Role of surrogate markers in assessing patients with diabetes mellitus and the metabolic syndrome and in evaluating lipid-lowering therapy.

Diabetes mellitus and the metabolic syndrome (MS) are reaching epidemic proportions in the United States, and cardiovascular disease continues to be the leading cause of death among patients with diabetes. A range of noninvasive screening tools may help reduce the morbidity and mortality of patients with diabetes because of early detection of subclinical cardiovascular disease and active monitoring of the effectiveness of therapy. Surrogate markers of subclinical disease include conventional and contrast-enhanced ultrasound imaging of carotid artery intima-media thickness (c-IMT), 2-dimensional echocardiography, coronary artery calcium imaging, cardiac magnetic resonance imaging, ankle-brachial indices, and brachial artery reactivity testing. Because these noninvasive imaging tools are relatively comfortable and entail relatively low risk to the patient, they are ideal for initial screening and for the repeated imaging that is required for monitoring the effectiveness of therapy. Moreover, when used in large numbers of patients with diabetes, prediabetes, and the MS, these imaging tools may be useful in developing and validating thresholds for the use of lipid-lowering therapy as well as clear therapeutic goals for this population. In addition, contrast-enhanced c-IMT scans now produce real-time images of the vasa vasorum and neovascularization of atherosclerotic plaque, potentially causing a paradigm shift in our view of the genesis of atherosclerosis and affecting treatment options for all populations. Thus, surrogate markers may not only help improve individual patient outcomes, they also may help direct scarce medical resources to maximize medical benefits, improve overall medical care, and minimize costs and untoward side effects.

Comparison of echocardiography using tissue harmonics and contrast harmonics with radionuclide angiography for the assessment of left ventricular function.

BACKGROUND: Left ventricular ejection fraction (LVEF) is a significant predictor of morbidity and mortality; however, the optimal noninvasive modality for the quantitative determination of LVEF is not apparent. HYPOTHESIS: We verified the hypothesis that the various echocardiographic methods of assessing LVEF using the Method of Discs with contrast (Optison human albumin microspheres; Amersham Health, Princeton, NJ) and visual assessment of LVEF using tissue harmonics and contrast harmonics compare favorably with radionuclide angiography (RNA). METHODS: In a prospective analysis, 24 consecutive patients scheduled to undergo RNA had an echocardiogram using tissue harmonics and contrast harmonics on the same day. LVEF was assessed by RNA by an experienced, blinded reader using manual determination of the region of interest. LVEF was calculated using the Method of Discs (Simpson's Rule) by a blinded sonographer. LVEF was visually estimated by two blinded readers using echocardiography with tissue harmonics and contrast harmonics on separate occasions. RESULTS: By linear regression analysis, LVEF determination by echocardiography with contrast using the Method of Discs correlated well with RNA (r = .835, p < .0005). Using Bland-Altman analysis, the second echocardiogram reader had excellent agreement with RNA, whereas the first reader had a mean difference of 5.25% (CI 1.3-9.2; p = .012) with visual assessment using tissue harmonics and a mean difference of 4.67% (CI 0.4-8.8; p = .031) with visual assessment using contrast harmonics compared with RNA. Thus, a small difference in agreement between RNA and echocardiographic visual estimation was noted that appeared to be primarily reader dependent. CONCLUSIONS: LVEF determination with echocardiography with contrast using the Method of Discs correlated well with RNA and provided agreement across a range of cardiac functions. Visual echocardiographic assessment of LVEF with both tissue harmonics and contrast harmonics correlated well with RNA, but contrast harmonics did not appear to offer an advantage over tissue harmonics alone.

Effect of contrast enhancement on measurement of carotid artery intimal medial thickness.

