Deborah L. Crabbe

Lower diagnostic accuracy of thallium-201 SPECT myocardial perfusion imaging in women: an effect of smaller chamber size.

OBJECTIVES We attempted to formally compare the diagnostic accuracy of thallium-201 single-photon emission computed tomographic (SPECT) myocardial perfusion imaging in men and women and the effect of chamber size on accuracy. BACKGROUND The diagnostic accuracy of conventional exercise testing has been shown to be lower in women. Less is known about the relative accuracy of perfusion imaging. Because of smaller body size, women have a smaller heart size than men, a factor that may reduce accuracy. METHODS We identified 323 patients undergoing thallium-201 SPECT myocardial perfusion imaging who either had < 5% probability of coronary artery disease (CAD) by Bayesian analysis or who underwent cardiac catheterization within 60 days of stress testing. Patients with documented history of infarction, coronary artery bypass grafting, pathologic Q waves on the electrocardiogram, left bundle branch block or nonischemic cardiomyopathy were not included. We performed strict quantitative analysis, and receiver operating characteristic (ROC) curves were generated and the area under the curve was calculated for men and women. A size index was generated from the number of short-axis slices and average radius of each slice, and the group was classified as having a large or a small chamber size. The ROC areas of men and women with a large and a small chamber size were then compared. RESULTS Diagnostic accuracy was lower in women than in men (ROC are 0.82 vs. 0.93, p < 0.05) despite similar values for peak heart rate and rate-pressure product and similar severity of CAD. There was a greater difference in accuracy between patients with a large versus a small chamber size (ROC area 0.94 vs. 0.73, p < 0.01) despite similar levels of exercise and severity of CAD. When we compared men and women in groups stratified by chamber size, we could not detect a significant difference between ROC area values of men and women (large: 0.94 men, 0.93 women, p = 0.77, power to detect difference in area of 0.15 = 91%; small: 0.79 men, 0.72 women, p = 0.58, power to detect difference in area of 0.15 = 35%). CONCLUSIONS The diagnostic accuracy of thallium SPECT myocardial perfusion imaging is lower in women than in men. Most of the difference appears to be due to smaller left ventricular chamber size in women, although a small residual gender effect in smaller heart sizes cannot be entirely excluded. It is proposed that the most likely cause for this difference is the relatively greater effect of imaging blurring on smaller hearts.

Targeting VEGF-encapsulated immunoliposomes to MI heart improves vascularity and cardiac function

Recent attempts at rebuilding the myocardium using stem cells have yielded disappointing results. The lack of a supporting vasculature may, in part, explain these disappointing findings. However, concerns over possible side effects have hampered attempts at revascularizing the infarcted myocardium using systemic delivery of proangiogenic compounds. In this study, we develop the technology to enhance the morphology and function of postinfarct neovasculature. Previously, we have shown that the up‐regulated expression of endothelial cell adhesion molecules in the myocardial infarction (MI) region provides a potential avenue for selectively targeting drugs to infarcted tissue. After treatment with anti‐P‐selectin‐conjugated liposomes containing vascular endothelial growth factor (VEGF), changes in cardiac function and vasculature post‐MI were quantified in a rat MI model. Targeted delivery of VEGF to post‐MI tissue resulted in significant increase in fractional shortening and improved systolic function. These functional improvements were accompanied by a 21% increase in the number of anatomical vessels and a 74% increase in the number of perfused vessels in the MI region of treated animals. No significant improvements in cardiac function were observed in untreated, systemic VEGF‐treated, nontargeted liposome‐treated, or blank immunoliposome‐treated animals. Targeted delivery of low doses of proangiogenic compounds to post‐MI tissue results in significant improvements in cardiac function and vascular structure.—Scott, R. C., Rosano, J. M., Ivanov, Z., Wang, B., Lee‐Gau Chong, P., Issekutz, I. C., Crabbe, D. L., Kiani, M. F. Targeting VEGF‐encapsulated immunoliposomes to MI heart improves vascularity and cardiac function. FASEB J. 23, 3361–3367 (2009). www.fasebj.org

Relationship of visit-to-visit and ambulatory blood pressure variability to vascular function in African Americans.

