Microparticle-Based Molecular MRI of Atherosclerosis, Thrombosis, and Tissue Ischemia

MRI is well suited for imaging vascular disease as it provides excellent soft tissue contrast and spatial resolution of the vessel wall. By generating potent contrast effects, iron oxide particles further enhance the ability of MRI to deliver functional information in a range of vascular syndromes. Larger microparticles of iron oxide (MPIO) generate sufficient contrast to enable detection of low-abundance vascular targets in vivo. Ligand-conjugated MPIO confer molecular specificity, facilitating molecular imaging of a range of specific endovascular targets. This review discusses the application of iron oxide particles in the molecular imaging of a variety of vascular syndromes. In particular, ligand-conjugated MPIO have been used for targeted molecular imaging in experimental models of atherosclerosis, thrombosis, and tissue ischemia syndromes. This provides a platform for vascular molecular imaging that could accelerate diagnosis, characterize disease progression, and measure response to treatment in a clinical setting.     

Pioglitazone administration decreases cardiovascular disease risk factors in insulin-resistant smokers

Insulin sensitivity varies in cigarette smokers, and there is evidence that cardiovascular disease (CVD) risk is greatest in those smokers who are also insulin resistant. To extend these observations, we sought to (1) compare CVD risk factors in smokers who do not plan to stop smoking, divided into insulin-resistant (IR) and insulin-sensitive (IS) subgroups, and (2) evaluate the ability of drug-induced changes in insulin sensitivity to decrease CVD risk. Thirty-six cigarette smokers were divided into IR (n = 19) and IS (n = 17) subgroups by determining their steady-state plasma glucose (SSPG) concentrations during the insulin suppression test (the higher the SSPG, the more insulin resistant the individual). In addition, baseline measurements were made of fasting lipid and lipoprotein concentrations; inflammatory markers; and daylong glucose, insulin, and free fatty acid responses to test meals. All subjects were treated with pioglitazone for 12 weeks, after which all baseline measurements were repeated. Baseline triglyceride and high-density lipoprotein cholesterol concentrations were significantly different in IR as compared with IS smokers (P < .05) both before and after adjustment for differences in sex and body mass index. After pioglitazone treatment, SSPG concentration significantly fell in the IR smokers (P < .001), associated with a significant improvement in the atherogenic lipoprotein profile seen at baseline (P ≤ .03) and a decrease in soluble intercellular adhesion molecule 1 and C-reactive protein concentrations (P = .01 and .02, respectively), whereas the IS smokers only had a significant increase in high-density lipoprotein cholesterol (P = .004) and a decrease in soluble intercellular adhesion molecule 1 (P = .02) and CRP (P = .07) levels. In conclusion, cigarette smokers have profound differences in CVD risk factors related to their degree of insulin sensitivity. It is suggested that, in addition to smoking cessation efforts, attention should be given to identifying the subgroup of smokers most at risk for CVD, but unwilling or unable to stop smoking, and to initiating appropriate therapeutic interventions to decrease CVD in this high-risk group.     

Identification of a mutation in the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy.

OBJECTIVE--To investigate the molecular genetic basis of the cause of disease in a family with hypertrophic cardiomyopathy. BACKGROUND--Mutation within the beta cardiac myosin heavy chain gene has been shown to be the pathogenetic mechanism underlying the disease in several families, though clear evidence of heterogeneity has been reported. PATIENTS--A family with a history of hypertrophic cardiomyopathy. RESULTS AND CONCLUSION--This paper reports a mutation at aminoacid position 908 within exon 23 of the beta cardiac myosin heavy chain gene, resulting in a conversion of a leucine to valine. This base substitution was identified in an individual with a confirmed family history but with equivocal symptoms of the disease. Inheritance of the mutation by his symptom free juvenile offspring demonstrates the application of the technique to presymptomatic diagnosis.     

Post-transplant infections: single center experience from the developing world.

