Keywords
INTRODUCTION
Ischemic heart disease is the most common cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The increased cardiovascular risk in this population results from the diabetes, itself, and the higher frequency of conventional risk factors.1 The prevalence of T2DM in individuals over 30 years old in Spain ranges from 6% to 10% and half these patients are unaware of the diagnosis.2
Silent myocardial ischemia (SMI) is 2 to 7 times more frequent in diabetic patients.3 Detection of this condition allows treatment to be optimized by adopting a strategy to assess the extent of coronary disease and the possibility to achieve revascularization.4,5 Nevertheless, there is no current consensus as to the recommended method for screening these patients.6 Along these lines, the importance of blood pressure (BP) status as a determinant of cardiovascular risk and the benefits of treating hypertension have been conclusively established. Among its various components, systolic arterial pressure (SAP) and differential pulse pressure (DPP), defined as the difference between SAP and diastolic arterial pressure (DAP), have shown the highest value as predictors of cardiovascular risk in relation to increased arterial wall rigidity.7
The main purpose of this study was to assess the usefulness of DPP for predicting SMI by 24-hour ambulatory blood pressure monitoring (ABPM) in patients with T2DM and no history of ischemic heart disease.
METHODS
Study Population
The study included 48 consecutive male patients with T2DM8 and no documented history of ischemic heart disease, selected from an endocrinology service to investigate the relationship between several parameters and detection of SMI. The exclusion criteria were physical disability or ECG alteration precluding exercise stress testing, and significant kidney disease (plasma creatinine ≥1.5 mg/dL). In accordance with the Declaration of Helsinki, all patients were informed of the objectives, risks, procedures, and possible benefits of the study and gave consent to participate.
Study Variables
After performing a meticulous anamnesis and physical examination, which included calculation of the waist-hip ratio, body mass index, ankle-brachial index, and study of the fundus of the eye by an ophthalmologist, ABPM was performed with recording of the diurnal, nocturnal, maximum, minimum, and mean SAP and DAP values. In addition, BP fluctuation patterns were examined according to the nocturnal BP dip, categorizing patients as non-dipper (0%-10%), dipper (10%-20%), extreme dipper (>20%) or riser, when there was an increase.
Blood samples were drawn from all patients to determine the following parameters:
Lipid profile (total cholesterol, high-density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C], and triglycerides)
Glycosylated hemoglobin (HbA1c)
Baseline insulin. The HOMA (Homeostasis Model Assessment) index was calculated according to the following formula: insulin (µU/mL)xglucose (mmol/L)/22.5. Insulin resistance was defined as a value ≥3.5
Screening Protocol for Silent Myocardial Ischemia (Figure)
Figure. Flow chart of the protocol used for the diagnosis of silent myocardial ischemia. ECG indicates electrocardiogram; SMI, silent myocardial ischemia.
We began with a baseline electrocardiogram (ECG). If a Q-wave indicating prior myocardial necrosis was seen (defined as duration >0.04 s and depth >1/3 of the QRS complex in at least 2 anatomically consecutive leads), echocardiography was performed. If this test showed regional contractility alterations consistent with the ECG findings, the patient was classified as positive. Otherwise, Holter monitoring of the ECG was continued for 24 hours. Positive status was defined as ≥1 mV of horizontal ST segment depression or 1.5 mV of ST segment elevation for at least 1 min of the recording in the absence of symptoms of angina. If the result was negative, the patient underwent exercise stress testing according to the Bruce protocol; the results were obtained following the recommendations of the Sociedad Española de Cardiología (Spanish Cardiology Society).9 When the results of this test were negative, SMI was ruled out. If the test was inconclusive, exercise stress testing and nuclear scanning were performed, with positive status established by the criteria of the Sociedad Española de Medicina Nuclear (Spanish Society of Nuclear Medicine).10
Statistical Analysis
Quantitative data are expressed as the mean (standard deviation [SD]), and as the median (interquartile range, 25th-75th percentile) when the distribution of the variables was not normal. Qualitative data are expressed as total number and percentage. Student t test was used to compare means and the χ2 test to compare percentages. For variables with a non-normal distribution, the nonparametric Mann-Whitney test was used. To assess the capacity of DPP to discriminate between patients with and without SMI, a ROC curve was constructed. The effect of DPP on the risk of presenting SMI was assessed after adjusting for age and other cardiovascular risk factors by a logistic regression model. A P value less than .05 was considered significant.