Visit-to-visit clinic blood pressure variability (BPV) and 24-h BPV have both been identified as independent risk factors for cardiovascular (CV) morbidity and mortality; however, the mechanisms contributing to the increased CV risk as yet are unclear. The purpose of this study was to assess the relationship between BPV and endothelial function in a cohort of putatively healthy African Americans. A total of 36 African Americans who were sedentary, non-diabetic, non-smoking, free of CV and renal disease and not on antihypertensive medication followed an American Heart Association low fat, low salt diet for 6 weeks. Upon completion of the 6-week dietary stabilization period, participants underwent 24-h ambulatory BP monitoring and had their office blood pressure (BP) measured on 3 separate days. Right brachial artery diameter was assessed at rest, during reactive hyperemia (flow-mediated vasodilation: FMD), and after nitroglycerin administration (nitroglycerin-mediated vasodilation: NMD). Participants classified as having decreased endothelial function according to either %FMD or the FMD/NMD ratio had significantly higher 24-h BPV and a trend for higher visit-to-visit BPV when compared with participants with normal endothelial function. Continuous variable analyses revealed a significant positive association between NMD and 24-h diastolic BPV (DBPV). Visit-to-visit systolic BPV (SBPV), 24-h SBPV and 24-h DBPV were all negatively associated with the FMD/NMD ratio. All relationships remained significant after adjustment for age, body mass index and mean BP levels. These results may suggest that BPV is increased in African Americans with decreased endothelial function and is associated with the vascular smooth muscle response to nitric oxide.

Gender differences in post-infarction hypertrophy in end-stage failing hearts.

OBJECTIVES We explored whether there are gender differences in cardiac remodeling and whether etiology influences organ and cellular remodeling in advanced heart failure (HF). BACKGROUND Several studies have shown a survival benefit for women compared to men with symptomatic HF. This observation may be related to gender differences in cardiac remodeling. METHODS We studied hearts from 100 patients (72 men and 28 women) receiving cardiac transplantation at our institution. Cardiac morphology was assessed with echocardiography and direct measurement of cardiac mass. Cardiac myocyte volume, length, width, cross-sectional area, and contraction were measured using previously validated techniques. RESULTS Among 50 patients with idiopathic cardiomyopathy (CM), we observed no gender-based differences in cardiac or cellular remodeling. In contrast, among 50 patients with ischemic cardiomyopathy (ICM), the heart weight index was significantly greater in men, and there was a strong trend toward an increased left ventricular (LV) mass index as well. These gender differences in cardiac and LV mass were paralleled by marked gender differences in myocyte volume, such that average myocyte volume was 36% greater in men than in women, in association with a 14% increase in resting cell length. CONCLUSIONS Our studies demonstrate a multilevel gender difference in post-infarction remodeling, with women exhibiting reduced hypertrophy. Our studies further demonstrate that gender differences in cardiac remodeling in ICM are largely related to fundamental differences in cellular remodeling rather than simply differences in infarct size or expansion. Distinctions observed between ischemic and idiopathic CM suggest that gender may influence local myocardial responses to injury.

Endothelial activation microparticles and inflammation status improve with exercise training in African Americans

African Americans have the highest prevalence of hypertension in the world which may emanate from their predisposition to heightened endothelial inflammation. The purpose of this study was to determine the effects of a 6-month aerobic exercise training (AEXT) intervention on the inflammatory biomarkers interleukin-10 (IL-10), interleukin-6 (IL-6), and endothelial microparticle (EMP) CD62E+ and endothelial function assessed by flow-mediated dilation (FMD) in African Americans. A secondary purpose was to evaluate whether changes in IL-10, IL-6, or CD62E+ EMPs predicted the change in FMD following the 6-month AEXT intervention. A pre-post design was employed with baseline evaluation including office blood pressure, FMD, fasting blood sampling, and graded exercise testing. Participants engaged in 6 months of AEXT. Following the AEXT intervention, all baseline tests were repeated. FMD significantly increased, CD62E+ EMPs and IL-6 significantly decreased, and IL-10 increased but not significantly following AEXT. Changes in inflammatory biomarkers did not significantly predict the change in FMD. The change in VO2 max significantly predicted the change in IL-10. Based on these results, AEXT may be a viable, nonpharmacological method to improve inflammation status and endothelial function and thereby contribute to risk reduction for cardiovascular disease in African Americans.

