improved compliance with risk factor intervention and treatment. These strategies could be clinically relevant for diabetic patients because 70% do not realize that they are at increased risk for cardiovascular disease.21 These figures are probably identical for hypertensive patients as judged by the low BP control rate (20%) and high incidence of CAD.22,23

Disclosures:

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Disclosures:
  8. References

This study was funded by grants from Fondation Hypertension Laurier and CHUL Research Center, Quebec, Canada. Statistical analysis was supported by an unrestricted grant from Bristol-Myers Squibb, Canada. Drs Lacourcière, Côté, and Dumont have received speaker's honoraria from Bristol-Myers Squibb, Canada.

References

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSIONS
  7. Disclosures:
  8. References
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    Grundy SM. Primary prevention of coronary heart disease. Integrating risk assessment with intervention. Circulation. 1999;100:988998.
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    Berman DS, Hachamovitch R, Kiat HV, et al. Incremental value of pronostic testing in patients with known or suspected ischemic heart disease: A basis for optimal utilization of exercise technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol. 1995;26:639647.
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    Hachamovitch R. Clinical value of combined perfusion and function imaging in the diagnosis, prognosis, and management of patients with suspect or known coronary artery disease. In: GermanoG, BermanDS, eds. Clinical Gated Cardiac SPECT. Armonk, NY: Futura Publishing Company, Inc. 1999:239258.
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    Etchells E, Meade M, Tomlinson G, et al. Semiquantitative dipyridamole myocardial stress perfusion imaging for cardiac risk assessment before noncardiac vascular surgery: a meta-analysis. J Vasc Surg. 2002;36(3):534540.
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    Joffres MR, Hamet P, MacLean DR, et al. Distribution of blood pressure and hypertension in Canada and the United States. Am J Hypertens. 2001;14(11, pt 1):10991105.
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    Giles T, Aranda JM Jr, Suh DC, et al. Ethnic/racial variations in blood pressure awareness, treatment, and control. J Clin Hypertens (Greenwich). 2007;9(5):345354.