Previous studies have used standard B-mode ultrasound to quantify the aggregate mean intimal medial thickness (IMT) of the near and far wall of the common carotid artery (CCA). Many investigators have had difficulty in accurately evaluating the near wall IMT secondary to difficulty in discerning the vessel lumen and intima. The purpose of this study is to determine the effect of contrast enhanced ultrasound on IMT measurement when compared with non-enhanced images. Twenty-six patients who had standard carotid ultrasounds completed over a 6-month period were evaluated, with 24 imaged by the same sonographer. Five to six measurements of the near and far walls were obtained over a 1 cm distance, beginning and ending 0.5 cm and 1.5 cm proximal to the carotid bifurcation. The measurements were made with and without the contrast agent Optison (perflutren protein type-A microspheres), which was given as an i.v. bolus (0.5-0.7 cc). Of those imaged by the same sonographer, 40 carotid arteries were examined and a total of 867 measurements were obtained. A total of 10% of the carotid ultrasounds were restudied approximately 1 month after the initial interpretation to assess observer accuracy. The near wall CCA mean (SD) IMT was 0.075 (0.019) cm for left with contrast versus 0.067 (0.023) cm for left without contrast and 0.089 (0.024) cm for right with versus 0.071 (0.022) cm for right without, p < or = 0.0001 both sides. For the far wall of the CCA, the mean (SD) IMT comparison was 0.075 (0.021) cm for left with versus 0.070 (0.016) cm for left without, p = 0.005, and 0.070 (0.023) cm for right with versus 0.070 (0.016) cm for right without, p = 0.68. In conclusion, contrast-enhanced IMT measurement showed a highly statistically significant difference in near carotid wall thickness determinations versus non-contrast values. The thicker measurement is in agreement with previously reported data showing that non-contrast images underestimated near wall common carotid IMT in histologic samples.

The effect of percutaneous transmyocardial laser revascularization on left ventricular function in a porcine model of hibernating myocardium: a pilot study.

BACKGROUND: Hibernating myocardium is defined as a state of persistently impaired myocardial function at rest due to reduced coronary blood flow that can partially or completely be restored to normal if the myocardial oxygen supply/demand relationship is favorably altered. Percutaneous laser revascularization (PMR) is an emerging catheter-based technique that involves creating channels in the myocardium, directly through a percutaneous approach with a laser delivery system, and has been shown to reduce symptoms in patients with severe refractory angina; however, its effect on improving regional wall motion abnormalities in hibernating myocardium has not been clearly established. We sought to determine the effect of PMR using the Eclipse System (Cardiogenesis) on left ventricular function in a porcine model of hibernating myocardium. METHODS: A model of hibernating myocardium was created by placement of an ameroid constrictor in the proximal left anterior descending artery of a 35 kg male Yorkshire pig. The presence of hibernating myocardium was confirmed with dobutamine stress echocardiography (DSE) and defined as severe hypocontractility at rest, with an improvement in systolic wall thickening with low-dose dobutamine in myocardial regions with a subsequent deterioration in function at peak stress (biphasic response). After the demonstration of hibernating myocardium, PMR was performed in the area of hypocontractile function, and the serial echocardiography was performed. The echocardiograms were reviewed by an experienced echocardiologist blinded to the results, and regional wall motion was assessed using the American Society of Echocardiography Wall Motion Score. Six weeks after PMR, the animal was sacrificed and the heart sent for histopathologic studies. RESULTS: A comparison of the regional wall motion function of the area distal to the ameroid constrictor and in the contralateral wall at baseline, post-ameroid placement, and post-PMR was performed. Hibernating myocardium was demonstrated 4 weeks after ameroid placement by DSE. Coronary angiography demonstrated a discrete 90%stenosis in the proximal LAD at the site of ameroid constrictor placement without evidence of collaterals. Using PMR, 17 bursts were successfully delivered to the anterior wall distal to the ameroid constrictor. Four weeks after PMR, there was improvement in wall motion function in the region distal to the ameroid placement by echocardiography. Histopathologic analysis demonstrated the absence of myocardial infarction in the anterior wall distal to the ameroid constrictor. CONCLUSIONS: The performance of PMR in a porcine model of hibernating myocardium is feasible and is associated with an improvement regional wall motion function after 4 weeks.