Endothelial-Dependent Flow-Mediated Dilation in African Americans With Masked-Hypertension

BACKGROUND Office-blood pressure (BP) measurements alone overlook a significant number of individuals with masked-hypertension (office-BP: 120/80-139/89 mm Hg and 24-h ambulatory BP monitoring (ABPM) daytime ≥135/85 mm Hg or night-time ≥120/70 mm Hg). Diminished endothelial function contributes to the pathogenesis of hypertension. To better understand the pathophysiology involved in the increased cardiovascular (CV) disease risk associated with masked-hypertension, we estimated the occurrence, assessed the endothelial function, compared plasma levels of inflammatory markers, white blood cell count (WBC count), tumor necrosis factor-α (TNF-α), and high sensitivity C-reactive protein (hsCRP) and examined the possible relationship between endothelial function and inflammatory markers in apparently healthy prehypertensive (office-BP: 120/80-139/89 mm Hg) African Americans. METHODS Fifty African Americans who were sedentary, nondiabetic, nonsmoking, devoid of CV disease were recruited. Office-BP was measured according to JNC-7 guidelines to identify prehypertensives in whom ABPM was then assessed. Fasting plasma samples were assayed for inflammatory markers. Brachial artery flow-mediated dilation (FMD) at rest and during reactive hyperemia was measured in a subset of prehypertensives. RESULTS Subjects in the masked-hypertension sub-group had a higher hsCRP (P = 0.04) and diminished endothelial function (P = 0.03) compared to the true-prehypertensive sub-group (office-BP: 120/80-139/89 mm Hg and ABPM: daytime <135/85 mm Hg or night-time <120/70 mm Hg). Regression analysis showed that endothelial function was inversely related to hsCRP amongst the masked-hypertensive sub-group (R(2) = 0.160; P = 0.04). CONCLUSIONS Masked-hypertension was identified in 58% of African Americans which suggests that a masking phenomenon may exist in a sub-group of prehypertensives who also seem to have a diminished endothelial function that could be mediated by an elevated subclinical inflammation leading to the increased CV disease.

High-resolution micro-CT evaluation of mid- to long-term effects of estrogen deficiency on rat trabecular bone1☆

RATIONALE AND OBJECTIVES Previous studies have shown dramatic short-term bone loss following ovariectomy. The purpose of this study was to evaluate mid- to long-term effects of estrogen deficiency on microarchitecture of tibial trabecular bone using a high-resolution microcomputed tomography (Micro-CT). MATERIALS AND METHODS Twenty-eight female rats were divided into two equal groups: ovariectomized (OVX, n = 14) and sham-operated (SOVX, n = 14), which in turn were divided into two equal subgroups (euthanized either 6 or 16 weeks after surgery). The left tibia of each animal was scanned with a high-resolution micro-CT (Skyscan 1072 micro-CT system; SkyScan, Aartselaar, Belgium). The Micro-CT system used an X-ray CCD-camera with a cooled 1024 x 1024-pixel 12-bit sensor. RESULTS Ovariectomy significantly decreased the ratio of bone volume:tissue volume (-42% at 6 weeks and -69% at 16 weeks) and trabecular thickness (-13% at 6 weeks and -30% at 16 weeks), while significantly increasing trabecular separation (+73% at 6 weeks and +100% at 16 weeks) and structure model index (+15% at 6 weeks and +48% at 16 weeks), when compared with SOVX, from 6 to 16 weeks. CONCLUSION Based on the experimental results, there are alterations of trabecular microarcihtecture in the tibia following mid- and long-term estrogen deficiency. More rod-shaped trabeculae are formed with increasing duration of estrogen deficiency. The high-resolution micro-CT imaging system is useful to evaluate the mid- to long-term trabecular changes seen with estrogen deficiency or osteoporosis.