OBJECTIVE: To describe our experience of post-transplant infections in allogeneic stem cell transplants at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan. METHODS: From July 2001 to September 2006, patients with malignant and non-malignant hematological disorders having human leukocyte antigen (HLA)-matched sibling donors were selected for transplant. Pre-transplant infection surveillance was carried out, and strict prophylaxis against infection was observed. After admission to the hospital, patients were kept in protective isolation rooms, equipped with a HEPA filter positive-pressure laminar airflow ventilation system. Bone marrow and/or peripheral blood stem cells were used as the stem cell source. Cyclosporin and prednisolone were used as prophylaxis against graft-versus-host disease (GVHD). The engraftment was monitored with cytogenetic/molecular analysis and change of blood group. Survival was calculated from the date of transplant to death or last follow-up. RESULTS: One hundred and fifty-four patients received allogeneic stem cell transplants from HLA-matched siblings for various hematological disorders at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan between July 2001 and September 2006. Indications for transplant included aplastic anemia (n=66), beta-thalassemia major (n=40), chronic myeloid leukemia (n=33), acute leukemia (n=8), and miscellaneous disorders (n=7). One hundred and twenty patients were male and 34 were female. The median age of the patient cohort was 14 years (range 1 1/4-54 years). One hundred and thirty-six patients and 135 donors were cytomegalovirus (CMV) IgG-positive. One hundred and forty patients (90.9%) developed febrile episodes in different phases of post-transplant recovery. Infective organisms were isolated in 150 microbiological culture specimens out of 651 specimens from different sites of infections (23.0% culture positivity). Post-transplant infections were confirmed in 120 patients (77.9%) on the basis of clinical assessment and microbiological, virological, and histopathological examination. Mortality related to infections was 13.0%. Fatal infections included CMV disease (100% mortality, 6/6), disseminated aspergillosis (66.7% mortality, 4/6), pseudomonas septicemia (42.9% mortality, 9/21), and tuberculosis (25% mortality, 1/4). CONCLUSIONS: More than 90% of our patients developed febrile episodes with relatively low culture yield. The majority of infections were treated effectively, however CMV, aspergillosis, and pseudomonas infections remained problematic with high mortality.     

Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice

Hyperglycemia derived advanced glycation endproducts (AGE) have been implicated in diabetic atherosclerosis (AS) but the role of exogenous (dietary) AGE in the development of this serious complication is not known. This study evaluates the influence of diet-related AGE on AS in genetically hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)), streptozotocin-induced diabetic mice. Diabetic and non-diabetic apoE(-/-) mice (6-8 weeks old) were randomized into either a standard AIN-93G chow (AGE 12,500+/-700 U/mg, termed high-AGE diet, H-AGE), or the same chow having four to fivefold lower AGE level (L-AGE: 2,700+/-830 U/mg) based on ELISA. After 2 months of diabetes, compared to the diabetic mice fed standard (H-AGE) diet, the AS lesions at the aortic root of the L-AGE group were >50% smaller (0.17+/-0.03 vs. 0.31+/-0.05 mm(2), P<0.05). Serum AGE were lower in the diabetic L-AGE than in the H-AGE mice (by approximately 53%) (P<0.00001), as were in the non-diabetic L-AGE vs. H-AGE groups (P<0.05). No diet-related changes were noted in plasma glucose, triglycerides, or plasma cholesterol. Immunohistochemical comparisons showed markedly suppressed tissue AGE, AGE-Receptor-1, -2 and RAGE expression, reduced numbers of inflammatory cells, tissue factor, vascular cell adhesion molecule-1 and MCP-1 in the L-AGE diabetic group. The findings are supportive of an important link between dietary intake of pre-formed glycoxidation products, tissue-incorporated AGE, and diabetes-accelerated AS. The marked anti-atherogenic effects of an AGE-restricted diet in this model may provide the basis for relevant clinical studies.     

Comparison of three treatment approaches to decreasing cardiovascular disease risk in nondiabetic insulin-resistant dyslipidemic subjects

The efficacy of fenofibrate (FEN), rosiglitazone (RSG), or a calorie-restricted diet (CRD) to reduce cardiovascular disease risk was compared in 37 overweight/obese insulin-resistant nondiabetic subjects. Insulin sensitivity, fasting lipids and lipoproteins, and postprandial plasma glucose, insulin, free fatty acid, and triglycerides were measured before and after 3 months of treatment with FEN, RSG, or CRD. Weight decreased in the CRD group, but did not change significantly after treatment with either drug. Insulin sensitivity improved significantly in the CRD- and RSG-treated groups, but to a greater extent in those administered RSG, without a significant difference comparing FEN treatment with the CRD. Total cholesterol was significantly lower after FEN and CRD treatment. Fasting plasma triglycerides decreased significantly in the FEN- and CRD-treated groups, but postprandial concentrations decreased in only FEN-treated subjects. Significant decreases in postprandial glucose and insulin were seen in only the RSG- and CRD-treated groups. FEN administration improved dyslipidemia in these subjects without changing insulin sensitivity, whereas insulin sensitivity was enhanced in RSG-treated patients without improvement in dyslipidemia. Weight loss in the CRD group led to improvements in both insulin sensitivity and dyslipidemia, but the change in the former was less than in RSG-treated patients, and improvement in lipid metabolism not as great as with FEN. In conclusion, there did not appear to be 1 therapeutic intervention that effectively treated all metabolic abnormalities present in these patients at greatly increased risk of cardiovascular disease.     