RESULTS
Nine (19%) patients presented SMI (8 diagnosed by exercise stress testing and one by Holter-ECG). The clinical characteristics of these patients are shown in Table 1. Patients with SMI were older, and had a higher frequency of diabetic retinopathy, poorer recent diabetic metabolic control, higher DPP (only ABPM variable that reached statistical significance) (Table 2), and a nonsignificant trend (P=.08) toward longer duration of T2DM.
The DPP showed good discriminative capacity for determining the presence of SMI, as is deduced from the area under the curve (AUC) obtained from the ROC curve (AUC=0.83; 95% confidence interval [CI] 0.71-0.96; P=.002). The predictive effect was maintained in the logistic regression model after adjusting for age, major cardiovascular risk factors (hypertension, smoking, and dyslipidemia) and duration of T2DM, and was significant and independent (odds ratio [OR]=1.24; 95% CI, 1.04-1.49). An OR of 8.5 (95% CI, 1.7-31.2) was estimated for each 10-mm Hg increase in the DPP, for the risk of presenting SMI. The other variable showing an independent relationship in the model was age (OR=1.41; 95% CI, 1.04-1.91).
DISCUSSION
Type 2 diabetes mellitus causes earlier and more severe diffuse coronary atherosclerosis that progresses at a faster rate.11 Ischemic heart disease in patients with T2DM is often asymptomatic or shows few symptoms, a fact that can lead to a delay in the diagnosis. Scientific evidence indicates that the diabetic population has the same risk of presenting a first cardiovascular event as nondiabetic patients with established coronary disease.12 A diagnostic strategy that allows detection of coronary disease in the early phases can decrease later complications. Diabetic patients with no history of ischemic heart disease have shown a high incidence of SMI. Our results, in which 19% of patients presented SMI, are in line with those obtained in other studies using a similar diagnostic protocol (12%-22%).3
High blood pressure is a fully established cardiovascular risk factor. Recent debate has focused on the precise component of blood pressure assessment that best predicts the risk of developing cardiovascular disease. The latest data from the Framingham Heart Study,12 which are supported by other studies, have indicated that DPP, an indirect measure of arterial rigidity, is a better predictive factor of coronary risk than SAP or DAP alone, at least in persons over 50 years of age; the value of this parameter decreases in younger individuals.13,14
Increased arterial rigidity can be a component of the association between cardiovascular risk factors and the development of atherosclerosis. In our study, DPP was associated with the presence of SMI, independently of the remaining cardiovascular risk factors analyzed or the baseline clinical characteristics of the patients. Although this association does not necessarily predict atheroma plaque vulnerability, plaque rupture, and subsequent coronary syndrome, follow-up studies in patients with T2DM have demonstrated that the DPP is a good predictor of cardiovascular events.7
Although mean SAP was higher in the SMI group, neither this parameter nor DAP, in themselves, were predictive of myocardial ischemia. The related literature contains discordant data on the prognostic value of BP fluctuation patterns determined by ABPM with respect to cardiovascular risk. In a study performed in a hospitalized population, Sander et al15 showed that high BP variation was associated with an increase in cardiovascular events. On the other hand, in a population with hypertension, a wide BP range, and a baseline risk profile, Verdecchia et al16 reported no association between BP fluctuation and an adverse prognosis after adjusting for confounding factors. Our study also found no significant differences between the various ABPM patterns and the incidence of SMI, possibly because of the limited size of the sample.
Taking into account the high risk diabetic patients have of presenting coronary disease, the results of the present study are applicable to this population and to male patients followed up in endocrinology and family medicine services, who have not developed any clinical signs or symptoms of this condition.
In conclusion, the frequency of SMI in patients with T2DM and no history of cardiac disease was 19% in this study. Differential pulse pressure and age were independent predictive factors of SMI. Moreover, SAP or DAP alone were not predictive of myocardial ischemia, and ABPM patterns did not prove to be useful for this purpose.
Dr Antonio Hernández Mijares declares that this study has been carried out with partial support from the FISS project, 04/2175.
Correspondence: Dr. M.J. Gómez Martínez.
Servicio de Cardiología. Hospital Universitario Dr. Peset.
Avda. Gaspar Aguilar, 90. 46017 Valencia. España.
E-mail: magomar@comv.es
Received June 14, 2006
Accepted for publication January 31, 2007