Visit-to-visit and 24-h blood pressure variability: association with endothelial and smooth muscle function in African Americans

The purpose of this study was to investigate the association of visit-to-visit and 24-h blood pressure (BP) variability with markers of endothelial injury and vascular function. We recruited 72 African Americans who were non-diabetic, non-smoking and free of cardiovascular (CV) and renal disease. Office BP was measured at three visits and 24-h ambulatory BP monitoring was conducted to measure visit-to-visit and 24-h BP variability, respectively. The 5-min time-course of brachial artery flow-mediated dilation and nitroglycerin-mediated dilation were assessed as measures of endothelial and smooth muscle function. Fasted blood samples were analyzed for circulating endothelial microparticles (EMPs). Significantly lower CD31+CD42− EMPs were found in participants with high visit-to-visit systolic blood pressure (SBP) variability or high 24-h diastolic blood pressure (DBP) variability. Participants with high visit-to-visit DBP variability had significantly lower flow-mediated dilation and higher nitroglycerin-mediated dilation at multiple time-points. When analyzed as continuous variables, 24-h mean arterial pressure variability was inversely associated with CD62+ EMPs; visit-to-visit DBP variability was inversely associated with flow-mediated dilation normalized by smooth muscle function and was positively associated with nitroglycerin-mediated dilation; and 24-h DBP variability was positively associated with nitroglycerin-mediated dilation. All associations were independent of age, gender, body mass index and mean BP. In conclusion, in this cohort of African Americans visit-to-visit and 24-h BP variability were associated with measures of endothelial injury, endothelial function and smooth muscle function. These results suggest that BP variability may influence the pathogenesis of CV disease, in part, through influences on vascular health.

CardioClasp: a new passive device to reshape cardiac enlargement.

In dilated heart failure, geometric distortions place an extra load on the myocardial cells. If this extra burden can be eliminated, the myocardial wall stress would decrease leading to improved systolic ventricular performance. In a dilated heart failure model, we wanted to see whether the CardioClasp™ (which uses two indenting bars to reshape the left ventricle [LV] as two widely communicating “lobes” of reduced radius) could improve systolic performance by passively reshaping the LV and reducing the wall stress.In mongrel dogs (n = 7; 25–27 kg), rapid ventricular pacing (210 ppm 1st week to 240 ppm 4th week) induced dilated heart failure. After 4 weeks, LV performance was evaluated at baseline and with the CardioClasp™ by measuring LV end-diastolic and peak LV systolic pressure, LV +dP/dt, LV −dP/dt, and cardiac output. With the Clasp on, LV wall stress was reduced to 58.6 ± 3.5 from 108.3 ± 8.2 g/cm2. The fractional area of contraction (FAC) with the Clasp on (28.4 ± 4.4) was significantly increased (p < 0.05) from baseline (20.8 ± 4.6) and consistent with improved systolic performance. Cardiac output, LV peak systolic and end-diastolic pressures, and regional myocardial blood flow were unaltered.The Clasp was able to acutely reshape the left ventricle, while preserving the contractile mass, and reduced the tension on the myocardial cells and increased the fractional area of contraction without decreasing the systolic blood pressure.

Enhanced blood pressure variability in a high cardiovascular risk group of African Americans: FIT4Life Study

High blood pressure (BP) levels in African Americans elicit vascular inflammation resulting in vascular remodeling. BP variability (BPV) correlates with target organ damage. We aimed to investigate the relationship between inflammatory markers and BPV in African Americans. Thirty-six African Americans underwent 24-hour ambulatory BP monitoring (ABPM). BPV was calculated using the average real variability index. Fasting blood samples were assayed for high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-alpha), and white blood cell (WBC) count. Significant associations between hs-CRP and 24-hour systolic variability (r=0.50; P=.012) and awake systolic variability (r=0.45; P=.02) were identified after adjusting for age, body mass index, and 24-hour mean BP. ABPM variables were compared between the hs-CRP tertile groups. In post-hoc analysis, there was a significant difference in 24-hour and awake periods for both systolic and diastolic variability among the groups. TNF-alpha and WBC count showed no associations with ABPM variables. hs-CRP was associated with systolic variability, and higher levels of hs-CRP were related with greater BPV. Higher inflammatory status influences wider fluctuations in systolic BP, which in turn could facilitate early progression to target organ damage independent of absolute BP levels in African Americans.