Myocardial beta adrenoceptor density in primary and secondary left ventricular hypertrophy

OBJECTIVES: Myocardial ß-adrenoceptor density has been found tobe reduced in hypertrophic cardiomyopathy, even when systolicfunction is preserved. Our purpose in the current study wasto investigate whether ß-adrenoceptor down-regulationwas unique to hypertrophic cardiomyopathy, or is also presentin secondary myocardial hypertrophy. METHODS: Myocardial ß-adrenoceptor density was measured in11 patients with hypertrophic cardiomyopathy, eight patientswith left ventricular hypertrophy secondary to arterial hypertensionor aortic valve disease and 18 normal control subjects, usingpositron emission tomography with ¹¹C-CGP-12177 as the myocardialß-adrenoceptor ligand. RESULTS: Reflecting the natural incidence of the conditions, the ageof the hypertrophic cardiomyopathy patients was 37 (10) [mean(SD), range 20–51] years and that of the secondary hypertrophypatients 64 (18), [range 26–80] years; P<0.01. Thecontrols' ages were 50 (13), [range 21–65] years; however,since ß-adrenoceptor density is known to be influencedby age, the controls' data was split into groups matched tothe hypertrophic cardiomyopathy and secondary hypertrophy patientsets. For the hypertrophic cardiomyopathy patients, mean leftventricular ß-adrenoceptor was 7.70 (186) pmol . g^–1compared to 10.17 (244) pmol . g^–1 for a matched set of15 controls; P<0.01. In secondary left ventricular hypertrophy,ß-adrenoceptor was 6.35 (1.70) pmol . g^–1 comparedto 9.16 (2.00)pmol . g^–1 for a matched set of 10 controls;P<0.01. Plasma noradrenaline was 5.5 (2.2)nmol . 1^–1in hypertrophic cardiomyopathy and 2.5 (1.0)nmol. 1^–1for the matched controls; P<0.01. The results for adrenalinewere 2.2 (1.1) vs 0.4 (0.3) nmol . 1^–1 respectively; P<0.001.For the secondary hypertrophy patients, the corresponding figureswere 2.5 (1.2) vs 2.5 (1.0) nmol . 1^–1 for noradrenalinefor patients and controls respectively (P=ns); and for adrenaline0.2 (0.1) and 0.3 (0.2) nmol . 1^–1 respectively, P=ns.On multiple regression analysis, no relationships could be demonstratedamongst plasma catecholamines, ß-adrenoceptor, myocardialblood flow and echocardiographic E/A ratio and fractional shortening. CONCLUSION: Myocardial ß-adrenoceptor density appears to be comparablydecreased in both primary and secondary left ventricular hypertrophyin the presence of preserved left ventricular systolic function.     

Circadian Rhythms of Heart Rate Variability in Hypertrophic Cardiomyopathy

Background: It has been hypothesized that an interaction between sympathetic nervous activity and an abnormal myocardium plays a role in the development and progression of hypertrophic cardiomyopathy (HCM). Methods: In the present study we investigated cardiac autonomic function by 24-hour spectral analysis of heart rate variability (HRV) in 18 patients with HCM, without evidence of heart failure, and 18 controls of similar age. Results: We found a significant reduction of 24 hour variance in HCM patients relative to controls (15,000 ± 9480 ms² vs 24,720 ± 12,450 ms² respectively; p < 0.05). Moreover, a loss of the expected day-night changes in the low frequency (LF) spectral component (expressed in normalized units), and LF/HF ratio (HF; high frequency component) were observed in HCM patients. Decreased day-night changes in LF/HF ratio were previously reported in patients with mild hypertension, uncomplicated coronary disease, and after myocardial infarction, conditions in which it seems to exist a higher than normal sympathetic activity. No significant correlations were found between HRV indices and echocardiographic standard measures of systolic and diastolic function parameters. Conclusions: These data are consistent with the presence of an alteration in neural modulation of heart period in HCM patients, noninvasively detectable by continuous 24 hour HRV analysis.